Effect of acetylcholinesterase inhibitors on post-surgical complications and mortality following a hip fracture: a cohort study

PubMed Central

Tamimi, I.; Madathil, S.A.; Kezouh, A.; Nicolau, B.; Karp, I.; Tamimi, F.

2017-01-01

There is increasing evidence suggesting that the use of acetylcholinesterase inhibitors may have beneficial effects on bone. Data on the potential post-surgical effects of these medications on orthopedic interventions are very limited. This study was designed to determine whether the use of acetylcholinesterase inhibitors is associated with a decrease in post-surgical mortality and complications in hip fracture patients with Alzheimer’s disease. To accomplish this objective, a retrospective cohort study was performed using data from the Clinical Practice Research Database, UK. The study included 532 Alzheimer’s disease patients of age 65 years and older, who sustained a hip fracture between 1998 and 2012. During the follow-up period, 34% of the patients died (n=182), 22% sustained a second hip fracture (n=118) and 5% (n=29) required reintervention. The users of acetylcholinesterase inhibitors had a 56% reduction in all-cause mortality (HR= 0.44, 95% CI 0.30-0.63) and a 41% reduction in second hip fracture incidence during a year of post-surgical follow-up (HR= 0.59, 95% CI 0.38-0.94) after adjusting for potential confounders. Our results show that acetylcholinesterase inhibitors may have the potential to reduce all-cause mortality and the risk of suffering a second hip fracture during the first year after surgery. PMID:28574413

[Pleural procedures in patients treated by platelet aggregation inhibitors: An opinion survey].

PubMed

Dangers, L; Similowski, T; Chenivesse, C

2016-01-01

When pleural procedures (thoracocentesis, blind pleural biopsies and chest tube insertion) are required in patients taking long-term platelet aggregation inhibitors, the risk of bleeding must be balanced against the risk of arterial thrombosis. Currently, the bleeding risk of pleural procedures is poorly understood. The objective of the survey was to gather the opinion of respiratory physicians regarding the bleeding risk of pleural procedures in patients taking platelet aggregation inhibitors. We emailed a standardized questionnaire designed by the French National Authority for Health to 2697 French respiratory physicians. One hundred and eighty-eight of the 2697 questionnaires were returned (response rate: 7 %). The respiratory physicians declared that they performed an average of 8 pleural procedures per month. One hundred and seventy-five responders (95 %) practised pleural procedures in patients receiving platelet aggregation inhibitors; 68 of them (39 %) reported experiencing haemorrhagic complications. The bleeding risk associated with thoracentesis and chest tube insertion was considered minor by 97.8 and 65 % of responders respectively, whereas it was considered major for blind pleural biopsies by 73.4 %. Respiratory physicians were more reticent about performing pleural procedures in patients treated with clopidogrel than in those taking aspirin. This study provides an overview of how respiratory physicians perceive the bleeding risk associated with pleural procedures in patients taking platelet aggregation inhibitors. Copyright © 2016 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Gender differences in symptoms in partial responders to proton pump inhibitors for gastro-oesophageal reflux disease

PubMed Central

Niklasson, A; Denison, H; Rydén, A

2015-01-01

Background Gender differences may exist in the symptom experience of patients with gastro-oesophageal reflux disease (GERD) who have a partial response to proton pump inhibitors (PPIs). Objective The purpose of this study was to analyse gender differences in partial responders to PPIs. Methods Patients with GERD who responded partially to PPIs (n = 580; NCT00703534) completed the Reflux Symptom Questionnaire 7-day recall (RESQ-7) and the Gastrointestinal Symptom Rating Scale (GSRS). Anxiety and depression were evaluated using the Hospital Anxiety and Depression Scale. Results Women had significantly higher RESQ-7 domain scores than men for Heartburn (frequency: 4.3 vs 3.9; intensity: 3.1 vs 2.8), Burping (frequency: 4.9 vs 4.4; intensity: 3.1 vs 2.8) and Hoarseness, cough and difficulty swallowing (frequency: 2.6 vs 2.2; intensity: 1.8 vs 1.5), and had higher GSRS domain discomfort scores than men for Abdominal pain (3.51 vs 3.23), Indigestion (3.80 vs 3.45) and Constipation (2.69 vs 2.17) (all p < 0.05). Anxiety and depression were significantly more prevalent in women than in men. Conclusion In this population of partial responders, women had more frequent/intense heartburn and extra-oesophageal symptoms and more discomfort from abdominal pain, indigestion and constipation than men. Comorbid anxiety and depression may contribute to the increased symptom burden in women. PMID:26535123

Tocilizumab for uncontrollable systemic inflammatory response syndrome complicating adult-onset Still disease

PubMed Central

Masui-Ito, Asami; Okamoto, Ryuji; Ikejiri, Kaoru; Fujimoto, Mika; Tanimura, Muneyoshi; Nakamori, Shiro; Murata, Tomohiro; Ishikawa, Eiji; Yamada, Norikazu; Imai, Hiroshi; Ito, Masaaki

2017-01-01

Abstract Rationale: Adult-onset Still disease (AOSD) is a rare systemic inflammatory disease of unknown etiology characterized by evanescent salmon-pink rash, fever spikes, arthralgia, and lymphadenopathy. AOSD usually has a good prognosis, but it can sometimes be fatal, especially when it is complicated by systemic inflammatory response syndrome (SIRS) and multiple organ failure. Patient concerns: A previously healthy 26-year-old woman was referred to our hospital for persistent high fever and mild systemic edema. Five days later, the patient presented with dyspnea, hypotension, and anuria. Anasarca developed with massive pleural effusion, ascites, and systemic edema, resulting in an increase of 47 kg in body weight. Diagnoses: The patient was diagnosed as AOSD after infection, malignancy, hematologic disorders, and other autoimmune diseases were excluded. Interventions: We administered tocilizumab, an IL-6 receptor inhibitor, intravenously in addition to cyclosporine, prednisolone, plasma exchange, and continuous hemodiafiltration. Outcomes: The patient's systemic condition improved. After stabilization by all medications, the patient was managed and responded to tocilizumab alone. To the best of our knowledge, this was the first case of severe SIRS complicating AOSD that was successfully treated with an anti- IL-6 receptor antibody. Lessons: SIRS should not be overlooked in a patient with steroid-resistant AOSD and edema. Inhibitors of the IL-6 receptor can be used safely and effectively to control AOSD complicated with severe SIRS. PMID:28723802

Relationship between secretory leukocyte protease inhibitor levels in bronchoalveolar lavage fluid and postoperative pulmonary complications in patients with esophageal cancer.

PubMed

Tsukada, Katsuhiko; Miyazaki, Tatsuya; Katoh, Hiroyuki; Masuda, Norihiro; Ojima, Hitoshi; Fukuchi, Minoru; Manda, Ryokuhei; Fukai, Yasuyuki; Nakajima, Masanobu; Sohda, Makoto; Kuwano, Hiroyuki

2005-04-01

We investigated whether secretory leukocyte protease inhibitor (SLPI) is associated with pulmonary complications after esophagectomy. We measured serial changes in the SLPI concentration in the bronchoalveolar lavage fluid (BALF) of 34 patients who underwent and examined the relationship between SLPI and postoperative morbidity. Fifteen (44%) of 34 patients (high group) had a BALF SLPI concentration >90,000 pg/mL at the end of the surgery (postoperative day [POD] 0). There was no significant difference between the high group and other 19 patients (low group) with respect to age, sex, preoperative comorbid conditions, tumor stage, surgical technique, operating time, or blood loss volume. Days of intubation and pulmonary complication rate were significantly increased in the high group compared with the low group. Logistic regression analysis revealed that the BALF SLPI level on POD 0 was significant for pulmonary complications. Our results indicate that assaying SLPI levels in BALF can be useful for the prediction of pulmonary complications after esophagectomy.

[Euglycemic ketoacidosis : a complication of SGLT2 inhibitors].

PubMed

Mizuno, Aki; Lolachi, Sanaz; Pernet, Alain

2017-05-31

Sodium-glucose cotransporter 2 (SGLT2) inhibitors constitute a new category of oral antidiabetics recently indicated for the treatment of type 2 diabetes. Their mechanism of action (inhibition of renal reabsorption of glucose) and the fact that they do not induce hypoglycemia (as monotherapy) make their clinical use interesting. Various adverse events have however been reported regarding these drugs with the euglycemic ketoacidosis being the most serious. In this article we aim to review the possible mechanism of this side effect and recommendations for use of SGLT2 inhibitors by means of a case report.

[Concentration of cysteine proteinase inhibitors in urine, amniotic fluid and serum from women in pregnancy complicated by EPH-gestosis].

PubMed

Karmowski, A; Sobiech, K A; Kertyńska, I; Terpiłowski, L; Słowińska-Lisowska, M; Pałczyński, B; Malik, B

2000-10-01

Cysteine proteinase inhibitors (IPC) concentration was measured by the modified Barrett method using papaine in urine, amniotic fluid and serum obtained from the healthy labored women and from labored women in pregnancy complicated by EPH-gestosis. It was noticed the statistically significant increase in the IPC concentration in the material from the pregnant women with EPH-gestosis comparing to the women, which pregnancy had the physiologically normal course.

Decreasing incidence of peptic ulcer complications after the introduction of the proton pump inhibitors, a study of the Swedish population from 1974–2002

PubMed Central

2009-01-01

Background Despite a decreasing incidence of peptic ulcer disease, most previous studies report a stabile incidence of ulcer complications. We wanted to investigate the incidence of peptic ulcer complications in Sweden before and after the introduction of the proton pump inhibitors (PPI) in 1988 and compare these data to the sales of non-steroid anti-inflammatory drugs (NSAID) and acetylsalicylic acid (ASA). Methods All cases of gastric and duodenal ulcer complications diagnosed in Sweden from 1974 to 2002 were identified using the National hospital discharge register. Information on sales of ASA/NSAID was obtained from the National prescription survey. Results When comparing the time-periods before and after 1988 we found a significantly lower incidence of peptic ulcer complications during the later period for both sexes (p < 0.001). Incidence rates varied from 1.5 to 7.8/100000 inhabitants/year regarding perforated peptic ulcers and from 5.2 to 40.2 regarding peptic ulcer bleeding. The number of sold daily dosages of prescribed NSAID/ASA tripled from 1975 to 2002. The number of prescribed sales to women was higher than to males. Sales of low-dose ASA also increased. The total volume of NSAID and ASA, i.e. over the counter sale and sold on prescription, increased by 28% during the same period. Conclusion When comparing the periods before and after the introduction of the proton pump inhibitors we found a significant decrease in the incidence of peptic ulcer complications in the Swedish population after 1988 when PPI were introduced on the market. The cause of this decrease is most likely multifactorial, including smoking habits, NSAID consumption, prevalence of Helicobacter pylori and the introduction of PPI. Sales of prescribed NSAID/ASA increased, especially in middle-aged and elderly women. This fact seems to have had little effect on the incidence of peptic ulcer complications. PMID:19379513

Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A. A critical literature review.

PubMed

Franchini, Massimo; Lippi, Giuseppe

2010-11-01

The development of inhibitors that neutralise the function of factor VIII (FVIII) is currently not only the most challenging complication associated with the treatment of haemophilia A but it also increases the disease-related morbidity as bleeding episodes do not respond to standard therapy. The main short-term goal of the treatment of inhibitor patients is to control bleeding episodes while the long-term one is to permanently eradicate the inhibitor by immune tolerance induction, particularly in the case of high-titer antibodies. Due to some in vitro studies and clinical observations, some investigators have suggested that FVIII concentrates containing von Willebrand factor (VWF) may be less immunogenic than high-purity or recombinant FVIII products. It has also been suggested that success rates for immune tolerance induction are higher when plasma-derived FVIII products are used. The currently available data from laboratory and clinical studies on the role of VWF in inhibitor development and eradication in haemophilia A is critically analysed in this review. As a result, we have not found definitive evidence supporting a role for product type on inhibitor incidence and inhibitor eradication in haemophilia A patients.

Chelation: A Fundamental Mechanism of Action of AGE Inhibitors, AGE Breakers, and Other Inhibitors of Diabetes Complications

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

Nagai, Rhoji; Murray, David B.; Metz, Thomas O.

2012-03-01

Advanced glycation or glycoxidation end-products (AGE) increase in tissue proteins with age, and their rate of accumulation is increased in diabetes, nephropathy and inflammatory diseases. AGE inhibitors include a range of compounds that are proposed to act by trapping carbonyl and dicarbonyl intermediates in AGE formation. However, some among the newer generation of AGE inhibitors lack reactive functional groups that would trap reaction intermediates, indicating an alternative mechanism of action. We propose that AGE inhibitors function primarily as chelators, inhibiting metal-catalyzed oxidation reactions. The AGE-inhibitory activity of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is also consistent with their chelatingmore » activity. Finally, compounds described as AGE breakers, or their hydrolysis products, also have strong chelating activity, suggesting that these compounds also act through their chelating activity. We conclude that chelation is the common, and perhaps the primary, mechanism of action of AGE inhibitors and breakers, and that chronic, mild chelation therapy should prove useful in treatment of diabetes and age-related diseases characterized by oxidative stress, inflammation and increased chemical modification of tissue proteins by advanced glycoxidation and lipoxidation end-products.« less

Complications of hyperglycaemia with PI3K–AKT–mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials

PubMed Central

Geuna, E; Roda, D; Rafii, S; Jimenez, B; Capelan, M; Rihawi, K; Montemurro, F; Yap, T A; Kaye, S B; De Bono, J S; Molife, L R; Banerji, U

2015-01-01

Background: PI3K–AKT–mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and is becoming increasingly important with their use in larger numbers of patients. Methods: Retrospective case-control study comparing incidence and severity of hyperglycaemia (all grades) between a case group of 387 patients treated on 18 phase I clinical trials with PAMi (78 patients with PI3Ki, 138 with mTORi, 144 with AKTi and 27 with PI3K/mTORi) and a control group of 109 patients treated on 10 phase I clinical trials with agents not directly targeting the PAM pathway. Diabetic patients were excluded in both groups. Results: The incidence of hyperglycaemia was not significantly different between cases and controls (86.6% vs 80.7%, respectively, P=0.129). However, high grade (grade 3–4) hyperglycaemia was more frequent in the PAMi group than in controls (6.7% vs 0%, respectively, P=0.005). The incidence of grade 3–4 hyperglycaemia was greater with AKT and multikinase inhibitors compared with other PAMi (P<0.001). All patients with high-grade hyperglycaemia received antihyperglycemic treatment and none developed severe metabolic complications (diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic state). High-grade hyperglycaemia was the cause of permanent PAMi discontinuation in nine patients. Conclusions: PI3K–AKT–mTOR inhibitors are associated with small (6.7%) but statistically significant increased risk of high-grade hyperglycaemia compared with non-PAM targeting agents. However, PAMi-induced hyperglycaemia was not found to be associated with severe metabolic complications in this non-diabetic population of patients with advanced cancers. PMID:26554652

Complications of hyperglycaemia with PI3K-AKT-mTOR inhibitors in patients with advanced solid tumours on Phase I clinical trials.

PubMed

Geuna, E; Roda, D; Rafii, S; Jimenez, B; Capelan, M; Rihawi, K; Montemurro, F; Yap, T A; Kaye, S B; De Bono, J S; Molife, L R; Banerji, U

2015-12-01

PI3K-AKT-mTOR inhibitors (PAMi) are promising anticancer treatments. Hyperglycaemia is a mechanism-based toxicity of these agents and is becoming increasingly important with their use in larger numbers of patients. Retrospective case-control study comparing incidence and severity of hyperglycaemia (all grades) between a case group of 387 patients treated on 18 phase I clinical trials with PAMi (78 patients with PI3Ki, 138 with mTORi, 144 with AKTi and 27 with PI3K/mTORi) and a control group of 109 patients treated on 10 phase I clinical trials with agents not directly targeting the PAM pathway. Diabetic patients were excluded in both groups. The incidence of hyperglycaemia was not significantly different between cases and controls (86.6% vs 80.7%, respectively, P=0.129). However, high grade (grade 3-4) hyperglycaemia was more frequent in the PAMi group than in controls (6.7% vs 0%, respectively, P=0.005). The incidence of grade 3-4 hyperglycaemia was greater with AKT and multikinase inhibitors compared with other PAMi (P<0.001). All patients with high-grade hyperglycaemia received antihyperglycemic treatment and none developed severe metabolic complications (diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic state). High-grade hyperglycaemia was the cause of permanent PAMi discontinuation in nine patients. PI3K-AKT-mTOR inhibitors are associated with small (6.7%) but statistically significant increased risk of high-grade hyperglycaemia compared with non-PAM targeting agents. However, PAMi-induced hyperglycaemia was not found to be associated with severe metabolic complications in this non-diabetic population of patients with advanced cancers.

Designing of Protein Kinase C β-II Inhibitors against Diabetic complications: Structure Based Drug Design, Induced Fit docking and analysis of active site conformational changes

PubMed Central

Vijayakumar, Balakrishnan; Velmurugan, Devadasan

2012-01-01

Protein Kinase C β-II (PKC β-II) is an important enzyme in the development of diabetic complications like cardiomyopathy, retinopathy, neuropathy, nephropathy and angiopathy. PKC β-II is activated in vascular tissues during diabetic vascular abnormalities. Thus, PKC β-II is considered as a potent drug target and the crystal structure of the kinase domain of PKC β-II (PDB id: 2I0E) was used to design inhibitors using Structure-Based Drug Design (SBDD) approach. Sixty inhibitors structurally similar to Staurosporine were retrieved from PubChem Compound database and High Throughput Virtual screening (HTVs) was carried out with PKC β-II. Based on the HTVs results and the nature of active site residues of PKC β-II, Staurosporine inhibitors were designed using SBDD. Induced Fit Docking (IFD) studies were carried out between kinase domain of PKC β-II and the designed inhibitors. These IFD complexes showed favorable docking score, glide energy, glide emodel and hydrogen bond and hydrophobic interactions with the active site of PKC β-II. Binding free energy was calculated for IFD complexes using Prime MM-GBSA method. The conformational changes induced by the inhibitor at the active site of PKC β-II were observed for the back bone Cα atoms and side-chain chi angles. PASS prediction tool was used to analyze the biological activities for the designed inhibitors. The various physicochemical properties were calculated for the compounds. One of the designed inhibitors successively satisfied all the in silico parameters among the others and seems to be a potent inhibitor against PKC β-II. PMID:22829732

Naringin Reverses Hepatocyte Apoptosis and Oxidative Stress Associated with HIV-1 Nucleotide Reverse Transcriptase Inhibitors-Induced Metabolic Complications

PubMed Central

Adebiyi, Oluwafeyisetan O.; Adebiyi, Olubunmi A.; Owira, Peter M. O.

2015-01-01

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) have not only improved therapeutic outcomes in the treatment of HIV infection but have also led to an increase in associated metabolic complications of NRTIs. Naringin’s effects in mitigating NRTI-induced complications were investigated in this study. Wistar rats, randomly allotted into seven groups (n = 7) were orally treated daily for 56 days with 100 mg/kg zidovudine (AZT) (groups I, II III), 50 mg/kg stavudine (d4T) (groups IV, V, VI) and 3 mL/kg of distilled water (group VII). Additionally, rats in groups II and V were similarly treated with 50 mg/kg naringin, while groups III and VI were treated with 45 mg/kg vitamin E. AZT or d4T treatment significantly reduced body weight and plasma high density lipoprotein concentrations but increased liver weights, plasma triglycerides and total cholesterol compared to controls, respectively. Furthermore, AZT or d4T treatment significantly increased oxidative stress, adiposity index and expression of Bax protein, but reduced Bcl-2 protein expression compared to controls, respectively. However, either naringin or vitamin E significantly mitigated AZT- or d4T-induced weight loss, dyslipidemia, oxidative stress and hepatocyte apoptosis compared to AZT- or d4T-only treated rats. Our results suggest that naringin reverses metabolic complications associated with NRTIs by ameliorating oxidative stress and apoptosis. This implies that naringin supplements could mitigate lipodystrophy and dyslipidemia associated with NRTI therapy. PMID:26690471

Low-Intensity Extracorporeal Shockwave Therapy Can Improve Erectile Function in Patients Who Failed to Respond to Phosphodiesterase Type 5 Inhibitors

PubMed Central

Tsai, Chia-Chun; Wang, Chii-Jye; Lee, Yung-Chin; Kuo, Yen-Ting; Lin, Hsiao-Hua; Li, Ching-Chia; Wu, Wen-Jeng; Liu, Chia-Chu

2017-01-01

Managing patients with erectile dysfunction (ED) who failed to respond to phosphodiesterase type 5 inhibitors (PDE5is) is a challenging task. Recently, low-intensity extracorporeal shockwave therapy (LI-ESWT) was reported to improve ED by enhancing perfusion of the penis. The current study was performed to evaluate whether combined treatment with LI-ESWT and PDE5is can restore erectile function in patients who failed to respond to PDE5is alone. This was an open-label single-arm prospective study. ED patients with an erection hardness score (EHS) ≦2 under a maximal dosage of PDE5is were enrolled. Sociodemographic information and detailed medical history were recorded. LI-ESWT treatment consisted of 3,000 shockwaves once weekly for 12 weeks. All patients continued their regular PDE5is use. The EHS and the 5-item version of the International Index of Erectile Function (IIEF-5) were used to evaluate the change in erectile function 1 and 3 months after LI-ESWT. A total of 52 patients were enrolled. After LI-ESWT treatment, 35 of the 52 patients (67.3%) could achieve an erection hard enough for intercourse (EHS ≧ 3) under PDE5is use at the 1-month follow-up. Initial severity of ED was the only significant predictor of a successful response (EHS1: 35.7% vs. EHS2: 78.9%, p = .005). Thirty-three of the 35 (94.3%) subjects who responded to LI-ESWT could still maintain their erectile function at the 3-month follow-up. LI-ESWT can serve as a salvage therapy for ED patients who failed to respond to PDE5is. Initial severity of ED was an important predictor of a successful response. PMID:28884638

[Proton pump inhibitor - side effects and complications of long-term proton pump inhibitor administration].

PubMed

Ueberschaer, Hendrik; Allescher, Hans-Dieter

2017-01-01

Proton Pump Inhibitors are among the most common drugs taken. The indication is for treatment of heartburn, reflux disease, prophylaxis and treatment of peptic ulcers, in combination with NSAIDs and steroids as well as H. pylori-eradication. PPI's are widely used, even with non-specific symptoms. This certainly has to do with good tolerability and a previously considered low side effect profile. At the moment, there is growing evidence that the long-term intake of PPI's may not be as safe as assumed. In addition to interactions with some drugs, including platelet aggregation inhibitors, recent studies have shown an increased risk of myocardial infarction, interstitial nephritis, chronic renal injury, infections, vitamin deficiencies and electrolyte shifts as well developing dementia. © Georg Thieme Verlag KG Stuttgart · New York.

How we use recombinant activated Factor VII in patients with haemophilia A or B complicated by inhibitors. Working group of hematology experts from Australia and New Zealand, Melbourne, April 2011.

PubMed

Brown, S A; Barnes, C; Curtin, J; Dunkley, S; Ockelford, P; Phillips, J; Rowell, J; Smith, M; Tran, H

2012-11-01

The management of bleeds in patients with haemophilia A or B complicated by inhibitors is complex. Recombinant activated Factor VII (rFVIIa; NovoSeven RT) is an established therapy in these patients. To develop a consensus-based guide on the practical usage of rFVIIa in haemophilia complicated by inhibitors, nine expert haemophilia specialists from Australia and New Zealand developed practice points on the usage of rFVIIa, based on their experience and supported by published data. Practice points were developed for 13 key topics: control of acute bleeding; prophylaxis; surgical prophylaxis; control of breakthrough bleeding during surgery or treatment of acute bleeds; paediatric use; use in elderly; intracranial haemorrhage; immune tolerance induction; difficult bleeds; clinical monitoring of therapy; laboratory monitoring of therapy; concomitant antifibrinolytic medication; practical dosing. Access to home therapy with rFVIIa is important in allowing patients to administer treatment early in bleed management. In adults, 90-120 μg/kg is the favoured starting dose in most settings. Initial dosing using 90-180 μg/kg is recommended for children due to the effect of age on the pharmacokinetics of rFVIIa. In the management of acute bleeds, 2-hourly dosing is appropriate until bleeding is controlled, with concomitant antifibrinolytic medication unless contraindicated. The practice points provide guidance on the usage of rFVIIa for all clinicians involved in the management of haemophilia complicated by inhibitors. © 2012 The Authors; Internal Medicine Journal © 2012 Royal Australasian College of Physicians.

Cost per responder of TNF-α therapies in Germany.

PubMed

Gissel, Christian; Repp, Holger

2013-12-01

Tumor necrosis factor α (TNF-α) inhibitors ranked highest in German pharmaceutical expenditure in 2011. Their most important application is the treatment of rheumatoid arthritis (RA). Our objective is to analyze cost per responder of TNF-α inhibitors for RA from the German Statutory Health Insurance funds' perspective. We aim to conduct the analysis based on randomized comparative effectiveness studies of the relevant treatments for the German setting. For inclusion of effectiveness studies, we require results in terms of response rates as defined by European League Against Rheumatism (EULAR) or American College of Rheumatology (ACR) criteria. We identify conventional triple therapy as the relevant comparator. We calculate cost per responder based on German direct medical costs. Direct clinical comparisons could be identified for both etanercept and infliximab compared to triple therapy. For infliximab, cost per responder was 216,392 euros for ACR50 and 432,784 euros for ACR70 responses. For etanercept, cost per ACR70 responder was 321,527 euros. Cost was lower for response defined by EULAR criteria, but data was only available for infliximab. Cost per responder is overestimated by 40% due to inclusion of taxes and mandatory rebates in German drugs' list prices. Our analysis shows specific requirements for cost-effectiveness analysis in Germany. Cost per responder for TNF-α treatment in the German setting is more than double the cost estimated in a similar analysis for the USA, which measured against placebo. The difference in results shows the critical role of the correct comparator for a specific setting.

EGFR-SGLT1 interaction does not respond to EGFR modulators, but inhibition of SGLT1 sensitizes prostate cancer cells to EGFR tyrosine kinase inhibitors.

PubMed

Ren, Jiangong; Bollu, Lakshmi R; Su, Fei; Gao, Guang; Xu, Lei; Huang, Wei-Chien; Hung, Mien-Chie; Weihua, Zhang

2013-09-01

Overexpression of epidermal growth factor receptor (EGFR) is associated with poor prognosis in malignant tumors. Sodium/glucose co-transporter 1 (SGLT1) is an active glucose transporter that is overexpressed in many cancers including prostate cancer. Previously, we found that EGFR interacts with and stabilizes SGLT1 in cancer cells. In this study, we determined the micro-domain of EGFR that is required for its interaction with SGLT1 and the effects of activation/inactivation of EGFR on EGFR-SGLT1 interaction, measured the expression of EGFR and SGLT1 in prostate cancer tissues, and tested the effect of inhibition of SGLT1 on the sensitivity of prostate cancer cells to EGFR tyrosine inhibitors. We found that the autophosphorylation region (978-1210 amino acids) of EGFR was required for its sufficient interaction with SGLT1 and that this interaction was independent of EGFR's tyrosine kinase activity. Most importantly, the EGFR-SGLT1 interaction does not respond to EGFR tyrosine kinase modulators (EGF and tyrosine kinase inhibitors). EGFR and SGLT1 co-localized in prostate cancer tissues, and inhibition of SGLT1 by a SGLT1 inhibitor (Phlorizin) sensitized prostate cancer cells to EGFR inhibitors (Gefitinib and Erlotinib). These data suggest that EGFR in cancer cells can exist as either a tyrosine kinase modulator responsive status or an irresponsive status. SGLT1 is a protein involved in EGFR's functions that are irresponsive to EGFR tyrosine kinase inhibitors and, therefore, the EGFR-SGLT1 interaction might be a novel target for prostate cancer therapy. © 2013 Wiley Periodicals, Inc. This article is a U.S. Government work and is in the public domain in the USA.

