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Sample records for additional clinically relevant

  1. ADDITIONAL DEMOGRAPHIC AND CLINICAL EVIDENCES ON THE RELEVANCE OF THE SYSTEMIC THERAPY IN ALCOHOL DEPENDENCE.

    PubMed

    Alexinschi, Ovidiu; Chirita, Roxana; Manuela, Padurariu; Ciobica, Alin; Dobrin, Romeo; Petrariu, F D; Timofte, Daniel; Chirita, Vasile

    2015-01-01

    The modern treatment for alcohol dependence is still problematic, in many cases with the costs exceeding benefits. In these conditions a new management approach was developed lately, known as the systemic therapy. In this way, the crystallization and practical transposition of this new treatment approach is represented by the Clubs of Alcoholics in Treatment. These clubs are in fact a form of psycho-social intervention consisting of multi-family communities in order to maintain long-term abstinence from alcohol and to change their lifestyle and behavior. Thus, in the present paper we were interested in understanding the demographics of this systemic theory and how these aspects are influencing the final results of the therapy, as well as studying/confirming how relevant is this systemic approach on the management of alcohol dependence. Our results presented in this report bring additional evidences for the superiority of the systemic, multi-family approach of alcohol-related problems, as complemented to the standard medicinal therapy. Moreover, the data collected from patients in this study might suggest that patients with a higher educational level and therefore better capacity of understanding the information, with family support, and also with a better occupational insertion, have accepted to follow The Clubs of Alcoholics in Treatment program, with a subsequently better evolution. PMID:26793858

  2. Valerian: No Evidence for Clinically Relevant Interactions

    PubMed Central

    Nieber, Karen; Kraft, Karin

    2014-01-01

    In recent popular publications as well as in widely used information websites directed to cancer patients, valerian is claimed to have a potential of adverse interactions with anticancer drugs. This questions its use as a safe replacement for, for example, benzodiazepines. A review on the interaction potential of preparations from valerian root (Valeriana officinalis L. root) was therefore conducted. A data base search and search in a clinical drug interaction data base were conducted. Thereafter, a systematic assessment of publications was performed. Seven in vitro studies on six CYP 450 isoenzymes, on p-glycoprotein, and on two UGT isoenzymes were identified. However, the methodological assessment of these studies did not support their suitability for the prediction of clinically relevant interactions. In addition, clinical studies on various valerian preparations did not reveal any relevant interaction potential concerning CYP 1A2, 2D6, 2E1, and 3A4. Available animal and human pharmacodynamic studies did not verify any interaction potential. The interaction potential of valerian preparations therefore seems to be low and thereby without clinical relevance. We conclude that there is no specific evidence questioning their safety, also in cancer patients. PMID:25093031

  3. Valerian: no evidence for clinically relevant interactions.

    PubMed

    Kelber, Olaf; Nieber, Karen; Kraft, Karin

    2014-01-01

    In recent popular publications as well as in widely used information websites directed to cancer patients, valerian is claimed to have a potential of adverse interactions with anticancer drugs. This questions its use as a safe replacement for, for example, benzodiazepines. A review on the interaction potential of preparations from valerian root (Valeriana officinalis L. root) was therefore conducted. A data base search and search in a clinical drug interaction data base were conducted. Thereafter, a systematic assessment of publications was performed. Seven in vitro studies on six CYP 450 isoenzymes, on p-glycoprotein, and on two UGT isoenzymes were identified. However, the methodological assessment of these studies did not support their suitability for the prediction of clinically relevant interactions. In addition, clinical studies on various valerian preparations did not reveal any relevant interaction potential concerning CYP 1A2, 2D6, 2E1, and 3A4. Available animal and human pharmacodynamic studies did not verify any interaction potential. The interaction potential of valerian preparations therefore seems to be low and thereby without clinical relevance. We conclude that there is no specific evidence questioning their safety, also in cancer patients. PMID:25093031

  4. Clinical effects of sulphite additives.

    PubMed

    Vally, H; Misso, N L A; Madan, V

    2009-11-01

    Sulphites are widely used as preservative and antioxidant additives in the food and pharmaceutical industries. Topical, oral or parenteral exposure to sulphites has been reported to induce a range of adverse clinical effects in sensitive individuals, ranging from dermatitis, urticaria, flushing, hypotension, abdominal pain and diarrhoea to life-threatening anaphylactic and asthmatic reactions. Exposure to the sulphites arises mainly from the consumption of foods and drinks that contain these additives; however, exposure may also occur through the use of pharmaceutical products, as well as in occupational settings. While contact sensitivity to sulphite additives in topical medications is increasingly being recognized, skin reactions also occur after ingestion of or parenteral exposure to sulphites. Most studies report a 3-10% prevalence of sulphite sensitivity among asthmatic subjects following ingestion of these additives. However, the severity of these reactions varies, and steroid-dependent asthmatics, those with marked airway hyperresponsiveness, and children with chronic asthma, appear to be at greater risk. In addition to episodic and acute symptoms, sulphites may also contribute to chronic skin and respiratory symptoms. To date, the mechanisms underlying sulphite sensitivity remain unclear, although a number of potential mechanisms have been proposed. Physicians should be aware of the range of clinical manifestations of sulphite sensitivity, as well as the potential sources of exposure. Minor modifications to diet or behaviour lead to excellent clinical outcomes for sulphite-sensitive individuals.

  5. [Clinical relevance of cardiopulmonary reflexes in anesthesiology].

    PubMed

    Guerri-Guttenberg, R A; Siaba-Serrate, F; Cacheiro, F J

    2013-10-01

    The baroreflex, chemoreflex, pulmonary reflexes, Bezold-Jarisch and Bainbridge reflexes and their interaction with local mechanisms, are a demonstration of the richness of cardiovascular responses that occur in human beings. As well as these, the anesthesiologist must contend with other variables that interact by attenuating or accentuating cardiopulmonary reflexes such as, anesthetic drugs, surgical manipulation, and patient positioning. In the present article we review these reflexes and their clinical relevance in anesthesiology.

  6. [The relevance of clinical risk management].

    PubMed

    Gulino, Matteo; Vergallo, Gianluca Montanari; Frati, Paola

    2011-01-01

    Medical activity includes a risk of possible injury or complications for the patients, that should drive the Health Care Institutions to introduce and/ or improve clinical Risk management instruments. Although Italy is still lacking a National project of Clinical Risk Management, a number of efforts have been made by different Italian Regions to introduce instruments of risk management. In addition, most of National Health Care Institutions include actually a Department specifically in charge to manage the clinical risk. Despite the practical difficulties, the results obtained until now suggest that the risk management may represent a useful instrument to contribute to the reduction of errors in clinical conduct. Indeed, the introduction of adequate instruments of prevention and management of clinical risk may help to ameliorate the quality of health care Institution services.

  7. Women with epilepsy: clinically relevant issues.

    PubMed

    Bangar, S; Shastri, Abhishek; El-Sayeh, Hany; Cavanna, Andrea E

    2016-01-01

    Women with epilepsy (WWE) face specific challenges throughout their lifespan due to the effects of seizures and antiepileptic drugs on hormonal function, potentially affecting both sexual and reproductive health. This review article addresses the most common issues of practical relevance to clinicians treating WWE: epidemiology and clinical presentations (including catamenial epilepsy), contraception, reproductive and sexual dysfunction, pregnancy, lactation, menopause-related issues (including bone health), and mental health aspects. Awareness of these gender-specific issues and implementation/adaptation of effective interventions for WWE results in significantly improved health-related quality of life in this patient population. PMID:27678205

  8. Mirror neurons and their clinical relevance.

    PubMed

    Rizzolatti, Giacomo; Fabbri-Destro, Maddalena; Cattaneo, Luigi

    2009-01-01

    One of the most exciting events in neurosciences over the past few years has been the discovery of a mechanism that unifies action perception and action execution. The essence of this 'mirror' mechanism is as follows: whenever individuals observe an action being done by someone else, a set of neurons that code for that action is activated in the observers' motor system. Since the observers are aware of the outcome of their motor acts, they also understand what the other individual is doing without the need for intermediate cognitive mediation. In this Review, after discussing the most pertinent data concerning the mirror mechanism, we examine the clinical relevance of this mechanism. We first discuss the relationship between mirror mechanism impairment and some core symptoms of autism. We then outline the theoretical principles of neurorehabilitation strategies based on the mirror mechanism. We conclude by examining the relationship between the mirror mechanism and some features of the environmental dependency syndromes.

  9. Clinical Relevance of Biomarkers of Oxidative Stress

    PubMed Central

    Frijhoff, Jeroen; Winyard, Paul G.; Zarkovic, Neven; Davies, Sean S.; Stocker, Roland; Cheng, David; Knight, Annie R.; Taylor, Emma Louise; Oettrich, Jeannette; Ruskovska, Tatjana; Gasparovic, Ana Cipak; Cuadrado, Antonio; Weber, Daniela; Poulsen, Henrik Enghusen; Grune, Tilman; Schmidt, Harald H.H.W.

    2015-01-01

    Abstract Significance: Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. Critical Issues: The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clinical use. Future Directions: Several markers of oxidative stress still represent a viable biomarker opportunity for clinical use. However, positive findings with currently used biomarkers still need to be validated in larger sample sizes and compared with current clinical standards to establish them as clinical diagnostics. It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others. The vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker. Antioxid. Redox Signal. 23, 1144–1170. PMID:26415143

  10. [Genomic diagnosis of thrombophilia in women: clinical relevance].

    PubMed

    Luxembourg, B; Lindhoff-Last, E

    2007-02-01

    The detection of the DNA-sequence of human coagulation factors and inhibitors has introduced the possibility of differentiated mutation analysis in patients with venous thrombosis. Since venous thromboembolism is a multifactorial disease, women are at an increased risk to develop venous thrombosis due to hormonal contraception, during pregnancy and the puerperium. In addition, pregnancy complications like early or late fetal loss, pregnancy-induced hypertensive disorders and very recently recurrent embryo implantation failure have been suspected to be associated with thrombophilia. Therefore, it is of major importance to define inherited thrombophilic disorders, in which genetic diagnosis is of clinical relevance. While most of the genetic defects described so far represent a risk factor for venous thrombosis, only a minority of these defects actually needs DNA analysis to be detected: mutation analysis is clinically relevant, when factor V Leiden mutation is suspected, because relative risks concerning venous thrombosis as well as pregnancy complications clearly differ between homozygote and heterozygote forms of this frequently observed mutation. Similarly detection of the prothrombin mutation G20210A is of clinical relevance, although data for the very rarely observed homozygote variant are not sufficiently available. In contrast, detection of the homozygote variant of the MTHFR-mutation C677T is not useful, since clinical relevance could not be proven in a majority of studies concerning women specific risk situations. Inherited deficiencies of antithrombin, protein C and protein S are rare with high rates of different mutations. Genetic analysis seems only useful in patients with wide intraindividual variations of coagulation inhibitor activities. Genetic analysis concerning the PAI-1 4G/5G polymorphism or the factor XIII Val34Leu polymorphism can not be recommended in women specific risk situations because of insufficient data. PMID:17279273

  11. Race and hypertension. What is clinically relevant?

    PubMed

    Rutledge, D R

    1994-06-01

    Hypertension, once considered rare in Africa, occurs frequently in most Black populations outside of the continent as well as within more urban areas of Africa. The frequency of hypertension in Black citizens of the US is among the highest in the world. Pathophysiological mechanisms suggest the frequency of salt-sensitive blood pressure is more common in Black patients. More Black than White patients initially present with volume expansion. However, in Black patients there appears to be no significant relationship between plasma renin activity, plasma volume and blood pressure. The syndrome of insulin resistance has also been reported in African Americans. Future studies should address this issue, both because it relates to identifying individuals at risk for development of high blood pressure and because it has implications for initial selection of antihypertensive therapy. Hypertensive kidney disease is prevalent in Black people. Lowering the blood pressure with diuretic-based therapies has not been shown to delay or prevent the loss of kidney function in patients with this condition, suggesting that this treatment approach may not be optimal. Lifestyle modifications remain the initial therapeutic regimen. Because diuretics and beta-blockers have been shown to reduce cardiovascular morbidity and mortality in controlled clinical trials, they are preferred therapies. The Hypertension Detection and Follow-up Program showed significant reductions in morbidity and mortality in Black patients using primarily diuretic-based therapies. However, controversy persists regarding use of diuretics since some investigators believe that greater reductions in overall cardiovascular risk may be achieved in Black patients using other agents. These agents may eventually be able to exert a beneficial cardiovascular effect in addition to and independent of their blood pressure-lowering effect. Long term data documenting reduced morbidity and mortality rates with other agents are

  12. DENDRITIC CELLS: ARE THEY CLINICALLY RELEVANT?

    PubMed Central

    Palucka, Karolina; Ueno, Hideki; Roberts, Lee; Fay, Joseph; Banchereau, Jacques

    2010-01-01

    Cancer vaccines have undergone a renaissance due to recent clinical trials showing promising immunological data and some clinical benefit to patients. Current trials exploiting dendritic cells (DCs) as vaccines have shown durable tumor regressions in a fraction of patients. Clinical efficacy of current vaccines is hampered by myeloid-derived suppressor cells, inflammatory type 2 T cells and regulatory T cells (Tregs), all of which prevent the generation of effector cells. To improve the clinical efficacy of DC vaccines, we need to design novel and improved strategies that can boost adaptive immunity to cancer, help overcome Tregs and allow the breakdown of the immunosuppressive tumor microenvironment. This can be achieved by exploiting the fast increasing knowledge about the DC system, including the existence of distinct DC subsets. Critical to the design of better vaccines is the concept of distinct DC subsets and distinct DC activation pathways, all contributing to the generation of unique adaptive immune responses. Such novel DC vaccines will be used as monotherapy in patients with resected disease and in combination with antibodies and/or drugs targeting suppressor pathways and modulation of the tumor environment in patients with metastatic disease. PMID:20693842

  13. Engineering clinically relevant volumes of vascularized bone.

    PubMed

    Roux, Brianna M; Cheng, Ming-Huei; Brey, Eric M

    2015-05-01

    Vascularization remains one of the most important challenges that must be overcome for tissue engineering to be consistently implemented for reconstruction of large volume bone defects. An extensive vascular network is needed for transport of nutrients, waste and progenitor cells required for remodelling and repair. A variety of tissue engineering strategies have been investigated in an attempt to vascularize tissues, including those applying cells, soluble factor delivery strategies, novel design and optimization of bio-active materials, vascular assembly pre-implantation and surgical techniques. However, many of these strategies face substantial barriers that must be overcome prior to their ultimate translation into clinical application. In this review recent progress in engineering vascularized bone will be presented with an emphasis on clinical feasibility.

  14. Engineering clinically relevant volumes of vascularized bone

    PubMed Central

    Roux, Brianna M; Cheng, Ming-Huei; Brey, Eric M

    2015-01-01

    Vascularization remains one of the most important challenges that must be overcome for tissue engineering to be consistently implemented for reconstruction of large volume bone defects. An extensive vascular network is needed for transport of nutrients, waste and progenitor cells required for remodelling and repair. A variety of tissue engineering strategies have been investigated in an attempt to vascularize tissues, including those applying cells, soluble factor delivery strategies, novel design and optimization of bio-active materials, vascular assembly pre-implantation and surgical techniques. However, many of these strategies face substantial barriers that must be overcome prior to their ultimate translation into clinical application. In this review recent progress in engineering vascularized bone will be presented with an emphasis on clinical feasibility. PMID:25877690

  15. Clinical relevance of fascial tissue and dysfunctions.

    PubMed

    Klingler, W; Velders, M; Hoppe, K; Pedro, M; Schleip, R

    2014-01-01

    Fascia is composed of collagenous connective tissue surrounding and interpenetrating skeletal muscle, joints, organs, nerves, and vascular beds. Fascial tissue forms a whole-body, continuous three-dimensional viscoelastic matrix of structural support. The classical concept of its mere passive role in force transmission has recently been disproven. Fascial tissue contains contractile elements enabling a modulating role in force generation and also mechanosensory fine-tuning. This hypothesis is supported by in vitro studies demonstrating an autonomous contraction of human lumbar fascia and a pharmacological induction of temporary contraction in rat fascial tissue. The ability of spontaneous regulation of fascial stiffness over a time period ranging from minutes to hours contributes more actively to musculoskeletal dynamics. Imbalance of this regulatory mechanism results in increased or decreased myofascial tonus, or diminished neuromuscular coordination, which are key contributors to the pathomechanisms of several musculoskeletal pathologies and pain syndromes. Here, we summarize anatomical and biomechanical properties of fascial tissue with a special focus on fascial dysfunctions and resulting clinical manifestations. Finally, we discuss current and future potential treatment options that can influence clinical manifestations of pain syndromes associated with fascial tissues.

  16. Clinically relevant subgroups in COPD and asthma.

    PubMed

    Turner, Alice M; Tamasi, Lilla; Schleich, Florence; Hoxha, Mehmet; Horvath, Ildiko; Louis, Renaud; Barnes, Neil

    2015-06-01

    As knowledge of airways disease has grown, it has become apparent that neither chronic obstructive pulmonary disease (COPD) nor asthma is a simple, easily defined disease. In the past, treatment options for both diseases were limited; thus, there was less need to define subgroups. As treatment options have grown, so has our need to predict who will respond to new drugs. To date, identifying subgroups has been largely reported by detailed clinical characterisation or differences in pathobiology. These subgroups are commonly called "phenotypes"; however, the problem of defining what constitutes a phenotype, whether this should include comorbid diseases and how to handle changes over time has led to the term being used loosely. In this review, we describe subgroups of COPD and asthma patients whose clinical characteristics we believe have therapeutic or major prognostic implications specific to the lung, and whether these subgroups are constant over time. Finally, we will discuss whether the subgroups we describe are common to both asthma and COPD, and give some examples of how treatment might be tailored in patients where the subgroup is clear, but the label of asthma or COPD is not. PMID:26028640

  17. Biofilms: Survival Mechanisms of Clinically Relevant Microorganisms

    PubMed Central

    Donlan, Rodney M.; Costerton, J. William

    2002-01-01

    Though biofilms were first described by Antonie van Leeuwenhoek, the theory describing the biofilm process was not developed until 1978. We now understand that biofilms are universal, occurring in aquatic and industrial water systems as well as a large number of environments and medical devices relevant for public health. Using tools such as the scanning electron microscope and, more recently, the confocal laser scanning microscope, biofilm researchers now understand that biofilms are not unstructured, homogeneous deposits of cells and accumulated slime, but complex communities of surface-associated cells enclosed in a polymer matrix containing open water channels. Further studies have shown that the biofilm phenotype can be described in terms of the genes expressed by biofilm-associated cells. Microorganisms growing in a biofilm are highly resistant to antimicrobial agents by one or more mechanisms. Biofilm-associated microorganisms have been shown to be associated with several human diseases, such as native valve endocarditis and cystic fibrosis, and to colonize a wide variety of medical devices. Though epidemiologic evidence points to biofilms as a source of several infectious diseases, the exact mechanisms by which biofilm-associated microorganisms elicit disease are poorly understood. Detachment of cells or cell aggregates, production of endotoxin, increased resistance to the host immune system, and provision of a niche for the generation of resistant organisms are all biofilm processes which could initiate the disease process. Effective strategies to prevent or control biofilms on medical devices must take into consideration the unique and tenacious nature of biofilms. Current intervention strategies are designed to prevent initial device colonization, minimize microbial cell attachment to the device, penetrate the biofilm matrix and kill the associated cells, or remove the device from the patient. In the future, treatments may be based on inhibition of genes

  18. The clinical relevance of autoantibodies in scleroderma.

    PubMed

    Ho, Khanh T; Reveille, John D

    2003-01-01

    Scleroderma (systemic sclerosis) is associated with several autoantibodies, each of which is useful in the diagnosis of affected patients and in determining their prognosis. Anti-centromere antibodies (ACA) and anti-Scl-70 antibodies are very useful in distinguishing patients with systemic sclerosis (SSc) from healthy controls, from patients with other connective tissue disease, and from unaffected family members. Whereas ACA often predict a limited skin involvement and the absence of pulmonary involvement, the presence of anti-Scl-70 antibodies increases the risk for diffuse skin involvement and scleroderma lung disease. Anti-fibrillarin autoantibodies (which share significant serologic overlap with anti-U3-ribonucleoprotein antibodies) and anti-RNA-polymerase autoantibodies occur less frequently and are also predictive of diffuse skin involvement and systemic disease. Anti-Th/To and PM-Scl, in contrast, are associated with limited skin disease, but anti-Th/To might be a marker for the development of pulmonary hypertension. Other autoantibodies against extractable nuclear antigens have less specificity for SSc, including anti-Ro, which is a risk factor for sicca symptoms in patients with SSc, and anti-U1-ribonucleoprotein, which in high titer is seen in patients with SSc/systemic lupus erythematosus/polymyositis overlap syndromes. Limited reports of other autoantibodies (anti-Ku, antiphospholipid) have not established them as being clinically useful in following patients with SSc.

  19. Pharmacogenetic analysis of clinically relevant genetic polymorphisms.

    PubMed

    McLeod, Howard L

    2005-11-15

    The ascertainment of the human genome sequence has generated great enthusiasm for the use of gene-based approaches to improve virtually all aspects of medical care. Particular interest has focused on the field of pharmacogenetics--for example, the use of an individual's genetic profile to optimize drug prescription. This approach takes advantage of the presence of single-nucleotide polymorphisms (SNPs) or other genetic variants in every gene in the human genome. There are currently > 9 million SNPs in the human SNP database dbSNP, with an estimated 11 million variants ultimately to be found in the human population. To date, the preponderance of interest in this field has centered on the potential of applying this approach to subacute or chronic illnesses, such as cancer, cardiovascular disease, human immunodeficiency virus infection, or rheumatologic disorders. In contrast, little attention has been devoted to the potential utility of implementing the pharmacogenomic methodology for guiding drug selection for acutely ill patients in the critical care environment. Although such an approach has theoretical appeal as a means of enhancing quality and improving outcomes in this setting, several obstacles currently exist and slow the progress toward clinical application. PMID:16237646

  20. Allergy to peanut oil--clinically relevant?

    PubMed

    Ring, J; Möhrenschlager, M

    2007-04-01

    The increasing prevalence of food allergies (especially allergy to peanuts) has led to a discussion of how safe topical preparations containing peanut oil are with respect to allergy. The major allergens from peanuts are proteins that have been characterized at a molecular level and cloned. Clinical signs of peanut allergy symptoms can be observed on the skin (urticaria), or in the gastrointestinal and/or respiratory tract culminating in cardiovascular symptoms and anaphylactic reactions. In most cases, symptoms are elicited by oral uptake; rarely, a contact urticaria has been described. In vegetable oils, the contents of protein differ depending on the production process: crude oils contain approximately 100 times more proteins than refined oils. This has clear-cut implications for allergic individuals. Quantitative data are available regarding elicitation of symptoms in allergic individuals with a threshold dose of 0.1-1 mg peanut allergen in oral provocation tests. There are anecdotal reports of adverse reactions after topical use of peanut oils. In one epidemiological trial, an association between topical use of skin care products containing peanut oil and the development of peanut allergy was observed; however, the data reflect a retrospective analysis without specifying skin care products containing peanut oil and also without analysing the quantity of topicals used. In contrast, oral tolerance was prevented and allergic sensitization was enhanced in a mouse model using high concentrations of peanut protein. So far, no reliable data are available regarding doses required to induce sensitization against peanut allergen via the epidermal route. A possible induction of sensitization against peanut proteins through contact with the skin via skin care products and the respective protein concentrations is a matter of speculation. Patients with atopic diseases, namely eczema, need appropriate skin care because of the disturbed skin barrier function. The benefit of

  1. The clinically relevant pharmacogenomic changes in acute myelogenous leukemia.

    PubMed

    Emadi, Ashkan; Karp, Judith E

    2012-08-01

    Acute myelogenous leukemia (AML) is an extremely heterogeneous neoplasm with several clinical, pathological, genetic and molecular subtypes. Combinations of various doses and schedules of cytarabine and different anthracyclines have been the mainstay of treatment for all forms of AMLs in adult patients. Although this combination, with the addition of an occasional third agent, remains effective for treatment of some young-adult patients with de novo AML, the prognosis of AML secondary to myelodysplastic syndromes or myeloproliferative neoplasms, treatment-related AML, relapsed or refractory AML, and AML that occurs in older populations remains grim. Taken into account the heterogeneity of AML, one size does not and should not be tried to fit all. In this article, the authors review currently understood, applicable and relevant findings related to cytarabine and anthracycline drug-metabolizing enzymes and drug transporters in adult patients with AML. To provide a prime-time example of clinical applicability of pharmacogenomics in distinguishing a subset of patients with AML who might be better responders to farnesyltransferase inhibitors, the authors also reviewed findings related to a two-gene transcript signature consisting of high RASGRP1 and low APTX, the ratio of which appears to positively predict clinical response in AML patients treated with farnesyltransferase inhibitors.

  2. Relevance of molecular medicine to clinical obstetrics and gynecology.

    PubMed

    Cohen, D P; Layman, L C

    1997-01-01

    Understanding molecular biology can improve the clinical acumen of the practicing obstetrician/gynecologist. An area of basic research now becoming clinically relevant involves the G proteins and G protein-coupled receptors. Clinicians already manipulate G protein-coupled receptors in their daily practice. Examples include the administration of oxytocin (oxytocin receptors), beta-2 tocolytic agents (beta 2-adrenergic receptors), GnRH agonists (GnRH receptors), exogenous gonadotropins (FSH and LH receptors), and bromocriptine (dopamine receptor). Clinically important disorders presenting to the obstetrician/gynecologist include some forms of precocious puberty, delayed puberty, premature ovarian failure, and pituitary adenomas which are due to mutations of G proteins and G protein-coupled receptors. The importance of these proteins is demonstrated by the fact that G protein-related genes comprise about 1 percent of the human genome. Additionally, the knowledge that some G protein gene mutations are present in the germ line, and others are somatic cell in origin (and not heritable), aids in more accurate genetic counseling to patients.

  3. [Relevancy of the clinical subjects in medical training].

    PubMed

    de Juan, J; Mateo Martínez, M; Cuenca, N; Fernández Jover, E; García Barbero, M

    1989-09-01

    A judgment of the relevance of twelve clinical science courses for preparing the students to the practice of medicine and to the development of the scientific mind, was tested by the Pair Comparison and Equal-Appearing Interval methods. The test groups consisted of medical school faculty members, medical students and physicians. Three groups of clinical sciences, according its relevancy for preparing the students for a career as physicians, were identified Internal Medicine, Pediatrics, Surgery and Public Health, comprised the group of maximum relevancy; History of Medicine, Medicolegal and Radiological studies, formed a group of lowest relevancy. The remainder sciences (Ophthalmology, Obstetrics and Gynecology, Otorhinolaryngology, Dermatology and Psychiatry, formed a middle group. Few differences were found when we considered the relevancy to the development of the scientific mind.

  4. Clinically relevant pharmacokinetic herb-drug interactions in antiretroviral therapy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    For healthcare professionals, the volume of literature available on herb-drug interactions often makes it difficult to separate experimental/potential interactions from those deemed clinically relevant. There is a need for concise and conclusive information to guide pharmacotherapy in HIV/AIDS. In t...

  5. Clinical writing: additional ethical and practical issues.

    PubMed

    Woodhouse, Susan S

    2012-03-01

    The recommendations by Sieck (2011, Obtaining clinical writing informed consent versus using client disguise and recommendations for practice, Psychotherapy, 49, pp. 3-11.) are a helpful starting point for considering the ethical issues involved in the decision to seek or not to seek informed consent from clients before writing about them. Sieck makes a compelling case for the idea that there are circumstances in which the most ethical choice would be to engage in clinical writing about a client without seeking informed consent, but instead disguising the client's identity. The present response raises a number of questions not considered in the article by Sieck. First, how should one disguise a case? Moreover, how should one assess whether the disguise is sufficient to preserve confidentiality while not distorting the clinical material to the point that the material is no longer useful to the field? Second, how can we estimate the likelihood of clients reading clinical writing, particularly in the age of the Internet? Given that psychologist-authored blogs that include reference to clinical material are beginning to emerge, it is crucial that we engage in a much deeper dialogue about the ethics of clinical writing. Third, how does the presentation of clinical material influence public perceptions of psychotherapy and confidentiality? If these public perceptions, in turn, could influence the likelihood of seeking psychotherapy, might these attitudes be important to consider in ethical thinking about clinical writing? Finally, where do we draw the line between clinical writing and single case study research (which requires informed consent)?

  6. Clinical writing: additional ethical and practical issues.

    PubMed

    Woodhouse, Susan S

    2012-03-01

    The recommendations by Sieck (2011, Obtaining clinical writing informed consent versus using client disguise and recommendations for practice, Psychotherapy, 49, pp. 3-11.) are a helpful starting point for considering the ethical issues involved in the decision to seek or not to seek informed consent from clients before writing about them. Sieck makes a compelling case for the idea that there are circumstances in which the most ethical choice would be to engage in clinical writing about a client without seeking informed consent, but instead disguising the client's identity. The present response raises a number of questions not considered in the article by Sieck. First, how should one disguise a case? Moreover, how should one assess whether the disguise is sufficient to preserve confidentiality while not distorting the clinical material to the point that the material is no longer useful to the field? Second, how can we estimate the likelihood of clients reading clinical writing, particularly in the age of the Internet? Given that psychologist-authored blogs that include reference to clinical material are beginning to emerge, it is crucial that we engage in a much deeper dialogue about the ethics of clinical writing. Third, how does the presentation of clinical material influence public perceptions of psychotherapy and confidentiality? If these public perceptions, in turn, could influence the likelihood of seeking psychotherapy, might these attitudes be important to consider in ethical thinking about clinical writing? Finally, where do we draw the line between clinical writing and single case study research (which requires informed consent)? PMID:22369079

  7. Walnut allergens: molecular characterization, detection and clinical relevance.

    PubMed

    Costa, J; Carrapatoso, I; Oliveira, M B P P; Mafra, I

    2014-03-01

    Food-induced allergies have been regarded as an emergent problem of public health. Classified as important allergenic ingredients, the presence of walnut and other nuts as hidden allergens in processed foods constitutes a risk for sensitized individuals, being a real problem of allergen management. Attending to the increasing importance dedicated to walnut allergy, this review intends to provide the relevant and up-to-date information on main issues such as the prevalence of walnut allergy, the clinical threshold levels, the molecular characterization of walnut allergens and their clinical relevance, as well as the methodologies for walnut allergen detection in foods. As the walnut used in human diet comes from Juglans regia and Juglans nigra, the molecular characterization of the allergens from both species included in the prolamins (Jug r 1, Jug n 1 and Jug r 3), cupins (Jug r 2, Jug n 2 and Jug r 4) and profilins (Jug r 5), together with respective clinical relevance, were compiled in this review. The most recent progresses on walnut allergen detection techniques (protein- and DNA-based) are described and critically compared, including the emergent multitarget approaches.

  8. Real time and label free profiling of clinically relevant exosomes.

    PubMed

    Sina, Abu Ali Ibn; Vaidyanathan, Ramanathan; Dey, Shuvashis; Carrascosa, Laura G; Shiddiky, Muhammad J A; Trau, Matt

    2016-01-01

    Tumor-derived exosomes possess significant clinical relevance due to their unique composition of genetic and protein material that is representative of the parent tumor. Specific isolation as well as identification of proportions of these clinically relevant exosomes (CREs) from biological samples could help to better understand their clinical significance as cancer biomarkers. Herein, we present a simple approach for quantification of the proportion of CREs within the bulk exosome population isolated from patient serum. This proportion of CREs can potentially inform on the disease stage and enable non-invasive monitoring of inter-individual variations in tumor-receptor expression levels. Our approach utilises a Surface Plasmon Resonance (SPR) platform to quantify the proportion of CREs in a two-step strategy that involves (i) initial isolation of bulk exosome population using tetraspanin biomarkers (i.e., CD9, CD63), and (ii) subsequent detection of CREs within the captured bulk exosomes using tumor-specific markers (e.g., human epidermal growth factor receptor 2 (HER2)). We demonstrate the isolation of bulk exosome population and detection of as low as 10% HER2(+) exosomes from samples containing designated proportions of HER2(+) BT474 and HER2(-) MDA-MB-231 cell derived exosomes. We also demonstrate the successful isolation of exosomes from a small cohort of breast cancer patient samples and identified that approximately 14-35% of their bulk population express HER2. PMID:27464736

  9. Real time and label free profiling of clinically relevant exosomes

    PubMed Central

    Sina, Abu Ali Ibn; Vaidyanathan, Ramanathan; Dey, Shuvashis; Carrascosa, Laura G.; Shiddiky, Muhammad J. A.; Trau, Matt

    2016-01-01

    Tumor-derived exosomes possess significant clinical relevance due to their unique composition of genetic and protein material that is representative of the parent tumor. Specific isolation as well as identification of proportions of these clinically relevant exosomes (CREs) from biological samples could help to better understand their clinical significance as cancer biomarkers. Herein, we present a simple approach for quantification of the proportion of CREs within the bulk exosome population isolated from patient serum. This proportion of CREs can potentially inform on the disease stage and enable non-invasive monitoring of inter-individual variations in tumor-receptor expression levels. Our approach utilises a Surface Plasmon Resonance (SPR) platform to quantify the proportion of CREs in a two-step strategy that involves (i) initial isolation of bulk exosome population using tetraspanin biomarkers (i.e., CD9, CD63), and (ii) subsequent detection of CREs within the captured bulk exosomes using tumor-specific markers (e.g., human epidermal growth factor receptor 2 (HER2)). We demonstrate the isolation of bulk exosome population and detection of as low as 10% HER2(+) exosomes from samples containing designated proportions of HER2(+) BT474 and HER2(−) MDA-MB-231 cell derived exosomes. We also demonstrate the successful isolation of exosomes from a small cohort of breast cancer patient samples and identified that approximately 14–35% of their bulk population express HER2. PMID:27464736

  10. Nonmotor Symptoms in Parkinson's Disease in 2012: Relevant Clinical Aspects

    PubMed Central

    Bonnet, Anne Marie; Jutras, Marie France; Czernecki, Virginie; Corvol, Jean Christophe; Vidailhet, Marie

    2012-01-01

    Nonmotor symptoms (NMSs) of Parkinson's disease (PD) are common, but they are often underrecognized in clinical practice, because of the lack of spontaneous complaints by the patients, and partly because of the absence of systematic questioning by the consulting physician. However, valid specific instruments for identification and assessment of these symptoms are available in 2012. The administration of the self-completed screening tool, NMSQuest, associated with questioning during the consultation, improves the diagnosis of NMSs. NMSs play a large role in degradation of quality of life. More relevant NMSs are described in this review, mood disorders, impulse control disorders, cognitive deficits, hallucinations, pain, sleep disorders, and dysautonomia. PMID:22888466

  11. Lifestyle interventions for type 2 diabetes. Relevance for clinical practice.

    PubMed Central

    Harris, Stewart B.; Petrella, Robert J.; Leadbetter, Wendy

    2003-01-01

    OBJECTIVE: To review evidence from literature on type 2 diabetes pertinent to physical activity and diet and lifestyle modification, and to determine the relevance of this evidence to clinical practice. QUALITY OF EVIDENCE: Direct (level I) evidence supports interventions for physical activity and diet modification for primary prevention and management of type 2 diabetes. Few studies examine the effectiveness of primary health care providers' making such interventions. MAIN MESSAGE: Family physicians have an important role in identifying people at risk of developing type 2 diabetes and managing those diagnosed with the disease, yet they struggle to deliver practice-based interventions that promote sustainable behaviour change among their patients. CONCLUSION: It is evident that supporting patients to make changes in their physical activity and dietary habits can prevent onset of type 2 diabetes. Translating this finding into effective recommendations for clinical practice requires further effort and evaluation. PMID:14708927

  12. [Cross reactivity of food allergens and its clinical relevance].

    PubMed

    Moneret-Vautrin, Denise Anne

    2005-10-01

    Cross-reactions between food allergens and other allergens are a major focus of interest. They include cross-allergies between Betulaceae and Compositae pollen, and also between fruits and vegetables (Prunoideae and Apiaceae). Cross-allergies between animal allergens include mites, cockroaches and crustaceans, milk and meat, animal epithelia, meat and egg. Cross-reactivity results from homology between protein sequences, and is highly likely when this homology reaches about 70%. Phylogenetically similar proteins occur in all species and are known as pan allergens. Profilins, Bet v1 homologues, and lipid transfer proteins have varying degrees of clinical relevance. The involvement of cross-reactivity in the persistence of sensitization and in allergic disorders is unclear. The consequences of cross-reactivity during specific immunotherapy with total allergenic extracts are random. Interpretation of biological tests of IgE binding is also biased by cross-reactivity. The use of panels of major recombinant allergens should help to identify specific sensitization profiles as well as clinically relevant sensitization. Cross-reactivity between epitopes of inhalants and of food allergens may perpetuate and intensify allergic disorders. The consequences of cross-reactivity between allergens and autologous proteins are unknown. PMID:16669147

  13. Development of Clinically Relevant Implantable Pressure Sensors: Perspectives and Challenges

    PubMed Central

    Clausen, Ingelin; Glott, Thomas

    2014-01-01

    This review describes different aspects to consider when developing implantable pressure sensor systems. Measurement of pressure is in general highly important in clinical practice and medical research. Due to the small size, light weight and low energy consumption Micro Electro Mechanical Systems (MEMS) technology represents new possibilities for monitoring of physiological parameters inside the human body. Development of clinical relevant sensors requires close collaboration between technological experts and medical clinicians. Site of operation, size restrictions, patient safety, and required measurement range and resolution, are only some conditions that must be taken into account. An implantable device has to operate under very hostile conditions. Long-term in vivo pressure measurements are particularly demanding because the pressure sensitive part of the sensor must be in direct or indirect physical contact with the medium for which we want to detect the pressure. New sensor packaging concepts are demanded and must be developed through combined effort between scientists in MEMS technology, material science, and biology. Before launching a new medical device on the market, clinical studies must be performed. Regulatory documents and international standards set the premises for how such studies shall be conducted and reported. PMID:25248071

  14. Cognitive control in alcohol use disorder: deficits and clinical relevance

    PubMed Central

    Wilcox, Claire E.; Dekonenko, Charlene J.; Mayer, Andrew R.; Bogenschutz, Michael P.; Turner, Jessica A.

    2014-01-01

    Cognitive control refers to the internal representation, maintenance, and updating of context information in the service of exerting control over thoughts and behavior. Deficits in cognitive control likely contribute to difficulty in maintaining abstinence in individuals with alcohol use disorders (AUD). In this article, we define three cognitive control processes in detail (response inhibition, distractor interference control, and working memory), review the tasks measuring performance in these areas, and summarize the brain networks involved in carrying out these processes. Next, we review evidence of deficits in these processes in AUD, including both metrics of task performance and functional neuroimaging. Finally, we explore the clinical relevance of these deficits by identifying predictors of clinical outcome and markers that appear to change (improve) with treatment. We observe that individuals with AUD experience deficits in some, but not all, metrics of cognitive control. Deficits in cognitive control may predict clinical outcome in AUD, but more work is necessary to replicate findings. It is likely that performance on tasks requiring cognitive control improves with abstinence, and with some psychosocial and medication treatments. Future work should clarify which aspects of cognitive control are most important to target during treatment of AUD. PMID:24361772

  15. The Current and Potential Clinical Relevance of Heart Failure Biomarkers.

    PubMed

    Gandhi, Parul U; Testani, Jeffrey M; Ahmad, Tariq

    2015-10-01

    Heart failure is a growing epidemic, and our understanding of the intricacies of its pathophysiology continues to evolve. Over the last decade, biomarkers of heart failure have been extensively investigated, particularly for diagnosis and risk stratification. While the natriuretic peptides remain the gold standard heart failure biomarker, they are plagued by their non-specific nature; furthermore, the strategy of natriuretic peptide-guided care remains elusive. Multiple candidate markers indicative of other physiologic aspects of heart failure have been identified and studied, including soluble ST2, galectin-3, and high-sensitivity cardiac troponins. Each of these biomarkers has the potential to provide unique therapeutically relevant information. Ultimately, a multi-marker approach may be applied to improve care of patients with heart failure. Definitive clinical trials and the use of advanced statistical analytic techniques are needed to truly determine the optimal strategy of biomarker-assisted diagnosis, prognostication, and management of patients who suffer from this devastating condition.

  16. Clinical relevance of advanced glycation endproducts for vascular surgery.

    PubMed

    Meerwaldt, R; van der Vaart, M G; van Dam, G M; Tio, R A; Hillebrands, J-L; Smit, A J; Zeebregts, C J

    2008-08-01

    Atherosclerosis is the main contributor to cardiovascular disease and leads to intimal plaque formation, which may progress to plaque rupture with subsequent thromboembolic events and/or occlusion of the arterial lumen. There is increasing evidence that the development or progression of atherosclerosis is associated with advanced glycation endproducts (AGEs). AGEs are a heterogeneous group of compounds formed by the non-enzymatic reaction of reducing sugars with proteins, lipids, and nucleic acids. An increased understanding of the mechanisms of formation and interaction of AGEs has allowed the development of several potential anti-AGE strategies. This review summarizes AGE formation and biochemistry, the pathogeneic role of AGEs in cardiovascular disease, anti-AGE therapies and clinical relevance to vascular surgery. PMID:18356091

  17. [Endpoints in clinical trials and their relevance for patients].

    PubMed

    Faber, Ulrike

    2010-01-01

    Patient participation, which has been established since 2004, has brought more attention to patients' concerns in healthcare. More and more endpoints in clinical trials are defined with respect to their relevance for patients. But this development has still been found wanting. For important drugs, no evidence-based benefit has been demonstrated in the benefit assessment, which also has become possible since 2004. Furthermore, this assessment has arrived too late for patients who have been medicated for a long time. Healthcare policies, applicants and stakeholders have contributed a lot to the patients' scepticism towards benefit assessments, though, in principle, patients are interested in high evidence levels and reasonable pricing. New drugs are often licensed under less ambitious conditions. Whether this is in the patients' interest needs to be put up for a large-scale, and societal, discussion. PMID:20608257

  18. Clinical relevance of advanced glycation endproducts for vascular surgery.

    PubMed

    Meerwaldt, R; van der Vaart, M G; van Dam, G M; Tio, R A; Hillebrands, J-L; Smit, A J; Zeebregts, C J

    2008-08-01

    Atherosclerosis is the main contributor to cardiovascular disease and leads to intimal plaque formation, which may progress to plaque rupture with subsequent thromboembolic events and/or occlusion of the arterial lumen. There is increasing evidence that the development or progression of atherosclerosis is associated with advanced glycation endproducts (AGEs). AGEs are a heterogeneous group of compounds formed by the non-enzymatic reaction of reducing sugars with proteins, lipids, and nucleic acids. An increased understanding of the mechanisms of formation and interaction of AGEs has allowed the development of several potential anti-AGE strategies. This review summarizes AGE formation and biochemistry, the pathogeneic role of AGEs in cardiovascular disease, anti-AGE therapies and clinical relevance to vascular surgery.

  19. Streptococcus pyogenes biofilms—formation, biology, and clinical relevance

    PubMed Central

    Fiedler, Tomas; Köller, Thomas; Kreikemeyer, Bernd

    2015-01-01

    Streptococcus pyogenes (group A streptococci, GAS) is an exclusive human bacterial pathogen. The virulence potential of this species is tremendous. Interactions with humans range from asymptomatic carriage over mild and superficial infections of skin and mucosal membranes up to systemic purulent toxic-invasive disease manifestations. Particularly the latter are a severe threat for predisposed patients and lead to significant death tolls worldwide. This places GAS among the most important Gram-positive bacterial pathogens. Many recent reviews have highlighted the GAS repertoire of virulence factors, regulators and regulatory circuits/networks that enable GAS to colonize the host and to deal with all levels of the host immune defense. This covers in vitro and in vivo studies, including animal infection studies based on mice and more relevant, macaque monkeys. It is now appreciated that GAS, like many other bacterial species, do not necessarily exclusively live in a planktonic lifestyle. GAS is capable of microcolony and biofilm formation on host cells and tissues. We are now beginning to understand that this feature significantly contributes to GAS pathogenesis. In this review we will discuss the current knowledge on GAS biofilm formation, the biofilm-phenotype associated virulence factors, regulatory aspects of biofilm formation, the clinical relevance, and finally contemporary treatment regimens and future treatment options. PMID:25717441

  20. Resveratrol and calcium signaling: molecular mechanisms and clinical relevance.

    PubMed

    McCalley, Audrey E; Kaja, Simon; Payne, Andrew J; Koulen, Peter

    2014-06-05

    Resveratrol is a naturally occurring compound contributing to cellular defense mechanisms in plants. Its use as a nutritional component and/or supplement in a number of diseases, disorders, and syndromes such as chronic diseases of the central nervous system, cancer, inflammatory diseases, diabetes, and cardiovascular diseases has prompted great interest in the underlying molecular mechanisms of action. The present review focuses on resveratrol, specifically its isomer trans-resveratrol, and its effects on intracellular calcium signaling mechanisms. As resveratrol's mechanisms of action are likely pleiotropic, its effects and interactions with key signaling proteins controlling cellular calcium homeostasis are reviewed and discussed. The clinical relevance of resveratrol's actions on excitable cells, transformed or cancer cells, immune cells and retinal pigment epithelial cells are contrasted with a review of the molecular mechanisms affecting calcium signaling proteins on the plasma membrane, cytoplasm, endoplasmic reticulum, and mitochondria. The present review emphasizes the correlation between molecular mechanisms of action that have recently been identified for resveratrol and their clinical implications.

  1. Clinically relevant interpretation of solid phase assays for HLA antibody

    PubMed Central

    Bettinotti, Maria P.; Zachary, Andrea A.; Leffell, Mary S.

    2016-01-01

    Purpose of review Accurate and timely detection and characterization of human leukocyte antigen (HLA) antibodies are critical for pre-transplant and post-transplant immunological risk assessment. Solid phase immunoassays have provided increased sensitivity and specificity, but test interpretation is not always straightforward. This review will discuss the result interpretation considering technical limitations; assessment of relative antibody strength; and the integration of data for risk stratification from complementary testing and the patient's immunological history. Recent findings Laboratory and clinical studies have provided insight into causes of test failures – false positive reactions because of antibodies to denatured HLA antigens and false negative reactions resulting from test interference and/or loss of native epitopes. Test modifications permit detection of complement-binding antibodies and determination of the IgG subclasses. The high degree of specificity of single antigen solid phase immunoassays has revealed the complexity and clinical relevance of antibodies to HLA-C, HLA-DQ, and HLA-DP antigens. Determination of antibody specificity for HLA epitopes enables identification of incompatible antigens not included in test kits. Summary Detection and characterization of HLA antibodies with solid phase immunoassays has led to increased understanding of the role of those antibodies in graft rejection, improved treatment of antibody-mediated rejection, and increased opportunities for transplantation. However, realization of these benefits requires careful and accurate interpretation of test results. PMID:27200498

  2. Clinically and pharmacologically relevant interactions of antidiabetic drugs.

    PubMed

    May, Marcus; Schindler, Christoph

    2016-04-01

    Patients with type 2 diabetes mellitus often require multifactorial pharmacological treatment due to different comorbidities. An increasing number of concomitantly taken medications elevate the risk of the patient experiencing adverse drug effects or drug interactions. Drug interactions can be divided into pharmacokinetic and pharmacodynamic interactions affecting cytochrome (CYP) enzymes, absorption properties, transporter activities and receptor affinities. Furthermore, nutrition, herbal supplements, patient's age and gender are of clinical importance. Relevant drug interactions are predominantly related to sulfonylureas, thiazolidinediones and glinides. Although metformin has a very low interaction potential, caution is advised when drugs that impair renal function are used concomitantly. With the exception of saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitors also show a low interaction potential, but all drugs affecting the drug transporter P-glycoprotein should be used with caution. Incretin mimetics and sodium-glucose cotransporter-2 (SGLT-2) inhibitors comprise a very low interaction potential and are therefore recommended as an ideal combination partner from the clinical-pharmacologic point of view. PMID:27092232

  3. Almond allergens: molecular characterization, detection, and clinical relevance.

    PubMed

    Costa, Joana; Mafra, Isabel; Carrapatoso, Isabel; Oliveira, Maria Beatriz P P

    2012-02-15

    Almond ( Prunus dulcis ) has been widely used in all sorts of food products (bakery, pastry, snacks), mostly due to its pleasant flavor and health benefits. However, it is also classified as a potential allergenic seed known to be responsible for triggering several mild to life-threatening immune reactions in sensitized and allergic individuals. Presently, eight groups of allergenic proteins have been identified and characterized in almond, namely, PR-10 (Pru du 1), TLP (Pru du 2), prolamins (Pru du 2S albumin, Pru du 3), profilins (Pru du 4), 60sRP (Pru du 5), and cupin (Pru du 6, Pru du γ-conglutin), although only a few of them have been tested for reactivity with almond-allergic sera. To protect sensitized individuals, labeling regulations have been implemented for foods containing potential allergenic ingredients, impelling the development of adequate analytical methods. This work aims to present an updated and critical overview of the molecular characterization and clinical relevance of almond allergens, as well as review the main methodologies used to detect and quantitate food allergens with special emphasis on almond. PMID:22260748

  4. Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria

    PubMed Central

    Piddock, Laura J. V.

    2006-01-01

    Efflux pump genes and proteins are present in both antibiotic-susceptible and antibiotic-resistant bacteria. Pumps may be specific for one substrate or may transport a range of structurally dissimilar compounds (including antibiotics of multiple classes); such pumps can be associated with multiple drug (antibiotic) resistance (MDR). However, the clinical relevance of efflux-mediated resistance is species, drug, and infection dependent. This review focuses on chromosomally encoded pumps in bacteria that cause infections in humans. Recent structural data provide valuable insights into the mechanisms of drug transport. MDR efflux pumps contribute to antibiotic resistance in bacteria in several ways: (i) inherent resistance to an entire class of agents, (ii) inherent resistance to specific agents, and (iii) resistance conferred by overexpression of an efflux pump. Enhanced efflux can be mediated by mutations in (i) the local repressor gene, (ii) a global regulatory gene, (iii) the promoter region of the transporter gene, or (iv) insertion elements upstream of the transporter gene. Some data suggest that resistance nodulation division systems are important in pathogenicity and/or survival in a particular ecological niche. Inhibitors of various efflux pump systems have been described; typically these are plant alkaloids, but as yet no product has been marketed. PMID:16614254

  5. Biology and Clinical Relevance of Acute Myeloid Leukemia Stem Cells.

    PubMed

    Reinisch, Andreas; Chan, Steven M; Thomas, Daniel; Majeti, Ravindra

    2015-07-01

    Evidence for the cancer stem cell model was first demonstrated in xenotransplanted blood and bone marrow samples from patients with acute myeloid leukemia (AML) almost two decades ago, supporting the concept that a rare clonal and mutated leukemic stem cell (LSC) population is sufficient to drive leukemic growth. The inability to eliminate LSCs with conventional therapies is thought to be the primary cause of disease relapse in AML patients, and as such, novel therapies with the ability to target this population are required to improve patient outcomes. An important step towards this goal is the identification of common immunophenotypic surface markers and biological properties that distinguish LSCs from normal hematopoietic stem and progenitor cells (HSPCs) across AML patients. This work has resulted in the development of a large number of potential LSC-selective therapies that target cell surface molecules, intracellular signaling pathways, and the bone marrow microenvironment. Here, we will review the basic biology, immunophenotypic detection, and clinical relevance of LSCs, as well as emerging biological and small-molecule strategies that either directly target LSCs or indirectly target these cells through modulation of their microenvironment.

  6. Clinical relevance: an issue in biostatistical training of medical students.

    PubMed

    Knapp, R G; Miller, M C

    1987-01-01

    Significant trends in teaching biostatistics to medical students include: recognition of the dependence of advancement in the medical sciences upon the quantitative sciences; integration of biostatistics and other disciplines such as epidemiology and community medicine; increased emphasis on clinical relevance through the introduction of such topics as medical decision-making, evaluation of diagnostic test, genetic counselling and evaluating health-science literature; growing emphasis on analytic skills and computer literacy as precipitated by the presence of computer-based patient and medical information systems, expert systems, imaging and signal analysis systems; the emergence of new applications of statistics in health and medicine; and changes in the learning environment, for example emphasis on small-group discussions and problem-solving sessions. The evolution and future directions of biometrical training in medicine as precipitated by these trends, and the response of course directors at the Medical University of South Carolina to the demand for a 'new' curriculum in biostatistics for medical students are described. PMID:3821598

  7. Clinical Relevance of HLA Gene Variants in HBV Infection

    PubMed Central

    Wang, Li; Zou, Zhi-Qiang; Wang, Kai

    2016-01-01

    Host gene variants may influence the natural history of hepatitis B virus (HBV) infection. The human leukocyte antigen (HLA) system, the major histocompatibility complex (MHC) in humans, is one of the most important host factors that are correlated with the clinical course of HBV infection. Genome-wide association studies (GWASs) have shown that single nucleotide polymorphisms (SNPs) near certain HLA gene loci are strongly associated with not only persistent HBV infection but also spontaneous HBV clearance and seroconversion, disease progression, and the development of liver cirrhosis and HBV-related hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). These variations also influence the efficacy of interferon (IFN) and nucleot(s)ide analogue (NA) treatment and response to HBV vaccines. Meanwhile, discrepant conclusions were reached with different patient cohorts. It is therefore essential to identify the associations of specific HLA allele variants with disease progression and viral clearance in chronic HBV infection among different ethnic populations. A better understanding of HLA polymorphism relevance in HBV infection outcome would enable us to elucidate the roles of HLA SNPs in the pathogenesis and clearance of HBV in different areas and ethnic groups, to improve strategies for the prevention and treatment of chronic HBV infection. PMID:27243039

  8. Almond allergens: molecular characterization, detection, and clinical relevance.

    PubMed

    Costa, Joana; Mafra, Isabel; Carrapatoso, Isabel; Oliveira, Maria Beatriz P P

    2012-02-15

    Almond ( Prunus dulcis ) has been widely used in all sorts of food products (bakery, pastry, snacks), mostly due to its pleasant flavor and health benefits. However, it is also classified as a potential allergenic seed known to be responsible for triggering several mild to life-threatening immune reactions in sensitized and allergic individuals. Presently, eight groups of allergenic proteins have been identified and characterized in almond, namely, PR-10 (Pru du 1), TLP (Pru du 2), prolamins (Pru du 2S albumin, Pru du 3), profilins (Pru du 4), 60sRP (Pru du 5), and cupin (Pru du 6, Pru du γ-conglutin), although only a few of them have been tested for reactivity with almond-allergic sera. To protect sensitized individuals, labeling regulations have been implemented for foods containing potential allergenic ingredients, impelling the development of adequate analytical methods. This work aims to present an updated and critical overview of the molecular characterization and clinical relevance of almond allergens, as well as review the main methodologies used to detect and quantitate food allergens with special emphasis on almond.

  9. Epileptic neuronal networks: methods of identification and clinical relevance.

    PubMed

    Stefan, Hermann; Lopes da Silva, Fernando H

    2013-01-01

    The main objective of this paper is to examine evidence for the concept that epileptic activity should be envisaged in terms of functional connectivity and dynamics of neuronal networks. Basic concepts regarding structure and dynamics of neuronal networks are briefly described. Particular attention is given to approaches that are derived, or related, to the concept of causality, as formulated by Granger. Linear and non-linear methodologies aiming at characterizing the dynamics of neuronal networks applied to EEG/MEG and combined EEG/fMRI signals in epilepsy are critically reviewed. The relevance of functional dynamical analysis of neuronal networks with respect to clinical queries in focal cortical dysplasias, temporal lobe epilepsies, and "generalized" epilepsies is emphasized. In the light of the concepts of epileptic neuronal networks, and recent experimental findings, the dichotomic classification in focal and generalized epilepsy is re-evaluated. It is proposed that so-called "generalized epilepsies," such as absence seizures, are actually fast spreading epilepsies, the onset of which can be tracked down to particular neuronal networks using appropriate network analysis. Finally new approaches to delineate epileptogenic networks are discussed.

  10. Clinically and pharmacologically relevant interactions of antidiabetic drugs

    PubMed Central

    May, Marcus; Schindler, Christoph

    2016-01-01

    Patients with type 2 diabetes mellitus often require multifactorial pharmacological treatment due to different comorbidities. An increasing number of concomitantly taken medications elevate the risk of the patient experiencing adverse drug effects or drug interactions. Drug interactions can be divided into pharmacokinetic and pharmacodynamic interactions affecting cytochrome (CYP) enzymes, absorption properties, transporter activities and receptor affinities. Furthermore, nutrition, herbal supplements, patient’s age and gender are of clinical importance. Relevant drug interactions are predominantly related to sulfonylureas, thiazolidinediones and glinides. Although metformin has a very low interaction potential, caution is advised when drugs that impair renal function are used concomitantly. With the exception of saxagliptin, dipeptidyl peptidase-4 (DPP-4) inhibitors also show a low interaction potential, but all drugs affecting the drug transporter P-glycoprotein should be used with caution. Incretin mimetics and sodium–glucose cotransporter-2 (SGLT-2) inhibitors comprise a very low interaction potential and are therefore recommended as an ideal combination partner from the clinical–pharmacologic point of view. PMID:27092232

  11. Anatomical features and clinical relevance of a persistent trigeminal artery

    PubMed Central

    Alcalá-Cerra, Gabriel; Tubbs, R S; Niño-Hernández, Lucía M

    2012-01-01

    Background: Although persistent trigeminal artery (PTA) is uncommonly identified, knowledge of this structure is essential for clinicians who interpret cranial imaging, perform invasive studies of the cerebral vasculature, and operate this region. Methods: A review of the medical literature using standard search engines was performed to locate articles regarding the PTA, with special attention with anatomical descriptions. Results: Although anatomical reports of PTA anatomy are very scarce, those were analyzed to describe in detail the current knowledge about its anatomical relationships and variants. Additionally, the embryology, classification, clinical implications, and imaging modalities of this vessel are extensively discussed. Conclusions: Through a comprehensive review of isolated reports of the PTA, the clinician can better understand and treat patients with such an anatomical derailment. PMID:23087827

  12. [Neurodermatitis and food allergy. Clinical relevance of testing procedures].

    PubMed

    Stiening, H; Szczepanski, R; von Mühlendahl, K E; Kalveram, C

    1990-12-01

    In 132 children with neurodermitis, we measured specific IgG and IgE antibodies against components of cow's milk, soy milk, and egg. In addition we performed epidermal tests by rubbing the nutrients onto the intact skin. The results were compared to the effect of complete omission of milk, egg, and soy during four weeks and with the outcome of subsequent reexposition. We used standardized scales to evaluate the neurodermitis and the skin reactions and for the clinical response to the oral challenge. The best prediction for the outcome of the oral challenge was obtained by the epidermal test which had to be done with whole milk, soy milk and egg white; there was no further advantage in testing egg yolk or soy oil. IgE antibodies followed next in their predictive value. No further precision was gained by the combination of epidermal testing with IgE results, by the measurement of IgE antibodies to the constituents of cow's milk, of IgG antibodies, and of the platelet count during oral challenging. Positive reactions to oral administration after four weeks' omission of allergenic food were relatively frequent in the age group below three years, but rare in school children and adolescents. PMID:2087240

  13. Clinically Relevant Genetic Variations in Drug Metabolizing Enzymes

    PubMed Central

    Pinto, Navin; Dolan, M. Eileen

    2011-01-01

    In the field of pharmacogenetics, we currently have a few markers to guide physicians as to the best course of therapy for patients. For the most part, these genetic variants are within a drug metabolizing enzyme that has a large effect on the degree or rate at which a drug is converted to its metabolites. For many drugs, response and toxicity are multi-genic traits and understanding relationships between a patient's genetic variation in drug metabolizing enzymes and the efficacy and/or toxicity of a medication offers the potential to optimize therapies. This review will focus on variants in drug metabolizing enzymes with predictable and relatively large impacts on drug efficacy and/or toxicity; some of these drug/gene variant pairs have impacted drug labels by the United States Food and Drug Administration. The challenges in identifying genetic markers and implementing clinical changes based on known markers will be discussed. In addition, the impact of next generation sequencing in identifying rare variants will be addressed. PMID:21453273

  14. High Prevalence and Clinical Relevance of Genes Affected by Chromosomal Breaks in Colorectal Cancer

    PubMed Central

    van den Broek, Evert; Dijkstra, Maurits J. J.; Krijgsman, Oscar; Sie, Daoud; Haan, Josien C.; Traets, Joleen J. H.; van de Wiel, Mark A.; Nagtegaal, Iris D.; Punt, Cornelis J. A.; Carvalho, Beatriz; Ylstra, Bauke; Abeln, Sanne; Meijer, Gerrit A.; Fijneman, Remond J. A.

    2015-01-01

    Background Cancer is caused by somatic DNA alterations such as gene point mutations, DNA copy number aberrations (CNA) and structural variants (SVs). Genome-wide analyses of SVs in large sample series with well-documented clinical information are still scarce. Consequently, the impact of SVs on carcinogenesis and patient outcome remains poorly understood. This study aimed to perform a systematic analysis of genes that are affected by CNA-associated chromosomal breaks in colorectal cancer (CRC) and to determine the clinical relevance of recurrent breakpoint genes. Methods Primary CRC samples of patients with metastatic disease from CAIRO and CAIRO2 clinical trials were previously characterized by array-comparative genomic hybridization. These data were now used to determine the prevalence of CNA-associated chromosomal breaks within genes across 352 CRC samples. In addition, mutation status of the commonly affected APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, BRAF and NRAS genes was determined for 204 CRC samples by targeted massive parallel sequencing. Clinical relevance was assessed upon stratification of patients based on gene mutations and gene breakpoints that were observed in >3% of CRC cases. Results In total, 748 genes were identified that were recurrently affected by chromosomal breaks (FDR <0.1). MACROD2 was affected in 41% of CRC samples and another 169 genes showed breakpoints in >3% of cases, indicating that prevalence of gene breakpoints is comparable to the prevalence of well-known gene point mutations. Patient stratification based on gene breakpoints and point mutations revealed one CRC subtype with very poor prognosis. Conclusions We conclude that CNA-associated chromosomal breaks within genes represent a highly prevalent and clinically relevant subset of SVs in CRC. PMID:26375816

  15. Clinical relevance of host immunity in breast cancer: from TILs to the clinic.

    PubMed

    Savas, Peter; Salgado, Roberto; Denkert, Carsten; Sotiriou, Christos; Darcy, Phillip K; Smyth, Mark J; Loi, Sherene

    2016-04-01

    The clinical relevance of the host immune system in breast cancer has long been unexplored. Studies developed over the past decade have highlighted the biological heterogeneity of breast cancer, prompting researchers to investigate whether the role of the immune system in this malignancy is similar across different molecular subtypes of the disease. The presence of high levels of lymphocytic infiltration has been consistently associated with a more-favourable prognosis in patients with early stage triple-negative and HER2-positive breast cancer. These infiltrates seem to reflect favourable host antitumour immune responses, suggesting that immune activation is important for improving survival outcomes. In this Review, we discuss the composition of the immune infiltrates observed in breast cancers, as well as data supporting the clinical relevance of host antitumour immunity, as represented by lymphocytic infiltration, and how this biomarker could be used in the clinical setting. We also discuss the rationale for enhancing immunity in breast cancer, including early data on the efficacy of T-cell checkpoint inhibition in this setting.

  16. [The clinical relevance of opioid-induced hyperalgesia remains unresolved].

    PubMed

    Sørensen, Jakob; Sjøgren, Per

    2011-03-28

    Opioids are widely used as analgesics in chronic pain of malignant as well as non-malignant origin. During opioid treatment, pain is occasionally worsened. This could be due to progression of the disease or tolerance or opioid-induced hyperalgesia (OIH). The present article summarizes the preclinical and clinical data in support of the existence of OIH. Further, possible mechanisms and potential treatments are outlined. We conclude that only a few clinical studies on OIH are available. However, a growing body of experimental data supports the presence of OIH in clinical settings. Diagnostic tools for assessment of OIH have yet to be developed.

  17. Opioid-induced hyperalgesia: clinically relevant or extraneous research phenomenon?

    PubMed

    Tompkins, D Andrew; Campbell, Claudia M

    2011-04-01

    Opioids have become the unequivocal therapy of choice in treating many varieties of chronic pain. With the increased prescription of opioids, some unintended consequences have occurred. After prolonged opioid exposure, opioid-induced hyperalgesia (OIH), the paradoxical effect that opioid therapy may in fact enhance or aggravate preexisting pain, may occur. Over the past several decades, an increasing number of laboratory and clinical reports have suggested lowered pain thresholds and heightened atypical pain unrelated to the original perceived pain sensations as hallmarks of OIH. However, not all evidence supports the clinical importance of OIH, and some question whether the phenomenon exists at all. Here, we present a nonexhaustive, brief review of the recent literature. OIH will be reviewed in terms of preclinical and clinical evidence for and against its existence; recommendations for clinical evaluation and intervention also will be discussed.

  18. A Laboratory Course in Clinical Biochemistry Emphasizing Interest and Relevance

    ERIC Educational Resources Information Center

    Schwartz, Peter L.

    1975-01-01

    Ten laboratory experiments are described which are used in a successful clinical biochemistry laboratory course (e.g. blood alcohol, glucose tolerance, plasma triglycerides, coronary risk index, gastric analysis, vitamin C and E). Most of the experiments are performed on the students themselves using simple equipment with emphasis on useful…

  19. Efficacy of mirtazapine in clinically relevant subgroups of depressed patients.

    PubMed

    Nutt, D J

    1998-01-01

    Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) with a novel mode of action that differs from other antidepressants that are currently available. Clinical trials have demonstrated it to have good antidepressant efficacy and excellent tolerability. Analysis of the results of placebo-controlled trials in moderately or severely depressed patients have shown mirtazapine to be effective in clinically important subgroups of depressed patients, particularly anxious patients, patients with sleep disturbance, retarded patients, and agitated patients. The efficacy and tolerability of mirtazapine are attributable to its pharmacological profile. It is likely that the overall antidepressant activity arises from its dual action, enhancing both noradrenergic and 5-HT1 receptor-mediated serotonergic neurotransmission, while the anxiolytic and sleep-improving properties of mirtazapine are attributable to the specific blockade of 5-HT2 and 5-HT3 receptors. PMID:9597345

  20. Tolerance in liver transplantation: Biomarkers and clinical relevance

    PubMed Central

    Baroja-Mazo, Alberto; Revilla-Nuin, Beatriz; Parrilla, Pascual; Martínez-Alarcón, Laura; Ramírez, Pablo; Pons, José Antonio

    2016-01-01

    Transplantation is the optimal treatment for end-stage organ failure, and modern immunosuppression has allowed important progress in short-term outcomes. However, immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus, a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor FoxP3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise, other immune cells, such as dendritic cells, monocyte/macrophages or natural killer cells, have been described as part of the process known as “operational tolerance”. However, translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way, a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multi-center clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio. PMID:27678350

  1. [Antipsychotics and hyperpolactinaemia: pathophysiology, clinical relevance, diagnosis and therapy].

    PubMed

    Riecher-Rössler, Anita; Schmid, Christoph; Bleuer, Stefan; Birkhäuser, Martin

    2009-01-01

    Hyperprolactinaemia is a frequent but often neglected side effect of typical, but also of many atypical antipsychotics such as amisulpiride, risperidone or ziprasidone. Besides galactorrhoea, potential consequences are suppression of the hypothalamic-pituitary-gonadal axis with hypogonadism, sexual dysfunction, infertility and in women also irregularities of the menstrual cycle and amenorrhoea. Potential long term consequences are mainly osteopenia and osteoporosis with an enhanced risk of fractures. Hyperprolactinaemia, if not clearly caused by a prolactin inducing antipsychotic, should always be thoroughly investigated. Ideally, prolactin should be measured before starting a patient on a new antipsychotic. Furthermore, before neuroleptic treatment is begun, and also in regular intervals after that, patients should be asked about potential clinical signs of hyperprolactinaemia. Hyperprolactinaemia which is clearly due to antipsychotics but without clinical symptoms only requires regular controls of bone mineral density. However, if clinical symptoms occur, switching to a prolactin sparing antipsychotic may be necessary. In these cases fertility is often regained and the women concerned have to be informed about the enhanced risk of pregnancy and counselled regarding contraception. If switching is not possible, estradiol has to be substituted in women. Also in men with hypogonadism hormonesubstitution (with testosterone) is usually indicated. Generally hyperprolactinaemia in psychiatric patients should be taken more seriously in the future.

  2. The Clinical Relevance of Beta Blockers in Ovarian Carcinoma

    PubMed Central

    Hefner, J.; Csef, H.

    2016-01-01

    The last ten years have seen hardly any improvement in the prognosis of ovarian carcinoma. There is a great need for new treatment strategies, and a recent retrospective study showing a survival advantage with the use of beta blockers met with a very positive response. This systematic review summarizes the current state of knowledge and research on the topic: A database analysis identified six clinical studies showing inconsistent results with respect to the administration of beta blockers and disease course. The 13 preclinical studies identified showed almost without exception both that catecholamines had detrimental effects on tumour progression, and that these effects could be influenced by pharmacological blockade. Overall the available evidence does not justify the use of beta blockers in clinical practice for ovarian carcinoma at the present time. This article also outlines details of research design required for further studies needed on the subject. Preclinical research findings are however very impressive: They not only form an important basis for the development of future clinical studies but also, through revealing new pathomechanisms, they already make an important contribution towards the development of new treatment strategies for ovarian carcinoma. PMID:27761025

  3. Tolerance in liver transplantation: Biomarkers and clinical relevance.

    PubMed

    Baroja-Mazo, Alberto; Revilla-Nuin, Beatriz; Parrilla, Pascual; Martínez-Alarcón, Laura; Ramírez, Pablo; Pons, José Antonio

    2016-09-14

    Transplantation is the optimal treatment for end-stage organ failure, and modern immunosuppression has allowed important progress in short-term outcomes. However, immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus, a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor FoxP3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise, other immune cells, such as dendritic cells, monocyte/macrophages or natural killer cells, have been described as part of the process known as "operational tolerance". However, translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way, a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multi-center clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio. PMID:27678350

  4. The Assessment of Schizotypy and Its Clinical Relevance

    PubMed Central

    Mason, Oliver J.

    2015-01-01

    This article reviews several approaches to assessing schizotypal traits using a wide variety of self-report and interview measures. It makes a distinction between clinical approaches largely based on syndrome and symptom definitions, and psychometric approaches to measuring personality traits. The review presents a brief description of the content and psychometric properties of both sets of measures; these cover both the broad rubric of schizotypy often, but not exclusively based on DSM conceptions, as well as measures with a more specific focus. Measurement of schizotypy has taken place within clinical and nonclinical research utilizing a range of designs and methodologies. Several of these are elucidated with respect to the assessment choices open to researchers, and the implications of the measures chosen. These paradigms include the case–control study, “high risk”/“ultra-high risk” groups, a variety of nonclinical groups and other groups of interest, large scale epidemiology and “in vivo” designs. Evidence from a wide variety of designs continues to provide evidence of the validity of both clinical and personality approaches to schizotypal assessment. PMID:25810054

  5. Tolerance in liver transplantation: Biomarkers and clinical relevance

    PubMed Central

    Baroja-Mazo, Alberto; Revilla-Nuin, Beatriz; Parrilla, Pascual; Martínez-Alarcón, Laura; Ramírez, Pablo; Pons, José Antonio

    2016-01-01

    Transplantation is the optimal treatment for end-stage organ failure, and modern immunosuppression has allowed important progress in short-term outcomes. However, immunosuppression poorly influences chronic rejection and elicits chronic toxicity in current clinical practice. Thus, a major goal in transplantation is to understand and induce tolerance. It is well established that human regulatory T cells expressing the transcription factor FoxP3 play important roles in the maintenance of immunological self-tolerance and immune homeostasis. The major regulatory T cell subsets and mechanisms of expansion that are critical for induction and long-term maintenance of graft tolerance and survival are being actively investigated. Likewise, other immune cells, such as dendritic cells, monocyte/macrophages or natural killer cells, have been described as part of the process known as “operational tolerance”. However, translation of these results towards clinical practice needs solid tools to identify accurately and reliably patients who are going to be tolerant. In this way, a plethora of genetic and cellular biomarkers is raising and being validated worldwide in large multi-center clinical trials. Few of the studies performed so far have provided a detailed analysis of the impact of immunosuppression withdrawal on pre-existing complications derived from the long-term administration of immunosuppressive drugs and the side effects associated with them. The future of liver transplantation is aimed to develop new therapies which increase the actual low tolerant vs non-tolerant recipients ratio.

  6. The clinical relevance of sexual dysfunction in systemic sclerosis.

    PubMed

    Bruni, C; Raja, J; Denton, C P; Matucci-Cerinic, M

    2015-12-01

    Systemic sclerosis is a chronic multi-organ autoimmune disease, leading to important clinical and psychological implications. Among organ complications, sexual dysfunction is a major issue for both male and female gender, with high prevalence and great impact on quality of life, although frequently not addressed by both clinicians and patients. While erectile dysfunction is the most common cause of sexual problems in males, genital tract and general physical changes are major contributors to sexual impairment in females. This review presents current state of the art on this topic, discussing published data on presentation, evaluation and therapeutic options.

  7. Thyroid Autoantibodies in Pregnancy: Their Role, Regulation and Clinical Relevance

    PubMed Central

    Balucan, Francis S.; Morshed, Syed A.; Davies, Terry F.

    2013-01-01

    Autoantibodies to thyroglobulin and thyroid peroxidase are common in the euthyroid population and are considered secondary responses and indicative of thyroid inflammation. By contrast, autoantibodies to the TSH receptor are unique to patients with Graves' disease and to some patients with Hashimoto's thyroiditis. Both types of thyroid antibodies are useful clinical markers of autoimmune thyroid disease and are profoundly influenced by the immune suppression of pregnancy and the resulting loss of such suppression in the postpartum period. Here, we review these three types of thyroid antibodies and their antigens and how they relate to pregnancy itself, obstetric and neonatal outcomes, and the postpartum. PMID:23691429

  8. Relevance of guideline-based ICD indications to clinical practice.

    PubMed

    Al-Jefairi, Nora; Burri, Haran

    2014-01-01

    The implantable cardioverter-defibrillator (ICD) has established itself as life-saving therapy in patients at risk for sudden cardiac death. Remarkable technological advances have made ICDs easier and safer to implant, with improved therapeutic and diagnostic functions and reduced morbidity. Guidelines on ICD indications have been proposed by American and European scientific societies since a number of years, based upon trials and expert opinion. In the context of variable economic and political constraints, it is questionable whether these guidelines may be applied to all settings. This review discusses the guideline-based indications, critically examines their applicability to clinical practice, and discusses alternatives to ICD therapy.

  9. [Opioid-induced hyperalgesia. Pathophysiology and clinical relevance].

    PubMed

    Koppert, W

    2004-05-01

    Opioids are the drugs of choice for the treatment of moderate to severe acute and chronic pain. However, clinical evidence suggests that opioids can elicit increased sensitivity to noxious stimuli suggesting that administration of opioids can activate both pain inhibitory and pain facilitatory systems. Acute receptor desensitization via uncoupling of the receptor from G-proteins, up-regulation of the cAMP pathway, activation of the N-methyl-D-aspartate (NMDA) receptor system, as well as descending facilitation, have been proposed as potential mechanisms underlying opioid-induced hyperalgesia. Numerous reports exist demonstrating that opioid-induced hyperalgesia is observed both in animal and human experimental models. Brief exposures to micro-receptor agonists induce long-lasting hyperalgesic effects for days, which might by reflected by clinical observations that large doses of intraoperative micro-receptor agonists increased postoperative pain and morphine consumption. Furthermore, the prolonged use of opioids in patients often requires increasing doses and may be accompanied by the development of abnormal pain. Successful strategies that may decrease or prevent opioid-induced hyperalgesia include the concomitant administration of drugs like NMDA-antagonists, alpha(2)-agonists, or non-steroidal anti-inflammatory drugs (NSAIDs), opioid rotation or combinations of opioids with different receptor selectivity.

