The General Assessment of Personality Disorder (GAPD): factor structure, incremental validity of self-pathology, and relations to DSM-IV personality disorders.

PubMed

Hentschel, Annett G; Livesley, W John

2013-01-01

Recent developments in the classification of personality disorder, especially moves toward more dimensional systems, create the need to assess general personality disorder apart from individual differences in personality pathology. The General Assessment of Personality Disorder (GAPD) is a self-report questionnaire designed to evaluate general personality disorder. The measure evaluates 2 major components of disordered personality: self or identity problems and interpersonal dysfunction. This study explores whether there is a single factor reflecting general personality pathology as proposed by the Diagnostic and Statistical Manual of Mental Disorders (5th ed.), whether self-pathology has incremental validity over interpersonal pathology as measured by GAPD, and whether GAPD scales relate significantly to Diagnostic and Statistical Manual of Mental Disorders (4th ed. [DSM-IV]) personality disorders. Based on responses from a German psychiatric sample of 149 participants, parallel analysis yielded a 1-factor model. Self Pathology scales of the GAPD increased the predictive validity of the Interpersonal Pathology scales of the GAPD. The GAPD scales showed a moderate to high correlation for 9 of 12 DSM-IV personality disorders.

Tau pathology does not affect experience-driven single-neuron and network-wide Arc/Arg3.1 responses.

PubMed

Rudinskiy, Nikita; Hawkes, Jonathan M; Wegmann, Susanne; Kuchibhotla, Kishore V; Muzikansky, Alona; Betensky, Rebecca A; Spires-Jones, Tara L; Hyman, Bradley T

2014-06-10

Intraneuronal neurofibrillary tangles (NFTs) - a characteristic pathological feature of Alzheimer's and several other neurodegenerative diseases - are considered a major target for drug development. Tangle load correlates well with the severity of cognitive symptoms and mouse models of tauopathy are behaviorally impaired. However, there is little evidence that NFTs directly impact physiological properties of host neurons. Here we used a transgenic mouse model of tauopathy to study how advanced tau pathology in different brain regions affects activity-driven expression of immediate-early gene Arc required for experience-dependent consolidation of long-term memories. We demonstrate in vivo that visual cortex neurons with tangles are as likely to express comparable amounts of Arc in response to structured visual stimulation as their neighbors without tangles. Probability of experience-dependent Arc response was not affected by tau tangles in both visual cortex and hippocampal pyramidal neurons as determined postmortem. Moreover, whole brain analysis showed that network-wide activity-driven Arc expression was not affected by tau pathology in any of the brain regions, including brain areas with the highest tangle load. Our findings suggest that intraneuronal NFTs do not affect signaling cascades leading to experience-dependent gene expression required for long-term synaptic plasticity.

Sequential PET/CT with [18F]-FDG Predicts Pathological Tumor Response to Preoperative Short Course Radiotherapy with Delayed Surgery in Patients with Locally Advanced Rectal Cancer Using Logistic Regression Analysis

PubMed Central

Pecori, Biagio; Lastoria, Secondo; Caracò, Corradina; Celentani, Marco; Tatangelo, Fabiana; Avallone, Antonio; Rega, Daniela; De Palma, Giampaolo; Mormile, Maria; Budillon, Alfredo; Muto, Paolo; Bianco, Francesco; Aloj, Luigi; Petrillo, Antonella; Delrio, Paolo

2017-01-01

Previous studies indicate that FDG PET/CT may predict pathological response in patients undergoing neoadjuvant chemo-radiotherapy for locally advanced rectal cancer (LARC). Aim of the current study is evaluate if pathological response can be similarly predicted in LARC patients after short course radiation therapy alone. Methods: Thirty-three patients with cT2-3, N0-2, M0 rectal adenocarcinoma treated with hypo fractionated short course neoadjuvant RT (5x5 Gy) with delayed surgery (SCRTDS) were prospectively studied. All patients underwent 3 PET/CT studies at baseline, 10 days from RT end (early), and 53 days from RT end (delayed). Maximal standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) and total lesion glycolysis (TLG) of the primary tumor were measured and recorded at each PET/CT study. We use logistic regression analysis to aggregate different measures of metabolic response to predict the pathological response in the course of SCRTDS. Results: We provide straightforward formulas to classify response and estimate the probability of being a major responder (TRG1-2) or a complete responder (TRG1) for each individual. The formulas are based on the level of TLG at the early PET and on the overall proportional reduction of TLG between baseline and delayed PET studies. Conclusions: This study demonstrates that in the course of SCRTDS it is possible to estimate the probabilities of pathological tumor responses on the basis of PET/CT with FDG. Our formulas make it possible to assess the risks associated to LARC borne by a patient in the course of SCRTDS. These risk assessments can be balanced against other health risks associated with further treatments and can therefore be used to make informed therapy adjustments during SCRTDS. PMID:28060889

Sequential PET/CT with [18F]-FDG Predicts Pathological Tumor Response to Preoperative Short Course Radiotherapy with Delayed Surgery in Patients with Locally Advanced Rectal Cancer Using Logistic Regression Analysis.

PubMed

Pecori, Biagio; Lastoria, Secondo; Caracò, Corradina; Celentani, Marco; Tatangelo, Fabiana; Avallone, Antonio; Rega, Daniela; De Palma, Giampaolo; Mormile, Maria; Budillon, Alfredo; Muto, Paolo; Bianco, Francesco; Aloj, Luigi; Petrillo, Antonella; Delrio, Paolo

2017-01-01

Previous studies indicate that FDG PET/CT may predict pathological response in patients undergoing neoadjuvant chemo-radiotherapy for locally advanced rectal cancer (LARC). Aim of the current study is evaluate if pathological response can be similarly predicted in LARC patients after short course radiation therapy alone. Thirty-three patients with cT2-3, N0-2, M0 rectal adenocarcinoma treated with hypo fractionated short course neoadjuvant RT (5x5 Gy) with delayed surgery (SCRTDS) were prospectively studied. All patients underwent 3 PET/CT studies at baseline, 10 days from RT end (early), and 53 days from RT end (delayed). Maximal standardized uptake value (SUVmax), mean standardized uptake value (SUVmean) and total lesion glycolysis (TLG) of the primary tumor were measured and recorded at each PET/CT study. We use logistic regression analysis to aggregate different measures of metabolic response to predict the pathological response in the course of SCRTDS. We provide straightforward formulas to classify response and estimate the probability of being a major responder (TRG1-2) or a complete responder (TRG1) for each individual. The formulas are based on the level of TLG at the early PET and on the overall proportional reduction of TLG between baseline and delayed PET studies. This study demonstrates that in the course of SCRTDS it is possible to estimate the probabilities of pathological tumor responses on the basis of PET/CT with FDG. Our formulas make it possible to assess the risks associated to LARC borne by a patient in the course of SCRTDS. These risk assessments can be balanced against other health risks associated with further treatments and can therefore be used to make informed therapy adjustments during SCRTDS.

Does chronomodulated radiotherapy improve pathological response in locally advanced rectal cancer?

PubMed

Squire, Tim; Buchanan, Grant; Rangiah, David; Davis, Ian; Yip, Desmond; Chua, Yu Jo; Rich, Tyvin; Elsaleh, Hany

2017-01-01

The predominant mode of radiation-induced cell death for solid tumours is mitotic catastrophe, which is in part dependent on sublethal damage repair being complete at around 6 h. Circadian variation appears to play a role in normal cellular division, and this could influence tumour response of radiation treatment depending on the time of treatment delivery. We tested the hypothesis that radiation treatment later in the day may improve tumour response and nodal downstaging in rectal cancer patients treated neoadjuvantly with radiation therapy. Recruitment was by retrospective review of 267 rectal cancer patients treated neoadjuvantly in the Department of Radiation Oncology at the Canberra Hospital between January 2010 and November 2015. One hundred and fifty-five patients met the inclusion criteria for which demographic, pathological and imaging data were collected, as well as the time of day patients received treatment with each fraction of radiotherapy. Data analysis was performed using the Statistical Package R with nonparametric methods of significance for all tests set at p < 0.05. Of the 45 female and 110 male patients, the median age was 64. Seventy-three percent had cT3 disease and there was a mean tumour distance from the anal verge of 7 cm. Time to surgical resection following radiotherapy ranged from 4 to 162 days with a median of 50 days, with a complete pathological response seen in 21% of patients. Patients exhibiting a favourable pathological response had smaller median pre- and postradiotherapy tumour size and had a greater change in tumour size following treatment (p < 0.01). Patients who received the majority of their radiotherapy fractions after 12:00 pm were more likely to show a complete or moderate pathological response (p = 0.035) and improved nodal downstaging. There were also more favourable responses amongst patients with longer time to surgical resection postradiotherapy (p < 0.004), although no relationship was seen between response and tumour distance from the anal verge. Females were less likely to exhibit several of the above responses. Neoadjuvant radiotherapy for locally advanced rectal cancer performed later in the day coupled with a longer time period to surgical resection may improve pathological tumour response rates and nodal downstaging. A prospective study in chronomodulated radiotherapy in this disease is warranted.

High-resolution Imaging of Neural Anatomy and Pathology of the Neck.

PubMed

Lee, Jeong Hyun; Cheng, Kai-Lung; Choi, Young Jun; Baek, Jung Hwan

2017-01-01

The neck has intricately connected neural structures, including cervical and brachial plexi, the sympathetic system, lower cranial nerves, and their branches. Except for brachial plexus, there has been little research regarding the normal imaging appearance or corresponding pathologies of neural structures in the neck. The development in imaging techniques with better spatial resolution and signal-to-noise ratio has made it possible to see many tiny nerves to predict complications related to image-guided procedures and to better assess treatment response, especially in the management of oncology patients. The purposes of this review is to present imaging-based anatomy of major nerves in the neck and explain their relevant clinical significance according to representative pathologies of regarded nerves in the neck.

Underlying chronic inflammation alters the profile and mechanisms of acute neutrophil recruitment.

PubMed

Ma, Bin; Whiteford, James R; Nourshargh, Sussan; Woodfin, Abigail

2016-11-01

Chronically inflamed tissues show altered characteristics that include persistent populations of inflammatory leukocytes and remodelling of the vascular network. As the majority of studies on leukocyte recruitment have been carried out in normal healthy tissues, the impact of underlying chronic inflammation on ongoing leukocyte recruitment is largely unknown. Here, we investigate the profile and mechanisms of acute inflammatory responses in chronically inflamed and angiogenic tissues, and consider the implications for chronic inflammatory disorders. We have developed a novel model of chronic ischaemia of the mouse cremaster muscle that is characterized by a persistent population of monocyte-derived cells (MDCs), and capillary angiogenesis. These tissues also show elevated acute neutrophil recruitment in response to locally administered inflammatory stimuli. We determined that Gr1 low MDCs, which are widely considered to have anti-inflammatory and reparative functions, amplified acute inflammatory reactions via the generation of additional proinflammatory signals, changing both the profile and magnitude of the tissue response. Similar vascular and inflammatory responses, including activation of MDCs by transient ischaemia-reperfusion, were observed in mouse hindlimbs subjected to chronic ischaemia. This response demonstrates the relevance of the findings to peripheral arterial disease, in which patients experience transient exercise-induced ischaemia known as claudication.These findings demonstrate that chronically inflamed tissues show an altered profile and altered mechanisms of acute inflammatory responses, and identify tissue-resident MDCs as potential therapeutic targets. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Consequences of inhibiting amyloid precursor protein processing enzymes on synaptic function and plasticity.

PubMed

Wang, Hui; Megill, Andrea; He, Kaiwen; Kirkwood, Alfredo; Lee, Hey-Kyoung

2012-01-01

Alzheimer's disease (AD) is a neurodegenerative disease, one of whose major pathological hallmarks is the accumulation of amyloid plaques comprised of aggregated β-amyloid (Aβ) peptides. It is now recognized that soluble Aβ oligomers may lead to synaptic dysfunctions early in AD pathology preceding plaque deposition. Aβ is produced by a sequential cleavage of amyloid precursor protein (APP) by the activity of β- and γ-secretases, which have been identified as major candidate therapeutic targets of AD. This paper focuses on how Aβ alters synaptic function and the functional consequences of inhibiting the activity of the two secretases responsible for Aβ generation. Abnormalities in synaptic function resulting from the absence or inhibition of the Aβ-producing enzymes suggest that Aβ itself may have normal physiological functions which are disrupted by abnormal accumulation of Aβ during AD pathology. This interpretation suggests that AD therapeutics targeting the β- and γ-secretases should be developed to restore normal levels of Aβ or combined with measures to circumvent the associated synaptic dysfunction(s) in order to have minimal impact on normal synaptic function.

Increasing CAD system efficacy for lung texture analysis using a convolutional network

NASA Astrophysics Data System (ADS)

Tarando, Sebastian Roberto; Fetita, Catalin; Faccinetto, Alex; Brillet, Pierre-Yves

2016-03-01

The infiltrative lung diseases are a class of irreversible, non-neoplastic lung pathologies requiring regular follow-up with CT imaging. Quantifying the evolution of the patient status imposes the development of automated classification tools for lung texture. For the large majority of CAD systems, such classification relies on a two-dimensional analysis of axial CT images. In a previously developed CAD system, we proposed a fully-3D approach exploiting a multi-scale morphological analysis which showed good performance in detecting diseased areas, but with a major drawback consisting of sometimes overestimating the pathological areas and mixing different type of lung patterns. This paper proposes a combination of the existing CAD system with the classification outcome provided by a convolutional network, specifically tuned-up, in order to increase the specificity of the classification and the confidence to diagnosis. The advantage of using a deep learning approach is a better regularization of the classification output (because of a deeper insight into a given pathological class over a large series of samples) where the previous system is extra-sensitive due to the multi-scale response on patient-specific, localized patterns. In a preliminary evaluation, the combined approach was tested on a 10 patient database of various lung pathologies, showing a sharp increase of true detections.

Stochastic Modulations of the Pace and Patterns of Ageing: Impacts on Quasi-Stochastic Distributions of Multiple Geriatric Pathologies

PubMed Central

Martin, George M.

2011-01-01

All phenotypes result from interactions between Nature, Nurture and Chance. The constitutional genome is clearly the dominant factor in explaining the striking differences in the pace and patterns of ageing among species. We are now in a position to reveal salient features underlying these differential modulations, which are likely to be dominated by regulatory domains. By contrast, I shall argue that stochastic events are the major players underlying the surprisingly large intra-specific variations in lifespan and healthspan. I shall review well established as well as more speculative categories of chance events – somatic mutations, protein synthesis error catastrophe and variegations of gene expression (epigenetic drift), with special emphasis upon the latter. I shall argue that stochastic drifts in variegated gene expression are the major contributors to intra-specific differences in the pace and patterns of ageing within members of the same species. They may be responsible for the quasi-stochastic distributions of major types of geriatric pathologies, including the “big three” of Alzheimer's disease, atherosclerosis and, via the induction of hyperplasis, cancer. They may be responsible for altered stoichiometries of heteromultimeric mitochondrial complexes, potentially leading to such disorders as sarcopenia, nonischemic cardiomyopathy and Parkinson's disease. PMID:21963385

Genetics of Host Response to Leishmania tropica in Mice – Different Control of Skin Pathology, Chemokine Reaction, and Invasion into Spleen and Liver

PubMed Central

Grekov, Igor; Volkova, Valeriya; Vojtíšková, Jarmila; Slapničková, Martina; Kurey, Iryna; Sohrabi, Yahya; Svobodová, Milena; Demant, Peter; Lipoldová, Marie

2012-01-01

Background Leishmaniasis is a disease caused by protozoan parasites of genus Leishmania. The frequent involvement of Leishmania tropica in human leishmaniasis has been recognized only recently. Similarly as L. major, L. tropica causes cutaneous leishmaniasis in humans, but can also visceralize and cause systemic illness. The relationship between the host genotype and disease manifestations is poorly understood because there were no suitable animal models. Methods We studied susceptibility to L. tropica, using BALB/c-c-STS/A (CcS/Dem) recombinant congenic (RC) strains, which differ greatly in susceptibility to L. major. Mice were infected with L. tropica and skin lesions, cytokine and chemokine levels in serum, and parasite numbers in organs were measured. Principal Findings Females of BALB/c and several RC strains developed skin lesions. In some strains parasites visceralized and were detected in spleen and liver. Importantly, the strain distribution pattern of symptoms caused by L. tropica was different from that observed after L. major infection. Moreover, sex differently influenced infection with L. tropica and L. major. L. major-infected males exhibited either higher or similar skin pathology as females, whereas L. tropica-infected females were more susceptible than males. The majority of L. tropica-infected strains exhibited increased levels of chemokines CCL2, CCL3 and CCL5. CcS-16 females, which developed the largest lesions, exhibited a unique systemic chemokine reaction, characterized by additional transient early peaks of CCL3 and CCL5, which were not present in CcS-16 males nor in any other strain. Conclusion Comparison of L. tropica and L. major infections indicates that the strain patterns of response are species-specific, with different sex effects and largely different host susceptibility genes. PMID:22679519

The Characteristics of Herpes Simplex Virus Type 1 Infection in Rhesus Macaques and the Associated Pathological Features.

PubMed

Fan, Shengtao; Cai, Hongzhi; Xu, Xingli; Feng, Min; Wang, Lichun; Liao, Yun; Zhang, Ying; He, Zhanlong; Yang, Fengmei; Yu, Wenhai; Wang, Jingjing; Zhou, Jumin; Li, Qihan

2017-01-30

As one of the major pathogens for human herpetic diseases, herpes simplex virus type 1 (HSV1) causes herpes labialis, genital herpes and herpetic encephalitis. Our aim here was to investigate the infectious process of HSV1 in rhesus macaques and the pathological features induced during this infection. Clinical symptoms that manifested in the rhesus macaque during HSV1 infection included vesicular lesions and their pathological features. Viral distribution in the nervous tissues and associated pathologic changes indicated the typical systematic pathological processes associated with viral distribution of HSV1.Interestingly, vesicular lesions recurred in oral skin or in mucosa associated with virus shedding in macaques within four to five months post-infection,and viral latency-associated transcript (LAT) mRNA was found in the trigeminal ganglia (TG)on day 365 post-infection. Neutralization testing and enzyme-linked immunospot (ELISpot) detection of specific T cell responses confirmed the specific immunity induced by HSV1 infection. Thus, rhesus macaques could serve as an infectious model for HSV1 due to their typical clinical symptoms and the pathological recurrence associated with viral latency in nervous tissues.

Aversive Startle Potentiation and Fear Pathology: Mediating Role of Threat Sensitivity and Moderating Impact of Depression

PubMed Central

Yancey, James R.; Vaidyanathan, Uma; Patrick, Christopher J.

2015-01-01

Enhanced startle during exposure to unpleasant cues (aversive startle potentiation; ASP) appears in the RDoC matrix as a physiological index of acute threat response. Increased ASP has been linked to focal fear disorders and to scale measures of dispositional fearfulness (i.e., threat sensitivity; THT+). However, some studies have reported reduced ASP for fear pathology accompanied by major depressive disorder (MDD) or pervasive distress. The current study evaluated whether (a) THT+ as indexed by reported dispositional fearfulness mediates the relationship between fear disorders (when unaccompanied by depression) and ASP, and (b) depression moderates relations of THT+ and fear disorders with ASP. Fear disorder participants without MDD showed enhanced ASP whereas those with MDD (or other distress conditions) showed evidence of reduced ASP. Continuous THT+ scores also predicted ASP, and this association: (a) was likewise moderated by depression/distress, and (b) accounted for the relationship between ASP and fear pathology without MDD. These findings point to a role for the RDoC construct of acute threat, operationalized dispositionally, in enhanced ASP shown by individuals with fear pathology unaccompanied by distress pathology. PMID:25448265

Mitochondrial Dysregulation and Protection in Cisplatin Nephrotoxicity

PubMed Central

Yang, Yuan; Liu, Hong; Liu, Fuyou; Dong, Zheng

2014-01-01

Nephrotoxicity is a major side effect of cisplatin in chemotherapy. Pathologically, cisplatin nephrotoxicity is characterized by cell injury and death in renal tubules. The research in the past decade has gained significant understanding of the cellular and molecular mechanisms of tubular cell death, revealing a central role of mitochondrial dysregulation. The pathological changes of mitochondria in cisplatin nephrotoxicity are mainly triggered by DNA damage response, pro-apoptotic protein attack, disruption of mitochondrial dynamics, and oxidative stress. As such, inhibitory strategies targeting these cytotoxic events may provide renal protection. Nonetheless, ideal approaches for renoprotection should not only protect kidneys but also enhance the anti-cancer efficacy of cisplatin in chemotherapy. PMID:24859930

Pathologic response after preoperative therapy predicts prognosis of Chinese colorectal cancer patients with liver metastases.

PubMed

Wang, Yun; Yuan, Yun-Fei; Lin, Hao-Cheng; Li, Bin-Kui; Wang, Feng-Hua; Wang, Zhi-Qiang; Ding, Pei-Rong; Chen, Gong; Wu, Xiao-Jun; Lu, Zhen-Hai; Pan, Zhi-Zhong; Wan, De-Sen; Sun, Peng; Yan, Shu-Mei; Xu, Rui-Hua; Li, Yu-Hong

2017-10-02

Pathologic response is evaluated according to the extent of tumor regression and is used to estimate the efficacy of preoperative treatment. Several studies have reported the association between the pathologic response and clinical outcomes of colorectal cancer patients with liver metastases who underwent hepatectomy. However, to date, no data from Chinese patients have been reported. In this study, we aimed to evaluate the association between the pathologic response to pre-hepatectomy chemotherapy and prognosis in a cohort of Chinese patients. In this retrospective study, we analyzed the data of 380 liver metastases in 159 patients. The pathologic response was evaluated according to the tumor regression grade (TRG). The prognostic role of pathologic response in recurrence-free survival (RFS) and overall survival (OS) was assessed using Kaplan-Meier curves with the log-rank test and multivariate Cox models. Factors that had potential influence on pathologic response were also analyzed using multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests. Patients whose tumors achieved pathologic response after preoperative chemotherapy had significant longer RFS and OS than patients whose tumor had no pathologic response to chemotherapy (median RFS: 9.9 vs. 6.5 months, P = 0.009; median OS: 40.7 vs. 28.1 months, P = 0.040). Multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests showed that metastases with small diameter, metastases from the left-side primary tumors, and metastases from patients receiving long-duration chemotherapy had higher pathologic response rates than their control metastases (all P < 0.05). A decrease in the serum carcinoembryonic antigen (CEA) level after preoperative chemotherapy predicted an increased pathologic response rate (P < 0.05). Although the application of targeted therapy did not significantly influence TRG scores of all cases of metastases, the addition of cetuximab to chemotherapy resulted in a higher pathologic response rate when combined with irinotecan-based regimens rather than with oxaliplatin-based regimens. We found that the evaluation of pathologic response may predict the prognosis of Chinese colorectal cancer patients with liver metastases after preoperative chemotherapy. Small tumor diameter, long-duration chemotherapy, left primary tumor, and decreased serum CEA level after chemotherapy are associated with increased pathologic response rates.

Pathology during acute infections: contributions of intracellular pathogens and the CTL response.

PubMed

Ganusov, Vitaly V; Antia, Rustom

2005-06-22

Previous work has shown how, in the case of cytotoxic T-lymphocyte (CTL) responses to persistent viral infections, pathology may arise as a consequence of cell destruction directly by the virus or indirectly due to the CTL response, leading to maximum pathology at intermediate efficacy of the immune response. We expand these studies to consider pathology arising during acute infections with intracellular pathogens controlled by the CTL response. We show that, in contrast to persistent infections, pathology during acute infections is minimized with increasing efficacy of the immune response. The implications of these results for vaccination are discussed.

Phase II Trial of Induction Chemotherapy Followed by Surgery for Squamous Cell Carcinoma of the Oral Tongue in Young Adults

PubMed Central

Kies, Merrill S.; Boatright, Dowin H.; Li, Guojun; Blumenschein, George; El-Naggar, Adel K.; Lewin, Jan S.; Steinhaus, Ganene; Sturgis, Erich M.

2013-01-01

Background We conducted a phase II clinical trial of induction chemotherapy followed by surgery ± radiotherapy for squamous cell carcinoma of the oral tongue (SCCOT) in young adults. Methods From September 2001 to October 2004, 23 patients aged 18–49 years with clinical T2-3N0-2M0 SCCOT and no prior radiotherapy, chemotherapy, or neck dissection underwent induction chemotherapy (paclitaxel, ifosfamide, and carboplatin) followed by glossectomy and neck dissection ± radiotherapy and chemotherapy. Results On final surgical pathology, 9 (39%) patients had a complete/major (2 complete) histologic response at the primary tumor site; 8 (35%) had no response or progression. Similarly, 9 (39%) patients had a complete response in the neck or remained node negative; 6 (26%) had an increase in nodal category. No treatment-associated deaths occurred, and toxicity was modest. At a median follow-up from the end of treatment of 52 months (minimum, 23 months), 10 (43%) patients developed recurrence, and all 10 died of cancer. Crude recurrence/cancer death rates were associated with ≤ a partial response at the tongue (P = .029), poor histologic differentiation (P = .012), and multiple adverse features on final surgical pathology (P = .040). Conclusions Response rates and overall survival with this induction chemotherapy regimen were limited, but complete/major response at the tongue was associated with excellent prognosis. Additionally, improved patient selection and predictive tumor biomarkers will be needed for induction chemotherapy to be routinely incorporated into the treatment of oral tongue cancer in young adults. PMID:22009800

Phase II trial of induction chemotherapy followed by surgery for squamous cell carcinoma of the oral tongue in young adults.

PubMed

Kies, Merrill S; Boatright, Dowin H; Li, Guojun; Blumenschein, George; El-Naggar, Adel K; Brandon Gunn, G; Lewin, Jan S; Steinhaus, Ganene D; Sturgis, Erich M

2012-09-01

We conducted a phase II clinical trial of induction chemotherapy followed by surgery ± radiotherapy for squamous cell carcinoma of the oral tongue (SCCOT) in young adults. From September 2001 to October 2004, 23 patients aged 18 to 49 years with clinical T2-3 N0-2 M0 SCCOT and no prior radiotherapy, chemotherapy, or neck dissection underwent induction chemotherapy (paclitaxel, ifosfamide, and carboplatin) followed by glossectomy and neck dissection ± radiotherapy and chemotherapy. On final surgical pathology, 9 patients (39%) had a complete/major (2 complete) histologic response at the primary tumor site; 8 patients (35%) had no response or progression. Similarly, 9 patients (39%) had a complete response in the neck or remained node negative; 6 patients (26%) had an increase in nodal category. No treatment-associated deaths occurred, and toxicity was modest. At a median follow-up from the end of treatment of 52 months (minimum, 23 months), 10 patients (43%) developed recurrence, and all 10 died of cancer. Crude recurrence/cancer death rates were associated with ≤ a partial response at the tongue (p = .029), poor histologic differentiation (p = .012), and multiple adverse features on final surgical pathology (p = .040). Response rates and overall survival with this induction chemotherapy regimen were limited, but complete/major response at the tongue was associated with excellent prognosis. Additionally, improved patient selection and predictive tumor biomarkers will be needed for induction chemotherapy to be routinely incorporated into the treatment of oral tongue cancer in young adults. Copyright © 2011 Wiley Periodicals, Inc.

Automated Decision-Support Technologies for Prehospital Care of Trauma Casualties

DTIC Science & Technology

2010-04-01

insensitive to prehospital major traumatic pathology . Second, there are numerous potential sources of decision-support failure, and it is not possible...been speculated to be insensitive to prehospital major traumatic pathology . Second, there are numerous potential sources of decision-support failure...the soldiers, and the diagnostic value of prehospital vital signs for major traumatic pathologies has often been questioned [4-8]. Indeed, our

The Role of Personality Pathology in Depression Treatment Outcome With Psychotherapy and Pharmacotherapy

PubMed Central

Levenson, Jessica C.; Wallace, Meredith L.; Fournier, Jay C.; Rucci, Paola; Frank, Ellen

2012-01-01

Background Depressed patients with comorbid personality pathology may fare worse in treatment for depression than those without this additional pathology, and comorbid personality pathology may be associated with superior response in one form of treatment relative to another, though recent findings have been mixed. We aimed to evaluate the effect of personality pathology on time to remission of patients randomly assigned to 1 of 2 treatment strategies for depression and to determine whether personality pathology moderated the effect of treatment assignment on outcome. Method Individuals undergoing an episode of unipolar major depression (n = 275) received interpersonal psychotherapy (Klerman, Weissman, Rounsaville, & Chevron, 1984) or selective serotonin reuptake inhibitor (SSRI) pharmacotherapy for depression. Depressive symptoms were measured with the HRSD-17. Remission was a mean HRSD-17 score of 7 or below over a period of 3 weeks. Personality disorders were measured according to SCID-II diagnoses, and personality pathology was measured dimensionally by summing the positive probes on the SCID-II. Results The presence of at least 1 personality disorder was not a significant predictor of time to remission, but a higher level of dimensionally measured personality pathology and the presence of borderline personality disorder were associated with a longer time to remission. Personality pathology did not moderate the effect of treatment assignment on time to remission. Conclusions The findings suggest that depressed individuals with comorbid personality pathology generally fare worse in treatment for depression, although in this report, the effect of personality pathology did not differ by the type of treatment received. PMID:22823857

The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

PubMed Central

Backs, Johannes; Backs, Thea; Neef, Stefan; Kreusser, Michael M.; Lehmann, Lorenz H.; Patrick, David M.; Grueter, Chad E.; Qi, Xiaoxia; Richardson, James A.; Hill, Joseph A.; Katus, Hugo A.; Bassel-Duby, Rhonda; Maier, Lars S.; Olson, Eric N.

2009-01-01

Acute and chronic injuries to the heart result in perturbation of intracellular calcium signaling, which leads to pathological cardiac hypertrophy and remodeling. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the transduction of calcium signals in the heart, but the specific isoforms of CaMKII that mediate pathological cardiac signaling have not been fully defined. To investigate the potential involvement in heart disease of CaMKIIδ, the major CaMKII isoform expressed in the heart, we generated CaMKIIδ-null mice. These mice are viable and display no overt abnormalities in cardiac structure or function in the absence of stress. However, pathological cardiac hypertrophy and remodeling are attenuated in response to pressure overload in these animals. Cardiac extracts from CaMKIIδ-null mice showed diminished kinase activity toward histone deacetylase 4 (HDAC4), a substrate of stress-responsive protein kinases and suppressor of stress-dependent cardiac remodeling. In contrast, phosphorylation of the closely related HDAC5 was unaffected in hearts of CaMKIIδ-null mice, underscoring the specificity of the CaMKIIδ signaling pathway for HDAC4 phosphorylation. We conclude that CaMKIIδ functions as an important transducer of stress stimuli involved in pathological cardiac remodeling in vivo, which is mediated, at least in part, by the phosphorylation of HDAC4. These findings point to CaMKIIδ as a potential therapeutic target for the maintenance of cardiac function in the setting of pressure overload. PMID:19179290

Pathologically Diagnosed Placenta Accreta and Hemorrhagic Morbidity in a Subsequent Pregnancy.

PubMed

Roeca, Cassandra; Little, Sarah E; Carusi, Daniela A

2017-02-01

To identify the relationship between pathologically diagnosed placenta accreta and risk of major morbidity in a subsequent pregnancy. We conducted a retrospective cohort study of patients with pathologically diagnosed placenta accreta in an index pregnancy who returned with a subsequent pregnancy at our academic center from 2007 to 2015. Subsequent delivery outcomes included minor, major, or no morbidity. Minor morbidity included estimated blood loss 500-1,500 cc for vaginal and 1,000-1,500 cc for cesarean delivery, transfusion of one to three units of red cells, and minor surgical procedures. Major morbidity included estimated blood loss greater than 1,500 cc, transfusion of greater than three units of red cells, uterine artery embolization, unplanned laparotomy, or hysterectomy. Three hundred thirty-nine patients with pathologically diagnosed accreta did not undergo hysterectomy, and 39 (11.5%) of these returned for subsequent delivery. Of these, 14 (36%) had accretas that had been identified clinically in the index pregnancy. Twenty-one (54%) experienced morbidity in the index pregnancy, 16 of these (76%) minor and five (24%) major. Of patients without morbidity in the first pregnancy, none experienced major morbidity in a subsequent pregnancy, whereas 6 of 21 (29%) with any index morbidity had a subsequent major morbid outcome (P=.02). Of those with a morbid index delivery, 25% had either a clinical or pathologic accreta diagnosis at follow-up compared with none of those who index accreta was nonmorbid (P=.05). Risk for major hemorrhagic morbidity after a prior pathologically diagnosed accreta depends on the clinical context. Preparation for major blood loss is indicated after any prior pregnancy complicated by hemorrhage or treatment of retained placenta with a pathologic accreta.

Pericytes in kidney fibrosis.

PubMed

Ren, Shuyu; Duffield, Jeremy S

2013-07-01

Pericytes and perivascular fibroblasts have emerged as poorly appreciated yet extensive populations of mesenchymal cells in the kidney that play important roles in homeostasis and responses to injury. This review will update readers on the evolving understanding of the biology of these cells. Fate mapping has identified pericytes and perivascular fibroblasts as the major source of pathological fibrillar matrix-forming cells in interstitial kidney disease. In other organs similar cells have been described and independent fate mapping indicates that pericytes or perivascular cells are myofibroblast progenitors in multiple organs. Over the last year, new insights into the function of pericytes in kidney homeostasis has been uncovered and new molecular pathways that regulate detachment and their transdifferentiation into pathological myofibroblasts, including Wingless/Int, ephrin, transforming growth factor β, platelet derived growth factor, and Hedgehog signaling pathways, have been reported. In addition provocative studies indicate that microRNAs, which regulate posttranscriptional gene expression, may also play important roles in their transdifferentiation. Pericytes and perivascular fibroblasts are the major source of pathological collagen fiber-forming cells in interstitial kidney diseases. New avenues of research into their activation and differentiation has identified new drug candidates for the treatment of interstitial kidney disease.

Adequacy of pathology resident training for employment: a survey report from the Future of Pathology Task Group.

PubMed

Kass, Mary E; Crawford, James M; Bennett, Betsy; Cox, Teresa M; Grimes, Margaret M; LiVolsi, Virginia; Fletcher, Christopher D M; Wilkinson, David S

2007-04-01

The recent change in accreditation requirements for anatomic pathology and clinical pathology residency training from 5 to 4 years and the rapid advances in technologies for pathology services have sparked a renewed debate over the adequacy of pathology residency training. In particular, perceived deficiencies in training have been declared from a variety of sources, both in the form of recent editorial opinions and from surveys of community hospital pathologist employers in 1998, 2003, and 2005 by Dr Richard Horowitz. To obtain more comprehensive data on the perceptions of strengths and weaknesses in pathology residency training. The College of American Pathologists conducted a survey of potential pathology employers (senior College of American Pathologists members, members designated as head of group, and members of the Association of Directors of Anatomic and Surgical Pathology). Also surveyed were recent graduates of pathology residency programs, who were identified as being junior members of the College of American Pathologists, were recent recipients of certification from the American Board of Pathology, or were contacted through their directors of pathology residency programs. There were 559 employer respondents, of whom 384 were responsible for hiring and/or supervising new pathologists. There were 247 recent graduates of pathology residency training programs who responded. From the employers' standpoint, the majority expressed overall satisfaction with recent graduates, but almost one third of employers indicated that new hires had a major deficiency in a critical area. Specific areas of deficiency were clinical laboratory management and judgment in ordering special stains and studies. In addition, one half of employers agreed that more guidance and support for newly trained pathologists is needed now than was required 10 years ago. Academic employers generally were more satisfied than private sector employers. Newly trained pathologists did not appear to be inappropriately overconfident in their abilities. In addition, their perceptions of those specific areas in which they are most and least prepared are very similar to the ratings provided by employers. On average, newly trained pathologists' ratings of their own preparedness are highest for specific aspects of general pathology and anatomic pathology, and lowest for specific aspects of clinical pathology and administration. In selecting new pathologists, employers perceived medical knowledge and interpersonal skills as the most important discriminating applicant characteristics. When new employees were asked why they thought they were offered their position, the discriminating qualifications cited most often were academic background and training, as well as completion of a fellowship and subspecialty training. It is our hope that the results of this survey can be used as input for further discussions and recommendations for training of pathology residents so as to further advance the ability of pathologists to provide quality patient care upon their graduation from training.

Between DSM and ICD: Paraphilias and the Transformation of Sexual Norms.

PubMed

Giami, Alain

2015-07-01

The simultaneous revision of the two major international classifications of disease, the Diagnostic and Statistical Manual of Mental Disorders and the International Classification of Diseases, serves as an opportunity to observe the dynamic processes through which social norms of sexuality are constructed and are subject to change in relation to social, political, and historical context. This article argues that the classifications of sexual disorders, which define pathological aspects of "sexually arousing fantasies, sexual urges or behaviors" are representations of contemporary sexual norms, gender identifications, and gender relations. It aims to demonstrate how changes in the medical treatment of sexual perversions/paraphilias passed, over the course of the 20th century, from a model of pathologization (and sometimes criminalization) of non-reproductive sexual behaviors to a model that reflects and privileges sexual well-being and responsibility, and pathologizes the absence or the limitation of consent in sexual relations.

Complex Pathologic Roles of RIPK1 and RIPK3: Moving Beyond Necroptosis

PubMed Central

Wegner, Kelby W.; Saleh, Danish; Degterev, Alexei

2017-01-01

A process of regulated necrosis, termed necroptosis, has been recognized as a major contributor to cell death and inflammation occurring under a wide range of pathologic settings. The core event in necroptosis is the formation of the detergent-insoluble “necrosome” complex of homologous Ser/Thr kinases Receptor Interacting Kinase 1 (RIPK1) and Receptor Interacting Kinase 3 (RIPK3), which promotes phosphorylation of a key pro-death effector Mixed Lineage Kinase Domain-like (MLKL) by RIPK3. Core necroptosis mediators are under multiple controls, which have been a subject of intense investigation. Additional, non-necroptotic functions of these factors, primarily in controlling apoptosis and inflammatory responses, have also begun to emerge. This review will provide an overview of the current understanding of the human disease relevance of this pathway, and potential therapeutic strategies, targeting necroptosis mediators in various pathologies. PMID:28126382

Margin Status Remains an Important Determinant of Survival after Surgical Resection of Colorectal Liver Metastases in the Era of Modern Chemotherapy

PubMed Central

Andreou, Andreas; Aloia, Thomas A.; Brouquet, Antoine; Dickson, Paxton V.; Zimmitti, Giuseppe; Maru, Dipen M.; Kopetz, Scott; Loyer, Evelyne M.; Curley, Steven A.; Abdalla, Eddie K.; Vauthey, Jean-Nicolas

2013-01-01

Objective To determine the impact of surgical margin status on overall survival (OS) of patients undergoing hepatectomy for colorectal liver metastases (CLM) after modern preoperative chemotherapy. Summary Background Data In the era of effective chemotherapy for CLM, the association between surgical margin status and survival has become controversial. Methods Clinicopathologic data and outcomes for 378 patients treated with modern preoperative chemotherapy and hepatectomy were analyzed. The effect of positive margins on OS was analyzed in relation to pathologic and computed tomography-based morphologic response to chemotherapy. Results Fifty-two of 378 resections (14%) were R1 resections (tumor-free margin < 1 mm). The 5-year OS rates for patients with R0 resection (margin ≥ 1 mm) and R1 resection were 55% and 26%, respectively (P=0.017). Multivariate analysis identified R1 resection (P=0.03) and minor pathologic response to chemotherapy (P=0.002) as the 2 factors independently associated with worse survival. The survival benefit associated with negative margins (R0 vs. R1 resection) was greater in patients with suboptimal morphologic response (5-year OS rate: 62% vs. 11%, P=0.007) than in patients with optimal response (3-year OS rate: 92% vs. 88%, P=0.917) and greater in patients with minor pathologic response (5-year OS rate: 46% vs. 0%, P=0.002) than in patients with major response (5-year OS rate: 63% vs. 67%, P=0.587). Conclusions In the era of modern chemotherapy, negative margins remain an important determinant of survival and should be the primary goal of surgical therapy. The impact of positive margins is most pronounced in patients with suboptimal response to systemic therapy. PMID:23426338

Margin status remains an important determinant of survival after surgical resection of colorectal liver metastases in the era of modern chemotherapy.

PubMed

Andreou, Andreas; Aloia, Thomas A; Brouquet, Antoine; Dickson, Paxton V; Zimmitti, Giuseppe; Maru, Dipen M; Kopetz, Scott; Loyer, Evelyne M; Curley, Steven A; Abdalla, Eddie K; Vauthey, Jean-Nicolas

2013-06-01

To determine the impact of surgical margin status on overall survival (OS) of patients undergoing hepatectomy for colorectal liver metastases after modern preoperative chemotherapy. In the era of effective chemotherapy for colorectal liver metastases, the association between surgical margin status and survival has become controversial. Clinicopathologic data and outcomes for 378 patients treated with modern preoperative chemotherapy and hepatectomy were analyzed. The effect of positive margins on OS was analyzed in relation to pathologic and computed tomography-based morphologic response to chemotherapy. Fifty-two of 378 resections (14%) were R1 resections (tumor-free margin <1 mm). The 5-year OS rates for patients with R0 resection (margin ≥1 mm) and R1 resection were 55% and 26%, respectively (P = 0.017). Multivariate analysis identified R1 resection (P = 0.03) and a minor pathologic response to chemotherapy (P = 0.002) as the 2 factors independently associated with worse survival. The survival benefit associated with negative margins (R0 vs R1 resection) was greater in patients with suboptimal morphologic response (5-year OS rate: 62% vs 11%; P = 0.007) than in patients with optimal response (3-year OS rate: 92% vs 88%; P = 0.917) and greater in patients with a minor pathologic response (5-year OS rate: 46% vs 0%; P = 0.002) than in patients with a major response (5-year OS rate: 63% vs 67%; P = 0.587). In the era of modern chemotherapy, negative margins remain an important determinant of survival and should be the primary goal of surgical therapy. The impact of positive margins is most pronounced in patients with suboptimal response to systemic therapy.

RNA-Binding Proteins in Female Reproductive Pathologies.

PubMed

Khalaj, Kasra; Miller, Jessica E; Fenn, Christian R; Ahn, SooHyun; Luna, Rayana L; Symons, Lindsey; Monsanto, Stephany P; Koti, Madhuri; Tayade, Chandrakant

2017-06-01

RNA-binding proteins are key regulatory molecules involved primarily in post-transcriptional gene regulation of RNAs. Post-transcriptional gene regulation is critical for adequate cellular growth and survival. Recent reports have shown key interactions between these RNA-binding proteins and other regulatory elements, such as miRNAs and long noncoding RNAs, either enhancing or diminishing their response to RNA stabilization. Many RNA-binding proteins have been reported to play a functional role in mediation of cytokines involved in inflammation and immune dysfunction, and some have been classified as global post-transcriptional regulators of inflammation. The ubiquitous expression of RNA-binding proteins in a wide variety of cell types and their unique mechanisms of degradative action provide evidence that they are involved in reproductive tract pathologies. Aberrant inflammation and immune dysfunction are major contributors to the pathogenesis and disease pathophysiology of many reproductive pathologies, including ovarian and endometrial cancers in the female reproductive tract. Herein, we discuss various RNA-binding proteins and their unique contributions to female reproductive pathologies with a focus on those mediated by aberrant inflammation and immune dysfunction. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Understanding Caries From the Oral Microbiome Perspective.

PubMed

Tanner, Anne C R; Kressirer, Christine A; Faller, Lina L

2016-07-01

Dental caries is a major disease of the oral cavity with profound clinical significance. Caries results from a transition of a healthy oral microbiome into an acidogenic community of decreased microbial diversity in response to excessive dietary sugar intake. Microbiological cultivation, molecular identification, gene expression and metabolomic analyses show the importance of the entire microbial community in understanding the role of the microbiome in the pathology of caries.

Correlation of tumor response on computed tomography with pathological necrosis in hepatocellular carcinoma treated by chemoembolization before liver transplantation.

PubMed

Dioguardi Burgio, Marco; Ronot, Maxime; Bruno, Onorina; Francoz, Claire; Paradis, Valérie; Castera, Laurent; Durand, François; Soubrane, Olivier; Vilgrain, Valérie

2016-11-01

The purpose of this article was to compare the results of Response Evaluation Criteria in Solid Tumors (RECIST), modified Response Evaluation Criteria in Solid Tumors (mRECIST), and European Association for the Study of the Liver (EASL) criteria for the evaluation of tumor necrosis in patients treated with transarterial chemoembolization before liver transplantation (LT) for hepatocellular carcinoma. Response to treatment was evaluated on computed tomography scan by 2 independent readers based on RECIST, mRECIST, and EASL criteria, and compared with tumor necrosis assessed by explant pathology. Necrosis was defined as major when >90%. Factors associated with major necrosis were tested by multivariate analysis. Fifty-eight patients (53 males; mean age, 54 years; range, 31-64 years) were included with 88 nodules. Fifty-one (58%) nodules were shown to have major necrosis. Among them readers 1 and 2 identified a complete response (CR) according to RECIST, mRECIST, and EASL criteria in 2 (4%), 47 (92%), and 47 (92%), and 1 (2%), 45 (88%), and 45 (88%) nodules, respectively. However, 12-14 of 59 nodules classified as CR on mRECIST or EASL criteria were found to have intermediate or minor necrosis (overestimation in 20%-24% of the patients). Combining the classification of CR by mRECIST and EASL criteria and complete lipiodol deposition reduced the overestimation to 11%. Among 59 nodules classified with a CR according to mRECIST or EASL, those with complete lipiodol deposition (n = 36, 61%) had a higher rate of necrosis than those with incomplete lipiodol deposition (n = 23, 39%): 95% versus 68% and 95% versus 63% for reader 1 and 2, respectively. In conclusion, CR based on mRECIST/EASL combined with complete lipiodol deposition was better for identification of major tumor necrosis. Even in the presence of CR according to mRECIST/EASL, incomplete lipiodol deposition should be considered indicative of substantial viable tumor remnant. Liver Transplantation 22 1491-1500 2016 AASLD. © 2016 by the American Association for the Study of Liver Diseases.

Influence of the baseline 18F-fluoro-2-deoxy-D-glucose positron emission tomography results on survival and pathologic response in patients with gastroesophageal cancer undergoing chemoradiation.

PubMed

Javeri, Heta; Xiao, Lianchun; Rohren, Eric; Komaki, Ritsuko; Hofstetter, Wayne; Lee, Jeffrey H; Maru, Dipen; Bhutani, Manoop S; Swisher, Stephen G; Wang, Xuemei; Ajani, Jaffer A

2009-02-01

In patients with esophageal cancer who receive chemoradiation, tools to predict/prognosticate outcome before administering therapy are lacking. The authors evaluated initial standardized unit value (iSUV) of 18F-fluoro-2-deoxy-D-glucose positron emission tomography and its association with overall survival and the degree of pathologic response after surgery. The authors analyzed 161 patients with esophageal adenocarcinoma who had chemoradiation followed by surgery. The log-rank test, univariate Cox proportional hazards model, Kaplan-Meier survival plot, and Fisher exact test were used to analyze dichotomized iSUV and its association with overall survival and pathologic response. The median age of 161 patients was 61 years (range, 26-80 years) and the majority of patients had lower esophageal or gastroesophageal junction involvement. All patients received fluoropyrimidine and, most commonly, a taxane or platinum compound with concomitant radiation. The median radiation dose was 45 grays (Gy) (range, 45 Gy-50.4 Gy). The median iSUV for all patients was 10.1 (range, 0-58). Using the Fisher exact test, iSUV was not found to be associated with the location of the primary cancer. iSUV higher than the median (10.1) was associated with a better pathologic response (P = .06). Patients with primary cancer with iSUV >10.1 had a lower risk for death (hazards ratio of 0.56) compared with those with iSUV < or = 10.1. Higher iSUV was nonsignificantly associated with improved survival (P = .07). Data from the current study suggest that lower iSUV is associated with poor survival and lower probability of response to chemoradiation. iSUV needs to be further evaluated because it may be used to complement other imaging or biomarker assessments to individualize therapy. (c) 2008 American Cancer Society.

Central pathology review with two-stage quality assurance for pathological response after neoadjuvant chemotherapy in the ARTemis Trial.

PubMed

Thomas, Jeremy St John; Provenzano, Elena; Hiller, Louise; Dunn, Janet; Blenkinsop, Clare; Grybowicz, Louise; Vallier, Anne-Laure; Gounaris, Ioannis; Abraham, Jean; Hughes-Davies, Luke; McAdam, Karen; Chan, Stephen; Ahmad, Rizvana; Hickish, Tamas; Houston, Stephen; Rea, Daniel; Caldas, Carlos; Bartlett, John Ms; Cameron, David Allan; Hayward, Richard Laurence; Earl, Helena Margaret

2017-08-01

The ARTemis Trial tested standard neoadjuvant chemotherapy±bevacizumab in the treatment of HER2-negative early breast cancer. We compare data from central pathology review with report review and also the reporting behavior of the two central pathologists. Eight hundred women with HER2-negative early invasive breast cancer were recruited. Response to chemotherapy was assessed from local pathology reports for pathological complete response in breast and axillary lymph nodes. Sections from the original core biopsy and surgical excision were centrally reviewed by one of two trial pathologists blinded to the local pathology reports. Pathologists recorded response to chemotherapy descriptively and also calculated residual cancer burden. 10% of cases were double-reported to compare the central pathologists' reporting behavior. Full sample retrieval was obtained for 681 of the 781 patients (87%) who underwent surgery within the trial and were evaluable for pathological complete response. Four hundred and eighty-three (71%) were assessed by JSJT, and 198 (29%) were assessed by EP. Residual cancer burden calculations were possible in 587/681 (86%) of the centrally reviewed patients, as 94/681 (14%) had positive sentinel nodes removed before neoadjuvant chemotherapy invalidating residual cancer burden scoring. Good concordance was found between the two pathologists for residual cancer burden classes within the 65-patient quality assurance exercise (kappa 0.63 (95% CI: 0.57-0.69)). Similar results were obtained for the between-treatment arm comparison both from the report review and the central pathology review. For pathological complete response, report review was as good as central pathology review but for minimal residual disease, report review overestimated the extent of residual disease. In the ARTemis Trial central pathology review added little in the determination of pathological complete response but had a role in evaluating low levels of residual disease. Calculation of residual cancer burden was a simple and reproducible method of quantifying response to neoadjuvant chemotherapy as demonstrated by performance comparison of the two pathologists.

Towards Building a High Performance Spatial Query System for Large Scale Medical Imaging Data.

PubMed

Aji, Ablimit; Wang, Fusheng; Saltz, Joel H

2012-11-06

Support of high performance queries on large volumes of scientific spatial data is becoming increasingly important in many applications. This growth is driven by not only geospatial problems in numerous fields, but also emerging scientific applications that are increasingly data- and compute-intensive. For example, digital pathology imaging has become an emerging field during the past decade, where examination of high resolution images of human tissue specimens enables more effective diagnosis, prediction and treatment of diseases. Systematic analysis of large-scale pathology images generates tremendous amounts of spatially derived quantifications of micro-anatomic objects, such as nuclei, blood vessels, and tissue regions. Analytical pathology imaging provides high potential to support image based computer aided diagnosis. One major requirement for this is effective querying of such enormous amount of data with fast response, which is faced with two major challenges: the "big data" challenge and the high computation complexity. In this paper, we present our work towards building a high performance spatial query system for querying massive spatial data on MapReduce. Our framework takes an on demand index building approach for processing spatial queries and a partition-merge approach for building parallel spatial query pipelines, which fits nicely with the computing model of MapReduce. We demonstrate our framework on supporting multi-way spatial joins for algorithm evaluation and nearest neighbor queries for microanatomic objects. To reduce query response time, we propose cost based query optimization to mitigate the effect of data skew. Our experiments show that the framework can efficiently support complex analytical spatial queries on MapReduce.

Towards Building a High Performance Spatial Query System for Large Scale Medical Imaging Data

PubMed Central

Aji, Ablimit; Wang, Fusheng; Saltz, Joel H.

2013-01-01

Support of high performance queries on large volumes of scientific spatial data is becoming increasingly important in many applications. This growth is driven by not only geospatial problems in numerous fields, but also emerging scientific applications that are increasingly data- and compute-intensive. For example, digital pathology imaging has become an emerging field during the past decade, where examination of high resolution images of human tissue specimens enables more effective diagnosis, prediction and treatment of diseases. Systematic analysis of large-scale pathology images generates tremendous amounts of spatially derived quantifications of micro-anatomic objects, such as nuclei, blood vessels, and tissue regions. Analytical pathology imaging provides high potential to support image based computer aided diagnosis. One major requirement for this is effective querying of such enormous amount of data with fast response, which is faced with two major challenges: the “big data” challenge and the high computation complexity. In this paper, we present our work towards building a high performance spatial query system for querying massive spatial data on MapReduce. Our framework takes an on demand index building approach for processing spatial queries and a partition-merge approach for building parallel spatial query pipelines, which fits nicely with the computing model of MapReduce. We demonstrate our framework on supporting multi-way spatial joins for algorithm evaluation and nearest neighbor queries for microanatomic objects. To reduce query response time, we propose cost based query optimization to mitigate the effect of data skew. Our experiments show that the framework can efficiently support complex analytical spatial queries on MapReduce. PMID:24501719

Poly-N-Acetylglucosamine Production by Staphylococcus epidermidis Cells Increases Their In Vivo Proinflammatory Effect

PubMed Central

Ferreirinha, Pedro; Pérez-Cabezas, Begoña; Correia, Alexandra; Miyazawa, Bruna; França, Angela; Carvalhais, Virgínia; Faustino, Augusto; Cordeiro-da-Silva, Anabela; Teixeira, Luzia; Pier, Gerald B.

2016-01-01

Poly-N-acetylglucosamine (PNAG) is a major component of the Staphylococcus epidermidis biofilm extracellular matrix. However, it is not yet clear how this polysaccharide impacts the host immune response and infection-associated pathology. Faster neutrophil recruitment and bacterial clearance were observed in mice challenged intraperitoneally with S. epidermidis biofilm cells of the PNAG-producing 9142 strain than in mice similarly challenged with the isogenic PNAG-defective M10 mutant. Moreover, intraperitoneal priming with 9142 cells exacerbated liver inflammatory pathology induced by a subsequent intravenous S. epidermidis challenge, compared to priming with M10 cells. The 9142-primed mice had elevated splenic CD4+ T cells producing gamma interferon and interleukin-17A, indicating that PNAG promoted cell-mediated immunity. Curiously, despite having more marked liver tissue pathology, 9142-primed mice also had splenic T regulatory cells with greater suppressive activity than those of their M10-primed counterparts. By showing that PNAG production by S. epidermidis biofilm cells exacerbates host inflammatory pathology, these results together suggest that this polysaccharide contributes to the clinical features associated with biofilm-derived infections. PMID:27481237

Interferons and Interferon Regulatory Factors in Malaria

PubMed Central

Claser, Carla; Tan, Kevin Shyong Wei; Rénia, Laurent

2014-01-01

Malaria is one of the most serious infectious diseases in humans and responsible for approximately 500 million clinical cases and 500 thousand deaths annually. Acquired adaptive immune responses control parasite replication and infection-induced pathologies. Most infections are clinically silent which reflects on the ability of adaptive immune mechanisms to prevent the disease. However, a minority of these can become severe and life-threatening, manifesting a range of overlapping syndromes of complex origins which could be induced by uncontrolled immune responses. Major players of the innate and adaptive responses are interferons. Here, we review their roles and the signaling pathways involved in their production and protection against infection and induced immunopathologies. PMID:25157202

How host regulation of Helicobacter pylori-induced gastritis protects against peptic ulcer disease and gastric cancer.

PubMed

Dhar, Poshmaal; Ng, Garrett Z; Sutton, Philip

2016-09-01

The bacterial pathogen Helicobacter pylori is the etiological agent of a range of gastrointestinal pathologies including peptic ulcer disease and the major killer, gastric adenocarcinoma. Infection with this bacterium induces a chronic inflammatory response in the gastric mucosa (gastritis). It is this gastritis that, over decades, eventually drives the development of H. pylori-associated disease in some individuals. The majority of studies investigating H. pylori pathogenesis have focused on factors that promote disease development in infected individuals. However, an estimated 85% of those infected with H. pylori remain completely asymptomatic, despite the presence of pathogenic bacteria that drive a chronic gastritis that lasts many decades. This indicates the presence of highly effective regulatory processes in the host that, in most cases, keeps a check on inflammation and protect against disease. In this minireview we discuss such known host factors and how they prevent the development of H. pylori-associated pathologies. Copyright © 2016 the American Physiological Society.

Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology.

PubMed

Harizi, Hedi; Corcuff, Jean-Benoît; Gualde, Norbert

2008-10-01

Arachidonic acid (AA)-derived eicosanoids belong to a complex family of lipid mediators that regulate a wide variety of physiological responses and pathological processes. They are produced by various cell types through distinct enzymatic pathways and act on target cells via specific G-protein-coupled receptors. Although originally recognized for their capacity to elicit biological responses such as vascular homeostasis, protection of the gastric mucosa and platelet aggregation, eicosanoids are now understood to regulate immunopathological processes ranging from inflammatory responses to chronic tissue remodelling, cancer, asthma, rheumatoid arthritis and autoimmune disorders. Here, we review the major properties of eicosanoids and their expanding roles in biology and medicine.

Complicated grief and posttraumatic stress disorder in humans' response to the death of pets/animals.

PubMed

Adrian, Julie A Luiz; Deliramich, Aimee N; Frueh, B Christopher

2009-01-01

The present exploratory project represents a cross-sectional study designed to determine the percentage of people reporting significant symptoms of complicated grief (CG) and/or posttraumatic stress disorder (PTSD) in response to the death of companion pets/animals. Human participants (N = 106) were sampled from a veterinary clinic. Fifty-two percent of participants had lost one to three pets from natural causes, 60% had never lost a pet to euthanasia, and 37% had lost one to three pets to euthanasia. The study suggests that many people experience significant attachment to their pets/animals and experience significant features of grief reactions (about 20%) after the death of a pet/animal. However, the percentage of people experiencing major pathological disruption is relatively low (<5%-12%). Thus, subclinical levels of grief and sadness are relatively common human responses to the death of companion pets/animals and last 6 months or more for about 30% of those sampled. Severe pathological reactions do occur but are quite rare among human survivors. Implications for mental health clinicians working with affected populations are discussed.

Dose-Effect Relationship in Chemoradiotherapy for Locally Advanced Rectal Cancer: A Randomized Trial Comparing Two Radiation Doses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jakobsen, Anders, E-mail: anders.jakobsen@slb.regionsyddanmark.dk; University of Southern Denmark, Odense; Ploen, John

2012-11-15

Purpose: Locally advanced rectal cancer represents a major therapeutic challenge. Preoperative chemoradiation therapy is considered standard, but little is known about the dose-effect relationship. The present study represents a dose-escalation phase III trial comparing 2 doses of radiation. Methods and Materials: The inclusion criteria were resectable T3 and T4 tumors with a circumferential margin of {<=}5 mm on magnetic resonance imaging. The patients were randomized to receive 50.4 Gy in 28 fractions to the tumor and pelvic lymph nodes (arm A) or the same treatment supplemented with an endorectal boost given as high-dose-rate brachytherapy (10 Gy in 2 fractions; armmore » B). Concomitant chemotherapy, uftoral 300 mg/m{sup 2} and L-leucovorin 22.5 mg/d, was added to both arms on treatment days. The primary endpoint was complete pathologic remission. The secondary endpoints included tumor response and rate of complete resection (R0). Results: The study included 248 patients. No significant difference was found in toxicity or surgical complications between the 2 groups. Based on intention to treat, no significant difference was found in the complete pathologic remission rate between the 2 arms (18% and 18%). The rate of R0 resection was different in T3 tumors (90% and 99%; P=.03). The same applied to the rate of major response (tumor regression grade, 1+2), 29% and 44%, respectively (P=.04). Conclusions: This first randomized trial comparing 2 radiation doses indicated that the higher dose increased the rate of major response by 50% in T3 tumors. The endorectal boost is feasible, with no significant increase in toxicity or surgical complications.« less

The clinico-pathology and mechanisms of trypanosomosis in captive and free-living wild animals: a review.

PubMed

Mbaya, A W; Aliyu, M M; Ibrahim, U I

2009-10-01

Reports on the clinico-pathology and mechanisms of trypanosomosis in free-living and captive wild animals showed that clinical disease and outbreaks occur more commonly among captive than free-living wild animals. This is because the free-living wild animals co-exist with the disease until subjected to captivity. In exceptional cases however, draught, starvation and intercurrent diseases often compromised trypanotolerance leading to overt trypanosomosis in free-living wild animals. Meanwhile, in captivity, space restriction, reduced social interactions, change in social herd structure, reduced specie-to-specie specific behaviors, altered habitat and translocation were the major stressors that precipitated the disease. The cumulative effect of these factors produced severe physiological and somatic stress leading to diminished immune response due to increased blood cortisol output from adrenal cortex. The major symptoms manifested were pyrexia, innapetence, increased respiration, anaemia, cachexia and death. At necropsy, pulmonary oedema, splenomegally, hepatomegally, lympadenopathy and atrophy of body fats were the gross changes encountered. At the ultra-structural level, the tissues manifested degenerative changes, haemorghages, necrosis and mononuclear cellular infiltrations. The mechanisms of cellular and tissue injuries were primarily associated with physical and metabolic activities of the organisms. From the foregoing, it is evident that stress is the underlying mechanism that compromises trypanotolerance in wild animals leading to severe clinico-pathological effects.

Inflammation in Chronic Wounds

PubMed Central

Zhao, Ruilong; Liang, Helena; Clarke, Elizabeth; Jackson, Christopher; Xue, Meilang

2016-01-01

Non-healing chronic wounds present a major biological, psychological, social, and financial burden on both individual patients and the broader health system. Pathologically extensive inflammation plays a major role in the disruption of the normal healing cascade. The causes of chronic wounds (venous, arterial, pressure, and diabetic ulcers) can be examined through a juxtaposition of normal healing and the rogue inflammatory response created by the common components within chronic wounds (ageing, hypoxia, ischaemia-reperfusion injury, and bacterial colonisation). Wound bed care through debridement, dressings, and antibiotics currently form the basic mode of treatment. Despite recent setbacks, pharmaceutical adjuncts form an interesting area of research. PMID:27973441

Inflammation in Chronic Wounds.

PubMed

Zhao, Ruilong; Liang, Helena; Clarke, Elizabeth; Jackson, Christopher; Xue, Meilang

2016-12-11

Non-healing chronic wounds present a major biological, psychological, social, and financial burden on both individual patients and the broader health system. Pathologically extensive inflammation plays a major role in the disruption of the normal healing cascade. The causes of chronic wounds (venous, arterial, pressure, and diabetic ulcers) can be examined through a juxtaposition of normal healing and the rogue inflammatory response created by the common components within chronic wounds (ageing, hypoxia, ischaemia-reperfusion injury, and bacterial colonisation). Wound bed care through debridement, dressings, and antibiotics currently form the basic mode of treatment. Despite recent setbacks, pharmaceutical adjuncts form an interesting area of research.

MYC Amplification as a Predictive Factor of Complete Pathologic Response to Docetaxel-based Neoadjuvant Chemotherapy for Breast Cancer.

PubMed

Pereira, Cynthia Brito Lins; Leal, Mariana Ferreira; Abdelhay, Eliana Saul Furquim Werneck; Demachki, Sâmia; Assumpção, Paulo Pimentel; de Souza, Mirian Carvalho; Moreira-Nunes, Caroline Aquino; Tanaka, Adriana Michiko da Silva; Smith, Marília Cardoso; Burbano, Rommel Rodríguez

2017-06-01

Neoadjuvant chemotherapy is a standard treatment for stage II and III breast cancer. The identification of biomarkers that may help in the prediction of response to neoadjuvant therapies is necessary for a more precise definition of the best drug or drug combination to induce a better response. We assessed the role of Ki67, hormone receptors expression, HER2, MYC genes and their protein status, and KRAS codon 12 mutations as predictor factors of pathologic response to anthracycline-cyclophosphamide (AC) followed by taxane docetaxel (T) neoadjuvant chemotherapy (AC+T regimen) in 51 patients with invasive ductal breast cancer. After neoadjuvant chemotherapy, 82.4% of patients showed pathologic partial response, with only 9.8% showing pathologic complete response. In multivariate analysis, MYC immunoreactivity and high MYC gain defined as MYC/nucleus ≥ 5 were significant predictor factors for pathologic partial response. Using the receiver operating characteristic curve analysis, the ratio of 2.5 MYC/CEP8 (sensitivity of 80% and specificity of 89.1%) or 7 MYC/nuclei copies (sensitivity of 80% and specificity of 73.9%) as the best cutoff in predicting a pathologic complete response was identified. Thus, MYC may have a role in chemosensitivity to AC and/or docetaxel drugs. Additionally, MYC amplification may be a predictor factor of pathologic response to the AC+T regimen in patients with breast cancer. Moreover, patients with an increased number of MYC copies showed pathologic complete response to this neoadjuvant treatment more frequently. The analysis of MYC amplification may help in the identification of patients that may have a better response to AC+T treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

Pre-treatment neutrophil to lymphocyte ratio as a predictive marker for pathological response to preoperative chemoradiotherapy in pancreatic cancer

PubMed Central

HASEGAWA, SHINICHIRO; EGUCHI, HIDETOSHI; TOMOKUNI, AKIRA; TOMIMARU, YOSHITO; ASAOKA, TADAFUMI; WADA, HIROSHI; HAMA, NAOKI; KAWAMOTO, KOICHI; KOBAYASHI, SHOGO; MARUBASHI, SHIGERU; KONNNO, MASAMITSU; ISHII, HIDESHI; MORI, MASAKI; DOKI, YUICHIRO; NAGANO, HIROAKI

2016-01-01

An elevated neutrophil to lymphocyte ratio (NLR) has been reported to be associated with the pathological response to neoadjuvant therapies in numerous types of cancer. The aim of the current study was to clarify the association between pre-treatment NLR and the pathological response to preoperative chemoradiotherapy in pancreatic cancer patients. This retrospective analysis included data from 56 consecutive patients whose tumors were completely surgically resected. All patients received preoperative therapy, consisting of gemcitabine-based chemotherapy (alone or in combination with S-1) combined with 40 or 50.4 Gy irradiation, prior to surgery. Predictive factors, including NLR, platelet to lymphocyte ratio (PLR), modified Glasgow prognostic score and prognostic nutrition index, were measured prior to treatment. A comparison was made between those who responded well pathologically (good response group, Evans classification IIb/III) and those with a poor response (Evans I/IIa). NLR was determined to be significantly higher in the poor response group. Multivariate analysis identified an elevated NLR as an independent risk factor for the poor pathological response [odds ratio (OR), 5.35; P=0.0257]. The pre-treatment NLR (≥2.2/<2.2) was found to be a statistically significant predictive indicator of pathological response (P=0.00699). The results demonstrate that pre-treatment NLR may be a useful predictive marker for the pathological response to preoperative therapy in pancreatic cancer patients. PMID:26893780

Glial Biomarkers in Human Central Nervous System Disease

PubMed Central

Garden, Gwenn A.; Campbell, Brian M.

2017-01-01

There is a growing understanding that aberrant GLIA function is an underlying factor in psychiatric and neurological disorders. As drug discovery efforts begin to focus on glia-related targets, a key gap in knowledge includes the availability of validated biomarkers to help determine which patients suffer from dysfunction of glial cells or who may best respond by targeting glia-related drug mechanisms. Biomarkers are biological variables with a significant relationship to parameters of disease states and can be used as surrogate markers of disease pathology, progression, and/or responses to drug treatment. For example, imaging studies of the CNS enable localization and characterization of anatomical lesions without the need to isolate tissue for biopsy. Many biomarkers of disease pathology in the CNS involve assays of glial cell function and/or response to injury. Each major glia subtype (oligodendroglia, astroglia and microglia) are connected to a number of important and useful biomarkers. Here, we describe current and emerging glial based biomarker approaches for acute CNS injury and the major categories of chronic nervous system dysfunction including neurodegenerative, neuropsychiatric, neoplastic, and autoimmune disorders of the CNS. These descriptions are highlighted in the context of how biomarkers are employed to better understand the role of glia in human CNS disease and in the development of novel therapeutic treatments. PMID:27228454

Pathology-related cases in the Norwegian System of Patient Injury Compensation in the period 2010-2015.

PubMed

Alfsen, G Cecilie; Chen, Ying; Kähler, Hanne; Bukholm, Ida Rashida Khan

2016-12-01

The Norwegian System of Patient Injury Compensation (NPE) processes compensation claims from patients who complain about malpractice in the health services. A wrong diagnosis in pathology may cause serious injury to the patient, but the incidence of compensation claims is unknown, because pathology is not specified as a separate category in NPE’s statistics. Knowledge about errors is required to assess quality-enhancing measures. We have therefore searched through the NPE records to identify cases whose background stems from errors committed in pathology departments and laboratories. We have searched through the NPE records for cases related to pathology for the years 2010 – 2015. During this period the NPE processed a total of 26 600 cases, of which 93 were related to pathology. The compensation claim was upheld in 66 cases, resulting in total compensation payments amounting to NOK 63 million. False-negative results in the form of undetected diagnoses were the most frequent grounds for compensation claims (63 cases), with an undetected malignant melanoma (n = 23) or atypia in cell samples from the cervix uteri (n = 16) as the major groups. Sixteen cases involved non-diagnostic issues such as mix-up of samples (n = 8), contamination of samples (n = 4) or delayed responses (n = 4). The number of compensation claims caused by errors in pathology diagnostics is low in relative terms. The errors may, however, be of a serious nature, especially if malignant conditions are overlooked or samples mixed up.

Whole Slide Imaging Versus Microscopy for Primary Diagnosis in Surgical Pathology

PubMed Central

Mukhopadhyay, Sanjay; Feldman, Michael D.; Abels, Esther; Ashfaq, Raheela; Beltaifa, Senda; Cacciabeve, Nicolas G.; Cathro, Helen P.; Cheng, Liang; Cooper, Kumarasen; Dickey, Glenn E.; Gill, Ryan M.; Heaton, Robert P.; Kerstens, René; Lindberg, Guy M.; Malhotra, Reenu K.; Mandell, James W.; Manlucu, Ellen D.; Mills, Anne M.; Mills, Stacey E.; Moskaluk, Christopher A.; Nelis, Mischa; Patil, Deepa T.; Przybycin, Christopher G.; Reynolds, Jordan P.; Rubin, Brian P.; Saboorian, Mohammad H.; Salicru, Mauricio; Samols, Mark A.; Sturgis, Charles D.; Turner, Kevin O.; Wick, Mark R.; Yoon, Ji Y.; Zhao, Po

2018-01-01

Most prior studies of primary diagnosis in surgical pathology using whole slide imaging (WSI) versus microscopy have focused on specific organ systems or included relatively few cases. The objective of this study was to demonstrate that WSI is noninferior to microscopy for primary diagnosis in surgical pathology. A blinded randomized noninferiority study was conducted across the entire range of surgical pathology cases (biopsies and resections, including hematoxylin and eosin, immunohistochemistry, and special stains) from 4 institutions using the original sign-out diagnosis (baseline diagnosis) as the reference standard. Cases were scanned, converted to WSI and randomized. Sixteen pathologists interpreted cases by microscopy or WSI, followed by a wash-out period of ≥4 weeks, after which cases were read by the same observers using the other modality. Major discordances were identified by an adjudication panel, and the differences between major discordance rates for both microscopy (against the reference standard) and WSI (against the reference standard) were calculated. A total of 1992 cases were included, resulting in 15,925 reads. The major discordance rate with the reference standard diagnosis was 4.9% for WSI and 4.6% for microscopy. The difference between major discordance rates for microscopy and WSI was 0.4% (95% confidence interval, −0.30% to 1.01%). The difference in major discordance rates for WSI and microscopy was highest in endocrine pathology (1.8%), neoplastic kidney pathology (1.5%), urinary bladder pathology (1.3%), and gynecologic pathology (1.2%). Detailed analysis of these cases revealed no instances where interpretation by WSI was consistently inaccurate compared with microscopy for multiple observers. We conclude that WSI is noninferior to microscopy for primary diagnosis in surgical pathology, including biopsies and resections stained with hematoxylin and eosin, immunohistochemistry and special stains. This conclusion is valid across a wide variety of organ systems and specimen types. PMID:28961557

Whole Slide Imaging Versus Microscopy for Primary Diagnosis in Surgical Pathology: A Multicenter Blinded Randomized Noninferiority Study of 1992 Cases (Pivotal Study).

PubMed

Mukhopadhyay, Sanjay; Feldman, Michael D; Abels, Esther; Ashfaq, Raheela; Beltaifa, Senda; Cacciabeve, Nicolas G; Cathro, Helen P; Cheng, Liang; Cooper, Kumarasen; Dickey, Glenn E; Gill, Ryan M; Heaton, Robert P; Kerstens, René; Lindberg, Guy M; Malhotra, Reenu K; Mandell, James W; Manlucu, Ellen D; Mills, Anne M; Mills, Stacey E; Moskaluk, Christopher A; Nelis, Mischa; Patil, Deepa T; Przybycin, Christopher G; Reynolds, Jordan P; Rubin, Brian P; Saboorian, Mohammad H; Salicru, Mauricio; Samols, Mark A; Sturgis, Charles D; Turner, Kevin O; Wick, Mark R; Yoon, Ji Y; Zhao, Po; Taylor, Clive R

2018-01-01

Most prior studies of primary diagnosis in surgical pathology using whole slide imaging (WSI) versus microscopy have focused on specific organ systems or included relatively few cases. The objective of this study was to demonstrate that WSI is noninferior to microscopy for primary diagnosis in surgical pathology. A blinded randomized noninferiority study was conducted across the entire range of surgical pathology cases (biopsies and resections, including hematoxylin and eosin, immunohistochemistry, and special stains) from 4 institutions using the original sign-out diagnosis (baseline diagnosis) as the reference standard. Cases were scanned, converted to WSI and randomized. Sixteen pathologists interpreted cases by microscopy or WSI, followed by a wash-out period of ≥4 weeks, after which cases were read by the same observers using the other modality. Major discordances were identified by an adjudication panel, and the differences between major discordance rates for both microscopy (against the reference standard) and WSI (against the reference standard) were calculated. A total of 1992 cases were included, resulting in 15,925 reads. The major discordance rate with the reference standard diagnosis was 4.9% for WSI and 4.6% for microscopy. The difference between major discordance rates for microscopy and WSI was 0.4% (95% confidence interval, -0.30% to 1.01%). The difference in major discordance rates for WSI and microscopy was highest in endocrine pathology (1.8%), neoplastic kidney pathology (1.5%), urinary bladder pathology (1.3%), and gynecologic pathology (1.2%). Detailed analysis of these cases revealed no instances where interpretation by WSI was consistently inaccurate compared with microscopy for multiple observers. We conclude that WSI is noninferior to microscopy for primary diagnosis in surgical pathology, including biopsies and resections stained with hematoxylin and eosin, immunohistochemistry and special stains. This conclusion is valid across a wide variety of organ systems and specimen types.

Forensic molecular pathology of violent deaths.

PubMed

Maeda, Hitoshi; Zhu, Bao-li; Ishikawa, Takaki; Michiue, Tomomi

2010-12-15

In forensic pathology, while classical morphology remains a core procedure to investigate deaths, a spectrum of ancillary procedures has been developed and incorporated to detail the pathology. Among them, postmortem biochemistry is important to investigate the systemic pathophysiological changes involved in the dying process that cannot be detected by morphology. In addition, recent advances in molecular biology have provided a procedure to investigate genetic bases of diseases that might present with sudden death, which is called 'molecular autopsy'. Meanwhile, the practical application of RNA analyses to postmortem investigation has not been accepted due to rapid decay after death; however, recent experimental and practical studies using real-time reverse transcription-PCR have suggested that the relative quantification of mRNA transcripts can be applied in molecular pathology for postmortem investigation of deaths, which may be called 'advanced molecular autopsy'. In a broad sense, forensic molecular pathology implies applied medical sciences to investigate the genetic basis of diseases, and the pathophysiology of diseases and traumas leading to death at a biological molecular level in the context of forensic pathology. The possible applications include analyses of local pathology, including tissue injury, ischemia/hypoxia and inflammation at the site of insult or specific tissue damage from intoxication, systemic responses to violence or environmental hazards, disorders due to intoxication, and systemic pathophysiology of fatal process involving major life-support organs. A review of previous studies suggests that systematic postmortem quantitative analysis of mRNA transcripts can be established from multi-faceted aspects of molecular biology and incorporated into death investigations in forensic pathology, to support and reinforce morphological evidence. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Pathological narcissism and the obstruction of love.

PubMed

Kealy, David; Ogrodniczuk, John S

2014-03-01

Pathological narcissism is a form of maladaptive self-regulation that impedes the capacity to love. Although narcissism is often construed as excessive self-love, individuals with pathological narcissism are impaired in being able to love themselves as well as others. With the subject of impaired love in mind, we review selected conceptualizations from an enormous and diverse psychodynamic literature on narcissism. Major theoretical approaches illustrate a number of psychodynamics associated with narcissistic self-regulatory problems. This paper provides a concise overview of major conceptual themes regarding pathological narcissism and impaired capacity to love.

Second Opinion Reviews for Cancer Diagnoses in Anatomic Pathology: A Comprehensive Cancer Center's Experience.

PubMed

Strosberg, Carolina; Gibbs, Julie; Braswell, Diana; Leslie, Ronni R; Messina, Jane; Centeno, Barbara A; Coppola, Domenico

2018-05-01

The objective of this study was to define the rates of discrepancy between outside pathological diagnoses and secondary reviews. We assessed the rates of discordance between outside diagnoses and secondary reviews, categorizing by organ site and minor or major (affecting patient care) discordances. A total of 9,289 consecutive surgical pathology (SP) and cytopathology (CP) cases reviewed in 2015 were identified. For 8,191 outside SP cases reviewed, the overall discordance rate (DR) was 14.2% (2.2% major, 12.0% minor). Specifically, neuropathology had the highest DR (10.9%), cutaneous and breast the lowest (1.1% each). Among 1,098 CP cases, the total DR was 13.7% (3.0% major, 10.7% minor). The majority of CP cases (1,066) were non-gynecological and had a total DR of 13.4% (2.7% major, 10.7% minor). While major DR was low, certain subspecialties had high DRs. This project can help identify areas where focused education could help improve pathological diagnostic accuracy for cancer. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Pathological response of locally advanced rectal cancer to preoperative chemotherapy without pelvic irradiation.

PubMed

Bensignor, T; Brouquet, A; Dariane, C; Thirot-Bidault, A; Lazure, T; Julié, C; Nordlinger, B; Penna, C; Benoist, S

2015-06-01

Pathological response to chemotherapy without pelvic irradiation is not well defined in rectal cancer. This study aimed to evaluate the objective pathological response to preoperative chemotherapy without pelvic irradiation in middle or low locally advanced rectal cancer (LARC). Between 2008 and 2013, 22 patients with middle or low LARC (T3/4 and/or N+ and circumferential resection margin < 2 mm) and synchronous metastatic disease or a contraindication to pelvic irradiation underwent rectal resection after preoperative chemotherapy. The pathological response of rectal tumour was analysed according to the Rödel tumour regression grading (TRG) system. Predictive factors of objective pathological response (TRG 2-4) were analysed. All patients underwent rectal surgery after a median of six cycles of preoperative chemotherapy. Of these, 20 (91%) had sphincter saving surgery and an R0 resection. Twelve (55%) patients had an objective pathological response (TRG 2-4), including one complete response. Poor response (TRG 0-1) to chemotherapy was noted in 10 (45%) patients. In univariate analyses, none of the factors examined was found to be predictive of an objective pathological response to chemotherapy. At a median follow-up of 37.2 months, none of the 22 patients experienced local recurrence. Of the 19 patients with Stage IV rectal cancer, 15 (79%) had liver surgery with curative intent. Preoperative chemotherapy without pelvic irradiation is associated with objective pathological response and adequate local control in selected patients with LARC. Further prospective controlled studies will address the question of whether it can be used as a valuable alternative to radiochemotherapy in LARC. Colorectal Disease © 2014 The Association of Coloproctology of Great Britain and Ireland.

A retrospective analysis of oral and maxillofacial pathology in an Australian paediatric population.

PubMed

Ha, W N; Kelloway, E; Dost, F; Farah, C S

2014-06-01

The prevalence of oral and maxillofacial pathology has not previously been reported in the Australian paediatric population. This study aimed to audit a large pathology service to provide insight into the prevalence of oral and maxillofacial pathology. Written records of a major Australian oral pathology service were imported into an electronic database. Age, gender and histological diagnosis were assessed. Prevalence of histological diagnoses as a percentage of the major diagnostic categories and of the whole sample were calculated, as well as gender predilections and mean age of presentation of disease. A total of 1305 oral pathology specimens, collected from paediatric patients aged 16 and under were included in the analysis. The most common pathology was dental pathology (24.4%), followed by odontogenic cysts (18.5%) and mucosal pathology (17.0%). The most frequently encountered lesion was the dentigerous cyst (9.4%), followed by fibrous hyperplasia (8.3%), radicular cyst (5.2%) and chronic periapical granuloma (5.2%). In the paediatric population, dental pathology and specifically, the dentigerous cyst is the most common pathology type sent for histopathology, suggesting a high prevalence of pathology of dental origin occurring in Australian children. © 2014 Australian Dental Association.

Institutional pathology consultation.

PubMed

Tsung, Jeffrey S H

2004-03-01

Sun Yat-Sen Cancer Center is the only cancer center in Taiwan. The hospital maintains a policy, and the division of oncology makes a concerted effort to obtain and review pertinent pathologic specimens in all patients who had pathologic diagnosis performed at other institution before rendering therapy. A 1-year retrospective study was undertaken to assess the frequency of discordant diagnosis of our second-opinion pathology slide review and determine its impact on patient care. Discrepancies were classified into four basic categories: A) no diagnostic disagreement; B) no diagnostic disagreement but pertinent information not included, such as tumor size, lymphovascular invasion, perineural invasion, histologic grading, margin status, extracapsular spread in metastatic lymph nodes; and C) major diagnostic disagreement, which was defined as follows; 1) change from benign to malignant, 2) change from malignant to benign, 3) a different type of neoplasm, and 4) change in N and M classification in TMN staging framework. Of 715 cases, a total of 673 (94%) showed no discrepancy. However, 35 of 673 (5.2%) cases failed to offer pertinent information (category B). Major disagreement was found in 42 16%) cases (category C). This study illustrated the fact that second pathology slide review prior to therapy can identify a small group of cases that result in a major change in their therapeutic plan. Admittedly, the review of pathology slides involves additional time and effort for both consulting and referring institutions. It can ensure quality medical care and limit medicolegal liability. As the Association of Directors of Anatomic and Surgical Pathology recommended, second pathology review should be standard practice. It is necessary that our major Pathology Association and Societies adopt a strong position on this matter to influence government or insurance company to pay for this service rendered by pathologists.

Informatics for practicing anatomical pathologists: marking a new era in pathology practice.

PubMed

Gabril, Manal Y; Yousef, George M

2010-03-01

Informatics can be defined as using highly advanced technologies to improve patient diagnosis or management. Pathology informatics had evolved as a response to the overwhelming amount of information that was available, in an attempt to better use and maintain them. The most commonly used tools of informatics can be classified into digital imaging, telepathology, as well as Internet and electronic data mining. Digital imaging is the storage of anatomical pathology information, either gross pictures or microscopic slides, in an electronic format. These images can be used for education, archival, diagnosis, and consultation. Virtual microscopy is the more advanced form of digital imaging with enhanced efficiency and accessibility. Telepathology is now increasingly becoming a useful tool in anatomical pathology practice. Different types of telepathology communications are available for both diagnostic and consultation services. The spectrum of applications of informatics in the field of anatomical pathology is broad and encompasses medical education, clinical services, and pathology research. Informatics is now settling on solid ground as an important tool for pathology teaching, with digital teaching becoming the standard tool in many institutions. After a slow start, we now witness the transition of informatics from the research bench to bedside. As we are moving into a new era of extensive pathology informatics utilization, several challenges have to be addressed, including the cost of the new technology, legal issues, and resistance of pathologists. It is clear from the current evidence that pathology informatics will continue to grow and have a major role in the future of our specialty. However, it is also clear that it is not going to fully replace the human factor or the regular microscope.

The short-term outcomes of induction SOX (S-1 + oxaliplatin) ± cetuximab chemotherapy followed by short-course chemoradiotherapy in patients with poor-risk locally advanced rectal cancer.