Gastroesophageal reflux symptoms not responding to proton pump inhibitor: GERD, NERD, NARD, esophageal hypersensitivity or dyspepsia?

PubMed Central

Bashashati, Mohammad; Hejazi, Reza A; Andrews, Christopher N; Storr, Martin A

2014-01-01

Gastroesophageal reflux (GER) is a common gastrointestinal process that can generate symptoms of heartburn and chest pain. Proton pump inhibitors (PPIs) are the gold standard for the treatment of GER; however, a substantial group of GER patients fail to respond to PPIs. In the past, it was believed that acid reflux into the esophagus causes all, or at least the majority, of symptoms attributed to GER, with both erosive esophagitis and nonerosive outcomes. However, with modern testing techniques it has been shown that, in addition to acid reflux, the reflux of nonacid gastric and duodenal contents into the esophagus may also induce GER symptoms. It remains unknown how weakly acidic or alkaline refluxate with a pH similar to a normal diet induces GER symptoms. Esophageal hypersensitivity or functional dyspepsia with superimposed heartburn may be other mechanisms of symptom generation, often completely unrelated to GER. Detailed studies investigating the pathophysiology of esophageal hypersensitivity are not conclusive, and definitions of the various disease states may overlap and are often confusing. The authors aim to clarify the pathophysiology, definition, diagnostic techniques and medical treatment of patients with heartburn symptoms who fail PPI therapy. PMID:24719900

Inhibitors in Hemophilia B.

PubMed

Santoro, Cristina; Quintavalle, Gabriele; Castaman, Giancarlo; Baldacci, Erminia; Ferretti, Antonietta; Riccardi, Federica; Tagliaferri, Annarita

2018-06-20

Hemophilia B (HB) is an X-linked bleeding disorder caused by deficiency of factor IX (FIX). Patients with the severe form (FIX <1%) account approximately for 30 to 45% of persons with HB and usually suffer from recurrent joint, soft-tissue, and muscle bleeds. The availability of safe plasma-derived and recombinant products has virtually abolished the risk of viral infections and the adoption of prophylactic regimens has attenuated the impact of hemophilic arthropathy. Therefore, the development of an inhibitor against FIX is currently the most serious complication that can still occur in the new generations of HB patients. The development of an inhibitor in HB is a rare event (1.5-3% of all patients) but is associated with a significant morbidity, related not only to the bleeding risk but also to the frequent occurrence of allergic/anaphylactic reactions and nephrotic syndrome. Due to the relative rarity of this event, few data exist about risk factors, pathophysiology, and clinical aspects of inhibitors in HB. The induction of immune tolerance is often unsuccessful and can be otherwise affected by many complications in patients with history of allergy or anaphylaxis. Therefore, alternative therapeutic strategies and new approaches are developing. The aim of this narrative review is to discuss current knowledge about risk factors, pathophysiology, and clinical aspects of this rare but serious complication. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Severe and acute complications of biologics in psoriasis.

PubMed

Oussedik, Elias; Patel, Nupur U; Cash, Devin R; Gupta, Angela S; Feldman, Steven R

2017-12-01

Biologic therapies have revolutionized the approach to immune-mediated diseases such as psoriasis. Due to their favorable safety profiles and excellent efficacy, biologic agents are considered the gold standard for moderate-to-severe psoriasis. The aim of this paper is to saliently review the severe and acute complications of the Food and Drug Administration (FDA) approved biologic agents for psoriasis. Reviewed agents include tumor necrosis factor alpha inhibitors (etanercept, infliximab, and adalimumab), interleukin 12/23 inhibitors (ustekinumab), and interleukin 17 (IL-17) inhibitors (secukinumab and ixekizumab). While malignancies, serious infections, and major adverse cardiovascular events have been reported, their association with biologic therapy are not hypothesized as causal. However, IL-17 inhibitors appear to cause exacerbations and new cases of inflammatory bowel disease. While more long-term studies are warranted in understanding the biologic's long-term side effect profile, short-term studies have confirmed that the biologics are some of the safest treatment options for psoriasis. Nevertheless, certain populations yield higher risk to acute complications with the biologics than others - physicians must use their judgement and vigilance when monitoring and treating patients undergoing therapy with biological agents.

Collateral damage: the effect of patient complications on the surgeon's psyche.

PubMed

Patel, Amit M; Ingalls, Nichole K; Mansour, M Ashraf; Sherman, Stanley; Davis, Alan T; Chung, Mathew H

2010-10-01

The effect of patient complications on physicians is not well understood. Our objective was to determine the impact of a surgeon's complication(s) on his/her emotional state and job performance. An anonymous survey was distributed to Midwest Surgical Society members and attending surgeons within the Grand Rapids, Michigan, community. There were 123 respondents (30.5% response rate). For the majority of participants, the first complication that had a significant emotional impact on them occurred during residency (51.2%). Most respondents reported this did not impair their professional functioning (77.2%). If a major complication was first experienced after residency, this had a greater likelihood of causing impairment (P < .05). Surgeons primarily dealt with the emotional impact by discussing it with a surgical partner (87.8%). Alcohol or other substance use increased in 6.5% of those surveyed. Most respondents (58.5%) felt it was difficult to handle the emotional effects of complications throughout their careers and this did not improve with experience. The majority of surgeons agreed that it was difficult to handle the emotional effects of complications throughout their careers. Efforts should be made to increase awareness of unrecognized emotional effects of patient complications and improve access to support systems for surgeons. Published by Mosby, Inc.

Incretin-Based Therapies for Diabetic Complications: Basic Mechanisms and Clinical Evidence

PubMed Central

Kawanami, Daiji; Matoba, Keiichiro; Sango, Kazunori; Utsunomiya, Kazunori

2016-01-01

An increase in the rates of morbidity and mortality associated with diabetic complications is a global concern. Glycemic control is important to prevent the development and progression of diabetic complications. Various classes of anti-diabetic agents are currently available, and their pleiotropic effects on diabetic complications have been investigated. Incretin-based therapies such as dipeptidyl peptidase (DPP)-4 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are now widely used in the treatment of patients with type 2 diabetes. A series of experimental studies showed that incretin-based therapies have beneficial effects on diabetic complications, independent of their glucose-lowering abilities, which are mediated by anti-inflammatory and anti-oxidative stress properties. Based on these findings, clinical studies to assess the effects of DPP-4 inhibitors and GLP-1RA on diabetic microvascular and macrovascular complications have been performed. Several but not all studies have provided evidence to support the beneficial effects of incretin-based therapies on diabetic complications in patients with type 2 diabetes. We herein discuss the experimental and clinical evidence of incretin-based therapy for diabetic complications. PMID:27483245

Do non-nucleoside reverse transcriptase inhibitors contribute to lipodystrophy?

PubMed

Nolan, David

2005-01-01

Lipodystrophy complications, including lipoatrophy (pathological fat loss) and metabolic complications, have emerged as important long-term toxicities associated with antiretroviral therapy in the current era. The wealth of data that has accumulated over the past 6 years has now clarified the contribution of specific antiretroviral drugs to the risk of these clinical endpoints, with evidence that lipoatrophy is strongly associated with the choice of nucleoside reverse transcriptase inhibitor therapy (specifically, stavudine and to a lesser extent zidovudine). The aetiological basis of metabolic complications of antiretroviral therapy has proven to be complex, in that the risk appears to be modulated by a number of lifestyle factors that have made the metabolic syndrome highly prevalent in the general population, with additional contributions from HIV disease status itself, as well as from individual drugs within the HIV protease inhibitor class. The currently licensed non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs, efavirenz and nevirapine, have been proven to have a favourable safety profile in terms of lipodystrophy complications. However, it must be noted that NNRTI drugs also have individual toxicity profiles that must be accounted for when considering and/or monitoring their use in the treatment of HIV infection.

The effects of joint disease, inhibitors and other complications on health-related quality of life among males with severe haemophilia A in the United States.

PubMed

Soucie, J M; Grosse, S D; Siddiqi, A-E-A; Byams, V; Thierry, J; Zack, M M; Shapiro, A; Duncan, N

2017-07-01

Health-related quality of life (HRQoL) is reduced among persons with haemophilia. Little is known about how HRQoL varies with complications of haemophilia such as inhibitors and joint disease. Estimates of preference-based HRQoL measures are needed to model the cost-effectiveness of prevention strategies. We examined the characteristics of a national sample of persons with severe haemophilia A for associations with two preference-based measures of HRQoL. We analysed utility weights converted from EuroQol 5 Dimensions (EQ-5D) and the Short Form 6 Dimensions (SF-6D) scores from 1859 males aged ≥14 years with severe haemophilia A treated at 135 US haemophilia treatment centres in 2005-2011. Bivariate and regression analyses examined age-group-specific associations of HRQoL with inhibitor status, overweight/obesity, number of bleeds, viral infections, indicators of liver and joint disease, and severe bleeding at the time of the first HRQoL measurement. Overall mean HRQoL utility weight values were 0.71 using the SF-6D and 0.78 using the EQ-5D. All studied patient characteristics except for overweight/obesity were significantly associated with HRQoL in bivariate analyses. In a multivariate analysis, only joint disease was significantly associated with utility weights from both HRQoL measures and across all age groups. After adjustment for joint disease and other variables, the presence of an inhibitor was not significantly associated with HRQoL scores from either of the standardized assessment tools. Clinically significant complications of haemophilia, especially joint disease, are strongly associated with HRQoL and should be accounted for in studies of preference-based health utilities for people with haemophilia. © 2017 John Wiley & Sons Ltd.

[Macular Edema in Uveitis - Steroids or VEGF Inhibitors?

PubMed

Heinz, Carsten; Heiligenhaus, Arnd

2017-06-09

Macular edema in uveitis patients is certainly the most frequent complication leading to a permanent and irreversible reduction in vision during the course of the disease. Thanks to optical coherence tomography (OCT) technology and fluorescein angiography (FAG), significantly more macular edemas are detected. Macular edema can be found in various uveitis varieties and can show different clinical patterns. All macular edema should be treated. Macular edema with active inflammation usually reacts very well to general uveitis treatment. In the case of eyes without visible inflammation, however, the response to such therapy is usually less effective. According to the latest treatment recommendations, dexamethasone implants should be used as the first intravitreal therapy. Vascular endothelial growth factor inhibitors (VEGF inhibitors) are second-line treatment regimens. The choice of therapy is, therefore, primarily based on the degree of inflammation and the individual complications, such as glaucoma, lens situation or previous increase in IOP after steroid administration. These individual complications may allow using VEGF inhibitors as first line treatment. An improvement in the macular edema can be achieved with both groups of active substances. Georg Thieme Verlag KG Stuttgart · New York.

Increase of weakly acidic gas esophagopharyngeal reflux (EPR) and swallowing-induced acidic/weakly acidic EPR in patients with chronic cough responding to proton pump inhibitors.

PubMed

Kawamura, O; Shimoyama, Y; Hosaka, H; Kuribayashi, S; Maeda, M; Nagoshi, A; Zai, H; Kusano, M

2011-05-01

Gastro-esophageal reflux disease (GERD)-related chronic cough (CC) may have multifactorial causes. To clarify the characteristics of esophagopharyngeal reflux (EPR) events in CC patients whose cough was apparently influenced by gastro-esophageal reflux (GER), we studied patients with CC clearly responding to full-dose proton pump inhibitor (PPI) therapy (CC patients). Ten CC patients, 10 GERD patients, and 10 healthy controls underwent 24-h ambulatory pharyngo-esophageal impedance and pH monitoring. Weakly acidic reflux was defined as a decrease of pH by >1 unit with a nadir pH >4. In six CC patients, monitoring was repeated after 8 weeks of PPI therapy. The number of each EPR event and the symptom association probability (SAP) were calculated. Symptoms were evaluated by a validated GERD symptom questionnaire. Weakly acidic gas EPR and swallowing-induced acidic/weakly acidic EPR only occurred in CC patients, and the numbers of such events was significantly higher in the CC group than in the other two groups (P < 0.05, respectively). Symptom association probability analysis revealed a positive association between GER and cough in three CC patients. Proton pump inhibitor therapy abolished swallowing-induced acidic/weakly acidic EPR, reduced weakly acidic gas EPR, and improved symptoms (all P < 0.05). Most patients with CC responding to PPI therapy had weakly acidic gas EPR and swallowing-induced acidic/weakly acidic EPR. A direct effect of acidic mist or liquid refluxing into the pharynx may contribute to chronic cough, while cough may also arise indirectly from reflux via a vago-vagal reflex in some patients. © 2011 Blackwell Publishing Ltd.

Do insulin cartridges really provide a lower risk of potential diabetes complications than traditional vials?

PubMed Central

Al-Sharayri, Mohammad G.; Aljbori, Tariq M.; Migdadi, Qusai M.; Al-Omoush, Marwa B.; Jaarah, Ayman R.

2013-01-01

Scope Recently, many publicly funded healthcare organizations suffered from an economical crisis. This forced some organizations to utilize less costly alternatives where possible. Insulin cartridges and vials are examples. Many patients are questioning the difference between the two alternatives as they contain the same active ingredient. Objective To find out if insulin cartridges really provide a lower risk of potential diabetes complications than traditional vials. Method A questionnaire was used to ask two random samples of diabetic patients about the development of some diabetes complications. The first sample (n = 41) consisted of patients using cartridges; the second sample (n = 40) consisted of patients using vials. Patients were randomly selected from the endocrine clinic and the out-patient pharmacy in Al-Hussein Hospital in King Hussein Medical Center in Amman- Jordan. Results 44% of respondents in the first sample did not suffer from any complication; on the other hand, the percentage was only 15% of respondents in the second sample. All respondents (100%) in the first sample suffered from only 2 complications or less; however, 25% of the respondents in the second sample suffered from 3 or more complications. Nephropathy complications, were slightly higher in the first sample; 22% compared to 15% in the second sample. On the other hand, all complications reported in the second sample were higher; 30% for neuropathy, 65% for retinopathy complications and 42.5% for extremities damage compared to only 9.7%, 7.3% and 26.8% respectively in the first sample. Conclusion In general, respondents who were using cartridges reported a lesser incidence of diabetes complications. Although many organizations suffered from an economical crisis, the cost-effectiveness aspect should be taken into consideration when purchasing medical alternatives. This will provide higher quality of life for patients and eventually lower hidden and future costs for the organizations

Do insulin cartridges really provide a lower risk of potential diabetes complications than traditional vials?

PubMed

Al-Sharayri, Mohammad G; Aljbori, Tariq M; Migdadi, Qusai M; Al-Omoush, Marwa B; Jaarah, Ayman R

2014-09-01

Recently, many publicly funded healthcare organizations suffered from an economical crisis. This forced some organizations to utilize less costly alternatives where possible. Insulin cartridges and vials are examples. Many patients are questioning the difference between the two alternatives as they contain the same active ingredient. To find out if insulin cartridges really provide a lower risk of potential diabetes complications than traditional vials. A questionnaire was used to ask two random samples of diabetic patients about the development of some diabetes complications. The first sample (n = 41) consisted of patients using cartridges; the second sample (n = 40) consisted of patients using vials. Patients were randomly selected from the endocrine clinic and the out-patient pharmacy in Al-Hussein Hospital in King Hussein Medical Center in Amman- Jordan. 44% of respondents in the first sample did not suffer from any complication; on the other hand, the percentage was only 15% of respondents in the second sample. All respondents (100%) in the first sample suffered from only 2 complications or less; however, 25% of the respondents in the second sample suffered from 3 or more complications. Nephropathy complications, were slightly higher in the first sample; 22% compared to 15% in the second sample. On the other hand, all complications reported in the second sample were higher; 30% for neuropathy, 65% for retinopathy complications and 42.5% for extremities damage compared to only 9.7%, 7.3% and 26.8% respectively in the first sample. In general, respondents who were using cartridges reported a lesser incidence of diabetes complications. Although many organizations suffered from an economical crisis, the cost-effectiveness aspect should be taken into consideration when purchasing medical alternatives. This will provide higher quality of life for patients and eventually lower hidden and future costs for the organizations.

Inga laurina trypsin inhibitor (ILTI) obstructs Spodoptera frugiperda trypsins expressed during adaptive mechanisms against plant protease inhibitors.

PubMed

Machado, Suzy Wider; de Oliveira, Caio Fernando Ramalho; Zério, Neide Graciano; Parra, José Roberto Postali; Macedo, Maria Lígia Rodrigues

2017-08-01

Plant protease inhibitors (PIs) are elements of a common plant defense mechanism induced in response to herbivores. The fall armyworm, Spodoptera frugiperda, a highly polyphagous lepidopteran pest, responds to various PIs in its diet by expressing genes encoding trypsins. This raises the question of whether the PI-induced trypsins are also inhibited by other PIs, which we posed as the hypothesis that Inga laurina trypsin inhibitor (ILTI) inhibits PI-induced trypsins in S. frugiperda. In the process of testing our hypothesis, we compared its properties with those of selected PIs, soybean Kunitz trypsin inhibitor (SKTI), Inga vera trypsin inhibitor (IVTI), Adenanthera pavonina trypsin inhibitor (ApTI), and Entada acaciifolia trypsin inhibitor (EATI). We report that ILTI is more effective in inhibiting the induced S. frugiperda trypsins than SKTI and the other PIs, which supports our hypothesis. ILTI may be more appropriate than SKTI for studies regarding adaptive mechanisms to dietary PIs. © 2017 Wiley Periodicals, Inc.

Complicated grief therapy as a new treatment approach.

PubMed

Wetherell, Julie Loebach

2012-06-01

Complicated grief therapy (CGT) is a relatively new psychotherapy model designed to address symptoms of complicated grief. Drawn from attachment theory and with roots in both interpersonal therapy (IPT) and cognitive-behavioral therapy, CGT includes techniques similar to prolonged exposure (repeatedly telling the story of the death and in vivo exposure activities). The treatment also involves focusing on personal goals and relationships. CGT has been demonstrated to be effective in a trial in which participants with complicated grief were randomly assigned to CGT or IPT; individuals receiving CGT responded more quickly and were more likely to respond overall (51% vs 28%). This article briefly summarizes the conceptual underpinnings of CGT, discusses the empirical evidence for its efficacy, describes its techniques, and presents a case example of a client treated in a 16-session manualized CGT protocol. The article concludes with a description of future research directions for CGT.

Complicated grief therapy as a new treatment approach

PubMed Central

Wetherell, Julie Loebach

2012-01-01

Complicated grief therapy (CGT) is a relatively new psychotherapy model designed to address symptoms of complicated grief. Drawn from attachment theory and with roots in both interpersonal therapy (IPT) and cognitive-behavioral therapy, CGT includes techniques similar to prolonged exposure (repeatedly telling the story of the death and in vivo exposure activities). The treatment also involves focusing on personal goals and relationships. CGT has been demonstrated to be effective in a trial in which participants with complicated grief were randomly assigned to CGT or IPT; individuals receiving CGT responded more quickly and were more likely to respond overall (51 % vs 28%). This article briefly summarizes the conceptual underpinnings of CGT, discusses the empirical evidence for its efficacy, describes its techniques, and presents a case example of a client treated in a 16-session manualized CGT protocol. The article concludes with a description of future research directions for CGT. PMID:22754288

Cardiovascular Toxicity of Cyclooxygenase Inhibitors and Promising Natur a l Substitutes.

PubMed

Bahmani, Mahmoud; Sarrafchi, Amir; Shirzad, Hedayatollah; Asgari, Sedigheh; Rafieian-Kopaei, Mahmoud

2017-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are a group of drugs which are used for a wide variety of diseases including pain and inflammatory conditions such as osteoarthritis, rheumatoid arthritis, musculoskeletal disorders, and other comorbid complications. However, this group of drugs have undesirable effects such as peptic ulcer, bleeding and renal failure. Some of these side effects are associated with or caused by generation of oxidative stress. Following the withdrawal of a cyclo-oxygenase-2 (COX-2) inhibitor drug, rofecoxib (VIOXX®) due to cardiovascular complications, scientists suggested that natural COX-2 inhibitors might provide valuable alternatives to COX inhibitors. Although, most of medicinal plants reduce pain and inflammation in a similar manner to synthetic medications, however, they often have fewer side effects and are better tolerated. The present review other than focusing on cardiovascular and some other complications of NSAIDs, is trying to introduce the natural alternative remedies for these medications. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The effect of tumor necrosis factor inhibitor therapy on the incidence of myocardial infarction in patients with psoriasis: a retrospective study.

PubMed

Shaaban, Dalia; Al-Mutairi, Nawaf

2018-02-01

Psoriasis has been shown to be associated with increased incidence of myocardial infarction (MI). The data on the effect of tumor necrosis factor (TNF) inhibitors on MI in psoriasis are scarce. To evaluate the effect of TNF inhibitors on the risk of MI in psoriasis patients compared with methotrexate (MTX) and topical agents. Data were obtained from the Electronic Health Records database of Farwaniya Hospital from psoriasis patients seen from January 2008 to December 2014. Patients were categorized into TNF inhibitor, MTX and topical cohorts. The study included 4762 psoriasis patients. Both TNF inhibitor and MTX cohorts showed a statistically lower rate of MI compared with topical cohort. However, there was no statistically significant difference in MI rate between TNF inhibitor and MTX cohorts (P = .32). The probability of MI was lower in TNF inhibitor responders compared with non-responders (p = .001). The use of TNF inhibitors in psoriasis showed a significant reduction in the risk of MI compared with topical agents and a non-significant reduction compared with MTX. Responders to TNF inhibitor therapy showed a reduction in MI rate compared with non-responders.

Combining neuroendocrine inhibitors in heart failure: reflections on safety and efficacy.

PubMed

Jneid, Hani; Moukarbel, George V; Dawson, Bart; Hajjar, Roger J; Francis, Gary S

2007-12-01

Neuroendocrine activation in heart failure has become the major target of pharmacotherapy for this growing epidemic. Agents targeting the renin-angiotensin-aldosterone and sympathetic nervous systems have shown cardiovascular and survival benefits in clinical trials. Beta-blockers and angiotensin-converting enzyme (ACE) inhibitors remain the mainstream initial therapy. The benefits of aldosterone antagonists have been demonstrated in advanced heart failure (spironolactone) and after myocardial infarction complicated by left ventricular dysfunction and heart failure (eplerenone). Emerging clinical evidence demonstrated that angiotensin receptor blockers may be a reasonable alternative to ACE inhibitors in patients with heart failure (candesartan) and following myocardial infarction complicated by heart failure or left ventricular dysfunction (valsartan). Angiotensin receptor blockers (candesartan) also provided incremental benefits when added to ACE inhibitors in chronic heart failure. Thus, combining neuroendocrine inhibitors in heart failure appears both biologically plausible and evidence-based. However, this approach raised concerns about side effects, such as hypotension, renal insufficiency, hyperkalemia, and others. Close follow-up and implementation of evidence-based medicine (ie, using agents and doses proven beneficial in clinical trials) should therefore be undertaken when combining neuroendocrine inhibitors.

QUANTITATIVE STUDIES ON THE TOTAL PLASMIN AND THE TRYPSIN INHIBITOR OF HUMAN BLOOD SERUM

PubMed Central

Todd, Edgar W.

1949-01-01

The total plasmin and the trypsin inhibitor were titrated separately in samples of serum taken at weekly intervals from three different groups of scarlet fever patients: (a) those who did not develop any complications, (b) those who developed purulent complications, and (c) those who developed rheumatic fever. When these determinations were plotted, it was found that the resulting curves showed characteristic patterns for each of the diseases investigated. The uncomplicated cases had plasmin curves which were considerably higher on the charts than the inhibitor curves. The septic cases had plasmin and inhibitor curves which were closer together on the charts. The rheumatic cases had plasmin and inhibitor curves which were close together and which crossed at the time of rheumatic activity so that the inhibitor curve reached a higher level than the plasmin curve. PMID:18110885

Complications associated with radiofrequency ablation of pulmonary veins.

PubMed

Madrid Pérez, J M; García Barquín, P M; Villanueva Marcos, A J; García Bolao, J I; Bastarrika Alemañ, G

Radiofrequency ablation is an efficacious alternative in patients with symptomatic atrial fibrillation who do not respond to or are intolerant to at least one class I or class III antiarrhythmic drug. Although radiofrequency ablation is a safe procedure, complications can occur. Depending on the location, these complications can be classified into those that affect the pulmonary veins themselves, cardiac complications, extracardiac intrathoracic complications, remote complications, and those that result from vascular access. The most common complications are hematomas, arteriovenous fistulas, and pseudoaneurysms at the puncture site. Some complications are benign and transient, such as gastroparesis or diaphragmatic elevation, whereas others are potentially fatal, such as cardiac tamponade. Radiologists must be familiar with the complications that can occur secondary to pulmonary vein ablation to ensure early diagnosis and treatment. Copyright © 2016 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

New treatments for levodopa-induced motor complications.

PubMed

Rascol, Olivier; Perez-Lloret, Santiago; Ferreira, Joaquim J

2015-09-15

Levodopa (l-dopa)-induced motor complications, including motor fluctuations and dyskinesia, affect almost all patients with Parkinson's disease (PD) at some point during the disease course, with relevant implications in global health status. Various dopaminergic and nondopaminergic pharmacological approaches as well as more invasive strategies including devices and functional surgery are available to manage such complications. In spite of undisputable improvements during the last decades, many patients remain significantly disabled, and a fully satisfying management of l-dopa-induced motor complications is still an important unmet need of PD therapy. This article reviews the recent trial results published from 2013 to April 2015 about pharmacological and nonpharmacological interventions to treat motor complications. Randomized controlled trials conducted in patients suffering from already established complications showed that new levodopa (l-dopa) formulations such as intrajejunal l-dopa-carbidopa infusion and bilayered extended-release l-dopa-carbidopa (IPX066) can improve motor fluctuations. Positive results were also obtained with a new monoamine oxidase B (MAO-B) inhibitor (safinamide) and a catechol-O-methyltransferase COMT inhibitor (opicapone). Pilot data suggest that new formulations of dopamine agonists (inhaled apomorphine) are also of potential interest. The development of novel nondopaminergic adenosine A2A antagonists (istradefylline, preladenant, and tozadenant) to treat motor fluctuations showed conflicting results in phase 2 and phase 3 trials. For dyskinesia, trials with new amantadine extended-release formulations confirmed the interest of the glutamatergic N-methyl-d-aspartate (NMDA) antagonist approach. Positive pilot antidyskinetic effects were also recently reported using serotonin agents such as eltoprazine and glutamate mGluR5 modulators such as mavoglurant. However, the translation to clinical practice of such innovative concepts remains

Matrix Metalloproteinase Responsive Delivery of Myostatin Inhibitors.

PubMed

Braun, Alexandra C; Gutmann, Marcus; Ebert, Regina; Jakob, Franz; Gieseler, Henning; Lühmann, Tessa; Meinel, Lorenz

2017-01-01

The inhibition of myostatin - a member of the transforming growth factor (TGF-β) family - drives regeneration of functional skeletal muscle tissue. We developed a bioresponsive drug delivery system (DDS) linking release of a myostatin inhibitor (MI) to inflammatory flares of myositis to provide self-regulated MI concentration gradients within tissues of need. A protease cleavable linker (PCL) - responding to MMP upregulation - is attached to the MI and site-specifically immobilized on microparticle surfaces. The PCL disintegrated in a matrix metalloproteinase (MMP) 1, 8, and particularly MMP-9 concentration dependent manner, with MMP-9 being an effective surrogate biomarker correlating with the activity of myositis. The bioactivity of particle-surface bound as well as released MI was confirmed by luciferase suppression in stably transfected HEK293 cells responding to myostatin induced SMAD phosphorylation. We developed a MMP-responsive DDS for MI delivery responding to inflammatory flare of a diseased muscle matching the kinetics of MMP-9 upregulation, with MMP-9 kinetics matching (patho-) physiological myostatin levels. ᅟ: Graphical Abstract Schematic illustration of the matrix metalloproteinase responsive delivery system responding to inflammatory flares of muscle disease. The protease cleavable linker readily disintegrates upon entry into the diseased tissue, therby releasing the mystatin inhibitor.