  10. Update on Eosinophilic Meningoencephalitis and Its Clinical Relevance

    PubMed Central

    Graeff-Teixeira, Carlos; da Silva, Ana Cristina Arámburu; Yoshimura, Kentaro

    2009-01-01

    Summary: Eosinophilic meningoencephalitis is caused by a variety of helminthic infections. These worm-specific infections are named after the causative worm genera, the most common being angiostrongyliasis, gnathostomiasis, toxocariasis, cysticercosis, schistosomiasis, baylisascariasis, and paragonimiasis. Worm parasites enter an organism through ingestion of contaminated water or an intermediate host and can eventually affect the central nervous system (CNS). These infections are potentially serious events leading to sequelae or death, and diagnosis depends on currently limited molecular methods. Identification of parasites in fluids and tissues is rarely possible, while images and clinical examinations do not lead to a definitive diagnosis. Treatment usually requires the concomitant administration of corticoids and anthelminthic drugs, yet new compounds and their extensive and detailed clinical evaluation are much needed. Eosinophilia in fluids may be detected in other infectious and noninfectious conditions, such as neoplastic disease, drug use, and prosthesis reactions. Thus, distinctive identification of eosinophils in fluids is a necessary component in the etiologic diagnosis of CNS infections. PMID:19366917

  11. Osteoprotegerin and Vascular Calcification: Clinical and Prognostic Relevance.

    PubMed

    Makarović, Sandra; Makarović, Zorin; Steiner, Robert; Mihaljević, Ivan; Milas-Ahić, Jasminka

    2015-06-01

    Osteoprotegerin (OPG) is a key regulator in bone metabolism, that also has effect in vascular system. Studies suggest that osteoprotegerin is a critical arterial calcification inhibitor, and is released by endothelial cells as a protective mechanism for their survival in certain pathological conditions, such as diabetes mellitus, chronic kidney disease, and other metabolic disorders. That has been shown in studies in vitro and in animal models. The discovery that OPG deficient mice (OPG -/- mice) develop severe osteoporosis and arterial calcification, has led to conclusion that osteoprotegerin might be mulecule linking vascular and bone system. Paradoxically however, clinical trials have shown recently that OPG serum levels is increased in coronary artery disease and correlates with its severity, ischemic cardial decompensation, and future cardiovascular events. Therefore it is possible that osteoprotegerin could have a new function as a potential biomarker in early identification and monitoring patients with cardiovascular disease. Amongst that osteoprotegerin is in association with well known atherosclerosis risc factors: undoubtedly it is proven its relationship with age, smoking and diabetes mellitus. There is evidence regarding presence of hyperlipoproteinemia and increased serum levels of osteoprotegerin. Also the researches have been directed in genetic level, linking certain single nucleotid genetic polymorphisms of osteoprotegerin and vascular calcification appearance. This review emphasises multifactorial role of OPG, presenting numerous clinical and experimental studies regarding its role in vascular pathology, suggesting a novel biomarker in cardiovascular diseases, showing latest conclusions about this interesting topic that needs to be further explored. PMID:26753467

  12. Clinical relevance of molecular diagnosis in pet allergy.

    PubMed

    Uriarte, S A; Sastre, J

    2016-07-01

    We describe the pattern of sensitisation to pet IgE components and its association with clinical symptoms. Hundred and fifty nine consecutive patients with rhinitis/asthma sensitised to dog, cat, and horse were recruited. Specific IgE to whole extracts and to pet recombinant allergens were performed. Only 5% of patients were monosensitised to animal allergens. Specific IgE to Can f 1 was significantly associated with persistent rhinitis, Can f 2 with asthma diagnosis, Can f 3 with moderate/severe rhinitis (M/S-R) and asthma diagnosis (AD), and Can f 5 with persistent and M/S-R. Positive IgE to Fel d 2 was significantly associated with M/S-R and AD, Equ c 1 with M/S-R and Equ c 3 with persistent rhinitis, AD and severe asthma. Sensitisation to ≥2 molecules or to pet albumins was associated with more severe respiratory symptoms. Molecular diagnosis in patients with pet allergy may also help clinicians to predict clinical symptoms and their severity. PMID:27108666

  13. Taxonomy, epidemiology, and clinical relevance of the genus Arcobacter.

    PubMed

    Collado, Luis; Figueras, Maria José

    2011-01-01

    The genus Arcobacter, defined almost 20 years ago from members of the genus Campylobacter, has become increasingly important because its members are being considered emergent enteropathogens and/or potential zoonotic agents. Over recent years information that is relevant for microbiologists, especially those working in the medical and veterinary fields and in the food safety sector, has accumulated. Recently, the genus has been enlarged with several new species. The complete genomes of Arcobacter butzleri and Arcobacter nitrofigilis are available, with the former revealing diverse pathways characteristic of free-living microbes and virulence genes homologous to those of Campylobacter. The first multilocus sequence typing analysis showed a great diversity of sequence types, with no association with specific hosts or geographical regions. Advances in detection and identification techniques, mostly based on molecular methods, have been made. These microbes have been associated with water outbreaks and with indicators of fecal pollution, with food products and water as the suspected routes of transmission. This review updates this knowledge and provides the most recent data on the taxonomy, species diversity, methods of detection, and identification of these microbes as well as on their virulence potential and implication in human and animal diseases.

  14. Taxonomy, Epidemiology, and Clinical Relevance of the Genus Arcobacter

    PubMed Central

    Collado, Luis; Figueras, Maria José

    2011-01-01

    Summary: The genus Arcobacter, defined almost 20 years ago from members of the genus Campylobacter, has become increasingly important because its members are being considered emergent enteropathogens and/or potential zoonotic agents. Over recent years information that is relevant for microbiologists, especially those working in the medical and veterinary fields and in the food safety sector, has accumulated. Recently, the genus has been enlarged with several new species. The complete genomes of Arcobacter butzleri and Arcobacter nitrofigilis are available, with the former revealing diverse pathways characteristic of free-living microbes and virulence genes homologous to those of Campylobacter. The first multilocus sequence typing analysis showed a great diversity of sequence types, with no association with specific hosts or geographical regions. Advances in detection and identification techniques, mostly based on molecular methods, have been made. These microbes have been associated with water outbreaks and with indicators of fecal pollution, with food products and water as the suspected routes of transmission. This review updates this knowledge and provides the most recent data on the taxonomy, species diversity, methods of detection, and identification of these microbes as well as on their virulence potential and implication in human and animal diseases. PMID:21233511

  15. Clinical relevance of endothelium-derived relaxing factor (EDRF)

    PubMed Central

    Bassenge, E.

    1992-01-01

    1 In addition to metabolic and neurohumoral factors endothelium-derived autacoids like the nitric oxide radical NO and prostacyclin are effective regulators of vascular tone and thus tissue perfusion. NO is produced in endothelial cells from L-arginine by a Ca2+/calmodulin-dependent enzyme NO synthase. In addition, the NO radical is ultimately cleaved from all nitrovasodilators and resembles their vasoactive and antiaggregatory principle, which is used under pathological conditions as substitution therapy for impaired endothelial function and autacoid production. Impaired endothelium-dependent vasomotor control has been documented in hypercholesterolaemia, atheromatosis, diabetes, hypertension, and in reperfusion damage. L-arginine supplementation is effective in a few instances. PMID:1633078

  16. [Dualistic classification of epithelial ovarian cancer: Is it clinically relevant?].

    PubMed

    Devouassoux-Shisheboran, Mojgan; Genestie, Catherine; Ray-Coquard, Isabelle

    2016-03-01

    Malignant epithelial tumors (carcinomas) are the most common ovarian cancers and the most lethal gynecological malignancies. Based on their heterogeneous morphology, a dualistic model of carcinogenesis was proposed in 2004. Type I carcinomas, composed of low grade serous, endometrioid, mucinous, clear cell carcinomas and malignant Brenner tumors, were distinct from type II carcinomas (high grade serous, undifferentiated carcinomas and carcinosarcomas). However, clinical studies failed to demonstrate the prognostic value of such a classification. The main reproach to this dualistic model was that it lumped together in type I tumors, heterogeneous lesions such as clear cell and mucinous carcinomas. Recent advances on molecular genetic alterations and precursor lesions favor the classification of ovarian carcinomas as five distinct diseases. The dualistic model of carcinogenesis in type I and II can finally be applied only to serous ovarian carcinomas (low grade and high grade).

  17. Developments in ghrelin biology and potential clinical relevance.

    PubMed

    Smith, Roy G; Jiang, Hong; Sun, Yuxiang

    2005-11-01

    The spiropiperidine, MK0677, has been exploited to characterize and expression clone the growth hormone secretagogue receptor (GHS-R). Cloning of this receptor led to identification of its natural ligands, ghrelin and adenosine. Targeted disruption of the Ghsr gene demonstrated unambiguously that the GH-releasing and orexigenic properties of ghrelin are dependent on Ghsr expression and that the orexigenic signal is mediated through neuropeptide Y and agouti-related peptide neurons. This review summarizes new developments in our understanding of the physiological roles of ghrelin and its receptor (GHS-R). Recent discoveries of the effects of ghrelin on the thymus and proinflammatory and chemotactic cytokine pathways stimulate renewed interest in potential clinical applications, which include age-associated disorders, such as metabolic disease, sarcopenia, congestive heart failure, atherosclerosis and anorexia. PMID:16213742

  18. [Clinical relevance of the early detection of arthrosis].

    PubMed

    Willauschus, W; Herrmann, J; Wirtz, P; Weseloh, G

    1995-01-01

    In the years 1989 to 1992 615 local persons underwent yearly examinations for analysis of osteoarthrosis of the hip and knee by means of comprehensive documentation of orthopaedic health history and clinical findings. Of special interest in our investigation were the Altman ACR criteria for osteoarthrosis of the hip and knee over the years. We can show, that finding the diagnosis is as accurate with the ACR criteria as well as the far more extensive Lequesne and Tegner-Lysholm score. Analysis of the investigations over the years revealed clearly different results in the frequency of osteoarthrosis. The reason is the nature of osteoarthrosis changing between silent and active phases especially during time of onset. Our investigations show, that valuable criteria exists for detection of early osteoarthrosis, however apparent are deficits for observing its course. PMID:8571651

  19. The clinical relevance of attentional bias in substance use disorders.

    PubMed

    Field, Matt; Marhe, Reshmi; Franken, Ingmar H A

    2014-06-01

    Individuals with substance use disorders typically show an "attentional bias" for substance-related cues: Those cues are able to grab and hold the attention, in preference to other cues in the environment. We discuss the theoretical context for this work before reviewing the measurement of attentional bias, and its relationship to motivational state and relapse to substance use after a period of abstinence. Finally, we discuss the implications of this research for the treatment of substance use disorders. We conclude that attentional bias is associated with subjective craving, and that moment-by-moment fluctuations in attentional bias may precede relapse to substance use. The evidence regarding the predictive relationship between attentional bias assessed in treatment contexts and subsequent relapse is inconsistent. Furthermore, there is currently insufficient evidence to endorse attentional bias modification as a treatment for substance use disorders. Clinical implications and suggestions for future research are highlighted.

  20. Evidence of clinically relevant efficacy for dietary supplements and nutraceuticals.

    PubMed

    Cicero, Arrigo F G; Borghi, Claudio

    2013-06-01

    Beyond the well-known effects on blood pressure (BP) of the DASH and the Mediterranean diets, a large number of studies have investigated the possible a BP-lowering effect from different dietary supplements and nutraceuticals, mostly antioxidant agents with a high tolerability and safety profile. In particular, a relatively large body of evidence support the use of potassium, L-arginine, vitamin C, cocoa flavonoids, coenzyme Q10, controlled-release melatonin, and aged garlic extract. However there is a need for data about the long-term safety of a large part of these products. Moreover, further clinical research is advisable to identify between the available active nutraceuticals and those with the best cost-effectiveness and risk-benefit ratio for widespread use in a general population with low added cardiovascular risk related to uncomplicated hypertension. PMID:23430658

  1. The development of left ventricular torsion and its clinical relevance.

    PubMed

    Shaw, Steven M; Fox, David J; Williams, Simon G

    2008-11-28

    Left ventricular torsion is a measurement derived from the twisting or wringing motion of the heart around its long axis. The calculation is made by measuring the magnitude of rotation at the apex of the heart, and subtracting the rotation at the base. Although the phenomenon of left ventricular twisting was first described in the 17th Century, it wasn't until the 1960s that the first invasive method of measurement was demonstrated. Silver tantalum clips were sutured into the epicardium during cardiac surgery and viewed using cineradiography. Non-invasive torsion measurement has been subsequently developed, adopting Magnetic Resonance Imaging and 2D echocardiography. Interest in the changes of different components of torsion, during various cardiac disease states has developed with the advent of these non-invasive measurement techniques. This review article summarises the history of the development of torsion analysis and describes the known changes of torsion during different clinical circumstances.

  2. [Bacterial genomics and metagenomics: clinical applications and medical relevance].

    PubMed

    Diene, S M; Bertelli, C; Pillonel, T; Schrenzel, J; Greub, G

    2014-11-12

    New sequencing technologies provide in a short time and at low cost high amount of genomic sequences useful for applications such as: a) development of diagnostic PCRs and/or serological tests; b) detection of virulence factors (virulome) or genes/SNPs associated with resistance to antibiotics (resistome) and c) investigation of transmission and dissemination of bacterial pathogens. Thus, bacterial genomics of medical importance is useful to clinical microbiologists, to infectious diseases specialists as well as to epidemiologists. Determining the microbial composition of a sample by metagenomics is another application of new sequencing technologies, useful to understand the impact of bacteria on various non-infectious diseases such as obesity, asthma, or diabetes. Genomics and metagenomics will likely become a specialized diagnostic analysis.

  3. [Nitrofurantoin--clinical relevance in uncomplicated urinary tract infections].

    PubMed

    Stock, Ingo

    2014-07-01

    The nitrofuran derivative nitrofurantoin has been used for more than 60 years for the antibacterial therapy of uncomplicated urinary tract infections (UTI). Despite its long application, this antibiotic retained good activity against Escherichia coli and some other pathogens of uncomplicated urinary tract infections such as Staphylococcus saprophyticus and Enterococcus species. Nitrofurantoin therapy has been shown to be accompanied by numerous adverse drug effects. Among these, there are also serious side effects such as pulmonary reactions and polyneuropathy, which mainly occur in long-term use. Recent studies, however, have shown a good efficacy and tolerability of short-term nitrofurantoin therapy comparable to previous established standard therapeutic regimens applying cotrimoxazole or quinolones. Because of these data and the alarming resistance rates of uropathogenic Escherichia coli to cotrimoxazole and quinolones that have been increased markedly in several countries, the clinical significance ofnitrofurantoin has been raised again. In many current treatment guidelines, e. g., the international clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women published by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases, nitrofurantoin has been recommended as one first-line antibiotic of empiric antibacterial treatment of uncomplicated cystitis in otherwise healthy women. In Germany, however, nitrofurantoin should only be applied if more effective and less risky antibiotics cannot be used. Nitrofurantoin is contraindicated in the last three months of pregnancy and in patients suffering from renal impairment of each degree. Despite compatibility concerns, nitrofurantoin has also been recommended for the re-infection prophylaxis of recurrent uncomplicated urinary tract infections in Germany and several other countries.

  4. [Nitrofurantoin--clinical relevance in uncomplicated urinary tract infections].

    PubMed

    Stock, Ingo

    2014-07-01

    The nitrofuran derivative nitrofurantoin has been used for more than 60 years for the antibacterial therapy of uncomplicated urinary tract infections (UTI). Despite its long application, this antibiotic retained good activity against Escherichia coli and some other pathogens of uncomplicated urinary tract infections such as Staphylococcus saprophyticus and Enterococcus species. Nitrofurantoin therapy has been shown to be accompanied by numerous adverse drug effects. Among these, there are also serious side effects such as pulmonary reactions and polyneuropathy, which mainly occur in long-term use. Recent studies, however, have shown a good efficacy and tolerability of short-term nitrofurantoin therapy comparable to previous established standard therapeutic regimens applying cotrimoxazole or quinolones. Because of these data and the alarming resistance rates of uropathogenic Escherichia coli to cotrimoxazole and quinolones that have been increased markedly in several countries, the clinical significance ofnitrofurantoin has been raised again. In many current treatment guidelines, e. g., the international clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women published by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases, nitrofurantoin has been recommended as one first-line antibiotic of empiric antibacterial treatment of uncomplicated cystitis in otherwise healthy women. In Germany, however, nitrofurantoin should only be applied if more effective and less risky antibiotics cannot be used. Nitrofurantoin is contraindicated in the last three months of pregnancy and in patients suffering from renal impairment of each degree. Despite compatibility concerns, nitrofurantoin has also been recommended for the re-infection prophylaxis of recurrent uncomplicated urinary tract infections in Germany and several other countries. PMID:25065160

  5. Bioterrorism: relevance to allergy and immunology in clinical practice.

    PubMed

    Fritz, Stephen B; Singer, Andrew M; Revan, Vidyashankar B; Baker, James R

    2002-02-01

    It has become clear in recent months that the threat of bioterrorism is very real. All physicians need to be aware of the presenting signs and symptoms of the most likely agents. Allergists and immunologists care for a unique population of patients with several alterations of their immune system that might change the expected course of illnesses from biologic terror agents. In this review, we discuss specific bioterrorism agents, focusing on their presentation, pathogenesis, and immunology. In addition, we describe how these illnesses might differ in the population of patients followed by allergists and immunologists. PMID:11842289

  6. Old and new basal insulin formulations: understanding pharmacodynamics is still relevant in clinical practice.

    PubMed

    Rossetti, P; Ampudia-Blasco, F J; Ascaso, J F

    2014-08-01

    Long-acting insulin analogues have been developed to mimic the physiology of basal insulin secretion more closely than human insulin formulations (Neutral Protamine Hagedorn, NPH). However, the clinical evidence in favour of analogues is still controversial. Although their major benefit as compared with NPH is a reduction in the hypoglycaemia risk, some cost/effectiveness analyses have not been favourable to analogues, largely because of their higher price. Nevertheless, these new formulations have conquered the insulin market. Human insulin represents currently no more than 20% of market share. Despite (in fact because of) the widespread use of insulin analogues it remains critical to analyse the pharmacodynamics (PD) of basal insulin formulations appropriately to interpret the results of clinical trials correctly. Importantly, these data may help physicians in tailoring insulin therapy to patients' individual needs and, additionally, when clinical evidence is not available, to optimize insulin treatment. For patients at low risk for/from hypoglycaemia, it might be acceptable and also cost-effective not to use long-acting insulin analogues as basal insulin replacement. Conversely, in patients with a higher degree of insulin deficiency and increased risk for hypoglycaemia, analogues are the best option due to their more physiological profile, as has been shown in PD and clinical studies. From this perspective optimizing basal insulin treatment, especially in type 2 diabetes patients who are less prone to hypoglycaemia, would be suitable making significant resources available for other relevant aspects of diabetes care. PMID:24401118

  7. Colonization, Pathogenicity, Host Susceptibility and Therapeutics for Staphylococcus aureus: What is the Clinical Relevance?1

    PubMed Central

    Tong, Steven Y.C.; Chen, Luke F.; Fowler, Vance G.

    2011-01-01

    Staphylococcus aureus is a human commensal that can also cause a broad spectrum of clinical disease. Factors associated with clinical disease are myriad and dynamic and include pathogen virulence, antimicrobial resistance and host susceptibility. Additionally, infection control measures aimed at the environmental niches of S. aureus and therapeutic advances continue to impact upon the incidence and outcomes of staphylococcal infections. This review article focuses on the clinical relevance of advances in our understanding of staphylococcal colonization, virulence, host susceptibility and therapeutics. Over the past decade key developments have arisen. First, rates of nosocomial methicillin-resistant S. aureus (MRSA) infections have significantly declined in many countries. Second, we have made great strides in our understanding of the molecular pathogenesis of S. aureus in general and community-associated MRSA in particular. Third, host risk factors for invasive staphylococcal infections, such as advancing age, increasing numbers of invasive medical interventions, and a growing proportion of patients with healthcare contact, remain dynamic. Finally, several new antimicrobial agents active against MRSA have become available for clinical use. Humans and S. aureus co-exist and the dynamic interface between host, pathogen and our attempts to influence these interactions will continue to rapidly change. Although progress has been made in the past decade, we are likely to face further surprises such as the recent waves of community-associated MRSA. PMID:22160374

  8. Clinically relevant concentrations of di (2-ethylhexyl) phthalate (DEHP) uncouple cardiac syncytium

    SciTech Connect

    Gillum, Nikki; Karabekian, Zaruhi; Swift, Luther M.; Brown, Ronald P.; Kay, Matthew W.; Sarvazyan, Narine

    2009-04-01

    Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer found in a variety of polyvinyl chloride (PVC) medical products. The results of studies in experimental animals suggest that DEHP leached from flexible PVC tubing may cause health problems in some patient populations. While the cancerogenic and reproductive effects of DEHP are well recognized, little is known about the potential adverse impact of phthalates on the heart. This study examined the effects of clinically relevant concentrations of DEHP on neonatal rat cardiomyocytes. It was found that application of DEHP to a confluent, synchronously beating cardiac cell network, leads to a marked, concentration-dependent decrease in conduction velocity and asynchronous cell beating. The mechanism behind these changes was a loss of gap junctional connexin-43, documented using Western blot analysis, dye-transfer assay and immunofluorescence. In addition to its effect on electrical coupling, DEHP treatment also affected the mechanical movement of myocyte layers. The latter was linked to the decreased stiffness of the underlying fibroblasts, as the amount of triton-insoluble vimentin was significantly decreased in DEHP-treated samples. The data indicate that DEHP, in clinically relevant concentrations, can impair the electrical and mechanical behavior of a cardiac cell network. Applicability of these findings to human patients remains to be established.

  9. Clinically relevant copy number variations detected in cerebral palsy.

    PubMed

    Oskoui, Maryam; Gazzellone, Matthew J; Thiruvahindrapuram, Bhooma; Zarrei, Mehdi; Andersen, John; Wei, John; Wang, Zhuozhi; Wintle, Richard F; Marshall, Christian R; Cohn, Ronald D; Weksberg, Rosanna; Stavropoulos, Dimitri J; Fehlings, Darcy; Shevell, Michael I; Scherer, Stephen W

    2015-08-03

    Cerebral palsy (CP) represents a group of non-progressive clinically heterogeneous disorders that are characterized by motor impairment and early age of onset, frequently accompanied by co-morbidities. The cause of CP has historically been attributed to environmental stressors resulting in brain damage. While genetic risk factors are also implicated, guidelines for diagnostic assessment of CP do not recommend for routine genetic testing. Given numerous reports of aetiologic copy number variations (CNVs) in other neurodevelopmental disorders, we used microarrays to genotype a population-based prospective cohort of children with CP and their parents. Here we identify de novo CNVs in 8/115 (7.0%) CP patients (∼1% rate in controls). In four children, large chromosomal abnormalities deemed likely pathogenic were found, and they were significantly more likely to have severe neuromotor impairments than those CP subjects without such alterations. Overall, the CNV data would have impacted our diagnosis or classification of CP in 11/115 (9.6%) families.

  10. Longitudinal Metagenomic Analysis of Hospital Air Identifies Clinically Relevant Microbes

    PubMed Central

    King, Paula; Pham, Long K.; Waltz, Shannon; Sphar, Dan; Yamamoto, Robert T.; Conrad, Douglas; Taplitz, Randy; Torriani, Francesca

    2016-01-01

    We describe the sampling of sixty-three uncultured hospital air samples collected over a six-month period and analysis using shotgun metagenomic sequencing. Our primary goals were to determine the longitudinal metagenomic variability of this environment, identify and characterize genomes of potential pathogens and determine whether they are atypical to the hospital airborne metagenome. Air samples were collected from eight locations which included patient wards, the main lobby and outside. The resulting DNA libraries produced 972 million sequences representing 51 gigabases. Hierarchical clustering of samples by the most abundant 50 microbial orders generated three major nodes which primarily clustered by type of location. Because the indoor locations were longitudinally consistent, episodic relative increases in microbial genomic signatures related to the opportunistic pathogens Aspergillus, Penicillium and Stenotrophomonas were identified as outliers at specific locations. Further analysis of microbial reads specific for Stenotrophomonas maltophilia indicated homology to a sequenced multi-drug resistant clinical strain and we observed broad sequence coverage of resistance genes. We demonstrate that a shotgun metagenomic sequencing approach can be used to characterize the resistance determinants of pathogen genomes that are uncharacteristic for an otherwise consistent hospital air microbial metagenomic profile. PMID:27482891

  11. Alternaria infections: laboratory diagnosis and relevant clinical features.

    PubMed

    Pastor, F J; Guarro, J

    2008-08-01

    The genus Alternaria contains several species of melanized hyphomycetes that cause opportunistic human infections. The published literature contains 210 reported cases of human alternarioses between 1933 and the present day. The most frequent clinical manifestations are cutaneous and subcutaneous infections (74.3%), followed by oculomycosis (9.5%), invasive and non-invasive rhinosinusitis (8.1%) and onychomycosis (8.1%). Immunosuppression is frequently associated with cutaneous and subcutaneous infections and rhinosinusitis. The most important risk factors for cutaneous and subcutaneous infections are solid organ transplantation and Cushing's syndrome, and those for rhinosinusitis are bone marrow transplants. Having been exposed to soil and garbage is common in all cases of oculomycosis, with corticotherapy being a risk factor in 50% of these cases. Previous contact with soil and/or trauma to the nails is associated with most cases of onychomycosis. In general, alternariosis shows a good response to conventional antifungal drugs. On some occasions, steroid suppression or reduction is sufficient to resolve an infection. Itraconazole is the antifungal drug used most frequently to successfully treat onychomycosis and cutaneous and subcutaneous infections. Posaconazole and voriconazole are promising therapeutic options, with the latter being especially so for oculomycosis.

  12. MicroRNAs: Clinical Relevance in Colorectal Cancer

    PubMed Central

    Thomas, Joe; Ohtsuka, Masahisa; Pichler, Martin; Ling, Hui

    2015-01-01

    Colorectal cancer is one of the most common cancer diagnoses and causes of mortality worldwide. MicroRNAs are a class of small, non-coding regulatory RNAs that have shown strong associations with colorectal cancer. Through the repression of target messenger RNAs, microRNAs modulate many cellular pathways, such as those involved in cell proliferation, apoptosis, and differentiation. The utilization of microRNAs has shown significant promise in the diagnosis and prognosis of colorectal cancer, owing to their unique expression profile associations with cancer types and malignancies. Moreover, microRNA therapeutics with mimics or antagonists show great promise in preclinical studies, which encourages further development of their clinical use for colorectal cancer patients. The unique ability of microRNAs to affect multiple downstream pathways represents a novel approach for cancer therapy. Although still early in its development, we believe that microRNAs can be used in the near future as biomarkers and therapeutic targets for colorectal cancer. PMID:26602923

  13. Gathering and Learning From Relevant Clinical Data: A New Framework

    PubMed Central

    Farias, Michael; Friedman, Kevin G.; Lock, James E.; Rathod, Rahul H.

    2015-01-01

    Given the rising costs of health care in today’s economic environment, the need for effective, value-driven care has never been more pressing. While the U.S. health care system strives continually to improve patient outcomes, it struggles with the inadequacies due to variation in care and the inefficiencies of unnecessary resource utilization. The tools traditionally used to study care, from retrospective studies to randomized controlled trials, may be inadequate to address the complicated, interdependent questions related to defining effective care. To overcome the deficiencies of these traditional tools and better optimize our health care system, a new kind of methodology is required—one that integrates the functionality of previously existing tools in a novel way. Standardized Clinical Assessment and Management Plans (SCAMPs) were designed to accomplish this goal. A SCAMP is a care pathway, designed by clinicians, to guide medical decision making around a particular disorder. SCAMPs are unique in that they invite knowledge-based diversions from their recommendations and are accompanied by data collection and continuous improvement processes. Through these mechanisms, SCAMPs successfully reduce practice variation, optimize resource use, and create an integrated medical learning system which overcomes many of the inadequacies of traditional research tools. As such, the SCAMP paradigm may represent an important breakthrough in the effort to define and implement effective health care. PMID:25295963

  14. Clinically relevant drug-drug interactions between antiretrovirals and antifungals

    PubMed Central

    Vadlapatla, Ramya Krishna; Patel, Mitesh; Paturi, Durga K; Pal, Dhananjay; Mitra, Ashim K

    2015-01-01

    Introduction Complete delineation of the HIV-1 life cycle has resulted in the development of several antiretroviral drugs. Twenty-five therapeutic agents belonging to five different classes are currently available for the treatment of HIV-1 infections. Advent of triple combination antiretroviral therapy has significantly lowered the mortality rate in HIV patients. However, fungal infections still represent major opportunistic diseases in immunocompromised patients worldwide. Areas covered Antiretroviral drugs that target enzymes and/or proteins indispensable for viral replication are discussed in this article. Fungal infections, causative organisms, epidemiology and preferred treatment modalities are also outlined. Finally, observed/predicted drug-drug interactions between antiretrovirals and antifungals are summarized along with clinical recommendations. Expert opinion Concomitant use of amphotericin B and tenofovir must be closely monitored for renal functioning. Due to relatively weak interactive potential with the CYP450 system, fluconazole is the preferred antifungal drug. High itraconazole doses (> 200 mg/day) are not advised in patients receiving booster protease inhibitor (PI) regimen. Posaconazole is contraindicated in combination with either efavirenz or fosamprenavir. Moreover, voriconazole is contraindicated with high-dose ritonavir-boosted PI. Echino-candins may aid in overcoming the limitations of existing antifungal therapy. An increasing number of documented or predicted drug-drug interactions and therapeutic drug monitoring may aid in the management of HIV-associated opportunistic fungal infections. PMID:24521092

  15. Spectrum of clinically relevant Exophiala species in the United States.

    PubMed

    Zeng, J S; Sutton, D A; Fothergill, A W; Rinaldi, M G; Harrak, M J; de Hoog, G S

    2007-11-01

    Numerous members of the genus Exophiala are potential agents of human and animal mycoses. The majority of these infections are cutaneous and superficial, but also fatal systemic infections are known. We re-identified 188 clinical isolates from the United States, which had a preliminary morphological identification of Exophiala species, by sequencing internal transcribed spacer (ITS) region of the rRNA. Molecular identifications of the strains were as follows, in order of frequency: 55 E. dermatitidis (29.3%), 37 E. xenobiotica (19.7%), 35 E. oligosperma (18.6%), 13 E. lecanii-corni (6.9%), 12 E. phaeomuriformis (6.4%), 7 E. jeanselmei (3.7%), 7 E. bergeri (3.7%), 6 E. mesophila (3.2%), 5 E. spinifera (2.7%), 3 Exophiala sp. 1 (1.6%), 3 E. attenuata (1.6%), 3 Phialophora europaea (1.3%), 1 E. heteromorpha (0.5%), and 1 Exophiala sp. 2 (0.5%) strains. Exophiala strains were repeatedly isolated from deep infections (39.9%) involving lung, pleural fluid, sputum, digestive organs (stomach, intestines, bile), heart, brain, spleen, bone marrow, blood, dialysis fluid, lymph node, joint, breast, middle ear, throat, and intraocular tissues. About 38.3% of the Exophiala spp. strains were agents of cutaneous infections including skin, mucous membranes, nail, and corneal epithelium lesions. The other strains caused superficial infections (0.5%, including hair) or subcutaneous infection (12.0%, including paranasal sinusitis, mycetoma, and subcutaneous cyst). The systemic infections were preponderantly caused by E. dermatitidis, E. oligosperma, E. phaeomuriformis, E. xenobiotica, and E. lecanii-corni. Strains of E. bergeri, E. spinifera, E. jeanselmei, E. mesophila, and E. attenuata mainly induced cutaneous and subcutaneous infections. Since relatively few unknown ITS motifs were encountered, we suppose that the list of opportunistic Exophiala species in temperate climates is nearing completion, but a number of species still have to be described. PMID:17596364

  16. Spectrum of Clinically Relevant Exophiala Species in the United States▿

    PubMed Central

    Zeng, J. S.; Sutton, D. A.; Fothergill, A. W.; Rinaldi, M. G.; Harrak, M. J.; de Hoog, G. S.

    2007-01-01

    Numerous members of the genus Exophiala are potential agents of human and animal mycoses. The majority of these infections are cutaneous and superficial, but also fatal systemic infections are known. We re-identified 188 clinical isolates from the United States, which had a preliminary morphological identification of Exophiala species, by sequencing internal transcribed spacer (ITS) region of the rRNA. Molecular identifications of the strains were as follows, in order of frequency: 55 E. dermatitidis (29.3%), 37 E. xenobiotica (19.7%), 35 E. oligosperma (18.6%), 13 E. lecanii-corni (6.9%), 12 E. phaeomuriformis (6.4%), 7 E. jeanselmei (3.7%), 7 E. bergeri (3.7%), 6 E. mesophila (3.2%), 5 E. spinifera (2.7%), 3 Exophiala sp. 1 (1.6%), 3 E. attenuata (1.6%), 3 Phialophora europaea (1.3%), 1 E. heteromorpha (0.5%), and 1 Exophiala sp. 2 (0.5%) strains. Exophiala strains were repeatedly isolated from deep infections (39.9%) involving lung, pleural fluid, sputum, digestive organs (stomach, intestines, bile), heart, brain, spleen, bone marrow, blood, dialysis fluid, lymph node, joint, breast, middle ear, throat, and intraocular tissues. About 38.3% of the Exophiala spp. strains were agents of cutaneous infections including skin, mucous membranes, nail, and corneal epithelium lesions. The other strains caused superficial infections (0.5%, including hair) or subcutaneous infection (12.0%, including paranasal sinusitis, mycetoma, and subcutaneous cyst). The systemic infections were preponderantly caused by E. dermatitidis, E. oligosperma, E. phaeomuriformis, E. xenobiotica, and E. lecanii-corni. Strains of E. bergeri, E. spinifera, E. jeanselmei, E. mesophila, and E. attenuata mainly induced cutaneous and subcutaneous infections. Since relatively few unknown ITS motifs were encountered, we suppose that the list of opportunistic Exophiala species in temperate climates is nearing completion, but a number of species still have to be described. PMID:17596364

  17. Stone culture retrieved during percutaneous nephrolithotomy: is it clinically relevant?

    PubMed

    Osman, Yasser; Elshal, Ahmed M; Elawdy, Mohamed M; Omar, Helmy; Gaber, Asaad; Elsawy, Essam; El-Nahas, Ahmed R

    2016-08-01

    Stone culture has been frequently investigated following percutaneous nephrolithotomy (PNL) in the last decade. We aimed to crucially define the clinical role of stone culture in modifying the treatment plan in patients with postoperative sepsis. Between June 2012 and April 2013, a total of 79 consecutive PNL procedures were included. Perioperative data were prospectively maintained. Preoperative urine sample, retrieved stone fragments and postoperative nephrostomy tube urine sample were cultured and antibiotic sensitivity tests were performed. The occurrence of at least two of the systemic inflammatory response syndrome (SIRS) events during their inpatient stay was diagnostic of SIRS. The antibiotic regimen utilized and its modifications were reported. The preoperative culture was positive in 26 patients (32.9 %). The culture of stone fragments showed significant bacterial growth in 23 (29.1 %) cases. Significant growth on stone culture was significantly associated with the presence of preoperative urinary catheters and positive preoperative urine culture (P = 0.001, 0.006 respectively). Postoperative culture was positive in only six patients (7.6 %). SIRS was diagnosed in the first postoperative day in 12 patients (15.2 %). Leukocytosis was the only predictor of SIRS. Neither preoperative culture, stone culture nor postoperative culture was predictor of SIRS. Stone culture was positive in four patients with SIRS. Stone culture changed the treatment plan in only one patient. Our data do not support the routine implementation of stone culture in the PNL workup, as it did not indicate a change of antibiotic regimen in most of the cases. PMID:26781741

  18. Phylogenetic Relationships Matter: Antifungal Susceptibility among Clinically Relevant Yeasts

    PubMed Central

    Schmalreck, A. F.; Becker, K.; Fegeler, W.; Czaika, V.; Ulmer, H.; Lass-Flörl, C.

    2014-01-01

    The objective of this study was 2-fold: to evaluate whether phylogenetically closely related yeasts share common antifungal susceptibility profiles (ASPs) and whether these ASPs can be predicted from phylogeny. To address this question, 9,627 yeast strains were collected and tested for their antifungal susceptibility. Isolates were reidentified by considering recent changes in taxonomy and nomenclature. A phylogenetic (PHYLO) code based on the results of multilocus sequence analyses (large-subunit rRNA, small-subunit rRNA, translation elongation factor 1α, RNA polymerase II subunits 1 and 2) and the classification of the cellular neutral sugar composition of coenzyme Q and 18S ribosomal DNA was created to group related yeasts into PHYLO groups. The ASPs were determined for fluconazole, itraconazole, and voriconazole in each PHYLO group. The majority (95%) of the yeast strains were Ascomycetes. After reclassification, a total of 23 genera and 54 species were identified, resulting in an increase of 64% of genera and a decrease of 5% of species compared with the initial identification. These taxa were assigned to 17 distinct PHYLO groups (Ascomycota, n = 13; Basidiomycota, n = 4). ASPs for azoles were similar among members of the same PHYLO group and different between the various PHYLO groups. Yeast phylogeny may be an additional tool to significantly enhance the assessment of MIC values and to predict antifungal susceptibility, thereby more rapidly initiating appropriate patient management. PMID:24366735

  19. Transitional cardiovascular physiology and comprehensive hemodynamic monitoring in the neonate: relevance to research and clinical care.

    PubMed

    Azhibekov, Timur; Noori, Shahab; Soleymani, Sadaf; Seri, Istvan

    2014-02-01

    A thorough understanding of developmental cardiovascular physiology is essential for early recognition of cardiovascular compromise, selective screening of at-risk groups of neonates, and individualized management using pathophysiology-targeted interventions. Although we have gained a better understanding of the physiology and pathophysiology of postnatal cardiovascular transition over the past decade with the use of sophisticated methods to study neonatal hemodynamics, most aspects of neonatal hemodynamics remain incompletely understood. In addition, targeted therapeutic interventions of neonatal hemodynamic compromise have not been shown to improve mortality and clinically relevant outcomes. However, the recent development of comprehensive hemodynamic monitoring systems capable of non-invasive, continuous and simultaneous bedside assessment of cardiac output, organ blood flow, microcirculation, and tissue oxygen delivery has made sophisticated analysis of the obtained physiologic data possible and has created new research opportunities with the potential of direct implications to patient care.

  20. Prognostic Factors Toward Clinically Relevant Radiographic Progression in Patients With Rheumatoid Arthritis in Clinical Practice

    PubMed Central

    Koga, Tomohiro; Okada, Akitomo; Fukuda, Takaaki; Hidaka, Toshihiko; Ishii, Tomonori; Ueki, Yukitaka; Kodera, Takao; Nakashima, Munetoshi; Takahashi, Yuichi; Honda, Seiyo; Horai, Yoshiro; Watanabe, Ryu; Okuno, Hiroshi; Aramaki, Toshiyuki; Izumiyama, Tomomasa; Takai, Osamu; Miyashita, Taiichiro; Sato, Shuntaro; Kawashiri, Shin-ya; Iwamoto, Naoki; Ichinose, Kunihiro; Tamai, Mami; Origuchi, Tomoki; Nakamura, Hideki; Aoyagi, Kiyoshi; Eguchi, Katsumi; Kawakami, Atsushi

    2016-01-01

    Abstract To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) in clinical practice. We performed a multicenter prospective study in Japan of biological disease-modifying antirheumatic drug (bDMARD)-naive RA patients with moderate to high disease activity treated with conventional synthetic DMARDs (csDMARDs) at study entry. We longitudinally observed 408 patients for 1 year and assessed disease activity every 3 months. CRRP was defined as yearly progression of modified total Sharp score (mTSS) > 3.0 U. We also divided the cohort into 2 groups based on disease duration (<3 vs ≥3 years) and performed a subgroup analysis. CRRP was found in 10.3% of the patients. A multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: CRP at baseline (0.30 mg/dL increase, 95% confidence interval [CI] 1.01–1.11), time-integrated Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) during the 1 year postbaseline (12.4-unit increase, 95%CI 1.17–2.59), RA typical erosion at baseline (95%CI 1.56–21.1), and the introduction of bDMARDs (95%CI 0.06–0.38). The subgroup analysis revealed that time-integrated DAS28-ESR is not a predictor whereas the introduction of bDMARDs is a significant protective factor for CRRP in RA patients with disease duration <3 years. We identified factors that could be used to predict the development of CRRP in RA patients treated with DMARDs. These variables appear to be different based on the RA patients’ disease durations. PMID:27124044

  1. Clonal spread and interspecies transmission of clinically relevant ESBL-producing Escherichia coli of ST410--another successful pandemic clone?

    PubMed

    Schaufler, Katharina; Semmler, Torsten; Wieler, Lothar H; Wöhrmann, Michael; Baddam, Ramani; Ahmed, Niyaz; Müller, Kerstin; Kola, Axel; Fruth, Angelika; Ewers, Christa; Guenther, Sebastian

    2016-01-01

    Clinically relevant extended-spectrum beta-lactamase (ESBL)-producing multi-resistant Escherichia coli have been on the rise for years. Initially restricted to mostly a clinical context, recent findings prove their prevalence in extraclinical settings independent of the original occurrence of antimicrobial resistance in the environment. To get further insights into the complex ecology of potentially clinically relevant ESBL-producing E. coli, 24 isolates from wild birds in Berlin, Germany, and 40 ESBL-producing human clinical E. coli isolates were comparatively analyzed. Isolates of ST410 occurred in both sample groups (six). In addition, three ESBL-producing E. coli isolates of ST410 from environmental dog feces and one clinical dog isolate were included. All 10 isolates were clonally analyzed showing almost identical macrorestriction patterns. They were chosen for whole-genome sequencing revealing that the whole-genome content of these 10 E. coli isolates showed a very high genetic similarity, differing by low numbers of single nucleotide polymorphisms only. This study gives initial evidence for a recent interspecies transmission of a new successful clone of ST410 E. coli between wildlife, humans, companion animals and the environment. The results underline the zoonotic potential of clinically relevant multi-resistant bacteria found in the environment as well as the mandatory nature of the 'One Health' approach.

  2. Clonal spread and interspecies transmission of clinically relevant ESBL-producing Escherichia coli of ST410--another successful pandemic clone?

    PubMed

    Schaufler, Katharina; Semmler, Torsten; Wieler, Lothar H; Wöhrmann, Michael; Baddam, Ramani; Ahmed, Niyaz; Müller, Kerstin; Kola, Axel; Fruth, Angelika; Ewers, Christa; Guenther, Sebastian

    2016-01-01

    Clinically relevant extended-spectrum beta-lactamase (ESBL)-producing multi-resistant Escherichia coli have been on the rise for years. Initially restricted to mostly a clinical context, recent findings prove their prevalence in extraclinical settings independent of the original occurrence of antimicrobial resistance in the environment. To get further insights into the complex ecology of potentially clinically relevant ESBL-producing E. coli, 24 isolates from wild birds in Berlin, Germany, and 40 ESBL-producing human clinical E. coli isolates were comparatively analyzed. Isolates of ST410 occurred in both sample groups (six). In addition, three ESBL-producing E. coli isolates of ST410 from environmental dog feces and one clinical dog isolate were included. All 10 isolates were clonally analyzed showing almost identical macrorestriction patterns. They were chosen for whole-genome sequencing revealing that the whole-genome content of these 10 E. coli isolates showed a very high genetic similarity, differing by low numbers of single nucleotide polymorphisms only. This study gives initial evidence for a recent interspecies transmission of a new successful clone of ST410 E. coli between wildlife, humans, companion animals and the environment. The results underline the zoonotic potential of clinically relevant multi-resistant bacteria found in the environment as well as the mandatory nature of the 'One Health' approach. PMID:26656065

  3. Clinically-Relevant Measures Associated with Altered Contact Forces in Patients with Anterior Cruciate Ligament Deficiency

    PubMed Central

    Gardinier, Emily S.; Manal, Kurt; Buchanan, Thomas S.; Snyder-Mackler, Lynn

    2014-01-01

    Background Knee joint contact forces are altered after anterior cruciate ligament injury during walking and may be related to clinically-relevant measures of impairments or self-reported function. The purpose of this study was to investigate the association of several clinically-relevant measures with altered knee contact forces in patients with anterior cruciate ligament injury. Methods Data for this study represent a cross-sectional observational analysis of thirty-seven (23 M, 14 F) patients with complete unilateral anterior cruciate ligament injury. Gait analysis with electromyography was used to obtain estimates of tibiofemoral joint contact force using an electromyography-driven musculoskeletal model. Multivariable linear regression was used to identify measures associated with tibiofemoral joint contact force. Findings Involved knee extensor muscle strength and patient-reported knee function on the Global Rating Scale of Perceived Function were significantly associated with peak tibiofemoral contact force for the involved limb. Patients who were stronger and who perceived higher knee function walked with greater contact forces on their involved knees. After controlling for walking speed, involved extensor strength explained 8.9% of the variance in involved peak tibiofemoral contact force and score on the Global Rating Scale explained an additional 9.4% of the variance. Interpretation Improvements in involved quadriceps strength and overall function as measured by patient self-report may be important for increasing involved limb contact forces, thereby restoring loading symmetry in these patients who demonstrate decreased involved limb loading after injury. These results highlight the potential value of studying the recovery of strength, self-reported function and joint loading symmetry in patients with anterior cruciate ligament injury. PMID:24746854

  4. Early Benefit Assessments in Oncology in Germany: How Can a Clinically Relevant Endpoint Not Be Relevant to Patients?

    PubMed

    Ruof, Jörg; Flückiger, Olivier; Andre, Niko

    2015-09-01

    After 4 years of early benefit assessment (EBA) in Germany, it is becoming evident that the Federal Joint Committee (FJC) frequently considers well-established clinical endpoints as not being relevant to patients. Focusing on assessments of oncology medicines, we analysed the FJC's view on primary endpoints and compared it with the approach used by regulatory authorities. Mortality data were accepted by both stakeholders. Whereas regulatory authorities accepted primary morbidity endpoints such as progression-free survival and response rates, the FJC mostly excluded these from its assessments. Health-related quality of life (HRQoL) data have been poorly reflected in the approval process; for EBAs, those data have rarely impacted on benefit ratings. We argue that agreement between regulatory authorities and the FJC is required regarding primary study endpoints that are relevant to patients, and that clarification of acceptable endpoints by the FJC, especially in the morbidity domain, has to be provided. Moreover, in order to fully acknowledge the benefit of a new medicinal product, mortality, morbidity and HRQoL should be weighted differentially, according to the condition. PMID:26286202

  5. Sample Level Enrichment Analysis of KEGG Pathways Identifies Clinically Relevant Subtypes of Glioblastoma

    PubMed Central

    Wanggou, Siyi; Feng, Chengyuan; Xie, Yuanyang; Ye, Linrong; Wang, Feiyifan; Li, Xuejun

    2016-01-01

    Background: Glioblastoma is the most lethal primary brain tumor in adults. Aberrant signal transduction pathways, associated with the progression of glioblastoma, have been identified recently and may offer a potential gene therapy strategy. Methods and Findings: We first used the sample level enrichment analysis to transfer gene expression profile of TCGA dataset into pathway enrichment z-score matrix. Then, we classified glioblastoma into five subtypes (Cluster A to Cluster E) by the consensus clustering and silhouette analysis. Principle component analysis showed the five subtype could be separated by first three principle components. Integrative omics data showed that mesenchymal subtype was rich in Cluster A, neural subtype was centered in Cluster D and proneural subtype was gathered in Cluster E, while Cluster E showed a high percentage of G-CIMP subtype. Additionally, according to analyze the overall survival and progression free survival of each subtype by Kaplan-Merie analysis and Cox hazard proportion model, we identified Cluster D and Cluster E received a better prognosis. Conclusions: We report a clinically relevant classification of glioblastoma based on sample level KEGG pathway enrichment profile and this novel classification system provided new insights into the heterogeneity of glioblastoma, and may be used as an important clinical tool to predict the prognosis.

  6. Using Language Models to Identify Relevant New Information in Inpatient Clinical Notes

    PubMed Central

    Zhang, Rui; Pakhomov, Serguei V.; Lee, Janet T.; Melton, Genevieve B.

    2014-01-01

    Redundant information in clinical notes within electronic health record (EHR) systems is ubiquitous and may negatively impact the use of these notes by clinicians, and, potentially, the efficiency of patient care delivery. Automated methods to identify redundant versus relevant new information may provide a valuable tool for clinicians to better synthesize patient information and navigate to clinically important details. In this study, we investigated the use of language models for identification of new information in inpatient notes, and evaluated our methods using expert-derived reference standards. The best method achieved precision of 0.743, recall of 0.832 and F1-measure of 0.784. The average proportion of redundant information was similar between inpatient and outpatient progress notes (76.6% (SD=17.3%) and 76.7% (SD=14.0%), respectively). Advanced practice providers tended to have higher rates of redundancy in their notes compared to physicians. Future investigation includes the addition of semantic components and visualization of new information. PMID:25954438

  7. Power and sample size determination when assessing the clinical relevance of trial results by 'responder analyses'.

    PubMed

    Kieser, Meinhard; Röhmel, Joachim; Friede, Tim

    2004-11-15

    A fundamental issue in regulatory decision making is the assessment of the benefit/risk profile of a compound. In order to do this, establishing the existence of a treatment effect by a significance test is not sufficient, but the clinical relevance of a potential benefit must also be taken into account. A number of regulatory guidelines propose that clinical relevance should be assessed by considering the rate of responders, i.e. the proportion of patients who are observed to achieve an apparently meaningful benefit. In this paper, we present methods for planning clinical trials that aim at demonstrating both statistical and clinical significance in superiority trials. Procedures based on analytical calculations are derived for normally distributed data and the case of a single endpoint as well as multiple primary outcomes. A bootstrap procedure is proposed that can be applied to non-normal data. Application is illustrated by a clinical trial in Alzheimer's disease. PMID:15490433

  8. The Clinical Urine Culture: Enhanced Techniques Improve Detection of Clinically Relevant Microorganisms

    PubMed Central

    Price, Travis K.; Dune, Tanaka; Hilt, Evann E.; Thomas-White, Krystal J.; Kliethermes, Stephanie; Brincat, Cynthia; Brubaker, Linda; Wolfe, Alan J.

    2016-01-01

    Enhanced quantitative urine culture (EQUC) detects live microorganisms in the vast majority of urine specimens reported as “no growth” by the standard urine culture protocol. Here, we evaluated an expanded set of EQUC conditions (expanded-spectrum EQUC) to identify an optimal version that provides a more complete description of uropathogens in women experiencing urinary tract infection (UTI)-like symptoms. One hundred fifty adult urogynecology patient-participants were characterized using a self-completed validated UTI symptom assessment (UTISA) questionnaire and asked “Do you feel you have a UTI?” Women responding negatively were recruited into the no-UTI cohort, while women responding affirmatively were recruited into the UTI cohort; the latter cohort was reassessed with the UTISA questionnaire 3 to 7 days later. Baseline catheterized urine samples were plated using both standard urine culture and expanded-spectrum EQUC protocols: standard urine culture inoculated at 1 μl onto 2 agars incubated aerobically; expanded-spectrum EQUC inoculated at three different volumes of urine onto 7 combinations of agars and environments. Compared to expanded-spectrum EQUC, standard urine culture missed 67% of uropathogens overall and 50% in participants with severe urinary symptoms. Thirty-six percent of participants with missed uropathogens reported no symptom resolution after treatment by standard urine culture results. Optimal detection of uropathogens could be achieved using the following: 100 μl of urine plated onto blood (blood agar plate [BAP]), colistin-nalidixic acid (CNA), and MacConkey agars in 5% CO2 for 48 h. This streamlined EQUC protocol achieved 84% uropathogen detection relative to 33% detection by standard urine culture. The streamlined EQUC protocol improves detection of uropathogens that are likely relevant for symptomatic women, giving clinicians the opportunity to receive additional information not currently reported using standard urine culture

  9. A Model of Auditory-Cognitive Processing and Relevance to Clinical Applicability.

    PubMed

    Edwards, Brent

    2016-01-01

    Hearing loss and cognitive function interact in both a bottom-up and top-down relationship. Listening effort is tied to these interactions, and models have been developed to explain their relationship. The Ease of Language Understanding model in particular has gained considerable attention in its explanation of the effect of signal distortion on speech understanding. Signal distortion can also affect auditory scene analysis ability, however, resulting in a distorted auditory scene that can affect cognitive function, listening effort, and the allocation of cognitive resources. These effects are explained through an addition to the Ease of Language Understanding model. This model can be generalized to apply to all sounds, not only speech, representing the increased effort required for auditory environmental awareness and other nonspeech auditory tasks. While the authors have measures of speech understanding and cognitive load to quantify these interactions, they are lacking measures of the effect of hearing aid technology on auditory scene analysis ability and how effort and attention varies with the quality of an auditory scene. Additionally, the clinical relevance of hearing aid technology on cognitive function and the application of cognitive measures in hearing aid fittings will be limited until effectiveness is demonstrated in real-world situations. PMID:27355775

  10. Excitotoxic food additives--relevance of animal studies to human safety.

    PubMed

    Olney, J W

    1984-01-01

    Evidence is reviewed supporting the view that excitotoxic food additives pose a significant hazard to the developing nervous system of young children. The following points are stressed: (1) although blood-brain barriers protect most central neurons from excitotoxins, certain brain regions lack such protection (a characteristic common to all vertebrate species); (2) regardless of species, it requires only a transient increase in blood excitotoxin levels for neurons in unprotected brain regions to be "silently" destroyed; (3) humans may be at particularly high risk for this kind of brain damage, since ingestion of a given amount of excitotoxin causes much higher blood excitotoxin levels in humans than in other species; (4) in addition to the heightened risk on a species basis, risk may be further increased for certain consumer sub-populations due to youth, disease or genetic factors; (5) despite these reasons for maintaining a wide margin of safety in the use of excitotoxins in foods, no safety margin is currently being observed, i.e., a comparative evaluation of animal (extensive) and human (limited) data supports the conclusion that excitotoxins, as used in foods today, may produce blood elevations high enough to cause damage to the nervous system of young children, damage which is not detectable at the time of occurrence but which may give rise to subtle disturbances in neuroendocrine function in adolescence and/or adulthood.

  11. How relevant is undergraduate medical law teaching to clinical practice? A graduates' perspective.

    PubMed

    Koehler, Nicole; McMenamin, Christine

    2012-12-01

    The Monash University medical law tutorial program was implemented in 2002. A major aim of this program is to enable medical students to recognise and understand their legal obligations in clinical practice, thereby improving clinical standards and contributing to better patient outcomes. The present study examined whether, from a graduate perspective, the medical law tutorial program provides adequate legal information of relevance for a clinical context. Monash University medical graduates from 2007 to 2009 who were working at a Victorian hospital or who were members of the Royal Australian College of General Practitioners were invited to participate in the study. Fifty-six participants completed the survey. Overall, participants had positive perceptions of the medical law program. The medical law program is an essential component of students' medical education and provides information relevant to future clinical practice.

  12. A Bridge between Two Cultures: Uncovering the Chemistry Concepts Relevant to the Nursing Clinical Practice

    ERIC Educational Resources Information Center

    Brown, Corina E.; Henry, Melissa L. M.; Barbera, Jack; Hyslop, Richard M.

    2012-01-01

    This study focused on the undergraduate course that covers basic topics in general, organic, and biological (GOB) chemistry at a mid-sized state university in the western United States. The central objective of the research was to identify the main topics of GOB chemistry relevant to the clinical practice of nursing. The collection of data was…

  13. Clinically Relevant Changes in Emotional Expression in Children with ADHD Treated with Lisdexamfetamine Dimesylate

    ERIC Educational Resources Information Center

    Katic, Alain; Ginsberg, Lawrence; Jain, Rakesh; Adeyi, Ben; Dirks, Bryan; Babcock, Thomas; Scheckner, Brian; Richards, Cynthia; Lasser, Robert; Turgay, Atilla; Findling, Robert L.

    2012-01-01

    Objective: To describe clinically relevant effects of lisdexamfetamine dimesylate (LDX) on emotional expression (EE) in children with ADHD. Method: Children with ADHD participated in a 7-week, open-label, LDX dose-optimization study. Expression and Emotion Scale for Children (EESC) change scores were analyzed post hoc using two methods to…

  14. There’s an App for That? Highlighting the Difficulty in Finding Clinically Relevant Smartphone Applications

    PubMed Central

    Wiechmann, Warren; Kwan, Daniel; Bokarius, Andrew; Toohey, Shannon L.

    2016-01-01

    Introduction The use of personal mobile devices in the medical field has grown quickly, and a large proportion of physicians use their mobile devices as an immediate resource for clinical decision-making, prescription information and other medical information. The iTunes App Store (Apple, Inc.) contains approximately 20,000 apps in its “Medical” category, providing a robust repository of resources for clinicians; however, this represents only 2% of the entire App Store. The App Store does not have strict criteria for identifying content specific to practicing physicians, making the identification of clinically relevant content difficult. The objective of this study is to quantify the characteristics of existing medical applications in the iTunes App Store that could be used by emergency physicians, residents, or medical students. Methods We found applications related to emergency medicine (EM) by searching the iTunes App Store for 21 terms representing core content areas of EM, such as “emergency medicine,” “critical care,” “orthopedics,” and “procedures.” Two physicians independently reviewed descriptions of these applications in the App Store and categorized each as the following: Clinically Relevant, Book/Published Source, Non-English, Study Tools, or Not Relevant. A third physician reviewer resolved disagreements about categorization. Descriptive statistics were calculated. Results We found a total of 7,699 apps from the 21 search terms, of which 17.8% were clinical, 9.6% were based on a book or published source, 1.6% were non-English, 0.7% were clinically relevant patient education resources, and 4.8% were study tools. Most significantly, 64.9% were considered not relevant to medical professionals. Clinically relevant apps make up approximately 6.9% of the App Store’s “Medical” Category and 0.1% of the overall App Store. Conclusion Clinically relevant apps represent only a small percentage (6.9%) of the total App volume within the

  15. Developments in FINDbase worldwide database for clinically relevant genomic variation allele frequencies.

    PubMed

    Papadopoulos, Petros; Viennas, Emmanouil; Gkantouna, Vassiliki; Pavlidis, Cristiana; Bartsakoulia, Marina; Ioannou, Zafeiria-Marina; Ratbi, Ilham; Sefiani, Abdelaziz; Tsaknakis, John; Poulas, Konstantinos; Tzimas, Giannis; Patrinos, George P

    2014-01-01

    FINDbase (http://www.findbase.org) aims to document frequencies of clinically relevant genomic variations, namely causative mutations and pharmacogenomic markers, worldwide. Each database record includes the population, ethnic group or geographical region, the disorder name and the related gene, accompanied by links to any related databases and the genetic variation together with its frequency in that population. Here, we report, in addition to the regular data content updates, significant developments in FINDbase, related to data visualization and querying, data submission, interrelation with other resources and a new module for genetic disease summaries. In particular, (i) we have developed new data visualization tools that facilitate data querying and comparison among different populations, (ii) we have generated a new FINDbase module, built around Microsoft's PivotViewer (http://www.getpivot.com) software, based on Microsoft Silverlight technology (http://www.silverlight.net), that includes 259 genetic disease summaries from five populations, systematically collected from the literature representing the documented genetic makeup of these populations and (iii) the implementation of a generic data submission tool for every module currently available in FINDbase.

  16. Characterization and identification of clinically relevant microorganisms using rapid evaporative ionization mass spectrometry.

    PubMed

    Strittmatter, Nicole; Rebec, Monica; Jones, Emrys A; Golf, Ottmar; Abdolrasouli, Alireza; Balog, Julia; Behrends, Volker; Veselkov, Kirill A; Takats, Zoltan

    2014-07-01

    Rapid evaporative ionization mass spectrometry (REIMS) was investigated for its suitability as a general identification system for bacteria and fungi. Strains of 28 clinically relevant bacterial species were analyzed in negative ion mode, and corresponding data was subjected to unsupervised and supervised multivariate statistical analyses. The created supervised model yielded correct cross-validation results of 95.9%, 97.8%, and 100% on species, genus, and Gram-stain level, respectively. These results were not affected by the resolution of the mass spectral data. Blind identification tests were performed for strains cultured on different culture media and analyzed using different instrumental platforms which led to 97.8-100% correct identification. Seven different Escherichia coli strains were subjected to different culture conditions and were distinguishable with 88% accuracy. In addition, the technique proved suitable to distinguish five pathogenic Candida species with 98.8% accuracy without any further modification to the experimental workflow. These results prove that REIMS is sufficiently specific to serve as a culture condition-independent tool for the identification and characterization of microorganisms.

  17. Comparative Transcriptional Analysis of Clinically Relevant Heat Stress Response in Clostridium difficile Strain 630

    PubMed Central

    Ternan, Nigel G.; Jain, Shailesh; Srivastava, Malay; McMullan, Geoff

    2012-01-01

    Clostridium difficile is considered to be one of the most important causes of health care-associated infections worldwide. In order to understand more fully the adaptive response of the organism to stressful conditions, we examined transcriptional changes resulting from a clinically relevant heat stress (41°C versus 37°C) in C. difficile strain 630 and identified 341 differentially expressed genes encompassing multiple cellular functional categories. While the transcriptome was relatively resilient to the applied heat stress, we noted upregulation of classical heat shock genes including the groEL and dnaK operons in addition to other stress-responsive genes. Interestingly, the flagellin gene (fliC) was downregulated, yet genes encoding the cell-wall associated flagellar components were upregulated suggesting that while motility may be reduced, adherence – to mucus or epithelial cells – could be enhanced during infection. We also observed that a number of phage associated genes were downregulated, as were genes associated with the conjugative transposon Tn5397 including a group II intron, thus highlighting a potential decrease in retromobility during heat stress. These data suggest that maintenance of lysogeny and genome wide stabilisation of mobile elements could be a global response to heat stress in this pathogen. PMID:22860125

  18. Anatomical Description and Clinical Relevance of a Rare Variation in the Mesenteric Arterial Arcade Pattern

    PubMed Central

    Hansdak, Ranjeeta; Thakur, Avinash; Mehta, Vandana; Rath, Gayatri

    2015-01-01

    Solitary vascular variations of the mesenteric arteries are extremely rare and have been seldom reported in the past. The aim of this study is to emphasize the anatomical and clinical relevance of one such rare variation of inferior mesenteric artery (IMA). The current case anomaly was incidentally observed while guiding the undergraduate medical students in the dissection of the mesenteric region of the abdomen in an Indian cadaver. An Accessory left colic artery was seen to be branching off from the Inferior Mesenteric artery and further dividing into two transverse branches which took part in the formation of arterial arc for the perfusion of the transverse and the descending colon. Awareness of such aberrant branches of Inferior Mesenteric artery helps in optimal selection of the mode of treatment or operative planning. Additionally, this knowledge minimizes possible iatrogenic injuries resulting from surgeries. Moreover, surgical anatomy of anomalous branches of Inferior Mesenteric artery is extremely essential for planning and successfully executing reconstructive procedures using these branches as pedicles for the transposed part of the colon. PMID:26435936

  19. Marine omega-3 fatty acids and inflammatory processes: Effects, mechanisms and clinical relevance.

    PubMed

    Calder, Philip C

    2015-04-01

    Inflammation is a condition which contributes to a range of human diseases. It involves a multitude of cell types, chemical mediators, and interactions. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 (n-3) fatty acids found in oily fish and fish oil supplements. These fatty acids are able to partly inhibit a number of aspects of inflammation including leukocyte chemotaxis, adhesion molecule expression and leukocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines, and T-helper 1 lymphocyte reactivity. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of marine n-3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti-inflammatory transcription factor peroxisome proliferator activated receptor γ and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked, although the full extent of this is not yet elucidated. Animal experiments demonstrate benefit from marine n-3 fatty acids in models of rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in RA demonstrate benefit, but clinical trials of fish oil in IBD and asthma are inconsistent with no overall clear evidence of efficacy. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance". PMID:25149823

  20. A Software System to Collect Expert Relevance Ratings of Medical Record Items for Specific Clinical Tasks

    PubMed Central

    Krishnaraj, Arun; Alkasab, Tarik K

    2014-01-01

    Development of task-specific electronic medical record (EMR) searches and user interfaces has the potential to improve the efficiency and safety of health care while curbing rising costs. The development of such tools must be data-driven and guided by a strong understanding of practitioner information requirements with respect to specific clinical tasks or scenarios. To acquire this important data, this paper describes a model by which expert practitioners are leveraged to identify which components of the medical record are most relevant to a specific clinical task. We also describe the computer system that was created to efficiently implement this model of data gathering. The system extracts medical record data from the EMR of patients matching a given clinical scenario, de-identifies the data, breaks the data up into separate medical record items (eg, radiology reports, operative notes, laboratory results, etc), presents each individual medical record item to experts under the hypothetical of the given clinical scenario, and records the experts’ ratings regarding the relevance of each medical record item to that specific clinical scenario or task. After an iterative process of data collection, these expert relevance ratings can then be pooled and used to design point-of-care EMR searches and user interfaces tailored to the task-specific needs of practitioners. PMID:25600925

  1. Clinical challenges and the relevance of materials testing for posterior composite restorations.

    PubMed

    Sarrett, David C

    2005-01-01

    Posterior composite restorations have been in use for approximately 30 years. The early experiences with this treatment indicated there were more clinical challenges and higher failure rates than amalgam restorations. Since the early days of posterior composites, many improvements in materials, techniques, and instruments for placing these restorations have occurred. This paper reviews what is known regarding current clinical challenges with posterior composite restorations and reviews the primary method for collecting clinical performance data. This review categorizes the challenges as those related to the restorative materials, those related to the dentist, and those related to the patient. The clinical relevance of laboratory tests is discussed from the perspective of solving the remaining clinical challenges of current materials and of screening new materials. The clinical problems related to early composite materials are no longer serious clinical challenges. Clinical data indicate that secondary caries and restoration fracture are the most common clinical problems and merit further investigation. The effect of the dentist and patient on performance of posterior composite restorations is unclear and more clinical data from hypothesis-driven clinical trials are needed to understand these factors. Improvements in handling properties to ensure void-free placement and complete cure should be investigated to improve clinical outcomes. There is a general lack of data that correlates clinical performance with laboratory materials testing. A proposed list of materials tests that may predict performance in a variety of clinical factors is presented. Polymerization shrinkage and the problems that have been attributed to this property of composite are reviewed. There is a lack of evidence that indicates polymerization shrinkage is the primary cause of secondary caries. It is recommended that composite materials be developed with antibacterial properties as a way of

  2. Music's relevance for children with cancer: music therapists' qualitative clinical data-mining research.

    PubMed

    O'Callaghan, Clare; Dun, Beth; Baron, Annette; Barry, Philippa

    2013-01-01

    Music is central in most children's lives. Understanding its relevance will advance efficacious pediatric supportive cancer care. Qualitative clinical data-mining uncovered four music therapists' perspectives about music and music therapy's relevance for pediatric oncology patients up to 14 years old. Inductive and comparative thematic analysis was performed on focus group transcripts and qualitative interrater reliability integrated. Music can offer children a safe haven for internalizing a healthy self-image alongside patient identity. Music therapy can calm, relieve distress, promote supportive relationships, enable self-care, and inspire playful creativity, associated with "normalcy" and hope. Preferred music and music therapy should be available in pediatric oncology. PMID:23521381

  3. Clinical relevance of as-needed treatment with nalmefene in alcohol-dependent patients.

    PubMed

    Aubin, Henri-Jean; Reimer, Jens; Nutt, David J; Bladström, Anna; Torup, Lars; François, Clément; Chick, Jonathan

    2015-01-01

    Nalmefene is the first drug approved for reduction of alcohol consumption. The aim of this study was to evaluate the clinical relevance of treatment with nalmefene in alcohol-dependent patients with a high drinking risk level from two randomised placebo-controlled 6-month studies (NCT00811720 and NCT00812461). Response criteria were based on alcohol consumption, Clinical Global Impression, and Short Form Health Survey mental component summary scores at month 6, analysed using logistic regression. The proportion of responders was higher in the nalmefene group than in the placebo group with odds ratios significantly in favour of nalmefene for all responder criteria; numbers-needed-to-treat ranged from 6 to 10. Significant differences from placebo in clinician-rated and patient-reported outcomes, and liver enzymes further supported the clinical relevance of the treatment effect. In conclusion, this study supports the clinical relevance of nalmefene treatment in patients with alcohol dependence. Nalmefene may help to reduce the alcohol-related burden and the large treatment gap, with currently less than 10% of alcohol-dependent patients in Europe receiving treatment.

  4. Improving biological relevancy of transcriptional biomarkers experiments by applying the MIQE guidelines to pre-clinical and clinical trials.

    PubMed

    Dooms, M; Chango, A; Barbour, E; Pouillart, P; Abdel Nour, A M

    2013-01-01

    The "Minimum Information for the Publication of qPCR Experiments" (MIQE [3]) guidelines are very much targeted at basic research experiments and have to our knowledge not been applied to qPCR assays carried out in the context of clinical trials. This report details the use of the MIQE qPCR app for iPhone (App Store, Apple) to assess the MIQE compliance of one clinical and five pre-clinical trials. This resulted in the need to include 14 modifications that make the guidelines more relevant for the assessment of this special type of application. We also discuss the need for flexibility, since while some parameters increase experimental quality, they also require more reagents and more time, which is not always feasible in a clinical setting. PMID:22910527

  5. Interference of cationic polymeric nanoparticles with clinical chemistry tests--clinical relevance.

    PubMed

    Shcharbin, Dzmitry; Shcharbina, Natallia; Milowska, Katarzyna; de la Mata, Francisco Javier; Muñoz-Fernandez, Maria Angeles; Mignani, Serge; Gomez-Ramirez, Rafael; Majoral, Jean-Pierre; Bryszewska, Maria

    2014-10-01

    The development of medical nanosystems requires knowledge of their behavior in vivo. Clinical chemistry tests are widely used to estimate the systemic toxicity of nanoparticles. In this paper we have explored the impact of small positively charged nanoparticles-poly(amidoamine), phosphorous and carbosilane dendrimers - on biochemical parameters of standardized serum in vitro. All the dendrimers could shift the main biochemical parameters. Thus, in the case of patients having the normal, but 'boundary', values of biochemical parameters, nanoparticle-induced changes can be wrongly interpreted as evidence of some dysfunctions (hepatic, renal, etc.). Moreover, the effects of nanoparticles of metals, carbon nanotubes, quantum dots, fullerenes, dendrimers having been sized up to 4000 nm and the hundreds of reactive groups, can be significantly higher. Thus, preliminary evaluation of any nanomaterial in vitro is required in clinical chemistry tests before its application in vivo to draw the correct conclusions and benefit animals.

  6. Clinically relevant exaggerated pharmacodynamic response to dual antiplatelet therapy detected by Thromboelastogram® Platelet Mapping™

    PubMed Central

    Hiller, Kenneth N.

    2016-01-01

    Dual antiplatelet therapy (DAPT) is the standard of care for primary and secondary prevention strategies in patients with coronary artery disease after stenting. Current guidelines recommend that DAPT be continued for 12 months in patients after receiving drug eluting stents. Approximately 5% of these patients will present within this 12-month period for noncardiac surgery. This case report describes a clinically relevant exaggerated pharmacodynamic response to DAPT detected by preoperative assessment of platelet function. Based on the clinical history and physical exam and subsequent lab results, a general anesthetic was performed rather than a spinal anesthetic and the surgical procedure was changed. An exaggerated pharmacodynamic response to DAPT poses its own set of risks (unexpected uncontrolled bleeding, epidural hematoma following neuraxial block placement) that point-of-care aggregation testing may decrease or mitigate by altering clinical decision making. If the clinical history and physical exam reveal possible platelet dysfunction in patients receiving DAPT, preoperative platelet function testing should be considered. PMID:27006555

  7. Clinically Relevant Transmitted Drug Resistance to First Line Antiretroviral Drugs and Implications for Recommendations

    PubMed Central

    Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Peña, Alejandro; Delgado, Rafael; Córdoba, Juan; Aguilera, Antonio; Vidal, Carmen; García, Federico; CoRIS

    2014-01-01

    Background The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. Methods We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007–2011. Using the Stanford algorithm “Low-level resistance”, “Intermediate resistance” and “High-level resistance” categories were considered as “Resistant”. Results 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8–7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9–9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8–2.9) vs. 3.6% (2.9–4.3) by the WHO list] and PIs [0.8% (0.4–1.1) vs. 1.7% (1.2–2.2)], while it was higher for NNRTIs [4.6% (3.8–5.3) vs. 3.7% (3.0–4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02). Conclusions Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations. PMID:24637804

  8. Detection of clinically relevant levels of protein analyte under physiologic buffer using planar field effect transistors.

    PubMed

    Gupta, Samit; Elias, Mark; Wen, Xuejin; Shapiro, John; Brillson, Leonard; Lu, Wu; Lee, Stephen Craig

    2008-12-01

    Electrochemical detection of protein binding at physiological salt concentration by planar field effect transistor platforms has yet to be documented convincingly. Here we report detection of streptavidin and clinically relevant levels of biotinylated monokine induced by interferon gamma (MIG) at physiological salt concentrations with AlGaN heterojunction field effect transistors (HFETs). The AlGaN HFETs are functionalized with a silane linker and analyte-specific affinity elements. Polarity of sensor responses is as expected from n-type HFETs to negatively and positively charged analytes. Sensitivity of the HFET sensors increases when salt concentration decreases, and the devices also exhibit dose-dependent responses to analyte. Detection of clinically relevant MIG concentrations at physiological salt levels demonstrates the potential for AlGaN devices to be used in development of in vivo biosensors.

  9. Clinically Relevant Physical Benefits of Exercise Interventions in Breast Cancer Survivors.

    PubMed

    Kirkham, Amy A; Bland, Kelcey A; Sayyari, Sarah; Campbell, Kristin L; Davis, Margot K

    2016-02-01

    Evidence is currently limited for the effect of exercise on breast cancer clinical outcomes. However, several of the reported physical benefits of exercise, including peak oxygen consumption, functional capacity, muscle strength and lean mass, cardiovascular risk factors, and bone health, have established associations with disability, cardiovascular disease risk, morbidity, and mortality. This review will summarize the clinically relevant physical benefits of exercise interventions in breast cancer survivors and discuss recommendations for achieving these benefits. It will also describe potential differences in intervention delivery that may impact outcomes and, lastly, describe current physical activity guidelines for cancer survivors. PMID:26769117

  10. Taijin Kyofusho and Social Anxiety and Their Clinical Relevance in Indonesia and Switzerland

    PubMed Central

    Vriends, N.; Pfaltz, M. C.; Novianti, P.; Hadiyono, J.

    2013-01-01

    Background: Taijin Kyofusho Scale (TKS) is an interpersonal fear to offend others and is defined by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) as a culturally bound syndrome that occurs in Japan and Korea. Recently, cases with TKS have also been recognized in other cultures. The present questionnaire study investigated self-report TKS symptoms and social anxiety symptoms, and their clinical relevance in an Indonesian and Swiss sample. It also investigated whether self-construal is associated with TKS and social anxiety, and if self-construal is a mediator of the expected association between cultural background and social anxiety and TKS symptoms. Method: 311 Indonesian and 349 Swiss university students filled out the Liebowitz Social Anxiety Scale, the Taijin Kyofusho Scale, the Self-Construal Scale, self-report social phobia DSM-IV criteria, and rated their wish for professional help to deal with social fears. Results: TKS and social anxiety symptoms were higher in the Indonesian than the Swiss sample. TKS symptoms were associated with clinical relevance in Indonesia, whereas in Switzerland only social anxiety symptoms were associated with clinical relevance. Independent self-construal was negatively associated and interdependent self-construal was positively associated with TKS and social anxiety symptoms. Interdependent self-construal mediated the association between cultural background and these symptoms. Discussion: TKS might be a clinically relevant syndrome in all individuals or cultures with an interdependent self-construal or less independent self-construal. The proposal to include the fear of offending others in the DSM-V criteria of social phobia is supported by the present findings. PMID:23382720

  11. Clinical relevance of cyclic GMP modulators: A translational success story of network pharmacology.

    PubMed

    Oettrich, J M; Dao, V T; Frijhoff, J; Kleikers, Pwm; Casas, A I; Hobbs, A J; Schmidt, H H H W

    2016-04-01

    Therapies that modulate cyclic guanosine-3'-5'-monophosphate (cGMP) have emerged as one of the most successful areas in recent drug discovery and clinical pharmacology. Historically, their focus has been on cardiovascular disease phenotypes; however, cGMP's relevance is likely to go beyond this rather limited organ-based set of indications. Moreover, the multitude of targets and their apparent interchangeability is a proof-of-concept of network pharmacology.

  12. Molecular Mechanisms of Glutamine Synthetase Mutations that Lead to Clinically Relevant Pathologies

    PubMed Central

    Frieg, Benedikt; Görg, Boris; Homeyer, Nadine; Keitel, Verena; Häussinger, Dieter; Gohlke, Holger

    2016-01-01

    Glutamine synthetase (GS) catalyzes ATP-dependent ligation of ammonia and glutamate to glutamine. Two mutations of human GS (R324C and R341C) were connected to congenital glutamine deficiency with severe brain malformations resulting in neonatal death. Another GS mutation (R324S) was identified in a neurologically compromised patient. However, the molecular mechanisms underlying the impairment of GS activity by these mutations have remained elusive. Molecular dynamics simulations, free energy calculations, and rigidity analyses suggest that all three mutations influence the first step of GS catalytic cycle. The R324S and R324C mutations deteriorate GS catalytic activity due to loss of direct interactions with ATP. As to R324S, indirect, water-mediated interactions reduce this effect, which may explain the suggested higher GS residual activity. The R341C mutation weakens ATP binding by destabilizing the interacting residue R340 in the apo state of GS. Additionally, the mutation is predicted to result in a significant destabilization of helix H8, which should negatively affect glutamate binding. This prediction was tested in HEK293 cells overexpressing GS by dot-blot analysis: Structural stability of H8 was impaired through mutation of amino acids interacting with R341, as indicated by a loss of masking of an epitope in the glutamate binding pocket for a monoclonal anti-GS antibody by L-methionine-S-sulfoximine; in contrast, cells transfected with wild type GS showed the masking. Our analyses reveal complex molecular effects underlying impaired GS catalytic activity in three clinically relevant mutants. Our findings could stimulate the development of ATP binding-enhancing molecules by which the R324S mutant can be repaired extrinsically. PMID:26836257

  13. Molecular Mechanisms of Glutamine Synthetase Mutations that Lead to Clinically Relevant Pathologies.

    PubMed

    Frieg, Benedikt; Görg, Boris; Homeyer, Nadine; Keitel, Verena; Häussinger, Dieter; Gohlke, Holger

    2016-02-01

    Glutamine synthetase (GS) catalyzes ATP-dependent ligation of ammonia and glutamate to glutamine. Two mutations of human GS (R324C and R341C) were connected to congenital glutamine deficiency with severe brain malformations resulting in neonatal death. Another GS mutation (R324S) was identified in a neurologically compromised patient. However, the molecular mechanisms underlying the impairment of GS activity by these mutations have remained elusive. Molecular dynamics simulations, free energy calculations, and rigidity analyses suggest that all three mutations influence the first step of GS catalytic cycle. The R324S and R324C mutations deteriorate GS catalytic activity due to loss of direct interactions with ATP. As to R324S, indirect, water-mediated interactions reduce this effect, which may explain the suggested higher GS residual activity. The R341C mutation weakens ATP binding by destabilizing the interacting residue R340 in the apo state of GS. Additionally, the mutation is predicted to result in a significant destabilization of helix H8, which should negatively affect glutamate binding. This prediction was tested in HEK293 cells overexpressing GS by dot-blot analysis: Structural stability of H8 was impaired through mutation of amino acids interacting with R341, as indicated by a loss of masking of an epitope in the glutamate binding pocket for a monoclonal anti-GS antibody by L-methionine-S-sulfoximine; in contrast, cells transfected with wild type GS showed the masking. Our analyses reveal complex molecular effects underlying impaired GS catalytic activity in three clinically relevant mutants. Our findings could stimulate the development of ATP binding-enhancing molecules by which the R324S mutant can be repaired extrinsically.

  14. Additives

    NASA Technical Reports Server (NTRS)

    Smalheer, C. V.

    1973-01-01

    The chemistry of lubricant additives is discussed to show what the additives are chemically and what functions they perform in the lubrication of various kinds of equipment. Current theories regarding the mode of action of lubricant additives are presented. The additive groups discussed include the following: (1) detergents and dispersants, (2) corrosion inhibitors, (3) antioxidants, (4) viscosity index improvers, (5) pour point depressants, and (6) antifouling agents.