PubMed

Beppu, Naohito; Yoshie, Hidenori; Kimura, Fumihiko; Aihara, Tsukasa; Doi, Hiroshi; Kamikonya, Norihiko; Matsubara, Nagahide; Tomita, Naohiro; Yanagi, Hidenori; Yamanaka, Naoki

2016-10-01

To evaluate the safety and efficacy of induction SOX (S-1 + oxaliplatin) ± cetuximab chemotherapy followed by short-course chemoradiotherapy and surgery in patients with poor-risk locally advanced rectal cancer. We enrolled eligible patients with poor-risk rectal cancer defined as T3 lower rectal cancer with mesorectal fascia involvement, T4a or T4b tumors or cases with lateral lymph node swelling. The primary endpoint was a pathological complete response (pCR), and the secondary endpoints were the objective response rate (ORR) and the pathological high response rate (Grade 2 plus 3). Twenty eligible patients were enrolled. The majority (75.0 %, 15/20) of the patients completed four cycles of induction chemotherapy, and all patients completed the radiotherapy (25 Gy/10 fractions/5 days). The global rate of Grade 3-4 toxicities was 30.0 % (6/20 patients). The ORRs were 85.0 % (17/20) and 95.0 % (19/20) in the patients who underwent R0 and R1 resection, respectively. The pathological high response rate was 70.0 % (14/20) and the pCR was 10.0 % (2/20). The regimen of induction SOX (S-1 + oxaliplatin) ± cetuximab chemotherapy followed by short-course chemoradiotherapy is safe and is associated with good tumor regression in patients with poor-risk locally advanced rectal cancer.

Knowledge, Attitudes, and Practices of Pediatric Dentists Regarding Speech Evaluation of Patients: Implications for Dental Education.

PubMed

Van Eyndhoven, Lisa; Chussid, Steven; Yoon, Richard K

2015-11-01

The aim of this cross-sectional study was to determine pediatric dentists' attitudes about speech evaluation in the dental setting and assess their knowledge of speech development and pathology. In October 2013, members of the American Academy of Pediatric Dentistry were invited to participate in an electronic questionnaire. Categories of questions were demographics, attitudes and confidence in speech pathology, and theoretical and practical knowledge of speech development and speech pathology. Theoretical knowledge was assessed using questions about phonetics and speech milestones. Practical knowledge was determined with three 30-second interview-style video clips. A total of 539 responses were received for a response rate of 10.4%. The majority of respondents reported feeling that speech evaluation should be part of the pediatric dental visit (72.8%) and felt confident in their ability to detect speech issues (73.2%). However, they did poorly on the theoretical knowledge questions (41.9%) as well as the practical knowledge questions (8.5%). There was a statistically significant difference in theoretical score between gender and type of occupation (p<0.05). This difference was not observed when examining practical knowledge. This study suggests that although pediatric dentists are in an ideal position to aid in the detection of speech issues, they currently have insufficient training and knowledge to do so.

Gambling pathology is associated with dampened cortisol response among men and women.

PubMed

Paris, J J; Franco, C; Sodano, R; Frye, C A; Wulfert, E

2010-02-09

Pathological gambling has many similarities to pharmacological addiction. Notably, both pathological gambling and drug addiction are characterized by aberrations in hypothalamic-pituitary-adrenal (HPA) axis responding. As well, there are indications that gender differences may play a role in these processes. Whether gender and/or HPA response are associated with pathological gambling was of interest. Recreational and pathological gamblers (15 men and 6 women per group) had the HPA factor, cortisol, assessed in saliva before and after watching a video of their preferred mode of gambling (slot machines, horse race betting, scratch-off tickets, blackjack, video poker, craps, sports betting, online casino games, or lottery tickets), and a video of neutral stimuli (a rollercoaster ride). Basal levels of salivary cortisol did not significantly differ among recreational and pathological gamblers. However, recreational gamblers demonstrated significantly increased salivary cortisol levels after the gambling and rollercoaster videos, whereas pathological gamblers demonstrated no salivary cortisol increase in response to either video stimulus. There was also a non-significant trend for women to have a greater cortisol response to video stimuli compared to men. These data suggest that pathological gambling is associated with hypoactive HPA response to gambling stimuli, similar to chronic drug exposure, and gender may contribute to this effect. Published by Elsevier Inc.

Regulatory T cells and liver pathology in a murine graft versus host response model.

PubMed

Miyazaki, Teruo; Doy, Mikio; Unno, Rie; Honda, Akira; Ikegami, Tadashi; Itoh, Shinichi; Bouscarel, Bernard; Matsuzaki, Yasushi

2009-06-01

We have previously reported in mice the hepatic inflammatory in graft versus host response (GVHR) model due to the disparity of major histocompatibility complex class-II. The regulatory T (Treg) cells have been reported to control excessive immune response and prevent immune-related diseases. This study aimed to investigate the pathogenesis profiles of chronic GVHR progression, focusing on the Treg cells. GVHR mice induced by parental spleen CD4(+) T cell injection were sacrificed after 0, 2, 4, and 8 weeks (G0, G2, G4, G8). Further, one GVHR group received anti-IL-10 antibody in advance and were maintained for 2 weeks. Pathologic profiles of hepatic infiltrating inflammatory cells were evaluated by haematoxylin and eosin and immunohistochemistry staining with surface markers including Treg cell markers. Remarkable hepatic inflammatory in G2 significantly and gradually improved over time up to G8. In immunohistochemical staining, the increased IL-10 receptor beta(+) Tr1 cells in G2 were maintained through to G8; although other inflammatory cells decreased from G2 to G8. By contrast, in the anti-IL-10 antibody received-GVHR mice, the Tr1 cells were not detectable with significant inflammatory aggravation, while FoxP3(+) Treg cells significantly enhanced. These findings in the GVHR mice suggest that the expression and activity of Treg cells, especially the Tr1 cells, might be key factors for pathologic alteration in immune-related liver disease.

RECIST 1.1-Update and clarification: From the RECIST committee.

PubMed

Schwartz, Lawrence H; Litière, Saskia; de Vries, Elisabeth; Ford, Robert; Gwyther, Stephen; Mandrekar, Sumithra; Shankar, Lalitha; Bogaerts, Jan; Chen, Alice; Dancey, Janet; Hayes, Wendy; Hodi, F Stephen; Hoekstra, Otto S; Huang, Erich P; Lin, Nancy; Liu, Yan; Therasse, Patrick; Wolchok, Jedd D; Seymour, Lesley

2016-07-01

The Response Evaluation Criteria in Solid Tumours (RECIST) were developed and published in 2000, based on the original World Health Organisation guidelines first published in 1981. In 2009, revisions were made (RECIST 1.1) incorporating major changes, including a reduction in the number of lesions to be assessed, a new measurement method to classify lymph nodes as pathologic or normal, the clarification of the requirement to confirm a complete response or partial response and new methodologies for more appropriate measurement of disease progression. The purpose of this paper was to summarise the questions posed and the clarifications provided as an update to the 2009 publication. Copyright © 2016. Published by Elsevier Ltd.

Cancer of the esophagus and esophagogastric junction-Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual.

PubMed

Rice, Thomas W; Gress, Donna M; Patil, Deepa T; Hofstetter, Wayne L; Kelsen, David P; Blackstone, Eugene H

2017-07-08

Answer questions and earn CME/CNE New to the eighth edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual for epithelial cancers of the esophagus and esophagogastric junction are separate, temporally related cancer classifications: 1) before treatment decision (clinical); 2) after esophagectomy alone (pathologic); and 3) after preresection therapy followed by esophagectomy (postneoadjuvant pathologic). The addition of clinical and postneoadjuvant pathologic stage groupings was driven by a lack of correspondence of survival, and thus prognosis, between both clinical and postneoadjuvant pathologic cancer categories (facts about the cancer) and pathologic categories. This was revealed by a machine-learning analysis of 6-continent data from the Worldwide Esophageal Cancer Collaboration, with consensus of the AJCC Upper GI Expert Panel. Survival is markedly affected by histopathologic cell type (squamous cell carcinoma and adenocarcinoma) in clinically and pathologically staged patients, requiring separate stage grouping for each cell type. However, postneoadjuvant pathologic stage groups are identical. For the future, more refined and granular data are needed. This requires: 1) more accurate clinical staging; 2) innovative solutions to pathologic staging challenges in endoscopically resected cancers; 3) integration of genomics into staging; and 4) precision cancer care with targeted therapy. It is the responsibility of the oncology team to accurately determine and record registry data, which requires eliminating both common errors and those related to incompleteness and inconsistency. Despite the new complexity of eighth edition staging of cancers of the esophagus and esophagogastric junction, these key concepts and new directions will facilitate precision cancer care. CA Cancer J Clin 2017;67:304-317. © 2017 American Cancer Society. © 2017 American Cancer Society.

Immunisation of cattle with cysteine proteinases of Trypanosoma congolense: targetting the disease rather than the parasite.

PubMed

Authié, E; Boulangé, A; Muteti, D; Lalmanach, G; Gauthier, F; Musoke, A J

2001-11-01

In order to test the hypothesis that trypanosome cysteine proteinases (CPs) contribute to pathology of trypanosomosis, cattle were immunised with CP1 and/or CP2, the major CPs of Trypanosoma congolense, and subsequently challenged with T. congolense. Immunisation had no effect on the establishment of infection and the development of acute anaemia. However, immunised cattle, unlike control cattle, maintained or gained weight during infection. Their haematocrit and leukocyte counts showed a tendency to recovery after 2-3 months of infection. Cattle immunised with CP2 mounted early and prominent IgG responses to CPs and to the variable surface glycoprotein following challenge. Thus trypanosome CPs may play a role in anaemia and immunosuppression; conversely, anti-CP antibody may modulate the trypanosome-induced pathology.

[Guidelines for adult diffuse gliomas WHO grade II, III and IV: pathology and biology. Société franc¸aise de neuropathologie . Réseau de neuro-oncologie pathologique].

PubMed

Figarella-Branger, Dominique; Labrousse, François; Mohktari, Karima

2012-10-01

Pathological diagnosis plays a major role in the therapeutic management of adult diffuse gliomas. It is based on the histopathological analysis of a representative specimen. Therefore pathologists might be aware of the neuroradiological features of the lesions. Pathologists play a major role in the management of biological resources. Pathologists should classify adult gliomas according to WHO 2007 classification (histological subtype and grade). In addition, in order to provide the histomolecular classification of adult gliomas, search for molecular markers of diagnostic, prognostic or predictive of therapeutic responses must be performed by appropriate and validated immunohistochemical and molecular techniques. In all diffuse gliomas, whatever their grade, search for IDH1 R132H and P53 expression is required. Search for IDH1 minor mutations and IDH2 mutations is required in grade II and III IDH1 R132H negative gliomas whereas 1p19q codeletion should be searched for in grade II and III gliomas with an oligodendroglial component. Search for EGFR amplification and MGMT promoter methylation is recommended. It is strongly recommended to fill the standardized form for pathology and molecular features (validated by the French Society of Neuropathology) in all adult diffuse gliomas. Copyright © 2012. Published by Elsevier Masson SAS.

Macrophages - sensors and effectors coordinating skin damage and repair.

PubMed

Willenborg, Sebastian; Eming, Sabine A

2014-03-01

Restoration of skin integrity and homeostasis following injury is a vital process. Wound healing disorders, including chronic skin ulcers and pathological scarring, are of major clinical impact. The current therapeutic approaches are often not sufficient. The development of novel efficient therapies requires a thorough understanding of the underlying molecular mechanisms. A cardinal feature of non-healing skin ulcers and excessive scarring is a prolonged inflammatory response at the wound site, which aborts the healing response. Modulation of the local immune response may be an effective therapeutic strategy to correct impaired healing conditions. Yet, the specific mechanisms of inflammation, particularly the role of the diverse leukocyte lineages attracted to the site of tissue damage, have not been resolved. Recent findings in diverse experimental model systems and clinical studies have refined the understanding of monocyte/macrophage biology and the role of cells of the monocytic lineage in tissue regeneration. Thus, monocytes/macrophages are emerging as novel and interesting therapeutic targets to interfere in wound healing pathologies. In this article we will review the role of monocytes/macrophages in skin repair in the light of the recent literature and findings from our own group. This article will provide a rationale for monocyte/macrophage-based therapies to facilitate the healing response. © 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.

Contrast media enhancement reduction predicts tumor response to presurgical molecular-targeting therapy in patients with advanced renal cell carcinoma.

PubMed

Hosogoe, Shogo; Hatakeyama, Shingo; Kusaka, Ayumu; Hamano, Itsuto; Tanaka, Yoshimi; Hagiwara, Kazuhisa; Hirai, Hideaki; Morohashi, Satoko; Kijima, Hiroshi; Yamamoto, Hayato; Tobisawa, Yuki; Yoneyama, Tohru; Yoneyama, Takahiro; Hashimoto, Yasuhiro; Koie, Takuya; Ohyama, Chikara

2017-07-25

A quantitative tumor response evaluation to molecular-targeting agents in advanced renal cell carcinoma (RCC) is debatable. We aimed to evaluate the relationship between radiologic tumor response and pathological response in patients with advanced RCC who underwent presurgical therapy. Of 34 patients, 31 underwent scheduled radical nephrectomy. Presurgical therapy agents included axitinib (n = 26), everolimus (n = 3), sunitinib (n = 1), and axitinib followed by temsirolimus (n = 1). The major presurgical treatment-related adverse event was grade 2 or 3 hypertension (44%). The median radiologic tumor response by RECIST, Choi, and CMER were -19%, -24%, and -49%, respectively. Among the radiologic tumor response tests, CMER showed a higher association with tumor necrosis in surgical specimens than others. Ki67/MIB1 status was significantly decreased in surgical specimens than in biopsy specimens. The magnitude of the slope of the regression line associated with the tumor necrosis percentage was greater in CMER than in Choi and RECIST. Between March 2012 and December 2016, we prospectively enrolled 34 locally advanced and/or metastatic RCC who underwent presurgical molecular-targeting therapy followed by radical nephrectomy. Primary endpoint was comparison of radiologic tumor response among Response Evaluation Criteria in Solid Tumors (RECIST), Choi, and contrast media enhancement reduction (CMER). Secondary endpoint included pathological downstaging, treatment related adverse events, postoperative complications, Ki67/MIB1 status, and tumor necrosis. CMER may predict tumor response after presurgical molecular-targeting therapy. Larger prospective studies are needed to develop an optimal tumor response evaluation for molecular-targeting therapy.

Regeneration of the Adult Rat Spinal Cord in Response to Ensheathing Cells and Methylprednisolone

DTIC Science & Technology

2002-01-01

me in academics and research, and also as my friend. I thank Dr. Linda L. Porter, for her continuous efforts on my behalf as the Chairperson of...and Spinal Cord Injury Program. We are grateful to Drs. Barbara S. Bregman and Linda L. Porter for their wonderful suggestions and guidance; to Anna...ES, Pietronigro DD, Seligman ML (1980) The free radical pathology and the microcirculation in the major central nervous system disorders. Acta

Promoting change through political consciousness: a South African speech-language pathology response to the World Report on Disability.

PubMed

Kathard, Harsha; Pillay, Mershen

2013-02-01

In the context of the World Report on Disability, Wylie, McAllister, Davidson, and Marshall (2013) question how speech-language pathologists (SLPs) change practices to benefit under-served people with communication disability. This commentary provides a South African response premised on Political Consciousness. In South Africa, a grossly unequal society, the under-served population is not only those with communication disability but also include those who are at a communication disadvantage due to disabling conditions. As a consequence of the combined effects of a severe shortage of SLPs as well as maldistribution in service provision, the under-served are mainly poor Black South Africans who are the majority population. Political Consciousness allows one to examine how selected forces at the macro-level, meso-level, and micro-level may enable or limit services to the under-served majority. At a macro-level, this study appraises policies and actions advancing and impeding service delivery. At the meso-level it is argued that hegemonic professional knowledge is limiting and an equity-driven population-based approach is advocated. At a micro-level, the Relationship of Labouring Affinities is offered as a conceptual tool for critical engagement. In conclusion, it is suggested that the speech-language pathology profession must collectively become political actors at all levels to effect change.

Interinstitutional review of slides for forensic pathology: types of inconsistencies.

PubMed

Ersoy, Gokhan; Akyildiz, Elif Ulker; Korkmaz, Gulay; Albek, Emre

2010-09-01

Because of the specific structure of forensic medicine in Turkey, reexamination of histopathologic specimens is a frequent practice. The aim of the present study is the assessment of microscopic diagnostic consistency in forensic pathology between different laboratories. Reports of the Council of Forensic Medicine between 2001 and 2004 were examined, and 150 cases with second pathologic examination were found. Results of histopathologic reports from peripheral laboratories were compared with those made by the Council pathologists with regard to diagnostic consistency. Consistency was assessed in 3 groups and 1 subgroup. Group 1, consistent and minor inconsistency; includes a major consistency subgroup. Group 2, major inconsistency, is the second diagnosis which is lethal; group 3, major inconsistency, is the first diagnosis which is lethal. The lung was found to be the organ with the highest frequency of diagnostic major inconsistency (group 2 and 3) and major consistency. Bronchopneumonia was the most common diagnosis. The brain had the highest frequency of intercenter diagnostic overall consistency (90.2%, group 1). Myocardial infarction was the diagnosis most frequently rejected on reevaluation (group 3). In conclusion, forensic pathology requires different experience than surgical ones. In cases of discrepancy between the anamnesis of the lethal event and pathologic findings, reevaluation of specimen is mandatory to avoid any diagnostic errors. Quality assurance systems with all include internal and external control mechanisms will improve the diagnostic reliability.

Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis.

PubMed

Uzhachenko, Roman; Boyd, Kelli; Olivares-Villagomez, Danyvid; Zhu, Yueming; Goodwin, J Shawn; Rana, Tanu; Shanker, Anil; Tan, Winston J T; Bondar, Tanya; Medzhitov, Ruslan; Ivanova, Alla V

2017-03-26

Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response.Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies.

Mitochondrial protein Fus1/Tusc2 in premature aging and age-related pathologies: critical roles of calcium and energy homeostasis

PubMed Central

Uzhachenko, Roman; Boyd, Kelli; Olivares-Villagomez, Danyvid; Zhu, Yueming; Goodwin, J. Shawn; Rana, Tanu; Shanker, Anil; Tan, Winston J.T.; Bondar, Tanya; Medzhitov, Ruslan; Ivanova, Alla V.

2017-01-01

Decreased energy production and increased oxidative stress are considered to be major contributors to aging and aging-associated pathologies. The role of mitochondrial calcium homeostasis has also been highlighted as an important factor affecting different pathological conditions. Here, we present evidence that loss of a small mitochondrial protein Fus1 that maintains mitochondrial homeostasis results in premature aging, aging-associated pathologies, and decreased survival. We showed that Fus1KO mice develop multiple early aging signs including lordokyphosis, lack of vigor, inability to accumulate fat, reduced ability to tolerate stress, and premature death. Other prominent pathological changes included low sperm counts, compromised ability of adult stem cells to repopulate tissues, and chronic inflammation. At the molecular level, we demonstrated that mitochondria of Fus1 KO cells have low reserve respiratory capacity (the ability to produce extra energy during sudden energy demanding situations), and show significantly altered dynamics of cellular calcium response. Our recent studies on early hearing and memory loss in Fus1 KO mice combined with the new data presented here suggest that calcium and energy homeostasis controlled by Fus1 may be at the core of its aging-regulating activities. Thus, Fus1 protein and Fus1-dependent pathways and processes may represent new tools and targets for anti-aging strategies. PMID:28351997

Differential Pathological and Immune Responses in Newly Weaned Ferrets Are Associated with a Mild Clinical Outcome of Pandemic 2009 H1N1 Infection

PubMed Central

Huang, Stephen S. H.; Banner, David; Degousee, Norbert; Leon, Alberto J.; Xu, Louling; Paquette, Stephane G.; Kanagasabai, Thirumagal; Fang, Yuan; Rubino, Salvatore; Rubin, Barry; Kelvin, Alyson A.

2012-01-01

Young children are typically considered a high-risk group for disease associated with influenza virus infection. Interestingly, recent clinical reports suggested that young children were the smallest group of cases with severe pandemic 2009 H1N1 (H1N1pdm) influenza virus infection. Here we established a newly weaned ferret model for the investigation of H1N1pdm infection in young age groups compared to adults. We found that young ferrets had a significantly milder fever and less weight loss than adult ferrets, which paralleled the mild clinical symptoms in the younger humans. Although there was no significant difference in viral clearance, disease severity was associated with pulmonary pathology, where newly weaned ferrets had an earlier pathology improvement. We examined the immune responses associated with protection of the young age group during H1N1pdm infection. We found that interferon and regulatory interleukin-10 responses were more robust in the lungs of young ferrets. In contrast, myeloperoxidase and major histocompatibility complex responses were persistently higher in the adult lungs; as well, the numbers of inflammation-prone granulocytes were highly elevated in the adult peripheral blood. Importantly, we observed that H1N1pdm infection triggered formation of lung structures that resembled inducible bronchus-associated lymphoid tissues (iBALTs) in young ferrets which were associated with high levels of homeostatic chemokines CCL19 and CXCL13, but these were not seen in the adult ferrets with severe disease. These results may be extrapolated to a model of the mild disease seen in human children. Furthermore, these mechanistic analyses provide significant new insight into the developing immune system and effective strategies for intervention and vaccination against respiratory viruses. PMID:23055557

Differential pathological and immune responses in newly weaned ferrets are associated with a mild clinical outcome of pandemic 2009 H1N1 infection.

PubMed

Huang, Stephen S H; Banner, David; Degousee, Norbert; Leon, Alberto J; Xu, Louling; Paquette, Stephane G; Kanagasabai, Thirumagal; Fang, Yuan; Rubino, Salvatore; Rubin, Barry; Kelvin, David J; Kelvin, Alyson A

2012-12-01

Young children are typically considered a high-risk group for disease associated with influenza virus infection. Interestingly, recent clinical reports suggested that young children were the smallest group of cases with severe pandemic 2009 H1N1 (H1N1pdm) influenza virus infection. Here we established a newly weaned ferret model for the investigation of H1N1pdm infection in young age groups compared to adults. We found that young ferrets had a significantly milder fever and less weight loss than adult ferrets, which paralleled the mild clinical symptoms in the younger humans. Although there was no significant difference in viral clearance, disease severity was associated with pulmonary pathology, where newly weaned ferrets had an earlier pathology improvement. We examined the immune responses associated with protection of the young age group during H1N1pdm infection. We found that interferon and regulatory interleukin-10 responses were more robust in the lungs of young ferrets. In contrast, myeloperoxidase and major histocompatibility complex responses were persistently higher in the adult lungs; as well, the numbers of inflammation-prone granulocytes were highly elevated in the adult peripheral blood. Importantly, we observed that H1N1pdm infection triggered formation of lung structures that resembled inducible bronchus-associated lymphoid tissues (iBALTs) in young ferrets which were associated with high levels of homeostatic chemokines CCL19 and CXCL13, but these were not seen in the adult ferrets with severe disease. These results may be extrapolated to a model of the mild disease seen in human children. Furthermore, these mechanistic analyses provide significant new insight into the developing immune system and effective strategies for intervention and vaccination against respiratory viruses.

Challenges of multimorbidity of the aging brain: a critical update.

PubMed

Jellinger, Kurt A; Attems, Johannes

2015-04-01

A major problem in elderly patients is the high incidence of multiple pathologies, referred to as multimorbidity, in the aging brain. It has been increasingly recognized that co-occurrence of neurodegenerative proteinopathies and other pathologies including cerebrovascular disorders is a frequent event in the brains of both cognitively intact and impaired aged subjects. Although clinical and neuropathological diagnostic criteria of the major neurodegenerative diseases have been improved, major challenges arise from cerebral multimorbidity, and the thresholds to cause clinical overt dementia are ill defined. More than 80% of aged human brains show neurodegenerative non-Alzheimer type proteinopathies and other pathologies which, however, frequently have been missed clinically and are even difficult to identify at neuropathological examination. Autopsy studies differ in selection criteria and the applied evaluation methods. Therefore, irrespective of the clinical symptoms, the frequency of cerebral pathologies vary considerably: Alzheimer-related pathology is seen in 19-100%, with "pure" Alzheimer's disease (AD) in 17-72%, Lewy pathology in 6-39% (AD + Lewy disease 9-28%), vascular pathologies in 28-93% (10.7-78% "pure" vascular dementia), TDP-43 proteinopathy in 6-39%, hippocampal sclerosis in 8-1%, and mixed pathologies in 10-93%. These data clearly suggest that pathologically deposited proteins in neurodegenerating diseases mutually interact and are influenced by other factors, in particular cardiovascular and cerebrovascular ones, to promote cognitive decline and other clinical symptoms. It is obvious that cognitive and other neuropsychiatric impairment in the aged result from a multimorbid condition in the CNS rather than from a single disease and that the number of complex pathologies progresses with increasing age. These facts have implications for improvement of the clinical diagnosis and prognosis, the development of specific biomarkers, preventive strategies and better treatment of cerebral multimorbidity.

Selective pathology fellowships: diverse, innovative, and valuable subspecialty training.

PubMed

Iezzoni, Julia C; Ewton, April; Chévez-Barrios, Patricia; Moore, Stephen; Thorsen, Linda M; Naritoku, Wesley Y

2014-04-01

Although selective pathology fellowships have a long-standing history of developing trainees with advanced expertise in specific areas of pathology other than those of the American Board of Pathology-certified subspecialties, the widespread interest in this training continues to grow. To describe the historical background and current status of selective pathology fellowships, and to provide examples of 3 programs. In addition, Accreditation Council for Graduate Medical Education (ACGME)-accredited programs and nonaccredited programs in Selective Pathology are compared. ACGME data banks and publicly available online materials were used. Program directors of the fellowships examples in this paper provided program-specific information. Additionally, an online survey of the program directors and program coordinators of ACGME-accredited programs and nonaccredited programs in selective pathology was performed. There are currently 76 ACGME-accredited selective pathology programs. The programs are distributed between 3 major categories: surgical pathology, focused anatomic pathology, and focused clinical pathology. Although the vast majority of programs are concerned that their funding source may be cut in the next 3 years, most programs will not change the number of fellowship positions in their programs. Program requirements devoted specifically and solely to selective pathology have been developed and are in effect. The value of this training is recognized not only by pathologists, but by clinicians as well, in both academia and private practice. Importantly, the diversity and innovation inherent in selective pathology allow these programs to adeptly address new subspecialty areas and technologic advances in the current and evolving practice of pathology.

Treatment of AIDS related non-Hodgkin's lymphoma with combination mitoguazone dihydrochloride and low dose CHOP chemotherapy: results of a phase II study.

PubMed

Tulpule, Anil; Espina, Byron M; Pedro Santabarbara, A B; Palmer, Maria; Schiflett, Joanne; Boswell, William; Smith, Susan; Levine, Alexandra M

2004-01-01

To evaluate the response and side effects of combination therapy with low dose CHOP chemotherapy and mitoguazone dihydrochloride in patients with non-Hodgkin's lymphoma associated with the acquired immunodeficiency syndrome (AIDS-NHL). Eighteen patients newly diagnosed with intermediate or high-grade AIDS-NHL were treated with low dose CHOP as follows: day 1, cyclophosphamide 350 mg/m(2), intravenously (IV); doxorubicin 25mg/m(2) IV; vincristine 2mg IV; and prednisone 100mg given orally on days 1 through 5. In addition, mitoguazone dihydrochloride was given at a dose of 600 mg/m(2) IV on days 1 and 15 of each 28-day treatment cycle. Seventeen males and one female patient were accrued. Twelve patients had high-grade pathologies while the remainder had an intermediate grade pathology (diffuse large cell). The median CD4+ lymphocyte count was 98/dl (range 1-924). Three patients (17%) reported an AIDS-defining illness prior to lymphoma diagnosis. Of 14 evaluable patients, 6 (43%) achieved a complete remission and 5 (35%) a partial remission. The median failure free and overall survival times were 6.5 and 8.4 months, respectively. Major toxicity was hematologic with grade 3 or 4 neutropenia in 72%; two patients died of neutropenic sepsis. Mitoguazone in combination with low dose CHOP is a safe regimen, associated with a response rate of 79% (CR 43%, PR 36%, 95% CI=49-95%). These preliminary results suggest no major improvement in terms of response over use of CHOP without mitoguazone.

New Insights Contributing to the Development of Effective Vaccines and Therapies to Reduce the Pathology Caused by hRSV.

PubMed

Gálvez, Nicolás M S; Soto, Jorge A; Kalergis, Alexis M

2017-08-11

Human Respiratory Syncytial Virus (hRSV) is one of the major causes of acute lower respiratory tract infections (ALRTI) worldwide, leading to significant levels of immunocompromisation as well as morbidity and mortality in infants. Its main target of infection is the ciliated epithelium of the lungs and the host immune responses elicited is ineffective at achieving viral clearance. It is thought that the lack of effective immunity against hRSV is due in part to the activity of several viral proteins that modulate the host immune response, enhancing a Th2-like pro-inflammatory state, with the secretion of cytokines that promote the infiltration of immune cells to the lungs, with consequent damage. Furthermore, the adaptive immunity triggered by hRSV infection is characterized by weak cytotoxic T cell responses and secretion of low affinity antibodies by B cells. These features of hRSV infection have meant that, to date, no effective and safe vaccines have been licensed. In this article, we will review in detail the information regarding hRSV characteristics, pathology, and host immune response, along with several prophylactic treatments and vaccine prototypes. We will also expose significant data regarding the newly developed BCG-based vaccine that promotes protective cellular and humoral response against hRSV infection, which is currently undergoing clinical evaluation.

Vaccination of calves using the BRSV nucleocapsid protein in a DNA prime-protein boost strategy stimulates cell-mediated immunity and protects the lungs against BRSV replication and pathology.

PubMed

Letellier, Carine; Boxus, Mathieu; Rosar, Laurent; Toussaint, Jean-François; Walravens, Karl; Roels, Stefan; Meyer, Gilles; Letesson, Jean-Jacques; Kerkhofs, Pierre

2008-09-02

Respiratory syncytial virus (RSV) is a major cause of respiratory disease in both cattle and young children. Despite the development of vaccines against bovine (B)RSV, incomplete protection and exacerbation of subsequent RSV disease have occurred. In order to circumvent these problems, calves were vaccinated with the nucleocapsid protein, known to be a major target of CD8(+) T cells in cattle. This was performed according to a DNA prime-protein boost strategy. The results showed that DNA vaccination primed a specific T-cell-mediated response, as indicated by both a lymphoproliferative response and IFN-gamma production. These responses were enhanced after protein boost. After challenge, mock-vaccinated calves displayed gross pneumonic lesions and viral replication in the lungs. In contrast, calves vaccinated by successive administrations of plasmid DNA and protein exhibited protection against the development of pneumonic lesions and the viral replication in the BAL fluids and the lungs. The protection correlated to the cell-mediated immunity and not to the antibody response.

Clinical characteristics in focal cortical dysplasia: a retrospective evaluation in a series of 120 patients.

PubMed

Fauser, Susanne; Huppertz, Hans-Juergen; Bast, Thomas; Strobl, Karl; Pantazis, Georgios; Altenmueller, Dirk-Matthias; Feil, Bertram; Rona, Sabine; Kurth, Christoph; Rating, Dietz; Korinthenberg, Rudolf; Steinhoff, Bernhard J; Volk, Benedikt; Schulze-Bonhage, Andreas

2006-07-01

Focal cortical dysplasias (FCDs) are increasingly diagnosed as a cause of symptomatic focal epilepsy in paediatric and adult patients. However, little is known about the clinical characteristics of epilepsy in these patients. In order to elucidate the clinical characteristics of their epilepsy, 120 pharmacoresistant patients including children and adults with histologically proven FCD were studied retrospectively. Age at seizure onset was analysed in the total group and compared between subgroups with different localization and different histological subtypes of FCD. The role of febrile seizures with respect to dual pathology was investigated. Seizure semiology was analysed focusing on initial seizure type and change of seizure semiology during the course of disease. Finally, transient responsiveness to antiepileptic drug therapy was studied. In the majority of patients, epilepsy began in the first 5 years of life. However, onset of epilepsy could also occur in the second or third decade until the age of 60. Age at epilepsy onset was not significantly different between temporal, extratemporal and multilobar localization of FCD. Patients without cytoarchitectural abnormalities (mild malformations of cortical development, FCD 1a according to Palmini) had significantly later epilepsy onset (P= 0.001) compared with patients with cytoarchitectural abnormalities (FCD 1b, 2a and 2b according to Palmini). In patients with additional hippocampal sclerosis (dual pathology) febrile seizures were significantly more frequently reported (P = 0.02) than in patients without dual pathology. Moreover, patients with dual pathology and febrile seizures significantly more frequently presented with severe hippocampal sclerosis (Wyler Grade 3-4) as compared with patients with dual pathology in the absence of febrile seizures (P = 0.03). First observed seizures were mainly tonic or generalized tonic-clonic. A change of seizure semiology seemed to be age-dependent and occurred between the age of >1 and 14 years. About 15.8% of the patients presented with status epilepticus during the course of disease. About 17% of the patients showed transient responsiveness (> or =1 year seizure freedom) to antiepileptic drug therapy either after initial therapy (50%) or later in the course of epilepsy (50%). Patients with FCD represent a heterogeneous group. Different age at epilepsy onset and transient responsiveness to antiepileptic drugs in approximately 17% of patients may reflect different dynamics in epileptogenicity of the underlying FCD. Dual pathology may be associated with different pathomechanisms in patients with and without febrile seizures.

High-dose interleukin2 - a 10-year single-site experience in the treatment of metastatic renal cell carcinoma: careful selection of patients gives an excellent outcome.

PubMed

Chow, S; Galvis, V; Pillai, M; Leach, R; Keene, E; Spencer-Shaw, A; Shablak, A; Shanks, J; Liptrot, T; Thistlethwaite, F; Hawkins, R E

2016-01-01

VEGF-targeted therapy has become the mainstay of treatment for majority of mRCC patients. For most patients, benefit is short-lived and therefore treatment remains palliative in intent. HD IL2 is an effective immunotherapy treatment capable of durable remission in some patients but its unselected use has been difficult due to its modest response rate and considerable adverse effects. Using set pathology criteria as a selection tool in clinical practice, we have been able to show improved outcomes in our previous report. Here, we present an updated and extended report of this treatment and seek to explore any pathological, clinical and treatment variables likely to predict better outcomes. This is an extension of a previously reported clinical audit, which includes mRCC cases treated with HD IL2 between 2003 and 2013. Since 2006, tumour specimens of potential candidates were routinely reviewed prospectively and stratified into Favourable or Other categories based on constitution of histological growth pattern, namely alveolar or solid versus papillary and/or sarcomatoid architecture; clear cell versus granular cell cytoplasmic morphology. HD IL2 was preferentially offered to patients with Favourable pathology. Outcome evaluation includes response rates, survival, and treatment tolerance. Multivariate analysis was performed to explore potential prognostic and predictive factors. Among prospectively selected patients with Favourable pathology ( n  = 106), overall response rate was 48.1 % (51/106) with CR rate of 21.6 % (23/106). Median OS was 58.1 months. Factors associated with significantly better response and/or survival includes favourable pathology pattern, higher cycle 1 tolerance and lower number of metastatic organ sites (<3). CAIX (Carbonic anhydrase 9) has prognostic value but is not predictive of response. Toxicities were those expected of IL2 but were manageable on general medical wards, with no treatment-related death. Importantly most complete responses were durable with 76 % (23/30) cases remained relapse-free (median 39 months follow up) and 2 of the seven who relapsed had had long-term disease free survival after resection of oligometastatic relapse. Our experience shows that HD IL2 remains an effective and safe treatment in well-selected cases of mRCC. The result in this single-institution patient series confirms similar outcomes to our previously reported retrospective series. Given the prospect of long-term remission, fit patients with Favourable histology and low disease burden should be considered for HD IL2 in an experienced centre. Better understanding has been gained from this in-depth analysis especially the examination of possible response predictors and strategies that can improve treatment outcome.

Barium enema and CT volumetry for predicting pathologic response to preoperative chemoradiotherapy in rectal cancer patients.

PubMed

Murono, Koji; Kawai, Kazushige; Tsuno, Nelson H; Ishihara, Soichiro; Yamaguchi, Hironori; Sunami, Eiji; Kitayama, Joji; Watanabe, Toshiaki

2014-06-01

Preoperative chemoradiotherapy has been widely used for the prevention of local recurrence of locally advanced rectal cancer, and the effect of chemoradiotherapy is known to be associated with overall survival. We aimed to evaluate the association of the pathologic response grade with tumor recurrence rate after chemoradiotherapy, using radiographic analysis and the Response Evaluation Criteria in Solid Tumors as the parameters. This study was conducted at a single tertiary care institution in Japan. This was a retrospective cohort study of patients undergoing preoperative chemoradiotherapy. A total of 101 low rectal cancer patients receiving preoperative chemoradiotherapy from July 2004 to August 2012 were enrolled. The tumor reduction rate was measured with the use of traditional Response Evaluation Criteria in Solid Tumors, barium enema, and CT volumetry, and the correlation between the reduction rate and the pathologic response grade was examined. The tumor reduction rate assessed according to Response Evaluation Criteria in Solid Tumors showed no association with the pathologic response grade (p =0.61). In contrast, the radiographic response rate by both barium enema and CT volumetry strongly correlated with the pathologic response grade (p < 0.0001 and p = 0.001).In terms of local tumor recurrence, those diagnosed as high responders by the pathologic response grade, Response Evaluation Criteria in Solid Tumors, barium enema, and CT volumetry had a lower recurrence rate (p =0.03, p =0.03, p =0.0002, and p =0.001). The difference between high responders and low responders was especially prominent by barium enema and CT volumetry. The study is limited by its retrospective nature. Double-contrast barium enema and CT volumetry were superior to Response Evaluation Criteria in Solid Tumors in evaluating the effect of chemoradiotherapy and predicting the likelihood of tumor recurrence.

The Oral Pathology Related Articles Published in Iranian Journal of Pathology from 2006 to 2015.

PubMed

Shamim, Thorakkal

2016-01-01

There is a paucity of information about the oral pathology related articles published in a pathology journal. This study aimed to audit the oral pathology related articles published in Iranian Journal of Pathology (Iran J Pathol) from 2006 to 2015. Bibliometric analysis of issues of Iran J Pathol from 2006 to 2015 was performed using web-based search. The articles published were analyzed for type of article and individual topic of oral pathology. The articles published were also checked for authorship trends. Out of the total 49 published articles related to oral pathology, case reports (21) and original articles (18) contributed the major share. The highest number of oral pathology related articles was published in 2011, 2014 and 2015 with 8 articles each and the least published year was 2012 with 1 article. Among the oral pathology related articles published, spindle cell neoplasms (7) followed by salivary gland tumors (5), jaw tumors (4), oral granulomatous conditions (4), lymphomas (4), oral cancer (3) and odontogenic cysts (3) form the major attraction of the contributors. The largest numbers of published articles related to oral pathology were received from Tehran University of Medical Sciences; Tehran (7) followed by Mashhad University of Medical Sciences, Mashhad (6) and Shahid Beheshti University of Medical Sciences, Tehran (5). This paper may be considered as a baseline study for the bibliometric information regarding oral pathology related articles published in a pathology journal.

The Oral Pathology Related Articles Published in Iranian Journal of Pathology from 2006 to 2015

PubMed Central

Shamim, Thorakkal

2016-01-01

Background: There is a paucity of information about the oral pathology related articles published in a pathology journal. This study aimed to audit the oral pathology related articles published in Iranian Journal of Pathology (Iran J Pathol) from 2006 to 2015. Methods: Bibliometric analysis of issues of Iran J Pathol from 2006 to 2015 was performed using web-based search. The articles published were analyzed for type of article and individual topic of oral pathology. The articles published were also checked for authorship trends. Results: Out of the total 49 published articles related to oral pathology, case reports (21) and original articles (18) contributed the major share. The highest number of oral pathology related articles was published in 2011, 2014 and 2015 with 8 articles each and the least published year was 2012 with 1 article. Among the oral pathology related articles published, spindle cell neoplasms (7) followed by salivary gland tumors (5), jaw tumors (4), oral granulomatous conditions (4), lymphomas (4), oral cancer (3) and odontogenic cysts (3) form the major attraction of the contributors. The largest numbers of published articles related to oral pathology were received from Tehran University of Medical Sciences; Tehran (7) followed by Mashhad University of Medical Sciences, Mashhad (6) and Shahid Beheshti University of Medical Sciences, Tehran (5). Conclusion: This paper may be considered as a baseline study for the bibliometric information regarding oral pathology related articles published in a pathology journal. PMID:27799973

The impact of stress on body function: A review

PubMed Central

Yaribeygi, Habib; Panahi, Yunes; Sahraei, Hedayat; Johnston, Thomas P.; Sahebkar, Amirhossein

2017-01-01

Any intrinsic or extrinsic stimulus that evokes a biological response is known as stress. The compensatory responses to these stresses are known as stress responses. Based on the type, timing and severity of the applied stimulus, stress can exert various actions on the body ranging from alterations in homeostasis to life-threatening effects and death. In many cases, the pathophysiological complications of disease arise from stress and the subjects exposed to stress, e.g. those that work or live in stressful environments, have a higher likelihood of many disorders. Stress can be either a triggering or aggravating factor for many diseases and pathological conditions. In this study, we have reviewed some of the major effects of stress on the primary physiological systems of humans. PMID:28900385

BRCA mutations and their influence on pathological complete response and prognosis in a clinical cohort of neoadjuvantly treated breast cancer patients.

PubMed

Wunderle, Marius; Gass, Paul; Häberle, Lothar; Flesch, Vivien M; Rauh, Claudia; Bani, Mayada R; Hack, Carolin C; Schrauder, Michael G; Jud, Sebastian M; Emons, Julius; Erber, Ramona; Ekici, Arif B; Hoyer, Juliane; Vasileiou, Georgia; Kraus, Cornelia; Reis, Andre; Hartmann, Arndt; Lux, Michael P; Beckmann, Matthias W; Fasching, Peter A; Hein, Alexander

2018-05-03

BRCA1/2 mutations influence the molecular characteristics and the effects of systemic treatment of breast cancer. This study investigates the impact of germline BRCA1/2 mutations on pathological complete response and prognosis in patients receiving neoadjuvant systemic chemotherapy. Breast cancer patients were tested for a BRCA1/2 mutation in clinical routine work and were treated with anthracycline-based or platinum-based neoadjuvant chemotherapy between 1997 and 2015. These patients were identified in the tumor registry of the Breast Center of the University of Erlangen (Germany). Logistic regression and Cox regression analyses were performed to investigate the associations between BRCA1/2 mutation status, pathological complete response, disease-free survival, and overall survival. Among 355 patients, 59 had a mutation in BRCA1 or in BRCA2 (16.6%), 43 in BRCA1 (12.1%), and 16 in BRCA2 (4.5%). Pathological complete response defined as "ypT0; ypN0" was observed in 54.3% of BRCA1/2 mutation carriers, but only in 22.6% of non-carriers. The adjusted odds ratio was 2.48 (95% CI 1.26-4.91) for BRCA1/2 carriers versus non-carriers. Patients who achieved a pathological complete response had better disease-free survival and overall survival rates compared with those who did not achieve a pathological complete response, regardless of BRCA1/2 mutation status. BRCA1/2 mutation status leads to better responses to neoadjuvant chemotherapy in breast cancer. Pathological complete response is the main predictor of disease-free survival and overall survival, independently of BRCA1/2 mutation status.

Magnetic resonance imaging in breast cancer treated with neoadjuvant chemotherapy: radiologic-pathologic correlation of the response and disease-free survival depending on molecular subtype.

PubMed

Cruz Ciria, S; Jiménez Aragón, F; García Mur, C; Esteban Cuesta, H; Gros Bañeres, B

2014-01-01

To evaluate the radiologic and pathologic responses to neoadjuvant chemotherapy and their correlation in the molecular subtypes of breast cancer and to analyze their impact in disease-free survival. We included 205 patients with breast cancer treated with neoadjuvant chemotherapy. We evaluated the radiologic response by comparing MRI images acquired before and after chemotherapy. The pathologic response was classified on the Miller and Payne scale. For each subtype (HER2+, TN, luminal A, luminal B HER2-, and luminal B HER2+), we used the χ(2) test, Student's t-test, ANOVA, and Kendall's Tau-b to evaluate the radiologic response and the pathologic response, the radiologic-pathologic correlation, and the disease-free survival. The subtypes HER2+ (62.1%) and TN (45.2%) had higher rates of complete radiologic response. The pathologic response was 65.5% in the HER2+ subtype, 38.1% in the TN subtype, 2.6% in the luminal A subtype, 8.2% in the luminal B HER2- subtype, and 31% in the luminal B HER2+ subtype. The rate of radiologic-pathologic correlation was significant in all subtypes, higher in TN and HER2 (Tau-b coefficients 0.805 and 0.717, respectively). Disease-free survival was higher in HER2+ (91.9±3.3 months) and lower in TN (69.5±6.3 months), with significant differences between the cases with poor and good radiologic responses (P=.040). Survival was greater in cases with good radiologic response, except in cases with luminal A subtype. MRI can be a useful tool that provides information about the evolution of breast cancer treated with neoadjuvant chemotherapy, which varies with the immunohistochemical subtype. Copyright © 2012 SERAM. Published by Elsevier Espana. All rights reserved.

Standardizing of Pathology in Patients Receiving Neoadjuvant Chemotherapy.

PubMed

Bossuyt, Veerle; Symmans, W Fraser

2016-10-01

The use of neoadjuvant systemic therapy for the treatment of breast cancer patients is increasing. Pathologic response in the form of pathologic complete response (pCR) and grading systems of partial response, such as the residual cancer burden (RCB) system, gives valuable prognostic information for patients and is used as a primary endpoint in clinical trials. The breast cancer and pathology communities are responding with efforts to standardize pathology in patients receiving neoadjuvant chemotherapy. In this review, we summarize the challenges that postneoadjuvant systemic therapy surgical specimens pose and how pathologists and the multidisciplinary team can work together to optimize handling of these specimens. Multidisciplinary communication is essential. A single, standardized approach to macroscopic and microscopic pathologic examination makes it possible to provide reliable response information. This approach employs a map of tissue sections to correlate clinical, gross, microscopic, and imaging findings in order to report the presence of pCR (ypT0 ypN0 and ypT0/is ypN0) versus residual disease, the ypT and ypN stage using the current AJCC/UICC staging system, and the RCB.

Countermeasure development for Rift Valley fever: deletion, modification or targeting of major virulence factor NSs.

PubMed

Lihoradova, Olga; Ikegami, Tetsuro

2014-01-01

Rift Valley fever (RVF) is a mosquito-borne zoonotic disease characterized by a high rate of abortion in ruminants, and febrile illness, hemorrhagic fever, retinitis and encephalitis in humans. RVF is caused by the RVF virus (RVFV), belonging to the genus Phlebovirus of the family Bunyaviridae . RVFV encodes a major virulence factor, NSs , which is dispensable for viral replication, yet required for evasion of host innate immune responses. RVFV NSs inhibits host gene upregulation at the transcriptional level, while promoting viral translation in the cytoplasm. In this article, we summarize the virology and pathology of RVF, and countermeasure development for RVF, with emphasis on NSs function and applications.

Countermeasure development for Rift Valley fever: deletion, modification or targeting of major virulence factor NSs

PubMed Central

Lihoradova, Olga; Ikegami, Tetsuro

2014-01-01

Rift Valley fever (RVF) is a mosquito-borne zoonotic disease characterized by a high rate of abortion in ruminants, and febrile illness, hemorrhagic fever, retinitis and encephalitis in humans. RVF is caused by the RVF virus (RVFV), belonging to the genus Phlebovirus of the family Bunyaviridae. RVFV encodes a major virulence factor, NSs, which is dispensable for viral replication, yet required for evasion of host innate immune responses. RVFV NSs inhibits host gene upregulation at the transcriptional level, while promoting viral translation in the cytoplasm. In this article, we summarize the virology and pathology of RVF, and countermeasure development for RVF, with emphasis on NSs function and applications. PMID:24910709

Age related increase in mTOR activity contributes to the pathological changes in ovarian surface epithelium

PubMed Central

Bajwa, Preety; Nagendra, Prathima B.; Nielsen, Sarah; Sahoo, Subhransu S.; Bielanowicz, Amanda; Lombard, Janine M.; Wilkinson, Erby J.; Miller, Richard A.; Tanwar, Pradeep S.

2016-01-01

Ovarian cancer is a disease of older women. However, the molecular mechanisms of ovarian aging and their contribution to the pathogenesis of ovarian cancer are currently unclear. mTOR signalling is a major regulator of aging as suppression of this pathway extends lifespan in model organisms. Overactive mTOR signalling is present in up to 80% of ovarian cancer samples and is associated with poor prognosis. This study examined the role of mTOR signalling in age-associated changes in ovarian surface epithelium (OSE). Histological examination of ovaries from both aged mice and women revealed OSE cell hyperplasia, papillary growth and inclusion cysts. These pathological lesions expressed bonafide markers of ovarian cancer precursor lesions, Pax8 and Stathmin 1, and were presented with elevated mTOR signalling. To understand whether overactive mTOR signalling is responsible for the development of these pathological changes, we analysed ovaries of the Pten trangenic mice and found significant reduction in OSE lesions compared to controls. Furthermore, pharmacological suppression of mTOR signalling significantly decreased OSE hyperplasia in aged mice. Treatment with mTOR inhibitors reduced human ovarian cancer cell viability, proliferation and colony forming ability. Collectively, we have established the role of mTOR signalling in age-related OSE pathologies and initiation of ovarian cancer. PMID:27036037

Speech pathology student clinician attitudes and beliefs towards people who stutter: A mixed-method pilot study.

PubMed

Koutsodimitropoulos, Ellen; Buultjens, Melissa; St Louis, Kenneth O; Monfries, Melissa

2016-03-01

Stuttering is a disorder of fluency that extends beyond its physical nature and has social, emotional and vocational impacts. Research shows that individuals often exhibit negative attitudes towards people who stutter; however, there is limited research on the attitudes and beliefs of speech pathology students towards people who stutter in Australia. Existing research is predominantly quantitative; whereas this mixed-method study placed an emphasis on the qualitative component. The purpose of this study was to explore the attitudes and beliefs of final year Australian speech pathology students towards people who stutter. This mixed-method study applied the Public Opinion Survey of Human Attributes - Stuttering (POSHA-S) and semi-structured interviews to gather data from final year speech pathology students from a major university in Australia. The overall qualitative findings identified that final year Australian speech pathology students exhibit positive attitudes towards people who stutter. The results also illustrated the role of education in influencing attitudes of students as well as increasing their confidence to work with people who stutter. This research revealed that Australian final year speech pathology students exhibit positive attitudes towards people who stutter. They displayed an understanding that people who stutter may have acquired traits such as shyness as a response to their personal situation and environment, rather than those traits being endemic to them. Results also suggested that education can play a role in creating confident student clinicians in their transition to practice, and positively influence their attitudes and beliefs. Copyright © 2015 Elsevier Inc. All rights reserved.

[Systemic immunological response in children with chronic gingivitis and gastro-intestinal pathology].

PubMed

Romanenko, E G

2014-01-01

Study of the immune system mechanisms in chronic catarrhal gingivitis in children with gastrointestinal pathology was performed in 102 children (49 with chronic gastritis and duodenitis and 53 with no signs of gastrointestinal pathology). Forty-eight children with healthy periodontium constituted control group. Generalized chronic catarrhal gingivitis in children with gastroduodenal pathology is characterized by intense humoral response by simultaneous T-cell immunity suppression. Detection of high serum titers of circulating immune complexes in patients with chronic catarrhal gingivitis suggests a role of immune response in the pathogenesis of periodontal disease increases with concomitant diseases of the upper gastrointestinal tract.

Altering Response Chains in Pathological Gamblers Using a Response-Cost Procedure

ERIC Educational Resources Information Center

Johnson, Taylor E.; Dixon, Mark R.

2009-01-01

Two pathological gamblers could choose between emitting or having the dealer emit the response options when playing each of three casino games. A response-cost procedure was introduced in a multiple baseline design across games in which the participant had to pay to perform the responses himself, which was somewhat effective at reducing many of…

"Coerced Loss and Ambivalent Preservation": Racial Melancholia in "American Born Chinese"

ERIC Educational Resources Information Center

Sarigianides, Sophia Tatiana

2017-01-01

Recent applications of Freud's theory examine the social value of the lost love object as a way of understanding the suffering of non-majority groups. Rather than pathologizing the individual suffering the loss, the lens of racial melancholia pathologizes the discourse that constitutes racially marked others as alien to the majority. Through a…

Is Dysregulation of the HPA-Axis a Core Pathophysiology Mediating Co-Morbid Depression in Neurodegenerative Diseases?

PubMed Central

Du, Xin; Pang, Terence Y.

2015-01-01

There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson’s disease (PD) and Huntington’s disease (HD). These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic–pituitary–adrenal (HPA)-axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioral deficits and/or mood disorders. Dysregulation of the HPA-axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, antidepressant drugs, such as the selective serotonin reuptake inhibitors have been shown to alter HPA-axis activity. In this review, we will summarize the current state of knowledge regarding HPA-axis pathology in Alzheimer’s, PD and HD, differentiating between prodromal and later stages of disease progression when evidence is available. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the preclinical evidence to better inform prospective, intervention studies. PMID:25806005

A Multiple-Plasticity Spiking Neural Network Embedded in a Closed-Loop Control System to Model Cerebellar Pathologies.

PubMed

Geminiani, Alice; Casellato, Claudia; Antonietti, Alberto; D'Angelo, Egidio; Pedrocchi, Alessandra

2018-06-01

The cerebellum plays a crucial role in sensorimotor control and cerebellar disorders compromise adaptation and learning of motor responses. However, the link between alterations at network level and cerebellar dysfunction is still unclear. In principle, this understanding would benefit of the development of an artificial system embedding the salient neuronal and plastic properties of the cerebellum and operating in closed-loop. To this aim, we have exploited a realistic spiking computational model of the cerebellum to analyze the network correlates of cerebellar impairment. The model was modified to reproduce three different damages of the cerebellar cortex: (i) a loss of the main output neurons (Purkinje Cells), (ii) a lesion to the main cerebellar afferents (Mossy Fibers), and (iii) a damage to a major mechanism of synaptic plasticity (Long Term Depression). The modified network models were challenged with an Eye-Blink Classical Conditioning test, a standard learning paradigm used to evaluate cerebellar impairment, in which the outcome was compared to reference results obtained in human or animal experiments. In all cases, the model reproduced the partial and delayed conditioning typical of the pathologies, indicating that an intact cerebellar cortex functionality is required to accelerate learning by transferring acquired information to the cerebellar nuclei. Interestingly, depending on the type of lesion, the redistribution of synaptic plasticity and response timing varied greatly generating specific adaptation patterns. Thus, not only the present work extends the generalization capabilities of the cerebellar spiking model to pathological cases, but also predicts how changes at the neuronal level are distributed across the network, making it usable to infer cerebellar circuit alterations occurring in cerebellar pathologies.

Late-life depression is not associated with dementia-related pathology.

PubMed

Wilson, Robert S; Boyle, Patricia A; Capuano, Ana W; Shah, Raj C; Hoganson, George M; Nag, Sukriti; Bennett, David A

2016-02-01

To test the hypothesis that late-life depression is associated with dementia-related pathology. Older participants (n = 1,965) in 3 longitudinal clinical-pathologic cohort studies who had no cognitive impairment at baseline underwent annual clinical evaluations for a mean of 8.0 years (SD = 5.0). The authors defined depression diagnostically, as major depression during the study period, and psychometrically, as elevated depressive symptoms during the study period, and established their relation to cognitive outcomes (incident dementia, rate of cognitive decline). A total of 657 participants died and underwent a uniform neuropathologic examination. The authors estimated the association of depression with 6 dementia-related markers (tau tangles, beta-amyloid plaques, Lewy bodies, hippocampal sclerosis, gross and microscopic infarcts) in logistic regression models. In the full cohort, 9.4% were diagnosed with major depression and 8.6% had chronically elevated depressive symptoms, both of which were related to adverse cognitive outcomes. In the 657 persons who died and had a neuropathologic examination, higher beta-amyloid plaque burden was associated with higher likelihood of major depression (present in 11.0%; OR = 1.392, 95% CI = 1.088, 1.780) but not with elevated depressive symptoms (present in 11.3%; OR = 0.919, 95% CI = 0.726, 1.165). None of the other pathologic markers was related to either of the depression measures. Neither dementia nor antidepressant medication modified the relation of pathology to depression. The results do not support the hypothesis that major depression is associated with dementia-related pathology. PsycINFO Database Record (c) 2016 APA, all rights reserved.

Late-Life Depression is Not Associated with Dementia Related Pathology

PubMed Central

Wilson, Robert S.; Boyle, Patricia A.; Capuano, Ana W.; Shah, Raj C.; Hoganson, George M.; Nag, Sukriti; Bennett, David A.

2015-01-01

Objective To test the hypothesis that late-life depression is associated with dementia related pathology. Method Older participants (n=1,965) in 3 longitudinal clinical-pathologic cohort studies who had no cognitive impairment at baseline underwent annual clinical evaluations for a mean of 8.0 years (SD = 5.0). We defined depression diagnostically, as major depression during the study period, and psychometrically, as elevated depressive symptoms during the study period, and established their relation to cognitive outcomes (incident dementia, rate of cognitive decline). A total of 657 participants died and underwent a uniform neuropathologic examination. We estimated the association of depression with 6 dementia related markers (tau tangles, beta-amyloid plaques, Lewy bodies, hippocampal sclerosis, gross and microscopic infarcts) in logistic regression models. Results In the full cohort, 9.4% were diagnosed with major depression and 8.6% had chronically elevated depressive symptoms, both of which were related to adverse cognitive outcomes. In the 657 persons who died and had a neuropathologic examination, higher beta-amyloid plaque burden was associated with higher likelihood of major depression (present in 11.0%; odds ratio = 1.392, 95% confidence interval = 1.088, 1.780) but not with elevated depressive symptoms (present in 11.3%; odds ratio = 0.919, 95% confidence interval = 0.726, 1.165). None of the other pathologic markers was related to either of the depression measures. Neither dementia nor antidepressant medication modified the relation of pathology to depression. Conclusion The results do not support the hypothesis that major depression is associated with dementia related pathology. PMID:26237627

Why Don't You Try Harder? An Investigation of Effort Production in Major Depression

PubMed Central

Cléry-Melin, Marie-Laure; Schmidt, Liane; Lafargue, Gilles; Baup, Nicolas; Fossati, Philippe; Pessiglione, Mathias

2011-01-01

Depression is mainly characterized as an emotional disorder, associated with reduced approach behavior. It remains unclear whether the difficulty in energising behavior relates to abnormal emotional states or to a flattened response to potential rewards, as suggested by several neuroimaging studies. Here, we aimed to demonstrate a specific incentive motivation deficit in major depression, independent of patients' emotional state. We employed a behavioral paradigm designed to measure physical effort in response to both emotional modulation and incentive motivation. Patients did exert more effort following emotionally arousing pictures (whether positive or negative) but not for higher monetary incentives, contrary to healthy controls. These results show that emotional and motivational sources of effort production are dissociable in pathological conditions. In addition, patients' ratings of perceived effort increased for high incentives, whereas controls' ratings were decreased. Thus, depressed patients objectively behave as if they do not want to gain larger rewards, but subjectively feel that they try harder. We suggest that incentive motivation impairment is a core deficit of major depression, which may render everyday tasks abnormally effortful for patients. PMID:21853083

Treatment of ovarian cancer with surgery, short-course chemotherapy and whole abdominal radiation.

PubMed

Buser, K; Bacchi, M; Goldhirsch, A; Greiner, R; Diener, P; Sessa, C; Jungi, W F; Forni, M; Leyvraz, S; Engeler, V

1996-01-01

The primary aim was to induce a high number of pCR in early (FIGO IC, IIB + C) - and advanced (FIGO III-IV) - stage ovarian cancer with a surgery plus 4 cycles of cisplatin and melphalan (PAMP) regimen. The second objective was to prevent relapse with WAR in patients in remission after chemotherapy. 218 eligible patients were treated after staging laparotomy with cisplatin 80 mg/sqm i.v. on day 1 and melphalan 12 mg/sqm i.v. on day 2 q 4 weeks. Response was verified by second-look laparotomy. WAR was carried out with the open field technique on a linear accelerator (daily dose: 1.3 Gy, total dose: 29.9 Gy) in patients with pathological or clinical CR or pathological PR with microscopical residual disease. 146/218 patients (67%, 95% CI: 61%-73%) responded to PAMP: 56 (26%) achieved pCR, 24 (11%), cCR, 56 (26%) pPR and 10 (5%) cPR (c = clinical, p = pathological). Multivariate analyses revealed that in advanced stages (92 cases in remission), the achievement of pCR was the most important factor for longer time to failure (TTF) and survival. Only 51/118 (43%) patients in remission received WAR. Early-stage patients <= 55 years were more likely to have WAR than patients older than 55 years (77% vs. 23%; p = 0.02). Advanced-stage patients with cCR were less likely to be irradiated than patients with pCR or pPR (10% vs. 51%; p = 0.003). Toxicity of PAMP was acceptable with 10% of WHO grade 4 hematologic toxicity. Acute hematological toxicity of WAR caused interruption (33%) or incompleteness (33%) of irradiation in the majority of patients. PAMP is an effective treatment for advanced ovarian cancer with a 67% response rate after 4 cycles. For the majority of patients in remission, WAR as a consolidation treatment was hardly feasible. For these patients new treatment modalities to consolidate remission are needed.

ER stress and Parkinson's disease: Pathological inputs that converge into the secretory pathway.

PubMed

Mercado, Gabriela; Castillo, Valentina; Soto, Paulina; Sidhu, Anita

2016-10-01

The major clinical feature of Parkinson's disease (PD) is impairment in motor control as a result of extensive dopaminergic neuron loss in the substantia nigra pars compacta. The central pathological hallmark of PD is the formation of neuronal cytoplasmic inclusions of insoluble proteins called Lewy bodies, of which fibrillar aggregates of misfolded αSynuclein are the major components. Despite intense research on the pathogenic mechanism that trigger neuronal loss and disease progression, the neurogenesis of PD remains unknown. However, studies on genetics of PD have identified specific genes and proteins linked to this disease. Genetic mutations linked with different forms of familial PD have unveiled a closer relationship between pathology and impairments at different points in the secretory pathway. Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum and disruptions in protein clearance mechanisms result in activation of an adaptive stress pathway known as the unfolded protein response (UPR). UPR signaling is mediated by three stress sensors that induce independent and convergent signaling branches that help to maintain homeostasis, or eventually trigger cell death under chronic stress conditions. Signs of ER stress are observed in post-mortem tissue from sporadic human PD cases and in most animal models of the disease, implicating all three branches of this cellular response. However, the exact contribution of the UPR in the progression of PD or in dopaminergic neuron survival is not yet well understood. A large number of studies reveal a clear activation of the UPR in toxicological models resembling sporadic PD, where ATF6, XBP1 and CHOP have a functional role in controlling dopaminergic neuron survival in neurotoxin-based models of PD in vivo. Also pharmacological and gene therapy approaches aimed to target different points of this pathway have revealed an important functional role in PD pathogenesis. This article is part of a Special Issue entitled SI:ER stress. Copyright © 2016 Elsevier B.V. All rights reserved.

Combined effects of physiologically relevant disturbed wall shear stress and glycated albumin on endothelial cell functions associated with inflammation, thrombosis and cytoskeletal dynamics.

PubMed

Maria, Zahra; Yin, Wei; Rubenstein, David Alan

2014-07-01

Diabetes mellitus is a major risk factor in the development of cardiovascular diseases (CVDs). The presence of advanced glycation end-products (AGEs) promotes CVDs by upregulating endothelial cell (EC) inflammatory and thrombotic responses, in a similar manner as disturbed shear stress. However, the combined effect of disturbed shear stress and AGEs on EC function has yet to be determined. Our goal was to evaluate these effects on EC responses. ECs were incubated with AGEs for 5 days. ECs were then subjected to physiological or pathological shear stress. Cell metabolic activity, surface expression of intercellular adhesion molecule-1, thrombomodulin, connexin-43 and caveolin-1, and cytoskeleton organization were quantified. The results show that irreversibly glycated albumin and pathological shear stress increased EC metabolic activity, and upregulated and downregulated the EC surface expression of intercellular adhesion molecule-1 and thrombomodulin, respectively. Expression of connexin-43, caveolin-1 and cytoskeletal organization was independent of shear stress; however, the presence of irreversibly glycated AGEs markedly increased connexin-43, and decreased caveolin-1 expression and actin cytoskeletal connectivity. Our data suggest that irreversibly glycated albumin and disturbed shear stress could promote CVD pathogenesis by enhancing EC inflammatory and thrombotic responses, and through the deterioration of the cytoskeletal organization.

Retaining Pathological Gamblers in Cognitive Behavior Therapy through Motivational Enhancement

ERIC Educational Resources Information Center

Wulfert, Edelgard; Blanchard, Edward B.; Freidenberg, Brian M.; Martell, Rebecca S.

2006-01-01

Treatment for pathological gambling is in its infancy. Several cognitive and behavioral interventions have shown promise, but high attrition and relapse rates suggest that gamblers requesting treatment are not uniformly committed to change. This article describes an exploratory study with 9 severe pathological gamblers--in their majority horse…

Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: sex differences in regulation of stress responsivity.

PubMed

Oyola, Mario G; Handa, Robert J

2017-09-01

Gonadal hormones play a key role in the establishment, activation, and regulation of the hypothalamic-pituitary-adrenal (HPA) axis. By influencing the response and sensitivity to releasing factors, neurotransmitters, and hormones, gonadal steroids help orchestrate the gain of the HPA axis to fine-tune the levels of stress hormones in the general circulation. From early life to adulthood, gonadal steroids can differentially affect the HPA axis, resulting in sex differences in the responsivity of this axis. The HPA axis influences many physiological functions making an organism's response to changes in the environment appropriate for its reproductive status. Although the acute HPA response to stressors is a beneficial response, constant activation of this circuitry by chronic or traumatic stressful episodes may lead to a dysregulation of the HPA axis and cause pathology. Compared to males, female mice and rats show a more robust HPA axis response, as a result of circulating estradiol levels which elevate stress hormone levels during non-threatening situations, and during and after stressors. Fluctuating levels of gonadal steroids in females across the estrous cycle are a major factor contributing to sex differences in the robustness of HPA activity in females compared to males. Moreover, gonadal steroids may also contribute to epigenetic and organizational influences on the HPA axis even before puberty. Correspondingly, crosstalk between the hypothalamic-pituitary-gonadal (HPG) and HPA axes could lead to abnormalities of stress responses. In humans, a dysregulated stress response is one of the most common symptoms seen across many neuropsychiatric disorders, and as a result, such interactions may exacerbate peripheral pathologies. In this review, we discuss the HPA and HPG axes and review how gonadal steroids interact with the HPA axis to regulate the stress circuitry during all stages in life.

Hypothalamic–pituitary–adrenal and hypothalamic–pituitary–gonadal axes: sex differences in regulation of stress responsivity

PubMed Central

Oyola, Mario G.; Handa, Robert J.

2018-01-01

Gonadal hormones play a key role in the establishment, activation, and regulation of the hypothalamic–pituitary–adrenal (HPA) axis. By influencing the response and sensitivity to releasing factors, neurotransmitters, and hormones, gonadal steroids help orchestrate the gain of the HPA axis to fine-tune the levels of stress hormones in the general circulation. From early life to adulthood, gonadal steroids can differentially affect the HPA axis, resulting in sex differences in the responsivity of this axis. The HPA axis influences many physiological functions making an organism’s response to changes in the environment appropriate for its reproductive status. Although the acute HPA response to stressors is a beneficial response, constant activation of this circuitry by chronic or traumatic stressful episodes may lead to a dysregulation of the HPA axis and cause pathology. Compared to males, female mice and rats show a more robust HPA axis response, as a result of circulating estradiol levels which elevate stress hormone levels during non-threatening situations, and during and after stressors. Fluctuating levels of gonadal steroids in females across the estrous cycle are a major factor contributing to sex differences in the robustness of HPA activity in females compared to males. Moreover, gonadal steroids may also contribute to epigenetic and organizational influences on the HPA axis even before puberty. Correspondingly, crosstalk between the hypothalamic–pituitary–gonadal (HPG) and HPA axes could lead to abnormalities of stress responses. In humans, a dysregulated stress response is one of the most common symptoms seen across many neuropsychiatric disorders, and as a result, such interactions may exacerbate peripheral pathologies. In this review, we discuss the HPA and HPG axes and review how gonadal steroids interact with the HPA axis to regulate the stress circuitry during all stages in life. PMID:28859530

Portal vein thrombosis and arterioportal shunts: Effects on tumor response after chemoembolization of hepatocellular carcinoma

PubMed Central

Vogl, Thomas J; Nour-Eldin, Nour-Eldin; Emad-Eldin, Sally; Naguib, Nagy NN; Trojan, Joerg; Ackermann, Hans; Abdelaziz, Omar

2011-01-01

AIM: To evaluate the effect of portal vein thrombosis and arterioportal shunts on local tumor response in advanced cases of unresectable hepatocellular carcinoma treated by transarterial chemoembolization. METHODS: A retrospective study included 39 patients (mean age: 66.4 years, range: 45-79 years, SD: 7) with unresectable hepatocellular carcinoma (HCC) who were treated with repetitive transarterial chemoembolization (TACE) in the period between March 2006 and October 2009. The effect of portal vein thrombosis (PVT) (in 19 out of 39 patients), the presence of arterioportal shunt (APS) (in 7 out of 39), the underlying liver pathology, Child-Pugh score, initial tumor volume, number of tumors and tumor margin definition on imaging were correlated with the local tumor response after TACE. The initial and end therapy local tumor responses were evaluated according to the response evaluation criteria in solid tumors (RECIST) and magnetic resonance imaging volumetric measurements. RESULTS: The treatment protocols were well tolerated by all patients with no major complications. Local tumor response for all patients according to RECIST criteria were partial response in one patient (2.6%), stable disease in 34 patients (87.1%), and progressive disease in 4 patients (10.2%). The MR volumetric measurements showed that the PVT, APS, underlying liver pathology and tumor margin definition were statistically significant prognostic factors for the local tumor response (P = 0.018, P = 0.008, P = 0.034 and P = 0.001, respectively). The overall 6-, 12- and 18-mo survival rates from the initial TACE were 79.5%, 37.5% and 21%, respectively. CONCLUSION: TACE may be exploited safely for palliative tumor control in patients with advanced unresectable HCC; however, tumor response is significantly affected by the presence or absence of PVT and APS. PMID:21455325

Recent Advances in Type-2-Cell-Mediated Immunity: Insights from Helminth Infection.

PubMed

Harris, Nicola L; Loke, P'ng

2017-12-19

Type-2-cell-mediated immune responses play a critical role in mediating both host-resistance and disease-tolerance mechanisms during helminth infections. Recently, type 2 cell responses have emerged as major regulators of tissue repair and metabolic homeostasis even under steady-state conditions. In this review, we consider how studies of helminth infection have contributed toward our expanding cellular and molecular understanding of type-2-cell-mediated immunity, as well as new areas such as the microbiome. By studying how these successful parasites form chronic infections without overt pathology, we are gaining additional insights into allergic and inflammatory diseases, as well as normal physiology. Copyright © 2017 Elsevier Inc. All rights reserved.

The Paradox of Mitochondrial Dysfunction and Extended Longevity

PubMed Central

Munkácsy, Erin; Rea, Shane L.

2014-01-01

Mitochondria play numerous, essential roles in the life of eukaryotes. Disruption of mitochondrial function in humans is often pathological or even lethal. Surprisingly, in some organisms mitochondrial dysfunction can result in life extension. This paradox has been studied most extensively in the long-lived Mit mutants of the nematode Caenorhabditis elegans. In this review, we explore the major responses that are activated following mitochondrial dysfunction in these animals and how these responses potentially act to extend their life. We focus our attention on five broad areas of current research – reactive oxygen species signaling, the mitochondrial unfolded protein response, autophagy, metabolic adaptation, and the roles played by various transcription factors. Lastly, we also examine why disruption of complexes I and II differ in their ability to induce the Mit phenotype and extend lifespan. PMID:24699406

Evaluation of the deposition, translocation and pathological response of brake dust with and without added chrysotile in comparison to crocidolite asbestos following short-term inhalation: Interim results

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bernstein, David M., E-mail: davidb@itox.ch; Rogers, Rick, E-mail: rarogers5@yahoo.com; Sepulveda, Rosalina

Chrysotile has been frequently used in the past in manufacturing brakes and continues to be used in brakes in many countries. This study was designed to provide an understanding of the biokinetics and potential toxicology following inhalation of brake dust following short term exposure in rats. The deposition, translocation and pathological response of brake dust derived from brake pads manufactured with chrysotile were evaluated in comparison to the amphibole, crocidolite asbestos. Rats were exposed by inhalation 6 h/day for 5 days to either brake dust obtained by sanding of brake-drums manufactured with chrysotile, a mixture of chrysotile and the brakemore » dust or crocidolite asbestos. No significant pathological response was observed at any time point in either the brake dust or chrysotile/brake dust exposure groups. The long chrysotile fibers (> 20 μm) cleared quickly with T{sub 1/2} estimated as 30 and 33 days, respectively in the brake dust and the chrysotile/brake dust exposure groups. In contrast, the long crocidolite fibers had a T{sub 1/2} > 1000 days and initiated a rapid inflammatory response in the lung following exposure resulting in a 5-fold increase in fibrotic response within 91 days. These results provide support that brake dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung following short term inhalation. - Highlights: • We evaluated brake dust w/wo added chrysotile in comparison to crocidolite asbestos. • Persistence, translocation, pathological response in the lung and pleural cavity. • Chrysotile cleared rapidly from the lung while the crocidolite asbestos persisted. • No significant pathology observed at any time point in the brake-dust groups. • Crocidolite produced pathological response - Wagner 4 interstitial fibrosis by 32d.« less

Wasting Mechanisms in Muscular Dystrophy

PubMed Central

Shin, Jonghyun; Tajrishi, Marjan M.; Ogura, Yuji; Kumar, Ashok

2013-01-01

Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. PMID:23669245

Control of Bovine Mastitis: Old and Recent Therapeutic Approaches.

PubMed

Gomes, Fernanda; Henriques, Mariana

2016-04-01

Mastitis is defined as the inflammatory response resulting of the infection of the udder tissue and it is reported in numerous species, namely in domestic dairy animals. This pathology is the most frequent disease of dairy cattle and can be potentially fatal. Mastitis is an economically important pathology associated with reduced milk production, changes in milk composition and quality, being considered one of the most costly to dairy industry. Therefore, the majority of research in the field has focused on control of bovine mastitis and many efforts are being made for the development of new and effective anti-mastitis drugs. Antibiotic treatment is an established component of mastitis control programs; however, the continuous search for new therapeutic alternatives, effective in the control and treatment of bovine mastitis, is urgent. This review will provide an overview of some conventional and emerging approaches in the management of bovine mastitis' infections.

Diffuse Lewy body disease: clinical features in 15 cases.

PubMed Central

Byrne, E J; Lennox, G; Lowe, J; Godwin-Austen, R B

1989-01-01

Fifteen cases of diffuse Lewy body disease were diagnosed on pathological grounds during a single year in one health district. The range and frequency of clinical features contrast strikingly with previous reports. The majority of cases presented with classical levodopa-responsive Parkinson's disease either alone (6 cases) or with mild cognitive impairment (3 cases); the remaining 6 cases presented with cognitive impairment alone. In time almost all patients developed both dementia and Parkinsonism. The dementia was cortical in type, but unusual in that most (12 cases) showed day-to-day fluctuation in severity at some point in their illness. These findings suggest that diffuse Lewy body disease is not rare, and that it presents in a range of ways from dementia with subsequent Parkinsonism to Parkinson's disease with subsequent dementia. The latter mode of presentation suggests that it should be considered as a significant pathological substrate of dementia in Parkinson's disease. Images PMID:2545827

Low Reporting Quality of the Meta-Analyses in Diagnostic Pathology.

PubMed

Liu, Xulei; Kinzler, Michael; Yuan, Jiangfan; He, Guozhong; Zhang, Lanjing

2017-03-01

- Little is known regarding the reporting quality of meta-analyses in diagnostic pathology. - To compare reporting quality of meta-analyses in diagnostic pathology and medicine and to examine factors associated with reporting quality of diagnostic pathology meta-analyses. - Meta-analyses were identified in 12 major diagnostic pathology journals without specifying years and 4 major medicine journals in 2006 and 2011 using PubMed. Reporting quality of meta-analyses was evaluated using the 27-item checklist of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement published in 2009. A higher PRISMA score indicates higher reporting quality. - Forty-one diagnostic pathology meta-analyses and 118 medicine meta-analyses were included. Overall, reporting quality of meta-analyses in diagnostic pathology was lower than that in medicine (median [interquartile range] = 22 [15, 25] versus 27 [23, 28], P < .001). Compared with medicine meta-analyses, diagnostic pathology meta-analyses less likely reported 23 of the 27 items (85.2%) on the PRISMA checklist, but more likely reported the data items. Higher reporting quality of diagnostic pathology meta-analyses was associated with recent publication years (later than 2009 versus 2009 or earlier, P = .002) and non-North American first authors (versus North American, P = .001), but not journal publisher's location (P = .11). Interestingly, reporting quality was not associated with adjusted citation ratio for meta-analyses in either diagnostic pathology or medicine (P = .40 and P = .09, respectively). - Meta-analyses in diagnostic pathology had lower reporting quality than those in medicine. Reporting quality of diagnostic pathology meta-analyses is linked to publication year and first author's location, but not to journal publisher's location or article's adjusted citation ratios. More research and education on meta-analysis methodology may improve the reporting quality of diagnostic pathology meta-analyses.

Teaching forensic pathology to undergraduates at Zhongshan School of Medicine.

PubMed

Zhou, Nan; Wu, Qiu-Ping; Su, Terry; Zhao, Qian-Hao; Yin, Kun; Zheng, Da; Zheng, Jing-Jing; Huang, Lei; Cheng, Jian-Ding

2018-04-01

Producing qualified forensic pathological practitioners is a common difficulty around the world. In China, forensic pathology is one of the required major subspecialties for undergraduates majoring in forensic medicine, in contrast to forensic education in Western countries where forensic pathology is often optional. The enduring predicament is that the professional qualities and abilities of forensic students from different institutions vary due to the lack of an efficient forensic pedagogical model. The purpose of this article is to describe the new pedagogical model of forensic pathology at Zhongshan School of Medicine, Sun Yat-sen University, which is characterised by: (a) imparting a broad view of forensic pathology and basic knowledge of duties and tasks in future careers to students; (b) educating students in primary skills on legal and medical issues, as well as advanced forensic pathological techniques; (c) providing students with resources to broaden their professional minds, and opportunities to improve their professional qualities and abilities; and (d) mentoring students on occupational preparation and further forensic education. In the past few years, this model has resulted in numerous notable forensic students accomplishing achievements in forensic practice and forensic scientific research. We therefore expect this pedagogical model to establish the foundation for forensic pathological education and other subspecialties of forensic medicine in China and abroad.

Pathological response after neoadjuvant bevacizumab- or cetuximab-based chemotherapy in resected colorectal cancer liver metastases.

PubMed

Pietrantonio, Filippo; Mazzaferro, Vincenzo; Miceli, Rosalba; Cotsoglou, Christian; Melotti, Flavia; Fanetti, Giuseppe; Perrone, Federica; Biondani, Pamela; Muscarà, Cecilia; Di Bartolomeo, Maria; Coppa, Jorgelina; Maggi, Claudia; Milione, Massimo; Tamborini, Elena; de Braud, Filippo

2015-07-01

Neoadjuvant chemotherapy (NACT) prior to liver resection is advantageous for patients with colorectal cancer liver metastases (CLM). Bevacizumab- or cetuximab-based NACT may affect patient outcome and curative resection rate, but comparative studies on differential tumour regression grade (TRG) associated with distinct antibodies-associated regimens are lacking. Ninety-three consecutive patients received NACT plus bevacizumab (n = 46) or cetuximab (n = 47) followed by CLM resection. Pathological response was determined in each resected metastasis as TRG rated from 1 (complete) to 5 (no response). Except for KRAS mutations prevailing in bevacizumab versus cetuximab (57 vs. 21 %, p = 0.001), patients characteristics were well balanced. Median follow-up was 31 months (IQR 17-48). Bevacizumab induced significantly better pathological response rates (TRG1-3: 78 vs. 34 %, p < 0.001) as well as complete responses (TRG1: 13 vs. 0 %, p = 0.012) with respect to cetuximab. Three-year progression-free survival (PFS) and overall survival (OS) were not significantly different in the two cohorts. At multivariable analysis, significant association with pathological response was found for number of resected metastases (p = 0.015) and bevacizumab allocation (p < 0.001), while KRAS mutation showed only a trend. Significant association with poorer PFS and OS was found for low grades of pathological response (p = 0.009 and p < 0.001, respectively), R2 resection or presence of extrahepatic disease (both p < 0.001) and presence of KRAS mutation (p = 0.007 and p < 0.001, respectively). Bevacizumab-based regimens, although influenced by the number of metastases and KRAS status, improve significantly pathological response if compared to cetuximab-based NACT. Possible differential impact among regimens on patient outcome has still to be elucidated.

Changes in caseness of anxiety and depression in breast cancer patients during the first year following surgery: patterns of transiency and severity of the distress response.

PubMed

Saboonchi, Fredrik; Petersson, Lena-Marie; Wennman-Larsen, Agneta; Alexanderson, Kristina; Brännström, Richard; Vaez, Marjan

2014-12-01

Psychological distress is prevalent in patients with breast cancer and is viewed as a non-pathological occurrence. Severe distress and mental disorder display a substantial overlap in both conceptual contexts and studies in oncological settings. A domain that may contribute to distinguishing non-pathological distress from signs of potential disorder is the transiency of distress. To examine the transiency of distress response in breast cancer patients by investigating the changes in clinical caseness of depression and anxiety during one year following surgery. Data on the Hospital Anxiety and Depression Scale from a cohort of 715 women with breast cancer on three assessments within one year following breast surgery were subjected to Generalized Estimation Equation Analysis, McNemar's test, and logistic regression. There was a significant decrease in the proportions of anxiety cases from baseline (37.7%) to 4 months (26.7%) but no significant change from 4 to 12 months. Caseness in depression significantly increased from baseline (18.5%) to 4 months (21.5%) but decreased to 15.3% at 12 months. Only experience of major adverse life events contributed to 12 months caseness of anxiety and depression beyond baseline caseness. The average decrease in caseness of anxiety and depression a year following surgery lends support to the view of distress as a transient non-pathological response. A subgroup of patients, however, displayed enduring or recurrent severe distress indicating the presence of potential disorder. The findings emphasize the importance of screening and follow up monitoring of distress. Copyright © 2014 Elsevier Ltd. All rights reserved.

Molecular markers in bladder cancer: Novel research frontiers.

PubMed

Sanguedolce, Francesca; Cormio, Antonella; Bufo, Pantaleo; Carrieri, Giuseppe; Cormio, Luigi

2015-01-01

Bladder cancer (BC) is a heterogeneous disease encompassing distinct biologic features that lead to extremely different clinical behaviors. In the last 20 years, great efforts have been made to predict disease outcome and response to treatment by developing risk assessment calculators based on multiple standard clinical-pathological factors, as well as by testing several molecular markers. Unfortunately, risk assessment calculators alone fail to accurately assess a single patient's prognosis and response to different treatment options. Several molecular markers easily assessable by routine immunohistochemical techniques hold promise for becoming widely available and cost-effective tools for a more reliable risk assessment, but none have yet entered routine clinical practice. Current research is therefore moving towards (i) identifying novel molecular markers; (ii) testing old and new markers in homogeneous patients' populations receiving homogeneous treatments; (iii) generating a multimarker panel that could be easily, and thus routinely, used in clinical practice; (iv) developing novel risk assessment tools, possibly combining standard clinical-pathological factors with molecular markers. This review analyses the emerging body of literature concerning novel biomarkers, ranging from genetic changes to altered expression of a huge variety of molecules, potentially involved in BC outcome and response to treatment. Findings suggest that some of these indicators, such as serum circulating tumor cells and tissue mitochondrial DNA, seem to be easily assessable and provide reliable information. Other markers, such as the phosphoinositide-3-kinase (PI3K)/AKT (serine-threonine kinase)/mTOR (mammalian target of rapamycin) pathway and epigenetic changes in DNA methylation seem to not only have prognostic/predictive value but also, most importantly, represent valuable therapeutic targets. Finally, there is increasing evidence that the development of novel risk assessment tools combining standard clinical-pathological factors with molecular markers represents a major quest in managing this poorly predictable disease.

Fascia: A missing link in our understanding of the pathology of fibromyalgia.