Inhibitor development and mortality in non-severe hemophilia A.

PubMed

Eckhardt, C L; Loomans, J I; van Velzen, A S; Peters, M; Mauser-Bunschoten, E P; Schwaab, R; Mazzucconi, M G; Tagliaferri, A; Siegmund, B; Reitter-Pfoertner, S E; van der Bom, J G; Fijnvandraat, K

2015-07-01

The life expectancy of non-severe hemophilia A (HA) patients equals the life expectancy of the non-hemophilic population. However, data on the effect of inhibitor development on mortality and on hemophilia-related causes of death are scarce. The development of neutralizing factor VIII antibodies in non-severe HA patients may dramatically change their clinical outcome due to severe bleeding complications. We assessed the association between the occurrence of inhibitors and mortality in patients with non-severe HA. In this retrospective cohort study, clinical data and vital status were collected for 2709 non-severe HA patients (107 with inhibitors) who were treated between 1980 and 2011 in 34 European and Australian centers. Mortality rates for patients with and without inhibitors were compared. During 64,200 patient-years of follow-up, 148 patients died (mortality rate, 2.30 per 1000 person-years; 95% confidence interval (CI), 1.96-2.70) at a median age of 64 years (interquartile range [IQR], 49-76). In 62 patients (42%) the cause of death was hemophilia related. Sixteen inhibitor patients died at a median age of 71 years (IQR, 60-81). In ten patients the inhibitor was present at time of death; seven of them died of severe bleeding complications. The all-cause mortality rate in inhibitor patients was > 5 times increased compared with that for those without inhibitors (age-adjusted mortality rate ratio, 5.6). Inhibitor development in non-severe hemophilia is associated with increased mortality. High rates of hemophilia-related mortality in this study indicate that non-severe hemophilia is not mild at all and stress the importance of close follow-up for these patients. © 2015 International Society on Thrombosis and Haemostasis.

Cost of care of haemophilia with inhibitors.

PubMed

Di Minno, M N D; Di Minno, G; Di Capua, M; Cerbone, A M; Coppola, A

2010-01-01

In Western countries, the treatment of patients with inhibitors is presently the most challenging and serious issue in haemophilia management, direct costs of clotting factor concentrates accounting for >98% of the highest economic burden absorbed for the healthcare of patients in this setting. Being designed to address questions of resource allocation and effectiveness, decision models are the golden standard to reliably assess the overall economic implications of haemophilia with inhibitors in terms of mortality, bleeding-related morbidity, and severity of arthropathy. However, presently, most data analyses stem from retrospective short-term evaluations, that only allow for the analysis of direct health costs. In the setting of chronic diseases, the cost-utility analysis, that takes into account the beneficial effects of a given treatment/healthcare intervention in terms of health-related quality of life, is likely to be the most appropriate approach. To calculate net benefits, the quality adjusted life year, that significantly reflects such health gain, has to be compared with specific economic impacts. Differences in data sources, in medical practice and/or in healthcare systems and costs, imply that most current pharmacoeconomic analyses are confined to a narrow healthcare payer perspective. Long-term/lifetime prospective or observational studies, devoted to a careful definition of when to start a treatment; of regimens (dose and type of product) to employ, and of inhibitor population (children/adults, low-responding/high responding inhibitors) to study, are thus urgently needed to allow for newer insights, based on reliable data sources into resource allocation, effectiveness and cost-utility analysis in the treatment of haemophiliacs with inhibitors.

Complications of gastro-oesophageal reflux disease.

PubMed

Parasa, S; Sharma, P

2013-06-01

Gastro-oesophageal reflux disease (GORD) is on the rise with more than 20% of the western population reporting symptoms and is the most common gastrointestinal disorder in the United States. This increase in GORD is not exactly clear but has been attributed to the increasing prevalence of obesity, changing diet, and perhaps the decreasing prevalence of H. pylori infection. Complications of GORD could be either benign or malignant. Benign complications include erosive oesophagitis, bleeding and peptic strictures. Premalignant and malignant lesions include Barrett's metaplasia, and oesophageal cancer. Management of both the benign and malignant complications can be challenging. With the use of proton-pump inhibitors, peptic strictures (i.e., strictures related to reflux) have significantly declined. Several aspects of Barrett's management remain controversial including the stage in the disease process which needs to be intervened, type of the intervention and surveillance of these lesions to prevent development of high grade dysplasia and oesophageal adenocarcinoma. Copyright © 2013 Elsevier Ltd. All rights reserved.

[Immune checkpoints inhibitors: Recent data from ASCO's meeting 2017 and perspectives].

PubMed

Kfoury, Maria; Disdero, Valentine; Vicier, Cécilé; Le Saux, Olivia; Gougis, Paul; Sajous, Christophe; Vignot, Stéphane

2018-06-19

Immune checkpoint inhibitors anti-PD-1, anti-PD-L1 and anti-CTLA-4 have been in development in several indications and have changed the face of cancer patients' management. Cancer immunotherapy was central in ASCO's meeting 2017. The identification of patients who could benefit most from immune checkpoint inhibitors is essential. The predictive value of PD-L1 status remains insufficient to select patients who could respond to immunotherapy. An extended search for new biomarkers predictive of response (INF-γ, mutational load) is ongoing, in order to better select responders. Immune checkpoint inhibitors have mainly been developed as monotherapy. However, the low response rate, between 10 and 30%, and the occurrence of resistance, contributes to the increment of new therapeutic strategies. This review summarizes the results of combination trials of two immune checkpoint inhibitors, combination of immunotherapy with conventional chemotherapy, radiotherapy or targeted therapies active on the oncogenic addiction pathway. Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Achievements, challenges and unmet needs for haemophilia patients with inhibitors

PubMed Central

DARGAUD, Y.; PAVLOVA, A.; LACROIX-DESMAZES, S.; FISCHER, K.; SOUCIE, M.; CLAEYSSENS, S.; SCOTT, D.W.; d’OIRON, R.; LAVIGNE-LISSALDE, G.; KENET, G.; ETTINGSHAUSEN, C. ESCURIOLA; BOREL-DERLON, A.; LAMBERT, T.; PASTA, G.; NÉGRIER, C.

2016-01-01

Summary Over the past 20 years, there have been many advances in haemophilia treatment that have allowed patients to take greater control of their disease. However, the development of factor VIII (FVIII) inhibitors is the greatest complication of the disease and a challenge in the treatment of haemophilia making management of bleeding episodes difficult and surgical procedures very challenging. A meeting to discuss the unmet needs of haemophilia patients with inhibitors was held in Paris on 20 November 2014. Topics discussed were genetic and non-genetic risk factors for the development of inhibitors, immunological aspects of inhibitor development, FVIII products and inhibitor development, generation and functional properties of engineered antigen-specific T regulatory cells, suppression of immune responses to FVIII, prophylaxis in haemophilia patients with inhibitors, epitope mapping of FVIII inhibitors, current controversies in immune tolerance induction therapy, surgery in haemophilia patients with inhibitors and future perspectives for the treatment of haemophilia patients with inhibitors. A summary of the key points discussed is presented in this paper. PMID:26728503

ALK Inhibitor Response in Melanomas Expressing EML4-ALK Fusions and Alternate ALK Isoforms.

PubMed

Couts, Kasey L; Bemis, Judson; Turner, Jacqueline A; Bagby, Stacey M; Murphy, Danielle; Christiansen, Jason; Hintzsche, Jennifer D; Le, Anh; Pitts, Todd M; Wells, Keith; Applegate, Allison; Amato, Carol; Multani, Pratik; Chow-Maneval, Edna; Tentler, John J; Shellman, Yiqun G; Rioth, Matthew J; Tan, Aik-Choon; Gonzalez, Rene; Medina, Theresa; Doebele, Robert C; Robinson, William A

2018-01-01

Oncogenic ALK fusions occur in several types of cancer and can be effectively treated with ALK inhibitors; however, ALK fusions and treatment response have not been characterized in malignant melanomas. Recently, a novel isoform of ALK ( ALK ATI ) was reported in 11% of melanomas but the response of melanomas expressing ALK ATI to ALK inhibition has not been well characterized. We analyzed 45 melanoma patient-derived xenograft models for ALK mRNA and protein expression. ALK expression was identified in 11 of 45 (24.4%) melanomas. Ten melanomas express wild-type (wt) ALK and/or ALK ATI and one mucosal melanoma expresses multiple novel EML4-ALK fusion variants. Melanoma cells expressing different ALK variants were tested for response to ALK inhibitors. Whereas the melanoma expressing EML4-ALK were sensitive to ALK inhibitors in vitro and in vivo , the melanomas expressing wt ALK or ALK ATI were not sensitive to ALK inhibitors. In addition, a patient with mucosal melanoma expressing ALK ATI was treated with an ALK/ROS1/TRK inhibitor (entrectinib) on a phase I trial but did not respond. Our results demonstrate ALK fusions occur in malignant melanomas and respond to targeted therapy, whereas melanomas expressing ALK ATI do not respond to ALK inhibitors. Targeting ALK fusions is an effective therapeutic option for a subset of melanoma patients, but additional clinical studies are needed to determine the efficacy of targeted therapies in melanomas expressing wt ALK or ALK ATI Mol Cancer Ther; 17(1); 222-31. ©2017 AACR . ©2017 American Association for Cancer Research.

Myasthenia triggered by immune checkpoint inhibitors: New case and literature review.

PubMed

Gonzalez, Natalia L; Puwanant, Araya; Lu, Angela; Marks, Stanley M; Živković, Saša A

2017-03-01

Immune checkpoint molecules are potent regulators of immunologic homeostasis that prevent the development of autoimmunity while maintaining self-tolerance. Inhibitors of immune checkpoint molecules are used as immunotherapy in the treatment of melanoma and different types of refractory cancer, and can trigger various autoimmune complications including myositis and myasthenia gravis. We describe a case of generalized myasthenia gravis induced by pembrolizumab and review 11 other cases. Five patients also had elevated serum CK levels ranging from 1200 to 8729 IU/L, and biopsy showed myositis in one. Severity was highly variable as symptoms normalized spontaneously in one patient, but three others developed myasthenic crisis (including two with fatal outcomes). Steroids have been recommended as a preferred treatment of autoimmune complications of immune-checkpoint inhibitors. Myasthenia gravis should be considered when weakness, diplopia or bulbar symptoms are seen after treatment with immune checkpoint inhibitors, and additional studies are needed to characterize association with hyperCKemia. Copyright © 2017 Elsevier B.V. All rights reserved.

HIV-1 protease inhibitor mutations affect the development of HIV-1 resistance to the maturation inhibitor bevirimat.

PubMed

Fun, Axel; van Maarseveen, Noortje M; Pokorná, Jana; Maas, Renée Em; Schipper, Pauline J; Konvalinka, Jan; Nijhuis, Monique

2011-08-24

proteases. These findings highlight the complicated interactions between the viral protease and its substrate. By providing a better understanding of these interactions, we aim to help guide the development of second generation maturation inhibitors.

Preventing microvascular complications in type 1 diabetes mellitus

PubMed Central

Viswanathan, Vijay

2015-01-01

Patients with complications of diabetes such as retinopathy, nephropathy, and cardiovascular complications have increased hospital stay with greater economic burden. Prevention of complications should be started before the onset of type 1 diabetes mellitus (T1DM) by working on risk factors and thereafter by intervention upon confirmatory diagnosis which can prevent further damage to β-cells. The actual risk of getting microvascular complications like microalbuminuria and retinopathy progression starts at glycated hemoglobin (HbA1c) level of 7%. As per the American Diabetes Association, a new pediatric glycemic control target of HbA1c <7.5% across all ages replaces previous guidelines that had called for different targets by age. Evidence shows that prevalence of microvascular complications is greater in patients with age >20 years as compared to patients <10 years of age. Screening of these complications should be done regularly, and appropriate preventive strategies should be followed. Angiotensin converting enzyme inhibitors and angiotensin II receptor blocker reduce progression from microalbuminuria to macroalbuminuria and increase the regression rate to normoalbuminuria. Diabetic microvascular complications can be controlled with tight glycemic therapy, dyslipidemia management and blood pressure control along with renal function monitoring, lifestyle changes, including smoking cessation and low-protein diet. An integrated and personalized care would reduce the risk of development of microvascular complications in T1DM patients. The child with diabetes who receives limited care is more likely to develop long-term complications at an earlier age. Screening for subclinical complications and early interventions with intensive therapy is the need of the hour. PMID:25941647

Calcineurin-inhibitor pain syndrome.

PubMed

Prommer, Eric

2012-07-01

There has been increased recognition of calcineurin, a phosphoprotein serine/threonine phosphatase enzyme, in the regulation of many physiologic systems. Calcineurin mediates activation of lymphocytes, which play a role in immune response. Widely distributed in the central nervous system, calcinuerin also plays an important role in sensory neural function, via its role in the regulation of newly discovered 2-pore potassium channels, which greatly influence neuronal resting membrane potentials. Calcinuerin inhibition is the mechanism of action of immunomodulatory drugs such as cyclosporine and tacrolimus, which are widely used in transplantation medicine to prevent rejection. While important for immunosuppression, the use of calcineurin inhibitors has been associated with the development of a new pain syndrome called the calcineurin pain syndrome, which appears to be an untoward complication of the interruption of the physiologic function of calcineurin. This is a narrative review focusing on the epidemiology, pathophysiology, characterization of a newly recognized pain syndrome associated with the use of calcineurin inhibitors. The use of immunosuppressants however is associated with several well-known toxicities to which the calcineurin pain syndrome can be added. The development of this syndrome most likely involves altered nociceptive processing due to the effect of calcineurin inhibition on neuronal firing, as well as effects of calcineurin on vascular tone. The most striking aspect of the treatment of this syndrome is the response to calcium channel blockers, which suggest that the effects of calcineurin inhibition on vascular tone play an important role in the development of the calcineurin pain syndrome. The calcineurin syndrome is a newly recognized complication associated with the use of calcineurin inhibitors. There is no standard therapy at this time but anecdotal reports suggest the effectiveness of calcium channel blockers.

Ceftazidime-avibactam: novel antimicrobial combination for the treatment of complicated urinary tract infections.

PubMed

Alidjanov, Jakhongir F; Fritzenwanker, Moritz; Hoffman, Ivan; Wagenlehner, Florian M

2017-06-01

Ceftazidime-avibactam is a combination of a third-generation cephalosporin and a novel non-beta-lactam beta-lactamase inhibitor. This combination was recently recommended for the treatment of complicated urinary tract infections, including acute pyelonephritis, in adults with limited or no alternative treatment options. The current review is aimed to determine activity, efficacy and safety of ceftazidime-avibactam in the treatment of patients with complicated urinary tract infections.

Immunotherapy, an evolving approach for the management of triple negative breast cancer: Converting non-responders to responders.

PubMed

Tolba, Mai F; Omar, Hany A

2018-02-01

Immunotherapy comprises a promising new era in cancer therapy. Immune checkpoint inhibitors targeting either the programmed death (PD)-1 receptor or its ligand PD-L1 were first approved by the Food and Drug Administration (FDA) for the management of metastatic melanoma in 2011. The approval of this class is being extended to include other types of immunogenic tumors. Although breast cancer (BC) was first categorized as non-immunogenic tumor type, there are certain subsets of BC that showed a high level of tumor infiltrating lymphocytes (TILs). Those subsets include the triple negative breast cancer (TNBC) and HER-2 positive breast tumors. Preliminary data from clinical trials presented promising outcomes for patients with advanced stage/metastatic TNBC. While the objective response rate (ORR) was relatively low, it is still promising because of the observation that the patients who respond to the treatment with immune checkpoint blockade have favorable prognosis and often show a significant increase in the overall survival. Therefore, the main challenge is to find ways to enhance the tumor response to such therapy and to convert the non-responders to responders. This will consequently bring new hopes for patients with advanced stage metastatic TNBC and help to decrease death tolls from this devastating disease. In the current review, we are highlighting and discussing the up-to-date strategies adopted at either the preclinical or the clinical settings to enhance tumor responsiveness to immunotherapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Proton-pump inhibitors are associated with a reduced risk for bleeding and perforated gastroduodenal ulcers attributable to non-steroidal anti-inflammatory drugs: a nested case-control study

PubMed Central

Vonkeman, Harald E; Fernandes, Robert W; van der Palen, Job; van Roon, Eric N; van de Laar, Mart AFJ

2007-01-01

Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by gastrointestinal ulcer complications, such as ulcer bleeding and perforation. The efficacy of proton-pump inhibitors in the primary prevention of ulcer complications arising from the use of NSAIDs remains unproven. Selective cyclooxygenase-2 (COX-2) inhibitors reduce the risk for ulcer complications, but not completely in high-risk patients. This study determines which patients are especially at risk for NSAID ulcer complications and investigates the effectiveness of different preventive strategies in daily clinical practice. With the use of a nested case-control design, a large cohort of NSAID users was followed for 26 months. Cases were patients with NSAID ulcer complications necessitating hospitalisation; matched controls were selected from the remaining cohort of NSAID users who did not have NSAID ulcer complications. During the observational period, 104 incident cases were identified from a cohort of 51,903 NSAID users with 10,402 patient years of NSAID exposure (incidence 1% per year of NSAID use, age at diagnosis 70.4 ± 16.7 years (mean ± SD), 55.8% women), and 284 matched controls. Cases were characterised by serious, especially cardiovascular, co-morbidity. In-hospital mortality associated with NSAID ulcer complications was 10.6% (incidence 21.2 per 100,000 NSAID users). Concomitant proton-pump inhibitors (but not selective COX-2 inhibitors) were associated with a reduced risk for NSAID ulcer complications (the adjusted odds ratio 0.33; 95% confidence interval 0.17 to 0.67; p = 0.002). Especially at risk for NSAID ulcer complications are elderly patients with cardiovascular co-morbidity. Proton-pump inhibitors are associated with a reduced risk for NSAID ulcer complications. PMID:17521422

TRUST trial: BAY 86-6150 use in haemophilia with inhibitors and assessment for immunogenicity.

PubMed

Mahlangu, J; Paz, P; Hardtke, M; Aswad, F; Schroeder, J

2016-11-01

The most serious and challenging complication of haemophilia treatment is development of inhibitors to replacement factors VIII or IX. Innovative therapies currently being explored for patients with haemophilia and inhibitors include BAY 86-6150, a modified recombinant activated factor VII (FVIIa). Immunogenicity remains a substantial barrier in this endeavour. To present safety and efficacy results of the BAY 86-6150 study in patients with inhibitors and report detailed analysis of epitope mapping in a patient who developed anti-BAY 86-6150 antibodies. Patients aged 12-62 years with moderate or severe haemophilia A or B were eligible for the phase 3 TRUST trial if they had a history of high-titre inhibitors. Four escalating doses of BAY 86-6150 (6.5, 20, 50, 90 μg kg -1 ) were planned with ≥10 patients per dose level. Bleeding episodes were treated with BAY 86-6150. Development of anti-BAY 86-6150 antibodies was considered a serious adverse event. TRUST was discontinued after one patient in the 6.5-μg kg -1 cohort developed anti-BAY 86-6150 neutralizing antibodies following three exposures. The anti-BAY 86-6150 antibodies cross-reacted with and neutralized wild-type FVIIa (WT-FVIIa). Post hoc epitope mapping using peripheral blood mononuclear cells from the responding patient found that none of the 14 peptides unique to BAY 86-6150 were recognized by the patient's T cells, but strong responses were detected against 2 WT-FVIIa peptides. In the single patient with haemophilia A who developed anti-BAY 86-6150 antibodies, results of T-cell epitope mapping indicated BAY 86-6150 was no more immunogenic than WT-FVIIa. © 2016 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

A retrospective analysis and case series of glycoprotein IIb/IIIa inhibitor associated diffuse alveolar hemorrhage: two case reports

PubMed Central

Mikkilineni, Hima; Bruhl, Steven R; Pandya, Utpal

2009-01-01

Introduction Glycoprotein IIb/IIIa inhibitors have a key role in the treatment of patients with acute coronary syndromes undergoing percutaneous interventions. Although, an increased risk of bleeding complications is well recognized, its association with diffuse alveolar hemorrhage is much less recognized. Previous authors have suggested that the incidence of glycoprotein IIb/IIIa inhibitor associated diffuse alveolar hemorrhage has been significantly underestimated due to under reporting. Case presentations In order to help better determine the incidence of GP IIb/IIIa inhibitor associated DAH, a retrospective review of medical records was conducted over a 1 year period at a single high volume medical hospital. The medical records of all patients diagnosed with diffuse alveolar hemorrhage were evaluated for treatment with a GP IIb/IIIa inhibitor within 48 hours of its diagnosis. Each patient meeting the inclusion and exclusion criteria were included in the case series. This number was compared with the total number of patients receiving a GP IIb/IIIa inhibitor during the same time period and an incidence of the complication was calculated. 292 patients received either abciximab or eptifibatide during the one year review period and two patients were diagnosed with diffuse alveolar hemorrhage confirmed by serial bronchiolar lavage for an incidence of 0.68%. Of the total 292 patients receiving GP IIb/IIIa inhibitors, 172 patients received abciximab with one occurrence of diffuse alveolar hemorrhage for an incidence of 0.58% while 120 patients received eptifibatide with one occurrence for an incidence of 0.83%. Both patients developed significant morbidity as a result of the complication and 1 of the 2 patients died as a complication of the disease. Conclusions Our findings support the claim that the incidence of GP IIb/IIIa induced diffuse alveolar hemorrhage is substantially higher than initially suggested by drug manufacturer studies. Although these drugs have

Health complications of female genital mutilation in Sierra Leone

PubMed Central

Bjälkander, Owolabi; Bangura, Laurel; Leigh, Bailah; Berggren, Vanja; Bergström, Staffan; Almroth, Lars

2012-01-01

Sierra Leone has one of the highest rates of female genital mutilation (FGM) in the world, and yet little is known about the health consequences of the practice. Purpose To explore whether and what kind of FGM-related health complications girls and women in Sierra Leone experience, and to elucidate their health care-seeking behaviors. Patients and methods A feasibility study was conducted to test and refine questionnaires and methods used for this study. Thereafter, a cross-section of girls and women (n = 258) attending antenatal care and Well Women Clinics in Bo Town, Bo District, in the southern region and in Makeni Town, Bombali District, in the northern region of Sierra Leone were randomly selected. Participants answered interview-administrated pretested structured questionnaires with open- ended-questions, administrated by trained female personnel. Results All respondents had undergone FGM, most between 10 and 14 years of age. Complications were reported by 218 respondents (84.5%), the most common ones being excessive bleeding, delay in or incomplete healing, and tenderness. Fever was significantly more often reported by girls who had undergone FGM before 10 years of age compared with those who had undergone the procedure later. Out of those who reported complications, 187 (85.8%) sought treatment, with 89 of them visiting a traditional healer, 75 a Sowei (traditional circumciser), and 16 a health professional. Conclusion The high prevalence rate of FGM and the proportion of medical complications show that FGM is a matter for public health concern in Sierra Leone. Girls who undergo FGM before 10 years of age seem to be more vulnerable to serious complications than those who are older at the time of FGM. It is important that health care personnel are aware of, and look for possible complications from FGM, and encourage girls and women to seek medical care for their problems. PMID:22870046

BRAF-V600E mutant papillary craniopharyngioma dramatically responds to combination BRAF and MEK inhibitors.

PubMed

Roque, Ashley; Odia, Yazmin

2017-04-01

We present a patient with BRAF-V600E mutant papillary craniopharyngioma successfully treated with combination BRAF (dabrafenib 150 mg twice daily) and MEK (trametinib 2 mg daily) inhibitors after her unresectable tumor proved refractory to radiation. Serial brain MRIs and PET revealed marked tumor reduction with gradual neurological improvement and permanent panhypopituitarism.

Still Struggling: Characteristics of Youth with OCD Who Are Partial Responders to Medication Treatment

ERIC Educational Resources Information Center

Freeman, J.; Sapyta, J.; Garcia, A.; Fitzgerald, D.; Khanna, M.; Choate-Summers, M.; Moore, P.; Chrisman, A.; Haff, N.; Naeem, A.; March, J.; Franklin, M.

2011-01-01

The primary aim of this paper is to examine the characteristics of a large sample of youth with OCD who are partial responders (i.e., still have clinically significant symptoms) to serotonin reuptake inhibitor (SRI) medication. The sample will be described with regard to: demographics, treatment history, OCD symptoms/severity, family history and…

Fragment-based design of kinase inhibitors: a practical guide.

PubMed

Erickson, Jon A

2015-01-01

Fragment-based drug design has become an important strategy for drug design and development over the last decade. It has been used with particular success in the development of kinase inhibitors, which are one of the most widely explored classes of drug targets today. The application of fragment-based methods to discovering and optimizing kinase inhibitors can be a complicated and daunting task; however, a general process has emerged that has been highly fruitful. Here a practical outline of the fragment process used in kinase inhibitor design and development is laid out with specific examples. A guide to the overall process from initial discovery through fragment screening, including the difficulties in detection, to the computational methods available for use in optimization of the discovered fragments is reported.

Janus kinase 2 inhibitors in myeloproliferative disorders.

PubMed

Lucia, Eugenio; Recchia, Anna Grazia; Gentile, Massimo; Bossio, Sabrina; Vigna, Ernesto; Mazzone, Carla; Madeo, Antonio; Morabito, Lucio; Gigliotti, Vincenzo; De Stefano, Laura; Caruso, Nadia; Servillo, Pasquale; Franzese, Stefania; Bisconte, Maria Grazia; Gentile, Carlo; Morabito, Fortunato

2011-01-01

JAK2 is an obligatory kinase for the proliferation and differentiation of erythroid cells and megakaryocytes thus representing a relevant therapeutic target for agents that specifically inhibit its activity particularly in myeloproliferative disorders (MPD) harboring JAK2(V617F) mutations. We discuss the physiopathology of the JAK2 signaling pathway and review clinical trials of JAK2 inhibitors for the treatment of MPD using papers and meeting abstracts published up to September 2010. This review helps in understanding the potential role of JAK2 inhibitors in MPD clinical trials and provides a comprehensive review regarding their efficacy and safety in these disorders. JAK2 inhibitors may prove to be useful only for suppressing disease manifestations. However, unlike drugs such as IFN which are capable of eliminating the malignant clone, JAK2 inhibitors are unable to eradicate the disease. In fact, results to date indicate that although these inhibitors reduce splenomegaly and alleviate constitutional symptoms irrespective of JAK2 mutational status, most have only a modest impact on the JAK2(V617F) allele burden. Considering the relevant risk of serious complications in patients undergoing splenectomy, these drugs could find a suitable indication in patients with myelofibrosis awaiting bone marrow transplantation.

Hypertension complicating diabetic pregnancies: pathophysiology, management, and controversies.