  15. Advanced Multi-Axis Spine Testing: Clinical Relevance and Research Recommendations

    PubMed Central

    Holsgrove, Timothy P.; Nayak, Nikhil R.; Welch, William C.

    2015-01-01

    Back pain and spinal degeneration affect a large proportion of the general population. The economic burden of spinal degeneration is significant, and the treatment of spinal degeneration represents a large proportion of healthcare costs. However, spinal surgery does not always provide improved clinical outcomes compared to non-surgical alternatives, and modern interventions, such as total disc replacement, may not offer clinically relevant improvements over more established procedures. Although psychological and socioeconomic factors play an important role in the development and response to back pain, the variation in clinical success is also related to the complexity of the spine, and the multi-faceted manner by which spinal degeneration often occurs. The successful surgical treatment of degenerative spinal conditions requires collaboration between surgeons, engineers, and scientists in order to provide a multi-disciplinary approach to managing the complete condition. In this review, we provide relevant background from both the clinical and the basic research perspectives, which is synthesized into several examples and recommendations for consideration in increasing translational research between communities with the goal of providing improved knowledge and care. Current clinical imaging, and multi-axis testing machines, offer great promise for future research by combining invivo kinematics and loading with in-vitro testing in six degrees of freedom to offer more accurate predictions of the performance of new spinal instrumentation. Upon synthesis of the literature, it is recommended that in-vitro tests strive to recreate as many aspects of the in-vivo environment as possible, and that a physiological preload is a critical factor in assessing spinal biomechanics in the laboratory. A greater link between surgical procedures, and the outcomes in all three anatomical planes should be considered in both the in-vivo and in-vitro settings, to provide data relevant to

  16. Clinical relevance of circulating cell-free microRNAs in ovarian cancer.

    PubMed

    Nakamura, Koji; Sawada, Kenjiro; Yoshimura, Akihiko; Kinose, Yasuto; Nakatsuka, Erika; Kimura, Tadashi

    2016-01-01

    Ovarian cancer is the leading cause of death among gynecologic malignancies. Since ovarian cancer develops asymptomatically, it is often diagnosed at an advanced and incurable stage. Despite many years of research, there is still a lack of reliable diagnostic markers and methods for early detection and screening. Recently, it was discovered that cell-free microRNAs (miRNAs) circulate in the body fluids of healthy and diseased patients, suggesting that they may serve as a novel diagnostic marker. This review summarizes the current knowledge regarding the potential clinical relevance of circulating cell-free miRNA for ovarian cancer diagnosis, prognosis, and therapeutics. Despite the high levels of ribonucleases in many types of body fluids, most of the circulating miRNAs are packaged in microvesicles, exosomes, or apoptotic bodies, are binding to RNA-binding protein such as argonaute 2 or lipoprotein complexes, and are thus highly stable. Cell-free miRNA signatures are known to be parallel to those from the originating tumor cells, indicating that circulating miRNA profiles accurately reflect the tumor profiles. Since it is well established that the dysregulation of miRNAs is involved in the tumorigenesis of ovarian cancer, cell-free miRNAs circulating in body fluids such as serum, plasma, whole blood, and urine may reflect not only the existence of ovarian cancer but also tumor histology, stage, and prognoses of the patients. Several groups have successfully demonstrated that serum or plasma miRNAs are able to discriminate patients with ovarian cancer patients from healthy controls, suggesting that the addition of these miRNAs to current testing regimens may improve diagnosis accuracies for ovarian cancer. Furthermore, recent studies have revealed that changes in levels of cell-free circulating miRNAs are associated with the condition of cancer patients. Discrepancies between the results across studies due to the lack of an established endogenous miRNA control to

  17. Cortical atrophy patterns in multiple sclerosis are non-random and clinically relevant.

    PubMed

    Steenwijk, Martijn D; Geurts, Jeroen J G; Daams, Marita; Tijms, Betty M; Wink, Alle Meije; Balk, Lisanne J; Tewarie, Prejaas K; Uitdehaag, Bernard M J; Barkhof, Frederik; Vrenken, Hugo; Pouwels, Petra J W

    2016-01-01

    of two cortical thickness patterns (bilateral sensorimotor cortex and bilateral insula), and global cortical thickness. The final model predicting average cognition (adjusted R(2) = 0.469; P < 0.001) consisted of age, the loadings of two cortical thickness patterns (bilateral posterior cingulate cortex and bilateral temporal pole), overall white matter lesion load and normal-appearing white matter integrity. Although white matter pathology measures were part of the final clinical regression models, they explained limited incremental variance (to a maximum of 4%). Several cortical atrophy patterns relevant for multiple sclerosis were found. This suggests that cortical atrophy in multiple sclerosis occurs largely in a non-random manner and develops (at least partly) according to distinct anatomical patterns. In addition, these cortical atrophy patterns showed stronger associations with clinical (especially cognitive) dysfunction than global cortical atrophy.

  18. Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors.

    PubMed

    Papale, Alessandro; Morella, Ilaria Maria; Indrigo, Marzia Tina; Eugene Bernardi, Rick; Marrone, Livia; Marchisella, Francesca; Brancale, Andrea; Spanagel, Rainer; Brambilla, Riccardo; Fasano, Stefania

    2016-01-01

    Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction. PMID:27557444

  19. Impairment of cocaine-mediated behaviours in mice by clinically relevant Ras-ERK inhibitors

    PubMed Central

    Papale, Alessandro; Morella, Ilaria Maria; Indrigo, Marzia Tina; Bernardi, Rick Eugene; Marrone, Livia; Marchisella, Francesca; Brancale, Andrea; Spanagel, Rainer; Brambilla, Riccardo; Fasano, Stefania

    2016-01-01

    Ras-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self-administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction. DOI: http://dx.doi.org/10.7554/eLife.17111.001 PMID:27557444

  20. Current strategies and findings in clinically relevant post-translational modification-specific proteomics

    PubMed Central

    Pagel, Oliver; Loroch, Stefan; Sickmann, Albert; Zahedi, René P

    2015-01-01

    Mass spectrometry-based proteomics has considerably extended our knowledge about the occurrence and dynamics of protein post-translational modifications (PTMs). So far, quantitative proteomics has been mainly used to study PTM regulation in cell culture models, providing new insights into the role of aberrant PTM patterns in human disease. However, continuous technological and methodical developments have paved the way for an increasing number of PTM-specific proteomic studies using clinical samples, often limited in sample amount. Thus, quantitative proteomics holds a great potential to discover, validate and accurately quantify biomarkers in body fluids and primary tissues. A major effort will be to improve the complete integration of robust but sensitive proteomics technology to clinical environments. Here, we discuss PTMs that are relevant for clinical research, with a focus on phosphorylation, glycosylation and proteolytic cleavage; furthermore, we give an overview on the current developments and novel findings in mass spectrometry-based PTM research. PMID:25955281

  1. Retrieving clinically relevant diabetic retinopathy images using a multi-class multiple-instance framework

    NASA Astrophysics Data System (ADS)

    Chandakkar, Parag S.; Venkatesan, Ragav; Li, Baoxin

    2013-02-01

    Diabetic retinopathy (DR) is a vision-threatening complication from diabetes mellitus, a medical condition that is rising globally. Unfortunately, many patients are unaware of this complication because of absence of symptoms. Regular screening of DR is necessary to detect the condition for timely treatment. Content-based image retrieval, using archived and diagnosed fundus (retinal) camera DR images can improve screening efficiency of DR. This content-based image retrieval study focuses on two DR clinical findings, microaneurysm and neovascularization, which are clinical signs of non-proliferative and proliferative diabetic retinopathy. The authors propose a multi-class multiple-instance image retrieval framework which deploys a modified color correlogram and statistics of steerable Gaussian Filter responses, for retrieving clinically relevant images from a database of DR fundus image database.

  2. HEMATOPOIETIC STEM CELL GENE THERAPY: ASSESSING THE RELEVANCE OF PRE-CLINICAL MODELS

    PubMed Central

    Larochelle, Andre; Dunbar, Cynthia E.

    2013-01-01

    The modern laboratory mouse has become a central tool for biomedical research with a notable influence in the field of hematopoiesis. Application of retroviral-based gene transfer approaches to mouse hematopoietic stem cells (HSCs) has led to a sophisticated understanding of the hematopoietic hierarchy in this model. However, the assumption that gene transfer methodologies developed in the mouse could be similarly applied to human HSCs for the treatment of human diseases left the field of gene therapy in a decade-long quandary. It is not until more relevant humanized xenograft mouse models and phylogenetically related large animal species were used to optimize gene transfer methodologies that unequivocal clinical successes were achieved. However, the subsequent reporting of severe adverse events in these clinical trials casted doubts on the predictive value of conventional pre-clinical testing, and encouraged the development of new assays for assessing the relative genotoxicity of various vector designs. PMID:24014892

  3. Detection of clinically relevant exonic copy-number changes by array CGH.

    PubMed

    Boone, Philip M; Bacino, Carlos A; Shaw, Chad A; Eng, Patricia A; Hixson, Patricia M; Pursley, Amber N; Kang, Sung-Hae L; Yang, Yaping; Wiszniewska, Joanna; Nowakowska, Beata A; del Gaudio, Daniela; Xia, Zhilian; Simpson-Patel, Gayle; Immken, LaDonna L; Gibson, James B; Tsai, Anne C-H; Bowers, Jennifer A; Reimschisel, Tyler E; Schaaf, Christian P; Potocki, Lorraine; Scaglia, Fernando; Gambin, Tomasz; Sykulski, Maciej; Bartnik, Magdalena; Derwinska, Katarzyna; Wisniowiecka-Kowalnik, Barbara; Lalani, Seema R; Probst, Frank J; Bi, Weimin; Beaudet, Arthur L; Patel, Ankita; Lupski, James R; Cheung, Sau Wai; Stankiewicz, Pawel

    2010-12-01

    Array comparative genomic hybridization (aCGH) is a powerful tool for the molecular elucidation and diagnosis of disorders resulting from genomic copy-number variation (CNV). However, intragenic deletions or duplications--those including genomic intervals of a size smaller than a gene--have remained beyond the detection limit of most clinical aCGH analyses. Increasing array probe number improves genomic resolution, although higher cost may limit implementation, and enhanced detection of benign CNV can confound clinical interpretation. We designed an array with exonic coverage of selected disease and candidate genes and used it clinically to identify losses or gains throughout the genome involving at least one exon and as small as several hundred base pairs in size. In some patients, the detected copy-number change occurs within a gene known to be causative of the observed clinical phenotype, demonstrating the ability of this array to detect clinically relevant CNVs with subkilobase resolution. In summary, we demonstrate the utility of a custom-designed, exon-targeted oligonucleotide array to detect intragenic copy-number changes in patients with various clinical phenotypes.

  4. Detection of Clinically Relevant Exonic Copy-Number Changes by Array CGH

    PubMed Central

    Boone, Philip M.; Bacino, Carlos A.; Shaw, Chad A.; Eng, Patricia A.; Hixson, Patricia M.; Pursley, Amber N.; Kang, Sung-Hae L.; Yang, Yaping; Wiszniewska, Joanna; Nowakowska, Beata A.; Gaudio, Daniela del; Xia, Zhilian; Simpson-Patel, Gayle; Immken, LaDonna L.; Gibson, James B.; Tsai, Anne C.-H.; Bowers, Jennifer A.; Reimschisel, Tyler E.; Schaaf, Christian P.; Potocki, Lorraine; Scaglia, Fernando; Gambin, Tomasz; Sykulski, Maciej; Bartnik, Magdalena; Derwinska, Katarzyna; Wisniowiecka-Kowalnik, Barbara; Lalani, Seema R.; Probst, Frank J.; Bi, Weimin; Beaudet, Arthur L.; Patel, Ankita; Lupski, James R.; Cheung, Sau Wai; Stankiewicz, Pawel

    2011-01-01

    Array comparative genomic hybridization (aCGH) is a powerful tool for the molecular elucidation and diagnosis of disorders resulting from genomic copy-number variation (CNV). However, intragenic deletions or duplications—those including genomic intervals of a size smaller than a gene—have remained beyond the detection limit of most clinical aCGH analyses. Increasing array probe number improves genomic resolution, although higher cost may limit implementation, and enhanced detection of benign CNV can confound clinical interpretation. We designed an array with exonic coverage of selected disease and candidate genes and used it clinically to identify losses or gains throughout the genome involving at least one exon and as small as several hundred base pairs in size. In some patients, the detected copy-number change occurs within a gene known to be causative of the observed clinical phenotype, demonstrating the ability of this array to detect clinically relevant CNVs with subkilobase resolution. In summary, we demonstrate the utility of a custom-designed, exon-targeted oligonucleotide array to detect intragenic copy-number changes in patients with various clinical phenotypes. PMID:20848651

  5. Diagnostic Implication and Clinical Relevance of Ancillary Techniques in Clinical Pathology Practice

    PubMed Central

    Makki, Jaafar S.

    2016-01-01

    Hematoxylin–eosin-stained slide preparation is one of the most durable techniques in medicine history, which has remained unchanged since implemented. It allows an accurate microscopic diagnosis of the vast majority of tissue samples. In many circumstances, this technique cannot answer all the questions posed at the initial diagnostic level. The pathologist has always been looking for additional ancillary techniques to answer pending questions. In our daily histopathology practice, we referred to those techniques as special stains, but nowadays, they are more than stains and are collectively called ancillary tests. They include a wide range of techniques starting from histochemical stains and ending in one or more advanced techniques, such as immunohistochemistry, immunofluorescence, molecular studies, cytogenetic studies, electron microscopy, flow cytometry, and polymerase chain reaction. PMID:27042154

  6. Diagnostic Implication and Clinical Relevance of Ancillary Techniques in Clinical Pathology Practice.

    PubMed

    Makki, Jaafar S

    2016-01-01

    Hematoxylin-eosin-stained slide preparation is one of the most durable techniques in medicine history, which has remained unchanged since implemented. It allows an accurate microscopic diagnosis of the vast majority of tissue samples. In many circumstances, this technique cannot answer all the questions posed at the initial diagnostic level. The pathologist has always been looking for additional ancillary techniques to answer pending questions. In our daily histopathology practice, we referred to those techniques as special stains, but nowadays, they are more than stains and are collectively called ancillary tests. They include a wide range of techniques starting from histochemical stains and ending in one or more advanced techniques, such as immunohistochemistry, immunofluorescence, molecular studies, cytogenetic studies, electron microscopy, flow cytometry, and polymerase chain reaction. PMID:27042154

  7. Animal African Trypanosomiasis: Time to Increase Focus on Clinically Relevant Parasite and Host Species.

    PubMed

    Morrison, Liam J; Vezza, Laura; Rowan, Tim; Hope, Jayne C

    2016-08-01

    Animal African trypanosomiasis (AAT), caused by Trypanosoma congolense and Trypanosoma vivax, remains one of the most important livestock diseases in sub-Saharan Africa, particularly affecting cattle. Despite this, our detailed knowledge largely stems from the human pathogen Trypanosoma brucei and mouse experimental models. In the postgenomic era, the genotypic and phenotypic differences between the AAT-relevant species of parasite or host and their model organism counterparts are increasingly apparent. Here, we outline the timeliness and advantages of increasing the research focus on both the clinically relevant parasite and host species, given that improved tools and resources for both have been developed in recent years. We propose that this shift of emphasis will improve our ability to efficiently develop tools to combat AAT. PMID:27167665

  8. Animal African Trypanosomiasis: Time to Increase Focus on Clinically Relevant Parasite and Host Species.

    PubMed

    Morrison, Liam J; Vezza, Laura; Rowan, Tim; Hope, Jayne C

    2016-08-01

    Animal African trypanosomiasis (AAT), caused by Trypanosoma congolense and Trypanosoma vivax, remains one of the most important livestock diseases in sub-Saharan Africa, particularly affecting cattle. Despite this, our detailed knowledge largely stems from the human pathogen Trypanosoma brucei and mouse experimental models. In the postgenomic era, the genotypic and phenotypic differences between the AAT-relevant species of parasite or host and their model organism counterparts are increasingly apparent. Here, we outline the timeliness and advantages of increasing the research focus on both the clinically relevant parasite and host species, given that improved tools and resources for both have been developed in recent years. We propose that this shift of emphasis will improve our ability to efficiently develop tools to combat AAT.

  9. Prioritizing Clinically Relevant Copy Number Variation from Genetic Interactions and Gene Function Data

    PubMed Central

    Foong, Justin; Girdea, Marta; Stavropoulos, James; Brudno, Michael

    2015-01-01

    It is becoming increasingly necessary to develop computerized methods for identifying the few disease-causing variants from hundreds discovered in each individual patient. This problem is especially relevant for Copy Number Variants (CNVs), which can be cheaply interrogated via low-cost hybridization arrays commonly used in clinical practice. We present a method to predict the disease relevance of CNVs that combines functional context and clinical phenotype to discover clinically harmful CNVs (and likely causative genes) in patients with a variety of phenotypes. We compare several feature and gene weighing systems for classifying both genes and CNVs. We combined the best performing methodologies and parameters on over 2,500 Agilent CGH 180k Microarray CNVs derived from 140 patients. Our method achieved an F-score of 91.59%, with 87.08% precision and 97.00% recall. Our methods are freely available at https://github.com/compbio-UofT/cnv-prioritization. Our dataset is included with the supplementary information. PMID:26437450

  10. Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

    PubMed Central

    Korpal, Manav; Feala, Jacob; Puyang, Xiaoling; Zou, Jian; Ramos, Alex H.; Wu, Jeremy; Baumeister, Timm; Yu, Lihua; Warmuth, Markus; Zhu, Ping

    2015-01-01

    Although targeted therapies are initially effective, resistance inevitably emerges. Several methods, such as genetic analysis of resistant clinical specimens, have been applied to uncover these resistance mechanisms to facilitate follow-up care. Although these approaches have led to clinically relevant discoveries, difficulties in attaining the relevant patient material or in deconvoluting the genomic data collected from these specimens have severely hampered the path towards a cure. To this end, we here describe a tool for expeditious discovery that may guide improvement in first-line therapies and alternative clinical management strategies. By coupling preclinical in vitro or in vivo drug selection with next-generation sequencing, it is possible to identify genomic structural variations and/or gene expression alterations that may serve as functional drivers of resistance. This approach facilitates the spontaneous emergence of alterations, enhancing the probability that these mechanisms may be observed in the patients. In this protocol we provide guidelines to maximize the potential for uncovering single nucleotide variants that drive resistance using adherent lines. PMID:26710000

  11. MDMA, methamphetamine, and CYP2D6 pharmacogenetics: what is clinically relevant?

    PubMed

    de la Torre, Rafael; Yubero-Lahoz, Samanta; Pardo-Lozano, Ricardo; Farré, Magí

    2012-01-01

    In vitro human studies show that the metabolism of most amphetamine-like psychostimulants is regulated by the polymorphic cytochrome P450 isozyme CYP2D6. Two compounds, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), were selected as archetypes to discuss the translation and clinical significance of in vitro to in vivo findings. Both compounds were chosen based on their differential interaction with CYP2D6 and their high abuse prevalence in society. Methamphetamine behaves as both a weak substrate and competitive inhibitor of CYP2D6, while MDMA acts as a high affinity substrate and potent mechanism-based inhibitor (MBI) of the enzyme. The MBI behavior of MDMA on CYP2D6 implies that subjects, irrespective of their genotype/phenotype, are phenocopied to the poor metabolizer (PM) phenotype. The fraction of metabolic clearance regulated by CYP2D6 for both drugs is substantially lower than expected from in vitro studies. Other isoenzymes of cytochrome P450 and a relevant contribution of renal excretion play a part in their clearance. These facts tune down the potential contribution of CYP2D6 polymorphism in the clinical outcomes of both substances. Globally, the clinical relevance of CYP2D6 polymorphism is lower than that predicted by in vitro studies. PMID:23162568

  12. Impulsivity is relevant for trauma exposure and PTSD symptoms in a non-clinical population.

    PubMed

    Netto, Liana R; Pereira, Juliana L; Nogueira, José F; Cavalcanti-Ribeiro, Patrícia; Santana, Rejane Conceição; Teles, Carlos A; Koenen, Karestan C; Quarantini, Lucas C

    2016-05-30

    Impulsivity is a relevant construct for explaining both normal individual differences in personality and more extreme personality disorder, and is often investigated within clinical populations. This study aims to explore the college students' impulsivity patterns and to investigate the association across levels of impulsivity with trauma exposure and PTSD development in a non-clinical population. A one-phase census survey of seven college institutions assessed 2213 students in three metropolitan regions of Northeastern Brazil. All subjects anonymously completed a self-applied protocol consisting of: a socio-demographic questionnaire, Trauma History Questionnaire (THQ), PTSD Checklist (PCL-C), and Barratt Impulsiveness Scale (BIS-11). The median for frequency of trauma exposure was 4 events for people with low and normal impulsivity, and 6 for highly impulsive ones. Individuals with higher impulsivity presented earlier exposition than non-impulsive ones, and worst outcome: 12.4% with PTSD, against 8.4% and 2.3% (normal and low impulsivity). Of the three factors of impulsivity, the Attentional factor conferred the strongest association with PTSD development. Results suggest that impulsivity is also a relevant trait in a non-clinical population and is associated with trauma exposure and PTSD. Strategies to promote mental health in adolescents may be pertinent, especially with the aim of managing impulsivity. PMID:27016879

  13. Determination of clinically relevant content for a musculoskeletal anatomy curriculum for physical medicine and rehabilitation residents.

    PubMed

    Lisk, Kristina; Flannery, John F; Loh, Eldon Y; Richardson, Denyse; Agur, Anne M R; Woods, Nicole N

    2014-01-01

    To address the need for more clinical anatomy training in residency education, many postgraduate programs have implemented structured anatomy courses into their curriculum. Consensus often does not exist on specific content and level of detail of the content that should be included in such curricula. This article describes the use of the Delphi method to identify clinically relevant content to incorporate in a musculoskeletal anatomy curriculum for Physical Medicine and Rehabilitation (PM&R) residents. A two round modified Delphi involving PM&R experts was used to establish the curricular content. The anatomical structures and clinical conditions presented to the expert group were compiled using multiple sources: clinical musculoskeletal anatomy cases from the PM&R residency program at the University of Toronto; consultation with PM&R experts; and textbooks. In each round, experts rated the importance of each curricular item to PM&R residency education using a five-point Likert scale. Internal consistency (Cronbach's alpha) was used to determine consensus at the end of each round and agreement scores were used as an outcome measure to determine the content to include in the curriculum. The overall internal consistency in both rounds was 0.99. A total of 37 physiatrists from across Canada participated and the overall response rate over two rounds was 97%. The initial curricular list consisted of 361 items. After the second iteration, the list was reduced by 44%. By using a national consensus method we were able to objectively determine the relevant anatomical structures and clinical musculoskeletal conditions important in daily PM&R practice.

  14. The clinical relevance of the effect of ospemifene on symptoms of vulvar and vaginal atrophy

    PubMed Central

    Panay, N.; Bruyniks, N.; Castelo-Branco, C.; De Villiers, T. J.; Simon, J. A.

    2015-01-01

    Objectives To explore clinically relevant differences in severity of vulvar and vaginal atrophy (VVA) in postmenopausal women treated with ospemifene compared with placebo. Methods Analysis of two multicenter, randomized, double-blind, 12-week phase-III studies in postmenopausal women (40–80 years, with VVA, treated with ospemifene 60 mg/day or placebo (Study 310 and Study 821)). Severity of vaginal dryness and dyspareunia were evaluated using a four-point scoring system and clinically relevant differences between ospemifene and placebo were analyzed and are presented as improvement (reduction in ≥ 1 unit on four-point scoring system), substantial improvement (reduction in 2–3 units on four-point scoring system) and relief (severity score of mild/none after 12 weeks). Results In Study 310, significantly more women with a most bothersome symptom of dyspareunia had improvement (68.3% vs. 54.1%; p = 0.0255) or relief (57.5% vs. 41.8%; p = 0.0205) in the severity of dyspareunia from baseline to week 12 with ospemifene compared with placebo. For those with a most bothersome symptom of vaginal dryness, significantly more experienced improvement (74.6% vs. 57.7%; p = 0.0101), substantial improvement (42.4% vs. 26.9%; p = 0.0172) and relief (66.1% vs. 49.0%; p = 0.0140) of vaginal dryness from baseline to week 12 with ospemifene compared with placebo. Proportions of women with improvement/substantial improvement/relief of symptoms of vaginal dryness or dyspareunia were similar in Study 821. Clinically relevant differences were noticeable by week 4. Conclusions Treatment with ospemifene was consistently associated with greater improvement, substantial improvement or relief in the severity of the most bothersome symptoms of vaginal dryness or dyspareunia compared with placebo. PMID:25335119

  15. Finding the common core: evidence-based practices, clinically relevant evidence, and core mechanisms of change.

    PubMed

    Sexton, Thomas L; Kelley, Susan Douglas

    2010-03-01

    Improving the quality of children's mental health care can benefit from the adoption of evidence based and evidence informed treatments. However, the promise of moving science into practice is hampered by three core elements that need to be addressed in the current conversation among key stakeholders: (1) expanding our understanding of the clinical relevance of different types of evidence, (2) emphasizing the identification of core mechanisms of change, and (3) re-conceptualizing what evidence-based practice means. This paper focuses on these elements in an attempt to find a common core among stakeholders that may create opportunities for more inclusive conversation to move the field of children's mental health care forward.

  16. The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes.

    PubMed

    Meerwaldt, Robbert; Links, Thera; Zeebregts, Clark; Tio, Rene; Hillebrands, Jan-Luuk; Smit, Andries

    2008-01-01

    Cardiovascular disease is the major cause of morbidity and mortality associated with diabetes. There is increasing evidence that advanced glycation endproducts (AGEs) play a pivotal role in atherosclerosis, in particular in diabetes. AGE accumulation is a measure of cumulative metabolic and oxidative stress, and may so represent the "metabolic memory". Furthermore, increased AGE accumulation is closely related to the development of cardiovascular complications in diabetes. This review article will focus on the clinical relevance of measuring AGE accumulation in diabetic patients by focusing on AGE formation, AGEs as predictors of long-term complications, and interventions against AGEs. PMID:18840258

  17. Blood lactate concentration after exposure to conducted energy weapons (including TASER® devices): is it clinically relevant?

    PubMed

    Jauchem, James R

    2013-09-01

    In previous studies, blood lactate concentration (BLac) consistently increased in anesthetized animals and in human subjects after exposures to TASER(®) conducted energy weapons (CEWs). Some have suggested the increased BLac would have detrimental consequences. In the current review, the following are evaluated: (a) the nature of muscle contractions due to CEWs, (b) general aspects of increased BLac, (c) previous studies of conventional neuromuscular electrical stimulation and CEW exposures, and (d) BLac in disease states. On the basis of these analyses, one can conclude that BLac, per se (independent of acidemia), would not be clinically relevant immediately after short-duration CEW applications, due to the short time course of any increase.

  18. Clinically applied medical ethnography: relevance to cultural competence in patient care.

    PubMed

    Engebretson, Joan

    2011-06-01

    Medical anthropology provides an excellent resource for nursing research that is relevant to clinical nursing. By expanding the understanding of ethnographic research beyond ethnicity, nurses can conduct research that explores patient's constructions and explanatory models of health and healing and how they make meaning out of chronic conditions and negotiate daily life. These findings can have applicability to culturally competent care at both the organizational or systems level, as well as in the patient/provider encounter. Individual patient care can be improved by applying ethnographic research findings to build provider expertise and then using a cultural negotiation process for individualized patient care.

  19. The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes

    PubMed Central

    Meerwaldt, Robbert; Links, Thera; Zeebregts, Clark; Tio, Rene; Hillebrands, Jan-Luuk; Smit, Andries

    2008-01-01

    Cardiovascular disease is the major cause of morbidity and mortality associated with diabetes. There is increasing evidence that advanced glycation endproducts (AGEs) play a pivotal role in atherosclerosis, in particular in diabetes. AGE accumulation is a measure of cumulative metabolic and oxidative stress, and may so represent the "metabolic memory". Furthermore, increased AGE accumulation is closely related to the development of cardiovascular complications in diabetes. This review article will focus on the clinical relevance of measuring AGE accumulation in diabetic patients by focusing on AGE formation, AGEs as predictors of long-term complications, and interventions against AGEs. PMID:18840258

  20. The clinical relevance of assessing advanced glycation endproducts accumulation in diabetes.

    PubMed

    Meerwaldt, Robbert; Links, Thera; Zeebregts, Clark; Tio, Rene; Hillebrands, Jan-Luuk; Smit, Andries

    2008-10-07

    Cardiovascular disease is the major cause of morbidity and mortality associated with diabetes. There is increasing evidence that advanced glycation endproducts (AGEs) play a pivotal role in atherosclerosis, in particular in diabetes. AGE accumulation is a measure of cumulative metabolic and oxidative stress, and may so represent the "metabolic memory". Furthermore, increased AGE accumulation is closely related to the development of cardiovascular complications in diabetes. This review article will focus on the clinical relevance of measuring AGE accumulation in diabetic patients by focusing on AGE formation, AGEs as predictors of long-term complications, and interventions against AGEs.

  1. A systematic review on the effect of sweeteners on glycemic response and clinically relevant outcomes

    PubMed Central

    2011-01-01

    Background The major metabolic complications of obesity and type 2 diabetes may be prevented and managed with dietary modification. The use of sweeteners that provide little or no calories may help to achieve this objective. Methods We did a systematic review and network meta-analysis of the comparative effectiveness of sweetener additives using Bayesian techniques. MEDLINE, EMBASE, CENTRAL and CAB Global were searched to January 2011. Randomized trials comparing sweeteners in obese, diabetic, and healthy populations were selected. Outcomes of interest included weight change, energy intake, lipids, glycated hemoglobin, markers of insulin resistance and glycemic response. Evidence-based items potentially indicating risk of bias were assessed. Results Of 3,666 citations, we identified 53 eligible randomized controlled trials with 1,126 participants. In diabetic participants, fructose reduced 2-hour blood glucose concentrations by 4.81 mmol/L (95% CI 3.29, 6.34) compared to glucose. Two-hour blood glucose concentration data comparing hypocaloric sweeteners to sucrose or high fructose corn syrup were inconclusive. Based on two ≤10-week trials, we found that non-caloric sweeteners reduced energy intake compared to the sucrose groups by approximately 250-500 kcal/day (95% CI 153, 806). One trial found that participants in the non-caloric sweetener group had a decrease in body mass index compared to an increase in body mass index in the sucrose group (-0.40 vs 0.50 kg/m2, and -1.00 vs 1.60 kg/m2, respectively). No randomized controlled trials showed that high fructose corn syrup or fructose increased levels of cholesterol relative to other sweeteners. Conclusions Considering the public health importance of obesity and its consequences; the clearly relevant role of diet in the pathogenesis and maintenance of obesity; and the billions of dollars spent on non-caloric sweeteners, little high-quality clinical research has been done. Studies are needed to determine the role

  2. Rapid, accurate, and comparative differentiation of clinically and industrially relevant microorganisms via multiple vibrational spectroscopic fingerprinting.

    PubMed

    Muhamadali, Howbeer; Subaihi, Abdu; Mohammadtaheri, Mahsa; Xu, Yun; Ellis, David I; Ramanathan, Rajesh; Bansal, Vipul; Goodacre, Royston

    2016-08-15

    Despite the fact that various microorganisms (e.g., bacteria, fungi, viruses, etc.) have been linked with infectious diseases, their crucial role towards sustaining life on Earth is undeniable. The huge biodiversity, combined with the wide range of biochemical capabilities of these organisms, have always been the driving force behind their large number of current, and, as of yet, undiscovered future applications. The presence of such diversity could be said to expedite the need for the development of rapid, accurate and sensitive techniques which allow for the detection, differentiation, identification and classification of such organisms. In this study, we employed Fourier transform infrared (FT-IR), Raman, and surface enhanced Raman scattering (SERS) spectroscopies, as molecular whole-organism fingerprinting techniques, combined with multivariate statistical analysis approaches for the classification of a range of industrial, environmental or clinically relevant bacteria (P. aeruginosa, P. putida, E. coli, E. faecium, S. lividans, B. subtilis, B. cereus) and yeast (S. cerevisiae). Principal components-discriminant function analysis (PC-DFA) scores plots of the spectral data collected from all three techniques allowed for the clear differentiation of all the samples down to sub-species level. The partial least squares-discriminant analysis (PLS-DA) models generated using the SERS spectral data displayed lower accuracy (74.9%) when compared to those obtained from conventional Raman (97.8%) and FT-IR (96.2%) analyses. In addition, whilst background fluorescence was detected in Raman spectra for S. cerevisiae, this fluorescence was quenched when applying SERS to the same species, and conversely SERS appeared to introduce strong fluorescence when analysing P. putida. It is also worth noting that FT-IR analysis provided spectral data of high quality and reproducibility for the whole sample set, suggesting its applicability to a wider range of samples, and perhaps the

  3. Clinical Empathy and Narrative Competence: The Relevance of Reading Talmudic Legends as Literary Fiction

    PubMed Central

    Davidson, John H.

    2015-01-01

    The “curative potential” in almost any clinical setting depends on a caregiver establishing and maintaining an empathic connection with patients so as to achieve “narrative competence” in discerning and acting in accord with their preferences and best interests. The “narrative medicine” model of shared “close reading of literature and reflective writing” among clinicians as a means of fostering a capacity for clinical empathy has gained validation with recent empirical studies demonstrating the enhancement of theory of mind (ToM), broadly conceived as empathy, in readers of literary fiction. Talmudic legends, like that of Rabbi Judah’s death, are under-appreciated, relevant sources of literary fiction for these efforts. The limitations of narrative medicine are readily counterbalanced by simultaneously practiced attention to traditional bioethical principles, including—especially—beneficence, non-maleficence, and autonomy. PMID:25973266

  4. Developmental regulation of human cortex transcription and its clinical relevance at base resolution

    PubMed Central

    Jaffe, Andrew E.; Shin, Jooheon; Collado-Torres, Leonardo; Leek, Jeffrey T.; Tao, Ran; Li, Chao; Gao, Yuan; Jia, Yankai; Maher, Brady J.; Hyde, Thomas M.

    2014-01-01

    Transcriptome analysis of human brain provides fundamental insight about development and disease, but largely relies on existing annotation. We sequenced transcriptomes of 72 prefrontal cortex samples across six life stages, and identified 50,650 differentially expression regions (DERs) associated with developmental and aging, agnostic of annotation. While many DERs annotated to non-exonic sequence (41.1%), most were similarly regulated in cytosolic mRNA extracted from independent samples. The DERs were developmentally conserved across 16 brain regions and within the developing mouse cortex, and were expressed in diverse cell and tissue types. The DERs were further enriched for active chromatin marks and clinical risk for neurodevelopmental disorders like schizophrenia. Lastly, we demonstrate quantitatively that these DERs associate with a changing neuronal phenotype related to differentiation and maturation. These data highlight conserved molecular signatures of transcriptional dynamics across brain development, some potential clinical relevance and the incomplete annotation of the human brain transcriptome. PMID:25501035

  5. Clinical empathy and narrative competence: the relevance of reading talmudic legends as literary fiction.

    PubMed

    Davidson, John H

    2015-04-01

    The "curative potential" in almost any clinical setting depends on a caregiver establishing and maintaining an empathic connection with patients so as to achieve "narrative competence" in discerning and acting in accord with their preferences and best interests. The "narrative medicine" model of shared "close reading of literature and reflective writing" among clinicians as a means of fostering a capacity for clinical empathy has gained validation with recent empirical studies demonstrating the enhancement of theory of mind (ToM), broadly conceived as empathy, in readers of literary fiction. Talmudic legends, like that of Rabbi Judah's death, are under-appreciated, relevant sources of literary fiction for these efforts. The limitations of narrative medicine are readily counterbalanced by simultaneously practiced attention to traditional bioethical principles, including-especially-beneficence, non-maleficence, and autonomy.

  6. A high-throughput panel for identifying clinically relevant mutation profiles in melanoma.

    PubMed

    Dutton-Regester, Ken; Irwin, Darryl; Hunt, Priscilla; Aoude, Lauren G; Tembe, Varsha; Pupo, Gulietta M; Lanagan, Cathy; Carter, Candace D; O'Connor, Linda; O'Rourke, Michael; Scolyer, Richard A; Mann, Graham J; Schmidt, Christopher W; Herington, Adrian; Hayward, Nicholas K

    2012-04-01

    Success with molecular-based targeted drugs in the treatment of cancer has ignited extensive research efforts within the field of personalized therapeutics. However, successful application of such therapies is dependent on the presence or absence of mutations within the patient's tumor that can confer clinical efficacy or drug resistance. Building on these findings, we developed a high-throughput mutation panel for the identification of frequently occurring and clinically relevant mutations in melanoma. An extensive literature search and interrogation of the Catalogue of Somatic Mutations in Cancer database identified more than 1,000 melanoma mutations. Applying a filtering strategy to focus on mutations amenable to the development of targeted drugs, we initially screened 120 known mutations in 271 samples using the Sequenom MassARRAY system. A total of 252 mutations were detected in 17 genes, the highest frequency occurred in BRAF (n = 154, 57%), NRAS (n = 55, 20%), CDK4 (n = 8, 3%), PTK2B (n = 7, 2.5%), and ERBB4 (n = 5, 2%). Based on this initial discovery screen, a total of 46 assays interrogating 39 mutations in 20 genes were designed to develop a melanoma-specific panel. These assays were distributed in multiplexes over 8 wells using strict assay design parameters optimized for sensitive mutation detection. The final melanoma-specific mutation panel is a cost effective, sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular-based therapeutics for the treatment of melanoma. When used in a clinical research setting, the panel may rapidly and accurately identify potentially effective treatment strategies using novel or existing molecularly targeted drugs. PMID:22383533

  7. Covariate pharmacokinetic model building in oncology and its potential clinical relevance.

    PubMed

    Joerger, Markus

    2012-03-01

    When modeling pharmacokinetic (PK) data, identifying covariates is important in explaining interindividual variability, and thus increasing the predictive value of the model. Nonlinear mixed-effects modeling with stepwise covariate modeling is frequently used to build structural covariate models, and the most commonly used software-NONMEM-provides estimations for the fixed-effect parameters (e.g., drug clearance), interindividual and residual unidentified random effects. The aim of covariate modeling is not only to find covariates that significantly influence the population PK parameters, but also to provide dosing recommendations for a certain drug under different conditions, e.g., organ dysfunction, combination chemotherapy. A true covariate is usually seen as one that carries unique information on a structural model parameter. Covariate models have improved our understanding of the pharmacology of many anticancer drugs, including busulfan or melphalan that are part of high-dose pretransplant treatments, the antifolate methotrexate whose elimination is strongly dependent on GFR and comedication, the taxanes and tyrosine kinase inhibitors, the latter being subject of cytochrome p450 3A4 (CYP3A4) associated metabolism. The purpose of this review article is to provide a tool to help understand population covariate analysis and their potential implications for the clinic. Accordingly, several population covariate models are listed, and their clinical relevance is discussed. The target audience of this article are clinical oncologists with a special interest in clinical and mathematical pharmacology.

  8. Isoflurane and desflurane at clinically relevant concentrations induce amyloid {beta}-peptide oligomerization: An NMR study

    SciTech Connect

    Mandal, Pravat K Fodale, Vincenzo

    2009-02-13

    Current understanding on Alzheimer's disease (AD) reveals that soluble amyloid {beta}-peptide (A{beta}) oligomeric formation plays an important role in AD pathophysiology. A potential role for several inhaled anesthetics in promoting A{beta} oligomer formation has been suggested. Using a nuclear magnetic resonance (NMR) study, we previously demonstrated that at a high concentration (higher than clinically relevant concentrations), the inhaled anesthetics halothane and isoflurane, interact with specific amino acid residues (G29, A30, and I31) and induce A{beta} oligomerization. The present study confirms this is true at a clinically relevant concentration. Isoflurane and desflurane induce A{beta} oligomerization by inducing chemical shift changes of the critical amino acid residues (G29, A30, and I31), reinforcing the evidence that perturbation of these three crucial residues indeed plays an important role in oligomerization. These findings support the emerging hypothesis that several commonly used inhaled anesthetics could be involved in neurodegeneration, as well as risk factor for accelerating the onset of AD.

  9. Impact analysis studies of clinical prediction rules relevant to primary care: a systematic review

    PubMed Central

    Wallace, Emma; Uijen, Maike J M; Clyne, Barbara; Zarabzadeh, Atieh; Keogh, Claire; Galvin, Rose; Smith, Susan M; Fahey, Tom

    2016-01-01

    Objectives Following appropriate validation, clinical prediction rules (CPRs) should undergo impact analysis to evaluate their effect on patient care. The aim of this systematic review is to narratively review and critically appraise CPR impact analysis studies relevant to primary care. Setting Primary care. Participants Adults and children. Intervention Studies that implemented the CPR compared to usual care were included. Study design Randomised controlled trial (RCT), controlled before–after, and interrupted time series. Primary outcome Physician behaviour and/or patient outcomes. Results A total of 18 studies, incorporating 14 unique CPRs, were included. The main study design was RCT (n=13). Overall, 10 studies reported an improvement in primary outcome with CPR implementation. Of 6 musculoskeletal studies, 5 were effective in altering targeted physician behaviour in ordering imaging for patients presenting with ankle, knee and neck musculoskeletal injuries. Of 6 cardiovascular studies, 4 implemented cardiovascular risk scores, and 3 reported no impact on physician behaviour outcomes, such as prescribing and referral, or patient outcomes, such as reduction in serum lipid levels. 2 studies examined CPRs in decision-making for patients presenting with chest pain and reduced inappropriate admissions. Of 5 respiratory studies, 2 were effective in reducing antibiotic prescribing for sore throat following CPR implementation. Overall, study methodological quality was often unclear due to incomplete reporting. Conclusions Despite increasing interest in developing and validating CPRs relevant to primary care, relatively few have gone through impact analysis. To date, research has focused on a small number of CPRs across few clinical domains only. PMID:27008685

  10. Antibiofilm Activity of the Brown Alga Halidrys siliquosa against Clinically Relevant Human Pathogens.

    PubMed

    Busetti, Alessandro; Thompson, Thomas P; Tegazzini, Diana; Megaw, Julianne; Maggs, Christine A; Gilmore, Brendan F

    2015-06-01

    The marine brown alga Halidrys siliquosa is known to produce compounds with antifouling activity against several marine bacteria. The aim of this study was to evaluate the antimicrobial and antibiofilm activity of organic extracts obtained from the marine brown alga H. siliquosa against a focused panel of clinically relevant human pathogens commonly associated with biofilm-related infections. The partially fractionated methanolic extract obtained from H. siliquosa collected along the shores of Co. Donegal; Ireland; displayed antimicrobial activity against bacteria of the genus Staphylococcus; Streptococcus; Enterococcus; Pseudomonas; Stenotrophomonas; and Chromobacterium with MIC and MBC values ranging from 0.0391 to 5 mg/mL. Biofilms of S. aureus MRSA were found to be susceptible to the algal methanolic extract with MBEC values ranging from 1.25 mg/mL to 5 mg/mL respectively. Confocal laser scanning microscopy using LIVE/DEAD staining confirmed the antimicrobial nature of the antibiofilm activity observed using the MBEC assay. A bioassay-guided fractionation method was developed yielding 10 active fractions from which to perform purification and structural elucidation of clinically-relevant antibiofilm compounds. PMID:26058011

  11. Antibiofilm Activity of the Brown Alga Halidrys siliquosa against Clinically Relevant Human Pathogens

    PubMed Central

    Busetti, Alessandro; Thompson, Thomas P.; Tegazzini, Diana; Megaw, Julianne; Maggs, Christine A.; Gilmore, Brendan F.

    2015-01-01

    The marine brown alga Halidrys siliquosa is known to produce compounds with antifouling activity against several marine bacteria. The aim of this study was to evaluate the antimicrobial and antibiofilm activity of organic extracts obtained from the marine brown alga H. siliquosa against a focused panel of clinically relevant human pathogens commonly associated with biofilm-related infections. The partially fractionated methanolic extract obtained from H. siliquosa collected along the shores of Co. Donegal; Ireland; displayed antimicrobial activity against bacteria of the genus Staphylococcus; Streptococcus; Enterococcus; Pseudomonas; Stenotrophomonas; and Chromobacterium with MIC and MBC values ranging from 0.0391 to 5 mg/mL. Biofilms of S. aureus MRSA were found to be susceptible to the algal methanolic extract with MBEC values ranging from 1.25 mg/mL to 5 mg/mL respectively. Confocal laser scanning microscopy using LIVE/DEAD staining confirmed the antimicrobial nature of the antibiofilm activity observed using the MBEC assay. A bioassay-guided fractionation method was developed yielding 10 active fractions from which to perform purification and structural elucidation of clinically-relevant antibiofilm compounds. PMID:26058011

  12. Integrative topological analysis of mass spectrometry data reveals molecular features with clinical relevance in esophageal squamous cell carcinoma.

    PubMed

    Gao, She-Gan; Liu, Rui-Min; Zhao, Yun-Gang; Wang, Pei; Ward, Douglas G; Wang, Guang-Chao; Guo, Xiang-Qian; Gu, Juan; Niu, Wan-Bin; Zhang, Tian; Martin, Ashley; Guo, Zhi-Peng; Feng, Xiao-Shan; Qi, Yi-Jun; Ma, Yuan-Fang

    2016-02-22

    Combining MS-based proteomic data with network and topological features of such network would identify more clinically relevant molecules and meaningfully expand the repertoire of proteins derived from MS analysis. The integrative topological indexes representing 95.96% information of seven individual topological measures of node proteins were calculated within a protein-protein interaction (PPI) network, built using 244 differentially expressed proteins (DEPs) identified by iTRAQ 2D-LC-MS/MS. Compared with DEPs, differentially expressed genes (DEGs) and comprehensive features (CFs), structurally dominant nodes (SDNs) based on integrative topological index distribution produced comparable classification performance in three different clinical settings using five independent gene expression data sets. The signature molecules of SDN-based classifier for distinction of early from late clinical TNM stages were enriched in biological traits of protein synthesis, intracellular localization and ribosome biogenesis, which suggests that ribosome biogenesis represents a promising therapeutic target for treating ESCC. In addition, ITGB1 expression selected exclusively by integrative topological measures correlated with clinical stages and prognosis, which was further validated with two independent cohorts of ESCC samples. Thus the integrative topological analysis of PPI networks proposed in this study provides an alternative approach to identify potential biomarkers and therapeutic targets from MS/MS data with functional insights in ESCC.

  13. Integrative topological analysis of mass spectrometry data reveals molecular features with clinical relevance in esophageal squamous cell carcinoma

    PubMed Central

    Gao, She-Gan; Liu, Rui-Min; Zhao, Yun-Gang; Wang, Pei; Ward, Douglas G.; Wang, Guang-Chao; Guo, Xiang-Qian; Gu, Juan; Niu, Wan-Bin; Zhang, Tian; Martin, Ashley; Guo, Zhi-Peng; Feng, Xiao-Shan; Qi, Yi-Jun; Ma, Yuan-Fang

    2016-01-01

    Combining MS-based proteomic data with network and topological features of such network would identify more clinically relevant molecules and meaningfully expand the repertoire of proteins derived from MS analysis. The integrative topological indexes representing 95.96% information of seven individual topological measures of node proteins were calculated within a protein-protein interaction (PPI) network, built using 244 differentially expressed proteins (DEPs) identified by iTRAQ 2D-LC-MS/MS. Compared with DEPs, differentially expressed genes (DEGs) and comprehensive features (CFs), structurally dominant nodes (SDNs) based on integrative topological index distribution produced comparable classification performance in three different clinical settings using five independent gene expression data sets. The signature molecules of SDN-based classifier for distinction of early from late clinical TNM stages were enriched in biological traits of protein synthesis, intracellular localization and ribosome biogenesis, which suggests that ribosome biogenesis represents a promising therapeutic target for treating ESCC. In addition, ITGB1 expression selected exclusively by integrative topological measures correlated with clinical stages and prognosis, which was further validated with two independent cohorts of ESCC samples. Thus the integrative topological analysis of PPI networks proposed in this study provides an alternative approach to identify potential biomarkers and therapeutic targets from MS/MS data with functional insights in ESCC. PMID:26898710

  14. The effects of clinically relevant doses of amphetamine and methylphenidate on signal detection and DRL in rats.

    PubMed

    Andrzejewski, Matthew E; Spencer, Robert C; Harris, Rachel L; Feit, Elizabeth C; McKee, Brenda L; Berridge, Craig W

    2014-04-01

    Low dose amphetamine (AMPH) and methylphenidate (MPH, Ritalin(®)) are the most widely prescribed and most effective pharmacotherapy for attention-deficit/hyperactivity disorder (ADHD). Certain low, clinically relevant doses of MPH improve sustained attention and working memory in normal rats, in contrast to higher doses that impair cognitive ability and induce locomotor activity. However, the effects of AMPH of MPH on sustained attention and behavioral inhibition remain poorly characterized. The present experiments examined the actions of AMPH (0.1 and 0.25 mg/kg) and MPH (0.5 and 1.0 mg/kg) in a rat model of 1) sustained attention, where signal and blank trials were interspersed randomly and occurred at unpredictable times, and 2) behavioral inhibition, using a differential reinforcement of low rate (DRL) schedule. In a signal detection paradigm, both 0.5 mg/kg and 1.0 mg/kg MPH and 0.25 mg/kg AMPH improve sustained attention, however neither AMPH nor MPH improve behavioral inhibition on DRL. Taken together with other recent studies, it appears that clinically-relevant doses of AMPH and MPH may preferentially improve attention-related behavior while having little effect on behavioral inhibition. These observations provide additional insight into the basic behavioral actions of low-dose psychostimulants and further suggest that the use of sustained attention tasks may be important in the development of novel pharmacological treatments for ADHD.

  15. Structural brain MRI studies in eye diseases: are they clinically relevant? A review of current findings.

    PubMed

    Prins, Doety; Hanekamp, Sandra; Cornelissen, Frans W

    2016-03-01

    Many eye diseases reduce visual acuity or are associated with visual field defects. Because of the well-defined retinotopic organization of the connections of the visual pathways, this may affect specific parts of the visual pathways and cortex, as a result of either deprivation or transsynaptic degeneration. For this reason, over the past several years, numerous structural magnetic resonance imaging (MRI) studies have examined the association of eye diseases with pathway and brain changes. Here, we review structural MRI studies performed in human patients with the eye diseases albinism, amblyopia, hereditary retinal dystrophies, age-related macular degeneration (AMD) and glaucoma. We focus on two main questions. First, what have these studies revealed? Second, what is the potential clinical relevance of their findings? We find that all the aforementioned eye diseases are indeed associated with structural changes in the visual pathways and brain. As such changes have been described in very different eye diseases, in our view the most parsimonious explanation is that these are caused by the loss of visual input and the subsequent deprivation of the visual pathways and brain regions, rather than by transsynaptic degeneration. Moreover, and of clinical relevance, for some of the diseases - in particular glaucoma and AMD - present results are compatible with the view that the eye disease is part of a more general neurological or neurodegenerative disorder that also affects the brain. Finally, establishing structural changes of the visual pathways has been relevant in the context of new therapeutic strategies to restore retinal function: it implies that restoring retinal function may not suffice to also effectively restore vision. Future structural MRI studies can contribute to (i) further establish relationships between ocular and neurological neurodegenerative disorders, (ii) investigate whether brain degeneration in eye diseases is reversible, (iii) evaluate the use

  16. Orthoptic Sequelae Following Conservative Management of Pure Blowout Orbital Fractures: Anecdotal or Clinically Relevant?

    PubMed

    Steinegger, Ken; De Haller, Raoul; Courvoisier, Delphine; Scolozzi, Paolo

    2015-07-01

    The aim of this study was to prospectively assess the prevalence of orthoptic anomalies following conservative management of pure blowout orbital fractures and to evaluate their clinical relevance. Clinical and radiologic data of patients with unilateral conservatively managed pure blowout orbital fractures with a minimum follow-up of 6 months were reviewed. Eligible patients were contacted and invited to undergo an extended ophthalmologic examination as follows: distance and near visual acuities, Hertel exophthalmometry, corneal light reflex (Hirschberg test), ductions and versions in the 6 cardinal fields of gaze, eye deviation with prisms and alternate cover test in all of the 9-gaze directions with Maddox rod, degrees of incyclo/excyclotorsion with right and left eye fixation, horizontal and vertical deviation with Hess-Weiss coordimetry, degree of horizontal/vertical and incyclo/excyclotorsion deviation with Harms wall deviometry, and vertical deviation with Bielschowsky head-tilt test. Of the 69 patients contacted, 49 declined to participate given that they were asymptomatic. Twenty patients agreed to undergo the examination. One patient complained of minimal double vision limited to the extreme downgaze. Four patients had asymptomatic ocular motility disturbances limited to the extreme gaze. Seven patients had asymptomatic horizontal heterophoria. These disturbances did not interfere with daily or professional activities in any of the patients. The current study demonstrated that conservative management of pure orbital blowout fractures can result in orthoptic anomalies. These sequelae were restricted to a very limited portion of the binocular field of the vision and were not found to be clinically relevant. PMID:26102539

  17. Desktop transcriptome sequencing from archival tissue to identify clinically relevant translocations.

    PubMed

    Sweeney, Robert T; Zhang, Bing; Zhu, Shirley X; Varma, Sushama; Smith, Kevin S; Montgomery, Stephen B; van de Rijn, Matt; Zehnder, Jim; West, Robert B

    2013-06-01

    Somatic mutations, often translocations or single nucleotide variations, are pathognomonic for certain types of cancers and are increasingly of clinical importance for diagnosis and prediction of response to therapy. Conventional clinical assays only evaluate 1 mutation at a time, and targeted tests are often constrained to identify only the most common mutations. Genome-wide or transcriptome-wide high-throughput sequencing (HTS) of clinical samples offers an opportunity to evaluate for all clinically significant mutations with a single test. Recently a "desktop version" of HTS has become available, but most of the experience to date is based on data obtained from high-quality DNA from frozen specimens. In this study, we demonstrate, as a proof of principle, that translocations in sarcomas can be diagnosed from formalin-fixed paraffin-embedded (FFPE) tissue with desktop HTS. Using the first generation MiSeq platform, full transcriptome sequencing was performed on FFPE material from archival blocks of 3 synovial sarcomas, 3 myxoid liposarcomas, 2 Ewing sarcomas, and 1 clear cell sarcoma. Mapping the reads to the "sarcomatome" (all known 83 genes involved in translocations and mutations in sarcoma) and using a novel algorithm for ranking fusion candidates, the pathognomonic fusions and the exact breakpoints were identified in all cases of synovial sarcoma, myxoid liposarcoma, and clear cell sarcoma. The Ewing sarcoma fusion gene was detectable in FFPE material only with a sequencing platform that generates greater sequencing depth. The results show that a single transcriptome HTS assay, from FFPE, has the potential to replace conventional molecular diagnostic techniques for the evaluation of clinically relevant mutations in cancer.

  18. Doravirine Suppresses Common Nonnucleoside Reverse Transcriptase Inhibitor-Associated Mutants at Clinically Relevant Concentrations.

    PubMed

    Feng, Meizhen; Sachs, Nancy A; Xu, Min; Grobler, Jay; Blair, Wade; Hazuda, Daria J; Miller, Michael D; Lai, Ming-Tain

    2016-04-01

    Doravirine (DOR), which is currently in a phase 3 clinical trial, is a novel human immunodeficiency type 1 virus (HIV-1) nonnucleoside reverse transcriptase inhibitor (NNRTI). DOR exhibits potent antiviral activity against wild-type virus and K103N, Y181C, and K103N/Y181C mutant viruses, with 50% inhibitory concentrations (IC50s) of 12, 21, 31, and 33 nM, respectively, when measured in 100% normal human serum (NHS). To assess the potential for DOR to suppress NNRTI-associated and rilpivirine (RPV)-specific mutants at concentrations achieved in the clinic setting, inhibitory quotients (IQs) were calculated by determining the ratio of the clinical trough concentration over the antiviral IC50for each virus with DOR and RPV and efavirenz (EFV). DOR displayed IQs of 39, 27, and 25 against the K103N, Y181C, and K103N/Y181C mutants, respectively. In contrast, RPV exhibited IQs of 4.6, 1.4, and 0.8, and EFV showed IQs of 2.5, 60, and 1.9 against these viruses, respectively. DOR also displayed higher IQs than those of RPV and EFV against other prevalent NNRTI-associated mutants, with the exception of Y188L. Both DOR and EFV exhibited higher IQs than RPV when analyzed with RPV-associated mutants. Resistance selections were conducted with K103N, Y181C, G190A, and K103N/Y181C mutants at clinically relevant concentrations of DOR, RPV, and EFV. No viral breakthrough was observed with DOR, whereas breakthrough viruses were readily detected with RPV and EFV against Y181C and K103N viruses, respectively. These data suggest that DOR should impose a higher barrier to the development of resistance than RPV and EFV at the concentrations achieved in the clinic setting. PMID:26833152

  19. Clinical relevance and contemporary methods for counting blood cells in body fluids suspected of inflammatory disease.

    PubMed

    Fleming, Chérina; Russcher, Henk; Lindemans, Jan; de Jonge, Robert

    2015-10-01

    In many inflammatory diseases, the cellular components in body fluids [cerebrospinal fluid (CSF), serous fluids] are increased, rendering essential diagnostic information. The diagnostic value of the total white blood cell count (WBC) and differential count has been evaluated extensively over the years, and a remarkable amount of knowledge has been gained; yet, there is a great deal of clinical uncertainty whether the diagnosis should be based solely on these variables. In some diseases, such as peritonitis, the total WBC and differential count has high sensitivity; whereas, in differentiating pleural effusions, it lacks the sensitivity required to be clinically useful. Nevertheless, many guidelines consider these tests as cornerstone parameters, and in combination with clinical variables, they can successfully guide clinical decision making in initiating or postponing a treatment course for infection and/or inflammatory diseases while awaiting culture results. Although other methods are available for detecting and differentiating WBCs in body fluids, manual microscopy is still considered the gold standard despite its many limitations. During the last decade, automated analyzers have become a popular method for first line screening. Continued progress in their design has led to major improvements including their speed, improved accuracy and lower variability compared with microscopy. Disadvantages of this method include high imprecision in low ranges (depending on the method) and interfering factors. In a time where automation is at the front line in clinical laboratories, it is essential the results obtained are precise, accurate and reproducible. This review provides an overview of the relevance for cell counting in a variety of diagnostic body fluids, and highlights the current technologies used.

  20. Identification of relevant single-nucleotide polymorphisms in Pneumocystis jirovecii: relationship with clinical data.

    PubMed

    Esteves, F; Gaspar, J; Marques, T; Leite, R; Antunes, F; Mansinho, K; Matos, O

    2010-07-01

    Pneumocystis jirovecii is a poorly understood pathogen that causes opportunistic pneumonia (Pneumocystis pneumonia (PcP)) in patients with AIDS. The present study was aimed at correlating genetic differences in P. jirovecii isolates and clinical patient data. A description of genetic diversity in P. jirovecii isolates from human immunodeficiency virus-positive patients, based on the identification of multiple single-nucleotide polymorphisms (SNPs) at five distinct loci encoding mitochondrial large-subunit rRNA (mtLSU rRNA), cytochrome b (CYB), superoxide dismutase (SOD), dihydrofolate reductase (DHFR), and dihydropteroate synthase (DHPS), was achieved using PCR with DNA sequencing and restriction fragment length polymorphism analysis. The statistical analysis revealed several interesting correlations among the four most relevant SNPs (mt85, SOD110, SOD215, and DHFR312) and specific clinical parameters: mt85C was associated with undiagnosed or atypical PcP episodes and favourable follow-up; SOD215C was associated with favourable follow-up; and DHFR312T was associated with PcP cases presenting moderate to high parasite burdens. The genotypes mt85C/SOD215C and SOD110T/SOD215C were found to be associated with less virulent P. jirovecii infections, whereas the genotype SOD110T/SOD215T was found to be related to more virulent PcP episodes. The present work demonstrated that potential P. jirovecii haplotypes may be related to the clinical data and outcome of PcP.

  1. Cell-surface central nervous system autoantibodies: Clinical relevance and emerging paradigms

    PubMed Central

    Irani, Sarosh R; Gelfand, Jeffrey M; Al-Diwani, Adam; Vincent, Angela

    2014-01-01

    The recent discovery of several potentially pathogenic autoantibodies has helped identify patients with clinically distinctive central nervous system diseases that appear to benefit from immunotherapy. The associated autoantibodies are directed against the extracellular domains of cell-surface–expressed neuronal or glial proteins such as LGI1, N-methyl-D-aspartate receptor, and aquaporin-4. The original descriptions of the associated clinical syndromes were phenotypically well circumscribed. However, as availability of antibody testing has increased, the range of associated patient phenotypes and demographics has expanded. This in turn has led to the recognition of more immunotherapy-responsive syndromes in patients presenting with cognitive and behavioral problems, seizures, movement disorders, psychiatric features, and demyelinating disease. Although antibody detection remains diagnostically important, clinical recognition of these distinctive syndromes should ensure early and appropriate immunotherapy administration. We review the emerging paradigm of cell-surface–directed antibody–mediated neurological diseases, describe how the associated disease spectrums have broadened since the original descriptions, discuss some of the methodological issues regarding techniques for antibody detection and emphasize considerations surrounding immunotherapy administration. As these disorders continue to reach mainstream neurology and even psychiatry, more cell-surface–directed antibodies will be discovered, and their possible relevance to other more common disease presentations should become more clearly defined. PMID:24930434

  2. Clinical relevance of studies on the accuracy of visual inspection for detecting caries lesions: a systematic review.

    PubMed

    Gimenez, Thais; Piovesan, Chaiana; Braga, Mariana M; Raggio, Daniela P; Deery, Chris; Ricketts, David N; Ekstrand, Kim R; Mendes, Fausto Medeiros

    2015-01-01

    Although visual inspection is the most commonly used method for caries detection, and consequently the most investigated, studies have not been concerned about the clinical relevance of this procedure. Therefore, we conducted a systematic review in order to perform a critical evaluation considering the clinical relevance and methodological quality of studies on the accuracy of visual inspection for assessing caries lesions. Two independent reviewers searched several databases through July 2013 to identify papers/articles published in English. Other sources were checked to identify unpublished literature. The eligible studies were those which (1) assessed the accuracy of the visual method for detecting caries lesions on occlusal, approximal or smooth surfaces, in primary or permanent teeth, (2) used a reference standard, and (3) reported data about sample size and accuracy of the methods. Aspects related to clinical relevance and the methodological quality of the studies were evaluated. 96 of the 5,578 articles initially identified met the inclusion criteria. In general, most studies failed in considering some clinically relevant aspects: only 1 included study validated activity status of lesions, no study considered its prognosis, 79 studies did not consider a clinically relevant outcome, and only 1 evaluated a patient-centred outcome. Concerning methodological quality, the majority of the studies presented a high risk of bias in sample selection. In conclusion, studies on the accuracy of the visual method for caries detection should consider clinically relevant outcomes besides accuracy; moreover, they should be conducted with higher methodological quality, mainly regarding sample selection.

  3. Clinical relevance of surgical site infection as defined by the criteria of the Centers for Disease Control and Prevention.

    PubMed

    Henriksen, N A; Meyhoff, C S; Wetterslev, J; Wille-Jørgensen, P; Rasmussen, L S; Jorgensen, L N

    2010-07-01

    Surgical site infection (SSI) is a common complication after abdominal surgery and the Centers for Disease Control and Prevention (CDC) criteria are commonly used for diagnosis and surveillance. The aim of this study was to evaluate whether SSI diagnosed according to CDC is clinically relevant (CRSSI) and whether there is agreement between evaluations according to the CDC criteria, the ASEPSIS score (Additional treatment, presence of Serous discharge, Erythema, Purulent exudate, Separation of the deep tissues, Isolation of bacteria and duration of Stay) and CRSSI. We included 54 patients diagnosed with SSI and a matched control group (N=46) without SSI according to the CDC criteria after laparotomy. Two blinded experienced surgeons evaluated the hospital records and determined whether patients had CRSSI, based on the following criteria: antibiotic treatment, surgical intervention, prolonged hospital stay or referral to an intensive care unit for SSI. The rate of CRSSI was 38 of 54 (70%) in patients with CDC-diagnosed SSI and none in patients without a CDC-diagnosed SSI. Sixty-one percent of the CDC-diagnosed SSIs were superficial, of which 48% were considered clinically relevant. There was substantial agreement between the CDC criteria and CRSSI [kappa=0.69; 95% confidence interval (CI): 0.55-0.83] and fair agreement between the ASEPSIS score and the CDC criteria (kappa=0.23; 95% CI: 0-0.49) and between the ASEPSIS score and CRSSI (kappa=0.39; 95% CI: 0.17-0.61). The CDC criteria represent a suitable standard definition for monitoring and identifying SSI, even if some cases of less clinically significant superficial SSI are included.

  4. Incidence rate and pattern of clinically relevant potential drug-drug interactions in a large outpatient population of a developing country.

    PubMed

    Nabovati, Ehsan; Vakili-Arki, Hasan; Taherzadeh, Zhila; Saberi, Mohammad Reza; Abu-Hanna, Ameen; Eslami, Saeid

    2016-01-01

    The objective of this study was to determine incidence rate, type, and pattern of clinically relevant potential drug-drug interactions (pDDIs) in a large outpatient population of a developing country. A retrospective, descriptive cross-sectional study was conducted on outpatients' prescriptions in Khorasan Razavi province, Iran, over 12 months. A list of 25 clinically relevant DDIs, which are likely to occur in the outpatient setting, was used as the reference. Most frequent clinically relevant pDDIs, most common drugs contributing to the pDDIs, and the pattern of pDDIs for each medical specialty were determined. Descriptive statistics were used to report the results. In total, out of 8,169,142 prescriptions, 6,096 clinically relevant pDDIs were identified. The most common identified pDDIs were theophyllines-quinolones, warfarin-nonsteroidal anti-inflammatory drugs, benzodiazepines-azole antifungal agents, and anticoagulants-thyroid hormones. The most common drugs contributing to the identified pDDIs were ciprofloxacin, theophylline, warfarin, aminophylline, alprazolam, levothyroxine, and selegiline. While the incidence rate of clinically relevant pDDIs in prescriptions of general practitioners, internists, and cardiologists was the highest, the average pDDI incidence per 10,000 prescriptions of pulmonologists, infectious disease specialists, and cardiologists was highest. Although a small proportion of the analyzed prescriptions contained drug pairs with potential for clinically relevant DDIs, a significant number of outpatients have been exposed to the adverse effects associated with these interactions. It is recommended that in addition to training physicians and pharmacists, other effective interventions such as computerized alerting systems and electronic prescribing systems be designed and implemented. PMID:27499793

  5. Clinically Relevant Mutant DNA Gyrase Alters Supercoiling, Changes the Transcriptome, and Confers Multidrug Resistance

    PubMed Central

    Webber, Mark A.; Ricci, Vito; Whitehead, Rebekah; Patel, Meha; Fookes, Maria; Ivens, Alasdair; Piddock, Laura J. V.

    2013-01-01

    ABSTRACT Bacterial DNA is maintained in a supercoiled state controlled by the action of topoisomerases. Alterations in supercoiling affect fundamental cellular processes, including transcription. Here, we show that substitution at position 87 of GyrA of Salmonella influences sensitivity to antibiotics, including nonquinolone drugs, alters global supercoiling, and results in an altered transcriptome with increased expression of stress response pathways. Decreased susceptibility to multiple antibiotics seen with a GyrA Asp87Gly mutant was not a result of increased efflux activity or reduced reactive-oxygen production. These data show that a frequently observed and clinically relevant substitution within GyrA results in altered expression of numerous genes, including those important in bacterial survival of stress, suggesting that GyrA mutants may have a selective advantage under specific conditions. Our findings help contextualize the high rate of quinolone resistance in pathogenic strains of bacteria and may partly explain why such mutant strains are evolutionarily successful. PMID:23882012

  6. [Calcinosis of the carotid siphon--morphology, differential diagnosis and clinical relevance].

    PubMed

    Eppinger, B; Schumacher, M

    1986-11-01

    In order to determine the clinical significance and hemodynamic relevance of carotid siphon calcification 241 patients were investigated by doppler sonography and skull x-ray. Comparing 139 patients with and 60 patients without siphon calcification, we examined the predictive value of carotid calcification regarding obstructive vessel disease as indicated by doppler sonography. Both groups were compared with 42 patients who all had doppler sonographic signs of severe carotid stenosis. No significant difference was found regarding the incidence of stenosis between the groups with and without siphon calcification (13% vs. 15%). Interpreting siphon calcification as a general sign of atherosclerosis seems therefore not justified. An over proportionally high rate (61.9%) of siphon calcification can only be expected by selected patients with severe obstructive vessels disease. Etiological factors are discussed and differential diagnosis of siphon calcification is demonstrated by cases.

  7. Expanding the scope and relevance of health interventions: Moving beyond clinical trials and behavior change models

    PubMed Central

    Rigg, Khary K.; Cook, Hilary H.; Murphy, John W.

    2014-01-01

    An overemphasis on clinical trials and behavior change models has narrowed the knowledge base that can be used to design interventions. The overarching point is that the process of overanalyzing variables is impeding the process of gaining insight into the everyday experiences that shape how people define health and seek treatment. This claim is especially important to health decision-making and behavior change because subtle interpretations often influence the decisions that people make. This manuscript provides a critique of traditional approaches to developing health interventions, and theoretically justifies what and why changes are warranted. The limited scope of these models is also discussed, and an argument is made to adopt a strategy that includes the perceptions of people as necessary for understanding health and health-related decision-making. Three practical strategies are suggested to be used with the more standard approaches to assessing the effectiveness and relevance of health interventions. PMID:25053530

  8. In Vivo Photoacoustic and Fluorescence Cystography Using Clinically Relevant Dual Modal Indocyanine Green

    PubMed Central

    Park, Sungjo; Kim, Jeesu; Jeon, Mansik; Song, Jaewon; Kim, Chulhong

    2014-01-01

    Conventional X-ray-based cystography uses radio-opaque materials, but this method uses harmful ionizing radiation and is not sensitive. In this study, we demonstrate nonionizing and noninvasive photoacoustic (PA) and fluorescence (FL) cystography using clinically relevant indocyanine green (ICG) in vivo. After transurethral injection of ICG into rats through a catheter, their bladders were photoacoustically and fluorescently visualized. A deeply positioned bladder below the skin surface (i.e., ∼1.5–5 mm) was clearly visible in the PA and FL image using a laser pulse energy of less than 2 mJ/cm2 (1/15 of the safety limit). Then, the in vivo imaging results were validated through in situ studies. Our results suggest that dual modal cystography can provide a nonionizing and noninvasive imaging tool for bladder mapping. PMID:25337743

  9. B in TB: B Cells as Mediators of Clinically Relevant Immune Responses in Tuberculosis.

    PubMed

    Rao, Martin; Valentini, Davide; Poiret, Thomas; Dodoo, Ernest; Parida, Shreemanta; Zumla, Alimuddin; Brighenti, Susanna; Maeurer, Markus

    2015-10-15

    The protective role of B cells and humoral immune responses in tuberculosis infection has been regarded as inferior to cellular immunity directed to the intracellular pathogen Mycobacterium tuberculosis. However, B-cell-mediated immune responses in tuberculosis have recently been revisited in the context of B-cell physiology and antigen presentation. We discuss in this review the diverse functions of B cells in tuberculosis, with a focus on their biological and clinical relevance to progression of active disease. We also present the peptide microarray platform as a promising strategy to discover unknown antigenic targets of M. tuberculosis that could contribute to the better understanding of epitope focus of the humoral immune system against M. tuberculosis.

  10. Miniature Swine as a Clinically Relevant Model of Graft-Versus-Host Disease

    PubMed Central

    Duran-Struuck, Raimon; Huang, Christene A; Orf, Katherine; Bronson, Roderick T; Sachs, David H; Spitzer, Thomas R

    2015-01-01

    Miniature swine provide a preclinical model of hematopoietic cell transplantation (HCT) for studies of graft-versus-host disease. HCT between MHC-matched or ‑mismatched pigs can be performed to mimic clinical scenarios with outcomes that closely resemble those observed in human HCT recipients. With myeloablative conditioning, HCT across MHC barriers is typically fatal, with pigs developing severe (grade III or IV) GVHD involving the gastrointestinal tract, liver, and skin. Unlike rodent models, miniature swine provide an opportunity to perform extended longitudinal studies on individual animals, because multiple tissue biopsies can be harvested without the need for euthanasia. In addition, we have developed a swine GVHD scoring system that parallels that used in the human clinical setting. Given the similarities of GVHD in pigs and humans, we hope that the use of this scoring system facilitates clinical and scientific discourse between the laboratory and the clinic. We anticipate that results of swine studies will support the development of new strategies to improve the identification and treatment of GVHD in clinical HCT scenarios. PMID:26473348

  11. Miniature Swine as a Clinically Relevant Model of Graft-Versus-Host Disease.

    PubMed

    Duran-Struuck, Raimon; Huang, Christene A; Orf, Katherine; Bronson, Roderick T; Sachs, David H; Spitzer, Thomas R

    2015-10-01

    Miniature swine provide a preclinical model of hematopoietic cell transplantation (HCT) for studies of graft-versus-host disease. HCT between MHC-matched or -mismatched pigs can be performed to mimic clinical scenarios with outcomes that closely resemble those observed in human HCT recipients. With myeloablative conditioning, HCT across MHC barriers is typically fatal, with pigs developing severe (grade III or IV) GVHD involving the gastrointestinal tract, liver, and skin. Unlike rodent models, miniature swine provide an opportunity to perform extended longitudinal studies on individual animals, because multiple tissue biopsies can be harvested without the need for euthanasia. In addition, we have developed a swine GVHD scoring system that parallels that used in the human clinical setting. Given the similarities of GVHD in pigs and humans, we hope that the use of this scoring system facilitates clinical and scientific discourse between the laboratory and the clinic. We anticipate that results of swine studies will support the development of new strategies to improve the identification and treatment of GVHD in clinical HCT scenarios. PMID:26473348

  12. Per-beam, planar IMRT QA passing rates do not predict clinically relevant patient dose errors

    SciTech Connect

    Nelms, Benjamin E.; Zhen Heming; Tome, Wolfgang A.

    2011-02-15

    Purpose: The purpose of this work is to determine the statistical correlation between per-beam, planar IMRT QA passing rates and several clinically relevant, anatomy-based dose errors for per-patient IMRT QA. The intent is to assess the predictive power of a common conventional IMRT QA performance metric, the Gamma passing rate per beam. Methods: Ninety-six unique data sets were created by inducing four types of dose errors in 24 clinical head and neck IMRT plans, each planned with 6 MV Varian 120-leaf MLC linear accelerators using a commercial treatment planning system and step-and-shoot delivery. The error-free beams/plans were used as ''simulated measurements'' (for generating the IMRT QA dose planes and the anatomy dose metrics) to compare to the corresponding data calculated by the error-induced plans. The degree of the induced errors was tuned to mimic IMRT QA passing rates that are commonly achieved using conventional methods. Results: Analysis of clinical metrics (parotid mean doses, spinal cord max and D1cc, CTV D95, and larynx mean) vs IMRT QA Gamma analysis (3%/3 mm, 2/2, 1/1) showed that in all cases, there were only weak to moderate correlations (range of Pearson's r-values: -0.295 to 0.653). Moreover, the moderate correlations actually had positive Pearson's r-values (i.e., clinically relevant metric differences increased with increasing IMRT QA passing rate), indicating that some of the largest anatomy-based dose differences occurred in the cases of high IMRT QA passing rates, which may be called ''false negatives.'' The results also show numerous instances of false positives or cases where low IMRT QA passing rates do not imply large errors in anatomy dose metrics. In none of the cases was there correlation consistent with high predictive power of planar IMRT passing rates, i.e., in none of the cases did high IMRT QA Gamma passing rates predict low errors in anatomy dose metrics or vice versa. Conclusions: There is a lack of correlation between

  13. Gene expression profiling identifies distinct molecular subgroups of leiomyosarcoma with clinical relevance

    PubMed Central

    Lee, Yin-Fai; Roe, Toby; Mangham, D Chas; Fisher, Cyril; Grimer, Robert J; Judson, Ian

    2016-01-01

    Background: Soft tissue sarcomas are heterogeneous and a major complication in their management is that the existing classification scheme is not definitive and is still evolving. Leiomyosarcomas, a major histologic category of soft tissue sarcomas, are malignant tumours displaying smooth muscle differentiation. Although defined as a single group, they exhibit a wide range of clinical behaviour. We aimed to carry out molecular classification to identify new molecular subgroups with clinical relevance. Methods: We used gene expression profiling on 20 extra-uterine leiomyosarcomas and cross-study analyses for molecular classification of leiomyosarcomas. Clinical significance of the subgroupings was investigated. Results: We have identified two distinct molecular subgroups of leiomyosarcomas. One group was characterised by high expression of 26 genes that included many genes from the sub-classification gene cluster proposed by Nielsen et al. These sub-classification genes include genes that have importance structurally, as well as in cell signalling. Notably, we found a statistically significant association of the subgroupings with tumour grade. Further refinement led to a group of 15 genes that could recapitulate the tumour subgroupings in our data set and in a second independent sarcoma set. Remarkably, cross-study analyses suggested that these molecular subgroups could be found in four independent data sets, providing strong support for their existence. Conclusions: Our study strongly supported the existence of distinct leiomyosarcoma molecular subgroups, which have clinical association with tumour grade. Our findings will aid in advancing the classification of leiomyosarcomas and lead to more individualised and better management of the disease. PMID:27607470

  14. Hypersensitivities for acetaldehyde and other agents among cancer cells null for clinically relevant Fanconi anemia genes.