PubMed

Liptan, Ginevra L

2010-01-01

Significant evidence exists for central sensitization in fibromyalgia, however the cause of this process in fibromyalgia-and how it relates to other known abnormalities in fibromyalgia-remains unclear. Central sensitization occurs when persistent nociceptive input leads to increased excitability in the dorsal horn neurons of the spinal cord. In this hyperexcited state, spinal cord neurons produce an enhanced responsiveness to noxious stimulation, and even to formerly innocuous stimulation. No definite evidence of muscle pathology in fibromyalgia has been found. However, there is some evidence for dysfunction of the intramuscular connective tissue, or fascia, in fibromyalgia. This paper proposes that inflammation of the fascia is the source of peripheral nociceptive input that leads to central sensitization in fibromyalgia. The fascial dysfunction is proposed to be due to inadequate growth hormone production and HPA axis dysfunction in fibromyalgia. Fascia is richly innervated, and the major cell of the fascia, the fibroblast, has been shown to secrete pro-inflammatory cytokines, particularly IL-6, in response to strain. Recent biopsy studies using immuno-histochemical staining techniques have found increased levels of collagen and inflammatory mediators in the connective tissue surrounding the muscle cells in fibromyalgia patients. The inflammation of the fascia is similar to that described in conditions such as plantar fasciitis and lateral epicondylitis, and may be better described as a dysfunctional healing response. This may explain why NSAIDs and oral steroids have not been found effective in fibromyalgia. Inflammation and dysfunction of the fascia may lead to central sensitization in fibromyalgia. If this hypothesis is confirmed, it could significantly expand treatment options to include manual therapies directed at the fascia such as Rolfing and myofascial release, and direct further research on the peripheral pathology in fibromyalgia to the fascia.

Neoadjuvant Bevacizumab, Oxaliplatin, 5-Fluorouracil, and Radiation for Rectal Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dipetrillo, Tom; Pricolo, Victor; Lagares-Garcia, Jorge

Purpose: To evaluate the feasibility and pathologic complete response rate of induction bevacizumab + modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen followed by concurrent bevacizumab, oxaliplatin, continuous infusion 5-fluorouracil (5-FU), and radiation for patients with rectal cancer. Methods and Materials: Eligible patients received 1 month of induction bevacizumab and mFOLFOX6. Patients then received 50.4 Gy of radiation and concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m{sup 2}/week for 6 weeks), and continuous infusion 5-FU (200 mg/m{sup 2}/day). Because of gastrointestinal toxicity, the oxaliplatin dose was reduced to 40 mg/m{sup 2}/week. Resection was performedmore » 4-8 weeks after the completion of chemoradiation. Results: The trial was terminated early because of toxicity after 26 eligible patients were treated. Only 1 patient had significant toxicity (arrhythmia) during induction treatment and was removed from the study. During chemoradiation, Grade 3/4 toxicity was experienced by 19 of 25 patients (76%). The most common Grade 3/4 toxicities were diarrhea, neutropenia, and pain. Five of 25 patients (20%) had a complete pathologic response. Nine of 25 patients (36%) developed postoperative complications including infection (n = 4), delayed healing (n = 3), leak/abscess (n = 2), sterile fluid collection (n = 2), ischemic colonic reservoir (n = 1), and fistula (n = 1). Conclusions: Concurrent oxaliplatin, bevacizumab, continuous infusion 5-FU, and radiation causes significant gastrointestinal toxicity. The pathologic complete response rate of this regimen was similar to other fluorouracil chemoradiation regimens. The high incidence of postoperative wound complications is concerning and consistent with other reports utilizing bevacizumab with chemoradiation before major surgical resections.« less

Prevention of the Post-traumatic Fibrotic Response in Joints

DTIC Science & Technology

2014-10-01

The American journal of forensic medicine and pathology . 1988; 9(4):310-2. 14 APPENDICES: An abstract submitted for the ORS conference...clinical problem of posttraumatic joint stiffness, a pathology that reduces the range of motion (ROM) of injured joints and contributes to the...development of osteoarthritis. The fundamental hypothesis that drives the current study is that pathological fibrotic response of injured joint tissues

Arthroscopic findings of a diagnostic dilemma- hip pathology with normal imaging.

PubMed

Buikstra, Joel Glenn; Fary, Camdon; Tran, Phong

2017-03-21

Patients with groin, hip and pelvic pain but normal findings on MRI and minimal changes on x-ray can be a diagnostic problem. This paper looks at the arthroscopic findings of patients who have had hip pain and a positive response to an intra-articular anaesthetic but have non-contributory imaging. We hypothesized that standard MRI's were missing significant pathology and if there was a response to intra-articular local anaesthesia, pathology found during arthroscopy was likely. A retrospective review of all hip arthroscopies performed from March 2011 to January 2015 by two orthopaedic surgeons specializing in hip arthroscopy was conducted to identify patients with clinically suspected intra-articular hip pathology despite a normal MRI report and X-ray. Clinical suspicion of intra-articular hip pathology was confirmed with a positive response to a fluoroscopically guided intra-articular injection of local anaesthetic and corticosteroid. Pathologic findings were collated from the standardised operative notes. Fifty-three hip arthroscopies performed in 51 patients met the inclusion criteria from a total of 1348 hip arthroscopies performed over a 46-month period. All but one of the 53 (98%) hips had arthroscopically confirmed pathology. Mean patient age was 32.5 years [15 to 67 years] with 40 (78%) females and 11 (22%) males. 92.5% of the hips (49/53) were FADIR (flexion, adduction and internal rotation) positive on clinical examination, giving this test a positive predictive value of 98% (95% CI: 89.31 to 99.67%) for intra-articular pathology. In patients with a normal MRI without contrast and a positive response (relief of pain) to an intra-articular injection that failed conservative management, there is a 98% chance of intra-articular hip pathology being discovered on hip arthroscopy.

[Histopathological diagnostic concordance in bone and soft tissue sarcomas between two comprehensive cancer centers from eastern and western Europe: a collaborative experience].

PubMed

Somcutian, Oana; Buiga, Rares; Galatir, Mihaela; Tudor Eniu, Dan; Rachieru, Claudiu; Coza, Daniela; Terrier, Philippe

2015-01-01

This study aims to assess the degree of concordance of histological diagnosis of bone and soft tissue sarcomas between a Comprehensive Cancer Center (CCC) of Eastern Europe - not specialized in this area of pathology - and an important CCC of Western Europe, which is one of the coordinators of a clinical reference network in sarcoma pathology. The goal is to have an overview of the sarcomatous pathology in a region of Eastern Europe and to discover diagnostic discrepancies between the two centers, while determining their cause. The initial diagnosis was compared with the revised diagnosis on 110 specimens from 88 patients with bone or soft tissue sarcomas from East-European CCC, in a one-year period of time. Complete diagnostic agreement was observed in 55 cases (62.5%), a partial agreement in 23 cases (26.1%) and a major disagreement in 10 cases (11.4%). Major discrepancies of the histological type was observed in only 3 cases (3.4%): one case of discordance benign/malignant and 2 cases of discordance mesenchymal/non mesenchymal. Minor histological discrepancies - not affecting the management of the patient - were observed in 18 cases (20.4%). A major discordance in grading - potentially changing the management of the patient - was noted in 7 cases (7.9%), and a minor discrepancy in 5 cases (5.7%). Some histological types were clearly overdiagnosed, like "adult fibrosarcomas" and "malignant peripheral nerve sheet tumors" (MPNST), mostly converted after the audit into "undifferentiated spindle cell sarcomas" or other types of sarcomas. Some "unclassified" sarcomas and "undifferentiated pleomorphic sarcomas" could be re-classified with the aid of an extensive panel of antibodies. Overall, immunohistochemistry was responsible, but not in exclusivity, for half of the minor discrepancies, and for 2 out of 3 cases of major histological discrepancies. Otherwise, the main cause of discrepancies was the difficulties in the interpretation of the morphology. Molecular biology was decisive in one case. Most grading discrepancies resulted from the appreciation of the mitotic index. The profile of the sarcomatous pathology in the northwest region of Romania does not appear to differ significantly from other parts of Europe or the world, but a prospective epidemiological study would be necessary to confirm this assessment. The expansion of immunohistochemical antibody panel, the over-specialization of pathologists and, in the future, the establishment of a national network of referral centers in sarcoma pathology, are required for a high level of histological diagnosis in Eastern Europe. A periodic external audit, continuing this trans-European collaboration between the two centers, would be beneficial for monitoring progress. Copyright © 2014. Published by Elsevier Masson SAS.

THE REGULATION ROLE OF CAROTID BODY PERIPHERAL CHEMORECEPTORS IN PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL CONDITIONS.

PubMed

Lazovic, Biljana; Zlatkovic Svenda, Mirjana; Durmic, Tijana; Stajic, Zoran; Duric, Vesna; Zugic, Vladimir

2016-11-01

The major oxygen sensors in the human body are peripheral chemoreceptors. also known as interoreceptors- as connected with internal organs, located in the aortic arch and in the body of the common carotid artery. Chemoreceptor function under physiological conditions. Stimulation of peripheral chemoreceptors during enviromental hypoxia causes a reflex-mediated increased ventilation, followed by the increase of the muscle sympatic activity, aiming to maintain tissue oxygen homeostatis, as well as glucosae, homeostatis. Besides that, peripheral chemoreceptors interact with central chemoreceptors. responsible for carbon dioxide changes . and they are able to modulate each other. Chemoreceptor function in pathophysiological conditions. Investigations of respiratory function in many pathological processes, such as hypertension, obstructive sleep apnea, congestive heart failure and many other diseases that are presented with enhanced peripheral chemosensitivity and impaired functional sy mpatholysis ultimately determine the peripheral chemorcceptor role and significance of peripheral chemoreceptors in the process of those pathological conditions development. Considering this, the presumed influence of peripheral chemoreceptors is important in patients having the above mentioned pathology. The importance and the role of peripheral chemoreceptors in the course of the breathing control is still controversial, despite many scientific attempts to solve this problem. The main objective of this review is to give the latest data on the peripheral chemoreceptor role and to highlight the importance of peripheral chemoreceptors for maintaining of oxygen homeostasis in pateints with hypoxia caused by either physiological or pathological conditions.

Culturally diverse attitudes and beliefs of students majoring in speech-language pathology.

PubMed

Franca, Maria Claudia; Smith, Linda McCabe; Nichols, Jane Luanne; Balan, Dianna Santos

Academic education in speech-language pathology should prepare students to provide professional services that mirror current knowledge, skills, and scope of practice in a pluralistic society. This study seeks to examine the impact of speech-language pathology (SLP) students prior multicultural experiences and previous formal education on attitudes and beliefs toward language diversity. A survey to investigate SLP students attitudes toward language diversity was applied. After the research study and instructions to complete the consent form questionnaire was presented by a research assistant, an announcement was given by a graduate student who speaks English as a second language with an accent. The participants then completed a questionnaire containing questions related to attitudes about the presentation of the announcement in particular and toward language diversity in general. Responses suggested a relationship between self-reported cultural bias and ability to concentrate on speech with an accent, and the extent of interaction with individuals from a cultural and linguistic diverse (CLD) background. Additional outcomes revealed that cultural bias may be predicted by factors related to amount of CLD exposure. Results of this study indicated critical areas that need to be considered when developing curricula in speech-language pathology programs. The results will be useful in determining procedures applicable in larger investigations, and encourage future research on attitudes and beliefs toward aspects of cultural diversity.

From normal fear to pathological anxiety.

PubMed

Rosen, J B; Schulkin, J

1998-04-01

In this article the authors address how pathological anxiety may develop from adaptive fear states. Fear responses (e.g., freezing, startle, heart rate and blood pressure changes, and increased vigilance) are functionally adaptive behavioral and perceptual responses elicited during danger to facilitate appropriate defensive responses that can reduce danger or injury (e.g., escape and avoidance). Fear is a central motive state of action tendencies subserved by fear circuits, with the amygdala playing a central role. Pathological anxiety is conceptualized as an exaggerated fear state in which hyperexcitability of fear circuits that include the amygdala and extended amygdala (i.e., bed nucleus of the stria terminalis) is expressed as hypervigilance and increased behavioral responsivity to fearful stimuli. Reduced thresholds for activation and hyperexcitability in fear circuits develop through sensitization- or kindling-like processes that involve neuropeptides, hormones, and other proteins. Hyperexcitability in fear circuits is expressed as pathological anxiety that is manifested in the various anxiety disorders.

Mechanisms of physiological and pathological cardiac hypertrophy.

PubMed

Nakamura, Michinari; Sadoshima, Junichi

2018-04-19

Cardiomyocytes exit the cell cycle and become terminally differentiated soon after birth. Therefore, in the adult heart, instead of an increase in cardiomyocyte number, individual cardiomyocytes increase in size, and the heart develops hypertrophy to reduce ventricular wall stress and maintain function and efficiency in response to an increased workload. There are two types of hypertrophy: physiological and pathological. Hypertrophy initially develops as an adaptive response to physiological and pathological stimuli, but pathological hypertrophy generally progresses to heart failure. Each form of hypertrophy is regulated by distinct cellular signalling pathways. In the past decade, a growing number of studies have suggested that previously unrecognized mechanisms, including cellular metabolism, proliferation, non-coding RNAs, immune responses, translational regulation, and epigenetic modifications, positively or negatively regulate cardiac hypertrophy. In this Review, we summarize the underlying molecular mechanisms of physiological and pathological hypertrophy, with a particular emphasis on the role of metabolic remodelling in both forms of cardiac hypertrophy, and we discuss how the current knowledge on cardiac hypertrophy can be applied to develop novel therapeutic strategies to prevent or reverse pathological hypertrophy.

Prevention of the Post-traumatic Fibrotic Response in Joints

DTIC Science & Technology

2014-10-01

JJ, Wolman M. Aging of wound healing in an experimental model in mice. The American journal of forensic medicine and pathology . 1988; 9(4):310-2...SUPPLEMENTARY NOTES 14. ABSTRACT The ongoing study addresses the critical clinical problem of posttraumatic joint stiffness, a pathology that reduces...study is that pathological fibrotic response of injured joint tissues may be limited by targeting the formation of collagen fibrils, a main component

Bacterial meningitic deafness: historical development of epidemiology and cellular pathology.

PubMed

Ruben, Robert

2008-04-01

Meningitis resulting in labyrinthitis and its associated hearing loss was first described by several authors during 1864 and 1865 but it was not integrated into the otological cannon until H. Knapp's publications of 1871. These reports were incorporated by St John Rossa in his textbook of 1873. Politzer, in 1882, included a fuller description of the clinical symptoms. Analysis of records of the etiologies of students in 90 schools for the deaf in North America from 1817 to 1893 showed that before the mid-1870s meningitis was rarely identified as an etiology (<1%) but by the 1880s it accounted for 10-20% of all etiologies, with male preponderance. Cellular pathology of meningitic labyrinthitis from the 1860s to the 1990s examined the ways in which bacteria invaded the inner ear. Human temporal bone studies were a major source of understanding of the pathological processes. Honda, in 1927, injected guinea pigs intracranially with live bacteria, and observed the effects on the membranous labyrinth. In 1988 Lebel's observation of the effectiveness of dexamethasone in preventing much deafness from meningitis stimulated the examination of the labyrinthine immune response. Immunological mechanisms can account for some of the variable morbidity of unilateral, progressive, less-than-severe deafness.

Scavenging nucleic acid debris to combat autoimmunity and infectious disease

NASA Astrophysics Data System (ADS)

Holl, Eda K.; Shumansky, Kara L.; Borst, Luke B.; Burnette, Angela D.; Sample, Christopher J.; Ramsburg, Elizabeth A.; Sullenger, Bruce A.

2016-08-01

Nucleic acid-containing debris released from dead and dying cells can be recognized as damage-associated molecular patterns (DAMPs) or pattern-associated molecular patterns (PAMPs) by the innate immune system. Inappropriate activation of the innate immune response can engender pathological inflammation and autoimmune disease. To combat such diseases, major efforts have been made to therapeutically target the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs) that recognize such DAMPs and PAMPs, or the downstream effector molecules they engender, to limit inflammation. Unfortunately, such strategies can limit the ability of the immune system to combat infection. Previously, we demonstrated that nucleic acid-binding polymers can act as molecular scavengers and limit the ability of artificial nucleic acid ligands to activate PRRs. Herein, we demonstrate that nucleic acid scavengers (NASs) can limit pathological inflammation and nucleic acid-associated autoimmunity in lupus-prone mice. Moreover, we observe that such NASs do not limit an animal’s ability to combat viral infection, but rather their administration improves survival when animals are challenged with lethal doses of influenza. These results indicate that molecules that scavenge extracellular nucleic acid debris represent potentially safer agents to control pathological inflammation associated with a wide range of autoimmune and infectious diseases.

The Contribution of α-Synuclein Spreading to Parkinson's Disease Synaptopathy

PubMed Central

Faustini, Gaia; Missale, Cristina; Pizzi, Marina; Spano, PierFranco

2017-01-01

Synaptopathies are diseases with synapse defects as shared pathogenic features, encompassing neurodegenerative disorders such as Parkinson's disease (PD). In sporadic PD, the most common age-related neurodegenerative movement disorder, nigrostriatal dopaminergic deficits are responsible for the onset of motor symptoms that have been related to α-synuclein deposition at synaptic sites. Indeed, α-synuclein accumulation can impair synaptic dopamine release and induces the death of nigrostriatal neurons. While in physiological conditions the protein can interact with and modulate synaptic vesicle proteins and membranes, numerous experimental evidences have confirmed that its pathological aggregation can compromise correct neuronal functioning. In addition, recent findings indicate that α-synuclein pathology spreads into the brain and can affect the peripheral autonomic and somatic nervous system. Indeed, monomeric, oligomeric, and fibrillary α-synuclein can move from cell to cell and can trigger the aggregation of the endogenous protein in recipient neurons. This novel “prion-like” behavior could further contribute to synaptic failure in PD and other synucleinopathies. This review describes the major findings supporting the occurrence of α-synuclein pathology propagation in PD and discusses how this phenomenon could induce or contribute to synaptic injury and degeneration. PMID:28133550

Bile Mediates Intestinal Pathology in Endotoxemia in Rats

PubMed Central

Jackson, Graham D. F.; Dai, Yung; Sewell, William A.

2000-01-01

Intestinal pathology frequently accompanies experimental endotoxic shock and is mediated by proinflammatory cytokines. Our hypotheses are that hepatobiliary factors operating from the luminal side of the gut make a major contribution to this damage and that tumor necrosis factor alpha (TNF-α) is involved in the pathology. We treated rats with lipopolysaccharide (LPS) intravenously and found that external drainage of bile totally protected the gastrointestinal tract, macroscopically and microscopically, 4 h after LPS administration and dramatically improved survival of the animals for 48 h after LPS administration. The concentration of TNF-α in bile increased markedly after LPS administration and was over 30 times higher in bile than in serum. Tissue damage and the biliary TNF-α response were abrogated when animals were pretreated with gadolinium chloride to eliminate Kupffer cells. TNF-α infusion into the duodenal lumen caused intestinal damage similar to that elicited by intravenous LPS. In rats treated with LPS, survival was significantly increased during the first 36 h in animals given an infusion of anti-TNF-α antibody into the duodenum. These results demonstrate that in endotoxemia, intestinal damage is mediated by factors derived from the bile. The findings indicate that luminally acting TNF-α contributes to the intestinal damage. PMID:10899877

Stretch Injury of Human Induced Pluripotent Stem Cell Derived Neurons in a 96 Well Format

PubMed Central

Sherman, Sydney A.; Phillips, Jack K.; Costa, J. Tighe; Cho, Frances S.; Oungoulian, Sevan R.; Finan, John D.

2016-01-01

Traumatic brain injury (TBI) is a major cause of mortality and morbidity with limited therapeutic options. Traumatic axonal injury (TAI) is an important component of TBI pathology. It is difficult to reproduce TAI in animal models of closed head injury, but in vitro stretch injury models reproduce clinical TAI pathology. Existing in vitro models employ primary rodent neurons or human cancer cell line cells in low throughput formats. This in vitro neuronal stretch injury model employs human induced pluripotent stem cell-derived neurons (hiPSCNs) in a 96 well format. Silicone membranes were attached to 96 well plate tops to create stretchable, culture substrates. A custom-built device was designed and validated to apply repeatable, biofidelic strains and strain rates to these plates. A high content approach was used to measure injury in a hypothesis-free manner. These measurements are shown to provide a sensitive, dose-dependent, multi-modal description of the response to mechanical insult. hiPSCNs transition from healthy to injured phenotype at approximately 35% Lagrangian strain. Continued development of this model may create novel opportunities for drug discovery and exploration of the role of human genotype in TAI pathology. PMID:27671211

CD8+IL-17+ T Cells Mediate Neutrophilic Airway Obliteration in T-bet–Deficient Mouse Lung Allograft Recipients

PubMed Central

Dodd-o, Jeffrey M.; Coon, Tiffany A.; Miller, Hannah L.; Ganguly, Sudipto; Popescu, Iulia; O'Donnell, Christopher P.; Cardenes, Nayra; Levine, Melanie; Rojas, Mauricio; Weathington, Nathaniel M.; Zhao, Jing; Zhao, Yutong; McDyer, John F.

2015-01-01

Acute cellular rejection is a known risk factor for the development of obliterative bronchiolitis, which limits the long-term survival of lung transplant recipients. However, the T cell effector mechanisms in both of these processes remain incompletely understood. Using the mouse orthotopic lung transplant model, we investigated whether C57BL/6 T-bet−/− recipients of major histocompatibility complex (MHC)-mismatched BALB/c lung grafts develop rejection pathology and allospecific cytokine responses that differ from wild-type mice. T-bet−/− recipients demonstrated vigorous allograft rejection at 10 days, characterized by neutrophilic inflammation and predominantly CD8+ T cells producing allospecific IL-17 and/or IFN-γ, in contrast to IFN-γ–dominant responses in WT mice. CD4+ T cells produced IL-17 but not IFN-γ responses in T-bet−/− recipients, in contrast to WT controls. Costimulation blockade using anti-CD154 Ab significantly reduced allospecific CD8+IFN-γ+ responses in both T-bet−/− and WT mice but had no attenuating effect on lung rejection pathology in T-bet−/− recipients or on the development of obliterative airway inflammation that occurred only in T-bet−/− recipients. However, neutralization of IL-17A significantly attenuated costimulation blockade–resistant rejection pathology and airway inflammation in T-bet−/− recipients. In addition, CXCL1 (neutrophil chemokine) was increased in T-bet−/− allografts, and IL-17 induced CXCL1 from mouse lung epithelial cells in vitro. Taken together, our data show that T-bet–deficient recipients of complete MHC-mismatched lung allografts develop costimulation blockade–resistant rejection characterized by neutrophilia and obliterative airway inflammation that is predominantly mediated by CD8+IL-17+ T cells. Our data support T-bet–deficient mouse recipients of lung allografts as a viable animal model to study the immunopathogenesis of small airway injury in lung transplantation. PMID:25286244

Five years of experience teaching pathology to dental students using the WebMicroscope

PubMed Central

2011-01-01

Background We describe development and evaluation of the user-friendly web based virtual microscopy - WebMicroscope for teaching and learning dental students basic and oral pathology. Traditional students microscopes were replaced by computer workstations. Methods The transition of the basic and oral pathology courses from light to virtual microscopy has been completed gradually over a five-year period. A pilot study was conducted in academic year 2005/2006 to estimate the feasibility of integrating virtual microscopy into a traditional light microscopy-based pathology course. The entire training set of glass slides was subsequently converted to virtual slides and placed on the WebMicroscope server. Giving access to fully digitized slides on the web with a browser and a viewer plug-in, the computer has become a perfect companion of the student. Results The study material consists now of over 400 fully digitized slides which covering 15 entities in basic and systemic pathology and 15 entities in oral pathology. Digitized slides are linked with still macro- and microscopic images, organized with clinical information into virtual cases and supplemented with text files, syllabus, PowerPoint presentations and animations on the web, serving additionally as material for individual studies. After their examinations, the students rated the use of the software, quality of the images, the ease of handling the images, and the effective use of virtual slides during the laboratory practicals. Responses were evaluated on a standardized scale. Because of the positive opinions and support from the students, the satisfaction surveys had shown a progressive improvement over the past 5 years. The WebMicroscope as a didactic tool for laboratory practicals was rated over 8 on a 1-10 scale for basic and systemic pathology and 9/10 for oral pathology especially as various students’ suggestions were implemented. Overall, the quality of the images was rated as very good. Conclusions An overwhelming majority of our students regarded a possibility of using virtual slides at their convenience as highly desirable. Our students and faculty consider the use of the virtual microscope for the study of basic as well as oral pathology as a significant improvement over the light microscope. PMID:21489183

Giovanni-Battista Morgagni (1682-1773): creator of pathological anatomy.

PubMed

Androutsos, G

2006-01-01

The great anatomist Giovanni-Battista Morgagni by his major textbook De Sedibus is the creator of pathological anatomy and the one who rendered this new discipline an indispensable specialization of modern medicine.

Prostaglandins in the kidney: developments since Y2K.

PubMed

Nasrallah, Rania; Clark, Jordan; Hébert, Richard L

2007-10-01

There are five major PGs (prostaglandins/prostanoids) produced from arachidonic acid via the COX (cyclo-oxygenase) pathway: PGE(2), PGI(2) (prostacyclin), PGD(2), PGF(2alpha) and TXA(2) (thromboxane A(2)). They exert many biological effects through specific G-protein-coupled membrane receptors, namely EP (PGE(2) receptor), IP (PGI(2) receptor), DP (PGD(2) receptor), FP (PGF(2alpha) receptor) and TP (TXA(2) receptor) respectively. PGs are implicated in physiological and pathological processes in all major organ systems, including cardiovascular function, gastrointestinal responses, reproductive processes, renal effects etc. This review highlights recent insights into the role of each prostanoid in regulating various aspects of renal function, including haemodynamics, renin secretion, growth responses, tubular transport processes and cell fate. A thorough review of the literature since Y2K (year 2000) is provided, with a general overview of PGs and their synthesis enzymes, and then specific considerations of each PG/prostanoid receptor system in the kidney.

Extracellular vesicles in parasitic diseases

PubMed Central

Marcilla, Antonio; Martin-Jaular, Lorena; Trelis, Maria; de Menezes-Neto, Armando; Osuna, Antonio; Bernal, Dolores; Fernandez-Becerra, Carmen; Almeida, Igor C.; del Portillo, Hernando A.

2014-01-01

Parasitic diseases affect billions of people and are considered a major public health issue. Close to 400 species are estimated to parasitize humans, of which around 90 are responsible for great clinical burden and mortality rates. Unfortunately, they are largely neglected as they are mainly endemic to poor regions. Of relevance to this review, there is accumulating evidence of the release of extracellular vesicles (EVs) in parasitic diseases, acting both in parasite–parasite inter-communication as well as in parasite–host interactions. EVs participate in the dissemination of the pathogen and play a role in the regulation of the host immune systems. Production of EVs from parasites or parasitized cells has been described for a number of parasitic infections. In this review, we provide the most relevant findings of the involvement of EVs in intercellular communication, modulation of immune responses, involvement in pathology, and their potential as new diagnostic tools and therapeutic agents in some of the major human parasitic pathogens. PMID:25536932

Self-stimulatory behavior and perceptual reinforcement.

PubMed Central

Lovaas, I; Newsom, C; Hickman, C

1987-01-01

Self-stimulatory behavior is repetitive, stereotyped, functionally autonomous behavior seen in both normal and developmentally disabled populations, yet no satisfactory theory of its development and major characteristics has previously been offered. We present here a detailed hypothesis of the acquisition and maintenance of self-stimulatory behavior, proposing that the behaviors are operant responses whose reinforcers are automatically produced interoceptive and exteroceptive perceptual consequences. The concept of perceptual stimuli and reinforcers, the durability of self-stimulatory behaviors, the sensory extinction effect, the inverse relationship between self-stimulatory and other behaviors, the blocking effect of self-stimulatory behavior on new learning, and response substitution effects are discussed in terms of the hypothesis. Support for the hypothesis from the areas of sensory reinforcement and sensory deprivation is also reviewed. Limitations of major alternative theories are discussed, along with implications of the perceptual reinforcement hypothesis for the treatment of excessive self-stimulatory behavior and for theoretical conceptualizations of functionally related normal and pathological behaviors. PMID:3583964

A clinico-pathological study of lupus nephritis based on the International Society of Nephrology-Renal Pathology Society 2003 classification system.

PubMed

Satish, Suchitha; Deka, Pallavi; Shetty, Manjunath Sanjeev

2017-01-01

Lupus nephritis (LN) is a major complication of systemic lupus erythematosus (SLE). Renal involvement is a major determinant of the prognosis of SLE. The histological classification of LN is a key factor in determining the renal survival of patients with LN. Prompt recognition and treatment of renal disease are important, as early response to therapy is correlated with better outcome and renal biopsy plays an important role in achieving this. The objective of this study was to correlate the clinical and laboratory findings with histopathological classes of LN as per the 2003 International Society of Nephrology-Renal Pathology Society (ISN/RPS) classification system. Fifty-six patients with SLE, undergoing a renal biopsy for renal dysfunction were studied. The comparison of data from multiple groups was made by Pearson's Chi-square test and between two groups by independent samples t -test. The values of P < 0.05 were considered statistically significant. Of the 56 cases studied, 51 (91.1%) were females. The most common presenting symptoms were edema, arthralgia, and hypertension. Class IV (55.4%) was the most common class. Thirty-nine (69.6%) cases showed full house immunostaining. Hypertension, hematuria, proteinuria, and tubulo-interstitial disease showed a significant correlation ( P < 0.05) with ISN/RPS classification, 2003. Assessment and management of patients with suspected LN are greatly facilitated through information obtained by renal biopsy. Since renal morphology may predict long-term prognosis, and no clinical or laboratory feature uniformly predicts prognosis, it is important to study the constellation of features in LN for better patient management.

Impaired Decisional Impulsivity in Pathological Videogamers

PubMed Central

Irvine, Michael A.; Worbe, Yulia; Bolton, Sorcha; Harrison, Neil A.; Bullmore, Edward T.; Voon, Valerie

2013-01-01

Background Pathological gaming is an emerging and poorly understood problem. Impulsivity is commonly impaired in disorders of behavioural and substance addiction, hence we sought to systematically investigate the different subtypes of decisional and motor impulsivity in a well-defined pathological gaming cohort. Methods Fifty-two pathological gaming subjects and age-, gender- and IQ-matched healthy volunteers were tested on decisional impulsivity (Information Sampling Task testing reflection impulsivity and delay discounting questionnaire testing impulsive choice), and motor impulsivity (Stop Signal Task testing motor response inhibition, and the premature responding task). We used stringent diagnostic criteria highlighting functional impairment. Results In the Information Sampling Task, pathological gaming participants sampled less evidence prior to making a decision and scored fewer points compared with healthy volunteers. Gaming severity was also negatively correlated with evidence gathered and positively correlated with sampling error and points acquired. In the delay discounting task, pathological gamers made more impulsive choices, preferring smaller immediate over larger delayed rewards. Pathological gamers made more premature responses related to comorbid nicotine use. Greater number of hours played also correlated with a Motivational Index. Greater frequency of role playing games was associated with impaired motor response inhibition and strategy games with faster Go reaction time. Conclusions We show that pathological gaming is associated with impaired decisional impulsivity with negative consequences in task performance. Decisional impulsivity may be a potential target in therapeutic management. PMID:24146789

Host regulation of liver fibroproliferative pathology during experimental schistosomiasis via interleukin-4 receptor alpha.

PubMed

Nono, Justin Komguep; Ndlovu, Hlumani; Aziz, Nada Abdel; Mpotje, Thabo; Hlaka, Lerato; Brombacher, Frank

2017-08-01

Interleukin-4 receptor (IL-4Rα) is critical for the initiation of type-2 immune responses and implicated in the pathogenesis of experimental schistosomiasis. IL-4Rα mediated type-2 responses are critical for the control of pathology during acute schistosomiasis. However, type-2 responses tightly associate with fibrogranulomatous inflammation that drives host pathology during chronic schistosomiasis. To address such controversy on the role of IL-4Rα, we generated a novel inducible IL-4Rα-deficient mouse model that allows for temporal knockdown of il-4rα gene after oral administration of Tamoxifen. Interrupting IL-4Rα mediated signaling during the acute phase impaired the development of protective type-2 immune responses, leading to rapid weight loss and premature death, confirming a protective role of IL-4Rα during acute schistosomiasis. Conversely, IL-4Rα removal at the chronic phase of schistosomiasis ameliorated the pathological fibro-granulomatous pathology and reversed liver scarification without affecting the host fitness. This amelioration of the morbidity was accompanied by a reduced Th2 response and increased frequencies of FoxP3+ Tregs and CD1dhiCD5+ Bregs. Collectively, these data demonstrate that IL-4Rα mediated signaling has two opposing functions during experimental schistosomiasis depending on the stage of advancement of the disease and indicate that interrupting IL-4Rα mediated signaling is a viable therapeutic strategy to ameliorate liver fibroproliferative pathology in diseases like chronic schistosomiasis.

Neuropathologic assessment of dementia markers in identical and fraternal twins

PubMed Central

Iacono, Diego; Volkman, Inga; Nennesmo, Inger; Pedersen, Nancy L.; Fratiglioni, Laura; Johansson, Boo; Karlsson, David; Winblad, Bengt; Gatz, Margaret

2014-01-01

Twin studies are an incomparable source of investigation to shed light on genetic and non-genetic components of neurodegenerative diseases, as Alzheimer’s disease (AD). Detailed clinicopathologic correlations using twin longitudinal data and postmortem examinations are mostly missing. We describe clinical and pathologic findings of 7 monozygotic (MZ) and dizygotic (DZ) twin pairs. Our findings show good agreement between clinical and pathologic diagnoses in the majority of the twin pairs, with greater neuropathologic concordance in MZ than DZ twins. Greater neuropathologic concordance was found for β-amyloid than tau pathology within the pairs. ApoE4 was associated with higher β-amyloid and earlier dementia onset, and importantly, higher frequency of other co-occurring brain pathologies, regardless of the zygosity. Dementia onset, dementia duration, difference between twins in age at dementia onset and at death, did not correlate with AD pathology. These clinicopathologic correlations of older identical and fraternal twins support the relevance of genetic factors in AD, but not their sufficiency to determine the pathology, and consequently the disease, even in monozygotic twins. It is the interaction among genetic and non-genetic risks which plays a major role in influencing, or probably determining, the degeneration of those brain circuits associated with pathology and cognitive deficits in AD. PMID:24450926

Evaluation of the fate and pathological response in the lung and pleura of brake dust alone and in combination with added chrysotile compared to crocidolite asbestos following short-term inhalation exposure

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bernstein, D.M., E-mail: davidb@itox.ch; Rogers, R.A., E-mail: rarogers5@yahoo.com; Sepulveda, R.

This study was designed to provide an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake dust following short term exposure in rats. The deposition, translocation and pathological response of brake-dust derived from brake pads manufactured with chrysotile were evaluated in comparison to the amphibole, crocidolite asbestos. Rats were exposed by inhalation 6 h/day for 5 days to either brake-dust obtained by sanding of brake-drums manufactured with chrysotile, a mixture of chrysotile and the brake-dust or crocidolite asbestos. The chrysotile fibers were relatively biosoluble whereas the crocidolite asbestos fibers persisted through the life-timemore » of the animal. This was reflected in the lung and the pleura where no significant pathological response was observed at any time point in the brake dust or chrysotile/brake dust exposure groups through 365 days post exposure. In contrast, crocidolite asbestos produced a rapid inflammatory response in the lung parenchyma and the pleura, inducing a significant increase in fibrotic response in both of these compartments. Crocidolite fibers were observed embedded in the diaphragm with activated mesothelial cells immediately after cessation of exposure. While no chrysotile fibers were found in the mediastinal lymph nodes, crocidolite fibers of up to 35 μm were observed. These results provide support that brake-dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung or the pleural cavity following short term inhalation. - Highlights: • Evaluated brake dust w/wo added chrysotile in comparison to crocidolite asbestos. • Persistence, translocation, pathological response in the lung and pleural cavity. • Chrysotile cleared rapidly from the lung while the crocidolite asbestos persisted. • No significant pathology in lung or pleural cavity observed at any time point in the brake-dust groups. • Crocidolite quickly produced pathological response in the lung and pleural cavity.« less

Gambling disorders, gambling type preferences, and psychiatric comorbidity among the Thai general population: Results of the 2013 National Mental Health Survey.

PubMed

Assanangkornchai, Sawitri; McNeil, Edward B; Tantirangsee, Nopporn; Kittirattanapaiboon, Phunnapa

2016-09-01

Background and aims To estimate the prevalence of problem and pathological gambling, gender and age-group differences in gambling types, and comorbidities with other psychiatric disorders among the Thai general population. Methods Analysis was conducted on 4,727 participants of Thailand's 2013 National Mental Health Survey, a multistage stratified cluster survey, using the Composite International Diagnostic Interview. Diagnoses of problem and pathological gambling and other psychiatric disorders were based on the DSM-IV-TR criteria with the following additional criteria for gamblers: more than 10 lifetime gambling episodes and a single year loss of at least 365 USD from gambling. Results The estimated lifetime prevalence rates of pathological and problem gambling were 0.90% [95% confidence interval (CI): 0.51-1.29] and 1.14% (95% CI: 0.58-1.70), respectively. The most popular type of gambling was playing lotteries [69.5%, standard error (SE) = 1.9], the prevalence of which was significantly higher among females and older age groups. The most common psychiatric disorders seen among pathological gamblers were alcohol abuse (57.4%), nicotine dependence (49.5%), and any drug use disorder (16.2%). Pathological gambling was highly prevalent among those who ever experienced major depressive episodes (5.5%), any drug dependence (5.1%), and intermittent explosive disorder (4.8%). The association between pathological gambling was strongest with a history of major depressive episode [adjusted odds ratio (AOR) = 10.4, 95% CI: 2.80-38.4]. Conclusion The study confirms the recognition of gambling disorders as a public health concern in Thailand and suggests a need for culturally specific preventive measures for pathological gamblers and those with a history of substance use disorders or major depression.

Gambling disorders, gambling type preferences, and psychiatric comorbidity among the Thai general population: Results of the 2013 National Mental Health Survey

PubMed Central

Assanangkornchai, Sawitri; McNeil, Edward B.; Tantirangsee, Nopporn; Kittirattanapaiboon, Phunnapa

2016-01-01

Background and aims To estimate the prevalence of problem and pathological gambling, gender and age-group differences in gambling types, and comorbidities with other psychiatric disorders among the Thai general population. Methods Analysis was conducted on 4,727 participants of Thailand’s 2013 National Mental Health Survey, a multistage stratified cluster survey, using the Composite International Diagnostic Interview. Diagnoses of problem and pathological gambling and other psychiatric disorders were based on the DSM-IV-TR criteria with the following additional criteria for gamblers: more than 10 lifetime gambling episodes and a single year loss of at least 365 USD from gambling. Results The estimated lifetime prevalence rates of pathological and problem gambling were 0.90% [95% confidence interval (CI): 0.51–1.29] and 1.14% (95% CI: 0.58–1.70), respectively. The most popular type of gambling was playing lotteries [69.5%, standard error (SE) = 1.9], the prevalence of which was significantly higher among females and older age groups. The most common psychiatric disorders seen among pathological gamblers were alcohol abuse (57.4%), nicotine dependence (49.5%), and any drug use disorder (16.2%). Pathological gambling was highly prevalent among those who ever experienced major depressive episodes (5.5%), any drug dependence (5.1%), and intermittent explosive disorder (4.8%). The association between pathological gambling was strongest with a history of major depressive episode [adjusted odds ratio (AOR) = 10.4, 95% CI: 2.80–38.4]. Conclusion The study confirms the recognition of gambling disorders as a public health concern in Thailand and suggests a need for culturally specific preventive measures for pathological gamblers and those with a history of substance use disorders or major depression. PMID:27648744

Quantification of the pathological response and fate in the lung and pleura of chrysotile in combination with fine particles compared to amosite-asbestos following short-term inhalation exposure

PubMed Central

Bernstein, DM; Rogers, RA; Sepulveda, R; Donaldson, K; Schuler, D; Gaering, S; Kunzendorf, P; Chevalier, J; Holm, SE

2011-01-01

The marked difference in biopersistence and pathological response between chrysotile and amphibole asbestos has been well documented. This study is unique in that it has examined a commercial chrysotile product that was used as a joint compound. The pathological response was quantified in the lung and translocation of fibers to and pathological response in the pleural cavity determined. This paper presents the final results from the study. Rats were exposed by inhalation 6 h/day for 5 days to a well-defined fiber aerosol. Subgroups were examined through 1 year. The translocation to and pathological response in the pleura was examined by scanning electron microscopy and confocal microscopy (CM) using noninvasive methods.The number and size of fibers was quantified using transmission electron microscopy and CM. This is the first study to use such techniques to characterize fiber translocation to and the response of the pleural cavity. Amosite fibers were found to remain partly or fully imbedded in the interstitial space through 1 year and quickly produced granulomas (0 days) and interstitial fibrosis (28 days). Amosite fibers were observed penetrating the visceral pleural wall and were found on the parietal pleural within 7 days postexposure with a concomitant inflammatory response seen by 14 days. Pleural fibrin deposition, fibrosis, and adhesions were observed, similar to that reported in humans in response to amphibole asbestos. No cellular or inflammatory response was observed in the lung or the pleural cavity in response to the chrysotile and sanded particles (CSP) exposure. These results provide confirmation of the important differences between CSP and amphibole asbestos. PMID:21639706

Brain-derived neurotrophic factor signaling and subgenual anterior cingulate cortex dysfunction in major depressive disorder.

PubMed

Tripp, Adam; Oh, Hyunjung; Guilloux, Jean-Philippe; Martinowich, Keri; Lewis, David A; Sibille, Etienne

2012-11-01

The subgenual anterior cingulate cortex is implicated in the pathology and treatment response of major depressive disorder. Low levels of brain-derived neurotrophic factor (BDNF) and reduced markers for GABA function, including in the amygdala, are reported in major depression, but their contribution to subgenual anterior cingulate cortex dysfunction is not known. Using polymerase chain reaction, we first assessed the degree to which BDNF controls mRNA expression (defined as BDNF dependency) of 15 genes relating to GABA and neuropeptide functions in the cingulate cortex of mice with reduced BDNF function (BDNF-heterozygous [Bdnf(+/-)] mice and BDNF exon-IV knockout [Bdnf(KIV)] mice). Gene expression was then quantified in the subgenual anterior cingulate cortex of 51 postmortem subjects with major depressive disorder and comparison subjects (total subjects, N=102; 49% were women) and compared with previous amygdala results. Based on the results in Bdnf(+/-) and Bdnf(KIV) mice, genes were sorted into high, intermediate, and no BDNF dependency sets. In postmortem human subjects with major depression, BDNF receptor (TRKB) expression, but not BDNF, was reduced. Postmortem depressed subjects exhibited down-regulation in genes with high and intermediate BDNF dependency, including markers of dendritic targeting interneurons (SST, NPY, and CORT) and a GABA synthesizing enzyme (GAD2). Changes extended to BDNF-independent genes (PVALB and GAD1). Changes were greater in men (potentially because of low baseline expression in women), displayed notable differences from prior amygdala results, and were not explained by demographic or clinical factors other than sex. These parallel human/mouse analyses provide direct (low TRKB) and indirect (low expression of BDNF-dependent genes) evidence in support of decreased BDNF signaling in the subgenual anterior cingulate cortex in individuals with major depressive disorder, implicate dendritic targeting GABA neurons and GABA synthesis, and, together, suggest a common BDNF-/GABA-related pathology in major depression with sex- and brain region-specific features.

A flexible, open, decentralized system for digital pathology networks.

PubMed

Schuler, Robert; Smith, David E; Kumaraguruparan, Gowri; Chervenak, Ann; Lewis, Anne D; Hyde, Dallas M; Kesselman, Carl

2012-01-01

High-resolution digital imaging is enabling digital archiving and sharing of digitized microscopy slides and new methods for digital pathology. Collaborative research centers, outsourced medical services, and multi-site organizations stand to benefit from sharing pathology data in a digital pathology network. Yet significant technological challenges remain due to the large size and volume of digitized whole slide images. While information systems do exist for managing local pathology laboratories, they tend to be oriented toward narrow clinical use cases or offer closed ecosystems around proprietary formats. Few solutions exist for networking digital pathology operations. Here we present a system architecture and implementation of a digital pathology network and share results from a production system that federates major research centers.

A Flexible, Open, Decentralized System for Digital Pathology Networks

PubMed Central

SMITH, David E.; KUMARAGURUPARAN, Gowri; CHERVENAK, Ann; LEWIS, Anne D.; HYDE, Dallas M.; KESSELMAN, Carl

2014-01-01

High-resolution digital imaging is enabling digital archiving and sharing of digitized microscopy slides and new methods for digital pathology. Collaborative research centers, outsourced medical services, and multi-site organizations stand to benefit from sharing pathology data in a digital pathology network. Yet significant technological challenges remain due to the large size and volume of digitized whole slide images. While information systems do exist for managing local pathology laboratories, they tend to be oriented toward narrow clinical use cases or offer closed ecosystems around proprietary formats. Few solutions exist for networking digital pathology operations. Here we present a system architecture and implementation of a digital pathology network and share results from a production system that federates major research centers. PMID:22941985

Antiviral macrophage responses in flavivirus encephalitis

PubMed Central

Ashhurst, Thomas Myles; van Vreden, Caryn; Munoz-Erazo, Luis; Niewold, Paula; Watabe, Kanami; Terry, Rachael L.; Deffrasnes, Celine; Getts, Daniel R.; King, Nicholas Jonathan Cole

2013-01-01

Mosquito-borne flaviviruses are a major current and emerging threat, affecting millions of people worldwide. Global climate change, combined with increasing proximity of humans to animals and mosquito vectors by expansion into natural habitats, coupled with the increase in international travel, have resulted in significant spread and concomitant increase in the incidence of infection and severe disease. Although neuroinvasive disease has been well described for some viral infections such as Japanese Encephalitis virus (JEV) and West Nile virus (WNV), others such as dengue virus (DENV) have recently displayed an emerging pattern of neuroinvasive disease, distinct from the previously observed, systemically-induced encephalomyelopathy. In this setting, the immune response is a crucial component of host defence, in preventing viral dissemination and invasion of the central nervous system (CNS). However, subversion of the anti-viral activities of macrophages by flaviviruses can facilitate viral replication and spread, enhancing the intensity of immune responses, leading to severe immune-mediated disease which may be further exacerbated during the subsequent infection with some flaviviruses. Furthermore, in the CNS myeloid cells may be responsible for inducing specific inflammatory changes, which can lead to significant pathological damage during encephalitis. The interaction of virus and cells of the myeloid lineage is complex, and this interaction is likely responsible at least in part, for crucial differences between viral clearance and pathology. Recent studies on the role of myeloid cells in innate immunity and viral control, and the mechanisms of evasion and subversion used by flaviviruses are rapidly advancing our understanding of the immunopathological mechanisms involved in flavivirus encephalitis and will lead to the development of therapeutic strategies previously not considered. PMID:24434318

Impulsivity and Stress Response in Pathological Gamblers During the Trier Social Stress Test.

PubMed

Maniaci, G; Goudriaan, A E; Cannizzaro, C; van Holst, R J

2018-03-01

Gambling has been associated with increased sympathetic nervous system output and stimulation of the hypothalamic-pituitary-adrenal axis. However it is unclear how these systems are affected in pathological gambling. This study aimed to investigate the effect of the Trier Social Stress Test (TSST) on cortisol and on cardiac interbeat intervals in relation to impulsivity, in a sample of male pathological gamblers compared to healthy controls. In addition, we investigated the correlation between the TSST, duration of the disorder and impulsivity. A total of 35 pathological gamblers and 30 healthy controls, ranging from 19 to 58 years old and all male, participated in this study. Stress response was measured during and after the TSST by salivary cortisol and cardiac interbeat intervals; impulsivity was assessed with the Barratt Impulsiveness Scale (BIS-11). Exposure to the TSST produced a significant increase in salivary cortisol and interbeat intervals in both groups, without differences between groups. We found a negative correlation between baseline cortisol and duration of pathological gambling indicating that the longer the duration of the disorder the lower the baseline cortisol levels. Additionally, we found a main effect of impulsivity across groups on interbeat interval during the TSST, indicating an association between impulsivity and the intensity of the neurovegetative stress response during the TSST. Involvement of the hypothalamic-pituitary-adrenal axis in pathological gambling was confirmed together with evidence of a correlation between length of the disorder and diminished baseline cortisol levels. Impulsivity emerged as a personality trait expressed by pathological gamblers; however the neurovegetative response to the TSST, although associated with impulsivity, appeared to be independent of the presence of pathological gambling.

Prediction of response to chemoradiation in rectal cancer by a gene polymorphism in the epidermal growth factor receptor promoter region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Spindler, Karen-Lise Garm; Nielsen, Jens Nederby; Lindebjerg, Jan

2006-10-01

Purpose: Epidermal growth factor receptor (EGFR) has been associated with radioresistance in solid tumors. Recently a polymorphism in the Sp1 recognition site of the EGFR promoter region was identified. The present study investigated the predictive value of this polymorphism for the outcome of chemoradiation in locally advanced rectal cancer. Methods and Materials: The study included 77 patients with locally advanced T3 rectal tumors. Treatment consisted of preoperative radiation therapy at a total tumor dose of 65 Gy and concomitant chemotherapy with Uftoral. Blood samples from 63 patients were evaluated for Sp1 -216 G/T polymorphism by polymerase chain reaction analysis. Forty-eightmore » primary tumor biopsies were available for EGFR immunostaining. Patients underwent surgery 8 weeks after treatment. Pathologic response evaluation was performed according to the tumor regression grade (TRG) system. Results: Forty-nine percent had major response (TRG1-2) and 51% moderate response (TRG 3-4) to chemoradiation. The rates of major response were 34% (10/29) in GG homozygote patients compared with 65% (22/34) in patients with T containing variants (p = 0.023). Fifty-eight percent of biopsies were positive for EGFR expression (28/48). The major response rates with regard to EGFR immunostaining were not significantly different. EGFR-positive tumors were found in 83% of the GG homozygote patients compared with 38% of patients with TT or GT variants (p = 0.008). Conclusions: There was a significant correlation between EGFR Sp1 -216 G/T polymorphism and treatment response to chemoradiation in locally advanced rectal cancer. Further investigations of a second set of patient and other treatment schedules are warranted.« less

The Role of Personality Pathology in Depression Treatment Outcome with Psychotherapy and Pharmacotherapy

ERIC Educational Resources Information Center

Levenson, Jessica C.; Wallace, Meredith L.; Fournier, Jay C.; Rucci, Paola; Frank, Ellen

2012-01-01

Background: Depressed patients with comorbid personality pathology may fare worse in treatment for depression than those without this additional pathology, and comorbid personality pathology may be associated with superior response in one form of treatment relative to another, though recent findings have been mixed. We aimed to evaluate the effect…

Chronic pancreatitis.

PubMed

Kleeff, Jorg; Whitcomb, David C; Shimosegawa, Tooru; Esposito, Irene; Lerch, Markus M; Gress, Thomas; Mayerle, Julia; Drewes, Asbjørn Mohr; Rebours, Vinciane; Akisik, Fatih; Muñoz, J Enrique Domínguez; Neoptolemos, John P

2017-09-07

Chronic pancreatitis is defined as a pathological fibro-inflammatory syndrome of the pancreas in individuals with genetic, environmental and/or other risk factors who develop persistent pathological responses to parenchymal injury or stress. Potential causes can include toxic factors (such as alcohol or smoking), metabolic abnormalities, idiopathic mechanisms, genetics, autoimmune responses and obstructive mechanisms. The pathophysiology of chronic pancreatitis is fairly complex and includes acinar cell injury, acinar stress responses, duct dysfunction, persistent or altered inflammation, and/or neuro-immune crosstalk, but these mechanisms are not completely understood. Chronic pancreatitis is characterized by ongoing inflammation of the pancreas that results in progressive loss of the endocrine and exocrine compartment owing to atrophy and/or replacement with fibrotic tissue. Functional consequences include recurrent or constant abdominal pain, diabetes mellitus (endocrine insufficiency) and maldigestion (exocrine insufficiency). Diagnosing early-stage chronic pancreatitis is challenging as changes are subtle, ill-defined and overlap those of other disorders. Later stages are characterized by variable fibrosis and calcification of the pancreatic parenchyma; dilatation, distortion and stricturing of the pancreatic ducts; pseudocysts; intrapancreatic bile duct stricturing; narrowing of the duodenum; and superior mesenteric, portal and/or splenic vein thrombosis. Treatment options comprise medical, radiological, endoscopic and surgical interventions, but evidence-based approaches are limited. This Primer highlights the major progress that has been made in understanding the pathophysiology, presentation, prevalence and management of chronic pancreatitis and its complications.

Salubrious effects of oxytocin on social stress-induced deficits

PubMed Central

Smith, Adam S.; Wang, Zuoxin

2012-01-01

Social relationships are a fundamental aspect of life, affecting social, psychological, physiological, and behavioral functions. While social interactions can attenuate stress and promote health, disruption, confrontations, isolation, or neglect in the social environment can each be major stressors. Social stress can impair the basal function and stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, impairing function of multiple biological systems and posing a risk to mental and physical health. In contrast, social support can ameliorate stress-induced physiological and immunological deficits, reducing the risk of subsequent psychological distress and improving an individual's overall well-being. For better clinical treatment of these physiological and mental pathologies, it is necessary to understand the regulatory mechanisms of stress-induced pathologies as well as determine the underlying biological mechanisms that regulate social buffering of the stress system. A number of ethologically relevant animal models of social stress and species that form strong adult social bonds have been utilized to study the etiology, treatment, and prevention of stress-related disorders. While undoubtedly a number of biological pathways contribute to the social buffering of the stress response, the convergence of evidence denotes the regulatory effects of oxytocin in facilitating social bond-promoting behaviors and their effect on the stress response. Thus, oxytocin may be perceived as a common regulatory element of the social environment, stress response, and stress-induced risks on mental and physical health. PMID:22178036

Towards understanding the pathology of erythema nodosum leprosum.

PubMed

Kahawita, I P; Lockwood, D N J

2008-04-01

Erythema nodosum leprosum (ENL) is an immune-mediated complication of leprosy presenting with inflammatory skin nodules and involvement of multiple organ systems, often running a protracted course. Immune complex production and deposition as well as complement activation have long been regarded as the principal aetiology of ENL. However, new data show that cell-mediated immunity is also important. We have performed a critical analysis of studies on the pathology of ENL. Our main findings are as follows. ENL is characterised by an inflammatory infiltrate of neutrophils with vasculitis and/or panniculitis. There is deposition of immune complexes and complement together with Mycobacterium leprae antigens in the skin. Changes in serum levels of Igs indicate a transient, localised immune response. The major T-cell subtype in ENL is the CD4 cell, in contrast to lepromatous leprosy where CD8 cells predominate. The cytokines TNFalpha and IL-6 are consistently found whilst IL-4 is low or absent in ENL lesions, indicating a T(H)1 type response. Keratinocyte 1a and intercellular adhesion molecule-1 (ICAM-1) have been shown to be present in the epidermis in ENL, which is evidence of a cell-mediated immune response. Co-stimulatory molecules such as B7-1 have also been studied but further work is needed to draw strong conclusions. We also highlight potential areas for future research.

[Histopathological analysis of organs submitted by legal medicine experts in Baojii City: 358 forensic identification cases].

PubMed

Dong, Du-xuan; Shi, Ping-xia; Li, Yun-li; Tian, San-hu; Yang, Jia; Gao, Gang; Zheng, Yun; Jia, Le; Ju, Hong-ya; Sun, Lu-ying; Chen, Ni; Wang, Xiao-bao

2014-08-01

To analyze pathological characteristics of organs recovered during forensic autopsy submitted by legal medicine experts. From Baoji city, 358 cases of forensic autopsy specimens from a series of routine exams were collected. And histopathological diagnoses were reviewed. Majority of the 358 cases were young men. The major causes of death were trauma, sudden death and poisoning. The cause of death was determined with histology in 250 cases. No typical histological changes were noted in 101 cases. The tissue autolysis and decomposition were present in 7 cases. The major pathological diagnosis was cardiovascular disease, followed by diseases in respiratory, nervous, and digestive systems. Forensic autopsy with its professional characteristics, is different from regular autopsy. When diagnosing cause of death by histopathological examination, pathologists should collaborate with legal medicine experts to know the details of the cases, circumstances surrounding the death, and specific forensic pathological characteristics.

[Causes of the people death from drunkenness and alcoholism].

PubMed

Erokhin, Iu A; Paukov, V S; Kirillov, Iu A

2012-01-01

We analyzed causes of 1008 people death, who abused by alcohol. Among them 2 groups were separated out: people died due to drunkenness and due to alcoholism. The structure of the death was similar in the both groups, however depended on alcoholism stages. The major cause of the death in group of drunkenness people was acute heart insufficiency, less commonly--lung pathology, and very rarely--brain vessels pathology and liver cirrhosis. In group of people, who died due to alcoholism, lung pathology was the major cause of these deaths, acute heart insufficiency was occurred less commonly, and very rare brain pathology because of delirium tremens or alcohol withdrawal syndrome, as so liver cirrhosis with complications. Hemorrhagic pancreonecrosis after alcoholic excess was found out in both groups, but it was more often in people, who died due to drunkenness. Obtained results show importance of chronic alcoholism identification as a disease with several stages including drunkenness and alcoholism.

Major histocompatibility complex class II molecule expression on muscle cells is regulated by differentiation: implications for the immunopathogenesis of muscle autoimmune diseases.

PubMed

Mantegazza, R; Gebbia, M; Mora, M; Barresi, R; Bernasconi, P; Baggi, F; Cornelio, F

1996-08-01

Major histocompatibility complex (MHC) class II molecules are expressed on myoblasts after interferon-gamma (IFN-gamma) treatment, suggesting a muscle cell involvement in antigen presentation in inflammatory myopathies. However, they were not observed on normal or pathological myofibers. This discrepancy might be related to different responsiveness of developmentally differentiated muscle cells to IFN-gamma. Myoblasts expressed class II transcripts and proteins after IFN-gamma, while myotubes and innervated contracting muscle cells did not show staining for class II molecules. At all cell stages no loss of IFN-gamma receptor was detected indicating that myofiber maturation blocks their capacity to express MHC class II molecules. This suggests that completely differentiated myofibers cannot participate in class II restricted immunological reactions.

Lack of shunt response in suspected idiopathic normal pressure hydrocephalus with Alzheimer disease pathology.

PubMed

Hamilton, Roy; Patel, Sunil; Lee, Edward B; Jackson, Eric M; Lopinto, Joanna; Arnold, Steven E; Clark, Christopher M; Basil, Anuj; Shaw, Leslie M; Xie, Sharon X; Grady, M Sean; Trojanowski, John Q

2010-10-01

To determine the impact of cortical Alzheimer disease pathology on shunt responsiveness in individuals treated for idiopathic normal pressure hydrocephalus (iNPH), 37 patients clinically diagnosed with iNPH participated in a prospective study in which performance on neurologic, psychometric, and gait measures before and 4 months after shunting was correlated with amyloid β plaques, neuritic plaques, and neurofibrillary tangles observed in cortical biopsies obtained during shunt insertion. No complications resulted from biopsy acquisition. Moderate to severe pathology was associated with worse baseline cognitive performance and diminished postoperative improvement on NPH symptom severity scales, gait measures, and cognitive instruments compared to patients lacking pathology.

Dysregulation of B Cell Activity During Proliferative Kidney Disease in Rainbow Trout.

PubMed

Abos, Beatriz; Estensoro, Itziar; Perdiguero, Pedro; Faber, Marc; Hu, Yehfang; Díaz Rosales, Patricia; Granja, Aitor G; Secombes, Christopher J; Holland, Jason W; Tafalla, Carolina

2018-01-01

Proliferative kidney disease (PKD) is a widespread disease caused by the endoparasite Tetracapsuloides bryosalmonae (Myxozoa: Malacosporea). Clinical disease, provoked by the proliferation of extrasporogonic parasite stages, is characterized by a chronic kidney pathology with underlying transcriptional changes indicative of altered B cell responses and dysregulated T-helper cell-like activities. Despite the relevance of PKD to European and North American salmonid aquaculture, no studies, to date, have focused on further characterizing the B cell response during the course of this disease. Thus, in this work, we have studied the behavior of diverse B cell populations in rainbow trout ( Oncorhynchus mykiss ) naturally infected with T. bryosalmonae at different stages of preclinical and clinical disease. Our results show a clear upregulation of all trout immunoglobulins (Igs) (IgM, IgD, and IgT) demonstrated by immunohistochemistry and Western blot analysis, suggesting the alteration of diverse B cell populations that coexist in the infected kidney. Substantial changes in IgM, IgD, and IgT repertoires were also identified throughout the course of the disease further pointing to the involvement of the three Igs in PKD through what appear to be independently regulated mechanisms. Thus, our results provide strong evidence of the involvement of IgD in the humoral response to a specific pathogen for the first time in teleosts. Nevertheless, it was IgT, a fish-specific Ig isotype thought to be specialized in mucosal immunity, which seemed to play a prevailing role in the kidney response to T. bryosalmonae . We found that IgT was the main Ig coating extrasporogonic parasite stages, IgT + B cells were the main B cell subset that proliferated in the kidney with increasing kidney pathology, and IgT was the Ig for which more significant changes in repertoire were detected. Hence, although our results demonstrate a profound dysregulation of different B cell subsets during PKD, they point to a major involvement of IgT in the immune response to the parasite. These results provide further insights into the pathology of PKD that may facilitate the future development of control strategies.

Combination chemotherapy of carboplatin and paclitaxel for advanced/metastatic salivary gland carcinoma patients: differences in responses by different pathological diagnoses.

PubMed

Nakano, Kenji; Sato, Yukiko; Sasaki, Tohru; Shimbashi, Wataru; Fukushima, Hirofumi; Yonekawa, Hiroyuki; Mitani, Hiroki; Kawabata, Kazuyoshi; Takahashi, Shunji

2016-09-01

A standard chemotherapy for recurrent/metastatic salivary gland cancers has not been established. Combination chemotherapy of carboplatin and paclitaxel should be evaluated as a treatment option. This study retrospectively reviewed salivary gland cancer patients who received combination chemotherapy of carboplatin and paclitaxel. The differences in objective responses and in the prognoses according to the different pathological diagnoses were evaluated. A total of 38 patients were enrolled in the study; of them, 18 had salivary duct carcinomas (SDCs), nine had adenoid cystic carcinomas (ACCs), and 11 had other pathological diagnoses. Objective responses were observed in 15 (39%) patients. The median progression-free survival (PFS) was 6.5 months, and the median overall survival (OS) was 26.5 months. ACC patients had relatively low response rates (9%), but there were no significant differences in PFS or OS compared to other sub-types. The treatment was well tolerated, with few adverse events. Salivary gland cancer patients showed a moderate clinical response to the combination chemotherapy of carboplatin and paclitaxel. The objective response rates differed according to the pathological diagnoses, but there were no significant differences in prognoses.

Altered expression of γ-secretase components in animal model of major depressive disorder induced by reserpine administration.

PubMed

Lee, Hye-Ryun; Hwang, In-Sik; Kim, Ji-Eun; Choi, Sun-Il; Lee, Young-Ju; Goo, Jun-Seo; Lee, Eon-Pil; Choi, Hae-Wook; Kim, Hong-Sung; Lee, Jae-Ho; Jung, Young-Jin; Hwang, Dae-Youn

2012-06-01

Altered expression of neurotrophic factors as well as neuroinflammation is commonly associated with Major depressive disorder (MDD) and Alzheimer's disease (AD). To investigate whether or not reserpine-induced MDD affects the expression of AD-related proteins, the expression of γ-secretase components and substrate were measured in brains of ICR mice following reserpine treatment for 15 days. In active avoidance test, total response time and peak slightly increased in the 2 mg/kg reserpine (RSP2)-treated group compared to vehicle-treated group (P<0.05). Expression and phosphorylation of MKP-1, which is a key factor in MDD pathology, were both higher in the RSP2-treated group than the vehicle- and 1 mg/kg reserpine (RSP1)-treated groups (P<0.02). Furthermore, full-length expression of amyloid precursor protein (APP) was enhanced in the RSP1 and RSP2-treated groups compared to the vehicle-treated group, whereas expression of γ-secretase components decreased (P<0.03). Among the three components of the γ-secretase complex, nicastrin protein underwent the largest decrease in expression, as detected by Western blotting (P<0.03). Therefore, the data presented here provide additional evidence about the pathological correlation between MDD and AD.

Noninvasive brain stimulation treatments for addiction and major depression

PubMed Central

Dunlop, Katharine; Hanlon, Colleen A.

2016-01-01

Major depressive disorder (MDD) and substance use disorders (SUDs) are prevalent, disabling, and challenging illnesses for which new treatment options are needed, particularly in comorbid cases. Neuroimaging studies of the functional architecture of the brain suggest common neural substrates underlying MDD and SUDs. Intrinsic brain activity is organized into a set of functional networks, of which two are particularly relevant to psychiatry. The salience network (SN) is crucial for cognitive control and response inhibition, and deficits in SN function are implicated across a wide variety of psychiatric disorders, including MDD and SUDs. The ventromedial network (VMN) corresponds to the classic reward circuit, and pathological VMN activity for drug cues/negative stimuli is seen in SUDs/MDD. Noninvasive brain stimulation (NIBS) techniques, including rTMS and tDCS, have been used to enhance cortico–striatal–thalamic activity through the core SN nodes in the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex, and anterior insula. Improvements in both MDD and SUD symptoms ensue, including in comorbid cases, via enhanced cognitive control. Inhibition of the VMN also appears promising in preclinical studies for quenching the pathological incentive salience underlying SUDs and MDD. Evolving techniques may further enhance the efficacy of NIBS for MDD and SUD cases that are unresponsive to conventional treatments. PMID:26849183

Analytical approaches to the diagnosis and treatment of aging and aging-related disease: redox status and proteomics.

PubMed

Calabrese, V; Dattilo, S; Petralia, A; Parenti, R; Pennisi, M; Koverech, G; Calabrese, V; Graziano, A; Monte, I; Maiolino, L; Ferreri, T; Calabrese, E J

2015-05-01

Basal levels of oxidants are indispensible for redox signaling to produce adaptive cellular responses such as vitagenes linked to cell survival; however, at higher levels, they are detrimental to cells, contributing to aging and to the pathogenesis of numerous age-related diseases. Aging is a complex systemic process and the major gap in aging research reminds the insufficient knowledge about pathways shifting from normal "healthy" aging to disease-associated pathological aging. The major complication of normal "healthy" aging is in fact the increasing risk of age-related diseases such as cardiovascular diseases, diabetes mellitus, and neurodegenerative pathologies that can adversely affect the quality of life in general, with enhanced incidences of comorbidities and mortality. In this context, global "omics" approaches may help to dissect and fully study the cellular and molecular mechanisms of aging and age-associated processes. The proteome, being more close to the phenotype than the transcriptome and more stable than the metabolome, represents the most promising "omics" field in aging research. In the present study, we exploit recent advances in the redox biology of aging and discuss the potential of proteomics approaches as innovative tools for monitoring at the proteome level the extent of protein oxidative insult and related modifications with the identification of targeted proteins.

Physician Scientist Research Pathway Leading to Certification by the American Board of Pathology.

PubMed

Weiss, Sharon W; Johnson, Rebecca L

2016-01-01

In 2014, the American Board of Pathology, in response to the pathology community, approved a physician scientist research pathway. This brief report summarizes the history of and objectives for creating the physician scientist research pathway and the requirements of the American Board of Pathology for the certification of physician scientist research pathway trainees.

Pathogenic outcome following experimental infection of sheep with Chlamydia abortus variant strains LLG and POS.

PubMed

Livingstone, Morag; Wheelhouse, Nicholas; Ensor, Hannah; Rocchi, Mara; Maley, Stephen; Aitchison, Kevin; Wattegedera, Sean; Wilson, Kim; Sait, Michelle; Siarkou, Victoria; Vretou, Evangelia; Entrican, Gary; Dagleish, Mark; Longbottom, David

2017-01-01

This study investigated the pathogenesis of two variant strains (LLG and POS) of Chlamydia abortus, in comparison to a typical wild-type strain (S26/3) which is known to be responsible for late term abortion in small ruminants. Challenge with the three strains at mid-gestation resulted in similar pregnancy outcomes, with abortion occurring in approximately 50-60% of ewes with the mean gestational lengths also being similar. However, differences were observed in the severity of placental pathology, with infection appearing milder for strain LLG, which was reflected in the lower number of organisms shed in vaginal swabs post-partum and less gross pathology and organisms present in placental smears. Results for strain POS were somewhat different than LLG with a more focal restriction of infection observed. Post-abortion antibody responses revealed prominent differences in seropositivity to the major outer membrane protein (MOMP) present in elementary body (EB) preparations under denaturing conditions, most notably with anti-LLG and anti-POS convalescent sera where there was no or reduced detection of MOMP present in EBs derived from the three strains. These results and additional analysis of whole EB and chlamydial outer membrane complex preparations suggest that there are conformational differences in MOMP for the three strains. Overall, the results suggest that gross placental pathology and clinical outcome is not indicative of bacterial colonization and the severity of infection. The results also highlight potential conformational differences in MOMP epitopes that perhaps impact on disease diagnosis and the development of new vaccines.

The serine/threonine-protein kinase/endoribonuclease IRE1α protects the heart against pressure overload-induced heart failure.

PubMed

Steiger, DeAnna; Yokota, Tomohiro; Li, Jin; Ren, Shuxun; Minamisawa, Susumu; Wang, Yibin

2018-05-16

Heart failure is associated with induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). The serine/threonine protein kinase/endoribonuclease IRE1α is a key protein in ER stress signal transduction. IRE1α activity can induce both protective UPR and apoptotic downstream signaling events, but the specific role for IRE1α activity in the heart is unknown. A major aim of this study was to characterize the specific contribution of IRE1α in cardiac physiology and pathogenesis. We used both cultured myocytes and a transgenic mouse line with inducible and cardiomyocyte-specific IRE1α overexpression as experimental models to achieve targeted IRE1α activation. IRE1α expression induced a potent but transient ER stress response in cardiomyocytes and did not cause significant effects in the intact heart under normal physiological condition. Furthermore, the IRE1α-activated transgenic heart responding to pressure overload exhibited preserved function and reduced fibrotic area, associated with increased adaptive UPR signaling and with blunted inflammatory and pathological gene expression. Therefore, we conclude that IRE1α induces transient ER stress signaling and confers a protective effect against pressure overload-induced pathological remodeling in the heart. To our knowledge, this report provides first direct evidence of a specific and protective role for IRE1α in the heart and reveals an interaction between ER stress signaling and inflammatory regulation in the pathologically stressed heart. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Pathological Imitative Behavior and Response Preparation in Schizophrenia.

PubMed

Dankinas, Denisas; Melynyte, Sigita; Siurkute, Aldona; Dapsys, Kastytis

2017-08-01

Pathological imitative behavior (ehopraxia) is occasionally observed in schizophrenia patients. However, only a severe form of echopraxia can be detected with the help of a direct observation. Therefore, our goal was to study a latent form of pathological imitative behavior in this disorder, which is indicated by an increase of imitative tendencies. In our study, 14 schizophrenia patients and 15 healthy subjects were employed in two tasks: (a) in an imitative task they had to copy a hand action seen on a screen; (b) in a counter-imitative task they had to make a different movement (which involves an inhibition of prepotent imitative tendency that is impaired in case of pathological imitative behavior). Imitative tendencies were assessed by an interference score - a difference between counter-imitative and imitative response parameters. We also studied a response preparation in both groups by employing precueing probabilistic information. Our results revealed that schizophrenia patients were able to employ probabilistic information to prepare properly not only the imitative, but also the counter-imitative responses, the same as the healthy subjects did. Nevertheless, we detected increased prepotent imitative tendencies in schizophrenia patients, what indicates the latent pathological imitative behavior in case of this disorder. The obtained results suggest that in the case of schizophrenia problems with pathological imitative behavior more likely occurred in executive rather than in the preparatory stage of response. Our findings can help to detect a latent echopraxia in schizophrenia patients that cannot be revealed by direct observation. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

PRospective Imaging of CErvical cancer and neoadjuvant treatment (PRICE) study: role of ultrasound to predict partial response in locally advanced cervical cancer patients undergoing chemoradiation and radical surgery.

PubMed

Testa, A C; Ferrandina, G; Moro, F; Pasciuto, T; Moruzzi, M C; De Blasis, I; Mascilini, F; Foti, E; Autorino, R; Collarino, A; Gui, B; Zannoni, G F; Gambacorta, M A; Valentini, A L; Rufini, V; Scambia, G

2018-05-01

Chemoradiation-based neoadjuvant treatment followed by radical surgery is an alternative therapeutic strategy for locally advanced cervical cancer (LACC), but ultrasound variables used to predict partial response to neoadjuvant treatment are not well defined. Our goal was to analyze prospectively the potential role of transvaginal ultrasound in early prediction of partial pathological response, assessed in terms of residual disease at histology, in a large, single-institution series of LACC patients triaged to neoadjuvant treatment followed by radical surgery. Between October 2010 and June 2014, we screened 108 women with histologically documented LACC Stage IB2-IVA, of whom 88 were included in the final analysis. Tumor volume, three-dimensional (3D) power Doppler indices and contrast parameters were obtained before (baseline examination) and after 2 weeks of treatment. The pathological response was defined as complete (absence of any residual tumor after treatment) or partial (microscopic and/or macroscopic residual tumor at pathological examination). Complete-response and partial-response groups were compared and receiver-operating characteristics (ROC) curves were generated for ultrasound variables that were statistically significant on univariate analysis to evaluate their diagnostic ability to predict partial pathological response. There was a complete pathological response to neoadjuvant therapy in 40 (45.5%) patients and a partial response in 48 (54.5%). At baseline examination, tumor volume did not differ between the two groups. However, after 2 weeks of neoadjuvant treatment, the tumor volume was significantly greater in patients with partial response than it was in those with complete response (P = 0.019). Among the 3D vascular indices, the vascularization index (VI) was significantly lower in the partial-response compared with the complete-response group, both before and after 2 weeks of treatment (P = 0.037 and P = 0.024, respectively). At baseline examination in the contrast analysis, women with partial response had lower tumor peak enhancement (PE) as well as lower tumor wash-in rate (WiR) and longer tumor rise time (RT) compared with complete responders (P = 0.006, P = 0.003, P = 0.038, respectively). There was no difference in terms of contrast parameters after 2 weeks of treatment. ROC-curve analysis of baseline parameters showed that the best cut-offs for predicting partial pathological response were 41.5% for VI (sensitivity, 63.6%; specificity, 66.7%); 16123.5 auxiliary units for tumor PE (sensitivity, 47.9%; specificity, 84.2%); 7.8 s for tumor RT (sensitivity, 68.8%; specificity, 57.9%); and 4902 for tumor WiR (sensitivity, 77.1%; specificity, 60.5%). ROC curves of parameters after 2 weeks of treatment showed that the best cut-off for predicting partial pathological response was 18.1 cm 3 for tumor volume (sensitivity, 70.8%; specificity 60.0%) and 39.5% for VI (sensitivity; 62.5%; specificity, 73.5%). Ultrasound and contrast parameters differ between LACC patients with complete response and those with partial response before and after 2 weeks of neoadjuvant treatment. However, neither ultrasound parameters before treatment nor those after 2 weeks of treatment had cut-off values with acceptable sensitivity and specificity for predicting partial pathological response to neoadjuvant therapy. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Demystified … Molecular pathology in oncology

PubMed Central

Crocker, J

2002-01-01

In the past 10 years, molecular biology has found major applications in pathology, particularly in oncology. This has been a field of enormous expansion, where pure science has found a place in clinical practice and is now of everyday use in any academic unit. This demystified review will discuss the techniques used in molecular pathology and then provide examples of how these can be used in oncology. PMID:12456768

The p38 pathway, a major pleiotropic cascade that transduces stress and metastatic signals in endothelial cells

PubMed Central

Corre, Isabelle; Paris, François; Huot, Jacques

2017-01-01

By gating the traffic of molecules and cells across the vessel wall, endothelial cells play a central role in regulating cardiovascular functions and systemic homeostasis and in modulating pathophysiological processes such as inflammation and immunity. Accordingly, the loss of endothelial cell integrity is associated with pathological disorders that include atherosclerosis and cancer. The p38 mitogen-activated protein kinase (MAPK) cascades are major signaling pathways that regulate several functions of endothelial cells in response to exogenous and endogenous stimuli including growth factors, stress and cytokines. The p38 MAPK family contains four isoforms p38α, p38β, p38γ and p38δ that are encoded by four different genes. They are all widely expressed although to different levels in almost all human tissues. p38α/MAPK14, that is ubiquitously expressed is the prototype member of the family and is referred here as p38. It regulates the production of inflammatory mediators, and controls cell proliferation, differentiation, migration and survival. Its activation in endothelial cells leads to actin remodeling, angiogenesis, DNA damage response and thereby has major impact on cardiovascular homeostasis, and on cancer progression. In this manuscript, we review the biology of p38 in regulating endothelial functions especially in response to oxidative stress and during the metastatic process. PMID:28903453

Postmenopausal osteoporosis in rheumatoid arthritis: The estrogen deficiency-immune mechanisms link.

PubMed

Sapir-Koren, Rony; Livshits, Gregory

2017-10-01

Rheumatoid arthritis (RA) is characterized, among other factors, by systemic bone loss, reaching ~50% prevalence of osteoporosis in postmenopausal women. This is roughly a doubled prevalence in comparison with age-matched non-RA women. Postmenopausal RA women are more likely to be sero-positive for the anti-citrullinated peptide antibody (ACPA). Our extensive review of recent scientific literature enabled us to propose several mechanisms as responsible for the accelerated bone loss in ACPA(+) RA postmenopausal women. Menopause-associated estrogen deficiency plays a major role in these pathological mechanisms, as follows. Copyright © 2017 Elsevier Inc. All rights reserved.

Asbestos: a perspective. I. An overview. II. An annotated literature collection, 1960--1974. III. A literature compilation, 1974--1977. [Health hazards

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huff, J.E.; Hammons, A.S.; Dinger, C.Y.

Although the general population is widely exposed to asbestos, both by inhalation and ingestion, the hazards of chronic, environmental exposure have not been determined. Reasons conflict but are attributed in part to a paucity of information on human dose response, effects of asbestos ingestion, ambient concentrations and distribution of asbestos in the environment, the environmental cycling of asbestos, and related biological interactions including transmission through foodchains. As distilled from the world's asbestos literature, conclusions representing a majority opinion on the pathological effects of asbestos on man are summarized. (38 references.)

TRPC6 fulfills a calcineurin signaling circuit during pathologic cardiac remodeling

PubMed Central

Kuwahara, Koichiro; Wang, Yanggan; McAnally, John; Richardson, James A.; Bassel-Duby, Rhonda; Hill, Joseph A.; Olson, Eric N.

2006-01-01

The heart responds to injury and chronic pressure overload by pathologic growth and remodeling, which frequently result in heart failure and sudden death. Calcium-dependent signaling pathways promote cardiac growth and associated changes in gene expression in response to stress. The calcium/calmodulin-dependent phosphatase calcineurin, which signals to nuclear factor of activated T cells (NFAT) transcription factors, serves as a transducer of calcium signals and is sufficient and necessary for pathologic cardiac hypertrophy and remodeling. Transient receptor potential (TRP) proteins regulate cation entry into cells in response to a variety of signals, and in skeletal muscle, expression of TRP cation channel, subfamily C, member 3 (TRPC3) is increased in response to neurostimulation and calcineurin signaling. Here we show that TRPC6 was upregulated in mouse hearts in response to activated calcineurin and pressure overload, as well as in failing human hearts. Two conserved NFAT consensus sites in the promoter of the TRPC6 gene conferred responsiveness to cardiac stress. Cardiac-specific overexpression of TRPC6 in transgenic mice resulted in heightened sensitivity to stress, a propensity for lethal cardiac growth and heart failure, and an increase in NFAT-dependent expression of β–myosin heavy chain, a sensitive marker for pathologic hypertrophy. These findings implicate TRPC6 as a positive regulator of calcineurin-NFAT signaling and a key component of a calcium-dependent regulatory loop that drives pathologic cardiac remodeling. PMID:17099778

Self-instructional "virtual pathology" laboratories using web-based technology enhance medical school teaching of pathology.

PubMed

Marchevsky, Alberto M; Relan, Anju; Baillie, Susan

2003-05-01

Second-year medical students have traditionally been taught pulmonary pathophysiology at the University of California-Los Angeles (UCLA) School of Medicine using lectures, discussion groups, and laboratory sessions. Since 1998, the laboratory sessions have been replaced by 4 interactive, self-instructional sessions using web-based technology and case-based instruction. This article addresses nature of transformation that occurred from within the course in response to the infusion of new technologies. The vast majority of the course content has been digitized and incorporated into the website of the Pathophysiology of Disease course. The teaching histological slides have been photographed digitally and organized into "cases" with clinical information, digital images and text, and audio descriptions. The students study the materials from these cases at their own pace in 2 "virtual pathology" laboratory, with a few instructors supervising the on-site sessions. The students discuss additional cases available on the website in 2 other laboratory sessions supervised by a pulmonologist and a pathologist. Marked improvement in student participation and satisfaction was seen with the use of web-based instruction. Attendance at laboratory sessions, where the students had previously been required to bring their own microscopes to study histological slides at their own pace, increased from approximately 30% to 40% of the class in previous years to almost 100%. Satisfaction surveys showed progressive improvement over the past 4 years, as various suggestions were implemented. The value of web-based instruction of pathology at the UCLA School of Medicine is discussed.

Innate Immune Signaling Activated by MDR Bacteria in the Airway

PubMed Central

Parker, Dane; Ahn, Danielle; Cohen, Taylor; Prince, Alice

2015-01-01

Health care-associated bacterial pneumonias due to multiple-drug resistant (MDR) pathogens are an important public health problem and are major causes of morbidity and mortality worldwide. In addition to antimicrobial resistance, these organisms have adapted to the milieu of the human airway and have acquired resistance to the innate immune clearance mechanisms that normally prevent pneumonia. Given the limited efficacy of antibiotics, bacterial clearance from the airway requires an effective immune response. Understanding how specific airway pathogens initiate and regulate innate immune signaling, and whether this response is excessive, leading to host-induced pathology may guide future immunomodulatory therapy. We will focus on three of the most important causes of health care-associated pneumonia, Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae, and review the mechanisms through which an inappropriate or damaging innate immune response is stimulated, as well as describe how airway pathogens cause persistent infection by evading immune activation. PMID:26582515

Role of the nicotinic acetylcholine receptor in Alzheimer's disease pathology and treatment.

PubMed

Lombardo, Sylvia; Maskos, Uwe

2015-09-01

Alzheimer's Disease (AD) is the major form of senile dementia, characterized by neuronal loss, extracellular deposits, and neurofibrillary tangles. It is accompanied by a loss of cholinergic tone, and acetylcholine (ACh) levels in the brain, which were hypothesized to be responsible for the cognitive decline observed in AD. Current medication is restricted to enhancing cholinergic signalling for symptomatic treatment of AD patients. The nicotinic acetylcholine receptor family (nAChR) and the muscarinic acetylcholine receptor family (mAChR) are the target of ACh in the brain. Both families of receptors are affected in AD. It was demonstrated that amyloid beta (Aβ) interacts with nAChRs. Here we discuss how Aβ activates or inhibits nAChRs, and how this interaction contributes to AD pathology. We will discuss the potential role of nAChRs as therapeutic targets. This article is part of the Special Issue entitled 'The Nicotinic Acetylcholine Receptor: From Molecular Biology to Cognition'. Copyright © 2014 Elsevier Ltd. All rights reserved.

Specific Receptor Usage in Plasmodium falciparum Cytoadherence Is Associated with Disease Outcome

PubMed Central

Ochola, Lucy B.; Siddondo, Bethsheba R.; Ocholla, Harold; Nkya, Siana; Kimani, Eva N.; Williams, Thomas N.; Makale, Johnstone O.; Liljander, Anne; Urban, Britta C.; Bull, Pete C.; Szestak, Tadge; Marsh, Kevin; Craig, Alister G.

2011-01-01

Our understanding of the basis of severe disease in malaria is incomplete. It is clear that pathology is in part related to the pro-inflammatory nature of the host response but a number of other factors are also thought to be involved, including the interaction between infected erythrocytes and endothelium. This is a complex system involving several host receptors and a major parasite-derived variant antigen (PfEMP1) expressed on the surface of the infected erythrocyte membrane. Previous studies have suggested a role for ICAM-1 in the pathology of cerebral malaria, although these have been inconclusive. In this study we have examined the cytoadherence patterns of 101 patient isolates from varying clinical syndromes to CD36 and ICAM-1, and have used variant ICAM-1 proteins to further characterise this adhesive phenotype. Our results show that increased binding to CD36 is associated with uncomplicated malaria while ICAM-1 adhesion is raised in parasites from cerebral malaria cases. PMID:21390226

Editorial--in this issue: innate immunity in normal and pathologic circumstances.

PubMed

Bot, Adrian

2014-01-01

In this issue of the International Reviews of Immunology, we host several reviews dedicated to the innate immunity in normal and diseased states. Tan et al. discuss the molecular nature of the innate immune response as a consequence of co-engagement of distinct Toll-like receptors. Schwarz et al. present a regulatory loop leading to increased myelopoiesis through the engagement of CD137L by CD137+ T cells. Kolandaswamy et al. present transcriptomic evidence that distinguishes between two major subsets of monocytes. In a different review, Minasyan presents an interesting hypothesis that erythrocytes have a dominant role in clearing bacteria within the blood stream while leukocytes' role is mostly extra-vascular. Yan et al. discuss the pivotal role of the liver, its pre-existing and associated pathology, in sepsis. Zhang outlines the implications of declining neutrophils and impact to long-term management of HIV-associated disease. Finally, Lal et al. discuss the multiple roles of γδT cells in innate and adaptive immunity.