PubMed

Sullivan, Shannon D; Umans, Jason G; Ratner, Robert

2011-04-01

Hypertensive disorders of pregnancy (HDP), including pre-existing hypertension, gestational hypertension, and preeclampsia, further complicate already high-risk pregnancies in women with diabetes mellitus (DM). Women with both pre-existing and gestational diabetes are at increased risk for HDP, leading to higher maternal and fetal morbidity. Further, particularly in diabetic women and women with a history of gestational diabetes, HDP significantly increases the risk for future cardiovascular events. For clinicians, women with hypertension and diabetes during pregnancy pose a management challenge. Specifically, preconception management should stress strict control of glycemia, blood pressure, and prevention of diabetic complications, specifically nephropathy, which specifically increases the risk for preeclampsia. During gestation, clinicians must be aware of potential maternal and fetal complications associated with various anti-hypertensive therapies, including known fetotoxicity of ACE inhibitors and ARBs when given in the 2nd or 3rd trimester, and the risks and benefits of expectant management versus delivery in cases of severe gestational hypertension or preeclampsia. Indeed, diabetic women must be followed closely prior to conception and throughout gestation to minimize the risk of HDP and its associated complications. © 2011 Wiley Periodicals, Inc.

Inhibitors of cyclin-dependent kinases as cancer therapeutics.

PubMed

Whittaker, Steven R; Mallinger, Aurélie; Workman, Paul; Clarke, Paul A

2017-05-01

Over the past two decades there has been a great deal of interest in the development of inhibitors of the cyclin-dependent kinases (CDKs). This attention initially stemmed from observations that different CDK isoforms have key roles in cancer cell proliferation through loss of regulation of the cell cycle, a hallmark feature of cancer. CDKs have now been shown to regulate other processes, particularly various aspects of transcription. The early non-selective CDK inhibitors exhibited considerable toxicity and proved to be insufficiently active in most cancers. The lack of patient selection biomarkers and an absence of understanding of the inhibitory profile required for efficacy hampered the development of these inhibitors. However, the advent of potent isoform-selective inhibitors with accompanying biomarkers has re-ignited interest. Palbociclib, a selective CDK4/6 inhibitor, is now approved for the treatment of ER+/HER2- advanced breast cancer. Current developments in the field include the identification of potent and selective inhibitors of the transcriptional CDKs; these include tool compounds that have allowed exploration of individual CDKs as cancer targets and the determination of their potential therapeutic windows. Biomarkers that allow the selection of patients likely to respond are now being discovered. Drug resistance has emerged as a major hurdle in the clinic for most protein kinase inhibitors and resistance mechanism are beginning to be identified for CDK inhibitors. This suggests that the selective inhibitors may be best used combined with standard of care or other molecularly targeted agents now in development rather than in isolation as monotherapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Context-Dependent Antagonism between Akt Inhibitors and Topoisomerase Poisons

PubMed Central

Gálvez-Peralta, Marina; Flatten, Karen S.; Loegering, David A.; Peterson, Kevin L.; Schneider, Paula A.; Erlichman, Charles

2014-01-01

Signaling through the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, which is aberrantly activated in >50% of carcinomas, inhibits apoptosis and contributes to drug resistance. Accordingly, several Akt inhibitors are currently undergoing preclinical or early clinical testing. To examine the effect of Akt inhibition on the activity of multiple widely used classes of antineoplastic agents, human cancer cell lines were treated with the Akt inhibitor A-443654 [(2S)-1-(1H-indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan-2-amine; ATP-competitive] or MK-2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one;dihydrochloride; allosteric inhibitor) or with small interfering RNA (siRNA) targeting phosphoinositide-dependent kinase 1 (PDK1) along with cisplatin, melphalan, camptothecin, or etoposide and assayed for colony formation. Surprisingly different results were observed when Akt inhibitors were combined with different drugs. Synergistic effects were observed in multiple cell lines independent of PI3K pathway status when A-443654 or MK-2206 was combined with the DNA cross-linking agents cisplatin or melphalan. In contrast, effects of the Akt inhibitors in combination with camptothecin or etoposide were more complicated. In HCT116 and DLD1 cells, which harbor activating PI3KCA mutations, A-443654 over a broad concentration range enhanced the effects of camptothecin or etoposide. In contrast, in cell lines lacking activating PI3KCA mutations, partial inhibition of Akt signaling synergized with camptothecin or etoposide, but higher A-443654 or MK-2206 concentrations (>80% inhibition of Akt signaling) or PDK1 siRNA antagonized the topoisomerase poisons by diminishing DNA synthesis, a process that contributes to effective DNA damage and killing by these agents. These results indicate that the effects of combining inhibitors of the PI3K/Akt pathway with certain classes of chemotherapeutic agents might be more

Context-dependent antagonism between Akt inhibitors and topoisomerase poisons.

PubMed

Gálvez-Peralta, Marina; Flatten, Karen S; Loegering, David A; Peterson, Kevin L; Schneider, Paula A; Erlichman, Charles; Kaufmann, Scott H

2014-05-01

Signaling through the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, which is aberrantly activated in >50% of carcinomas, inhibits apoptosis and contributes to drug resistance. Accordingly, several Akt inhibitors are currently undergoing preclinical or early clinical testing. To examine the effect of Akt inhibition on the activity of multiple widely used classes of antineoplastic agents, human cancer cell lines were treated with the Akt inhibitor A-443654 [(2S)-1-(1H-indol-3-yl)-3-[5-(3-methyl-2H-indazol-5-yl)pyridin-3-yl]oxypropan-2-amine; ATP-competitive] or MK-2206 (8-[4-(1-aminocyclobutyl)phenyl]-9-phenyl-2H-[1,2,4]triazolo[3,4-f][1,6]naphthyridin-3-one;dihydrochloride; allosteric inhibitor) or with small interfering RNA (siRNA) targeting phosphoinositide-dependent kinase 1 (PDK1) along with cisplatin, melphalan, camptothecin, or etoposide and assayed for colony formation. Surprisingly different results were observed when Akt inhibitors were combined with different drugs. Synergistic effects were observed in multiple cell lines independent of PI3K pathway status when A-443654 or MK-2206 was combined with the DNA cross-linking agents cisplatin or melphalan. In contrast, effects of the Akt inhibitors in combination with camptothecin or etoposide were more complicated. In HCT116 and DLD1 cells, which harbor activating PI3KCA mutations, A-443654 over a broad concentration range enhanced the effects of camptothecin or etoposide. In contrast, in cell lines lacking activating PI3KCA mutations, partial inhibition of Akt signaling synergized with camptothecin or etoposide, but higher A-443654 or MK-2206 concentrations (>80% inhibition of Akt signaling) or PDK1 siRNA antagonized the topoisomerase poisons by diminishing DNA synthesis, a process that contributes to effective DNA damage and killing by these agents. These results indicate that the effects of combining inhibitors of the PI3K/Akt pathway with certain classes of chemotherapeutic agents might be more

The economics of inpatient on-demand treatment for haemophilia with high-responding inhibitors: a US retrospective data analysis.

PubMed

Pokras, S M; Petrilla, A A; Weatherall, J; Lee, W C

2012-03-01

Inpatient costs comprise >50% of annual healthcare costs for haemophilia patients with inhibitors but no reports exist on inpatient resource use and costs at a US national level. To quantify inpatient resource use and costs for on-demand treatment of bleeds of US haemophilia patients with inhibitors and compare costs and treatment duration between Factor VIII bypassing agents (BAs). Stays with haemophilia A from 2003-2008 were identified from inpatient billing records. Presence of inhibitors was inferred through use of BA; recombinant activated Factor VII and plasma-derived activated prothrombin complex concentrate. Duration and number of infusions of BA, length of stay, use of opioid-containing analgesics and costs were assessed and compared. Among 1322 stays mean BA treatment duration was 4.6 days with 4.9 infusions, 6.1 nights spent in hospital, and 58% administered opioid-containing analgesics. In unadjusted analyses there were significant differences in the above mentioned outcomes by BA use, reflecting underlying differences between the two patient populations. Average inpatient costs were $82,911. In adjusted analyses, African-American race, greater disease severity, hospital region outside the southern US and older age (cost model only) were significant predictors of longer BA treatment duration and higher costs. The economic burden of inpatient on-demand treatment of haemophilia with inhibitors is substantial and is associated with lengthy stays, high costs and inadequate pain relief. Availability of more effective BAs could reduce the need for re-treatment, reducing treatment costs and other medical costs, while improving health related quality of life. © 2011 Blackwell Publishing Ltd.

Deregulation of arginase induces bone complications in high-fat/high-sucrose diet diabetic mouse model

PubMed Central

Bhatta, Anil; Sangani, Rajnikumar; Kolhe, Ravindra; Toque, Haroldo A.; Cain, Michael; Wong, Abby; Howie, Nicole; Shinde, Rahul; Elsalanty, Mohammed; Yao, Lin; Chutkan, Norman; Hunter, Monty; Caldwell, Ruth B.; Isales, Carlos; Caldwell, R. William; Fulzele, Sadanand

2016-01-01

A balanced diet is crucial for healthy development and prevention of musculoskeletal related diseases. Diets high in fat content are known to cause obesity, diabetes and a number of other disease states. Our group and others have previously reported that activity of the urea cycle enzyme arginase is involved in diabetes-induced dysregulation of vascular function due to decreases in nitric oxide formation. We hypothesized that diabetes may also elevate arginase activity in bone and bone marrow, which could lead to bone-related complications. To test this we determined the effects of diabetes on expression and activity of arginase, in bone and bone marrow stromal cells (BMSCs). We demonstrated that arginase 1 is abundantly present in the bone and BMSCs. We also demonstrated that arginase activity and expression in bone and bone marrow is up-regulated in models of diabetes induced by HFHS diet and streptozotocin (STZ). HFHS diet down-regulated expression of healthy bone metabolism markers (BMP2, COL-1, ALP, and RUNX2) and reduced bone mineral density, bone volume and trabecular thickness. However, treatment with an arginase inhibitor (ABH) prevented these bone-related complications of diabetes. In-vitro study of BMSCs showed that high glucose treatment increased arginase activity and decreased nitric oxide production. These effects were reversed by treatment with an arginase inhibitor (ABH). Our study provides evidence that deregulation of L-arginine metabolism plays a vital role in HFHS diet-induced diabetic complications and that these complications can be prevented by treatment with arginase inhibitors. The modulation of L-arginine metabolism in disease could offer a novel therapeutic approach for osteoporosis and other musculoskeletal related diseases. PMID:26704078

Fulminant ischaemic colitis with atypical clinical features complicating sickle cell disease.

PubMed

Karim, Anita; Ahmed, S; Rossoff, Leonard J; Siddiqui, R; Fuchs, A; Multz, A S

2002-06-01

Clinically significant ischaemic bowel injury is an exceedingly rare complication of sickle cell disease. It manifests as acute surgical abdomen and may respond to conservative treatment. An unusual fatal case of ischaemic colitis with minimal abdominal findings in a young male during a sickle cell vaso-occlusive pain crisis is described. This case demonstrates that an acute surgical abdomen should be considered in such patients who fail to respond to conservative management as untreated this condition may be fatal.

Real-Time Inhibitor Recession Measurements in the Space Shuttle Reusable Solid Rocket Motors

NASA Technical Reports Server (NTRS)

McWhorter, Bruce B.; Ewing, Mark E.; McCool, Alex (Technical Monitor)

2001-01-01

Real-time char line recession measurements were made on propellant inhibitors of the Space Shuttle Reusable Solid Rocket Motor (RSRM). The RSRM FSM-8 static test motor propellant inhibitors (composed of a rubber insulation material) were successfully instrumented with eroding potentiometers and thermocouples. The data was used to establish inhibitor recession versus time relationships. Normally, pre-fire and post-fire insulation thickness measurements establish the thermal performance of an ablating insulation material. However, post-fire inhibitor decomposition and recession measurements are complicated by the fact that most of the inhibitor is back during motor operation. It is therefore a difficult task to evaluate the thermal protection offered by the inhibitor material. Real-time measurements would help this task. The instrumentation program for this static test motor marks the first time that real-time inhibitors. This report presents that data for the center and aft field joint forward facing inhibitors. The data was primarily used to measure char line recession of the forward face of the inhibitors which provides inhibitor thickness reduction versus time data. The data was also used to estimate the inhibitor height versus time relationship during motor operation.

SGLT2 inhibitors: a promising new therapeutic option for treatment of type 2 diabetes mellitus.

PubMed

Misra, Monika

2013-03-01

Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose reabsorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications. Sodium glucose cotransporter 2 (SGLT2) has a key role in reabsorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes. To discuss the therapeutic potential of SGLT2 inhibitors currently in clinical development. A number of preclinical and clinical studies of SGLT2 inhibitors have demonstrated a good safety profile and beneficial effects in lowering plasma glucose levels, diminishing glucotoxicity, improving glycemic control and reducing weight in diabetes. Of all the SGLT2 inhibitors, dapagliflozin is a relatively advanced compound with regards to clinical development. SGLT2 inhibitors are emerging as a promising therapeutic option for the treatment of diabetes. Their unique mechanism of action offers them the potential to be used in combination with other oral anti-diabetic drugs as well as with insulin. © 2012 The Author. JPP © 2012 Royal Pharmaceutical Society.

Inhibitor development after liver transplantation in congenital factor VII deficiency.

PubMed

See, W-S Q; Chang, K-O; Cheuk, D K-L; Leung, Y-Y R; Chan, G C-F; Chan, S-C; Ha, S-Y

2016-09-01

Congenital factor VII (FVII) deficiency is the commonest type of the rare bleeding disorders. Very few cases of congenital FVII deficiency developed inhibitor and liver transplant is considered as definitive treatment. In the literature, twelve patients with congenital FVII deficiency developed inhibitors. Two had spontaneous resolution of inhibitors and one did not respond to high dose recombinant factor VIIa (rFVIIa) and died. Regarding liver transplant in congenital FVII patients, seven patients underwent liver transplant with good prognosis. We report a 5-year-old girl with confirmed severe congenital FVII deficiency since neonatal period. She suffered from recurrent intracranial bleeding despite rFVIIa replacement. After auxiliary liver transplant at the age of 4, she continued to show persistent deranged clotting profile and was found to have inhibitor towards FVII. Interestingly, she was still responsive to rFVIIa replacement. © 2016 John Wiley & Sons Ltd.

Predicting vascular complications in percutaneous coronary interventions.

PubMed

Piper, Winthrop D; Malenka, David J; Ryan, Thomas J; Shubrooks, Samuel J; O'Connor, Gerald T; Robb, John F; Farrell, Karen L; Corliss, Mary S; Hearne, Michael J; Kellett, Mirle A; Watkins, Matthew W; Bradley, William A; Hettleman, Bruce D; Silver, Theodore M; McGrath, Paul D; O'Mears, John R; Wennberg, David E

2003-06-01

Using a large, current, regional registry of percutaneous coronary interventions (PCI), we identified risk factors for postprocedure vascular complications and developed a scoring system to estimate individual patient risk. A vascular complication (access-site injury requiring treatment or bleeding requiring transfusion) is a potentially avoidable outcome of PCI. Data were collected on 18,137 consecutive patients undergoing PCI in northern New England from January 1997 to December 1999. Multivariate regression was used to identify characteristics associated with vascular complications and to develop a scoring system to predict risk. The rate of vascular complication was 2.98% (541 cases). Variables associated with increased risk in the multivariate analysis included age >or=70, odds ratio (OR) 2.7, female sex (OR 2.4), body surface area <1.6 m(2) (OR 1.9), history of congestive heart failure (OR 1.4), chronic obstructive pulmonary disease (OR 1.5), renal failure (OR 1.9), lower extremity vascular disease (OR 1.4), bleeding disorder (OR 1.68), emergent priority (OR 2.3), myocardial infarction (OR 1.7), shock (1.86), >or=1 type B2 (OR 1.32) or type C (OR 1.7) lesions, 3-vessel PCI (OR 1.5), use of thienopyridines (OR 1.4) or use of glycoprotein IIb/IIIa receptor inhibitors (OR 1.9). The model performed well in tests for significance, discrimination, and calibration. The scoring system captured 75% of actual vascular complications in its highest quintiles of predicted risk. Predicting the risk of post-PCI vascular complications is feasible. This information may be useful for clinical decision-making and institutional efforts at quality improvement.

Glycation, carbonyl stress and AGEs inhibitors: a patent review.

PubMed

Jahan, Humera; Choudhary, M Iqbal

2015-01-01

The glycation process, comprising a series of reactions, results in the formation of heterogeneous adducts, known as advanced glycation end products (AGEs). AGEs are involved in several pathologies, including diabetes-associated late complications, atherosclerosis, Alzheimer's disease and inflammatory arthritis. Several inhibitors of AGEs and/or reactive carbonyl species have been identified from various sources, including natural products and synthetic molecules, and have been investigated for their mechanism of action. This review covers the literature on AGEs inhibitors published as patents between 2001 and 2014. Initially, the earlier reported molecules with AGEs inhibitory properties, their mechanism of actions and reported adverse effects are discussed. The main focus has been on the chemical structures, methods for evaluation of the activity, modes of action, pharmacokinetics and therapeutic outcomes. The potential of these AGEs inhibitors in the treatment and management of a number of diseases are also discussed in this review. The reactive carbonyl species and AGEs have recently emerged as novel therapeutic targets for the prevention and treatment of several diseases. Currently, the major concerns with the use of AGEs inhibitors as therapeutic agents are low effectiveness, poor pharmacokinetics and undesirable side effects. Many of the AGEs inhibitors reviewed here possess potent antiglycation activity and are devoid of undesirable side effects. These small molecules inhibitors can, therefore, serve as scaffolds for the development and designing of new AGEs inhibitors as clinical agents.

Association between adherence to concomitant proton pump inhibitor therapy in current NSAID users and upper gastrointestinal complications.

PubMed

Jonasson, Christian; Hatlebakk, Jan G; Lundell, Lars; Kouri, Jukka P; Andersen, Morten; Granath, Fredrik

2013-05-01

Proton pump inhibitors (PPIs) play a well-documented role as a gastroprotective agent among NSAID users at an increased risk of peptic ulcer and bleeding. Observational studies have, however, suggested that the clinical efficacy of PPI therapy may be reduced because of poor adherence. To study the association between adherence to concomitant PPI in current NSAID users and the risk of peptic ulcer and bleeding. Case-control study linking nationwide data from the Swedish Patient Registry with the Swedish Drug Prescription Database. The study population included patients admitted for a first-time peptic ulcer or bleeding and who were incident users of NSAID. Each case was matched on age, sex, NSAID duration, and calendar month with five controls. PPI adherence was calculated as the proportion of NSAID days being covered by PPI therapy. Matched and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using conditional logistic regression. A total of 3649 cases were identified. Patients with poor adherence (<20% PPI coverage) had a significantly increased risk of upper gastrointestinal complications (OR=1.88, 95% CI 1.22-2.88) compared with fully adherent patients (≥80% PPI coverage). As a continuous variable, the risk of an event increased with 6% points for every 10% decrease in PPI adherence (OR=1.06, 95% CI 1.03-1.10). The gastroprotective effect of PPI in NSAID users is highly dependent on adherence, with about twice the risk in patients with poor adherence. Efforts to increase adherence should be an integrated part of clinical practice.

Fatal hyperkalemia related to combined therapy with a COX-2 inhibitor, ACE inhibitor and potassium rich diet.

PubMed

Hay, Emile; Derazon, Hashmonai; Bukish, Natalia; Katz, Leonid; Kruglyakov, Igor; Armoni, Michael

2002-05-01

We describe the case of a 77-year old mildly hypertensive woman with no underlying renal disease who was admitted to the Emergency Department (ED) in a comatose state with fever. The patient had been on low dose enalapril and a potassium rich diet. Five days before admission, rofecoxib, a new selective COX-2 inhibitor nonsteroidal anti-inflammatory drug (NSAID), was added for leg pain. She was found to have severe hyperkalemia and died 90 min after her arrival. We cannot absolutely determine whether the COX-2 inhibitor was the dominant contributor to the development of hyperkalemia or the combination itself, with an intercurrent infection and some degree of dehydration. Physicians should be aware of this possible complication and only prescribe NSAIDs, including the new COX-2 drugs, to the elderly under close monitoring of kidney function and electrolyte tests.

Boceprevir: a protease inhibitor for the treatment of hepatitis C.

PubMed

Chang, Mei H; Gordon, Lori A; Fung, Horatio B

2012-10-01

Boceprevir is a protease inhibitor indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in combination with peginterferon and ribavirin for treatment-naive patients and those who previously failed to improve with interferon and ribavirin treatment. This article provides an overview of the mechanism of action, pharmacologic and pharmacokinetic properties, clinical efficacy, and tolerability of boceprevir. Relevant information was identified through a search of PubMed (1990-July 2012), EMBASE (1990-July 2012), International Pharmaceutical Abstracts (1970-July 2012), and Google Scholar using the key words boceprevir, SCH 503034, non-structural protein 3 (NS3) serine protease inhibitor, and direct-acting antiviral agent (DAA). Additional information was obtained from the US Food and Drug Administration's Web site, review of the reference lists of identified articles, and posters and abstracts from scientific meetings. Clinical efficacy of boceprevir was assessed in 2 Phase III trials, Serine Protease Inhibitor Therapy-2 (SPRINT-2) for treatment-naive patients and Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2 (RESPOND-2) for treatment-experienced patients. In SPRINT-2, patients were randomized to receive peginterferon + ribavirin (PR) or peginterferon + ribavirin + boceprevir (PRB); duration of boceprevir therapy varied from 24, 32, to 44 weeks on the basis of HCV RNA results. The primary endpoint was achievement of sustained virologic response (SVR; lower limit of detection, 9.3 IU/mL). The addition of boceprevir was shown to be superior, with overall SVR rates ranging from 63% to 66% compared with 38% with PR (P < 0.001). Results of SVR in SPRINT-2 were also reorganized to monitor SVRs in black and non-black patients. Treatment-experienced patients were assessed in RESPOND-2; however, null responders were excluded. Patients were again randomized to PR or PRB; duration of boceprevir therapy varied from

Immune checkpoint inhibitors for metastatic bladder cancer.

PubMed

Massari, Francesco; Di Nunno, Vincenzo; Cubelli, Marta; Santoni, Matteo; Fiorentino, Michelangelo; Montironi, Rodolfo; Cheng, Liang; Lopez-Beltran, Anto; Battelli, Nicola; Ardizzoni, Andrea

2018-03-01

Chemotherapy has represented the standard therapy for unresectable or metastatic urothelial carcinoma for more than 20 years. The growing knowledge of the interaction between tumour and immune system has led to the advent of new classes of drugs, the immune-checkpoints inhibitors, which are intended to change the current scenario. To date, immunotherapy is able to improve the overall responses and survival. Moreover, thanks to its safety profile immune-checkpoint inhibitors could be proposed also to patients unfit for standard chemotherapy. No doubts that these agents have started a revolution expected for years, but despite this encouraging results it appears clear that not all subjects respond to these agents and requiring the development of reliable predictive response factors able to isolate patients who can more benefit from these treatments as well as new strategies aimed to improve immunotherapy clinical outcome. In this review we describe the active or ongoing clinical trials involving Programmed Death Ligand 1 (PD-L1), Programmed Death receptor 1 (PD-1) and Cytotoxic-T Lymphocyte Antigen 4 (CTLA 4) inhibitors in urothelial carcinoma focusing our attention on the developing new immune-agents and combination strategies with immune-checkpoint inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Risk factors for inhibitor development in severe hemophilia a.

PubMed

Garagiola, Isabella; Palla, Roberta; Peyvandi, Flora

2018-05-25

Although significant advances in hemophilia treatment have improved patient outcomes and quality of life, one of the greatest complications in severe hemophilia A is the development of anti-Factor VIII (FVIII) antibodies that inhibit FVIII activity in almost 30% of previously untreated patients (PUPs). Inhibitors make very difficult the management of patients and increase their morbidity and mortality reducing drastically their quality of life. Numerous studies have investigated the mechanisms leading to the development of FVIII inhibitors. However, the etiology of their onset is complex and not yet fully understood. Inhibitors develop from a multicausal immune response involving both genetic (unmodifiable) and environmental (modifiable) factors. F8 gene mutations are the most important genetic risk factor, with null mutations being associated with the highest risk of inhibitor development. Immune response genes (e.g. the human leukocyte antigen complex) and proteins (e.g. cytokines) were studied without any strong confirmation of their role in modulating of inhibitor development. Type of FVIII product is the most important modifiable risk factor. The plasma-derived products containing von Willebrand factor were recently suggested to determine a lower incidence of inhibitor development than recombinant products in PUPs, in the first 50 exposure days (EDs). Other environmental factors including, age at first treatment, treatment intensity and the danger signal effect (surgery, severe bleeds, vaccinations and infections) has also been postulated as an explanation for environment-related inhibitor risk. This review reports the current knowledge on genetic and environmental risk factors on inhibitor development in patients with severe hemophilia A. Copyright © 2018 Elsevier Ltd. All rights reserved.

Effect of H. pylori density by histopathology on its complications and eradication therapy.

PubMed

Shah, Dharmesh K; Jain, Samit S; Mohite, Ashok; Amarapurkar, Anjali D; Contractor, Q Q; Rathi, Pravin M

2015-01-01

Helicobacter pylori (H. pylori) infection causes chronic gastritis and is a major risk factor for duodenal and gastric ulceration, gastric adenocarcinoma, and primary gastric lymphoma. Increased gastric bacterial density may lead to increased levels of inflammation and epithelial injury. 1) To study the effect of H. pylori density by histological changes in stomach. 2) To study the effect of H. pylori density on the efficacy of standard triple drug eradication treatment. 3) To study the effect of H. pylori density on the complication related to H. pylori. All the patients visiting gastroenterology OPD with the symptoms of dyspepsia not responding to proton pump inhibitor or having alarm symptoms were subjected to upper GI endoscopy and biopsy. If H. pylori was present they were included in the study. The patients were given standard 14 day triple antibiotic combination for H. pylori eradication. H. pylori eradication was confirmed by urea breath test after six weeks of completion of treatment. Out of 250 patients screened, 120 patients enrolled in the study. On clinical history 41.5% patients had symptoms of heart burn where as 63.3% patients had dyspeptic symptoms. Success rate of anti H. pylori triple drug therapy was 80%. Rate of eradication was significantly lower among the patients with higher H. pylori density (p < 0.05) on histopathology by Sydney classification. Duodenal ulcer, Gastric ulcer and gastric erosion were noted in higher frequencies among the patients with higher H. pylori density (p < 0.05). H. pylori density by histopathology correlates with the complication related to H. pylori i.e. duodenal ulcer, reflux esophagitis and antral erosions. It also correlates with the success of the standard triple drug eradication treatment.

Differences in change in coping styles between good responders, moderate responders and non-responders to pulmonary rehabilitation.

PubMed

Stoilkova-Hartmann, Ana; Janssen, Daisy J A; Franssen, Frits M E; Wouters, Emiel F M

2015-12-01

Pulmonary rehabilitation (PR) improves exercise tolerance and health status in patients with chronic obstructive pulmonary disease (COPD). Data on the effects of PR on coping styles are limited. Aim of the present study was to compare changes in coping styles between patients who had a good, moderate and no improvement in either exercise tolerance or health status after PR. Coping styles of 439 COPD patients undergoing PR were assessed by the Utrecht Coping List (UCL) at baseline and after PR. Patients' pulmonary function, six-minute walking distance (6MWD), St. George's Respiratory Questionnaire (SGRQ) and Hospital Anxiety and Depression Scale (HADS-A and HADS-D) were recorded. Good, moderate and non-responders were defined on the basis of minimally clinically important difference (MCID) for SGRQ total score and/or 6MWD. Overall, 54.0% of the patients fulfilled the criteria for good responders, while 22.1% were moderate responders. Change in passive reaction pattern coping style differed significantly between good responders and non-responders following PR (p < 0.001). Moreover, within the groups, changes in coping styles after PR occurred among the good responders, whereas the majority of moderate responders' and non-responders' coping styles were not significantly influenced by PR. Good responders decreased their passive reaction pattern coping style in contrast to non-responders after PR. In general, PR did not change the coping among moderate and non-responders. Further research is warranted to determine whether including interventions targeting coping styles may modify coping behaviour of COPD patients, as well as improvement in exercise tolerance or health status after PR. Copyright © 2015 Elsevier Ltd. All rights reserved.