    PubMed

    Ghosh, Soma; Sur, Surojit; Yerram, Sashidhar R; Rago, Carlo; Bhunia, Anil K; Hossain, M Zulfiquer; Paun, Bogdan C; Ren, Yunzhao R; Iacobuzio-Donahue, Christine A; Azad, Nilofer A; Kern, Scott E

    2014-01-01

    Large-magnitude numerical distinctions (>10-fold) among drug responses of genetically contrasting cancers were crucial for guiding the development of some targeted therapies. Similar strategies brought epidemiological clues and prevention goals for genetic diseases. Such numerical guides, however, were incomplete or low magnitude for Fanconi anemia pathway (FANC) gene mutations relevant to cancer in FANC-mutation carriers (heterozygotes). We generated a four-gene FANC-null cancer panel, including the engineering of new PALB2/FANCN-null cancer cells by homologous recombination. A characteristic matching of FANCC-null, FANCG-null, BRCA2/FANCD1-null, and PALB2/FANCN-null phenotypes was confirmed by uniform tumor regression on single-dose cross-linker therapy in mice and by shared chemical hypersensitivities to various inter-strand cross-linking agents and γ-radiation in vitro. Some compounds, however, had contrasting magnitudes of sensitivity; a strikingly high (19- to 22-fold) hypersensitivity was seen among PALB2-null and BRCA2-null cells for the ethanol metabolite, acetaldehyde, associated with widespread chromosomal breakage at a concentration not producing breaks in parental cells. Because FANC-defective cancer cells can share or differ in their chemical sensitivities, patterns of selective hypersensitivity hold implications for the evolutionary understanding of this pathway. Clinical decisions for cancer-relevant prevention and management of FANC-mutation carriers could be modified by expanded studies of high-magnitude sensitivities.

  15. Expression, regulation and clinical relevance of the ATPase inhibitory factor 1 in human cancers

    PubMed Central

    Sánchez-Aragó, M; Formentini, L; Martínez-Reyes, I; García-Bermudez, J; Santacatterina, F; Sánchez-Cenizo, L; Willers, I M; Aldea, M; Nájera, L; Juarránz, Á; López, E C; Clofent, J; Navarro, C; Espinosa, E; Cuezva, J M

    2013-01-01

    Recent findings in colon cancer cells indicate that inhibition of the mitochondrial H+-adenosine triphosphate (ATP) synthase by the ATPase inhibitory factor 1 (IF1) promotes aerobic glycolysis and a reactive oxygen species (ROS)-mediated signal that enhances proliferation and cell survival. Herein, we have studied the expression, biological relevance, mechanism of regulation and potential clinical impact of IF1 in some prevalent human carcinomas. We show that IF1 is highly overexpressed in most (>90%) of the colon (n=64), lung (n=30), breast (n=129) and ovarian (n=10) carcinomas studied as assessed by different approaches in independent cohorts of cancer patients. The expression of IF1 in the corresponding normal tissues is negligible. By contrast, the endometrium, stomach and kidney show high expression of IF1 in the normal tissue revealing subtle differences by carcinogenesis. The overexpression of IF1 also promotes the activation of aerobic glycolysis and a concurrent ROS signal in mitochondria of the lung, breast and ovarian cancer cells mimicking the activity of oligomycin. IF1-mediated ROS signaling activates cell-type specific adaptive responses aimed at preventing death in these cell lines. Remarkably, regulation of IF1 expression in the colon, lung, breast and ovarian carcinomas is exerted at post-transcriptional levels. We demonstrate that IF1 is a short-lived protein (t1/2 ∼100 min) strongly implicating translation and/or protein stabilization as main drivers of metabolic reprogramming and cell survival in these human cancers. Analysis of tumor expression of IF1 in cohorts of breast and colon cancer patients revealed its relevance as a predictive marker for clinical outcome, emphasizing the high potential of IF1 as therapeutic target. PMID:23608753

  16. Direct toxic effects of aqueous extract of cigarette smoke on cardiac myocytes at clinically relevant concentrations

    SciTech Connect

    Yamada, Shigeyuki; Zhang Xiuquan; Kadono, Toshie; Matsuoka, Nobuhiro; Rollins, Douglas; Badger, Troy; Rodesch, Christopher K.; Barry, William H.

    2009-04-01

    Aims: Our goal was to determine if clinically relevant concentrations of aqueous extract of cigarette smoke (CSE) have direct deleterious effects on ventricular myocytes during simulated ischemia, and to investigate the mechanisms involved. Methods: CSE was prepared with a smoking chamber. Ischemia was simulated by metabolic inhibition (MI) with cyanide (CN) and 0 glucose. Adult rabbit and mouse ventricular myocyte [Ca{sup 2+}]{sub i} was measured by flow cytometry using fluo-3. Mitochondrial [Ca{sup 2+}] was measured with confocal microscopy, and Rhod-2 fluorescence. The mitochondrial permeability transition (MPT) was detected by TMRM fluorescence and myocyte contracture. Myocyte oxidative stress was quantified by dichlorofluorescein (DCF) fluorescence with confocal microscopy. Results: CSE 0.1% increased myocyte contracture caused by MI. The nicotine concentration (HPLC) in 0.1% CSE was 15 ng/ml, similar to that in humans after smoking cigarettes. CSE 0.1% increased mitochondrial Ca{sup 2+} uptake, and increased the susceptibility of mitochondria to the MPT. CSE 0.1% increased DCF fluorescence in isolated myocytes, and increased [Ca{sup 2+}]{sub i} in paced myocytes exposed to 2.0 mM CN, 0 glucose (P-MI). These effects were inhibited by the superoxide scavenger Tiron. The effect of CSE on [Ca{sup 2+}]{sub i} during P-MI was also prevented by ranolazine. Conclusions: CSE in clinically relevant concentrations increases myocyte [Ca{sup 2+}]{sub i} during simulated ischemia, and increases myocyte susceptibility to the MPT. These effects appear to be mediated at least in part by oxidative radicals in CSE, and likely contribute to the effects of cigarette smoke to increase myocardial infarct size, and to decrease angina threshold.

  17. Chromosomal patterns of gene expression from microarray data: methodology, validation and clinical relevance in gliomas

    PubMed Central

    Turkheimer, Federico E; Roncaroli, Federico; Hennuy, Benoit; Herens, Christian; Nguyen, Minh; Martin, Didier; Evrard, Annick; Bours, Vincent; Boniver, Jacques; Deprez, Manuel

    2006-01-01

    Background Expression microarrays represent a powerful technique for the simultaneous investigation of thousands of genes. The evidence that genes are not randomly distributed in the genome and that their coordinated expression depends on their position on chromosomes has highlighted the need for mathematical approaches to exploit this dependency for the analysis of expression data-sets. Results We have devised a novel mathematical technique (CHROMOWAVE) based on the Haar wavelet transform and applied it to a dataset obtained with the Affymetrix® HG-U133_Plus_2 array in 27 gliomas. CHROMOWAVE generated multi-chromosomal pattern featuring low expression in chromosomes 1p, 4, 9q, 13, 18, and 19q. This pattern was not only statistically robust but also clinically relevant as it was predictive of favourable outcome. This finding was replicated on a data-set independently acquired by another laboratory. FISH analysis indicated that monosomy 1p and 19q was a frequent feature of tumours displaying the CHROMOWAVE pattern but that allelic loss on chromosomes 4, 9q, 13 and 18 was much less common. Conclusion The ability to detect expression changes of spatially related genes and to map their position on chromosomes makes CHROMOWAVE a valuable screening method for the identification and display of regional gene expression changes of clinical relevance. In this study, FISH data showed that monosomy was frequently associated with diffuse low gene expression on chromosome 1p and 19q but not on chromosomes 4, 9q, 13 and 18. Comparative genomic hybridisation, allelic polymorphism analysis and methylation studies are in progress in order to identify the various mechanisms involved in this multi-chromosomal expression pattern. PMID:17140431

  18. Serology and clinical relevance of Corynebacterium pseudotuberculosis in native Korean goats (Capra hircus coreanae).

    PubMed

    Jung, Byeong Yeal; Lee, Seung-Hun; Kim, Ha-Young; Byun, Jae-Won; Shin, Dong-Ho; Kim, Daekeun; Kwak, Dongmi

    2015-04-01

    This study was conducted to assess the seroprevalence and clinical relevance of Corynebacterium pseudotuberculosis, which is the causative agent of caseous lymphadenitis (CLA), in native Korean goats (Capra hircus coreanae). A total of 466 native Korean goats from 40 herds (11 to 12 samples per herd) were randomly selected throughout the nation and evaluated by direct palpation, bacterial isolation, ELISA, and PCR. In serological examinations, 267 (57.3 %) of the goats tested were positive against C. pseudotuberculosis. When seroprevalence was analyzed according to age, region, and season, statistically significant differences were observed in relation to all three parameters (P < 0.05). For clinical examination, the superficial lymph nodes of all goats were palpated to diagnose CLA. Pus samples taken from superficial abscesses were used for bacterial isolation. Among the 466 goats tested, 34 (7.3 %) were presumptively diagnosed with CLA, and C. pseudotuberculosis was isolated from 24 goats (70.6 % of goats with CLA lesions) whose infections were confirmed by PCR. Considering the high seroprevalence and bacterial isolation rate from most of the superficial CLA lesions, it is suspected that many internal CLA lesions exist in this goat population. These results suggest that C. pseudotuberculosis infection is widespread in native Korean goats, and appropriate control programs need to be established.

  19. Detection of Adriamycin-DNA adducts by accelerator mass spectrometry at clinically relevant Adriamycin concentrations.

    PubMed

    Coldwell, Kate E; Cutts, Suzanne M; Ognibene, Ted J; Henderson, Paul T; Phillips, Don R

    2008-09-01

    Limited sensitivity of existing assays has prevented investigation of whether Adriamycin-DNA adducts are involved in the anti-tumour potential of Adriamycin. Previous detection has achieved a sensitivity of a few Adriamycin-DNA adducts/10(4) bp DNA, but has required the use of supra-clinical drug concentrations. This work sought to measure Adriamycin-DNA adducts at sub-micromolar doses using accelerator mass spectrometry (AMS), a technique with origins in geochemistry for radiocarbon dating. We have used conditions previously validated (by less sensitive decay counting) to extract [(14)C]Adriamycin-DNA adducts from cells and adapted the methodology to AMS detection. Here we show the first direct evidence of Adriamycin-DNA adducts at clinically-relevant Adriamycin concentrations. [(14)C]Adriamycin treatment (25 nM) resulted in 4.4 +/- 1.0 adducts/10(7) bp ( approximately 1300 adducts/cell) in MCF-7 breast cancer cells, representing the best sensitivity and precision reported to date for the covalent binding of Adriamycin to DNA. The exceedingly sensitive nature of AMS has enabled over three orders of magnitude increased sensitivity of Adriamycin-DNA adduct detection and revealed adduct formation within an hour of drug treatment. This method has been shown to be highly reproducible for the measurement of Adriamycin-DNA adducts in tumour cells in culture and can now be applied to the detection of these adducts in human tissues.

  20. Clinical and Neurobiological Relevance of Current Animal Models of Autism Spectrum Disorders

    PubMed Central

    Kim, Ki Chan; Gonzales, Edson Luck; Lázaro, María T.; Choi, Chang Soon; Bahn, Geon Ho; Yoo, Hee Jeong; Shin, Chan Young

    2016-01-01

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments, as well as repetitive and restrictive behaviors. The phenotypic heterogeneity of ASD has made it overwhelmingly difficult to determine the exact etiology and pathophysiology underlying the core symptoms, which are often accompanied by comorbidities such as hyperactivity, seizures, and sensorimotor abnormalities. To our benefit, the advent of animal models has allowed us to assess and test diverse risk factors of ASD, both genetic and environmental, and measure their contribution to the manifestation of autistic symptoms. At a broader scale, rodent models have helped consolidate molecular pathways and unify the neurophysiological mechanisms underlying each one of the various etiologies. This approach will potentially enable the stratification of ASD into clinical, molecular, and neurophenotypic subgroups, further proving their translational utility. It is henceforth paramount to establish a common ground of mechanistic theories from complementing results in preclinical research. In this review, we cluster the ASD animal models into lesion and genetic models and further classify them based on the corresponding environmental, epigenetic and genetic factors. Finally, we summarize the symptoms and neuropathological highlights for each model and make critical comparisons that elucidate their clinical and neurobiological relevance. PMID:27133257

  1. Clinical and Neurobiological Relevance of Current Animal Models of Autism Spectrum Disorders.

    PubMed

    Kim, Ki Chan; Gonzales, Edson Luck; Lázaro, María T; Choi, Chang Soon; Bahn, Geon Ho; Yoo, Hee Jeong; Shin, Chan Young

    2016-05-01

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication impairments, as well as repetitive and restrictive behaviors. The phenotypic heterogeneity of ASD has made it overwhelmingly difficult to determine the exact etiology and pathophysiology underlying the core symptoms, which are often accompanied by comorbidities such as hyperactivity, seizures, and sensorimotor abnormalities. To our benefit, the advent of animal models has allowed us to assess and test diverse risk factors of ASD, both genetic and environmental, and measure their contribution to the manifestation of autistic symptoms. At a broader scale, rodent models have helped consolidate molecular pathways and unify the neurophysiological mechanisms underlying each one of the various etiologies. This approach will potentially enable the stratification of ASD into clinical, molecular, and neurophenotypic subgroups, further proving their translational utility. It is henceforth paramount to establish a common ground of mechanistic theories from complementing results in preclinical research. In this review, we cluster the ASD animal models into lesion and genetic models and further classify them based on the corresponding environmental, epigenetic and genetic factors. Finally, we summarize the symptoms and neuropathological highlights for each model and make critical comparisons that elucidate their clinical and neurobiological relevance. PMID:27133257

  2. Education in the clinical context: establishing a strategic framework to ensure relevance.

    PubMed

    Henderson, Amanda; Fox, Robyn; Armit, Lyn

    2008-01-01

    Quality contemporary practice relies on nurses to provide health care within an embedded nexus of clinical, professional and organisational learning that leads them through a career trajectory that encourages lifelong development. Within complex health service environments this is fraught with difficulties. Enhancing practice is multifaceted requiring not just education for the acquisition of skills and abilities but time and space for reflection on experience within the clinical context. This ultimately leads to professional knowledge development. Queensland Health has developed a Nursing and Midwifery Staff Development Framework to assist nurses in structuring their experiences in the practice setting to enable their professional goals. Learning is guided within this framework through its collective modus operandi, that is, the development of teams that overlap to identify and progress the educational agenda; resources to develop consistent relevant learning material that incorporates evidence obtained through practices and the literature; and educator and clinician networks across health services throughout the state, and furthermore, links with the tertiary sector to assist in marketing, applicability and synergy with further education.

  3. Relevance of cellular to clinical electrophysiology in interpreting antiarrhythmic drug action.

    PubMed

    Vaughan Williams, E M

    1989-12-01

    The usefulness of cellular electrophysiologic techniques in elucidating the fundamental actions of antiarrhythmic drugs is contrasted with their apparent lack of relevance to the selection of drugs for the treatment of particular arrhythmias. Clinical electrophysiologists employ different techniques, but their results may be explained in terms of cellular drug actions. The varying clinical effects of class IA, IB and IC agents are due to differences in the speed of their attachment to, and detachment from, sodium channels. The role of sympathetic activity in arrhythmogenesis is complex, but again readily explicable in terms of the electrophysiologic cellular actions of stimulation of the individual types of adrenoceptors (alpha 1, alpha 2, beta 1 and beta 2) and the distribution of these receptors, and of the longterm effects of sympathetic deprivation, either by antisympathetic drugs (class II) or by sympathetic denervation. Delayed repolarization (e.g., by class III drugs or prolonged beta blockade) is antiarrhythmic because it is homogeneous, despite the incidental prolongation of QT. If, however, QT is prolonged by heterogeneity of conduction or repolarization, or by partial sympathetic denervation (long QT syndrome or post myocardial infarction), this indicates increased risk of arrhythmia. Finally, the efficacy of calcium antagonists (class IV) in supraventricular arrhythmias is attributable to the cellular electrophysiologic characteristics of sinoatrial and atrioventricular nodal and transitional elements.

  4. Assessment of viability after myocardial infarction. Clinical relevance and methodological problems.

    PubMed

    Fragasso, G; Margonato, A; Chierchia, S L

    1993-01-01

    In patients with myocardial infarction, the distinction between reversible and irreversible ventricular dysfunction has important clinical implications since dysfunctional but viable myocardium will resume contraction following revascularization. Various methods have been developed for the identification of potentially reversible myocardial dysfunction. Thallium reinjection, immediately after stress-redistribution imaging, may provide evidence of myocardial viability by demonstrating thallium uptake in regions with apparently 'irreversible' defects. Hypoperfused, hypocontractile segments may recover function after revascularization, when exhibiting increased 18F-fluoro-deoxy-glucose uptake on positron emission tomography. Improved contractile function by selective beta 1 adrenergic stimulation with low dose dobutamine may also indicate the presence of viable tissue and predict subsequent improvement upon restoration of adequate flow. Finally, exercise-induced ST segment elevation on leads exploring a recent myocardial infarction has also been shown to indicate the presence of viable, potentially salvageable tissue. We discuss here these and several other methods that have been proposed for the detection of residual myocardial viability. Their advantages, limitations, and relevance to clinical problems are also discussed.

  5. Standardizing Analysis of Circulating MicroRNA: Clinical and Biological Relevance

    PubMed Central

    Farina, Nicholas H.; Wood, Marie E.; Perrapato, Scott D.; Francklyn, Christopher S.; Stein, Gary S.; Stein, Janet L.; Lian, Jane B.

    2014-01-01

    Circulating microRNAs (c-miRNAs) provide a new dimension as clinical biomarkers for disease diagnosis, progression, and response to treatment. However, the discovery of individual miRNAs from biofluids that reliably reflect disease states is in its infancy. The highly variable nature of published studies exemplifies a need to standardize the analysis of miRNA in circulation. Here, we show that differential sample handling of serum leads to inconsistent and incomparable results. We present a standardized method of RNA isolation from serum that eliminates multiple freeze/thaw cycles, provides at least 3 normalization mechanisms, and can be utilized in studies that compare both archived and prospectively collected samples. It is anticipated that serum processed as described here can be profiled, either globally or on a gene by gene basis, for c-miRNAs and other non-coding RNA in the circulation to reveal novel, clinically relevant epigenetic signatures for a wide range of diseases. PMID:24357537

  6. Clinical relevance of nalmefene versus placebo in alcohol treatment: Reduction in mortality risk

    PubMed Central

    Roerecke, Michael; Sørensen, Per; Laramée, Philippe; Rahhali, Nora; Rehm, Jürgen

    2015-01-01

    Reduction of long-term mortality risk, an important clinical outcome for people in alcohol dependence treatment, can rarely be established in randomized controlled trials (RCTs). We calculated the reduction in all-cause mortality risk using data from short-term (6 and 12 months) double-blind RCTs comparing as-needed nalmefene treatment to placebo, and mortality risks from meta-analyses on all-cause-mortality risk by reduction of drinking in people with alcohol dependence. A reduction in drinking in the RCTs was defined by shifts in drinking risk levels established by the European Medicines Agency. Results showed that the reduction of drinking in the nalmefene group was associated with a reduction in mortality risk by 8% (95% CI: 2%, 13%) when compared to the placebo group. Sensitivity analyses confirmed a significant effect. Thus comparing the difference between nalmefene and placebo in reduction in drinking levels with results on all-cause mortality risk from meta-analyses indicated a clinically relevant reduction in mortality risk. Given the high mortality risk of people with alcohol dependence, abstinence or a reduction in drinking have been shown to reduce mortality risk and should be considered treatment goals. PMID:26349557

  7. Clinical relevance of nalmefene versus placebo in alcohol treatment: reduction in mortality risk.

    PubMed

    Roerecke, Michael; Sørensen, Per; Laramée, Philippe; Rahhali, Nora; Rehm, Jürgen

    2015-11-01

    Reduction of long-term mortality risk, an important clinical outcome for people in alcohol dependence treatment, can rarely be established in randomized controlled trials (RCTs). We calculated the reduction in all-cause mortality risk using data from short-term (6 and 12 months) double-blind RCTs comparing as-needed nalmefene treatment to placebo, and mortality risks from meta-analyses on all-cause-mortality risk by reduction of drinking in people with alcohol dependence. A reduction in drinking in the RCTs was defined by shifts in drinking risk levels established by the European Medicines Agency. Results showed that the reduction of drinking in the nalmefene group was associated with a reduction in mortality risk by 8% (95% CI: 2%, 13%) when compared to the placebo group. Sensitivity analyses confirmed a significant effect. Thus comparing the difference between nalmefene and placebo in reduction in drinking levels with results on all-cause mortality risk from meta-analyses indicated a clinically relevant reduction in mortality risk. Given the high mortality risk of people with alcohol dependence, abstinence or a reduction in drinking have been shown to reduce mortality risk and should be considered treatment goals.

  8. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use.

    PubMed

    Taylor, Charles P; Traynelis, Stephen F; Siffert, Joao; Pope, Laura E; Matsumoto, Rae R

    2016-08-01

    Dextromethorphan (DM) has been used for more than 50years as an over-the-counter antitussive. Studies have revealed a complex pharmacology of DM with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential. DM is rapidly metabolized to dextrorphan, which has hampered the exploration of DM therapy separate from its metabolites. Coadministration of DM with a low dose of quinidine inhibits DM metabolism, yields greater bioavailability and enables more specific testing of the therapeutic properties of DM apart from its metabolites. The development of the drug combination DM hydrobromide and quinidine sulfate (DM/Q), with subsequent approval by the US Food and Drug Administration for pseudobulbar affect, led to renewed interest in understanding DM pharmacology. This review summarizes the interactions of DM with brain receptors and transporters and also considers its metabolic and pharmacokinetic properties. To assess the potential clinical relevance of these interactions, we provide an analysis comparing DM activity from in vitro functional assays with the estimated free drug DM concentrations in the brain following oral DM/Q administration. The findings suggest that DM/Q likely inhibits serotonin and norepinephrine reuptake and also blocks NMDA receptors with rapid kinetics. Use of DM/Q may also antagonize nicotinic acetylcholine receptors, particularly those composed of α3β4 subunits, and cause agonist activity at sigma-1 receptors. PMID:27139517

  9. New insights of an old defense system: structure, function, and clinical relevance of the complement system.

    PubMed

    Ehrnthaller, Christian; Ignatius, Anita; Gebhard, Florian; Huber-Lang, Markus

    2011-01-01

    The complement system was discovered a century ago as a potent defense cascade of innate immunity. After its first description, continuous experimental and clinical research was performed, and three canonical pathways of activation were established. Upon activation by traumatic or surgical tissue damage, complement reveals beneficial functions of pathogen and danger defense by sensing and clearing injured cells. However, the latest research efforts have provided a more distinct insight into the complement system and its clinical subsequences. Complement has been shown to play a significant role in the pathogenesis of various inflammatory processes such as sepsis, multiorgan dysfunction, ischemia/reperfusion, cardiovascular diseases and many others. The three well-known activation pathways of the complement system have been challenged by newer findings that demonstrate direct production of central complement effectors (for example, C5a) by serine proteases of the coagulation cascade. In particular, thrombin is capable of producing C5a, which not only plays a decisive role on pathogens and infected/damaged tissues, but also acts systemically. In the case of uncontrolled complement activation, "friendly fire" is generated, resulting in the destruction of healthy host tissue. Therefore, the traditional research that focuses on a mainly positive-acting cascade has now shifted to the negative effects and how tissue damage originated by the activation of the complement can be contained. In a translational approach including structure-function relations of this ancient defense system, this review provides new insights of complement-mediated clinical relevant diseases and the development of complement modulation strategies and current research aspects.

  10. Vasopressin in preeclampsia: a novel very early human pregnancy biomarker and clinically relevant mouse model.

    PubMed

    Santillan, Mark K; Santillan, Donna A; Scroggins, Sabrina M; Min, James Y; Sandgren, Jeremy A; Pearson, Nicole A; Leslie, Kimberly K; Hunter, Stephen K; Zamba, Gideon K D; Gibson-Corley, Katherine N; Grobe, Justin L

    2014-10-01

    Preeclampsia, a cardiovascular disorder of late pregnancy, is characterized as a low-renin hypertensive state relative to normotensive pregnancy. Because other nonpregnant low-renin hypertensive disorders often exhibit and are occasionally dependent on elevated arginine vasopressin (AVP) secretion, we hypothesized a possible use for plasma AVP measurements in the prediction of preeclampsia. Copeptin is an inert prosegment of AVP that is secreted in a 1:1 molar ratio and exhibits a substantially longer biological half-life compared with AVP, rendering it a clinically useful biomarker of AVP secretion. Copeptin was measured throughout pregnancy in maternal plasma from preeclamptic and control women. Maternal plasma copeptin was significantly higher throughout preeclamptic pregnancies versus control pregnancies. While controlling for clinically significant confounders (age, body mass index, chronic essential hypertension, twin gestation, diabetes mellitus, and history of preeclampsia) using multivariate regression, the association of higher copeptin concentration and the development of preeclampsia remained significant. Receiver operating characteristic analyses reveal that as early as the sixth week of gestation, elevated maternal plasma copeptin concentration is a highly significant predictor of preeclampsia throughout pregnancy. Finally, chronic infusion of AVP during pregnancy (24 ng per hour) is sufficient to phenocopy preeclampsia in C57BL/6J mice, causing pregnancy-specific hypertension, renal glomerular endotheliosis, proteinuria, and intrauterine growth restriction. These data implicate AVP release as a novel predictive biomarker for preeclampsia very early in pregnancy, identify chronic AVP infusion as a novel and clinically relevant model of preeclampsia in mice, and are consistent with a potential causative role for AVP in preeclampsia in humans.

  11. Is a raised intraepithelial lymphocyte count with normal duodenal villous architecture clinically relevant?

    PubMed Central

    Mahadeva, S; Wyatt, J I; Howdle, P D

    2002-01-01

    Background: A raised intraepithelial lymphocyte (IEL) count with normal villous architecture is a recognised finding in latent coeliac disease. Little information is available in cases without gluten sensitive enteropathy in adults. Aims: To assess the frequency of such a finding in routine practice and to determine whether it is clinically relevant. Methods: Patients with subjectively increased IELs as the only abnormality were identified prospectively from a routine duodenal biopsy series over a 12 month period. The biopsy specimens in these index cases were re-examined together with two controls with normal histology for each case, and three counts of IEL/100 epithelial cells were made in all samples. The index cases were then contacted and interviewed to obtain clinical information, approximately 12 months from the initial biopsy. Further data were obtained from their clinical records. Results: Fourteen of 626 (2.2%) patients who had duodenal biopsies over the 12 month period had a subjective increase in IELs with normal villous architecture. Fifteen patients with newly diagnosed gluten sensitive enteropathy were also identified during the study period. Formal counting of the index cases and controls revealed a significant difference in IELs/100 epithelial cell counts between the two (mean, 38 (SD, 6.2) v 12.4 (4.6); p < 0.0001). Three of the 14 index cases tested had a positive coeliac antibody test compared with 12 of 15 newly diagnosed patients with coeliac disease and 10 of 93 patients with normal histology. The major clinical diagnostic categories in raised IEL cases were those with positive coeliac serology (n = 3), unexplained anaemia (n = 3), and chronic liver disease (n = 3). Six of 10 patients who were interviewed had ongoing gastrointestinal symptoms one year later. Three patients had had follow up duodenal biopsies, at the discretion of their responsible clinicians, with no change in IEL counts despite the commencement of a gluten free diet in two

  12. The Facts About Sexual (Dys)function in Schizophrenia: An Overview of Clinically Relevant Findings

    PubMed Central

    de Boer, Marrit K.; Castelein, Stynke; Wiersma, Durk; Schoevers, Robert A.; Knegtering, Henderikus

    2015-01-01

    A limited number of studies have evaluated sexual functioning in patients with schizophrenia. Most patients show an interest in sex that differs little from the general population. By contrast, psychiatric symptoms, institutionalization, and psychotropic medication contribute to frequently occurring impairments in sexual functioning. Women with schizophrenia have a better social outcome, longer lasting (sexual) relationships, and more offspring than men with schizophrenia. Still, in both sexes social and interpersonal impairments limit the development of stable sexual relationships. Although patients consider sexual problems to be highly relevant, patients and clinicians not easily discuss these spontaneously, leading to an underestimation of their prevalence and contributing to decreased adherence to treatment. Studies using structured interviews or questionnaires result in many more patients reporting sexual dysfunctions. Although sexual functioning can be impaired by different factors, the use of antipsychotic medication seems to be an important factor. A comparison of different antipsychotics showed high frequencies of sexual dysfunction for risperidone and classical antipsychotics, and lower frequencies for clozapine, olanzapine, quetiapine, and aripiprazole. Postsynaptic dopamine antagonism, prolactin elevation, and α1-receptor blockade may be the most relevant factors in the pathogenesis of antipsychotic-induced sexual dysfunction. Psychosocial strategies to treat antipsychotic-induced sexual dysfunction include psychoeducation and relationship counseling. Pharmacological strategies include lowering the dose or switching to a prolactin sparing antipsychotic. Also, the addition of a dopamine agonist, aripiprazole, or a phosphodiesterase-5 inhibitor has shown some promising results, but evidence is currently scarce. PMID:25721311

  13. The relevance of "non-criteria" clinical manifestations of antiphospholipid syndrome: 14th International Congress on Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features.

    PubMed

    Abreu, Mirhelen M; Danowski, Adriana; Wahl, Denis G; Amigo, Mary-Carmen; Tektonidou, Maria; Pacheco, Marcelo S; Fleming, Norma; Domingues, Vinicius; Sciascia, Savino; Lyra, Julia O; Petri, Michelle; Khamashta, Munther; Levy, Roger A

    2015-05-01

    The purpose of this task force was to critically analyze nine non-criteria manifestations of APS to support their inclusion as APS classification criteria. The Task Force Members selected the non-criteria clinical manifestations according to their clinical relevance, that is, the patient-important outcome from clinician perspective. They included superficial vein thrombosis, thrombocytopenia, renal microangiopathy, heart valve disease, livedo reticularis, migraine, chorea, seizures and myelitis, which were reviewed by this International Task Force collaboration, in addition to the seronegative APS (SN-APS). GRADE system was used to evaluate the quality of evidence of medical literature of each selected item. This critical appraisal exercise aimed to support the debate regarding the clinical picture of APS. We found that the overall GRADE analysis was very low for migraine and seizures, low for superficial venous thrombosis, thrombocytopenia, chorea, longitudinal myelitis and the so-called seronegative APS and moderate for APS nephropathy, heart valve lesions and livedo reticularis. The next step can be a critical redefinition of an APS gold standard, for instance derived from the APS ACTION registry that will include not only current APS patients but also those with antiphospholipid antibodies not meeting current classification criteria. PMID:25641203

  14. Clinical relevance of molecular aberrations in paediatric acute myeloid leukaemia at first relapse.

    PubMed

    Bachas, Costa; Schuurhuis, Gerrit Jan; Reinhardt, Dirk; Creutzig, Ursula; Kwidama, Zinia J; Zwaan, C Michel; van den Heuvel-Eibrink, Marry M; De Bont, Evelina S J M; Elitzur, Sarah; Rizzari, Carmelo; de Haas, Valérie; Zimmermann, Martin; Cloos, Jacqueline; Kaspers, Gertjan J L

    2014-09-01

    Outcome for relapsed paediatric acute myeloid leukaemia (AML) remains poor. Strong prognostic factors at first relapse are lacking, which hampers optimization of therapy. We assessed the frequency of molecular aberrations (FLT3, NRAS, KRAS, KIT, WT1 and NPM1 genes) at first relapse in a large set (n = 198) of relapsed non-French-American-British M3, non-Down syndrome AML patients that received similar relapse treatment. We correlated molecular aberrations with clinical and biological factors and studied their prognostic relevance. Hotspot mutations in the analysed genes were detected in 92 out of 198 patients (46·5%). In 72 of these 92 patients (78%), molecular aberrations were mutually exclusive for the currently analysed genes. FLT3-internal tandem repeat (ITD) (18% of total group) mutations were most frequent, followed by NRAS (10·2%), KRAS (8%), WT1 (8%), KIT (8%), NPM1 (5%) and FLT3-tyrosine kinase domain (3%) mutations. Presence of a WT1 aberration was an independent risk factor for second relapse (Hazard Ratio [HR] = 2·74, P = 0·013). In patients who achieved second complete remission (70·2%), WT1 and FLT3-ITD aberrations were independent risk factors for poor overall survival (HR = 2·32, P = 0·038 and HR = 1·89, P = 0·045 respectively). These data show that molecular aberrations at first relapse are of prognostic relevance and potentially useful for risk group stratification of paediatric relapsed AML and for identification of patients eligible for personalized treatment. PMID:24962064

  15. lncRNA profiling in early-stage chronic lymphocytic leukemia identifies transcriptional fingerprints with relevance in clinical outcome.

    PubMed

    Ronchetti, D; Manzoni, M; Agnelli, L; Vinci, C; Fabris, S; Cutrona, G; Matis, S; Colombo, M; Galletti, S; Taiana, E; Recchia, A G; Bossio, S; Gentile, M; Musolino, C; Di Raimondo, F; Grilli, A; Bicciato, S; Cortelezzi, A; Tassone, P; Morabito, F; Ferrarini, M; Neri, A

    2016-01-01

    Long non-coding RNAs (lncRNAs) represent a novel class of functional RNA molecules with an important emerging role in cancer. To elucidate their potential pathogenetic role in chronic lymphocytic leukemia (CLL), a biologically and clinically heterogeneous neoplasia, we investigated lncRNAs expression in a prospective series of 217 early-stage Binet A CLL patients and 26 different subpopulations of normal B-cells, through a custom annotation pipeline of microarray data. Our study identified a 24-lncRNA-signature specifically deregulated in CLL compared with the normal B-cell counterpart. Importantly, this classifier was validated on an independent data set of CLL samples. Belonging to the lncRNA signature characterizing distinct molecular CLL subgroups, we identified lncRNAs recurrently associated with adverse prognostic markers, such as unmutated IGHV status, CD38 expression, 11q and 17p deletions, and NOTCH1 mutations. In addition, correlation analyses predicted a putative lncRNAs interplay with genes and miRNAs expression. Finally, we generated a 2-lncRNA independent risk model, based on lnc-IRF2-3 and lnc-KIAA1755-4 expression, able to distinguish three different prognostic groups in our series of early-stage patients. Overall, our study provides an important resource for future studies on the functions of lncRNAs in CLL, and contributes to the discovery of novel molecular markers with clinical relevance associated with the disease. PMID:27611921

  16. Clinical relevance of the fractal dimension of F0 perturbations computed by the box-counting method.

    PubMed

    Boek, W; Wieneke, G H; Dejonckere, P H

    1997-12-01

    The box-counting method for determining the fractal dimension (Dfj) was applied to the fundamental frequency (F0) perturbations in normal and pathological voices in order to assess its clinical value. The upper limit of these Dfj values was similar for both groups, but the distribution for pathological voices extended to lower values than for the normal voices. However, these lower values were most probably the result of one or a few outlying frequency points due to incorrect determination of the vocal period. The Dfj of normal voices were within the range of values found for randomly varying F0 values. It was concluded, that the vocal perturbations in pathological voices are also more or less randomly distributed. So, the Dfj, at that least determined with the box-counting method, do not contain clinically relevant information in addition to the traditional measures for the extent of the vocal period perturbations. An exception is special perturbation types like diplophonia. The result of the computation is very sensitive for voice breaks and vibrato and depends on the number of periods. PMID:9422278

  17. lncRNA profiling in early-stage chronic lymphocytic leukemia identifies transcriptional fingerprints with relevance in clinical outcome

    PubMed Central

    Ronchetti, D; Manzoni, M; Agnelli, L; Vinci, C; Fabris, S; Cutrona, G; Matis, S; Colombo, M; Galletti, S; Taiana, E; Recchia, A G; Bossio, S; Gentile, M; Musolino, C; Di Raimondo, F; Grilli, A; Bicciato, S; Cortelezzi, A; Tassone, P; Morabito, F; Ferrarini, M; Neri, A

    2016-01-01

    Long non-coding RNAs (lncRNAs) represent a novel class of functional RNA molecules with an important emerging role in cancer. To elucidate their potential pathogenetic role in chronic lymphocytic leukemia (CLL), a biologically and clinically heterogeneous neoplasia, we investigated lncRNAs expression in a prospective series of 217 early-stage Binet A CLL patients and 26 different subpopulations of normal B-cells, through a custom annotation pipeline of microarray data. Our study identified a 24-lncRNA-signature specifically deregulated in CLL compared with the normal B-cell counterpart. Importantly, this classifier was validated on an independent data set of CLL samples. Belonging to the lncRNA signature characterizing distinct molecular CLL subgroups, we identified lncRNAs recurrently associated with adverse prognostic markers, such as unmutated IGHV status, CD38 expression, 11q and 17p deletions, and NOTCH1 mutations. In addition, correlation analyses predicted a putative lncRNAs interplay with genes and miRNAs expression. Finally, we generated a 2-lncRNA independent risk model, based on lnc-IRF2-3 and lnc-KIAA1755-4 expression, able to distinguish three different prognostic groups in our series of early-stage patients. Overall, our study provides an important resource for future studies on the functions of lncRNAs in CLL, and contributes to the discovery of novel molecular markers with clinical relevance associated with the disease. PMID:27611921

  18. Evaluation and clinically relevant applications of a fluorescent imaging analog to fluorodeoxyglucose positron emission tomography

    NASA Astrophysics Data System (ADS)

    Sheth, Rahul A.; Josephson, Lee; Mahmood, Umar

    2009-11-01

    A fluorescent analog to 2-deoxy-2 [18F] fluoro-D-glucose position emission tomography (FDG-PET) would allow for the introduction of metabolic imaging into intraoperative and minimally invasive settings. We present through in vitro and in vivo experimentation an evaluation of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG), a fluorescently labeled glucose molecule, as a molecular beacon of glucose utilization. The competitive inhibition of 2-NBDG uptake by excess free glucose is directly compared against FDG uptake inhibition in cultured cells. 2-NBDG uptake in the brain of a mouse experiencing a generalized seizure is measured, as well as in subcutaneously implanted tumors in mice during fed and fasting states. Localization of 2-NBDG into malignant tissues is studied by laser scanning microscopy. The clinical relevance of 2-NBDG imaging is examined by performing fluorescence colonoscopy, and by correlating preoperative FDG-PET with intraoperative fluorescence imaging. 2-NBDG exhibits a similar uptake inhibition to FDG by excess glucose in the growth media. Uptake is significantly increased in the brain of an animal experiencing seizures versus control, and in subcutaneous tumors after the animals are kept nil per os (NPO) for 24 h versus ad libidum feeding. The clinical utility of 2-NBDG is confirmed by the demonstration of very high target-to-background ratios in minimally invasive and intraoperative imaging of malignant lesions. We present an optical analog of FDG-PET to extend the applicability of metabolic imaging to minimally invasive and intraoperative settings.

  19. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

    PubMed Central

    Ivey, Adam; Huntly, Brian J. P.

    2016-01-01

    Recent major advances in understanding the molecular basis of acute myeloid leukemia (AML) provide a double-edged sword. Although defining the topology and key features of the molecular landscape are fundamental to development of novel treatment approaches and provide opportunities for greater individualization of therapy, confirmation of the genetic complexity presents a huge challenge to successful translation into routine clinical practice. It is now clear that many genes are recurrently mutated in AML; moreover, individual leukemias harbor multiple mutations and are potentially composed of subclones with differing mutational composition, rendering each patient’s AML genetically unique. In order to make sense of the overwhelming mutational data and capitalize on this clinically, it is important to identify (1) critical AML-defining molecular abnormalities that distinguish biological disease entities; (2) mutations, typically arising in subclones, that may influence prognosis but are unlikely to be ideal therapeutic targets; (3) mutations associated with preleukemic clones; and (4) mutations that have been robustly shown to confer independent prognostic information or are therapeutically relevant. The reward of identifying AML-defining molecular lesions present in all leukemic populations (including subclones) has been exemplified by acute promyelocytic leukemia, where successful targeting of the underlying PML-RARα oncoprotein has eliminated the need for chemotherapy for disease cure. Despite the molecular heterogeneity and recognizing that treatment options for other forms of AML are limited, this review will consider the scope for using novel molecular information to improve diagnosis, identify subsets of patients eligible for targeted therapies, refine outcome prediction, and track treatment response. PMID:26660431

  20. Evaluation and clinically relevant applications of a fluorescent imaging analog to fluorodeoxyglucose positron emission tomography.

    PubMed

    Sheth, Rahul A; Josephson, Lee; Mahmood, Umar

    2009-01-01

    A fluorescent analog to 2-deoxy-2 [(18)F] fluoro-D-glucose position emission tomography (FDG-PET) would allow for the introduction of metabolic imaging into intraoperative and minimally invasive settings. We present through in vitro and in vivo experimentation an evaluation of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG), a fluorescently labeled glucose molecule, as a molecular beacon of glucose utilization. The competitive inhibition of 2-NBDG uptake by excess free glucose is directly compared against FDG uptake inhibition in cultured cells. 2-NBDG uptake in the brain of a mouse experiencing a generalized seizure is measured, as well as in subcutaneously implanted tumors in mice during fed and fasting states. Localization of 2-NBDG into malignant tissues is studied by laser scanning microscopy. The clinical relevance of 2-NBDG imaging is examined by performing fluorescence colonoscopy, and by correlating preoperative FDG-PET with intraoperative fluorescence imaging. 2-NBDG exhibits a similar uptake inhibition to FDG by excess glucose in the growth media. Uptake is significantly increased in the brain of an animal experiencing seizures versus control, and in subcutaneous tumors after the animals are kept nil per os (NPO) for 24 h versus ad libitum feeding. The clinical utility of 2-NBDG is confirmed by the demonstration of very high target-to-background ratios in minimally invasive and intraoperative imaging of malignant lesions. We present an optical analog of FDG-PET to extend the applicability of metabolic imaging to minimally invasive and intraoperative settings.

  1. Headache and psychiatric comorbidity: historical context, clinical implications, and research relevance.

    PubMed

    Lake, Alvin E; Rains, Jeanetta C; Penzien, Donald B; Lipchik, Gay L

    2005-05-01

    The comorbidity of headache and psychiatric disorders is a well-recognized clinical phenomenon warranting further systematic research. Affective disorders occur with at least three-fold greater frequency among migraineurs than among the general population, and the prevalence increases in clinical populations, especially with chronic daily headache. When present, psychiatric comorbidity complicates headache management and portends a poorer prognosis for headache treatment. However, the relationship between headache and psychopathology has historically been misunderstood, and measures of psychopathology have not always met the standard of formal Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria. In some cases, headache has been inappropriately attributed to psychological or psychiatric features, based on anecdotal observations. The challenge for future studies is to employ research methods and designs that accurately identify and classify the subset of headache patients with psychiatric disorders, evaluate their impact on headache symptoms and treatment, and identify optimal behavioral and pharmacologic treatment strategies. This article offers methodological considerations and recommendations for future research including: (i) ascribing dual-International Classification of Headache Disorders, 2nd ed. (ICHD-2) headache and DSM-IV psychiatric diagnoses according to reliable and valid diagnostic criteria, (ii) differentiating subclinical levels of depression and anxiety from major psychiatric disorders, (iii) encouraging validation studies of the recently published ICHD-2 diagnoses for "headache attributed to psychiatric disorder," (iv) expanding epidemiological research to address the range of DSM-IV Axis I and II psychiatric diagnoses among various headache populations, (v) identifying relevant psychiatric and behavioral mediator/moderator variables, and (vi) developing empirically based screening and treatment algorithms.

  2. Clinically-relevant reperfusion in acute ischemic stroke MTT performs better than Tmax and TTP

    PubMed Central

    Kong, Linglong; Zhu, Hongtu; Vo, Katie D.; Powers, William J.; Lin, Weili; Lee, Jin-Moo

    2014-01-01

    Background While several MRI parameters are used to assess tissue perfusion during hyperacute stroke, it is unclear which is optimal for measuring clinically-relevant reperfusion. We directly compared MTT prolongation (MTTp), TTP, and time-to-maximum (Tmax) to determine which best predicted neurological improvement and tissue salvage following early reperfusion. Methods Acute ischemic stroke patients underwent three MRI's: <4.5hr (tp1), at 6hr (tp2), and at 1 month after onset. Perfusion deficits at tp1 and tp2 were defined by MTTp, TTP, or Tmax beyond four commonly-used thresholds. Percent reperfusion (%Reperf) was calculated for each parameter and threshold. Regression analysis was used to fit %Reperf for each parameter and threshold as a predictor of neurological improvement [defined as admission National Institutes of Health Stroke Scale (NIHSS) – 1 month NIHSS (ΔNIHSS)] after adjusting for baseline clinical variables. Volume of reperfusion, for each parameter and threshold, was correlated with tissue salvage, defined as tp1 perfusion deficit volume – final infarct volume. Results 50 patients were scanned at 2.7 hours and 6.2 hours after stroke onset. %Reperf predicted ΔNIHSS for all MTTp thresholds, for Tmax > 6s and > 8s, but for no TTP thresholds. Tissue salvage significantly correlated with reperfusion for all MTTp thresholds and with Tmax > 6s, while there was no correlation with any TTP threshold. Among all parameters, reperfusion defined by MTTp was most strongly associated with ΔNIHSS (MTTp>3s, p=0.0002) and tissue salvage (MTTp> 3s and 4s, P<0.0001). Conclusion MTT-defined reperfusion was the best predictor of neurological improvement and tissue salvage in hyperacute ischemic stroke. PMID:24500786

  3. Clinically relevant variants identified in thoracic aortic aneurysm patients by research exome sequencing.

    PubMed

    Schubert, Jeffrey A; Landis, Benjamin J; Shikany, Amy R; Hinton, Robert B; Ware, Stephanie M

    2016-05-01

    Thoracic aortic aneurysm (TAA) is a genetically heterogeneous disease involving subclinical and progressive dilation of the thoracic aorta, which can lead to life-threatening complications such as dissection or rupture. Genetic testing is important for risk stratification and identification of at risk family members, and clinically available genetic testing panels have been expanding rapidly. However, when past testing results are normal, there is little evidence to guide decision-making about the indications and timing to pursue additional clinical genetic testing. Results from research based genetic testing can help inform this process. Here we present 10 TAA patients who have a family history of disease and who enrolled in research-based exome testing. Nine of these ten patients had previous clinical genetic testing that did not identify the cause of disease. We sought to determine the number of rare variants in 23 known TAA associated genes identified by research-based exome testing. In total, we found 10 rare variants in six patients. Likely pathogenic variants included a TGFB2 variant in one patient and a SMAD3 variant in another. These variants have been reported previously in individuals with similar phenotypes. Variants of uncertain significance of particular interest included novel variants in MYLK and MFAP5, which were identified in a third patient. In total, clinically reportable rare variants were found in 6/10 (60%) patients, with at least 2/10 (20%) patients having likely pathogenic variants identified. These data indicate that consideration of re-testing is important in TAA patients with previous negative or inconclusive results. PMID:26854089

  4. Trabecular bone score (TBS): available knowledge, clinical relevance, and future prospects.

    PubMed

    Bousson, V; Bergot, C; Sutter, B; Levitz, P; Cortet, B

    2012-05-01

    The diagnosis of osteoporosis rests on areal bone mineral density (BMD) measurement using DXA. Cancellous bone microarchitecture is a key determinant of bone strength but cannot be measured using DXA. To meet the need for a clinical tool capable of assessing bone microarchitecture, the TBS was developed. The TBS is a texture parameter that evaluates pixel gray-level variations in DXA images of the lumbar spine. The TBS variations may reflect bone microarchitecture. We explain the general principles used to compute the TBS, and we report the correlations between TBS and microarchitectural parameters. Several limitations of the TBS as it is used now are pointed out. We discuss data from currently available clinical studies on the ability of the TBS to identify patients with fractures and to evaluate the fracture risk. We conclude that this new index emphasizes the failure of the BMD T-score to fully capture the fragility fracture risk. However, although microarchitecture may influence the TBS, today, to the best of our understanding, there is no sufficient evidence that a TBS measurement provides reliable information on the status of the bone microarchitecture for a given patient. The TBS depends on gray-level variations and in a projectional image obtained in vivo, these variations can have many causes. Nevertheless, as clinical studies suggest that the TBS predicts the risk of fracture even after adjustment for BMD, we are encouraged to learn more about this score. Additional studies will have to be performed to assess the advantages and limitations of the TBS, in order to ensure that it is used appropriately in clinical practice.

  5. Severe neuromuscular denervation of clinically relevant muscles in a mouse model of spinal muscular atrophy.

    PubMed

    Ling, Karen K Y; Gibbs, Rebecca M; Feng, Zhihua; Ko, Chien-Ping

    2012-01-01

    Spinal muscular atrophy (SMA), a motoneuron disease caused by a deficiency of the survival of motor neuron (SMN) protein, is characterized by motoneuron loss and muscle weakness. It remains unclear whether widespread loss of neuromuscular junctions (NMJs) is involved in SMA pathogenesis. We undertook a systematic examination of NMJ innervation patterns in >20 muscles in the SMNΔ7 SMA mouse model. We found that severe denervation (<50% fully innervated endplates) occurs selectively in many vulnerable axial muscles and several appendicular muscles at the disease end stage. Since these vulnerable muscles were located throughout the body and were comprised of varying muscle fiber types, it is unlikely that muscle location or fiber type determines susceptibility to denervation. Furthermore, we found a similar extent of neurofilament accumulation at NMJs in both vulnerable and resistant muscles before the onset of denervation, suggesting that neurofilament accumulation does not predict subsequent NMJ denervation. Since vulnerable muscles were initially innervated, but later denervated, loss of innervation in SMA may be attributed to defects in synapse maintenance. Finally, we found that denervation was amendable by trichostatin A (TSA) treatment, which increased innervation in clinically relevant muscles in TSA-treated SMNΔ7 mice. Our findings suggest that neuromuscular denervation in vulnerable muscles is a widespread pathology in SMA, and can serve as a preparation for elucidating the biological basis of synapse loss, and for evaluating therapeutic efficacy.

  6. Clinical Relevance and Mechanisms of Antagonism Between the BMP and Activin/TGF-β Signaling Pathways.

    PubMed

    Hudnall, Aaron M; Arthur, Jon W; Lowery, Jonathan W

    2016-07-01

    The transforming growth factor β (TGF-β) superfamily is a large group of signaling molecules that participate in embryogenesis, organogenesis, and tissue homeostasis. These molecules are present in all animal genomes. Dysfunction in the regulation or activity of this superfamily's components underlies numerous human diseases and developmental defects. There are 2 distinct arms downstream of the TGF-β superfamily ligands-the bone morphogenetic protein (BMP) and activin/TGF-β signaling pathways-and these 2 responses can oppose one another's effects, most notably in disease states. However, studies have commonly focused on a single arm of the TGF-β superfamily, and the antagonism between these pathways is unknown in most physiologic and pathologic contexts. In this review, the authors summarize the clinically relevant scenarios in which the BMP and activin/TGF-β pathways reportedly oppose one another and identify several molecular mechanisms proposed to mediate this interaction. Particular attention is paid to experimental findings that may be informative to human pathology to highlight potential therapeutic approaches for future investigation. PMID:27367950

  7. Clinical relevancy and risks of potential drug–drug interactions in intensive therapy

    PubMed Central

    Rodrigues, Aline Teotonio; Stahlschmidt, Rebeca; Granja, Silvia; Falcão, Antonio Luis Eiras; Moriel, Patricia; Mazzola, Priscila Gava

    2014-01-01

    Purpose Evaluate the potential Drug–Drug Interactions (pDDI) found in prescription orders of adult Intensive Care Unit (ICU) of a Brazilian public health system hospital; quantify and qualify the pDDI regarding their severity and risks to the critical patient, using the database from Micromedex®. Methods Prospective study (January–December of 2011) collecting and evaluating 369 prescription orders (convenient sampling), one per patient. Results During the study 1844 pDDIs were identified and distributed in 405 pairs (medication A × medication B combination). There was an average of 5.00 ± 5.06 pDDIs per prescription order, the most prevalent being moderate and important interactions, present in 74% and 67% of prescription orders, respectively. In total, there were 9 contraindicated, 129 important and 204 moderate pDDIs. Among them 52 had as management recommendation to “avoid concomitant use” or “suspension of medication”, while 306 had as recommendation “continuous and adequate monitoring”. Conclusion The high number of pDDIs found in the study combined with the evaluation of the clinical relevancy of the most frequent pDDIs in the ICU shows that moderate and important interactions are highly incident. As the majority of them demand monitoring and adequate management, being aware of these interactions is major information for the safe and individualized risk management. PMID:27134536

  8. HIV1-viral protein R (Vpr) mutations: associated phenotypes and relevance for clinical pathologies.

    PubMed

    Soares, Rui; Rocha, Graça; Meliço-Silvestre, António; Gonçalves, Teresa

    2016-09-01

    Over the last 30 years, research into HIV has advanced the knowledge of virus genetics and the development of efficient therapeutic strategies. HIV-1 viral protein R (Vpr) is a specialized and multifunctional protein that plays important roles at multiple stages of the HIV-1 viral life cycle. This protein interacts with a number of cellular and viral proteins and with multiple activities including nuclear transport of the pre-integration complex (PIC) to the nucleus, transcriptional activation, cell cycle arrest at G2/M transition phase and induction of cell death via apoptosis. Specifically, Vpr has been shown to control many host cell functions through a variety of biological processes and by interaction with several cellular pathways. The different functions of Vpr may enhance viral replication and impair the immune system in HIV-1 infected patients. Importantly, functional defects induced by mutations in the Vpr protein correlate with slow disease progression of HIV-infected patients. Vpr is also associated with other concomitant pathologies developed by these patients, which may lead it to be considered as a potential novel therapeutic target. This review will focus on HIV-1 Vpr, mainly on the importance of its structural mutations on the progression of HIV infection, associated phenotypes and relevance for clinical pathologies. Copyright © 2016 John Wiley & Sons, Ltd.

  9. Adaptive control of drug dosage regimens: basic foundations, relevant issues, and clinical examples.

    PubMed

    Jelliffe, R W; Maire, P; Sattler, F; Gomis, P; Tahani, B

    1994-06-01

    In this paper we examine several of the fundamental foundations and relevant clinical issues in adaptive control of drug dosage regimens for patients. Truly individualized therapy with drugs having narrow margins of safety first requires a practical pharmacokinetic/dynamic model of the behavior of a drug. Past experience with a drug is stored in the form of a population model. Next, using the information in such a model and its relationship to the incidence of adverse reactions, a specific, explicit therapeutic goal must be selected by the responsible clinician, based on the patient's need for the drug and the risk of adverse reactions felt to be justified by each patient's need, small, moderate, or great. Individualized drug therapy thus begins with the selection of individualized therapeutic goals (low, moderate, or high) for each patient. Using subsequent feedback from the patient's serum drug levels, and using Bayesian fitting, the model is then linked to each patient as a patient-specific model. Control of the model by the dosage regimen increasingly controls the patient, to better obtain the desired explicit therapeutic goals. This process is essentially similar to that of a flight control or missile guidance system.

  10. Presence and Persistence of Viable, Clinically Relevant Legionella pneumophila Bacteria in Garden Soil in the Netherlands

    PubMed Central

    van Heijnsbergen, E.; van Deursen, A.; Bouwknegt, M.; Bruin, J. P.; Schalk, J. A. C.

    2016-01-01

    ABSTRACT Garden soils were investigated as reservoirs and potential sources of pathogenic Legionella bacteria. Legionella bacteria were detected in 22 of 177 garden soil samples (12%) by amoebal coculture. Of these 22 Legionella-positive soil samples, seven contained Legionella pneumophila. Several other species were found, including the pathogenic Legionella longbeachae (4 gardens) and Legionella sainthelensi (9 gardens). The L. pneumophila isolates comprised 15 different sequence types (STs), and eight of these STs were previously isolated from patients according to the European Working Group for Legionella Infections (EWGLI) database. Six gardens that were found to be positive for L. pneumophila were resampled after several months, and in three gardens, L. pneumophila was again isolated. One of these gardens was resampled four times throughout the year and was found to be positive for L. pneumophila on all occasions. IMPORTANCE Tracking the source of infection for sporadic cases of Legionnaires' disease (LD) has proven to be hard. L. pneumophila ST47, the sequence type that is most frequently isolated from LD patients in the Netherlands, is rarely found in potential environmental sources. As L. pneumophila ST47 was previously isolated from a garden soil sample during an outbreak investigation, garden soils were investigated as reservoirs and potential sources of pathogenic Legionella bacteria. The detection of viable, clinically relevant Legionella strains indicates that garden soil is a potential source of Legionella bacteria, and future research should assess the public health implication of the presence of L. pneumophila in garden soil. PMID:27316958

  11. HIV1-viral protein R (Vpr) mutations: associated phenotypes and relevance for clinical pathologies.

    PubMed

    Soares, Rui; Rocha, Graça; Meliço-Silvestre, António; Gonçalves, Teresa

    2016-09-01

    Over the last 30 years, research into HIV has advanced the knowledge of virus genetics and the development of efficient therapeutic strategies. HIV-1 viral protein R (Vpr) is a specialized and multifunctional protein that plays important roles at multiple stages of the HIV-1 viral life cycle. This protein interacts with a number of cellular and viral proteins and with multiple activities including nuclear transport of the pre-integration complex (PIC) to the nucleus, transcriptional activation, cell cycle arrest at G2/M transition phase and induction of cell death via apoptosis. Specifically, Vpr has been shown to control many host cell functions through a variety of biological processes and by interaction with several cellular pathways. The different functions of Vpr may enhance viral replication and impair the immune system in HIV-1 infected patients. Importantly, functional defects induced by mutations in the Vpr protein correlate with slow disease progression of HIV-infected patients. Vpr is also associated with other concomitant pathologies developed by these patients, which may lead it to be considered as a potential novel therapeutic target. This review will focus on HIV-1 Vpr, mainly on the importance of its structural mutations on the progression of HIV infection, associated phenotypes and relevance for clinical pathologies. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27264019

  12. Clinical Relevance of Liver Kinase B1(LKB1) Protein and Gene Expression in Breast Cancer

    PubMed Central

    Chen, I-Chun; Chang, Yuan-Ching; Lu, Yen-Shen; Chung, Kuei-Pin; Huang, Chiun-Sheng; Lu, Tzu-Pin; Kuo, Wen-Hung; Wang, Ming-Yang; Kuo, Kuan-Ting; Wu, Pei-Fang; Hsueh, Tsu-Hsin; Shen, Chen-Yang; Lin, Ching-Hung; Cheng, Ann-Lii

    2016-01-01

    Liver kinase B1 (LKB1) is a tumor suppressor, and its loss might lead to activation of the mammalian target of rapamycin (mTOR) and tumorigenesis. This study aimed to determine the clinical relevance of LKB1 gene and protein expression in breast cancer patients. LKB1 protein expression was evaluated using immunohistochemistry in tumors from early breast cancer patients in two Taiwanese medical centers. Data on LKB1 gene expression were obtained from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) data set. The correlations between LKB1 expression, clinicopathologic factors, and patient outcome were analyzed. LKB1 expression was significantly associated with estrogen receptor (ER) expression in 2 of the 4 cohorts, but not with other clinicopathologic factors. LKB1 expression was not a predictor for relapse-free survival, overall survival (OS), or breast cancer-specific survival. In a subgroup analysis of the two Taiwanese cohorts, high LKB1 protein expression was predictive of high OS in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients (P = 0.013). Our study results indicate that LKB1 expression is not prognostic in the whole population of breast cancer patients, but it is a potential predictor of OS in the subset of HER2-positive patients PMID:26877155

  13. Analysis of clinically relevant mechanical and thermal characteristics of titanium foam spinal implants during drilling.

    PubMed

    Ito, Kiyoshi; Horiuchi, Tetsuyoshi; Murata, Takahiro; Hongo, Kazuhiro

    2015-09-01

    Although high biocompatibility promotes the use of titanium (Ti) alloy in spinal implants, this material shows high stiffness, which is an issue for removal by drilling. The recently developed, porous Ti foam implants, which have shown enhanced osteoformation, may overcome this flaw. Thus, this study aimed to compare the mechanical and thermal characteristics of Ti-foam (80 % porosity) and conventional Ti alloy (0 % porosity) implants drilled in clinically relevant conditions. Mechanical properties were analyzed by measuring axial and torque forces using a pressure sensor with a drill of 2.5-mm diameter at a rotation frequency of 20 Hz. Thermography was used to evaluate the heat generated by a diamond burr attached to a high-speed (80,000 rpm) drill. The torque and axial strengths of Ti foam (13.63 ± 1.43 and 82.60 ± 7.78 N, respectively) were significantly lower (P = 0.001) than those of Ti alloy (73.58 ± 13.60 and 850.72 ± 146.99 N, respectively). Furthermore, irrigation reduced the area of local heating for Ti foam to 56-82 % of that for Ti alloy, indicating lower thermal conductivity. These data suggest that the use of Ti foam implants may be advantageous in cases with a probability of implant drilling in the future.

  14. Protein abundance of clinically relevant multidrug transporters along the entire length of the human intestine.

    PubMed

    Drozdzik, Marek; Gröer, Christian; Penski, Jette; Lapczuk, Joanna; Ostrowski, Marek; Lai, Yurong; Prasad, Bhagwat; Unadkat, Jashvant D; Siegmund, Werner; Oswald, Stefan

    2014-10-01

    Intestinal transporters are crucial determinants in the oral absorption of many drugs. We therefore studied the mRNA expression (N = 33) and absolute protein content (N = 10) of clinically relevant transporters in healthy epithelium of the duodenum, the proximal and distal jejunum and ileum, and the ascending, transversal, descending, and sigmoidal colon of six organ donors (24-54 years). In the small intestine, the abundance of nearly all studied proteins ranged between 0.2 and 1.6 pmol/mg with the exception of those of OCT3 (<0.1 pmol/mg) and PEPT1 (2.6-4.9 pmol/mg) that accounted for ∼50% of all measured transporters. OATP1A2 was not detected in any intestinal segment. ABCB1, ABCG2, PEPT1, and ASBT were significantly more abundant in jejunum and ileum than in colon. In contrast to this, the level of expression of ABCC2, ABCC3, and OCT3 was found to be highest in colon. Site-dependent differences in the levels of gene and protein expression were observed for ABCB1 and ASBT. Significant correlations between mRNA and protein levels have been found for ABCG2, ASBT, OCT3, and PEPT1 in the small intestine. Our data provide further physiological pieces of the puzzle required to predict intestinal drug absorption in humans.

  15. TESTING FOR ADDITIVITY IN THE LOW DOSE REGION OF AN ENVIRONMENTALLY RELEVANT MIXTURE OF 18 OLYHALOGENATED AROMATIC HYDROCARBONS.

    EPA Science Inventory

    A common default assumption in risk assessment of chemical mixtures is that the chemicals combine additively in the low dose region. Under additivity, with information from single chemical dose-response data, the risk associated with the mixture can be estimated. The objective ...

  16. Identification and Differentiation of Clinically Relevant Mycobacterium Species Directly from Acid-Fast Bacillus-Positive Culture Broth ▿

    PubMed Central

    Li, Haijing; Turhan, Vedat; Chokhani, Laxmi; Stratton, Charles W.; Dunbar, Sherry A.; Tang, Yi-Wei

    2009-01-01

    Mycobacterium species cause a variety of clinical diseases, some of which may be species specific. Therefore, it is clinically desirable to rapidly identify and differentiate mycobacterial isolates to the species level. We developed a rapid and high-throughput system, MycoID, to identify Mycobacterium species directly from acid-fast bacillus (AFB)-positive mycobacterial culture broth. The MycoID system incorporated broad-range PCR followed by suspension array hybridization to identify 17 clinically relevant mycobacterial complexes, groups, and species in one single reaction. We evaluated a total of 271 AFB-positive culture broth specimens, which were identified by reference standard methods in combination with biochemical and molecular tests. The overall identification agreement between the standard and the MycoID system was 89.7% (perfect match) or 97.8% (one match in codetection). In comparison to the standard, the MycoID system possessed an overall sensitivity of 97.1% and specificity of 98.8%. The 159 Mycobacterium avium-M. intracellulare complex isolates were further identified to the species level by MycoID as being M. avium (n = 98; 61.1%), M. intracellulare (n = 57; 35.8%), and mixed M. avium and M. intracellulare (n = 2; 1.3%). M. avium was recovered more frequently from sterile sites than M. intracellulare (odds ratio, 4.6; P = 0.0092). The entire MycoID procedure, including specimen processing, can be completed within 5 h, providing rapid and reliable identification and differentiation of mycobacterium species that is amenable to automation. Additional differentiation of Mycobacterium avium-M. intracellulare complex strains into M. avium and M. intracellulare may provide a tool to better understand the role of Mycobacterium avium-M. intracellulare complex isolates in human disease. PMID:19794046

  17. The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers | Office of Cancer Genomics

    Cancer.gov

    Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6,236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions.

  18. Innovative perspectives of immunotherapy in head and neck cancer. From relevant scientific rationale to effective clinical practice.

    PubMed

    Lalami, Y; Awada, A

    2016-02-01

    It is now well established that head and neck cancer carcinogenesis is characterized by genetic instability and several immune defects, leading to unique host-tumor interactions. In such condition, recent improved comprehension and relevant findings could lead to identification of innovative molecular therapeutic targets, achieving considerable clinical and translational research. This review aims to summarize and to highlight most recent and relevant scientific rationale in this era of immunotherapy revival, and to correlate it to the near future clinical practice for the management of this challenging disease.

  19. [Triple therapy in cirrhotic patients and those with advanced fibrosis: relevant aspects in clinical practice].

    PubMed

    Albillos, Agustín; Luis Calleja, José; Molina, Esther; Planas, Ramon; Romero-Gómez, Manuel; Turnes, Juan; Hernández-Guerra, Manuel

    2014-07-01

    The first-line option in the treatment of patients with advanced fibrosis and cirrhosis due to genotype 1 hepatitis C virus is currently triple therapy with boceprevir/telaprevir and pegylated interferon-ribavirin. However, certain limitations could constitute a barrier to starting treatment or achieving sustained viral response in these patients. These limitations include the patient's or physician's perception of treatment effectiveness in routine clinical practice-which can weight against the decision to start treatment-, the advanced stage of the disease with portal hypertension and comorbidity, treatment interruption due to poor adherence, and adverse effects, mainly anemia. In addition, it is now possible to identify patients who could benefit from a shorter therapeutic regimen with a similar cure rate. This review discusses these issues and their possible effect on the use of triple therapy. PMID:25907434

  20. Gain-of-Function Research and the Relevance to Clinical Practice.

    PubMed

    Kilianski, Andy; Nuzzo, Jennifer B; Modjarrad, Kayvon

    2016-05-01

    The ongoing moratorium on gain-of-function (GOF) research with highly pathogenic avian influenza virus, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus has drawn attention to the current debate on these research practices and the potential benefits and risks they present. While much of the discussion has been steered by members of the microbiology and policy communities, additional input from medical practitioners will be highly valuable toward developing a broadly inclusive policy that considers the relative value and harm of GOF research. This review attempts to serve as a primer on the topic for the clinical community by providing a historical context for GOF research, summarizing concerns about its risks, and surveying the medical products that it has yielded. PMID:26416657

  1. Gain-of-Function Research and the Relevance to Clinical Practice.

    PubMed

    Kilianski, Andy; Nuzzo, Jennifer B; Modjarrad, Kayvon

    2016-05-01

    The ongoing moratorium on gain-of-function (GOF) research with highly pathogenic avian influenza virus, severe acute respiratory syndrome coronavirus, and Middle East respiratory syndrome coronavirus has drawn attention to the current debate on these research practices and the potential benefits and risks they present. While much of the discussion has been steered by members of the microbiology and policy communities, additional input from medical practitioners will be highly valuable toward developing a broadly inclusive policy that considers the relative value and harm of GOF research. This review attempts to serve as a primer on the topic for the clinical community by providing a historical context for GOF research, summarizing concerns about its risks, and surveying the medical products that it has yielded.

  2. Relevance of nucleic acid amplification techniques for diagnosis of respiratory tract infections in the clinical laboratory.

    PubMed Central

    Ieven, M; Goossens, H

    1997-01-01

    Clinical laboratories are increasingly receiving requests to perform nucleic acid amplification tests for the detection of a wide variety of infectious agents. In this paper, the efficiency of nucleic acid amplification techniques for the diagnosis of respiratory tract infections is reviewed. In general, these techniques should be applied only for the detection of microorganisms for which available diagnostic techniques are markedly insensitive or nonexistent or when turnaround times for existing tests (e.g., viral culture) are much longer than those expected with amplification. This is the case for rhinoviruses, coronaviruses, and hantaviruses causing a pulmonary syndrome, Bordetella pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae, and Coxiella burnetii. For Legionella spp. and fungi, contamination originating from the environment is a limiting factor in interpretation of results, as is the difficulty in differentiating colonization and infection. Detection of these agents in urine or blood by amplification techniques remains to be evaluated. In the clinical setting, there is no need for molecular diagnostic tests for the diagnosis of Pneumocystis carinii. At present, amplification methods for Mycobacterium tuberculosis cannot replace the classical diagnostic techniques, due to their lack of sensitivity and the absence of specific internal controls for the detection of inhibitors of the reaction. Also, the results of interlaboratory comparisons are unsatisfactory. Furthermore, isolates are needed for susceptibility studies. Additional work remains to be done on sample preparation methods, comparison between different amplification methods, and analysis of results. The techniques can be useful for the rapid identification of M. tuberculosis in particular circumstances, as well as the rapid detection of most rifampin-resistant isolates. The introduction of diagnostic amplification techniques into a clinical laboratory implies a level of proficiency for

  3. DGIdb 2.0: mining clinically relevant drug-gene interactions.

    PubMed

    Wagner, Alex H; Coffman, Adam C; Ainscough, Benjamin J; Spies, Nicholas C; Skidmore, Zachary L; Campbell, Katie M; Krysiak, Kilannin; Pan, Deng; McMichael, Joshua F; Eldred, James M; Walker, Jason R; Wilson, Richard K; Mardis, Elaine R; Griffith, Malachi; Griffith, Obi L

    2016-01-01

    The Drug-Gene Interaction Database (DGIdb, www.dgidb.org) is a web resource that consolidates disparate data sources describing drug-gene interactions and gene druggability. It provides an intuitive graphical user interface and a documented application programming interface (API) for querying these data. DGIdb was assembled through an extensive manual curation effort, reflecting the combined information of twenty-seven sources. For DGIdb 2.0, substantial updates have been made to increase content and improve its usefulness as a resource for mining clinically actionable drug targets. Specifically, nine new sources of drug-gene interactions have been added, including seven resources specifically focused on interactions linked to clinical trials. These additions have more than doubled the overall count of drug-gene interactions. The total number of druggable gene claims has also increased by 30%. Importantly, a majority of the unrestricted, publicly-accessible sources used in DGIdb are now automatically updated on a weekly basis, providing the most current information for these sources. Finally, a new web view and API have been developed to allow searching for interactions by drug identifiers to complement existing gene-based search functionality. With these updates, DGIdb represents a comprehensive and user friendly tool for mining the druggable genome for precision medicine hypothesis generation.

  4. Efficacy of clinically relevant temozolomide dosing schemes in glioblastoma cancer stem cell lines.

    PubMed

    Beier, Dagmar; Schriefer, Beate; Brawanski, Konstantin; Hau, Peter; Weis, Joachim; Schulz, Jörg B; Beier, Christoph P

    2012-08-01

    The effectiveness of temozolomide (TMZ) dosing schemes and the "rechallenge" of recurrent glioblastoma (GBM) with TMZ are controversial. We therefore compared the efficacy of different TMZ dosing schemes against GBM cancer stem cell (CSC) lines in vitro. In O(6)-methyl-guanidine-methyl-transferase (MGMT)-negative CSC lines, all schedules (1 day on/27 days off, 5 days on/23 days off, 7 days on/7 days off, 21 days on/7 days off, continuous low-dose TMZ) depleted clonogenic cells. In TMZ-resistant CSC lines, the 7 days on/7 days off scheme showed higher toxicity as compared with the other schemes. However, clinically feasible concentrations remained ineffective in highly resistant CSC lines. In addition, none of the schedules induced long-term depletion of clonogenic cells even at the highest concentrations (up to 250 μM). After sublethal TMZ treatment for 5 days, TMZ rechallenge of recovering CSC lines remained effective. Our data advocate CSC lines as in vitro model to address clinical questions. Using this model, our data suggest the effectiveness of TMZ in MGMT-negative CSC lines and support the concept of TMZ rechallenge. The 7 days on/7 days off scheme consistently showed the best activity of all schedules in TMZ-resistant CSC lines.

  5. Clinical relevance of copy number profiling in oral and oropharyngeal squamous cell carcinoma.

    PubMed

    van Kempen, Pauline M W; Noorlag, Rob; Braunius, Weibel W; Moelans, Cathy B; Rifi, Widad; Savola, Suvi; Koole, Ronald; Grolman, Wilko; van Es, Robert J J; Willems, Stefan M

    2015-10-01

    Current conventional treatment modalities in head and neck squamous cell carcinoma (HNSCC) are nonselective and have shown to cause serious side effects. Unraveling the molecular profiles of head and neck cancer may enable promising clinical applications that pave the road for personalized cancer treatment. We examined copy number status in 36 common oncogenes and tumor suppressor genes in a cohort of 191 oropharyngeal squamous cell carcinomas (OPSCC) and 164 oral cavity squamous cell carcinomas (OSCC) using multiplex ligation probe amplification. Copy number status was correlated with human papillomavirus (HPV) status in OPSCC, with occult lymph node status in OSCC and with patient survival. The 11q13 region showed gain or amplifications in 59% of HPV-negative OPSCC, whereas this amplification was almost absent in HPV-positive OPSCC. Additionally, in clinically lymph node-negative OSCC (Stage I-II), gain of the 11q13 region was significantly correlated with occult lymph node metastases with a negative predictive value of 81%. Multivariate survival analysis revealed a significantly decreased disease-free survival in both HPV-negative and HPV-positive OPSCC with a gain of Wnt-induced secreted protein-1. Gain of CCND1 showed to be an independent predictor for worse survival in OSCC. These results show that copy number aberrations, mainly of the 11q13 region, may be important predictors and prognosticators which allow for stratifying patients for personalized treatment of HNSCC. PMID:26194878

  6. DGIdb 2.0: mining clinically relevant drug–gene interactions

    PubMed Central

    Wagner, Alex H.; Coffman, Adam C.; Ainscough, Benjamin J.; Spies, Nicholas C.; Skidmore, Zachary L.; Campbell, Katie M.; Krysiak, Kilannin; Pan, Deng; McMichael, Joshua F.; Eldred, James M.; Walker, Jason R.; Wilson, Richard K.; Mardis, Elaine R.; Griffith, Malachi; Griffith, Obi L.

    2016-01-01

    The Drug–Gene Interaction Database (DGIdb, www.dgidb.org) is a web resource that consolidates disparate data sources describing drug–gene interactions and gene druggability. It provides an intuitive graphical user interface and a documented application programming interface (API) for querying these data. DGIdb was assembled through an extensive manual curation effort, reflecting the combined information of twenty-seven sources. For DGIdb 2.0, substantial updates have been made to increase content and improve its usefulness as a resource for mining clinically actionable drug targets. Specifically, nine new sources of drug–gene interactions have been added, including seven resources specifically focused on interactions linked to clinical trials. These additions have more than doubled the overall count of drug–gene interactions. The total number of druggable gene claims has also increased by 30%. Importantly, a majority of the unrestricted, publicly-accessible sources used in DGIdb are now automatically updated on a weekly basis, providing the most current information for these sources. Finally, a new web view and API have been developed to allow searching for interactions by drug identifiers to complement existing gene-based search functionality. With these updates, DGIdb represents a comprehensive and user friendly tool for mining the druggable genome for precision medicine hypothesis generation. PMID:26531824

  7. Nonphosphate-binding effects of sevelamer--are they of clinical relevance?

    PubMed

    Marangon, Nicola; Lindholm, Bengt; Stenvinkel, Peter

    2008-01-01

    Sevelamer is an ion-exchanging resin that binds phosphate in the gut. Because it does so without increasing the calcium load, treatment with sevelamer may lead to less vascular calcification and better survival in chronic kidney disease patients. However, the results of available clinical studies have not been consistent; recent observations challenge the hypothesis that the extra calcium load inherent in calcium-based phosphate binder therapy increases cardiovascular mortality by accelerating vascular calcification. This reemphasizes the fact that we still lack detailed understanding on the complex relationships between vascular calcification, bone metabolism, vascular disease and outcome in the context of uremia. Thus, the role of phosphate binders may be more complex than initially anticipated and not limited to the extra calcium load. Even if detailed mechanisms of action for sevelamer are not yet clearly established (except for its lipid-lowering action), sevelamer may have a number of additional nonphosphate-lowering actions (including lipid lowering as well as improvement in endothelial function, modulation of inflammation and oxidative stress and binding of uremic toxin absorption). Whether these potentially very interesting pleiotropic effects of sevelamer may be translated into significant clinical benefits remains to be established.