[A Case of Pathological Complete Response after Neoadjuvant Chemotherapy(S-1 plus Oxaliplatin)and Laparoscopic Low Anterior Resection for Rectal Cancer].

PubMed

Ichinohe, Daichi; Morohashi, Hajime; Umetsu, Satoko; Yoshida, Tatsuya; Wakasa, Yusuke; Odagiri, Tadashi; Kimura, Toshirou; Suto, Akiko; Saito, Takeshi; Yoshida, Eri; Akasaka, Harue; Jin, Hiroyuki; Miura, Takuya; Sakamoto, Yoshiyuki; Hakamada, Kenichi

2016-11-01

We report a case of pathological complete response after neoadjuvant chemotherapy(NAC)(S-1 plus oxaliplatin)for rectal cancer. The patient was a 50-year-old man who had type 3 circumferential rectal cancer. An abdominal CT scan revealed locally advanced rectal cancer(cT3N2H0P0M0, cStage III b)with severe stenosis and oral-side intestinal dilatation. The patient was treated with NAC after loop-ileostomy. After 3 courses of chemotherapy, a CT scan revealed significant tumor reduction. Laparoscopic low anterior resection and bilateral lymph node dissection were performed 5 weeks after the last course of chemotherapy. The pathological diagnosis was a pathological complete response(no residual cancer cells). This case suggests that laparoscopic low anterior resection after NAC with S-1 plus oxaliplatin for locally advanced rectal cancer is a potentially effective procedure.

Confounders in interpreting pathology for safety and risk assessment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolf, Douglas C.; Mann, Peter C.

2005-02-01

The contribution of pathology to toxicity assessment is invaluable but often not clearly understood. Pathology endpoints are the central response around which human health risk assessment is frequently determined; therefore, it is important that the general toxicology community understand current concepts and nomenclature of toxicologic pathology. Toxicologic pathology encompasses the study of changes in tissue morphology that help define the risk of exposure to xenobiotics. Toxicologic pathology is a discipline that has changed and adapted over time including methods of analysis and nomenclature of lesions. As risk assessments are updated for chemicals in commerce, frequently the older literature must bemore » reviewed and reevaluated. When interpreting pathology data from animal studies, it is important to consider the biological significance of a lesion as well as its relationship to the ultimate adverse health effect. Assessing the potential for a chemical to cause harm to humans must include the examination of the entire pathology database in context of the study design, the mode of action of the chemical of concern, and using the most current interpretation of a lesion to determine the significance for human health effects of a particular tissue response.« less

The Pathology of Chronic Obstructive Pulmonary Disease: Progress in the 20th and 21st Centuries.

PubMed

Berg, Kyra; Wright, Joanne L

2016-12-01

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and is the fourth leading cause of death worldwide. There has been significant progress in the pathologic description and pathophysiologic analysis of COPD in the 20th and 21st centuries. We review the history, progression, and significance of pathologic alterations in COPD, including emphysematous changes, airway alterations, and vascular alterations. We also indicate what pathologic features of COPD the practicing pathologist should be describing in standard surgical and autopsy specimens.

Molecular etiopathology of naturally occurring reproductive diseases in female goats

PubMed Central

Beena, V.; Pawaiya, R. V. S.; Gururaj, K.; Singh, D. D.; Mishra, A. K.; Gangwar, N. K.; Gupta, V. K.; Singh, R.; Sharma, A. K.; Karikalan, M.; Kumar, Ashok

2017-01-01

Aim: The aim of the present study was to investigate the molecular etiopathology of occurrence of reproductive diseases in female goats. Reproductive diseases in goats account for major economic losses to goat farmers in terms of valuable loss of offspring and animal productivity. Materials and Methods: A total of 660 female genitalia were examined for pathological conditions (macroscopic and microscopic lesions). The etiopathological study was carried out for the presence of pathogenic organisms such as Brucella, Chlamydia, and Campylobacter in the uterus and ovary. Based on the microscopic lesions, suspected samples were subjected to diagnostic polymerase chain reaction (PCR) for various etiological agents employing 16srRNA genus specific primers for Campylobacter and Chlamydophila and OMP31 gene-based PCR for Brucella melitensis and nested PCR using ITS-1 gene primers for Toxoplasma gondii. For Brucella suspected samples, immunohistochemistry (IHC) was also performed. Results: In studied female genitalia, 108 (16.30%) showed gross abnormalities with overall 23.32% occurrence of pathological conditions (macroscopic and microscopic lesions). Pathological involvement of the uterus was the highest 68 (62.96%), followed by the ovaries 27 (25%) and other organs. Major uterine condition observed was endometritis (5.60%). In uterine infections, 35 (5.30%) samples were found positive for Campylobacter spp., 12 (1.81%) samples for B. melitensis, and 3 (0.45%) samples were positive for Chlamydophila spp. Among the samples positive for B. melitensis by PCR, 3 were found positive by IHC also. Corynebacterium ovis was detected by PCR using specific primers in a case of hydrosalpinx. It was concluded that many pathological lesions in female genitalia of functional significance play a major role in infertility in goats. Conclusion: The present study concluded that many pathological lesions in female genitalia of functional significance play a major role in infertility in goats. PMID:28919691

Diagnostic Discrepancies in Mandatory Slide Review of Extradepartmental Head and Neck Cases: Experience at a Large Academic Center.

PubMed

Mehrad, Mitra; Chernock, Rebecca D; El-Mofty, Samir K; Lewis, James S

2015-12-01

Medical error is a significant problem in the United States, and pathologic diagnoses are a significant source of errors. Prior studies have shown that second-opinion pathology review results in clinically major diagnosis changes in approximately 0.6% to 5.8% of patients. The few studies specifically on head and neck pathology have suggested rates of changed diagnoses that are even higher. Objectives .- To evaluate the diagnostic discrepancy rates in patients referred to our institution, where all such cases are reviewed by a head and neck subspecialty service, and to identify specific areas with more susceptibility to errors. Five hundred consecutive, scanned head and neck pathology reports from patients referred to our institution were compared for discrepancies between the outside and in-house diagnoses. Major discrepancies were defined as those resulting in a significant change in patient clinical management and/or prognosis. Major discrepancies occurred in 20 cases (4% overall). Informative follow-up material was available on 11 of the 20 patients (55.0%), among whom, the second opinion was supported in 11 of 11 cases (100%). Dysplasia versus invasive squamous cell carcinoma was the most common (7 of 20; 35%) area of discrepancy, and by anatomic subsite, the sinonasal tract (4 of 21; 19.0%) had the highest rate of discrepant diagnoses. Of the major discrepant diagnoses, 12 (12 of 20; 60%) involved a change from benign to malignant, one a change from malignant to benign (1 of 20; 5%), and 6 involved tumor classification (6 of 20; 30%). Head and neck pathology is a relatively high-risk area, prone to erroneous diagnoses in a small fraction of patients. This study supports the importance of second-opinion review by subspecialized pathologists for the best care of patients.

Patients With Diabetic Foot Disease Fear Major Lower-Extremity Amputation More Than Death.

PubMed

Wukich, Dane K; Raspovic, Katherine M; Suder, Natalie C

2018-02-01

The aim of this study was to identify the most-feared complications of diabetes mellitus (DM), comparing those with diabetic foot pathology with those without diabetic foot pathology. We determined the frequency of patients ranking major lower-extremity amputation (LEA) as their greatest fear in comparison to blindness, death, diabetic foot infection (DFI), or end-stage renal disease (ESRD) requiring dialysis. We further categorized the study group patients (N = 207) by their pathology such as diabetic foot ulcer (DFU), Charcot neuroarthropathy, foot infection, or acute neuropathic fractures and dislocations. The control group (N = 254) was comprised of patients with diabetes who presented with common non-diabetes-related foot pathology. A total of 461 patients were enrolled in this study and included 254 patients without diabetic foot complications and 207 patients with diabetic foot problems. When comparing patients with and without diabetic disease, no significant differences were observed with regard to their fear of blindness, DFI, or ESRD requiring dialysis. Patients with diabetic foot disease (61 of 207, 31.9%) were 136% more likely (odds ratio [OR] = 2.36; 95% CI = 1.51-3.70; P = .002] to rank major LEA as their greatest fear when compared with diabetic patients without foot disease (42 of 254, 16.5%) and were 49% less likely (OR = 0.51; 95% CI = 0.34-0.79; P = .002) to rank death as their greatest fear compared with patients without diabetic foot disease. Patients with diabetic foot pathology fear major LEA more than death, foot infection, or ESRD. Variables that were associated with ranking LEA as the greatest fear were the presence of a diabetic-related foot complication, duration of DM ≥10 years, insulin use, and the presence of peripheral neuropathy. Level II: Prospective, Case controlled study.

On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia

PubMed Central

Geser, F.; O'Dwyer, L.; Hardiman, O.; Bede, P.; Bokde, A. L. W.; Prvulovic, D.; Trojanowski, John Q.; Hampel, H.

2011-01-01

Pathological 43-kDa transactive responsive sequence DNA-binding protein (TDP-43) has been recognized as the major disease protein in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin positive, tau and α-synuclein negative inclusions (FTLD-U) and the transitional forms between these multisystem conditions. In order to develop TDP-43 into a successful ALS biomarker, the natural history of TDP-43 pathology needs to be characterized and the underlying pathophysiology established. Here we propose a spatial and temporal “two-axis” model of central nervous system vulnerability for TDP-43 linked degeneration and discuss recent studies on potential biomarkers related to pathological TDP-43 in the cerebrospinal fluid (CSF), blood, and skeletal muscle. The model includes the following “two arms”: First, a “motor neuron disease” or “spinal cord/brainstem to motor cortex” axis (with degeneration possibly ascending from the lower motor neurons to the upper motor neurons); and secondly, a “dementia” or “corticoid/allocortical to neocortex” axis (with a probable spread of TDP-43 linked degeneration from the mediotemporal lobe to wider mesocortical and neocortical brain areas). At the cellular level, there is a gradual disappearance of normal TDP-43 in the nucleus in combination with the formation of pathological aggregates in the cell body and cellular processes, which can also be used to identify the stage of the disease process. Moreover, TDP-43 lesions in subpial/subependymal or perivascular localizations have been noted in TDP-43 linked neurodegeneration, and this might account for increased CSF and blood TDP-43 levels through mechanisms that remain to be elucidated. PMID:21911035

Lack of Shunt Response in Suspected Idiopathic Normal Pressure Hydrocephalus with Alzheimer Disease Pathology

PubMed Central

Hamilton, Roy; Patel, Sunil; Lee, Edward B.; Jackson, Eric M.; Lopinto, Joanna; Arnold, Steven E.; Clark, Christopher M.; Basil, Anuj; Shaw, Leslie M.; Xie, Sharon X.; Grady, M. Sean; Trojanowski, John Q.

2010-01-01

To determine the impact of cortical Alzheimer disease pathology on shunt responsiveness in individuals treated for idiopathic normal pressure hydrocephalus (iNPH), 37 patients clinically diagnosed with iNPH participated in a prospective study in which performance on neurologic, psychometric, and gait measures before and 4 months after shunting was correlated with amyloid β plaques, neuritic plaques, and neurofibrillary tangles observed in cortical biopsies obtained during shunt insertion. No complications resulted from biopsy acquisition. Moderate to severe pathology was associated with worse baseline cognitive performance and diminished postoperative improvement on NPH symptom severity scales, gait measures, and cognitive instruments compared to patients lacking pathology. PMID:20687117

Network pharmacology-based identification of key pharmacological pathways of Yin-Huang-Qing-Fei capsule acting on chronic bronchitis.

PubMed

Yu, Guohua; Zhang, Yanqiong; Ren, Weiqiong; Dong, Ling; Li, Junfang; Geng, Ya; Zhang, Yi; Li, Defeng; Xu, Haiyu; Yang, Hongjun

2017-01-01

For decades in China, the Yin-Huang-Qing-Fei capsule (YHQFC) has been widely used in the treatment of chronic bronchitis, with good curative effects. Owing to the complexity of traditional Chinese herbal formulas, the pharmacological mechanism of YHQFC remains unclear. To address this problem, a network pharmacology-based strategy was proposed in this study. At first, the putative target profile of YHQFC was predicted using MedChem Studio, based on structural and functional similarities of all available YHQFC components to the known drugs obtained from the DrugBank database. Then, an interaction network was constructed using links between putative YHQFC targets and known therapeutic targets of chronic bronchitis. Following the calculation of four topological features (degree, betweenness, closeness, and coreness) of each node in the network, 475 major putative targets of YHQFC and their topological importance were identified. In addition, a pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes pathway database indicated that the major putative targets of YHQFC are significantly associated with various pathways involved in anti-inflammation processes, immune responses, and pathological changes caused by asthma. More interestingly, eight major putative targets of YHQFC (interleukin [IL]-3, IL-4, IL-5, IL-10, IL-13, FCER1G, CCL11, and EPX) were demonstrated to be associated with the inflammatory process that occurs during the progression of asthma. Finally, a molecular docking simulation was performed and the results exhibited that 17 pairs of chemical components and candidate YHQFC targets involved in asthma pathway had strong binding efficiencies. In conclusion, this network pharmacology-based investigation revealed that YHQFC may attenuate the inflammatory reaction of chronic bronchitis by regulating its candidate targets, which may be implicated in the major pathological processes of the asthma pathway.

Network pharmacology-based identification of key pharmacological pathways of Yin–Huang–Qing–Fei capsule acting on chronic bronchitis

PubMed Central

Yu, Guohua; Zhang, Yanqiong; Ren, Weiqiong; Dong, Ling; Li, Junfang; Geng, Ya; Zhang, Yi; Li, Defeng; Xu, Haiyu; Yang, Hongjun

2017-01-01

For decades in China, the Yin–Huang–Qing–Fei capsule (YHQFC) has been widely used in the treatment of chronic bronchitis, with good curative effects. Owing to the complexity of traditional Chinese herbal formulas, the pharmacological mechanism of YHQFC remains unclear. To address this problem, a network pharmacology-based strategy was proposed in this study. At first, the putative target profile of YHQFC was predicted using MedChem Studio, based on structural and functional similarities of all available YHQFC components to the known drugs obtained from the DrugBank database. Then, an interaction network was constructed using links between putative YHQFC targets and known therapeutic targets of chronic bronchitis. Following the calculation of four topological features (degree, betweenness, closeness, and coreness) of each node in the network, 475 major putative targets of YHQFC and their topological importance were identified. In addition, a pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes pathway database indicated that the major putative targets of YHQFC are significantly associated with various pathways involved in anti-inflammation processes, immune responses, and pathological changes caused by asthma. More interestingly, eight major putative targets of YHQFC (interleukin [IL]-3, IL-4, IL-5, IL-10, IL-13, FCER1G, CCL11, and EPX) were demonstrated to be associated with the inflammatory process that occurs during the progression of asthma. Finally, a molecular docking simulation was performed and the results exhibited that 17 pairs of chemical components and candidate YHQFC targets involved in asthma pathway had strong binding efficiencies. In conclusion, this network pharmacology-based investigation revealed that YHQFC may attenuate the inflammatory reaction of chronic bronchitis by regulating its candidate targets, which may be implicated in the major pathological processes of the asthma pathway. PMID:28053519

Factors contributing to hearing impairment in patients with cleft lip/palate in Malaysia: A prospective study of 346 ears.

PubMed

Cheong, Jack Pein; Soo, Siew Shuin; Manuel, Anura Michelle

2016-09-01

To determine the factors contributing towards hearing impairment in patients with cleft lip/palate. A prospective analysis was conducted on 173 patients (346 ears) with cleft lip and palate (CL/P) who presented to the combined cleft clinic at University Malaya Medical Centre (UMMC) over 12 months. The patients' hearing status was determined using otoacoustic emission (OAE), pure tone audiometry (PTA) and auditory brainstem response (ABR). These results were analysed against several parameters, which included age, gender, race, types of cleft pathology, impact and timing of repair surgery. The patients' age ranged from 1-26 years old. They comprised 30% with unilateral cleft lip and palate (UCLP), 28% with bilateral cleft lip and palate (BCLP), 28% with isolated cleft palate (ICP) and 14% with isolated cleft lip (ICL). Majority of the patients (68.2%) had normal otoscopic findings. Out of the 346 ears, 241 ears (70%) ears had passed the hearing tests. There was no significant relationship between patients' gender and ethnicity with their hearing status. The types of cleft pathology significantly influenced the outcome of PTA and ABR screening results (p < 0.001). There was no significant difference between the repaired and unrepaired cleft groups and the outcome of hearing tests. However, hearing improvement occurred when palatal repair was performed at the age of <1year old (OR = 2.37, CI 1.2 = 4.6, p = 0.01). Majority of the cleft patients had normal hearing (70%). Hearing threshold varied significantly between the different types of cleft pathology. Surgery conferred no significant impact on the hearing outcome unless surgery was performed at the age of <1 year old. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Treatment of persistent post-concussion syndrome due to mild traumatic brain injury: current status and future directions.

PubMed

Hadanny, Amir; Efrati, Shai

2016-08-01

Persistent post-concussion syndrome caused by mild traumatic brain injury has become a major cause of morbidity and poor quality of life. Unlike the acute care of concussion, there is no consensus for treatment of chronic symptoms. Moreover, most of the pharmacologic and non-pharmacologic treatments have failed to demonstrate significant efficacy on both the clinical symptoms as well as the pathophysiologic cascade responsible for the permanent brain injury. This article reviews the pathophysiology of PCS, the diagnostic tools and criteria, the current available treatments including pharmacotherapy and different cognitive rehabilitation programs, and promising new treatment directions. A most promising new direction is the use of hyperbaric oxygen therapy, which targets the basic pathological processes responsible for post-concussion symptoms; it is discussed here in depth.

Cytokine mediated tissue fibrosis☆

PubMed Central

Borthwick, Lee A.; Wynn, Thomas A.; Fisher, Andrew J.

2013-01-01

Acute inflammation is a recognised part of normal wound healing. However, when inflammation fails to resolve and a chronic inflammatory response is established this process can become dysregulated resulting in pathological wound repair, accumulation of permanent fibrotic scar tissue at the site of injury and the failure to return the tissue to normal function. Fibrosis can affect any organ including the lung, skin, heart, kidney and liver and it is estimated that 45% of deaths in the western world can now be attributed to diseases where fibrosis plays a major aetiological role. In this review we examine the evidence that cytokines play a vital role in the acute and chronic inflammatory responses that drive fibrosis in injured tissues. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease. PMID:23046809

Neural correlates of the impact of control on decision making in pathological gambling.

PubMed

Hudgens-Haney, Matthew E; Hamm, Jordan P; Goodie, Adam S; Krusemark, Elizabeth A; McDowell, Jennifer E; Clementz, Brett A

2013-02-01

Perceived control over a gambling outcome leads individuals to accept more and larger bets, increased risk-taking. Pathological gamblers, however, do not diminish risk-taking when control is absent, suggesting an illusion of control. To evaluate neural correlates of perceived control in gamblers, this study compared magnetoencephalography responses of 36 pathological (PG) and 36 non-pathological gamblers (NPG) during the Georgia Gambling Task. PGs exhibited greater activity in bilateral primary sensory regions. An interaction between pathology and control over the gambling task was observed bilaterally throughout dorsal and ventral visual processing streams, and lateral PFC. NPGs showed decreased activity when control was absent. Groups did not differ in response to potential bet cost. These findings provide neurophysiological evidence that PGs suffer from the pattern of risk-taking associated with perceived control, even when no control exists. They suggest that gambling pathology contributes to differential processing of gambling stimuli other than potential costs or rewards. Copyright © 2012 Elsevier B.V. All rights reserved.

Oxidative Stress and Metabolic Pathologies: From an Adipocentric Point of View

PubMed Central

Le Lay, Soazig; Martinez, Maria Carmen; Andriantsitohaina, Ramaroson

2014-01-01

Oxidative stress plays a pathological role in the development of various diseases including diabetes, atherosclerosis, or cancer. Systemic oxidative stress results from an imbalance between oxidants derivatives production and antioxidants defenses. Reactive oxygen species (ROS) are generally considered to be detrimental for health. However, evidences have been provided that they can act as second messengers in adaptative responses to stress. Obesity represents a major risk factor for deleterious associated pathologies such as type 2 diabetes, liver, and coronary heart diseases. Many evidences regarding obesity-induced oxidative stress accumulated over the past few years based on established correlations of biomarkers or end-products of free-radical-mediated oxidative stress with body mass index. The hypothesis that oxidative stress plays a significant role in the development of metabolic disorders, especially insulin-resistance state, is supported by several studies where treatments reducing ROS production reverse metabolic alterations, notably through improvement of insulin sensitivity, hyperlipidemia, or hepatic steatosis. In this review, we will develop the mechanistic links between oxidative stress generated by adipose tissue in the context of obesity and its impact on metabolic complications development. We will also attempt to discuss potential therapeutic approaches targeting obesity-associated oxidative stress in order to prevent associated-metabolic complications. PMID:25143800

Macrophage Polarization in Chronic Inflammatory Diseases: Killers or Builders?

PubMed Central

Baci, Denisa; Tremolati, Marco; Fanuli, Matteo; Farronato, Giampietro; Mortara, Lorenzo

2018-01-01

Macrophages are key cellular components of the innate immunity, acting as the main player in the first-line defence against the pathogens and modulating homeostatic and inflammatory responses. Plasticity is a major feature of macrophages resulting in extreme heterogeneity both in normal and in pathological conditions. Macrophages are not homogenous, and they are generally categorized into two broad but distinct subsets as either classically activated (M1) or alternatively activated (M2). However, macrophages represent a continuum of highly plastic effector cells, resembling a spectrum of diverse phenotype states. Induction of specific macrophage functions is closely related to the surrounding environment that acts as a relevant orchestrator of macrophage functions. This phenomenon, termed polarization, results from cell/cell, cell/molecule interaction, governing macrophage functionality within the hosting tissues. Here, we summarized relevant cellular and molecular mechanisms driving macrophage polarization in “distant” pathological conditions, such as cancer, type 2 diabetes, atherosclerosis, and periodontitis that share macrophage-driven inflammation as a key feature, playing their dual role as killers (M1-like) and/or builders (M2-like). We also dissect the physio/pathological consequences related to macrophage polarization within selected chronic inflammatory diseases, placing polarized macrophages as a relevant hallmark, putative biomarkers, and possible target for prevention/therapy. PMID:29507865

Imbalance in the sensitivity to different types of rewards in pathological gambling.

PubMed

Sescousse, Guillaume; Barbalat, Guillaume; Domenech, Philippe; Dreher, Jean-Claude

2013-08-01

Pathological gambling is an addictive disorder characterized by a persistent and compulsive desire to engage in gambling activities. This maladaptive behaviour has been suggested to result from a decreased sensitivity to experienced rewards, regardless of reward type. Alternatively, pathological gambling might reflect an imbalance in the sensitivity to monetary versus non-monetary incentives. To directly test these two hypotheses, we examined how the brain reward circuit of pathological gamblers responds to different types of rewards. Using functional magnetic resonance imaging, we compared the brain responses of 18 pathological gamblers and 20 healthy control subjects while they engaged in a simple incentive task manipulating both monetary and visual erotic rewards. During reward anticipation, the ventral striatum of pathological gamblers showed a differential response to monetary versus erotic cues, essentially driven by a blunted reactivity to cues predicting erotic stimuli. This differential response correlated with the severity of gambling symptoms and was paralleled by a reduced behavioural motivation for erotic rewards. During reward outcome, a posterior orbitofrontal cortex region, responding to erotic rewards in both groups, was further recruited by monetary gains in pathological gamblers but not in control subjects. Moreover, while ventral striatal activity correlated with subjective ratings assigned to monetary and erotic rewards in control subjects, it only correlated with erotic ratings in gamblers. Our results point to a differential sensitivity to monetary versus non-monetary rewards in pathological gambling, both at the motivational and hedonic levels. Such an imbalance might create a bias towards monetary rewards, potentially promoting addictive gambling behaviour.

X-Ray Cross-Complementing Group 1 and Thymidylate Synthase Polymorphisms Might Predict Response to Chemoradiotherapy in Rectal Cancer Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lamas, Maria J., E-mail: mlamasd@yahoo.es; Duran, Goretti; Gomez, Antonio

2012-01-01

Purpose: 5-Fluorouracil-based chemoradiotherapy before total mesorectal excision is currently the standard treatment of Stage II and III rectal cancer patients. We used known predictive pharmacogenetic biomarkers to identify the responders to preoperative chemoradiotherapy in our series. Methods and Materials: A total of 93 Stage II-III rectal cancer patients were genotyped using peripheral blood samples. The genes analyzed were X-ray cross-complementing group 1 (XRCC1), ERCC1, MTHFR, EGFR, DPYD, and TYMS. The patients were treated with 225 mg/m{sup 2}/d continuous infusion of 5-fluorouracil concomitantly with radiotherapy (50.4 Gy) followed by total mesorectal excision. The outcomes were measured by tumor regression grade (TRG)more » as a major response (TRG 1 and TRG 2) or as a poor response (TRG3, TRG4, and TRG5). Results: The major histopathologic response rate was 47.3%. XRCC1 G/G carriers had a greater probability of response than G/A carriers (odds ratio, 4.18; 95% confidence interval, 1.62-10.74, p = .003) Patients with polymorphisms associated with high expression of thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) showed a greater pathologic response rate compared with carriers of low expression (odds ratio, 2.65; 95% confidence interval, 1.10-6.39, p = .02) No significant differences were seen in the response according to EGFR, ERCC1, MTHFR{sub C}677 and MTHFR{sub A}1298 expression. Conclusions: XRCC1 G/G and thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) are independent factors of a major response. Germline thymidylate synthase and XRCC1 polymorphisms might be useful as predictive markers of rectal tumor response to neoadjuvant chemoradiotherapy with 5-fluorouracil.« less

The role of nerve monitoring to predict postoperative recurrent laryngeal nerve function in thyroid and parathyroid surgery.

PubMed

Eid, Issam; Miller, Frank R; Rowan, Stephanie; Otto, Randal A

2013-10-01

To determine the role and efficacy of intraoperative recurrent laryngeal nerve (RLN) stimulation in the prediction of early and permanent postoperative nerve function in thyroid and parathyroid surgery. A retrospective review of thyroid and parathyroid surgeries was performed with calculation of sensitivity and specificity of the response of intraoperative stimulation for different pathological groups. Normal electromyography (EMG) response with 0.5 mAmp stimulation was considered a positive stimulation response with postoperative function determined by laryngoscopy. No EMG response at >1-2 mAmps was considered a negative response. The rates of early and permanent paralysis, as well as sensitivity, specificity, and positive and negative predictive values for postoperative nerve function were calculated for separate pathological groups. The number of nerves at risk analyzed was 909. The overall early and permanent paralysis rates were 3.1% and 1.2%, respectively, with the highest rate being for Grave's disease cases. The overall sensitivity was 98.4%. The specificity was lower at 62.5% but acceptable in thyroid carcinoma and Grave's disease patients. The majority of nerves with a positive stimulation result and postoperative paralysis on laryngoscopy recovered function in 3 to 12 weeks, showing positive stimulation to be a good predictor of eventual recovery. Stimulation of the RLN during thyroid and parathyroid surgery is a useful tool in predicting postoperative RLN function. The sensitivity of stimulation is high, showing positive stimulation to be an excellent predictor of normal nerve function. Negative stimulation is more predictive of paralysis in cases of thyroid carcinoma and Grave's disease. 2b. Copyright © 2013 The American Laryngological, Rhinological and Otological Society, Inc.

Amplified Striatal Responses to Near-Miss Outcomes in Pathological Gamblers

PubMed Central

Sescousse, Guillaume; Janssen, Lieneke K; Hashemi, Mahur M; Timmer, Monique H M; Geurts, Dirk E M; ter Huurne, Niels P; Clark, Luke; Cools, Roshan

2016-01-01

Near-misses in gambling games are losing events that come close to a win. Near-misses were previously shown to recruit reward-related brain regions including the ventral striatum, and to invigorate gambling behavior, supposedly by fostering an illusion of control. Given that pathological gamblers are particularly vulnerable to such cognitive illusions, their persistent gambling behavior might result from an amplified striatal sensitivity to near-misses. In addition, animal studies have shown that behavioral responses to near-miss-like events are sensitive to dopamine, but this dopaminergic influence has not been tested in humans. To investigate these hypotheses, we recruited 22 pathological gamblers and 22 healthy controls who played a slot machine task delivering wins, near-misses and full-misses, inside an fMRI scanner. Each participant played the task twice, once under placebo and once under a dopamine D2 receptor antagonist (sulpiride 400 mg), in a double-blind, counter-balanced design. Participants were asked about their motivation to continue gambling throughout the task. Across all participants, near-misses elicited higher motivation to continue gambling and increased striatal responses compared with full-misses. Crucially, pathological gamblers showed amplified striatal responses to near-misses compared with controls. These group differences were not observed following win outcomes. In contrast to our hypothesis, sulpiride did not induce any reliable modulation of brain responses to near-misses. Together, our results demonstrate that pathological gamblers have amplified brain responses to near-misses, which likely contribute to their persistent gambling behavior. However, there is no evidence that these responses are influenced by dopamine. These results have implications for treatment and gambling regulation. PMID:27006113

Value of Specialist Pathology Review in a Single Statewide Gynecologic Cancer Service.

PubMed

Melon, Jerome; Leung, Yee; Salfinger, Stuart G; Tan, Jason; Mohan, Ganendra; Cohen, Paul A

2017-01-01

A case review by specialist diagnostic pathologists as part of a Gynecologic Oncology Multi-disciplinary Tumor group has the potential to influence the management of patients with cancer. The primary aim of this study was to determine the frequency of diagnostic discrepancies between the initial (nonspecialist) and final pathological diagnoses in cases referred to the Gynecologic Oncology Tumor Conference (TC) in Western Australia and the impact of such revised diagnosis on clinical management. A secondary aim was to assess the evolving workload encountered by the TC during a 5-year interval. The records of the weekly TC for the 2 calendar years 2008 and 2013 were examined, and histological and cytological specimens that had been initially assessed by "outside" (nonspecialist) pathology departments, and subsequently reviewed by specialist pathologists, were assessed. The initial and final diagnoses were compared, and where the pathological findings were amended upon review, it was determined whether the change affected clinical management. Diagnostic discrepancies that resulted in a change in patient management were classified as major, whereas discrepancies that did not affect patient management were classified as minor. A total of 481 outside cases were included among 2387 cases presented for histological review at the TC during the 2 years. For outside cases alone, the incidence of major diagnostic discrepancies was 3.4% in 2008, 5.5% in 2013 (no significant difference, P = 0.3787), and 4.6% for the 2 years combined. A recommendation for surgery was the most common change in clinical management as a result of major discrepancy. The minor discrepancy rate was 4.4% of outside cases for both years combined. Pathological discrepancies (major and minor) of the uterine corpus and cervix were most frequent, followed by those of the vulva and ovary. There was a 48.4% increase in total case discussions at the TC during the interval period with a significant rise in nonmalignant cases, 29.8% of the total cases in 2008 compared with 36.8% in 2013 (P = 0.0004). Nonspecialist pathology departments maintained a high level of reporting accuracy during the interval period, with the major discrepancy rate not changing significantly between 2008 and 2013. Specimens from the uterine corpus and cervix in particular may prove diagnostically challenging on occasion. A pathology review of outside cases by a tertiary-based laboratory in conjunction with a TC can identify a small but clinically significant number of cases that lead to a change in clinical management. It is uncertain whether this affects patient outcomes.

Mitochondrial adaptations to physiological vs. pathological cardiac hypertrophy

PubMed Central

Abel, E. Dale; Doenst, Torsten

2011-01-01

Cardiac hypertrophy is a stereotypic response of the heart to increased workload. The nature of the workload increase may vary depending on the stimulus (repetitive, chronic, pressure, or volume overload). If the heart fully adapts to the new loading condition, the hypertrophic response is considered physiological. If the hypertrophic response is associated with the ultimate development of contractile dysfunction and heart failure, the response is considered pathological. Although divergent signalling mechanisms may lead to these distinct patterns of hypertrophy, there is some overlap. Given the close relationship between workload and energy demand, any form of cardiac hypertrophy will impact the energy generation by mitochondria, which are the key organelles for cellular ATP production. Significant changes in the expression of nuclear and mitochondrially encoded transcripts that impact mitochondrial function as well as altered mitochondrial proteome composition and mitochondrial energetics have been described in various forms of cardiac hypertrophy. Here, we review mitochondrial alterations in pathological and physiological hypertrophy. We suggest that mitochondrial adaptations to pathological and physiological hypertrophy are distinct, and we shall review potential mechanisms that might account for these differences. PMID:21257612

Assessment of the In Vivo Toxicity of Gold Nanoparticles

NASA Astrophysics Data System (ADS)

Chen, Yu-Shiun; Hung, Yao-Ching; Liau, Ian; Huang, G. Steve

2009-08-01

The environmental impact of nanoparticles is evident; however, their toxicity due to their nanosize is rarely discussed. Gold nanoparticles (GNPs) may serve as a promising model to address the size-dependent biological response to nanoparticles because they show good biocompatibility and their size can be controlled with great precision during their chemical synthesis. Naked GNPs ranging from 3 to 100 nm were injected intraperitoneally into BALB/C mice at a dose of 8 mg/kg/week. GNPs of 3, 5, 50, and 100 nm did not show harmful effects; however, GNPs ranging from 8 to 37 nm induced severe sickness in mice. Mice injected with GNPs in this range showed fatigue, loss of appetite, change of fur color, and weight loss. Starting from day 14, mice in this group exhibited a camel-like back and crooked spine. The majority of mice in these groups died within 21 days. Injection of 5 and 3 nm GNPs, however, did not induce sickness or lethality in mice. Pathological examination of the major organs of the mice in the diseased groups indicated an increase of Kupffer cells in the liver, loss of structural integrity in the lungs, and diffusion of white pulp in the spleen. The pathological abnormality was associated with the presence of gold particles at the diseased sites, which were verified by ex vivo Coherent anti-Stoke Raman scattering microscopy. Modifying the surface of the GNPs by incorporating immunogenic peptides ameliorated their toxicity. This reduction in the toxicity is associated with an increase in the ability to induce antibody response. The toxicity of GNPs may be a fundamental determinant of the environmental toxicity of nanoparticles.

Mechanisms Underlying Motivational Deficits in Psychopathology: Similarities and Differences in Depression and Schizophrenia.

PubMed

Barch, Deanna M; Pagliaccio, David; Luking, Katherine

2016-01-01

Motivational and hedonic impairments are core aspects of a variety of types of psychopathology. These impairments cut across diagnostic categories and may be critical to understanding major aspects of the functional impairments accompanying psychopathology. Given the centrality of motivational and hedonic systems to psychopathology, the Research Domain Criteria (RDoC) initiative includes a "positive valence" systems domain that outlines a number of constructs that may be key to understanding the nature and mechanisms of motivational and hedonic impairments in psychopathology. These component constructs include initial responsiveness to reward, reward anticipation or expectancy, incentive or reinforcement learning, effort valuation, and action selection. Here, we review behavioral and neuroimaging studies providing evidence for impairments in these constructs in individuals with psychosis versus in individuals with depressive pathology. There are important differences in the nature of reward-related and hedonic deficits associated with psychosis versus depression that have major implications for our understanding of etiology and treatment development. In particular, the literature strongly suggests the presence of impairments in in-the-moment hedonics or "liking" in individuals with depressive pathology, particularly among those who experience anhedonia. Such deficits may propagate forward and contribute to impairments in other constructs that are dependent on hedonic responses, such as anticipation, learning, effort, and action selection. Such hedonic impairments could reflect alterations in dopamine and/or opioid signaling in the striatum related to depression or specifically to anhedonia in depressed populations. In contrast, the literature points to relatively intact in-the-moment hedonic processing in psychosis, but provides much evidence for impairments in other components involved in translating reward to action selection. Particularly, individuals with schizophrenia exhibit altered reward prediction and associated striatal and prefrontal activation, impaired reward learning, and impaired reward-modulated action selection.

Masculine Process/Masculine Pathology: A New Psychodynamic Approach.

ERIC Educational Resources Information Center

Goldberg, Herb

1993-01-01

Notes that traditional masculine conditioning and its underlying unconscious defenses are a major unrecognized cause of psychopathology for men today. Discusses psychodynamics of gender and manifestations of the masculine experience, and illustrates symptoms of male pathology. Hopes that this awareness provides important insights for effective…

[Pulmonary pathology in fatal human influenza A (H1N1) infection].

PubMed

Duan, Xue-jing; Li, Yong; Gong, En-cong; Wang, Jue; Lü, Fu-dong; Zhang, He-qiu; Sun, Lin; Yue, Zhu-jun; Song, Chen-chao; Zhang, Shi-Jie; Li, Ning; Dai, Jie

2011-12-01

To study the pulmonary pathology in patients died of fatal human influenza A(H1N1) infection. Eight cases of fatal human influenza A (H1N1) infection, including 2 autopsy cases and 6 paramortem needle puncture biopsies, were enrolled into the study. Histologic examination, immunohistochemitry, flow cytometry and Western blotting were carried out. The major pathologic changes included necrotizing bronchiolitis with surrounding inflammation, diffuse alveolar damage and pulmonary hemorrhage. Influenza viral antigen expression was detected in the lung tissue by Western blotting. Immunohistochemical study demonstrated the presence of nuclear protein and hemagglutinin virus antigens in parts of trachea, bronchial epithelium and glands, alveolar epithelium, macrophages and endothelium. Flow cytometry showed that the apoptotic rate of type II pneumocytes (32.15%, 78.15%) was significantly higher than that of the controls (1.93%, 3.77%). Necrotizing bronchiolitis, diffuse alveolar damage and pulmonary hemorrhage followed by pulmonary fibrosis in late stage are the major pathologic changes in fatal human influenza A (H1N1) infection.

Next-Generation Pathology.

PubMed

Caie, Peter D; Harrison, David J

2016-01-01

The field of pathology is rapidly transforming from a semiquantitative and empirical science toward a big data discipline. Large data sets from across multiple omics fields may now be extracted from a patient's tissue sample. Tissue is, however, complex, heterogeneous, and prone to artifact. A reductionist view of tissue and disease progression, which does not take this complexity into account, may lead to single biomarkers failing in clinical trials. The integration of standardized multi-omics big data and the retention of valuable information on spatial heterogeneity are imperative to model complex disease mechanisms. Mathematical modeling through systems pathology approaches is the ideal medium to distill the significant information from these large, multi-parametric, and hierarchical data sets. Systems pathology may also predict the dynamical response of disease progression or response to therapy regimens from a static tissue sample. Next-generation pathology will incorporate big data with systems medicine in order to personalize clinical practice for both prognostic and predictive patient care.

Whole slide images and digital media in pathology education, testing, and practice: the Oklahoma experience.

PubMed

Fung, Kar-Ming; Hassell, Lewis A; Talbert, Michael L; Wiechmann, Allan F; Chaser, Brad E; Ramey, Joel

2012-01-01

Examination of glass slides is of paramount importance in pathology training. Until the introduction of digitized whole slide images that could be accessed through computer networks, the sharing of pathology slides was a major logistic issue in pathology education and practice. With the help of whole slide images, our department has developed several online pathology education websites. Based on a modular architecture, this program provides online access to whole slide images, still images, case studies, quizzes and didactic text at different levels. Together with traditional lectures and hands-on experiences, it forms the back bone of our histology and pathology education system for residents and medical students. The use of digitized whole slide images has a.lso greatly improved the communication between clinicians and pathologist in our institute.

PC61 (Anti-CD25) Treatment Inhibits Influenza A Virus-Expanded Regulatory T Cells and Severe Lung Pathology during a Subsequent Heterologous Lymphocytic Choriomeningitis Virus Infection

PubMed Central

Kraft, Anke R. M.; Wlodarczyk, Myriam F.; Kenney, Laurie L.

2013-01-01

Prior immunity to influenza A virus (IAV) in mice changes the outcome to a subsequent lymphocytic choriomeningitis virus (LCMV) infection and can result in severe lung pathology, similar to that observed in patients that died of the 1918 H1N1 pandemic. This pathology is induced by IAV-specific memory CD8+ T cells cross-reactive with LCMV. Here, we discovered that IAV-immune mice have enhanced CD4+ Foxp3+ T-regulatory (Treg) cells in their lungs, leading us to question whether a modulation in the normal balance of Treg and effector T-cell responses also contributes to enhancing lung pathology upon LCMV infection of IAV-immune mice. Treg cell and interleukin-10 (IL-10) levels remained elevated in the lungs and mediastinal lymph nodes (mLNs) throughout the acute LCMV response of IAV-immune mice. PC61 treatment, used to decrease Treg cell levels, did not change LCMV titers but resulted in a surprising decrease in lung pathology upon LCMV infection in IAV-immune but not in naive mice. Associated with this decrease in pathology was a retention of Treg in the mLN and an unexpected partial clonal exhaustion of LCMV-specific CD8+ T-cell responses only in IAV-immune mice. PC61 treatment did not affect cross-reactive memory CD8+ T-cell proliferation. These results suggest that in the absence of IAV-expanded Treg cells and in the presence of cross-reactive memory, the LCMV-specific response was overstimulated and became partially exhausted, resulting in a decreased effector response. These studies suggest that Treg cells generated during past infections can influence the characteristics of effector T-cell responses and immunopathology during subsequent heterologous infections. Thus, in humans with complex infection histories, PC61 treatment may lead to unexpected results. PMID:24049180

Molecular, physiological and behavioral responses of honey bee (Apis mellifera) drones to infection with microsporidian parasites.

PubMed

Holt, Holly L; Villar, Gabriel; Cheng, Weiyi; Song, Jun; Grozinger, Christina M

2018-06-01

Susceptibility to pathogens and parasites often varies between sexes due to differences in life history traits and selective pressures. Nosema apis and Nosema ceranae are damaging intestinal pathogens of European honey bees (Apis mellifera). Nosema pathology has primarily been characterized in female workers where infection is energetically costly and accelerates worker behavioral maturation. Few studies, however, have examined infection costs in male honey bees (drones) to determine if Nosema similarly affects male energetic status and sexual maturation. We infected newly emerged adult drones with Nosema spores and conducted a series of molecular, physiological, and behavioral assays to characterize Nosema etiology in drones. We found that infected drones starved faster than controls and exhibited altered patterns of flight activity in the field, consistent with energetic distress or altered rates of sexual maturation. Moreover, expression of candidate genes with metabolic and/or hormonal functions, including members of the insulin signaling pathway, differed by infection status. Of note, while drone molecular responses generally tracked predictions based on worker studies, several aspects of infected drone flight behavior contrasted with previous observations of infected workers. While Nosema infection clearly imposed energetic costs in males, infection had no impact on drone sperm numbers and had only limited effects on antennal responsiveness to a major queen sex pheromone component (9-ODA). We compare Nosema pathology in drones with previous studies describing symptoms in workers and discuss ramifications for drone and colony fitness. Copyright © 2018. Published by Elsevier Inc.

IgE and mast cells in host defense against parasites and venoms

PubMed Central

Mukai, Kaori; Tsai, Mindy; Galli, Stephen J.

2016-01-01

IgE-dependent mast cell activation is a major effector mechanism underlying the pathology associated with allergic disorders. The most dramatic of these IgE-associated disorders is the fatal anaphylaxis which can occur in some people who have developed IgE antibodies to otherwise innocuous antigens, such as those contained in certain foods and medicines. Why would such a highly “maladaptive” immune response develop in evolution, and be retained to the present day? Host defense against parasites has long been considered the only beneficial function that might be conferred by IgE and mast cells. However, recent studies have provided evidence that, in addition to participating in host resistance to certain parasites, mast cells and IgE are critical components of innate (mast cells) and adaptive (mast cells and IgE) immune responses that can enhance host defense against the toxicity of certain arthropod and animal venoms, including enhancing the survival of mice injected with such venoms. Yet, in some people, developing IgE antibodies to insect or snake venoms puts them at risk for having a potentially fatal anaphylactic reaction upon subsequent exposure to such venoms. Delineating the mechanisms underlying beneficial versus detrimental innate and adaptive immune responses associated with mast cell activation and IgE is likely to enhance our ability to identify potential therapeutic targets in such settings, not only for reducing the pathology associated with allergic disorders but perhaps also for enhancing immune protection against pathogens and animal venoms. PMID:27225312

IgE and mast cells in host defense against parasites and venoms.

PubMed

Mukai, Kaori; Tsai, Mindy; Starkl, Philipp; Marichal, Thomas; Galli, Stephen J

2016-09-01

IgE-dependent mast cell activation is a major effector mechanism underlying the pathology associated with allergic disorders. The most dramatic of these IgE-associated disorders is the fatal anaphylaxis which can occur in some people who have developed IgE antibodies to otherwise innocuous antigens, such as those contained in certain foods and medicines. Why would such a highly "maladaptive" immune response develop in evolution and be retained to the present day? Host defense against parasites has long been considered the only beneficial function that might be conferred by IgE and mast cells. However, recent studies have provided evidence that, in addition to participating in host resistance to certain parasites, mast cells and IgE are critical components of innate (mast cells) and adaptive (mast cells and IgE) immune responses that can enhance host defense against the toxicity of certain arthropod and animal venoms, including enhancing the survival of mice injected with such venoms. Yet, in some people, developing IgE antibodies to insect or snake venoms puts them at risk for having a potentially fatal anaphylactic reaction upon subsequent exposure to such venoms. Delineating the mechanisms underlying beneficial versus detrimental innate and adaptive immune responses associated with mast cell activation and IgE is likely to enhance our ability to identify potential therapeutic targets in such settings, not only for reducing the pathology associated with allergic disorders but perhaps also for enhancing immune protection against pathogens and animal venoms.

Physician scientist research pathway leading to certification by the American Board of Pathology.

PubMed

Weiss, Sharon W; Johnson, Rebecca L

2016-06-01

In 2014, the American Board of Pathology, in response to the pathology community, approved a physician scientist research pathway (PSRP). This brief report summarizes the history of and objectives for creating the physician scientist research pathway and the requirements of the American Board of Pathology for the certification of physician scientist research pathway trainees. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

An altered peripheral IL6 response in major depressive disorder.

PubMed

Money, Kelli M; Olah, Zita; Korade, Zeljka; Garbett, Krassimira A; Shelton, Richard C; Mirnics, Karoly

2016-05-01

Major depressive disorder (MDD) is one of the most prevalent major psychiatric disorders with a lifetime prevalence of 17%. Recent evidence suggests MDD is not only a brain dysfunction, but a systemic disease affecting the whole body. Central and peripheral inflammatory changes seem to be a centerpiece of MDD pathology: a subset of patients show elevated blood cytokine and chemokine levels that partially normalize with symptom improvement over the course of anti-depressant treatment. As this inflammatory process in MDD is poorly understood, we hypothesized that the peripheral tissues of MDD patients will respond differently to inflammatory stimuli, resulting in an aberrant transcriptional response to elevated pro-inflammatory cytokines. To test this, we used MDD patient- and control-derived dermal fibroblast cultures to investigate their response to an acute treatment with IL6, IL1β, TNFα, or vehicle. Following RNA isolation and subsequent cDNA synthesis, quantitative PCR was used to determine the relative expression level of several families of inflammation-responsive genes. Our results showed comparable expression of the tested genes between MDD patients and controls at baseline. In contrast, MDD patient fibroblasts had a diminished transcriptional response to IL6 in all the gene sets tested (oxidative stress response, mitochondrial function, and lipid metabolism). We also found a significant increase in baseline and IL6 stimulated transcript levels of the IL6 receptor gene. This IL6 receptor transcript increase in MDD fibroblasts was accompanied by an IL6 stimulated increase in induction of SOCS3, which dampens IL6 receptor signaling. Altogether our results demonstrate that there is an altered transcriptional response to IL6 in MDD, which may represent one of the molecular mechanisms contributing to disease pathophysiology. Ultimately we hope that these studies will lead to validation of novel MDD drug targets focused on normalizing the altered IL6 response in patients. Copyright © 2016 Elsevier Inc. All rights reserved.

An altered peripheral IL6 response in major depressive disorder

PubMed Central

Money, Kelli M.; Olah, Zita; Korade, Zeljka; Garbett, Krassimira A.; Shelton, Richard C.; Mirnics, Karoly

2016-01-01

Major depressive disorder (MDD) is one of the most prevalent major psychiatric disorders with a lifetime prevalence of 17%. Recent evidence suggests MDD is not only a brain dysfunction, but a systemic disease affecting the whole body. Central and peripheral inflammatory changes seem to be a centerpiece of MDD pathology: a subset of patients show elevated blood cytokine and chemokine levels that partially normalize with symptom improvement over the course of antidepressant treatment. As this inflammatory process in MDD is poorly understood, we hypothesized that the peripheral tissues of MDD patients will respond differently to inflammatory stimuli, resulting in an aberrant transcriptional response to elevated proinflammatory cytokines. To test this, we used MDD patient- and control-derived dermal fibroblast cultures to investigate their response to an acute treatment with IL6, IL1β, TNFα, or vehicle. Following RNA isolation and subsequent cDNA synthesis, quantitative PCR was used to determine the relative expression level of several families of inflammation-responsive genes. Our results showed comparable expression of the tested genes between MDD patients and controls at baseline. In contrast, MDD patient fibroblasts had a diminished transcriptional response to IL6 in all the gene sets tested (oxidative stress response, mitochondrial function, and lipid metabolism). We also found a significant increase in baseline and IL6 stimulated transcript levels of the IL6 receptor gene. This IL6 receptor transcript increase in MDD fibroblasts was accompanied by an IL6 stimulated increase in induction of SOCS3, which dampens IL6 receptor signaling. Altogether our results demonstrate that there is an altered transcriptional response to IL6 in MDD, which may represent one of the molecular mechanisms contributing to disease pathophysiology. Ultimately we hope that these studies will lead to validation of novel MDD drug targets focused on normalizing the altered IL6 response in patients. PMID:26804030

A neurocognitive comparison of cognitive flexibility and response inhibition in gamblers with varying degrees of clinical severity.

PubMed

Odlaug, B L; Chamberlain, S R; Kim, S W; Schreiber, L R N; Grant, J E

2011-10-01

As a behavioral addiction with clinical and phenomenological similarities to substance addiction, recreational and pathological gambling represent models for studying the neurobiology of addiction, without the confounding deleterious brain effects which may occur from chronic substance abuse. A community sample of individuals aged 18-65 years who gamble was solicited through newspaper advertising. Subjects were grouped a priori into three groups (no-risk, at-risk, and pathological gamblers) based on a diagnostic interview. All subjects underwent a psychiatric clinical interview and neurocognitive tests assessing motor impulsivity and cognitive flexibility. Subjects with a current axis I disorder, history of brain injury/trauma, or implementation or dose changes of psychoactive medication within 6 weeks of study enrollment were excluded. A total of 135 no-risk, 69 at-risk and 46 pathological gambling subjects were assessed. Pathological gamblers were significantly older, and exhibited significant deficiencies in motor impulse control (stop-signal reaction times), response speed (median 'go' trial response latency) and cognitive flexibility [total intra-dimensional/extra-dimensional (IDED) errors] versus controls. The finding of impaired impulse control and cognitive flexibility was robust in an age-matched subgroup analysis of pathological gamblers. The no-risk and at-risk gambling groups did not significantly differ from each other on task performance. Impaired response inhibition and cognitive flexibility exist in people with pathological gambling compared with no-risk and at-risk gamblers. The early identification of such illness in adolescence or young adulthood may aid in the prevention of addiction onset of such disabling disorders.

The Warrens and other pioneering clinician pathologists of the Massachusetts General Hospital during its early years: an appreciation on the 200th anniversary of the hospital founding.

PubMed

Young, Robert H; Louis, David N

2011-10-01

To celebrate the bicentennial of the 1811 charter to establish the Massachusetts General Hospital, we tell the stories of the physicians and surgeons of the hospital who practiced pathology until the discipline was more firmly established with the recruitment of James Homer Wright who became the first full-time pathologist at the hospital in 1896. One of the two co-founders of the hospital, John Collins Warren (famed primarily for being the surgeon at the first public demonstration of ether anesthesia) had a major interest in pathology; he published a book focused on gross pathology (1837) and began the important specimen collection subsequently known as the Warren Anatomical Museum at Harvard Medical School (HMS). An early physician, John Barnard Swett Jackson, became the first professor of pathology in the United States (1847) and was a noted collector whose specimens were added to the Warren Museum. Dr Jackson showed no interest in microscopy when it became available, but microscopy was promoted from circa the late 1840s at Harvard and likely at the hospital by Oliver Wendell Holmes, the famed essayist who was on the staff of the hospital and faculty at the medical school. Microscopy was probably first used at the Hospital with any frequency on examination of fluids by the first officially designated 'Microscopist,' John Bacon Jr, in 1851, and after the mid-1850s by Calvin Ellis on anatomic specimens; Ellis went on to pioneering reform of the HMS curriculum. Reginald Heber Fitz succeeded Ellis in 1871 and was the first to be officially designated as 'Pathologist' at the hospital. Fitz is remembered for two major contributions: his paper showing the nature of, and potential surgical cure for, the disease that he termed 'appendicitis'; and his description of acute pancreatitis. With the microscope now firmly entrenched and with the increase in surgery after Fitz's work on appendicitis, surgical pathology grew quickly. J Collins Warren, the grandson of the co-founder, had a major interest in pathology and in 1895 published an impressive volume entitled 'Surgical Pathology and Therapeutics.' Dr Warren had a major interest in breast disease and was a pioneer of needle biopsy in the evaluation of breast masses. In 1888, William Fiske Whitney joined the staff of the hospital and spent his nearly 30-year career practicing primarily as a surgical pathologist, making particular innovations in intraoperative consultation. The contributions of these individuals brought the field from a gross pathology-oriented discipline mostly oriented around teaching to a microscopy-dependent practice integral to patient care, and hence set the stage for the formal founding of the Pathology department in 1896.

Disrupted sensory gating in pathological gambling.

PubMed

Stojanov, Wendy; Karayanidis, Frini; Johnston, Patrick; Bailey, Andrew; Carr, Vaughan; Schall, Ulrich

2003-08-15

Some neurochemical evidence as well as recent studies on molecular genetics suggest that pathologic gambling may be related to dysregulated dopamine neurotransmission. The current study examined sensory (motor) gating in pathologic gamblers as a putative measure of endogenous brain dopamine activity with prepulse inhibition of the acoustic startle eye-blink response and the auditory P300 event-related potential. Seventeen pathologic gamblers and 21 age- and gender-matched healthy control subjects were assessed. Both prepulse inhibition measures were recorded under passive listening and two-tone prepulse discrimination conditions. Compared to the control group, pathologic gamblers exhibited disrupted sensory (motor) gating on all measures of prepulse inhibition. Sensory motor gating deficits of eye-blink responses were most profound at 120-millisecond prepulse lead intervals in the passive listening task and at 240-millisecond prepulse lead intervals in the two-tone prepulse discrimination task. Sensory gating of P300 was also impaired in pathologic gamblers, particularly at 500-millisecond lead intervals, when performing the discrimination task on the prepulse. In the context of preclinical studies on the disruptive effects of dopamine agonists on prepulse inhibition, our findings suggest increased endogenous brain dopamine activity in pathologic gambling in line with previous neurobiological findings.

IL-10 restrains IL-17 to limit lung pathology characteristics following pulmonary infection with Francisella tularensis live vaccine strain.

PubMed

Slight, Samantha R; Monin, Leticia; Gopal, Radha; Avery, Lyndsay; Davis, Marci; Cleveland, Hillary; Oury, Tim D; Rangel-Moreno, Javier; Khader, Shabaana A

2013-11-01

IL-10 production during intracellular bacterial infections is generally thought to be detrimental because of its role in suppressing protective T-helper cell 1 (Th1) responses. Francisella tularensis is a facultative intracellular bacterium that activates both Th1 and Th17 protective immune responses. Herein, we report that IL-10-deficient mice (Il10(-/-)), despite having increased Th1 and Th17 responses, exhibit increased mortality after pulmonary infection with F. tularensis live vaccine strain. We demonstrate that the increased mortality observed in Il10(-/-)-infected mice is due to exacerbated IL-17 production that causes increased neutrophil recruitment and associated lung pathology. Thus, although IL-17 is required for protective immunity against pulmonary infection with F. tularensis live vaccine strain, its production is tightly regulated by IL-10 to generate efficient induction of protective immunity without mediating pathology. These data suggest a critical role for IL-10 in maintaining the delicate balance between host immunity and pathology during pulmonary infection with F. tularensis live vaccine strain. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Selective Memory to Apoptotic Cell-Derived Self-Antigens with Implications for Systemic Lupus Erythematosus Development.

PubMed

Duhlin, Amanda; Chen, Yunying; Wermeling, Fredrik; Sedimbi, Saikiran K; Lindh, Emma; Shinde, Rahul; Halaby, Marie Jo; Kaiser, Ylva; Winqvist, Ola; McGaha, Tracy L; Karlsson, Mikael C I

2016-10-01

Autoimmune diseases are characterized by pathogenic immune responses to self-antigens. In systemic lupus erythematosus (SLE), many self-antigens are found in apoptotic cells (ACs), and defects in removal of ACs from the body are linked to a risk for developing SLE. This includes pathological memory that gives rise to disease flares. In this study, we investigated how memory to AC-derived self-antigens develops and the contribution of self-memory to the development of lupus-related pathology. Multiple injections of ACs without adjuvant into wild-type mice induce a transient primary autoimmune response without apparent anti-nuclear Ab reactivity or kidney pathology. Interestingly, as the transient Ab response reached baseline, a single boost injection fully recalled the immune response to ACs, and this memory response was furthermore transferable into naive mice. Additionally, the memory response contains elements of pathogenicity, accompanied by selective memory to selective Ags. Thus, we provide evidence for a selective self-memory that underlies progression of the response to self-antigens with implications for SLE development therapy. Copyright © 2016 by The American Association of Immunologists, Inc.

The Rehabilitation Counselor's Guide to Psychopathology. Final Report.

ERIC Educational Resources Information Center

Atkinson, John; Phelps, William R.

This paper is prepared for the rehabilitation practitioner and hopefully will meet some of the needs of the academician as well. The data covers the following major areas: How personality develops, How emotional pathology develops, Defense mechanisms, Classification of psychological makeup, Treatment of emotional pathology, Commonly used glossary,…

Phase 2 trial of neoadjuvant chemotherapy and transoral endoscopic surgery with risk-adapted adjuvant therapy for squamous cell carcinoma of the head and neck.

PubMed

Weiss, Jared M; Grilley-Olson, Juneko E; Deal, Allison Mary; Zevallos, Jose P; Chera, Bhishamjit S; Paul, Jennifer; Knowles, Mary Fleming; Usenko, Dmitriy; Weissler, Mark C; Patel, Samip; Hayes, David N; Hackman, Trevor

2018-05-09

The objective of this study was to demonstrate the feasibility and efficacy of induction chemotherapy, surgery, and pathology-guided adjuvant therapy to treat transorally resectable squamous head and neck cancer. Patients had squamous head and neck cancer that was resectable by the transoral route and advanced-stage disease (American Joint Committee on Cancer stage III-IV, T3-T4 tumors, and/or positive lymph nodes). They received treatment with weekly carboplatin at an area under the curve of 2, plus paclitaxel 135 mg/m 2 , and daily lapatinib 1000mg for 6 weeks followed by surgical resection. Pathology that revealed margins <5 mm, extracapsular extension, N2a of N2b lymph node status, perineural invasion, or lymphovascular space invasion resulted in adjuvant radiotherapy concurrent with weekly cisplatin. Pathology with N2c/N3 lymph node status or positive margins resulted in radiation with bolus cisplatin. The primary endpoint was the clinical response rate to induction chemotherapy, and a key secondary endpoint was feasibility. Toxicity was modest, and 37 of 40 patients completed study procedures as planned. The clinical response rate was 93%, the pathologic complete response rate was 36%, and the clinical response did not predict for a pathologic complete response. No patient on study follow-up has recurred or died. Twenty-nine of 39 patients who underwent surgery avoided radiation. Speech and swallowing function were well preserved. The study met both its primary efficacy endpoint and the secondary feasibility endpoint. Neoadjuvant, systemic therapy and surgical resection followed by risk-adapted adjuvant therapy resulted in high response rates and excellent long-term outcomes and should be further studied. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

How Useful Are Indices of Personality Pathology when Assessing Domestic Violence Perpetrators?

ERIC Educational Resources Information Center

Gibbons, Peter; Collins, Marjorie; Reid, Corinne

2011-01-01

There has been considerable debate about profiling personality pathology when assessing and treating male perpetrators of domestic violence (DV). This study used the Millon Clinical Multiaxial Inventory (MCMI-III) to explore the severity and diversity of male perpetrator personality pathology and response bias in a group of DV perpetrators being…

Mitochondrial multifaceted dysfunction in schizophrenia; complex I as a possible pathological target.

PubMed

Ben-Shachar, Dorit

2017-09-01

Mitochondria are key players in various essential cellular processes beyond being the main energy supplier of the cell. Accordingly, they are involved in neuronal synaptic transmission, neuronal growth and sprouting and consequently neuronal plasticity and connectivity. In addition, mitochondria participate in the modulation of gene transcription and inflammation as well in physiological responses in health and disease. Schizophrenia is currently regarded as a neurodevelopmental disorder associated with impaired immune system, aberrant neuronal differentiation and abnormalities in various neurotransmitter systems mainly the dopaminergic, glutaminergic and GABAergic. Ample evidence has been accumulated over the last decade indicating a multifaceted dysfunction of mitochondria in schizophrenia. Indeed, mitochondrial deficit can be of relevance for the majority of the pathologies observed in this disease. In the present article, we overview specific deficits of the mitochondria in schizophrenia, with a focus on the first complex (complex I) of the mitochondrial electron transport chain (ETC). We argue that complex I, being a major factor in the regulation of mitochondrial ETC, is a possible key modulator of various functions of the mitochondria. We review biochemical, molecular, cellular and functional evidence for mitochondrial impairments and their possible convergence to impact in-vitro neuronal differentiation efficiency in schizophrenia. Mitochondrial function in schizophrenia may advance our knowledge of the disease pathophysiology and open the road for new treatment targets for the benefit of the patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Hyaluronic Acid in Vascular and Immune Homeostasis during Normal Pregnancy and Preeclampsia

PubMed Central

Ziganshina, M. M.; Pavlovich, S. V.; Bovin, N. V.; Sukhikh, G. T.

2016-01-01

Preeclampsia (PE) is a multisystem pathologic state that clinically manifests itself after the 20th week of pregnancy. It is characterized by high maternal and perinatal morbidity and mortality. According to modern concepts, the impairment of trophoblast invasion into maternal spiral arteries, leading to the development of ischemia in placenta, is considered to be the major pathogenetic factor of PE development. Ischemic lesions initiate the development of a systemic inflammatory response (SIR) and endothelial dysfunction, which is the main cause of the multiple organ failure in PE. Some data has appear indicating the importance of a glycans-forming endothelial glycocalyx and extracellular matrix (ECM) for placenta morphogenesis, as well as their role in the regulation of vascular permeability and vascular tone in hypertension disorders and, in particular, PE. Since intact glycocalyx and ECM are considered to be the major factors that maintain the physiological vascular tone and adequate intercellular interactions, their value in PE pathogenesis is underestimated. This review is focused on hyaluronic acid (HA) as the key glycan providing the organization and stabilization of the ECM and glycocalyx, its distribution in tissues in the case of presence or absence of placental pathology, as well as on the regulatory function of hyaluronic acids of various molecular weights in different physiological and pathophysiological processes. The summarized data will provide a better understanding of the PE pathogenesis, with the main focus on glycopathology. PMID:27795844

Apolipoprotein B, the villain in the drama?

PubMed

Yu, Qi; Zhang, Yaping; Xu, Cang-Bao

2015-02-05

Low-density lipoprotein (LDL) is the major atherogenic lipoprotein and the primary target of lipid-lowering therapy for treating ischemic cardiovascular disease. Apolipoprotein B (apoB), an important structural component of LDL, plays a key role in cholesterol transport and removal in vascular wall. On the other hand, under pathological process, apoB interacts with the arterial wall to initiate the cascade of events that leads to atherosclerosis. However, interactions between apoB and vascular wall remain to be determined. Here, we address a pathological role of apoB per se and whole LDL particle in dysfunction of vascular endothelium and smooth muscle cells i.e. decreased endothelium-dependent vasodilation and increased receptor-mediated vasoconstriction. We intend to discuss: i) how apoB is responsible for the deleterious effects of LDL in the development of ischemic cardiovascular disease; ii) why vaccine based on peptides derived from apoB-100 is a promising therapy for treating ischemic cardiovascular disease, and iii) direct inhibition of apoB production should be a better therapeutic option than simple LDL-cholesterol lowering therapy in the patients with severe hypercholesterolemia at high cardiovascular risk with statin intolerance. In conclusion, apoB, but not cholesterol, plays a major role in LDL-induced dysfunction of endothelium, suggesting that direct apoB-targeting agents might be a promising therapy for the treatment of ischemic cardiovascular disease. Copyright © 2014 Elsevier B.V. All rights reserved.

Role of Stereotactic Body Radiation Therapy Before Orthotopic Liver Transplantation: Retrospective Evaluation of Pathologic Response and Outcomes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mannina, Edward Michael, E-mail: emmannina@gmail.com; Cardenes, Higinia Rosa; Lasley, Foster D.

Purpose: To analyze the results of stereotactic body radiation therapy (SBRT) in patients with early-stage, localized hepatocellular carcinoma who underwent definitive orthotopic liver transplantation (OLT). Methods and Materials: The subjects of this retrospective report are 38 patients diagnosed with hepatocellular carcinoma who underwent SBRT per institutional phase 1 to 2 eligibility criteria, before definitive OLT. Pre-OLT radiographs were compared with pathologic gold standard. Analysis of treatment failures and deaths was undertaken. Results: With median follow-up of 4.8 years from OLT, 9 of 38 patients (24%) recurred, whereas 10 of 38 patients (26%) died. Kaplan-Meier estimates of 3-year overall survival and disease-free survivalmore » are 77% and 74%, respectively. Sum longest dimension of tumors was significantly associated with disease-free survival (hazard ratio 1.93, P=.026). Pathologic response rate (complete plus partial response) was 68%. Radiographic scoring criteria performed poorly; modified Response Evaluation Criteria in Solid Tumors produced highest concordance (κ = 0.224). Explants revealed viable tumor in 74% of evaluable patients. Treatment failures had statistically larger sum longest dimension of tumors (4.0 cm vs 2.8 cm, P=.014) and non–statistically significant higher rates of lymphovascular space invasion (44% vs 17%), cT2 disease (44% vs 21%), ≥pT2 disease (67% vs 34%), multifocal tumors at time of SBRT (44% vs 21%), and less robust mean α-fetoprotein response (−25 IU/mL vs −162 IU/mL). Conclusions: Stereotactic body radiation therapy before to OLT is a well-tolerated treatment providing 68% pathologic response, though 74% of explants ultimately contained viable tumor. Radiographic response criteria poorly approximate pathology. Our data suggest further stratification of patients according to initial disease burden and treatment response.« less

Hypothalamic inflammation and the central nervous system control of energy homeostasis.

PubMed

Pimentel, Gustavo D; Ganeshan, Kirthana; Carvalheira, José B C

2014-11-01

The control of energy homeostasis relies on robust neuronal circuits that regulate food intake and energy expenditure. Although the physiology of these circuits is well understood, the molecular and cellular response of this program to chronic diseases is still largely unclear. Hypothalamic inflammation has emerged as a major driver of energy homeostasis dysfunction in both obesity and anorexia. Importantly, this inflammation disrupts the action of metabolic signals promoting anabolism or supporting catabolism. In this review, we address the evidence that favors hypothalamic inflammation as a factor that resets energy homeostasis in pathological states. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Viral infection, proliferation, and hyperplasia of Hofbauer cells and absence of inflammation characterize the placental pathology of fetuses with congenital Zika virus infection.

PubMed

Schwartz, David A

2017-06-01

Attention is increasingly focused on the potential mechanism(s) for Zika virus infection to be transmitted from an infected mother to her fetus. This communication addresses current evidence for the role of the placenta in vertical transmission of the Zika virus. Placentas from second and third trimester fetuses with confirmed intrauterine Zika virus infection were examined with routine staining to determine the spectrum of pathologic changes. In addition, immunohistochemical staining for macrophages and nuclear proliferation antigens was performed. Viral localization was identified using RNA hybridization. These observations were combined with the recent published results of placental pathology to increase the strength of the pathology data. Results were correlated with published data from experimental studies of Zika virus infection in placental cells and chorionic villous explants. Placentas from fetuses with congenital Zika virus infection are concordant in not having viral-induced placental inflammation. Special stains reveal proliferation and prominent hyperplasia of placental stromal macrophages, termed Hofbauer cells, in the chorionic villi of infected placentas. Zika virus infection is present in Hofbauer cells from second and third trimester placentas. Experimental studies and placentae from infected fetuses reveal that the spectrum of placental cell types infected with the Zika virus is broader during the first trimester than later in gestation. Inflammatory abnormalities of the placenta are not a component of vertical transmission of the Zika virus. The major placental response in second and third trimester transplacental Zika virus infection is proliferation and hyperplasia of Hofbauer cells, which also demonstrate viral infection.

The microenvironment of proliferative diabetic retinopathy supports lymphatic neovascularization.

PubMed

Gucciardo, Erika; Loukovaara, Sirpa; Korhonen, Ani; Repo, Pauliina; Martins, Beatriz; Vihinen, Helena; Jokitalo, Eija; Lehti, Kaisa

2018-06-01

Proliferative diabetic retinopathy (PDR) is a major diabetic microvascular complication characterized by pathological angiogenesis. Several retinopathy animal models have been developed to study the disease mechanisms and putative targets. However, knowledge on the human proliferative disease remains incomplete, relying on steady-state results from thin histological neovascular tissue sections and vitreous samples. New translational models are thus required to comprehensively understand the disease pathophysiology and develop improved therapeutic interventions. We describe here a clinically relevant model, whereby the native multicellular PDR landscape and neo(fibro)vascular processes can be analysed ex vivo and related to clinical data. As characterized by three-dimensional whole-mount immunofluorescence and electron microscopy, heterogeneity in patient-derived PDR neovascular tissues included discontinuous capillaries coupled with aberrantly differentiated, lymphatic-like and tortuous endothelia. Spatially confined apoptosis and proliferation coexisted with inflammatory cell infiltration and unique vascular islet formation. Ex vivo-cultured explants retained multicellularity, islet patterning and capillary or fibrotic outgrowth in response to vitreoretinal factors. Strikingly, PDR neovascular tissues, whose matched vitreous samples enhanced lymphatic endothelial cell sprouting, contained lymphatic-like capillaries in vivo and developed Prox1 + capillaries and sprouts with lymphatic endothelial ultrastructures ex vivo. Among multiple vitreal components, vascular endothelial growth factor C was one factor found at lymphatic endothelium-activating concentrations. These results indicate that the ischaemia-induced and inflammation-induced human PDR microenvironment supports pathological neolymphovascularization, providing a new concept regarding PDR mechanisms and targeting options. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Quality of warfarin control in atrial fibrillation patients in South East Queensland, Australia.

PubMed

Bernaitis, N; Badrick, T; Davey, A K; Anoopkumar-Dukie, S

2016-08-01

Warfarin is widely prescribed to decrease the risk of stroke in atrial fibrillation (AF) patients. Due to patient variability in response, regular monitoring is required, and time in therapeutic range (TTR) used to indicate quality of warfarin control with a TTR>60% is recommended. Recently, an Australian Government review of anticoagulants identified the need to establish current warfarin control and determine the potential place of the newer oral anticoagulants. To determine warfarin control by a pathology practice in Queensland, Australia and identify factors influencing TTR. Retrospective data were collected from Sullivan Nicolaides Pathology, a major pathology practice offering a warfarin care programme in Australia. Patients enrolled in their programme as of September 2014 were included in the study. TTR was calculated using INR test results, and test dates using the Rosendaal method with mean patient TTR were used for analysis and comparison. Exclusions were target therapeutic range outside 2.0-3.0, less than two INR tests and programme treatment time of less than 30 days. The eligible 3692 AF patients had 73.6% of INR tests within the therapeutic range. The mean TTR was 81%, with 97% of patients above a TTR of 60%. TTR was not significantly influenced by age, gender or socioeconomic factors. The observed mean TTR of over 80% is superior to the minimum recommended threshold of 60%. The TTR achieved by the Queensland pathology practice demonstrates that dedicated warfarin programmes can produce high-quality warfarin care, ensuring the full benefit of warfarin for Australian patients. © 2016 Royal Australasian College of Physicians.

Whole Slide Images and Digital Media in Pathology Education, Testing, and Practice: The Oklahoma Experience

PubMed Central

Fung, Kar-Ming; Hassell, Lewis A.; Talbert, Michael L.; Wiechmann, Allan F.; Chaser, Brad E.; Ramey, Joel

2012-01-01

Examination of glass slides is of paramount importance in pathology training. Until the introduction of digitized whole slide images that could be accessed through computer networks, the sharing of pathology slides was a major logistic issue in pathology education and practice. With the help of whole slide images, our department has developed several online pathology education websites. Based on a modular architecture, this program provides online access to whole slide images, still images, case studies, quizzes and didactic text at different levels. Together with traditional lectures and hands-on experiences, it forms the back bone of our histology and pathology education system for residents and medical students. The use of digitized whole slide images has a.lso greatly improved the communication between clinicians and pathologist in our institute. PMID:21965282

A Systematic Review and Meta-Analysis of Proteomics Literature on the Response of Human Skeletal Muscle to Obesity/Type 2 Diabetes Mellitus (T2DM) Versus Exercise Training.

PubMed

Srisawat, Kanchana; Shepherd, Sam O; Lisboa, Paulo J; Burniston, Jatin G

2017-11-11

We performed a systematic review and meta-analysis of proteomics literature that reports human skeletal muscle responses in the context of either pathological decline associated with obesity/T2DM and physiological adaptations to exercise training. Literature was collected from PubMed and DOAJ databases following PRISMA guidelines using the search terms 'proteom*', and 'skeletal muscle' combined with either 'obesity, insulin resistance, diabetes, impaired glucose tolerance' or 'exercise, training'. Eleven studies were included in the systematic review, and meta-analysis was performed on a sub-set (four studies) of the reviewed literature that reported the necessary primary data. The majority of proteins ( n = 73) more abundant in the muscle of obese/T2DM individuals were unique to this group and not reported to be responsive to exercise training. The main response of skeletal muscle to exercise training was a greater abundance of proteins of the mitochondrial electron transport chain, tricarboxylic acid cycle and mitochondrial respiratory chain complex I assembly. In total, five proteins were less abundant in muscle of obese/T2DM individuals and were also reported to be more abundant in the muscle of endurance-trained individuals, suggesting one of the major mechanisms of exercise-induced protection against the deleterious effects of obesity/T2DM occurs at complex I of the electron transport chain.

Expectations and essentials for the community practice of pathology.

PubMed

Horowitz, Richard E

2006-08-01

In 3 surveys during the past 10 years, community hospital pathologists were asked what they want, need, or look for when employing a pathologist and, more specifically, what skills and knowledge a newly minted pathologist should have to be successful in the community practice of pathology. The most recent survey, done in spring of 2005, cited surgical pathology diagnosis, frozen section diagnosis, gross dissection, cytology, and fine-needle aspiration as essentials in anatomic pathology. For clinical pathology, knowledge of clinical medicine and test strategies that use the laboratory for clinical problem solving was paramount. New expectations in the latest survey were knowledge of molecular pathology and experience in quality assurance procedures. New pathologists generally meet the expectations of the community hospital workplace; however, there were some deficiencies: they were not proficient in gross pathology or autopsy pathology, they were slow, and many lack the clinical knowledge and experience to be effective consultants. The principal attribute that determines success in the practice of pathology, however, is skill in communication and interpersonal relations, and this remains the major deficiency of the fledgling pathologist.

Behaviour, physiology and experience of pathological laughing and crying in amyotrophic lateral sclerosis.

PubMed

Olney, Nicholas T; Goodkind, Madeleine S; Lomen-Hoerth, Catherine; Whalen, Patrick K; Williamson, Craig A; Holley, Deborah E; Verstaen, Alice; Brown, Laurel M; Miller, Bruce L; Kornak, John; Levenson, Robert W; Rosen, Howard J

2011-12-01

Pathological laughing and crying is a disorder of emotional expression seen in a number of neurological diseases. The aetiology is poorly understood, but clinical descriptions suggest a disorder of emotion regulation. The goals of this study were: (i) to characterize the subjective, behavioural and physiological emotional reactions that occur during episodes of pathological laughing and crying; (ii) to compare responses during these episodes to those that occur when emotions are elicited under standard conditions (watching sad and amusing emotional films, being startled); and (iii) to examine the ability of patients with this disorder to regulate their emotions under standardized conditions. Twenty-one patients with pathological laughing and crying due to amyotrophic lateral sclerosis and 14 with amyotrophic lateral sclerosis but no pathological laughing and crying were studied. Emotional measures included self-reported emotional experience, video recordings of facial reactivity and peripheral physiological responses (skin conductance, heart rate and somatic activity). Nineteen of the 21 patients with histories of pathological laughing and crying had at least one episode in the laboratory that they agreed constituted pathological laughing or crying (a total of 56 episodes were documented). Compared with viewing sad and amusing films, the episodes were associated with greater facial and physiological activation. Contrary to many clinical descriptions, episodes were often induced by contextually appropriate stimuli and associated with strong experiences of emotion that were consistent with the display. When instructed to regulate their facial responses to emotion-eliciting films, patients with pathological laughing and crying showed impairments compared with patients who did not have a history of this disorder. These findings support the idea that pathological laughing and crying represents activation of all channels of emotional responding (i.e. behavioural, physiological and subjective). Furthermore, they support previously advanced theories that, rather than being associated with general emotional hyperreactivity, this disorder may be due to dysfunction in frontal neural systems that support voluntary regulation of emotion.

Behaviour, physiology and experience of pathological laughing and crying in amyotrophic lateral sclerosis

PubMed Central

Olney, Nicholas T.; Goodkind, Madeleine S.; Lomen-Hoerth, Catherine; Whalen, Patrick K.; Williamson, Craig A.; Holley, Deborah E.; Verstaen, Alice; Brown, Laurel M.; Miller, Bruce L.; Kornak, John; Levenson, Robert W.

2011-01-01

Pathological laughing and crying is a disorder of emotional expression seen in a number of neurological diseases. The aetiology is poorly understood, but clinical descriptions suggest a disorder of emotion regulation. The goals of this study were: (i) to characterize the subjective, behavioural and physiological emotional reactions that occur during episodes of pathological laughing and crying; (ii) to compare responses during these episodes to those that occur when emotions are elicited under standard conditions (watching sad and amusing emotional films, being startled); and (iii) to examine the ability of patients with this disorder to regulate their emotions under standardized conditions. Twenty-one patients with pathological laughing and crying due to amyotrophic lateral sclerosis and 14 with amyotrophic lateral sclerosis but no pathological laughing and crying were studied. Emotional measures included self-reported emotional experience, video recordings of facial reactivity and peripheral physiological responses (skin conductance, heart rate and somatic activity). Nineteen of the 21 patients with histories of pathological laughing and crying had at least one episode in the laboratory that they agreed constituted pathological laughing or crying (a total of 56 episodes were documented). Compared with viewing sad and amusing films, the episodes were associated with greater facial and physiological activation. Contrary to many clinical descriptions, episodes were often induced by contextually appropriate stimuli and associated with strong experiences of emotion that were consistent with the display. When instructed to regulate their facial responses to emotion-eliciting films, patients with pathological laughing and crying showed impairments compared with patients who did not have a history of this disorder. These findings support the idea that pathological laughing and crying represents activation of all channels of emotional responding (i.e. behavioural, physiological and subjective). Furthermore, they support previously advanced theories that, rather than being associated with general emotional hyperreactivity, this disorder may be due to dysfunction in frontal neural systems that support voluntary regulation of emotion. PMID:22155983

Evaluation of Response to Preoperative Chemotherapy Versus Surgery Alone in Gastroesophageal Cancer: Tumor Resectability, Pathologic Results and Post-Operative Complications.

PubMed

Kashefi Marandi, Aref; Shojaiefard, Abolfazl; Soroush, Ahmadreza; Ghorbani Abdegah, Ali; Jafari, Mehdi; Khodadost, Mahmoud; Mahmoudzade, Hossein

2016-01-01

Gastroesophageal cancer is one of the most common types of cancer worldwide. Despite significant developments in management, 5-year survival in the developing world is less than 20 percent. Due to restricted research about the impact of preoperative chemotherapy (POC) on tumor resection, pathological response and postoperative complications in Iran, we designed and implemented ‎the present retrospective cross- sectional study on 156 patients with gastroesophageal cancer (GEc) between 2013 and 2015 at Shariati Hospital of Tehran. Two groups were included, the first group had previously received preoperative chemotherapy and the second group had only undergone surgery. All patients were followed for at least one year after the operation in terms of tumor recurrence, relapse free survival and one-year survival. The two groups were eventually compared regarding tumor resection, pathological response, postoperative complications, recurrence rate and survival. The mean age was 66.5± 7.3 years and 78 percent were male. The tumor resectability, pathological response and postoperative complications in the group which received POC were 93.5%, 21.8% and 12.8%, respectively, and in the surgery alone group figures for tumor resection and postoperative complications were 76% and 29.5%, respectively. Also based on our study the 5-year survival in the POC group was better (79.5% vs. 66.5%). Using standard neoadjuvant regimens (preoperative chemotherapy/ chemoradiotherapy) beforesurgery could increase tumor resectability, pathological response, and improve the general status of the patients. Therefore using POC may be recommended over surgery alone.

Noncanonical spike-related BOLD responses in focal epilepsy

PubMed Central

Lemieux, Louis; Laufs, Helmut; Carmichael, David; Paul, Joseph Suresh; Walker, Matthew C; Duncan, John S

2008-01-01

Till now, most studies of the Blood Oxygen Level-Dependent (BOLD) response to interictal epileptic discharges (IED) have assumed that its time course matches closely to that of brief physiological stimuli, commonly called the canonical event-related haemodynamic response function (canonical HRF). Analyses based on that assumption have produced significant response patterns that are generally concordant with prior electroclinical data. In this work, we used a more flexible model of the event-related response, a Fourier basis set, to investigate the presence of other responses in relation to individual IED in 30 experiments in patients with focal epilepsy. We found significant responses that had a noncanonical time course in 37% of cases, compared with 40% for the conventional, canonical HRF-based approach. In two cases, the Fourier analysis suggested activations where the conventional model did not. The noncanonical activations were almost always remote from the presumed generator of epileptiform activity. In the majority of cases with noncanonical responses, the noncanonical responses in single-voxel clusters were suggestive of artifacts. We did not find evidence for IED-related noncanonical HRFs arising from areas of pathology, suggesting that the BOLD response to IED is primarily canonical. Noncanonical responses may represent a number of phenomena, including artefacts and propagated epileptiform activity. Hum Brain Mapp 2008. © 2007 Wiley-Liss, Inc. PMID:17510926

Surrogate marker analysis in cancer clinical trials through time-to-event mediation techniques.

PubMed

Vandenberghe, Sjouke; Duchateau, Luc; Slaets, Leen; Bogaerts, Jan; Vansteelandt, Stijn

2017-01-01

The meta-analytic approach is the gold standard for validation of surrogate markers, but has the drawback of requiring data from several trials. We refine modern mediation analysis techniques for time-to-event endpoints and apply them to investigate whether pathological complete response can be used as a surrogate marker for disease-free survival in the EORTC 10994/BIG 1-00 randomised phase 3 trial in which locally advanced breast cancer patients were randomised to either taxane or anthracycline based neoadjuvant chemotherapy. In the mediation analysis, the treatment effect is decomposed into an indirect effect via pathological complete response and the remaining direct effect. It shows that only 4.2% of the treatment effect on disease-free survival after five years is mediated by the treatment effect on pathological complete response. There is thus no evidence from our analysis that pathological complete response is a valuable surrogate marker to evaluate the effect of taxane versus anthracycline based chemotherapies on progression free survival of locally advanced breast cancer patients. The proposed analysis strategy is broadly applicable to mediation analyses of time-to-event endpoints, is easy to apply and outperforms existing strategies in terms of precision as well as robustness against model misspecification.

Induction process of trainees in pathology residency

PubMed Central

Siddiqui, Imran; Ali, Natasha

2016-01-01

This article describes the evolution of the induction process of pathology residency at The Aga Khan University hospital. The Department of Postgraduate Medical Education was established in 1985. The induction process is an exhaustive exercise that includes an admission test held simultaneously in Karachi, Hyderabad, Lahore, and Rawalpindi, followed by an interview of the shortlisted candidates. The pathology residency program was started 25 years ago and since then the induction process has undergone major changes with the course of time. PMID:27313487

Cue-induced craving in pathological buying: empirical evidence and clinical implications.