Genetic risk factors for inhibitors in haemophilia A.

PubMed

Bardi, Edit; Astermark, Jan

2015-02-01

The current most serious side effect of haemophilia treatment is inhibitor development. Significant progress has been made over the last decades to understand why this complication occurs in some patients and it seems clear that both genetic and non-genetic factors are involved. Several issues however remain to be settled. A review was undertaken to summarise some key findings regarding the current view and available data on genetic markers of potential importance within this area. The causative F8 mutation, together with the HLA class II alleles, plays a pivotal pathophysiological role in inhibitor development. The types of mutation most frequently associated with inhibitors are large deletions, nonsense mutations, inversions, small deletions/insertions without A-runs, splice-site mutations at conserved nucleotides and certain missense mutations. Regarding HLA class II allele, it has been hard to consistently identify risk alleles. Ethnicity has consistently been associated with inhibitor risk, but the causality of this has so far not been resolved. Among immune regulatory molecules, several polymorphic molecules have been suggested to be of importance. Most of these need additional studies and immune system challenges have to be fully evaluated. Inhibitor risk should be further defined, as patients in the future may be offered non-immunogenic treatments. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pneumatocele during sorafenib therapy: first report of an unusual complication

PubMed Central

Sangro, Paloma; Bilbao, Idoia; Fernández-Ros, Nerea; Iñarrairaegui, Mercedes; Zulueta, Javier; Bilbao, JI; Sangro, Bruno

2018-01-01

Sorafenib is a multi-kinase inhibitor and a vascular endothelial growth factor (VEGF) inhibitor approved to treat patients with advanced hepatocellular carcinoma, renal cell carcinoma and differentiated thyroid carcinoma. Its most common side effects are asthenia/fatigue, skin toxicity, diarrhea and arterial hypertension. Reported respiratory adverse reactions include dyspnea, cough, pleural effusion and hoarseness. The aim of this report is to describe for the first time the occurrence of pneumatocele in two patients treated with Sorafenib. Patients had no respiratory symptoms and alternative diagnoses were ruled out. Primary tumors were different (liver metastases from a pancreatic neuroendocrine tumor and hepatocellular carcinoma) but both patients had been treated with yttrium 90 radioembolization 9 and 17 months before starting on Sorafenib, respectively. No complications occurred and Sorafenib withdrawal was followed by radiologic improvement. PMID:29464101

Global health resource utilization associated with pacemaker complications.

PubMed

Waweru, Catherine; Steenrod, Anna; Wolff, Claudia; Eggington, Simon; Wright, David Jay; Wyrwich, Kathleen W

2017-07-01

To estimate health resource utilization (HRU) associated with the management of pacemaker complications in various healthcare systems. Electrophysiologists (EPs) from four geographical regions (Western Europe, Australia, Japan, and North America) were invited to participate. Survey questions focused on HRU in the management of three chronic pacemaker complications (i.e. pacemaker infections requiring extraction, lead fractures/insulation breaches requiring replacement, and upper extremity deep venous thrombosis [DVT]). Panelists completed a maximum of two web-based surveys (iterative rounds). Mean, median values, and interquartile ranges were calculated and used to establish consensus. Overall, 32 and 29 panelists participated in the first and second rounds of the Delphi panel, respectively. Consensus was reached on treatment and HRU associated with a typical pacemaker implantation and complications. HRU was similar across regions, except for Japan, where panelists reported the longest duration of hospital stay in all scenarios. Infections were the most resource-intensive complications and were characterized by intravenous antibiotics days of 9.6?13.5 days and 21.3?29.2 days for pocket and lead infections respectively; laboratory and diagnostic tests, and system extraction and replacement procedures. DVT, on the other hand, was the least resource intensive complication. The results of the panel represent the views of the respondents who participated and may not be generalizable outside of this panel. The surveys were limited in scope and, therefore, did not include questions on management of acute complications (e.g. hematoma, pneumothorax). The Delphi technique provided a reliable and efficient approach to estimating resource utilization associated with chronic pacemaker complications. Estimates from the Delphi panel can be used to generate costs of pacemaker complications in various regions.

HER2 mutated breast cancer responds to treatment with single agent neratinib, a second generation HER2/EGFR tyrosine kinase inhibitor

PubMed Central

Ben–Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M.; Ma, Cynthia X.; Ellis, Matthew J.

2015-01-01

Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2 targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. In this case report, we describe a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second generation HER2/EGFR tyrosine kinase inhibitor, neratinib, resulted in partial response and dramatic improvement in the patient’s function status. This partial response lasted 11 months and when the patient’s cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2 amplified breast cancer after disease progression. This case is the first report, to our knowledge, of successful single agent treatment of HER2 mutated breast cancer. Two clinical trials of neratinib for HER2 mutated, metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancer, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2 mutated solid tumors is warranted. PMID:26358790

HER2-Mutated Breast Cancer Responds to Treatment With Single-Agent Neratinib, a Second-Generation HER2/EGFR Tyrosine Kinase Inhibitor.

PubMed

Ben-Baruch, Noa Efrat; Bose, Ron; Kavuri, Shyam M; Ma, Cynthia X; Ellis, Matthew J

2015-09-01

Activating mutations in the HER2 tyrosine kinase have been identified in human breast cancers that lack HER2 gene amplification. These patients are not candidates for HER2-targeted drugs under current standards of care, but preclinical data strongly suggest that these patients will benefit from anti-HER2 drugs. This case report describes a young woman with metastatic breast cancer whose tumor was found to carry a HER2 L755S mutation, which is in the kinase domain of HER2. Treatment with the second-generation HER2/EGFR tyrosine kinase inhibitor neratinib resulted in partial response and dramatic improvement in the patient's functional status. This partial response lasted 11 months, and when the patient's cancer progressed, she was treated with neratinib plus capecitabine and her cancer again responded. This second response parallels the benefit seen with continuing trastuzumab in HER2-amplified breast cancer after disease progression. This case represents the first report, to our knowledge, of successful single-agent treatment of HER2-mutated breast cancer. Two clinical trials of neratinib for HER2-mutated metastatic breast cancer are currently enrolling patients. Further, data from The Cancer Genome Atlas project have identified HER2 mutations in a wide range of solid tumors, including bladder, colorectal, and non-small cell lung cancers, suggesting that clinical trials of neratinib or neratinib-based combinations for HER2-mutated solid tumors is warranted. Copyright © 2015 by the National Comprehensive Cancer Network.

U.S. Complicity and Japan's Wartime Medical Atrocities: Time for a Response.

PubMed

Devolder, Katrien

2015-01-01

Shortly before and during the Second World War, Japanese doctors and medical researchers conducted large-scale human experiments in occupied China that were at least as gruesome as those conducted by Nazi doctors. Japan never officially acknowledged the occurrence of the experiments, never tried any of the perpetrators, and never provided compensation to the victims or issued an apology. Building on work by Jing-Bao Nie, this article argues that the U.S. government is heavily complicit in this grave injustice, and should respond in an appropriate way in order to reduce this complicity, as well as to avoid complicity in future unethical medical experiments. It also calls on other U.S. institutions, in particular the Presidential Commission for the Study of Bioethical Issues, to urge the government to respond, or to at least inform the public and initiate a debate about this dark page of American and Japanese history.

Use of tissue adhesive as a field expedient barrier dressing for hand wounds in disaster responders.

PubMed

Levy, Matthew J; Tang, Nelson

2014-02-01

Injuries sustained by disaster responders can impede the affected individuals' ability to perform critical functions and often require the redirection of already scarce resources. Soft-tissue injuries to the hand are commonly experienced by disaster workers and even seemingly mild lacerations can pose the potential for significant complications in such hazard-filled environments. In this report, the authors describe their experience utilizing tissue adhesive to create a functional and effective barrier dressing for a hand injury sustained by a responder at the West, Texas USA fertilizer plant explosion. This technique of wound management allowed the patient to continue performing essential onsite functions for a sustained period following the explosion and the subsequent investigative processes. At the 30-day follow-up, the wound was well healed and without complications. This technique proved to be a valuable method of field expedient wound management and is worthy of consideration in similar future circumstances.

A Phenomenological Study of Urban Search and Rescue Members Who Responded to a Disaster

ERIC Educational Resources Information Center

Kerns, Terry L.

2012-01-01

The complicated world of disaster management requires urban search and rescue (US&R) members to be well trained to respond to complex, unpredictable, and difficult to manage disasters anywhere in the world on short notice. Disasters are becoming more complex and difficult to manage as was witnessed by the multi-faceted disaster in Japan in…

X-linked juvenile retinoschisis in females and response to carbonic anhydrase inhibitors: case report and review of the literature.

PubMed

Ali, Syed; Seth, Rajeev

2013-01-01

A 63 year old woman was referred to the retina clinic after her vision failed to improve in her left eye after cataract surgery. X-linked retinoschisis was diagnosed in the patient after her retina exam revealed an area of retinoschisis and a foveal cyst. The OCT confirmed the macular cyst and the ERG showed loss of B waves. The florescein angiogram showed no significant perifoveal leakage. Her foveal cyst resolved after treatment with carbonic anhydrase inhibitors. The patient's son was examined and his ophthalmologic exam, ERG and imaging findings were consistent with X-linked retinoschisis. However, his bilateral foveal cysts did not respond to treatment with carbonic anhydrase inhibitors. X-linked retinoschisis is a very rare disease in women due to its X-linked recessive inheritance and the foveal cysts associated with it can respond to carbonic anhydrase inhibitors.

Variance Estimation, Design Effects, and Sample Size Calculations for Respondent-Driven Sampling

PubMed Central

2006-01-01

Hidden populations, such as injection drug users and sex workers, are central to a number of public health problems. However, because of the nature of these groups, it is difficult to collect accurate information about them, and this difficulty complicates disease prevention efforts. A recently developed statistical approach called respondent-driven sampling improves our ability to study hidden populations by allowing researchers to make unbiased estimates of the prevalence of certain traits in these populations. Yet, not enough is known about the sample-to-sample variability of these prevalence estimates. In this paper, we present a bootstrap method for constructing confidence intervals around respondent-driven sampling estimates and demonstrate in simulations that it outperforms the naive method currently in use. We also use simulations and real data to estimate the design effects for respondent-driven sampling in a number of situations. We conclude with practical advice about the power calculations that are needed to determine the appropriate sample size for a study using respondent-driven sampling. In general, we recommend a sample size twice as large as would be needed under simple random sampling. PMID:16937083

Bubbles Responding to Ultrasound Pressure

NASA Technical Reports Server (NTRS)

2003-01-01

The Bubble and Drop Nonlinear Dynamics (BDND) experiment was designed to improve understanding of how the shape and behavior of bubbles respond to ultrasound pressure. By understanding this behavior, it may be possible to counteract complications bubbles cause during materials processing on the ground. This 12-second sequence came from video downlinked from STS-94, July 5 1997, MET:3/19:15 (approximate). The BDND guest investigator was Gary Leal of the University of California, Santa Barbara. The experiment was part of the space research investigations conducted during the Microgravity Science Laboratory-1R mission (STS-94, July 1-17 1997). Advanced fluid dynamics experiments will be a part of investigations plarned for the International Space Station. (435KB, 13-second MPEG, screen 160 x 120 pixels; downlinked video, higher quality not available) A still JPG composite of this movie is available at http://mix.msfc.nasa.gov/ABSTRACTS/MSFC-0300162.html.

Serine proteinase inhibitors from nematodes and the arms race between host and pathogen.

PubMed

Zang, X; Maizels, R M

2001-03-01

Serine proteinase inhibitors are encoded by a large gene family of long evolutionary standing. Recent discoveries of parasite proteins that inhibit human serine proteinases, together with the complete genomic sequence from Caenorhabditis elegans, have provided a set of new serine proteinase inhibitors from more primitive metazoan animals such as nematodes. The structural features (e.g. reactive centre residues), gene organization (including intron arrangements) and inhibitory function and targets (e.g. inflammatory and coagulation pathway proteinase) all contribute important new insights into proteinase inhibitor evolution. Some parasite products have evolved that block enzymes in the mammalian host, but the human host responds with a significant immune response to the parasite inhibitors. Thus, infection produces a finely balanced conflict between host and pathogen at the molecular level, and this might have accelerated the evolution of these proteins in parasitic species as well as their hosts.

Responding for a conditioned reinforcer or unconditioned sensory reinforcer in mice: interactions with environmental enrichment, social isolation, and monoamine reuptake inhibitors.

PubMed

Browne, Caleb J; Fletcher, Paul J; Zeeb, Fiona D

2016-03-01

Environmental factors influence the etiology of many psychiatric disorders. Likewise, environmental factors can alter processes central to motivation. Therefore, motivational deficits present in many disorders may be influenced by early life environmental conditions. We examined whether housing animals in different environmental conditions influenced the ability of sensory stimuli to acquire incentive value and whether elevated monoamine activity altered responsing for these stimuli. Isolation-housed (IH), pair-housed (PH), and environmentally enriched (EE) male C57BL/6N mice were examined in tests of responding for a conditioned reinforcer (CRf) or an unconditioned sensory reinforcer (USRf). The CRf was previously paired with saccharin delivery through Pavlovian conditioning, while the USRf was not conditioned with a reward. Following baseline tests of responding for the CRf or USRf, the effects of elevated monoamine activity were examined. At baseline, PH and EE mice responded similarly for the CRf or USRf. IH mice responded more for the CRf but exhibited slower acquisition of responding for the USRf. Administration of citalopram, a serotonin transporter blocker, or atomoxetine, a norepinephrine transporter blocker, decreased responding for the CRf and USRf in all groups. The dopamine transporter blocker GBR 12909 generally increased responding for the CRf and USRf, but further analysis revealed enhanced responding for both reinforcers only in EE mice. Baseline incentive motivation is strongly influenced by the social component of housing conditions. Furthermore, environmental enrichment increased the sensitivity to elevated dopamine activity, while acute elevations in serotonin and norepinephrine inhibit incentive motivation irrespective of housing condition.

Expected Paradigm Shift in Brain Metastases Therapy-Immune Checkpoint Inhibitors.

PubMed

Jindal, Vishal; Gupta, Sorab

2018-01-30

Brain metastasis (BM) is one of the dreadful complications of malignancies. The prognosis after BM is extremely poor and life expectancy is meager. Currently, our treatment modalities are limited to radiotherapy and surgical resection, which also has poor outcomes and leads to various neurological deficits and affects the quality of life of patients. New treatment modality, i.e., immune checkpoint inhibitors, has brought revolution in management of melanoma, renal cancer, and non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors basically enhance the immune response of the body to fight against cancers. Immune response in the brain is highly regulated; therefore, it is challenging to use immune-modulator drugs in BM. The microenvironment of BM is rich in cytotoxic T lymphocytes and which is the target of immune checkpoint inhibitors. Few studies have shown some hope regarding use of immune checkpoint inhibitors in management of BM. It works through inhibiting immune check point gates, i.e., CTLA-4 (cytotoxic T-lymphocyte-associated protein) and PD-1/PD-L1 (programmed cell death protein-1/program death ligand-1). This article explains the basic mechanism of immune check point inhibitors, rationale behind their usage in BM, and some of the clinical studies which have shown the efficacy of immune check point inhibitors in BM.

Neurologic Complications of Transplantation.

PubMed

Dhar, Rajat

2018-02-01

Neurologic disturbances including encephalopathy, seizures, and focal deficits complicate the course 10-30% of patients undergoing organ or stem cell transplantation. While much or this morbidity is multifactorial and often associated with extra-cerebral dysfunction (e.g., graft dysfunction, metabolic derangements), immunosuppressive drugs also contribute significantly. This can either be through direct toxicity (e.g., posterior reversible encephalopathy syndrome from calcineurin inhibitors such as tacrolimus in the acute postoperative period) or by facilitating opportunistic infections in the months after transplantation. Other neurologic syndromes such as akinetic mutism and osmotic demyelination may also occur. While much of this neurologic dysfunction may be reversible if related to metabolic factors or drug toxicity (and the etiology is recognized and reversed), cases of multifocal cerebral infarction, hemorrhage, or infection may have poor outcomes. As transplant patients survive longer, delayed infections (such as progressive multifocal leukoencephalopathy) and post-transplant malignancies are increasingly reported.

Complication with Intraosseous Access: Scandinavian Users’ Experience

PubMed Central

Hallas, Peter; Brabrand, Mikkel; Folkestad, Lars

2013-01-01

Introduction: Intraosseous access (IO) is indicated if vascular access cannot be quickly established during resuscitation. Complication rates are estimated to be low, based on small patient series, model or cadaver studies, and case reports. However, user experience with IO use in real-life emergency situations might differ from the results in the controlled environment of model studies and small patient series. We performed a survey of IO use in real-life emergency situations to assess users’ experiences of complications. Methods: An online questionnaire was sent to Scandinavian emergency physicians, anesthesiologists and pediatricians. Results: 1,802 clinical cases of IO use was reported by n=386 responders. Commonly reported complications with establishing IO access were patient discomfort/pain (7.1%), difficulties with penetration of periosteum with IO needle (10.3%), difficulties with aspiration of bone marrow (12.3%), and bended/broken needle (4.0%). When using an established IO access the reported complications were difficulties with injection fluid and drugs after IO insertion (7.4%), slow infusion (despite use of pressure bag) (8.8%), displacement after insertion (8.5%), and extravasation (3.7%). Compartment syndrome and osteomyelitis occurred in 0.6% and 0.4% of cases respectively. Conclusion: In users’ recollection of real-life IO use, perceived complications were more frequent than usually reported from model studies. The perceived difficulties with using IO could affect the willingness of medical staff to use IO. Therefore, user experience should be addressed both in education of how to use, and research and development of IOs. PMID:24106537

Metabolic complications associated with use of diuretics.

PubMed

Palmer, Biff F

2011-11-01

Diuretics are commonly used therapeutic agents that act to inhibit sodium transport systems along the length of the renal tubule. The most effective diuretics are inhibitors of sodium chloride transport in the thick ascending limb of Henle. Loop diuretics mobilize large amounts of sodium chloride and water and produce a copious diuresis with a sharp reduction of extracellular fluid volume. As the site of action of diuretics moves downstream (thiazide and potassium-sparing diuretics), their effectiveness declines because the transport systems they inhibit have low transport capacity. Depending on the site of action diuretics can influence the renal handling of electrolyte-free water, calcium, potassium, protons, sodium bicarbonate, and uric acid. As a result, electrolyte and acid-base disorders commonly accompany diuretic use. Glucose and lipid abnormalities also can occur, particularly with the use of thiazide diuretics. This review focuses on the biochemical complications associated with the use of diuretics. The development of these complications can be minimized with careful monitoring, dosage adjustment, and replacement of electrolyte losses. Copyright © 2011 Elsevier Inc. All rights reserved.

Development of Poly Lactic/Glycolic Acid (PLGA) Microspheres for Controlled Release of Rho-Associated Kinase Inhibitor.

PubMed

Koda, Sho; Okumura, Naoki; Kitano, Junji; Koizumi, Noriko; Tabata, Yasuhiko

2017-01-01

The purpose of this study was to investigate the feasibility of poly lactic/glycolic acid (PLGA) as a drug delivery carrier of Rho kinase (ROCK) inhibitor for the treatment of corneal endothelial disease. ROCK inhibitor Y-27632 and PLGA were dissolved in water with or without gelatin (W1), and a double emulsion [(W1/O)/W2] was formed with dichloromethane (O) and polyvinyl alcohol (W2). Drug release curve was obtained by evaluating the released Y-27632 by using high performance liquid chromatography. PLGA was injected into the anterior chamber or subconjunctiva in rabbit eyes, and ocular complication was evaluated by slitlamp microscope and histological analysis. Y-27632 incorporated PLGA microspheres with different molecular weights, and different composition ratios of lactic acid and glycolic acid were fabricated. A high molecular weight and low content of glycolic acid produced a slower and longer release. The Y-27632 released from PLGA microspheres significantly promoted the cell proliferation of cultured corneal endothelial cells. The injection of PLGA did not induce any evident eye complication. ROCK inhibitor-incorporated PLGA microspheres were fabricated, and the microspheres achieved the sustained release of ROCK inhibitor over 7-10 days in vitro. Our data should encourage researchers to use PLGA microspheres for treating corneal endothelial diseases.

Hemodialysis in a patient with severe hemophilia A and factor VIII inhibitor.

PubMed

Gopalakrishnan, Natarajan; Usha, Thiruvengadam; Thopalan, Balasubramaniyan; Dhanapriya, Jeyachandran; Dineshkumar, Thanigachalam; Thirumalvalavan, Kaliaperumal; Sakthirajan, Ramanathan

2016-10-01

Hemophilia A is a hereditary X-linked recessive disease caused by mutations in the gene encoding factor VIII (FVIII), occurring in 1 out of 10,000 persons. Life expectancy and quality of life have dramatically improved recently in patients with hemophilia. Chronic kidney disease and need for renal replacement therapy in these patients are rare. The development of inhibitors to FVIII is the most serious complication of hemophilia and makes treatment of bleeds very challenging. We describe here a 28-year-old male patient with severe hemophilia A with presence of factor VIII inhibitor, who had end stage renal disease. Central venous access device was inserted along with infusion of factor eight inhibitor bypass activity before and after the procedure. He is currently on thrice weekly hemodialysis and doing well for 6 months without bleeding episodes. To our knowledge, hemophilia A with factor VIII inhibitor managed with hemodialysis has not been reported so far. © 2016 International Society for Hemodialysis.

Hypovolemic Shock Caused by Angiotensin-Converting Enzyme Inhibitor-Induced Visceral Angioedema: A Case Series and A Simple Method to Diagnose this Complication in the Emergency Department.

PubMed

Myslinski, Joseph; Heiser, Andrew; Kinney, Ashley

2018-03-01

Visceral angioedema is a rarely reported side effect of angiotensin-converting-enzyme inhibitors (ACEI). Because signs and symptoms tend to be nonspecific, the diagnosis is difficult to make, especially in the emergency department (ED). We describe 2 patients presenting with signs of hypovolemic shock, in which the diagnosis of ACEI-induced visceral angioedema was made in the ED. We surmise that patients with abdominal pain, who present with hypovolemic shock and are taking medications that can predispose to angioedema, may have this complication if their hemoglobin level is elevated compared with their previous levels. An abdominal computed tomography scan, if it does not identify any other significant etiology, will increase the probability that ACEI-induced visceral angioedema is the diagnosis when there is nonspecific bowel wall thickening or edema. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Identification of ACEI-induced visceral angioedema in the ED will avoid prolonged admissions, unnecessary procedures, and future recurrences. Copyright © 2017 Elsevier Inc. All rights reserved.

SGLT2 Inhibitors and the Diabetic Kidney.

PubMed

Fioretto, Paola; Zambon, Alberto; Rossato, Marco; Busetto, Luca; Vettor, Roberto

2016-08-01

Diabetic nephropathy (DN) is the most common cause of end-stage renal disease worldwide. Blood glucose and blood pressure control reduce the risk of developing this complication; however, once DN is established, it is only possible to slow progression. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, the most recent glucose-lowering oral agents, may have the potential to exert nephroprotection not only through improving glycemic control but also through glucose-independent effects, such as blood pressure-lowering and direct renal effects. It is important to consider, however, that in patients with impaired renal function, given their mode of action, SGLT2 inhibitors are less effective in lowering blood glucose. In patients with high cardiovascular risk, the SGLT2 inhibitor empagliflozin lowered the rate of cardiovascular events, especially cardiovascular death, and substantially reduced important renal outcomes. Such benefits on DN could derive from effects beyond glycemia. Glomerular hyperfiltration is a potential risk factor for DN. In addition to the activation of the renin-angiotensin-aldosterone system, renal tubular factors, including SGLT2, contribute to glomerular hyperfiltration in diabetes. SGLT2 inhibitors reduce sodium reabsorption in the proximal tubule, causing, through tubuloglomerular feedback, afferent arteriole vasoconstriction and reduction in hyperfiltration. Experimental studies showed that SGLT2 inhibitors reduced hyperfiltration and decreased inflammatory and fibrotic responses of proximal tubular cells. SGLT2 inhibitors reduced glomerular hyperfiltration in patients with type 1 diabetes, and in patients with type 2 diabetes, they caused transient acute reductions in glomerular filtration rate, followed by a progressive recovery and stabilization of renal function. Interestingly, recent studies consistently demonstrated a reduction in albuminuria. Although these data are promising, only dedicated renal outcome trials will clarify whether

HDAC Inhibitors Restore the Capacity of Aged Mice to Respond to Haloperidol through Modulation of Histone Acetylation

PubMed Central

Montalvo-Ortiz, Janitza L; Keegan, Jack; Gallardo, Christopher; Gerst, Nicolas; Tetsuka, Kazuhiro; Tucker, Chris; Matsumoto, Mitsuyuki; Fang, Deyu; Csernansky, John G; Dong, Hongxin

2014-01-01

Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psychopathological conditions, including psychosis and the behavioral disturbances associated with dementia. However, clinical experience suggests that these drugs may be less efficacious in the elderly individuals than in the young. Recent studies suggest that aging may be associated with epigenetic changes and that valproic acid (VPA), a histone deacetylase inhibitor, may reverse such changes. However, it is not yet known whether HDAC inhibitors can modulate age-related epigenetic changes that may impact antipsychotic drug action. In this study, we analyzed conditioned avoidance response (CAR) and c-Fos expression patterns to elucidate the effect of HDAC inhibitors VPA and entinostat (MS-275) on behavioral and molecular markers of the effects of haloperidol (HAL) in aged mice. Our results showed that HAL administration failed to suppress the avoidance response during the CAR test, suggesting an age-related decrease in drug efficacy. In addition, HAL-induced c-Fos expression in the nucleus accumbens shell and prefrontal cortex was significantly lower in aged mice as compared with young mice. Pretreatment with VPA and MS-275 significantly improved HAL effects on the CAR test in aged mice. Also, VPA and MS-275 pretreatment restored HAL-induced increases in c-Fos expression in the nucleus accumbens shell and prefrontal cortex of aged mice to levels comparable with those observed in young mice. Lastly, but most importantly, increases in c-Fos expression and HAL efficacy in the CAR test of the HAL+VPA and HAL+MS-275 groups were correlated with elevated histone acetylation at the c-fos promoter region in aged mice. These findings suggest that pretreatment with VPA or MS-275 increases the behavioral and molecular effects of HAL in aged mice and that these effects occur via modulation of age-related histone hypoacetylation in the nucleus accumbens shell and prefrontal cortex

Complications of cochlear implant surgery: A ten-year experience in a referral hospital in Peru, 2006-2015.

PubMed

Alcas, Olenka; Salazar, Miguel A

2016-09-01

To describe the frequency and characteristics of complications of cochlear implant (CI) surgery at Edgardo Rebagliati Martins Hospital of social security in Lima-Peru between 2006 and 2015. A retrospective descriptive study of patients that underwent CI surgery between August 2006 and December 2015. Among the 107 patients with CIs, the overall proportion of complications was 18.7% (20/107): 14.9% (16/107) of minor complications, and 3.7% (4/107) of major complications. Regarding the time of onset of complications, 2.8% (3/107) were intraoperative and 14% (15/107) postoperative. CI surgery in Peru is a safe procedure with a low frequency of major complications, representing an effective therapy for patients with sensorineural hearing loss who do not respond to hearing aids.

Patient preferences for diabetes-related complications in Taiwan.