  8. Ciclopirox: recent nonclinical and clinical data relevant to its use as a topical antimycotic agent.

    PubMed

    Subissi, Alessandro; Monti, Daniela; Togni, Giuseppe; Mailland, Federico

    2010-11-12

    Ciclopirox is a topical antimycotic agent belonging to the chemical class of hydroxypyridones and not related to azoles or any other class of antifungal agents. Its antimicrobial profile includes nearly all of the clinically relevant dermatophytes, yeasts and moulds, and is therefore broader than that of most other antimycotics. It is also active against certain frequently azole-resistant Candida species and against some bacteria. The mechanism of action of ciclopirox is different from that of other topical antifungal drugs, which generally act through ergosterol inhibition. The high affinity of ciclopirox for trivalent metal cations, resulting in inhibition of the metal-dependent enzymes that are responsible for the degradation of peroxides within the fungal cell, appears to be the major determinant of its antimicrobial activity. This unique and multilevel mechanism of action provides a very low potential for the development of resistance in pathogenic fungi, with cases of resistance rarely reported. Ciclopirox also displays mild anti-inflammatory effects in biochemical and pharmacological models; effects also shown in small clinical studies. Scavenging of reactive oxygen species released from inflammatory cells is a likely contributor to these anti-inflammatory effects. Ciclopirox, and its olamine salt, is available in multiple topical formulations, suitable for administration onto the skin and nails and into the vagina. The pharmaceutical forms most widely investigated are 1% ciclopirox olamine cream and 8% ciclopirox acid nail lacquer, but lotion, spray, shampoo, pessary, solution, gel and douche formulations have also been used. Ciclopirox penetrates into the deep layers of the skin, mucosal membranes and nail keratin, reaching concentrations exceeding the minimal fungicidal concentrations for most medically important fungi. A large number of clinical trials were and are still being performed with ciclopirox, starting in the early 1980s. Ciclopirox was first

  9. The clinical relevance of axillary reverse mapping (ARM): study protocol for a randomized controlled trial

    PubMed Central

    2013-01-01

    Background Axillary lymph node dissection (ALND) in patients with breast cancer has the potential to induce side-effects, including upper-limb lymphedema. Axillary reverse mapping (ARM) is a technique that enables discrimination of the lymphatic drainage of the breast from that of the upper limb in the axillary lymph node (LN) basin. If lymphedema is caused by removing these lymphatics and nodes in the upper limb, the possibility of identifying these lymphatics would enable surgeons to preserve them. The aim of this study is to determine the clinical relevance of selective axillary LN and lymphatic preservation by means of ARM. To minimize the risk of overlooking tumor-positive ARM nodes and the associated risk of undertreatment, we will only include patients with a tumor-positive sentinel lymph node (SLN). Patients who are candidates for ALND because of a proven positive axillary LN at clinical examination can be included in a registration study. Methods/design The study will enroll 280 patients diagnosed with SLN biopsy-proven metastasis of invasive breast cancer with an indication for a completion ALND. Patients will be randomized to undergo standard ALND or an ALND in which the ARM nodes and their corresponding lymphatics will be left in situ. Primary outcome is the presence of axillary surgery-related lymphedema at 6, 12, and 24 months post-operatively, measured by the water-displacement method. Secondary outcome measures include pain, paresthesia, numbness, and loss of shoulder mobility, quality of life, and axillary recurrence risk. Discussion The benefit of ALND in patients with a positive SLN is a subject of debate. For many patients, an ALND will remain the treatment of choice. This multicenter randomized trial will provide evidence of whether or not axillary LN preservation by means of ARM decreases the side-effects of an ALND. Enrolment of patients will start in April 2013 in five breast-cancer centers in the Netherlands, and is expected to conclude by

  10. NT-ProBNP Levels in Saliva and Its Clinical Relevance to Heart Failure

    PubMed Central

    Foo, Jared Yong Yang; Wan, Yunxia; Kostner, Karam; Arivalagan, Alicia; Atherton, John; Cooper-White, Justin; Dimeski, Goce; Punyadeera, Chamindie

    2012-01-01

    Background Current blood based diagnostic assays to detect heart failure (HF) have large intra-individual and inter-individual variations which have made it difficult to determine whether the changes in the analyte levels reflect an actual change in disease activity. Human saliva mirrors the body’s health and well being and ∼20% of proteins that are present in blood are also found in saliva. Saliva has numerous advantages over blood as a diagnostic fluid which allows for a non-invasive, simple, and safe sample collection. The aim of our study was to develop an immunoassay to detect NT-proBNP in saliva and to determine if there is a correlation with blood levels. Methods Saliva samples were collected from healthy volunteers (n = 40) who had no underlying heart conditions and HF patients (n = 45) at rest. Samples were stored at −80°C until analysis. A customised homogeneous sandwich AlphaLISA(R) immunoassay was used to quantify NT-proBNP levels in saliva. Results Our NT-proBNP immunoassay was validated against a commercial Roche assay on plasma samples collected from HF patients (n = 37) and the correlation was r2 = 0.78 (p<0.01, y = 1.705× +1910.8). The median salivary NT-proBNP levels in the healthy and HF participants were <16 pg/mL and 76.8 pg/mL, respectively. The salivary NT-proBNP immunoassay showed a clinical sensitivity of 82.2% and specificity of 100%, positive predictive value of 100% and negative predictive value of 83.3%, with an overall diagnostic accuracy of 90.6%. Conclusion We have firstly demonstrated that NT-proBNP can be detected in saliva and that the levels were higher in heart failure patients compared with healthy control subjects. Further studies will be needed to demonstrate the clinical relevance of salivary NT-proBNP in unselected, previously undiagnosed populations. PMID:23119023

  11. Effect of ethanol at clinically relevant concentrations on atrial inward rectifier potassium current sensitive to acetylcholine.

    PubMed

    Bébarová, Markéta; Matejovič, Peter; Pásek, Michal; Hořáková, Zuzana; Hošek, Jan; Šimurdová, Milena; Šimurda, Jiří

    2016-10-01

    Alcohol intoxication tends to induce arrhythmias, most often the atrial fibrillation. To elucidate arrhythmogenic mechanisms related to alcohol consumption, the effect of ethanol on main components of the ionic membrane current is investigated step by step. Considering limited knowledge, we aimed to examine the effect of clinically relevant concentrations of ethanol (0.8-80 mM) on acetylcholine-sensitive inward rectifier potassium current I K(Ach). Experiments were performed by the whole-cell patch clamp technique at 23 ± 1 °C on isolated rat and guinea-pig atrial myocytes, and on expressed human Kir3.1/3.4 channels. Ethanol induced changes of I K(Ach) in the whole range of concentrations applied; the effect was not voltage dependent. The constitutively active component of I K(Ach) was significantly increased by ethanol with the maximum effect (an increase by ∼100 %) between 8 and 20 mM. The changes were comparable in rat and guinea-pig atrial myocytes and also in expressed human Kir3.1/3.4 channels (i.e., structural correlate of I K(Ach)). In the case of the acetylcholine-induced component of I K(Ach), a dual ethanol effect was apparent with a striking heterogeneity of changes in individual cells. The effect correlated with the current magnitude in control: the current was increased by eth-anol in the cells showing small current in control and vice versa. The average effect peaked at 20 mM ethanol (an increase of the current by ∼20 %). Observed changes of action potential duration agreed well with the voltage clamp data. Ethanol significantly affected both components of I K(Ach) even in concentrations corresponding to light alcohol consumption.

  12. Pharmacological characterization of lysophosphatidic acid-induced pain with clinically relevant neuropathic pain drugs.

    PubMed

    Ogawa, K; Takasu, K; Shinohara, S; Yoneda, Y; Kato, A

    2012-08-01

    Lysophosphatidic acid (LPA), an initiator of neuropathic pain, causes allodynia. However, few studies have evaluated the pharmacological profile of LPA-induced pain. In this study, a LPA-induced pain model was developed and pharmacologically characterized with clinically relevant drugs used for neuropathic pain, including antiepileptics, non-steroidal anti-inflammatory agents, analgesics, local anaesthetics/antiarrhythmics and antidepressants. Gabapentin (1-30 mg/kg, p.o.) significantly reversed LPA-induced allodynia, but neither indomethacin (30 mg/kg, p.o.) nor morphine (0.3-3 mg/kg, s.c.) did, which indicates that LPA-induced pain consists mostly of neuropathic rather than inflammatory pain. Both pregabalin (0.3-10 mg/kg, p.o.) and ω-CgTX MVIIA (0.01-0.03 μg/mouse, i.t.) completely reversed LPA-induced allodynia in a dose-dependent manner. Lidocaine (1-30 mg/kg, s.c.), mexiletine (1-30 mg/kg, p.o.) and carbamazepine (10-100 mg/kg, p.o.) significantly ameliorated LPA-induced allodynia dose dependently. Milnacipran (30 mg/kg, i.p.) produced no significant analgesic effect in LPA-induced allodynia. In LPA-injected mice, expression of the α2δ1 subunit of the voltage-gated calcium channel (VGCC) was increased in the dorsal root ganglion (DRG) and spinal dorsal horn. Furthermore, the VGCC current was potentiated in both the DRG from LPA-injected mice and LPA (1 μM)-treated DRG from saline-injected mice, and the potentiated VGCC current was amended by treatment with gabapentin (100 μM). The LPA-induced pain model described here mimics aspects of the neuropathic pain state, including the sensitization of VGCC, and may be useful for the early assessment of drug candidates to treat neuropathic pain. PMID:22337641

  13. [Clinical relevance of N-acetyltransferase type 2 (NAT2) genetic polymorphism].

    PubMed

    Furet, Y; Bechtel, Y; Le Guellec, C; Bechtel, P R; Autret-Leca, E; Paintaud, G

    2002-01-01

    Polymorphic N-acetyltransferase (NAT2) is involved in the metabolism of several compounds relevant in pharmacology or toxicology, with diverse clinical consequences. Inter-ethnic variations in distribution of the acetylation phenotype are significant. The caffeine test is most often used to assess the acetylation phenotype and to identify rapid and slow acetylators. The NAT2 phenotype could account for the increased risk of certain side effects in slow acetylators treated with isoniazid (particularly peripheral neuropathies and lupus erythematosus), although therapeutic efficacy seems to be independent of the acetylation status. Hypersensibility reactions with sulfonamides (including Lyell and Stevens-Johnson syndromes) are more frequent in slow acetylators, who also show poor tolerance to sulfasalazine and dapsone. In contrast, myelotoxicity induced by amonafide is more frequent in rapid acetylators, probably because of increased production of a toxic metabolite of the drug. In carcinogenesis, NAT2 may play a protective role against bladder cancer, although studies have shown contradictory results. Slow acetylators may have a risk of developing primitive liver cancer. For lung cancer, data are not conclusive, but slow acetylation status may predispose to mesothelioma in subjects exposed to asbestos. No relation has been found between acetylation phenotype and breast cancer. Contradictory results were reported on its role in colorectal cancer. Non-smoking type 1 diabetics may be at increased risk of nephropathy if they are rapid acetylators. Parkinson's disease may be more frequent among slow acetylators, but again, data have shown contradictory results. Finally, a poor acetylator phenotype may predispose to atopic diseases. PMID:12611196

  14. Automated detection of retinal landmarks for the identification of clinically relevant regions in fundus photography

    NASA Astrophysics Data System (ADS)

    Ometto, Giovanni; Calivá, Francesco; Al-Diri, Bashir; Bek, Toke; Hunter, Andrew

    2016-03-01

    Automatic, quick and reliable identification of retinal landmarks from fundus photography is key for measurements used in research, diagnosis, screening and treating of common diseases affecting the eyes. This study presents a fast method for the detection of the centre of mass of the vascular arcades, optic nerve head (ONH) and fovea, used in the definition of five clinically relevant areas in use for screening programmes for diabetic retinopathy (DR). Thirty-eight fundus photographs showing 7203 DR lesions were analysed to find the landmarks manually by two retina-experts and automatically by the proposed method. The automatic identification of the ONH and fovea were performed using template matching based on normalised cross correlation. The centre of mass of the arcades was obtained by fitting an ellipse on sample coordinates of the main vessels. The coordinates were obtained by processing the image with hessian filtering followed by shape analyses and finally sampling the results. The regions obtained manually and automatically were used to count the retinal lesions falling within, and to evaluate the method. 92.7% of the lesions were falling within the same regions based on the landmarks selected by the two experts. 91.7% and 89.0% were counted in the same areas identified by the method and the first and second expert respectively. The inter-repeatability of the proposed method and the experts is comparable, while the 100% intra-repeatability makes the algorithm a valuable tool in tasks like analyses in real-time, of large datasets and of intra-patient variability.

  15. Experiences of clinical tutors with English as an additional language (EAL) students.

    PubMed

    Lu, Hongyan; Maithus, Caroline

    2012-11-01

    Clinical tutors, referred to in the international literature as clinical supervisors, facilitators, mentors or instructors, are responsible for providing and supervising workplace learning opportunities for groups of Bachelor of Nursing (BN) students. They also play a key role in assessing students. The role modeling and support provided by both clinical tutors and registered nurses (RN) or nurse preceptors helps students become familiar with the language in which nursing work is realised. As BN student cohorts in New Zealand have become more diverse in terms of cultures, ethnicities and language backgrounds, clinical tutors have to directly facilitate the development of context-specific and client-focused communication skills for students who speak English as an additional language. We undertook a study which looked at the perceptions of new nursing graduates with English as an additional language (EAL) on the development of spoken language skills for the clinical workplace. As well as interviewing graduates, we spoke to four clinical tutors in order to elicit their views on the language development of EAL students in previous cohorts. This article reports on the themes which emerged from the interviews with the tutors. These include goal setting for communication, integrating students into nursing work, making assessment less stressful, and endorsing independent learning strategies. Based on their observations and on other published research we make some suggestions about ways both clinical tutors and EAL students within their teaching groups could be supported in the development of communication skills for clinical practice.

  16. Experiences of clinical tutors with English as an additional language (EAL) students.

    PubMed

    Lu, Hongyan; Maithus, Caroline

    2012-11-01

    Clinical tutors, referred to in the international literature as clinical supervisors, facilitators, mentors or instructors, are responsible for providing and supervising workplace learning opportunities for groups of Bachelor of Nursing (BN) students. They also play a key role in assessing students. The role modeling and support provided by both clinical tutors and registered nurses (RN) or nurse preceptors helps students become familiar with the language in which nursing work is realised. As BN student cohorts in New Zealand have become more diverse in terms of cultures, ethnicities and language backgrounds, clinical tutors have to directly facilitate the development of context-specific and client-focused communication skills for students who speak English as an additional language. We undertook a study which looked at the perceptions of new nursing graduates with English as an additional language (EAL) on the development of spoken language skills for the clinical workplace. As well as interviewing graduates, we spoke to four clinical tutors in order to elicit their views on the language development of EAL students in previous cohorts. This article reports on the themes which emerged from the interviews with the tutors. These include goal setting for communication, integrating students into nursing work, making assessment less stressful, and endorsing independent learning strategies. Based on their observations and on other published research we make some suggestions about ways both clinical tutors and EAL students within their teaching groups could be supported in the development of communication skills for clinical practice. PMID:23421011

  17. Enterobacter and Klebsiella species isolated from fresh vegetables marketed in Valencia (Spain) and their clinically relevant resistances to chemotherapeutic agents.

    PubMed

    Falomir, María Pilar; Rico, Hortensia; Gozalbo, Daniel

    2013-12-01

    Occurrence of antibiotic-resistant pathogenic or commensal enterobacteria in marketed agricultural foodstuffs may contribute to their incorporation into the food chain and constitutes an additional food safety concern. In this work, we have determined the clinically relevant resistances to 11 common chemotherapeutic agents in Enterobacter and Klebsiella isolates from fresh vegetables from various sources (supermarkets and greengrocers' shops in Valencia, Spain). A total of 96 isolates were obtained from 160 vegetables analyzed (50% positive samples): 68 Enterobacter isolates (59 E. cloacae, two E. aerogenes, two E. cancerogenus, one E. gergoviae, and four E. sakazakii, currently Cronobacter spp.), and 28 Klebsiella isolates (19 K. oxytoca and 9 K. pneumoniae). Only seven isolates were susceptible to all agents tested, and no resistances to ceftazidime, ciprofloxacin, gentamicin, and chloramphenicol were detected. Most isolates were resistant to amoxicillin/clavulanic acid (74 [58 Enterobacter and 16 Klebsiella]) or to ampicillin (80 [55/25]). Other resistances were less frequent: nitrofurantoin (13 isolates [12/1]), tetracycline (6 [5/1]), co-trimoxazole (3 [3/0]), cefotaxime (1 [1/0]), and streptomycin (2 [1/1]). Multiresistant isolates to two (56 [41/15]), three (10 E. cloacae isolates), four (one E. cloacae and one K. pneumoniae isolate), and five (two E. cloacae isolates) chemotherapeutic agents were also detected. The presence of potential pathogens points to marketed fresh produce, which often is eaten raw, as a risk factor for consumer health. In addition, these results support the usefulness of these bacterial species as indicators of the spreading of antibiotic resistances into the environment, particularly in the food chain, and suggest their role as carriers of resistance determinants from farms to consumers, which may constitute an additional "silent" food safety concern. Therefore, there is a need to improve the hygienic quality of marketed fresh

  18. Time-driven activity-based costing in an outpatient clinic environment: development, relevance and managerial impact.

    PubMed

    Demeere, Nathalie; Stouthuysen, Kristof; Roodhooft, Filip

    2009-10-01

    Healthcare managers are continuously urged to provide better patient services at a lower cost. To cope with these cost pressures, healthcare management needs to improve its understanding of the relevant cost drivers. Through a case study, we show how to perform a time-driven activity-based costing of five outpatient clinic's departments and provide evidence of the benefits of such an analysis.

  19. The clinical relevance and management of monoclonal gammopathy of undetermined significance and related disorders: recommendations from the European Myeloma Network

    PubMed Central

    van de Donk, Niels W.C.J.; Palumbo, Antonio; Johnsen, Hans Erik; Engelhardt, Monika; Gay, Francesca; Gregersen, Henrik; Hajek, Roman; Kleber, Martina; Ludwig, Heinz; Morgan, Gareth; Musto, Pellegrino; Plesner, Torben; Sezer, Orhan; Terpos, Evangelos; Waage, Anders; Zweegman, Sonja; Einsele, Hermann; Sonneveld, Pieter; Lokhorst, Henk M.

    2014-01-01

    Monoclonal gammopathy of undetermined significance is one of the most common pre-malignant disorders. IgG and IgA monoclonal gammopathy of undetermined significance are precursor conditions of multiple myeloma; light-chain monoclonal gammopathy of undetermined significance of light-chain multiple myeloma; and IgM monoclonal gammopathy of undetermined significance of Waldenström’s macroglobulinemia and other lymphoproliferative disorders. Clonal burden, as determined by bone marrow plasma cell percentage or M-protein level, as well as biological characteristics, including heavy chain isotype and light chain production, are helpful in predicting risk of progression of monoclonal gammopathy of undetermined significance to symptomatic disease. Furthermore, alterations in the bone marrow microenvironment of monoclonal gammopathy of undetermined significance patients result in an increased risk of venous and arterial thrombosis, infections, osteoporosis, and bone fractures. In addition, the small clone may occasionally be responsible for severe organ damage through the production of a monoclonal protein that has autoantibody activity or deposits in tissues. These disorders are rare and often require therapy directed at eradication of the underlying plasma cell or lymphoplasmacytic clone. In this review, we provide an overview of the clinical relevance of monoclonal gammopathy of undetermined significance. We also give general recommendations of how to diagnose and manage patients with monoclonal gammopathy of undetermined significance. PMID:24658815

  20. Clinical and Pharmacotherapeutic Relevance of the Double-Chain Domain of the Angiotensin II Type 1 Receptor Blocker Olmesartan

    PubMed Central

    Kiya, Yoshihiro; Miura, Shin-ichiro; Fujino, Masahiro; Imaizumi, Satoshi; Karnik, Sadashiva S.; Saku, Keijiro

    2014-01-01

    We previously reported that the angiotensin II type 1 (AT1) receptor blocker (ARB) olmesartan has two important interactions to evoke inverse agonism (IA). We refer to these interactions as the “double-chain domain (DCD).” Since the clinical pharmacotherapeutic relevance of olmesartan is still unclear, we examined these effects in rats and humans. We analyzed the effects at an advanced stage of renal insufficiency in Dahl salt-sensitive hypertensive rats (Study 1). Rats were fed a high-salt diet from age 9 weeks and arbitrarily assigned to three treatment regimens at age 16 to 21 weeks: olmesartan (2 mg/kg/day) with DCD, a compound related to olmesartan without DCD (6 mg/kg/day, R-239470) or placebo. We also compared the depressor effects of olmesartan to those of other ARBs in patients with essential hypertension (Study 2). Thirty essential hypertensive outpatients who had been receiving ARBs other than olmesartan were recruited for this study. Our protocol was approved by the hospital ethics committee and informed consent was obtained from all patients 12 weeks prior to switching from ARBs other than olmesartan to olmesartan. In Study 1, olmesartan induced a more prominent suppression of the ratio of urinary protein excretion to creatinine at age 21 weeks without lowering blood pressure among the three groups. In Study 2, the depressor effect of olmesartan was significantly stronger than those of other ARBs, which do not contain the DCD. These additive effects by olmesartan may be due to DCD. PMID:20374187

  1. Lipase catalysis and thiol-Michael addition: a relevant association for the synthesis of new surface-active carbohydrate esters.

    PubMed

    Boyère, Cédric; Favrelle, Audrey; Broze, Guy; Laurent, Pascal; Nott, Katherine; Paquot, Michel; Blecker, Christophe; Jérôme, Christine; Debuigne, Antoine

    2011-10-18

    A novel class of surface-active carbohydrate esters is prepared by a two-step strategy that takes advantage of the selectivity of enzymatic catalysis and the versatility of the thiol-Michael addition reaction. The surfactant performance of the produced aliphatic, fluorinated and silicon based sugar esters are evaluated by surface tension measurements. The novel thiolated mannose, made available in this work, appears as a powerful building block for the incorporation of unprotected sugar moieties into complex molecules.

  2. Use of the VITEK 2 system to identify and test the antifungal susceptibility of clinically relevant yeast species.

    PubMed

    Melhem, M S C; Bertoletti, A; Lucca, H R L; Silva, R B O; Meneghin, F A; Szeszs, M W

    2013-12-01

    Eleven quality control isolates (Candida albicans ATCC 64548, C. tropicalis ATCC 200956, C. glabrata ATCC 90030, C. lusitaniae ATCC 200951, C. parapsilosis ATCC 22019, C. krusei ATCC 6258, C. dubliniensis ATCC 6330, Saccharomyces cerevisiae ATCC 9763, Cryptococcus neoformans ATCC 90012, C. gattii FIOCRUZ-CPF 60, and Trichosporon mucoides ATCC 204094) and 32 bloodstream isolates, including C. albicans, C. tropicalis, C. parapsilosis, C. glabrata, C. krusei, C. guilliermondii, C. pelliculosa (Pichia anomala), C. haemulonii, C. lusitaniae, and C. kefyr were identified at the species level by the VITEK 2 system. A set of clinical isolates (32 total) were used as challenge strains to evaluate the ability of the VITEK 2 system to determine the antifungal susceptibility of yeasts compared with the CLSI and EUCAST BMD reference standards. The VITEK 2 system correctly identified 100% of the challenge strains. The identification of yeast species and the evaluation of their susceptibility profiles were performed in an automated manner by the VITEK 2 system after approximately 15 h of growth for most species of Candida. The VITEK 2 system ensures that each test is performed in a standardized manner and provides quantitative MIC results that are reproducible and accurate when compared with the BMD reference methods. This system was able to determine the MICs of amphotericin B, flucytosine, voriconazole, and fluconazole in 15 h or less for the most common clinically relevant Candida species. In addition, the VITEK 2 system could reliably identify resistance to flucytosine, voriconazole, and fluconazole and exhibits excellent quantitative and qualitative agreement with the CLSI or EUCAST broth microdilution reference methods. PMID:24688520

  3. Use of the VITEK 2 system to identify and test the antifungal susceptibility of clinically relevant yeast species

    PubMed Central

    Melhem, MSC; Bertoletti, A; Lucca, HRL; Silva, RBO; Meneghin, FA; Szeszs, MW

    2013-01-01

    Eleven quality control isolates (Candida albicans ATCC 64548, C. tropicalis ATCC 200956, C. glabrata ATCC 90030, C. lusitaniae ATCC 200951, C. parapsilosis ATCC 22019, C. krusei ATCC 6258, C. dubliniensis ATCC 6330, Saccharomyces cerevisiae ATCC 9763, Cryptococcus neoformans ATCC 90012, C. gattii FIOCRUZ-CPF 60, and Trichosporon mucoides ATCC 204094) and 32 bloodstream isolates, including C. albicans, C. tropicalis, C. parapsilosis, C. glabrata, C. krusei, C. guilliermondii, C. pelliculosa (Pichia anomala), C. haemulonii, C. lusitaniae, and C. kefyr were identified at the species level by the VITEK 2 system. A set of clinical isolates (32 total) were used as challenge strains to evaluate the ability of the VITEK 2 system to determine the antifungal susceptibility of yeasts compared with the CLSI and EUCAST BMD reference standards. The VITEK 2 system correctly identified 100% of the challenge strains. The identification of yeast species and the evaluation of their susceptibility profiles were performed in an automated manner by the VITEK 2 system after approximately 15 h of growth for most species of Candida. The VITEK 2 system ensures that each test is performed in a standardized manner and provides quantitative MIC results that are reproducible and accurate when compared with the BMD reference methods. This system was able to determine the MICs of amphotericin B, flucytosine, voriconazole, and fluconazole in 15 h or less for the most common clinically relevant Candida species. In addition, the VITEK 2 system could reliably identify resistance to flucytosine, voriconazole, and fluconazole and exhibits excellent quantitative and qualitative agreement with the CLSI or EUCAST broth microdilution reference methods. PMID:24688520

  4. Structure-activity relationship studies on clinically relevant HIV-1 NNRTIs.

    PubMed

    Rawal, R K; Murugesan, V; Katti, S B

    2012-01-01

    In addition to the nucleoside reverse transcriptase inhibitors (NRTIs), protease inhibitors (PIs) and integrase inhibitors (INIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) have contributed significantly in the treatment of HIV-1 infections. More than 60 structurally different classes of compounds have been identified as NNRTIs, which are specifically inhibiting HIV-1 reverse transcriptase (RT). Five NNRTIs (nevirapine, delavirdine, efavirenz, etravirine and rilpivirine) have been approved by US Food and Drug Administration (FDA) for clinical use. The NNRTIs bind with a specific 'pocket' site of HIV-1 RT (allosteric site) that is closely associated with the NRTI binding site. Due to mutations of the amino acid residues surrounding the NNRTI-binding site, NNRTIs are notorious for rapidly eliciting resistance. Though, the emergence of resistant HIV strains can be circumvented if the NNRTIs are used either alone or in combination with NRTIs (AZT, 3TC, ddI, ddC, TVD or d4T) and PIs (Indinavir, nelfinavir, saquinavir, ritonavir and lopinavir etc.) as shown by both a decrease in plasma HIV-1 RNA levels and increased CD4 T-cells. Here we are going to discuss recent advances in structure activity relationship studies on nevirapine, delavirdine, efavirenz, etravirine, rilpivirine and 4-thiazolidinones (privileged scaffold) HIV-1 NNRTIs.

  5. Endoscopic Pancreas Fluid Collection: Methods and Relevance for Clinical Care and Translational Science.

    PubMed

    Hart, Phil A; Topazian, Mark; Raimondo, Massimo; Cruz-Monserrate, Zobeida; Fisher, William E; Lesinski, Gregory B; Steen, Hanno; Conwell, Darwin L

    2016-09-01

    Pancreatic secretions have an important role in the regulation of a normal nutritional state but can be altered owing to a variety of pathophysiological mechanisms in the context of exocrine pancreatic disease. The development of an endoscopic technique for collection of pancreatic fluid, termed endoscopic pancreatic function testing, has led to improved understanding of these alterations and is particularly helpful to characterize chronic pancreatitis. In addition, investigators have found endoscopically collected pancreatic fluid to be a valuable biofluid for the purposes of translational science. Techniques such as proteomic, cytokine, genetic mutation, DNA methylation, and microRNA analyses, among others, can be utilized to gain a better understanding of the molecular characteristics of chronic pancreatitis and other pancreatic diseases. Endoscopic collection of pancreatic fluid is safe and relatively straightforward, permitting opportunities for longitudinal analysis of these translational markers throughout the course of disease. This manuscript summarizes our current knowledge of pancreatic fluid, with an emphasis on proper techniques for sample collection and handling, its clinical utility, and preliminary observations in translational science. PMID:27481304

  6. Reciprocal regulation of the nitric oxide and cyclooxygenase pathway in pathophysiology: relevance and clinical implications

    PubMed Central

    Kim, Sangwon F.; Mollace, Vincenzo

    2013-01-01

    The nitric oxide (NO) and cyclooxygenase (COX) pathways share a number of similarities. Nitric oxide is the mediator generated from the NO synthase (NOS) pathway, and COX converts arachidonic acid to prostaglandins, prostacyclin, and thromboxane A2. Two major forms of NOS and COX have been identified to date. The constitutive isoforms critically regulate several physiological states. The inducible isoforms are overexpressed during inflammation in a variety of cells, producing large amounts of NO and prostaglandins, which may underlie pathological processes. The cross-talk between the COX and NOS pathways was initially reported by Salvemini and colleagues in 1993, when they demonstrated in a series of in vitro and in vivo studies that NO activates the COX enzymes to produce increased amounts of prostaglandins. Those studies led to the concept that COX enzymes represent important endogenous “receptor” targets for amplifying or modulating the multifaceted roles of NO in physiology and pathology. Since then, numerous studies have furthered our mechanistic understanding of these interactions in pathophysiological settings and delineated potential clinical outcomes. In addition, emerging evidence suggests that the canonical nitroxidative species (NO, superoxide, and/or peroxynitrite) modulate biosynthesis of prostaglandins through non-COX-related pathways. This article provides a comprehensive state-of-the art overview in this area. PMID:23389111

  7. Do not just do it, do it right: urinary metabolomics--establishing clinically relevant baselines.

    PubMed

    Trivedi, Drupad K; Iles, Ray K

    2014-11-01

    Metabolomics is currently being adopted as a tool to understand numerous clinical pathologies. It is essential to choose the best combination of techniques in order to optimize the information gained from the biological sample examined. For example, separation by reverse-phase liquid chromatography may be suitable for biological fluids in which lipids, proteins and small organic compounds coexist in a relatively nonpolar environment, such as serum. However, urine is a highly polar environment and metabolites are often specifically altered to render them polar suitable for normal phase/hydrophilic interaction liquid chromatography. Similarly, detectors such as high-resolution mass spectrometry (MS) may negate the need for a pre-separation but specific detection and quantification of less abundant analytes in targeted metabolomics may require concentration of the ions by methods such an ion trap MS. In addition, the inherent variability of metabolomic profiles need to be established in appropriately large sample sets of normal controls. This review aims to explore various techniques that have been tried and tested over the past decade. Consideration is given to various key drawbacks and positive alternatives published by active research groups and an optimum combination that should be used for urinary metabolomics is suggested to generate a reliable dataset for baseline studies.

  8. Copper and Anesthesia: Clinical Relevance and Management of Copper Related Disorders

    PubMed Central

    Langley, Adrian; Dameron, Charles T.

    2013-01-01

    Recent research has implicated abnormal copper homeostasis in the underlying pathophysiology of several clinically important disorders, some of which may be encountered by the anesthetist in daily clinical practice. The purpose of this narrative review is to summarize the physiology and pharmacology of copper, the clinical implications of abnormal copper metabolism, and the subsequent influence of altered copper homeostasis on anesthetic management. PMID:23762044

  9. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

    PubMed

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-12-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

  10. Anti-apoptotic role and clinical relevance of neurotrophins in diffuse large B-cell lymphomas

    PubMed Central

    Dubanet, Lydie; Bentayeb, Hafidha; Petit, Barbara; Olivrie, Agnès; Saada, Sofiane; de la Cruz-Morcillo, Miguel A; Lalloué, Fabrice; Gourin, Marie-Pierre; Bordessoule, Dominique; Faumont, Nathalie; Delage-Corre, Manuela; Fauchais, Anne-Laure; Jauberteau, Marie-Odile; Troutaud, Danielle

    2015-01-01

    Background: Diffuse large B-cell lymphoma (DLBCL) is a fatal malignancy that needs to identify new targets for additional therapeutic options. This study aimed to clarify the clinical and biological significance of endogenous neurotrophin (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) in DLBCL biopsy samples and cell lines. Methods: We analysed expression of NGF, BDNF, and their receptors (Trk, p75NTR) in 51 biopsies and cell lines by immunohistochemistry, immunofluorescence, and western blotting. To investigate the biological role of BDNF/TrkB/p75NTR axis, effects of neurotrophin signalling inhibition were determined on tumour cell survival and vascular endothelial growth factor (VEGF) secretion. The pharmacological pan-Trk inhibitor K252a was used for in vitro and in vivo studies. Results: A BDNF/TrkB axis was expressed in all biopsies, which was independent of the germinal centre B-cell (GCB)/non-GCB profile. p75NTR, TrkB, and BDNF tumour scores were significantly correlated and high NGF expression was significantly associated with MUM1/IRF4, and the non-GCB subtype. Diffuse large B-cell lymphoma cell lines co-expressed neurotrophins and their receptors. The full-length TrkB receptor was found in all cell lines, which was also phosphorylated at Tyr-817. p75NTR was associated to Trk and not to its cell death co-receptor sortilin. In vitro, inhibition of neurotrophin signalling induced cell apoptosis. K252a caused cell apoptosis, decreased VEGF secretion, and potentiated rituximab effect, notably in less rituximab-sensitive cells. In vivo, K252a significantly reduced tumour growth and potentiated the effects of rituximab in a GCB-DLBCL xenograft model. Conclusions: This work argues for a pro-survival role of endogenous neurotrophins in DLBCLs and inhibition of Trk signalling might be a potential treatment strategy for rituximab resistant subgroups. PMID:26284337

  11. Is (18)F-FDG PET really a promising marker for clinically relevant atherosclerosis?

    PubMed

    Brammen, Lindsay; Palumbo, Barbara; Lupattelli, Graziana; Sinzinger, Helmut

    2014-01-01

    Bural et al (2013), retrospectively investigated 143 subjects who received whole body fluorine-18-fluorodeoxyglucose- positron emission tomography ((18)F-FDG-PET) imaging for the assessment of non-cardiovascular diseases. They reported an increase of (18)F-FDG-positive lesions in various aortic segments, which increased with age, and were more pronounced in subjects being aged below 50 years as compared to those above 50. Bural et al also found the highest segmental (18)F-FDG-uptake in the descending thoracic aorta, but not in the abdominal aorta, where the majority of the most severe atherosclerotic lesions essentially appear. In addition, they did not appreciate any significant gender difference. Despite the severe limitation that no correlation to vascular disease, risk factors, or any clinical parameter was available, this report again raises the question as to what positive (18)F-FDG imaging really reflects and whether it will ever reach the great expectations. Conventional radiotracers revealed an excellent experimental correlation, as well as morphology. Uptake ratios of symptomatic lesion vs. contralateral unaffected side were comparable between (111)In-platelets, (123)I-LDL and (18)FFDG. There was also a mass strategic correlation, but no individual prediction of events at all. Due to better statistics, image quality and solution PET imaging of atherosclerosis holds great promise. However, correlations between various tracers and vascular wall characteristics (and staining methodologies) in 1% cholesterol fed rabbits reveal that (18)F-FDG is not always the best tracer. Vascular foam cell content is reflected by (111)In-HIG > (125)I-oxLp(a) > (18)F-FDG > (125)I-LDL (Brammen L, Palumbo B, Lupattelli G et al. Unpublished data). A close correlation to Framingham risk score is for example not helpful, as this score has a low predictive value of only 0.6. The available clinical correlations between (18)F-FDG-uptake and arterial wall characteristics are poor. For

  12. High-Fidelity Patient Simulators to Expose Undergraduate Students to the Clinical Relevance of Physiology Concepts

    ERIC Educational Resources Information Center

    Harris, David M.; Bellew, Christine; Cheng, Zixi J.; Cendán, Juan C.; Kibble, Jonathan D.

    2014-01-01

    The use of high-fidelity patient simulators (HFPSs) has expanded throughout medical, nursing, and allied health professions education in the last decades. These manikins can be programmed to represent pathological states and are used to teach clinical skills as well as clinical reasoning. First, the students are typically oriented either to the…

  13. How to Respond to a Paranoid Thought: A Comparison of Patients With Clinically Relevant Delusions and Healthy Controls in Chile.

    PubMed

    Wüsten, Caroline; Lincoln, Tania M

    2015-09-01

    Although paranoid thoughts occur frequently in the population, most people do not develop clinically relevant delusions. The main purpose of the study was to explore whether participants without a mental disorder will respond in a more functional way to paranoid thoughts and be more flexible in their cognitive processes than patients with clinically relevant delusions. The Responses to Paranoid Thoughts Scale was translated into Spanish and was completed by patients (n = 36) and healthy controls (n = 39) in Chile (South America). The Beck Cognitive Insight Scale was used to assess cognitive insight. The patients responded in a more depressive, physical, and concealing way to paranoid thoughts than the healthy controls. Moreover, they showed significantly less cognitive insight and self-reflectiveness. Higher cognitive insight and self-reflectiveness were associated with more normalizing and communicative responses to paranoid thoughts.

  14. Time-driven activity-based costing in an outpatient clinic environment: development, relevance and managerial impact.

    PubMed

    Demeere, Nathalie; Stouthuysen, Kristof; Roodhooft, Filip

    2009-10-01

    Healthcare managers are continuously urged to provide better patient services at a lower cost. To cope with these cost pressures, healthcare management needs to improve its understanding of the relevant cost drivers. Through a case study, we show how to perform a time-driven activity-based costing of five outpatient clinic's departments and provide evidence of the benefits of such an analysis. PMID:19505741

  15. Effects of clinically relevant doses of methyphenidate on spatial memory, behavioral sensitization and open field habituation: a time related study.

    PubMed

    Haleem, Darakhshan Jabeen; Inam, Qurrat-ul-Aen; Haleem, Muhammad Abdul

    2015-03-15

    The psychostimulant methylphenidate (MPD) is a first-line drug for the treatment of attention deficit hyperactivity disorder (ADHD). Despite acceptable therapeutic efficacy, there is limited data regarding the long-term consequences of MPD exposure over extended periods. The present study concerns effects of clinically relevant doses of MPD, administered orally to rats for an extended period, on spatial memory, behavioral sensitization and habituation to an open field. Water maze test was used to monitor memory acquisition (2 h after training), retention (day next to training), extinction (1 week after training) and reconsolidation (weekly for 4 weeks). Administration of MPD at doses of 0.25-1.0 mg/kg improved memory acquisition, retention, reconsolidation and impaired memory extinction. Treatment with 0.25 and 0.5 mg/kg MPD for 6 weeks produced a sustained increase in motor activity but higher dose (1.0 mg/kg) elicited behavioral sensitization. High as well as low doses MPD impaired open field habituation. We conclude that clinically relevant doses of MPD enhance memory even if used for extended period. It is suggested that higher (1.0 mg/kg) clinically relevant doses of MPD, if used for extended period, may exacerbate hyperactivity and impulsivity associated with the disease.

  16. Compressive Sensing of Foot Gait Signals and Its Application for the Estimation of Clinically Relevant Time Series.

    PubMed

    Pant, Jeevan K; Krishnan, Sridhar

    2016-07-01

    A new signal reconstruction algorithm for compressive sensing based on the minimization of a pseudonorm which promotes block-sparse structure on the first-order difference of the signal is proposed. Involved optimization is carried out by using a sequential version of Fletcher-Reeves' conjugate-gradient algorithm, and the line search is based on Banach's fixed-point theorem. The algorithm is suitable for the reconstruction of foot gait signals which admit block-sparse structure on the first-order difference. An additional algorithm for the estimation of stride-interval, swing-interval, and stance-interval time series from the reconstructed foot gait signals is also proposed. This algorithm is based on finding zero crossing indices of the foot gait signal and using the resulting indices for the computation of time series. Extensive simulation results demonstrate that the proposed signal reconstruction algorithm yields improved signal-to-noise ratio and requires significantly reduced computational effort relative to several competing algorithms over a wide range of compression ratio. For a compression ratio in the range from 88% to 94%, the proposed algorithm is found to offer improved accuracy for the estimation of clinically relevant time-series parameters, namely, the mean value, variance, and spectral index of stride-interval, stance-interval, and swing-interval time series, relative to its nearest competitor algorithm. The improvement in performance for compression ratio as high as 94% indicates that the proposed algorithms would be useful for designing compressive sensing-based systems for long-term telemonitoring of human gait signals.

  17. Compressive Sensing of Foot Gait Signals and Its Application for the Estimation of Clinically Relevant Time Series.

    PubMed

    Pant, Jeevan K; Krishnan, Sridhar

    2016-07-01

    A new signal reconstruction algorithm for compressive sensing based on the minimization of a pseudonorm which promotes block-sparse structure on the first-order difference of the signal is proposed. Involved optimization is carried out by using a sequential version of Fletcher-Reeves' conjugate-gradient algorithm, and the line search is based on Banach's fixed-point theorem. The algorithm is suitable for the reconstruction of foot gait signals which admit block-sparse structure on the first-order difference. An additional algorithm for the estimation of stride-interval, swing-interval, and stance-interval time series from the reconstructed foot gait signals is also proposed. This algorithm is based on finding zero crossing indices of the foot gait signal and using the resulting indices for the computation of time series. Extensive simulation results demonstrate that the proposed signal reconstruction algorithm yields improved signal-to-noise ratio and requires significantly reduced computational effort relative to several competing algorithms over a wide range of compression ratio. For a compression ratio in the range from 88% to 94%, the proposed algorithm is found to offer improved accuracy for the estimation of clinically relevant time-series parameters, namely, the mean value, variance, and spectral index of stride-interval, stance-interval, and swing-interval time series, relative to its nearest competitor algorithm. The improvement in performance for compression ratio as high as 94% indicates that the proposed algorithms would be useful for designing compressive sensing-based systems for long-term telemonitoring of human gait signals. PMID:25675451

  18. An academic, clinical and industrial update on electrospun, additive manufactured and imprinted medical devices.

    PubMed

    Ryan, Christina N M; Fuller, Kieran P; Larrañaga, Aitor; Biggs, Manus; Bayon, Yves; Sarasua, Jose R; Pandit, Abhay; Zeugolis, Dimitrios I

    2015-01-01

    Electrospinning, additive manufacturing and imprint lithography scaffold fabrication technologies have attracted great attention in biomedicine, as they allow production of two- and three- dimensional constructs with tuneable topographical and geometrical features. In vitro data demonstrate that electrospun and imprinted substrates offer control over permanently differentiated and stem cell function. Advancements in functionalisation strategies have further enhanced the bioactivity and reparative capacity of electrospun and additive manufactured devices, as has been evidenced in several preclinical models. Despite this overwhelming success in academic setting, only a few technologies have reached the clinic and only a fraction of them have become commercially available products.

  19. Clinical Psychopharmacology Update: Additional Safety Concerns for Using Varenicline (Chantix) for Smoking Cessation Treatment.

    PubMed

    Tobin, Thomas J; Tobin, Mary L

    2015-01-01

    Smoking cessation remains a positive therapeutic goal and should be encouraged for the millions of individuals who continue to smoke and struggle to quit. While psychiatric nurses should encourage patients to start or continue smoking cessation therapies, they must be aware of the additional safety concerns relating to the use of varenicline (Chantix). Research published subsequent to the last clinical update in this journal (Tobin, 2007 ) has prompted additional warnings from the Food and Drug Administration concerning varenicline for smoking cessation therapy. In particular, clinicians need to be aware of increased concerns about varenicline's association with neuropsychiatric side effects, seizures, and alcohol interactions. PMID:26514264

  20. Opioid-induced hyperalgesia: is it clinically relevant for the treatment of pain patients?

    PubMed

    Raffa, Robert B; Pergolizzi, Joseph V

    2013-09-01

    There is a curious and paradoxic phenomenon, reliably demonstrated in animal models, that consists of an increased sensitivity to pain that is apparently induced by the very opioid drugs used to ameliorate the pain. This phenomenon is termed "opioid-induced hyperalgesia." Whether opioid-induced hyperalgesia occurs in humans, and, if so, to what extent and consequence, is far less established. This is a critical question for attempting to treat pain. If opioid-induced hyperalgesia develops in a patient, it would masquerade as tolerance (because the clinical effectiveness of the opioid would be diminished), yet the appropriate clinical adjustment would be precisely the opposite to that of tolerance. It would be to decrease, rather than increase, the dose of opioid. We review the evidence, particularly the clinical evidence, about opioid-induced hyperalgesia and the postulated mechanisms. We conclude that given the clinical ramifications, opioid-induced hyperalgesia is one of the most understudied important aspects of opioid research.

  1. Clinical relevance of autophagic therapy in cancer: Investigating the current trends, challenges, and future prospects.

    PubMed

    Mukhopadhyay, Subhadip; Sinha, Niharika; Das, Durgesh Nandini; Panda, Prashanta Kumar; Naik, Prajna Paramita; Bhutia, Sujit Kumar

    2016-08-01

    Oncophagy (cancer-related autophagy) has a complex dual character at different stages of tumor progression. It remains an important clinical problem to unravel the reasons that propel the shift in the role of oncophagy from tumor inhibition to a protective mechanism that shields full-blown malignancy. Most treatment strategies emphasize curbing protective oncophagy while triggering the oncophagy that is lethal to tumor cells. In this review, we focus on the trends in current therapeutics as well as various challenges in clinical trials to address the oncophagic dilemma and evaluate the potential of these developing therapies. A detailed analysis of the clinical and pre-clinical scenario of the anticancer medicines highlights the various inducers and inhibitors of autophagy. The ways in which tumor stage, the microenvironment and combination drug treatment continue to play an important tactical role are discussed. Moreover, autophagy targets also play a crucial role in developing the best possible solution to this oncophagy paradox. In this review, we provide a comprehensive update on the current clinical impact of autophagy-based cancer therapeutic drugs and try to lessen the gap between translational medicine and clinical science.

  2. Clinical proteomic biomarkers: relevant issues on study design & technical considerations in biomarker development

    PubMed Central

    2014-01-01

    Biomarker research is continuously expanding in the field of clinical proteomics. A combination of different proteomic–based methodologies can be applied depending on the specific clinical context of use. Moreover, current advancements in proteomic analytical platforms are leading to an expansion of biomarker candidates that can be identified. Specifically, mass spectrometric techniques could provide highly valuable tools for biomarker research. Ideally, these advances could provide with biomarkers that are clinically applicable for disease diagnosis and/ or prognosis. Unfortunately, in general the biomarker candidates fail to be implemented in clinical decision making. To improve on this current situation, a well-defined study design has to be established driven by a clear clinical need, while several checkpoints between the different phases of discovery, verification and validation have to be passed in order to increase the probability of establishing valid biomarkers. In this review, we summarize the technical proteomic platforms that are available along the different stages in the biomarker discovery pipeline, exemplified by clinical applications in the field of bladder cancer biomarker research. PMID:24679154

  3. Study of photoacoustic measurement of bone health based on clinically relevant models

    NASA Astrophysics Data System (ADS)

    Feng, Ting; Kozloff, Ken; Cao, Meng; Cheng, Qian; Yuan, Jie; Wang, Xueding

    2016-02-01

    Photoacoustic (PA) technique involving both ultrasound and light has been explored for potential application in the assessment of bone health. The optical and ultrasound penetration in bone have been studied. The feasibility of conducting 3D PA imaging of bone, and performing quantitative evaluation of bone microstructures by using photoacoustic spectrum analysis (PASA) has also been investigated. The findings from the experiments demonstrate that PA measurement could offer information of bone mineral density and bone microstructure, both relevant to bone health.

  4. Peri-operative anaesthetic myocardial preconditioning and protection – cellular mechanisms and clinical relevance in cardiac anaesthesia

    PubMed Central

    Kunst, G; Klein, A A

    2015-01-01

    Preconditioning has been shown to reduce myocardial damage caused by ischaemia–reperfusion injury peri-operatively. Volatile anaesthetic agents have the potential to provide myocardial protection by anaesthetic preconditioning and, in addition, they also mediate renal and cerebral protection. A number of proof-of-concept trials have confirmed that the experimental evidence can be translated into clinical practice with regard to postoperative markers of myocardial injury; however, this effect has not been ubiquitous. The clinical trials published to date have also been too small to investigate clinical outcome and mortality. Data from recent meta-analyses in cardiac anaesthesia are also not conclusive regarding intra-operative volatile anaesthesia. These inconclusive clinical results have led to great variability currently in the type of anaesthetic agent used during cardiac surgery. This review summarises experimentally proposed mechanisms of anaesthetic preconditioning, and assesses randomised controlled clinical trials in cardiac anaesthesia that have been aimed at translating experimental results into the clinical setting. PMID:25764404

  5. Microbiological quality of ready-to-eat salads: an underestimated vehicle of bacteria and clinically relevant antibiotic resistance genes.

    PubMed

    Campos, Joana; Mourão, Joana; Pestana, Nazaré; Peixe, Luísa; Novais, Carla; Antunes, Patrícia

    2013-09-16

    The increase demand for fresh vegetables is causing an expansion of the market for minimally processed vegetables along with new recognized food safety problems. To gain further insight on this topic we analyzed the microbiological quality of Portuguese ready-to-eat salads (RTS) and their role in the spread of bacteria carrying acquired antibiotic resistance genes, food products scarcely considered in surveillance studies. A total of 50 RTS (7 brands; split or mixed leaves, carrot, corn) were collected in 5 national supermarket chains in Porto region (2010). They were tested for aerobic mesophilic counts, coliforms and Escherichia coli counts as well as for the presence of Salmonella and Listeria monocytogenes. Samples were also plated in different selective media with/without antibiotics before and after enrichment. The E. coli, other coliforms and Enterococcus recovered were characterized for antibiotic resistance profiles and clonality with phenotypic and genetic approaches. A high number of RTS presented poor microbiological quality (86%--aerobic mesophilic counts, 74%--coliforms, 4%--E. coli), despite the absence of screened pathogens. In addition, a high diversity of bacteria (species and clones) and antibiotic resistance backgrounds (phenotypes and genotypes) were observed, mostly with enrichment and antibiotic selective media. E. coli was detected in 13 samples (n=78; all types and 4 brands; phylogenetic groups A, B1 and D; none STEC) with resistance to tetracycline [72%; tet(A) and/or tet(B)], streptomycin (58%; aadA and/or strA-strB), sulfamethoxazole (50%; sul1 and/or sul2), trimethoprim (50%; dfrA1 or dfrA12), ampicillin (49%; blaTEM), nalidixic acid (36%), ciprofloxacin (5%) or chloramphenicol (3%; catA). E. coli clones, including the widespread group D/ST69, were detected in different samples from the same brand or different brands pointing out to a potential cross-contamination. Other clinically relevant resistance genes were detected in 2 Raoultella

  6. Development and application of two independent real-time PCR assays to detect clinically relevant Mucorales species.

    PubMed

    Springer, Jan; Goldenberger, Daniel; Schmidt, Friderike; Weisser, Maja; Wehrle-Wieland, Elisabeth; Einsele, Hermann; Frei, Reno; Löffler, Jürgen

    2016-03-01

    PCR-based detection of Mucorales species could improve diagnosis of suspected invasive fungal infection, leading to a better patient outcome. This study describes two independent probe-based real-time PCR tests for detection of clinically relevant Mucorales, targeting specific fragments of the 18S and the 28S rRNA genes. Both assays have a short turnaround time, allow fast, specific and very sensitive detection of clinically relevant Mucorales and have the potential to be used as quantitative tests. They were validated on various clinical samples (fresh and formalin-fixed paraffin-embedded specimens, mainly biopsies, n = 17). The assays should be used as add-on tools to complement standard techniques; a combined approach of both real-time PCR assays has 100 % sensitivity. Genus identification by subsequent sequencing is possible for amplicons of the 18S PCR assay. In conclusion, combination of the two independent Mucorales assays described in this study, 18S and 28S, detected all clinical samples associated with proven Mucorales infection (n = 10). Reliable and specific identification of Mucorales is a prerequisite for successful antifungal therapy as these fungi show intrinsic resistance to voriconazole and caspofungin.

  7. The relevance of clinical balance assessment tools to differentiate balance deficits

    PubMed Central

    Mancini, Martina; Horak, Fay B

    2011-01-01

    Control of balance is complex and involves maintaining postures, facilitating movement, and recovering equilibrium. Balance control consists of controlling the body center of mass over its limits of stability. Clinical balance assessment can help assess fall risk and/or determine the underlying reasons for balance disorders. Most functional balance assessment scales assess fall risk and the need for balance rehabilitation but do not differentiate types of balance deficits. A system approach to clinical balance assessment can differentiate different kinds of balance disorders and a physiological approach can determine underlying sensorimotor mechanisms contributing to balance disorders. Objective measures of balance using computerized systems and wearable inertial sensors can bring more sensitive, specific and responsive balance testing to clinical practice. PMID:20485226

  8. A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials

    PubMed Central

    de Sola, Susana; de la Torre, Rafael; Sánchez-Benavides, Gonzalo; Benejam, Bessy; Cuenca-Royo, Aida; del Hoyo, Laura; Rodríguez, Joan; Catuara-Solarz, Silvina; Sanchez-Gutierrez, Judit; Dueñas-Espin, Ivan; Hernandez, Gimena; Peña-Casanova, Jordi; Langohr, Klaus; Videla, Sebastia; Blehaut, Henry; Farre, Magi; Dierssen, Mara; Cuenca-Royo, Aida

    2015-01-01

    The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of

  9. A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials.

    PubMed

    de Sola, Susana; de la Torre, Rafael; Sánchez-Benavides, Gonzalo; Benejam, Bessy; Cuenca-Royo, Aida; Del Hoyo, Laura; Rodríguez, Joan; Catuara-Solarz, Silvina; Sanchez-Gutierrez, Judit; Dueñas-Espin, Ivan; Hernandez, Gimena; Peña-Casanova, Jordi; Langohr, Klaus; Videla, Sebastia; Blehaut, Henry; Farre, Magi; Dierssen, Mara

    2015-01-01

    The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of

  10. A new cognitive evaluation battery for Down syndrome and its relevance for clinical trials.

    PubMed

    de Sola, Susana; de la Torre, Rafael; Sánchez-Benavides, Gonzalo; Benejam, Bessy; Cuenca-Royo, Aida; Del Hoyo, Laura; Rodríguez, Joan; Catuara-Solarz, Silvina; Sanchez-Gutierrez, Judit; Dueñas-Espin, Ivan; Hernandez, Gimena; Peña-Casanova, Jordi; Langohr, Klaus; Videla, Sebastia; Blehaut, Henry; Farre, Magi; Dierssen, Mara

    2015-01-01

    The recent prospect of pharmaceutical interventions for cognitive impairment of Down syndrome (DS) has boosted a number of clinical trials in this population. However, running the trials has raised some methodological challenges and questioned the prevailing methodology used to evaluate cognitive functioning of DS individuals. This is usually achieved by comparing DS individuals to matched healthy controls of the same mental age. We propose a new tool, the TESDAD Battery that uses comparison with age-matched typically developed adults. This is an advantageous method for probing the clinical efficacy of DS therapies, allowing the interpretation and prediction of functional outcomes in clinical trials. In our DS population the TESDAD battery permitted a quantitative assessment of cognitive defects, which indicated language dysfunction and deficits in executive function, as the most important contributors to other cognitive and adaptive behavior outcomes as predictors of functional change in DS. Concretely, auditory comprehension and functional academics showed the highest potential as end-point measures of therapeutic intervention for clinical trials: the former as a cognitive key target for therapeutic intervention, and the latter as a primary functional outcome measure of clinical efficacy. Our results also emphasize the need to explore the modulating effects of IQ, gender and age on cognitive enhancing treatments. Noticeably, women performed significantly better than men of the same age and IQ in most cognitive tests, with the most consistent differences occurring in memory and executive functioning and negative trends rarely emerged on quality of life linked to the effect of age after adjusting for IQ and gender. In sum, the TESDAD battery is a useful neurocognitive tool for probing the clinical efficacy of experimental therapies in interventional studies in the DS population suggesting that age-matched controls are advantageous for determining normalization of

  11. Clinical relevance of β₂-glycoprotein-I plasma levels in antiphospholipid syndrome (APS).

    PubMed

    Banzato, Alessandra; Pengo, Vittorio

    2014-06-01

    Antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid (aPL) antibodies associated with thrombosis or pregnancy morbidity. The antibodies mainly involved in this disorder are directed against β2-glycoprotein I (β2-GPI). β2-GPI plasma level is usually not reported in studies on APS, because it is not regarded as relevant to the diagnosis and prognosis of APS. Nevertheless its measurement may be important for understanding the pathophysiology of the syndrome. This review summarizes available data from the literature on plasma concentrations of β2-GPI in patients with different antibody profiles.

  12. Determination of Clinically Relevant Content for a Musculoskeletal Anatomy Curriculum for Physical Medicine and Rehabilitation Residents

    ERIC Educational Resources Information Center

    Lisk, Kristina; Flannery, John F.; Loh, Eldon Y.; Richardson, Denyse; Agur, Anne M. R.; Woods, Nicole N.

    2014-01-01

    To address the need for more clinical anatomy training in residency education, many postgraduate programs have implemented structured anatomy courses into their curriculum. Consensus often does not exist on specific content and level of detail of the content that should be included in such curricula. This article describes the use of the Delphi…

  13. [Chronic cervical vagal stimulation. Mechanisms of action and clinical relevance for heart failure].

    PubMed

    Kuschyk, J; Doesch, C; Akin, I; Borggrefe, M; Roeger, S

    2015-11-01

    Increased sympathetic nerve activity and reduced vagal activity are associated with increased mortality in patients after myocardial infarction and patients with chronic heart failure; furthermore, vagal withdrawal has been documented to precede acute decompensation. Experimental studies have indicated that increased parasympathetic activity by means of vagal stimulation may reduce mortality in animal models of postinfarction sudden cardiac death and of chronic heart failure. First clinical results have demonstrated that chronic vagus nerve stimulation in heart failure patients with severe systolic dysfunction appears to be safe and tolerable and may improve the quality of life and left ventricular (LV) function. Vagus nerve stimulation gives rise to these potential clinical benefits by multiple mechanisms of action, including reduced heart rate, restoration of heart rate variability and baroreflex sensitivity, suppression of proinflammatory cytokines and antiarrhythmic effects. First clinical results suggest that vagal nerve stimulation is safe and tolerable and could lead to a marked clinical improvement but discrepancies in the findings due to different study designs warrant further discussion. PMID:26555481

  14. Bridging the Divide: Sustainability and Relevance of a Distance Learning Module for Clinical Officers in Tanzania

    ERIC Educational Resources Information Center

    Brigley, Stephen; Hosein, I.; Myemba, I. R.

    2009-01-01

    This paper reports on work by a team from Wales, supported by UNESCO Cymru-Wales, to develop a distance learning module for Tanzanian clinical officers (COs) on the syndromic management and counselling of sexually transmissible infection (STI) and HIV patients. Preparation included documentary analysis and a questionnaire survey to ascertain COs'…

  15. Cato Guldberg and Peter Waage, the history of the Law of Mass Action, and its relevance to clinical pharmacology.

    PubMed

    Ferner, Robin E; Aronson, Jeffrey K

    2016-01-01

    We have traced the historical link between the Law of Mass Action and clinical pharmacology. The Law evolved from the work of the French chemist Claude Louis Berthollet, was first formulated by Cato Guldberg and Peter Waage in 1864 and later clarified by the Dutch chemist Jacobus van 't Hoff in 1877. It has profoundly influenced our qualitative and quantitative understanding of a number of physiological and pharmacological phenomena. According to the Law of Mass Action, the velocity of a chemical reaction depends on the concentrations of the reactants. At equilibrium the concentrations of the chemicals involved bear a constant relation to each other, described by the equilibrium constant, K. The Law of Mass Action is relevant to various physiological and pharmacological concepts, including concentration-effect curves, dose-response curves, and ligand-receptor binding curves, all of which are important in describing the pharmacological actions of medications, the Langmuir adsorption isotherm, which describes the binding of medications to proteins, activation curves for transmembrane ion transport, enzyme inhibition and the Henderson-Hasselbalch equation, which describes the relation between pH, as a measure of acidity and the concentrations of the contributory acids and bases. Guldberg and Waage recognized the importance of dynamic equilibrium, while others failed to do so. Their ideas, over 150 years old, are embedded in and still relevant to clinical pharmacology. Here we explain the ideas and in a subsequent paper show how they are relevant to understanding adverse drug reactions.

  16. Sex offending and sexual appetite: the clinical and theoretical relevance of hypersexual desire.

    PubMed

    Kafka, Martin P

    2003-08-01

    Disinhibited sexual desire, clinically manifested as hypersexual desire disorders, can be operationally defined by considering three behavioral domains associated with sexual motivation or appetitive behavior: (a) sexual preoccupation (time/day consumed by fantasies, urges, and activities), (b) the repetitive frequency of enacted sexual behavior (total sexual outlet/week), and (c) adverse consequences associated with repetitive sexual behavior: Data are presented suggesting that clinical samples of males with paraphilias, paraphilia-related disorders, and sexual coercion may be associated with disinhibited sexual appetite. These conditions need to be addressed by an integrated combination of psychotherapeutic and psychopharmacologic interventions that specifically target disinhibited sexual appetitive behaviors, their antecedents, and consequences. Although combination therapies (empirically based specific psychotherapies in conjunction with psychopharmacological treatments) have demonstrated superior efficacy in many Axis I psychiatric disorders, such combination therapies to reduce paraphilias, paraphilia-related disorders, and adult sexual coercion are currently underutilized in both North and South America and Europe.

  17. [Basic symptoms in schizophrenia, their clinical study and relevance in research].

    PubMed

    Miret, Salvador; Fatjó-Vilas, Mar; Peralta, Víctor; Fañanás, Lourdes

    2016-01-01

    Basic symptoms consist of subtle sub-clinical disturbances subjectively experienced by schizophrenia patients. These are mainly related to drive, affect, thinking and language, perception, memory, motor action, central vegetative functions, control of cognitive processes, and stress tolerance. Initially described by Huber, from a phenomenological approach, basic symptoms are part of the earliest features of schizophrenia, and they can evolve along the course of the disorder. Their assessment during the prodromal phase of the disease (together with ultra-high risk criteria) is one of the 2 main approaches that allow the definition of states of clinical risk for the development of psychosis. The present review provides an updated view of the concept of basic symptoms, highlighting its potential value in establishing neurobiological correlates of interest in aetiopathogenic research.

  18. The Clinical Relevance of Long Non-Coding RNAs in Cancer

    PubMed Central

    Silva, Andreia; Bullock, Marc; Calin, George

    2015-01-01

    Non-coding RNAs have long been associated with cancer development and progression, and since their earliest discovery, their clinical potential in identifying and characterizing the disease has been pursued. Long non-coding (lncRNAs), a diverse class of RNA transcripts >200 nucleotides in length with limited protein coding potential, has been only modestly studied relative to other categories of non-coding RNAs. However, recent data suggests they too may be important players in cancer. In this article, we consider the value of lncRNAs in the clinical setting, and in particular their potential roles as diagnostic and prognostic markers in cancer. Furthermore, we summarize the most significant studies linking lncRNA expression in human biological samples to cancer outcomes. The diagnostic sensitivity, specificity and validity of these non-coding RNA transcripts is compared in the various biological compartments in which they have been detected including tumor tissue, whole body fluids and exosomes. PMID:26516918

  19. The Clinical Relevance of Long Non-Coding RNAs in Cancer.

    PubMed

    Silva, Andreia; Bullock, Marc; Calin, George

    2015-10-27

    Non-coding RNAs have long been associated with cancer development and progression, and since their earliest discovery, their clinical potential in identifying and characterizing the disease has been pursued. Long non-coding (lncRNAs), a diverse class of RNA transcripts >200 nucleotides in length with limited protein coding potential, has been only modestly studied relative to other categories of non-coding RNAs. However, recent data suggests they too may be important players in cancer. In this article, we consider the value of lncRNAs in the clinical setting, and in particular their potential roles as diagnostic and prognostic markers in cancer. Furthermore, we summarize the most significant studies linking lncRNA expression in human biological samples to cancer outcomes. The diagnostic sensitivity, specificity and validity of these non-coding RNA transcripts is compared in the various biological compartments in which they have been detected including tumor tissue, whole body fluids and exosomes.

  20. Circulating tumour cells as tumour biomarkers in melanoma: detection methods and clinical relevance.

    PubMed

    Khoja, L; Lorigan, P; Dive, C; Keilholz, U; Fusi, A

    2015-01-01

    Circulating tumour cells (CTCs) are cells of solid tumour origin detectable in the peripheral blood. Their occurrence is considered a prerequisite step for establishing distant metastases. Metastatic melanoma was the first malignancy in which CTCs were detected and numerous studies have been published on CTC detection in melanoma at various stages of disease. In spite of this, there is no general consensus as to the clinical utility of CTCs in melanoma, largely due to conflicting results from heterogeneous studies and discrepancies in methods of detection between studies. In this review, we examine the possible clinical significance of CTCs in cutaneous, mucosal and ocular melanoma, focusing on detection methods and prognostic value of CTC detection.

  1. Phylogeny of the clinically relevant species of the emerging fungus Trichoderma and their antifungal susceptibilities.

    PubMed

    Sandoval-Denis, Marcelo; Sutton, Deanna A; Cano-Lira, José F; Gené, Josepa; Fothergill, Annette W; Wiederhold, Nathan P; Guarro, Josep

    2014-06-01

    A set of 73 isolates of the emerging fungus Trichoderma isolated from human and animal clinical specimens were characterized morphologically and molecularly using a multilocus sequence analysis that included the internal transcribed spacer (ITS) regions of the nuclear ribosomal DNA and fragments of the translation elongation factor 1 alpha (Tef1), endochitinase CHI18-5 (Chi18-5), and actin 1 (Act1) genes. The most frequent species was Trichoderma longibrachiatum (26%), followed by Trichoderma citrinoviride (18%), the Hypocrea lixii/Trichoderma harzianum species complex (15%), the newly described species Trichoderma bissettii (12%), and Trichoderma orientale (11%). The most common anatomical sites of isolation in human clinical specimens were the respiratory tract (40%), followed by deep tissue (30%) and superficial tissues (26%), while all the animal-associated isolates were obtained from superficial tissue samples. Susceptibilities of the isolates to eight antifungal drugs in vitro showed mostly high MICs, except for voriconazole and the echinocandins.

  2. [Basic symptoms in schizophrenia, their clinical study and relevance in research].

    PubMed

    Miret, Salvador; Fatjó-Vilas, Mar; Peralta, Víctor; Fañanás, Lourdes

    2016-01-01

    Basic symptoms consist of subtle sub-clinical disturbances subjectively experienced by schizophrenia patients. These are mainly related to drive, affect, thinking and language, perception, memory, motor action, central vegetative functions, control of cognitive processes, and stress tolerance. Initially described by Huber, from a phenomenological approach, basic symptoms are part of the earliest features of schizophrenia, and they can evolve along the course of the disorder. Their assessment during the prodromal phase of the disease (together with ultra-high risk criteria) is one of the 2 main approaches that allow the definition of states of clinical risk for the development of psychosis. The present review provides an updated view of the concept of basic symptoms, highlighting its potential value in establishing neurobiological correlates of interest in aetiopathogenic research. PMID:26774677

  3. The default network and self-generated thought: component processes, dynamic control, and clinical relevance

    PubMed Central

    Andrews-Hanna, Jessica R.; Smallwood, Jonathan; Spreng, R. Nathan

    2014-01-01

    Though only a decade has elapsed since the default network was first emphasized as being a large-scale brain system, recent years have brought great insight into the network’s adaptive functions. A growing theme highlights the default network as playing a key role in internally-directed—or self-generated—thought. Here, we synthesize recent findings from cognitive science, neuroscience, and clinical psychology to focus attention on two emerging topics as current and future directions surrounding the default network. First, we present evidence that self-generated thought is a multi-faceted construct whose component processes are supported by different subsystems within the network. Second, we highlight the dynamic nature of the default network, emphasizing its interaction with executive control systems when regulating aspects of internal thought. We conclude by discussing clinical implications of disruptions to the integrity of the network, and consider disorders when thought content becomes polarized or network interactions become disrupted or imbalanced. PMID:24502540

  4. Circulating tumour cells as tumour biomarkers in melanoma: detection methods and clinical relevance.

    PubMed

    Khoja, L; Lorigan, P; Dive, C; Keilholz, U; Fusi, A

    2015-01-01

    Circulating tumour cells (CTCs) are cells of solid tumour origin detectable in the peripheral blood. Their occurrence is considered a prerequisite step for establishing distant metastases. Metastatic melanoma was the first malignancy in which CTCs were detected and numerous studies have been published on CTC detection in melanoma at various stages of disease. In spite of this, there is no general consensus as to the clinical utility of CTCs in melanoma, largely due to conflicting results from heterogeneous studies and discrepancies in methods of detection between studies. In this review, we examine the possible clinical significance of CTCs in cutaneous, mucosal and ocular melanoma, focusing on detection methods and prognostic value of CTC detection. PMID:24907634

  5. Phylogeny of the Clinically Relevant Species of the Emerging Fungus Trichoderma and Their Antifungal Susceptibilities

    PubMed Central

    Sandoval-Denis, Marcelo; Sutton, Deanna A.; Cano-Lira, José F.; Fothergill, Annette W.; Wiederhold, Nathan P.; Guarro, Josep

    2014-01-01

    A set of 73 isolates of the emerging fungus Trichoderma isolated from human and animal clinical specimens were characterized morphologically and molecularly using a multilocus sequence analysis that included the internal transcribed spacer (ITS) regions of the nuclear ribosomal DNA and fragments of the translation elongation factor 1 alpha (Tef1), endochitinase CHI18-5 (Chi18-5), and actin 1 (Act1) genes. The most frequent species was Trichoderma longibrachiatum (26%), followed by Trichoderma citrinoviride (18%), the Hypocrea lixii/Trichoderma harzianum species complex (15%), the newly described species Trichoderma bissettii (12%), and Trichoderma orientale (11%). The most common anatomical sites of isolation in human clinical specimens were the respiratory tract (40%), followed by deep tissue (30%) and superficial tissues (26%), while all the animal-associated isolates were obtained from superficial tissue samples. Susceptibilities of the isolates to eight antifungal drugs in vitro showed mostly high MICs, except for voriconazole and the echinocandins. PMID:24719448

  6. New insights into insulin: The anti-inflammatory effect and its clinical relevance.

    PubMed

    Sun, Qiang; Li, Jia; Gao, Feng

    2014-04-15

    Hyperglycemia, a commonly exhibited metabolic disorder in critically ill patients, activates the body's inflammatory defense mechanism, causing the waterfall release of numerous inflammatory mediators and cytokines, and eventually leads to organ damage. As the only glucose-lowering hormone in the body, insulin not only alleviates the detrimental effects of hyperglycemia through its metabolic regulation, but also directly modulates inflammatory mediators and acts upon immune cells to enhance immunocompetence. In this sense, hyperglycemia is pro-inflammatory whereas insulin is anti-inflammatory. Therefore, during the past 50 years, insulin has not only been used in the treatment of diabetes, but has also been put into practical use in dealing with cardiovascular diseases and critical illnesses. This review summarizes the recent advances regarding the anti-inflammatory effects of insulin in both basic research and clinical trials, with the hope of aiding in the design of further experimental research and promoting effective insulin administration in clinical practice. PMID:24765237

  7. Stem cell transplantation therapy: controversy over ethical issues and clinical relevance.

    PubMed

    Romano, Gaetano

    2004-12-01

    The possibility of regenerating tissues would provide an effective therapeutic tool for the treatment of many pathological conditions, including neurological diseases, spinal cord injuries, cardiopathies, diabetes, hematological illnesses and genetic disorders. While stem cells may have the potential of regenerating a variety of tissues, as indicated by a number of groundbreaking but preliminary reports, ethical issues and safety considerations seem to preclude the use of human embryonic stem cells in the clinical setting. Adult stem cells might circumvent the issues posed by embryonic stem cells, although the potential plasticity of adult stem cells is under scrutiny because of many conflicting and contradictory reports in the field of stem cell research. Indeed, many aspects of the biology of stem cells are still not known. In this respect, stem cell biologists have to address several pressing issues. A better understanding of stem cell biology would almost certainly allow for the establishment of efficient and reliable cell transplantation experimental programs in the clinic.

  8. Couples Counseling in Alzheimer's Disease: Additional Clinical Findings from a Novel Intervention Study.

    PubMed

    Auclair, Ursula; Epstein, Cynthia; Mittelman, Mary

    2009-04-01

    This article describes the clinical findings of a study designed to assess the benefit of counseling for couples, one of whom is in the early stage of Alzheimer's disease (AD). We previously reported our findings based on the first 12 couples that enrolled in the study. Based on the treatment of 30 additional couples, we have refined our treatment strategy to include concepts of Gestalt Therapy and Transactional Analysis and identified prevalent issues of concern to this cohort. The study design has remained as described in the earlier article (Epstein et al., 2006), and has proven to be appropriate to meet the goals of this intervention as indicated by our clinical experience and feedback from the participating couples. Case vignettes demonstrate how to conduct the sessions so that the experience of each member of the dyad is validated, while acknowledging the differential impact of the disease on them. PMID:19865591

  9. Imaging in inflammatory bowel disease mucosal healing in ulcerative colitis: relevance for clinical outcomes.

    PubMed

    Schirbel, Anja; Sturm, Andreas

    2012-09-01

    There is growing evidence of the importance of mucosal healing (MH) in ulcerative colitis, but whether or not it should be a future primary treatment goal is still under intense discussion. Within the last decade many clinical trials have focused not only on response and remission rates but also on achievement of MH, while in clinical practice we still make treatment decisions on the basis of clinical symptoms. There is so far no internationally accepted definition of MH and the tools for assessment of MH vary from biomarkers to endoscopy with histological evaluation on the basis of several different scores and indices. This review will focus on present data dealing with methods to assess MH and the importance of MH for the future course of disease, the need for colectomy or risk of developing colorectal cancer and the patient's quality of life. Many questions remain: How and when do we best assess MH? How rapidly do we need to achieve MH? What is the optimal time point to discontinue treatment after achieving MH? Well defined prospective studies are needed to address these important questions. PMID:22664079

  10. A targeted next-generation sequencing method for identifying clinically relevant mutation profiles in lung adenocarcinoma

    PubMed Central

    Shao, Di; Lin, Yongping; Liu, Jilong; Wan, Liang; Liu, Zu; Cheng, Shaomin; Fei, Lingna; Deng, Rongqing; Wang, Jian; Chen, Xi; Liu, Liping; Gu, Xia; Liang, Wenhua; He, Ping; Wang, Jun; Ye, Mingzhi; He, Jianxing

    2016-01-01

    Molecular profiling of lung cancer has become essential for prediction of an individual’s response to targeted therapies. Next-generation sequencing (NGS) is a promising technique for routine diagnostics, but has not been sufficiently evaluated in terms of feasibility, reliability, cost and capacity with routine diagnostic formalin-fixed, paraffin-embedded (FFPE) materials. Here, we report the validation and application of a test based on Ion Proton technology for the rapid characterisation of single nucleotide variations (SNVs), short insertions and deletions (InDels), copy number variations (CNVs), and gene rearrangements in 145 genes with FFPE clinical specimens. The validation study, using 61 previously profiled clinical tumour samples, showed a concordance rate of 100% between results obtained by NGS and conventional test platforms. Analysis of tumour cell lines indicated reliable mutation detection in samples with 5% tumour content. Furthermore, application of the panel to 58 clinical cases, identified at least one actionable mutation in 43 cases, 1.4 times the number of actionable alterations detected by current diagnostic tests. We demonstrated that targeted NGS is a cost-effective and rapid platform to detect multiple mutations simultaneously in various genes with high reproducibility and sensitivity. PMID:26936516

  11. Free radicals and other reactive oxygen metabolites: clinical relevance and the therapeutic efficacy of antioxidant therapy.

    PubMed

    Bulkley, G B

    1993-05-01

    As in any new field, justifiable enthusiasm for the potential for antioxidant therapy has led to hyperbole, hastily designed, poorly conceived clinical trials, and premature reporting of uncontrolled, anecdotal indicators of efficacy that have not held up when subjected to close scrutiny or more careful, controlled trial design. This tendency has been augmented by strong pressure for early positive results from a few, but not most, members of the pharmaceutical industry and by a few clinicians in highly competitive fields who were anxious not to be left behind. The sobering reality of negative or, even worse, indeterminate clinical trials has culled the field and educated those that remain. As a result, we are beginning to see the publication of quite promising results from large, well-controlled, carefully designed clinical studies, many, but not all, of which are quite promising. This has been associated with a much better understanding of the basic mechanism of free radical-mediated human disease, without which further substantial progress would be quite limited. Because the manipulation of oxidant-mediated tissue injury represents treating disease at its most basic level, the therapeutic potential of this approach remains not only promising but exciting. PMID:8488463

  12. Pharmacogenetics and pharmacogenomics: recent developments, their clinical relevance and some ethical, social, and legal implications.

    PubMed

    Norbert, Paul W; Roses, Allen D

    2003-03-01

    In recent debates on novel procedures of molecular medicine pharmacogenomics is attracting more and more attention as a genotype-based approach for improving safety and efficacy of the use of therapeutic substances. Promoted by basic knowledge generated in the field of medical genomics, facilitated by novel technological tools for mapping genetic variation in individuals, and supported by results of initial clinical studies linking specific genotypes to metabolic characteristics of individuals important for assessing drug response, procedures of pharmacogenetics and pharmacogenomics now are starting to impact significantly on clinical research and development and medical practice. In this situation assessing the goals, risk, and benefits of pharmacogenetics and pharmacogenomics is essential for the medically successful, ethically justifiable, and socially acceptable implementation of genotype-based diagnosis and pharmacotherapy. We discuss the current state of the art in pharmacogenetics and pharmacogenomics and introduce a model for evidence based assessment of its goals, risk, and benefits. We differentiate here between pragmatic and normative issues in the development of pharmacogenomics in order to contrast prevailing, insufficiently interest-based modes of public technology assessment with the evidence-based mode that can be established as part of clinical study design. Finally, we provide a framework for the analysis of social accountability that can be used for technology development and technology assessment with regard to pharmacogenomics in particular and molecular medicine in general.

  13. Clinical relevance of IL-6 gene polymorphism in severely injured patients

    PubMed Central

    Jeremić, Vasilije; Alempijević, Tamara; Mijatović, Srđan; Šijački, Ana; Dragašević, Sanja; Pavlović, Sonja; Miličić, Biljana; Krstić, Slobodan

    2014-01-01

    In polytrauma, injuries that may be surgically treated under regular circumstances due to a systemic inflammatory response become life-threatening. The inflammatory response involves a complex pattern of humoral and cellular responses and the expression of related factors is thought to be governed by genetic variations. This aim of this paper is to examine the influence of interleukin (IL) 6 single nucleotide polymorphism (SNP) -174C/G and -596G/A on the treatment outcome in severely injured patients. Forty-seven severely injured patients were included in this study. Patients were assigned an Injury Severity Score. Blood samples were drawn within 24 h after admission (designated day 1) and on subsequent days (24, 48, 72 hours and 7days) of hospitalization. The IL-6 levels were determined through ELISA technique. Polymorphisms were analyzed by a method of Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR). Among subjects with different outcomes, no statistically relevant difference was found with regards to the gene IL-6 SNP-174G/C polymorphism. More than a half of subjects who died had the SNP-174G/C polymorphism, while this polymorphism was represented in a slightly lower number in survivors. The incidence of subjects without polymorphism and those with heterozygous and homozygous gene IL-6 SNP-596G/A polymorphism did not present statistically significant variations between survivors and those who died. The levels of IL-6 over the observation period did not present any statistically relevant difference among subjects without the IL-6 SNP-174 or IL-6 SNP -596 gene polymorphism and those who had either a heterozygous or a homozygous polymorphism. PMID:24856384

  14. Prazosin addition to fluvoxamine: A preclinical study and open clinical trial in OCD.

    PubMed

    Feenstra, Matthijs G P; Klompmakers, André; Figee, Martijn; Fluitman, Sjoerd; Vulink, Nienke; Westenberg, Herman G M; Denys, Damiaan

    2016-02-01

    The efficacy of selective serotonin reuptake inhibitors (SRIs) in psychiatric disorders may be "augmented" through the addition of atypical antipsychotic drugs. A synergistic increase in dopamine (DA) release in the prefrontal cortex has been suggested to underlie this augmentation effect, though the mechanism of action is not clear yet. We used in vivo microdialysis in rats to study DA release following the administration of combinations of fluvoxamine (10 mg/kg) and quetiapine (10 mg/kg) with various monoamine-related drugs. The results confirmed that the selective 5-HT1A antagonist WAY-100635 (0.05 mg/kg) partially blocked the fluvoxamine-quetiapine synergistic effect (maximum DA increase dropped from 325% to 214%). A novel finding is that the α1-adrenergic blocker prazosin (1 mg/kg), combined with fluvoxamine, partially mimicked the effect of augmentation (maximum DA increase 205%; area-under-the-curve 163%). As this suggested that prazosin augmentation might be tested in a clinical study, we performed an open clinical trial of prazosin 20 mg addition to SRI in therapy-resistant patients with obsessive-compulsive disorder applying for neurosurgery. A small, non-significant reduction in Yale Brown Obsessive Compulsive Scale (Y-BOCS) scores was observed in 10 patients and one patient was classified as a responder with a reduction in Y-BOCS scores of more than 25%. We suggest that future clinical studies augmenting SRIs with an α1-adrenergic blocker in less treatment resistant cases should be considered. The clinical trial "Prazosin in combination with a serotonin reuptake inhibitor for patients with Obsessive Compulsive disorder: an open label study" was registered at 24/05/2011 under trial number ISRCTN61562706: http://www.controlled-trials.com/ISRCTN61562706. PMID:26712326

  15. Dose Addition Models Based on Biologically Relevant Reductions in Fetal Testosterone Accurately Predict Postnatal Reproductive Tract Alterations by a Phthalate Mixture in Rats.