PubMed

Trotzke, Patrick; Starcke, Katrin; Pedersen, Anya; Brand, Matthias

2014-01-01

Pathological buying is associated with marked distress and impaired functioning in important life domains. It is currently under debate whether pathological buying can be considered a behavioral addiction. In analogy to results reported in addicted individuals, craving reactions elicited by addiction-related cues might be an underlying mechanism for the etiology and pathogenesis of pathological buying. In the present study, 30 pathological buyers and 30 matched control participants were examined with a cue-reactivity paradigm consisting of shopping and control cues. Skin conductance responses, as well as subjective ratings for arousal, valence, and urge to buy, were assessed. Subjective craving reactions were measured before and after the cue-reactivity paradigm. On a physiological level, skin conductance responses toward shopping cues were higher in pathological buyers (mean [M; standard deviation {SD}] = 0.26 [0.13]) compared with control participants (M [SD] = 0.19 [0.09]; t(58) = 2.29, p = .025, d = 0.60). On a behavioral level, the individuals with pathological buying rated the shopping cues as more arousing and more positive, and reported a greater urge to buy compared with control participants and with control cues. An increase in subjective craving after completing the cue-reactivity paradigm was observed only in the pathological buyers (Mpre [SD] = 1.95 [1.47], Mpost [SD] = 2.87 [1.79]; t(29) = 5.07, p < .001, d = 0.97). Cue-reactivity and craving might be potential correlates for the development and maintenance of pathological buying. The results demonstrate similarities between pathological buying and substance or behavioral addictions and provide implications for clinical treatment.

A core curriculum for clinical fellowship training in pathology informatics

PubMed Central

McClintock, David S.; Levy, Bruce P.; Lane, William J.; Lee, Roy E.; Baron, Jason M.; Klepeis, Veronica E.; Onozato, Maristela L.; Kim, JiYeon; Dighe, Anand S.; Beckwith, Bruce A.; Kuo, Frank; Black-Schaffer, Stephen; Gilbertson, John R.

2012-01-01

Background: In 2007, our healthcare system established a clinical fellowship program in Pathology Informatics. In 2010 a core didactic course was implemented to supplement the fellowship research and operational rotations. In 2011, the course was enhanced by a formal, structured core curriculum and reading list. We present and discuss our rationale and development process for the Core Curriculum and the role it plays in our Pathology Informatics Fellowship Training Program. Materials and Methods: The Core Curriculum for Pathology Informatics was developed, and is maintained, through the combined efforts of our Pathology Informatics Fellows and Faculty. The curriculum was created with a three-tiered structure, consisting of divisions, topics, and subtopics. Primary (required) and suggested readings were selected for each subtopic in the curriculum and incorporated into a curated reading list, which is reviewed and maintained on a regular basis. Results: Our Core Curriculum is composed of four major divisions, 22 topics, and 92 subtopics that cover the wide breadth of Pathology Informatics. The four major divisions include: (1) Information Fundamentals, (2) Information Systems, (3) Workflow and Process, and (4) Governance and Management. A detailed, comprehensive reading list for the curriculum is presented in the Appendix to the manuscript and contains 570 total readings (current as of March 2012). Discussion: The adoption of a formal, core curriculum in a Pathology Informatics fellowship has significant impacts on both fellowship training and the general field of Pathology Informatics itself. For a fellowship, a core curriculum defines a basic, common scope of knowledge that the fellowship expects all of its graduates will know, while at the same time enhancing and broadening the traditional fellowship experience of research and operational rotations. For the field of Pathology Informatics itself, a core curriculum defines to the outside world, including departments, companies, and health systems considering hiring a pathology informatician, the core knowledge set expected of a person trained in the field and, more fundamentally, it helps to define the scope of the field within Pathology and healthcare in general. PMID:23024890

Arenaviruses. Genes, proteins, and expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Oldstone, M.B.A.

1987-01-01

This book provides a discussion of current knowledge on Arenaviruses. These viruses are the cause of major health problems, such as Lassa fever and Junin virus disease, and have been the Rosetta stone on which many of the major concepts in viral pathogenesis and immunobiology have been built. For example, study of lymphocytic choriomeningitis naturally and experimentally induced infection in the normal mouse host presented the scientific community with the first and definitive work on the following topics: virus induced immune response disease, immunologic tolerance, virus induced immune complex disease, presence and generation of cytotoxic T cells in vitro andmore » in vivo, H-2 restriction and dual recognition phenomena, and viral disease induced by altering physiologic or differential functions of a cell without causing alterations of house keeping or vital functions, i.e. pathology in the absence of cell or tissue lysis.« less

The Effect of Mental Rotation on Surgical Pathological Diagnosis.

PubMed

Park, Heejung; Kim, Hyun Soo; Cha, Yoon Jin; Choi, Junjeong; Minn, Yangki; Kim, Kyung Sik; Kim, Se Hoon

2018-05-01

Pathological diagnosis involves very delicate and complex consequent processing that is conducted by a pathologist. The recognition of false patterns might be an important cause of misdiagnosis in the field of surgical pathology. In this study, we evaluated the influence of visual and cognitive bias in surgical pathologic diagnosis, focusing on the influence of "mental rotation." We designed three sets of the same images of uterine cervix biopsied specimens (original, left to right mirror images, and 180-degree rotated images), and recruited 32 pathologists to diagnose the 3 set items individually. First, the items found to be adequate for analysis by classical test theory, Generalizability theory, and item response theory. The results showed statistically no differences in difficulty, discrimination indices, and response duration time between the image sets. Mental rotation did not influence the pathologists' diagnosis in practice. Interestingly, outliers were more frequent in rotated image sets, suggesting that the mental rotation process may influence the pathological diagnoses of a few individual pathologists. © Copyright: Yonsei University College of Medicine 2018.

The Benefit of Chemotherapy in Esophageal Cancer Patients With Residual Disease After Trimodality Therapy.

PubMed

Kim, Grace J; Koshy, Matthew; Hanlon, Alexandra L; Horiba, M Naomi; Edelman, Martin J; Burrows, Whitney M; Battafarano, Richard J; Suntharalingam, Mohan

2016-04-01

The objective of this retrospective study was to determine the potential benefits of chemotherapy in esophageal cancer patients treated with chemoradiation followed by surgery. At our institution, 145 patients completed trimodality therapy from 1993 to 2009. Neoadjuvant treatment predominantly consisted of 5-fluorouracil and cisplatin with a concurrent median radiation dose of 50.4 Gy. Sixty-two patients received chemotherapy postoperatively. The majority (49/62) received 3 cycles of docetaxel. Within the entire cohort, a 5-year overall survival (OS) benefit was found in those who received postoperative chemotherapy, OS 37.1% versus 18.0% (P=0.024). The response after neoadjuvant chemoradiation was as follows: 33.8% had a pathologic complete response and 62.8% with residual disease. A 5-year OS and cause-specific survival (CSS) advantage were associated with postoperative chemotherapy among those with macroscopic residual disease after neoadjuvant therapy: OS 38.7% versus 13.9% (P=0.016), CSS 42.8% versus 18.8% (P=0.048). This benefit was not seen in those with a pathologic complete response or those with microscopic residual. A stepwise multivariate Cox regression model evaluating the partial response group revealed that postoperative chemotherapy and M stage were independent predictors of overall and CSS. This analysis revealed that patients with gross residual disease after trimodality therapy for esophageal cancer who received postoperative chemotherapy had an improved overall and CSS. These data suggest that patients with residual disease after trimodality therapy and a reasonable performance status may benefit from postoperative chemotherapy. Prospective trials are needed to confirm these results to define the role of postoperative treatment after trimodality therapy.

Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling.

PubMed

Tourki, Bochra; Halade, Ganesh

2017-10-01

In response to myocardial infarction (MI), time-dependent leukocyte infiltration is critical to program the acute inflammatory response. Post-MI leukocyte density, residence time in the infarcted area, and exit from the infarcted injury predict resolving or nonresolving inflammation. Overactive or unresolved inflammation is the primary determinant in heart failure pathology post-MI. Here, our review describes supporting evidence that the acute inflammatory response also guides the generation of healing and regenerative mediators after cardiac damage. Time-dependent leukocyte density and diversity and the magnitude of myocardial injury is responsible for the resolving and nonresolving pathway in myocardial healing. Post MI, the diversity of leukocytes, such as neutrophils, macrophages, and lymphocytes, has been explored that regulate the clearance of deceased cardiomyocytes by using the classic and reparative pathways. Among the innovative factors and intermediates that have been recognized as essential in acute the self-healing and clearance mechanism, we highlight specialized proresolving mediators as the emerging factor for post-MI reparative mechanisms-translational leukocyte modifiers, such as aging, the source of leukocytes, and the milieu around the leukocytes. In the clinical setting, it is possible that leukocyte diversity is more prominent as a result of risk factors, such as obesity, diabetes, and hypertension. Pharmacologic agents are critical modifiers of leukocyte diversity in healing mechanisms that may impair or stimulate the clearance mechanism. Future research is needed, with a focused approach to understand the molecular targets, cellular effectors, and receptors. A clear understanding of resolving and nonresolving inflammation in myocardial healing will help to develop novel targets with major emphasis on the resolution of inflammation in heart failure pathology.-Tourki, B., Halade, G. Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling. © FASEB.

Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka.

PubMed

Nanayakkara, Shanika; Komiya, Toshiyuki; Ratnatunga, Neelakanthi; Senevirathna, S T M L D; Harada, Kouji H; Hitomi, Toshiaki; Gobe, Glenda; Muso, Eri; Abeysekera, Tilak; Koizumi, Akio

2012-05-01

Chronic kidney disease of uncertain etiology (CKDu) in North Central Province of Sri Lanka has become a key public health concern in the agricultural sector due to the dramatic rise in its prevalence and mortality among young farmers. Although cadmium has been suspected as a causative pathogen, there have been controversies. To date, the pathological characteristics of the disease have not been reported. Histopathological observations of 64 renal biopsies obtained at Anuradhapura General Hospital from October 2008 to July 2009 were scored according to Banff 97 Working Classification of Renal Allograft pathology. The correlations between the histological observations and clinical parameters were statistically analyzed. Interstitial fibrosis and tubular atrophy with or without nonspecific interstitial mononuclear cell infiltration was the dominant histopathological observation. Glomerular sclerosis, glomerular collapse, and features of vascular pathology such as fibrous intimal thickening and arteriolar hyalinosis were also common. Although hypertension was identified as one of the common clinical features among the cases, it did not influence the histopathological lesions in all the cases. This study concludes that tubulointerstitial damage is the major pathological lesion in CKDu. Exposure(s) to an environmental pathogen(s) should be systematically investigated to elucidate such tubulointerstitial damage in CKDu.

Updates of pathologic myopia.

PubMed

Ohno-Matsui, Kyoko; Lai, Timothy Y Y; Lai, Chi-Chun; Cheung, Chiu Ming Gemmy

2016-05-01

Complications from pathologic myopia are a major cause of visual impairment and blindness, especially in east Asia. The eyes with pathologic myopia may develop loss of the best-corrected vision due to various pathologies in the macula, peripheral retina and the optic nerve. Despite its importance, the definition of pathologic myopia has been inconsistent. The refractive error or axial length alone often does not adequately reflect the 'pathologic myopia'. Posterior staphyloma, which is a hallmark lesion of pathologic myopia, can occur also in non-highly myopic eyes. Recently a revised classification system for myopic maculopathy has been proposed to standardize the definition among epidemiological studies. In this META-PM (meta analyses of pathologic myopia) study classification, pathologic myopia was defined as the eyes having chorioretinal atrophy equal to or more severe than diffuse atrophy. In addition, the advent of new imaging technologies such as optical coherence tomography (OCT) and three dimensional magnetic resonance imaging (3D MRI) has enabled the detailed observation of various pathologies specific to pathologic myopia. New therapeutic approaches including intravitreal injections of anti-vascular endothelial growth factor agents and the advance of vitreoretinal surgeries have greatly improved the prognosis of patients with pathologic myopia. The purpose of this review article is to provide an update on topics related to the field of pathologic myopia, and to outline the remaining issues which need to be solved in the future. Copyright © 2016 Elsevier Ltd. All rights reserved.

Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta.

PubMed

Holton, Janice L; Lashley, Tammaryn; Ghiso, Jorge; Braendgaard, Hans; Vidal, Ruben; Guerin, Christopher J; Gibb, Graham; Hanger, Diane P; Rostagno, Agueda; Anderton, Brian H; Strand, Catherine; Ayling, Hilary; Plant, Gordon; Frangione, Blas; Bojsen-Møller, Marie; Revesz, Tamas

2002-03-01

Familial Danish dementia (FDD) is pathologically characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal protein deposits, and neurofibrillary degeneration. FDD is associated with a mutation of the BRI2 gene located on chromosome 13. In FDD there is a decamer duplication, which abolishes the normal stop codon, resulting in an extended precursor protein and the release of an amyloidogenic fragment, ADan. The aim of this study was to describe the major neuropathological changes in FDD and to assess the distribution of ADan lesions, neurofibrillary pathology, glial, and microglial response using conventional techniques, immunohistochemistry, confocal microscopy, and immunoelectron microscopy. We showed that ADan is widely distributed in the central nervous system (CNS) in the leptomeninges, blood vessels, and parenchyma. A predominance of parenchymal pre-amyloid (non-fibrillary) lesions was found. Abeta was also present in a proportion of both vascular and parenchymal lesions. There was severe neurofibrillary pathology, and tau immunoblotting revealed a triplet electrophoretic migration pattern comparable with PHF-tau. FDD is a novel form of CNS amyloidosis with extensive neurofibrillary degeneration occurring with parenchymal, predominantly pre-amyloid rather than amyloid, deposition. These findings support the notion that parenchymal amyloid fibril formation is not a prerequisite for the development of neurofibrillary tangles. The significance of concurrent ADan and Abeta deposition in FDD is under further investigation.

Microglia: An Interface between the Loss of Neuroplasticity and Depression

PubMed Central

Singhal, Gaurav; Baune, Bernhard T.

2017-01-01

Depression has been widely accepted as a major psychiatric disease affecting nearly 350 million people worldwide. Research focus is now shifting from studying the extrinsic and social factors of depression to the underlying molecular causes. Microglial activity is shown to be associated with pathological conditions, such as psychological stress, pathological aging, and chronic infections. These are primary immune effector cells in the CNS and regulate the extensive dialogue between the nervous and the immune systems in response to different immunological, physiological, and psychological stressors. Studies have suggested that during stress and pathologies, microglia play a significant role in the disruption of neuroplasticity and have detrimental effects on neuroprotection causing neuroinflammation and exacerbation of depression. After a systematic search of literature databases, relevant articles on the microglial regulation of bidirectional neuroimmune pathways affecting neuroplasticity and leading to depression were reviewed. Although, several hypotheses have been proposed for the microglial role in the onset of depression, it is clear that all molecular pathways to depression are linked through microglia-associated neuroinflammation and hippocampal degeneration. Molecular factors such as an excess of glucocorticoids and changes in gene expression of neurotrophic factors, as well as neuro active substances secreted by gut microbiota have also been shown to affect microglial morphology and phenotype resulting in depression. This review aims to critically analyze the various molecular pathways associated with the microglial role in depression. PMID:28943841

Clinical characteristics of catamenial and non-catamenial thoracic endometriosis-related pneumothorax.

PubMed

Fukuoka, Mizuki; Kurihara, Masatoshi; Haga, Takahiro; Ebana, Hiroki; Kataoka, Hideyuki; Mizobuchi, Teruaki; Tatsumi, Koichiro

2015-11-01

A major pathogenic factor for catamenial pneumothorax is thoracic endometriosis. However, thoracic endometriosis-related pneumothorax (TERP) can develop as either catamenial or non-catamenial pneumothorax (CP). Therefore, the aim of this study was to elucidate the clinical differences between catamenial and non-catamenial TERP. The clinical and pathological data in female patients who underwent video-assisted thoracoscopic surgery at the Pneumothorax Research Center during an 8-year period were retrospectively reviewed. This study included 150 female patients with surgico-pathologically confirmed TERP. The subjects were divided into two groups, those having all of the pneumothorax episodes in the catamenial period (CP group) and those who did not (non-CP group). We compared the clinical characteristics and surgico-pathological findings between these two groups. Of the 150 TERP patients, 55 (36.7%) were classified in the CP group, and 95 (63.3%) in the non-CP group. In regard to the locations of endometriosis, all TERP patients had diaphragmatic endometriosis, while pleural implantation was recognized in 34 of the 55 (61.8%) patients in the CP group and 42 of the 95 (44.2%) patients in the non-CP group (P < 0.05). A significant difference in the proportion of patients with pleural endometriosis was observed between catamenial and non-catamenial TERP. The ectopic sites of the endometriosis may be responsible for the timing of the pneumothorax episodes. © 2015 Asian Pacific Society of Respirology.

Consequences of "going digital" for pathology professionals - entering the cloud.

PubMed

Laurinavicius, Arvydas; Raslavicus, Paul

2012-01-01

New opportunities and the adoption of digital technologies will transform the way pathology professionals and services work. Many areas of our daily life as well as medical professions have experienced this change already which has resulted in a paradigm shift in many activities. Pathology is an image-based discipline, therefore, arrival of digital imaging into this domain promises major shift in our work and required mentality. Recognizing the physical and digital duality of the pathology workflow, we can prepare for the imminent increase of the digital component, synergize and enjoy its benefits. Development of a new generation of laboratory information systems along with seamless integration of digital imaging, decision-support, and knowledge databases will enable pathologists to work in a distributed environment. The paradigm of "cloud pathology" is proposed as an ultimate vision of digital pathology workstations plugged into the integrated multidisciplinary patient care systems.

Matrix metalloproteinase-9 expression correlated with tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Unsal, Diclehan; Uner, Aytug; Akyurek, Nalan

2007-01-01

Purpose: To analyze whether the expression of matrix metalloproteinases (MMPs) and their tissue inhibitors are associated with tumor response to preoperative chemoradiotherapy in rectal cancer patients. Methods and Materials: Forty-four patients who had undergone preoperative chemoradiotherapy were evaluated retrospectively. Treatment consisted of pelvic radiotherapy and two cycles of 5-fluorouracil plus leucovorin. Surgery was performed 6-8 weeks later. MMP-2, MMP-9, and tissue inhibitors of metalloproteinase-1 and -2 expression was analyzed by immunohistochemistry of the preradiation biopsy and surgical specimens. The intensity and extent of staining were evaluated separately, and a final score was calculated by multiplying the two scores. The primarymore » endpoint was the correlation of expression with tumor response, with the secondary endpoint the effect of chemoradiotherapy on the expression. Results: Preoperative treatment resulted in downstaging in 20 patients (45%) and no clinical response in 24 (55%). The pathologic tumor response was complete in 11 patients (25%), partial in 23 (52%), and none in 10 (23%). Positive MMP-9 staining was observed in 20 tumors (45%) and was associated with the clinical nodal stage (p = 0.035) and the pathologic and clinical response (p < 0.0001). The staining status of the other markers was associated with neither stage nor response. The overall pathologic response rate was 25% in MMP-9-positive patients vs. 52% in MMP-9-negative patients (p = 0.001). None of the 11 patients with pathologic complete remission was MMP-9 positive. Conclusions: Matrix metalloproteinase-9 expression correlated with a poor tumor response to preoperative chemoradiotherapy in rectal carcinoma patients.« less

Clinico-pathological features of kidney disease in diabetic cases.

PubMed

Furuichi, Kengo; Shimizu, Miho; Okada, Hirokazu; Narita, Ichiei; Wada, Takashi

2018-03-21

Diabetic kidney disease is the major cause of end-stage kidney disease in developed countries. However, the onset of kidney disorder and the progression pattern of kidney dysfunction and proteinuria greatly vary cases by cases. Therefore, risk classification with clinical data and pathological findings is important. Recent clinico-pathological study with kidney biopsy samples from diabetic patients revealed that pathological changes of diabetic nephropathy are characteristic and have special impacts on prognosis in each clinical stage. Moreover, comparison of the clinico-pathological findings of diabetic nephropathy with hypertensive nephrosclerosis revealed that there are few differences in their pathological findings in cases with low albuminuria and preserved estimated glomerular filtration rate (eGFR). Because it is so difficult to clearly distinguish pure kidney lesions caused by diabetes and kidney lesions due to effects other than diabetes, it is vital that these overlapped pathological findings be confirmed on kidney biopsy in cases of early stage diabetes. Further research is warranted regarding the pathogenesis of diabetic nephropathy and indication of kidney biopsy in diabetic cases.

Pathway modulations and epigenetic alterations in ovarian tumorbiogenesis

PubMed Central

Saldanha, Sabita N.; Tollefsbol, Trygve O.

2013-01-01

Cellular pathways are numerous and are highly integrated in function in the control of cellular systems. They collectively regulate cell division, proliferation, survival and apoptosis of cells and mutagenesis of key genes that control these pathways can initiate neoplastic transformations. Understanding these pathways is crucial to future therapeutic and preventive strategies of the disease. Ovarian cancers are of three major types; epithelial, germ-cell and stromal. However, ovarian cancers of epithelial origin, arising from the mesothelium, are the predominant form. Of the subtypes of ovarian cancer, the high-grade serous tumors are fatal, with low survival rate due to late detection and poor response to treatments. Close examination of preserved ovarian tissues and in vitro studies have provided insights into the mechanistic changes occurring in cells mediated by a few key genes. This review will focus on pathways and key genes of the pathways that are mutated or have aberrant functions in the pathology of ovarian cancer. Non-genetic mechanisms that are gaining prominence in the pathology of ovarian cancer, miRNAs and epigenetics, will also be discussed in the review. PMID:24105793

Lysine-Directed Post-translational Modifications of Tau Protein in Alzheimer's Disease and Related Tauopathies

PubMed Central

Kontaxi, Christiana; Piccardo, Pedro; Gill, Andrew C.

2017-01-01

Tau is a microtubule-associated protein responsible mainly for stabilizing the neuronal microtubule network in the brain. Under normal conditions, tau is highly soluble and adopts an “unfolded” conformation. However, it undergoes conformational changes resulting in a less soluble form with weakened microtubule stabilizing properties. Altered tau forms characteristic pathogenic inclusions in Alzheimer's disease and related tauopathies. Although, tau hyperphosphorylation is widely considered to be the major trigger of tau malfunction, tau undergoes several post-translational modifications at lysine residues including acetylation, methylation, ubiquitylation, SUMOylation, and glycation. We are only beginning to define the site-specific impact of each type of lysine modification on tau biology as well as the possible interplay between them, but, like phosphorylation, these modifications are likely to play critical roles in tau's normal and pathobiology. This review summarizes the latest findings focusing on lysine post-translational modifications that occur at both endogenous tau protein and pathological tau forms in AD and other tauopathies. In addition, it highlights the significance of a site-dependent approach of studying tau post-translational modifications under normal and pathological conditions. PMID:28848737

MRI Predictive Factors for Tumor Response in Rectal Cancer Following Neoadjuvant Chemoradiation Therapy - Implications for Induction Chemotherapy?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yu, Stanley K.T.; Tait, Diana; Chau, Ian

2013-11-01

Purpose: Clinical and magnetic resonance imaging (MRI) characteristics at baseline and following chemoradiation therapy (CRT) most strongly associated with histopathologic response were investigated and survival outcomes evaluated in accordance with imaging and pathological response. Methods and Materials: Responders were defined as mrT3c/d-4 downstaged to ypT0-2 on pathology or low at risk mrT2 downstaged to ypT1 or T0. Multivariate logistic regression of baseline and posttreatment MRI: T, N, extramural venous invasion (EMVI), circumferential resection margin, craniocaudal length <5 cm, and MRI tumor height ≤5 cm were used to identify independent predictor(s) for response. An association between induction chemotherapy and EMVI statusmore » was analyzed. Survival outcomes for pathologic and MRI responders and nonresponders were analyzed. Results: Two hundred eighty-one patients were eligible; 114 (41%) patients were pathology responders. Baseline MRI negative EMVI (odds ratio 2.94, P=.007), tumor height ≤5 cm (OR 1.96, P=.02), and mrEMVI status change (positive to negative) following CRT (OR 3.09, P<.001) were the only predictors for response. There was a strong association detected between induction chemotherapy and ymrEMVI status change after CRT (OR 9.0, P<.003). ymrT0-2 gave a positive predictive value of 80% and OR of 9.1 for ypT0-2. ymrN stage accuracy of ypN stage was 75%. Three-year disease-free survival for pathology and MRI responders were similar at 80% and 79% and significantly better than poor responders. Conclusions: Tumor height and mrEMVI status are more important than baseline size and stage of the tumor as predictors of response to CRT. Both MRI- and pathologic-defined responders have significantly improved survival. “Good response” to CRT in locally advanced rectal cancer with ypT0-2 carries significantly better 3-year overall survival and disease-free survival. Use of induction chemotherapy for improving mrEMVI status and knowledge of MRI predictive factors could be taken into account in the pursuit of individualized neoadjuvant treatments for patients with rectal cancer.« less

Anatomy, pathology, and physiology of the tracheobronchial tree: emphasis on the distal airways.

PubMed

Hyde, Dallas M; Hamid, Qutayba; Irvin, Charles G

2009-12-01

This article covers the airway tree with respect to anatomy, pathology, and physiology. The anatomic portion discusses various primate groups so as to help investigators understand similarities and differences between animal models. An emphasis is on distal airway findings. The pathology section focuses on the inflammatory responses that occur in proximal and distal airways. The physiologic review brings together the anatomic and pathologic components to the functional state and proposes ways to evaluate the small airways in patients with asthma.

Efficacy of a Fatty Acids Dietary Supplement in a Polyethylene Glycol-Induced Mouse Model of Retinal Degeneration

PubMed Central

Locri, Filippo; Lardner, Emma; Kvanta, Anders; Rusciano, Dario; Bagnoli, Paola

2017-01-01

Current knowledge of the benefits of nutrition supplements for eye pathologies is based largely on the use of appropriate animal models, together with defined dietary supplementation. Here, C57BL6 mice were subretinally injected with polyethylene glycol (PEG)-400, an established model of retinal degeneration with a dry age-related macular degeneration (AMD)-like phenotype, an eye pathology that lacks treatment. In response to PEG-400, markers of the complement system, angiogenesis, inflammation, gliosis, and macrophage infiltration were upregulated in both retinas and retinal pigment epithelium (RPE)/choroids, whereas dietary supplementation with a mixture based on fatty acids counteracted their upregulation. Major effects include a reduction of inflammation, in both retinas and RPE/choroids, and an inhibition of macrophage infiltration in the choroid, yet not in the retina, suggesting a targeted action through the choroidal vasculature. Histological analysis revealed a thinning of the outer nuclear layer (ONL), together with dysregulation of the epithelium layer in response to PEG-400. In addition, immunohistofluorescence demonstrated Müller cell gliosis and macrophage infiltration into subretinal tissues supporting the molecular findings. Reduced ONL thickness, gliosis, and macrophage infiltration were counteracted by the diet supplement. The present data suggest that fatty acids may represent a useful form of diet supplementation to prevent or limit the progression of dry AMD. PMID:28961167

Reduced expression of APC-1B but not APC-1A by the deletion of promoter 1B is responsible for familial adenomatous polyposis.

PubMed

Yamaguchi, Kiyoshi; Nagayama, Satoshi; Shimizu, Eigo; Komura, Mitsuhiro; Yamaguchi, Rui; Shibuya, Tetsuo; Arai, Masami; Hatakeyama, Seira; Ikenoue, Tsuneo; Ueno, Masashi; Miyano, Satoru; Imoto, Seiya; Furukawa, Yoichi

2016-05-24

Germline mutations in the tumor suppressor gene APC are associated with familial adenomatous polyposis (FAP). Here we applied whole-genome sequencing (WGS) to the DNA of a sporadic FAP patient in which we did not find any pathological APC mutations by direct sequencing. WGS identified a promoter deletion of approximately 10 kb encompassing promoter 1B and exon1B of APC. Additional allele-specific expression analysis by deep cDNA sequencing revealed that the deletion reduced the expression of the mutated APC allele to as low as 11.2% in the total APC transcripts, suggesting that the residual mutant transcripts were driven by other promoter(s). Furthermore, cap analysis of gene expression (CAGE) demonstrated that the deleted promoter 1B region is responsible for the great majority of APC transcription in many tissues except the brain. The deletion decreased the transcripts of APC-1B to 39-45% in the patient compared to the healthy controls, but it did not decrease those of APC-1A. Different deletions including promoter 1B have been reported in FAP patients. Taken together, our results strengthen the evidence that analysis of structural variations in promoter 1B should be considered for the FAP patients whose pathological mutations are not identified by conventional direct sequencing.

Emerging Themes in Image Informatics and Molecular Analysis for Digital Pathology.

PubMed

Bhargava, Rohit; Madabhushi, Anant

2016-07-11

Pathology is essential for research in disease and development, as well as for clinical decision making. For more than 100 years, pathology practice has involved analyzing images of stained, thin tissue sections by a trained human using an optical microscope. Technological advances are now driving major changes in this paradigm toward digital pathology (DP). The digital transformation of pathology goes beyond recording, archiving, and retrieving images, providing new computational tools to inform better decision making for precision medicine. First, we discuss some emerging innovations in both computational image analytics and imaging instrumentation in DP. Second, we discuss molecular contrast in pathology. Molecular DP has traditionally been an extension of pathology with molecularly specific dyes. Label-free, spectroscopic images are rapidly emerging as another important information source, and we describe the benefits and potential of this evolution. Third, we describe multimodal DP, which is enabled by computational algorithms and combines the best characteristics of structural and molecular pathology. Finally, we provide examples of application areas in telepathology, education, and precision medicine. We conclude by discussing challenges and emerging opportunities in this area.

Emerging Themes in Image Informatics and Molecular Analysis for Digital Pathology

PubMed Central

Bhargava, Rohit; Madabhushi, Anant

2017-01-01

Pathology is essential for research in disease and development, as well as for clinical decision making. For more than 100 years, pathology practice has involved analyzing images of stained, thin tissue sections by a trained human using an optical microscope. Technological advances are now driving major changes in this paradigm toward digital pathology (DP). The digital transformation of pathology goes beyond recording, archiving, and retrieving images, providing new computational tools to inform better decision making for precision medicine. First, we discuss some emerging innovations in both computational image analytics and imaging instrumentation in DP. Second, we discuss molecular contrast in pathology. Molecular DP has traditionally been an extension of pathology with molecularly specific dyes. Label-free, spectroscopic images are rapidly emerging as another important information source, and we describe the benefits and potential of this evolution. Third, we describe multimodal DP, which is enabled by computational algorithms and combines the best characteristics of structural and molecular pathology. Finally, we provide examples of application areas in telepathology, education, and precision medicine. We conclude by discussing challenges and emerging opportunities in this area. PMID:27420575

The contribution of Chlamydia-specific CD8⁺ T cells to upper genital tract pathology.

PubMed

Vlcek, Kelly R; Li, Weidang; Manam, Srikanth; Zanotti, Brian; Nicholson, Bruce J; Ramsey, Kyle H; Murthy, Ashlesh K

2016-02-01

Genital chlamydial infections lead to severe upper reproductive tract pathology in a subset of untreated women. We demonstrated previously that tumor necrosis factor (TNF)-α-producing CD8(+) T cells contribute significantly to chlamydial upper genital tract pathology in female mice. In addition, we observed that minimal chlamydial oviduct pathology develops in OT-1 transgenic (OT-1) mice, wherein the CD8(+) T-cell repertoire is restricted to recognition of the ovalbumin peptide Ova(257-264), suggesting that non-Chlamydia-specific CD8(+) T cells may not be responsible for chlamydial pathogenesis. In the current study, we evaluated whether antigen-specific CD8(+) T cells mediate chlamydial pathology. Groups of wild-type (WT) C57BL/6J, OT-1 mice, and OT-1 mice replete with WT CD8(+) T cells (1 × 10(6) cells per mouse intravenously) were infected intravaginally with C. muridarum (5 × 10(4) IFU/mouse). Serum total anti-Chlamydia antibody and total splenic anti-Chlamydia interferon (IFN)-γ and TNF-α responses were comparable among the three groups of animals. However, Chlamydia-specific IFN-γ and TNF-α production from purified splenic CD8(+) T cells of OT-1 mice was minimal, whereas responses in OT-1 mice replete with WT CD8(+) T cells were comparable to those in WT animals. Vaginal chlamydial clearance was comparable between the three groups of mice. Importantly, the incidence and severity of oviduct and uterine horn pathology was significantly reduced in OT-1 mice but reverted to WT levels in OT-1 mice replete with WT CD8(+) T cells. Collectively, these results demonstrate that Chlamydia-specific CD8(+) T cells contribute significantly to upper genital tract pathology.

Active tissue stiffness modulation controls valve interstitial cell phenotype and osteogenic potential in 3D culture.

PubMed

Duan, Bin; Yin, Ziying; Hockaday Kang, Laura; Magin, Richard L; Butcher, Jonathan T

2016-05-01

Calcific aortic valve disease (CAVD) progression is a highly dynamic process whereby normally fibroblastic valve interstitial cells (VIC) undergo osteogenic differentiation, maladaptive extracellular matrix (ECM) composition, structural remodeling, and tissue matrix stiffening. However, how VIC with different phenotypes dynamically affect matrix properties and how the altered matrix further affects VIC phenotypes in response to physiological and pathological conditions have not yet been determined. In this study, we develop 3D hydrogels with tunable matrix stiffness to investigate the dynamic interplay between VIC phenotypes and matrix biomechanics. We find that VIC populated within hydrogels with valve leaflet like stiffness differentiate towards myofibroblasts in osteogenic media, but surprisingly undergo osteogenic differentiation when cultured within lower initial stiffness hydrogels. VIC differentiation progressively stiffens the hydrogel microenvironment, which further upregulates both early and late osteogenic markers. These findings identify a dynamic positive feedback loop that governs acceleration of VIC calcification. Temporal stiffening of pathologically lower stiffness matrix back to normal level, or blocking the mechanosensitive RhoA/ROCK signaling pathway, delays the osteogenic differentiation process. Therefore, direct ECM biomechanical modulation can affect VIC phenotypes towards and against osteogenic differentiation in 3D culture. These findings highlight the importance of the homeostatic maintenance of matrix stiffness to restrict pathological VIC differentiation. We implement 3D hydrogels with tunable matrix stiffness to investigate the dynamic interaction between valve interstitial cells (VIC, major cell population in heart valve) and matrix biomechanics. This work focuses on how human VIC responses to changing 3D culture environments. Our findings identify a dynamic positive feedback loop that governs acceleration of VIC calcification, which is the hallmark of calcific aortic valve disease. Temporal stiffening of pathologically lower stiffness matrix back to normal level, or blocking the mechanosensitive signaling pathway, delays VIC osteogenic differentiation. Our findings provide an improved understanding of VIC-matrix interactions to aid in interpretation of VIC calcification studies in vitro and suggest that ECM disruption resulting in local tissue stiffness decreases may promote calcific aortic valve disease. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Opportunistic disease in yellow perch in response to decadal changes in the chemistry of oil sands-affected waters.

PubMed

Hogan, Natacha S; Thorpe, Karen L; van den Heuvel, Michael R

2018-03-01

Oil sands-affected water from mining must eventually be incorporated into the reclaimed landscape or treated and released. However, this material contains petrogenic organic compounds, such as naphthenic acids and traces of polycyclic aromatic hydrocarbons. This has raised concerns for impacts of oil sands process-affected waters on the heath of wildlife and humans downstream of receiving environments. The objective of this study was to evaluate the temporal association of disease states in fish with water chemistry of oil sands-affected waters over more than a decade and determine the pathogens associated with disease pathologies. Yellow perch (Perca flavescens) captured from nearby lakes were stocked into two experimental ponds during 1995-1997 and 2008-2010. South Bison Pond is a drainage basin that has received unextracted oil sands-contaminated material. Demonstration Pond is a constructed pond containing mature fine tailings capped with fresh water. Two disease pathologies, fin erosion for which a suspected bacterial pathogen (Acinetobacter Iwoffi) is identified, and lymphocystis (confirmed using a real-time PCR) were associated with oil sands-affected water exposure. From 1995 to 1997 pathologies were most prevalent in the South Bison Pond; however, from 2008 to 2009, disease was more frequently observed in the Demonstration Pond. CYP1A activity was 3-16 fold higher in fish from experimental ponds as compared to reference populations and this pattern was consistent across all sampling years. Bile fluorescence displayed a gradient of exposure with experimental ponds being elevated over local perch populations. Naphthenic acids decreased in the Bison Pond from approximately 12 mg/L to <4 mg/L while naphthenic acids increased in the Demonstration Pond from 6 mg/L to 12 mg/L due to tailings densification. Temporal changes in naphthenic acid levels, CYP1A activity and bile fluorescent metabolites correlate positively with incidence of disease pathologies whereas all inorganic water quality changes (major ions, pH, metals) were not associated with disease responses. Copyright © 2017 Elsevier Ltd. All rights reserved.

Social Information Processing and Cluster B Personality Pathology among Clinic-Referred Adolescents.

PubMed

Hessels, Christel; van Aken, Marcel A G; Orobio de Castro, Bram; Laceulle, Odilia M; van Voorst, Guus

2016-01-01

This study investigated relations between personality pathology and mentalizing capacities reflected in social information processing (SIP) of adolescents. 96 adolescent outpatients completed a structured interview regarding SIP. Their clinicians completed a checklist based on DSM-IV, assessing severity of personality pathology. Significant relations were found between the severity of personality pathology and SIP: the more severe the personality pathology, the higher the intensity of reported emotions, the more likely adolescents were to choose inadequate coping strategies and aggressive reactions in social situations, and the more positively they evaluated aggressive reactions. Severity of traits of antisocial (ASPD) and borderline personality disorder (BPD) had unique associations with distinctive SIP variables: ASPD being more related to inadequate coping strategies, less reflection on other's motives and aggressive responses, and BPD being more related to avoidant or prosocial responses and in particular to memories of frustrating events. This study provides evidence for difficulties in SIP among adolescents with more severe personality pathology, suggesting that the steps in the SIP model can be used to operationalize mentalizing problems. The results seem to paint a picture of ASPD and BPD having a shared background, but their own specific problems concerning SIP. © 2016 S. Karger AG, Basel.

Effect of neoadjuvant chemotherapy on HER-2 expression in surgically treated gastric and oesophagogastric junction carcinoma: a multicentre Italian study.

PubMed

Chiari, Damiano; Orsenigo, Elena; Guarneri, Giovanni; Baiocchi, Gian Luca; Mazza, Elena; Albarello, Luca; Bissolati, Massimiliano; Molfino, Sarah; Staudacher, Carlo

2017-03-01

Predictors of response to neoadjuvant chemotherapy are not available for gastric and oesophago-gastric junction carcinoma. HER-2 over-expression in breast cancer correlates with poor prognosis and high incidence of recurrence. First aim of this study was to evaluate if the HER-2 expression/amplification is predictive of response to neoadjuvant chemotherapy in terms of pathologic regression. Secondary aim was to evaluate if HER-2 expression varies after neoadjuvant treatment. Thirty-five patients with locally advanced gastric or oesophago-gastric junction carcinoma underwent preoperative chemotherapy and surgical resection at San Raffaele Scientific Institute and Spedali Civili of Brescia. HER-2 expression/amplification was evaluated on every biopsy at diagnosis time and on every surgical sample after neoadjuvant chemotherapy. Pathologic response to chemotherapy was evaluated according to TNM classification (ypT status and ypN status) and Mandard's tumour regression grade classification. In our series 10 patients (28.6%) showed a reduction in HER-2 overexpression and in 6 of them (17.1%) HER-2 expression completely disappeared. Only three of the six patients with HER-2 disappearance had a complete pathological response to neoadjuvant chemotherapy. There was a strong correlation between HER-2 negativity on biopsy and absence of lymph node metastasis in surgical samples after neoadjuvant chemotherapy, irrespective of nodal status before chemotherapy. A direct correlation between HER-2 reduction after neoadjuvant chemotherapy and pathologic regression (primary tumour and lymph nodes) in surgical samples was found. HER-2 negativity may represent a predictor of pathologic response to neoadjuvant chemotherapy for gastric and oesophago-gastric junction adenocarcinoma. Neoadjuvant treatment can reduce HER-2 overexpression.

Induction of a pathological complete response by four courses of neoadjuvant chemotherapy for gastric cancer: early results of the randomized phase II COMPASS trial.

PubMed

Yoshikawa, Takaki; Tanabe, Kazuaki; Nishikawa, Kazuhiro; Ito, Yuichi; Matsui, Takanori; Kimura, Yutaka; Hirabayashi, Naoki; Mikata, Shoki; Iwahashi, Makoto; Fukushima, Ryoji; Takiguchi, Nobuhiro; Miyashiro, Isao; Morita, Satoshi; Miyashita, Yumi; Tsuburaya, Aakira; Sakamoto, Junichi

2014-01-01

The prognosis for stage 3 gastric cancer is not satisfactory, even with S-1 adjuvant chemotherapy. A randomized phase II trial was conducted to compare two and four courses of neoadjuvant S-1/cisplatin (SC) and paclitaxel/cisplatin (PC) using a two-by-two factorial design for locally advanced gastric cancer. The primary endpoint was overall survival. We clarified the impact of these regimens on the secondary endpoints, including the clinical and pathological responses, chemotherapy-related toxicities, and surgical results. Patients received S-1 (80 mg/m(2) for 21 days with 1 week's rest)/cisplatin (60 mg/m(2) at day 8) or paclitaxel/cisplatin (80 and 25 mg/m(2), respectively, on days 1, 8, and 15 with 1 week's rest) as neoadjuvant chemotherapy. Eighty-three patients were assigned to arm A (two courses of SC, n = 21), arm B (four courses of SC, n = 20), arm C (two courses of PC, n = 21), and arm D (four courses of PC, n = 21). Pathological response rate was 43 % in arm A, 40 % in arm B, 29 % in arm C, and 38 % in arm D. Pathological complete response was only observed in arms B (10 %) and D (10 %). Most bone marrow toxicities, nausea, vomiting, alopecia, and fatigue were slightly higher but acceptable in arms B and D. Grade 3/4 surgical morbidities were not commonly observed in all four arms. Pathological complete response could be induced by four courses of neoadjuvant chemotherapy without a marked increase of toxicities, regardless of a SC or PC regimen.

[Pathological gambling: risk factors].

PubMed

Bouju, G; Grall-Bronnec, M; Landreat-Guillou, M; Venisse, J-L

2011-09-01

In France, consumption of gambling games increased by 148% between 1960 and 2005. In 2004, gamblers lost approximately 0.9% of household income, compared to 0.4% in 1960. This represents approximately 134 Euros per year and per head. In spite of this important increase, the level remains lower than the European average (1%). However, gambling practices may continue to escalate in France in the next few years, particularly with the recent announce of the legalisation of online games and sports betting. With the spread of legalised gambling, pathological gambling rates may increase in France in the next years, in response to more widely available and more attractive gambling opportunities. In this context, there is a need for better understanding of the risk factors that are implicated in the development and maintenance of pathological gambling. This paper briefly describes the major risk factors for pathological gambling by examining the recent published literature available during the first quarter of 2008. This documentary basis was collected by Inserm for the collective expert report procedure on Gambling (contexts and addictions). Seventy-two articles focusing on risk factors for pathological gambling were considered in this review. Only 47 of them were taken into account for analysis. The selection of these 47 publications was based on the guide on literature analysis established by the French National Agency for Accreditation and Assessment in Health (ANAES, 2000). Some publications from more recent literature have also been added, mostly about Internet gambling. We identify three major types of risk factors implicated in gambling problems: some of them are related to the subject (individual factors), others are related to the object of the addiction, here the gambling activity by itself (structural factors), and the last are related to environment (contextual or situational factors). Thus, the development and maintenance of pathological gambling seems to be conditioned by the interaction of a person and a gambling activity, in a particular context. This conceptual model is based on the well-known theory of Olivenstein on toxicomania, which was proposed in the seventies. The structural factors that appeared to be highly related to pathological gambling development and maintenance are payment modality, entertaining dimension, temporality, reward level, educational messages, gambling ambiance, gambling medium and part of hazard. Among contextual factors, availability and accessibility of gambling opportunities are well known. However, social and economic factors (e.g. culture, ethnicity, religion, education) are also important. Lastly, among individual factors, psychosocial factors are gender, age, familial and personal antecedents and psychiatric comorbidities. Neurobiological factors are not discussed here. This paper briefly summarises risk factors for development and maintenance of pathological gambling. It highlights that these factors are very similar to those that are implicated in substance use disorders, except for the gambling activity and context. Prevention regarding behavioural addictions should, in the future, take advantage of the findings on substance use disorder, since behavioural addictions are less known. Conversely, it seems obvious that findings on pathological gambling, and more widely behavioural addictions, could highlight all types of addiction. It appears that this fact is especially valid with regards to the evolution and stability of addictive status, which must be taken into account for treatment proposals. Copyright © 2011 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Insulin dysfunction and Tau pathology.

PubMed

El Khoury, Noura B; Gratuze, Maud; Papon, Marie-Amélie; Bretteville, Alexis; Planel, Emmanuel

2014-01-01

The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques of β-amyloid (Aβ) peptides (a cleavage product of the Amyloid Precursor Protein, or APP) and neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF). NFT pathology is important since it correlates with the degree of cognitive impairment in AD. Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99%) is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease. Insulin dysfunction, manifested by diabetes mellitus (DM) might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since Tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment. Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.

Insulin dysfunction and Tau pathology

PubMed Central

El Khoury, Noura B.; Gratuze, Maud; Papon, Marie-Amélie; Bretteville, Alexis; Planel, Emmanuel

2013-01-01

The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques of β-amyloid (Aβ) peptides (a cleavage product of the Amyloid Precursor Protein, or APP) and neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF). NFT pathology is important since it correlates with the degree of cognitive impairment in AD. Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99%) is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease. Insulin dysfunction, manifested by diabetes mellitus (DM) might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since Tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment. Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia. PMID:24574966

A Pediatric Cardiology Fellowship Boot Camp improves trainee confidence.

PubMed

Allan, Catherine K; Tannous, Paul; DeWitt, Elizabeth; Farias, Michael; Mansfield, Laura; Ronai, Christina; Schidlow, David; Sanders, Stephen P; Lock, James E; Newburger, Jane W; Brown, David W

2016-12-01

Introduction New paediatric cardiology trainees are required to rapidly assimilate knowledge and gain clinical skills to which they have limited or no exposure during residency. The Pediatric Cardiology Fellowship Boot Camp (PCBC) at Boston Children's Hospital was designed to provide incoming fellows with an intensive exposure to congenital cardiac pathology and a broad overview of major areas of paediatric cardiology practice. The PCBC curriculum was designed by core faculty in cardiac pathology, echocardiography, electrophysiology, interventional cardiology, exercise physiology, and cardiac intensive care. Individual faculty contributed learning objectives, which were refined by fellowship directors and used to build a programme of didactics, hands-on/simulation-based activities, and self-guided learning opportunities. A total of 16 incoming fellows participated in the 4-week boot camp, with no concurrent clinical responsibilities, over 2 years. On the basis of pre- and post-PCBC surveys, 80% of trainees strongly agreed that they felt more prepared for clinical responsibilities, and a similar percentage felt that PCBC should be offered to future incoming fellows. Fellows showed significant increase in their confidence in all specific knowledge and skills related to the learning objectives. Fellows rated hands-on learning experiences and simulation-based exercises most highly. We describe a novel 4-week-long boot camp designed to expose incoming paediatric cardiology fellows to the broad spectrum of knowledge and skills required for the practice of paediatric cardiology. The experience increased trainee confidence and sense of preparedness to begin fellowship-related responsibilities. Given that highly interactive activities were rated most highly, boot camps in paediatric cardiology should strongly emphasise these elements.

Immunotherapy of tuberculosis with Mycobacterium leprae Hsp65 as a DNA vaccine triggers cross-reactive antibodies against mammalian Hsp60 but not pathological autoimmunity.

PubMed

Doimo, Nayara T S; Zárate-Bladés, Carlos R; Rodrigues, Rodrigo F; Tefé-Silva, Cristiane; Trotte, Marcele N S; Souza, Patrícia R M; Soares, Luana S; Rios, Wendy M; Floriano, Elaine M; Brandão, Izaira T; Masson, Ana P; Coelho, Verônica; Ramos, Simone G; Silva, Celio L

2014-01-01

Despite substantial efforts in recent years toward the development of new vaccines and drugs against tuberculosis (TB), success has remained elusive. Immunotherapy of TB with mycobacterial Hsp65 as a DNA vaccine (DNA-hsp65) results in a reduction of systemic bacterial loads and lung tissue damage, but the high homology of Hsp65 with the mammalian protein raises concern that pathological autoimmune responses may also be triggered. We searched for autoimmune responses elicited by DNA-hsp65 immunotherapy in mice chronically infected with TB by evaluating the humoral immune response and comprehensive histopathology using stereology. Cross-reactive antibodies between mycobacterial and mammalian Hsp60/65 were detected; however, no signs of pathological autoimmunity were found up to 60 days after the end of the therapy.

Survey of point-of-care instrumentation, analysis, and quality assurance in veterinary practice.

PubMed

Bell, Regan; Harr, Kendal; Rishniw, Mark; Pion, Paul

2014-06-01

While there have been ASVCP meeting discussions regarding quality assurance plans and lack thereof for in-clinic analyzers, there are little published data regarding in-clinic quality assurance and control practices. The purpose of this study was the identification of the common equipment used in hematologic, biochemical, urinalysis, and other testing, and assessment of quality control and assurance programs currently being performed in-clinic. All members of the Veterinary Information Network (VIN) were solicited to participate in an online survey between July and September 2007. In total, 452 complete or partial responses were received. Eighty-nine percent of respondents (361/404) said that veterinary technicians (unlicensed, licensed, and registered) performed the majority of analyses. Eighty-eight percent (366/417) of respondents performed some quality assurance on their laboratory equipment, most commonly on chemistry (91%, 324/357), and hematology (84%, 292/347) analyzers, and least commonly on fecal analyses (57%, 148/260) and ELISA assays (25%, 65/256). Ignorance of how to perform quality assurance was the most commonly stated reason (49%, 25/51) for lack of a quality assurance program. The majority of practices (316/374) utilized manufacturer-provided reference intervals without further adjustment or assessment. Roughly one-third of respondents (126/374) used reference intervals from textbooks, which is discouraged by ASVCP guidelines. This study found that the majority of respondents were not in compliance with ASVCP guidelines, illustrating the need for improved education of technical staff, veterinary students, and veterinarians regarding limitations of in-clinic laboratory equipment and the importance of regular quality control, maintenance, training, and reference interval development. © 2014 American Society for Veterinary Clinical Pathology and European Society for Veterinary Clinical Pathology.

[Somatotype of the patients with obesity and associated cardio-vascular patholodgy. Clinical and anthropological bonds].

PubMed

Bukavneva, N S; Pozdniakov, A L; Nikitiuk, D B

2008-01-01

In the article there are presented major anthropometric parameters of patients (male and female) with obesity, combined with cardiovascular pathology, before and after treatment. Constitutional predisposition to obesity is defined. Efficacy of dietary therapy is estimated and with obesity are defined on the basil of associated cardio-vascular pathology.

Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: implications for studying obesity-brain interactions in mice.

PubMed

Zhang, Le; Dasuri, Kalavathi; Fernandez-Kim, Sun-Ok; Bruce-Keller, Annadora J; Freeman, Linnea R; Pepping, Jennifer K; Beckett, Tina L; Murphy, M Paul; Keller, Jeffrey N

2013-09-01

Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aβ levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1β and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aβ in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aβ pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aβ pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease. Copyright © 2012. Published by Elsevier B.V.

The Pathology Laboratory Act 2007 explained.

PubMed

Looi, Lai-Meng

2008-06-01

The past century has seen tremendous changes in the scope and practice of pathology laboratories in tandem with the development of the medical services in Malaysia. Major progress was made in the areas of training and specialization of pathologists and laboratory technical staff. Today the pathology laboratory services have entered the International arena, and are propelled along the wave of globalization. Many new challenges have emerged as have new players in the field. Landmark developments over the past decade include the establishment of national quality assurance programmes, the mushrooming of private pathology laboratories, the establishment of a National Accreditation Standard for medical testing laboratories based on ISO 15189, and the passing of the Pathology Laboratory Act in Parliament in mid-2007. The Pathology Laboratory Act 2007 seeks to ensure that the pathology laboratory is accountable to the public, meets required standards of practice, participates in Quality Assurance programmes, is run by qualified staff, complies with safety requirements and is subject to continuous audit. The Act is applicable to all private laboratories (stand alone or hospital) and laboratories in statutory bodies (Universities, foundations). It is not applicable to public laboratories (established and operated by the government) and side-room laboratories established in clinics of registered medical or dental practitioners for their own patients (tests as in the First and Second Schedules respectively). Tests of the Third Schedule (home test blood glucose, urine glucose, urine pregnancy test) are also exempted. The Act has 13 Parts and provides for control of the pathology laboratory through approval (to establish and maintain) and licensing (to operate or provide). The approval or license may only be issued to a sole proprietor, partnership or body corporate, and then only if the entity includes a registered medical practitioner. Details of personnel qualifications and laboratory practices are left to be specified by the Director-General of Health, providing for a formal recognition process and room for revision as pathology practices evolve. Encompassed in the responsibilities of the licensee is the requirement that samples are received and results issued through, and management vested in, a registered medical or dental practitioner. This effectively prohibits "walk-ins" to the laboratory and indiscriminate public screening. The requirement for a person-in-charge in accordance with class and speciality of laboratory ensures that the laboratory is under the charge of the pathology profession. Examined carefully, the requirements of the Act are similar to laboratory accreditation, but are backed by legislation. Many of these details will be spelt out in the Regulations, and these in turn are likely to fall back on National professional guidelines, as accreditation does. Although not at first obvious, enforcement of the Act is based on self-regulation by pathology laboratory professionals. Sincere professional input is thus required to embrace its philosophy, ensure rational and transparent enforcement of legislation, and develop National guidelines for good pathology practices upon which enforcement may be based.

Attention problems and pathological gaming: resolving the 'chicken and egg' in a prospective analysis.

PubMed

Ferguson, Christopher J; Ceranoglu, T Atilla

2014-03-01

Pathological gaming (PG) behaviors are behaviors which interfere with other life responsibilities. Continued debate exists regarding whether symptoms of PG behaviors are a unique phenomenon or arise from other mental health problems, including attention problems. Development of attention problems and occurrence of pathological gaming in 144 adolescents were followed during a 1-year prospective analysis. Teens and their parents reported on pathological gaming behaviors, attention problems, and current grade point average, as well as several social variables. Results were analyzed using regression and path analysis. Attention problems tended to precede pathological gaming behaviors, but the inverse was not true. Attention problems but not pathological gaming predicted lower GPA 1 year later. Current results suggest that pathological gaming arises from attention problems, but not the inverse. These results suggest that pathological gaming behaviors are symptomatic of underlying attention related mental health issues, rather than a unique phenomenon.

The Evoked Potential. An Experimental Method for Biomechanical Analysis of Brain and Spinal Injury

DTIC Science & Technology

1980-01-01

Newtons produced marked changes in blood pressure, heart rate and distraction of the cervical spinal column with minimal ligamentous disruption...pathologic distraction and pathologic flexion of the thoracic ver- tebral column (8). Cerebral responses were lost within two minutes aftex complete...However, the immediate flexion and distraction responses were not altered. These findings suggest that mechanical trauma alters the spinal cord evoked

Molecular Pathology Informatics.

PubMed

Roy, Somak

2015-06-01

Molecular informatics (MI) is an evolving discipline that will support the dynamic landscape of molecular pathology and personalized medicine. MI provides a fertile ground for development of clinical solutions to bridge the gap between clinical informatics and bioinformatics. Rapid adoption of next generation sequencing (NGS) in the clinical arena has triggered major endeavors in MI that are expected to bring a paradigm shift in the practice of pathology. This brief review presents a broad overview of various aspects of MI, particularly in the context of NGS based testing. Copyright © 2015 Elsevier Inc. All rights reserved.

Longitudinal optical monitoring of blood flow in breast tumors during neoadjuvant chemotherapy

NASA Astrophysics Data System (ADS)

Cochran, J. M.; Chung, S. H.; Leproux, A.; Baker, W. B.; Busch, D. R.; DeMichele, A. M.; Tchou, J.; Tromberg, B. J.; Yodh, A. G.

2017-06-01

We measure tissue blood flow markers in breast tumors during neoadjuvant chemotherapy and investigate their correlation to pathologic complete response in a pilot longitudinal patient study (n  =  4). Tumor blood flow is quantified optically by diffuse correlation spectroscopy (DCS), and tissue optical properties, blood oxygen saturation, and total hemoglobin concentration are derived from concurrent diffuse optical spectroscopic imaging (DOSI). The study represents the first longitudinal DCS measurement of neoadjuvant chemotherapy in humans over the entire course of treatment; it therefore offers a first correlation between DCS flow indices and pathologic complete response. The use of absolute optical properties measured by DOSI facilitates significant improvement of DCS blood flow calculation, which typically assumes optical properties based on literature values. Additionally, the combination of the DCS blood flow index and the tissue oxygen saturation from DOSI permits investigation of tissue oxygen metabolism. Pilot results from four patients suggest that lower blood flow in the lesion-bearing breast is correlated with pathologic complete response. Both absolute lesion blood flow and lesion flow relative to the contralateral breast exhibit potential for characterization of pathological response. This initial demonstration of the combined optical approach for chemotherapy monitoring provides incentive for more comprehensive studies in the future and can help power those investigations.

Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities.

PubMed

Roybal, Kole T; Lim, Wendell A

2017-04-26

The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases.

Pathology of experimental Ebola virus infection in African green monkeys. Involvement of fibroblastic reticular cells.

PubMed

Davis, K J; Anderson, A O; Geisbert, T W; Steele, K E; Geisbert, J B; Vogel, P; Connolly, B M; Huggins, J W; Jahrling, P B; Jaax, N K

1997-08-01

Ebola virus has been responsible for explosive lethal outbreaks of hemorrhagic fever in both humans and nonhuman primates. Previous studies showed a predilection of Ebola virus for cells of the mononuclear phagocyte system and endothelial cells. To examine the distribution of lesions and Ebola virus antigen in the tissues of six adult male African green monkeys (Cercopithecus aethiops) that died 6 to 7 days after intraperitoneal inoculation of Ebola-Zaire (Mayinga) virus. Tissues were examined histologically, immunohistochemically, and ultrastructurally. A major novel finding of this study was that fibroblastic reticular cells were immunohistochemically and ultrastructurally identified as targets of Ebola virus infection. The role of Ebola virus-infected fibroblastic reticular cells in the pathogenesis of Ebola hemorrhagic fever warrants further investigation. This is especially important because of recent observations indicating that fibroblastic reticular cells, along with the reticular fibers they produce, maximize the efficiency of the immune response.

Synthetic Immunology: Hacking Immune Cells to Expand Their Therapeutic Capabilities

PubMed Central

Roybal, Kole T.; Lim, Wendell A.

2017-01-01

The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases. PMID:28446063

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

PubMed Central

Araya, Jun; Cambier, Stephanie; Markovics, Jennifer A.; Wolters, Paul; Jablons, David; Hill, Arthur; Finkbeiner, Walter; Jones, Kirk; Broaddus, V. Courtney; Sheppard, Dean; Barzcak, Andrea; Xiao, Yuanyuan; Erle, David J.; Nishimura, Stephen L.

2007-01-01

Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1β, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-β activation in amplifying SM and driving IL-1β–dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin αvβ8, which is the major mediator of airway fibroblast TGF-β activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-β as a potential therapeutic target for COPD. PMID:17965775

The endocrine and paracrine control of menstruation.

PubMed

Henriet, Patrick; Gaide Chevronnay, Héloïse P; Marbaix, Etienne

2012-07-25

During the reproductive life, the human endometrium undergoes cycles of substantial remodeling including, at menstruation, a massive but delimited tissue breakdown immediately followed by scarless repair. The present review aims at summarizing the current knowledge on the endocrine and paracrine control of menstruation in the light of recent observations that undermine obsolete dogmas. Menstruation can be globally considered as a response to falling progesterone concentration. However, tissue breakdown is heterogeneous and tightly controlled in space and time by a complex network of regulators and effectors, including cytokines, chemokines, proteases and various components of an inflammatory response. Moreover, menstruation must be regarded as part of a complex and integrated mechanism of tissue remodeling including features that precede and follow tissue lysis, i.e. decidualization and immediate post-menstrual regeneration. The understanding of the regulation of menstruation is of major basic and clinical interest. Indeed, these mechanisms largely overlap with those controlling other histopathological occurrences of tissue remodeling, such as development and cancer, and inappropriate control of menstrual features is a major potential cause of two frequent endometrial pathologies (i.e. abnormal uterine bleeding and endometriosis). Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Molecular Mechanisms Underlying Cardiac Adaptation to Exercise

PubMed Central

Vega, Rick B.; Konhilas, John P.; Kelly, Daniel P.; Leinwand, Leslie A.

2017-01-01

Exercise elicits coordinated multi-organ responses including skeletal muscle, vasculature, heart and lung. In the short term, the output of the heart increases to meet the demand of strenuous exercise. Long term exercise instigates remodeling of the heart including growth and adaptive molecular and cellular re-programming. Signaling pathways such as the insulin-like growth factor 1/PI3K/Akt pathway mediate many of these responses. Exercise-induced, or physiologic, cardiac growth contrasts with growth elicited by pathological stimuli such as hypertension. Comparing the molecular and cellular underpinnings of physiologic and pathologic cardiac growth has unveiled phenotype-specific signaling pathways and transcriptional regulatory programs. Studies suggest that exercise pathways likely antagonize pathological pathways, and exercise training is often recommended for patients with chronic stable heart failure or following myocardial infarction. Herein, we summarize the current understanding of the structural and functional cardiac responses to exercise as well as signaling pathways and downstream effector molecules responsible for these adaptations. PMID:28467921

Signal Transducer and Activator of Transcription Factor 6 Signaling Contributes to Control Host Lung Pathology but Favors Susceptibility against Toxocara canis Infection

PubMed Central

Faz-López, Berenice; Ledesma-Soto, Yadira; Romero-Sánchez, Yolanda; Calleja, Elsa; Martínez-Labat, Pablo; Terrazas, Luis I.

2013-01-01

Using STAT6−/− BALB/c mice, we have analyzed the role of STAT6-induced Th2 response in determining the outcome of experimental toxocariasis caused by embryonated eggs of the helminth parasite Toxocara canis. Following T. canis infection wild-type BALB/c mice developed a strong Th2-like response, produced high levels of IgG1, IgE, and IL-4, recruited alternatively activated macrophages, and displayed a moderate pathology in the lungs; however, they harbored heavy parasite loads in different tissues. In contrast, similarly infected STAT6−/− BALB/c mice mounted a weak Th2-like response, did not recruit alternatively activated macrophages, displayed a severe pathology in the lungs, but efficiently controlled T. canis infection. These findings demonstrate that Th2-like response induced via STAT6-mediated signaling pathway mediates susceptibility to larval stage of T. canis. Furthermore, they also indicate that unlike most gastrointestinal helminths, immunity against larvae of T. canis is not mediated by a Th2-dominant response. PMID:23509764

Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer.

PubMed

Irshad, Shazia; Bansal, Mukesh; Guarnieri, Paolo; Davis, Hayley; Al Haj Zen, Ayman; Baran, Brygida; Pinna, Claudia Maria Assunta; Rahman, Haseeb; Biswas, Sujata; Bardella, Chiara; Jeffery, Rosemary; Wang, Lai Mun; East, James Edward; Tomlinson, Ian; Lewis, Annabelle; Leedham, Simon John

2017-06-01

The functional role of bone morphogenetic protein (BMP) signalling in colorectal cancer (CRC) is poorly defined, with contradictory results in cancer cell line models reflecting the inherent difficulties of assessing a signalling pathway that is context-dependent and subject to genetic constraints. By assessing the transcriptional response of a diploid human colonic epithelial cell line to BMP ligand stimulation, we generated a prognostic BMP signalling signature, which was applied to multiple CRC datasets to investigate BMP heterogeneity across CRC molecular subtypes. We linked BMP and Notch signalling pathway activity and function in human colonic epithelial cells, and normal and neoplastic tissue. BMP induced Notch through a γ-secretase-independent interaction, regulated by the SMAD proteins. In homeostasis, BMP/Notch co-localization was restricted to cells at the top of the intestinal crypt, with more widespread interaction in some human CRC samples. BMP signalling was downregulated in the majority of CRCs, but was conserved specifically in mesenchymal-subtype tumours, where it interacts with Notch to induce an epithelial-mesenchymal transition (EMT) phenotype. In intestinal homeostasis, BMP-Notch pathway crosstalk is restricted to differentiating cells through stringent pathway segregation. Conserved BMP activity and loss of signalling stringency in mesenchymal-subtype tumours promotes a synergistic BMP-Notch interaction, and this correlates with poor patient prognosis. BMP signalling heterogeneity across CRC subtypes and cell lines can account for previous experimental contradictions. Crosstalk between the BMP and Notch pathways will render mesenchymal-subtype CRC insensitive to γ-secretase inhibition unless BMP activation is concomitantly addressed. © 2017 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Early vs late age at onset frontotemporal dementia and frontotemporal lobar degeneration.

PubMed

Seo, Sang Won; Thibodeau, Marie-Pierre; Perry, David C; Hua, Alice; Sidhu, Manu; Sible, Isabel; Vargas, Jose Norberto S; Gaus, Stephanie E; Rabinovici, Gil D; Rankin, Katherine D; Boxer, Adam L; Kramer, Joel H; Rosen, Howard J; Gorno-Tempini, Maria Luisa; Grinberg, Lea T; Huang, Eric J; DeArmond, Stephen J; Trojanowski, John Q; Miller, Bruce L; Seeley, William W

2018-03-20

To examine clinicopathologic correlations in early vs late age at onset frontotemporal dementia (FTD) and frontotemporal lobar degeneration (FTLD). All patients were clinically evaluated and prospectively diagnosed at the UCSF Memory and Aging Center. Two consecutive series were included: (1) patients with a clinically diagnosed FTD syndrome who underwent autopsy (cohort 1) and (2) patients with a primary pathologic diagnosis of FTLD, regardless of the clinical syndrome (cohort 2). These series were divided by age at symptom onset (cutoff 65 years). In cohort 1, 48 (25.3%) were 65 years or older at symptom onset. Pathologic causes of behavioral variant FTD (bvFTD) were similar in the early age at onset (EO) and late age at onset (LO) bvFTD groups. In corticobasal syndrome (CBS), however, the most common pathologic substrate differed according to age at onset: progressive supranuclear palsy (42.9%) in LO-CBS and Alzheimer disease (AD; 40.7%) in EO-CBS. In cohort 2, 57 (28.4%) were classified as LO-FTLD. Regarding FTLD major molecular classes, FTLD with transactive response DNA-binding protein of 43 kDa was most common in EO-FTLD (44.4%), whereas FTLD-tau (58.3%) was most common in LO-FTLD. Antemortem diagnosis of a non-FTD syndrome, usually AD-type dementia, was more frequent in LO-FTLD than EO-FTLD (19.3% vs 7.7%, p = 0.017). LO-FTLD was also associated with more prevalent comorbid pathologic changes. Of these, moderate to severe AD neuropathologic change and argyrophilic grain disease were overrepresented among patients who received an antemortem diagnosis of AD-type dementia. Patients with FTD and FTLD often develop symptoms after age 65, and age at onset represents an important consideration when making antemortem neuropathologic predictions. © 2018 American Academy of Neurology.

Src homology 2 domain-containing phosphatase 2 (Shp2) is a component of the A-kinase-anchoring protein (AKAP)-Lbc complex and is inhibited by protein kinase A (PKA) under pathological hypertrophic conditions in the heart.

PubMed

Burmeister, Brian T; Taglieri, Domenico M; Wang, Li; Carnegie, Graeme K

2012-11-23

AKAP-Lbc is a scaffold protein that coordinates cardiac hypertrophic signaling. AKAP-Lbc interacts with Shp2, facilitating its regulation by PKA. AKAP-Lbc integrates PKA and Shp2 signaling in the heart. Under pathological hypertrophic conditions Shp2 is phosphorylated by PKA, and phosphatase activity is inhibited. Inhibition of Shp2 activity through AKAP-Lbc-anchored PKA is a previously unrecognized mechanism that may promote pathological cardiac hypertrophy. Pathological cardiac hypertrophy (an increase in cardiac mass resulting from stress-induced cardiac myocyte growth) is a major factor underlying heart failure. Our results identify a novel mechanism of Shp2 inhibition that may promote cardiac hypertrophy. We demonstrate that the tyrosine phosphatase, Shp2, is a component of the A-kinase-anchoring protein (AKAP)-Lbc complex. AKAP-Lbc facilitates PKA phosphorylation of Shp2, which inhibits its protein-tyrosine phosphatase activity. Given the important cardiac roles of both AKAP-Lbc and Shp2, we investigated the AKAP-Lbc-Shp2 interaction in the heart. AKAP-Lbc-tethered PKA is implicated in cardiac hypertrophic signaling; however, mechanism of PKA action is unknown. Mutations resulting in loss of Shp2 catalytic activity are also associated with cardiac hypertrophy and congenital heart defects. Our data indicate that AKAP-Lbc integrates PKA and Shp2 signaling in the heart and that AKAP-Lbc-associated Shp2 activity is reduced in hypertrophic hearts in response to chronic β-adrenergic stimulation and PKA activation. Thus, while induction of cardiac hypertrophy is a multifaceted process, inhibition of Shp2 activity through AKAP-Lbc-anchored PKA is a previously unrecognized mechanism that may promote compensatory cardiac hypertrophy.

Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans

PubMed Central

Johnson, Victoria E.; Stewart, William; Trojanowski, John Q.

2012-01-01

The pathologic phosphorylation and sub-cellular translocation of neuronal transactive response-DNA binding protein (TDP-43) was identified as the major disease protein in frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions, now termed FTLD-TDP, and amyotrophic lateral sclerosis (ALS). More recently, TDP-43 proteinopathy has been reported in dementia pugilistica or chronic traumatic encephalopathy caused by repetitive traumatic brain injury (TBI). While a single TBI has been linked to the development of Alzheimer’s disease and an increased frequency of neurofibrillary tangles, TDP-43 proteinopathy has not been examined with survival following a single TBI. Using immunohistochemistry specific for both pathological phosphorylated TDP-43 (p-TDP-43) and phosphorylation-independent TDP-43 (pi-TDP-43), we examined acute (n = 23: Survival < 2 weeks) and long-term (n = 39; 1–47 years survival) survivors of a single TBI versus age-matched controls (n = 47). Multiple regions were examined including the hippocampus, medial temporal lobe, cingulate gyrus, superior frontal gyrus and brainstem. No association was found between a history of single TBI and abnormally phosphorylated TDP-43 (p-TDP-43) inclusions. Specifically, just 3 of 62 TBI cases displayed p-TDP-43 pathology versus 2 of 47 control cases. However, while aggregates of p-TDP-43 were not increased acutely or long-term following TBI, immunoreactivity to phosphorylation-independent TDP-43 was commonly increased in the cytoplasm following TBI with both acute and long-term survival. Moreover, while single TBI can induce multiple long-term neurodegenerative changes, the absence of TDP-43 proteinopathy may indicate a fundamental difference in the processes induced following single TBI from those of repetitive TBI. PMID:22101322

Mechanical disruption of the blood-brain barrier following experimental concussion.

PubMed

Johnson, Victoria E; Weber, Maura T; Xiao, Rui; Cullen, D Kacy; Meaney, David F; Stewart, William; Smith, Douglas H

2018-05-01

Although concussion is now recognized as a major health issue, its non-lethal nature has limited characterization of the underlying pathophysiology. In particular, potential neuropathological changes have typically been inferred from non-invasive techniques or post-mortem examinations of severe traumatic brain injury (TBI). Here, we used a swine model of head rotational acceleration based on human concussion to examine blood-brain barrier (BBB) integrity after injury in association with diffuse axonal injury and glial responses. We then determined the potential clinical relevance of the swine concussion findings through comparisons with pathological changes in human severe TBI, where post-mortem examinations are possible. At 6-72 h post-injury in swine, we observed multifocal disruption of the BBB, demonstrated by extravasation of serum proteins, fibrinogen and immunoglobulin-G, in the absence of hemorrhage or other focal pathology. BBB disruption was observed in a stereotyped distribution consistent with biomechanical insult. Specifically, extravasated serum proteins were frequently observed at interfaces between regions of tissue with differing material properties, including the gray-white boundary, periventricular and subpial regions. In addition, there was substantial overlap of BBB disruption with regions of axonal pathology in the white matter. Acute perivascular cellular uptake of blood-borne proteins was observed to be prominent in astrocytes (GFAP-positive) and neurons (MAP-2-positive), but not microglia (IBA1-positive). Parallel examination of human severe TBI revealed similar patterns of serum extravasation and glial uptake of serum proteins, but to a much greater extent than in the swine model, attributed to the higher injury severity. These data suggest that BBB disruption represents a new and important pathological feature of concussion.

Simulation of brain tumors in MR images for evaluation of segmentation efficacy.

PubMed

Prastawa, Marcel; Bullitt, Elizabeth; Gerig, Guido

2009-04-01

Obtaining validation data and comparison metrics for segmentation of magnetic resonance images (MRI) are difficult tasks due to the lack of reliable ground truth. This problem is even more evident for images presenting pathology, which can both alter tissue appearance through infiltration and cause geometric distortions. Systems for generating synthetic images with user-defined degradation by noise and intensity inhomogeneity offer the possibility for testing and comparison of segmentation methods. Such systems do not yet offer simulation of sufficiently realistic looking pathology. This paper presents a system that combines physical and statistical modeling to generate synthetic multi-modal 3D brain MRI with tumor and edema, along with the underlying anatomical ground truth, Main emphasis is placed on simulation of the major effects known for tumor MRI, such as contrast enhancement, local distortion of healthy tissue, infiltrating edema adjacent to tumors, destruction and deformation of fiber tracts, and multi-modal MRI contrast of healthy tissue and pathology. The new method synthesizes pathology in multi-modal MRI and diffusion tensor imaging (DTI) by simulating mass effect, warping and destruction of white matter fibers, and infiltration of brain tissues by tumor cells. We generate synthetic contrast enhanced MR images by simulating the accumulation of contrast agent within the brain. The appearance of the the brain tissue and tumor in MRI is simulated by synthesizing texture images from real MR images. The proposed method is able to generate synthetic ground truth and synthesized MR images with tumor and edema that exhibit comparable segmentation challenges to real tumor MRI. Such image data sets will find use in segmentation reliability studies, comparison and validation of different segmentation methods, training and teaching, or even in evaluating standards for tumor size like the RECIST criteria (response evaluation criteria in solid tumors).

Role of docosahexaenoic acid treatment in improving liver histology in pediatric nonalcoholic fatty liver disease.

PubMed

Nobili, Valerio; Carpino, Guido; Alisi, Anna; De Vito, Rita; Franchitto, Antonio; Alpini, Gianfranco; Onori, Paolo; Gaudio, Eugenio

2014-01-01

Nonalcoholic fatty liver disease (NAFLD) is one of the most important causes of liver-related morbidity and mortality in children. Recently, we have reported the effects of docosahexaenoic acid (DHA), the major dietary long-chain polyunsaturated fatty acids, in children with NAFLD. DHA exerts a potent anti-inflammatory activity through the G protein-coupled receptor (GPR)120. Our aim was to investigate in pediatric NAFLD the mechanisms underlying the effects of DHA administration on histo-pathological aspects, GPR120 expression, hepatic progenitor cell activation and macrophage pool. 20 children with untreated NAFLD were included. Children were treated with DHA for 18 months. Liver biopsies before and after the treatment were analyzed. Hepatic progenitor cell activation, macrophage pool and GPR120 expression were evaluated and correlated with clinical and histo-pathological parameters. GPR120 was expressed by hepatocytes, liver macrophages, and hepatic progenitor cells. After DHA treatment, the following modifications were present: i) the improvement of histo-pathological parameters such as NAFLD activity score, ballooning, and steatosis; ii) the reduction of hepatic progenitor cell activation in correlation with histo-pathological parameters; iii) the reduction of the number of inflammatory macrophages; iv) the increase of GPR120 expression in hepatocytes; v) the reduction of serine-311-phosphorylated nuclear factor kappa B (NF-κB) nuclear translocation in hepatocytes and macrophages in correlation with serum inflammatory cytokines. DHA could modulate hepatic progenitor cell activation, hepatocyte survival and macrophage polarization through the interaction with GPR120 and NF-κB repression. In this scenario, the modulation of GPR120 exploits a novel crucial role in the regulation of the cell-to-cell cross-talk that drives inflammatory response, hepatic progenitor cell activation and hepatocyte survival.

Perforant path synaptic loss correlates with cognitive impairment and Alzheimer's disease in the oldest-old.

PubMed

Robinson, John L; Molina-Porcel, Laura; Corrada, Maria M; Raible, Kevin; Lee, Edward B; Lee, Virginia M-Y; Kawas, Claudia H; Trojanowski, John Q

2014-09-01

Alzheimer's disease, which is defined pathologically by abundant amyloid plaques and neurofibrillary tangles concurrent with synaptic and neuronal loss, is the most common underlying cause of dementia in the elderly. Among the oldest-old, those aged 90 and older, other ageing-related brain pathologies are prevalent in addition to Alzheimer's disease, including cerebrovascular disease and hippocampal sclerosis. Although definite Alzheimer's disease pathology can distinguish dementia from normal individuals, the pathologies underlying cognitive impairment, especially in the oldest-old, remain poorly understood. We therefore conducted studies to determine the relative contributions of Alzheimer's disease pathology, cerebrovascular disease, hippocampal sclerosis and the altered expression of three synaptic proteins to cognitive status and global cognitive function. Relative immunohistochemistry intensity measures were obtained for synaptophysin, Synaptic vesicle transporter Sv2 (now known as SV2A) and Vesicular glutamate transporter 1 in the outer molecular layer of the hippocampal dentate gyrus on the first 157 participants of 'The 90+ Study' who came to autopsy, including participants with dementia (n = 84), those with cognitive impairment but no dementia (n = 37) and those with normal cognition (n = 36). Thal phase, Braak stage, cerebrovascular disease, hippocampal sclerosis and Pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) were also analysed. All measures were obtained blind to cognitive diagnosis. Global cognition was tested by the Mini-Mental State Examinaton. Logistic regression analysis explored the association between the pathological measures and the odds of being in the different cognitive groups whereas multiple regression analyses explored the association between pathological measures and global cognition scores. No measure clearly distinguished the control and cognitive impairment groups. Comparing the cognitive impairment and dementia groups, synaptophysin and SV2 were reduced, whereas Braak stage, TDP-43 and hippocampal sclerosis frequency increased. Thal phase and VGLUT1 did not distinguish the cognitive impairment and dementia groups. All measures distinguished the dementia and control groups and all markers associated with the cognitive test scores. When all markers were analysed simultaneously, a reduction in synaptophysin, a high Braak stage and the presence of TDP-43 and hippocampal sclerosis associated with global cognitive function. These findings suggest that tangle pathology, hippocampal sclerosis, TDP-43 and perforant pathway synaptic loss are the major contributors to dementia in the oldest-old. Although an increase in plaque pathology and glutamatergic synaptic loss may be early events associated with cognitive impairment, we conclude that those with cognitive impairment, but no dementia, are indistinguishable from cognitively normal subjects based on the measures reported here. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Vasculogenesis and Angiogenesis: Molecular and Cellular Controls

PubMed Central

Kubis, N.; Levy, B.I.

2003-01-01

Summary Angiogenesis characterizes embryonic development, but also occurs in adulthood in physiological situations such as adaptation to muscle exercise, and in pathological conditions like cancer. Major advances have been made in understanding the molecular mechanisms responsible for vasculogenesis and angiogenesis, largely due to the use of “knock-out mice”, i.e. mice in which the gene coding for the protein under investigation has been inactivated. Interestingly, the same growth factors and their receptors are equally involved in the different aspects of vasculogenesis and angiogenesis during development and in adulthood. This review aims to describe in detail their respective roles and how interactions between them lead to a newly formed vessel. PMID:20591248

Neoadjuvant trials in ER+ breast cancer: A tool for acceleration of drug development and discovery

PubMed Central

Guerrero-Zotano, Angel L.; Arteaga, Carlos L.

2017-01-01

Neoadjuvant therapy trials offer an excellent strategy for drug development and discovery in breast cancer, particularly in triple negative and HER2-overexpressing subtypes, where pathologic complete response is a good surrogate of long term patient benefit. For estrogen receptor (ER)-positive breast cancers, however, use of this strategy has been challenging because of the lack of validated surrogates of long term efficacy and the overall good prognosis of the majority of patients with this cancer subtype. We review below the clinical benefits of neodjuvant endocrine therapy for ER+/HER2-negative breast cancer, its use and limitations for drug development, prioritization of adjuvant and metastatic trials, and biomarker discovery. PMID:28495849

[Establishing Individualized Medicine for Intractable Cancer Based on Clinical Molecular Pathogenesis].

PubMed

Jono, Hirofumi

2018-01-01

　Although cancer treatment has dramatically improved with the development of molecular-targeted agents over the past decade, identifying eligible patients and predicting the therapeutic effects remain a major challenge. Because intratumoral heterogeneity represents genetic and molecular differences affecting patients' responses to these therapeutic agents, establishing individualized medicine based on precise molecular pathological analysis of tumors is urgently required. This review focuses on the pathogenesis of oral squamous cell carcinoma (OSCC), a common head and neck neoplasm, and introduces our approaches toward developing novel anticancer therapies particularly based on clinical molecular pathogenesis. Deeper understanding of more precise molecular pathogenesis in clinical settings may open up novel strategies for establishing individualized medicine for OSCC.

[The physical methods for the prevention and management of weather-dependent pathological reactions (a literature review)].

PubMed

Vasilenko, A M; Agasarov, L G; Sharipova, M M

The review presents data on the non-pharmacological methods and technologies for the prevention and management of meteopathic reactions (MPR) applied in Russia for the treatment of the patients suffering from obstructive and cardiovascular diseases. It is assumed, based on the concept of heliogeophysical imprinting, that the major factors responsible for the development of MPR are the disturbances of electromagnetic homeostasis. The acupuncture points and channels are regarded as a system designed for the maintenance of electromagnetic balance in the human body. In this context, it is proposed to encourage the application of the methods of electro-diagnostics and reflexology for the prevention and correction of meteopathic reactions.

Prevention of the Post-traumatic Fibrotic Response in Joints

DTIC Science & Technology

2014-10-01

an experimental model in mice. The American journal of forensic medicine and pathology . 1988; 9(4):310-2. 14 APPENDICES: An abstract...ongoing study addresses the critical clinical problem of posttraumatic joint stiffness, a pathology that reduces the range of motion (ROM) of injured...joints and contributes to the development of osteoarthritis. The fundamental hypothesis that drives the current study is that pathological fibrotic

Prediction of Pathological Complete Response Using Endoscopic Findings and Outcomes of Patients Who Underwent Watchful Waiting After Chemoradiotherapy for Rectal Cancer.

PubMed

Kawai, Kazushige; Ishihara, Soichiro; Nozawa, Hiroaki; Hata, Keisuke; Kiyomatsu, Tomomichi; Morikawa, Teppei; Fukayama, Masashi; Watanabe, Toshiaki

2017-04-01

Nonoperative management for patients with rectal cancer who have achieved a clinical complete response after chemoradiotherapy is becoming increasingly important in recent years. However, the definition of and modality used for patients with clinical complete response differ greatly between institutions, and the role of endoscopic assessment as a nonoperative approach has not been fully investigated. This study aimed to investigate the ability of endoscopic assessments to predict pathological regression of rectal cancer after chemoradiotherapy and the applicability of these assessments for the watchful waiting approach. This was a retrospective comparative study. This study was conducted at a single referral hospital. A total of 198 patients with rectal cancer underwent preoperative endoscopic assessments after chemoradiotherapy. Of them, 186 patients underwent radical surgery with lymph node dissection. The histopathological findings of resected tissues were compared with the preoperative endoscopic findings. Twelve patients refused radical surgery and chose watchful waiting; their outcomes were compared with the outcomes of patients who underwent radical surgery. The endoscopic criteria correlated well with tumor regression grading. The sensitivity and specificity for a pathological complete response were 65.0% to 87.1% and 39.1% to 78.3%. However, endoscopic assessment could not fully discriminate pathological complete responses, and the outcomes of patients who underwent watchful waiting were considerably poorer than the patients who underwent radical surgery. Eventually, 41.7% of the patients who underwent watchful waiting experienced uncontrollable local failure, and many of these occurrences were observed more than 3 years after chemoradiotherapy. The number of the patients treated with the watchful waiting strategy was limited, and the selection was not randomized. Although endoscopic assessment after chemoradiotherapy correlated with pathological response, it is unsuitable for surveillance of patients treated via a nonoperative approach. Incorporation of a "watchful waiting" strategy without establishing proper surveillance protocols and salvage strategies might result in poor local control.