PubMed

Lin, Yi-Ju; Wang, Chin-Yuan; Cheng, Ssu-Wei; Ko, Yu

2018-05-25

As the prevalence of diabetes mellitus (DM) continues to increase rapidly, there has been a rising need not only to assess the clinical outcomes but also the impact of DM on the health-related quality of life (HRQoL) of affected individuals. Most previous studies have found that having complications is strongly associated with decreased HRQoL in DM patients. As such, it is crucial to measure individuals' preferences for DM-related complications in order to assess the magnitude of complications' effect on overall HRQoL. In addition, preference scores are an essential component of cost-utility analyses (CUAs), which studies can incorporate healthcare costs, HRQoL and clinical outcomes of DM into one analysis. The aims of this study were to assess the preference scores of DM-related complications using both the standard gamble (SG), a choice-based method, and visual analogue scale (VAS), a scaling method. We also aimed to assess several possible factors that might be associated with the preference scores of the complications. This is a cross-sectional interview-administered survey, and 213 patients with type 2 DM were interviewed. The respondents' preference scores of eleven DM-related complications were obtained using VAS and SG techniques. Demographic information, clinical characteristics and risk attitudes were also collected to explore factors that may affect patients' preference scores. Nearly one quarter of participants in Taiwan ranked at least one of the complications worse than death. The mean VAS scores ranged from 0.004 (amputation) to 0.47 (nocturnal hypoglycemia) while the mean adjusted SG scores ranged from 0.30 (blindness) to 0.66 (nocturnal hypoglycemia). There were significant differences in all of the complications' preference scores depending on risk attitudes. Both the VAS and SG methods were used to elicit the preference scores of DM-related complications, and the preference scores derived could be useful for future cost utility analyses.

A Systematic Review and Meta-Analysis on the Safety of Vascular Endothelial Growth Factor (VEGF) Inhibitors for the Treatment of Retinopathy of Prematurity

PubMed Central

Pertl, Laura; Steinwender, Gernot; Mayer, Christoph; Hausberger, Silke; Pöschl, Eva-Maria; Wackernagel, Werner; Wedrich, Andreas; El-Shabrawi, Yosuf; Haas, Anton

2015-01-01

Introduction Laser photocoagulation is the current gold standard treatment for proliferative retinopathy of prematurity (ROP). However, it permanently reduces the visual field and might induce myopia. Vascular endothelial growth factor (VEGF) inhibitors for the treatment of ROP may enable continuing vascularization of the retina, potentially allowing the preservation of the visual field. However, for their use in infants concern remains. This meta-analysis explores the safety of VEGF inhibitors. Methods The Ovid Interface was used to perform a systematic review of the literature in the databases PubMed, EMBASE and the Cochrane Library. Results This meta-analysis included 24 original reports (including 1.457 eyes) on VEGF inhibitor treatment for ROP. The trials were solely observational except for one randomized and two case-control studies. We estimated a 6-month risk of retreatment per eye of 2.8%, and a 6-month risk of ocular complication without the need of retreatment of 1.6% per eye. Systemic complications were only reported as isolated incidents. Discussion VEGF inhibitors seem to be associated with low recurrence rates and ocular complication rates. They may have the benefit of potentially allowing the preservation of visual field and lower rates of myopia. Due to the lack of data, the risk of systemic side effects cannot be assessed. PMID:26083024

Buccal mucosal graft urethroplasty in men-risk factors for recurrence and complications: a third referral centre experience in anterior urethroplasty using buccal mucosal graft.

PubMed

Spilotros, Marco; Sihra, Neha; Malde, Sachin; Pakzad, Mahreen H; Hamid, Rizwan; Ockrim, Jeremy L; Greenwell, Tamsin J

2017-06-01

Urethral stricture disease is a challenging condition to treat and several approaches including direct visual internal urethrotomy (DVIU) and anastomotic or augmentation urethroplasties based on the use of flaps and graft have been reported. The aim of this study is to determine risk factors for stricture recurrence and complications in patients having buccal mucosal graft (BMG) urethroplasty for anterior urethral stricture under a single surgeon in a third referral centre in UK. We conducted a retrospective review of a prospectively gathered database of 128 patients having various forms of BMG urethroplasty between 2001 and 2015. Success and failure in terms of stricture recurrence, patient demographics, stricture aetiology and anatomy, and the adverse outcomes of: post-micturition dribbling (PMD), erectile dysfunction (ED) >12 months and complications were recorded in order to determine risk factors for recurrent stricture and complications. The mean age of all patients was 42.8 years (range, 16-74 years). Average follow-up was 45 months (range, 3-159 months). The total re-stricture rate was 19% (24 men). PMD was reported in 16% (n=20) and ED in 12.5% (n=16). All ED was none organic and responded to oral PDE5 inhibitor treatment. Post-operative complications were reported in 16 patients (12.5%). The most frequent complications recorded were urinary fistula (n=4; 3.1%), graft contracture (n=4; 3.1%) and graft failure (n=4; 3.1%), all reported after penile urethroplasty. Univariate analysis indicated that age at surgery, stricture length, site and aetiology were all significant risk factors for stricture recurrence. On multivariate analysis penile site was the only significant independent variable for restricture. BMG urethroplasty represents a reliable therapeutic option for patient with urethral strictures with a success rate of 81% at 45 months of follow-up. Complications are more common in complex stricture of the penile urethra. On multivariate analysis penile

Buccal mucosal graft urethroplasty in men—risk factors for recurrence and complications: a third referral centre experience in anterior urethroplasty using buccal mucosal graft

PubMed Central

Sihra, Neha; Malde, Sachin; Pakzad, Mahreen H.; Hamid, Rizwan; Ockrim, Jeremy L.; Greenwell, Tamsin J.

2017-01-01

Background Urethral stricture disease is a challenging condition to treat and several approaches including direct visual internal urethrotomy (DVIU) and anastomotic or augmentation urethroplasties based on the use of flaps and graft have been reported. The aim of this study is to determine risk factors for stricture recurrence and complications in patients having buccal mucosal graft (BMG) urethroplasty for anterior urethral stricture under a single surgeon in a third referral centre in UK. Methods We conducted a retrospective review of a prospectively gathered database of 128 patients having various forms of BMG urethroplasty between 2001 and 2015. Success and failure in terms of stricture recurrence, patient demographics, stricture aetiology and anatomy, and the adverse outcomes of: post-micturition dribbling (PMD), erectile dysfunction (ED) >12 months and complications were recorded in order to determine risk factors for recurrent stricture and complications. Results The mean age of all patients was 42.8 years (range, 16–74 years). Average follow-up was 45 months (range, 3–159 months). The total re-stricture rate was 19% (24 men). PMD was reported in 16% (n=20) and ED in 12.5% (n=16). All ED was none organic and responded to oral PDE5 inhibitor treatment. Post-operative complications were reported in 16 patients (12.5%). The most frequent complications recorded were urinary fistula (n=4; 3.1%), graft contracture (n=4; 3.1%) and graft failure (n=4; 3.1%), all reported after penile urethroplasty. Univariate analysis indicated that age at surgery, stricture length, site and aetiology were all significant risk factors for stricture recurrence. On multivariate analysis penile site was the only significant independent variable for restricture. Conclusions BMG urethroplasty represents a reliable therapeutic option for patient with urethral strictures with a success rate of 81% at 45 months of follow-up. Complications are more common in complex stricture of the

Antibiotic-associated diarrhea and the older dental patient: how do dentists respond?

PubMed

Zwetchkenbaum, Samuel R; Overbeck, Kevin J; Pomerantz, Sherry C

2015-01-01

Gastrointestinal complications from antibiotic use, including Clostridium difficile infection (CDI), can have significant morbidity, especially among older patients. This descriptive study surveyed dentists to find out how they would respond to a patient with signs indicating potential CDI. A survey on prescribing medications for older patients was mailed to 1,000 dentists in New Jersey. Questions were asked regarding antibiotic selection, probiotic use, and approach to a patient scenario of diarrhea after antibiotic use. Respondents chose amoxicillin most frequently as an antibiotic, and clindamycin if penicillin allergy. When informed their patients had diarrhea, 64.5% advised them to stop the antibiotic. If the patient continued to have diarrhea on follow-up, 75.5% contacted the patient's physician. Most (61.6%) do not prescribe probiotics prophylactically. Most dentists respond appropriately to antibiotic-associated diarrhea in advising to stop the antibiotic, and seeking physician involvement if no improvement, but there are still many who make recommendations that could delay appropriate care. Dentists may wish to learn more about benefits of probiotics. © 2015 Special Care Dentistry Association and Wiley Periodicals, Inc.

Practical approaches to minimizing gastrointestinal and cardiovascular safety concerns with COX-2 inhibitors and NSAIDs

PubMed Central

2005-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are highly effective in treating the pain and inflammation associated with osteoarthritis and rheumatoid arthritis, but it is well recognized that these agents are associated with substantial gastrointestinal toxicity. Treatment guidelines suggest that patients with one or more risk factors for NSAID associated ulcers should be prescribed preventive treatment. However, well over 80% of such patients may not receive an appropriate therapeutic intervention. Multiple strategies are available to reduce the risk for NSAID associated gastrointestinal complications. First, risk may be reduced by using non-NSAID analgesics. Second, use of the minimum effective dose of the NSAID may reduce risk. Third, co-therapy with a proton pump inhibitor or misoprostol may be desirable in at-risk patients. Use of cyclo-oxygenase-2 inhibitors may also reduce the risk for gastrointestinal events, although this benefit is eliminated in patients who receive aspirin, and cyclo-oxygenase-2 inhibitors may increase cardiovascular adverse events. The optimal management of NSAID related gastrointestinal complications must be based on the individual patient's risk factors for gastrointestinal and cardiovascular disease, as well as on the efficacy and tolerability of both the NSAID and accompanying gastroprotective agent. PMID:16168078

The comparision of effect of microdose GnRH-a flare-up, GnRH antagonist/aromatase inhibitor letrozole and GnRH antagonist/clomiphene citrate protocols on IVF outcomes in poor responder patients.

PubMed

Ozcan Cenksoy, Pinar; Ficicioglu, Cem; Kizilkale, Ozge; Suhha Bostanci, Mehmet; Bakacak, Murat; Yesiladali, Mert; Kaspar, Cigdem

2014-07-01

To compare the effects of microdose GnRH-a flare-up, GnRH antagonist/aromatase inhibitor letrozole and GnRH antagonist/clomiphene citrate protocols on IVF outcomes in poor responder patients. Of 225 patients, 83 patients were in microdose flare-up group (Group 1), 70 patients were in GnRH antagonist/letrozole group (Group 2) and 72 patients were in GnRH antagonist/clomiphene citrate group (Group 3). Demographic and endocrine characteristics, the total number of oocytes retrieved, cancellation rate and clinical pregnancy rate were collected Results: Total dosage of gonadotropins (p=0.002) and serum E2 levels on the day of hCG administration (p=0.010) were significantly higher and duration of stimulations (p=0.03) was significantly longer in group 1. The number of oocytes retrieved was significantly greater in group 1 and 2 when compare to those of group 3 (p=0,000). There was a trend towards increasing cycle cancellation rates with GnRH antagonist/clomiphene citrate and GnRH antagonist/letrozole. Our finding suggest that the results of microdose flare-up protocol are better than other two used treatment protocols, in terms of maximum estradiol levels, number of mature oocytes retrieved, and cancellation rate and it still seems to be superior the ovarian stimulation regime for the poor responder patients.

Novel aldose reductase inhibitors: a patent survey (2006--present).

PubMed

Chatzopoulou, Maria; Alexiou, Polyxeni; Kotsampasakou, Eleni; Demopoulos, Vassilis J

2012-11-01

Initially studied for its central role in the pathogenesis of chronic diabetic complications, aldose reductase (ALR2) gains more attention over the years as its implication in inflammatory diseases is being established, along with the therapeutic potential of its inhibitors. Reviewing the patents that were published since 2006, it is getting clear that the search for new chemical entities has subsided, giving rise to natural products and plant extracts with ALR2 inhibitory activity. Other aspects that were prominent were the search for proper forms of known inhibitors, in a way to improve their impaired physicochemical profile, as well as potential combination therapies with other compounds of pharmaceutical interest. On the spotlight were patents enhancing the therapeutic usage of aldose reductase inhibitors (ARIs) to various pathological conditions including cancer and inflammation-mediated diseases such as sepsis, asthma, and cancer. Although new chemical entities are scarcely registered and patented after many years of inconclusive clinical trials, the involvement of ALR2 to inflammatory pathologies might renew the interest in the field of ARIs.

The genetic basis of obesity complications.

PubMed

Skrypnik, Katarzyna; Suliburska, Joanna; Skrypnik, Damian; Pilarski, Łukasz; Reguła, Julita; Bogdański, Paweł

2017-01-01

Intensive research is currently being performed into the genetic background of excess body mass compli- cations such as diabetes, cardiovascular disorders, especially atherosclerosis and coronary heart disease. Chronic inflammation is an important process in the pathogenesis of obesity, wherein there is an aberrant ex- pression of genes encoding adipokines. Visceral tissue is characterized by a higher expression and secretion of interleukin-8, interleukin-1ß and plasminogen activator inhibitor 1 in the subcutaneous tissue secretion of leptin prevails. An important complication of obesity is obstructive sleep apnea, often observed in Prader- Willi syndrome. The genetic background of sleep apnea may be a polymorphism of the SREBF1 gene. The consequence of excess body mass is metabolic syndrome, which may be related to the occurrence of the rs926198 variant of gene encoding caveolin-1. The genes of transcription factor TCF7L2 and PPAR-γ2 take part in the pathogenesis of diabetes development. It has been demonstrated that oncogenes FOS, FOSB, and JUN may be co-responsible not only for obesity but also for osteoporosis and colorectal cancer. It has been shown that weight loss causes a modification in the expression of about 100 genes involvedt in the production of substances such as cytokines and other responsible for chronic inflammation in obesity. In future studies on the complications of obesity, such scientific disciplines as proteomics, peptidomics, metabolomics and transcriptomics should be used. The aim of this study is to present the current state of knowledge about the genetic basis of obesity complications.

In vitro evaluation of the Aurora kinase inhibitor VX-680 for Hepatoblastoma.

PubMed

Dewerth, Alexander; Wonner, Timo; Lieber, Justus; Ellerkamp, Verena; Warmann, Steven W; Fuchs, Jörg; Armeanu-Ebinger, Sorin

2012-06-01

Hepatoblastoma (HB) has a poor prognosis in advanced stages. The aim of this study was to enhance effectiveness of chemotherapy with antineoplastic kinase inhibitors. Viability was monitored in HB cells (HUH6, HepT1) in monolayer and spheroid cultures treated with kinase inhibitors VX-680, Wee1-InhibitorII, and SU11274 alone or in combination with cisplatin (CDDP) using MTT assays. Apoptosis was revealed by Caspase-3 assay. Western blot and immunohistochemical analyses were performed to determine histone H3 phosphorylation. Among the kinase inhibitors strongest anti-proliferative effect on HB cells was documented for VX-680. HUH6 cells responded more sensitively to the Aurora kinase inhibitor as HepT1 cells (IC(50) 8 and 16.6 μM, respectively). While VX-680 and CDDP showed no additive effects, the combination of VX-680 and histone deacetylase inhibitor SAHA had a synergistic effect on the proliferation of HUH6 cells. The inhibition with VX-680 led to reduced histone H3 phosphorylation, to an increase of apoptotic cells, and to morphological changes such as vacuolization and swelling of the cells and nuclei. The data provide evidence that VX-680 might improve treatment results in HB with increased Aurora kinase activity by inhibiting cell proliferation and induction of apoptosis.

Predictors of Complicated Grief after a Natural Disaster: A Population Study Two Years after the 2004 South-East Asian Tsunami

ERIC Educational Resources Information Center

Kristensen, Pal; Weisaeth, Lars; Heir, Trond

2010-01-01

The authors examined predictors of complicated grief (CG) in Norwegians 2 years after bereavement in the 2004 South-East Asian tsunami. A cross-sectional postal survey retrospectively covering disaster experiences and assessing CG according to the Inventory of Complicated Grief yielded 130 respondents (35 directly disaster-exposed and 95 not…

Proteases and protease inhibitors of urinary extracellular vesicles in diabetic nephropathy.

PubMed

Musante, Luca; Tataruch, Dorota; Gu, Dongfeng; Liu, Xinyu; Forsblom, Carol; Groop, Per-Henrik; Holthofer, Harry

2015-01-01

Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM), leads to chronic kidney disease (CKD), and, ultimately, is the main cause for end-stage kidney disease (ESKD). Beyond urinary albumin, no reliable biomarkers are available for accurate early diagnostics. Urinary extracellular vesicles (UEVs) have recently emerged as an interesting source of diagnostic and prognostic disease biomarkers. Here we used a protease and respective protease inhibitor array to profile urines of type 1 diabetes patients at different stages of kidney involvement. Urine samples were divided into groups based on the level of albuminuria and UEVs isolated by hydrostatic dialysis and screened for relative changes of 34 different proteases and 32 protease inhibitors, respectively. Interestingly, myeloblastin and its natural inhibitor elafin showed an increase in the normo- and microalbuminuric groups. Similarly, a characteristic pattern was observed in the array of protease inhibitors, with a marked increase of cystatin B, natural inhibitor of cathepsins L, H, and B as well as of neutrophil gelatinase-associated Lipocalin (NGAL) in the normoalbuminuric group. This study shows for the first time the distinctive alterations in comprehensive protease profiles of UEVs in diabetic nephropathy and uncovers intriguing mechanistic, prognostic, and diagnostic features of kidney damage in diabetes.

Proteases and Protease Inhibitors of Urinary Extracellular Vesicles in Diabetic Nephropathy

PubMed Central

Tataruch, Dorota; Gu, Dongfeng; Liu, Xinyu; Forsblom, Carol; Groop, Per-Henrik; Holthofer, Harry

2015-01-01

Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM), leads to chronic kidney disease (CKD), and, ultimately, is the main cause for end-stage kidney disease (ESKD). Beyond urinary albumin, no reliable biomarkers are available for accurate early diagnostics. Urinary extracellular vesicles (UEVs) have recently emerged as an interesting source of diagnostic and prognostic disease biomarkers. Here we used a protease and respective protease inhibitor array to profile urines of type 1 diabetes patients at different stages of kidney involvement. Urine samples were divided into groups based on the level of albuminuria and UEVs isolated by hydrostatic dialysis and screened for relative changes of 34 different proteases and 32 protease inhibitors, respectively. Interestingly, myeloblastin and its natural inhibitor elafin showed an increase in the normo- and microalbuminuric groups. Similarly, a characteristic pattern was observed in the array of protease inhibitors, with a marked increase of cystatin B, natural inhibitor of cathepsins L, H, and B as well as of neutrophil gelatinase-associated Lipocalin (NGAL) in the normoalbuminuric group. This study shows for the first time the distinctive alterations in comprehensive protease profiles of UEVs in diabetic nephropathy and uncovers intriguing mechanistic, prognostic, and diagnostic features of kidney damage in diabetes. PMID:25874235

Evaluation of potential interactions between mycophenolic acid derivatives and proton pump inhibitors.

PubMed

Gabardi, Steven; Olyaei, Ali

2012-01-01

To evaluate the incidence of gastrointestinal (GI) complications in solid organ transplant (SOT) recipients, impact of the complications on transplant outcomes, and the potential interactions between mycophenolic acid (MPA) derivatives and proton pump inhibitors (PPIs). An unrestricted literature search (1980-January 2012) was performed with MEDLINE and EMBASE using the following key words: drug-drug interaction, enteric-coated mycophenolic acid, GI complications, mycophenolate mofetil, solid organ transplant, and proton pump inhibitor, including individual agents within the class. Abstracts from scientific meetings were also evaluated. Additionally, reference citations from identified publications were reviewed. Relevant English-language, original research articles and review articles were evaluated if they focused on any of the topics identified in the search or included substantial content addressing GI complications in SOT recipients or drug interactions. GI complications are frequent among SOT recipients, with some studies showing prevalence rates as high as 70%. Transplant outcomes among renal transplant recipients are significantly impacted by GI complications, especially in patients requiring immunosuppressant dosage reductions or premature discontinuation. To this end, PPI use among patients receiving transplants is common. Recent data demonstrate that PPIs significantly reduce the overall exposure to MPA after oral administration of mycophenolate mofetil. Similar studies show this interaction does not exist between PPIs and enteric-coated mycophenolic acid (EC-MPA). Unfortunately, most of the available data evaluating this interaction are pharmacokinetic analyses that do not investigate the clinical impact of this interaction. A significant interaction exists between PPIs and mycophenolate mofetil secondary to reduced dissolution of mycophenolate mofetil in higher pH environments. EC-MPA is not absorbed in the stomach; therefore, low intragastric acidity

Persistent gastro-oesophageal reflux symptoms despite proton pump inhibitor therapy

PubMed Central

Ang, Daphne; How, Choon How; Ang, Tiing Leong

2016-01-01

About one-third of patients with suspected gastro-oesophageal reflux disease (GERD) do not respond symptomatically to proton pump inhibitors (PPIs). Many of these patients do not suffer from GERD, but may have underlying functional heartburn or atypical chest pain. Other causes of failure to respond to PPIs include inadequate acid suppression, non-acid reflux, oesophageal hypersensitivity, oesophageal dysmotility and psychological comorbidities. Functional oesophageal tests can exclude cardiac and structural causes, as well as help to confi rm or exclude GERD. The use of PPIs should only be continued in the presence of acid reflux or oesophageal hypersensitivity for acid reflux-related events that is proven on functional oesophageal tests. PMID:27779277

Persistent gastro-oesophageal reflux symptoms despite proton pump inhibitor therapy.

PubMed

Ang, Daphne; How, Choon How; Ang, Tiing Leong

2016-10-01

About one-third of patients with suspected gastro-oesophageal reflux disease (GERD) do not respond symptomatically to proton pump inhibitors (PPIs). Many of these patients do not suffer from GERD, but may have underlying functional heartburn or atypical chest pain. Other causes of failure to respond to PPIs include inadequate acid suppression, non-acid reflux, oesophageal hypersensitivity, oesophageal dysmotility and psychological comorbidities. Functional oesophageal tests can exclude cardiac and structural causes, as well as help to confi rm or exclude GERD. The use of PPIs should only be continued in the presence of acid reflux or oesophageal hypersensitivity for acid reflux-related events that is proven on functional oesophageal tests. Copyright: © Singapore Medical Association.

JAK2 inhibition sensitizes resistant EGFR-mutant lung adenocarcinoma to tyrosine kinase inhibitors

PubMed Central

Gao, Sizhi P.; Chang, Qing; Mao, Ninghui; Daly, Laura A.; Vogel, Robert; Chan, Tyler; Liu, Shu Hui; Bournazou, Eirini; Schori, Erez; Zhang, Haiying; Brewer, Monica Red; Pao, William; Morris, Luc; Ladanyi, Marc; Arcila, Maria; Manova-Todorova, Katia; de Stanchina, Elisa; Norton, Larry; Levine, Ross L.; Altan-Bonnet, Gregoire; Solit, David; Zinda, Michael; Huszar, Dennis; Lyden, David; Bromberg, Jacqueline F.

2016-01-01

Lung adenocarcinomas with mutant epidermal growth factor receptor (EGFR) respond to EGFR-targeted tyrosine kinase inhibitors (TKIs), but resistance invariably occurs. We found that the Janus kinase (JAK)/signal transduction and activator of transcription 3 (STAT3) signaling pathway was aberrantly increased in TKI-resistant EGFR-mutant non–small cell lung cancer (NSCLC) cells. JAK2 inhibition restored sensitivity to the EGFR inhibitor erlotinib in TKI-resistant cell lines and xenograft models of EGFR-mutant TKI-resistant lung cancer. JAK2 inhibition uncoupled EGFR from its negative regulator, suppressor of cytokine signaling 5 (SOCS5), consequently increasing EGFR abundance and restoring the tumor cells’ dependence on EGFR signaling. Furthermore, JAK2 inhibition led to heterodimerization of mutant and wild-type EGFR subunits, the activity of which was then blocked by TKIs. Our results reveal a mechanism whereby JAK2 inhibition overcomes acquired resistance to EGFR inhibitors and support the use of combination therapy with JAK and EGFR inhibitors for the treatment of EGFR-dependent NSCLC. PMID:27025877

Prevalence of the intron 22 inversion of the factor VIII gene and inhibitor development in Polish patients with severe hemophilia A.

PubMed

Sawecka, Jadwiga; Skulimowska, Joanna; Windyga, Jerzy; Lopaciuk, Stanisław; Kościelak, Jerzy

2005-01-01

Patients with severe hemophilia A often develop inhibitors (antibodies) against transfused factor VIII. One hundred thirteen Polish patients with severe hemophilia A, who had been treated on demand with cryoprecipitate until 1992 and exclusively with factor VIII concentrates after 1995, were examined for intron 22 inversion by Southern blotting and the presence and magnitude of inhibitor activity in blood as determined by the Bethesda assay. The patients' ages ranged 4--67 years (mean: 33.7+/-12.4 years, median: 32 years). The number of patients with the inversion amounted to 57, while in 56 patients the mutation types were unknown; 47 patients had a distal and 10 patients a proximal type of inversion. Thirteen patients with inversions (22.8%) were found to have inhibitor in their blood. Most patients (14 out of 15) who developed inhibitors in the course of cryoprecipitate therapy were high responders. Conversely, 4 of 5 patients treated between 1992 and 1995 with both cryoprecipitate and intermediate-purity factor VIII concentrates were low responders. One multitransfused patient who had remained inhibitor-free on cryoprecipitate therapy developed inhibitor after receiving a large dose of factor VIII concentrate during surgery. None of these 5 patients developed inhibitors during their 12--40 years of treatment with cryoprecipitate, suggesting that it was less immunogenic than factor VIII concentrates. The prevalence of the intron 22 inversion mutation of the factor VIII gene in Polish hemophiliacs is similar to that in other European countries. Treatment regimens with either cryoprecipitate or virus-inactivated plasma-derived factor VIII concentrates may affect inhibitor formation in hemophilia A patients.

Long-term safety concerns with proton pump inhibitors.

PubMed

Ali, Tauseef; Roberts, David Neil; Tierney, William M

2009-10-01

Proton pump inhibitors (PPIs) are among the most widely prescribed medications worldwide. Their use has resulted in dramatic improvements in treatment of peptic ulcer disease and gastroesophageal reflux disease. Despite an acceptable safety profile, mounting data demonstrate concerns about the long-term use of PPIs. To provide a comprehensive review regarding the concerns of long-term PPI use, a literature search was performed to identify pertinent original and review articles. Despite study shortcomings, the collective body of information overwhelmingly suggests an increased risk of infectious complications and nutritional deficiencies. Data regarding any increased risk in gastric or colon malignancy are less convincing. PPIs have revolutionized the management and complications of acid-related disorders with a high margin of safety; however, with the data available, efforts to reduce the dosing of or discontinue the use of PPIs must be reassessed frequently.

Δ9-Tetrahydrocannabinol and Endocannabinoid Degradative Enzyme Inhibitors Attenuate Intracranial Self-Stimulation in Mice

PubMed Central

Grim, Travis W.; Owens, Robert A.; Lazenka, Matthew F.; Sim-Selley, Laura J.; Abdullah, Rehab A.; Niphakis, Micah J.; Vann, Robert E.; Cravatt, Benjamin F.; Wiley, Jenny L.; Negus, S. Stevens; Lichtman, Aron H.

2015-01-01

A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS

Δ9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice.

PubMed

Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A; Lazenka, Matthew F; Sim-Selley, Laura J; Abdullah, Rehab A; Niphakis, Micah J; Vann, Robert E; Cravatt, Benjamin F; Wiley, Jenny L; Negus, S Stevens; Lichtman, Aron H

2015-02-01

A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle [intracranial self-stimulation (ICSS)], which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on

Should anti-inhibitor coagulant complex and tranexamic acid be used concomitantly?