    PubMed

    Howdeshell, Kembra L; Rider, Cynthia V; Wilson, Vickie S; Furr, Johnathan R; Lambright, Christy R; Gray, L Earl

    2015-12-01

    Challenges in cumulative risk assessment of anti-androgenic phthalate mixtures include a lack of data on all the individual phthalates and difficulty determining the biological relevance of reduction in fetal testosterone (T) on postnatal development. The objectives of the current study were 2-fold: (1) to test whether a mixture model of dose addition based on the fetal T production data of individual phthalates would predict the effects of a 5 phthalate mixture on androgen-sensitive postnatal male reproductive tract development, and (2) to determine the biological relevance of the reductions in fetal T to induce abnormal postnatal reproductive tract development using data from the mixture study. We administered a dose range of the mixture (60, 40, 20, 10, and 5% of the top dose used in the previous fetal T production study consisting of 300 mg/kg per chemical of benzyl butyl (BBP), di(n)butyl (DBP), diethyl hexyl phthalate (DEHP), di-isobutyl phthalate (DiBP), and 100 mg dipentyl (DPP) phthalate/kg; the individual phthalates were present in equipotent doses based on their ability to reduce fetal T production) via gavage to Sprague Dawley rat dams on GD8-postnatal day 3. We compared observed mixture responses to predictions of dose addition based on the previously published potencies of the individual phthalates to reduce fetal T production relative to a reference chemical and published postnatal data for the reference chemical (called DAref). In addition, we predicted DA (called DAall) and response addition (RA) based on logistic regression analysis of all 5 individual phthalates when complete data were available. DA ref and DA all accurately predicted the observed mixture effect for 11 of 14 endpoints. Furthermore, reproductive tract malformations were seen in 17-100% of F1 males when fetal T production was reduced by about 25-72%, respectively. PMID:26350170

  16. Biologically effective dose distribution based on the linear quadratic model and its clinical relevance

    SciTech Connect

    Lee, S.P.; Smathers, J.B.; Withers, H.R.

    1995-09-30

    Radiotherapy plans based on physical dose distributions do not necessarily entirely reflect the biological effects under various fractionation schemes. Over the past decade, the linear-quadratic (LQ) model has emerged as a convenient tool to quantify biological effects for radiotherapy. In this work, we set out to construct a mechanism to display biologically oriented dose distribution based on the LQ model. A computer program that converts a physical dose distribution calculated by a commercially available treatment planning system to a biologically effective dose (BED) distribution has been developed and verified against theoretical calculations. This software accepts a user`s input of biological parameters for each structure of interest (linear and quadratic dose-response and repopulation kinetic parameters), as well as treatment scheme factors (number of fractions, fractional dose, and treatment time). It then presents a two-dimensional BED display in conjunction with anatomical structures. Furthermore, to facilitate clinicians` intuitive comparison with conventional fractionation regimen, a conversion of BED to normalized isoeffective dose (NID) is also allowed. We have demonstrated the feasibility of constructing a biologically oriented dose distribution for clinical practice of radiotherapy. The discordance between physical dose distributions and the biological counterparts based on the given treatment schemes was quantified. The computerized display of BED at nonprescription points greatly enhanced the versatility of this tool. Although the routine use of this implementation in clinical radiotherapy should be cautiously done, depending largely on the accuracy of the published biological parameters, it may, nevertheless, help the clinicians derive an optimal treatment plan with a particular fractionation scheme or use it as a quantitative tool for outcome analysis in clinical research. 45 refs., 3 figs., 5 tabs.

  17. Clinical Relevance of Telomere Status and Telomerase Activity in Colorectal Cancer.

    PubMed

    Fernández-Marcelo, Tamara; Sánchez-Pernaute, Andrés; Pascua, Irene; De Juan, Carmen; Head, Jacqueline; Torres-García, Antonio-José; Iniesta, Pilar

    2016-01-01

    The role of telomeres and telomerase in colorectal cancer (CRC) is well established as the major driving force in generating chromosomal instability. However, their potential as prognostic markers remains unclear. We investigated the outcome implications of telomeres and telomerase in this tumour type. We considered telomere length (TL), ratio of telomere length in cancer to non-cancer tissue (T/N ratio), telomerase activity and TERT levels; their relation with clinical variables and their role as prognostic markers. We analyzed 132 CRCs and paired non-cancer tissues. Kaplan-Meier curves for disease-free survival were calculated for TL, T/N ratio, telomerase activity and TERT levels. Overall, tumours had shorter telomeres than non-tumour tissues (P < 0.001) and more than 80% of CRCs displayed telomerase activity. Telomere lengths of non-tumour tissues and CRCs were positively correlated (P < 0.001). Considering telomere status and clinical variables, the lowest degree of telomere shortening was shown by tumours located in the rectum (P = 0.021). Regarding prognosis studies, patients with tumours showing a mean TL < 6.35 Kb experienced a significantly better clinical evolution (P < 0.001) and none of them with the highest degree of tumour telomere shortening relapsed during the follow-up period (P = 0.043). The mean TL in CRCs emerged as an independent prognostic factor in the Cox analysis (P = 0.017). Telomerase-positive activity was identified as a marker that confers a trend toward a poor prognosis. In CRC, our results support the use of telomere status as an independent prognostic factor. Telomere status may contribute to explaining the different molecular identities of this tumour type.

  18. A Core-tailored Platform for Pinpointing Clinically Relevant Variants in Human Genomes and Exomes

    PubMed Central

    Richards, D.; Flannery, R.; Kramer, A.; Kutchma, A.; Lerman, J.; Leschly, J.; Majumdar, S.; Marshall, N.; Molloy, M.; Muthiah, A.; Ning, A.; O'Connor, R.; Patel, K.; Rajaraman, V.; Rebres, R.; Sarver, A.; Su, H.; Zhou, W.; Zhu, X.; Bassett, D.; Pearson, Nathan

    2013-01-01

    Genomic studies of human disease and drug response aim to find one or a few causal variants among millions of possible candidates. A streamlined platform for quickly and reliably assessing each variant called in such studies can save months of tedious effort, speeding discoveries for core labs' clinical and research clients, and freeing core staff to solve other data analysis challenges posed by broader clientele. Made to help cores and their clients quickly interpret human genomes, the Ingenuity® Variant Analysis™ platform (www.ingenuity.com/variants) lets users upload, annotate, and thoroughly compare whole or partial human genomes, to smartly shortlist candidate variants, genes, and pathways that may best explain user-specified phenotype(s). Leveraging Ingenuity's deep, structured knowledge base of published findings and robust predictive insight, Variant Analysis runs sophisticated tests of family- and population-scale genetic association, tailored to the user's study design and phenotype, via a simple, fluid interface that also lets one easily review, revise, and share findings. To meet the distinctive challenges of clinical genome interpretation, we have comprehensively curated published clinical assessments and population incidence of individual human sequence variants, supplementing gene- and pathway-level functional knowledge. To help researchers identify new causal candidates, we have built and validated Variant Analysis to run gene- and pathway-level burden tests ∼100x faster than conventional methods. And, by letting users easily and securely share genome data and findings with collaborators, the platform mediates efficient collaborative discovery among researchers studying similar or (as mutual controls) distinct rare diseases. Combining sophisticated functional analytics; statistically robust genetic analysis at the variant, gene, and pathway levels in an intuitive interface, the Variant Analysis platform is built to meet the varied genome

  19. The relevance of cellular to clinical electrophysiology in classifying antiarrhythmic actions.

    PubMed

    Vaughan Williams, E M

    1992-01-01

    The division of class I antiarrhythmic agents (sodium-channel blockers) into Ia, Ib, and Ic subgroups was based on clinical observations. Lidocaine, mexiletine, and tocainide (Ib) did not alter the QRS or H-V interval in sinus rhythm, but prolonged effective refractory period (ERP) in spite of some shortening of the J-T interval. Encainide, flecainide, and lorcainide (Ic) widened the QRS and prolonged H-V in sinus rhythm and at low concentration, but had little effect on the ERP or J-T. These clinical findings could be explained by fast onset/offset kinetics of Ib drugs, that when used in high concentrations, blocked most sodium channels during the action potential plateau; therefore, at the beginning of diastole, insufficient drug-free channels were available to support conduction, and the ERP was prolonged. Rapid dissociation of the drugs after repolarization insured that by the end of diastole most channels were again drug free, so that the QRS and H-V were normal. The Ic compounds were more potent, but of slow onset, so that a steady-state block of Na channels was not achieved until after many beats. Offset was also slow, so that a proportion of channels was persistently unavailable, Na current was reduced, and conduction slowed, causing widening of the QRS and lengthening of H-V. Because the remaining drug-free channels were normal, they recovered rapidly from inactivation, and the ERP was not prolonged. By clinical criteria, moricizine also must be classed as Ic, and its offset/onset kinetics are much slower than those of Ib drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

  20. Clinical relevance of electrophysiological tests in the assessment of patients with Huntington's disease.

    PubMed

    Lefaucheur, Jean-Pascal; Bachoud-Levi, Anne-Catherine; Bourdet, Catherine; Grandmougin, Thierry; Hantraye, Philippe; Cesaro, Pierre; Degos, Jean-Denis; Peschanski, Marc; Lisovoski, Fabrice

    2002-11-01

    Assessment programs recently designed to follow-up patients with Huntington's disease (HD) in therapeutic trials have not included electrophysiological testing in the list of mandatory examinations. This omission is likely due to the current lack of data establishing a clear correlation between the electrophysiological results and those of clinical assessment. We address this issue in a cohort of 36 patients at relatively early stages of the disease (I and II). Electrophysiological studies comprised the recording of palmar sympathetic skin responses (SSRs), blink reflexes (BRs), thenar long latency reflexes (LLRs), cortical somatosensory evoked potentials (SEPs), and electromyographic silent periods evoked by transcranial magnetic stimulation (SPs). Results were analyzed with reference to disease duration and staging and to specific cognitive, psychiatric, and motor alteration. SEPs were the most and very sensitive markers, because they were abnormal in 94% of patients. Except for LLRs, alteration of electrophysiological results increased in parallel to the evolution of the disease. Except for LLRs and SSR latency, electrophysiological results correlated with those of specific clinical examinations. In particular, an increased BR latency or a reduced amplitude of the N20 component of SEPs correlated with the extent of bradykinesia, whereas a reduced amplitude of SSRs or of the N30 component of SEPs correlated with hyperkinesia. Overall, electrophysiological tests, in particular SEPs and BRs, appeared sensitive and interesting in the follow-up of HD patients and correlated with various clinical parameters, suggesting that these easy to perform and noninvasive repeatable examinations could be added fruitfully to the assessment programs for HD. PMID:12465071

  1. Perceptual accuracy of upper airway compromise in children: Clinical relevance and future directions for research

    PubMed Central

    Esteban, Cynthia; Kopel, Sheryl J.; Jandasek, Barbara; Dansereau, Katie; Fritz, Gregory K.; Klein, Robert B.

    2013-01-01

    Approximately 80% of children with asthma have coexisting allergic rhinitis. The accurate recognition and assessment of asthma and rhinitis symptoms is an integral component of guideline-based treatment for both conditions. This article describes the development and preliminary evaluation of a novel paradigm for testing the accuracy of children's assessment of their upper airway (rhinitis) symptoms. This work is guided by our previous research showing the clinical efficacy of tools to evaluate children's perceptual accuracy of asthma symptoms and linking accurate asthma symptom perception to decreased asthma morbidity (Fritz G, et al., Ethnic differences in perception of lung function: A factor in pediatric asthma disparities? Am J Respir Crit Care Med 182:12–18, 2010; Klein RB, et al., The Asthma Risk Grid: Clinical interpretation of symptom perception, Allergy Asthma Proc 251–256, 2004). The pilot study tests a paradigm that allows for the examination of the correspondence of children's assessment of their upper airway functioning with actual values of upper airway flow through the use of a portable, handheld nasal peak flowmeter. Nine children with persistent asthma were evaluated over a 4-week period. The article describes the rhinitis perceptual accuracy paradigm and reviews the results of a pilot study, showing a large proportion of inaccurate rhinitis symptoms “guesses” by the sample of children with persistent asthma. Patterns of inaccuracy, rhinitis control, and asthma morbidity are also described. Directions for future work are reviewed. The development of clinical tools to evaluate children's accuracy of rhinitis symptoms are needed, given the central role of the self-assessment of symptoms in guideline-based care. Accurate perception of the severity of rhinitis symptoms may enhance rhinitis control, lessen the burden of asthma, and prevent unnecessary emergency use among this high-risk group of children. PMID:24124637

  2. Thirty years of human pineal research: do we know its clinical relevance?

    PubMed

    García-Patterson, A; Puig-Domingo, M; Webb, S M

    1996-01-01

    A role for melatonin in humans is becoming evident in an increasing number of clinical situations. Marked variations in the magnitude of the nocturnal melatonin peak are observed throughout the human lifespan. The highest levels occur in children and then fall during puberty and further during adulthood. A negative correlation between circulating melatonin and sex steroids has been observed in a number of instances, and appears to be independent of concomitant gonadotrophins. No clear melatonin pattern has been observed in pituitary tumors, but in large lesions that involve the hypothalamus, a reduced nocturnal rise has been reported. Reported effects of exogenously administered melatonin are variable, probably reflecting differences in dose and timing; a slight stimulation of prolactin, as well as a partial inhibition of gonadotrophins, has been reported, which explains its utility as an oral contraceptive, associated with a progestogen. A potential clinical use of melatonin as an oncostatic drug still awaits confirmation, although experimental data firmly support this possibility. The indole has also been used to hasten entrainment of subjects travelling across various time zones, and has been found to be specially useful in eastward travel. Finally, changes in the normal melatonin circadian pattern have been reported in psychiatric diseases and in sudden infant death syndrome. PMID:8648556

  3. Maintaining the clinical relevance of animal models in translational studies of post-traumatic stress disorder.

    PubMed

    Cohen, Hagit; Matar, Michael A; Zohar, Joseph

    2014-01-01

    The diagnosis of Post-Traumatic Stress Disorder (PTSD) is conditional on directly experiencing or witnessing a significantly threatening event and the presence of a certain minimal number of symptoms from each of four symptom clusters (re-experiencing, avoidance, negative cognition and mood, and hyperarousal) at least one month after the event (DSM 5) (American Psychiatric Association 2013). Only a proportion of the population exposed develops symptoms fulfilling the criteria. The individual heterogeneity in responses of stress-exposed animals suggested that adapting clearly defined and reliably reproducible "diagnostic", i.e. behavioral, criteria for animal responses would augment the clinical validity of the analysis of study data. We designed cut-off (inclusion/exclusion) behavioral criteria (CBC) which classify study subjects as being severely, minimally or partially affected by the stress paradigm, to be applied retrospectively in the analysis of behavioral data. Behavioral response classification enables the researcher to correlate (retrospectively) specific anatomic, bio-molecular and physiological parameters with the degree and pattern of the individual behavioral response, and also introduces "prevalence rates" as a valid study-parameter. The cumulative results of our studies indicate that, by classifying the data from individual subjects according to their response patterns, the animal study can more readily be translated into clinical "follow-up" studies and back again. This article will discuss the concept of the model and its background, and present a selection of studies employing and examining the model, alongside the underlying translational rationale of each.

  4. Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.

    PubMed

    Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

    2016-01-01

    MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results.

  5. Teaching clinically relevant dental anatomy in the dental curriculum: description and assessment of an innovative module.

    PubMed

    Obrez, Ales; Briggs, Charlotte; Buckman, James; Goldstein, Loren; Lamb, Courtney; Knight, William G

    2011-06-01

    The primary objective of the preclinical dental anatomy course in the predoctoral dental curriculum is to introduce students to cognitive and psychomotor skills related to the morphology and spatial and functional relationships of human dentition. Traditionally, didactic content for the subject is found in textbooks and course manuals and summarized by the faculty in lectures to the entire class. Psychomotor skills associated with recognition and reproduction of tooth morphology are traditionally learned by examining preserved tooth specimens and their cross-sections, combined with producing two-dimensional line drawings and carving teeth from wax blocks. These activities have little direct clinical application. In most cases, students are passive in the learning process, and assessment of student performance is unilateral and subjective. A recently revised dental anatomy module at the University of Illinois at Chicago College of Dentistry integrates independent class preparation with active small-group discussion and patient scenario-based wax-up exercises to replace missing tooth structure on manikin teeth. The goal of the revision is to shift emphasis away from decontextualized technical learning toward more active and clinically applicable learning that improves conceptual understanding while contributing to early acquisition of psychomotor skills. This article describes the rationale, components, and advantages of the revised module and presents a pre-post comparison of student learning outcomes for three class cohorts (N=203).

  6. Physiologic and clinical relevance of the insulin-like growth factor binding proteins.

    PubMed

    Cohen, P; Rosenfeld, R G

    1994-08-01

    The insulin-like growht factors (IGFs) are potent mitogenic agents that have been recognized for three decades. Recently, however, the complex milieu in which they operate has begun to be unraveled. Endocrine and autocrine patterns of IGF secretion have been identified and specific receptors that bind IGFs and mediate their biologic actions have been characterized. A family of six peptides, which bind IGFs with high affinity, the IGF binding proteins (IGFBPs), have been recognized as a new class of growth modulators. The IGFBPs can inhibit IGF actions, enhance IGF actions, or function as independent cell regulatory factors, possibly by interacting with their own receptors on the cell membrane. The IGFBPs, in turn, are regulated by a group of proteolytic enzymes, which are capable of cleaving IGFBPs into smaller fragments with lower affinity for the IGFs, thus enhancing IGF action. The size IGFBPs, although similar, have unique biologic properties, and appear to have specific patterns of expression and function. Radioimmunoassays for IGFBP-1, -2, and -3 are currently commercially available and information is accumulating on their diagnostic usefulness. This includes several clinical situations, such as growth disorders, where serum IGFBP-3 is a highly specific screening tool for growth hormone deficiency, various malignancies in which serum IGFBP-2 levels are elevated, and disorders of carbohydrate metabolism that display an inverse relationship between serum IGFBP-1 and insulin secretion. Current clinical practice may include the judicious use of these tests for the diagnosis and for monitoring the therapeutic response, of such disorders. PMID:7951670

  7. Heterochromatin protein 1α: a hallmark of cell proliferation relevant to clinical oncology

    PubMed Central

    De Koning, Leanne; Savignoni, Alexia; Boumendil, Charlène; Rehman, Haniya; Asselain, Bernard; Sastre-Garau, Xavier; Almouzni, Geneviève

    2009-01-01

    Mammalian cells contain three closely related heterochromatin protein 1 (HP1) isoforms, HP1α, β and γ, which, by analogy to their unique counterpart in Schizosaccharomyces pombe, have been implicated in gene silencing, genome stability and chromosome segregation. However, the individual importance of each isoform during normal cell cycle and disease has remained an unresolved issue. Here, we reveal that HP1α shows a proliferation-dependent regulation, which neither HP1β nor γ display. During transient cell cycle exit, the HP1α mRNA and protein levels diminish. Transient depletion of HP1α, but not HP1β or γ, in tumoural and primary human cells leads to defects in chromosome segregation. Notably, analysis of an annotated collection of samples derived from carcinomas reveals an overexpression of HP1α mRNA and protein, which correlates with clinical data and disease outcome. Our results unveil a specific expression pattern for the HP1α isoform, suggesting a unique function related to cell division and tumour growth. The overexpression of HP1α constitutes a new example of a potential epigenetic contribution to tumourigenesis that is of clinical interest for cancer prognosis. PMID:20049717

  8. Genotypes and viral variants in chronic hepatitis B: A review of epidemiology and clinical relevance

    PubMed Central

    Croagh, Catherine MN; Desmond, Paul V; Bell, Sally J

    2015-01-01

    The Hepatitis B Virus (HBV) has a worldwide distribution and is endemic in many populations. It is constantly evolving and 10 genotypic strains have been identified with varying prevalences in different geographic regions. Numerous stable mutations in the core gene and in the surface gene of the HBV have also been identified in untreated HBV populations. The genotypes and viral variants have been associated with certain clinical features of HBV related liver disease and Hepatocellular carcinoma. For example Genotype C is associated with later hepatitis B e antigen (HBeAg) seroconversion, and more advanced liver disease. Genotype A is associated with a greater risk of progression to chronicity in adult acquired HBV infections. Genotype D is particularly associated with the precore mutation and HBeAg negative chronic hepatitis B (CHB). The genotypes prevalent in parts of West Africa, Central and South America, E, F and H respectively, are less well studied. Viral variants especially the Basal Core Promotor mutation is associated with increased risk of fibrosis and cancer of the liver. Although not currently part of routine clinical care, evaluation of genotype and viral variants may provide useful adjunctive information in predicting risk about liver related morbidity in patients with CHB. PMID:25848459

  9. Clinically Relevant Pharmacological Strategies That Reverse MDMA-Induced Brain Hyperthermia Potentiated by Social Interaction.

    PubMed

    Kiyatkin, Eugene A; Ren, Suelynn; Wakabayashi, Ken T; Baumann, Michael H; Shaham, Yavin

    2016-01-01

    MDMA-induced hyperthermia is highly variable, unpredictable, and greatly potentiated by the social and environmental conditions of recreational drug use. Current strategies to treat pathological MDMA-induced hyperthermia in humans are palliative and marginally effective, and there are no specific pharmacological treatments to counteract this potentially life-threatening condition. Here, we tested the efficacy of mixed adrenoceptor blockers carvedilol and labetalol, and the atypical antipsychotic clozapine, in reversing MDMA-induced brain and body hyperthermia. We injected rats with a moderate non-toxic dose of MDMA (9 mg/kg) during social interaction, and we administered potential treatment drugs after the development of robust hyperthermia (>2.5 °C), thus mimicking the clinical situation of acute MDMA intoxication. Brain temperature was our primary focus, but we also simultaneously recorded temperatures from the deep temporal muscle and skin, allowing us to determine the basic physiological mechanisms of the treatment drug action. Carvedilol was modestly effective in attenuating MDMA-induced hyperthermia by moderately inhibiting skin vasoconstriction, and labetalol was ineffective. In contrast, clozapine induced a marked and immediate reversal of MDMA-induced hyperthermia via inhibition of brain metabolic activation and blockade of skin vasoconstriction. Our findings suggest that clozapine, and related centrally acting drugs, might be highly effective for reversing MDMA-induced brain and body hyperthermia in emergency clinical situations, with possible life-saving results. PMID:26105141

  10. Tests for bactericidal effects of antimicrobial agents: technical performance and clinical relevance.

    PubMed Central

    Peterson, L R; Shanholtzer, C J

    1992-01-01

    Bactericidal testing has been used for several decades as a guide for antimicrobial therapy of serious infections. Such testing is most frequently performed when bactericidal antimicrobial agent therapy is considered necessary (such as when treating infectious endocarditis or infection in an immunocompromised host). It has also been used to ensure that the infecting organism is killed by (not tolerant to) usually bactericidal compounds. However, few data are available to support the role of such tests in direct patient care. Several important variables affect the reproducibility of the test results; however, proposed reference methods are now available for performing the MBC test. With minor modifications, these can provide a standardized approach for laboratories that need to perform them. Currently, little evidence is available to support the routine use of such testing for the care of individual patients. However, testing of new (investigational) antimicrobial agents can be beneficial in determining their potential to provide bactericidal antimicrobial activity during clinical use. New methods to assess bactericidal activity are being developed, but as yet none have been rigorously tested in patient care settings; further, for most of these methods, little information is available as to which technical parameters affect their results. In clinical laboratories, all bactericidal tests must be performed with rigorously standardized techniques and adequate controls, bearing in mind the limitations of the currently available test procedures. PMID:1423219

  11. The clinical effect and relevant mechanism of combined sorafenib and radiofrequency ablation in the treatment of early small hepatocellular carcinoma

    PubMed Central

    Yan, Shi-Yan; Zhang, Yi; Sun, Chao; Cao, Hai-Xia; Li, Guang-Ming; Wang, Yu-Qin; Fan, Jian-Gao

    2016-01-01

    The number of cases with hepatocellular carcinoma (HCC) are on the increase. The aim of the present study was to investigate the clinical effect and relevant mechanism of combined sorafenib and radiofrequency ablation (RFA) in the treatment of the early small HCC. A total of 120 cases of patients with small HCC that presented during the period of May 2007 to June 2010 were selected and divided into the surgery (n=60) and RF (n=60) groups according to the treatment method employed. The surgery group was treated with a laparotomy resection and the RF group was treated with combined sorafenib and RFA, and a comparative analysis was made between the two groups with regard to recurrence rates, adverse reactions, and survival rates. After treatment of 1 month, the radical effective rate of the surgery and RF groups was 100%. Contrast-enhanced ultrasound images of the patients in the RF group were taken. During the 5-year follow-up, the tumor recurrence rate in the surgery group was 18.3%, significantly lower than that in the RF group where the tumor recurrence rate was 38.3% (P<0.05). The occurrence rate of postoperative pain, fever, abdominal bleeding, infection, and other complications of patients in the surgery group was significantly higher than the complication occurrence rate (P<0.05) of the patients in the RF group. The average survival time of the patients in the surgery group was 51.2±1.5 months and the survival rates during the first, third and fifth year were 90.7, 71.5 and 56.7%, respectively. Additionally, the average survival time of the patients in the RF group was 64.6±2.4 months and the survival rates during the first, third and fifth year were 91.1, 72.8 and 57.5%, respectively. The difference between the two groups was not statistically significant. The tumor-free survival rates in the surgery group during the first, third and fifth year were 87.8, 44.3 and 33.2%, respectively, while the tumor-free survival rates in the RF group during the first

  12. Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma

    PubMed Central

    Jasinski-Bergner, Simon; Reches, Adi; Stoehr, Christine; Massa, Chiara; Gonschorek, Evamaria; Huettelmaier, Stefan; Braun, Juliane; Wach, Sven; Wullich, Bernd; Spath, Verena; Wang, Ena; Marincola, Francesco M.; Mandelboim, Ofer; Hartmann, Arndt; Seliger, Barbara

    2016-01-01

    The non-classical human leukocyte antigen G (HLA-G) is expressed at a high frequency in renal cell carcinoma (RCC) and is associated with a higher tumor grade and a poor clinical outcome. This might be caused by the HLA-G-mediated inhibition of the cytotoxicity of T and NK cells. Therefore a selective targeting of HLA-G might represent a powerful strategy to enhance the immunogenicity of RCC lesions. Recent studies identified a number of HLA-G-regulating microRNAs (miRs) and demonstrated an inverse expression of some of these miRs with HLA-G in RCC in vitro and in vivo. However, it was postulated that further miRs might exist contributing to the tightly controlled selective HLA-G expression. By application of a miR enrichment assay (miTRAP) in combination with in silico profiling two novel HLA-G-regulatory miRs, miR-548q and miR-628-5p, were identified. Direct interactions of both miRs with the 3′ untranslated region of HLA-G were confirmed with luciferase reporter gene assays. In addition, qPCR analyses and immunohistochemical staining revealed an inverse, expression of miR-628-5p, but not of miR-548q to the HLA-G protein in primary RCC lesions and cell lines. Stable overexpression of miR-548q and miR-628-5p caused a downregulation of HLA-G mRNA and protein. This leads in case of miR-548q to an enhanced NK cell-mediated HLA-G-dependent cytotoxicity, which could be reverted by ILT2 blockade suggesting a control of the immune effector cell activity at least by this miR. The identification of two novel HLA-G-regulatory miRs extends the number of HLA-G-relevant miRs tuning the HLA-G expression and might serve as future therapeutic targets. PMID:27057628

  13. Identification of novel microRNAs regulating HLA-G expression and investigating their clinical relevance in renal cell carcinoma.

    PubMed

    Jasinski-Bergner, Simon; Reches, Adi; Stoehr, Christine; Massa, Chiara; Gonschorek, Evamaria; Huettelmaier, Stefan; Braun, Juliane; Wach, Sven; Wullich, Bernd; Spath, Verena; Wang, Ena; Marincola, Francesco M; Mandelboim, Ofer; Hartmann, Arndt; Seliger, Barbara

    2016-05-01

    The non-classical human leukocyte antigen G (HLA-G) is expressed at a high frequency in renal cell carcinoma (RCC) and is associated with a higher tumor grade and a poor clinical outcome. This might be caused by the HLA-G-mediated inhibition of the cytotoxicity of T and NK cells. Therefore a selective targeting of HLA-G might represent a powerful strategy to enhance the immunogenicity of RCC lesions. Recent studies identified a number of HLA-G-regulating microRNAs (miRs) and demonstrated an inverse expression of some of these miRs with HLA-G in RCC in vitro and in vivo. However, it was postulated that further miRs might exist contributing to the tightly controlled selective HLA-G expression.By application of a miR enrichment assay (miTRAP) in combination with in silico profiling two novel HLA-G-regulatory miRs, miR-548q and miR-628-5p, were identified. Direct interactions of both miRs with the 3' untranslated region of HLA-G were confirmed with luciferase reporter gene assays. In addition, qPCR analyses and immunohistochemical staining revealed an inverse, expression of miR-628-5p, but not of miR-548q to the HLA-G protein in primary RCC lesions and cell lines. Stable overexpression of miR-548q and miR-628-5p caused a downregulation of HLA-G mRNA and protein. This leads in case of miR-548q to an enhanced NK cell-mediated HLA-G-dependent cytotoxicity, which could be reverted by ILT2 blockade suggesting a control of the immune effector cell activity at least by this miR. The identification of two novel HLA-G-regulatory miRs extends the number of HLA-G-relevant miRs tuning the HLA-G expression and might serve as future therapeutic targets.

  14. Squalene epoxidase is a bona fide oncogene by amplification with clinical relevance in breast cancer

    PubMed Central

    Brown, David N.; Caffa, Irene; Cirmena, Gabriella; Piras, Daniela; Garuti, Anna; Gallo, Maurizio; Alberti, Saverio; Nencioni, Alessio; Ballestrero, Alberto; Zoppoli, Gabriele

    2016-01-01

    SQLE encodes squalene epoxidase, a key enzyme in cholesterol synthesis. SQLE has sporadically been reported among copy-number driven transcripts in multi-omics cancer projects. Yet, its functional relevance has never been subjected to systematic analyses. Here, we assessed the correlation of SQLE copy number (CN) and gene expression (GE) across multiple cancer types, focusing on the clinico-pathological associations in breast cancer (BC). We then investigated whether any biological effect of SQLE inhibition could be observed in BC cell line models. Breast, ovarian, and colorectal cancers showed the highest CN driven GE among 8,783 cases from 22 cancer types, with BC presenting the strongest one. SQLE overexpression was more prevalent in aggressive BC, and was an independent prognostic factor of unfavorable outcome. Through SQLE pharmacological inhibition and silencing in a panel of BC cell lines portraying the diversity of SQLE CN and GE, we demonstrated that SQLE inhibition resulted in a copy-dosage correlated decrease in cell viability, and in a noticeable increase in replication time, only in lines with detectable SQLE transcript. Altogether, our results pinpoint SQLE as a bona fide metabolic oncogene by amplification, and as a therapeutic target in BC. These findings could have implications in other cancer types. PMID:26777065

  15. The anatomy of the sacrococcygeal cornual region and its clinical relevance.

    PubMed

    Woon, Jason T K; Stringer, Mark D

    2014-09-01

    There has been no systematic study of the anatomy of the region between the sacral and coccygeal cornua. Reference texts describe an intercornual ligament connecting these structures. The aim of this study was to investigate the anatomy of this region, which may be relevant to unexplained cases of coccygeal pain (coccydynia) and local nerve blocks. The bony anatomy of the sacrococcygeal (SC) cornual region was analyzed in 33 CT scans obtained from supine adults of mostly European origin with no known SC pathology, 7 μCT scans of cadaver SC specimens, and 105 Asian Indian adult skeletons. A further five cadaver SC specimens were examined histologically. SC cornual fusion was seen in 45% of CT/μCT scans (mean age 67 years, 20 males) and in 20% of adult skeletons (78 males); there was no association with age or sex. In the absence of SC fusion, the mean intersacrococcygeal cornual gap was 7.1 ± 2.4 mm; this was bridged by an intercornual ligament composed of parallel vertical collagen fibers reinforced by elastin fibers on its anterior surface. Small nerve branches were observed adjacent to the ventral aspect of the intercornual ligament and, in one case, traversing the ligament. Ipsilateral sacral and coccygeal cornua are therefore normally bridged by an intercornual ligament that is probably innervated. The cornua are fused on one or both sides in 20-45% of adults. These findings may have implications for some cases of coccydynia and for anesthetists performing local nerve blocks.

  16. Targeting and intracellular trafficking of clinically relevant hTHTR1 mutations in human cell lines.

    PubMed

    Subramanian, Veedamali S; Marchant, Jonathan S; Said, Hamid M

    2007-07-01

    The micronutrient thiamine is required for normal growth and development of human tissues, and is accumulated into cells through the activity of plasma membrane thiamine transporters, e.g. hTHTR1 (human thiamine transporter 1). Recent genetic evidence has linked mutations in hTHTR1 with the manifestation of TRMA (thiamine-responsive megaloblastic anaemia), a condition also associated with diabetes mellitus, sensorineural deafness and retinal disorders. To examine how mutations in hTHTR1 impair thiamine accumulation, we have investigated the targeting and functional properties of several different hTHTR1 mutants in human cell lines derived from epithelia relevant to thiamine absorption or tissues implicated in TRMA pathology. These constructs encompassed two newly identified point mutations (P51L and T158R) and two truncations of hTHTR1 identical with those found in TRMA kindreds (W358X and Delta383fs). Our results reveal a spectrum of mutant phenotypes, underlining that TRMA can result from decreased thiamine transport activity underpinned by changes in hTHTR1 expression levels, cellular targeting and/or protein transport activity.

  17. Valuing health for clinical and economic decisions: directions relevant for rheumatologists.

    PubMed

    Harrison, Mark J; Bansback, Nick J; Marra, Carlo A; Drummond, Michael; Tugwell, Peter S; Boonen, Annelies

    2011-08-01

    The quality-adjusted life-year (QALY) is a construct that integrates the value or preference for a health state over the period of time in that health state. The main use of QALY is in cost-utility analysis, to help make resource allocation decisions when faced with choices. Although the concept of the QALY is appealing, there is ongoing debate regarding their usefulness and approaches to deriving QALY. In 2008, OMERACT engaged in an effort to agree on QALY approaches that can be used in rheumatology. Based on a Web questionnaire and a subsequent meeting, rheumatologists questioned whether it was relevant for OMERACT (1) to investigate use of a QALY that represents the patients' perspective, (2) to explore the validity of the visual analog scale (VAS) to value health, and (3) to understand the validity of mapping health-specific instruments on existing preference instruments. This article discusses the pros and cons of these points in light of current insight from the point of view of health economics and decision-making theory. It also considers the further research agenda toward a QALY approach in rheumatology. PMID:21807800

  18. Cisplatin Resistant Spheroids Model Clinically Relevant Survival Mechanisms in Ovarian Tumors

    PubMed Central

    Miller, Daniel H.; Medina, Jamie E.; Hamilton, Joshua W.; Messerli, Mark A.; Brodsky, Alexander S.

    2016-01-01

    The majority of ovarian tumors eventually recur in a drug resistant form. Using cisplatin sensitive and resistant cell lines assembled into 3D spheroids we profiled gene expression and identified candidate mechanisms and biological pathways associated with cisplatin resistance. OVCAR-8 human ovarian carcinoma cells were exposed to sub-lethal concentrations of cisplatin to create a matched cisplatin-resistant cell line, OVCAR-8R. Genome-wide gene expression profiling of sensitive and resistant ovarian cancer spheroids identified 3,331 significantly differentially expressed probesets coding for 3,139 distinct protein-coding genes (Fc >2, FDR < 0.05) (S2 Table). Despite significant expression changes in some transporters including MDR1, cisplatin resistance was not associated with differences in intracellular cisplatin concentration. Cisplatin resistant cells were significantly enriched for a mesenchymal gene expression signature. OVCAR-8R resistance derived gene sets were significantly more biased to patients with shorter survival. From the most differentially expressed genes, we derived a 17-gene expression signature that identifies ovarian cancer patients with shorter overall survival in three independent datasets. We propose that the use of cisplatin resistant cell lines in 3D spheroid models is a viable approach to gain insight into resistance mechanisms relevant to ovarian tumors in patients. Our data support the emerging concept that ovarian cancers can acquire drug resistance through an epithelial-to-mesenchymal transition. PMID:26986722

  19. Preclinical Models Provide Scientific Justification and Translational Relevance for Moving Novel Therapeutics into Clinical Trials for Pediatric Cancer.

    PubMed

    Langenau, David M; Sweet-Cordero, Alejandro; Wechsler-Reya, Robert J; Dyer, Michael A

    2015-12-15

    Despite improvements in survival rates for children with cancer since the 1960s, progress for many pediatric malignancies has slowed over the past two decades. With the recent advances in our understanding of the genomic landscape of pediatric cancer, there is now enthusiasm for individualized cancer therapy based on genomic profiling of patients' tumors. However, several obstacles to effective personalized cancer therapy remain. For example, relatively little data from prospective clinical trials demonstrate the selective efficacy of molecular-targeted therapeutics based on somatic mutations in the patient's tumor. In this commentary, we discuss recent advances in preclinical testing for pediatric cancer and provide recommendations for providing scientific justification and translational relevance for novel therapeutic combinations for childhood cancer. Establishing rigorous criteria for defining and validating druggable mutations will be essential for the success of ongoing and future clinical genomic trials for pediatric malignancies.

  20. Detection of glycopeptide resistance genotypes and identification to the species level of clinically relevant enterococci by PCR.

    PubMed Central

    Dutka-Malen, S; Evers, S; Courvalin, P

    1995-01-01

    A PCR assay that allows simultaneous detection of glycopeptide resistance genotypes and identification to the species level of clinically relevant enterococci (Enterococcus faecium, E. faecalis, E. gallinarum, and E. casseliflavus) was developed. This assay was based on specific amplification of internal fragments of genes encoding D-alanine:D-alanine ligases and related glycopeptide resistance proteins. The specificity of the assay was tested on 5 well-characterized glycopeptide-resistant strains and on 15 susceptible enterococcal type strains. Clinical isolates of enterococci that could not be identified to the species level by conventional methods were identified by the PCR test. This assay offers a specific and rapid alternative to antibiotic susceptibility tests, in particular for detection of low-level vancomycin resistance. PMID:7699051

  1. Morphogenetic fields within the human dentition: a new, clinically relevant synthesis of an old concept.

    PubMed

    Townsend, Grant; Harris, Edward F; Lesot, Herve; Clauss, Francois; Brook, Alan

    2009-12-01

    This paper reviews the concept of morphogenetic fields within the dentition that was first proposed by Butler (Butler PM. Studies of the mammalian dentition. Differentiation of the post-canine dentition. Proc Zool Soc Lond B 1939;109:1-36), then adapted for the human dentition by Dahlberg (Dahlberg AA. The changing dentition of man. J Am Dent Assoc 1945;32:676-90; Dahlberg AA. The dentition of the American Indian. In: Laughlin WS, editor. The Physical Anthropology of the American Indian. New York: Viking Fund Inc.; 1951. p. 138-76). The clone theory of dental development, proposed by Osborn (Osborn JW. Morphogenetic gradients: fields versus clones. In: Butler PM, Joysey KA, editors Development, function and evolution of teeth. London: Academic Press, 1978. p. 171-201), is then considered before these two important concepts are interpreted in the light of recent findings from molecular, cellular, genetic and theoretical and anthropological investigation. Sharpe (Sharpe PT. Homeobox genes and orofacial development. Connect Tissue Res 1995;32:17-25) put forward the concept of an odontogenic homeobox code to explain how different tooth classes are initiated in different parts of the oral cavity in response to molecular cues and the expression of specific groups of homeobox genes. Recently, Mitsiadis and Smith (Mitsiadis TA, Smith MM. How do genes make teeth to order through development? J Exp Zool (Mol Dev Evol) 2006; 306B:177-82.) proposed that the field, clone and homeobox code models could all be incorporated into a single model to explain dental patterning. We agree that these three models should be viewed as complementary rather than contradictory and propose that this unifying view can be extended into the clinical setting using findings on dental patterning in individuals with missing and extra teeth. The proposals are compatible with the unifying aetiological model developed by Brook (Brook AH. A unifying aetiological explanation for anomalies of tooth number

  2. Morphogenetic fields within the human dentition: a new, clinically relevant synthesis of an old concept.

    PubMed

    Townsend, Grant; Harris, Edward F; Lesot, Herve; Clauss, Francois; Brook, Alan

    2009-12-01

    This paper reviews the concept of morphogenetic fields within the dentition that was first proposed by Butler (Butler PM. Studies of the mammalian dentition. Differentiation of the post-canine dentition. Proc Zool Soc Lond B 1939;109:1-36), then adapted for the human dentition by Dahlberg (Dahlberg AA. The changing dentition of man. J Am Dent Assoc 1945;32:676-90; Dahlberg AA. The dentition of the American Indian. In: Laughlin WS, editor. The Physical Anthropology of the American Indian. New York: Viking Fund Inc.; 1951. p. 138-76). The clone theory of dental development, proposed by Osborn (Osborn JW. Morphogenetic gradients: fields versus clones. In: Butler PM, Joysey KA, editors Development, function and evolution of teeth. London: Academic Press, 1978. p. 171-201), is then considered before these two important concepts are interpreted in the light of recent findings from molecular, cellular, genetic and theoretical and anthropological investigation. Sharpe (Sharpe PT. Homeobox genes and orofacial development. Connect Tissue Res 1995;32:17-25) put forward the concept of an odontogenic homeobox code to explain how different tooth classes are initiated in different parts of the oral cavity in response to molecular cues and the expression of specific groups of homeobox genes. Recently, Mitsiadis and Smith (Mitsiadis TA, Smith MM. How do genes make teeth to order through development? J Exp Zool (Mol Dev Evol) 2006; 306B:177-82.) proposed that the field, clone and homeobox code models could all be incorporated into a single model to explain dental patterning. We agree that these three models should be viewed as complementary rather than contradictory and propose that this unifying view can be extended into the clinical setting using findings on dental patterning in individuals with missing and extra teeth. The proposals are compatible with the unifying aetiological model developed by Brook (Brook AH. A unifying aetiological explanation for anomalies of tooth number

  3. Use of generalised additive models to categorise continuous variables in clinical prediction

    PubMed Central

    2013-01-01

    Background In medical practice many, essentially continuous, clinical parameters tend to be categorised by physicians for ease of decision-making. Indeed, categorisation is a common practice both in medical research and in the development of clinical prediction rules, particularly where the ensuing models are to be applied in daily clinical practice to support clinicians in the decision-making process. Since the number of categories into which a continuous predictor must be categorised depends partly on the relationship between the predictor and the outcome, the need for more than two categories must be borne in mind. Methods We propose a categorisation methodology for clinical-prediction models, using Generalised Additive Models (GAMs) with P-spline smoothers to determine the relationship between the continuous predictor and the outcome. The proposed method consists of creating at least one average-risk category along with high- and low-risk categories based on the GAM smooth function. We applied this methodology to a prospective cohort of patients with exacerbated chronic obstructive pulmonary disease. The predictors selected were respiratory rate and partial pressure of carbon dioxide in the blood (PCO2), and the response variable was poor evolution. An additive logistic regression model was used to show the relationship between the covariates and the dichotomous response variable. The proposed categorisation was compared to the continuous predictor as the best option, using the AIC and AUC evaluation parameters. The sample was divided into a derivation (60%) and validation (40%) samples. The first was used to obtain the cut points while the second was used to validate the proposed methodology. Results The three-category proposal for the respiratory rate was ≤ 20;(20,24];> 24, for which the following values were obtained: AIC=314.5 and AUC=0.638. The respective values for the continuous predictor were AIC=317.1 and AUC=0.634, with no statistically

  4. Multicentre study highlighting clinical relevance of new high-throughput methodologies in molecular epidemiology of Pneumocystis jirovecii pneumonia.

    PubMed

    Esteves, F; de Sousa, B; Calderón, E J; Huang, L; Badura, R; Maltez, F; Bassat, Q; de Armas, Y; Antunes, F; Matos, O

    2016-06-01

    Pneumocystis jirovecii causes severe interstitial pneumonia (PcP) in immunosuppressed patients. This multicentre study assessed the distribution frequencies of epidemiologically relevant genetic markers of P. jirovecii in different geographic populations from Portugal, the USA, Spain, Cuba and Mozambique, and the relationship between the molecular data and the geographical and clinical information, based on a multifactorial approach. The high-throughput typing strategy for P. jirovecii characterization consisted of DNA pooling using quantitative real-time PCR followed by multiplex-PCR/single base extension. The frequencies of relevant P. jirovecii single nucleotide polymorphisms (mt85, SOD110, SOD215, DHFR312, DHPS165 and DHPS171) encoded at four loci were estimated in ten DNA pooled samples representing a total of 182 individual samples. Putative multilocus genotypes of P. jirovecii were shown to be clustered due to geographic differences but were also dependent on clinical characteristics of the populations studied. The haplotype DHFR312T/SOD110C/SOD215T was associated with severe AIDS-related PcP and high P. jirovecii burdens. The frequencies of this genetic variant of P. jirovecii were significantly higher in patients with AIDS-related PcP from Portugal and the USA than in the colonized patients from Portugal, and Spain, and children infected with P. jirovecii from Cuba or Mozambique, highlighting the importance of this haplotype, apparently associated with the severity of the disease and specific clinical groups. Patients from the USA and Mozambique showed higher rates of DHPS mutants, which may suggest the circulation of P. jirovecii organisms potentially related with trimethoprim-sulfamethoxazole resistance in those geographical regions. This report assessed the worldwide distribution of P. jirovecii haplotypes and their epidemiological impact in distinct geographic and clinical populations.

  5. Correction of Hyperbilirubinemia in Gunn Rats Using Clinically Relevant Low Doses of Helper-Dependent Adenoviral Vectors

    PubMed Central

    Dimmock, David; Brunetti-Pierri, Nicola; Palmer, Donna J.; Beaudet, Arthur L.

    2011-01-01

    Abstract Crigler–Najjar syndrome type I is a severe inborn error of bilirubin metabolism caused by a complete deficiency of uridine diphospho-glucuronosyl transferase 1A1 (UGT1A1) and results in life-threatening unconjugated hyperbilirubinemia. Lifelong correction of hyperbilirubinemia by liver-directed gene therapy using a helper-dependent adenoviral (HDAd) vector has been previously reported in the Gunn rat, a model of Crigler–Najjar syndrome, but was only achieved using high doses (≥3 × 1012 viral particles [vp]/kg), which are likely to elicit a severe toxic response in humans. Therefore, in this study, we investigate strategies to achieve correction of hyperbilirubinemia in the Gunn rat using clinically relevant low HDAd doses. We have found that correction of hyperbilirubinemia in the Gunn rat can be achieved with a low dose of 5 × 1011 vp/kg by using an HDAd vector bearing a more potent UGT1A1 expression cassette. Furthermore, by using hydrodynamic injection of the improved HDAd vector, correction of hyperbilirubinemia in the Gunn rat can be achieved using an even lower dose of 5 × 1010 vp/kg. Although hydrodynamic injection as performed in rats is not acceptable in humans, clinically attractive, minimally invasive methods have been successfully developed to mimic hydrodynamic injection of HDAd vector in non-human primates. Therefore, using an improved expression cassette combined with a more efficient method of vector delivery permits correction of hyperbilirubinemia in the Gunn rat using clinically relevant low HDAd doses and may thus pave the way to clinical application of HDAd vectors for Crigler–Najjar syndrome gene therapy. PMID:20973621

  6. Multicentre study highlighting clinical relevance of new high-throughput methodologies in molecular epidemiology of Pneumocystis jirovecii pneumonia.

    PubMed

    Esteves, F; de Sousa, B; Calderón, E J; Huang, L; Badura, R; Maltez, F; Bassat, Q; de Armas, Y; Antunes, F; Matos, O

    2016-06-01

    Pneumocystis jirovecii causes severe interstitial pneumonia (PcP) in immunosuppressed patients. This multicentre study assessed the distribution frequencies of epidemiologically relevant genetic markers of P. jirovecii in different geographic populations from Portugal, the USA, Spain, Cuba and Mozambique, and the relationship between the molecular data and the geographical and clinical information, based on a multifactorial approach. The high-throughput typing strategy for P. jirovecii characterization consisted of DNA pooling using quantitative real-time PCR followed by multiplex-PCR/single base extension. The frequencies of relevant P. jirovecii single nucleotide polymorphisms (mt85, SOD110, SOD215, DHFR312, DHPS165 and DHPS171) encoded at four loci were estimated in ten DNA pooled samples representing a total of 182 individual samples. Putative multilocus genotypes of P. jirovecii were shown to be clustered due to geographic differences but were also dependent on clinical characteristics of the populations studied. The haplotype DHFR312T/SOD110C/SOD215T was associated with severe AIDS-related PcP and high P. jirovecii burdens. The frequencies of this genetic variant of P. jirovecii were significantly higher in patients with AIDS-related PcP from Portugal and the USA than in the colonized patients from Portugal, and Spain, and children infected with P. jirovecii from Cuba or Mozambique, highlighting the importance of this haplotype, apparently associated with the severity of the disease and specific clinical groups. Patients from the USA and Mozambique showed higher rates of DHPS mutants, which may suggest the circulation of P. jirovecii organisms potentially related with trimethoprim-sulfamethoxazole resistance in those geographical regions. This report assessed the worldwide distribution of P. jirovecii haplotypes and their epidemiological impact in distinct geographic and clinical populations. PMID:27021425

  7. Clinical relevance of circulating antibodies and B lymphocyte markers in allograft rejection.

    PubMed

    Vallin, Patrice; Désy, Olivier; Béland, Stéphanie; Wagner, Eric; De Serres, Sacha A

    2016-03-01

    The main challenge in solid organ transplantation remains to tackle antibody-mediated rejection. Our understanding of the antibody-mediated response and the capacity to detect it has improved in the last decade. However, the sensitivity and specificity of the current clinical tools to monitor B cell activation are perfectible. New strategies, including the refinement in the characterization of HLA and non-HLA antibodies, as well as a better understanding of the circulating B cell phenotype will hopefully help to non-invasively identify patients at risk or undergoing antibody-mediated allograft damage. The current review discusses the current knowledge of the B cell biomarkers in solid organ transplantation, with a focus on circulating antibodies and peripheral B cells. PMID:26721422

  8. Molecular Identification and Susceptibility of Clinically Relevant Scedosporium spp. in China

    PubMed Central

    Wang, Hong; Wan, Zhe; Li, Ruoyu; Lu, Qiaoyun; Yu, Jin

    2015-01-01

    As various new sibling species within the Scedosporium spp. have been described recently, this study was conducted to investigate distribution and antifungal susceptibility profiles of the different species of Scedosporium spp. in China. Twenty-one clinical strains of Scedosporium from China and two strains from Japan were reidentified by MLSA. The analysis included BT2, CAL, RPB, SOD, and ACT and the combination of the five loci. Pseudallescheria boydii complex (17 strains) and S. apiospermum (6 strains) were identified. P. boydii complex included four closely related subgroups: P. boydii (9 strains), P. ellipsoidea (6 strains), P. fusoidea (1 strain), and P. angusta (1 strain). There were no significant differences in MICs for neither VOR, POS, nor AMB over all the five species in study. For itraconazole, intraspecific diversity was evident. PMID:26550562

  9. The type I interferons: Basic concepts and clinical relevance in immune-mediated inflammatory diseases.

    PubMed

    López de Padilla, Consuelo M; Niewold, Timothy B

    2016-01-15

    There is increasing scientific and clinical interest in elucidating the biology of type I Interferons, which began approximately 60 years ago with the concept of "viral interference", a property that reduces the ability of a virus to infect cells. Although our understanding of the multiple cellular and molecular functions of interferons has advanced significantly, much remains to be learned and type I Interferons remain an active and fascinating area of inquiry. In this review, we cover some general aspects of type I interferon genes, with emphasis on interferon-alpha, and various aspects of molecular mechanisms triggered by type I interferons and toll-like receptor signaling by the Janus activated kinase/signal transducer activation of transcription (JAK-STAT) pathway and interferon regulatory factor pathway. We will also describe the role of type I interferons in autoimmune and inflammatory diseases, and its potential use as therapeutic agent.

  10. Molecular identification and susceptibility of clinically relevant Scedosporium spp. in China.

    PubMed

    Wang, Hong; Wan, Zhe; Li, Ruoyu; Lu, Qiaoyun; Yu, Jin

    2015-01-01

    As various new sibling species within the Scedosporium spp. have been described recently, this study was conducted to investigate distribution and antifungal susceptibility profiles of the different species of Scedosporium spp. in China. Twenty-one clinical strains of Scedosporium from China and two strains from Japan were reidentified by MLSA. The analysis included BT2, CAL, RPB, SOD, and ACT and the combination of the five loci. Pseudallescheria boydii complex (17 strains) and S. apiospermum (6 strains) were identified. P. boydii complex included four closely related subgroups: P. boydii (9 strains), P. ellipsoidea (6 strains), P. fusoidea (1 strain), and P. angusta (1 strain). There were no significant differences in MICs for neither VOR, POS, nor AMB over all the five species in study. For itraconazole, intraspecific diversity was evident. PMID:26550562

  11. Challenging present concepts in compression therapy: static stiffness index is not consistent and not clinically relevant.

    PubMed

    Kravitz, S; Hegarty-Craver, M; Reid, L

    2016-02-01

    Once a circumferential force is delivered to a limb by a compression device, assuming the tension within the device remains constant, any change in the total force is dependent upon a change in circumference of the limb, with the rate of change (excluding fabric creep) being dependent on the stress strain curve of the device. This article addresses the pre-conceived and well-accepted principle that interface compression delivered by a compression device substantially increases with the position of the limb, based on the positions of sitting (non-weight bearing) to standing and/or during muscle activity (ankle dorsiflexion). Using engineering parameters and clinical measurements, the authors demonstrate that changes in interface pressure are minimal if any, and that the current concept should be modified accordingly. Declaration of interest: This study was sponsored by Carolon. L. Reid, and S. Kravitz are employees of Carolon. M. Hegarty-Craver has received monetary compensation as a researcher for Carolon.

  12. A clinical report of Type III dens invaginatus: relevant aspects of a combined therapeutic approach.

    PubMed

    Silva E Souza, Patricia de Almeida Rodrigues; de Almeida, Bruno Vila Nova; Tartari, Talita; Alves, Ana Claudia Braga Amoras; Tuji, Farbicio Mesquita; Silva E Souza, Mario Honorato

    2013-01-01

    Dens invaginatus is a developmental abnormality that alters dental morphology; as a result, treating this condition is a challenge for endodontic practices. This article describes how a combination of nonsurgical and surgical therapies was utilized to treat a maxillary central incisor with Type III dens invaginatus and vital pulp. The treatment plan included using computed tomography (CT) for a detailed analysis of the dental anatomy and periapical area, endodontic and surgical procedures, and a 4-year follow-up period that included periodic clinical and radiographic examinations. The follow-up examinations revealed a regression of the apical lesion and no other signs or symptoms. Based on the present case report, the authors concluded that this combination of surgical and nonsurgical approaches was effective and that CT is a valuable auxiliary tool for the study of dental anatomy.

  13. Challenging present concepts in compression therapy: static stiffness index is not consistent and not clinically relevant.

    PubMed

    Kravitz, S; Hegarty-Craver, M; Reid, L

    2016-02-01

    Once a circumferential force is delivered to a limb by a compression device, assuming the tension within the device remains constant, any change in the total force is dependent upon a change in circumference of the limb, with the rate of change (excluding fabric creep) being dependent on the stress strain curve of the device. This article addresses the pre-conceived and well-accepted principle that interface compression delivered by a compression device substantially increases with the position of the limb, based on the positions of sitting (non-weight bearing) to standing and/or during muscle activity (ankle dorsiflexion). Using engineering parameters and clinical measurements, the authors demonstrate that changes in interface pressure are minimal if any, and that the current concept should be modified accordingly. Declaration of interest: This study was sponsored by Carolon. L. Reid, and S. Kravitz are employees of Carolon. M. Hegarty-Craver has received monetary compensation as a researcher for Carolon. PMID:26878373

  14. Novel Paths to Relevance: How Clinical Ethics Committees Promote Ethical Reflection.

    PubMed

    Magelssen, Morten; Pedersen, Reidar; Førde, Reidun

    2016-09-01

    How may clinical ethics committees (CECs) inspire ethical reflection among healthcare professionals? How may they deal with organizational ethics issues? In recent years, Norwegian CECs have attempted different activites that stretch or go beyond the standard trio of education, consultation, and policy work. We studied the novel activities of Norwegian CECs by examining annual reports and interviewing CEC members. Through qualitative analysis we identified nine categories of novel CEC activities, which we describe by way of examples. In light of the findings, we argue that some novel working methods may be well suited to promote ethical reflection among clinicians, and that the CEC may be a suitable venue for discussing issues of organizational ethics.

  15. A clinical report of Type III dens invaginatus: relevant aspects of a combined therapeutic approach.

    PubMed

    Silva E Souza, Patricia de Almeida Rodrigues; de Almeida, Bruno Vila Nova; Tartari, Talita; Alves, Ana Claudia Braga Amoras; Tuji, Farbicio Mesquita; Silva E Souza, Mario Honorato

    2013-01-01

    Dens invaginatus is a developmental abnormality that alters dental morphology; as a result, treating this condition is a challenge for endodontic practices. This article describes how a combination of nonsurgical and surgical therapies was utilized to treat a maxillary central incisor with Type III dens invaginatus and vital pulp. The treatment plan included using computed tomography (CT) for a detailed analysis of the dental anatomy and periapical area, endodontic and surgical procedures, and a 4-year follow-up period that included periodic clinical and radiographic examinations. The follow-up examinations revealed a regression of the apical lesion and no other signs or symptoms. Based on the present case report, the authors concluded that this combination of surgical and nonsurgical approaches was effective and that CT is a valuable auxiliary tool for the study of dental anatomy. PMID:23302365

  16. Clinical food hypersensitivity: the relevance of duodenal immunoglobulin E-positive cells.

    PubMed

    Caffarelli, C; Romanini, E; Caruana, P; Street, M E; de' Angelis, G

    1998-10-01

    Owing to poor reliability of laboratory tests, diagnosis of food allergy is based on clinical response to double-blind placebo-controlled food challenge. The aim of the present study was to assess the value of duodenal IgE-positive cells in the diagnosis of food allergy. Thirty-one children with a history of possible food allergy underwent duodenal biopsies, skin prick tests, and measurement of serum IgE antibodies, and were put on an elimination diet followed by food challenge. Open food challenges were performed in patients under 12 mo of age, and double-blind placebo-controlled challenges were for suspected foods. On the basis of clinical food hypersensitivity, patients were divided into two groups. Group 1 consisted of 13 children with food allergy. Thirteen of 20 positive provocations elicited reactions within 12 h from the end of the challenge, seven later. Group 2 was the control group and included 18 patients with negative food challenges. The number of IgE-positive cells in biopsy specimens was significantly more elevated in group 1 with respect to group 2 (153.24 +/- 83.13 versus 18.4 +/- 18.9; p < 0.01). Total serum IgE levels were elevated compared with that of the control group (p < 0.01) and correlated with the number of IgE-positive cells (p < 0.001, r = 0.62). Enhanced IgE-containing cells were found in all delayed reactors, but about one-third had negative skin prick tests or specific serum IgE antibodies to the offending foods. Our results showed that systemic reactions to foods are associated with an IgE-mediated response in the duodenal mucosa. Larger studies would be required to assess the predictive value of an increased number of IgE-positive cells in the diagnosis of allergy to food, especially in children with delayed reactions.

  17. Clinical relevance of voltage-gated potassium channel–complex antibodies in children

    PubMed Central

    Hacohen, Yael; Singh, Rahul; Rossi, Meghan; Lang, Bethan; Hemingway, Cheryl; Lim, Ming

    2015-01-01

    Objective: To assess the clinical and immunologic findings in children with voltage-gated potassium channel (VGKC)-complex antibodies (Abs). Methods: Thirty-nine of 363 sera, referred from 2 pediatric centers from 2007 to 2013, had been reported positive (>100 pM) for VGKC-complex Abs. Medical records were reviewed retrospectively and the patients' condition was independently classified as inflammatory (n = 159) or noninflammatory (n = 204). Positive sera (>100 pM) were tested/retested for the VGKC-complex Ab–positive complex proteins LGI1 and CASPR2, screened for binding to live hippocampal neurons, and 12 high-titer sera (>400 pM) tested by radioimmunoassay for binding to VGKC Kv1 subunits with or without intracellular postsynaptic density proteins. Results: VGKC-complex Abs were found in 39 children, including 20% of encephalopathies and 7.6% of other conditions (p = 0.001). Thirty children had inflammatory conditions and 9 had noninflammatory etiologies but titers >400 pM (n = 12) were found only in inflammatory diseases (p < 0.0001). Four sera, including from 2 children with coexisting NMDA receptor Abs and one with Guillain-Barré syndrome and Abs to both LGI1 and CASPR2, bound to hippocampal neurons. None of the sera bound detectably to VGKC Kv1 subunits on live HEK cells, but 4 of 12 >400 pM sera immunoprecipitated VGKC Kv1 subunits, with or without postsynaptic densities, extracted from transfected cells. Conclusion: Positive VGKC-complex Abs cannot be taken to indicate a specific clinical syndrome in children, but appear to be a nonspecific biomarker of inflammatory neurologic diseases, particularly of encephalopathy. Some of the Abs may bind to intracellular epitopes on the VGKC subunits, or to the intracellular interacting proteins, but in many the targets remain undefined. PMID:26296514

  18. Relationship of Premenstrual Syndrome and Premenstrual Dysphoric Disorder with Major Depression: Relevance to Clinical Practice

    PubMed Central

    Padhy, Susanta Kumar; Sarkar, Sidharth; Beherre, Prakash B.; Rathi, Rajesh; Panigrahi, Mahima; Patil, Pradeep Sriram

    2015-01-01

    Background: Premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD) and depressive disorder are fairly common; symptoms do overlap, often under-identified and under-emphasized, particularly in rural India. Objective: The objective was to assess the occurrence of PMS and PMDD in a sample of students and staff of a nursing college and to find their correlation with depression. Materials and Methods: A prospective cohort study; Tertiary Care Hospital in Rural India (Wardha, Maharashtra); 118 female nursing students or staff aged between 18 and 40 years, who were likely to stay within the institution for the study period. The participants were rated on Penn daily symptom report prospectively for a period of 3-month. Those who scored positive were applied diagnostic and statistical manual of mental disorders, 4th edition, text revision (DSM-IV TR) criteria for PMDD; and were applied primary care evaluation of mental disorders depression screening followed by DSM-IV TR criteria for depression. Severity of depression was measured using Hamilton Depression Rating Scale. Results: Main outcome measures were frequency and severity of depression in individuals with PMS and PMDD and their clinical and sociodemographic correlation. The age range of the sample was 18-37 years. Some PMS symptoms were observed in 67%; diagnosis of PMDD in 10%; depressive symptoms in 28% of the sample. 46.4% of those with depressive symptoms had major depression. The diagnosis of major depression was significantly associated with the severity of PMS symptoms as well as the presence of PMDD. Conclusion: Premenstrual syndrome is present in a substantial proportion of young females. Concurrent depression is increased by the severity of PMS symptoms and the presence of PMDD. Gynecologist needs to screen such subjects for depression and refer to mental-health professional early, in routine clinical practice. PMID:25969600

  19. Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing

    PubMed Central

    Jiang, Yong-hui; Yuen, Ryan K.C.; Jin, Xin; Wang, Mingbang; Chen, Nong; Wu, Xueli; Ju, Jia; Mei, Junpu; Shi, Yujian; He, Mingze; Wang, Guangbiao; Liang, Jieqin; Wang, Zhe; Cao, Dandan; Carter, Melissa T.; Chrysler, Christina; Drmic, Irene E.; Howe, Jennifer L.; Lau, Lynette; Marshall, Christian R.; Merico, Daniele; Nalpathamkalam, Thomas; Thiruvahindrapuram, Bhooma; Thompson, Ann; Uddin, Mohammed; Walker, Susan; Luo, Jun; Anagnostou, Evdokia; Zwaigenbaum, Lonnie; Ring, Robert H.; Wang, Jian; Lajonchere, Clara; Wang, Jun; Shih, Andy; Szatmari, Peter; Yang, Huanming; Dawson, Geraldine; Li, Yingrui; Scherer, Stephen W.

    2013-01-01

    Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms. PMID:23849776

  20. Clinical relevance of CHEK2 and NBN mutations in the macedonian population

    PubMed Central

    Kostovska, I Maleva; Jakimovska, M; Kubelka-Sabit, K; Karadjozov, M; Arsovski, A; Stojanovska, L; Plaseska-Karanfilska, D

    2015-01-01

    Clinical importance of the most common CHEK2 (IVS2+1 G>A, 1100delC, I157T and del5395) and NBN (R215W and 657del5) gene mutations for breast cancer development in Macedonian breast cancer patients is unknown. We performed a case-control study including 300 Macedonian breast cancer patients and 283 Macedonian healthy controls. Genotyping was done using a fast and highly accurate single-nucleotide primer extension method for the detection of five mutations in a single reaction. The detection of the del5395 was performed using an allele-specific duplex polymerase chain reaction (PCR) assay. We have found that mutations were more frequent in breast cancer patients (n = 13, 4.3%) than in controls (n = 5, 1.8%), although without statistical significance. Twelve patients were heterozygous for one of the analyzed mutations, while one patient had two mutations (NBN R215W and CHEK2 I157T). The most frequent variant was I157T, found in 10 patients and four controls (p = 0.176) and was found to be associated with familial breast cancer (p = 0.041). CHEK2 1100delC and NBN 657del5 were each found in one patient and not in the control group. CHEK2 IVS2+1G>A and del5395 were not found in our cohort. Frequencies of the studied mutations are low and they are not likely to represent alleles of clinical importance in the Macedonian population. PMID:26929905

  1. Clinical Relevance of Trace Bands on Serum Electrophoresis in Patients Without a History of Gammopathy

    PubMed Central

    Gwathmey, TanYa M.; Willis, Monte S.; Tatreau, Jason; Wang, Shaobin; McCudden, Christopher R.

    2015-01-01

    Serum protein electrophoresis (SPE) and immunofixation is commonly used to screen for plasma cell dyscrasias. Interpretation of these tests is qualitative by nature and can yield trace, faint, or scarcely visible immunoglobulin bands (TFS), which can be difficult to classify. Whether these bands should be reported at all is challenging given their unknown clinical significance. In the present study, we retrospectively analyzed 14,036 physician-ordered protein SPE and immunofixation electrophoresis (IFE) tests on serum and urine specimens (from 4,091 patients) during the period of 2000-2010. We found that 17% of all IFE results evaluated for the presence of monoclonal gammopathies (2,389 out of 14,036) contained TFS bands, representing 4.2% (173 out of 4091) of all patients evaluated. Sixty of these patients (42%) had no previous history of gammopathy, and were clinically evaluated over a mean period of up to five years from the original diagnosis of plasma cell pathology. None of these patients had progressed to multiple myeloma, lymphoplasmacytic lymphoma, plasmacytoma, or leukemia. The remaining 82 patients (58%) had a previous history of gammopathy, but had not progressed to any symptomatic plasma cell dyscrasia. Evaluation of these patients was followed for a median period of 4.3 years, with a mean of 21.5 IFE tests per individual. These data suggest that for patients without a previous history of gammopathy, the presence of TFS bands on serum protein electrophoresis does not warrant frequent follow up investigation as commonly practiced. Routine follow up of patients with a prior history of gammopathy, conversely, are warranted and may contribute to overall survival with multiple treatment options now available. For those interpreting IFE results, it may be worth considering these data when composing comments regarding suggested repeat testing frequency by SPE/IFE or alternate test methods.

  2. Assessment of elasticity of colorectal cancer tissue, clinical utility, pathological and phenotypical relevance

    PubMed Central

    Kawano, Shingo; Kojima, Motohiro; Higuchi, Yoichi; Sugimoto, Motokazu; Ikeda, Koji; Sakuyama, Naoki; Takahashi, Shinichiro; Hayashi, Ryuichi; Ochiai, Atsushi; Saito, Norio

    2015-01-01

    Generally, cancer tissue is palpated as a hard mass. However, the elastic nature of cancer tissue is not well understood. The aim of the present study was to evaluate the clinical utility of measuring the elastic modulus (EM) in colorectal cancer tissue. Using a tactile sensor, we measured the EM of 106 surgically resected colorectal cancer tissues. Data on the EM were compared with clinicopathological findings, including stromal features represented by Azan staining and the α-SMA positive area ratio of the tumor area. Finally, a cDNA microarray profile of the tumors with high EM were compared with the findings of tumors with low EM. A higher EM in tumors was associated with pathological T, N, and M-stage tumors (P < 0.001, P = 0.001 and P = 0.011, respectively). Patients with high EM tumors had shorter disease-free survival than had patients with low EM. The EM showed strongly positive correlation with the Azan staining positive area ratio (r = 0.908) and the α-SMA positive area ratio (r = 0.921). Finally, the cDNA microarray data of the tumors with high EM revealed a distinct gene expression profile compared with data from those tumors with low EM. The assessment of the elasticity of colorectal cancer tissue may allow a more accurate clinical stage and prognosis estimation. The distinct phenotypical features of the high EM tumors and their strong association with stromal features suggest the existence of a biological mechanism involved in this phenomenon that may contribute to future therapy. PMID:26083008

  3. Clinical Relevance of the Tumor Location-Modified Lauren Classification System of Gastric Cancer

    PubMed Central

    Choi, Jang Kyu; Park, Young Suk; Jung, Do Hyun; Son, Sang Yong; Ahn, Sang Hoon; Kim, Hyung Ho

    2015-01-01

    Purpose The Lauren classification system is a very commonly used pathological classification system of gastric adenocarcinoma. A recent study proposed that the Lauren classification should be modified to include the anatomical location of the tumor. The resulting three types were found to differ significantly in terms of genomic expression profiles. This retrospective cohort study aimed to evaluate the clinical significance of the modified Lauren classification (MLC). Materials and Methods A total of 677 consecutive patients who underwent curative gastrectomy from January 2005 to December 2007 for histologically confirmed gastric cancer were included. The patients were divided according to the MLC into proximal non-diffuse (PND), diffuse (D), and distal non-diffuse (DND) type. The groups were compared in terms of clinical features and overall survival. Multivariate analysis served to assess the association between MLC and prognosis. Results Of the 677 patients, 48, 358, and 271 had PND, D, and DND, respectively. Their 5-year overall survival rates were 77.1%, 77.7%, and 90.4%. Compared to D and PND, DND was associated with significantly better overall survival (both P<0.01). Multivariate analysis showed that age, differentiation, lympho-vascular invasion, T and N stage, but not MLC, were independent prognostic factors for overall survival. Multivariate analysis of early gastric cancer patients showed that MLC was an independent prognostic factor for overall survival (odds ratio, 5.946; 95% confidence intervals, 1.524~23.197; P=0.010). Conclusions MLC is prognostic for survival in patients with gastric adenocarcinoma, in early gastric cancer. DND was associated with an improved prognosis compared to PND or D. PMID:26468416

  4. Epigenetic regulation of EFEMP1 in prostate cancer: biological relevance and clinical potential

    PubMed Central

    Almeida, Mafalda; Costa, Vera L; Costa, Natália R; Ramalho-Carvalho, João; Baptista, Tiago; Ribeiro, Franclim R; Paulo, Paula; Teixeira, Manuel R; Oliveira, Jorge; Lothe, Ragnhild A; Lind, Guro E; Henrique, Rui; Jerónimo, Carmen

    2014-01-01

    Epigenetic alterations are common in prostate cancer (PCa) and seem to contribute decisively to its initiation and progression. Moreover, aberrant promoter methylation is a promising biomarker for non-invasive screening. Herein, we sought to characterize EFEMP1 as biomarker for PCa, unveiling its biological relevance in prostate carcinogenesis. Microarray analyses of treated PCa cell lines and primary tissues enabled the selection of differentially methylated genes, among which EFEMP1 was further validated by MSP and bisulfite sequencing. Assessment of biomarker performance was accomplished by qMSP. Expression analysis of EFEMP1 and characterization of histone marks were performed in tissue samples and cancer cell lines to determine the impact of epigenetic mechanisms on EFEMP1 transcriptional regulation. Phenotypic assays, using transfected cell lines, permitted the evaluation of EFEMP1’s role in PCa development. EFEMP1 methylation assay discriminated PCa from normal prostate tissue (NPT; P < 0.001, Kruskall–Wallis test) and renal and bladder cancers (96% sensitivity and 98% specificity). EFEMP1 transcription levels inversely correlated with promoter methylation and histone deacetylation, suggesting that both epigenetic mechanisms are involved in gene regulation. Phenotypic assays showed that EFEMP1 de novo expression reduces malignant phenotype of PCa cells. EFEMP1 promoter methylation is prevalent in PCa and accurately discriminates PCa from non-cancerous prostate tissues and other urological neoplasms. This epigenetic alteration occurs early in prostate carcinogenesis and, in association with histone deacetylation, progressively leads to gene down-regulation, fostering cell proliferation, invasion and evasion of apoptosis. PMID:25211630

  5. Diagnostic and clinical relevance of the autophago-lysosomal network in human gliomas

    PubMed Central

    Jennewein, Lukas; Ronellenfitsch, Michael W.; Antonietti, Patrick; Ilina, Elena I.; Jung, Jennifer; Stadel, Daniela; Flohr, Lisa-Marie; Zinke, Jenny; von Renesse, Janusz; Drott, Ulrich; Baumgarten, Peter; Braczynski, Anne K.; Penski, Cornelia; Burger, Michael C.; Theurillat, Jean-Philippe; Steinbach, Joachim P.; Plate, Karl-Heinz; Dikic, Ivan; Fulda, Simone; Brandts, Christian; Kögel, Donat; Behrends, Christian; Harter, Patrick N.; Mittelbronn, Michel

    2016-01-01

    Recently, the conserved intracellular digestion mechanism ‘autophagy’ has been considered to be involved in early tumorigenesis and its blockade proposed as an alternative treatment approach. However, there is an ongoing debate about whether blocking autophagy has positive or negative effects in tumor cells. Since there is only poor data about the clinico-pathological relevance of autophagy in gliomas in vivo, we first established a cell culture based platform for the in vivo detection of the autophago-lysosomal components. We then investigated key autophagosomal (LC3B, p62, BAG3, Beclin1) and lysosomal (CTSB, LAMP2) molecules in 350 gliomas using immunohistochemistry, immunofluorescence, immunoblotting and qPCR. Autophagy was induced pharmacologically or by altering oxygen and nutrient levels. Our results show that autophagy is enhanced in astrocytomas as compared to normal CNS tissue, but largely independent from the WHO grade and patient survival. A strong upregulation of LC3B, p62, LAMP2 and CTSB was detected in perinecrotic areas in glioblastomas suggesting micro-environmental changes as a driver of autophagy induction in gliomas. Furthermore, glucose restriction induced autophagy in a concentration-dependent manner while hypoxia or amino acid starvation had considerably lesser effects. Apoptosis and autophagy were separately induced in glioma cells both in vitro and in vivo. In conclusion, our findings indicate that autophagy in gliomas is rather driven by micro-environmental changes than by primary glioma-intrinsic features thus challenging the concept of exploitation of the autophago-lysosomal network (ALN) as a treatment approach in gliomas. PMID:26956048

  6. [Clinical relevance of unloading in cartilage therapy of the knee--shoe insoles, knee braces or additional operative procedure?].

    PubMed

    Kraus, T M; Imhoff, A B; Ateschrang, A; Stöckle, U; Schröter, S

    2015-02-01

    Restoration of a neutral biomechanical environment and reduction of overload is an important factor contributing to the success of any cartilage repair procedure. Reduction of overload can by achieved by so called unloading procedures in order to reduce intraarticular pressure from the repair zone. Unloading can be achieved via loss of weight, wedged shoe insoles, knee braces or via operations such as osteotomies around the knee joint. The cartilage therapy and the concomitant unloading procedure should be adapted to the individual pathology and realistic aims of the patient. Wedged insoles and braces are the least invasive treatment methods. In comparison, however, beneficial effects of braces outline those of laterally wedged heels. Nevertheless long-term compliance with insoles and braces is poor. Concerning braces either because the positive effects of the braces are too small or because the adverse effects are too large. Unloading in the long run may only be achieved through operative procedures. When an osteotomy seems to be too invasive the arthroscopic release of the posterior oblique ligament might be an option. Patients with an intact contralateral chondral status, medium to slight malalignment who want to remain at high activity levels, remain good candidates for unloading osteotomies.