Perfusion alterations converge with patterns of pathological spread in transactive response DNA-binding protein 43 proteinopathies.

PubMed

Ferraro, Pilar M; Jester, Charles; Olm, Christopher A; Placek, Katerina; Agosta, Federica; Elman, Lauren; McCluskey, Leo; Irwin, David J; Detre, John A; Filippi, Massimo; Grossman, Murray; McMillan, Corey T

2018-04-17

Amyotrophic lateral sclerosis (ALS) and the behavioral variant of frontotemporal dementia (bvFTD) commonly share the presence of transactive response DNA-binding protein 43 (TDP-43) inclusions. Structural magnetic resonance imaging studies demonstrated evidence for TDP-43 pathology spread, but while structural imaging usually reveals overt neuronal loss, perfusion imaging may detect more subtle neural activity alterations. We evaluated perfusion as an early marker for incipient pathology-associated brain alterations in TDP-43 proteinopathies. Cortical thickness (CT) and perfusion measurements were obtained in ALS (N = 18), pathologically and/or genetically confirmed bvFTD-TDP (N = 12), and healthy controls (N = 33). bvFTD showed reduced frontotemporal CT, hypoperfusion encompassing orbitofrontal and temporal cortices, and hyperperfusion in motor and occipital regions. ALS did not show reduced CT, but exhibited hypoperfusion in motor and temporal regions, and hyperperfusion in frontal and occipital cortices. Frontotemporal hypoperfusion and reduced CT correlated with cognitive and behavioral impairments as investigated using Mini-Mental State Examination and Philadelphia Brief Assessment of Cognition in bvFTD, and hypoperfusion in motor regions correlated with motor disability as measured by the ALS Functional Rating Scale-Revised in ALS. Hypoperfusion marked early pathologically involved regions, while hyperperfusion characterized regions of late pathological involvement. Distinct perfusion patterns may provide early markers of pathology distribution in TDP-43 proteinopathies. Copyright © 2018 Elsevier Inc. All rights reserved.

A Biomarker to Differentiate between Primary and Cocaine-Induced Major Depression in Cocaine Use Disorder: The Role of Platelet IRAS/Nischarin (I1-Imidazoline Receptor).

PubMed

Keller, Benjamin; Mestre-Pinto, Joan-Ignasi; Álvaro-Bartolomé, María; Martinez-Sanvisens, Diana; Farre, Magí; García-Fuster, M Julia; García-Sevilla, Jesús A; Torrens, Marta

2017-01-01

The association of cocaine use disorder (CUD) and comorbid major depressive disorder (MDD; CUD/MDD) is characterized by high prevalence and poor treatment outcomes. CUD/MDD may be primary (primary MDD) or cocaine-induced (CUD-induced MDD). Specific biomarkers are needed to improve diagnoses and therapeutic approaches in this dual pathology. Platelet biomarkers [5-HT 2A receptor and imidazoline receptor antisera selected (IRAS)/nischarin] were assessed by Western blot in subjects with CUD and primary MDD ( n  = 16) or CUD-induced MDD ( n  = 9; antidepressant free, AD-; antidepressant treated, AD+) and controls ( n  = 10) at basal level and/or after acute tryptophan depletion (ATD). Basal platelet 5-HT 2A receptor (monomer) was reduced in comorbid CUD/MDD subjects (all patients: 43%) compared to healthy controls, and this down-regulation was independent of AD medication (decreases in AD-: 47%, and in AD+: 40%). No basal differences were found for IRAS/nischarin contents in AD+ and AD- comorbid CUD/MDD subjects. The comparison of IRAS/nischarin in the different subject groups during/after ATD showed opposite modulations (i.e., increases and decreases) in response to low plasma tryptophan levels with significant differences discriminating between the subgroups of CUD with primary MDD and CUD-induced MDD. These specific alterations suggested that platelet IRAS/nischarin might be useful as a biomarker to discriminate between primary and CUD-induced MDD in this dual pathology.

A French-speaking speech-language pathology program in West Africa: transfer of training between Minority and Majority World countries.

PubMed

Topouzkhanian, Sylvia; Mijiyawa, Moustafa

2013-02-01

In West Africa, as in Majority World countries, people with a communication disability are generally cut-off from the normal development process. A long-term involvement of two partners (Orthophonistes du Monde and Handicap International) allowed the implementation in 2003 of the first speech-language pathology qualifying course in West Africa, within the Ecole Nationale des Auxiliaires Medicaux (ENAM, National School for Medical Auxiliaries) in Lome, Togo. It is a 3-year basic training (after the baccalaureate) in the only academic training centre for medical assistants in Togo. This department has a regional purpose and aims at training French-speaking African students. French speech-language pathology lecturers had to adapt their courses to the local realities they discovered in Togo. It was important to introduce and develop knowledge and skills in the students' system of reference. African speech-language pathologists have to face many challenges: creating an African speech and language therapy, introducing language disorders and their possible cure by means other than traditional therapies, and adapting all the evaluation tests and tools for speech-language pathology to each country, each culture, and each language. Creating an African speech-language pathology profession (according to its own standards) with a real influence in West Africa opens great opportunities for schooling and social and occupational integration of people with communication disabilities.

A Systematic Review and Meta-Analysis of Proteomics Literature on the Response of Human Skeletal Muscle to Obesity/Type 2 Diabetes Mellitus (T2DM) Versus Exercise Training

PubMed Central

Srisawat, Kanchana; Shepherd, Sam O.; Lisboa, Paulo J.

2017-01-01

We performed a systematic review and meta-analysis of proteomics literature that reports human skeletal muscle responses in the context of either pathological decline associated with obesity/T2DM and physiological adaptations to exercise training. Literature was collected from PubMed and DOAJ databases following PRISMA guidelines using the search terms ‘proteom*’, and ‘skeletal muscle’ combined with either ‘obesity, insulin resistance, diabetes, impaired glucose tolerance’ or ‘exercise, training’. Eleven studies were included in the systematic review, and meta-analysis was performed on a sub-set (four studies) of the reviewed literature that reported the necessary primary data. The majority of proteins (n = 73) more abundant in the muscle of obese/T2DM individuals were unique to this group and not reported to be responsive to exercise training. The main response of skeletal muscle to exercise training was a greater abundance of proteins of the mitochondrial electron transport chain, tricarboxylic acid cycle and mitochondrial respiratory chain complex I assembly. In total, five proteins were less abundant in muscle of obese/T2DM individuals and were also reported to be more abundant in the muscle of endurance-trained individuals, suggesting one of the major mechanisms of exercise-induced protection against the deleterious effects of obesity/T2DM occurs at complex I of the electron transport chain. PMID:29137117

Toxicologic Pathology: The Basic Building Block of Risk Assessment

EPA Science Inventory

Human health risk assessment is a critical factor in many risk management decisions. Evaluation of human health risk requires research the provides information that appropriately characterizes potential hazards from exposure. Pathology endpoints are the central response around ...

At the centre of neuronal, synaptic and axonal pathology in murine prion disease: degeneration of neuroanatomically linked thalamic and brainstem nuclei

PubMed Central

Reis, Renata; Hennessy, Edel; Murray, Caoimhe; Griffin, Éadaoin W.

2015-01-01

Aims The processes by which neurons degenerate in chronic neurodegenerative diseases remain unclear. Synaptic loss and axonal pathology frequently precede neuronal loss and protein aggregation demonstrably spreads along neuroanatomical pathways in many neurodegenerative diseases. The spread of neuronal pathology is less studied. Methods We previously demonstrated severe neurodegeneration in the posterior thalamus of multiple prion disease strains. Here we used the ME7 model of prion disease to examine the nature of this degeneration in the posterior thalamus and the major brainstem projections into this region. Results We objectively quantified neurological decline between 16 and 18 weeks post‐inoculation and observed thalamic subregion‐selective neuronal, synaptic and axonal pathology while demonstrating relatively uniform protease‐resistant prion protein (PrP) aggregation and microgliosis across the posterior thalamus. Novel amyloid precursor protein (APP) pathology was particularly prominent in the thalamic posterior (PO) and ventroposterior lateral (VPL) nuclei. The brainstem nuclei forming the major projections to these thalamic nuclei were examined. Massive neuronal loss in the PO was not matched by significant neuronal loss in the interpolaris (Sp5I), while massive synaptic loss in the ventral posteromedial nucleus (VPM) did correspond with significant neuronal loss in the principal trigeminal nucleus. Likewise, significant VPL synaptic loss was matched by significant neuronal loss in the gracile and cuneate nuclei. Conclusion These findings demonstrate significant spread of neuronal pathology from the thalamus to the brainstem in prion disease. The divergent neuropathological features in adjacent neuronal populations demonstrates that there are discrete pathways to neurodegeneration in different neuronal populations. PMID:25727649

MiRNA Expression Analysis of Pretreatment Biopsies Predicts the Pathological Response of Esophageal Squamous Cell Carcinomas to Neoadjuvant Chemoradiotherapy.

PubMed

Wen, Jing; Luo, Kongjia; Liu, Hui; Liu, Shiliang; Lin, Guangrong; Hu, Yi; Zhang, Xu; Wang, Geng; Chen, Yuping; Chen, Zhijian; Li, Yi; Lin, Ting; Xie, Xiuying; Liu, Mengzhong; Wang, Huiyun; Yang, Hong; Fu, Jianhua

2016-05-01

To identify miRNA markers useful for esophageal squamous cell carcinoma (ESCC) neoadjuvant chemoradiotherapy (neo-CRT) response prediction. Neo-CRT followed by surgery improves ESCC patients' survival compared with surgery alone. However, CRT outcomes are heterogeneous, and no current methods can predict CRT responses. Differentially expressed miRNAs between ESCC pathological responders and nonresponders after neo-CRT were identified by miRNA profiling and verified by real-time quantitative polymerase chain reaction (qPCR) of 27 ESCCs in the training set. Several class prediction algorithms were used to build the response-classifying models with the qPCR data. Predictive powers of the models were further assessed with a second set of 79 ESCCs. Ten miRNAs with greater than a 1.5-fold change between pathological responders and nonresponders were identified and verified, respectively. A support vector machine (SVM) prediction model, composed of 4 miRNAs (miR-145-5p, miR-152, miR-193b-3p, and miR-376a-3p), were developed. It provided overall accuracies of 100% and 87.3% for discriminating pathological responders and nonresponders in the training and external validation sets, respectively. In multivariate analysis, the subgroup determined by the SVM model was the only independent factor significantly associated with neo-CRT response in the external validation sets. Combined qPCR of the 4 miRNAs provides the possibility of ESCC neo-CRT response prediction, which may facilitate individualized ESCC treatment. Further prospective validation in larger independent cohorts is necessary to fully assess its predictive power.

Terms used in invertebrate pathology in five languages: English, French, German, Italian, Spanish.

Treesearch

Mauro E. Martignoni; Aloysius Krieg; Harold W. Rossmoore; Constantin Vago

1984-01-01

The exchange of information among invertebrate pathologists of the major linguistic areas of Western Europe and North America has created a demand for a multilingual glossary. This list of specialized terms used in invertebrate pathology and related fields, such as microbial control, comprises over 2200 entries gathered by the four authors with the help of several...

Immunotherapy of tuberculosis with Mycobacterium leprae Hsp65 as a DNA vaccine triggers cross-reactive antibodies against mammalian Hsp60 but not pathological autoimmunity

PubMed Central

Doimo, Nayara TS; Zárate-Bladés, Carlos R; Rodrigues, Rodrigo F; Tefé-Silva, Cristiane; Trotte, Marcele NS; Souza, Patrícia RM; Soares, Luana S; Rios, Wendy M; Floriano, Elaine M; Brandão, Izaira T; Masson, Ana P; Coelho, Verônica; Ramos, Simone G; Silva, Celio L

2014-01-01

Despite substantial efforts in recent years toward the development of new vaccines and drugs against tuberculosis (TB), success has remained elusive. Immunotherapy of TB with mycobacterial Hsp65 as a DNA vaccine (DNA-hsp65) results in a reduction of systemic bacterial loads and lung tissue damage, but the high homology of Hsp65 with the mammalian protein raises concern that pathological autoimmune responses may also be triggered. We searched for autoimmune responses elicited by DNA-hsp65 immunotherapy in mice chronically infected with TB by evaluating the humoral immune response and comprehensive histopathology using stereology. Cross-reactive antibodies between mycobacterial and mammalian Hsp60/65 were detected; however, no signs of pathological autoimmunity were found up to 60 days after the end of the therapy. PMID:24607935

Neuroinflammation: The Devil is in the Details

PubMed Central

DiSabato, Damon; Quan, Ning; Godbout, Jonathan P.

2016-01-01

There is significant interest in understanding inflammatory responses within the brain and spinal cord. Inflammatory responses that are centralized within the brain and spinal cord are generally referred to as “neuroinflammatory”. Aspects of neuroinflammation vary within the context of disease, injury, infection or stress. The context, course, and duration of these inflammatory responses are all critical aspects in the understanding of these processes and their corresponding physiological, biochemical and behavioral consequences. Microglia, innate immune cells of the central nervous system (CNS), play key roles in mediating these neuroinflammatory responses. Because the connotation of neuroinflammation is inherently negative and maladaptive, the majority of research focus is on the pathological aspects of neuroinflammation. There are, however, several degrees of neuroinflammatory responses, some of which are positive. In many circumstances including CNS injury, there is a balance of inflammatory and intrinsic repair processes that influences functional recovery. In addition, there are several other examples where communication between the brain and immune system involves neuroinflammatory processes that are beneficial and adaptive. The purpose of this review is to distinguish different variations of neuroinflammation in a context-specific manner and detail both positive and negative aspects of neuroinflammatory processes. PMID:26990767

Evaluation of chemotherapy response in patients with advanced head and neck cancer using [F-18]fluorodeoxyglucose positron emission tomography.

PubMed

Lowe, V J; Dunphy, F R; Varvares, M; Kim, H; Wittry, M; Dunphy, C H; Dunleavy, T; McDonough, E; Minster, J; Fletcher, J W; Boyd, J H

1997-12-01

[F-18]Fluorodeoxyglucose (FDG)-positron emission tomography (PET) can measure the metabolic activity of tissues; FDG-PET may be able to predict response to chemotherapy by identifying changes in tumor metabolism. Measurement of response to treatment may help improve survival in the management of advanced head and neck cancer. We evaluated this particular use of FDG-PET in patients participating in a neoadjuvant organ-preservation protocol using taxol and carboplatin and compared pathologic response after chemotherapy with changes in tumor metabolism measured by FDG-PET. Serial FDG-PET studies (n = 56) were performed in patients (n = 28) with stage III/IV head and neck cancer participating in a neoadjuvant organ-preservation protocol. The FDG-PET studies were performed before and after chemotherapy. All patients had tissue biopsies before and after chemotherapy. Patients were classified as pathologic complete response (PCR) or residual disease (RD) based on tissue biopsies. Visual analysis of PET scans was performed to identify patients with complete response by PET, and these findings were compared with pathology results. Metabolic changes were also evaluated using standardized uptake ratios (SUR) of FDG. The sensitivity and specificity of PET for residual cancer after therapy was 90% (19/21) and 83% (5/6), respectively. Two patients had initially negative biopsies and positive PET studies for persistent disease. Pathology review and rebiospy led to confirmation of the PET results in these cases, giving a sensitivity of 90% for initial tissue biopsy. In this preliminary analysis, FDG-PET was accurate in classifying response to chemotherapy in most patients. Fluorodeoxyglucose-PET may identify residual viable tumor when it is otherwise undetectable.

A survey study on student preferences regarding pathology teaching in Germany: a call for curricular modernization.

PubMed

Herrmann, Florian E M; Lenski, Markus; Steffen, Julius; Kailuweit, Magdalena; Nikolaus, Marc; Koteeswaran, Rajasekaran; Sailer, Andreas; Hanszke, Anna; Wintergerst, Maximilian; Dittmer, Sissi; Mayr, Doris; Genzel-Boroviczény, Orsolya; Eley, Diann S; Fischer, Martin R

2015-06-02

Pathology is a discipline that provides the basis of the understanding of disease in medicine. The past decades have seen a decline in the emphasis laid on pathology teaching in medical schools and outdated pathology curricula have worsened the situation. Student opinions and thoughts are central to the questions of whether and how such curricula should be modernized. A survey was conducted among 1018 German medical students regarding their preferences in pathology teaching modalities and their satisfaction with lecture-based courses. A qualitative analysis was performed comparing a recently modernized pathology curriculum with a traditional lecture-based curriculum. The differences in modalities of teaching used were investigated. Student satisfaction with the lecture-based curriculum positively correlated with student grades (spearman's correlation coefficient 0.24). Additionally, students with lower grades supported changing the curriculum (spearman's correlation coefficient 0.47). The majority supported virtual microscopy, autopsies, seminars and podcasts as preferred didactic methods. The data supports the implementation of a pathology curriculum where tutorials, autopsies and supplementary computer-based learning tools play important roles.

Virtual microscopy and digital pathology in training and education.

PubMed

Hamilton, Peter W; Wang, Yinhai; McCullough, Stephen J

2012-04-01

Traditionally, education and training in pathology has been delivered using textbooks, glass slides and conventional microscopy. Over the last two decades, the number of web-based pathology resources has expanded dramatically with centralized pathological resources being delivered to many students simultaneously. Recently, whole slide imaging technology allows glass slides to be scanned and viewed on a computer screen via dedicated software. This technology is referred to as virtual microscopy and has created enormous opportunities in pathological training and education. Students are able to learn key histopathological skills, e.g. to identify areas of diagnostic relevance from an entire slide, via a web-based computer environment. Students no longer need to be in the same room as the slides. New human-computer interfaces are also being developed using more natural touch technology to enhance the manipulation of digitized slides. Several major initiatives are also underway introducing online competency and diagnostic decision analysis using virtual microscopy and have important future roles in accreditation and recertification. Finally, researchers are investigating how pathological decision-making is achieved using virtual microscopy and modern eye-tracking devices. Virtual microscopy and digital pathology will continue to improve how pathology training and education is delivered. © 2012 The Authors APMIS © 2012 APMIS.

Computational pathology of pre-treatment biopsies identifies lymphocyte density as a predictor of response to neoadjuvant chemotherapy in breast cancer.

PubMed

Ali, H Raza; Dariush, Aliakbar; Provenzano, Elena; Bardwell, Helen; Abraham, Jean E; Iddawela, Mahesh; Vallier, Anne-Laure; Hiller, Louise; Dunn, Janet A; Bowden, Sarah J; Hickish, Tamas; McAdam, Karen; Houston, Stephen; Irwin, Mike J; Pharoah, Paul D P; Brenton, James D; Walton, Nicholas A; Earl, Helena M; Caldas, Carlos

2016-02-16

There is a need to improve prediction of response to chemotherapy in breast cancer in order to improve clinical management and this may be achieved by harnessing computational metrics of tissue pathology. We investigated the association between quantitative image metrics derived from computational analysis of digital pathology slides and response to chemotherapy in women with breast cancer who received neoadjuvant chemotherapy. We digitised tissue sections of both diagnostic and surgical samples of breast tumours from 768 patients enrolled in the Neo-tAnGo randomized controlled trial. We subjected digital images to systematic analysis optimised for detection of single cells. Machine-learning methods were used to classify cells as cancer, stromal or lymphocyte and we computed estimates of absolute numbers, relative fractions and cell densities using these data. Pathological complete response (pCR), a histological indicator of chemotherapy response, was the primary endpoint. Fifteen image metrics were tested for their association with pCR using univariate and multivariate logistic regression. Median lymphocyte density proved most strongly associated with pCR on univariate analysis (OR 4.46, 95 % CI 2.34-8.50, p < 0.0001; observations = 614) and on multivariate analysis (OR 2.42, 95 % CI 1.08-5.40, p = 0.03; observations = 406) after adjustment for clinical factors. Further exploratory analyses revealed that in approximately one quarter of cases there was an increase in lymphocyte density in the tumour removed at surgery compared to diagnostic biopsies. A reduction in lymphocyte density at surgery was strongly associated with pCR (OR 0.28, 95 % CI 0.17-0.47, p < 0.0001; observations = 553). A data-driven analysis of computational pathology reveals lymphocyte density as an independent predictor of pCR. Paradoxically an increase in lymphocyte density, following exposure to chemotherapy, is associated with a lack of pCR. Computational pathology can provide objective, quantitative and reproducible tissue metrics and represents a viable means of outcome prediction in breast cancer. ClinicalTrials.gov NCT00070278 ; 03/10/2003.

[The importance and possibilities of cognitive reconstructing in the therapy of pathological gambling].

PubMed

Körmendi, Attila

2009-01-01

Cognitive reconstructing is a major component of cognitive and cognitive-behavioural therapies. Cognitive reconstructing means identification and modification of cognitive distortions. Research into this field has shown that cognitive distortions about gambling are clearly implicated in the development and persistence of pathological gambling. This paper outlines the use of cognitive reconstructing for the therapy of pathological gambling. It highlights the type of cognitive distortions most common to this population and outlines the role of semistructured interviews as tool for exploring these distortions. Modification of these beliefs with Socratic dialog is also discussed in the paper. Finally, it describes the studies conducted so far to assess the therapeutic efficacy of cognitive reconstructing in treating pathological gambling.

Online teaching of inflammatory skin pathology by a French-speaking International University Network

PubMed Central

2014-01-01

Introduction Developments in technology, web-based teaching and whole slide imaging have broadened the teaching horizon in anatomic pathology. Creating online learning material including many types of media such as radiologic images, whole slides, videos, clinical and macroscopic photographs, is now accessible to most universities. Unfortunately, a major limiting factor to maintain and update the learning material is the amount of resources needed. In this perspective, a French-national university network was initiated in 2011 to build joint online teaching modules consisting of clinical cases and tests. The network has since expanded internationally to Québec, Switzerland and Ivory Coast. Method One of the first steps of the project was to build a learning module on inflammatory skin pathology for interns and residents in pathology and dermatology. A pathology resident from Québec spent 6 weeks in France and Switzerland to develop the contents and build the module on an e-learning Moodle platform under the supervision of two dermatopathologists. The learning module contains text, interactive clinical cases, tests with feedback, virtual slides, images and clinical photographs. For that module, the virtual slides are decentralized in 2 universities (Bordeaux and Paris 7). Each university is responsible of its own slide scanning, image storage and online display with virtual slide viewers. Results The module on inflammatory skin pathology includes more than 50 web pages with French original content, tests and clinical cases, links to over 45 virtual images and more than 50 microscopic and clinical photographs. The whole learning module is being revised by four dermatopathologists and two senior pathologists. It will be accessible to interns and residents in the spring of 2014. The experience and knowledge gained from that work will be transferred to the next international resident whose work will be aimed at creating lung and breast pathology learning modules. Conclusion The challenges of sustaining a project of this scope are numerous. The technical aspect of whole-slide imaging and storage needs to be developed by each university or group. The content needs to be regularly updated and its accuracy reviewed by experts in each individual domain. The learning modules also need to be promoted within the academic community to ensure maximal benefit for trainees. A collateral benefit of the project was the establishment of international partnerships between French-speaking universities and pathologists with the common goal of promoting pathology education through the use of multi-media technology including whole slide imaging. PMID:25564778

Online teaching of inflammatory skin pathology by a French-speaking International University Network.

PubMed

Perron, Emilie; Battistella, Maxime; Vergier, Béatrice; Fiche, Maryse; Bertheau, Philippe; Têtu, Bernard

2014-01-01

Developments in technology, web-based teaching and whole slide imaging have broadened the teaching horizon in anatomic pathology. Creating online learning material including many types of media such as radiologic images, whole slides, videos, clinical and macroscopic photographs, is now accessible to most universities. Unfortunately, a major limiting factor to maintain and update the learning material is the amount of resources needed. In this perspective, a French-national university network was initiated in 2011 to build joint online teaching modules consisting of clinical cases and tests. The network has since expanded internationally to Québec, Switzerland and Ivory Coast. One of the first steps of the project was to build a learning module on inflammatory skin pathology for interns and residents in pathology and dermatology. A pathology resident from Québec spent 6 weeks in France and Switzerland to develop the contents and build the module on an e-learning Moodle platform under the supervision of two dermatopathologists. The learning module contains text, interactive clinical cases, tests with feedback, virtual slides, images and clinical photographs. For that module, the virtual slides are decentralized in 2 universities (Bordeaux and Paris 7). Each university is responsible of its own slide scanning, image storage and online display with virtual slide viewers. The module on inflammatory skin pathology includes more than 50 web pages with French original content, tests and clinical cases, links to over 45 virtual images and more than 50 microscopic and clinical photographs. The whole learning module is being revised by four dermatopathologists and two senior pathologists. It will be accessible to interns and residents in the spring of 2014. The experience and knowledge gained from that work will be transferred to the next international resident whose work will be aimed at creating lung and breast pathology learning modules. The challenges of sustaining a project of this scope are numerous. The technical aspect of whole-slide imaging and storage needs to be developed by each university or group. The content needs to be regularly updated and its accuracy reviewed by experts in each individual domain. The learning modules also need to be promoted within the academic community to ensure maximal benefit for trainees. A collateral benefit of the project was the establishment of international partnerships between French-speaking universities and pathologists with the common goal of promoting pathology education through the use of multi-media technology including whole slide imaging.

Collateral non cardiac findings in clinical routine CT coronary angiography: results from a multi-center registry.

PubMed

La Grutta, Ludovico; Malagò, Roberto; Maffei, Erica; Barbiani, Camilla; Pezzato, Andrea; Martini, Chiara; Arcadi, Teresa; Clemente, Alberto; Mollet, Nico R; Zuccarelli, Alessandra; Krestin, Gabriel P; Lagalla, Roberto; Pozzi Mucelli, Roberto; Cademartiri, Filippo; Midiri, Massimo

2015-12-01

The aim of the study was to evaluate the prevalence of collateral findings detected in computed tomography coronary angiography (CTCA) in a multi-center registry. We performed a retrospective review of 4303 patients (2719 males, mean age 60.3 ± 10.2 years) undergoing 64-slice CTCA for suspected or known coronary artery disease (CAD) at various academic institutions between 01/2006 and 09/2010. Collateral findings were recorded and scored as: non-significant (no signs of relevant pathology, not necessary to be reported), significant (clear signs of pathology, mandatory to be reported), or major (remarkable pathology, mandatory to be reported and further investigated). We detected 6886 non-cardiac findings (1.6 non cardiac finding per patient). Considering all centers, only 865/4303 (20.1 %) patients were completely without any additional finding. Overall, 2095 (30.4 %) non-significant, 4486 (65.2 %) significant, and 305 (4.4 %) major findings were detected. Among major findings, primary lung cancer was reported in 21 cases. In every center, most prevalent significant findings were mediastinal lymph nodes >1 cm. In 256 patients, collateral findings were clinically more relevant than coexisting CAD and justified the symptoms of patients. The prevalence of significant and major collateral findings in CTCA is high. Radiologists should carefully evaluate the entire scan volume in each patient.

Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

PubMed Central

Chandele, Anmol; Sewatanon, Jaturong; Gunisetty, Sivaram; Singla, Mohit; Onlamoon, Nattawat; Akondy, Rama S.; Kissick, Haydn Thomas; Nayak, Kaustuv; Reddy, Elluri Seetharami; Kalam, Haroon; Kumar, Dhiraj; Verma, Anil; Panda, HareKrushna; Wang, Siyu; Angkasekwinai, Nasikarn; Pattanapanyasat, Kovit; Chokephaibulkit, Kulkanya; Lodha, Rakesh; Kabra, Sushil; Ahmed, Rafi

2016-01-01

ABSTRACT Epidemiological studies suggest that India has the largest number of dengue virus infection cases worldwide. However, there is minimal information about the immunological responses in these patients. CD8 T cells are important in dengue, because they have been implicated in both protection and immunopathology. Here, we provide a detailed analysis of HLA-DR+ CD38+ and HLA-DR− CD38+ effector CD8 T cell subsets in dengue patients from India and Thailand. Both CD8 T cell subsets expanded and expressed markers indicative of antigen-driven proliferation, tissue homing, and cytotoxic effector functions, with the HLA-DR+ CD38+ subset being the most striking in these effector qualities. The breadth of the dengue-specific CD8 T cell response was diverse, with NS3-specific cells being the most dominant. Interestingly, only a small fraction of these activated effector CD8 T cells produced gamma interferon (IFN-γ) when stimulated with dengue virus peptide pools. Transcriptomics revealed downregulation of key molecules involved in T cell receptor (TCR) signaling. Consistent with this, the majority of these CD8 T cells remained IFN-γ unresponsive even after TCR-dependent polyclonal stimulation (anti-CD3 plus anti-CD28) but produced IFN-γ by TCR-independent polyclonal stimulation (phorbol 12-myristate 13-acetate [PMA] plus ionomycin). Thus, the vast majority of these proliferating, highly differentiated effector CD8 T cells probably acquire TCR refractoriness at the time the patient is experiencing febrile illness that leads to IFN-γ unresponsiveness. Our studies open novel avenues for understanding the mechanisms that fine-tune the balance between CD8 T cell-mediated protective versus pathological effects in dengue. IMPORTANCE Dengue is becoming a global public health concern. Although CD8 T cells have been implicated both in protection and in the cytokine-mediated immunopathology of dengue, how the balance is maintained between these opposing functions remains unknown. We comprehensively characterized CD8 T cell subsets in dengue patients from India and Thailand and show that these cells expand massively and express phenotypes indicative of overwhelming antigenic stimulus and tissue homing/cytotoxic-effector functions but that a vast majority of them fail to produce IFN-γ in vitro. Interestingly, the cells were fully capable of producing the cytokine when stimulated in a T cell receptor (TCR)-independent manner but failed to do so in TCR-dependent stimulation. These results, together with transcriptomics, revealed that the vast majority of these CD8 T cells from dengue patients become cytokine unresponsive due to TCR signaling insufficiencies. These observations open novel avenues for understanding the mechanisms that fine-tune the balance between CD8-mediated protective versus pathological effects. PMID:27707928

Pathological gambling in Montreal's Chinese community: an anthropological perspective.

PubMed

Papineau, Elisabeth

2005-01-01

Pathological gambling has been identified as a major issue in Montreal's Chinese community. A variety of sources attest to the fact that, though we live in an increasingly heterogeneous society, the services provided to minority communities for preventing and treating pathological gambling are inadequate. An anthropological approach that takes into account cultural characteristics of one's community could lead to better strategies for acknowledgement, definition, diagnosis and treatment of pathological gambling among culturally different communities. Research paths that could help to provide effective treatment and services to specific populations are suggested. An overview of the way the Chinese view gambling, pathological gambling and treatment is presented. The concepts of fate, destiny and luck in Chinese thought, as well as Montreal's Chinese community social norms related to gambling are then described. The incorporation of those cultural understandings in future studies and treatment attempts is suggested.

Proteomic profiling of the brain of mice with experimental cerebral malaria.

PubMed

Moussa, Ehab; Huang, Honglei; Ahras, Malika; Lall, Amar; Thezenas, Marie L; Fischer, Roman; Kessler, Benedikt M; Pain, Arnab; Billker, Oliver; Casals-Pascual, Climent

2018-05-30

Cerebral malaria (CM) is a severe neurological complication of malaria infection in both adults and children. In pursuit of effective treatment of CM, clinical studies, postmortem analysis and animal models have been employed to understand the pathology and identify effective interventions. In this study, a shotgun proteomics analysis was conducted to profile the proteomic signature of the brain tissue of mice with experimental cerebral malaria (ECM) in order to further understand the underlying pathology. To identify CM-associated response, proteomic signatures of the brains of C57/Bl6N mice infected with P. berghei ANKA that developed neurological syndrome were compared to those of mice infected with P. berghei NK65 that developed equally high parasite burdens without neurological signs, and to those of non-infected mice. The results show that the CM-associated response in mice that developed neurological signs comprise mainly acute-phase reaction and coagulation cascade activation, and indicate the leakage of plasma proteins into the brain parenchyma. Cerebral malaria (CM) remains a major cause of death in children. The majority of these deaths occur in sub-Saharan Africa. Even with adequate access to treatment, mortality remains high and neurological sequelae can be found in up to 20% of survivors. No adjuvant treatment to date has been shown to reduce mortality and the pathophysiology of CM is largely unknown. Experimental cerebral malaria (ECM) is a well-established model that may contribute to identify and test druggable targets. In this study we have identified the disruption of the blood-brain barrier following inflammatory and vascular injury as a mechanism of disease. In this study we report a number of proteins that could be validated as potential biomarkers of ECM. Further studies, will be required to validate the clinical relevance of these biomarkers in human CM. Copyright © 2017 Elsevier B.V. All rights reserved.

TDP-43 stage, mixed pathologies, and clinical Alzheimer’s-type dementia

PubMed Central

James, Bryan D.; Wilson, Robert S.; Boyle, Patricia A.; Trojanowski, John Q.; Bennett, David A.; Schneider, Julie A.

2016-01-01

Hyperphosphorylated transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP) proteinopathy has recently been described in ageing and in association with cognitive impairment, especially in the context of Alzheimer’s disease pathology. To explore the role of mixed Alzheimer’s disease and TDP-43 pathologies in clinical Alzheimer’s-type dementia, we performed a comprehensive investigation of TDP-43, mixed pathologies, and clinical Alzheimer’s-type dementia in a large cohort of community-dwelling older subjects. We tested the hypotheses that TDP-43 with Alzheimer’s disease pathology is a common mixed pathology; is related to increased likelihood of expressing clinical Alzheimer’s-type dementia; and that TDP-43 pathologic stage is an important determinant of clinical Alzheimer’s-type dementia. Data came from 946 older adults with (n = 398) and without dementia (n = 548) from the Rush Memory and Aging Project and Religious Orders Study. TDP-43 proteinopathy (cytoplasmic inclusions) was present in 496 (52%) subjects, and the pattern of deposition was classified as stage 0 (none; 48%), stage 1 (amygdala; 18%), stage 2 (extension to hippocampus/entorhinal; 21%), or stage 3 (extension to neocortex; 14%). TDP-43 pathology combined with a pathologic diagnosis of Alzheimer’s disease was a common mixed pathology (37% of all participants), and the proportion of subjects with clinical Alzheimer’s-type dementia formerly labelled ‘pure pathologic diagnosis of Alzheimer’s disease’ was halved when TDP-43 was considered. In logistic regression models adjusted for age, sex, and education, TDP-43 pathology was associated with clinical Alzheimer’s-type dementia (odds ratio = 1.51, 95% confidence interval = 1.11, 2.05) independent of pathological Alzheimer’s disease (odds ratio = 4.30, 95% confidence interval = 3.08, 6.01) or other pathologies (infarcts, arteriolosclerosis, Lewy bodies, and hippocampal sclerosis). Mixed Alzheimer’s disease and TDP-43 pathologies were associated with higher odds of clinical Alzheimer’s-type dementia (odds ratio = 6.73, 95% confidence interval = 4.18, 10.85) than pathologic Alzheimer’s disease alone (odds ratio = 4.62, 95% confidence interval = 2.84, 7.52). In models examining TDP-43 stage, a dose-response relationship with clinical Alzheimer’s-type dementia was observed, and a significant association was observed starting at stage 2, extension beyond the amygdala. In this large sample from almost 1000 community participants, we observed that TDP-43 proteinopathy was very common, frequently mixed with pathological Alzheimer’s disease, and associated with a higher likelihood of the clinical expression of clinical Alzheimer’s-type dementia but only when extended beyond the amygdala. PMID:27694152

Coadministration of the Three Antigenic Leishmania infantum Poly (A) Binding Proteins as a DNA Vaccine Induces Protection against Leishmania major Infection in BALB/c Mice

PubMed Central

Corvo, Laura; Garde, Esther; Ramírez, Laura; Iniesta, Virginia; Bonay, Pedro; Gómez-Nieto, Carlos; González, Víctor M.; Martín, M. Elena; Alonso, Carlos; Coelho, Eduardo A. F.; Barral, Aldina; Barral-Netto, Manoel

2015-01-01

Background Highly conserved intracellular proteins from Leishmania have been described as antigens in natural and experimental infected mammals. The present study aimed to evaluate the antigenicity and prophylactic properties of the Leishmania infantum Poly (A) binding proteins (LiPABPs). Methodology/Principal Findings Three different members of the LiPABP family have been described. Recombinant tools based on these proteins were constructed: recombinant proteins and DNA vaccines. The three recombinant proteins were employed for coating ELISA plates. Sera from human and canine patients of visceral leishmaniasis and human patients of mucosal leishmaniasis recognized the three LiPABPs. In addition, the protective efficacy of a DNA vaccine based on the combination of the three Leishmania PABPs has been tested in a model of progressive murine leishmaniasis: BALB/c mice infected with Leishmania major. The induction of a Th1-like response against the LiPABP family by genetic vaccination was able to down-regulate the IL-10 predominant responses elicited by parasite LiPABPs after infection in this murine model. This modulation resulted in a partial protection against L. major infection. LiPABP vaccinated mice showed a reduction on the pathology that was accompanied by a decrease in parasite burdens, in antibody titers against Leishmania antigens and in the IL-4 and IL-10 parasite-specific mediated responses in comparison to control mice groups immunized with saline or with the non-recombinant plasmid. Conclusion/Significance The results presented here demonstrate for the first time the prophylactic properties of a new family of Leishmania antigenic intracellular proteins, the LiPABPs. The redirection of the immune response elicited against the LiPABP family (from IL-10 towards IFN-γ mediated responses) by genetic vaccination was able to induce a partial protection against the development of the disease in a highly susceptible murine model of leishmaniasis. PMID:25955652

Ethanol metabolism and oxidative stress are required for unfolded protein response activation and steatosis in zebrafish with alcoholic liver disease

PubMed Central

Tsedensodnom, Orkhontuya; Vacaru, Ana M.; Howarth, Deanna L.; Yin, Chunyue; Sadler, Kirsten C.

2013-01-01

SUMMARY Secretory pathway dysfunction and lipid accumulation (steatosis) are the two most common responses of hepatocytes to ethanol exposure and are major factors in the pathophysiology of alcoholic liver disease (ALD). However, the mechanisms by which ethanol elicits these cellular responses are not fully understood. Recent data indicates that activation of the unfolded protein response (UPR) in response to secretory pathway dysfunction can cause steatosis. Here, we examined the relationship between alcohol metabolism, oxidative stress, secretory pathway stress and steatosis using zebrafish larvae. We found that ethanol was immediately internalized and metabolized by larvae, such that the internal ethanol concentration in 4-day-old larvae equilibrated to 160 mM after 1 hour of exposure to 350 mM ethanol, with an average ethanol metabolism rate of 56 μmol/larva/hour over 32 hours. Blocking alcohol dehydrogenase 1 (Adh1) and cytochrome P450 2E1 (Cyp2e1), the major enzymes that metabolize ethanol, prevented alcohol-induced steatosis and reduced induction of the UPR in the liver. Thus, we conclude that ethanol metabolism causes ALD in zebrafish. Oxidative stress generated by Cyp2e1-mediated ethanol metabolism is proposed to be a major culprit in ALD pathology. We found that production of reactive oxygen species (ROS) increased in larvae exposed to ethanol, whereas inhibition of the zebrafish CYP2E1 homolog or administration of antioxidants reduced ROS levels. Importantly, these treatments also blocked ethanol-induced steatosis and reduced UPR activation, whereas hydrogen peroxide (H2O2) acted as a pro-oxidant that synergized with low doses of ethanol to induce the UPR. Collectively, these data demonstrate that ethanol metabolism and oxidative stress are conserved mechanisms required for the development of steatosis and hepatic dysfunction in ALD, and that these processes contribute to ethanol-induced UPR activation and secretory pathway stress in hepatocytes. PMID:23798569

The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces

PubMed Central

Statovci, Donjete; Aguilera, Mònica; MacSharry, John; Melgar, Silvia

2017-01-01

Recent findings point toward diet having a major impact on human health. Diets can either affect the gut microbiota resulting in alterations in the host’s physiological responses or by directly targeting the host response. The microbial community in the mammalian gut is a complex and dynamic system crucial for the development and maturation of both systemic and mucosal immune responses. Therefore, the complex interaction between available nutrients, the microbiota, and the immune system are central regulators in maintaining homeostasis and fighting against invading pathogens at mucosal sites. Westernized diet, defined as high dietary intake of saturated fats and sucrose and low intake of fiber, represent a growing health risk contributing to the increased occurrence of metabolic diseases, e.g., diabetes and obesity in countries adapting a westernized lifestyle. Inflammatory bowel diseases (IBD) and asthma are chronic mucosal inflammatory conditions of unknown etiology with increasing prevalence worldwide. These conditions have a multifactorial etiology including genetic factors, environmental factors, and dysregulated immune responses. Their increased prevalence cannot solely be attributed to genetic considerations implying that other factors such as diet can be a major contributor. Recent reports indicate that the gut microbiota and modifications thereof, due to a consumption of a diet high in saturated fats and low in fibers, can trigger factors regulating the development and/or progression of both conditions. While asthma is a disease of the airways, increasing evidence indicates a link between the gut and airways in disease development. Herein, we provide a comprehensive review on the impact of westernized diet and associated nutrients on immune cell responses and the microbiota and how these can influence the pathology of IBD and asthma. PMID:28804483

Type 2 responses at the interface between immunity and fat metabolism.

PubMed

Odegaard, Justin I; Chawla, Ajay

2015-10-01

Adipose tissue resident leukocytes are often cast solely as the effectors of obesity and its attendant pathologies; however, recent observations have demonstrated that these cells support and effect 'healthy' physiologic function as well as pathologic dysfunction. Importantly, these two disparate outcomes are underpinned by similarly disparate immune programs; type 2 responses instruct and promote metabolic normalcy, while type 1 responses drive tissue dysfunction. In this Review, we summarize the literature regarding type 2 immunity's role in adipose tissue physiology and allude to its potential therapeutic implications. Copyright © 2015 Elsevier Ltd. All rights reserved.

Role of genetic polymorphisms in NFKB-mediated inflammatory pathways in response to primary chemoradiation therapy for rectal cancer.

PubMed

Dzhugashvili, Maia; Luengo-Gil, Ginés; García, Teresa; González-Conejero, Rocío; Conesa-Zamora, Pablo; Escolar, Pedro Pablo; Calvo, Felipe; Vicente, Vicente; Ayala de la Peña, Francisco

2014-11-01

To investigate whether polymorphisms of genes related to inflammation are associated with pathologic response (primary endpoint) in patients with rectal cancer treated with primary chemoradiation therapy (PCRT). Genomic DNA of 159 patients with locally advanced rectal cancer treated with PCRT was genotyped for polymorphisms rs28362491 (NFKB1), rs1213266/rs5789 (PTGS1), rs5275 (PTGS2), and rs16944/rs1143627 (IL1B) using TaqMan single nucleotide polymorphism genotyping assays. The association between each genotype and pathologic response (poor response vs complete or partial response) was analyzed using logistic regression models. The NFKB1 DEL/DEL genotype was associated with pathologic response (odds ratio [OR], 6.39; 95% confidence interval [CI], 0.78-52.65; P=.03) after PCRT. No statistically significant associations between other polymorphisms and response to PCRT were observed. Patients with the NFKB1 DEL/DEL genotype showed a trend for longer disease-free survival (log-rank test, P=.096) and overall survival (P=.049), which was not significant in a multivariate analysis that included pathologic response. Analysis for 6 polymorphisms showed that patients carrying the haplotype rs28362491-DEL/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G (13.7% of cases) had a higher response rate to PCRT (OR, 8.86; 95% CI, 1.21-64.98; P=.034) than the reference group (rs28362491-INS/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G). Clinically significant (grade ≥2) acute organ toxicity was also more frequent in patients with that same haplotype (OR, 4.12; 95% CI, 1.11-15.36; P=.037). Our results suggest that genetic variation in NFKB-related inflammatory pathways might influence sensitivity to primary chemoradiation for rectal cancer. If confirmed, an inflammation-related radiogenetic profile might be used to select patients with rectal cancer for preoperative combined-modality treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Underlying pathology and associated factors of hemiplegic shoulder pain.

PubMed

Kalichman, Leonid; Ratmansky, Motti

2011-09-01

The prevalence of hemiplegic shoulder pain is approximately 22%-23% in the general population of stroke survivors and approximately 54%-55% among stroke patients in rehabilitation settings. Hemiplegic shoulder pain causes a reduced quality-of-life, poor functional recovery, depression, disturbed sleep, and prolonged hospitalization. Herein, we attempted to understand, based on a literature review and experts' opinion, the pathologic processes underlying hemiplegic shoulder pain and the major associated factors contributing to its development. The systematization of underlying pathologies was proposed, which might eventually enable a more constructive clinical approach in evaluating and treating patients with hemiplegic shoulder pain.

Interpersonal Pathoplasticity in the Course of Major Depression

ERIC Educational Resources Information Center

Cain, Nicole M.; Ansell, Emily B.; Wright, Aidan G. C.; Hopwood, Christopher J.; Thomas, Katherine M.; Pinto, Anthony; Markowitz, John C.; Sanislow, Charles A.; Zanarini, Mary C.; Shea, M. Tracie; Morey, Leslie C.; McGlashan, Thomas H.; Skodol, Andrew E.; Grilo, Carlos M.

2012-01-01

Objective: The identification of reliable predictors of course in major depressive disorder (MDD) has been difficult. Evidence suggests that the co-occurrence of personality pathology is associated with longer time to MDD remission. Interpersonal pathoplasticity, the mutually influencing nonetiological relationship between psychopathology and…

Targeting New Pharmacological Approaches for Alzheimer's Disease: Potential for Statins and Phosphodiesterase Inhibitors.

PubMed

Sallustio, Fabrizio; Studer, Valeria

2016-01-01

Alzheimer's disease (AD) is the most common cause of dementia among the elderly. It is pathologically characterized by diffused extracellular deposits, senile plaques, and intracellular neurofibrillary tangles in the brain, responsible for neuronal dysfunction and cell death. Memory, language and other cognitive functions can be affected to a limited extent in the initial stage called mild cognitive impairment (MCI) or in a more severe and daily life interfering manner in the later stage called dementia. Currently no effective disease-modifying treatment exists for the majority of neurodegenerative diseases. Failure of therapy aimed at affecting beta amyloid pathology has led research to investigate alternative approaches. Recent findings address statins and phosphodiesterase (PDE) inhibitors as compounds able to affect different mechanisms underlying AD. Statins could exert several effects based on their lipid-lowering and cerebral blood flow increasing abilities but also pleiotropic/antinflammatory and neuroprotective properties have been claimed. PDEs act as regulators of intracellular signaling cascades through the control of two second messengers, cyclic adenosine monophosphate and cyclic guanosine monophosphate. PDE inhibitors effects in animal models of AD have been promising and their proven safety in clinical use create high expectations for the treatment of AD. In this review, we will report main data and evidence on: 1. Current pathophysiological theories of AD in order to better understand which mechanisms lead to pathological changes and can be affected by therapies; 2. The use of statins and PDE inhibitors in animal models of AD and in humans, analyzing their mechanisms of action.

Acceleration of diabetic wound healing using a novel protease–anti-protease combination therapy

PubMed Central

Gao, Ming; Nguyen, Trung T.; Suckow, Mark A.; Wolter, William R.; Gooyit, Major; Mobashery, Shahriar; Chang, Mayland

2015-01-01

Nonhealing chronic wounds are major complications of diabetes resulting in >70,000 annual lower-limb amputations in the United States alone. The reasons the diabetic wound is recalcitrant to healing are not fully understood, and there are limited therapeutic agents that could accelerate or facilitate its repair. We previously identified two active forms of matrix metalloproteinases (MMPs), MMP-8 and MMP-9, in the wounds of db/db mice. We argued that the former might play a role in the body’s response to wound healing and that the latter is the pathological consequence of the disease with detrimental effects. Here we demonstrate that the use of compound ND-336, a novel highly selective inhibitor of gelatinases (MMP-2 and MMP-9) and MMP-14, accelerates diabetic wound healing by lowering inflammation and by enhancing angiogenesis and re-epithelialization of the wound, thereby reversing the pathological condition. The detrimental role of MMP-9 in the pathology of diabetic wounds was confirmed further by the study of diabetic MMP-9–knockout mice, which exhibited wounds more prone to healing. Furthermore, topical administration of active recombinant MMP-8 also accelerated diabetic wound healing as a consequence of complete re-epithelialization, diminished inflammation, and enhanced angiogenesis. The combined topical application of ND-336 (a small molecule) and the active recombinant MMP-8 (an enzyme) enhanced healing even more, in a strategy that holds considerable promise in healing of diabetic wounds. PMID:26598687

Acceleration of diabetic wound healing using a novel protease-anti-protease combination therapy.

PubMed

Gao, Ming; Nguyen, Trung T; Suckow, Mark A; Wolter, William R; Gooyit, Major; Mobashery, Shahriar; Chang, Mayland

2015-12-08

Nonhealing chronic wounds are major complications of diabetes resulting in >70,000 annual lower-limb amputations in the United States alone. The reasons the diabetic wound is recalcitrant to healing are not fully understood, and there are limited therapeutic agents that could accelerate or facilitate its repair. We previously identified two active forms of matrix metalloproteinases (MMPs), MMP-8 and MMP-9, in the wounds of db/db mice. We argued that the former might play a role in the body's response to wound healing and that the latter is the pathological consequence of the disease with detrimental effects. Here we demonstrate that the use of compound ND-336, a novel highly selective inhibitor of gelatinases (MMP-2 and MMP-9) and MMP-14, accelerates diabetic wound healing by lowering inflammation and by enhancing angiogenesis and re-epithelialization of the wound, thereby reversing the pathological condition. The detrimental role of MMP-9 in the pathology of diabetic wounds was confirmed further by the study of diabetic MMP-9-knockout mice, which exhibited wounds more prone to healing. Furthermore, topical administration of active recombinant MMP-8 also accelerated diabetic wound healing as a consequence of complete re-epithelialization, diminished inflammation, and enhanced angiogenesis. The combined topical application of ND-336 (a small molecule) and the active recombinant MMP-8 (an enzyme) enhanced healing even more, in a strategy that holds considerable promise in healing of diabetic wounds.

Prognostic value of neoadjuvant treatment response in locally advanced rectal cancer.

PubMed

Sada, Yvonne H; Tran Cao, Hop S; Chang, George J; Artinyan, Avo; Musher, Benjamin L; Smaglo, Brandon G; Massarweh, Nader N

2018-06-01

For locally advanced rectal cancer, response to neoadjuvant radiation has been associated with improved outcomes but has not been well characterized in general practice. The goals of this study were to describe disease response rates after neoadjuvant treatment and to evaluate the association between disease response and survival. Retrospective cohort study of patients aged 18-80 y with clinical stage II and III rectal adenocarcinoma in the National Cancer Database (2006-2012). All patients underwent radical resection after neoadjuvant treatment. Treatment responses were defined as follows: no tumor response; intermediate-T and/or N downstaging with residual disease; and complete-ypT0N0. Multivariable, multinomial regression was used to evaluate the association between neoadjuvant radiation use and disease response. Multivariable Cox regression was used to evaluate the association between disease response and overall risk of death. Among 12,024 patients, 12% had a complete and 30% an intermediate response. Neoadjuvant chemotherapy alone was less likely to achieve an intermediate (relative risk ratio: 0.70 [0.56-0.88]) or a complete response (relative risk ratio: 0.59 [0.41-0.84]) relative to neoadjuvant radiation. Tumor response was associated with improved 5-y overall survival (complete = 90.2%, intermediate = 82.0%, no response = 70.5%; log-rank, P < 0.001). Complete and intermediate pathologic responses were associated with decreases in risk of death (hazard ratio: 0.40 [0.34-0.48] and 0.63 [0.57-0.69], respectively) compared to no response. Primary tumor and nodal response were independently associated with decreased risk of death. Neoadjuvant radiation is associated with treatment response, and pathologic response is associated with improved survival. Pathologic response may be an early benchmark for the oncologic effectiveness of neoadjuvant treatment. Published by Elsevier Inc.

Discovery of pathologies by orthodontists on lateral cephalograms.

PubMed

Moffitt, Allen Hall

2011-01-01

To determine the frequency of significant pathologies on lateral cephalograms discovered by orthodontists during their careers. A five-statement survey was sent to the 417 active and affiliate members of the Edward H. Angle Society of Orthodontists. The survey asked orthodontists to identify any significant radiographic pathology that they had discovered on lateral cephalograms during their careers to date. The data were analyzed statistically. Of the 417 surveys, 201 were returned for a 48% response rate. Ninety-nine respondents or 49.3% of the sample had discovered at least one significant pathology. Of the 1.3 million patients observed by the orthodontists in the sample, 268 patients (0.02%) with significant pathologies had been identified. Younger orthodontists had a statistically greater potential to discover pathologies than older orthodontists. The general types of pathologies discovered were musculoskeletal (38%), glandular (28%), and dental groups (12%). About 50% of orthodontists will likely discover a significant, potentially life-affecting pathology on a lateral cephalogram.

Neurological soft signs in individuals with pathological gambling.

PubMed

Elman, Igor; Gurvits, Tamara V; Tschibelu, Evelyne; Spring, Justin D; Lasko, Natasha B; Pitman, Roger K

2013-01-01

Increased neurological soft signs (NSSs) have been found in a number of neuropsychiatric syndromes, including chemical addiction. The present study examined NSSs related to perceptual-motor and visuospatial processing in a behavioral addiction viz., pathological gambling (PG). As compared to mentally healthy individuals, pathological gamblers displayed significantly poorer ability to copy two- and three-dimensional figures, to recognize objects against a background noise, and to orient in space on a road-map test. Results indicated that PG is associated with subtle cerebral cortical abnormalities. Further prospective clinical research is needed to address the NSSs' origin and chronology (e.g., predate or follow the development of PG) as well as their response to therapeutic interventions and/or their ability to predict such a response.

Endoplasmic Reticulum Stress in Arterial Smooth Muscle Cells: A Novel Regulator of Vascular Disease

PubMed Central

Furmanik, Malgorzata; Shanahan, Catherine M.

2017-01-01

Cardiovascular disease continues to be the leading cause of death in industrialised societies. The idea that the arterial smooth muscle cell (ASMC) plays a key role in regulating many vascular pathologies has been gaining importance, as has the realisation that not enough is known about the pathological cellular mechanisms regulating ASMC function in vascular remodelling. In the past decade endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been recognised as a stress response underlying many physiological and pathological processes in various vascular cell types. Here we summarise what is known about how ER stress signalling regulates phenotypic switching, trans/dedifferentiation and apoptosis of ASMCs and contributes to atherosclerosis, hypertension, aneurysms and vascular calcification.

Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide.

PubMed

Murphy, T M; Crawford, B; Dempster, E L; Hannon, E; Burrage, J; Turecki, G; Kaminsky, Z; Mill, J

2017-01-03

Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers.

Methylomic profiling of cortex samples from completed suicide cases implicates a role for PSORS1C3 in major depression and suicide

PubMed Central

Murphy, T M; Crawford, B; Dempster, E L; Hannon, E; Burrage, J; Turecki, G; Kaminsky, Z; Mill, J

2017-01-01

Major depressive disorder (MDD) represents a major social and economic health issue and constitutes a major risk factor for suicide. The molecular pathology of suicidal depression remains poorly understood, although it has been hypothesised that regulatory genomic processes are involved in the pathology of both MDD and suicidality. In this study, genome-wide patterns of DNA methylation were assessed in depressed suicide completers (n=20) and compared with non-psychiatric, sudden-death controls (n=20) using tissue from two cortical brain regions (Brodmann Area 11 (BA11) and Brodmann Area 25 (BA25)). Analyses focused on identifying differentially methylated regions (DMRs) associated with suicidal depression and epigenetic variation were explored in the context of polygenic risk scores for major depression and suicide. Weighted gene co-methylation network analysis was used to identify modules of co-methylated loci associated with depressed suicide completers and polygenic burden for MDD and suicide attempt. We identified a DMR upstream of the PSORS1C3 gene, subsequently validated using bisulfite pyrosequencing and replicated in a second set of suicide samples, which is characterised by significant hypomethylation in both cortical brain regions in MDD suicide cases. We also identified discrete modules of co-methylated loci associated with polygenic risk burden for suicide attempt, but not major depression. Suicide-associated co-methylation modules were enriched among gene networks implicating biological processes relevant to depression and suicidality, including nervous system development and mitochondria function. Our data suggest that there are coordinated changes in DNA methylation associated with suicide that may offer novel insights into the molecular pathology associated with depressed suicide completers. PMID:28045465

New developments in digital pathology: from telepathology to virtual pathology laboratory.

PubMed

Kayser, Klaus; Kayser, Gian; Radziszowski, Dominik; Oehmann, Alexander

2004-01-01

To analyse the present status and future development of computerized diagnostic pathology in terms of work-flow integrative telepathology and virtual laboratory. Telepathology has left its childhood. The technical development of telepathology is mature, in contrast to that of virtual pathology. Two kinds of virtual pathology laboratories are emerging: a) those with distributed pathologists and distributed (>=1) laboratories associated to individual biopsy stations/surgical theatres, and b) distributed pathologists working in a centralized laboratory. Both are under technical development. Telepathology can be used for e-learning and e-training in pathology, as exemplarily demonstrated on Digital Lung Pathology Pathology (www.pathology-online.org). A virtual pathology institution (mode a) accepts a complete case with the patient's history, clinical findings, and (pre-selected) images for first diagnosis. The diagnostic responsibility is that of a conventional institution. The internet serves as platform for information transfer, and an open server such as the iPATH (http://telepath.patho.unibas.ch) for coordination and performance of the diagnostic procedure. The size of images has to be limited, and usual different magnifications have to be used. A group of pathologists is "on duty", or selects one member for a predefined duty period. The diagnostic statement of the pathologist(s) on duty is retransmitted to the sender with full responsibility. First experiences of a virtual pathology institution group working with the iPATH server (Dr. L. Banach, Dr. G. Haroske, Dr. I. Hurwitz, Dr. K. Kayser, Dr. K.D. Kunze, Dr. M. Oberholzer,) working with a small hospital of the Salomon islands are promising. A centralized virtual pathology institution (mode b) depends upon the digitalisation of a complete slide, and the transfer of large sized images to different pathologists working in one institution. The technical performance of complete slide digitalisation is still under development and does not completely fulfil the requirements of a conventional pathology institution at present. VIRTUAL PATHOLOGY AND E-LEARNING: At present, e-learning systems are "stand-alone" solutions distributed on CD or via internet. A characteristic example is the Digital Lung Pathology CD (www.pathology-online.org), which includes about 60 different rare and common lung diseases and internet access to scientific library systems (PubMed), distant measurement servers (EuroQuant), or electronic journals (Elec J Pathol Histol). A new and complete data base based upon this CD will combine e-learning and e-teaching with the actual workflow in a virtual pathology institution (mode a). The technological problems are solved and do not depend upon technical constraints such as slide scanning systems. Telepathology serves as promotor for a new landscape in diagnostic pathology, the so-called virtual pathology institution. Industrial and scientific efforts will probably allow an implementation of this technique within the next two years.

Liver resection for colorectal metastases after chemotherapy: impact of chemotherapy-related liver injuries, pathological tumor response, and micrometastases on long-term survival.

PubMed

Viganò, Luca; Capussotti, Lorenzo; De Rosa, Giovanni; De Saussure, Wassila Oulhaci; Mentha, Gilles; Rubbia-Brandt, Laura

2013-11-01

We analyzed the impact of chemotherapy-related liver injuries (CALI), pathological tumor regression grade (TRG), and micrometastases on long-term prognosis in patients undergoing liver resection for colorectal metastases after preoperative chemotherapy. CALI worsen the short-term outcomes of liver resection, but their impact on long-term prognosis is unknown. Recently, a prognostic role of TRG has been suggested. Micrometastases (microscopic vascular or biliary invasion) are reduced by preoperative chemotherapy, but their impact on survival is unclear. Patients undergoing liver resection for colorectal metastases between 1998 and 2011 and treated with oxaliplatin and/or irinotecan-based preoperative chemotherapy were eligible for the study. Patients with operative mortality or incomplete resection (R2) were excluded. All specimens were reviewed to assess CALI, TRG, and micrometastases. A total of 323 patients were included. Grade 2-3 sinusoidal obstruction syndrome (SOS) was present in 124 patients (38.4%), grade 2-3 steatosis in 73 (22.6%), and steatohepatitis in 30 (9.3%). Among all patients, 22.9% had TRG 1-2 (major response), whereas 55.7% had TRG 4-5 (no response). Microvascular invasion was detected in 37.8% of patients and microscopic biliary infiltration in 5.6%.The higher the SOS grade the lower the pathological response: TRG 1-2 occurred in 16.9% of patients with grade 2-3 SOS versus 26.6% of patients with grade 0-1 SOS (P = 0.032).After a median follow-up of 36.9 months, 5-year survival was 38.6%. CALI did not negatively impact survival. Multivariate analysis showed that grade 2-3 steatosis was associated with better survival than grade 0-1 steatosis (5-year survival rate of 52.5% vs 35.2%, P = 0.002). TRG better than the percentage of viable cells stratified patient prognosis: 5-year survival rate of 60.4% in TRG 1-2, 40.2% in TRG 3, and 29.8% in TRG 4-5 (P = 0.0001). Microscopic vascular and biliary invasion negatively impacted outcome (5-year survival rate of 23.3% vs 45.7% if absent, P = 0.017; 0% vs 42.3%, P = 0.032, respectively). TRG was confirmed to be a crucial prognostic determinant. CALI do not negatively impact long-term prognosis, but the tumor response is reduced in patients with grade 2-3 SOS. Steatosis was found to have a protective effect on survival. Micrometastases significantly impacted prognosis assessment.

Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody

PubMed Central

Luo, Wenjie; Liu, Wencheng; Hu, Xiaoyan; Hanna, Mary; Caravaca, April; Paul, Steven M.

2015-01-01

Microglia have been shown to contribute to the clearance of brain amyloid β peptides (Aβ), the major component of amyloid plaques, in Alzheimer’s disease (AD). However, it is not known whether microglia play a similar role in the clearance of tau, the major component of neurofibrillary tangles (NFTs). We now report that murine microglia rapidly internalize and degrade hyperphosphorylated pathological tau isolated from AD brain tissue in a time-dependent manner in vitro. We further demonstrate that microglia readily degrade human tau species released from AD brain sections and eliminate NFTs from brain sections of P301S tauopathy mice. The anti-tau monoclonal antibody MC1 enhances microglia-mediated tau degradation in an Fc-dependent manner. Our data identify a potential role for microglia in the degradation and clearance of pathological tau species in brain and provide a mechanism explaining the potential therapeutic actions of passively administered anti-tau monoclonal antibodies. PMID:26057852

Phytochemical Ginkgolide B Attenuates Amyloid-β1-42 Induced Oxidative Damage and Altered Cellular Responses in Human Neuroblastoma SH-SY5Y Cells.

PubMed

Gill, Iqbal; Kaur, Sukhchain; Kaur, Navrattan; Dhiman, Monisha; Mantha, Anil K

2017-01-01

Oxidative stress is an upsurge in reactive oxygen/nitrogen species (ROS/RNS), which aggravates damage to cellular components viz. lipids, proteins, and nucleic acids resulting in impaired cellular functions and neurological pathologies including Alzheimer's disease (AD). In the present study, we have examined amyloid-β (Aβ)-induced oxidative stress responses, a major cause for AD, in the undifferentiated and differentiated human neuroblastoma SH-SY5Y cells. Aβ1-42-induced oxidative damage was evaluated on lipids by lipid peroxidation; proteins by protein carbonyls; antioxidant status by SOD and GSH enzyme activities; and DNA and RNA damage levels by evaluating the number of AP sites and 8-OHG base damages produced. In addition, the neuro-protective role of the phytochemical ginkgolide B (GB) in countering Aβ1-42-induced oxidative stress was assessed. We report that the differentiated cells are highly vulnerable to Aβ1-42-induced oxidative stress events as exerted by the deposition of Aβ in AD. Results of the current study suggest that the pre-treatment of GB, followed by Aβ1-42 treatment for 24 h, displayed neuro-protective potential, which countered Aβ1-42-induced oxidative stress responses in both undifferentiated and differentiated SH-SY5Y neuronal cells by: 1) hampering production of ROS and RNS; 2) reducing lipid peroxidation; 3) decreasing protein carbonyl content; 4) restoring antioxidant activities of SOD and GSH enzymes; and 5) maintaining genome integrity by reducing the oxidative DNA and RNA base damages. In conclusion, Aβ1-42 induces oxidative damage to the cellular biomolecules, which are associated with AD pathology, and are protected by the pre-treatment of GB against Aβ-toxicity. Taken together, this study advocates for phytochemical-based therapeutic interventions against AD.

Helicobacter pylori Heat Shock Protein A: Serologic Responses and Genetic Diversity

PubMed Central

Ng, Enders K. W.; Thompson, Stuart A.; Pérez-Pérez, Guillermo I.; Kansau, Imad; van der Ende, Arie; Labigne, Agnès; Sung, Joseph J. Y.; Chung, S. C. Sydney; Blaser, Martin J.

1999-01-01

Helicobacter pylori synthesizes an unusual GroES homolog, heat shock protein A (HspA). The present study was aimed at an assessment of the serological response to HspA in a group of Chinese patients with defined gastroduodenal pathologies and determination of whether diversity is present in the nucleotide sequences encoding HspA in isolates from these patients. Serum samples collected from 154 patients who had an upper gastrointestinal pathology and the presence of H. pylori defined by biopsy were tested for an immunoglobulin G (IgG) serologic response to H. pylori HspA by an enzyme linked immunosorbant assay. HspA-encoding nucleotide sequences in H. pylori isolates from 14 patients (7 seropositive and 7 seronegative for HspA) were analyzed by PCR and direct sequencing of the PCR products. The sequencing results were compared to those of 48 isolates from other parts of the world. Of the 154 known H. pylori-positive patients, 54 (35.1%) were seropositive for HspA. The A domain (GroES homology) of HspA was highly conserved in the 14 isolates tested. Although the B domain (metal-binding site unique to H. pylori) resembled that in the known major variant, particular amino acid substitutions allowed definition of an HspA variant associated with isolates from East Asia. There were no associations between patient characteristics and HspA seropositivity or amino acid sequences. We confirmed in this study that the clinical outcomes of H. pylori infection are not related to HspA antigenicity or to sequence variation. However, B-domain sequence variation may be a marker for the study of the genetic diversity of H. pylori strains of different geographic origins. PMID:10225839

Impact of Race, Ethnicity and BMI on Achievement of Pathologic Complete Response Following Neoadjuvant Chemotherapy for Breast Cancer: A Pooled Analysis of Four Prospective Alliance Clinical Trials (A151426)

PubMed Central

Warner, Erica T.; Ballman, Karla V.; Strand, Carrie; Boughey, Judy; Buzdar, Aman U.; Carey, Lisa A.; Sikov, William M.; Partridge, H.

2016-01-01

Purpose Previous studies demonstrated poor response to neoadjuvant systemic therapy (NST) for breast cancer among black women and women who are overweight or obese but this may be due to chemotherapy under dosing. We assessed associations of race, ethnicity and body mass index (BMI) with pathologic complete response (pCR) in clinical trial populations. Methods 1797 women enrolled in four NST trials (CALGB 40601, 40603; ACOSOG Z1041, Z1071) were included. Tumor subtypes were defined by estrogen receptor (ER) and HER2 status. Logistic regression generated odds ratios (OR) and 95% confidence intervals (CI) for the associations of race, ethnicity, and BMI with pCR adjusting for subtype, study arm, lymph node status, tumor size, and tumor grade. Results 253 (14.1%) were black, 199 (11.1%) Hispanic, 520 (28.9%) overweight, and 743 (41.4%) obese. Compared to whites, Blacks and Hispanics were more likely to be obese and Blacks were more likely to have triple-negative cancer. pCR rates differed significantly by tumor subtype. In multivariate analyses, neither race (black vs. white: OR: 1.18, 95% CI: 0.85–1.62) nor ethnicity (Hispanic vs. non-Hispanic: OR: 1.30, 95% CI: 0.67–2.53) were significant predictors of pCR overall or by subtype. Overweight and obese women had lower pCR rates in ER+/HER2+, but higher pCR rates in ER−/HER2+ cancers. Conclusions There was no difference in breast pCR according to race or ethnicity. Overall, there was no major difference in pCR rates by BMI. These findings suggest that pCR with optimally dosed NST is a function of tumor, rather than patient, biology. PMID:27449492

Impact of race, ethnicity, and BMI on achievement of pathologic complete response following neoadjuvant chemotherapy for breast cancer: a pooled analysis of four prospective Alliance clinical trials (A151426).

PubMed

Warner, Erica T; Ballman, Karla V; Strand, Carrie; Boughey, Judy C; Buzdar, Aman U; Carey, Lisa A; Sikov, William M; Partridge, Ann H

2016-08-01

Previous studies demonstrated poor response to neoadjuvant systemic therapy (NST) for breast cancer among black women and women who are overweight or obese, but this may be due to chemotherapy underdosing. We assessed associations of race, ethnicity, and body mass index (BMI) with pathologic complete response (pCR) in clinical trial populations. 1797 women enrolled in four NST trials (CALGB 40601, 40603; ACOSOG Z1041, Z1071) were included. Tumor subtypes were defined by estrogen receptor (ER) and HER2 status. Logistic regression generated odds ratios (OR) and 95 % confidence intervals (CI) for the associations of race, ethnicity, and BMI with in-breast pCR adjusting for subtype, study arm, lymph node status, tumor size, and tumor grade. 253 (14.1 %) were black, 199 (11.1 %) Hispanic, 520 (28.9 %) overweight, and 743 (41.4 %) obese. Compared to whites, Blacks and Hispanics were more likely to be obese and Blacks were more likely to have triple-negative cancer. pCR rates differed significantly by tumor subtype. In multivariate analyses, neither race (black vs white: OR 1.18, 95 % CI 0.85-1.62) nor ethnicity (Hispanic vs non-Hispanic; OR 1.30, 95 % CI 0.67-2.53) were significant predictors of pCR overall or by subtype. Overweight and obese women had lower pCR rates in ER+/HER2+, but higher pCR rates in ER-/HER2+ cancers. There was no difference in pCR according to race or ethnicity. Overall, there was no major difference in pCR rates by BMI. These findings suggest that pCR with optimally dosed NST is a function of tumor, rather than patient, biology.

Learning needs in clinical biochemistry for doctors in foundation years.

PubMed

Khromova, Victoria; Gray, Trevor A

2008-01-01

Most medical school curricula have reduced the amount of time available for teaching in pathology despite the fact that junior staff in the early stages of their training were responsible for requesting the majority of pathology tests on acutely ill hospital patients. So, the lack of specific training in this area means that test requesting may be poorly performed and the results ill understood by these staff. This paper describes a questionnaire, which was designed to assist laboratory staff providing targeted teaching in this area. Doctors in Foundation year 1 (F1) and Foundation year 2 (F2) in Sheffield teaching hospitals were given a questionnaire to ascertain how confident they were in requesting and interpreting the results of clinical biochemistry tests. The doctors were also asked about which areas of laboratory medicine they would like to be taught. Responses were received from 82 doctors, about half those in F1 and F2. The survey revealed areas where juniors are less confident in requesting tests and interpreting results. Despite lack of confidence in interpreting the result, 18% were confident about requesting tests. Doctors were also unsure of the effects of common problems like haemolysis on the interpretation of results. More than 70% of the doctors requested specific teaching in these areas. Foundation doctors have learning needs in clinical biochemistry, addressing which would assist them in patient care. While better training in medical school may help in future, there are specific needs for those on the wards now that require targeted teaching.

Complement System Part II: Role in Immunity

PubMed Central

Merle, Nicolas S.; Noe, Remi; Halbwachs-Mecarelli, Lise; Fremeaux-Bacchi, Veronique; Roumenina, Lubka T.

2015-01-01

The complement system has been considered for a long time as a simple lytic cascade, aimed to kill bacteria infecting the host organism. Nowadays, this vision has changed and it is well accepted that complement is a complex innate immune surveillance system, playing a key role in host homeostasis, inflammation, and in the defense against pathogens. This review discusses recent advances in the understanding of the role of complement in physiology and pathology. It starts with a description of complement contribution to the normal physiology (homeostasis) of a healthy organism, including the silent clearance of apoptotic cells and maintenance of cell survival. In pathology, complement can be a friend or a foe. It acts as a friend in the defense against pathogens, by inducing opsonization and a direct killing by C5b–9 membrane attack complex and by triggering inflammatory responses with the anaphylatoxins C3a and C5a. Opsonization plays also a major role in the mounting of an adaptive immune response, involving antigen presenting cells, T-, and B-lymphocytes. Nevertheless, it can be also an enemy, when pathogens hijack complement regulators to protect themselves from the immune system. Inadequate complement activation becomes a disease cause, as in atypical hemolytic uremic syndrome, C3 glomerulopathies, and systemic lupus erythematosus. Age-related macular degeneration and cancer will be described as examples showing that complement contributes to a large variety of conditions, far exceeding the classical examples of diseases associated with complement deficiencies. Finally, we discuss complement as a therapeutic target. PMID:26074922

Correlation between expressions of ERCC1/TS mRNA and effects of gastric cancer to chemotherapy in the short term.

PubMed

Chen, Liqi; Li, Guoli; Li, Jieshou; Fan, Chaogang; Xu, Jian; Wu, Bo; Liu, Kun; Zhang, Caihua

2013-04-01

To study the correlation between expression levels of ERCC1/TS mRNA and the susceptibility of preoperative chemotherapy for patients with gastric cancer. A total of forty cases with advanced gastric cancer of T3-4N1-2M0 were treated with preoperative chemotherapy according to FLEEOX regimen based on endarterial-intravenous coadministration. Sufficient, fresh gastric tissue specimens were obtained with the help of gastroscope, and the expression levels of ERCC1/TS mRNA were detected by qRT-PCR before chemotherapy. The chemotherapeutic response was evaluated with Choi Criteria after chemotherapy, and pathologic remission extent was observed after surgery. The correlation between the expression levels of ERCC1/TS mRNA before chemotherapy and the chemotherapeutic effect based on imageology and pathology was analyzed. The response rate of Chemotherapy in this cohort was 80.0 % based on imageology and 51.43 % based on pathology. The expression levels of ERCC1/TS mRNA were significantly associated with imageology remission extent (P = 0.033, P = 0.025) and pathologic remission extent (P = 0.044, P = 0.016), respectively. The chemotherapeutic effect on patients with low-expression levels of ERCC1/TS mRNA was better. From the perspective of pathology and imageology evaluating the preoperative chemotherapeutic response for patients with gastric cancer, ERCC1 and TS were used as the molecular predictors and provided prognostic information in this study.

Intraoperative optical assessment of photodynamic therapy response of superficial oral squamous cell carcinoma

NASA Astrophysics Data System (ADS)

Rohrbach, Daniel J.; Rigual, Nestor; Arshad, Hassan; Tracy, Erin C.; Cooper, Michelle T.; Shafirstein, Gal; Wilding, Gregory; Merzianu, Mihai; Baumann, Heinz; Henderson, Barbara W.; Sunar, Ulas

2016-01-01

This study investigated whether diffuse optical spectroscopy (DOS) measurements could assess clinical response to photodynamic therapy (PDT) in patients with head and neck squamous cell carcinoma (HNSCC). In addition, the correlation between parameters measured with DOS and the crosslinking of signal transducer and activator of transcription 3 (STAT3), a molecular marker for PDT-induced photoreaction, was investigated. Thirteen patients with early stage HNSCC received the photosensitizer 2-[1-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH) and DOS measurements were performed before and after PDT in the operating room (OR). In addition, biopsies were acquired after PDT to assess the STAT3 crosslinking. Parameters measured with DOS, including blood volume fraction, blood oxygen saturation (StO2), HPPH concentration (cHPPH), HPPH fluorescence, and blood flow index (BFI), were compared to the pathologic response and the STAT3 crosslinking. The best individual predictor of pathological response was a change in cHPPH (sensitivity=60%, specificity=100%), while discrimination analysis using a two-parameter classifier (change in cHPPH and change in StO2) classified pathological response with 100% sensitivity and 100% specificity. BFI showed the best correlation with the crosslinking of STAT3. These results indicate that DOS-derived parameters can assess the clinical response in the OR, allowing for earlier reintervention if needed.

Ventromedial prefrontal cortex activity and pathological worry in generalised anxiety disorder.

PubMed

Via, E; Fullana, M A; Goldberg, X; Tinoco-González, D; Martínez-Zalacaín, I; Soriano-Mas, C; Davey, C G; Menchón, J M; Straube, B; Kircher, T; Pujol, J; Cardoner, N; Harrison, B J

2018-05-09

Pathological worry is a hallmark feature of generalised anxiety disorder (GAD), associated with dysfunctional emotional processing. The ventromedial prefrontal cortex (vmPFC) is involved in the regulation of such processes, but the link between vmPFC emotional responses and pathological v. adaptive worry has not yet been examined.AimsTo study the association between worry and vmPFC activity evoked by the processing of learned safety and threat signals. In total, 27 unmedicated patients with GAD and 56 healthy controls (HC) underwent a differential fear conditioning paradigm during functional magnetic resonance imaging. Compared to HC, the GAD group demonstrated reduced vmPFC activation to safety signals and no safety-threat processing differentiation. This response was positively correlated with worry severity in GAD, whereas the same variables showed a negative and weak correlation in HC. Poor vmPFC safety-threat differentiation might characterise GAD, and its distinctive association with GAD worries suggests a neural-based qualitative difference between healthy and pathological worries.Declaration of interestNone.

High wall shear stress and spatial gradients in vascular pathology: a review.

PubMed

Dolan, Jennifer M; Kolega, John; Meng, Hui

2013-07-01

Cardiovascular pathologies such as intracranial aneurysms (IAs) and atherosclerosis preferentially localize to bifurcations and curvatures where hemodynamics are complex. While extensive knowledge about low wall shear stress (WSS) has been generated in the past, due to its strong relevance to atherogenesis, high WSS (typically >3 Pa) has emerged as a key regulator of vascular biology and pathology as well, receiving renewed interests. As reviewed here, chronic high WSS not only stimulates adaptive outward remodeling, but also contributes to saccular IA formation (at bifurcation apices or outer curves) and atherosclerotic plaque destabilization (in stenosed vessels). Recent advances in understanding IA pathogenesis have shed new light on the role of high WSS in pathological vascular remodeling. In complex geometries, high WSS can couple with significant spatial WSS gradient (WSSG). A combination of high WSS and positive WSSG has been shown to trigger aneurysm initiation. Since endothelial cells (ECs) are sensors of WSS, we have begun to elucidate EC responses to high WSS alone and in combination with WSSG. Understanding such responses will provide insight into not only aneurysm formation, but also plaque destabilization and other vascular pathologies and potentially lead to improved strategies for disease management and novel targets for pharmacological intervention.

Cue-induced brain activity in pathological gamblers.

PubMed

Crockford, David N; Goodyear, Bradley; Edwards, Jodi; Quickfall, Jeremy; el-Guebaly, Nady

2005-11-15

Previous studies using functional magnetic resonance imaging (fMRI) have identified differential brain activity in healthy subjects performing gambling tasks and in pathological gambling (PG) subjects when exposed to motivational and emotional predecessors for gambling as well as during gambling or response inhibition tasks. The goal of the present study was to determine if PG subjects exhibit differential brain activity when exposed to visual gambling cues. Ten male DSM-IV-TR PG subjects and 10 matched healthy control subjects underwent fMRI during visual presentations of gambling-related video alternating with video of nature scenes. Pathological gambling subjects and control subjects exhibited overlap in areas of brain activity in response to the visual gambling cues; however, compared with control subjects, PG subjects exhibited significantly greater activity in the right dorsolateral prefrontal cortex (DLPFC), including the inferior and medial frontal gyri, the right parahippocampal gyrus, and left occipital cortex, including the fusiform gyrus. Pathological gambling subjects also reported a significant increase in mean craving for gambling after the study. Post hoc analyses revealed a dissociation in visual processing stream (dorsal vs. ventral) activation by subject group and cue type. These findings may represent a component of cue-induced craving for gambling or conditioned behavior that could underlie pathological gambling.

Quality of pathology reports for advanced ovarian cancer: are we missing essential information? An audit of 479 pathology reports from the EORTC-GCG 55971/NCIC-CTG OV13 neoadjuvant trial.

PubMed

Verleye, Leen; Ottevanger, Petronella B; Kristensen, Gunnar B; Ehlen, Tom; Johnson, Nick; van der Burg, Maria E L; Reed, Nick S; Verheijen, René H M; Gaarenstroom, Katja N; Mosgaard, Berit; Seoane, Jose M; van der Velden, Jacobus; Lotocki, Robert; van der Graaf, Winette; Penninckx, Björn; Coens, Corneel; Stuart, Gavin; Vergote, Ignace

2011-01-01

To assess the quality of surgical pathology reports of advanced stage ovarian, fallopian tube and primary peritoneal cancer. This quality assurance project was performed within the EORTC-GCG 55971/NCIC-CTG OV13 study comparing primary debulking surgery followed by chemotherapy with neoadjuvant chemotherapy and interval debulking surgery. Four hundred and seventy nine pathology reports from 40 institutions in 11 different countries were checked for the following quality indicators: macroscopic description of all specimens, measuring and weighing of major specimens, description of tumour origin and differentiation. All specimens were macroscopically described in 92.3% of the reports. All major samples were measured and weighed in 59.9% of the reports. A description of the origin of the tumour was missing in 20.5% of reports of the primary debulking group and in 23.4% of the interval debulking group. Assessment of tumour differentiation was missing in 10% of the reports after primary debulking and in 20.8% of the reports after interval debulking. Completeness of reports is positively correlated with accrual volume and adversely with hospital volume or type of hospital (academic versus non-academic). Quality of reports differs significantly by country. This audit of ovarian cancer pathology reports reveals that in a substantial number of reports basic pathologic data are missing, with possible adverse consequences for the quality of cancer care. Specialisation by pathologists and the use of standardised synoptic reports can lead to improved quality of reporting. Further research is needed to better define pre- and post-operative diagnostic criteria for ovarian cancer treated with neoadjuvant chemotherapy. Copyright © 2010 Elsevier Ltd. All rights reserved.

Characteristics of Left Atrial Deformation Parameters and Their Prognostic Impact in Patients with Pathological Left Ventricular Hypertrophy: Analysis by Speckle Tracking Echocardiography.

PubMed

Iio, Chiharuko; Inoue, Katsuji; Nishimura, Kazuhisa; Fujii, Akira; Nagai, Takayuki; Suzuki, Jun; Okura, Takafumi; Higaki, Jitsuo; Ogimoto, Akiyoshi

2015-12-01

The pathological process of left ventricular (LV) hypertrophy is associated with left atrial (LA) remodeling. This study was aimed to evaluate the prognostic value of LA strain parameters in patients with pathological LV hypertrophy. This study included 95 patients with hypertensive heart disease (HHD: n = 24), hypertrophic cardiomyopathy (HCM: n = 56), cardiac amyloidosis (CA: n = 15), and control subjects (n = 20). We used two-dimensional speckle tracking echocardiography (STE) to analyze LA global strain. LA electromechanical conduction time (EMT) at the septal (EMT-septal) and lateral wall (EMT-lateral), and their time difference (EMT-diff) were calculated. The incidence of cardiac death and heart failure hospitalization was defined as major cardiac events and that of atrial fibrillation as secondary outcome. Left atrial volume index was increased and LA booster strain was decreased in the HCM and CA groups compared with the HHD group. EMT-lateral was increased in the diseased groups compared with the control. EMT-diff was prolonged in the CA group compared with the HCM group. During the follow-up period (mean 3.4 years), major cardiac events and atrial fibrillation occurred in 17 and 13 patients, respectively. The occurrence of atrial fibrillation was associated with CA etiology, E/e', LA volume index, LAa, and EMT-lateral. The incidence of major cardiac events was independently correlated with LA volume index and EMT-diff in multivariate analysis. This study suggested that the EMT-diff could discriminate patients with a high risk of cardiac events among patients with pathological LV hypertrophy. © 2015, Wiley Periodicals, Inc.

Mammalian HspB1 (Hsp27) is a molecular sensor linked to the physiology and environment of the cell.

PubMed

Arrigo, André-Patrick

2017-07-01

Constitutively expressed small heat shock protein HspB1 regulates many fundamental cellular processes and plays major roles in many human pathological diseases. In that regard, this chaperone has a huge number of apparently unrelated functions that appear linked to its ability to recognize many client polypeptides that are subsequently modified in their activity and/or half-life. A major parameter to understand how HspB1 is dedicated to interact with particular clients in defined cellular conditions relates to its complex oligomerization and phosphorylation properties. Indeed, HspB1 structural organization displays dynamic and complex rearrangements in response to changes in the cellular environment or when the cell physiology is modified. These structural modifications probably reflect the formation of structural platforms aimed at recognizing specific client polypeptides. Here, I have reviewed data from the literature and re-analyzed my own studies to describe and discuss these fascinating changes in HspB1 structural organization.