PubMed

Valentino, L A; Holme, P A

2015-11-01

Inhibitor development in haemophilia patients is challenging especially when undergoing surgical procedures. The development of an inhibitor precludes using factor VIII (FVIII) therapy thereby requiring a bypassing agent (BPA) for surgical bleeding prophylaxis if the FVIII inhibitor titre >5 BU. Concomitant use of anti-inhibitor coagulant complex (AICC) and tranexamic acid has been reported in the literature as a beneficial treatment for this population. Anti-inhibitor coagulant complex is known to cause an increase in thrombin generation and tranexamic acid inhibits fibrinolysis. Hence, the combined used of AICC and tranexamic acid has been limited due to safety concerns over possibilities of increased risk of thrombotic events and disseminated intravascular coagulation. However, the rationale for concomitant therapy is to obtain a potential synergistic effect and to increase clot stability. We conducted a literature review of past studies and individual case reports of concomitant use of AICC and tranexamic acid, which was extensively used during dental procedures. Evidence also exists for concomitant use of the combined therapy in orthopaedic procedures, control of gastrointestinal bleeding, epistaxis and cerebral haemorrhages. Some patients who received the combined therapy had failed monotherapy with a single BPA prior to combined therapy. There were no reports of thrombotic complications related to the concomitant therapy and haemostasis was achieved in all cases. Anti-inhibitor coagulant complex and tranexamic acid therapy was found to be safe, well-tolerated and effective therapy in haemophilia patients with inhibitors. Additional randomized controlled studies should be performed to confirm these findings. © 2015 John Wiley & Sons Ltd.

Beauty from the beast: Avoiding errors in responding to client questions.

PubMed

Waehler, Charles A; Grandy, Natalie M

2016-09-01

Those rare moments when clients ask direct questions of their therapists likely represent a point when they are particularly open to new considerations, thereby representing an opportunity for substantial therapeutic gains. However, clinical errors abound in this area because clients' questions often engender apprehension in therapists, causing therapists to respond with too little or too much information or shutting down the discussion prematurely. These response types can damage the therapeutic relationship, the psychotherapy process, or both. We explore the nature of these clinical errors in response to client questions by providing examples from our own clinical work, suggesting potential reasons why clinicians may not make optimal use of client questions, and discussing how the mixed psychological literature further complicates the issue. We also present four guidelines designed to help therapists, trainers, and supervisors respond constructively to clinical questions in order to create constructive interactions. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

[Anemic syndrome frequency in complicated obstetrical patients].

PubMed

Martínez, Maria Guadalupe Veloz; Erasto, Luis Cruz; Maxines, Claudia García; Rodríguez, María Antonia Basavilvazo; Valencia, Marcelino Hernández

2008-09-01

The prevalence of anemia varies from country to country and there is not a trustworthy record. To determine the frequency of anemia in obstetric patients and the association among healthy pregnancy and aggregate complications. Was carried out as transversal, observational and comparative study. Obstetrical patients entered and responded in the period of a year, were formed a group with normal pregnancy and another with complicated pregnancy, with a total sample of 194 patients. In the statistical analysis was employed Student t test for independent groups, with value if p < 0.05. When was included all patients from both groups of study a general frequency of anemia was found in 22.4%. Hematological stage from group with normal pregnancy was mild anemia in 16.9% and anemia moderated in 4.1% of the cases. The anemia degrees in the group with associated illness and pregnancy were mild anemia in 19.2% and moderated anemia in 4.2%. Not any case was found with severe anemia. The statistical analysis showed difference significant among both groups p < 0.05. The most frequently causes of the obstetrical morbidity were preeclampsia severe (22.6%), type 2 diabetes (13.9%), gestational diabetes (12.2%) and the remainder with other complications that include to the hypertiroidism, rheumatoid arthritis, lupus, asthma and vein deep thrombosis. Frequency of anemia in this study was greater upon informing in the international literature. The obstetrical complication more frequently relates to diverse anemia degrees were the hypertensive stage during pregnancy. The anemia is presented with greater frequency in pregnancy patients with others associated illness.

A Case of Acute Budd-Chiari Syndrome Complicating Primary Antiphospholipid Syndrome Presenting as Acute Abdomen and Responding to Tight Anticoagulant Therapy.

PubMed

Chinen, Naofumi; Koyama, Yasushi; Sato, Shinji; Suzuki, Yasuo

2016-01-01

A 34-year-old woman with primary antiphospholipid syndrome was admitted to the Gastroenterology Department of our hospital with fever, acute abdomen, watery diarrhea, and extremely high levels of inflammatory parameters. She had a history of left lower limb deep vein thrombosis and pulmonary embolism and was taking warfarin potassium. Acute gastroenteritis was suspected and an antibiotic was administered, but symptoms progressed. Abdominal ultrasonography showed occlusion of the left hepatic vein and the middle hepatic vein and her D-dimer level was high. Accordingly, Budd-Chiari syndrome was diagnosed and high-dose intravenous infusion of heparin was initiated. Her abdominal symptoms improved and the levels of inflammatory parameters and D-dimer decreased rapidly. It is known that antiphospholipid syndrome can be complicated by Budd-Chiari syndrome that usually occurs as subacute or chronic onset, but acute onset is rare. It is difficult to diagnose acute Budd-Chiari syndrome complicating antiphospholipid syndrome and this complication generally has a poor outcome. However, the present case can get early diagnosis and successful treatment with tight anticoagulant therapy.

Prevention of non-enzymatic glycosylation (glycation): Implication in the treatment of diabetic complication

PubMed Central

Younus, H.; Anwar, S.

2016-01-01

Non-enzymatic glycosylation (glycation) plays an important role in the development of physiological and pathophysiological processes such as aging, diabetes, atherosclerosis, neurodegenerative diseases and chronic renal failure. Preventing glycation can minimize diabetic complications. Glycation can be prevented by the natural defence system in the body, synthetic inhibitors and natural inhibitors. Synthetic inhibitors may prevent glycation through several possible mechanisms. They might inhibit the glycation by interfering with the attachment of sugars with proteins, by inhibiting the late stage of glycation or by preventing Amadori product formation. Furthermore, their ability to scavenge free radicals and to break cross-links might be other mechanisms responsible for their potential to inhibit glycation. Naturally occurring phytochemicals/products have been found to be relatively non-toxic as compared to synthetic compounds, and are inexpensive and available in an ingestible form. A large number of plants and natural biomolecules have been shown to have antidiabetic effects. Several hypoglycaemic compounds have anti-oxidant properties. The present review describes the various ways in which glycation can be prevented. PMID:27103908

The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence

PubMed Central

Klintmalm, Goran B.; Nashan, Björn

2014-01-01

Despite the success of liver transplantation, long-term complications remain, including de novo malignancies, metabolic syndrome, and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). The current mainstay of treatment, calcineurin inhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need for better immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. The mammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressive agents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTOR inhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms, de novo tumors, and the recurrence of HCC and HCV. The results of our review indicate that mTOR inhibitors are associated with efficacy comparable to CNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit side effects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-related allograft fibrosis, metabolic syndrome, and neurotoxicity. PMID:24719752

Chronic blockade or constitutive deletion of the serotonin transporter reduces operant responding for food reward.

PubMed

Sanders, Amy Cecilia; Hussain, Ali J; Hen, René; Zhuang, Xiaoxi

2007-11-01

The therapeutic effects of chronic selective serotonin reuptake inhibitors (SSRIs) are well documented, yet the elementary behavioral processes that are affected by such treatment have not been fully investigated. We report here the effects of chronic fluoxetine treatment and genetic deletion of the serotonin transporter (SERT) on food reinforced behavior in three paradigms: the progressive ratio operant task, the concurrent choice operant task, and the Pavlovian-to-Instrumental transfer task. We consistently find that chronic pharmacological blockade or genetic deletion of SERT result in similar behavioral consequences: reduced operant responding for natural reward. This is in line with previous studies reporting declines in operant responding for drugs and intracranial self-stimulation with fluoxetine treatment, suggesting that the effect of SERT blockade can be generalized to different reward types. Detailed analyses of behavioral parameters indicate that this reduction in operant responding affect both goal-directed and non-goal-directed behaviors without affecting the Pavlovian cue-triggered excessive operant responding. In addition, both pharmacological and genetic manipulations reduce locomotor activity in the open field novel environment. Our data contrast with the effect of dopamine in increasing operant responding for natural reward specifically in goal-directed behaviors and in increasing Pavlovian cue-triggered excessive operant responding. Serotonin and dopamine have been proposed to serve opposing functions in motivational processes. Our data suggest that their interactions do not result in simple opponency. The fact that pharmacological blockade and genetic deletion of SERT have similar behavioral consequences reinforces the utility of the SERT null mice for investigation of the mechanisms underlying chronic SSRIs treatment.

Helicoid peripapillary chorioretinal degeneration complicated by choroidal neovascularization.

PubMed

Triantafylla, Magdalini; Panos, Georgios D; Dardabounis, Doukas; Nanos, Panagiotis; Konstantinidis, Aristeidis

2016-02-15

Helicoid peripapillary chorioretinal degeneration (HPCD) is a hereditary disease of the fundus that is characterized by atrophic chorioretinal areas that appear early in life and expand gradually from the optic disc towards the macula and the periphery. We describe the case of an elderly man with a known diagnosis of HPCD who developed choroidal neovascular membrane (CNV) in both eyes during the course of the disease. The patient was treated with intravitreal injection of ranibizumab, to which he had excellent response. The CNV subsided with 2 injections in the right eye and 1 in the left. Two years after the initial diagnosis of CNV in the right eye, visual acuity was 5/10 OD and 9/10 OS. Helicoid peripapillary chorioretinal degeneration is rarely complicated by CNV as the fundus lacks the trigger factors that would sustain this process. Although rare, HPCD complicated by CNV can be seen bilaterally, but responds well to few ranibizumab injections.

Proton pump inhibitor-refractory gastroesophageal reflux disease: challenges and solutions

PubMed Central

Mermelstein, Joseph; Chait Mermelstein, Alanna; Chait, Maxwell M

2018-01-01

A significant percentage of patients with gastroesophageal reflux disease (GERD) will not respond to proton pump inhibitor (PPI) therapy. The causes of PPI-refractory GERD are numerous and diverse, and include adherence, persistent acid, functional disorders, nonacid reflux, and PPI bioavailability. The evaluation should start with a symptom assessment and may progress to imaging, endoscopy, and monitoring of esophageal pH, impedance, and bilirubin. There are a variety of pharmacologic and procedural interventions that should be selected based on the underlying mechanism of PPI failure. Pharmacologic treatments can include antacids, prokinetics, alginates, bile acid binders, reflux inhibitors, and antidepressants. Procedural options include laparoscopic fundoplication and LINX as well as endoscopic procedures, such as transoral incisionless fundoplication and Stretta. Several alternative and complementary treatments of possible benefit also exist. PMID:29606884

Recent Progress in JAK Inhibitors for the Treatment of Rheumatoid Arthritis.

PubMed

Nakayamada, Shingo; Kubo, Satoshi; Iwata, Shigeru; Tanaka, Yoshiya

2016-10-01

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. Considerable advance in the treatment of RA has been made following the advent of biological disease-modifying anti-rheumatic drugs (DMARDs). However, these biologics require intravenous or subcutaneous injection and some patients fail to respond to biological DMARDs or lose their primary response. Various cytokines and cell surface molecules bind to receptors on the cell surface, resulting in the activation of various cell signaling pathways, including phosphorylation of kinase proteins. Among these kinases, the non-receptor tyrosine kinase family Janus kinase (JAK) plays a pivotal role in the pathological processes of RA. Several JAK inhibitors have been developed as new therapies for patients with RA. These are oral synthetic DMARDs that inhibit JAK1, 2, and 3. One JAK inhibitor, tofacitinib, has already been approved in many countries. Results of phase III clinical trials using a JAK1/2 inhibitor, baricitinib, have shown feasible efficacy and tolerable safety. Both drugs are effective in patients who showed inadequate response to biological DMARDs as well as synthetic DMARDs. In addition, clinical phase III trials using filgotinib and ABT-494, specific JAK1 inhibitors, are currently underway. JAK inhibitors are novel therapies for RA, but further studies are needed to determine their risk-benefit ratio and selection of the most appropriate patients for such therapy.

Impairment of hypoxia-induced HIF-1α signaling in keratinocytes and fibroblasts by sulfur mustard is counteracted by a selective PHD-2 inhibitor.

PubMed

Deppe, Janina; Popp, Tanja; Egea, Virginia; Steinritz, Dirk; Schmidt, Annette; Thiermann, Horst; Weber, Christian; Ries, Christian

2016-05-01

Skin exposure to sulfur mustard (SM) provokes long-term complications in wound healing. Similar to chronic wounds, SM-induced skin lesions are associated with low levels of oxygen in the wound tissue. Normally, skin cells respond to hypoxia by stabilization of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α). HIF-1α modulates expression of genes including VEGFA, BNIP3, and MMP2 that control processes such as angiogenesis, growth, and extracellular proteolysis essential for proper wound healing. The results of our studies revealed that exposure of primary normal human epidermal keratinocytes (NHEK) and primary normal human dermal fibroblasts (NHDF) to SM significantly impaired hypoxia-induced HIF-1α stabilization and target gene expression in these cells. Addition of a selective inhibitor of the oxygen-sensitive prolyl hydroxylase domain-containing protein 2 (PHD-2), IOX2, fully recovered HIF-1α stability, nuclear translocation, and target gene expression in NHEK and NHDF. Moreover, functional studies using a scratch wound assay demonstrated that the application of IOX2 efficiently counteracted SM-mediated deficiencies in monolayer regeneration under hypoxic conditions in NHEK and NHDF. Our findings describe a pathomechanism by which SM negatively affects hypoxia-stimulated HIF-1α signaling in keratinocytes and fibroblasts and thus possibly contributes to delayed wound healing in SM-injured patients that could be treated with PHD-2 inhibitors.

JAK inhibitors: A broadening approach in rheumatoid arthritis.

PubMed

Lam, S

2016-08-01

Pfizer's Xeljanz (tofacitinib citrate) was the first Janus kinase (JAK) inhibitor to reach the market for rheumatoid arthritis (RA) following its U.S. approval in November 2012, and it has since gained approval in more than 45 countries as a second-line therapy for RA after failure of disease-modifying antirheumatic drugs (DMARDs). This emerging category has heralded an attractive new class of oral treatment options in RA, with a notable opportunity in patients who stop responding to DMARDs, but they are facing a challenging market. Despite RA affecting approximately 23.7 million people worldwide, Xeljanz faces a market dominated by the anti-tumor necrosis factor (anti-TNF) biologicals, which have robust long-term safety and efficacy. The availability of biosimilars of these market leaders is also intensifying competition, and a high price and uncertainty over long-term safety is currently tempering the market for the JAK inhibitors. Copyright 2016 Prous Science, S.A.U. or its licensors. All rights reserved.

A study of prospective surveillance for inhibitors among persons with haemophilia in the United States.

PubMed

Soucie, J M; Miller, C H; Kelly, F M; Payne, A B; Creary, M; Bockenstedt, P L; Kempton, C L; Manco-Johnson, M J; Neff, A T

2014-03-01

Inhibitors are a rare but serious complication of treatment of patients with haemophilia. Phase III clinical trials enrol too few patients to adequately assess new product inhibitor risk. This project explores the feasibility of using a public health surveillance system to conduct national surveillance for inhibitors. Staff at 17 U.S. haemophilia treatment centres (HTC) enrolled patients with haemophilia A and B into this prospective study. HTC staff provided detailed historic data on product use and inhibitors at baseline, and postenrolment patients provided monthly detailed infusion logs. A central laboratory performed inhibitor tests on blood specimens that were collected at baseline, annually, prior to any planned product switch or when clinically indicated. The central laboratory also performed genotyping of all enrolled patients. From January 2006 through June 2012, 1163 patients were enrolled and followed up for 3329 person-years. A total of 3048 inhibitor tests were performed and 23 new factor VIII inhibitors were identified, 61% of which were not clinically apparent. Infusion logs were submitted for 113,205 exposure days. Genotyping revealed 431 distinct mutations causing haemophilia, 151 of which had not previously been reported elsewhere in the world. This study provided critical information about the practical issues that must be addressed to successfully implement national inhibitor surveillance. Centralized testing with routine monitoring and confirmation of locally identified inhibitors will provide valid and representative data with which to evaluate inhibitor incidence and prevalence, monitor trends in occurrence rates and identify potential inhibitor outbreaks associated with products. © 2013 John Wiley & Sons Ltd.

Manual therapy in the treatment of patients with hemophilia B and inhibitor.

PubMed

Cuesta-Barriuso, Rubén; Trelles-Martínez, Roberto O

2018-01-22

The main clinical manifestations of hemophilia are muscle and joint bleeding. Recurrent bleeding leads to a degenerative process known as hemophilic arthropathy. The development of inhibitors (antibodies against FVIII/FIX concentrates) is the main complication in the treatment of hemophilia. The objective was to assess the safety and efficacy of manual therapy treatment in a patient with hemophilia and inhibitor. A 26-year-old patient with hemophilia B and inhibitor received physiotherapy treatment based on manual therapy for 3 months, with a frequency of 2 sessions per week. The joint status was evaluated using the Hemophilia Joint Health Score; pain was assessed with the Visual Analog Scale; and the range of movement was evaluated using a universal goniometer. The patient developed no joint bleeding in the knees or ankles as a result of the physiotherapy treatment. Following treatment, improvements were noted in the range of movement of knees and ankles, the perception of pain in both knees, and ankle functionality. Until now, manual therapy using joint traction was contraindicated in patients with hemophilia and inhibitor, as it was feared to cause possible joint bleeding. This is the first case study to address the safety and efficacy of manual therapy in a patient with hemophilia and an inhibitor. The results of this study may help to establish which manual therapy treatments are indicated in patients with hemophilic arthropathy and inhibitors. Thus, a physiotherapy program based on manual therapy may be safe in patients with hemophilia and inhibitor and such therapy may improve joint condition, pain, and joint range of motion in patients with hemophilia and inhibitor. Randomized clinical trials are needed to confirm the results of this case study.

Aromatase Inhibitors and Bone Loss

PubMed Central

PEREZ, EDITH A.; M., Serene; Durling, Frances C.; WEILBAECHER, KATHERINE

2009-01-01

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor–positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment–related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < −2.5) and considered on an individual basis for those with osteopenia (T score < −1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor–positive breast cancer. PMID:16986348

CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials.

PubMed

Mallat, Samir G; Tanios, Bassem Y; Itani, Houssam S; Lotfi, Tamara; McMullan, Ciaran; Gabardi, Steven; Akl, Elie A; Azzi, Jamil R

2017-08-07

The objective of this meta-analysis is to compare the incidences of cytomegalovirus and BK polyoma virus infections in renal transplant recipients receiving a mammalian target of rapamycin inhibitor (mTOR)-based regimen compared with a calcineurin inhibitor-based regimen. We conducted a comprehensive search for randomized, controlled trials up to January of 2016 addressing our objective. Other outcomes included acute rejection, graft loss, serious adverse events, proteinuria, wound-healing complications, and eGFR. Two review authors selected eligible studies, abstracted data, and assessed risk of bias. We assessed quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology. We included 28 randomized, controlled trials with 6211 participants classified into comparison 1: mTOR inhibitor versus calcineurin inhibitor and comparison 2: mTOR inhibitor plus reduced dose of calcineurin inhibitor versus regular dose of calcineurin inhibitor. Results showed decreased incidence of cytomegalovirus infection in mTOR inhibitor-based group in both comparison 1 (risk ratio, 0.54; 95% confidence interval, 0.41 to 0.72), with high quality of evidence, and comparison 2 (risk ratio, 0.43; 95% confidence interval, 0.24 to 0.80), with moderate quality of evidence. The available evidence neither confirmed nor ruled out a reduction of BK polyoma virus infection in mTOR inhibitor-based group in both comparisons. Secondary outcomes revealed more serious adverse events and acute rejections in mTOR inhibitor-based group in comparison 1 and no difference in comparison 2. There was no difference in graft loss in both comparisons. eGFR was higher in the mTOR inhibitor-based group in comparison 1 (mean difference =4.07 ml/min per 1.73 m 2 ; 95% confidence interval, 1.34 to 6.80) and similar to the calcineurin inhibitor-based group in comparison 2. More proteinuria and wound-healing complications occurred in the mTOR inhibitor-based groups. We found

Celecoxib versus a non-selective NSAID plus proton-pump inhibitor: what are the considerations?.

PubMed

Chen, Judy T; Pucino, Frank; Resman-Targoff, Beth H

2006-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are extensively used worldwide. However, associated adverse gastrointestinal effects (NSAID gastropathy) such as bleeding, perforation and obstruction result in considerable morbidity, mortality, and expense. Although it is essential to employ gastroprotective strategies to minimize these complications in patients at risk, controversy remains on whether celecoxib alone or a non-selective NSAID in conjunction with a proton-pump inhibitor (PPI) is a superior choice. Recent concerns regarding potential cardiovascular toxicities associated with cox-2 selective inhibitors may favor non-selective NSAID/PPI co-therapy as the preferred choice. Concomitant use of low-dose aspirin with any NSAID increases the risk of gastrointestinal complications and diminishes the improved gastrointestinal safety profile of celecoxib; whereas use of ibuprofen plus PPI regimens may negate aspirin's antiplatelet benefits. Evidence shows that concurrent use of a non-selective NSAID (such as naproxen) plus a PPI is as effective in preventing NSAID gastropathy as celecoxib, and may be more cost-effective. Patients failing or intolerant to this therapy would be candidates for celecoxib at the lowest effective dose for the shortest duration of time. Potential benefits from using low-dose celecoxib with a PPI in patients previously experiencing bleeding ulcers while taking NSAIDs remains to be proven. An evidence-based debate is presented to assist clinicians with the difficult decision-making process of preventing NSAID gastropathy while minimizing other complications.

Responder analysis without dichotomization.

PubMed

Zhang, Zhiwei; Chu, Jianxiong; Rahardja, Dewi; Zhang, Hui; Tang, Li

2016-01-01

In clinical trials, it is common practice to categorize subjects as responders and non-responders on the basis of one or more clinical measurements under pre-specified rules. Such a responder analysis is often criticized for the loss of information in dichotomizing one or more continuous or ordinal variables. It is worth noting that a responder analysis can be performed without dichotomization, because the proportion of responders for each treatment can be derived from a model for the original clinical variables (used to define a responder) and estimated by substituting maximum likelihood estimators of model parameters. This model-based approach can be considerably more efficient and more effective for dealing with missing data than the usual approach based on dichotomization. For parameter estimation, the model-based approach generally requires correct specification of the model for the original variables. However, under the sharp null hypothesis, the model-based approach remains unbiased for estimating the treatment difference even if the model is misspecified. We elaborate on these points and illustrate them with a series of simulation studies mimicking a study of Parkinson's disease, which involves longitudinal continuous data in the definition of a responder.

Adjunctive pregabalin in partial responders with major depressive disorder and residual anxiety.

PubMed

Vitali, Mario; Tedeschini, Enrico; Mistretta, Martino; Fehling, Kiki; Aceti, Franca; Ceccanti, Mauro; Fava, Maurizio

2013-02-01

Anxiety symptoms in depression result often in treatment resistance, residual symptoms, and persistent functional impairment. To assess the effectiveness and safety of adjunctive pregabalin to antidepressants for residual anxiety in patients with major depressive disorder (MDD). A retrospective chart review was conducted to identify partial responders among patients with MDD with residual anxiety. Twenty such patients (age, 58.4 ± 11.2 years; 15 women; baseline Hamilton Depression Rating Scale [HDRS], 17.1 ± 3.5) who received adjunctive pregabalin for residual anxiety were included. Antidepressants augmented were the selective serotonin reuptake inhibitors (n = 12), mirtazapine (n = 2), and selective serotonin-norepinephrine reuptake inhibitors (n = 6). Twenty patients received at least 4 weeks of pregabalin treatment after 8 weeks of antidepressant therapy. At week 1 (9 weeks after initiating treatment), pregabalin was prescribed at a mean ± SD dose of 71.2 ± 31.7 mg, and the mean maximum pregabalin dose prescribed was 156.2 ± 76.5 mg (range, 75-300 mg). At week 8, there were 13 responders (13/20 [65%]), and 7 of these 13 patients achieved remission (HDRS17 < 8). There were significant decreases in HDRS scores (13.5 ± 3.1 vs 9.1 ± 2.9, P < 0.000), and HDRS anxiety/somatization subscale scores (6.3 ± 2 to 3.6 ± 1.7, P < 0.000). Adverse effects included somnolence (n = 7), weight gain (n = 3), dizziness (n = 4), dry mouth (n = 6), edema (n = 3), blurred vision (n = 3), difficulty with concentration/attention (n = 8), headache (n = 6), and diarrhea (n = 5). The results suggest a possible augmentation role for pregabalin when used in conjunction with conventional antidepressants for residual anxiety in MDD.

Peptic ulcer complications requiring surgery: what has changed in the last 50 years in Turkey.

PubMed

Güzel, Hakan; Kahramanca, Sahin; Şeker, Duray; Özgehan, Gülay; Tunç, Gündüz; Küçükpınar, Tevfik; Kargıcı, Hülagü

2014-04-01

The incidence and prevalence of peptic ulcer disease has decreased in recent years, but it is not so easy to make the same conclusion when complications of peptic ulcer are taken into consideration. The aim of this study is to determine the time trends in complicated peptic ulcer disease and to state the effects of H2 receptor blockers, proton pump inhibitors (PPI), and H. pylori eradication therapies on these complications. This study retrospectively evaluated the patients who were operated on for complications (perforation, bleeding, and obstruction) of peptic ulcer for the last 50 years. Patients were grouped into four groups (G1-G4) according to the dates in which H2 receptor blockers, PPIs, and eradication regimens for H. pylori were introduced The time periods that were studied were: (G1) 1962-1980, (G2) 1981-1990, (G3) 1991-1997, and (G4) 1998-2012. In total, 2953 patients were operated on for complications of peptic ulcer disease, of which 86% of the patients were male. In G1, perforation and obstruction were significantly the most frequent complications (p<0.001), followed by bleeding. In groups G2 and G3, obstruction was still the most frequent complication requiring surgery (p<0.001). In G2 and G3, obstruction was followed by perforation and bleeding, respectively. In G4, perforation was significantly the most frequent complication (p<0.001). From 1962 to 1990 obstruction was the most common complication requiring surgery. In the last decade, perforation became the most common complication. In contrast to reports in the literature, bleeding was the least common complication requiring surgery in Turkey.

Achievements, challenges and unmet needs for haemophilia patients with inhibitors: Report from a symposium in Paris, France on 20 November 2014.

PubMed

Dargaud, Y; Pavlova, A; Lacroix-Desmazes, S; Fischer, K; Soucie, M; Claeyssens, S; Scott, D W; d'Oiron, R; Lavigne-Lissalde, G; Kenet, G; Escuriola Ettingshausen, C; Borel-Derlon, A; Lambert, T; Pasta, G; Négrier, C

2016-01-01

Over the past 20 years, there have been many advances in haemophilia treatment that have allowed patients to take greater control of their disease. However, the development of factor VIII (FVIII) inhibitors is the greatest complication of the disease and a challenge in the treatment of haemophilia making management of bleeding episodes difficult and surgical procedures very challenging. A meeting to discuss the unmet needs of haemophilia patients with inhibitors was held in Paris on 20 November 2014. Topics discussed were genetic and non-genetic risk factors for the development of inhibitors, immunological aspects of inhibitor development, FVIII products and inhibitor development, generation and functional properties of engineered antigen-specific T regulatory cells, suppression of immune responses to FVIII, prophylaxis in haemophilia patients with inhibitors, epitope mapping of FVIII inhibitors, current controversies in immune tolerance induction therapy, surgery in haemophilia patients with inhibitors and future perspectives for the treatment of haemophilia patients with inhibitors. A summary of the key points discussed is presented in this paper. © 2016 John Wiley & Sons Ltd.