  7. Understanding the Supersensitive Anti-Drug Antibody Assay: Unexpected High Anti-Drug Antibody Incidence and Its Clinical Relevance

    PubMed Central

    2016-01-01

    Numbers of biotherapeutic products in development have increased over past decade. Despite providing significant benefits to patients with unmet needs, almost all protein-based biotherapeutics could induce unwanted immunogenicity, which result in a loss of efficacy and/or increase the risk of adverse reactions, such as infusion reactions, anaphylaxis, and even life-threatening response to endogenous proteins. Recognizing these possibilities, regulatory agencies request that immunogenicity be assessed as part of the approval process for biotherapeutics. Great efforts have been made to reduce drug immunogenicity through protein engineering. Accordingly the immunogenicity incidence has been reduced from around 80% in murine derived products to 0–10% in fully human products. However, recent improvements in immunogenicity assays have led to unexpectedly high immunogenicity rates, even in fully human products, leading to new challenges in assessing immunogenicity and its clinical relevance. These new immunogenicity assays are becoming supersensitive and able to detect more of anti-drug antibodies (ADA) than with earlier assays. This paper intends to review and discuss our understanding of the supersensitive ADA assay and the unexpected high ADA incidence and its potential clinical relevance. PMID:27340678

  8. Clinically-Relevant Cutaneous Lesions by Nitrogen Mustard: Useful Biomarkers of Vesicants Skin Injury in SKH-1 Hairless and C57BL/6 Mice

    PubMed Central

    Tewari-Singh, Neera; Jain, Anil K.; Inturi, Swetha; White, Carl W.; Agarwal, Rajesh

    2013-01-01

    A paucity of clinically applicable biomarkers to screen therapies in laboratory is a limitation in the development of countermeasures against cutaneous injuries by chemical weapon, sulfur mustard (SM), and its analog nitrogen mustard (NM). Consequently, we assessed NM-caused progression of clinical cutaneous lesions; notably, skin injury with NM is comparable to SM. Exposure of SKH-1 hairless and C57BL/6 (haired) mice to NM (3.2 mg) for 12–120 h caused clinical sequelae of toxicity, including microblister formation, edema, erythema, altered pigmentation, wounding, xerosis and scaly dry skin. These toxic effects of NM were similar in both mouse strains, except that wounding and altered pigmentation at 12–24 h and appearance of dry skin at 24 and 72 h post-NM exposure were more pronounced in C57BL/6 compared to SKH-1 mice. Conversely, edema, erythema and microblister formation were more prominent in SKH-1 than C57BL/6 mice at 24–72 h after NM exposure. In addition, 40–60% mortality was observed following 120 h of NM exposure in the both mouse strains. Overall, these toxic effects of NM are comparable to those reported in humans and other animal species with SM, and thus represent clinically-relevant cutaneous injury endpoints in screening and optimization of therapies for skin injuries by vesicating agents. PMID:23826320

  9. Clinical relevance of aberrant polypoid nodule scar after endoscopic submucosal dissection

    PubMed Central

    Arantes, Vitor; Uedo, Noriya; Pedrosa, Moises Salgado; Tomita, Yasuhiko

    2016-01-01

    AIM To describe a series of patients with aberrant polypoid nodule scar developed after gastric endoscopic submucosal dissection (ESD), and to discuss its pathogenesis and clinical management. METHODS We reviewed retrospectively the endoscopic database of two academic institutions located in Brazil and Japan and searched for all patients that underwent ESD to manage gastric neoplasms from 2003 to 2015. The criteria for admission in the study were: (1) successful en bloc ESD procedure with R0 and curative resection confirmed histologically; (2) postoperative endoscopic examination with identification of a polypoid nodule scar (PNS) at ESD scar; (3) biopsies of the PNS with hyperplastic or regenerative tissue, reviewed by two independent experienced gastrointestinal pathologists, one from each Institution. Data were examined for patient demographics, Helicobacter pylori status, precise neoplastic lesion location in the stomach, tumor size, histopathological assessment of the ESD specimen, and postoperative information including medical management, endoscopic and histological findings, and clinical outcome. RESULTS A total of 14 patients (10 men/4 women) fulfilled the inclusion criteria and were enrolled in this study. One center contributed with 8 cases out of 60 patients (13.3%) from 2008 to 2015. The second center contributed with 6 cases (1.7%) out of 343 patients from 2003 to 2015. Postoperative endoscopic follow-up revealed similar findings in all patients: A protruded polypoid appearing nodule situated in the center of the ESD scar surrounded by convergence of folds. Biopsies samples were taken from PNS, and histological assessment revealed in all cases regenerative and hyperplastic tissue, without recurrent tumor or dysplasia. Primary neoplastic lesions were located in the antrum in 13 patients and in the angle in one patient. PNS did not develop in any patient after ESD undertaken for tumors located in the corpus, fundus or cardia. All patients have been

  10. Clinical relevance of aberrant polypoid nodule scar after endoscopic submucosal dissection

    PubMed Central

    Arantes, Vitor; Uedo, Noriya; Pedrosa, Moises Salgado; Tomita, Yasuhiko

    2016-01-01

    AIM To describe a series of patients with aberrant polypoid nodule scar developed after gastric endoscopic submucosal dissection (ESD), and to discuss its pathogenesis and clinical management. METHODS We reviewed retrospectively the endoscopic database of two academic institutions located in Brazil and Japan and searched for all patients that underwent ESD to manage gastric neoplasms from 2003 to 2015. The criteria for admission in the study were: (1) successful en bloc ESD procedure with R0 and curative resection confirmed histologically; (2) postoperative endoscopic examination with identification of a polypoid nodule scar (PNS) at ESD scar; (3) biopsies of the PNS with hyperplastic or regenerative tissue, reviewed by two independent experienced gastrointestinal pathologists, one from each Institution. Data were examined for patient demographics, Helicobacter pylori status, precise neoplastic lesion location in the stomach, tumor size, histopathological assessment of the ESD specimen, and postoperative information including medical management, endoscopic and histological findings, and clinical outcome. RESULTS A total of 14 patients (10 men/4 women) fulfilled the inclusion criteria and were enrolled in this study. One center contributed with 8 cases out of 60 patients (13.3%) from 2008 to 2015. The second center contributed with 6 cases (1.7%) out of 343 patients from 2003 to 2015. Postoperative endoscopic follow-up revealed similar findings in all patients: A protruded polypoid appearing nodule situated in the center of the ESD scar surrounded by convergence of folds. Biopsies samples were taken from PNS, and histological assessment revealed in all cases regenerative and hyperplastic tissue, without recurrent tumor or dysplasia. Primary neoplastic lesions were located in the antrum in 13 patients and in the angle in one patient. PNS did not develop in any patient after ESD undertaken for tumors located in the corpus, fundus or cardia. All patients have been

  11. The Power of Phase I Studies to Detect Clinical Relevant QTc Prolongation: A Resampling Simulation Study

    PubMed Central

    Ferber, Georg; Lorch, Ulrike; Täubel, Jörg

    2015-01-01

    Concentration-effect (CE) models applied to early clinical QT data from healthy subjects are described in the latest E14 Q&A document as promising analysis to characterise QTc prolongation. The challenges faced if one attempts to replace a TQT study by thorough ECG assessments in Phase I based on CE models are the assurance to obtain sufficient power and the establishment of a substitute for the positive control to show assay sensitivity providing protection against false negatives. To demonstrate that CE models in small studies can reliably predict the absence of an effect on QTc, we investigated the role of some key design features in the power of the analysis. Specifically, the form of the CE model, inclusion of subjects on placebo, and sparse sampling on the performance and power of this analysis were investigated. In this study, the simulations conducted by subsampling subjects from 3 different TQT studies showed that CE model with a treatment effect can be used to exclude small QTc effects. The number of placebo subjects was also shown to increase the power to detect an inactive drug preventing false positives while an effect can be underestimated if time points around tmax are missed. PMID:26509147

  12. The evolution and clinical relevance of prognostic classification systems in myelofibrosis.

    PubMed

    Bose, Prithviraj; Verstovsek, Srdan

    2016-03-01

    Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by often debilitating constitutional symptoms and splenomegaly, bone marrow fibrosis and resultant cytopenias, extramedullary hematopoiesis, risk of leukemic transformation, and shortened survival. Post-polycythemia vera and post-essential thrombocythemia myelofibrosis represent similar entities, although some differences are being recognized. Attempts to classify patients with myelofibrosis into prognostic categories have been made since the late 1980s, and these scoring systems continue to evolve as new information becomes available. Over the last decade, the molecular pathogenesis of MPNs has been elucidated considerably, and the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is the first drug specifically approved by the US Food and Drug Administration to treat patients with intermediate-risk and high-risk myelofibrosis. This article reviews the evolution of prognostic criteria in myelofibrosis, emphasizing the major systems widely in use today, as well as recently described, novel systems that incorporate emerging data regarding somatic mutations. Risk factors for thrombosis and conversion to MPN blast phase also are discussed. Finally, the practical usefulness of the current prognostic classification systems in terms of clinical decision making is discussed, particularly within the context of some of their inherent weaknesses. Cancer 2016;122:681-692. © 2015 American Cancer Society. PMID:26717494

  13. Molecular Probes for Diagnosis of Clinically Relevant Bacterial Infections in Blood Cultures▿

    PubMed Central

    Hansen, Wendy L. J.; Beuving, Judith; Bruggeman, Cathrien A.; Wolffs, Petra F. G.

    2010-01-01

    Broad-range real-time PCR and sequencing of the 16S rRNA gene region is a widely known method for the detection and identification of bacteria in clinical samples. However, because of the need for sequencing, such identification of bacteria is time-consuming. The aim of our study was to develop a more rapid 16S real-time PCR-based identification assay using species- or genus-specific probes. The Gram-negative bacteria were divided into Pseudomonas species, Pseudomonas aeruginosa, Escherichia coli, and other Gram-negative species. Within the Gram-positive species, probes were designed for Staphylococcus species, Staphylococcus aureus, Enterococcus species, Streptococcus species, and Streptococcus pneumoniae. The assay also included a universal probe within the 16S rRNA gene region for the detection of all bacterial DNA. The assay was evaluated with a collection of 248 blood cultures. In this study, the universal probe and the probes targeting Pseudomonas spp., P. aeruginosa, E. coli, Streptococcus spp., S. pneumoniae, Enterococcus spp., and Staphylococcus spp. all had a sensitivity and specificity of 100%. The probe specific for S. aureus showed eight discrepancies, resulting in a sensitivity of 100% and a specificity of 93%. These data showed high agreement between conventional testing and our novel real-time PCR assay. Furthermore, this assay significantly reduced the time needed for identification. In conclusion, using pathogen-specific probes offers a faster alternative for pathogen detection and could improve the diagnosis of bloodstream infections. PMID:20962139

  14. Soluble Epidermal Growth Factor Receptors (sEGFRs) in Cancer: Biological Aspects and Clinical Relevance

    PubMed Central

    Maramotti, Sally; Paci, Massimiliano; Manzotti, Gloria; Rapicetta, Cristian; Gugnoni, Mila; Galeone, Carla; Cesario, Alfredo; Lococo, Filippo

    2016-01-01

    The identification of molecules that can reliably detect the presence of a tumor or predict its behavior is one of the biggest challenges of research in cancer biology. Biological fluids are intriguing mediums, containing many molecules that express the individual health status and, accordingly, may be useful in establishing the potential risk of cancer, defining differential diagnosis and prognosis, predicting the response to treatment, and monitoring the disease progression. The existence of circulating soluble growth factor receptors (sGFRs) deriving from their membrane counterparts has stimulated the interest of researchers to investigate the use of such molecules as potential cancer biomarkers. But what are the origins of circulating sGFRs? Are they naturally occurring molecules or tumor-derived products? Among these, the epidermal growth factor receptor (EGFR) is a cell-surface molecule significantly involved in cancer development and progression; it can be processed into biological active soluble isoforms (sEGFR). We have carried out an extensive review of the currently available literature on the sEGFRs and their mechanisms of regulation and biological function, with the intent to clarify the role of these molecules in cancer (and other pathological conditions) and, on the basis of the retrieved evidences, speculate about their potential use in the clinical setting. PMID:27104520

  15. Selection of diverse and clinically relevant integrase inhibitor-resistant human immunodeficiency virus type 1 mutants.

    PubMed

    Kobayashi, Masanori; Nakahara, Koichiro; Seki, Takahiro; Miki, Shigeru; Kawauchi, Shinobu; Suyama, Akemi; Wakasa-Morimoto, Chiaki; Kodama, Makoto; Endoh, Takeshi; Oosugi, Eiichi; Matsushita, Yoshihiro; Murai, Hitoshi; Fujishita, Toshio; Yoshinaga, Tomokazu; Garvey, Edward; Foster, Scott; Underwood, Mark; Johns, Brian; Sato, Akihiko; Fujiwara, Tamio

    2008-11-01

    Resistance passage studies were conducted with five INIs (integrase inhibitors) that have been tested in clinical trials to date: a new naphthyridinone-type INI S/GSK-364735, raltegravir, elvitegravir, L-870,810 and S-1360. In establishing the passage system and starting from concentrations several fold above the EC(50) value, resistance mutations against S-1360 and related diketoacid-type compounds could be isolated from infected MT-2 cell cultures from day 14 to 28. Q148R and F121Y were the two main pathways of resistance to S/GSK-364735. Q148R/K and N155H, which were found in patients failing raltegravir treatment in Phase IIb studies, were observed during passage with raltegravir with this method. The fold resistance of 40 mutant molecular clones versus wild type virus was compared with these five INIs. The overall resistance pattern of S/GSK-364735 was similar to that of raltegravir and other INIs. However, different fold resistances of particular mutations were noted among different INIs, reflecting a potential to develop INIs with distinctly different resistant profiles.

  16. Protective actions of administered mesenchymal stem cells in acute kidney injury: relevance to clinical trials.

    PubMed

    Westenfelder, Christof; Togel, Florian E

    2011-09-01

    Current therapies for acute kidney injury remain primarily supportive and have failed to reduce morbidity, mortality (>50%), and associated costs. This prompted our studies in which rats with bilateral ischemia/reperfusion-induced acute kidney injury were treated with bone marrow-derived, culture-expanded allogeneic mesenchymal stem cells. Their administration into the suprarenal aorta after reflow significantly protected renal function and hastened repair, mediated by complex antiapoptotic, mitogenic, anti-inflammatory, and immune modulating actions that were not elicited by isogeneic fibroblasts. Infused mesenchymal stem cells, recruited to renal sites of injury, did not significantly differentiate into target cells but rather disappeared from kidneys and other organs within 72 h. Furthermore, at 3 months, compared with vehicle-treated controls, renal function was well preserved and interstitial fibrosis was absent. These preclinical data served as the scientific basis for a recently completed Phase I Clinical Trial (http://www.clinicaltrials.gov; # NCT00733876), in which patients at high risk for cardiac surgery-associated AKI were treated with allogeneic mesenchymal stem cells. Until now, MSC therapy in the study subjects has been safe, and none of the patients has developed postoperative AKI or subsequent loss of renal function, suggesting that this novel form of therapy may have promise in this group of high-risk patients, which will be further investigated in a Phase II Trial.

  17. [Digital breast tomosynthesis : technical principles, current clinical relevance and future perspectives].

    PubMed

    Hellerhoff, K

    2010-11-01

    In recent years digital full field mammography has increasingly replaced conventional film mammography. High quality imaging is guaranteed by high quantum efficiency and very good contrast resolution with optimized dosing even for women with dense glandular tissue. However, digital mammography remains a projection procedure by which overlapping tissue limits the detectability of subtle alterations. Tomosynthesis is a procedure developed from digital mammography for slice examination of breasts which eliminates the effects of overlapping tissue and allows 3D imaging of breasts. A curved movement of the X-ray tube during scanning allows the acquisition of many 2D images from different angles. Subseqently, reconstruction algorithms employing a shift and add method improve the recognition of details at a defined level and at the same time eliminate smear artefacts due to overlapping structures. The total dose corresponds to that of conventional mammography imaging. The technical procedure, including the number of levels, suitable anodes/filter combinations, angle regions of images and selection of reconstruction algorithms, is presently undergoing optimization. Previous studies on the clinical value of tomosynthesis have examined screening parameters, such as recall rate and detection rate as well as information on tumor extent for histologically proven breast tumors. More advanced techniques, such as contrast medium-enhanced tomosynthesis, are presently under development and dual-energy imaging is of particular importance.

  18. Resistance to antibiotics of clinical relevance in the fecal microbiota of Mexican wildlife.

    PubMed

    Cristóbal-Azkarate, Jurgi; Dunn, Jacob C; Day, Jennifer M W; Amábile-Cuevas, Carlos F

    2014-01-01

    There are a growing number of reports of antibiotic resistance (ATBR) in bacteria living in wildlife. This is a cause for concern as ATBR in wildlife represents a potential public health threat. However, little is known about the factors that might determine the presence, abundance and dispersion of ATBR bacteria in wildlife. Here, we used culture and molecular methods to assess ATBR in bacteria in fecal samples from howler monkeys (Alouatta palliata), spider monkeys (Ateles geoffroyi), tapirs (Tapirus bairdii) and felids (jaguars, Panthera onca; pumas, Puma concolor; jaguarundis, Puma yagouaroundi; and ocelots, Leopardus pardalis) living freely in two regions of the Mexican state of Veracruz under different degrees of human influence. Overall, our study shows that ATBR is commonplace in bacteria isolated from wildlife in southeast Mexico. Most of the resistances were towards old and naturally occurring antibiotics, but we also observed resistances of potential clinical significance. We found that proximity to humans positively affected the presence of ATBR and that ATBR was higher in terrestrial than arboreal species. We also found evidence suggesting different terrestrial and aerial routes for the transmission of ATBR between humans and wildlife. The prevalence and potential ATBR transfer mechanisms between humans and wildlife observed in this study highlight the need for further studies to identify the factors that might determine ATBR presence, abundance and distribution. PMID:25233089

  19. Progressive muscle proteome changes in a clinically relevant pig model of Duchenne muscular dystrophy.

    PubMed

    Fröhlich, Thomas; Kemter, Elisabeth; Flenkenthaler, Florian; Klymiuk, Nikolai; Otte, Kathrin A; Blutke, Andreas; Krause, Sabine; Walter, Maggie C; Wanke, Rüdiger; Wolf, Eckhard; Arnold, Georg J

    2016-01-01

    Duchenne muscular dystrophy (DMD) is caused by genetic deficiency of dystrophin and characterized by massive structural and functional changes of skeletal muscle tissue, leading to terminal muscle failure. We recently generated a novel genetically engineered pig model reflecting pathological hallmarks of human DMD better than the widely used mdx mouse. To get insight into the hierarchy of molecular derangements during DMD progression, we performed a proteome analysis of biceps femoris muscle samples from 2-day-old and 3-month-old DMD and wild-type (WT) pigs. The extent of proteome changes in DMD vs. WT muscle increased markedly with age, reflecting progression of the pathological changes. In 3-month-old DMD muscle, proteins related to muscle repair such as vimentin, nestin, desmin and tenascin C were found to be increased, whereas a large number of respiratory chain proteins were decreased in abundance in DMD muscle, indicating serious disturbances in aerobic energy production and a reduction of functional muscle tissue. The combination of proteome data for fiber type specific myosin heavy chain proteins and immunohistochemistry showed preferential degeneration of fast-twitch fiber types in DMD muscle. The stage-specific proteome changes detected in this large animal model of clinically severe muscular dystrophy provide novel molecular readouts for future treatment trials. PMID:27634466

  20. AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity

    PubMed Central

    Blair, Jessica M. A.; Bavro, Vassiliy N.; Ricci, Vito; Modi, Niraj; Cacciotto, Pierpaolo; Kleinekathӧfer, Ulrich; Ruggerone, Paolo; Vargiu, Attilio V.; Baylay, Alison J.; Smith, Helen E.; Brandon, Yvonne; Galloway, David; Piddock, Laura J. V.

    2015-01-01

    The incidence of multidrug-resistant bacterial infections is increasing globally and the need to understand the underlying mechanisms is paramount to discover new therapeutics. The efflux pumps of Gram-negative bacteria have a broad substrate range and transport antibiotics out of the bacterium, conferring intrinsic multidrug resistance (MDR). The genomes of pre- and posttherapy MDR clinical isolates of Salmonella Typhimurium from a patient that failed antibacterial therapy and died were sequenced. In the posttherapy isolate we identified a novel G288D substitution in AcrB, the resistance-nodulation division transporter in the AcrAB-TolC tripartite MDR efflux pump system. Computational structural analysis suggested that G288D in AcrB heavily affects the structure, dynamics, and hydration properties of the distal binding pocket altering specificity for antibacterial drugs. Consistent with this hypothesis, recreation of the mutation in standard Escherichia coli and Salmonella strains showed that G288D AcrB altered substrate specificity, conferring decreased susceptibility to the fluoroquinolone antibiotic ciprofloxacin by increased efflux. At the same time, the substitution increased susceptibility to other drugs by decreased efflux. Information about drug transport is vital for the discovery of new antibacterials; the finding that one amino acid change can cause resistance to some drugs, while conferring increased susceptibility to others, could provide a basis for new drug development and treatment strategies. PMID:25737552

  1. Progressive muscle proteome changes in a clinically relevant pig model of Duchenne muscular dystrophy

    PubMed Central

    Fröhlich, Thomas; Kemter, Elisabeth; Flenkenthaler, Florian; Klymiuk, Nikolai; Otte, Kathrin A.; Blutke, Andreas; Krause, Sabine; Walter, Maggie C.; Wanke, Rüdiger; Wolf, Eckhard; Arnold, Georg J.

    2016-01-01

    Duchenne muscular dystrophy (DMD) is caused by genetic deficiency of dystrophin and characterized by massive structural and functional changes of skeletal muscle tissue, leading to terminal muscle failure. We recently generated a novel genetically engineered pig model reflecting pathological hallmarks of human DMD better than the widely used mdx mouse. To get insight into the hierarchy of molecular derangements during DMD progression, we performed a proteome analysis of biceps femoris muscle samples from 2-day-old and 3-month-old DMD and wild-type (WT) pigs. The extent of proteome changes in DMD vs. WT muscle increased markedly with age, reflecting progression of the pathological changes. In 3-month-old DMD muscle, proteins related to muscle repair such as vimentin, nestin, desmin and tenascin C were found to be increased, whereas a large number of respiratory chain proteins were decreased in abundance in DMD muscle, indicating serious disturbances in aerobic energy production and a reduction of functional muscle tissue. The combination of proteome data for fiber type specific myosin heavy chain proteins and immunohistochemistry showed preferential degeneration of fast-twitch fiber types in DMD muscle. The stage-specific proteome changes detected in this large animal model of clinically severe muscular dystrophy provide novel molecular readouts for future treatment trials. PMID:27634466

  2. Clinical Relevance of Single-Voxel 1H MRS Metabolites in Discriminating Suprasellar Tumors

    PubMed Central

    Virani, Rahul A

    2016-01-01

    Introdution Spatially resolved metabolic data obtained from Proton Magnetic Resonance Spectroscopy (1H MRS) provides information which increases the diagnostic accuracy of imaging sequences in predicting the histology of suprasellar tumors. Aim To evaluate the role of 1H MRS in the diagnosis of various suprasellar tumors. Materials and Methods Sixty cases of various suprasellar, hypothalamic and third ventricular neoplasms were investigated with long-echo single voxel 1H -MRS using 1.5 Tesla clinical imager. Single-voxel spectroscopic examinations were guided by T1-weighted or T2-weighted images. Statistical analysis was carried out using IBM SPSS software version 19. Results We observed that whenever brain tissue was damaged or replaced by any process, NAA was markedly reduced. Extra-axial lesions which do not infiltrate brain or contain neuroglial tissue, didn’t demonstrate any NAA resonances. Cr was used as an internal standard for semi-quantitative evaluation of metabolic changes of other brain metabolites. Increased Cho was seen in processes with elevated cell-membrane turnover. Conclusion Spectra obtained from different tumors exhibit reproducible differences while histologically similar tumors yield characteristic spectra with only minor differences. Pituitary tumors were typically characterized by significant reduction of NAA, Cr peak and moderate elevation of Cho peak. Gliomas were typically characterized by decrease of NAA and Cr peaks and increase of Cho peak. Craniopharyngiomas were typically characterized by significant decrease of all metabolites. PMID:27630921

  3. Resistance to antibiotics of clinical relevance in the fecal microbiota of Mexican wildlife.

    PubMed

    Cristóbal-Azkarate, Jurgi; Dunn, Jacob C; Day, Jennifer M W; Amábile-Cuevas, Carlos F

    2014-01-01

    There are a growing number of reports of antibiotic resistance (ATBR) in bacteria living in wildlife. This is a cause for concern as ATBR in wildlife represents a potential public health threat. However, little is known about the factors that might determine the presence, abundance and dispersion of ATBR bacteria in wildlife. Here, we used culture and molecular methods to assess ATBR in bacteria in fecal samples from howler monkeys (Alouatta palliata), spider monkeys (Ateles geoffroyi), tapirs (Tapirus bairdii) and felids (jaguars, Panthera onca; pumas, Puma concolor; jaguarundis, Puma yagouaroundi; and ocelots, Leopardus pardalis) living freely in two regions of the Mexican state of Veracruz under different degrees of human influence. Overall, our study shows that ATBR is commonplace in bacteria isolated from wildlife in southeast Mexico. Most of the resistances were towards old and naturally occurring antibiotics, but we also observed resistances of potential clinical significance. We found that proximity to humans positively affected the presence of ATBR and that ATBR was higher in terrestrial than arboreal species. We also found evidence suggesting different terrestrial and aerial routes for the transmission of ATBR between humans and wildlife. The prevalence and potential ATBR transfer mechanisms between humans and wildlife observed in this study highlight the need for further studies to identify the factors that might determine ATBR presence, abundance and distribution.

  4. Clinicians' emotional responses and Psychodynamic Diagnostic Manual adult personality disorders: A clinically relevant empirical investigation.

    PubMed

    Gazzillo, Francesco; Lingiardi, Vittorio; Del Corno, Franco; Genova, Federica; Bornstein, Robert F; Gordon, Robert M; McWilliams, Nancy

    2015-06-01

    The aim of this study is to explore the relationship between level of personality organization and type of personality disorder as assessed with the categories in the Psychodynamic Diagnostic Manual (PDM; PDM Task Force, 2006) and the emotional responses of treating clinicians. We asked 148 Italian clinicians to assess 1 of their adult patients in treatment for personality disorders with the Psychodiagnostic Chart (PDC; Gordon & Bornstein, 2012) and the Personality Diagnostic Prototype (PDP; Gazzillo, Lingiardi, & Del Corno, 2012) and to complete the Therapist Response Questionnaire (TRQ; Betan, Heim, Zittel-Conklin, & Westen, 2005). The patients' level of overall personality pathology was positively associated with helpless and overwhelmed responses in clinicians and negatively associated with positive emotional responses. A parental and disengaged response was associated with the depressive, anxious, and dependent personality disorders; an exclusively parental response with the phobic personality disorder; and a parental and criticized response with narcissistic disorder. Dissociative disorder evoked a helpless and parental response in the treating clinicians whereas somatizing disorder elicited a disengaged reaction. An overwhelmed and disengaged response was associated with sadistic and masochistic personality disorders, with the latter also associated with a parental and hostile/criticized reaction; an exclusively overwhelmed response with psychopathic patients; and a helpless response with paranoid patients. Finally, patients with histrionic personality disorder evoked an overwhelmed and sexualized response in their clinicians whereas there was no specific emotional reaction associated with the schizoid and the obsessive-compulsive disorders. Clinical implications of these findings were discussed.

  5. Donepezil across the spectrum of Alzheimer's disease: dose optimization and clinical relevance.

    PubMed

    Lee, J-H; Jeong, S-K; Kim, B C; Park, K W; Dash, A

    2015-05-01

    Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. AD is the most common cause of dementia worldwide, and its incidence is increasing in line with population aging. The primary feature of AD is progressive cognitive decline, and severe AD is characterized by reduced communication skills and mobility. However, successful treatment can substantially improve quality of life. Donepezil is an acetylcholinesterase inhibitor approved for use across the full spectrum of mild, moderate, and severe AD. Donepezil has been available at doses of 5 or 10 mg once daily for more than a decade and, more recently, a single high once-daily sustained-release 23-mg dose has been approved for treatment of patients with moderate to severe AD. The rationale for the higher dose formulation was the expected increase in acetylcholinesterase inhibition given the dose-response relationship of donepezil, with the benefits of the higher dose being most apparent in patients with more advanced AD. Donepezil 5 and 10 mg/day have been well studied in mild-to-moderate AD, and a clinical trial has confirmed the benefits of donepezil 23 mg/day in patients with moderate to severe AD, particularly for language and visuospatial ability. This review presents an overview of the evidence for donepezil across the spectrum of AD, with a focus on dose optimization for disease progression.

  6. Resistance to Antibiotics of Clinical Relevance in the Fecal Microbiota of Mexican Wildlife

    PubMed Central

    Cristóbal-Azkarate, Jurgi; Dunn, Jacob C.; Day, Jennifer M. W.; Amábile-Cuevas, Carlos F.

    2014-01-01

    There are a growing number of reports of antibiotic resistance (ATBR) in bacteria living in wildlife. This is a cause for concern as ATBR in wildlife represents a potential public health threat. However, little is known about the factors that might determine the presence, abundance and dispersion of ATBR bacteria in wildlife. Here, we used culture and molecular methods to assess ATBR in bacteria in fecal samples from howler monkeys (Alouatta palliata), spider monkeys (Ateles geoffroyi), tapirs (Tapirus bairdii) and felids (jaguars, Panthera onca; pumas, Puma concolor; jaguarundis, Puma yagouaroundi; and ocelots, Leopardus pardalis) living freely in two regions of the Mexican state of Veracruz under different degrees of human influence. Overall, our study shows that ATBR is commonplace in bacteria isolated from wildlife in southeast Mexico. Most of the resistances were towards old and naturally occurring antibiotics, but we also observed resistances of potential clinical significance. We found that proximity to humans positively affected the presence of ATBR and that ATBR was higher in terrestrial than arboreal species. We also found evidence suggesting different terrestrial and aerial routes for the transmission of ATBR between humans and wildlife. The prevalence and potential ATBR transfer mechanisms between humans and wildlife observed in this study highlight the need for further studies to identify the factors that might determine ATBR presence, abundance and distribution. PMID:25233089

  7. How Clinically Relevant Are Treatment Comparisons of Topical Calcineurin Inhibitor Trials for Atopic Eczema?

    PubMed

    Wilkes, Sally R; Nankervis, Helen; Tavernier, Elsa; Maruani, Annabel; Williams, Hywel C

    2016-10-01

    We sought to explore the architecture of trials of calcineurin inhibitors for atopic eczema to document the extent to which comparisons with active treatments such as topical corticosteroids might have been included or avoided. We identified all eligible randomized controlled trials using the Global Resource for EczemA Trials (GREAT) database. Network plots were produced where the nodes represented a treatment type and the lines between the nodes represented the number of trials or participants involved in the various treatment comparisons. A total of 174 randomized controlled trials for atopic eczema treatments were identified in which pimecrolimus, tacrolimus, or topical corticosteroids were compared with another intervention or a vehicle/emollient. Of 39 trials involving pimecrolimus and 41 trials involving tacrolimus, 8 (20.5%) and 13 (31.7%), respectively, made comparisons with topical corticosteroids, and 25 (64.1%) and 15 (36.6%), respectively, were vehicle-controlled studies. The high rate of comparisons with vehicle controls in randomized controlled trials that assessed the efficacy of pimecrolimus or tacrolimus long after efficacy had been established is a matter of concern. Active comparators (mild topical corticosteroids for pimecrolimus and moderate to potent topical corticosteroids for tacrolimus) are best placed to determine how topical calcineurin inhibitors compare with established clinical practice.

  8. Phosphoprotein Stability in Clinical Tissue and Its Relevance for Reverse Phase Protein Microarray Technology

    PubMed Central

    Espina, Virginia; Mueller, Claudius; Liotta, Lance A.

    2013-01-01

    Phosphorylated proteins reflect the activity of specific cell signaling nodes in biological kinase protein networks. Cell signaling pathways can be either activated or deactivated depending on the phosphorylation state of the constituent proteins. The state of these kinase pathways reflects the in vivo activity of the cells and tissue at any given point in time. As such, cell signaling pathway information can be extrapolated to infer which phosphorylated proteins/pathways are driving an individual tumor’s growth. Reverse Phase Protein Microarrays (RPMA) are a sensitive and precise platform that can be applied to the quantitative measurement of hundreds of phosphorylated signal proteins from a small sample of tissue. Pre-analytical variability originating from tissue procurement and preservation may cause significant variability and bias in downstream molecular analysis. Depending on the ex vivo delay time in tissue processing, and the manner of tissue handling, protein biomarkers such as signal pathway phosphoproteins will be elevated or suppressed in a manner that does not represent the biomarker levels at the time of excision. Consequently, assessment of the state of these kinase networks requires stabilization, or preservation, of the phosphoproteins immediately post tissue procurement. We have employed reverse phase protein microarray analysis of phosphoproteins to study the factors influencing stability of phosphoproteins in tissue following procurement. Based on this analysis we have established tissue procurement guidelines for clinical research with an emphasis on quantifying phosphoproteins by RPMA. PMID:21901591

  9. Microbiological Features and Clinical Relevance of New Species of the Genus Mycobacterium

    PubMed Central

    2014-01-01

    SUMMARY Nontuberculous mycobacteria (NTM) are present in the environment, mainly in water, and are occasionally responsible for opportunistic infections in humans. Despite the fact that NTM are characterized by a moderate pathogenicity, the diseases caused by NTM at various body sites are increasing on a worldwide level. Among over 150 officially recognized NTM species, only two or three dozen are familiar to clinicians, and even to most microbiologists. In this paper, approximately 50 new species described in the last 8 years are reviewed, and their role in human infections is assessed on the basis of reported clinical cases. The small number of reports concerning most of the “new” mycobacterial species is responsible for the widespread conviction that they are very rare. Their role is actually largely underestimated, mainly because they often remain unrecognized and misidentified. Aiming to minimize such bias, emphasis has been placed on more common identification pitfalls. Together with new NTM, new members of the Mycobacterium tuberculosis complex described in the last few years are also an object of the present review. PMID:25278573

  10. Raman spectroscopy of stored red blood cells: evaluating clinically-relevant biochemical markers in donated blood

    NASA Astrophysics Data System (ADS)

    Atkins, Chad G.; Buckley, Kevin; Chen, Deborah; Schulze, H. G.; Devine, Dana V.; Blades, Michael W.; Turner, Robin F. B.

    2015-07-01

    Modern transfusion medicine relies on the safe, secure, and cost-effective delivery of donated red blood cells (RBCs). Once isolated, RBCs are suspended in a defined additive solution and stored in plastic blood bags in which, over time, they undergo chemical, physiological, and morphological changes that may have a deleterious impact on some patients. Regulations limit the storage period to 42 days and the cells do not routinely undergo analytical testing before use. In this study, we use Raman spectroscopy to interrogate stored RBCs and we identify metabolic and cell-breakdown products, such as haemoglobin and membrane fragments, that build-up in the blood bags as the cells age. Our work points the way to the development of an instrument which could quickly and easily assess the biochemical nature of stored RBC units before they are transfused.

  11. Aspirin and clopidogrel resistance: possible mechanisms and clinical relevance. Part II: Potential causes and laboratory tests.

    PubMed

    Vadász, Dávid; Sztriha, László K; Sas, Katalin; Vécsei, László

    2013-01-30

    Recent meta-analyses have indicated that patients with vascular disease demonstrated by laboratory tests to be aspirin or clopidogrel-resistant are at an increased risk of major vascular events. The suggested mechanisms of aspirin resistance include genetic polymorphism, alternative pathways of platelet activation, aspirin-insensitive thromboxane biosynthesis, drug interactions, or a low aspirin dose. Clopidogrel resistance is likely to develop as a result of a decreased bioavailability of the active metabolite, due to genetic variation or concomitant drug treatment. Additional work is required to improve and validate laboratory tests of platelet function, so that they may become useful tools for selection of the most appropriate antiplatelet therapy for an individual patient. Improvements in antiplatelet treatment strategies in the future should lead to a reduction in premature vascular events. PMID:23607225

  12. Differential Effectiveness of Clinically-Relevant Analgesics in a Rat Model of Chemotherapy-Induced Mucositis

    PubMed Central

    Whittaker, Alexandra L.; Lymn, Kerry A.; Wallace, Georgia L.; Howarth, Gordon S.

    2016-01-01

    Chemotherapy-induced intestinal mucositis is characterized by pain and a pro-inflammatory tissue response. Rat models are frequently used in mucositis disease investigations yet little is known about the presence of pain in these animals, the ability of analgesics to ameliorate the condition, or the effect that analgesic administration may have on study outcomes. This study investigated different classes of analgesics with the aim of determining their analgesic effects and impact on research outcomes of interest in a rat model of mucositis. Female DA rats were allocated to 8 groups to include saline and chemotherapy controls (n = 8). Analgesics included opioid derivatives (buprenorphine; 0.05mg/kg and tramadol 12.5mg/kg) and NSAID (carprofen; 15mg/kg) in combination with either saline or 5-Fluorouracil (5-FU; 150mg/kg). Research outcome measures included daily clinical parameters, pain score and gut histology. Myeloperoxidase assay was performed to determine gut inflammation. At the dosages employed, all agents had an analgesic effect based on behavioural pain scores. Jejunal myeloperoxidase activity was significantly reduced by buprenorphine and tramadol in comparison to 5-FU control animals (53%, p = 0.0004 and 58%, p = 0.0001). Carprofen had no ameliorating effect on myeloperoxidase levels. None of the agents reduced the histological damage caused by 5-FU administration although tramadol tended to increase villus length even when administered to healthy animals. These data provide evidence that carprofen offers potential as an analgesic in this animal model due to its pain-relieving efficacy and minimal effect on measured parameters. This study also supports further investigation into the mechanism and utility of opioid agents in the treatment of chemotherapy-induced mucositis. PMID:27463799

  13. Rectal microbicides: clinically relevant approach to the design of rectal specific placebo formulations

    PubMed Central

    2011-01-01

    Background The objective of this study is to identify the critical formulation parameters controlling distribution and function for the rectal administration of microbicides in humans. Four placebo formulations were designed with a wide range of hydrophilic characteristics (aqueous to lipid) and rheological properties (Newtonian, shear thinning, thermal sensitive and thixotropic). Aqueous formulations using typical polymers to control viscosity were iso-osmotic and buffered to pH 7. Lipid formulations were developed from lipid solvent/lipid gelling agent binary mixtures. Testing included pharmaceutical function and stability as well as in vitro and in vivo toxicity. Results The aqueous fluid placebo, based on poloxamer, was fluid at room temperature, thickened and became shear thinning at 37°C. The aqueous gel placebo used carbopol as the gelling agent, was shear thinning at room temperature and showed a typical decrease in viscosity with an increase in temperature. The lipid fluid placebo, myristyl myristate in isopropyl myristate, was relatively thin and temperature independent. The lipid gel placebo, glyceryl stearate and PEG-75 stearate in caprylic/capric triglycerides, was also shear thinning at both room temperature and 37°C but with significant time dependency or thixotropy. All formulations showed no rectal irritation in rabbits and were non-toxic using an ex vivo rectal explant model. Conclusions Four placebo formulations ranging from fluid to gel in aqueous and lipid formats with a range of rheological properties were developed, tested, scaled-up, manufactured under cGMP conditions and enrolled in a formal stability program. Clinical testing of these formulations as placebos will serve as the basis for further microbicide formulation development with drug-containing products. PMID:21385339

  14. Clinical relevance of Neutral Endopeptidase (NEP/CD10) in melanoma

    PubMed Central

    Velazquez, Elsa F; Yancovitz, Molly; Pavlick, Anna; Berman, Russell; Shapiro, Richard; Bogunovic, Dusan; O'Neill, David; Yu, Yi-Lo; Spira, Joanna; Christos, Paul J; Zhou, Xi Kathy; Mazumdar, Madhu; Nanus, David M; Liebes, Leonard; Bhardwaj, Nina; Polsky, David; Osman, Iman

    2007-01-01

    Background Overexpression of Neutral Endopeptidase (NEP) has been reported in metastatic carcinomas, implicating NEP in tumor progression and suggesting a role for NEP inhibitors in its treatment. We investigated the role of NEP expression in the clinical progression of cutaneous melanoma. Methods We screened 7 melanoma cell lines for NEP protein expression. NEP-specific siRNA was transfected into the lines to examine the role of gene transcription in NEP expression. Immunohistochemistry was done for 93 specimens and correlated with clinicopathologic parameters. Thirty-seven metastatic melanoma specimens were examined for NEP transcript expression using Affymetrix GeneChips. In a subset of 25 specimens for which both transcript and protein expression was available, expression ratios were used to identify genes that co-express with NEP in GeneChip analysis. Results NEP was overexpressed in 4/7 human melanoma cell lines, and siRNA knock-down of NEP transcripts led to downregulation of its protein expression. NEP protein overexpression was significantly more common in metastatic versus primary tumors (P = 0.002). Twelve of 37 (32%) metastatic tumors had increased NEP transcript expression, and an association was observed between NEP transcript upregulation and protein overexpression (P < 0.0001). Thirty-eight genes were found to significantly co-express with NEP (p < 0.005). Thirty-three genes positively correlated with NEP, including genes involved in the MAP kinase pathway, antigen processing and presentation, apoptosis, and WNT signaling pathway, and 5 genes negatively correlated with NEP, including genes of focal adhesion and the notch signaling pathways. Conclusion NEP overexpression, which seems to be largely driven by increased transcription, is rare in primary melanoma and occurs late in melanoma progression. Functional studies are needed to better understand the mechanisms of NEP regulation in melanoma. PMID:17207277

  15. Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer.

    PubMed

    Shamanna, Raghavendra A; Lu, Huiming; Croteau, Deborah L; Arora, Arvind; Agarwal, Devika; Ball, Graham; Aleskandarany, Mohammed A; Ellis, Ian O; Pommier, Yves; Madhusudan, Srinivasan; Bohr, Vilhelm A

    2016-03-22

    Werner syndrome protein (WRN) is a RecQ helicase that participates in DNA repair, genome stability and cellular senescence. The five human RecQ helicases, RECQL1, Bloom, WRN, RECQL4 and RECQL5 play critical roles in DNA repair and cell survival after treatment with the anticancer drug camptothecin (CPT). CPT derivatives are widely used in cancer chemotherapy to inhibit topoisomerase I and generate DNA double-strand breaks during replication. Here we studied the effects of CPT on the stability and expression dynamics of human RecQ helicases. In the cells treated with CPT, we observed distinct effects on WRN compared to other human RecQ helicases. CPT altered the cellular localization of WRN and induced its degradation by a ubiquitin-mediated proteasome pathway. WRN knockdown cells as well as CPT treated cells became senescent and stained positive for senescence-associated β-galactosidase at a higher frequency compared to control cells. However, the senescent phenotype was attenuated by ectopic expression of WRN suggesting functional implication of WRN degradation in CPT treated cells. Approximately 5-23% of breast cancer tumors are known to respond to CPT-based chemotherapy. Interestingly, we found that the extent of CPT-induced WRN degradation correlates with increasing sensitivity of breast cancer cells to CPT. The abundance of WRN decreased in CPT-treated sensitive cells; however, WRN remained relatively stable in CPT-resistant breast cancer cells. In a large clinical cohort of breast cancer patients, we find that WRN and topoisomerase I expression correlate with an aggressive tumor phenotype and poor prognosis. Our novel observations suggest that WRN abundance along with CPT-induced degradation could be a promising strategy for personalizing CPT-based cancer chemotherapeutic regimens.

  16. D category IV: a group of clinically relevant and phylogenetically diverse partial D

    PubMed Central

    von Zabern, Inge; Wagner, Franz F.; Moulds, Joann M.; Moulds, John J.; Flegel, Willy A.

    2013-01-01

    Background The D typing strategies in several European countries protect carriers of D category VI (DVI) from anti-D immunization but not carriers of other partial D. Besides DVI, one of the clinically most important partial D is D category IV (DIV). A detailed description and direct comparison of the different DIV types was missing. Study design and methods RHD nucleotide sequences were determined from genomic DNA. D epitope patterns were established with commercial monoclonal anti-D panels. Results DIV comprises several variants of the D antigen with distinct serology, molecular structures, evolutionary origins and ethnic prevalences. The DIV phenotype is determined by 350H shared by all, but not limited to, DIV variants which are further divided into DIVa and DIVb. The DIVa phenotype is expressed by DIV type 1.0 harboring 350H and the dispersed amino acids 62F, 137V and 152T. The DIVb phenotype is expressed by DIV type 3 to type 5 representing RHD-CE-D hybrids. 4 of the 6 postulated DIV variants were encountered among 23 DIV samples analyzed. Of 12 DIV carriers with anti-D, 10 were female and 7 likely immunized by pregnancy. 2 DIV related alleles are newly described: DWN which differs from DIV type 4 by 350D and epitope pattern. DNT carries 152T, known to cause a large D antigen density. Conclusion DIV alleles arose from at least 2 independent evolutionary events. DIV type 1.0 with DIVa phenotype belongs to the oldest extant human RHD alleles. DIV type 2 to type 5 with DIVb phenotype arose from more recent gene conversions. Anti-D immunization, especially dreaded in pregnancies, will be avoided not only in carriers of DVI but also in carriers of other D variants like DIV, if our proposed D typing strategy is adopted. PMID:23461862

  17. Clinical and immunological relevance of anti-neuronal antibodies in celiac disease with neurological manifestations

    PubMed Central

    Caio, Giacomo; Giorgio, Roberto De; Venturi, Alessandro; Giancola, Fiorella; Latorre, Rocco; Boschetti, Elisa; Serra, Mauro; Ruggeri, Eugenio; Volta, Umberto

    2015-01-01

    Aim: To assess anti-neuronal antibodies (NA) prevalence and their correlation with neurological disorders and bowel habits in celiac disease (CD) patients. Background: Neurological manifestations are estimated to occur in about 10% of celiac disease patients and NA to central nervous system (CNS) and enteric nervous system (ENS) are found in a significant proportion of them. Little is known about the clinical and immunological features in CD patients with neurological manifestations. Patients and methods: NA to CNS and ENS were investigated in 106 CD patients and in 60 controls with autoimmune disorders by indirect immunofluorescence on rat / primate cerebellar cortex and intestinal (small and large bowel) sections. Results: IgG NA to CNS (titer 1:50 - 1:400) were positive in 23 celiacs (21%), being more frequently detected in those with neurological disorders that in those without neurological dysfunction (49% vs. 8%, P< 0.0001). Of the 26 celiacs (24%) with IgG NA to ENS, 11 out of 12 with an antibody titer > 1:200 had severe constipation. Only one patient with cerebellar ataxia and intestinal sub-occlusion was positive for NA to CNS and ENS. NA to CNS and ENS were found in 7% and 5% of controls, respectively. Conclusion: In CD the positivity of NA to CNS can be regarded as a marker of neurological manifestations. High titer NA to ENS are associated with severe constipation. The demonstration of NA to CNS and ENS suggests an immune-mediated pathogenesis leading to central neural impairment as well as gut dysfunction (hence constipation), respectively. PMID:25926940

  18. Interactions between the endocrine and exocrine pancreas and their clinical relevance.

    PubMed

    Czakó, László; Hegyi, Péter; Rakonczay, Zoltán; Wittmann, Tibor; Otsuki, Makoto

    2009-01-01

    In consequence of the close anatomical and functional links between the exocrine and endocrine pancreas, any disease affecting one of these parts will inevitably affect the other. Pancreatic conditions which might cause diabetes mellitus include acute and chronic pancreatitis, pancreatic surgery, cystic fibrosis and pancreatic cancer. The development of diabetes greatly influences the prognosis and quality of life of patients with exocrine pancreatic diseases. It may cause life-threatening complications, such as hypoglycemia, due to the lack of glucagon and the impaired absorption of nutrients, or the micro- and macrovascular complications may impair the organ functions. Diabetes mellitus is an independent risk factor of mortality in those with exocrine pancreatic diseases. The treatment of pancreatic diabetes, a distinct metabolic and clinical form of diabetes, requires special knowledge. Diet and pancreatic enzyme replacement therapy may be sufficient in the early stages. Oral antidiabetic drugs are not recommended. If the diet proves inadequate to reach the glycemic goals, insulin treatment with multiple injections is required. Impairments of the exocrine pancreatic function and morphology in diabetic patients are frequent and well known. Atrophy of the exocrine tissue may be caused by the lack of trophic insulin, whereas pancreatic fibrosis can result from activation of stellate cells by hyperglycemia, or from microangiopathy and neuropathy. The regulation of the exocrine pancreatic function is also damaged because of the impaired effect of islet hormones. In the event of a proven impairment of the pancreatic exocrine function in diabetes mellitus, pancreatic enzyme replacement therapy is indicated. This may improve the nutritional condition of the patient and decrease the metabolic instability.

  19. Anti-platelet therapy and aspirin resistance - clinically and chemically relevant?

    PubMed

    Rafferty, M; Walters, M R; Dawson, J

    2010-01-01

    Platelets play a central role in the pathogenesis of the atherothrombosis which ultimately causes myocardial infarction, stroke and peripheral vascular disease. Commonly used oral anti-platelet drugs include aspirin (an irreversible inhibitor of cyclo-oxygenase), clopidogrel (an ADP receptor antagonist), other thienopyridines such as ticlopidine and prasgruel, and dipyridamole (an inhibitor of adenosine reuptake and platelet phosphodiesterase). Newer agents are in development and one, ticagrelor, a reversible ADP receptor antagonist has shown promise. Despite their proven benefit, recurrent vascular events still occur in those taking anti-platelet drugs. This has led to the concept of anti-platelet resistance, most commonly aspirin resistance as this drug is the cornerstone of most regimens. The causes of aspirin resistance are numerous but potential mechanisms include lack of patient adherence, non COX-1 mediated thromboxane A2 synthesis, increased activity of alternate platelet activation pathways, interference of aspirin action by other drugs and probably pharmacogenetic factors. Measurement of platelet response to aspirin is made possible using a number of in-vitro laboratory assays of platelet function which include measurement of thromboxane A2 metabolites as well as newer point-of-care assays of platelet aggregation. The phenomenon of aspirin resistance is important as it raises the possibility of developing strategies to identify those who respond best to a particular anti-platelet regimen, or to development of newer anti-platelet therapies to which more patients respond. This review discusses important aspects of aspirin resistance both in terms of clinical medicine, alternative anti-platelet strategies, and the potential to overcome its various causes. PMID:21062249

  20. Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product-Drug Interaction.

    PubMed

    Gufford, Brandon T; Chen, Gang; Vergara, Ana G; Lazarus, Philip; Oberlies, Nicholas H; Paine, Mary F

    2015-09-01

    Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4'- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27-66 µM; UGT1A1, 3.2-8.3 µM; UGT1A8, 19-73 µM; and UGT1A10, 65-120 µM) encompassed reported intestinal tissue concentrations (20-310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product-drug interactions in the context of cancer prevention.

  1. Tendon and Ligament Regeneration and Repair: Clinical Relevance and Developmental Paradigm

    PubMed Central

    Tuan, Rocky S.

    2014-01-01

    Tendon and ligament (T/L) are dense connective tissues connecting bone to muscle and bone to bone, respectively. Similar to other musculoskeletal tissues, T/L arise from the somitic mesoderm, but they are derived from a recently discovered somitic compartment, the syndetome. The adjacent sclerotome and myotome provide inductive signals to the interposing syndetome, thereby upregulating the expression of the transcription factor Scleraxis, which in turn leads to further tenogenic and ligamentogenic differentiation. These advances in the understanding of T/L development have been sought to provide a knowledge base for improving the healing of T/L injuries, a common clinical challenge due to the intrinsically poor natural healing response. Specifically, the three most common tendon injuries involve tearing of the rotator cuff of the shoulder, the flexor tendon of the hand, and the Achilles tendon. At present, injuries to these tissues are treated by surgical repair and/or conservative approaches, including biophysical modalities such as physical rehabilitation and cryotherapy. Unfortunately, the healing tissue forms fibrovascular scar and possesses inferior mechanical and biochemical properties as compared to native T/L. Therefore, tissue engineers have sought to improve upon the natural healing response by augmenting the injured tissue with cells, scaffolds, bioactive agents, and mechanical stimulation. These strategies show promise, both in vitro and in vivo, for improving T/L healing. However, several challenges remain in restoring full T/L function following injury, including uncertainties over the optimal combination of these biological agents as well how to best deliver tissue engineered elements to the injury site. A greater understanding of the molecular mechanisms involved in T/L development and natural healing, coupled with the capability of producing complex biomaterials to deliver multiple growth factors with high spatiotemporal resolution and specificity

  2. Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product–Drug Interaction

    PubMed Central

    Gufford, Brandon T.; Chen, Gang; Vergara, Ana G.; Lazarus, Philip; Oberlies, Nicholas H.

    2015-01-01

    Women at high risk of developing breast cancer are prescribed selective estrogen response modulators, including raloxifene, as chemoprevention. Patients often seek complementary and alternative treatment modalities, including herbal products, to supplement prescribed medications. Milk thistle preparations, including silibinin and silymarin, are top-selling herbal products that may be consumed by women taking raloxifene, which undergoes extensive first-pass glucuronidation in the intestine. Key constituents in milk thistle, flavonolignans, were previously shown to be potent inhibitors of intestinal UDP-glucuronosyl transferases (UGTs), with IC50s ≤ 10 μM. Taken together, milk thistle preparations may perpetrate unwanted interactions with raloxifene. The objective of this work was to evaluate the inhibitory effects of individual milk thistle constituents on the intestinal glucuronidation of raloxifene using human intestinal microsomes and human embryonic kidney cell lysates overexpressing UGT1A1, UGT1A8, and UGT1A10, isoforms highly expressed in the intestine that are critical to raloxifene clearance. The flavonolignans silybin A and silybin B were potent inhibitors of both raloxifene 4′- and 6-glucuronidation in all enzyme systems. The Kis (human intestinal microsomes, 27–66 µM; UGT1A1, 3.2–8.3 µM; UGT1A8, 19–73 µM; and UGT1A10, 65–120 µM) encompassed reported intestinal tissue concentrations (20–310 µM), prompting prediction of clinical interaction risk using a mechanistic static model. Silibinin and silymarin were predicted to increase raloxifene systemic exposure by 4- to 5-fold, indicating high interaction risk that merits further evaluation. This systematic investigation of the potential interaction between a widely used herbal product and chemopreventive agent underscores the importance of understanding natural product–drug interactions in the context of cancer prevention. PMID:26070840

  3. Laser tumor thermotherapy: Is there a clinically relevant effect on the immune system?

    NASA Astrophysics Data System (ADS)

    Tranberg, Karl-G.

    2006-02-01

    Laser thermotherapy is interesting from an immunological point of view since it can reduce tumor volume without causing immunosuppression at the same time as it may induce and/or enhance tumor immunity. In a rat liver tumor model, we have demonstrated that laser thermotherapy 1) is superior to surgical resection, 2) gives a strong rejection immunity associated with an immune cellular response of tumor-infiltrating macrophages and CD8 lymphocytes, 3) results in pronounced suppression of the growth of a simultaneous untreated tumor (distant bystander effect), 4) produces an increased anti-tumor lymphocyte proliferative response in tumor-draining and systemic lymph nodes and spleen, and 5) results in increased HSP70 immunoreactivity in tumors and tumor-infiltrating macrophages. Thus, the evidence for a laser-induced immunologic effect in tumor-bearing rats is strong. Some observations suggest that laser thermotherapy may be used for inducing favorable immunologic effects also in patients. Thus, we have shown a laser-induced bystander effect in a patient with malignant melanoma. In patients with breast cancer we have shown that laser thermotherapy induces intratumoral infiltration of immunocompetent cells like CD68 macrophages and CD8 lymphocytes. Laser thermotherapy is likely to be beneficial mainly when tumor burden is small, that is, when treatment is performed with curative intent, either with laser alone or together with surgical resection. For optimal effect, it appears likely that thermotherapy should be combined with other therapies. Most likely, a clinically meaningful effect can only be proven in prospective randomized studies comparing thermotherapy with other methods, particularly surgical resection.

  4. Assessment of the translational value of mouse lupus models using clinically relevant biomarkers.

    PubMed

    Bender, Andrew T; Wu, Yin; Cao, Qiongfang; Ding, Yueyun; Oestreicher, Judith; Genest, Melinda; Akare, Sandeep; Ishizaka, Sally T; Mackey, Matthew F

    2014-06-01

    Lupus is an autoimmune disease with a poorly understood etiology that manifests with a diverse pathology. This heterogeneity has been a challenge to clinical drug development efforts. A related difficulty is the uncertain translational power of animal models used for evaluating potential drug targets and candidate therapeutics, because it is unlikely that any 1 preclinical model will recapitulate the spectrum of human disease. Therefore, multiple models, along with an understanding of the immune mechanisms that drive them, are necessary if we are to use them to identify valid drug targets and evaluate candidate therapies successfully. To this end, we have characterized several different mouse lupus models and report their differences with respect to biomarkers and symptoms that are representative of the human disease. We compared the pristane-induced mouse lupus disease model using 3 different strains (DBA/1, SJL, BALB/c), and the spontaneous NZB x NZW F1(NZB/W) mouse model. We show that the models differ significantly in their autoantibody profiles, disease manifestations such as nephritis and arthritis, and expression of type I interferon-regulated genes. Similar to the NZB/W model, pristane-induced disease in SJL mice manifests with nephritis and proteinuria, whereas the pristane-treated DBA/1 mice develop arthritis and an interferon-driven gene signature that closely resembles that in human patients. The elucidation of each model's strengths and the identification of translatable biomarkers yields insight for basic lupus research and drug development, and should assist in the proper selection of models for evaluating candidate targets and therapeutic strategies.

  5. Seizures during the management of high-grade gliomas: clinical relevance to disease progression.

    PubMed

    Kim, Young-Hoon; Park, Chul-Kee; Kim, Tae Min; Choi, Seung Hong; Kim, Yu Jung; Choi, Byung Se; Han, Jung Ho; Lee, Se-Hoon; Kim, Chae-Yong; Kim, In Ah; Heo, Dae Seog; Kim, Il Han; Kim, Dong Gyu; Jung, Hee-Won

    2013-05-01

    This study was performed to evaluate the incidence of seizures with its implications on disease progression and the diagnostic value of post-ictal magnetic resonance images (MRI) during the management of high-grade gliomas (HGGs). A total of 406 consecutive patients with newly diagnosed HGGs were retrospectively reviewed. The incidence of seizures during the management was investigated. In patients who experienced a seizure, the causality between seizures and disease progression was assessed by pre-ictal, post-ictal (<1 month), and follow-up (<3 months) MRI. After a median follow-up of 17.4 months (range 0.1-88.3), seizures developed in 127 patients (31 %). Of the 127 patients, radiological progression at the post-ictal MRI was found in 83 patients (65 %) and the follow-up MRI confirmed progression in 79 patients (62 %). Four other patients (3 %) were shown to be progression-free. Among those without radiological progression at the post-ictal MRI, the follow-up MRI confirmed progression-free in 31 patients (24 %); however, 13 patients (10 %) revealed eventual progression. In the patients with a seizure, absence of preoperative seizures (p = 0.003), <95 % tumor resection (p = 0.001), and pre-ictal Karnofsky Performance Scale score ≤ 70 (p = 0.025) were significantly associated with disease progression. During the management of HGG, 31 % of patients experienced seizures; of these patients, 72 % harbored progressive disease. The post-ictal MRI is useful for detecting disease progression; however, there are pitfalls. Clinical settings should be considered together for diagnosing disease progression in patients with seizures.

  6. Clinical usefulness and relevance of intermediate endpoints for cytotoxic neoadjuvant therapy.

    PubMed

    Fontanella, Caterina; Loibl, Sibylle; von Minckwitz, Gunter

    2015-11-01

    Intermediate endpoints are surrogate markers of treatment efficacy assessed earlier than the true outcome of interest. Tumor response after systemic neoadjuvant therapy is considered a suitable intermediate endpoint, especially for specific breast cancer subtypes. Response can be evaluated either after only 1 cycle of treatment by clinical evaluation or at the end of the planned neoadjuvant treatment by histomorphologic examination of all surgically removed tissues from the breast and regional nodes. Although several meta-analyses showed a lower risk of death among patients who attain a pathologic complete response (pCR) compared with patients with residual tumor in breast and/or lymph nodes after neoadjuvant therapy, a statistically significant linkage between increased pCR rate by a specific treatment and improvement of survival by the same treatment has not been demonstrated yet. Therefore, formal surrogacy of pCR is not established. Moreover, the better definition of pCR is still an open issue: a large pooled analysis demonstrated that patients who attained ypT0 ypN0 (no invasive or non-invasive residual cancer in breast and nodes) experienced longer DFS (p < 0.001) compared with patients who attained ypTis ypN0 (no invasive residual in breast and nodes irrespective of residual non-invasive disease). Nevertheless, the Food and Drug Administration (FDA) recently allowed using pCR as a surrogate endpoint for accelerated approval process. Several meta-analyses demonstrated the greatest prognostic value of pCR in more aggressive breast cancer subtypes (i.e. triple-negative, HER2-positive, or high grade breast cancer). Usefulness of an earlier intermediate endpoints was prospectively demonstrated in the GeparTrio trial in which patients showing an early response achieved 4-times more frequently a pCR than those without early response. PMID:26279131

  7. Out-of-Field Dose Equivalents Delivered by Passively Scattered Therapeutic Proton Beams for Clinically Relevant Field Configurations

    SciTech Connect

    Wroe, Andrew Clasie, Ben; Kooy, Hanne; Flanz, Jay; Schulte, Reinhard; Rosenfeld, Anatoly

    2009-01-01

    Purpose: Microdosimetric measurements were performed at Massachusetts General Hospital, Boston, MA, to assess the dose equivalent external to passively delivered proton fields for various clinical treatment scenarios. Methods and Materials: Treatment fields evaluated included a prostate cancer field, cranial and spinal medulloblastoma fields, ocular melanoma field, and a field for an intracranial stereotactic treatment. Measurements were completed with patient-specific configurations of clinically relevant treatment settings using a silicon-on-insulator microdosimeter placed on the surface of and at various depths within a homogeneous Lucite phantom. The dose equivalent and average quality factor were assessed as a function of both lateral displacement from the treatment field edge and distance downstream of the beam's distal edge. Results: Dose-equivalent value range was 8.3-0.3 mSv/Gy (2.5-60-cm lateral displacement) for a typical prostate cancer field, 10.8-0.58 mSv/Gy (2.5-40-cm lateral displacement) for the cranial medulloblastoma field, 2.5-0.58 mSv/Gy (5-20-cm lateral displacement) for the spinal medulloblastoma field, and 0.5-0.08 mSv/Gy (2.5-10-cm lateral displacement) for the ocular melanoma field. Measurements of external field dose equivalent for the stereotactic field case showed differences as high as 50% depending on the modality of beam collimation. Average quality factors derived from this work ranged from 2-7, with the value dependent on the position within the phantom in relation to the primary beam. Conclusions: This work provides a valuable and clinically relevant comparison of the external field dose equivalents for various passively scattered proton treatment fields.

  8. Permeation characteristics of 8-methoxypsoralen through human skin; relevance to clinical treatment.

    PubMed

    Anigbogu, A N; Williams, A C; Barry, B W

    1996-04-01

    The permeation characteristics through human skin of 8-methoxypsoralen (8-MOP) and its physical attributes were investigated. The log octanol/water partition coefficient and saturated aqueous solubility of 8-MOP at 32 degrees C were 1-98 and 55.8 micrograms mL-1 respectively, 8-MOP showed Fickian diffusion, with its flux being linearly related to the concentration of drug in the donor solution. The permeability coefficient of 8-MOP through human skin from different concentrations of aqueous solutions and a 2.6 micrograms mL-1 bath lotion (as used in clinics) were statistically identical with mean values of 1.76 +/- 0.12 x 10(-2) and 1.70 +/- 0.32 x 10(-2) cm h-1 respectively (P > or = 0.05). An ethanol/water (1:1 w/v) receptor solution did not improve the clearance of 8-MOP from the dermis when compared with an aqueous vehicle. Complete removal of the stratum corneum by tape stripping from full-thickness membranes produced a threefold increase in the flux of 8-MOP thus suggesting that the main barrier to 8-MOP permeation resides in the stratum corneum although the aqueous epidermal and dermal tissue provide a significant resistance to transdermal drug permeation. The equilibrium uptake of 8-MOP into psoriatic plaques and the 8-MOP aqueous plaque partition coefficient were found to be more than twofold greater than for normal stratum corneum. The absorption of 8-MOP from the total applied topical dose (396 mg) was assessed as approximately 0.25% and only 2.5% of an oral dose, a significant reduction in the possible toxic hazard. The peak concentration of 8-MOP permeating through the skin was observed at about 35 min after limited exposure for 15 min. Our results suggest that following a 15 min bath in the drug solution, there may be a need for an interval of about 20 min before patients are irradiated to ensure the optimization of photosensitizer with UVA irradiation (PUVA) therapy. Alternatively, UV irradiation could be applied at a lower flux over a longer time.

  9. Measurement of neonatal skinfold thickness--is it of any clinical relevance?

    PubMed

    Verma, M; Singh, D; Chhatwal, J; Jayaharan, S

    1991-11-01

    The skinfold thickness (SFT) was measured in 750 Punjabi newborns at triceps and subscapular sites using a Harpenden's Caliper. It was correlated with various maternal and neonatal factors. SFT increased with increasing gestation but showed a decline after 40 weeks. There was a positive correlation of SFT with birth weight and length of the baby in both sexes. The correlation co-efficient for all these parameters was 0.9. The female babies had a higher SFT at all weight and length groups. Increasing maternal age, parity, weight and height all influenced the neonatal SFT positively. Mothers with higher SFT produced babies with more skinfold thickness. Similar relationship was observed between birth weight and these maternal factors. While severe pre-eclampsia and eclampsia led to a significant fall in SFT, hypertension alone did not affect it. A higher than normal SFT was seen among infants of diabetic mothers. It was concluded that the SFT does not give any additional information than that provided by the commonly measured parameters like birth weight and length.

  10. Challenges with nitrate therapy and nitrate tolerance: prevalence, prevention, and clinical relevance.

    PubMed

    Thadani, Udho

    2014-08-01

    Nitrate therapy has been an effective treatment for ischemic heart disease for over 100 years. The anti-ischemic and exercise-promoting benefits of sublingually administered nitrates are well established. Nitroglycerin is indicated for the relief of an established attack of angina and for prophylactic use, but its effects are short lived. In an effort to increase the duration of beneficial effects, long-acting orally administered and topical applications of nitrates have been developed; however, following their continued or frequent daily use, patients soon develop tolerance to these long-acting nitrate preparations. Once tolerance develops, patients begin losing the protective effects of the long-acting nitrate therapy. By providing a nitrate-free interval, or declining nitrate levels at night, one can overcome or reduce the development of tolerance, but cannot provide 24-h anti-anginal and anti-ischemic protection. In addition, patients may be vulnerable to occurrence of rebound angina and myocardial ischemia during periods of absent nitrate levels at night and early hours of the morning, and worsening of exercise capacity prior to the morning dose of the medication. This has been a concern with nitroglycerin patches but not with oral formulations of isosorbide-5 mononitrates, and has not been adequately studied with isosorbide dinitrate. This paper describes problems associated with nitrate tolerance, reviews mechanisms by which nitrate tolerance and loss of efficacy develop, and presents strategies to avoid nitrate tolerance and maintain efficacy when using long-acting nitrate formulations.

  11. T-cell-mediated drug hypersensitivity: immune mechanisms and their clinical relevance.

    PubMed

    Yun, James; Cai, Fenfen; Lee, Frederick J; Pichler, Werner J

    2016-04-01

    T-cell-mediated drug hypersensitivity represents a significant proportion of immune mediated drug hypersensitivity reactions. In the recent years, there has been an increase in understanding the immune mechanisms behind T-cell-mediated drug hypersensitivity. According to hapten mechanism, drug specific T-cell response is stimulated by drug-protein conjugate presented on major histocompatibility complex (MHC) as it is presented as a new antigenic determinant. On the other hand, p-i concept suggests that a drug can stimulate T cells via noncovalent direct interaction with T-cell receptor and/or peptide-MHC. The drug binding site is quite variable and this leads to several different mechanisms within p-i concept. Altered peptide repertoire can be regarded as an 'atypical' subset of p-i concept since the mode of the drug binding and the binding site are essentially identical to p-i concept. However, the intracellular binding of abacavir to HLA-B(*)57:01 additionally results in alteration in peptide repertoire. Furthermore the T-cell response to altered peptide repertoire model is only shown for abacavir and HLA-B(*)57:01 and therefore it may not be generalised to other drug hypersensitivity. Danger hypothesis has been postulated to play an important role in drug hypersensitivity by providing signal 2 but its experimental data is lacking at this point in time. Furthermore, the recently described allo-immune response suggests that danger signal may be unnecessary. Finally, in view of these new understanding, the classification and the definition of type B adverse drug reaction should be revised. PMID:27141480

  12. T-cell-mediated drug hypersensitivity: immune mechanisms and their clinical relevance

    PubMed Central

    Cai, Fenfen; Lee, Frederick J; Pichler, Werner J

    2016-01-01

    T-cell-mediated drug hypersensitivity represents a significant proportion of immune mediated drug hypersensitivity reactions. In the recent years, there has been an increase in understanding the immune mechanisms behind T-cell-mediated drug hypersensitivity. According to hapten mechanism, drug specific T-cell response is stimulated by drug-protein conjugate presented on major histocompatibility complex (MHC) as it is presented as a new antigenic determinant. On the other hand, p-i concept suggests that a drug can stimulate T cells via noncovalent direct interaction with T-cell receptor and/or peptide-MHC. The drug binding site is quite variable and this leads to several different mechanisms within p-i concept. Altered peptide repertoire can be regarded as an 'atypical' subset of p-i concept since the mode of the drug binding and the binding site are essentially identical to p-i concept. However, the intracellular binding of abacavir to HLA-B*57:01 additionally results in alteration in peptide repertoire. Furthermore the T-cell response to altered peptide repertoire model is only shown for abacavir and HLA-B*57:01 and therefore it may not be generalised to other drug hypersensitivity. Danger hypothesis has been postulated to play an important role in drug hypersensitivity by providing signal 2 but its experimental data is lacking at this point in time. Furthermore, the recently described allo-immune response suggests that danger signal may be unnecessary. Finally, in view of these new understanding, the classification and the definition of type B adverse drug reaction should be revised. PMID:27141480

  13. Potential cross-reactivity of monoclonal antibodies against clinically relevant mycobacteria.

    PubMed

    Flores-Moreno, K; Celis-Meneses, J S; Meneses-Ruiz, D M; Castillo-Rodal, A I; Orduña, P; Montiel, B A; López-Vidal, Y

    2014-08-01

    Tuberculosis is a disease caused by the Mycobacterium tuberculosis complex (MTb). In 2011, global mortality due to tuberculosis was 1·4 million individuals. The only available vaccine is the attenuated M. bovis [bacillus Calmette-Guérin (BCG)] strain, which confers variable protection against pulmonary tuberculosis. Some widely distributed non-tuberculous mycobacteria (NTM), such as M. avium and M. arupense, are also potential pathogens for humans. This work aimed to produce and characterize monoclonal antibodies against the M. bovis BCG Mexico strain of the MTb, M. avium subs. hominissuis and the M. arupense strain from NTM. Hybridomas were produced from splenocytes of BALB/c female mice immunized with radiation-inactivated mycobacteria, and the immunoglobulin (Ig)G2a antibody-producing clones with the highest antigenic recognition were selected. The selected clones, Mbv 2A10 for M. bovis BCG Mexico, Mav 3H1 for M. avium and Mar 2D10 for M. arupense, were used in further studies. Enzyme-linked immunosorbent assay (ELISA) and immune proteomics analyses characterized the clones as having the highest cross-reactivity with mycobacteria. Using mass spectrometry, a number of proteins recognized by the monoclonal antibody (mAb) clones were identified. These proteins had roles in metabolic processes, hypoxia, cell cycle and dormancy. In addition, a Clustal W and Immune Epitope Database (IEDB) in-silico analysis was performed in protein sequences that result in the conserved regions within probability epitopes that could be recognized for Mbv2A10 and Mav3H1 clones.

  14. Potential cross-reactivity of monoclonal antibodies against clinically relevant mycobacteria

    PubMed Central

    Flores-Moreno, K; Celis-Meneses, J S; Meneses-Ruiz, D M; Castillo-Rodal, A I; Orduña, P; Montiel, B A; López-Vidal, Y

    2014-01-01

    Tuberculosis is a disease caused by the Mycobacterium tuberculosis complex (MTb). In 2011, global mortality due to tuberculosis was 1·4 million individuals. The only available vaccine is the attenuated M. bovis [bacillus Calmette–Guérin (BCG)] strain, which confers variable protection against pulmonary tuberculosis. Some widely distributed non-tuberculous mycobacteria (NTM), such as M. avium and M. arupense, are also potential pathogens for humans. This work aimed to produce and characterize monoclonal antibodies against the M. bovis BCG Mexico strain of the MTb, M. avium subs. hominissuis and the M. arupense strain from NTM. Hybridomas were produced from splenocytes of BALB/c female mice immunized with radiation-inactivated mycobacteria, and the immunoglobulin (Ig)G2a antibody-producing clones with the highest antigenic recognition were selected. The selected clones, Mbv 2A10 for M. bovis BCG Mexico, Mav 3H1 for M. avium and Mar 2D10 for M. arupense, were used in further studies. Enzyme-linked immunosorbent assay (ELISA) and immune proteomics analyses characterized the clones as having the highest cross-reactivity with mycobacteria. Using mass spectrometry, a number of proteins recognized by the monoclonal antibody (mAb) clones were identified. These proteins had roles in metabolic processes, hypoxia, cell cycle and dormancy. In addition, a Clustal W and Immune Epitope Database (IEDB) in-silico analysis was performed in protein sequences that result in the conserved regions within probability epitopes that could be recognized for Mbv2A10 and Mav3H1 clones. PMID:24580144

  15. Clinical relevance of positive voltage-gated potassium channel (VGKC)-complex antibodies: experience from a tertiary referral centre

    PubMed Central

    Paterson, Ross W; Zandi, Michael S; Armstrong, Richard; Vincent, Angela; Schott, Jonathan M

    2014-01-01

    Background Voltage-gated potassium channel (VGKC)-complex antibodies can be associated with a range of immunotherapy-responsive clinical presentations including limbic encephalitis, Morvan's syndrome and acquired neuromyotonia. However, there are patients with positive levels in whom the significance is uncertain. Objective To evaluate the clinical significance associated with positive (>100 pM) VGKC-complex antibodies. Methods Over a 4-year period, 1053 samples were sent for testing of which 55 were positive. The clinical presentations, final diagnoses and responses to immunotherapies, when given, were assessed retrospectively and the likelihood of autoimmunity was categorised as definite, possible, unlikely or undetermined (modified from Zuliani et al 2012). Results Only 4 of the 32 patients with low-positive (100–400 pM) levels were considered definitely autoimmune, 3 with peripheral nerve hyperexcitability and 1 with a thymoma; 3 were given immunotherapies. Of the remaining 28 with low-positive levels, 13 (3 of whom had tumours) were considered possibly autoimmune, and 15 were unlikely or undetermined; 1 was given immunotherapy unsuccessfully. Of the 23 patients with high-positive (>400 pM) levels, 12 were given immunotherapies, 11 of whom showed a good response. 11 were considered definitely autoimmune, 10 with limbic encephalitis (antibody specificity: 5 LGI1, 1 contactin2, 2 negative, 2 untested) and 1 with a tumour. In the remaining 12, autoimmunity was considered possible (n=9; most had not received immunotherapies), or unlikely (n=3). Conclusions As antibody testing becomes more widely available, and many samples are referred from patients with less clear-cut diagnoses, it is important to assess the utility of the results. VGKC-complex antibodies in the range of 100–400 pM (0.1–0.4 nM) were considered clinically relevant in rare conditions with peripheral nerve hyperexcitability and appeared to associate with tumours (12.5%). By contrast

  16. Duration-dependent effects of clinically relevant oral alendronate doses on cortical bone toughness in beagle dogs

    PubMed Central

    Burr, David B.; Liu, Ziyue; Allen, Matthew R.

    2014-01-01

    Bisphosphonates (BPs) have been shown to significantly reduce bone toughness in vertebrae within one year when given at clinical doses to dogs. Although BPs also reduce toughness in cortical bone when given at high doses, their effect on cortical bone material properties when given at clinical doses is less clear. In part, this may be due to the use of small sample sizes that were powered to demonstrate differences in bone mineral density rather than bone’s material properties. Our lab has conducted several studies in which dogs were treated with alendronate at a clinically relevant dose. The goal of this study was to examine these published and unpublished data collectively to determine whether there is a significant time-dependent effect of alendronate on toughness of cortical bone. This analysis seemed particularly relevant given the recent occurrence of atypical femoral fractures in humans. Differences in the toughness of ribs taken from dogs derived from five separate experiments were measured. The dogs were orally administered saline (CON, 1 ml/kg/day) or alendronate (ALN) at a clinical dose (0.2 mg/kg/day). Treatment duration ranged from 3 months to 3 years. Groups were compared using ANOVA, and time trends analyzed with linear regression analysis. Linear regressions of the percent difference in toughness between CON and ALN at each time point revealed a significant reduction in toughness with longer exposure to ALN. The downward trend was primarily driven by a downward trend in post-yield toughness, whereas toughness in the pre-yield region was not changed relative to CON. These data suggest that a longer duration of treatment with clinical doses of ALN results in deterioration of cortical bone toughness in a time-dependent manner. As the duration of treatment is lengthened, the cortical bone exhibits increasingly brittle behavior. This may be important in assessing the role that long-term BP treatments play in the risk of atypical fractures of femoral

  17. Evaluation of Luminex xTAG fungal analyte-specific reagents for rapid identification of clinically relevant fungi.

    PubMed

    Babady, N Esther; Miranda, Edwin; Gilhuley, Kathleen A

    2011-11-01

    Invasive fungal infections (IFI) remain a serious threat to immunocompromised hosts. Current diagnostic methods, including fungal culture and antigen detection, are slow and often lack specificity. Rapid diagnostic tools with increased sensitivity and specificity could improve the care of patients with IFI. Recently, Luminex Molecular Diagnostics (Toronto, Canada) developed 23 analyte-specific reagents (ASRs) for the detection of the most common clinically relevant fungi. This study's objective was to evaluate the sensitivity and specificity of a subset of these ASRs for fungal isolates and clinical specimens. Previously characterized fungal and bacterial isolates (n = 110), blood culture specimens (n = 34), and respiratory specimens (n = 44) were tested using either a Candida 7-plex panel (Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, Candida lusitaniae, Candida guilliermondii, and Candida krusei) or a mold 11-plex panel (Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Scedosporium prolificans, Scedosporium apiospermum, Fusarium oxysporum/Fusarium solani, Rhizopus arrhizus, Rhizopus microsporus, Mucor indicus, and Cunninghamella bertholletiae). The Candida 7-plex panel correctly identified all Candida isolates as confirmed by fungal culture and biochemical tests, for a sensitivity and specificity of 100%. The mold 11-plex panel correctly identified all mold isolates tested except for A. niger. Fungal isolates of Rhizopus and Mucor species were not detected, either, although they could represent species other than those targeted by the ASRs. Further evaluation will be necessary to confirm the sensitivities of some of the mold ASRs. Implementation of these ASRs will allow same-day detection of fungal DNA in clinical specimens.