Gut dysbiosis impairs recovery after spinal cord injury

PubMed Central

Wang, Lingling; Mo, Xiaokui

2016-01-01

The trillions of microbes that exist in the gastrointestinal tract have emerged as pivotal regulators of mammalian development and physiology. Disruption of this gut microbiome, a process known as dysbiosis, causes or exacerbates various diseases, but whether gut dysbiosis affects recovery of neurological function or lesion pathology after traumatic spinal cord injury (SCI) is unknown. Data in this study show that SCI increases intestinal permeability and bacterial translocation from the gut. These changes are associated with immune cell activation in gut-associated lymphoid tissues (GALTs) and significant changes in the composition of both major and minor gut bacterial taxa. Postinjury changes in gut microbiota persist for at least one month and predict the magnitude of locomotor impairment. Experimental induction of gut dysbiosis in naive mice before SCI (e.g., via oral delivery of broad-spectrum antibiotics) exacerbates neurological impairment and spinal cord pathology after SCI. Conversely, feeding SCI mice commercial probiotics (VSL#3) enriched with lactic acid–producing bacteria triggers a protective immune response in GALTs and confers neuroprotection with improved locomotor recovery. Our data reveal a previously unknown role for the gut microbiota in influencing recovery of neurological function and neuropathology after SCI. PMID:27810921

Thrombospondins: old players, new games.

PubMed

Stenina-Adognravi, Olga

2013-10-01

Thrombospondins (TSPs) are secreted extracellular matrix (ECM) proteins from TSP family, which consists of five homologous members. They share a complex domain structure and have numerous binding partners in ECM and multiple cell surface receptors. Information that has emerged over the past decade identifies TSPs as important mediators of cellular homeostasis, assigning new important roles in cardiovascular pathology to these proteins. Recent studies of the functions of TSP in the cardiovascular system, diabetes and aging, which placed several TSPs in a position of critical regulators, demonstrated the involvement of these proteins in practically every aspect of cardiovascular pathophysiology related to atherosclerosis: inflammation, immunity, leukocyte recruitment and function, function of vascular cells, angiogenesis, and responses to hypoxia, ischemia and hyperglycemia. TSPs are also critically important in the development and ultimate outcome of the complications associated with atherosclerosis--myocardial infarction, and heart hypertrophy and failure. Their expression and significance increase with age and with the progression of diabetes, two major contributors to the development of atherosclerosis and its complications. This overview of recent literature examines the latest information on the newfound functions of TSPs that emphasize the importance of ECM in cardiovascular homeostasis and pathology. The functions of TSPs in myocardium, vasculature, vascular complications of diabetes, aging and immunity are discussed.

Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair.

PubMed

Paiva, Katiucia B S; Granjeiro, José M

2017-01-01

Matrix metalloproteinases (MMPs) are the major protease family responsible for the cleavage of the matrisome (global composition of the extracellular matrix (ECM) proteome) and proteins unrelated to the ECM, generating bioactive molecules. These proteins drive ECM remodeling, in association with tissue-specific and cell-anchored inhibitors (TIMPs and RECK, respectively). In the bone, the ECM mediates cell adhesion, mechanotransduction, nucleation of mineralization, and the immobilization of growth factors to protect them from damage or degradation. Since the first description of an MMP in bone tissue, many other MMPs have been identified, as well as their inhibitors. Numerous functions have been assigned to these proteins, including osteoblast/osteocyte differentiation, bone formation, solubilization of the osteoid during bone resorption, osteoclast recruitment and migration, and as a coupling factor in bone remodeling under physiological conditions. In turn, a number of pathologies, associated with imbalanced bone remodeling, arise mainly from MMP overexpression and abnormalities of the ECM, leading to bone osteolysis or bone formation. In this review, we will discuss the functions of MMPs and their inhibitors in bone cells, during bone remodeling, pathological bone resorption (osteoporosis and bone metastasis), bone repair/regeneration, and emergent roles in bone bioengineering. © 2017 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dzhugashvili, Maia; Department of Radiation Oncology, Madrid Oncology Institute; Luengo-Gil, Ginés

Purpose: To investigate whether polymorphisms of genes related to inflammation are associated with pathologic response (primary endpoint) in patients with rectal cancer treated with primary chemoradiation therapy (PCRT). Methods and Materials: Genomic DNA of 159 patients with locally advanced rectal cancer treated with PCRT was genotyped for polymorphisms rs28362491 (NFKB1), rs1213266/rs5789 (PTGS1), rs5275 (PTGS2), and rs16944/rs1143627 (IL1B) using TaqMan single nucleotide polymorphism genotyping assays. The association between each genotype and pathologic response (poor response vs complete or partial response) was analyzed using logistic regression models. Results: The NFKB1 DEL/DEL genotype was associated with pathologic response (odds ratio [OR], 6.39; 95%more » confidence interval [CI], 0.78-52.65; P=.03) after PCRT. No statistically significant associations between other polymorphisms and response to PCRT were observed. Patients with the NFKB1 DEL/DEL genotype showed a trend for longer disease-free survival (log-rank test, P=.096) and overall survival (P=.049), which was not significant in a multivariate analysis that included pathologic response. Analysis for 6 polymorphisms showed that patients carrying the haplotype rs28362491-DEL/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G (13.7% of cases) had a higher response rate to PCRT (OR, 8.86; 95% CI, 1.21-64.98; P=.034) than the reference group (rs28362491-INS/rs1143627-A/rs1213266-G/rs5789-C/rs5275-A/rs16944-G). Clinically significant (grade ≥2) acute organ toxicity was also more frequent in patients with that same haplotype (OR, 4.12; 95% CI, 1.11-15.36; P=.037). Conclusions: Our results suggest that genetic variation in NFKB-related inflammatory pathways might influence sensitivity to primary chemoradiation for rectal cancer. If confirmed, an inflammation-related radiogenetic profile might be used to select patients with rectal cancer for preoperative combined-modality treatment.« less

Pathological responses to terrorism.

PubMed

Yehuda, Rachel; Bryant, Richard; Marmar, Charles; Zohar, Joseph

2005-10-01

Many important gains have been made in understanding PTSD and other responses to trauma as a result of neuroscience-based observations. Yet there are many gaps in our knowledge that currently impede our ability to predict those who will develop pathologic responses. Such knowledge is essential for developing appropriate strategies for mounting a mental health response in the aftermath of terrorism and for facilitating the recovery of individuals and society. This paper reviews clinical and biological studies that have led to an identification of pathologic responses following psychological trauma, including terrorism, and highlights areas of future-research. It is important to not only determine risk factors for the development of short- and long-term mental health responses to terrorism, but also apply these risk factors to the prediction of such responses on an individual level. It is also critical to consider the full spectrum of responses to terrorism, as well as the interplay between biological and psychological variables that contribute to these responses. Finally, it is essential to remove the barriers to collecting data in the aftermath of trauma by creating a culture of education in which the academic community can communicate to the public what is and is not known so that survivors of trauma and terrorism will understand the value of their participation in research to the generation of useful knowledge, and by maintaining the acquisition of knowledge as a priority for the government and those involved in the immediate delivery of services in the aftermath of large-scale disaster or trauma.

Preoperative Intensity Modulated Radiation Therapy and Chemotherapy for Locally Advanced Vulvar Carcinoma: Analysis of Pattern of Relapse

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beriwal, Sushil, E-mail: beriwals@upmc.edu; Shukla, Gaurav; Shinde, Ashwin

2013-04-01

Purpose: To examine clinical outcomes and relapse patterns in locally advanced vulvar carcinoma treated using preoperative chemotherapy and intensity modulated radiation therapy (IMRT). Methods and Materials: Forty-two patients with stage I-IV{sub A} (stage I, n=3; stage II, n=13; stage III, n=23; stage IV{sub A}, n=3) vulvar cancer were treated with chemotherapy and IMRT via a modified Gynecological Oncology Group schema using 5-fluorouracil and cisplatin with twice-daily IMRT during the first and last weeks of treatment or weekly cisplatin with daily radiation therapy. Median dose of radiation was 46.4 Gy. Results: Thirty-three patients (78.6%) had surgery for resection of vulva; 13more » of these patients also had inguinal lymph node dissection. Complete pathologic response was seen in 48.5% (n=16) of these patients. Of these, 15 had no recurrence at a median time of 26.5 months. Of the 17 patients with partial pathological response, 8 (47.1%) developed recurrence in the vulvar surgical site within a median of 8 (range, 5-34) months. No patient had grade ≥3 chronic gastrointestinal/genitourinary toxicity. Of those having surgery, 8 (24.2%) developed wound infections requiring debridement. Conclusions: Preoperative chemotherapy/IMRT was well tolerated, with good pathologic response and clinical outcome. The most common pattern of recurrence was local in patients with partial response, and strategies to increase pathologic response rate with increasing dose or adding different chemotherapy need to be explored to help further improve outcomes.« less

Heat illnesses: a hot topic in the setting of global climate change.

PubMed

Sankoff, Jeffrey

2015-01-01

Heat illnesses affect a large number of people every year and are becoming an increasing cause of pathology as climate change results in increasing global temperatures. This article will review the physiological responses to heat, as well as the pathophysiological processes that result in heat illnesses. The emphasis will be on providing general practitioners (GPs) with an understanding of how to prevent heat illness in their patients and how to predict who is most at risk. Heat illnesses may be thought of as minor or major illnesses, any of which may present to the GP. Consideration must be given to identifying those who need more critical intervention and on when to transfer for higher-level of care.

Targeting Interferon Regulatory Factor for Cardiometabolic Diseases: Opportunities and Challenges.

PubMed

Zhang, Yaxing; Zhang, Xiao-Jing; Li, Hongliang

2017-01-01

The pathological activation of innate immune system may contribute to the development of cardiometabolic diseases. The interferon regulatory factor (IRF) family members, which are the major transcription factors in innate immune signaling, are implicated in cardiometabolic diseases. The aim of this review is to summary the current knowledge of the biological functions of IRFs in innate immune responses and immune cell development, and highlight our contemporary understanding of the functions and molecular mechanisms of IRFs in metabolic diseases, cardiovascular remodeling, and stroke. IRFs are the essential regulators of cardiometabolic diseases via immune-dependent and - independent manners. IRFs signaling is the promising target to manage the initiation and progression of cardiometabolic disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Schistosomiasis

PubMed Central

Tucker, Matthew S.; Karunaratne, Laksiri B.; Lewis, Fred A.; Freitas, Tori C.; Liang, Yung-san

2014-01-01

Schistosomiasis is the second most important parasitic disease in the world in terms of public health impact. Globally, it is estimated that the disease affects over 200 million people and is responsible for 200,000 deaths each year. The three major schistosomes infecting humans are Schistosoma mansoni, S. japonicum, and S. haematobium. Much immunological research has focused on schistosomiasis because of the pathological effects of the disease, which include liver fibrosis and bladder dysfunction. This Unit covers a wide range of aspects of maintaining the life cycles of these parasites, including preparation of schistosome egg antigen, maintenance of intermediate snail hosts, infection of the definitive and intermediate hosts, and others. The Unit primariiy focues on S. mansoni, but also includes coverage of S. japonicum and S. haematobium life cycles. PMID:18432750

Curcumin in Cell Death Processes: A Challenge for CAM of Age-Related Pathologies

PubMed Central

Salvioli, S.; Sikora, E.; Cooper, E. L.

2007-01-01

Curcumin, the yellow pigment from the rhizoma of Curcuma longa, is a widely studied phytochemical which has a variety of biological activities: anti-inflammatory and anti-oxidative. In this review we discuss the biological mechanisms and possible clinical effects of curcumin treatment on cancer therapy, and neurodegenerative diseases such as Alzheimer's Disease, with particular attention to the cell death processes induced by curcumin. Since oxidative stress and inflammation are major determinants of the aging process, we also argue that curcumin can have a more general effect that slows down the rate of aging. Finally, the effects of curcumin can be described as xenohormetic, since it activates a sort of stress response in mammalian cells. PMID:17549234

Magnetic forces enable controlled drug delivery by disrupting endothelial cell-cell junctions

NASA Astrophysics Data System (ADS)

Qiu, Yongzhi; Tong, Sheng; Zhang, Linlin; Sakurai, Yumiko; Myers, David R.; Hong, Lin; Lam, Wilbur A.; Bao, Gang

2017-06-01

The vascular endothelium presents a major transport barrier to drug delivery by only allowing selective extravasation of solutes and small molecules. Therefore, enhancing drug transport across the endothelial barrier has to rely on leaky vessels arising from disease states such as pathological angiogenesis and inflammatory response. Here we show that the permeability of vascular endothelium can be increased using an external magnetic field to temporarily disrupt endothelial adherens junctions through internalized iron oxide nanoparticles, activating the paracellular transport pathway and facilitating the local extravasation of circulating substances. This approach provides a physically controlled drug delivery method harnessing the biology of endothelial adherens junction and opens a new avenue for drug delivery in a broad range of biomedical research and therapeutic applications.

Status Epilepticus

PubMed Central

Seinfeld, Syndi; Goodkin, Howard P.; Shinnar, Shlomo

2016-01-01

Although the majority of seizures are brief and cause no long-term consequences, a subset is sufficiently prolonged that long-term consequences can result. These very prolonged seizures are termed “status epilepticus” (SE) and are considered a neurological emergency. The clinical presentation of SE can be diverse. SE can occur at any age but most commonly occurs in the very young and the very old. There are numerous studies on SE in animals in which the pathophysiology, medication responses, and pathology can be rigorously studied in a controlled fashion. Human data are consistent with the animal data. In particular, febrile status epilepticus (FSE), a form of SE common in young children, is associated with injury to the hippocampus and subsequent temporal lobe epilepsy (TLE) in both animals and humans. PMID:26931807

Predictive factors in the evaluation of treatment response to neoadjuvant chemoradiotherapy in patients with advanced esophageal squamous cell cancer

PubMed Central

Wong, Claudia

2017-01-01

Neoadjuvant therapy before esophagectomy is evidence-based, and is a standard-of-care for locally advanced and operable esophageal cancer. However response to such treatment varies in individual patients, from no clinical response to pathological complete response. It has been consistently shown that a good pathological responses is of prognostic value, but perhaps in the expense of those who do not. It is important to identify suitable predictive factors for response, so that patients are not exposed to potentially harmful chemotherapy and/or radiotherapy without benefits. Alternative management strategies can be devised. Various clinical, radiological, serological and potential molecular markers have been studied. None has been shown to be sufficiently reliable to be used in daily practice. Certainly more understanding of the molecular basis for response to chemotherapy/radiotherapy is needed, so that patient treatment can be tailored and individualized. PMID:28815073

Drosophila hematopoiesis under normal conditions and in response to immune stress.

PubMed

Letourneau, Manon; Lapraz, Francois; Sharma, Anurag; Vanzo, Nathalie; Waltzer, Lucas; Crozatier, Michèle

2016-11-01

The emergence of hematopoietic progenitors and their differentiation into various highly specialized blood cell types constitute a finely tuned process. Unveiling the genetic cascades that control blood cell progenitor fate and understanding how they are modulated in response to environmental changes are two major challenges in the field of hematopoiesis. In the last 20 years, many studies have established important functional analogies between blood cell development in vertebrates and in the fruit fly, Drosophila melanogaster. Thereby, Drosophila has emerged as a powerful genetic model for studying mechanisms that control hematopoiesis during normal development or in pathological situations. Moreover, recent advances in Drosophila have highlighted how intricate cell communication networks and microenvironmental cues regulate blood cell homeostasis. They have also revealed the striking plasticity of Drosophila mature blood cells and the presence of different sites of hematopoiesis in the larva. This review provides an overview of Drosophila hematopoiesis during development and summarizes our current knowledge on the molecular processes controlling larval hematopoiesis, both under normal conditions and in response to an immune challenge, such as wasp parasitism. © 2016 Federation of European Biochemical Societies.

Antiviral activity of NK 1.1+ natural killer cells in C57BL/6 scid mice infected with murine cytomegalovirus.

PubMed

Welsh, R M; O'Donnell, C L; Shultz, L D

1994-01-01

The activation, proliferation, and antiviral effects of natural killer (NK) cells were examined in a newly developed stock of mice, C57BL/6JSz mice homozygous for the severe combined immunodeficiency (scid) mutation. These mice lack functional T and B cells and express the NK 1.1 alloantigen. Such NK 1.1 expression facilitates the analysis of NK cells and their depletion in vivo with a monoclonal anti-NK 1.1 antibody. These mice, therefore, provide an excellent model to examine unambiguously the interactions between viral infections and NK cells in a system devoid of adaptive immune response mechanisms. Here we show that murine cytomegalovirus (MCMV) and lymphocytic choriomeningitis virus (LCMV) infections resulted in profound levels of NK cell activation. NK cells also proliferated greatly in response to LCMV but generally to a lesser degree in response to MCMV. Depletion of the NK cell activity in vivo caused substantial increases in MCMV synthesis and MCMV-induced pathology. These results further support the concept that NK cells are major regulators of MCMV pathogenesis.

Biological determinants of depression following bereavement.

PubMed

Assareh, Amelia A; Sharpley, Christopher F; McFarlane, James R; Sachdev, Perminder S

2015-02-01

There is considerable variability among people in their response to bereavement. While most people adapt well to bereavement, some develop exaggerated and/or pathological responses and may meet criteria for a major depressive episode. Many studies have investigated the effect of psychosocial factors on bereavement outcome but biological factors have not received much attention, hence the focus of this paper. The biological factors studied to date in relation to bereavement outcomes include genetic polymorphisms, neuroendocrine factors, and immunologic/inflammatory markers. In addition, animal studies have shown the alterations of brain neurotransmitters as well as changes in the plasma levels of the neurotrophic growth factors under the influence of peer loss. Recent studies have also investigated the biological basis of stress resilience, and have found a few genetic polymorphisms and potential biomarkers as protective factors in the face of adversity. Longitudinal studies that include data collection prior to, and also after, bereavement and which chart both biological and psychological measures are needed to develop profiles for the prediction of response to bereavement and personalised interventions. Copyright © 2014 Elsevier Ltd. All rights reserved.

Different tracks for pathology informatics fellowship training: Experiences of and input from trainees in a large multisite fellowship program

PubMed Central

Levy, Bruce P.; McClintock, David S.; Lee, Roy E.; Lane, William J.; Klepeis, Veronica E.; Baron, Jason M.; Onozato, Maristela L.; Kim, JiYeon; Brodsky, Victor; Beckwith, Bruce; Kuo, Frank; Gilbertson, John R.

2012-01-01

Background: Pathology Informatics is a new field; a field that is still defining itself even as it begins the formalization, accreditation, and board certification process. At the same time, Pathology itself is changing in a variety of ways that impact informatics, including subspecialization and an increased use of data analysis. In this paper, we examine how these changes impact both the structure of Pathology Informatics fellowship programs and the fellows’ goals within those programs. Materials and Methods: As part of our regular program review process, the fellows evaluated the value and effectiveness of our existing fellowship tracks (Research Informatics, Clinical Two-year Focused Informatics, Clinical One-year Focused Informatics, and Clinical 1 + 1 Subspecialty Pathology and Informatics). They compared their education, informatics background, and anticipated career paths and analyzed them for correlations between those parameters and the fellowship track chosen. All current and past fellows of the program were actively involved with the project. Results: Fellows’ anticipated career paths correlated very well with the specific tracks in the program. A small set of fellows (Clinical – one or two year – Focused Informatics tracks) anticipated clinical careers primarily focused in informatics (Director of Informatics). The majority of the fellows, however, anticipated a career practicing in a Pathology subspecialty, using their informatics training to enhance that practice (Clinical 1 + 1 Subspecialty Pathology and Informatics Track). Significantly, all fellows on this track reported they would not have considered a Clinical Two-year Focused Informatics track if it was the only track offered. The Research and the Clinical One-year Focused Informatics tracks each displayed unique value for different situations. Conclusions: It seems a “one size fits all” fellowship structure does not fit the needs of the majority of potential Pathology Informatics candidates. Increasingly, these fellowships must be able to accommodate the needs of candidates anticipating a wide range of Pathology Informatics career paths, be able to accommodate Pathology's increasingly subspecialized structure, and do this in a way that respects the multiple fellowships needed to become a subspecialty pathologist and informatician. This is further complicated as Pathology Informatics begins to look outward and takes its place in the growing, and still ill-defined, field of Clinical Informatics, a field that is not confined to just one medical specialty, to one way of practicing medicine, or to one way of providing patient care. PMID:23024889

Pathology as the enabler of human research.

PubMed

Crawford, James M; Tykocinski, Mark L

2005-09-01

Academic Pathology is a key player in human molecular science and in the powerful initiatives of the National Institutes of Health. Pathologists generate data crucial to virtually every molecular study of human tissue, and have the necessary skills and authority to oversee processing of human tissues for research analysis. We advocate that Academic Pathology is optimally positioned to drive the molecular revolution in study of human disease, through human tissue collection, analysis, and databasing. This can be achieved through playing a major role in human tissue procurement and management; establishing high-quality 'Pathology Resource Laboratories'; providing the scientific expertise for pathology data sharing; and recruiting and training physician scientists. Pathology should position itself to be the local institutional driver of technology implementation and development, by operating the resource laboratories, providing the expertise for technical and conceptual design of research projects, maintaining the databases that link molecular and morphological information on human tissues with the requisite clinical databases, providing education and mentorship of technology users, and nurturing new research through the development of preliminary data. We also consider that outstanding pathology journals are available for the publication of research emanating from such studies, to the benefit of the pathology profession as an academic enterprise. It is our earnest hope that Academic Pathology can play a leading role in the remarkable advances to be made as the 21st century unfolds.

Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project.

PubMed

Weisenburger, Dennis D; Savage, Kerry J; Harris, Nancy Lee; Gascoyne, Randy D; Jaffe, Elaine S; MacLennan, Kenneth A; Rüdiger, Thomas; Pileri, Stefano; Nakamura, Shigeo; Nathwani, Bharat; Campo, Elias; Berger, Francoise; Coiffier, Bertrand; Kim, Won-Seog; Holte, Harald; Federico, Massimo; Au, Wing Y; Tobinai, Kensei; Armitage, James O; Vose, Julie M

2011-03-24

The International Peripheral T-cell Lymphoma Project is a collaborative effort to better understand peripheral T-cell lymphoma (PTCL). A total of 22 institutions submitted clinical and pathologic material on 1314 cases. One objective was to analyze the clinical and pathologic features of 340 cases of PTCL, not otherwise specified. The median age of the patients was 60 years, and the majority (69%) presented with advanced stage disease. Most patients (87%) presented with nodal disease, but extranodal disease was present in 62%. The 5-year overall survival was 32%, and the 5-year failure-free survival was only 20%. The majority of patients (80%) were treated with combination chemotherapy that included an anthracycline, but there was no survival advantage. The International Prognostic Index (IPI) was predictive of both overall survival and failure-free survival (P < .001). Multivariate analysis of clinical and pathologic prognostic factors, respectively, when controlling for the IPI, identified bulky disease (≥ 10 cm), thrombocytopenia (< 150 × 10(9)/L), and a high number of transformed tumor cells (> 70%) as adverse predictors of survival, but only the latter was significant in final analysis. Thus, the IPI and a single pathologic feature could be used to stratify patients with PTCL-not otherwise specified for novel and risk-adapted therapies.

Histopathology report of cutaneous melanoma and sentinel lymph node in Europe: a web-based survey by the Dermatopathology Working Group of the European Society of Pathology.

PubMed

Batistatou, Anna; Cook, Martin G; Massi, Daniela

2009-05-01

In order to survey the diagnostic reporting of melanomas by European pathologists and assess their current practice and opinions on the information required in the final report, a web-based questionnaire was diffused through the members of the Dermatopathology Working Group of the European Society of Pathology. Forty replies from different pathology laboratories were collected (49%). Main prognostic parameters related to the primary tumor, including Breslow thickness, presence of ulceration, and Clark's level, as well as additional features, are reported by a large majority of laboratories. Presence of regression is reported by 90% of respondents but with different recording items. For sentinel lymph node (SLN) biopsy for melanoma, the conventional panel of antibodies includes S-100, Melan A, and HMB45. Dissection of the SLN is performed by "bivalve" or "bread loaf" approach. The number of sections cut and stained varies. Forty-four percent of respondents report depths of metastases from the capsule, while the majority report maximum dimension of the largest deposit. Results indicate that pathology reports for primary cutaneous melanoma and SLN vary between laboratories across Europe. Although the most important prognostic features are universally reported, key features which impact on prognosis and treatment are often omitted and others still require standardization.

Diagnostic value of the 2011 International Federation for Cervical Pathology and Colposcopy Terminology in predicting cervical lesions.

PubMed

Fan, Aiping; Wang, Chen; Zhang, Liqin; Yan, Ye; Han, Cha; Xue, Fengxia

2018-02-06

To evaluate the diagnostic accuracy of the 2011 International Federation for Cervical Pathology and Colposcopy (IFCPC) colposcopic terminology. The clinicopathological data of 2262 patients who underwent colposcopy from September 2012 to September 2016 were reviewed. The colposcopic findings, colposcopic impression, and cervical histopathology of the patients were analyzed. Correlations between variables were evaluated using cervical histopathology as the gold standard. Colposcopic diagnosis matched biopsy histopathology in 1482 patients (65.5%), and the weighted kappa strength of agreement was 0.480 (P<0.01). Colposcopic diagnoses more often underestimated (22.1%) than overestimated (12.3%) cervical pathology. There was no significant difference between the colposcopic diagnosis and cervical pathology agreement among the various grades of lesions (P=0.282). The sensitivity, specificity for detecting high-grade lesions/carcinoma was 71.6% and 98.0%, respectively. Multivariate analysis showed that major changes were independent factors in predicting high-grade lesion/carcinoma, whereas transformation zone, lesion size, and non-stained were not statistically related to high-grade lesion/carcinoma. The 2011 IFCPC terminology can improve the diagnostic accuracy for all lesion severities. The categorization of major changes and minor changes is appropriate. However, colposcopic diagnosis remains unsatisfactory. Poor reproducibility of type 2 transformation zone and the significance of leukoplakia require further study.

Polyubiquitination events mediate polymethylmethacrylate (PMMA) particle activation of NF-kappaB pathway.

PubMed

Yamanaka, Yasuhiro; Karuppaiah, Kannan; Abu-Amer, Yousef

2011-07-08

The pathologic response to implant wear-debris constitutes a major component of inflammatory osteolysis and remains under intense investigation. Polymethylmethacrylate (PMMA) particles, which are released during implant wear and loosening, constitute a major culprit by virtue of inducing inflammatory and osteolytic responses by macrophages and osteoclasts, respectively. Recent work by several groups has identified important cellular entities and secreted factors that contribute to inflammatory osteolysis. In previous work, we have shown that PMMA particles contribute to inflammatory osteolysis through stimulation of major pathways in monocytes/macrophages, primarily NF-κB and MAP kinases. The former pathway requires assembly of large IKK complex encompassing IKK1, IKK2, and IKKγ/NEMO. We have shown recently that interfering with the NF-κB and MAPK activation pathways, through introduction of inhibitors and decoy molecules, impedes PMMA-induced inflammation and osteolysis in mouse models of experimental calvarial osteolysis and inflammatory arthritis. In this study, we report that PMMA particles activate the upstream transforming growth factor β-activated kinase-1 (TAK1), which is a key regulator of signal transduction cascades leading to activation of NF-κB and AP-1 factors. More importantly, we found that PMMA particles induce TAK1 binding to NEMO and UBC13. In addition, we show that PMMA particles induce TRAF6 and UBC13 binding to NEMO and that lack of TRAF6 significantly attenuates NEMO ubiquitination. Altogether, these observations suggest that PMMA particles induce ubiquitination of NEMO, an event likely mediated by TRAF6, TAK1, and UBC13. Our findings provide important information for better understanding of the mechanisms underlying PMMA particle-induced inflammatory responses.

Congenital Cytomegalovirus Infection: Molecular Mechanisms Mediating Viral Pathogenesis

PubMed Central

Schleiss, Mark R.

2013-01-01

Human cytomegalovirus (CMV) is responsible for approximately 40,000 congenital infections in the United States each year. Congenital CMV disease frequently produces serious neurodevelopmental disability, as well as vision impairment and sensorineural hearing loss. Development of a CMV vaccine is therefore considered to be a major public health priority. The mechanisms by which CMV injures the fetus are complex and likely include a combination of direct fetal injury induced by pathologic virally-encoded gene products, an inability of the maternal immune response to control infection, and the direct impact of infection on placental function. CMV encodes gene products that function, both at the RNA and the protein level, to interfere with many cellular processes. These include gene products that modify the cell cycle; interfere with apoptosis; induce an inflammatory response; mediate vascular injury; induce site-specific breakage of chromosomes; promote oncogenesis; dysregulate cellular proliferation; and facilitate evasion of host immune responses. This minireview summarizes current concepts regarding these aspects of the molecular virology of CMV and the potential pathogenic impact of viral gene expression on the developing fetus. Areas for potential development of novel therapeutic intervention are suggested for improving the outcome of this disabling congenital infection. PMID:21827434

Acquisition of Pneumococci Specific Effector and Regulatory Cd4+ T Cells Localising within Human Upper Respiratory-Tract Mucosal Lymphoid Tissue

PubMed Central

Pido-Lopez, Jeffrey; Kwok, William W.; Mitchell, Timothy J.; Heyderman, Robert S.; Williams, Neil A.

2011-01-01

The upper respiratory tract mucosa is the location for commensal Streptococcus (S.) pneumoniae colonization and therefore represents a major site of contact between host and bacteria. The CD4+ T cell response to pneumococcus is increasingly recognised as an important mediator of immunity that protects against invasive disease, with data suggesting a critical role for Th17 cells in mucosal clearance. By assessing CD4 T cell proliferative responses we demonstrate age-related sequestration of Th1 and Th17 CD4+ T cells reactive to pneumococcal protein antigens within mucosal lymphoid tissue. CD25hi T cell depletion and utilisation of pneumococcal specific MHCII tetramers revealed the presence of antigen specific Tregs that utilised CTLA-4 and PDL-1 surface molecules to suppress these responses. The balance between mucosal effector and regulatory CD4+ T cell immunity is likely to be critical to pneumococcal commensalism and the prevention of unwanted pathology associated with carriage. However, if dysregulated, such responses may render the host more susceptible to invasive pneumococcal infection and adversely affect the successful implementation of both polysaccharide-conjugate and novel protein-based pneumococcal vaccines. PMID:22144893

System for pathology categorization and retrieval in chest radiographs

NASA Astrophysics Data System (ADS)

Avni, Uri; Greenspan, Hayit; Konen, Eli; Sharon, Michal; Goldberger, Jacob

2011-03-01

In this paper we present an overview of a system we have been developing for the past several years for efficient image categorization and retrieval in large radiograph archives. The methodology is based on local patch representation of the image content, using a bag of visual words approach and similarity-based categorization with a kernel based SVM classifier. We show an application to pathology-level categorization of chest x-ray data, the most popular examination in radiology. Our study deals with pathology detection and identification of individual pathologies including right and left pleural effusion, enlarged heart and cases of enlarged mediastinum. The input from a radiologist provided a global label for the entire image (healthy/pathology), and the categorization was conducted on the entire image, with no need for segmentation algorithms or any geometrical rules. An automatic diagnostic-level categorization, even on such an elementary level as healthy vs pathological, provides a useful tool for radiologists on this popular and important examination. This is a first step towards similarity-based categorization, which has a major clinical implications for computer-assisted diagnostics.

Value of subjective visual reduction in patients with acute-onset floaters and/or flashes.

PubMed

Hurst, Jonathan; Johnson, Davin; Law, Christine; Schweitzer, Kelly; Sharma, Sanjay

2015-08-01

To quantify the association between subjective visual reduction (SVR) and retinal pathology in patients with acute-onset monocular floaters or flashes, or both. Prospective cohorts study involving all new patients referred for acute-onset floaters or flashes, or both, to a tertiary care emergency eye clinic in Kingston, Ontario, between July 1, 2011, and June 29, 2012 (n = 333). All patients were evaluated for the presence of SVR in a standardized fashion, as well as other known risk factors for retina pathology including a family history of retinal tear or retinal detachment, a personal history of retinal tear or detachment, high myopia, and ocular trauma. Our major outcome was urgent retinal pathology, defined as retina pathology requiring a same-day referral to a retina specialist for evaluation, management, or both. SVR was strongly associated with retinal pathology (likelihood ratio 7.9, 95% CI 5.2-12.1). Patients with SVR are at increased risk for urgent retinal pathology and should be triaged for urgent ophthalmologic examination. Copyright © 2015 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

TDP-43 stage, mixed pathologies, and clinical Alzheimer's-type dementia.

PubMed

James, Bryan D; Wilson, Robert S; Boyle, Patricia A; Trojanowski, John Q; Bennett, David A; Schneider, Julie A

2016-11-01

Hyperphosphorylated transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP ) proteinopathy has recently been described in ageing and in association with cognitive impairment, especially in the context of Alzheimer's disease pathology. To explore the role of mixed Alzheimer's disease and TDP-43 pathologies in clinical Alzheimer's-type dementia, we performed a comprehensive investigation of TDP-43, mixed pathologies, and clinical Alzheimer's-type dementia in a large cohort of community-dwelling older subjects. We tested the hypotheses that TDP-43 with Alzheimer's disease pathology is a common mixed pathology; is related to increased likelihood of expressing clinical Alzheimer's-type dementia; and that TDP-43 pathologic stage is an important determinant of clinical Alzheimer's-type dementia. Data came from 946 older adults with ( n = 398) and without dementia ( n = 548) from the Rush Memory and Aging Project and Religious Orders Study. TDP-43 proteinopathy (cytoplasmic inclusions) was present in 496 (52%) subjects, and the pattern of deposition was classified as stage 0 (none; 48%), stage 1 (amygdala; 18%), stage 2 (extension to hippocampus/entorhinal; 21%), or stage 3 (extension to neocortex; 14%). TDP-43 pathology combined with a pathologic diagnosis of Alzheimer's disease was a common mixed pathology (37% of all participants), and the proportion of subjects with clinical Alzheimer's-type dementia formerly labelled 'pure pathologic diagnosis of Alzheimer's disease' was halved when TDP-43 was considered. In logistic regression models adjusted for age, sex, and education, TDP-43 pathology was associated with clinical Alzheimer's-type dementia (odds ratio = 1.51, 95% confidence interval = 1.11, 2.05) independent of pathological Alzheimer's disease (odds ratio = 4.30, 95% confidence interval = 3.08, 6.01) or other pathologies (infarcts, arteriolosclerosis, Lewy bodies, and hippocampal sclerosis). Mixed Alzheimer's disease and TDP-43 pathologies were associated with higher odds of clinical Alzheimer's-type dementia (odds ratio = 6.73, 95% confidence interval = 4.18, 10.85) than pathologic Alzheimer's disease alone (odds ratio = 4.62, 95% confidence interval = 2.84, 7.52). In models examining TDP-43 stage, a dose-response relationship with clinical Alzheimer's-type dementia was observed, and a significant association was observed starting at stage 2, extension beyond the amygdala. In this large sample from almost 1000 community participants, we observed that TDP-43 proteinopathy was very common, frequently mixed with pathological Alzheimer's disease, and associated with a higher likelihood of the clinical expression of clinical Alzheimer's-type dementia but only when extended beyond the amygdala. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Culturally and linguistically diverse students in speech-language pathology courses: A platform for culturally responsive services.

PubMed

Attrill, Stacie; Lincoln, Michelle; McAllister, Sue

2017-06-01

Increasing the proportion of culturally and linguistically diverse (CALD) students and providing intercultural learning opportunities for all students are two strategies identified to facilitate greater access to culturally responsive speech-language pathology services. To enact these strategies, more information is needed about student diversity. This study collected descriptive information about CALD speech-language pathology students in Australia. Cultural and linguistic background information was collected through surveying 854 domestic and international speech-language pathology students from three Australian universities. Students were categorised according to defined or perceived CALD status, international student status, speaking English as an Additional Language (EAL), or speaking a Language Other than English at Home (LOTEH). Overall, 32.1% of students were either defined or perceived CALD. A total of 14.9% spoke EAL and 25.7% identified speaking a LOTEH. CALD students were more likely to speak EAL or a LOTEH than non-CALD students, were prominently from Southern and South-Eastern Asian backgrounds and spoke related languages. Many students reported direct or indirect connections with their cultural heritage and/or contributed linguistic diversity. These students may represent broader acculturative experiences in communities. The sociocultural knowledge and experience of these students may provide intercultural learning opportunities for all students and promote culturally responsive practices.

Comparative evaluation of differential laser-induced perturbation spectroscopy as a technique to discriminate emerging skin pathology

NASA Astrophysics Data System (ADS)

Kozikowski, Raymond T.; Smith, Sarah E.; Lee, Jennifer A.; Castleman, William L.; Sorg, Brian S.; Hahn, David W.

2012-06-01

Fluorescence spectroscopy has been widely investigated as a technique for identifying pathological tissue; however, unrelated subject-to-subject variations in spectra complicate data analysis and interpretation. We describe and evaluate a new biosensing technique, differential laser-induced perturbation spectroscopy (DLIPS), based on deep ultraviolet (UV) photochemical perturbation in combination with difference spectroscopy. This technique combines sequential fluorescence probing (pre- and post-perturbation) with sub-ablative UV perturbation and difference spectroscopy to provide a new spectral dimension, facilitating two improvements over fluorescence spectroscopy. First, the differential technique eliminates significant variations in absolute fluorescence response within subject populations. Second, UV perturbations alter the extracellular matrix (ECM), directly coupling the DLIPS response to the biological structure. Improved biosensing with DLIPS is demonstrated in vivo in a murine model of chemically induced skin lesion development. Component loading analysis of the data indicates that the DLIPS technique couples to structural proteins in the ECM. Analysis of variance shows that DLIPS has a significant response to emerging pathology as opposed to other population differences. An optimal likelihood ratio classifier for the DLIPS dataset shows that this technique holds promise for improved diagnosis of epithelial pathology. Results further indicate that DLIPS may improve diagnosis of tissue by augmenting fluorescence spectra (i.e. orthogonal sensing).

“End-Stage” Neurofibrillary Tangle Pathology in Preclinical Alzheimer's Disease: Fact or Fiction?

PubMed Central

Abner, Erin L.; Kryscio, Richard J.; Schmitt, Frederick A.; SantaCruz, Karen S.; Jicha, Gregory A.; Lin, Yushun; Neltner, Janna M.; Smith, Charles D.; Van Eldik, Linda J.; Nelson, Peter T.

2011-01-01

Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer's disease-type pathology. The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena. We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals. Data from the National Alzheimer's Coordinating Center database (n = 4,690 included initially) and from the Nun Study (n = 526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case. Global cognition (final Mini-Mental State Examination scores [MMSE] and clinical ‘dementia’ status) was correlated with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology. It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status. There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition. PMID:21471646

Quantifying the effect of side branches in endothelial shear stress estimates

PubMed Central

Giannopoulos, Andreas A.; Chatzizisis, Yiannis S.; Maurovich-Horvat, Pal; Antoniadis, Antonios P.; Hoffmann, Udo; Steigner, Michael L.; Rybicki, Frank J.; Mitsouras, Dimitrios

2016-01-01

Background and aims Low and high endothelial shear stress (ESS) is associated with coronary atherosclerosis progression and high-risk plaque features. Coronary ESS is currently assessed via computational fluid dynamic (CFD) simulation in the lumen geometry determined from invasive imaging such as intravascular ultrasound and optical coherence tomography. This process typically omits side branches of the target vessel in the CFD model as invasive imaging of those vessels is not clinically-indicated. The purpose of this study was to determine the extent to which this simplification affects the determination of those regions of the coronary endothelium subjected to pathologic ESS. Methods We determined the diagnostic accuracy of ESS profiling without side branches to detect pathologic ESS in the major coronary arteries of 5 hearts imaged ex vivo with CT angiography. ESS of the three major coronary arteries was calculated both without (test model), and with (reference model) inclusion of all side branches >1.5 mm in diameter, using previously-validated CFD approaches. Diagnostic test characteristics (accuracy, sensitivity, specificity and negative and positive predictive value [NPV/PPV]) with respect to the reference model were assessed for both the entire length as well as only the proximal portion of each major coronary artery, where the majority of high-risk plaques occur. Results Using the model without side branches overall accuracy, sensitivity, specificity, NPV and PPV were 83.4%, 54.0%, 96%, 95.9% and 55.1%, respectively to detect low ESS, and 87.0%, 67.7%, 90.7%, 93.7% and 57.5%, respectively to detect high ESS. When considering only the proximal arteries, test characteristics differed for low and high ESS, with low sensitivity (67.7%) and high specificity (90.7%) to detect low ESS, and low sensitivity (44.7%) and high specificity (95.5%) to detect high ESS. Conclusions The exclusion of side branches in ESS vascular profiling studies greatly reduces the ability to detect regions of the major coronary arteries subjected to pathologic ESS. Single-conduit models can in general only be used to rule out pathologic ESS. PMID:27372207

Quantifying the effect of side branches in endothelial shear stress estimates.

PubMed

Giannopoulos, Andreas A; Chatzizisis, Yiannis S; Maurovich-Horvat, Pal; Antoniadis, Antonios P; Hoffmann, Udo; Steigner, Michael L; Rybicki, Frank J; Mitsouras, Dimitrios

2016-08-01

Low and high endothelial shear stress (ESS) is associated with coronary atherosclerosis progression and high-risk plaque features. Coronary ESS is currently assessed via computational fluid dynamic (CFD) simulation of coronary blood flow in the lumen geometry determined from invasive imaging such as intravascular ultrasound and optical coherence tomography. This process typically omits side branches of the target vessel in the CFD model as invasive imaging of those vessels is not usually clinically-indicated. The purpose of this study was to determine the extent to which this simplification affects the determination of those regions of the coronary endothelium subjected to pathologic ESS. We determined the diagnostic accuracy of ESS profiling without side branches to detect pathologic ESS in the major coronary arteries of 5 hearts imaged ex vivo with computed tomography angiography (CTA). ESS of the three major coronary arteries was calculated both without (test model), and with (reference model) inclusion of all side branches >1.5 mm in diameter, using previously-validated CFD approaches. Diagnostic test characteristics (accuracy, sensitivity, specificity and negative and positive predictive value [NPV/PPV]) with respect to the reference model were assessed for both the entire length as well as only the proximal portion of each major coronary artery, where the majority of high-risk plaques occur. Using the model without side branches overall accuracy, sensitivity, specificity, NPV and PPV were 83.4%, 54.0%, 96%, 95.9% and 55.1%, respectively to detect low ESS, and 87.0%, 67.7%, 90.7%, 93.7% and 57.5%, respectively to detect high ESS. When considering only the proximal arteries, test characteristics differed for low and high ESS, with low sensitivity (67.7%) and high specificity (90.7%) to detect low ESS, and low sensitivity (44.7%) and high specificity (95.5%) to detect high ESS. The exclusion of side branches in ESS vascular profiling studies greatly reduces the ability to detect regions of the major coronary arteries subjected to pathologic ESS. Single-conduit models can in general only be used to rule out pathologic ESS. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Asthma and Chronic Obstructive Pulmonary Disease (COPD) – Differences and Similarities

PubMed Central

Cukic, Vesna; Lovre, Vladimir; Dragisic, Dejan; Ustamujic, Aida

2012-01-01

Bronchial asthma and COPD (chronic obstructive pulmonary disease) are obstructive pulmonary diseases that affected millions of people all over the world. Asthma is a serious global health problem with an estimated 300 million affected individuals. COPD is one of the major causes of chronic morbidity and mortality and one of the major public health problems worldwide. COPD is the fourth leading cause of death in the world and further increases in its prevalence and mortality can be predicted. Although asthma and COPD have many similarities, they also have many differences. They are two different diseases with differences in etiology, symptoms, type of airway inflammation, inflammatory cells, mediators, consequences of inflammation, response to therapy, course. Some similarities in airway inflammation in severe asthma and COPD and good response to combined therapy in both of these diseases suggest that they have some similar patophysiologic characteristics. The aim of this article is to show similarities and differences between these two diseases. Today asthma and COPD are not fully curable, not identified enough and not treated enough and the therapy is still developing. But in future better understanding of pathology, adequate identifying and treatment, may be and new drugs, will provide a much better quality of life, reduced morbidity and mortality of these patients. PMID:23678316

Errors and error rates in surgical pathology: an Association of Directors of Anatomic and Surgical Pathology survey.

PubMed

Cooper, Kumarasen

2006-05-01

This survey on errors in surgical pathology was commissioned by the Association of Directors of Anatomic and Surgical Pathology Council to explore broad perceptions and definitions of error in surgical pathology among its membership and to get some estimate of the perceived frequency of such errors. Overall, 41 laboratories were surveyed, with 34 responding to a confidential questionnaire. Six small, 13 medium, and 10 large laboratories (based on specimen volume), predominantly located in the United States, were surveyed (the remaining 5 laboratories did not provide this particular information). The survey questions, responses, and associated comments are presented. It is clear from this survey that we lack uniformity and consistency with respect to terminology, definitions, and the identification/documentation of errors in surgical pathology. An appeal is made for the urgent need to reach some consensus in order to address these discrepancies as we prepare to combat the issue of errors in surgical pathology.

Phase II Trial of Full-Dose Gemcitabine and Bevacizumab in Combination With Attenuated Three-Dimensional Conformal Radiotherapy in Patients With Localized Pancreatic Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Small, William, E-mail: wsmall@nmff.or; Mulcahy, Mary F.; Rademaker, Alfred

Purpose: To evaluate response rate, survival, and toxicity in patients with nonmetastatic pancreatic cancer treated with gemcitabine, bevacizumab, and radiotherapy. Methods and Materials: Patients received three cycles of therapy over 10 weeks. In total, treatment consisted of intravenous (IV) gemcitabine, 1,000 mg/m{sup 2}, every 1 to 2 weeks (7 doses), IV bevacizumab, 10 mg/kg every 2 weeks (5 doses), and 36 Gy of radiotherapy (2.4-Gy fractions during cycle two). Response was assessed by cross-sectional imaging and carbohydrate antigen 19-9 (CA 19-9) levels. Patients with resectable tumors underwent surgery 6 to 8 weeks after the last dose of bevacizumab. Maintenance gemcitabinemore » and bevacizumab doses were delivered to patients who had unresected tumors and no progression. Results: Twenty-eight of the 32 enrolled patients completed all three cycles. The median follow-up was 11.07 months. Most grade 3 or 4 toxicities occurred in the initial treatment phase; the most frequent toxicities were leukopenia (21%), neutropenia (17%), and nausea (17%). At week 10, 1 patient (4%) had a complete response, 2 patients (7%) had partial responses, 21 patients (75%) had stable disease, and 4 patients (14%) had progressive disease. The median pretreatment and posttreatment CA 19-9 levels (25 patients) were 184.3 and 57.9 U/ml, respectively (p = 0.0006). One of 10 patients proceeding to surgery experienced a major complication. Two of 6 patients undergoing resection had complete pathologic responses. The median progression-free and overall survival durations were 9.9 months and 11.8 months, respectively. Conclusions: The combination of full-dose gemcitabine, bevacizumab, and radiotherapy was active and was not associated with a high rate of major surgical complications.« less

Best practices for veterinary toxicologic clinical pathology, with emphasis on the pharmaceutical and biotechnology industries.

PubMed

Tomlinson, Lindsay; Boone, Laura I; Ramaiah, Lila; Penraat, Kelley A; von Beust, Barbara R; Ameri, Mehrdad; Poitout-Belissent, Florence M; Weingand, Kurt; Workman, Heather C; Aulbach, Adam D; Meyer, Dennis J; Brown, Diane E; MacNeill, Amy L; Bolliger, Anne Provencher; Bounous, Denise I

2013-09-01

The purpose of this paper by the Regulatory Affairs Committee (RAC) of the American Society for Veterinary Clinical Pathology (ASVCP) is to review the current regulatory guidances (eg, guidelines) and published recommendations for best practices in veterinary toxicologic clinical pathology, particularly in the pharmaceutical and biotechnology industries, and to utilize the combined experience of ASVCP RAC to provide updated recommendations. Discussion points include (1) instrumentation, validation, and sample collection, (2) routine laboratory variables, (3) cytologic laboratory variables, (4) data interpretation and reporting (including peer review, reference intervals and statistics), and (5) roles and responsibilities of clinical pathologists and laboratory personnel. Revision and improvement of current practices should be in alignment with evolving regulatory guidance documents, new technology, and expanding understanding and utility of clinical pathology. These recommendations provide a contemporary guide for the refinement of veterinary toxicologic clinical pathology best practices. © 2013 American Society for Veterinary Clinical Pathology.

Dietary fructose as a risk factor for non-alcoholic fatty liver disease (NAFLD).

PubMed

Alwahsh, Salamah Mohammad; Gebhardt, Rolf

2017-04-01

Glucose is a major energy source for the entire body, while fructose metabolism occurs mainly in the liver. Fructose consumption has increased over the last decade globally and is suspected to contribute to the increased incidence of non-alcoholic fatty liver disease (NAFLD). NAFLD is a manifestation of metabolic syndrome affecting about one-third of the population worldwide and has progressive pathological potential for liver cirrhosis and cancer through non-alcoholic steatohepatitis (NASH). Here we have reviewed the possible contribution of fructose to the pathophysiology of NAFLD. We critically summarize the current findings about several regulators, and their potential mechanisms, that have been studied in humans and animal models in response to fructose exposure. A novel hypothesis on fructose-dependent perturbation of liver regeneration and metabolism is advanced. Fructose intake could affect inflammatory and metabolic processes, liver function, gut microbiota, and portal endotoxin influx. The role of the brain in controlling fructose ingestion and the subsequent development of NAFLD is highlighted. Although the importance for fructose (over)consumption for NAFLD in humans is still debated and comprehensive intervention studies are invited, understanding of how fructose intake can favor these pathological processes is crucial for the development of appropriate noninvasive diagnostic and therapeutic approaches to detect and treat these metabolic effects. Still, lifestyle modification, to lessen the consumption of fructose-containing products, and physical exercise are major measures against NAFLD. Finally, promising drugs against fructose-induced insulin resistance and hepatic dysfunction that are emerging from studies in rodents are reviewed, but need further validation in human patients.

Maladaptive eating behavior assessment among bariatric surgery candidates: Evaluation of the Eating Disorder Diagnostic Scale.

PubMed

Williams, Gail A; Hawkins, Misty A W; Duncan, Jennifer; Rummell, Christina M; Perkins, Shannon; Crowther, Janis H

2017-07-01

Eating pathology among bariatric surgery candidates is common and associated with adverse outcomes. However, its assessment is complicated by the inconsistent use of standardized measures. We addressed this by examining the use of the Eating Disorder Diagnostic Scale (EDDS) in a large bariatric sample (N = 343). To evaluate the EDDS among bariatric surgery candidates via examination of: (1) Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) and fifth edition (DSM-5) rates of binge eating disorder, bulimia nervosa, and maladaptive eating behaviors, and (2) the relationship between response biases and self-reported eating disorder symptoms. Participants were bariatric surgery candidates at a large public hospital in the Midwest. As part of a larger preoperative evaluation, 343 patients seeking bariatric surgery completed the EDDS and measures of problematic response bias. Approximately 16% of the sample met full threshold criteria for binge eating disorder using DSM-5 criteria. Using the DSM-IV-TR, rates were lower but still substantial at 13%. Rates for bulimia nervosa were 8% (DSM-5) and 6% (DSM-IV-TR). The majority (66.1%) of participants reported at least one binge-eating episode per week. The most commonly used compensatory behavior was fasting (20.4%), followed by excessive exercise (11.7%), laxative use (5.6%), and vomiting (1.8%). An inverse relationship between severity of the eating symptomatology and problematic response bias emerged. The EDDS shows promise as a screening tool that uses diagnostic criteria to provide rates of binge eating and eating psychopathology among surgical candidates. Our findings suggest that subsequent validation studies of this measure are needed, should address potential response bias concerns, and should employ clear definitions of binge eating to promote standardization of eating pathology assessment in the bariatric population. Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

Cell-type specificity of lung cancer associated with low-dose soil heavy metal contamination in Taiwan: An ecological study

PubMed Central

2013-01-01

Background Numerous studies have examined the association between heavy metal contamination (including arsenic [As], cadmium [Cd], chromium [Cr], copper [Cu], mercury [Hg], nickel [Ni], lead [Pb], and zinc [Zn]) and lung cancer. However, data from previous studies on pathological cell types are limited, particularly regarding exposure to low-dose soil heavy metal contamination. The purpose of this study was to explore the association between soil heavy metal contamination and lung cancer incidence by specific cell type in Taiwan. Methods We conducted an ecological study and calculated the annual averages of eight soil heavy metals (i.e., As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) by using data from the Taiwan Environmental Protection Administration from1982 to 1986. The age-standardized incidence rates of lung cancer according to two major pathological types (adenocarcinoma [AC] and squamous cell carcinoma [SCC]) were obtained from the National Cancer Registry Program conducted in Taiwan from 2001 to 2005. A geographical information system was used to plot the maps of soil heavy metal concentration and lung cancer incidence rates. Poisson regression models were used to obtain the adjusted relative ratios (RR) and 95% confidence intervals (CI) for the lung cancer incidence associated with soil heavy metals. Results For males, the trend test for lung SCC incidence caused by exposure to Cr, Cu, Hg, Ni, and Zn showed a statistically significant dose–response relationship. However, for lung AC, only Cu and Ni had a significant dose–response relationship. As for females, those achieving a statistically significant dose–response relationship for the trend test were Cr (P = 0.02), Ni (P = 0.02), and Zn (P= 0.02) for lung SCC, and Cu (P < 0.01) and Zn (P = 0.02) for lung AC. Conclusion The current study suggests that a dose–response relationship exists between low-dose soil heavy metal concentration and lung cancer occurrence by specific cell-type; however, the relevant mechanism should be explored further. PMID:23575356

Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer.

PubMed

Datta, Jashodeep; Berk, Erik; Xu, Shuwen; Fitzpatrick, Elizabeth; Rosemblit, Cinthia; Lowenfeld, Lea; Goodman, Noah; Lewis, David A; Zhang, Paul J; Fisher, Carla; Roses, Robert E; DeMichele, Angela; Czerniecki, Brian J

2015-05-23

A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4(+) T-helper type 1 (Th1) immune responses is observed in HER2(pos)-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C. Anti-HER2 Th1 responses in 87 HER2(pos)-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/10(6) cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization. Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2(pos)-IBC patients (n = 22) did not improve globally in T + C-treated HER2(pos)-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C - utilized in 61.5 % - was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p < 0.0001), and cumulative response (148.2 vs. 22.4 SFC/10(6), p < 0.0001) versus non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ(+) immune disparity was mediated by anti-HER2 CD4(+)T-bet(+)IFN-γ(+) (i.e., Th1) - not CD4(+)GATA-3(+)IFN-γ(+) (i.e., Th2) - phenotypes, and not attributable to non-pCR patients' immune incompetence, host-level T-cell anergy, or increased immunosuppressive populations. In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination. Anti-HER2 CD4(+) Th1 response is a novel immune correlate to pathologic response following neoadjuvant T + C. In non-pCR patients, depressed Th1 responses are not immunologically "fixed" and can be restored with HER2-directed Th1 immune interventions. In such high-risk patients, combining HER2-targeted therapies with strategies to boost anti-HER2 Th1 immunity may improve outcomes and mitigate recurrence.

PHYSIOLOGICAL RESPONSE PATTERNS IN CARDIAC PATIENTS,

DTIC Science & Technology

CARDIOVASCULAR DISEASES, ETIOLOGY), HEART, DISEASES, ELECTROENCEPHALOGRAPHY, GALVANIC SKIN RESPONSE, PULSE RATE, BODY TEMPERATURE, SKIN(ANATOMY...HYPERTENSION, ATHEROSCLEROSIS , RHEUMATIC DISEASES, EMOTIONS, REACTION(PSYCHOLOGY), PERSONALITY, PSYCHOLOGY, PATHOLOGY, MEDICAL EXAMINATION

Enhancing preclinical year pathology exposure: the Angevine approach.

PubMed

Brooks, Erin G; Paus, Amanda M; Corliss, Robert F; Ranheim, Erik A

2016-07-01

Less than 2% of graduating US medical seniors select pathology residencies. One major obstacle to attracting prospective residents is the relative "invisibility" of pathology; medical students lacking positive preclinical exposure to pathology are unlikely to later select pathology clerkships or residencies. The Angevine Fellowship is a 10-week competitive pathology internship medical students may apply for the summer following their first year of preclinical training at our institution. We sought to determine whether it was an effective pathology recruitment tool and how it compared with the postsophomore pathology fellowship (PSF). Angevine fellow and PSF data from 2000 to 2014 were retrospectively analyzed. Specialty choices of former fellows already matched into residency programs were tabulated. Data regarding annual percentage of graduating seniors at our institution who matched into pathology during the years former fellow cohorts matched were also examined. Our results showed that of the former Angevine fellow cohorts already matched into residency programs, 40% (8/20) matched in pathology and 20% (4/20) at our own institution. Angevine fellows comprised a disproportionately high number of the graduating seniors matching in pathology at our medical school (26.7%). PSFs comprised 6.67%. Although we have endowment funding for 2 Angevine fellows annually, the level of interest among applicants has increased to the point that our department has consistently contributed funding for 1-2 additional fellowship spots since 2011. We conclude that the Angevine Fellowship offers an effective alternative to the postsophomore fellowship. It has proven successful at our institution and could be implemented at others to potentially improve pathology recruitment trends nationwide. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Genetic polymorphisms in 5-Fluorouracil-related enzymes predict pathologic response after neoadjuvant chemoradiation for rectal cancer.

PubMed

Nelson, Bailey; Carter, Jane V; Eichenberger, Maurice R; Netz, Uri; Galandiuk, Susan

2016-11-01

Many patients with rectal cancer undergo preoperative neoadjuvant chemoradiation, with approximately 70% exhibiting pathologic downstaging in response to treatment. Currently, there is no accurate test to predict patients who are likely to be complete responders to therapy. 5-Fluorouracil is used regularly in the neoadjuvant treatment of rectal cancer. Genetic polymorphisms affect the activity of thymidylate synthase, an enzyme involved in 5-Fluorouracil metabolism, which may account for observed differences in response to neoadjuvant treatment between patients. Detection of genetic polymorphisms might identify patients who are likely to have a complete response to neoadjuvant therapy and perhaps allow them to avoid operation. DNA was isolated from whole blood taken from patients with newly diagnosed rectal cancer who received neoadjuvant therapy (n = 50). Response to therapy was calculated with a tumor regression score based on histology from the time of operation. Polymerase chain reaction was performed targeting the promoter region of thymidylate synthase. Polymerase chain reaction products were separated using electrophoresis to determine whether patients were homozygous for a double-tandem repeat (2R), a triple-tandem repeat (3R), or were heterozygous (2R/3R). A single nucleotide polymorphism, 3G or 3C, also may be present in the second repeat unit of the triple-tandem repeat allele. Restriction fragment length polymorphism assays were performed in patients with at least one 3R allele using HaeIII. Patients with at least 1 thymidylate synthase 3G allele were more likely to have a complete or partial pathologic response to 5-Fluorouracil neoadjuvant therapy (odds ratio 10.4; 95% confidence interval, 1.3-81.6; P = .01) than those without at least one 3G allele. Identification of rectal cancer patients with specific genetic polymorphisms in enzymes involved in 5-Fluorouracil metabolism seems to predict the likelihood of complete or partial pathologic response to preoperative neoadjuvant therapy. Copyright © 2016 Elsevier Inc. All rights reserved.

Body Esteem as a Common Factor of a Tendency Toward Binge Eating and Sexual Dissatisfaction Among Women: The Role of Dissociation and Stress Response During Sex.

PubMed

Castellini, Giovanni; Lo Sauro, Carolina; Ricca, Valdo; Rellini, Alessandra H

2017-08-01

Several studies have suggested a relevant overlap between eating disorders and sexual dysfunction involving the emotional component of body image esteem and dissociative experiences. To evaluate the common maintaining factors of sexual dysfunction and vulnerability to pathologic eating behaviors and their relation to a physiologic stress response. In the present cross-sectional study, we evaluated a non-clinical sample of 60 heterosexual women (25-35 years old) for dissociation during sex with a partner, body image disturbance, and tendency toward pathologic eating behaviors. We also evaluated the stress-induced hypothalamic-pituitary-adrenal axis activation in response to a sexual stimulus and its association with binge eating and dissociation. Participants completed the Clinician-Administered Dissociative States Scale, the Sexual Satisfaction Scale-Women, the Body Esteem Scale for Adolescents and Adults, and the Eating Attitudes Test Short Version. Furthermore, we assessed cortisol levels before, during, and after exposure to explicit sexual stimuli shown within a laboratory setting. Dysfunctional body image esteem and a tendency toward binge-eating behaviors were associated with greater sexual distress in women. In particular, body esteem was significantly associated with greater dissociation during sex with a partner. Moreover, women who reported greater dissociation during sex with a partner and a tendency toward binge-eating behaviors showed higher levels of cortisol in response to sexual stimuli. These results support further research based on trans-diagnostic treatments targeted to dissociation and body image esteem, which could lessen sexual dysfunction and vulnerability to pathologic eating behaviors. Despite the small sample and self-reported questionnaires, this is the first study to consider the association of the stress response during sexual stimuli with sexual distress and with pathologic eating behaviors adopting a dimensional approach. Body uneasiness and dissociation represented factors underlying pathologic eating behaviors and sexual dysfunction. Women reporting a tendency toward binge-eating episodes and dissociation during sexual experiences represented a subpopulation with a higher stress response during sexual stimuli. Castellini G, Lo Sauro C, Ricca V, Rellini AH. Body Esteem as a Common Factor of a Tendency Toward Binge Eating and Sexual Dissatisfaction Among Women: The Role of Dissociation and Stress Response During Sex. J Sex Med 2017;14:1036-1045. Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

Evaluation of common elbow pathologies: a focus on physical examination.

PubMed

Laratta, Joseph; Caldwell, Jon-Michael; Lombardi, Joseph; Levine, William; Ahmad, Christopher

2017-05-01

Elbow tendinopathy accounts for the majority of elbow pathology in patients presenting to upper extremity and sports medicine surgeons. With increased participation in overhead sports in an aging population, the incidence of elbow injuries has risen. A comprehensive knowledge of elbow anatomy and biomechanical function of the elbow complex is prerequisite in the assessment of patients with elbow injuries; however, a thorough understanding of alternative and confounding pathologies is essential for accurate diagnosis. Because tendinopathy, tendonitis, and tendon tears have an anatomic basis for their pathology, a targeted history and meticulous physical examination often yields an accurate clinical diagnosis. The importance of physical examination and provocative examination maneuvers must be stressed in a technologically advanced era where clinical diagnosis is too commonly attained solely by advanced imaging modalities. A revived dedication to the physical examination may enhance our ability to correctly diagnose various pathologies about the elbow. Early and accurate clinical diagnosis is the first step in the proper initiation of treatment modalities and improvement in overall patient outcome.

Mathematical models of immune effector responses to viral infections: Virus control versus the development of pathology

NASA Astrophysics Data System (ADS)

Wodarz, Dominik

2005-12-01

This article reviews mathematical models which have investigated the importance of lytic and non-lytic immune responses for the control of viral infections. Lytic immune responses fight the virus by killing infected cells, while non-lytic immune responses fight the virus by inhibiting viral replication while leaving the infected cell alive. The models suggest which types or combinations of immune responses are required to resolve infections which vary in their characteristics, such as the rate of viral replication and the rate of virus-induced target cell death. This framework is then applied to persistent infections and viral evolution. It is investigated how viral evolution and antigenic escape can influence the relative balance of lytic and non-lytic responses over time, and how this might correlate with the transition from an asymptomatic infection to pathology. This is discussed in the specific context of hepatitis C virus infection.

Sex Differences in Workplace Satisfaction and Engagement of Academic Pathologists: Opportunities to Enhance Faculty Diversity.

PubMed

Howell, Lydia Pleotis; Lyons, Mary Lipscomb; Thor, Ann; Dandar, Valerie

2015-07-01

There is attrition of women across professorial ranks in academic pathology. Women are underrepresented as leaders; 15.4% of academic pathology departments are chaired by women, according to the Association of American Medical Colleges (AAMC). To identify areas for targeted interventions that can advance academic and leadership development of women faculty by examining (1) sex differences in career satisfaction in US medical school pathology departments participating in the AAMC's Faculty Forward Engagement Survey, and (2) findings from a survey of the Association of Pathology Chairs (APC). The AAMC Faculty Forward Engagement Survey data are from 14 US medical schools participating in the 2011-2012 survey. Pathologists' response rate was 66% (461 of 697). To investigate sex differences, t tests and χ(2) analyses were used. The APC survey, administered to academic department chairs, had a 55% response rate (104 of 189). According to the Faculty Forward Engagement Survey, women report more time in patient care and less time in research. Women consider formal mentorship, feedback, and career advancement more important than men do and are less satisfied with communication and governance. The APC survey shows that 20% to 40% of nonchair department leaders are women. More than half of chairs report satisfaction with the sex diversity of their departmental leaders. Opportunities exist for department chairs and professional organizations to create targeted interventions to support career satisfaction, recruitment, retention, and career and leadership development for women in academic pathology. Although chairs report satisfaction with diversity within department leadership, responses of women faculty indicate there is work to be done to grow more women leaders.

Current status of General Pathology training in Spain.

PubMed

Casademont, J; Porcel, J M; Vargas Núñez, J A; González Macías, J

2013-12-01

One of the core subjects in university training of the physicians has been General Pathology. Responsibility for this has historically fallen on Internal Medicine specialists. However, we are unaware if this situation is currently maintained. A questionnaire was sent to the coordinators of the subject of the 39 Spanish medical schools to know, among other things, the current denomination of the subjects (traditionally known as «General Pathology»), number of credits, teaching activities included in the subject and number and specialty of the professors responsible for it. Some data from the medical schools that did not respond were obtained from their web pages. A total of 28 of the 39 (72%) medical schools existing in Spain answered the survey. The current denomination of the subject «General Pathology» varied greatly. The mean number of credits (one credit=20-25 h) was 11.2 (range 3 to 29). In 22 of 34 schools (65%), the subject was taught in the third year of the studies, but in 21% of the schools, it was partially and in 15% of the schools, totally, taught in the second year. More than half of the professors (54%) who taught the subject were Internal Medicine specialists, although this responsibility was shared with other specialists in a large proportion. Teaching of General Pathology shows a marked heterogeneity that does not seem to be due to teaching or pedagogic criteria among the different schools of Spain. These facts may be due to less presence in the university setting of Internal Medicine compared to other specialties. Copyright © 2013 Elsevier España, S.L. All rights reserved.

T cell-derived IL-10 and its impact on the regulation of host responses during malaria.

PubMed

Freitas do Rosario, Ana Paula; Langhorne, Jean

2012-05-15

Despite intense research, malaria still is the one of the most devastating diseases killing more people than any other parasitic infection. In an attempt to control the infection, the host immune system produces a potent pro-inflammatory response. However, this response is also associated with complications, such as severe anaemia, hypoglycaemia and cerebral malaria. This pronounced production of pro-inflammatory cytokines response is a common feature of malaria caused by parasites infecting humans as well as rodents and primates. A balance between pro- and anti-inflammatory responses may be fundamental to the elimination of the parasite without inducing excessive host pathology. IL-10 is a key cytokine that has been shown to have an important regulatory function in establishing this balance in malaria. Here we discuss which cells can produce IL-10 during infection, and present an overview of the evidence showing that T-cell derived IL-10 plays an important role in regulating malaria pathology. Many different subsets of T cells can produce IL-10, however, evidence is accumulating that it is effector Th1 CD4(+) T cells which provide the crucial source that down-regulates inflammatory pathology during blood-stage malaria infections. Copyright © 2012 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

Thymidine phosphorylase and hypoxia-inducible factor 1-α expression in clinical stage II/III rectal cancer: association with response to neoadjuvant chemoradiation therapy and prognosis.

PubMed

Lin, Shuhan; Lai, Hao; Qin, Yuzhou; Chen, Jiansi; Lin, Yuan

2015-01-01

The aim of this study was to determine whether pretreatment status of thymidine phosphorylase (TP), and hypoxia-inducible factor alpha (HIF-1α) could predict pathologic response to neoadjuvant chemoradiation therapy with oxaliplatin and capecitabine (XELOXART) and outcomes for clinical stage II/III rectal cancer patients. A total of 180 patients diagnosed with clinical stage II/III rectal cancer received XELOXART. The status of TP, and HIF-1α were determined in pretreatment biopsies by immunohistochemistry (IHC). Tumor response was assessed in resected regimens using the tumor regression grade system and TNM staging system. 5-year disease free survival (DFS) and 5-year overall survival (OS) were evaluated with the Kaplan-Meier method and were compared by the log-rank test. Over expression of TP and low expression of HIF-1α were associated with pathologic response to XELOXART and better outcomes (DFS and OS) in clinical stage II/III rectal cancer patients (P < 0.05). Our result suggested that pretreatment status of TP and HIF-1α were found to predict pathologic response and outcomes in clinical stage II/III rectal cancer received XELOXART. Additional well-designed, large sample, multicenter, prospective studies are needed to confirm the result of this study.

BRAF V600E mutations in papillary craniopharyngioma

PubMed Central

Brastianos, Priscilla K.; Santagata, Sandro

2016-01-01

Papillary craniopharyngioma is an intracranial tumor that results in high levels of morbidity. We recently demonstrated that the vast majority of these tumors harbor the oncogenic BRAF V600E mutation. The pathologic diagnosis of papillary craniopharyngioma can now be confirmed using mutation specific immunohistochemistry and targeted genetic testing. Treatment with targeted agents is now also a possibility in select situations. We recently reported a patient with a multiply recurrent papillary craniopharyngioma in whom targeting both BRAF and MEK resulted in a dramatic therapeutic response with a marked anti-tumor immune response. This work shows that activation of the MAPK pathway is the likely principal oncogenic driver of these tumors. We will now investigate the efficacy of this approach in a multicenter phase II clinical trial. Post-treatment resection samples will be monitored for the emergence of resistance mechanisms. Further advances in the non-invasive diagnosis of papillary craniopharyngioma by radiologic criteria and by cell-free DNA testing could someday allow neo-adjuvant therapy for this disease in select patient populations. PMID:26563980

Aging Microglia—Phenotypes, Functions and Implications for Age-Related Neurodegenerative Diseases

PubMed Central

Spittau, Björn

2017-01-01

Aging of the central nervous system (CNS) is one of the major risk factors for the development of neurodegenerative pathologies such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). The molecular mechanisms underlying the onset of AD and especially PD are not well understood. However, neuroinflammatory responses mediated by microglia as the resident immune cells of the CNS have been reported for both diseases. The unique nature and developmental origin of microglia causing microglial self-renewal and telomere shortening led to the hypothesis that these CNS-specific innate immune cells become senescent. Age-dependent and senescence-driven impairments of microglia functions and responses have been suggested to play essential roles during onset and progression of neurodegenerative diseases. This review article summarizes the current knowledge of microglia phenotypes and functions in the aging CNS and further discusses the implications of these age-dependent microglia changes for the development and progression of AD and PD as the most common neurodegenerative diseases. PMID:28659790

Cell Connections by Tunneling Nanotubes: Effects of Mitochondrial Trafficking on Target Cell Metabolism, Homeostasis, and Response to Therapy

PubMed Central

2017-01-01

Intercellular communications play a major role in tissue homeostasis and responses to external cues. Novel structures for this communication have recently been described. These tunneling nanotubes (TNTs) consist of thin-extended membrane protrusions that connect cells together. TNTs allow the cell-to-cell transfer of various cellular components, including proteins, RNAs, viruses, and organelles, such as mitochondria. Mesenchymal stem cells (MSCs) are both naturally present and recruited to many different tissues where their interaction with resident cells via secreted factors has been largely documented. Their immunosuppressive and repairing capacities constitute the basis for many current clinical trials. MSCs recruited to the tumor microenvironment also play an important role in tumor progression and resistance to therapy. MSCs are now the focus of intense scrutiny due to their capacity to form TNTs and transfer mitochondria to target cells, either in normal physiological or in pathological conditions, leading to changes in cell energy metabolism and functions, as described in this review. PMID:28659978

Mechanisms of bile acid mediated inflammation in the liver.

PubMed

Li, Man; Cai, Shi-Ying; Boyer, James L

2017-08-01

Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury. Copyright © 2017 Elsevier Ltd. All rights reserved.

Uric Acid, Hyperuricemia and Vascular Diseases

PubMed Central

Jin, Ming; Yang, Fan; Yang, Irene; Yin, Ying; Luo, Jin Jun; Wang, Hong; Yang, Xiao-Feng

2011-01-01

Uric acid is the product of purine metabolism. It is known that hyperuricemia, defined as high levels of blood uric acid, is the major etiological factor of gout. A number of epidemiological reports have increasingly linked hyperuricemia with cardiovascular and neurological diseases. Studies highlighting the pathogenic mechanisms of uric acid point to an inflammatory response as the primary mechanism for inducing gout and possibly contributing to uric acid's vascular effects. Monosodium urate (MSU) crystals induce an inflammatory reaction, which are recognized by Toll-like receptors (TLRs). These TLRs then activate NALP3 inflammasome. MSU also triggers neutrophil activation and further produces immune mediators, which lead to a proinflammatory response. In addition, soluble uric acid can also mediate the generation of free radicals and function as a pro-oxidant. This review summarizes the epidemiological studies of hyperuricemia and cardiovascular disease, takes a brief look at hyperuricemia and its role in neurological diseases, and highlights the studies of the advanced pathological mechanisms of uric acid and inflammation. PMID:22201767

Comparison of Heterosubtypic Protection in Ferrets and Pigs Induced by a Single-Cycle Influenza Vaccine.

PubMed

Holzer, Barbara; Morgan, Sophie B; Matsuoka, Yumi; Edmans, Matthew; Salguero, Francisco J; Everett, Helen; Brookes, Sharon M; Porter, Emily; MacLoughlin, Ronan; Charleston, Bryan; Subbarao, Kanta; Townsend, Alain; Tchilian, Elma

2018-06-15

Influenza is a major health threat, and a broadly protective influenza vaccine would be a significant advance. Signal Minus FLU (S-FLU) is a candidate broadly protective influenza vaccine that is limited to a single cycle of replication, which induces a strong cross-reactive T cell response but a minimal Ab response to hemagglutinin after intranasal or aerosol administration. We tested whether an H3N2 S-FLU can protect pigs and ferrets from heterosubtypic H1N1 influenza challenge. Aerosol administration of S-FLU to pigs induced lung tissue-resident memory T cells and reduced lung pathology but not the viral load. In contrast, in ferrets, S-FLU reduced viral replication and aerosol transmission. Our data show that S-FLU has different protective efficacy in pigs and ferrets, and that in the absence of Ab, lung T cell immunity can reduce disease severity without reducing challenge viral replication. Copyright © 2018 The Authors.

Comparison of Heterosubtypic Protection in Ferrets and Pigs Induced by a Single-Cycle Influenza Vaccine

PubMed Central

Holzer, Barbara; Morgan, Sophie B.; Edmans, Matthew; Everett, Helen; Brookes, Sharon M.; Charleston, Bryan

2018-01-01

Influenza is a major health threat, and a broadly protective influenza vaccine would be a significant advance. Signal Minus FLU (S-FLU) is a candidate broadly protective influenza vaccine that is limited to a single cycle of replication, which induces a strong cross-reactive T cell response but a minimal Ab response to hemagglutinin after intranasal or aerosol administration. We tested whether an H3N2 S-FLU can protect pigs and ferrets from heterosubtypic H1N1 influenza challenge. Aerosol administration of S-FLU to pigs induced lung tissue-resident memory T cells and reduced lung pathology but not the viral load. In contrast, in ferrets, S-FLU reduced viral replication and aerosol transmission. Our data show that S-FLU has different protective efficacy in pigs and ferrets, and that in the absence of Ab, lung T cell immunity can reduce disease severity without reducing challenge viral replication. PMID:29703861

A spotlight on liquefaction: evidence from clinical settings and experimental models in tuberculosis.

PubMed

Cardona, Pere-Joan

2011-01-01

Liquefaction is one of the most intriguing aspects of human tuberculosis. It is a major cause of the transition from the infection to active disease (tuberculosis, TB) as well as the transmission of M. tuberculosis to other persons. This paper reviews the natural history of liquefaction in humans from a pathological and radiological point of view and discusses how the experimental models available can be used to address the topic of liquefaction and cavity formation. Different concepts that have been related to liquefaction, from the influence of immune response to mechanical factors, are reviewed. Synchronic necrosis or apoptosis of infected macrophages in a close area, together with an ineffective fibrosis, appears to be clue in this process, in which macrophages, the immune response, and bacillary load interact usually in a particular scenario: the upper lobes of the lung. The summary would be that even if being a stochastic effect, liquefaction would result if the organization of the intragranulomatous necrosis (by means of fibrosis) would be disturbed.

A Spotlight on Liquefaction: Evidence from Clinical Settings and Experimental Models in Tuberculosis

PubMed Central

Cardona, Pere-Joan

2011-01-01

Liquefaction is one of the most intriguing aspects of human tuberculosis. It is a major cause of the transition from the infection to active disease (tuberculosis, TB) as well as the transmission of M. tuberculosis to other persons. This paper reviews the natural history of liquefaction in humans from a pathological and radiological point of view and discusses how the experimental models available can be used to address the topic of liquefaction and cavity formation. Different concepts that have been related to liquefaction, from the influence of immune response to mechanical factors, are reviewed. Synchronic necrosis or apoptosis of infected macrophages in a close area, together with an ineffective fibrosis, appears to be clue in this process, in which macrophages, the immune response, and bacillary load interact usually in a particular scenario: the upper lobes of the lung. The summary would be that even if being a stochastic effect, liquefaction would result if the organization of the intragranulomatous necrosis (by means of fibrosis) would be disturbed. PMID:21437230

Expression profiling of lymph node cells from deer mice infected with Andes virus.

PubMed

Schountz, Tony; Shaw, Timothy I; Glenn, Travis C; Feldmann, Heinz; Prescott, Joseph

2013-04-09

Deer mice (Peromyscus maniculatus) are the principal reservoir hosts of Sin Nombre virus (SNV), the cause of the great majority of hantavirus cardiopulmonary syndrome (HCPS) cases in North America. SNV, like all hantaviruses with their reservoirs, causes persistent infection without pathology in deer mice and appear to elicit a regulatory T cell response. Deer mice are also susceptible to Andes virus (ANDV), which causes the great majority of HCPS cases in South America, but they clear infection by 56 days post infection without signs of disease. We examined lymph node cell responses of deer mice infected with ANDV to determine expression profiles upon in vitro recall challenge with viral antigen. Because the deer mouse genome is currently unannotated, we developed a bioinformatics pipeline to use known lab mouse (Mus musculus) cDNAs to predict genes within the deer mouse genome and design primers for quantitative PCR (http://dna.publichealth.uga.edu/BlastPrimer/BlastPrimer.php). Of 94 genes examined, 20 were elevated, the plurality of which were Th2-specific, whereas 12 were downregulated. Other expressed genes represented Th1, regulatory T cells and follicular helper T cells, and B cells, but not Th17 cells, indicating that many cellular phenotypes participate in the host response to Andes virus. The ability to examine expression levels of nearly any gene from deer mice should allow direct comparison of infection with SNV or ANDV to determine the immunological pathways used for clearance of hantavirus infection in a reservoir host species.

The protective effect of some Thai plants and their bioactive compounds in UV light-induced skin carcinogenesis.

PubMed

de Silva, Madhura B; Tencomnao, Tewin

2018-05-02

Skin cancer, represents a major public health concern. While the vast majority is non-melanoma skin cancers, melanomas are mostly responsible for mortality. Solar UVB radiation is mutagenic and carcinogenic. It is primarily responsible for both non-melanoma and melanoma skin cancers via excessive production of reactive oxygen species (ROS), which mediate changes in inflammation and immunity, and have been implicated in all three stages of skin cancer development. Due to their regulatory role in numerous functions of cells, signaling pathways are targets for chemoprevention. The current standards in melanoma therapy are targeted and combination therapies, which, albeit prolong survival responses, are still prone to development of drug resistance. To this extent, drugs of natural origin continue to spark great interest. Thailand has a rich biodiversity of indigenous flora, which have traditionally been used to treat a variety of pathologies. The active components in plant extracts that have medicinal properties, termed 'bioactive compounds,' are efficient chemopreventive agents due to their antioxidant, antimutagenic, anticarcinogenic, and carcinogen detoxification properties. Thai plants and their bioactive compounds have shown protective effects on UV light-induced skin cancer in different experimental models. This warrants further in vivo investigations and translation to clinical studies to determine efficacy and safety, for use as lead compounds in targeted/combination therapy or adjuvant therapy with existing regimes. Coupled with a strategy for prevention, this offers a promising outlook for protection against photocarcinogenesis. Copyright © 2018 Elsevier B.V. All rights reserved.

Fluorine-18-fluorodeoxyglucose positron emission tomography as an objective substitute for CT morphologic response criteria in patients undergoing chemotherapy for colorectal liver metastases.

PubMed

Nishioka, Yujiro; Yoshioka, Ryuji; Gonoi, Wataru; Sugawara, Toshitaka; Yoshida, Shuntaro; Hashimoto, Masaji; Shindoh, Junichi

2018-05-01

The computed tomography (CT) morphologic response of colorectal liver metastases (CLM) after chemotherapy is reportedly correlated with pathologic response and survival outcomes of patients undergoing surgery. However, they are rather subjective criteria and not evaluable without adequate quality of contrast-enhanced CT images. This study sought the potential use of fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) as an objective substitute for predicting pathological viability of CLM after chemotherapy. Predictive ability of tumor viability of ≤10% was compared between FDG-PET/CT and contrast-enhanced CT in 34 patients who underwent curative surgical resection for CLM after chemotherapy. The CT morphology and response were defined according to the reported criteria (Chun YS, JAMA 2009). The mean standard uptake value (SUV-mean) in CLM was significantly lower in patients with group 1 and group 2 CT morphology (median, 2.53 and 3.00, respectively) than in group 3 (median, 3.32). The tumor SUV-mean showed moderate correlation with the tumor pathologic viability (r = 0.660, P < 0.0001). A receiver operating characteristic curve analysis revealed that both the tumor SUV-mean (area under the curve [AUC], 0.916; the cut-off value, 3.00) and the CT morphology (AUC, 0.882) have excellent predictive power for ≤10% of tumor viability, while degree of tumor shrinkage showed lower predictive power (AUC, 0.692). FDG-PET shows significant correlation with pathologic viability of CLM after chemotherapy and may offer additional objective information for estimating tumor viability when the CT morphologic response is not evaluable.

[Pathological changes in rats with acute Dysosma versipellis poisoning].

PubMed

Xu, Xiang; Xu, Mao-sheng; Zhu, Jian-hua; Huang, Guang-zhao

2013-10-01

To observe the pathological changes of major organs in rats with acute Dysosma versipellis poisoning and investigate the toxic mechanism and the injuries of target tissues and organs. Forty Sprague-Dawley (SD) rats were randomly divided into three experimental groups, which were given the gavage with 0.5, 1.0 and 2.0 LDo doses of Dysosma versipellis decoction, and one control group, which was given the gavage with 1.0 LD0 dose of normal saline. The rats were sacrificed 14 days after Dysosma versipellis poisoning and samples including brain, heart, liver, lung, and kidney were taken. After pathological process, the pathological changes of the major organs and tissues were observed by light microscope and electron microscope. The experimental data were statistical analyzed by chi2 test. The observations of light microscopy: loose cytoplasm of neurons with loss of most Nissl bodies; swelling of myocardial cells with disappearance of intercalated disk and striations; hepatocellular edema with ballooning degeneration; and swelling epithelial cells of renal proximal convoluted tubule with red light coloring protein-like substances in the tube. The observations of electron microscopy: the structures of cell membrane and nuclear membrane of neurons were destroyed; cytoplasm of neurons, obvious edema; and most organelles, destroyed and disappeared. The mortalities of rats after acute poisoning of the four groups increased with doses (P < 0.05). Acute Dysosma versipellis poisoning can cause multi-organ pathological changes. There is a positive correlation between the toxic effect and the dosage. The target tissues and organs are brain (neurons), heart, liver and kidney.

ASTROCYTE PATHOLOGY IN MAJOR DEPRESSIVE DISORDER: INSIGHTS FROM HUMAN POSTMORTEM BRAIN TISSUE

PubMed Central

Rajkowska, Grazyna; Stockmeier, Craig A.