  18. Clinical obsessions in obsessive-compulsive patients and obsession-relevant intrusive thoughts in non-clinical, depressed and anxious subjects: where are the differences?

    PubMed

    Morillo, Carmen; Belloch, Amparo; García-Soriano, Gemma

    2007-06-01

    Contemporary cognitive models of obsessive-compulsive disorder (OCD) assume that clinical obsessions evolve from some modalities of intrusive thoughts (ITs) that are experienced by the vast majority of the population. These approaches also consider that the differences between "abnormal" obsessions and "normal" ITs rely on quantitative parameters rather than qualitative. The present paper examines the frequency, contents, emotional impact, consequences, cognitive appraisals and control strategies associated with clinical obsessions in a group of 31 OCD patients compared with the obsession-relevant ITs in three control groups: 22 depressed patients, 31 non-obsessive anxious patients, and 30 non-clinical community subjects. Between-group differences indicated that the ITs frequency, the unpleasantness and uncontrollability of having the IT, and the avoidance of thought triggers obtained the highest effect sizes, and they were specific to OCD patients. Moreover, two dysfunctional appraisals (worry that the thought will come true, and the importance of controlling thoughts) were specific to OCD patients. The OCD and depressed patients shared some dysfunctional appraisals about their most disturbing obsession or IT (guilt, unacceptability, likelihood thought would come true, danger, and responsibility for having the IT), whereas the non-obsessive anxious were nearer to the non-clinical participants than to the other two groups of patients. The OCD patients showed an increased use of thought control strategies, with overt neutralizing, thought suppression, and searching for reassurance being highly specific to this group.

  19. Comprehensive genomic profiling of inflammatory breast cancer cases reveals a high frequency of clinically relevant genomic alterations.

    PubMed

    Ross, Jeffrey S; Ali, Siraj M; Wang, Kai; Khaira, Depinder; Palma, Norma A; Chmielecki, Juliann; Palmer, Gary A; Morosini, Deborah; Elvin, Julia A; Fernandez, Sandra V; Miller, Vincent A; Stephens, Philip J; Cristofanilli, Massimo

    2015-11-01

    Inflammatory breast cancer (IBC) is a distinct clinicopathologic entity that carries a worse prognosis relative to non-IBC breast cancer even when matched for standard biomarkers (ER/PR/HER2). The objective of this study was to identify opportunities for benefit from targeted therapy, which are not currently identifiable in the standard workup for advanced breast cancer. Comprehensive genomic profiling on 53 IBC formalin-fixed paraffin-embedded specimens (mean, 800× + coverage) using the hybrid capture-based FoundationOne assay. Academic and community oncology clinics. From a series of 2208 clinical cases of advanced/refractory invasive breast cancers, 53 cases with IBC were identified. The presence of clinically relevant genomic alterations (CRGA) in IBC and responses to targeted therapies. CRGA were defined as genomic alterations (GA) associated with on label targeted therapies and targeted therapies in mechanism-driven clinical trials. For the 44 IBCs with available biomarker data, 19 (39 %) were ER-/PR-/HER2- (triple-negative breast cancer, TNBC). For patients in which the clinical HER2 status was known, 11 (25 %) were HER2+ with complete (100 %) concordance with ERBB2 (HER2) amplification detected by the CGP assay. The 53 sequenced IBC cases harbored a total of 266 GA with an average of 5.0 GA/tumor (range 1-15). At least one alteration associated with an FDA approved therapy or clinical trial was identified in 51/53 (96 %) of cases with an average of 2.6 CRGA/case. The most frequently altered genes were TP53 (62 %), MYC (32 %), PIK3CA (28 %), ERBB2 (26 %), FGFR1 (17 %), BRCA2 (15 %), and PTEN (15 %). In the TNBC subset of IBC, 8/19 (42 %) showed MYC amplification (median copy number 8X, range 7-20) as compared to 9/32 (28 %) in non-TNBC IBC (median copy number 7X, range 6-21). Comprehensive genomic profiling uncovered a high frequency of GA in IBC with 96 % of cases harboring at least 1 CRGA. The clinical benefit of selected targeted

  20. Cephalic arch stenosis in dialysis patients: review of clinical relevance, anatomy, current theories on etiology and management.

    PubMed

    Sivananthan, Gajan; Menashe, Leo; Halin, Neil J

    2014-01-01

    Arteriovenous hemodialysis fistulas (AVFs) serve as a lifeline for many individuals with end-stage renal failure. A common cause of AVF failure is cephalic arch stenosis. Its high prevalence compounded with its resistance to treatment makes cephalic arch stenosis important to understand. Proposed etiologies include altered flow in a fistulized cephalic vein, external compression by fascia, the unique morphology of the cephalic arch, large number of valves in the cephalic outflow tract and biochemical changes that accompany renal failure. Management options are also in debate and include angioplasty, cutting balloon angioplasty, bare metal stents, stent grafts and surgical techniques including flow reduction with minimally invasive banding as well as more invasive venovenostomy with transposition surgeries for refractory cases. In this review, the evidence for the clinical relevance of cephalic arch stenosis, its etiology and management are summarized.

  1. Identification, clinical distribution, and susceptibility to methicillin and 18 additional antibiotics of clinical Staphylococcus isolates: nationwide investigation in Italy.

    PubMed

    Varaldo, P E; Cipriani, P; Focá, A; Geraci, C; Giordano, A; Madeddu, M A; Orsi, A; Pompei, R; Prenna, M; Repetto, A

    1984-06-01

    A multicentric study of clinical Staphylococcus isolates was performed by seven operative units working in different areas of Italy. Over a 6-month period, a total of 3,226 staphylococci, isolated from in- and outpatients, were identified and tested for antimicrobial susceptibility by a protocol agreed upon by all units. On the basis of their bacteriolytic-activity patterns and other conventional tests, the isolates were identified by lyogroups , which closely correlate with human Staphylococcus species. Lyogroup I (Staphylococcus aureus) and lyogroup III (Staphylococcus capitis) were the most and the least frequently isolated staphylococci, respectively. Significant differences depending on strain origin from in- or outpatients were only observed with lyogroup IV (i.e., novobiocin- resistant staphylococci), whose isolation from outpatients was three times greater than from inpatients. Lyogroup I was predominant among isolates from most clinical sources. Lyogroup IV predominated in strains isolated from the urinary tract; lyogroup V (Staphylococcus epidermidis) predominated in strains from blood, cerebrospinal fluid, and indwelling artificial devices; and lyogroup VI ( Staphylococcus hominis, Staphylococcus haemolyticus, and Staphylococcus warneri ) predominated in strains from bile and the male genital tract. The incidence of methicillin resistance within the different lyogroups varied from unit to unit, suggesting epidemiological differences among different hospitals and different geographical areas. On the whole, methicillin resistance was more frequent in coagulase-negative staphylococci than in S. aureus and ranged from 19% for lyogroups I and III to 30% for lyogroup II (Staphylococcus simulans). Laboratory testing with 18 additional antibiotics suggested the occurrence of some specific differences in susceptibility among the different lyogroups . The rate of organisms resistant to the various antibiotics was greater among methicillin-resistant than among

  2. Identification, clinical distribution, and susceptibility to methicillin and 18 additional antibiotics of clinical Staphylococcus isolates: nationwide investigation in Italy.

    PubMed

    Varaldo, P E; Cipriani, P; Focá, A; Geraci, C; Giordano, A; Madeddu, M A; Orsi, A; Pompei, R; Prenna, M; Repetto, A

    1984-06-01

    A multicentric study of clinical Staphylococcus isolates was performed by seven operative units working in different areas of Italy. Over a 6-month period, a total of 3,226 staphylococci, isolated from in- and outpatients, were identified and tested for antimicrobial susceptibility by a protocol agreed upon by all units. On the basis of their bacteriolytic-activity patterns and other conventional tests, the isolates were identified by lyogroups , which closely correlate with human Staphylococcus species. Lyogroup I (Staphylococcus aureus) and lyogroup III (Staphylococcus capitis) were the most and the least frequently isolated staphylococci, respectively. Significant differences depending on strain origin from in- or outpatients were only observed with lyogroup IV (i.e., novobiocin- resistant staphylococci), whose isolation from outpatients was three times greater than from inpatients. Lyogroup I was predominant among isolates from most clinical sources. Lyogroup IV predominated in strains isolated from the urinary tract; lyogroup V (Staphylococcus epidermidis) predominated in strains from blood, cerebrospinal fluid, and indwelling artificial devices; and lyogroup VI ( Staphylococcus hominis, Staphylococcus haemolyticus, and Staphylococcus warneri ) predominated in strains from bile and the male genital tract. The incidence of methicillin resistance within the different lyogroups varied from unit to unit, suggesting epidemiological differences among different hospitals and different geographical areas. On the whole, methicillin resistance was more frequent in coagulase-negative staphylococci than in S. aureus and ranged from 19% for lyogroups I and III to 30% for lyogroup II (Staphylococcus simulans). Laboratory testing with 18 additional antibiotics suggested the occurrence of some specific differences in susceptibility among the different lyogroups . The rate of organisms resistant to the various antibiotics was greater among methicillin-resistant than among

  3. The Soil Microbiota Harbors a Diversity of Carbapenem-Hydrolyzing β-Lactamases of Potential Clinical Relevance.

    PubMed

    Gudeta, Dereje Dadi; Bortolaia, Valeria; Amos, Greg; Wellington, Elizabeth M H; Brandt, Kristian K; Poirel, Laurent; Nielsen, Jesper Boye; Westh, Henrik; Guardabassi, Luca

    2016-01-01

    The origin of carbapenem-hydrolyzing metallo-β-lactamases (MBLs) acquired by clinical bacteria is largely unknown. We investigated the frequency, host range, diversity, and functionality of MBLs in the soil microbiota. Twenty-five soil samples of different types and geographical origins were analyzed by antimicrobial selective culture, followed by phenotypic testing and expression of MBL-encoding genes in Escherichia coli, and whole-genome sequencing of MBL-producing strains was performed. Carbapenemase activity was detected in 29 bacterial isolates from 13 soil samples, leading to identification of seven new MBLs in presumptive Pedobacter roseus (PEDO-1), Pedobacter borealis (PEDO-2), Pedobacter kyungheensis (PEDO-3), Chryseobacterium piscium (CPS-1), Epilithonimonas tenax (ESP-1), Massilia oculi (MSI-1), and Sphingomonas sp. (SPG-1). Carbapenemase production was likely an intrinsic feature in Chryseobacterium and Epilithonimonas, as it occurred in reference strains of different species within these genera. The amino acid identity to MBLs described in clinical bacteria ranged between 40 and 69%. Remarkable features of the new MBLs included prophage integration of the encoding gene (PEDO-1), an unusual amino acid residue at a key position for MBL structure and catalysis (CPS-1), and overlap with a putative OXA β-lactamase (MSI-1). Heterologous expression of PEDO-1, CPS-1, and ESP-1in E. coli significantly increased the MICs of ampicillin, ceftazidime, cefpodoxime, cefoxitin, and meropenem. Our study shows that MBL producers are widespread in soil and include four genera that were previously not known to produce MBLs. The MBLs produced by these bacteria are distantly related to MBLs identified in clinical samples but constitute resistance determinants of clinical relevance if acquired by pathogenic bacteria. PMID:26482314

  4. The Soil Microbiota Harbors a Diversity of Carbapenem-Hydrolyzing β-Lactamases of Potential Clinical Relevance.

    PubMed

    Gudeta, Dereje Dadi; Bortolaia, Valeria; Amos, Greg; Wellington, Elizabeth M H; Brandt, Kristian K; Poirel, Laurent; Nielsen, Jesper Boye; Westh, Henrik; Guardabassi, Luca

    2015-10-19

    The origin of carbapenem-hydrolyzing metallo-β-lactamases (MBLs) acquired by clinical bacteria is largely unknown. We investigated the frequency, host range, diversity, and functionality of MBLs in the soil microbiota. Twenty-five soil samples of different types and geographical origins were analyzed by antimicrobial selective culture, followed by phenotypic testing and expression of MBL-encoding genes in Escherichia coli, and whole-genome sequencing of MBL-producing strains was performed. Carbapenemase activity was detected in 29 bacterial isolates from 13 soil samples, leading to identification of seven new MBLs in presumptive Pedobacter roseus (PEDO-1), Pedobacter borealis (PEDO-2), Pedobacter kyungheensis (PEDO-3), Chryseobacterium piscium (CPS-1), Epilithonimonas tenax (ESP-1), Massilia oculi (MSI-1), and Sphingomonas sp. (SPG-1). Carbapenemase production was likely an intrinsic feature in Chryseobacterium and Epilithonimonas, as it occurred in reference strains of different species within these genera. The amino acid identity to MBLs described in clinical bacteria ranged between 40 and 69%. Remarkable features of the new MBLs included prophage integration of the encoding gene (PEDO-1), an unusual amino acid residue at a key position for MBL structure and catalysis (CPS-1), and overlap with a putative OXA β-lactamase (MSI-1). Heterologous expression of PEDO-1, CPS-1, and ESP-1in E. coli significantly increased the MICs of ampicillin, ceftazidime, cefpodoxime, cefoxitin, and meropenem. Our study shows that MBL producers are widespread in soil and include four genera that were previously not known to produce MBLs. The MBLs produced by these bacteria are distantly related to MBLs identified in clinical samples but constitute resistance determinants of clinical relevance if acquired by pathogenic bacteria.

  5. The Soil Microbiota Harbors a Diversity of Carbapenem-Hydrolyzing β-Lactamases of Potential Clinical Relevance

    PubMed Central

    Gudeta, Dereje Dadi; Bortolaia, Valeria; Amos, Greg; Wellington, Elizabeth M. H.; Brandt, Kristian K.; Poirel, Laurent; Nielsen, Jesper Boye; Westh, Henrik

    2015-01-01

    The origin of carbapenem-hydrolyzing metallo-β-lactamases (MBLs) acquired by clinical bacteria is largely unknown. We investigated the frequency, host range, diversity, and functionality of MBLs in the soil microbiota. Twenty-five soil samples of different types and geographical origins were analyzed by antimicrobial selective culture, followed by phenotypic testing and expression of MBL-encoding genes in Escherichia coli, and whole-genome sequencing of MBL-producing strains was performed. Carbapenemase activity was detected in 29 bacterial isolates from 13 soil samples, leading to identification of seven new MBLs in presumptive Pedobacter roseus (PEDO-1), Pedobacter borealis (PEDO-2), Pedobacter kyungheensis (PEDO-3), Chryseobacterium piscium (CPS-1), Epilithonimonas tenax (ESP-1), Massilia oculi (MSI-1), and Sphingomonas sp. (SPG-1). Carbapenemase production was likely an intrinsic feature in Chryseobacterium and Epilithonimonas, as it occurred in reference strains of different species within these genera. The amino acid identity to MBLs described in clinical bacteria ranged between 40 and 69%. Remarkable features of the new MBLs included prophage integration of the encoding gene (PEDO-1), an unusual amino acid residue at a key position for MBL structure and catalysis (CPS-1), and overlap with a putative OXA β-lactamase (MSI-1). Heterologous expression of PEDO-1, CPS-1, and ESP-1in E. coli significantly increased the MICs of ampicillin, ceftazidime, cefpodoxime, cefoxitin, and meropenem. Our study shows that MBL producers are widespread in soil and include four genera that were previously not known to produce MBLs. The MBLs produced by these bacteria are distantly related to MBLs identified in clinical samples but constitute resistance determinants of clinical relevance if acquired by pathogenic bacteria. PMID:26482314

  6. The U.N. Convention on the Rights of the Child: Relevance and Application to Pediatric Clinical Bioethics.

    PubMed

    Lansdown, Gerison; Lundy, Laura; Goldhagen, Jeffrey

    2016-01-01

    This article provides an overview of the relevance and import of the U.N. Convention on the Rights of the Child (CRC) to child health practice and pediatric bioethics. We discuss the four general principles of the CRC that apply to the implementation of all rights contained in the document, the right to health articulated in Article 24, and the important position ascribed to parents in fulfilling the rights of their children. We then examine how the CRC is implemented and monitored in law and practice. The CRC and associated principles of child rights provide strategies for rights-based approaches to clinical practice and health systems, as well as to policy design, professional training, and health services research. In light of the relevance of the CRC and principles of child rights to children's health and child health practice, it follows that there is an intersection between child rights and pediatric bioethics. Pediatric bioethicists and child rights advocates should work together to define this intersection in all domains of pediatric practice.

  7. Clinical relevance of novel Otarine herpesvirus-3 in California sea lions (Zalophus californianus): lymphoma, esophageal ulcers, and strandings.

    PubMed

    Venn-Watson, Stephanie; Benham, Celeste; Gulland, Frances M; Smith, Cynthia R; St Leger, Judy; Yochem, Pam; Nollens, Hendrik; Blas-Machado, Uriel; Saliki, Jeremiah; Colegrove, Katie; Wellehan, James Fx; Rivera, Rebecca

    2012-12-12

    Herpesviruses have been recognized in marine mammals, but their clinical relevance is not always easy to assess. A novel otarine herpesvirus-3 (OtHV3) was detected in a geriatric California sea lion (Zalophus californianus), and using a newly developed quantitative PCR assay paired with histology, OtHV3 was associated with esophageal ulcers and B cell lymphoblastic lymphoma in this animal. The prevalence and quantities of OtHV3 were then determined among buffy coats from 87 stranded and managed collection sea lions. Stranded sea lions had a higher prevalence of OtHV3 compared to managed collection sea lions (34.9% versus 12.5%; p = 0.04), and among the stranded sea lions, yearlings were most likely to be positive. Future epidemiological studies comparing the presence and viral loads of OtHV3 among a larger population of California sea lions with and without lymphoid neoplasia or esophageal ulcers would help elucidate the relevance of OtHV3-associated pathologies to these groups.

  8. Clinical relevance of novel Otarine herpesvirus-3 in California sea lions (Zalophus californianus): lymphoma, esophageal ulcers, and strandings

    PubMed Central

    2012-01-01

    Herpesviruses have been recognized in marine mammals, but their clinical relevance is not always easy to assess. A novel otarine herpesvirus-3 (OtHV3) was detected in a geriatric California sea lion (Zalophus californianus), and using a newly developed quantitative PCR assay paired with histology, OtHV3 was associated with esophageal ulcers and B cell lymphoblastic lymphoma in this animal. The prevalence and quantities of OtHV3 were then determined among buffy coats from 87 stranded and managed collection sea lions. Stranded sea lions had a higher prevalence of OtHV3 compared to managed collection sea lions (34.9% versus 12.5%; p = 0.04), and among the stranded sea lions, yearlings were most likely to be positive. Future epidemiological studies comparing the presence and viral loads of OtHV3 among a larger population of California sea lions with and without lymphoid neoplasia or esophageal ulcers would help elucidate the relevance of OtHV3-associated pathologies to these groups. PMID:23234600

  9. Molecular weight and galloylation affect grape seed extract constituents’ ability to cross-link dentin collagen in clinically relevant time

    PubMed Central

    Liu, Yi; Bai, Xinyan; Li, Shaohua; Liu, Ying; Keightley, Andrew; Wang, Yong

    2015-01-01

    Objective To investigate the relationship between the structures of polyphenolic compounds found in grape seed extract (GSE) and their activity in cross-linking dentin collagen in clinically relevant settings. Methods Representative monomeric and dimeric GSE constituents including (+)-catechin (pCT), (−)-catechin (CT), (−)-epicatechin (EC), (−)-epigallocatechin (EGC), (−)-epicatechin gallate (ECG), (−)-epigallocatechin gallate (EGCG), procyanidin B2 and a pCT-pCT dimer were purchased or synthesized. GSE was separated into low (PALM) and high molecular weight (PAHM) fractions. Human molars were processed into dentin films and beams. After demineralization, 11 groups of films (n=5) were treated for 1 min with the aforementioned reagents (1 wt% in 50/50 ethanol/water) and 1 group remained untreated. The films were studied by Fourier transform infrared spectroscopy (FTIR) followed by a quantitative mass spectroscopy-based digestion assay. Tensile properties of demineralized dentin beams were evaluated (n=7) after treatments (2h and 24h) with selective GSE species that were found to protect dentin collagen from collagenase. Results Efficacy of GSE constituents in cross-linking dentin collagen was dependent on molecular size and galloylation. Non-galloylated species with degree of polymerization up to two, including pCT, CT, EC, EGC, procyanidin B2 and pCT-pCT dimer were not active. Galloylated species were active starting from monomeric form, including ECG, EGCG, PALM, GSE and PAHM. PALM induced the best overall improvement in tensile properties of dentin collagen. Significance Identification under clinically relevant settings of structural features that contribute to GSE constituents’ efficacy in stabilizing demineralized dentin matrix has immediate impact on optimizing GSE’s use in dentin bonding. PMID:25958268

  10. An integrated framework for reporting clinically relevant biomarkers from paired tumor/normal genomic and transcriptomic sequencing data in support of clinical trials in personalized medicine.

    PubMed

    Nasser, Sara; Kurdolgu, Ahmet A; Izatt, Tyler; Aldrich, Jessica; Russell, Megan L; Christoforides, Alexis; Tembe, Wiabhav; Keifer, Jeffery A; Corneveaux, Jason J; Byron, Sara A; Forman, Karen M; Zuccaro, Clarice; Keats, Jonathan J; Lorusso, Patricia M; Carpten, John D; Trent, Jeffrey M; Craig, David W

    2015-01-01

    The ability to rapidly sequence the tumor and germline DNA of an individual holds the eventual promise of revolutionizing our ability to match targeted therapies to tumors harboring the associated genetic biomarkers. Analyzing high throughput genomic data consisting of millions of base pairs and discovering alterations in clinically actionable genes in a structured and real time manner is at the crux of personalized testing. This requires a computational architecture that can monitor and track a system within a regulated environment as terabytes of data are reduced to a small number of therapeutically relevant variants, delivered as a diagnostic laboratory developed test. These high complexity assays require data structures that enable real-time and retrospective ad-hoc analysis, with a capability of updating to keep up with the rapidly changing genomic and therapeutic options, all under a regulated environment that is relevant under both CMS and FDA depending on application. We describe a flexible computational framework that uses a paired tumor/normal sample allowing for complete analysis and reporting in approximately 24 hours, providing identification of single nucleotide changes, small insertions and deletions, chromosomal rearrangements, gene fusions and gene expression with positive predictive values over 90%. In this paper we present the challenges in integrating clinical, genomic and annotation databases to provide interpreted draft reports which we utilize within ongoing clinical research protocols. We demonstrate the need to retire from existing performance measurements of accuracy and specificity and measure metrics that are meaningful to a genomic diagnostic environment. This paper presents a three-tier infrastructure that is currently being used to analyze an individual genome and provide available therapeutic options via a clinical report. Our framework utilizes a non-relational variant-centric database that is scaleable to a large amount of data and

  11. Efficient, Long-term Hepatic Gene Transfer Using Clinically Relevant HDAd Doses by Balloon Occlusion Catheter Delivery in Nonhuman Primates

    PubMed Central

    Brunetti-Pierri, Nicola; Stapleton, Gary E; Law, Mark; Breinholt, John; Palmer, Donna J; Zuo, Yu; Grove, Nathan C; Finegold, Milton J; Rice, Karen; Beaudet, Arthur L; Mullins, Charles E; Ng, Philip

    2008-01-01

    Helper-dependent adenoviral vectors (HDAd) are devoid of all viral coding sequences and are thus an improvement over early generation Ad because they can provide long-term transgene expression in vivo without chronic toxicity. However, high vector doses are required to achieve efficient hepatic transduction by systemic intravenous injection, and this unfortunately results in dose-dependent acute toxicity. To overcome this important obstacle, we have developed a minimally invasive method to preferentially deliver HDAd into the liver of nonhuman primates. Briefly, a balloon occlusion catheter was percutaneously positioned in the inferior vena cava to occlude hepatic venous outflow. HDAd was injected directly into the occluded liver via a percutaneously placed hepatic artery catheter. Compared to systemic vector injection, this approach resulted in substantially higher hepatic transduction efficiency using clinically relevant low vector doses and was accompanied by mild-to-moderate acute but transient toxicities. Transgene expression was sustained for up to 964 days. These results suggest that our minimally invasive method of delivery can significantly improve the vector's therapeutic index and may be a first step toward clinical application of HDAd for liver-directed gene therapy. PMID:19050700

  12. Establishing a Clinically Relevant Large Animal Model Platform for TBI Therapy Development: Using Cyclosporin A as a Case Study

    PubMed Central

    Margulies, Susan S.; Kilbaugh, Todd; Sullivan, Sarah; Smith, Colin; Propert, Kathleen; Byro, Melissa; Saliga, Kristen; Costine, Beth A.; Duhaime, Ann-Christine

    2015-01-01

    We have developed the first immature large animal translational treatment trial of a pharmacologic intervention for traumatic brain injury (TBI) in children. The preclinical trial design includes multiple doses of the intervention in two different injury types (focal and diffuse) to bracket the range seen in clinical injury and uses two post-TBI delays to drug administration. Cyclosporin A (CsA) was used as a case study in our first implementation of the platform because of its success in multiple preclinical adult rodent TBI models and its current use in children for other indications. Tier 1 of the therapy development platform assessed the short-term treatment efficacy after 24 h of agent administration. Positive responses to treatment were compared with injured controls using an objective effect threshold established prior to the study. Effective CsA doses were identified to study in Tier 2. In the Tier 2 paradigm, agent is administered in a porcine intensive care unit utilizing neurological monitoring and clinically relevant management strategies, and intervention efficacy is defined as improvement in longer term behavioral endpoints above untreated injured animals. In summary, this innovative large animal preclinical study design can be applied to future evaluations of other agents that promote recovery or repair after TBI. PMID:25904045

  13. The Netherlands XTC Toxicity (NeXT) study: objectives and methods of a study investigating causality, course, and clinical relevance.

    PubMed

    De Win, Maartje M L; Jager, Gerry; Vervaeke, Hylke K E; Schilt, Thelma; Reneman, Liesbeth; Booij, Jan; Verhulst, Frank C; Den Heeten, Gerard J; Ramsey, Nick F; Korf, Dirk J; Van den Brink, Wim

    2005-01-01

    This paper describes the objectives and methods of The Netherlands XTC Toxicity (NeXT) study focussing on the causality, course, and clinical relevance of ecstasy neurotoxicity. Previous studies suggest that ecstasy (3,4 methylene-dioxymethamphetamine, MDMA, XTC) is toxic toward brain serotonin axons, but most of these studies have serious methodological limitations. The current study is a combination of different approaches with three substudies: (1) a crosssectional substudy among heavy ecstasy users and controls with variation in drug use, which will provide information about potential neurotoxic consequences of ecstasy in relation to other drugs; (2) a prospective cohort substudy in ecstasy-naive subjects with high risk for future ecstasy use, which will provide information on the causality and short-term course of ecstasy use and potential neurotoxicity, and (3) a retrospective cohort substudy in lifetime ecstasy users and matched controls of an existing epidemiological sample that will provide information on long-term course and outcome of ecstasy use in the general population. Neurotoxicity is studied using (a) different imaging techniques (beta-CIT SPECT, 1H-MR spectroscopy, diffusion tensor imaging, perfusion weighted imaging and functional magnetic resonance imaging), and (b) neuropsychological and psychiatric assessments of memory, depression, and personality. The combined results will lead to conclusions that can be used in prevention messages, clinical decision making, and the development of an (inter)national ecstasy policy.

  14. Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

    PubMed

    Rizzo, Alicia N; Sammani, Saad; Esquinca, Adilene E; Jacobson, Jeffrey R; Garcia, Joe G N; Letsiou, Eleftheria; Dudek, Steven M

    2015-12-01

    Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak.

  15. Precolumn affinity capillary electrophoresis for the identification of clinically relevant proteins in human serum: application to human cardiac troponin I.

    PubMed

    Dalluge, J J; Sander, L C

    1998-12-15

    An approach has been developed to the on-line extraction and identification of clinical disease-state marker proteins in human serum. Fabrication of capillaries with integral packed beds for the online determination of human cardiac troponin I (cTnI), a diagnostic marker for myocardial infarction, at clinically relevant levels (2 nmol/L) in serum is demonstrated. The technique, termed precolumn affinity capillary electrophoresis (PA-CE), utilizes a short (approximately 5 mm) packed bed of porous silica containing covalently immobilized monoclonal anti-cTnI antibodies directly integrated within a separation capillary for the selective retention of cTnI from a complex matrix. Following a rinsing step to eliminate nonspecifically bound serum proteins and other impurities from the column, desorption of the antigen into the separation region of the PA-CE capillary for subsequent measurement of femto-molar amounts of cTnI by CE is effected by the injection of an appropriate elution buffer. Advantages of this approach over previously reported affinity preconcentration techniques, related applications for PA-CE technology, and its potential for use in the development of a certified reference material for cTnI in serum are discussed. PMID:9868922

  16. Addition of meloxicam to the treatment of clinical mastitis improves subsequent reproductive performance.

    PubMed

    McDougall, S; Abbeloos, E; Piepers, S; Rao, A S; Astiz, S; van Werven, T; Statham, J; Pérez-Villalobos, N

    2016-03-01

    A blinded, negative controlled, randomized intervention study was undertaken to test the hypothesis that addition of meloxicam, a nonsteroidal anti-inflammatory drug, to antimicrobial treatment of mild to moderate clinical mastitis would improve fertility and reduce the risk of removal from the herd. Cows (n=509) from 61 herds in 8 regions (sites) in 6 European countries were enrolled. Following herd-owner diagnosis of mild to moderate clinical mastitis within the first 120 d of lactation in a single gland, the rectal temperature, milk appearance, and California Mastitis Test score were assessed. Cows were randomly assigned within each site to be treated either with meloxicam or a placebo (control). All cows were additionally treated with 1 to 4 intramammary infusions of cephalexin and kanamycin at 24-h intervals. Prior to treatment and at 14 and 21 d posttreatment, milk samples were collected for bacteriology and somatic cell count. Cows were bred by artificial insemination and pregnancy status was subsequently defined. General estimating equations were used to determine the effect of treatment (meloxicam versus control) on bacteriological cure, somatic cell count, the probability of being inseminated by 21 d after the voluntary waiting period, the probability of conception to first artificial insemination, the number of artificial insemination/conception, the probability of pregnancy by 120 or 200 d postcalving, and the risk of removal by 300 d after treatment. Cox's proportional hazards models were used to test the effect of treatment on the calving to first insemination and calving to conception intervals. Groups did not differ in terms of age, clot score, California Mastitis Test score, rectal temperature, number of antimicrobial treatments given or bacteria present at the time of enrollment, but cows treated with meloxicam had greater days in milk at enrollment. Cows treated with meloxicam had a higher bacteriological cure proportion than those treated with

  17. Addition of meloxicam to the treatment of clinical mastitis improves subsequent reproductive performance.

    PubMed

    McDougall, S; Abbeloos, E; Piepers, S; Rao, A S; Astiz, S; van Werven, T; Statham, J; Pérez-Villalobos, N

    2016-03-01

    A blinded, negative controlled, randomized intervention study was undertaken to test the hypothesis that addition of meloxicam, a nonsteroidal anti-inflammatory drug, to antimicrobial treatment of mild to moderate clinical mastitis would improve fertility and reduce the risk of removal from the herd. Cows (n=509) from 61 herds in 8 regions (sites) in 6 European countries were enrolled. Following herd-owner diagnosis of mild to moderate clinical mastitis within the first 120 d of lactation in a single gland, the rectal temperature, milk appearance, and California Mastitis Test score were assessed. Cows were randomly assigned within each site to be treated either with meloxicam or a placebo (control). All cows were additionally treated with 1 to 4 intramammary infusions of cephalexin and kanamycin at 24-h intervals. Prior to treatment and at 14 and 21 d posttreatment, milk samples were collected for bacteriology and somatic cell count. Cows were bred by artificial insemination and pregnancy status was subsequently defined. General estimating equations were used to determine the effect of treatment (meloxicam versus control) on bacteriological cure, somatic cell count, the probability of being inseminated by 21 d after the voluntary waiting period, the probability of conception to first artificial insemination, the number of artificial insemination/conception, the probability of pregnancy by 120 or 200 d postcalving, and the risk of removal by 300 d after treatment. Cox's proportional hazards models were used to test the effect of treatment on the calving to first insemination and calving to conception intervals. Groups did not differ in terms of age, clot score, California Mastitis Test score, rectal temperature, number of antimicrobial treatments given or bacteria present at the time of enrollment, but cows treated with meloxicam had greater days in milk at enrollment. Cows treated with meloxicam had a higher bacteriological cure proportion than those treated with

  18. Clinically Relevant In Vitro Testing of Orally Inhaled Products-Bridging the Gap Between the Lab and the Patient.

    PubMed

    Mitchell, Jolyon P; Suggett, Jason; Nagel, Mark

    2016-08-01

    Current pharmacopeial methods for in vitro orally inhaled product (OIP) performance testing were developed primarily to support requirements for drug product registration and quality control. In addition, separate clinical studies are undertaken in order to quantify safety and efficacy in the hands of the patient. However, both laboratory and clinical studies are time-consuming and expensive and generally do not investigate either the effects of misuse or the severity of the respiratory disease being treated. The following modifications to laboratory evaluation methodologies can be incorporated without difficulty to provide a better linkage from in vitro testing to clinical reality: (1) examine all types of OIP with patient-representative breathing profiles which represent normal inhaler operation in accordance with the instructions for use (IFU); (2) evaluate OIP misuse, prioritizing the importance of such testing on the basis of (a) probability of occurrence and (b) consequential impact in terms of drug delivery in accordance with the label claim; and (3) use age-appropriate patient-simulated face and upper airway models for the evaluation of OIPs with a facemask. Although it is not necessarily foreseen that these suggestions would form part of future routine quality control testing of inhalers, they should provide a closer approximation to the clinical setting and therefore be useful in the preparation for in vivo studies and in improving guidance for correct use.

  19. Influence of an alloy addition on the physical and clinical behaviour of glass ionomer cement

    NASA Astrophysics Data System (ADS)

    Abour, Mohamed Abour Bashir

    These in vitro studies compared the various properties of an experimental high powder liquid content glass ionomer cement (EXPT) with those of a metal addition GIC (Hi-Dense) and disperse phase amalgam (Dispersalloy). Bi-axial, four point flexural and compressive tests were used to evaluate strength. Six groups of ten specimens were constructed for each test for each material and allowed to set in an oven at 37°C for 60 minutes. Specimens were stored in distilled water at 37°C until testing at one day, one week, one, three, six months and year. It was found that the strength of Hi-Dense increased and then maintained over extended time, whereas the strength of EXPT showed a declined at 3 months. The bond strengths of the materials to both enamel and dentine were also evaluated. Ten groups of ten teeth, five for each surface for each glass ionomer materials, were prepared. Teeth were aligned leaving the enamel and dentine surfaces exposed. The mixed material was condensed into a cylinder placed on the appropriate surface. These specimens were also stored in distilled water at 37°C. It was found that Hi-Dense had a higher bond strength to enamel that increased with time. The bond strength to dentine was maintained over the test period. The erosion rate of the materials was evaluated using the lactic acid erosion test. Three groups of six specimens for each material were constructed and tested after one hour, one day and at six months. Each specimen was subjected to an impinging jet of lactic acid solution. The erosion rate was determined by weight loss and dimensional change. It was found that Hi-Dense had a high erosion resistance which was slightly better than the experimental material. The microleakage, around restorations prepared, using the glass ionomer materials, was evaluated after cyclical loading the restoration-tooth complex. It was found that there was less leakage around Hi-Dense than EXPT at both the cervical and occlusal margins. In a clinical

  20. Evaluation of Luminex xTAG Fungal Analyte-Specific Reagents for Rapid Identification of Clinically Relevant Fungi▿

    PubMed Central

    Babady, N. Esther; Miranda, Edwin; Gilhuley, Kathleen A.

    2011-01-01

    Invasive fungal infections (IFI) remain a serious threat to immunocompromised hosts. Current diagnostic methods, including fungal culture and antigen detection, are slow and often lack specificity. Rapid diagnostic tools with increased sensitivity and specificity could improve the care of patients with IFI. Recently, Luminex Molecular Diagnostics (Toronto, Canada) developed 23 analyte-specific reagents (ASRs) for the detection of the most common clinically relevant fungi. This study's objective was to evaluate the sensitivity and specificity of a subset of these ASRs for fungal isolates and clinical specimens. Previously characterized fungal and bacterial isolates (n = 110), blood culture specimens (n = 34), and respiratory specimens (n = 44) were tested using either a Candida 7-plex panel (Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, Candida lusitaniae, Candida guilliermondii, and Candida krusei) or a mold 11-plex panel (Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus terreus, Scedosporium prolificans, Scedosporium apiospermum, Fusarium oxysporum/Fusarium solani, Rhizopus arrhizus, Rhizopus microsporus, Mucor indicus, and Cunninghamella bertholletiae). The Candida 7-plex panel correctly identified all Candida isolates as confirmed by fungal culture and biochemical tests, for a sensitivity and specificity of 100%. The mold 11-plex panel correctly identified all mold isolates tested except for A. niger. Fungal isolates of Rhizopus and Mucor species were not detected, either, although they could represent species other than those targeted by the ASRs. Further evaluation will be necessary to confirm the sensitivities of some of the mold ASRs. Implementation of these ASRs will allow same-day detection of fungal DNA in clinical specimens. PMID:21880976

  1. Prospective Molecular Profiling of Canine Cancers Provides a Clinically Relevant Comparative Model for Evaluating Personalized Medicine (PMed) Trials

    PubMed Central

    Mazcko, Christina; Cherba, David; Hendricks, William; Lana, Susan; Ehrhart, E. J.; Charles, Brad; Fehling, Heather; Kumar, Leena; Vail, David; Henson, Michael; Childress, Michael; Kitchell, Barbara; Kingsley, Christopher; Kim, Seungchan; Neff, Mark; Davis, Barbara

    2014-01-01

    Background Molecularly-guided trials (i.e. PMed) now seek to aid clinical decision-making by matching cancer targets with therapeutic options. Progress has been hampered by the lack of cancer models that account for individual-to-individual heterogeneity within and across cancer types. Naturally occurring cancers in pet animals are heterogeneous and thus provide an opportunity to answer questions about these PMed strategies and optimize translation to human patients. In order to realize this opportunity, it is now necessary to demonstrate the feasibility of conducting molecularly-guided analysis of tumors from dogs with naturally occurring cancer in a clinically relevant setting. Methodology A proof-of-concept study was conducted by the Comparative Oncology Trials Consortium (COTC) to determine if tumor collection, prospective molecular profiling, and PMed report generation within 1 week was feasible in dogs. Thirty-one dogs with cancers of varying histologies were enrolled. Twenty-four of 31 samples (77%) successfully met all predefined QA/QC criteria and were analyzed via Affymetrix gene expression profiling. A subsequent bioinformatics workflow transformed genomic data into a personalized drug report. Average turnaround from biopsy to report generation was 116 hours (4.8 days). Unsupervised clustering of canine tumor expression data clustered by cancer type, but supervised clustering of tumors based on the personalized drug report clustered by drug class rather than cancer type. Conclusions Collection and turnaround of high quality canine tumor samples, centralized pathology, analyte generation, array hybridization, and bioinformatic analyses matching gene expression to therapeutic options is achievable in a practical clinical window (<1 week). Clustering data show robust signatures by cancer type but also showed patient-to-patient heterogeneity in drug predictions. This lends further support to the inclusion of a heterogeneous population of dogs with cancer

  2. High-Resolution Microfluidic Single-Cell Transcriptional Profiling Reveals Clinically Relevant Subtypes among Human Stem Cell Populations Commonly Utilized in Cell-Based Therapies.

    PubMed

    Rennert, Robert C; Schäfer, Richard; Bliss, Tonya; Januszyk, Michael; Sorkin, Michael; Achrol, Achal S; Rodrigues, Melanie; Maan, Zeshaan N; Kluba, Torsten; Steinberg, Gary K; Gurtner, Geoffrey C

    2016-01-01

    Stem cell therapies can promote neural repair and regeneration, yet controversy regarding optimal cell source and mechanism of action has slowed clinical translation, potentially due to undefined cellular heterogeneity. Single-cell resolution is needed to identify clinically relevant subpopulations with the highest therapeutic relevance. We combine single-cell microfluidic analysis with advanced computational modeling to study for the first time two common sources for cell-based therapies, human NSCs and MSCs. This methodology has the potential to logically inform cell source decisions for any clinical application. PMID:27047447

  3. The antimicrobial efficacy of a silver alginate dressing against a broad spectrum of clinically relevant wound isolates.

    PubMed

    Percival, Steven L; Slone, Will; Linton, Sara; Okel, Tyler; Corum, Linda; Thomas, John G

    2011-06-01

    Wound dressings impregnated with silver have a role to play in aiding to reduce both the dressing and wound microbial bioburden. It is therefore imperative that antimicrobial wound dressings have efficacy on a broad range of clinical significant microorganisms. Accordingly, this study aimed to determine the antimicrobial efficacy of a silver alginate dressing against 115 wound isolates that had been isolated routinely from patients at West Virginia University Hospital. Standardised corrected zones of inhibition (CZOIs) were performed on all clinical isolates. It was found that the silver alginate dressing was able to inhibit the growth of all microorganisms tested. In particular, the silver alginate dressing inhibited the growth of Candida albicans and yeasts with CZOI of 3-11·5 mm. All meticillin-resistant Staphylococcus aureus (MRSA) strains were found to be sensitive to the silver alginate dressing with a CZOI range calculated at 3-7·8 mm. Sensitivity to the silver alginate dressing was also evident for S. aureus and vancomycin-resistant Enterococci. CZOIs of 4·25 mm were calculated for Enterococcus faecium and 9·8 mm for viridans streptococcus. The bacteria which demonstrated the highest tolerance to ionic silver included Enterobacter cloacae and Acinetobacter baumannii. Contrary to this the most responsive microorganisms to ionic silver included strains of staphylococci, viridans streptococcus and Candida albicans. No antibiotic-resistant isolates, as identified by Kirby Bauer Clinical Laboratory Standards Institute classification system, were found to be resistant to ionic silver. When a selected number of microorganisms were grown in the biofilm phenotypic state enhanced tolerance to silver was observed, compared to their non biofilm counterparts. Overall, this study has demonstrated the broad antimicrobial activity of a silver alginate dressing on wound isolates grown in the non biofilm and biofilm state. This finding is clinically relevant as both the

  4. Clinical effect of additional electroacupuncture on thoracolumbar intervertebral disc herniation in 80 paraplegic dogs.

    PubMed

    Han, Hyun-Jung; Yoon, Hun-Young; Kim, Joon-Young; Jang, Ha-Young; Lee, Bora; Choi, Seok Hwa; Jeong, Soon-Wuk

    2010-01-01

    The clinical efficacy of electroacupuncture and acupuncture in combination with medication for the treatment of thoracolumbar intervertebral disc herniation was investigated in paraplegic dogs with intact deep pain perception. To evaluate the additional effect of electroacupuncture, dogs treated with conventional medicines alone were compared to dogs treated with electroacupuncture and acupuncture and conventional medicine. Medical records of 80 dogs were reviewed for this investigation and classified into two groups undergoing different treatment methods: (1) treatment with conventional medicine alone (Group C, n = 37) and (2) treatment with conventional medicine combined with electroacupuncture and acupuncture (Group CE, n = 43). Prednisone was the conventional medicine and electroacupuncture was applied at GV07 and GV02-1 at 0.5-2.5 mV, mixed Hz of 2 and 15 Hz for 25-30 min. Acupuncture was performed locally at urinary bladder meridian points near the lesion, and bilaterally distantly at GB30, GB34, and ST36. Treatment efficacy was evaluated by post-operative neurologic function, ambulation, relapse, complication, and urinary function. Ambulation recovery was more prevalent in Group CE than Group C (p = 0.01) and recovery of ambulation and back pain relief time was shorter in Group CE compared to Group C (p = 0.011 and 0.001, respectively). Relapse rate was significantly lower in Group CE (p = 0.031). The results suggest that a combination of electroacupuncture and acupuncture with conventional medicine is more effective than conventional medicine alone in recovering ambulation, relieving back pain, and decreasing relapse. Electroacupuncture and acupuncture is thus a reasonable option for the treatment of intervertebral disc herniation in paraplegic dogs with intact deep pain perception. PMID:21061457

  5. SMARCE1, a rare cause of Coffin-Siris Syndrome: Clinical description of three additional cases.

    PubMed

    Zarate, Yuri A; Bhoj, Elizabeth; Kaylor, Julie; Li, Dong; Tsurusaki, Yoshinori; Miyake, Noriko; Matsumoto, Naomichi; Phadke, Shubha; Escobar, Luis; Irani, Afifa; Hakonarson, Hakon; Schrier Vergano, Samantha A

    2016-08-01

    Coffin-Siris syndrome (CSS, MIM 135900), is a well-described, multiple congenital anomaly syndrome characterized by coarse facial features, hypertrichosis, sparse scalp hair, and hypo/aplastic digital nails and phalanges, typically of the 5th digits. Mutations in the BAF (SWI/SNF)-complex subunits (SMARCA4, SMARCE1, SMARCB1, SMARCA2, ARID1B, and ARID1A) have been shown to cause not only CSS, but also related disorders including Nicolaides-Baraitser (MIM 601358) syndrome and ARID1B-intellectual disability syndrome (MIM 614562). At least 200 individuals with CSS have been found to have a mutation in the BAF pathway. However, to date, only three individuals with CSS have been reported to have pathogenic variants in SMARCE1. We report here three additional individuals with clinical features consistent with CSS and alterations in SMARCE1, one of which is novel. The probands all exhibited dysmorphic facial features, moderate developmental and cognitive delay, poor growth, and hypoplastic digital nails/phalanges, including digits not typically affected in the other genes associated with CSS. Two of the three probands had a variety of different organ system anomalies, including cardiac disease, genitourinary abnormalities, feeding difficulties, and vision abnormalities. The 3rd proband has not had further investigative studies. Although an increasing number of individuals are being diagnosed with disorders in the BAF pathway, SMARCE1 is the least common of these genes. This report doubles the number of probands with these mutations, and allows for better phenotypic information of this rare syndrome. © 2016 Wiley Periodicals, Inc. PMID:27264197

  6. A 2015 update on predictive molecular pathology and its role in targeted cancer therapy: a review focussing on clinical relevance.

    PubMed

    Dietel, M; Jöhrens, K; Laffert, M V; Hummel, M; Bläker, H; Pfitzner, B M; Lehmann, A; Denkert, C; Darb-Esfahani, S; Lenze, D; Heppner, F L; Koch, A; Sers, C; Klauschen, F; Anagnostopoulos, I

    2015-09-01

    In April 2013 our group published a review on predictive molecular pathology in this journal. Although only 2 years have passed many new facts and stimulating developments have happened in diagnostic molecular pathology rendering it worthwhile to present an up-date on this topic. A major technical improvement is certainly given by the introduction of next-generation sequencing (NGS; amplicon, whole exome, whole genome) and its application to formalin-fixed paraffin-embedded (FFPE) tissue in routine diagnostics. Based on this 'revolution' the analyses of numerous genetic alterations in parallel has become a routine approach opening the chance to characterize patients' malignant tumors much more deeply without increasing turn-around time and costs. In the near future this will open new strategies to apply 'off-label' targeted therapies, e.g. for rare tumors, otherwise resistant tumors etc. The clinically relevant genetic aberrations described in this review include mutation analyses of RAS (KRAS and NRAS), BRAF and PI3K in colorectal cancer, KIT or PDGFR alpha as well as BRAF, NRAS and KIT in malignant melanoma. Moreover, we present several recent advances in the molecular characterization of malignant lymphoma. Beside the well-known mutations in NSCLC (EGFR, ALK) a number of chromosomal aberrations (KRAS, ROS1, MET) have become relevant. Only very recently has the clinical need for analysis of BRCA1/2 come up and proven as a true challenge for routine diagnostics because of the genes' special structure and hot-spot-free mutational distribution. The genetic alterations are discussed in connection with their increasingly important role in companion diagnostics to apply targeted drugs as efficient as possible. As another aspect of the increasing number of druggable mutations, we discuss the challenges personalized therapies pose for the design of clinical studies to prove optimal efficacy particularly with respect to combination therapies of multiple targeted drugs and

  7. Influence of clinically relevant factors on the immediate biomechanical surrounding for a series of dental implant designs.

    PubMed

    Shunmugasamy, Vasanth Chakravarthy; Gupta, Nikhil; Pessoa, Roberto Sales; Janal, Malvin N; Coelho, Paulo G

    2011-03-01

    The objective of the present study was to assess the influence of various clinically relevant scenarios on the strain distribution in the biomechanical surrounding of five different dental implant macrogeometries. The biomechanical environment surrounding an implant, i.e., the cortical and trabecular bone, was modeled along with the implant. These models included two different values of the study parameters including loading conditions, trabecular bone elastic modulus, cortical/trabecular bone thickness ratio, and bone loss for five implant designs. Finite element analysis was conducted on the models and strain in the bones surrounding the implant was calculated. Bone volumes having strains in four different windows of 0-200 με, 200-1000 με, 1000-3000 με, and > 3000 με were measured and the effect of each biomechanical variable and their two-way interactions were statistically analyzed using the analysis of variance method. This study showed that all the parameters included in this study had an effect on the volume of bones in all strain windows, except the implant design, which affected only the 0-200 με and >3000 με windows. The two-way interaction results showed that interactions existed between implant design and bone loss, and loading condition, bone loss in the 200-1000 με window, and between implant design and loading condition in the 0-200 με window. Within the limitations of the present methodology, it can be concluded that although some unfavorable clinical scenarios demonstrated a higher volume of bone in deleterious strain levels, a tendency toward the biomechanical equilibrium was evidenced regardless of the implant design.

  8. Inhibition of human aldehyde oxidase activity by diet-derived constituents: structural influence, enzyme-ligand interactions, and clinical relevance.

    PubMed

    Barr, John T; Jones, Jeffrey P; Oberlies, Nicholas H; Paine, Mary F

    2015-01-01

    The mechanistic understanding of interactions between diet-derived substances and conventional medications in humans is nascent. Most investigations have examined cytochrome P450-mediated interactions. Interactions mediated by other phase I enzymes are understudied. Aldehyde oxidase (AO) is a phase I hydroxylase that is gaining recognition in drug design and development programs. Taken together, a panel of structurally diverse phytoconstituents (n = 24) was screened for inhibitors of the AO-mediated oxidation of the probe substrate O(6)-benzylguanine. Based on the estimated IC50 (<100 μM), 17 constituents were advanced for Ki determination. Three constituents were described best by a competitive inhibition model, whereas 14 constituents were described best by a mixed-mode model. The latter model consists of two Ki terms, Kis and Kii, which ranged from 0.26-73 and 0.80-120 μM, respectively. Molecular modeling was used to glean mechanistic insight into AO inhibition. Docking studies indicated that the tested constituents bound within the AO active site and elucidated key enzyme-inhibitor interactions. Quantitative structure-activity relationship modeling identified three structural descriptors that correlated with inhibition potency (r(2) = 0.85), providing a framework for developing in silico models to predict the AO inhibitory activity of a xenobiotic based solely on chemical structure. Finally, a simple static model was used to assess potential clinically relevant AO-mediated dietary substance-drug interactions. Epicatechin gallate and epigallocatechin gallate, prominent constituents in green tea, were predicted to have moderate to high risk. Further characterization of this uncharted type of interaction is warranted, including dynamic modeling and, potentially, clinical evaluation. PMID:25326286

  9. Effects of Clinically Relevant MPL Mutations in the Transmembrane Domain Revealed at the Atomic Level through Computational Modeling

    PubMed Central

    Lee, Tai-Sung; Kantarjian, Hagop; Ma, Wanlong; Yeh, Chen-Hsiung; Giles, Francis; Albitar, Maher

    2011-01-01

    Background Mutations in the thrombopoietin receptor (MPL) may activate relevant pathways and lead to chronic myeloproliferative neoplasms (MPNs). The mechanisms of MPL activation remain elusive because of a lack of experimental structures. Modern computational biology techniques were utilized to explore the mechanisms of MPL protein activation due to various mutations. Results Transmembrane (TM) domain predictions, homology modeling, ab initio protein structure prediction, and molecular dynamics (MD) simulations were used to build structural dynamic models of wild-type and four clinically observed mutants of MPL. The simulation results suggest that S505 and W515 are important in keeping the TM domain in its correct position within the membrane. Mutations at either of these two positions cause movement of the TM domain, altering the conformation of the nearby intracellular domain in unexpected ways, and may cause the unwanted constitutive activation of MPL's kinase partner, JAK2. Conclusions Our findings represent the first full-scale molecular dynamics simulations of the wild-type and clinically observed mutants of the MPL protein, a critical element of the MPL-JAK2-STAT signaling pathway. In contrast to usual explanations for the activation mechanism that are based on the relative translational movement between rigid domains of MPL, our results suggest that mutations within the TM region could result in conformational changes including tilt and rotation (azimuthal) angles along the membrane axis. Such changes may significantly alter the conformation of the adjacent and intrinsically flexible intracellular domain. Hence, caution should be exercised when interpreting experimental evidence based on rigid models of cytokine receptors or similar systems. PMID:21858098

  10. Clinical relevance of and risk factors for HSV-related tracheobronchitis or pneumonia: results of an outbreak investigation

    PubMed Central

    Engelmann, Ilka; Gottlieb, Jens; Meier, Astrid; Sohr, Dorit; Ruhparwar, Arjang; Henke-Gendo, Cornelia; Gastmeier, Petra; Welte, Tobias; Schulz, Thomas Friedrich; Mattner, Frauke

    2007-01-01

    Introduction Herpes simplex virus (HSV) type 1 was identified in respiratory specimens from a cluster of eight patients on a surgical intensive care unit within 8 weeks. Six of these patients suffered from HSV-related tracheobronchitis and one from HSV-related pneumonia only. Our outbreak investigation aimed to determine the clinical relevance of and risk factors associated with HSV-related tracheobronchitis or pneumonia in critically ill patients, and to investigate whether the cluster was caused by nosocomial transmission. Methods A retrospective cohort study was performed to identify risk factors for the outcomes of HSV-related tracheobronchitis or pneumonia and death using univariable analysis as well as logistic regression analysis. Viruses were typed by molecular analysis of a fragment of the HSV type 1 glycoprotein G. Results The cohort of patients covering the outbreak period comprised 53 patients, including six patients with HSV-related tracheobronchitis and one patient with pneumonia only. HSV-related tracheobronchitis or pneumonia was associated with increased mortality (100% in patients with versus 17.8% in patients without HSV-related tracheobronchitis or pneumonia; P < 0.0001). The interaction of longer duration of ventilation and tracheotomy was associated with HSV-related tracheobronchitis or pneumonia in multivariable analysis. Identical HSV type 1 glycoprotein G sequences were found in three patients and in two patients. The group of three identical viral sequences belonged to a widely circulating strain. The two identical viral sequences were recovered from bronchoalveolar lavages of one patient with HSV-related tracheobronchitis and of one patient without clinical symptoms. These viral sequences showed unique polymorphisms, indicating probable nosocomial transmission. Conclusion HSV-related tracheobronchitis or pneumonia is associated with increased mortality in critically ill patients. Care should be taken to avoid nosocomial transmission and

  11. Pharmacogenetics of cytochrome P450 2B6 (CYP2B6): advances on polymorphisms, mechanisms, and clinical relevance

    PubMed Central

    Zanger, Ulrich M.; Klein, Kathrin

    2013-01-01

    Cytochrome P450 2B6 (CYP2B6) belongs to the minor drug metabolizing P450s in human liver. Expression is highly variable both between individuals and within individuals, owing to non-genetic factors, genetic polymorphisms, inducibility, and irreversible inhibition by many compounds. Drugs metabolized mainly by CYP2B6 include artemisinin, bupropion, cyclophosphamide, efavirenz, ketamine, and methadone. CYP2B6 is one of the most polymorphic CYP genes in humans and variants have been shown to affect transcriptional regulation, splicing, mRNA and protein expression, and catalytic activity. Some variants appear to affect several functional levels simultaneously, thus, combined in haplotypes, leading to complex interactions between substrate-dependent and -independent mechanisms. The most common functionally deficient allele is CYP2B6*6 [Q172H, K262R], which occurs at frequencies of 15 to over 60% in different populations. The allele leads to lower expression in liver due to erroneous splicing. Recent investigations suggest that the amino acid changes contribute complex substrate-dependent effects at the activity level, although data from recombinant systems used by different researchers are not well in agreement with each other. Another important variant, CYP2B6*18 [I328T], occurs predominantly in Africans (4–12%) and does not express functional protein. A large number of uncharacterized variants are currently emerging from different ethnicities in the course of the 1000 Genomes Project. The CYP2B6 polymorphism is clinically relevant for HIV-infected patients treated with the reverse transcriptase inhibitor efavirenz, but it is increasingly being recognized for other drug substrates. This review summarizes recent advances on the functional and clinical significance of CYP2B6 and its genetic polymorphism, with particular emphasis on the comparison of kinetic data obtained with different substrates for variants expressed in different recombinant expression systems. PMID

  12. Quantum Dots: An Insight and Perspective of Their Biological Interaction and How This Relates to Their Relevance for Clinical Use

    PubMed Central

    Clift, Martin J. D.; Stone, Vicki

    2012-01-01

    Due to their novel physico-chemical characteristics, semi-conductor nanocrystal quantum dots (QDs) provide an advantageous perspective towards numerous different consumer and medical applications. The most notable potential application of QDs is their use as therapeutic and diagnostic tools in nanomedicine. Despite the many benefits posed by QDs, the proposed, intentional exposure to humans has raised concerns towards their potential impact upon human health. These concerns are predominantly based upon the heterogeneous composition of QDs, which most commonly comprises of a cadmium-based core and zinc sulphide shell. Whilst other nanoparticle (NP) types possess a similar structure to QDs (i.e. core-shell technology (e.g. Fe2O3, Au and superparamagnetic iron oxide NPs)), the importance of the concerns surrounding human exposure to QDs is amplified further since, due to the sophisticated chemical and light-emitting properties of QDs, the use of these NPs within any (nano)medical setting/application could be suggested as realistic, rather than simply an advantageous possibility. It is therefore imperative that a thorough understanding of how QDs interact with various biological systems, predominantly those relative to humans and what the consequences of such interactions are is gained with extreme alacrity. It is the aim of this review to highlight the current knowledge base of QD-biological system interactions, where the knowledge gaps (still) remain and how the understanding of this interaction relates to the most notable of applications for QDs; their clinical relevance. PMID:22896769

  13. Variable tellurite resistance profiles of clinically-relevant Shiga toxin-producing Escherichia coli (STEC) influence their recovery from foodstuffs.

    PubMed

    Kerangart, Stéphane; Douëllou, Thomas; Delannoy, Sabine; Fach, Patrick; Beutin, Lothar; Sergentet-Thévenot, Delphine; Cournoyer, Benoit; Loukiadis, Estelle

    2016-10-01

    Tellurite (Tel)-amended selective media and resistance (Tel-R) are widely used for detecting Shiga toxin-producing Escherichia coli (STEC) from foodstuffs. Tel-R of 81 O157 and non-O157 STEC strains isolated from animal, food and human was thus investigated. Variations of STEC tellurite minimal inhibitory concentration (MIC) values have been observed and suggest a multifactorial and variable tellurite resistome between strains. Some clinically-relevant STEC were found highly susceptible and could not be recovered using a tellurite-based detection scheme. The ter operon was highly prevalent among highly Tel-R STEC but was not always detected among intermediately-resistant strains. Many STEC serogroup strains were found to harbor sublines showing a gradient of MIC values. These Tel-R sublines showed statistically significant log negative correlations with increasing tellurite concentration. Whatever the tellurite concentration, the highest number of resistant sublines was observed for STEC belonging to the O26 serogroup. Variations in the number of these Tel-R sublines could explain the poor recovery of some STEC serogroups on tellurite-amended media especially from food products with low levels of contamination. Comparison of tellurite MIC values and distribution of virulence-related genes showed Tel-R and virulence to be related. PMID:27375242

  14. Application of Viscoelastic Fracture Model and Non-uniform Crack Initiation at Clinically Relevant Notches in Crosslinked UHMWPE

    PubMed Central

    Sirimamilla, P. Abhiram; Furmanski, Jevan; Rimnac, Clare M.

    2012-01-01

    The mechanism of crack initiation from a clinically relevant notch is not well-understood for crosslinked ultra high molecular weight polyethylene (UHMWPE) used in total joint replacement components. Static mode driving forces, rather than the cyclic mode conditions typically associated with fatigue processes, have been shown to drive crack propagation in this material. Thus, in this study, crack initiation in a notched specimen under a static load was investigated. A video microscope was used to monitor the notch surface of the specimen and crack initiation time was measured from the video by identifying the onset of crack initiation at the notch. Crack initiation was considered using a viscoelastic fracture theory. It was found that the mechanism of crack initiation involved both single layer and a distributed multi-layer phenomenon and that multi-layer crack initiation delayed the crack initiation time for all loading conditions examined. The findings of this study support that the viscoelastic fracture theory governs fracture mechanics in crosslinked UHMWPE. The findings also support that crack initiation from a notch in UHMWPE is a more complex phenomenon than treated by traditional fracture theories for polymers. PMID:23127638

  15. Sourcing of an Alternative Pericyte-Like Cell Type from Peripheral Blood in Clinically Relevant Numbers for Therapeutic Angiogenic Applications

    PubMed Central

    Blocki, Anna; Wang, Yingting; Koch, Maria; Goralczyk, Anna; Beyer, Sebastian; Agarwal, Nikita; Lee, Michelle; Moonshi, Shehzahdi; Dewavrin, Jean-Yves; Peh, Priscilla; Schwarz, Herbert; Bhakoo, Kishore; Raghunath, Michael

    2015-01-01

    Autologous cells hold great potential for personalized cell therapy, reducing immunological and risk of infections. However, low cell counts at harvest with subsequently long expansion times with associated cell function loss currently impede the advancement of autologous cell therapy approaches. Here, we aimed to source clinically relevant numbers of proangiogenic cells from an easy accessible cell source, namely peripheral blood. Using macromolecular crowding (MMC) as a biotechnological platform, we derived a novel cell type from peripheral blood that is generated within 5 days in large numbers (10–40 million cells per 100 ml of blood). This blood-derived angiogenic cell (BDAC) type is of monocytic origin, but exhibits pericyte markers PDGFR-β and NG2 and demonstrates strong angiogenic activity, hitherto ascribed only to MSC-like pericytes. Our findings suggest that BDACs represent an alternative pericyte-like cell population of hematopoietic origin that is involved in promoting early stages of microvasculature formation. As a proof of principle of BDAC efficacy in an ischemic disease model, BDAC injection rescued affected tissues in a murine hind limb ischemia model by accelerating and enhancing revascularization. Derived from a renewable tissue that is easy to collect, BDACs overcome current short-comings of autologous cell therapy, in particular for tissue repair strategies. PMID:25582709

  16. Nitric oxide‐mediated dispersal in single‐ and multi‐species biofilms of clinically and industrially relevant microorganisms

    PubMed Central

    Barraud, Nicolas; Storey, Michael V.; Moore, Zoe P.; Webb, Jeremy S.; Rice, Scott A.; Kjelleberg, Staffan

    2009-01-01

    Summary Strategies to induce biofilm dispersal are of interest due to their potential to prevent biofilm formation and biofilm‐related infections. Nitric oxide (NO), an important messenger molecule in biological systems, was previously identified as a signal for dispersal in biofilms of the model organism Pseudomonas aeruginosa. In the present study, the use of NO as an anti‐biofilm agent more broadly was assessed. Various NO donors, at concentrations estimated to generate NO levels in the picomolar and low nanomolar range, were tested on single‐species biofilms of relevant microorganisms and on multi‐species biofilms from water distribution and treatment systems. Nitric oxide‐induced dispersal was observed in all biofilms assessed, and the average reduction of total biofilm surface was 63%. Moreover, biofilms exposed to low doses of NO were more susceptible to antimicrobial treatments than untreated biofilms. For example, the efficacy of conventional chlorine treatments at removing multi‐species biofilms from water systems was increased by 20‐fold in biofilms treated with NO compared with untreated biofilms. These data suggest that combined treatments with NO may allow for novel and improved strategies to control biofilms and have widespread applications in many environmental, industrial and clinical settings. PMID:21261931

  17. Variable tellurite resistance profiles of clinically-relevant Shiga toxin-producing Escherichia coli (STEC) influence their recovery from foodstuffs.

    PubMed

    Kerangart, Stéphane; Douëllou, Thomas; Delannoy, Sabine; Fach, Patrick; Beutin, Lothar; Sergentet-Thévenot, Delphine; Cournoyer, Benoit; Loukiadis, Estelle

    2016-10-01

    Tellurite (Tel)-amended selective media and resistance (Tel-R) are widely used for detecting Shiga toxin-producing Escherichia coli (STEC) from foodstuffs. Tel-R of 81 O157 and non-O157 STEC strains isolated from animal, food and human was thus investigated. Variations of STEC tellurite minimal inhibitory concentration (MIC) values have been observed and suggest a multifactorial and variable tellurite resistome between strains. Some clinically-relevant STEC were found highly susceptible and could not be recovered using a tellurite-based detection scheme. The ter operon was highly prevalent among highly Tel-R STEC but was not always detected among intermediately-resistant strains. Many STEC serogroup strains were found to harbor sublines showing a gradient of MIC values. These Tel-R sublines showed statistically significant log negative correlations with increasing tellurite concentration. Whatever the tellurite concentration, the highest number of resistant sublines was observed for STEC belonging to the O26 serogroup. Variations in the number of these Tel-R sublines could explain the poor recovery of some STEC serogroups on tellurite-amended media especially from food products with low levels of contamination. Comparison of tellurite MIC values and distribution of virulence-related genes showed Tel-R and virulence to be related.

  18. Polymyxin Resistance in Acinetobacter baumannii: Genetic Mutations and Transcriptomic Changes in Response to Clinically Relevant Dosage Regimens

    PubMed Central

    Cheah, Soon-Ee; Johnson, Matthew D.; Zhu, Yan; Tsuji, Brian T.; Forrest, Alan; Bulitta, Jurgen B.; Boyce, John D.; Nation, Roger L.; Li, Jian

    2016-01-01

    Polymyxins are often last-line therapeutic agents used to treat infections caused by multidrug-resistant A. baumannii. Recent reports of polymyxin-resistant A. baumannii highlight the urgent need for research into mechanisms of polymyxin resistance. This study employed genomic and transcriptomic analyses to investigate the mechanisms of polymyxin resistance in A. baumannii AB307-0294 using an in vitro dynamic model to mimic four different clinically relevant dosage regimens of polymyxin B and colistin over 96 h. Polymyxin B dosage regimens that achieved peak concentrations above 1 mg/L within 1 h caused significant bacterial killing (~5 log10CFU/mL), while the gradual accumulation of colistin resulted in no bacterial killing. Polymyxin resistance was observed across all dosage regimens; partial reversion to susceptibility was observed in 6 of 8 bacterial samples during drug-free passaging. Stable polymyxin-resistant samples contained a mutation in pmrB. The transcriptomes of stable and non-stable polymyxin-resistant samples were not substantially different and featured altered expression of genes associated with outer membrane structure and biogenesis. These findings were further supported via integrated analysis of previously published transcriptomics data from strain ATCC19606. Our results provide a foundation for understanding the mechanisms of polymyxin resistance following exposure to polymyxins and the need to explore effective combination therapies. PMID:27195897

  19. Clinically-Relevant Design Features of a Three-Dimensional Correct Molar Crown and Related Maximum Principal Stress. A Finite Element Model Study

    PubMed Central

    Rafferty, Brian T.; Janal, Malvin N.; Zavanelli, Ricardo A.; Silva, Nelson R. F. A.; Rekow, E. Dianne; Thompson, Van P.; Coelho, Paulo G.

    2009-01-01

    Objective To evaluate the effects of clinically relevant variables on the maximum principal stress (MPS) in the veneer layer of an anatomically correct veneer-core-cement-tooth model. Methods The average dimensions of a mandibular first molar crown were imported into CAD software; a tooth preparation was modeled by reducing the proximal walls by 1.5 mm and the occlusal surface by 2.0 mm. ‘Crown systems’ were composed by varying characteristics of a cement layer, structural core, and veneer solid, all designed to fit the tooth preparation. The main and interacting effects of proximal wall height reduction, core material, core thickness, cement modulus, cement thickness, and load position on the maximum stress distribution were derived from a series of nite element models and analyzed in a factorial analysis of variance. Results The average MPS in the veneer layer over the 64 models was 488 MPa (range= 248 to 840 MPa). MPS increased significantly with the addition of horizontal load components and with increasing cement thickness. In addition, MPS levels varied as a function of interactions between: proximal wall height reduction and load position; load position and cement thickness; core thickness and cement thickness; cement thickness and proximal wall height reduction; and core thickness, cement thickness and proximal wall height reduction. Conclusion Rational design of veneered structural ceramics must consider the complex geometry of the crown-tooth system and integrate the in uence of both the main effects and interactions among design parameters. PMID:19857888

  20. [Determination of torsion angle after shaft fractures of the lower extremity--clinical relevance and measurement techniques].

    PubMed

    Grützner, P; Hochstein, P; Simon, R; Wentzensen, A

    1999-03-01

    In the treatment of femoral and tibial fractures the frontal and sagittal planes are controlled and documented by conventional X-ray films. Computed tomography permits exact measurement of the coronal plane. Between June 1993 and December 1997, 161 computed tomographic measurements of femoral torsion and 55 of tibial torsion after shaft fracture were carried out. The results were analyzed in a clinical study. A CT examination was carried out if the clinical examination aroused suspicion of a difference in torsion. 28.5% of the patients examined with femoral fractures and 23.8% of those with tibial fractures and torsion differences of more than 20 degrees. Between June 1993 and June 1997, 30 corrective derotating osteotomies of the femur and 9 of the tibia were carried out. The average preoperative difference of torsion of the femur was 29 degrees and of the tibia 25 degrees. After the operation the average femur difference was 7 degrees and of the lower leg 6.5 degrees, which are inside normal physiological limits. The osteotomies were carried out in the metaphysis near the fracture. Additional corrections in other planes were necessary on the femur in 27% and on the lower leg in 46%. With the aim of avoiding torsion differences, or at least to recognize them at an early stage, CT measurements of torsion after osteosythetic treatment of fresh unilateral femur-shaft fractures were carried out in 49 patients between October 1996 and December 1997. The torsion measurements during the operations had to be carried out clinically. No sufficiently exact method of measurement is available in the operating room. Three patients with increased differences of 28 degrees, 26 degrees or 19 degrees had their osteosyntheses corrected. The measurements after correction were inside the normal spread.

  1. Association of ISMav6 with the Pattern of Antibiotic Resistance in Korean Mycobacterium avium Clinical Isolates but No Relevance between Their Genotypes and Clinical Features

    PubMed Central

    Kim, Su-Young; Jeong, Byeong-Ho; Park, Hye Yun; Jeon, Kyeongman; Han, Seung Jung; Shin, Sung Jae; Koh, Won-Jung

    2016-01-01

    The aim of this study was to genetically characterize clinical isolates from patients diagnosed with Mycobacterium avium lung disease and to investigate the clinical significance. Multi-locus sequencing analysis (MLSA) and pattern of insertion sequence analysis of M. avium isolates from 92 Korean patients revealed that all isolates were M. avium subspecies hominissuis. In hsp65 sequevar analysis, codes 2, 15, and 16 were most frequently found (88/92) with similar proportions among cases additionally two isolates belonging to code N2 and an unreported code were identified, respectively. In insertion element analysis, all isolates were IS1311 positive and IS900 negative. Four of the M. avium subsp. hominissuis isolates did not harbor IS1245 and 1 of the M. avium isolates intriguingly harbored DT1, which is thought to be a M. intracellulare-specific element. M. avium subsp. hominissuis harboring ISMav6 is prevalent in Korea. No significant association between clinical manifestation and treatment response has been found in patients with the hsp65 code type and ISMav6, indicating that no specific strain/genotype among M. avium subsp. hominissuis organisms was a major source of M. avium lung disease. Interestingly, the presence of ISMav6 was correlated with greater resistance to moxifloxacin. Conclusively, the genotype of Korean M. avium subsp. hominissuis isolates is not a disease determinant responsible for lung disease and specific virulent factors of M. avium subsp. hominissuis need to be investigated further. PMID:26859598

  2. The evolution of nonimmune histological injury and its clinical relevance in adult-sized kidney grafts in pediatric recipients.

    PubMed

    Naesens, M; Kambham, N; Concepcion, W; Salvatierra, O; Sarwal, M

    2007-11-01

    To describe the evolution, risk factors and impact of nonimmune histological injury after pediatric kidney transplantation, we analyzed 245 renal allograft protocol biopsies taken regularly from the time of transplantation to 2 years thereafter in 81 consecutive rejection-free pediatric recipients of an adult-sized kidney. Isometric tubular vacuolization was present early after transplantation was not progressive, and was associated with higher tacrolimus pre-dose trough levels. Chronic tubulo-interstitial damage and tubular microcalcifications were already noted at 3 months, were progressive and had a greater association with small recipient size, male donor gender, higher donor age and female recipient gender, but not with tacrolimus exposure. Renal function assessment showed that older recipients had a significant increase in absolute glomerular filtration rate with time after transplantation, which differed from small recipients who showed no increase. It is concluded that progressive, functionally relevant, nonimmune injury is detected early after adult-sized kidney transplantation in pediatric recipients. Renal graft ischemia associated with the donor-recipient size discrepancy appears to be a greater risk factor for this chronic histological injury, suggesting that the exploration of additional therapeutic approaches to increase allograft perfusion could further extend the graft survival benefit of adult-sized kidneys transplanted into small children.

  3. [Academic discussion of adverse reaction of clinical trials of new traditional Chinese medicines and relevant influencing factors].

    PubMed

    Wang, Wen-ping; Yu, Ming; Wang, Li; Jiang, Xi-ren; Li, Xiao-bin; Wang, Hua-wei; Cao, Ying; Liu, Kai; Huang, Lu-qi

    2015-01-01

    Data of clinical trial projects involved by clinical trial institutions certified by the State Food and Drug Administration from 2002 to November 2012 were collected to summarize adverse reactions in project summary/statistical reports, analyze the rate of adverse reactions of clinical trials of new traditional Chinese medicines and relevant influencing factors, and increase the awareness of the safety of new traditional Chinese medicines. A total of 73 050 cases in 209 projects of 14 specialties were collected, including 49 689 cases in the new traditional Chinese medicine group and 271 adverse reaction cases, with an incidence rate of adverse reactions at 0.55%. The adverse reaction rate in 3 months < middle long course ≤ 6 months was the highest (1.04%), whereas that in short course ≤ half a month was the lowest (0.48%). The adverse reaction was closely related with the route of administration, 1.28% for topical > 0.63% for injection > 0.50% for oral. In the administration of only the test drug, the adverse reaction rate of patches was the highest (2.68%), whereas that of aerosols and suppositories was lowest (0). In the combined administration of the test drug and the simulation agent, the adverse reaction rate of external test patch + capsule was the highest (3.38%), whereas that of capsule + oral liquid, pills + granules, tablets + oral liquid, tablets + pills, tablet + capsule was the lowest (0). In the administration of only the test drug, the adverse reaction rate was 0.47%; In the combined administration with simulation agent (drug volume increase), the adverse reaction rate was 0.74%. Different doses caused adverse reaction different rates; The adverse reaction rate of drugs with whole-course dose between 1 100-1 200 g was the highest (3.36%), that for whole-course doses of 500-600, 900-1 000, 1 400-1 500, 1 600-1 700, 1 800-1 900 g was the lowest (0). In conclusion, the adverse reaction rate of new traditional Chinese medicines was still up to 0

  4. Prevalence and Clinical Relevance of Schmorl’s Nodes on Magnetic Resonance Imaging in a Tertiary Hospital in Southern India

    PubMed Central

    Indiran, Venkatraman; Hithaya, Fouzal

    2016-01-01

    Introduction Schmorl’s Nodes (SN), which appear as defects in superior and inferior endplates of vertebrae, are commonly seen around the thoracolumbar junction. They may be asymptomatic or symptomatic. Their prevalence varies with respect to age, gender, regions involved and other associated disc or vertebral findings. Aim SN is quite a common finding on the Magnetic Resonance Imaging (MRI) of the spine. The purpose of the study was to evaluate the prevalence of SN in the patients who underwent MRI whole spine in the radiology department, ascertain its clinical relevance and to compare the prevalence of SN in the study population with the prevalence in rest of the Indian and global population described already in the literature. Materials and Methods Clinical history and MRI images of the patients who underwent whole spine MRI study in the Radiology Department during the period of 6 months from June to December 2015 were retrospectively reviewed. The prevalence of SN, their location and associated imaging findings were studied. Results Of the 509 patients in the study, 47 had SN at one or more levels with prevalence of 9.2%. Maximum cases were seen in the 4th decade with least cases in the extremes of age. Twenty five patients had SN at thoracic levels. Twenty five patients had SN at lumbar levels. Twenty eight patients had SN at one intervertebral disc level. Other 19 patients had SN at multiple levels. Of the total 103 SN found, 57 were seen in the superior endplates and 46 in the inferior endplates. All SNs were in central position, except for one. Twelve of the 47 patients had disc degeneration at the same level as SN. Forty two of the 47 patients (89%) with Schmorl’s nodes had associated spinal disc degenerative disease at the same