2013-01-01

The present paper reviews astrocyte pathology in major depressive disorder (MDD) and proposes that reductions in astrocytes and related markers are key features in the pathology of MDD. Astrocytes are the most numerous and versatile of all types of glial cells. They are crucial to the neuronal microenvironment by regulating glucose metabolism, neurotransmitter uptake (particularly for glutamate), synaptic development and maturation and the blood brain barrier. Pathology of astrocytes has been consistently noted in MDD as well as in rodent models of depressive-like behavior. This review summarizes evidence from human postmortem tissue showing alterations in the expression of protein and mRNA for astrocyte markers such as glial fibrillary acidic protein (GFAP), gap junction proteins (connexin 40 and 43), the water channel aquaporin-4 (AQP4), a calcium-binding protein S100B and glutamatergic markers including the excitatory amino acid transporters 1 and 2 (EAAT1, EAAT2) and glutamine synthetase. Moreover, preclinical studies are presented that demonstrate the involvement of GFAP and astrocytes in animal models of stress and depressive-like behavior and the influence of different classes of antidepressant medications on astrocytes. In light of the various astrocyte deficits noted in MDD, astrocytes may be novel targets for the action of antidepressant medications. Possible functional consequences of altered expression of astrocytic markers in MDD are also discussed. Finally, the unique pattern of cell pathology in MDD, characterized by prominent reductions in the density of astrocytes and in the expression of their markers without obvious neuronal loss, is contrasted with that found in other neuropsychiatric and neurodegenerative disorders. PMID:23469922

A Complete Pathological Response to Pembrolizumab following ex vivo Liver Resection in a Patient with Colorectal Liver Metastases.

PubMed

Baimas-George, Maria; Baker, Erin; Kamionek, Michal; Salmon, J Stuart; Sastry, Amit; Levi, David; Vrochides, Dionisios

2018-04-05

Advances in the systemic treatment of stage IV colorectal cancer with liver metastases has offered improved survival rates for patients who otherwise face a dismal prognosis. However, a pathologically complete response (PCR) to chemotherapy for colorectal liver metastases is still rare, and its significance is not fully understood. In this case report, we describe a patient who achieved PCR after neoadjuvant immunotherapy with pembrolizumab and a left hepatectomy using an ex vivo resection technique. © 2018 S. Karger AG, Basel.

A study of the human rod and cone electroretinogram a-wave component

NASA Astrophysics Data System (ADS)

Barraco, R.; Persano Adorno, D.; Bellomonte, L.; Brai, M.

2009-03-01

The study of the electrical response of the retina to a luminous stimulus is one of the main fields of research in ocular electrophysiology. The features of the first component (a-wave) of the retinal response reflect the functional integrity of the two populations of photoreceptors: rods and cones. We fit the a-wave for pathological subjects with functions that account for possible mechanisms governing the kinetics of the photoreceptors. The paper extends a previous analysis, carried out for normal subjects, in which both populations are active, to patients affected by two particular diseases that reduce the working populations to only one. The pathologies investigated are Achromatopsia, a cone disease, and Congenital Stationary Night Blindness, a rod problem. We present evidence that the analysis of a pathological a-wave can be employed to quantitatively measure either cone or rod activities and to test hypotheses about their responses. The results show that the photoreceptoral responses differ in the two cases and functions implying a different number of photocascade stages are necessary to achieve a correct modeling of the early phototransduction process. Numerical values of the parameters characterizing the best-fit functions are given and discussed.

Expanding the spectrum of neuronal pathology in multiple system atrophy

PubMed Central

Cykowski, Matthew D.; Coon, Elizabeth A.; Powell, Suzanne Z.; Jenkins, Sarah M.; Benarroch, Eduardo E.; Low, Phillip A.; Schmeichel, Ann M.

2015-01-01

Multiple system atrophy is a sporadic alpha-synucleinopathy that typically affects patients in their sixth decade of life and beyond. The defining clinical features of the disease include progressive autonomic failure, parkinsonism, and cerebellar ataxia leading to significant disability. Pathologically, multiple system atrophy is characterized by glial cytoplasmic inclusions containing filamentous alpha-synuclein. Neuronal inclusions also have been reported but remain less well defined. This study aimed to further define the spectrum of neuronal pathology in 35 patients with multiple system atrophy (20 male, 15 female; mean age at death 64.7 years; median disease duration 6.5 years, range 2.2 to 15.6 years). The morphologic type, topography, and frequencies of neuronal inclusions, including globular cytoplasmic (Lewy body-like) neuronal inclusions, were determined across a wide spectrum of brain regions. A correlation matrix of pathologic severity also was calculated between distinct anatomic regions of involvement (striatum, substantia nigra, olivary and pontine nuclei, hippocampus, forebrain and thalamus, anterior cingulate and neocortex, and white matter of cerebrum, cerebellum, and corpus callosum). The major finding was the identification of widespread neuronal inclusions in the majority of patients, not only in typical disease-associated regions (striatum, substantia nigra), but also within anterior cingulate cortex, amygdala, entorhinal cortex, basal forebrain and hypothalamus. Neuronal inclusion pathology appeared to follow a hierarchy of region-specific susceptibility, independent of the clinical phenotype, and the severity of pathology was duration-dependent. Neuronal inclusions also were identified in regions not previously implicated in the disease, such as within cerebellar roof nuclei. Lewy body-like inclusions in multiple system atrophy followed the stepwise anatomic progression of Lewy body-spectrum disease inclusion pathology in 25.7% of patients with multiple system atrophy, including a patient with visual hallucinations. Further, the presence of Lewy body-like inclusions in neocortex, but not hippocampal alpha-synuclein pathology, was associated with cognitive impairment (P = 0.002). However, several cases had the presence of isolated Lewy body-like inclusions at atypical sites (e.g. thalamus, deep cerebellar nuclei) that are not typical for Lewy body-spectrum disease. Finally, interregional correlations (rho ≥ 0.6) in pathologic glial and neuronal lesion burden suggest shared mechanisms of disease progression between both discrete anatomic regions (e.g. basal forebrain and hippocampus) and cell types (neuronal and glial inclusions in frontal cortex and white matter, respectively). These findings suggest that in addition to glial inclusions, neuronal pathology plays an important role in the developmental and progression of multiple system atrophy. See Halliday (doi:10.1093/brain/awv151) for a scientific commentary on this article. PMID:25981961

Multimodal assessment of emotional reactivity in borderline personality pathology: The moderating role of posttraumatic stress disorder symptoms

PubMed Central

Dixon-Gordon, Katherine L.; Gratz, Kim L.; Tull, Matthew T.

2013-01-01

Emotional reactivity has been theorized to play a central role in borderline personality (BP) pathology. Although growing research provides evidence for subjective emotional reactivity in BP pathology, research on physiological or biological reactivity among people with BP pathology is less conclusive. With regard to biological reactivity in particular, research on cortisol reactivity (a neurobiological marker of emotional reactivity) in response to stressors among individuals with BP pathology has produced contradictory results and highlighted the potential moderating role of PTSD-related pathology. Thus, this study sought to examine the moderating role of PTSD symptoms in the relation between BP pathology and both subjective (self-report) and biological (cortisol) emotional reactivity to a laboratory stressor. Participants were 171 patients in a residential substance use disorder treatment center. Consistent with hypotheses, results revealed a significant main effect of BP pathology on subjective emotional reactivity to the laboratory stressor. Furthermore, results revealed a significant interaction between BP pathology and PTSD symptoms in the prediction of cortisol reactivity, such that BP pathology was associated with heightened cortisol reactivity only among participants with low levels of PTSD symptoms. Similar findings were obtained when examining the interaction between BP pathology and the reexperiencing and avoidance/numbing symptoms of PTSD specifically. Results highlight the moderating role of PTSD symptoms in the BP-reactivity relation. PMID:23375184

New Therapeutic Window of Regenerative Opportunity in Diabetic Retinopathy by VESGEN Analysis

NASA Technical Reports Server (NTRS)

Parsons-Wingert, Patricia A.

2012-01-01

Vascular pattern may serve as a useful new biomarker principle of complex, multi-scale signaling in pathological, physiological angiogenesis and microvascular remodeling. Each angiogenesis stimulator or inhibitor we have analyzed, including VEGF, bFGF, TGF-beta1, angiostatin and triamcinolone acetonide, has induced a novel "fingerprint" or "signature" biomarker vascular pattern that is spatio-temporally unique. Remodeling vasculature thereby provides an informative read-out of dominant molecular signaling, when analyzed by innovative, fractal-based VESsel GENeration (VESGEN) Analysis software. Using VESGEN to analyze ophthalmic clinical vascular images, we recently introduced a potential paradigm shift to the understanding of early-stage progression that suggests new regenerative opportunities for human diabetic retinopathy (DR), the major blinding disease for working-aged adults. In a pilot study, we discovered that angiogenesis oscillates as a surprising, homeostatic-like regeneration of retinal vessels during early progression of DR (IOVS 51(1):498). Results suggest that the term non-proliferative DR may be a misnomer. In new studies, normalization of the vasculature will be determined from the response of vascular pattern to therapeutic monitoring and treatment. We have mapped and quantified in vivo experimental models of angiogenesis, lymphangiogenesis and intravital blood flow from cellular/molecular to higher systems levels that include a murine model of infant retinopathy of prematurity (ROP); developing and pathological coronary and placental-like vessel models; progressive intestinal inflammation, growing murine tumors, and other pathological, physiological and therapeutically treated tissues of transgenic mice and avian embryos. Vascular Alterations, Visual Impairments (VIIP) & Increased Intracranial Pressure (ICP), Immunosuppression & Bone Loss: NASA-defined risk categories for human space exploration and ISS Utilization

Analysis of global and absorption, distribution, metabolism, and elimination gene expression in the progressive stages of human nonalcoholic fatty liver disease.

PubMed

Lake, April D; Novak, Petr; Fisher, Craig D; Jackson, Jonathan P; Hardwick, Rhiannon N; Billheimer, D Dean; Klimecki, Walter T; Cherrington, Nathan J

2011-10-01

Nonalcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that range from simple fatty liver to nonalcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of human NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism, and elimination (ADME) of drugs. Differential gene expression between three clinically defined pathological groups-normal, steatosis, and NASH-was analyzed. Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChip Human 1.0ST arrays. A total of 11,633 genes exhibited altered expression out of 33,252 genes at a 5% false discovery rate. Most gene expression changes occurred in the progression from steatosis to NASH. Principal component analysis revealed that hepatic disease status was the major determinant of differential ADME gene expression rather than age or sex of sample donors. Among the 515 drug transporters and 258 drug-metabolizing enzymes (DMEs) examined, uptake transporters but not efflux transporters or DMEs were significantly over-represented in the number of genes down-regulated. These results suggest that uptake transporter genes are coordinately targeted for down-regulation at the global level during the pathological development of NASH and that these patients may have decreased drug uptake capacity. This coordinated regulation of uptake transporter genes is indicative of a hepatoprotective mechanism acting to prevent accumulation of toxic intermediates in disease-compromised hepatocytes.

Innate immune memory in the brain shapes neurological disease hallmarks.

PubMed

Wendeln, Ann-Christin; Degenhardt, Karoline; Kaurani, Lalit; Gertig, Michael; Ulas, Thomas; Jain, Gaurav; Wagner, Jessica; Häsler, Lisa M; Wild, Katleen; Skodras, Angelos; Blank, Thomas; Staszewski, Ori; Datta, Moumita; Centeno, Tonatiuh Pena; Capece, Vincenzo; Islam, Md Rezaul; Kerimoglu, Cemil; Staufenbiel, Matthias; Schultze, Joachim L; Beyer, Marc; Prinz, Marco; Jucker, Mathias; Fischer, André; Neher, Jonas J

2018-04-01

Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished-training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral β-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology.

Study report on combining diagnostic and therapeutic considerations with subsystem and whole-body simulation

NASA Technical Reports Server (NTRS)

Furukawa, S.

1975-01-01

Current applications of simulation models for clinical research described included tilt model simulation of orthostatic intolerance with hemorrhage, and modeling long term circulatory circulation. Current capabilities include: (1) simulation of analogous pathological states and effects of abnormal environmental stressors by the manipulation of system variables and changing inputs in various sequences; (2) simulation of time courses of responses of controlled variables by the altered inputs and their relationships; (3) simulation of physiological responses of treatment such as isotonic saline transfusion; (4) simulation of the effectiveness of a treatment as well as the effects of complication superimposed on an existing pathological state; and (5) comparison of the effectiveness of various treatments/countermeasures for a given pathological state. The feasibility of applying simulation models to diagnostic and therapeutic research problems is assessed.

Pathological and Protective Immunity to Pneumocystis Infection

PubMed Central

Eddens, Taylor; Kolls, Jay K.

2014-01-01

Pneumocystis jirovecii is a common opportunistic infection in the HIV-positive population and is re-emerging as a growing clinical concern in the HIV-negative immunosuppressed population. Newer targeted immunosuppressive therapies and the discovery of rare genetic mutations have furthered our understanding of the immunity required to clear Pneumocystis infection. The immune system can also mount a pathologic response against Pneumocystis following removal of immunosuppression and result in severe damage to the host lung. The current review will examine the most recent epidemiologic studies about the incidence of Pneumocystis in the HIV-positive and HIV-negative populations in the developing and developed world and will detail methods of diagnosis for Pneumocystis pneumonia. Finally, this review aims to summarize the known mediators of immunity to Pneumocystis and detail the pathologic immune response leading to Pneumocystis-related immune reconstitution inflammatory syndrome. PMID:25420451

Pathology Dynamics Predict Spinal Cord Injury Therapeutic Success

PubMed Central

Mitchell, Cassie S.

2008-01-01

Abstract Secondary injury, the complex cascade of cellular events following spinal cord injury (SCI), is a major source of post-insult neuron death. Experimental work has focused on the details of individual factors or mechanisms that contribute to secondary injury, but little is known about the interactions among factors leading to the overall pathology dynamics that underlie its propagation. Prior hypotheses suggest that the pathology is dominated by interactions, with therapeutic success lying in combinations of neuroprotective treatments. In this study, we provide the first comprehensive, system-level characterization of the entire secondary injury process using a novel relational model methodology that aggregates the findings of ~250 experimental studies. Our quantitative examination of the overall pathology dynamics suggests that, while the pathology is initially dominated by “fire-like,” rate-dependent interactions, it quickly switches to a “flood-like,” accumulation-dependent process with contributing factors being largely independent. Our evaluation of ~20,000 potential single and combinatorial treatments indicates this flood-like pathology results in few highly influential factors at clinically realistic treatment time frames, with multi-factor treatments being merely additive rather than synergistic in reducing neuron death. Our findings give new fundamental insight into the understanding of the secondary injury pathology as a whole, provide direction for alternative therapeutic strategies, and suggest that ultimate success in treating SCI lies in the pursuit of pathology dynamics in addition to individually involved factors. PMID:19125684

Constant-Murley Score: systematic review and standardized evaluation in different shoulder pathologies.

PubMed

Vrotsou, Kalliopi; Ávila, Mónica; Machón, Mónica; Mateo-Abad, Maider; Pardo, Yolanda; Garin, Olatz; Zaror, Carlos; González, Nerea; Escobar, Antonio; Cuéllar, Ricardo

2018-05-10

The objective of this study was to evaluate the psychometric properties of the Constant-Murley Score (CMS) in various shoulder pathologies, based on a systematic review and expert standardized evaluations. A systematic review was performed in MEDLINE and EMBASE databases. Titles and abstracts were reviewed and finally the included articles were grouped according to patients' pathologies. Two expert evaluators independently assessed the CMS properties of reliability, validity, responsiveness to change, interpretability and burden score in each group, using the EMPRO (Evaluating Measures of Patient Reported Outcomes) tool. The CMS properties were assessed per attribute and overall for each considered group. Only the concept and measurement model was assessed globally. Five individual pathologies (i.e. subacromial, fractures, arthritis, instability and frozen shoulder) and two additional groups (i.e. various pathologies and healthy subjects) were considered. Overall EMPRO scores ranged from 58.6 for subacromial to 30.6 points for instability. Responsiveness to change was the only quality to obtain at least 50 points across all groups, but for frozen shoulder. Insufficient information was obtained in relation to the concept and measurement model and great variability was seen in the other evaluated attributes. The current evidence does not support the CMS as a gold standard in shoulder evaluation. Its use is advisable for subacromial pathology; but data are inconclusive for other shoulder conditions. Prospective studies exploring the psychometric properties of the scale, particularly for fractures, arthritis, instability and frozen shoulder are needed. Systematic review.

Optimal morphologic response to preoperative chemotherapy: an alternate outcome end point before resection of hepatic colorectal metastases.

PubMed

Shindoh, Junichi; Loyer, Evelyne M; Kopetz, Scott; Boonsirikamchai, Piyaporn; Maru, Dipen M; Chun, Yun Shin; Zimmitti, Giuseppe; Curley, Steven A; Charnsangavej, Chusilp; Aloia, Thomas A; Vauthey, Jean-Nicolas

2012-12-20

The purposes of this study were to confirm the prognostic value of an optimal morphologic response to preoperative chemotherapy in patients undergoing chemotherapy with or without bevacizumab before resection of colorectal liver metastases (CLM) and to identify predictors of the optimal morphologic response. The study included 209 patients who underwent resection of CLM after preoperative chemotherapy with oxaliplatin- or irinotecan-based regimens with or without bevacizumab. Radiologic responses were classified as optimal or suboptimal according to the morphologic response criteria. Overall survival (OS) was determined, and prognostic factors associated with an optimal response were identified in multivariate analysis. An optimal morphologic response was observed in 47% of patients treated with bevacizumab and 12% of patients treated without bevacizumab (P < .001). The 3- and 5-year OS rates were higher in the optimal response group (82% and 74%, respectively) compared with the suboptimal response group (60% and 45%, respectively; P < .001). On multivariate analysis, suboptimal morphologic response was an independent predictor of worse OS (hazard ratio, 2.09; P = .007). Receipt of bevacizumab (odds ratio, 6.71; P < .001) and largest metastasis before chemotherapy of ≤ 3 cm (odds ratio, 2.12; P = .025) were significantly associated with optimal morphologic response. The morphologic response showed no specific correlation with conventional size-based RECIST criteria, and it was superior to RECIST in predicting major pathologic response. Independent of preoperative chemotherapy regimen, optimal morphologic response is sufficiently correlated with OS to be considered a surrogate therapeutic end point for patients with CLM.

Optimal Morphologic Response to Preoperative Chemotherapy: An Alternate Outcome End Point Before Resection of Hepatic Colorectal Metastases

PubMed Central

Shindoh, Junichi; Loyer, Evelyne M.; Kopetz, Scott; Boonsirikamchai, Piyaporn; Maru, Dipen M.; Chun, Yun Shin; Zimmitti, Giuseppe; Curley, Steven A.; Charnsangavej, Chusilp; Aloia, Thomas A.; Vauthey, Jean-Nicolas

2012-01-01

Purpose The purposes of this study were to confirm the prognostic value of an optimal morphologic response to preoperative chemotherapy in patients undergoing chemotherapy with or without bevacizumab before resection of colorectal liver metastases (CLM) and to identify predictors of the optimal morphologic response. Patients and Methods The study included 209 patients who underwent resection of CLM after preoperative chemotherapy with oxaliplatin- or irinotecan-based regimens with or without bevacizumab. Radiologic responses were classified as optimal or suboptimal according to the morphologic response criteria. Overall survival (OS) was determined, and prognostic factors associated with an optimal response were identified in multivariate analysis. Results An optimal morphologic response was observed in 47% of patients treated with bevacizumab and 12% of patients treated without bevacizumab (P < .001). The 3- and 5-year OS rates were higher in the optimal response group (82% and 74%, respectively) compared with the suboptimal response group (60% and 45%, respectively; P < .001). On multivariate analysis, suboptimal morphologic response was an independent predictor of worse OS (hazard ratio, 2.09; P = .007). Receipt of bevacizumab (odds ratio, 6.71; P < .001) and largest metastasis before chemotherapy of ≤ 3 cm (odds ratio, 2.12; P = .025) were significantly associated with optimal morphologic response. The morphologic response showed no specific correlation with conventional size-based RECIST criteria, and it was superior to RECIST in predicting major pathologic response. Conclusion Independent of preoperative chemotherapy regimen, optimal morphologic response is sufficiently correlated with OS to be considered a surrogate therapeutic end point for patients with CLM. PMID:23150701

Defective bacterial clearance is responsible for the enhanced lung pathology characteristic of Mannheimia haemolytica pneumonia in bighorn sheep

USDA-ARS?s Scientific Manuscript database

The molecular and cellular basis for the enhanced lung pathology and mortality caused by Mannheimia haemolytica in bighorn sheep (BHS, Ovis canadenesis), in comparison to domestic sheep (DS, Ovis aries), is not clear. Polymorphonuclear leukocytes (PMNs) of BHS are four- to eight-fold more susceptibl...

Immunity and immune response, pathology and pathologic changes: progress and challenges in the immunopathology of yellow fever.

PubMed

Quaresma, Juarez A S; Pagliari, Carla; Medeiros, Daniele B A; Duarte, Maria I S; Vasconcelos, Pedro F C

2013-09-01

Yellow fever is a viral hemorrhagic fever, which affects people living in Africa and South America and is caused by the yellow fever virus, the prototype species in the Flavivirus genus (Flaviviridae family). Yellow fever virus infection can produce a wide spectrum of symptoms, ranging from asymptomatic infection or oligosymptomatic illness to severe disease with a high fatality rate. In this review, we focus in the mechanisms associated with the physiopathology of yellow fever in humans and animal models. It has been demonstrated that several factors play a role in the pathological outcome of the severe form of the disease including direct viral cytopathic effect, necrosis and apoptosis of hepatocyte cells in the midzone, and a minimal inflammatory response as well as low-flow hypoxia and cytokine overproduction. New information has filled several gaps in the understanding of yellow fever pathogenesis and helped comprehend the course of illness. Finally, we discuss prospects for an immune therapy in the light of new immunologic, viral, and pathologic tools. Copyright © 2013 John Wiley & Sons, Ltd.

Prevalence of alcohol-related pathologies at autopsy: Estonian Forensic Study of Alcohol and Premature Death

PubMed Central

Tuusov, Jana; Lang, Katrin; Väli, Marika; Pärna, Kersti; Tõnisson, Mailis; Ringmets, Inge; McKee, Martin; Helander, Anders; Leon, David A

2014-01-01

Aims Alcohol can induce diverse serious pathologies, yet this complexity may be obscured when alcohol-related deaths are classified according to a single underlying cause. We sought to quantify this issue and its implications for analysing mortality data. Design, Setting and Participants Cross-sectional study included 554 men aged 25–54 in Estonia undergoing forensic autopsy in 2008–09. Measurements Potentially alcohol-related pathologies were identified following macroscopic and histological examination. Alcohol biomarkers levels were determined. For a subset (26%), drinking behaviour was provided by next-of-kin. The Estonian Statistics Office provided underlying cause of death. Findings Most deaths (75%) showed evidence of potentially alcohol-related pathologies, and 32% had pathologies in two or more organs. The liver was most commonly affected [60.5%, 95% confidence interval (CI) = 56.3–64.6] followed by the lungs (18.6%, 95% CI = 15.4–22.1), stomach (17.5%, 95% CI = 14.4–20.9), pancreas (14.1%, 95% CI = 11.3–17.3), heart (4.9%, 95% CI = 3.2–7.0) and oesophagus (1.4%, 95% CI = 0.6–2.8). Only a minority with liver pathology had a second pathology. The number of pathologies correlated with alcohol biomarkers (phosphatidylethanol, gamma-glytamyl transpeptidase in blood, ethylglucuronide, ethylsulphate in urine). Despite the high prevalence of liver pathology, few deaths had alcoholic liver disease specified as the underlying cause. Conclusion The majority of 554 men aged 25–54 undergoing forensic autopsy in Estonia in 2008–09 showed evidence of alcohol-related pathology. However, the recording of deaths by underlying cause failed to capture the scale and nature of alcohol-induced pathologies found. PMID:25066373

Pathology crossword competition: an active and easy way of learning pathology in undergraduate medical education.

PubMed

Htwe, T T; Sabaridah, I; Rajyaguru, K M; Mazidah, A M

2012-02-01

In line with the trend to engage students in active learning, it is imperative to introduce new strategies that make learning more interesting, especially in undergraduate curricula. This study aimed to determine students' performance and perception in pathology crosswords as an active way of learning and to assess their ability to memorise difficult terms in pathology. A crossword competition in pathology was conducted for two batches (year 2009 and 2010) of Phase 2 medical students in Malaysia. Crossword puzzles were prepared using an online application. Two sets of puzzles were prepared, with 20 questions for the assessment of general pathology and 20 for systemic pathology. The purpose was to compare the students' recent and remote memorising abilities, as general pathology was taught a year before proceeding to systemic pathology teaching. There were 12 groups per batch, with 8-10 students in a group. Survey questionnaires were used to assess the students' perception of the competition. Descriptive analysis was performed for comparison of performance. The mean score of correctly answered questions in general pathology was 12.75 and 11.50 in batch 2009 and 2010, respectively. The mean score for systemic pathology was 14.50 in 2009 and 13.83 in 2010. Students in the 2009 batch performed better, but this was not statistically significant (p-value > 0.05). A positive response was observed from the questionnaires. Applying crossword puzzles as a new strategy is a useful and easy way for undergraduate medical students to learn pathology.

Flexible intramedullary nailing for the treatment of unicameral bone cysts in long bones.

PubMed

Roposch, A; Saraph, V; Linhart, W E

2000-10-01

Unicameral bone cyst is characterized by its tenacity and risk of recurrence. Pathological fracture is common and is often the presenting symptom. The objective of the present study was to evaluate the results of flexible intramedullary nailing for the treatment of a unicameral bone cyst with or without a pathological fracture. Flexible intramedullary nailing for the treatment of a unicameral bone cyst was performed in thirty-two patients. Thirty of these patients presented with a pathological fracture; twenty-four were managed immediately with intramedullary nailing, and the other six had been managed conservatively at other clinics before they were referred to our department. The remaining two cysts were detected incidentally. The cyst was located in the humerus in twenty-one patients, in the femur in nine, and in the radius in two. The mean age of the patients at the time of surgery was 9.8 years, and the mean duration of follow-up was 53.7 months. Radiographic evaluation was performed according to the criteria of Capanna et al., and the cyst was classified as completely healed, healed with residual radiolucency (osteolysis), recurred, or having no response. The healing period ranged from three to 105 months. Fourteen cysts healed completely, and sixteen healed with residual radiolucent areas visible on radiographs. There was recurrence of two cysts that had healed with residual radiolucency. All of the cysts in the present study responded to treatment. A change of nails was necessary in nine patients, as the nails had become too short after bone growth. No major complications were observed. Flexible intramedullary nailing provides early stability, which allows early mobilization and thus obviates the need for a plaster cast and decreases the prevalence of the most common complication: a pathological fracture. This method of treatment also allows for an early return to normal activity.

Bipolar Radiofrequency Facet Ablation of the Lumbar Facet Capsule: An Adjunct to Conventional Radiofrequency Ablation for Pain Management

PubMed Central

Palea, Ovidiu; Granville, Michelle

2017-01-01

Radiofrequency facet ablation (RFA) has been performed using the same technique for over 50 years. Except for variations in electrode size, tip shape, and change in radiofrequency (RF) stimulation parameters, using standard, pulsed, and cooled RF wavelengths, the target points have remained absolutely unchanged from the original work describing RFA for lumbar pain control. Degenerative changes in the facet joint and capsule are the primary location for the majority of lumbar segmental pathology and pain. Multiple studies show that the degenerated facet joint is richly innervated as a result of the inflammatory overgrowth of the synovium. The primary provocative clinical test to justify an RFA is to perform an injection with local anesthetic into the facet joint and the posterior capsule and confirm pain relief. However, after a positive response, the radiofrequency lesion is made not to the facet joint but to the more proximal fine nerve branches that innervate the joint. The accepted target points for the recurrent sensory branch ignore the characteristic rich innervation of the pathologic lumbar facet capsule and assume that lesioning of these recurrent branches is sufficient to denervate the painful pathologic facet joint. This report describes the additional targets and technical steps for further coagulation points along the posterior capsule of the lumbar facet joint and the physiologic studies of the advantage of the bipolar radiofrequency current in this location. Bipolar RF to the facet capsule is a simple, extra step that easily creates a large thermo-coagulated lesion in this capsule region of the pathologic facet joint. Early studies demonstrate bipolar RF to the facet capsule can provide long-term pain relief when used alone for specific localized facet joint pain, to coagulate lumbar facet cysts to prevent recurrence, and to get more extensive pain control by combining it with traditional lumbar RFA, especially when RFA is repeated. PMID:29119066

Bipolar Radiofrequency Facet Ablation of the Lumbar Facet Capsule: An Adjunct to Conventional Radiofrequency Ablation for Pain Management.

PubMed

Jacobson, Robert E; Palea, Ovidiu; Granville, Michelle

2017-09-01

Radiofrequency facet ablation (RFA) has been performed using the same technique for over 50 years. Except for variations in electrode size, tip shape, and change in radiofrequency (RF) stimulation parameters, using standard, pulsed, and cooled RF wavelengths, the target points have remained absolutely unchanged from the original work describing RFA for lumbar pain control. Degenerative changes in the facet joint and capsule are the primary location for the majority of lumbar segmental pathology and pain. Multiple studies show that the degenerated facet joint is richly innervated as a result of the inflammatory overgrowth of the synovium. The primary provocative clinical test to justify an RFA is to perform an injection with local anesthetic into the facet joint and the posterior capsule and confirm pain relief. However, after a positive response, the radiofrequency lesion is made not to the facet joint but to the more proximal fine nerve branches that innervate the joint. The accepted target points for the recurrent sensory branch ignore the characteristic rich innervation of the pathologic lumbar facet capsule and assume that lesioning of these recurrent branches is sufficient to denervate the painful pathologic facet joint. This report describes the additional targets and technical steps for further coagulation points along the posterior capsule of the lumbar facet joint and the physiologic studies of the advantage of the bipolar radiofrequency current in this location. Bipolar RF to the facet capsule is a simple, extra step that easily creates a large thermo-coagulated lesion in this capsule region of the pathologic facet joint. Early studies demonstrate bipolar RF to the facet capsule can provide long-term pain relief when used alone for specific localized facet joint pain, to coagulate lumbar facet cysts to prevent recurrence, and to get more extensive pain control by combining it with traditional lumbar RFA, especially when RFA is repeated.

Silencing Alpha Synuclein in Mature Nigral Neurons Results in Rapid Neuroinflammation and Subsequent Toxicity

PubMed Central

Benskey, Matthew J.; Sellnow, Rhyomi C.; Sandoval, Ivette M.; Sortwell, Caryl E.; Lipton, Jack W.; Manfredsson, Fredric P.

2018-01-01

Human studies and preclinical models of Parkinson’s disease implicate the involvement of both the innate and adaptive immune systems in disease progression. Further, pro-inflammatory markers are highly enriched near neurons containing pathological forms of alpha synuclein (α-syn), and α-syn overexpression recapitulates neuroinflammatory changes in models of Parkinson’s disease. These data suggest that α-syn may initiate a pathological inflammatory response, however the mechanism by which α-syn initiates neuroinflammation is poorly understood. Silencing endogenous α-syn results in a similar pattern of nigral degeneration observed following α-syn overexpression. Here we aimed to test the hypothesis that loss of α-syn function within nigrostriatal neurons results in neuronal dysfunction, which subsequently stimulates neuroinflammation. Adeno-associated virus (AAV) expressing an short hairpin RNA (shRNA) targeting endogenous α-syn was unilaterally injected into the substantia nigra pars compacta (SNc) of adult rats, after which nigrostriatal pathology and indices of neuroinflammation were examined at 7, 10, 14 and 21 days post-surgery. Removing endogenous α-syn from nigrostriatal neurons resulted in a rapid up-regulation of the major histocompatibility complex class 1 (MHC-1) within transduced nigral neurons. Nigral MHC-1 expression occurred prior to any overt cell death and coincided with the recruitment of reactive microglia and T-cells to affected neurons. Following the induction of neuroinflammation, α-syn knockdown resulted in a 50% loss of nigrostriatal neurons in the SNc and a corresponding loss of nigrostriatal terminals and dopamine (DA) concentrations within the striatum. Expression of a control shRNA did not elicit any pathological changes. Silencing α-syn within glutamatergic neurons of the cerebellum did not elicit inflammation or cell death, suggesting that toxicity initiated by α-syn silencing is specific to DA neurons. These data provide evidence that loss of α-syn function within nigrostriatal neurons initiates a neuronal-mediated neuroinflammatory cascade, involving both the innate and adaptive immune systems, which ultimately results in the death of affected neurons. PMID:29497361

Epidemiology of trace elements deficiencies in Belgian beef and dairy cattle herds.

PubMed

Guyot, Hugues; Saegerman, Claude; Lebreton, Pascal; Sandersen, Charlotte; Rollin, Frédéric

2009-01-01

Selenium (Se), iodine (I), zinc (Zn) and copper (Cu) deficiencies in cattle have been reported in Europe. These deficiencies are often associated with diseases. The aim of the study was to assess trace element status in Belgian cattle herds showing pathologies and to compare them to healthy cattle herds. Eighty-two beef herds with pathologies, 11 healthy beef herds, 65 dairy herds with pathologies and 20 healthy dairy herds were studied during barn period. Blood and/or milk samples were taken in healthy animals. Plasma Zn, Cu, inorganic I (PII) and activity of glutathione peroxidase in erythrocytes (GPX) were assayed. In milk, I concentration was measured. Data about pathologies and nutrition in the herds were collected. According to defined thresholds, it appeared that a large proportion of deficient herds belonged to "sick" group of herds. This conclusion was supported by the mean value of trace elements and by the fact that a majority of individual values of trace elements was below the threshold. Dairy herds had mean values of trace elements higher than beef herds. More concentrates and minerals were used in healthy herds versus "sick" herds. These feed supplements were also used more often in dairy herds, compared to beef herds. Trace elements deficiencies are present in cattle herds in Belgium and are linked to diseases. Nutrition plays a major role in the trace elements status.

Linking Essential Tremor to the Cerebellum: Physiological Evidence.

PubMed

Filip, Pavel; Lungu, Ovidiu V; Manto, Mario-Ubaldo; Bareš, Martin

2016-12-01

Essential tremor (ET), clinically characterized by postural and kinetic tremors, predominantly in the upper extremities, originates from pathological activity in the dynamic oscillatory network comprising the majority of nodes in the central motor network. Evidence indicates dysfunction in the thalamus, the olivocerebellar loops, and intermittent cortical engagement. Pathology of the cerebellum, a structure with architecture intrinsically predisposed to oscillatory activity, has also been implicated in ET as shown by clinical, neuroimaging, and pathological studies. Despite electrophysiological studies assessing cerebellar impairment in ET being scarce, their impact is tangible, as summarized in this review. The electromyography-magnetoencephalography combination provided the first direct evidence of pathological alteration in cortico-subcortical communication, with a significant emphasis on the cerebellum. Furthermore, complex electromyography studies showed disruptions in the timing of agonist and antagonist muscle activation, a process generally attributed to the cerebellum. Evidence pointing to cerebellar engagement in ET has also been found in electrooculography measurements, cerebellar repetitive transcranial magnetic stimulation studies, and, indirectly, in complex analyses of the activity of the ventral intermediate thalamic nucleus (an area primarily receiving inputs from the cerebellum), which is also used in the advanced treatment of ET. In summary, further progress in therapy will require comprehensive electrophysiological and physiological analyses to elucidate the precise mechanisms leading to disease symptoms. The cerebellum, as a major node of this dynamic oscillatory network, requires further study to aid this endeavor.

Diagnostic value of the 2011 International Federation for Cervical Pathology and Colposcopy Terminology in predicting cervical lesions

PubMed Central

Zhang, Liqin; Yan, Ye; Han, Cha; Xue, Fengxia

2018-01-01

Objective To evaluate the diagnostic accuracy of the 2011 International Federation for Cervical Pathology and Colposcopy (IFCPC) colposcopic terminology. Methods The clinicopathological data of 2262 patients who underwent colposcopy from September 2012 to September 2016 were reviewed. The colposcopic findings, colposcopic impression, and cervical histopathology of the patients were analyzed. Correlations between variables were evaluated using cervical histopathology as the gold standard. Results Colposcopic diagnosis matched biopsy histopathology in 1482 patients (65.5%), and the weighted kappa strength of agreement was 0.480 (P<0.01). Colposcopic diagnoses more often underestimated (22.1%) than overestimated (12.3%) cervical pathology. There was no significant difference between the colposcopic diagnosis and cervical pathology agreement among the various grades of lesions (P=0.282). The sensitivity, specificity for detecting high-grade lesions/carcinoma was 71.6% and 98.0%, respectively. Multivariate analysis showed that major changes were independent factors in predicting high-grade lesion/carcinoma, whereas transformation zone, lesion size, and non-stained were not statistically related to high-grade lesion/carcinoma. Conclusions The 2011 IFCPC terminology can improve the diagnostic accuracy for all lesion severities. The categorization of major changes and minor changes is appropriate. However, colposcopic diagnosis remains unsatisfactory. Poor reproducibility of type 2 transformation zone and the significance of leukoplakia require further study. PMID:29507681

Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of Alzheimer's disease.

PubMed

Kotze, Maritha J; van Rensburg, Susan J

2012-09-01

Chronic, multi-factorial conditions caused by a complex interaction between genetic and environmental risk factors frequently share common disease mechanisms, as evidenced by an overlap between genetic risk factors for cardiovascular disease (CVD) and Alzheimer's disease (AD). Single nucleotide polymorphisms (SNPs) in several genes including ApoE, MTHFR, HFE and FTO are known to increase the risk of both conditions. The E4 allele of the ApoE polymorphism is the most extensively studied risk factor for AD and increases the risk of coronary heart disease by approximately 40%. It furthermore displays differential therapeutic responses with use of cholesterol-lowering statins and acetylcholinesterase inhibitors, which may also be due to variation in the CYP2D6 gene in some patients. Disease expression may be triggered by gene-environment interaction causing conversion of minor metabolic abnormalities into major brain disease due to cumulative risk. A growing body of evidence supports the assessment and treatment of CVD risk factors in midlife as a preventable cause of cognitive decline, morbidity and mortality in old age. In this review, the concept of pathology supported genetic testing (PSGT) for CVD is described in this context. PSGT combines DNA testing with biochemical measurements to determine gene expression and to monitor response to treatment. The aim is to diagnose treatable disease subtypes of complex disorders, facilitate prevention of cumulative risk and formulate intervention strategies guided from the genetic background. CVD provides a model to address the lifestyle link in most chronic diseases with a genetic component. Similar preventative measures would apply for optimisation of heart and brain health.

Mixed Neurodevelopmental and Neurodegenerative Pathology in Nhe6-Null Mouse Model of Christianson Syndrome

PubMed Central

Xu, Meiyu; Ouyang, Qing; Gong, Jingyi; Pescosolido, Matthew F.; Mishra, Sasmita; Schmidt, Michael; Jones, Richard N.; Gamsiz Uzun, Ece D.; Lizarraga, Sofia B.

2017-01-01

Abstract Christianson syndrome (CS) is an X-linked disorder resulting from loss-of-function mutations in SLC9A6, which encodes the endosomal Na+/H+ exchanger 6 (NHE6). Symptoms include early developmental delay, seizures, intellectual disability, nonverbal status, autistic features, postnatal microcephaly, and progressive ataxia. Neuronal development is impaired in CS, involving defects in neuronal arborization and synaptogenesis, likely underlying diminished brain growth postnatally. In addition to neurodevelopmental defects, some reports have supported neurodegenerative pathology in CS with age. The objective of this study was to determine the nature of progressive changes in the postnatal brain in Nhe6-null mice. We examined the trajectories of brain growth and atrophy in mutant mice from birth until very old age (2 yr). We report trajectories of volume changes in the mutant that likely reflect both brain undergrowth as well as tissue loss. Reductions in volume are first apparent at 2 mo, particularly in the cerebellum, which demonstrates progressive loss of Purkinje cells (PCs). We report PC loss in two distinct Nhe6-null mouse models. More widespread reductions in tissue volumes, namely, in the hippocampus, striatum, and cortex, become apparent after 2 mo, largely reflecting delays in growth with more limited tissue losses with aging. Also, we identify pronounced glial responses, particularly in major fiber tracts such as the corpus callosum, where the density of activated astrocytes and microglia are substantially increased. The prominence of the glial response in axonal tracts suggests a primary axonopathy. Importantly, therefore, our data support both neurodevelopmental and degenerative mechanisms in the pathobiology of CS. PMID:29349289

Response monitoring of breast cancer patients receiving neoadjuvant chemotherapy using quantitative ultrasound, texture, and molecular features

PubMed Central

Gangeh, Mehrdad; Tadayyon, Hadi; Sadeghi-Naini, Ali; Gandhi, Sonal; Wright, Frances C.; Slodkowska, Elzbieta; Curpen, Belinda; Tran, William; Czarnota, Gregory J.

2018-01-01

Background Pathological response of breast cancer to chemotherapy is a prognostic indicator for long-term disease free and overall survival. Responses of locally advanced breast cancer in the neoadjuvant chemotherapy (NAC) settings are often variable, and the prediction of response is imperfect. The purpose of this study was to detect primary tumor responses early after the start of neoadjuvant chemotherapy using quantitative ultrasound (QUS), textural analysis and molecular features in patients with locally advanced breast cancer. Methods The study included ninety six patients treated with neoadjuvant chemotherapy. Breast tumors were scanned with a clinical ultrasound system prior to chemotherapy treatment, during the first, fourth and eighth week of treatment, and prior to surgery. Quantitative ultrasound parameters and scatterer-based features were calculated from ultrasound radio frequency (RF) data within tumor regions of interest. Additionally, texture features were extracted from QUS parametric maps. Prior to therapy, all patients underwent a core needle biopsy and histological subtypes and biomarker ER, PR, and HER2 status were determined. Patients were classified into three treatment response groups based on combination of clinical and pathological analyses: complete responders (CR), partial responders (PR), and non-responders (NR). Response classifications from QUS parameters, receptors status and pathological were compared. Discriminant analysis was performed on extracted parameters using a support vector machine classifier to categorize subjects into CR, PR, and NR groups at all scan times. Results Of the 96 patients, the number of CR, PR and NR patients were 21, 52, and 23, respectively. The best prediction of treatment response was achieved with the combination mean QUS values, texture and molecular features with accuracies of 78%, 86% and 83% at weeks 1, 4, and 8, after treatment respectively. Mean QUS parameters or clinical receptors status alone predicted the three response groups with accuracies less than 60% at all scan time points. Recurrence free survival (RFS) of response groups determined based on combined features followed similar trend as determined based on clinical and pathology. Conclusions This work demonstrates the potential of using QUS, texture and molecular features for predicting the response of primary breast tumors to chemotherapy early, and guiding the treatment planning of refractory patients. PMID:29298305

Effectiveness of Radiotherapy in Myxoid Sarcomas Is Associated With a Dense Vascular Pattern

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vreeze, Ronald S.A. de; Jong, Daphne de; Haas, Rick L.

2008-12-01

Purpose: Surgery and adjuvant radiotherapy (RT) have long been the standard treatment for most deep-seated sarcomas; however, since the randomized trial from the National Cancer Institute of Canada, which described similar local control for pre- vs. postoperative RT, both modalities are now widely accepted. As a group, sarcomas are classified as radiation resistant. The subgroup of myxoid liposarcoma (MLS), a sarcoma with a typical vascular crow's feet pattern, is highly radiosensitive, but a mechanism for this phenomenon is unknown. Here we describe our results with preoperative RT and propose a mechanism explaining the high sensitivity based on the distinctive vascularizationmore » pattern of MLS. Methods and Materials: Between 2002 and 2006, 31 sarcoma patients, including 10 with MLS, underwent preoperative RT at our institute. Resected specimens were histologically evaluated, focusing on classification, grade, and vascularization patterns. Results: Twenty sarcomas showed more than 80% pathologic response after preoperative RT. A pathologic complete response was found in all 'pure' MLS specimens after preoperative RT (n = 8). There were no pathologic complete responses in the remaining sarcoma patients (n = 23), although 12 showed 80% to 90% pathologic response. In contrast to the remaining RT-resistant sarcomas, the highly responding specimens contained branching vasculature, partial thrombus formation and inflammation of medium sized arterioles, similar to the vascular changes in MLS. Conclusions: Both MLS and sarcomas with MLS-like vasculature are highly radiosensitive. Radiation sensitivity may be explained by changes in medium-sized arterioles, obstructing the specific crow's feet vascularization and inducing hypoxia with secondary tumor cell death.« less

Role of metabolic phenotyping in understanding obesity and related conditions in Gulf Co-operation Council countries.

PubMed

Ahmad, M S; Ashrafian, H; Alsaleh, M; Holmes, E

2015-12-01

Obesity is a major health concern in the Middle East and the incidence is rising in all sections of the population. Efforts to control obesity through diet and lifestyle interventions, and by surgical means, have had limited effect, and the gene-environment interactions underpinning the development of obesity and related pathologies such as metabolic syndrome, cardiovascular disease and certain cancers are poorly defined. Lifestyle, genetics, inflammation and the interaction between the intestinal bacteria and host metabolism have all been implicated in creating an obesogenic environment. We summarize the role of metabolic and microbial phenotyping in understanding the aetiopathogenesis of obesity and in characterizing the metabolic responses to surgical and non-surgical interventions, and explore the potential for clinical translation of this approach. © 2015 World Obesity.

Hepatic encephalomyelopathy in a calf with congenital portosystemic shunt (CPSS)

PubMed Central

Oevermann, Anna; Bley, Tim; Pfister, Patrizia; Miclard, Julien

2008-01-01

A 4-month-old female Holstein Friesian calf was referred to the Veterinary Teaching Hospital, University of Berne, Switzerland for evaluation of ataxia, weakness, apathy and stunted growth. Clinical examination revealed generalized ataxia, propioceptive deficits, decreased menace response and sensibility. Postmortem examination did not reveal macroscopic changes of major organs. Histologically, the brain and the spinal cord lesions were characterized by polymicrocavitation, preferentially affecting the white matter fibers at the junction of grey and white matter and by the presence of Alzheimer type II cells. The liver revealed lesions consistent with a congenital portosystemic shunt, characterized by increased numbers of arteriolar profiles and hypoplasia to absence of portal veins. The pathological investigations along with the animal history and clinical signs indicated a hepatic encephalomyelopathy due to a congenital portosystemic shunt. PMID:18296896

Genome Engineering for Personalized Arthritis Therapeutics.

PubMed

Adkar, Shaunak S; Brunger, Jonathan M; Willard, Vincent P; Wu, Chia-Lung; Gersbach, Charles A; Guilak, Farshid

2017-10-01

Arthritis represents a family of complex joint pathologies responsible for the majority of musculoskeletal conditions. Nearly all diseases within this family, including osteoarthritis, rheumatoid arthritis, and juvenile idiopathic arthritis, are chronic conditions with few or no disease-modifying therapeutics available. Advances in genome engineering technology, most recently with CRISPR-Cas9, have revolutionized our ability to interrogate and validate genetic and epigenetic elements associated with chronic diseases such as arthritis. These technologies, together with cell reprogramming methods, including the use of induced pluripotent stem cells, provide a platform for human disease modeling. We summarize new evidence from genome-wide association studies and genomics that substantiates a genetic basis for arthritis pathogenesis. We also review the potential contributions of genome engineering in the development of new arthritis therapeutics. Copyright © 2017 Elsevier Ltd. All rights reserved.

The Role of Neuroimaging Techniques in Establishing Diagnosis, Prognosis and Therapy in Disorders of Consciousness

PubMed Central

Gosseries, Olivia; Pistoia, Francesca; Charland-Verville, Vanessa; Carolei, Antonio; Sacco, Simona; Laureys, Steven

2016-01-01

Non-communicative brain damaged patients raise important clinical and scientific issues. Here, we review three major pathological disorders of consciousness: coma, the unresponsive wakefulness syndrome and the minimally conscious state. A number of clinical studies highlight the difficulty in making a correct diagnosis in patients with disorders of consciousness based only on behavioral examinations. The increasing use of neuroimaging techniques allows improving clinical characterization of these patients. Recent neuroimaging studies using positron emission tomography, functional magnetic resonance imaging, electroencephalography and transcranial magnetic stimulation can help assess diagnosis, prognosis, and therapeutic treatment. These techniques, using resting state, passive and active paradigms, also highlight possible dissociations between consciousness and responsiveness, and are facilitating a more accurate understanding of brain function in this challenging population. PMID:27347265

Bone marrow failure in childhood: central pathology review of a nationwide registry.

PubMed

Ito, Masafumi

2017-01-01

Refractory cytopenia of childhood (RCC) was proposed as a provisional entity in the 2008 WHO classification of myelodysplastic syndromes (MDS). It is defined as a childhood MDS featuring persistent cytopenia without increase blasts in bone marrow (BM) or peripheral blood (PB). Because the majority of RCC cases feature hypocellularity and pancytopenia, it is quite challenging to differentiate RCC from acquired aplastic anemia (AA) and many kinds of inherited bone marrow failure syndromes (IBMFS). Diagnosis of RCC requires BM histology of characteristic features such as isolated erythroid islet with left shift, abnormal localization and micromegakaryocytes. The Japanese Society of Pediatric Hematology/Oncology has opened the central registry review system since 2009 to evaluate childhood cases of bone marrow failure (BMF). It has reviewed cytology and BM pathology of all registered BMF cases, which number more than 1,700. In the evaluation of BMF, BM pathology is important to assess the mechanism of hematopoiesis. Pathological dysplasia should be differentiated from cytological dysplasia. A central review system is important for rare diseases, such as pediatric BMF. Standardization of pathological diagnosis should be established upon consensus findings, descriptions, and diagnostic approaches. In this review, the pathology of pediatric BMF syndromes is summarized.

Improving the pathologic evaluation of lung cancer resection specimens.

PubMed

Osarogiagbon, Raymond U; Hilsenbeck, Holly L; Sales, Elizabeth W; Berry, Allen; Jarrett, Robert W; Giampapa, Christopher S; Finch-Cruz, Clara N; Spencer, David

2015-08-01

Accurate post-operative prognostication and management heavily depend on pathologic nodal stage. Patients with nodal metastasis benefit from post-operative adjuvant chemotherapy, those with mediastinal nodal involvement may also benefit from adjuvant radiation therapy. However, the quality of pathologic nodal staging varies significantly, with major survival implications in large populations of patients. We describe the quality gap in pathologic nodal staging, and provide evidence of its potential reversibility by targeted corrective interventions. One intervention, designed to improve the surgical lymphadenectomy, specimen labeling, and secure transfer between the operating theatre and the pathology laboratory, involves use of pre-labeled specimen collection kits. Another intervention involves application of an improved method of gross dissection of lung resection specimens, to reduce the inadvertent loss of intrapulmonary lymph nodes to histologic examination for metastasis. These corrective interventions are the subject of a regional dissemination and implementation project in diverse healthcare systems in a tri-state region of the United States with some of the highest lung cancer incidence and mortality rates. We discuss the potential of these interventions to significantly improve the accuracy of pathologic nodal staging, risk stratification, and the quality of specimens available for development of stage-independent prognostic markers in lung cancer.

Understanding the Importance of the Teres Minor for Shoulder Function: Functional Anatomy and Pathology.

PubMed

Williams, Matthew D; Edwards, Thomas Bradley; Walch, Gilles

2018-03-01

Although the teres minor is often overlooked in a normal shoulder, it becomes a key component in maintaining shoulder function when other rotator cuff tendons fail. The teres minor maintains a balanced glenohumeral joint and changes from an insignificant to the most significant external rotator in the presence of major rotator cuff pathology. The presence or absence of the teres minor provides prognostic information on the outcomes of reverse total shoulder arthroplasty and tendon transfers. Clinical tests include the Patte test, the Neer dropping sign, the external rotation lag sign, and the Hertel drop sign. Advanced imaging of the teres minor can be used for classification using the Walch system. Understanding the function and pathology surrounding the teres minor is paramount in comprehensive management of the patient with shoulder pathology. Appropriate clinical examination and imaging of the teres minor are important for preoperative stratification and postoperative expectations.

Pathological narcissism and narcissistic personality disorder in Axis I disorders.

PubMed

Ronningstam, E

1996-01-01

This paper presents available information on the comorbidity of narcissistic personality disorder (NPD) and pathological narcissism with major mental illness. A review of empirical studies reporting on the prevalence of NPD in Axis I disorders, and of theoretical and clinical literature on narcissistic pathology in major mental illness, forms the basis for an analysis of this interface. The results show that prevalence rates of NPD in Axis I disorders rarely exceed those found in the general psychiatric or personality disorder populations (i.e., less than 22%). NPD was found at high rates in individuals with a substance use disorder (12-38%) or bipolar disorder (4-47%); it was present at very low rates or absent in persons with obsessive-compulsive disorder. Higher prevalence rates were reported in the studies that used the Millon Clinical Multiaxial Inventory I or II than in those that employed the Structured interview for DSM-III Personality Disorders or the Structured Interview for DSM-III-R Personality Disorders--Revised. There is no evidence implicating a significant relationship between NPD and any specific Axis I disorder. A comparison of theoretical and clinical studies with empirical ones reveals major differences in the views regarding the presence and significance of NPD in Axis I disorders. However, the results highlight trends of interacting comorbidity between NPD and substance use disorders, bipolar disorder, depression, and anorexia nervosa.

Improvement of the quality of BRAF testing in melanomas with nationwide external quality assessment, for the BRAF EQA group

PubMed Central

2013-01-01

Background Knowledge about tumour gene mutation status is essential for the treatment of increasing numbers of cancer patients, and testing quality has a major impact on treatment response and cost. In 2012, 4,629 tests for BRAF p.V600 were performed in France, in patients with melanomas. Methods Two batches of unstained melanoma sections were sent, in May and November 2012, to the 46 laboratories supported by the French National Institute of Cancer (INCa). An external quality assessment (EQA) evaluated mutation status, response times and compliance with INCa recommendations. Results All the French laboratories involved in testing participated in the EQA. Fourteen different methods were used to detect BRAF mutations, most consisting of combinations of in-house techniques. False responses were noted in 25/520 cases (4.8%), 11 of which concerned confusion between p.V600E and p.V600K. Thus, 2.7% of responses would have led to inappropriate treatment. Within six months, mean response times decreased from 22 to 12 days (P<0.001), and the percentage of samples evaluated by a pathologist for tumour cell content increased, from 75.2% to 96.9% (P<0.001). Conclusion Despite the use of non-certified methods, the false response rate was low. Nationwide EQA can improve the quality of molecular pathology tests on tumours. PMID:24119386

Gene expression levels of gamma-glutamyl hydrolase in tumor tissues may be a useful biomarker for the proper use of S-1 and tegafur-uracil/leucovorin in preoperative chemoradiotherapy for patients with rectal cancer.

PubMed

Sadahiro, Sotaro; Suzuki, T; Tanaka, A; Okada, K; Saito, G; Miyakita, H; Ogimi, T; Nagase, H

2017-06-01

Preoperative chemoradiotherapy (CRT) using 5-fluorouracil (5-FU)-based chemotherapy is the standard of care for rectal cancer. The effect of additional chemotherapy during the period between the completion of radiotherapy and surgery remains unclear. Predictive factors for CRT may differ between combination chemotherapy with S-1 and with tegafur-uracil/leucovorin (UFT/LV). The subjects were 54 patients with locally advanced rectal cancer who received preoperative CRT with S-1 or UFT/LV. The pathological tumor response was assessed according to the tumor regression grade (TRG). The expression levels of 18 CRT-related genes were determined using RT-PCR assay. A pathological response (TRG 1-2) was observed in 23 patients (42.6%). In a multivariate logistic regression analysis for pathological response, the overall expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, were significant, and the accuracy rate of the predictive model was 83.3%. The effects of the gene expression levels of GGH on the response differed significantly according to the treatment regimen. The total pathological response rate of both high-GGH patients in the S-1 group and low-GGH patients in the UFT/LV group was 58.3%. Additional treatment with 5-FU-based chemotherapy during the interval between radiotherapy and surgery is not beneficial in patients who have received 5-FU-based CRT. The expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, in tumor tissues can predict the response to preoperative CRT including either S-1 or UFT/LV. In particular, the gene expression level of GGH in tumor tissues may be a useful biomarker for the appropriate use of S-1 and UFT/LV in CRT.

Metabolic response of rectal cancer assessed by 18-FDG PET following chemoradiotherapy is prognostic for patient outcome.

PubMed

Yeung, J M C; Kalff, V; Hicks, R J; Drummond, E; Link, E; Taouk, Y; Michael, M; Ngan, S; Lynch, A C; Heriot, A G

2011-05-01

Complete pathological response has proven prognostic benefits in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy. Sequential 18-FDG PET may be an early surrogate for pathological response to chemoradiotherapy. The aim of this study was to identify whether metabolic response measured by FDG PET following chemoradiotherapy is prognostic for tumor recurrence and survival following neoadjuvant therapy and surgical treatment for primary rectal cancer. Patients with primary rectal cancer treated by long-course neoadjuvant chemoradiotherapy followed by surgery had FDG PET performed before and 4 weeks after treatment, before surgical resection was performed. Retrospective chart review was undertaken for patient demographics, tumor staging, recurrence rates, and survival. : Between 2000 and 2007, 78 patients were identified (53 male, 25 female; median age, 64 y). After chemoradiotherapy, 37 patients (47%) had a complete metabolic response, 26 (33%) had a partial metabolic response, and 14 (18%) had no metabolic response as assessed by FDG PET (1 patient had missing data). However, only 4 patients (5%) had a complete pathological response. The median postoperative follow-up period was 3.1 years during which 14 patients (19%) had a recurrence: 2 local, 9 distant, and 3 with both local and distant. The estimated percentage without recurrence was 77% at 5 years (95% CI 66%-89%). There was an inverse relationship between FDG PET metabolic response and the incidence of recurrence within 3 years (P = .04). Kaplan-Meier analysis of FDG PET metabolic response and overall survival demonstrated a significant difference in survival among patients in the 3 arms: complete, partial, and no metabolic response (P = .04); the patients with complete metabolic response had the best prognosis. Complete or partial metabolic response on PET following neoadjuvant chemoradiotherapy and surgery predicts a lower local recurrence rate and improved survival compared with patients with no metabolic response. Metabolic response may be used to stratify prognosis in patients with rectal cancer.

Pathological gambling and age: differences in personality, psychopathology, and response to treatment variables.

PubMed

González-Ibáñez, A; Mora, M; Gutiérrez-Maldonado, J; Ariza, A; Lourido-Ferreira, M R

2005-02-01

The aim of this study was to ascertain the possible differences in personality, psychopathology, and response to treatment in pathological gambling according to age. The sample, comprising 67 participants, was divided into three groups: 32.6% with ages ranging between 17 and 26 years, 31.3% between 27 and 43 years, and 35.8% over 44 years of age. The participants were administered the following tests, Minnesota Multiphasic Personality Inventory [MMPI; Hathaway, S.R. & McKinley, J.C. (1943, 1961). Cuestionario de personalidad MMPI. Madrid Seccion de Estudios de TEA ed. 1970, 1975], sensation-seeking questionnaire [SSS; Zuckerman, M. (1979). Sensation seeking; beyond the optimal level of arousal. Hillsdale, NJ: Lawrence Erlbaum Associates], and the Symptom Check List Revised [SCL-90-R; Derogatis, L.R. (1977). Symptom check list-90 revised. Administration scoring and procedures manual. Baltimore]. All underwent a group treatment programme that was carried out in the Pathological Gambling Unit at Ciutat Sanitaria i Universitaria de Bellvitge (CSUB), Teaching hospital, Barcelona, Spain. The findings show differences depending on age in the participants' personality and in psychopathology and in their response to treatment.

CNS infiltration of peripheral immune cells: D-Day for neurodegenerative disease?

PubMed

Rezai-Zadeh, Kavon; Gate, David; Town, Terrence

2009-12-01

While the central nervous system (CNS) was once thought to be excluded from surveillance by immune cells, a concept known as "immune privilege," it is now clear that immune responses do occur in the CNS-giving rise to the field of neuroimmunology. These CNS immune responses can be driven by endogenous (glial) and/or exogenous (peripheral leukocyte) sources and can serve either productive or pathological roles. Recent evidence from mouse models supports the notion that infiltration of peripheral monocytes/macrophages limits progression of Alzheimer's disease pathology and militates against West Nile virus encephalitis. In addition, infiltrating T lymphocytes may help spare neuronal loss in models of amyotrophic lateral sclerosis. On the other hand, CNS leukocyte penetration drives experimental autoimmune encephalomyelitis (a mouse model for the human demyelinating disease multiple sclerosis) and may also be pathological in both Parkinson's disease and human immunodeficiency virus encephalitis. A critical understanding of the cellular and molecular mechanisms responsible for trafficking of immune cells from the periphery into the diseased CNS will be key to target these cells for therapeutic intervention in neurodegenerative diseases, thereby allowing neuroregenerative processes to ensue.

Relationship between the Temporal Changes in Positron-Emission-Tomography-Imaging-Based Textural Features and Pathologic Response and Survival in Esophageal Cancer Patients.

PubMed

Yip, Stephen S F; Coroller, Thibaud P; Sanford, Nina N; Mamon, Harvey; Aerts, Hugo J W L; Berbeco, Ross I

2016-01-01

Although change in standardized uptake value (SUV) measures and PET-based textural features during treatment have shown promise in tumor response prediction, it is unclear which quantitative measure is the most predictive. We compared the relationship between PET-based features and pathologic response and overall survival with the SUV measures in esophageal cancer. Fifty-four esophageal cancer patients received PET/CT scans before and after chemoradiotherapy. Of these, 45 patients underwent surgery and were classified into complete, partial, and non-responders to the preoperative chemoradiation. SUVmax and SUVmean, two cooccurrence matrix (Entropy and Homogeneity), two run-length matrix (RLM) (high-gray-run emphasis and Short-run high-gray-run emphasis), and two size-zone matrix (high-gray-zone emphasis and short-zone high-gray emphasis) textures were computed. The relationship between the relative difference of each measure at different treatment time points and the pathologic response and overall survival was assessed using the area under the receiver-operating-characteristic curve (AUC) and Kaplan-Meier statistics, respectively. All Textures, except Homogeneity, were better related to pathologic response than SUVmax and SUVmean. Entropy was found to significantly distinguish non-responders from the complete (AUC = 0.79, p = 1.7 × 10(-4)) and partial (AUC = 0.71, p = 0.01) responders. Non-responders can also be significantly differentiated from partial and complete responders by the change in the run-length and size-zone matrix textures (AUC = 0.71-0.76, p ≤ 0.02). Homogeneity, SUVmax, and SUVmean failed to differentiate between any of the responders (AUC = 0.50-0.57, p ≥ 0.46). However, none of the measures were found to significantly distinguish between complete and partial responders with AUC <0.60 (p = 0.37). Median Entropy and RLM textures significantly discriminated patients with good and poor survival (log-rank p < 0.02), while all other textures and survival were poorly related (log-rank p > 0.25). For the patients studied, temporal changes in Entropy and all RLM were better correlated with pathological response and survival than the SUV measures. The hypothesis that these metrics can be used as clinical predictors of better patient outcomes will be tested in a larger patient dataset in the future.

Development of a Brief Version of the Pathological Narcissism Inventory

PubMed Central

Schoenleber, Michelle; Roche, Michael J.; Wetzel, Eunike; Pincus, Aaron L.; Roberts, Brent W.

2015-01-01

With theoretical and empirical interest in narcissism growing, there is a need for brief measures of pathological narcissism that can be used more practically while assessing the construct comprehensively. Data from four samples (total n = 3,851) collected across two separate research groups and representing undergraduate, community, and clinical populations was used to establish the reliability, validity, and utility of the Brief-Pathological Narcissism Inventory (B-PNI). Item response theory and confirmatory factor analyses were used to determine the best-performing 28 items from the original PNI and ensure that the B-PNI exhibited a factor structure consistent with the original PNI. Items were retained for all seven pathological narcissism facet scales. Additional results also support the criterion validity of the B-PNI, suggesting it can be used in place of the original PNI to assess the various facets of pathological narcissism effectively and without loss of information, which may enhance the ability of researchers to investigate pathological narcissism in future work. PMID:26011478

Development of a brief version of the Pathological Narcissism Inventory.

PubMed

Schoenleber, Michelle; Roche, Michael J; Wetzel, Eunike; Pincus, Aaron L; Roberts, Brent W

2015-12-01

With theoretical and empirical interest in narcissism growing, there is a need for brief measures of pathological narcissism that can be used more practically while assessing the construct comprehensively. Data from four samples (total N = 3,851) collected across two separate research groups and representing undergraduate, community, and clinical populations were used to establish the reliability, validity, and utility of the Brief-Pathological Narcissism Inventory (B-PNI). Item response theory and confirmatory factor analyses were used to determine the best-performing 28 items from the original PNI and ensure that the B-PNI exhibited a factor structure consistent with the original PNI. Items were retained for all seven pathological narcissism facet scales. Additional results also support the criterion validity of the B-PNI, suggesting that it can be used in place of the original PNI to assess the various facets of pathological narcissism effectively and without loss of information, which may enhance the ability of researchers to investigate pathological narcissism in future work. (c) 2015 APA, all rights reserved).

Revitalizing pathology laboratories in a gastrointestinal pathophysiology course using multimedia and team-based learning techniques.

PubMed

Carbo, Alexander R; Blanco, Paola G; Graeme-Cooke, Fiona; Misdraji, Joseph; Kappler, Steven; Shaffer, Kitt; Goldsmith, Jeffrey D; Berzin, Tyler; Leffler, Daniel; Najarian, Robert; Sepe, Paul; Kaplan, Jennifer; Pitman, Martha; Goldman, Harvey; Pelletier, Stephen; Hayward, Jane N; Shields, Helen M

2012-05-15

In 2008, we changed the gastrointestinal pathology laboratories in a gastrointestinal pathophysiology course to a more interactive format using modified team-based learning techniques and multimedia presentations. The results were remarkably positive and can be used as a model for pathology laboratory improvement in any organ system. Over a two-year period, engaging and interactive pathology laboratories were designed. The initial restructuring of the laboratories included new case material, Digital Atlas of Video Education Project videos, animations and overlays. Subsequent changes included USMLE board-style quizzes at the beginning of each laboratory, with individual readiness assessment testing and group readiness assessment testing, incorporation of a clinician as a co-teacher and role playing for the student groups. Student responses for pathology laboratory contribution to learning improved significantly compared to baseline. Increased voluntary attendance at pathology laboratories was observed. Spontaneous student comments noted the positive impact of the laboratories on their learning. Pathology laboratory innovations, including modified team-based learning techniques with individual and group self-assessment quizzes, multimedia presentations, and paired teaching by a pathologist and clinical gastroenterologist led to improvement in student perceptions of pathology laboratory contributions to their learning and better pathology faculty evaluations. These changes can be universally applied to other pathology laboratories to improve student satisfaction. Copyright © 2012 Elsevier GmbH. All rights reserved.

For Medical Technologists: The Frontier of Clinical Pathology. Six Interviews Conducted at the National Institutes of Health.

ERIC Educational Resources Information Center

National Institutes of Health (DHEW), Bethesda, MD. Clinical Center.

The responses of six medical technologists to an interviewer's questions give a view of the working life in the clinical pathology laboratory of the National Institutes of Health (NIH). The technologists cite the competence of co-workers, sophisticated equipment, opportunities to further their education, and the challenge of participation in…

[Allergy and autoimmunity: Molecular diagnostics, therapy, and presumable pathogenesis].

PubMed

Arefieva, A S; Smoldovskaya, O V; Tikhonov, A A; Rubina, A Yu

2017-01-01

Allergic and autoimmune diseases represent immunopathological reactions of an organism to antigens. Despite that the allergy is a result of exaggerated immune response to foreign antigens (allergens) and autoimmune diseases are characterized by the pathological response to internal antigens (autoantigens), the underlying mechanisms of these diseases are probably common. Thus, both types of diseases represent variations in the hypersensitivity reaction. A large percentage of both the adult and pediatric population is in need of early diagnostics of these pathologies of the immune system. Considering the diversity of antibodies produced in allergic and autoimmune disease and the difficulties accompanying clinical diagnosing, molecular diagnostics of these pathological processes should be carried out in several stages, including screening and confirmatory studies. In this review, we summarize the available data on the molecular diagnostics and therapy of allergic and autoimmune diseases and discuss the basic similarities and differences in the mechanisms of their development.

Pathological Lesions and Inducible Nitric Oxide Synthase Expressions in the Liver of Mice Experimentally Infected with Clonorchis sinensis.

PubMed

Yang, Qing-Li; Shen, Ji-Qing; Xue, Yan; Cheng, Xiao-Bing; Jiang, Zhi-Hua; Yang, Yi-Chao; Chen, Ying-Dan; Zhou, Xiao-Nong

2015-12-01

The nitric oxide (NO) formation and intrinsic nitrosation may be involved in the possible mechanisms of liver fluke-associated carcinogenesis. We still do not know much about the responses of inducible NO synthase (iNOS) induced by Clonorchis sinensis infection. This study was conducted to explore the pathological lesions and iNOS expressions in the liver of mice with different infection intensity levels of C. sinensis. Extensive periductal inflammatory cell infiltration, bile duct hyperplasia, and fibrosis were commonly observed during the infection. The different pathological responses in liver tissues strongly correlated with the infection intensity of C. sinensis. Massive acute spotty necrosis occurred in the liver parenchyma after a severe infection. The iNOS activity in liver tissues increased, and iNOS-expressing cells with morphological differences were observed after a moderate or severe infection. The iNOS-expressing cells in liver tissues had multiple origins.

Megakaryocyte pathology and bone marrow fibrosis: the lysyl oxidase connection

PubMed Central

Matsuura, Shinobu

2012-01-01

Megakaryocytes (MKs), the platelet precursors, are capable of accumulating DNA greater than a diploid content as part of their cell cycle. MKs have been recognized as mediating fibrosis in a subset of hematologic malignancies, including acute megakaryoblastic leukemia and a subset of myeloproliferative neoplasms. The mechanisms responsible for fibrosis remain only partially understood. Past studies highlighted the role of growth factors in such pathologies, and recently, the protein lysyl oxidase (LOX) has been implicated in proliferation of MKs, ploidy and deposition of fibers. LOX was initially characterized as a protein responsible for the intermolecular cross-linking of elastin and collagen, and in recent years it has been identified as regulator of various pathologies, such as cancer and inflammation. Here, we review recent advances in the understanding of the contribution of MKs to the progression of myelofibrosis, highlighting the newly identified role of LOX. PMID:22767499

Mapping pathological phenotypes in a mouse model of CDKL5 disorder.

PubMed

Amendola, Elena; Zhan, Yang; Mattucci, Camilla; Castroflorio, Enrico; Calcagno, Eleonora; Fuchs, Claudia; Lonetti, Giuseppina; Silingardi, Davide; Vyssotski, Alexei L; Farley, Dominika; Ciani, Elisabetta; Pizzorusso, Tommaso; Giustetto, Maurizio; Gross, Cornelius T

2014-01-01

Mutations in cyclin-dependent kinase-like 5 (CDKL5) cause early-onset epileptic encephalopathy, a neurodevelopmental disorder with similarities to Rett Syndrome. Here we describe the physiological, molecular, and behavioral phenotyping of a Cdkl5 conditional knockout mouse model of CDKL5 disorder. Behavioral analysis of constitutive Cdkl5 knockout mice revealed key features of the human disorder, including limb clasping, hypoactivity, and abnormal eye tracking. Anatomical, physiological, and molecular analysis of the knockout uncovered potential pathological substrates of the disorder, including reduced dendritic arborization of cortical neurons, abnormal electroencephalograph (EEG) responses to convulsant treatment, decreased visual evoked responses (VEPs), and alterations in the Akt/rpS6 signaling pathway. Selective knockout of Cdkl5 in excitatory and inhibitory forebrain neurons allowed us to map the behavioral features of the disorder to separable cell-types. These findings identify physiological and molecular deficits in specific forebrain neuron populations as possible pathological substrates in CDKL5 disorder.

Original research in pathology: judgment, or evidence-based medicine?

PubMed

Crawford, James M

2007-02-01

Pathology is both a medical specialty and an investigative scientific discipline, concerned with understanding the essential nature of human disease. Ultimately, pathology is accountable as well, as measured by the accuracy of our diagnoses and the resultant patient care outcomes. As such, we must consider the evidence base underlying our practices. Within the realm of Laboratory Medicine, extensive attention has been given to testing accuracy and precision. Critical examination of the evidence base supporting the clinical use of specific laboratory tests or technologies is a separate endeavor, to which specific attention must be given. In the case of anatomic pathology and more specifically surgical pathology, the expertise required to render a diagnosis is derived foremost from experience, both personal and literature-based. In the first instance, knowledge of the linkage between one's own diagnoses and individual patient outcomes is required, to validate the role of one's own interpretations in the clinical course of patients. Experience comes from seeing this linkage first hand, from which hopefully comes wisdom and, ultimately, good clinical judgment. In the second instance, reading the literature and learning from experts is required. Only a minority of the relevant literature is published in pathology journals to which one may subscribe. A substantial portion of major papers relevant to the practice of anatomic pathology are published in collateral clinical specialty journals devoted to specific disease areas or organs. Active effort is therefore required to seek out the literature beyond the domain of pathology journals. In examining the published literature, the essential question then becomes: Does the practice of anatomic pathology fulfill the tenets of 'evidence-based medicine' (EBM)? If the pinnacle of EBM is 'systematic review of randomized clinical trials, with or without meta-analysis', then anatomic pathology falls far short. Our published literature is largely observational in nature, with reports of case series (with or without statistical analysis) constituting the majority of our 'evidence base'. Moreover, anatomic pathology is subject to 'interobserver variation', and potentially to 'error'. Taken further, individual interpretation of tissue samples is not an objective endeavor, and it is not easy to fulfill the role of a 'gold standard'. Both for rendering of an overall interpretation, and for providing the semi-quantitative and quantitative numerical 'scores' which support evidence-based clinical treatment algorithms, the Pathologist has to exercise a high level of interpretive judgment. Nevertheless, the contribution of anatomic pathology to 'EBM' is remarkably strong. To the extent that our judgmental interpretations become data, our tissue interpretations become the arbiters of patient care management decisions. In a more global sense, we support highly successful cancer screening programs, and play critical roles in the multidisciplinary management of complex patients. The true error is for the clinical practitioners of 'EBM' to forget the contribution to the supporting evidence base of the physicians that are Anatomic Pathologists. Finally, the academic productivity of pathology faculty who operate in the clinical realm must be considered. A survey of six North American academic pathology departments reveals that 26% of all papers published in 2005 came from 'unfunded' clinical faculty. While it is likely that their academic productivity is lower than that of 'funded' research faculty, the contribution of clinical faculty to the knowledge base for the practice of modern medicine, and to the academic reputation of the department, must not be overlooked. The ability of clinical faculty in academic departments of pathology to pursue original scholarship must be supported if our specialty is to retain its preeminence as an investigative scientific discipline in the age of EBM.

The Edinburgh Primary Care Depression Study: personality disorder and outcome.

PubMed

Patience, D A; McGuire, R J; Scott, A I; Freeman, C P

1995-09-01

Little is known about the impact of personality pathology on the treatment outcome of major depressive illness in primary care in the UK. Patients meeting criteria for DSM-III major depressive disorder were randomly allocated to one of four treatments each lasting 16 weeks, then followed up for 18 months. Assessments were made of depressive symptoms, personality and social functioning. Personality was assessed at maximum improvement or 16 weeks. The prevalence of personality disorder (PD) in the sample of 113 patients was 26%. Patients with a PD were significantly younger and rated more depressed at entry than patients with no personality disorder (NoPD). On completion of treatment patients with a PD were significantly more depressed and had poorer social functioning than the NoPD group. After 18 months there were no differences in ratings of depression or social functioning between the groups. There was substantial improvement in both the PD and NoPD groups. The presence of personality pathology delays recovery from major depressive illness.

Overactive bladder and pontine reticular formation.

PubMed

Zorba, Orhan Ünal; Kırbaş, Serkan; Uzun, Hakkı; Cetinkaya, Mehmet; Önem, Kadir; Rifaioğlu, Mehmet Murat

2013-01-01

The etiology of overactive bladder (OAB) remains unclear. Observed neurogenic factors in the literature are limited to suprapontine or spinal pathologies. The blink reflex is a useful tool in the evaluation of brainstem functions. Blink reflex latency times were evaluated in order to reveal pathology in the brainstem. A total of 60 women, 30 patients with idiopathic OAB and 30 healthy controls, were enrolled in the study. Blink reflex latency times were analyzed by electrical stimulation of the supraorbital nerve. Two responses in the orbicularis oculi muscle, early ipsilateral response (R1) and late bilateral response (R2) latency times, were recorded. Mean ages of the patients and controls were 51.9 ± 5.3 and 49.2 ± 6.2 years, respectively. R2 latency times were significantly higher in patients than in controls. However, R1 latency times were similar between the two groups. The results of the study suggest a significant relation between late blink latency times and OAB. An oligosynaptic path via the trigeminal nuclei is responsible for R1; however, R2 response is relayed through the reticular formation. Stimulation of pontine reticular formation inhibits micturition contraction. In some patients, idiopathic OAB may result from reticular formation-originated pathology. Additional studies on other reticular formation-mediated reflexes are needed to reveal possible dysfunction of reticular formation. Copyright © 2013 S. Karger AG, Basel.

Addition of zoledronic acid to neoadjuvant chemotherapy does not enhance tumor response in patients with HER2-negative stage II/III breast cancer: the NEOZOTAC trial (BOOG 2010-01).

PubMed

Charehbili, A; van de Ven, S; Smit, V T H B M; Meershoek-Klein Kranenbarg, E; Hamdy, N A T; Putter, H; Heijns, J B; van Warmerdam, L J C; Kessels, L; Dercksen, M; Pepels, M J; Maartense, E; van Laarhoven, H W M; Vriens, B; Wasser, M N; van Leeuwen-Stok, A E; Liefers, G J; van de Velde, C J H; Nortier, J W R; Kroep, J R

2014-05-01

The role of zoledronic acid (ZA) when added to the neoadjuvant treatment of breast cancer (BC) in enhancing the clinical and pathological response of tumors is unclear. The effect of ZA on the antitumor effect of neoadjuvant chemotherapy has not prospectively been studied before. NEOZOTAC is a national, multicenter, randomized study comparing the efficacy of TAC (docetaxel, adriamycin and cyclophosphamide i.v.) followed by granulocyte colony-stimulating factor on day 2 with or without ZA 4 mg i.v. q 3 weeks inpatients withstage II/III, HER2-negative BC. We present data on the pathological complete response (pCR in breast and axilla), on clinical response using MRI, and toxicity. Post hoc subgroup analyses were undertaken to address the predictive value of menopausal status. Addition of ZA to chemotherapy did not improve pCR rates (13.2% for TAC+ZA versus 13.3% for TAC). Postmenopausal women (N = 96) had a numerical benefit from ZA treatment (pCR 14.0% for TAC+ZA versus 8.7% for TAC, P = 0.42). Clinical objective response did not differ between treatment arms (72.9% versus 73.7%). There was no difference in grade III/IV toxicity between treatment arms. Addition of ZA to neoadjuvant chemotherapy did not improve pathological or clinical response to chemotherapy. Further investigations are warranted in postmenopausal women with BC, since this subgroup might benefit from ZA treatment.

Neurocircuit function in eating disorders.

PubMed

Friederich, Hans-Christoph; Wu, Mudan; Simon, Joe J; Herzog, Wolfgang

2013-07-01

Eating disorders are serious psychosomatic disorders with high morbidity and lifetime mortality. Inadequate response to current therapeutic interventions constitutes a challenging clinical problem. A better understanding of the underlying neurobiological mechanisms could improve psychotherapeutic and drug treatment strategies. A review highlighting the current state of brain imaging in eating disorders related to the anxiety and pathological fear learning model of anorexia nervosa (AN) and the impulsivity model of binge eating in bulimia nervosa (BN). Available neuroimaging studies in patients with acute AN primarily suggest a hyper-responsive emotional and fear network to food, but not necessarily to eating disorder-unrelated, salient stimuli. Furthermore, patients with AN show decreased activation in the ventral fronto-striatal circuits during the performance of a cognitive flexibility task. Results in patients with BN primarily suggest a hypo-responsive reward system to food stimuli, especially to taste reward. Additionally, patients with BN exhibit impaired brain activation in the inhibitory control network during the performance of general response-inhibition tasks. Anxiety and pathological fear learning may lead to conditioned neural stimulus-response patterns to food stimuli and increased cognitive rigidity, which could account for the phobic avoidance of food intake in patients with acute AN. However, further neurobiological studies are required to investigate pathological fear learning in patients with AN. Patients with BN may binge eat to compensate for a hypo-responsive reward system. The impaired brain activation in the inhibitory control network may facilitate the loss of control over food intake in patients with BN. Copyright © 2013 Wiley Periodicals, Inc.

Induction of CNS α-synuclein pathology by fibrillar and non-amyloidogenic recombinant α-synuclein

PubMed Central

2013-01-01

Background α-Synuclein (αS) is the major component of several types of brain inclusions including Lewy bodies, a hallmark of Parkinson’s disease. Aberrant aggregation of αS also is associated with cellular demise in multiple neurologic disorders collectively referred to as synucleinopathies. Recent studies demonstrate the induction of αS pathology by a single intracerebral injection of exogenous amyloidogenic αS in adult non-transgenic and transgenic mice expressing human αS. To further investigate the mechanism of pathology induction and evaluate an experimental paradigm with potential for higher throughput, we performed similar studies in neonatal mice injected with αS. Results In non-transgenic mice, we observed limited induction of neuronal αS inclusions predominantly 8 months after brain injection of aggregated, amyloidogenic human αS. More robust inclusion pathology was induced in transgenic mice expressing wild-type human αS (line M20), and inclusion pathology was observed at earlier time points. Injection of a non-amyloidogenic (Δ71-82) deletion protein of αS was also able to induce similar pathology in a subset of M20 transgenic mice. M20 transgenic mice injected with amyloidogenic or non-amyloidogenic αS demonstrated a delayed and robust induction of brain neuroinflammation that occurs in mice with or without αS pathological inclusions implicating this mechanism in aggregate formation. Conclusions The finding that a non-amyloidogenic Δ71-82 αS can induce pathology calls into question the simple interpretation that exogenous αS catalyzes aggregation and spread of intracellular αS pathology solely through a nucleation dependent conformational templating mechanism. These results indicate that several mechanisms may act synergistically or independently to promote the spread of αS pathology. PMID:24252149

Factors leading to overutilisation of hospital pathology testing: the junior doctor.

PubMed

Ericksson, William; Bothe, Janine; Cheung, Heidi; Zhang, Kate; Kelly, Simone

2017-05-25

Objective Pathology overutilisation is a significant issue affecting the quality and cost of health care. Because junior medical officers (JMOs) order most pathology tests in the hospital setting, the aim of the present study was to identify the main reasons for hospital pathology overutilisation from the perspective of the JMO. Methods A qualitative method, using focus group methodology, was undertaken. Sixteen JMOs from two hospitals participated in three focus groups. Data were analysed using thematic analysis. Results Three major themes contributed to overutilisation: the real and perceived expectations of senior colleagues, the level of JMO clinical experience and strategies to manage JMO workload around clinical systems. Within these themes, 12 subthemes were identified. Conclusions Overutilisation of hospital pathology testing occurs when there are high social costs to JMOs for underordering, with little cost for overordering. Interventions should restore this balance through reframing overutilisation as both a costly and potentially harmful activity, promoting a supportive culture with regular senior guidance, and addressing clinical systems in which missed tests create an excessive workload. What is known about the topic? Mean overutilisation rates of pathology testing are reported to be as high as 44%. Although numerous studies have reported successful efforts to decrease hospital pathology overutilisation, no primary research was identified that examined the JMO perspective on this subject. What does this paper add? Clinical need is not the primary factor guiding the pathology-ordering decisions of junior practitioners; rather, medical team culture, limited JMO experience and systems factors have a significant role. What are the implications for practitioners? The social and behavioural determinants of pathology ordering must be considered to achieve appropriate pathology test utilisation. These include senior medical officer engagement, the guidance of JMOs and clinical workflows.

A New Classification for Pathologies of Spinal Meninges, Part 1: Dural Cysts, Dissections, and Ectasias.

PubMed

Klekamp, Jörg

2017-07-01

The clinical significance of pathologies of the spinal dura is often unclear and their management controversial. To classify spinal dural pathologies analogous to vascular aneurysms, present their symptoms and surgical results. Among 1519 patients with spinal space-occupying lesions, 66 patients demonstrated dural pathologies. Neuroradiological and surgical features were reviewed and clinical data analyzed. Saccular dural diverticula (type I, n = 28) caused by defects of both dural layers, dissections between dural layers (type II, n = 29) due to defects of the inner layer, and dural ectasias (type III, n = 9) related to structural changes of the dura were distinguished. For all types, symptoms consisted of local pain followed by signs of radiculopathy or myelopathy, while one patient with dural ectasia presented a low-pressure syndrome and 10 patients with dural dissections additional spinal cord herniation. Type I and type II pathologies required occlusion of their dural defects via extradural (type I) or intradural (type II) approaches. For type III pathologies of the dural sac no surgery was recommended. Favorable results were obtained in all 14 patients with type I and 13 of 15 patients with type II pathologies undergoing surgery. The majority of dural pathologies involving root sleeves remain asymptomatic, while those of the dural sac commonly lead to pain and neurological symptoms. Type I and type II pathologies were treated with good long-term results occluding their dural defects, while ectasias of the dural sac (type III) were managed conservatively. Copyright © 2017 by the Congress of Neurological Surgeons