Discriminant cognitive factors in responder and non-responder patients with schizophrenia.

PubMed

Stip, E; Lussier, I; Ngan, E; Mendrek, A; Liddle, P

1999-12-01

To identify which improvements in cognitive function are associated with symptom resolution in schizophrenic patients treated with atypical antipsychotics. a prospective open trial with atypical neuroleptics (risperidone, clozapine, quetiapine). Inpatient and outpatient units, Institute of Psychiatry. Thirty-nine patients with schizophrenia according to DSM-IV criteria were included. Clinical and cognitive assessment were done at baseline (T0) and again after six months of treatment (T2). Twenty-five patients completed the trial. New-generation antipsychotics during six months. Patients were considered as responders if their PANSS score decreased at least 20% (n = 15) and non-responders if it did not (n = 10). a computerized cognitive assessment comprised tests of short-term-memory (digit span), explicit long-term memory (word pair learning), divided attention, selective attention and verbal fluency (orthographic and semantic). Clinical assessment included PANSS and ESRS. A discriminant function analysis was performed to determine which changes in cognitive performance predicted symptomatic response status. Semantic fluency and orthographic fluency were significant predictors. Together they correctly predicted responder status in 88% of cases. Memory was not a significant predictor of symptomatic response. Verbal fluency discriminated the responder from the non-responder group during a pharmacological treatment.

Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis.

PubMed

Franklin, Cindy; Rooms, Isabelle; Fiedler, Melanie; Reis, Henning; Milsch, Laura; Herz, Saskia; Livingstone, Elisabeth; Zimmer, Lisa; Schmid, Kurt Werner; Dittmer, Ulf; Schadendorf, Dirk; Schilling, Bastian

2017-11-01

Immune checkpoint inhibitors can cause severe immune-related adverse events, with immune-related diarrhea and colitis (irColitis) being among the most frequent ones. While the majority of patients with irColitis respond well to corticosteroid treatment ± other immunomodulatory drugs such as infliximab, some patients do not show resolution of their symptoms. In the present study, we analysed the frequency of therapy-refractory irColitis, the underlying cause, and useful diagnostic approaches. Between 2006 and 2016, 370 patients with metastatic malignant melanoma were treated with checkpoint inhibitors at the Department of Dermatology at the University Hospital Essen. All patients were identified for whom diarrhea and/or colitis was documented in the digital patient records. Patients who did not respond to standard immunosuppressive therapy within 2 weeks were classified as refractory. Demographic and clinical data of all patients were collected. We identified 41 patients with irColitis, the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%) were refractory to standard immunomodulatory treatment with corticosteroids and infliximab. Therapy-refractory cases tended to show more severe inflammation in colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005, in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis (p=0.021; p = 0.053). This report on CMV reactivation during management of checkpoint inhibitor-induced colitis emphasises the need for repetitive diagnostic measures in treatment-refractory irColitis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Combination of hemostatic therapies for treatment of patients with hemophilia A and inhibitors.

PubMed

Livnat, Tami; Budnik, Ivan; Levy-Mendelovich, Sarina; Avishai, Einat; Misgav, Mudi; Barg, Assaf Arie; Lubetsky, Aharon; Brutman-Barazani, Tami; Kenet, Gili

2017-07-01

Therapy application and monitoring of patients with hemophilia A (HA) and inhibitors are challenging. In the current study, combined FVIII - bypass therapy was implemented for a cohort of severe HA patients with inhibitors. Plasma of 15 HA patients with inhibitors was spiked ex vivo with FVIII, rFVIIa, FEIBA and their combinations and thrombin generation (TG) was studied. Some patients who experienced hemarthroses or required minor surgeries were treated by a combined concomitant administration of FVIII+FEIBA as IV bolus doses. TG spiking studies showed individual responses not correlated to inhibitor titer. Combinations of agents augmented TG as compared to any single agent, while combined FVIII+FEIBA yielded the highest TG, supporting it as a potential treatment. Following emergent successful surgery of child treated by concomitant FVIII+FEIBA, a total of 396 episodes in 7/15 patients were treated with concomitant FVIII+FEIBA. Five patients were treated for bleeding episodes only, whereas 2 were children undergoing immune tolerance induction (ITI) with FEIBA prophylaxis. Four minor surgeries were performed on FVIII+FEIBA repeated infusions. Neither thrombosis nor any other adverse events were documented. A combination of FVIII+FEIBA may be effective and safe as an alternative treatment option for some high-responding inhibitor patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Acquired factor V inhibitor in a patient receiving venous-venous extracorporeal membrane oxygenation for Legionella pneumonia.

PubMed

Leung, Anne K H; Ng, George W Y; Sin, K C; Au, S Y; Lai, K Y; Lee, K L; Law, K I

2015-04-01

We report a rare complication of factor V deficiency in a patient having Legionella pneumonia. This patient also had other complications like severe acute respiratory distress syndrome, acute kidney injury, and septic shock that required venous-venous extracorporeal membrane oxygenation support. This is the first reported case of acquired factor V deficiency in a patient receiving extracorporeal membrane oxygenation for Legionella pneumonia. With the combined use of intravenous immunoglobulin, rituximab and plasma exchange, we achieved rapid clearance of the factor V inhibitor within 1 week so as to allow safe decannulation of extracorporeal membrane oxygenation.

Safety, effectiveness, and cost of dipeptidyl peptidase-4 inhibitors versus intermediate acting insulin for type 2 diabetes: protocol for a systematic review and network meta-analysis.

PubMed

Tricco, Andrea C; Antony, Jesmin; Soobiah, Charlene; Hemmelgarn, Brenda; Moher, David; Hutton, Brian; Yu, Catherine H; Majumdar, Sumit R; Straus, Sharon E

2013-06-28

Type 2 diabetes mellitus (T2DM) results from insulin resistance and relative insulin deficiency. T2DM treatment is a step-wise approach beginning with lifestyle modifications (for example, diet, exercise), followed by the addition of oral hypoglycemic agents (for example, metformin). Patients who do not respond to first-line therapy are offered second-line therapy (for example, sulfonylureas). Third-line therapy may include insulin and/or dipeptidyl peptidase-4 (DPP-4) inhibitors.It is unclear whether DPP-4 inhibitors are safer and more effective than intermediate acting insulin for third-line management of T2DM. As such, our objective is to evaluate the comparative effectiveness, safety and cost-effectiveness of DPP-4 inhibitors versus intermediate acting insulin for T2DM patients who have failed both first- and second-line diabetes treatments. Electronic searches of MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, and grey literature (for example, trial registries, public health websites) will be conducted to identify studies examining DPP-4 inhibitors compared with each other, intermediate acting insulin, no treatment, or placebo for adults with T2DM. The outcomes of interest include glycosylated hemoglobin (A1C) (primary outcome), as well as emergency department visits, physician visits, hospital admissions, weight gain, quality of life, microvascular complications, macrovascular complications, all-cause mortality, and cost (secondary outcomes). Randomized clinical trials (RCTs), quasi-RCTs, non-RCTs, controlled before-after, interrupted time series, cohort studies, and cost studies reporting data on these outcomes will be included. Eligibility will not be restricted by publication status, language of dissemination, duration of study follow-up, or time period of study conduct.Two reviewers will screen the titles and abstracts resulting from the literature search, as well as potentially relevant full-text articles, in duplicate. Data will be

Medical management of levodopa-associated motor complications in patients with Parkinson's disease.

PubMed

Jankovic, Joseph; Stacy, Mark

2007-01-01

Parkinson's disease is a neurodegenerative disorder that affects approximately 1% of people over the age of 60 years. Levodopa is standard, and often initial, therapy for patients with this condition; however, with continued treatment and as the disease progresses, up to 80% of patients experience 'wearing-off' symptoms, dyskinesias and other motor complications. These levodopa-associated problems may become disabling and profoundly affect quality of life. Medications commonly used to manage these symptoms include monoamine oxidase type B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, the NMDA receptor antagonist amantadine and dopamine receptor agonists. Agents that block MAO-B, such as rasagiline and selegiline, are used as both initial and adjunctive therapy in patients with Parkinson's disease. These medications increase concentrations of dopamine in the brain by blocking its reuptake from the synaptic cleft, a mechanism that can slow motor decline, increase 'on' time and improve symptoms of Parkinson's disease. Adverse events with these agents can include confusion, hallucination and orthostatic hypotension. MAO-B inhibition may elicit drug-drug interactions if administered with TCAs, SSRIs or SNRIs. Conventional oral selegiline is associated with potentially harmful plasma concentrations of three major amphetamine metabolites, although metabolite concentrations are significantly lower with a new orally disintegrating tablet (ODT) selegiline formulation. Selegiline ODT is also absorbed more efficiently and shows less pharmacokinetic variability than conventional oral selegiline.COMT mediates peripheral catabolism of levodopa. Therefore, agents that block COMT, such as tolcapone and entacapone, increase the elimination half-life of levodopa. Given adjunctively with levodopa, COMT inhibitors can decrease 'off' time and increase 'on' time, as well as lower the daily levodopa dose. Although more potent than entacapone, tolcapone requires

Synthesis, biological evaluation and molecular docking of N-phenyl thiosemicarbazones as urease inhibitors.

PubMed

Hameed, Abdul; Khan, Khalid Mohammed; Zehra, Syeda Tazeen; Ahmed, Ramasa; Shafiq, Zahid; Bakht, Syeda Mahwish; Yaqub, Muhammad; Hussain, Mazhar; de la Vega de León, Antonio; Furtmann, Norbert; Bajorath, Jürgen; Shad, Hazoor Ahmad; Tahir, Muhammad Nawaz; Iqbal, Jamshed

2015-08-01

Urease is an important enzyme which breaks urea into ammonia and carbon dioxide during metabolic processes. However, an elevated activity of urease causes various complications of clinical importance. The inhibition of urease activity with small molecules as inhibitors is an effective strategy for therapeutic intervention. Herein, we have synthesized a series of 19 benzofurane linked N-phenyl semithiocarbazones (3a-3s). All the compounds were screened for enzyme inhibitor activity against Jack bean urease. The synthesized N-phenyl thiosemicarbazones had varying activity levels with IC50 values between 0.077 ± 0.001 and 24.04 ± 0.14 μM compared to standard inhibitor, thiourea (IC50 = 21 ± 0.11 μM). The activities of these compounds may be due to their close resemblance of thiourea. A docking study with Jack bean urease (PDB ID: 4H9M) revealed possible binding modes of N-phenyl thiosemicarbazones. Copyright © 2015 Elsevier Inc. All rights reserved.

Angiotensin-Converting Enzyme Inhibitors and the Risk of Congenital Malformations.

PubMed

Bateman, Brian T; Patorno, Elisabetta; Desai, Rishi J; Seely, Ellen W; Mogun, Helen; Dejene, Sara Z; Fischer, Michael A; Friedman, Alexander M; Hernandez-Diaz, Sonia; Huybrechts, Krista F

2017-01-01

To examine the association between first-trimester angiotensin-converting enzyme (ACE) inhibitor exposure and the risk of overall major congenital, cardiac, and central nervous system malformations. We used a cohort of completed pregnancies linked to liveborn neonates derived from Medicaid claims from 2000 to 2010. We examined the risk of malformations associated with first-trimester exposure to an ACE inhibitor. Propensity score-based methods were used to control for potential confounders including maternal demographics, medical conditions, exposure to other medications, and measures of health care utilization. The cohort included 1,333,624 pregnancies, of which 4,107 (0.31%) were exposed to ACE inhibitors during the first trimester. The prevalence of overall malformations in the ACE inhibitor-exposed pregnancies was 5.9% compared with 3.3% in the unexposed (unadjusted relative risk, 1.82; 95% confidence interval [CI] 1.61-2.06), of cardiac malformations was 3.4% compared with 1.2% (relative risk 2.95, 95% CI 2.50-3.47), and of central nervous system malformations was 0.27% compared with 0.18% (relative risk 1.46, 95% CI 0.81-2.64). After restricting the cohort to pregnancies complicated by chronic hypertension (both exposed and unexposed) and accounting for other confounding factors, there was no significant increase in the risk of any of the outcomes assessed. Relative risks associated with first-trimester ACE inhibitor exposure were 0.89 (95% CI 0.75-1.06) for overall malformations, 0.95 (95% CI 0.75-1.21) for cardiac malformations, and 0.54 (95% CI 0.26-1.11) for CNS malformations. After accounting for confounders, among women with hypertension, exposure to ACE inhibitors during the first trimester was not associated with an increased risk of major congenital malformations.

Effect of quantifying peptide release on ruminal protein degradation determined using the inhibitor in vitro system

USDA-ARS?s Scientific Manuscript database

The aim of this work was to compare use of an o-phthaldialdehyde (OPA) colorimetric assay (OPA-C), which responds to both free AA and peptides, with an OPA fluorimetric assay (OPA-F), which is insensitive to peptides, to quantify rates of ruminal protein degradation in the inhibitor in vitro system ...

Initial Assessment, Surveillance, and Management of Blood Pressure in Patients Receiving Vascular Endothelial Growth Factor Signaling Pathway Inhibitors

PubMed Central

Bakris, George L.; Black, Henry R.; Chen, Helen X.; Durand, Jean-Bernard; Elliott, William J.; Ivy, S. Percy; Leier, Carl V.; Lindenfeld, JoAnn; Liu, Glenn; Remick, Scot C.; Steingart, Richard; Tang, W. H. Wilson

2010-01-01

Hypertension is a mechanism-based toxic effect of drugs that inhibit the vascular endothelial growth factor signaling pathway (VSP). Substantial evidence exists for managing hypertension as a chronic condition, but there are few prospectively collected data on managing acute hypertension caused by VSP inhibitors. The Investigational Drug Steering Committee of the National Cancer Institute convened an interdisciplinary cardiovascular toxicities expert panel to evaluate this problem, to make recommendations to the Cancer Therapy Evaluation Program on further study, and to structure an approach for safe management by treating physicians. The panel reviewed: the published literature on blood pressure (BP), hypertension, and specific VSP inhibitors; abstracts from major meetings; shared experience with the development of VSP inhibitors; and established principles of hypertension care. The panel generated a consensus report including the recommendations on clinical concerns summarized here. To support the greatest possible number of patients to receive VSP inhibitors safely and effectively, the panel had four recommendations: 1) conduct and document a formal risk assessment for potential cardiovascular complications, 2) recognize that preexisting hypertension will be common in cancer patients and should be identified and addressed before initiation of VSP inhibitor therapy, 3) actively monitor BP throughout treatment with more frequent assessments during the first cycle of treatment, and 4) manage BP with a goal of less than 140/90 mmHg for most patients (and to lower, prespecified goals in patients with specific preexisting cardiovascular risk factors). Proper agent selection, dosing, and scheduling of follow-up should enable maintaining VSP inhibition while avoiding the complications associated with excessive or prolonged elevation in BP. PMID:20351338

Repigmentation in vitiligo using the Janus kinase inhibitor tofacitinib may require concomitant light exposure.

PubMed

Liu, Lucy Y; Strassner, James P; Refat, Maggi A; Harris, John E; King, Brett A

2017-10-01

Vitiligo is an autoimmune disease in which cutaneous depigmentation occurs. Existing therapies are often inadequate. Prior reports have shown benefit of the Janus kinase (JAK) inhibitors. To evaluate the efficacy of the JAK 1/3 inhibitor tofacitinib in the treatment of vitiligo. This is a retrospective case series of 10 consecutive patients with vitiligo treated with tofacitinib. Severity of disease was assessed by body surface area of depigmentation. Ten consecutive patients were treated with tofacitinib. Five patients achieved some repigmentation at sites of either sunlight exposure or low-dose narrowband ultraviolet B phototherapy. Suction blister sampling revealed that the autoimmune response was inhibited during treatment in both responding and nonresponding lesions, suggesting that light rather than immunosuppression was primarily required for melanocyte regeneration. Limitations include the small size of the study population, retrospective nature of the study, and lack of a control group. Treatment of vitiligo with JAK inhibitors appears to require light exposure. In contrast to treatment with phototherapy alone, repigmentation during treatment with JAK inhibitors may require only low-level light. Maintenance of repigmentation may be achieved with JAK inhibitor monotherapy. These results support a model wherein JAK inhibitors suppress T cell mediators of vitiligo and light exposure is necessary for stimulation of melanocyte regeneration. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

The perception of complications in pediatric spine surgery: a comparative survey of surgeons, caregivers and patients.

PubMed

Fulkerson, Daniel H; Vachhrajani, Shobhan; Brayton, Alison; Kulkarni, Abhaya V; Jea, Andrew

2010-01-01

The perception of a surgical complication may differ between surgeons and patients. In pediatric spine surgery, the perception of the parent or primary caregiver may also differ. In order to better define these relationships, we performed a pilot study surveying a convenience sample of pediatric spinal surgeons, patients and their parent or primary caregiver. We hope to use this initial pilot study as a starting point for future research into this incompletely defined, yet increasingly relevant topic. A survey of case vignettes describing a potential perioperative complication was administered to 14 pediatric spine surgeons at the Texas Children's Hospital Pediatric NeuroSpine Clinic from June 1 to July 31, 2009. The same survey, with modified language, was presented to a group of 13 pediatric patients (age range: 12-18 years). In addition, the surveys were separately presented to 34 primary caregivers of pediatric patients evaluated in a spine surgery clinic. The 61 respondents were asked to evaluate the cases and determine if there was a minor, a major or no complication present. Fisher's exact test was employed to evaluate associations of respondent groups and complication severity. There were no statistically significant differences in the proportion of patients and caregivers rating the presence of complications. In 8 of 13 cases, a majority of surgeons and a majority of patients/caregivers felt a complication was present (all p > 0.06). A greater proportion of surgeons than patients/caregivers felt a complication was present in 2 cases of transient neurological deficit/paraparesis (6 weeks to 6 months; p < 0.04) and 1 case of cosmetically significant pressure sores to the face (p = 0.0002). A greater proportion of patients/caregivers identified a complication in a loss of range of motion after occipitocervical fusion (p < 0.0001) and a loss of motor evoked potentials without a neurological deficit. Amongst those who identified a complication, a greater

Resilience among first responders.

PubMed

Pietrantoni, Luca; Prati, Gabriele

2008-12-01

Emergency rescue personnel can be considered a "high risk" occupational group in that they could experience a broad range of health and mental health consequences as a result of work-related exposures to critical incidents. This study examined the resilience factors that protect mental health among first responders. Nine hundred and sixty-one first responders filled out an on-line questionnaire, containing measure of sense of community, collective efficacy, self-efficacy and work-related mental health outcomes (compassion fatigue, burnout and compassion satisfaction). First responders reported high level of compassion satisfaction and low level of burnout and compassion fatigue. Compassion fatigue was predicted by self-efficacy, burnout was predicted by self-efficacy, collective efficacy and sense of community, compassion satisfaction was predicted by self-efficacy and sense of community. Resilience following critical events is common among first responders. Self-efficacy, collective efficacy and sense of community could be considered resilience factors that preserve first responders' work-related mental health.

Travel habits and complications in patients treated with vitamin K antagonists: a cross sectional analysis.

PubMed

Ringwald, Juergen; Lehmann, Marina; Niemeyer, Nicole; Seifert, Isabell; Daubmann, Anne; Wegscheider, Karl; Salzwedel, Annett; Luxembourg, Beate; Eckstein, Reinhold; Voeller, Heinz

2014-01-01

Travel-related conditions have impact on the quality of oral anticoagulation therapy (OAT) with vitamin K-antagonists. No predictors for travel activity and for travel-associated haemorrhage or thromboembolic complications of patients on OAT are known. A standardised questionnaire was sent to 2500 patients on long-term OAT in Austria, Switzerland and Germany. 997 questionnaires were received (responder rate 39.9%). Ordinal or logistic regression models with travel activity before and after onset of OAT or travel-associated haemorrhages and thromboembolic complications as outcome measures were applied. 43.4% changed travel habits since onset of OAT with 24.9% and 18.5% reporting decreased or increased travel activity, respectively. Long-distance worldwide before OAT or having suffered from thromboembolic complications was associated with reduced travel activity. Increased travel activity was associated with more intensive travel experience, increased duration of OAT, higher education, or performing patient self-management (PSM). Travel-associated haemorrhages or thromboembolic complications were reported by 6.5% and 0.9% of the patients, respectively. Former thromboembolic complications, former bleedings and PSM were significant predictors of travel-associated complications. OAT also increases travel intensity. Specific medical advice prior travelling to prevent complications should be given especially to patients with former bleedings or thromboembolic complications and to those performing PSM. Copyright © 2014 Elsevier Ltd. All rights reserved.

Pseudoprogression and hyperprogression during immune checkpoint inhibitor therapy for urothelial and kidney cancer.

PubMed

Soria, Francesco; Beleni, Andrea I; D'Andrea, David; Resch, Irene; Gust, Kilian M; Gontero, Paolo; Shariat, Shahrokh F

2018-03-16

A small subset of patients treated with immune checkpoint inhibitors manifest atypical patterns of response, the so-called pseudoprogression (PP) and hyperprogression (HP). Their prevalence in urothelial (UC) and renal cancer (RCC) remains, to date, mostly uninvestigated. Therefore, we aimed to provide a summary of the current knowledge about PP and HP during immune checkpoint inhibitor therapy in UC and RCC patients. A systematic medline/pubmed © literature search was performed. The atypical patterns of response to systemic immunotherapy were reviewed. Endpoints were PP and HP in UC and RCC. Tumors respond differently to immunotherapy compared to systemic chemotherapy. To evaluate response to immunotherapy, new guidelines (iRECIST) have been developed. To date, no studies focused on PP in UC and RCC, and the only way to evaluate its role is to take patients who respond to treatment beyond progression as surrogate for pseudoprogressors. PP seems to occur in a non-negligible rate of UC and RCC (from 1.5 to 17% and from 5 to 15%, respectively). The concept of HP, defined as a rapid progression after treatment, just took the first steps, and therefore, data from ongoing trials are awaited to elucidate its impact in genitourinary cancers. PP and HP are not uncommon entities in UC and RCC patients, treated with PD-1/PD-L1 inhibitors. Further investigation is warranted to define which patients are likely to experience PP and could benefit from treatment beyond progression and which ones will instead rapidly experience progression despite treatment and should, therefore, avoid systemic immunotherapy.

Short- and long-term outcomes of surgical management of peptic ulcer complications in the era of proton pump inhibitors.

PubMed

Hasadia, Rabea; Kopelman, Yael; Olsha, Oded; Alfici, Ricardo; Ashkenazi, Itamar

2018-01-22

We evaluated the short-term and long-term outcomes of emergency operations for peptic ulcer (PUD) complications in a period of time in which the need for surgery is infrequent. Retrospective review of operated patients (2007-2015) in one medical center. 81 patients were included (8.9 patients/year): 70 (86.4%) male; 11 (13.6%) female. Indications for operation were hemorrhage in 18 (22.2%), perforation in 62 (76.5%) and gastric-outlet obstruction in one (1.2%). Only 16 (19.8%) operations included a procedure to reduce gastric acid secretion. Six (7.4%) patients had a second operation for recurrent or persistent complication. Of these, two had a procedure to reduce gastric acid secretion in their first operation. 16 (19.8%) patients died during the index hospitalization. Three (3.7%) patients were rehospitalized for a PUD complication following 3-24 months. One patient, who had surgery for a second perforation 3 months following the first operation, was treated empirically for Helicobacter Pylori (HP) between the two operations. In comparison to perforation, patients with hemorrhage were older (69.9 ± 20.3 vs. 52.1 ± 19.9 years; p = 0.0015), more commonly had a history of PUD or treatment by nonsteroidal anti-inflammotry drugs (55.6 vs. 19.4%; p = 0.0054), more commonly had a procedure to reduce gastric acid secretion during their index operation (61.1 vs. 6.5%; p < 0.0001), and had a higher mortality (38.9 vs. 14.5%; p = 0.0406). Mortality is high following surgery for the complications of PUD, moreso in patients undergoing surgery for hemorrhage. Reoperations and repeated hospitalizations for complications are not uncommon, even in patients who have had procedures to reduce gastric acid secretion and HP eradication.

Large FVIII gene deletion confers very high risk of inhibitor development in three related severe haemophiliacs.

PubMed

Salviato, R; Belvini, D; Are, A; Radossi, P; Tagariello, G

2002-01-01

Haemophilia A displays a broad heterogeneity of genetic defects and of clinical severity. Inhibitor development is the main complication of replacement therapy in severe cases and most patients with inhibitors have gross gene rearrangement or point mutations, which hamper the production of normal circulating factor VIII (FVIII). We have investigated three related severe haemophilia A patients, all of whom have high titre inhibitors. By using long-range polymerase chain reaction (PCR) for FVIII gene inversion, we observed an unusual pattern in these patients. We therefore decided to screen the whole FVIII gene by conformation-sensitive gel electrophoresis. A large FVIII gene deletion spanning exon 2 to exon 25 was identified and we were able to obtain a 18.5 kb PCR product, which is specific for this mutation and useful for determining the carrier state in this family. All three haemophiliacs carrying this very large gene deletion show similar clinical history and very high-titre inhibitors, supporting the observation that inhibitor development seems to be an inherited characteristic. On the basis of our observations we think that this subgroup of patients at very high risk of inhibitor development should be identified by mutation analysis whenever possible, before the beginning of replacement therapy.

Discovering Anti-platelet Drug Combinations with an Integrated Model of Activator-Inhibitor Relationships, Activator-Activator Synergies and Inhibitor-Inhibitor Synergies

PubMed Central

Lombardi, Federica; Golla, Kalyan; Fitzpatrick, Darren J.; Casey, Fergal P.; Moran, Niamh; Shields, Denis C.

2015-01-01

Identifying effective therapeutic drug combinations that modulate complex signaling pathways in platelets is central to the advancement of effective anti-thrombotic therapies. However, there is no systems model of the platelet that predicts responses to different inhibitor combinations. We developed an approach which goes beyond current inhibitor-inhibitor combination screening to efficiently consider other signaling aspects that may give insights into the behaviour of the platelet as a system. We investigated combinations of platelet inhibitors and activators. We evaluated three distinct strands of information, namely: activator-inhibitor combination screens (testing a panel of inhibitors against a panel of activators); inhibitor-inhibitor synergy screens; and activator-activator synergy screens. We demonstrated how these analyses may be efficiently performed, both experimentally and computationally, to identify particular combinations of most interest. Robust tests of activator-activator synergy and of inhibitor-inhibitor synergy required combinations to show significant excesses over the double doses of each component. Modeling identified multiple effects of an inhibitor of the P2Y12 ADP receptor, and complementarity between inhibitor-inhibitor synergy effects and activator-inhibitor combination effects. This approach accelerates the mapping of combination effects of compounds to develop combinations that may be therapeutically beneficial. We integrated the three information sources into a unified model that predicted the benefits of a triple drug combination targeting ADP, thromboxane and thrombin signaling. PMID:25875950

Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study.

PubMed

Antony, Priya; Vijayan, Ranjit

2015-01-01

Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors.

Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study

PubMed Central

Antony, Priya; Vijayan, Ranjit

2015-01-01

Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors. PMID:26384019

Attitude toward depression, its complications, prevention and barriers to seeking help among ethnic groups in Penang, Malaysia

PubMed Central

2009-01-01

This study aims to explore attitudes towards, complications of and preventive measures for depression and the barriers that result in delays in seeking help among the various ethnic groups in Penang, Malaysia. In June 2007 a questionnaire‐based survey was undertaken in Penang. Face‐to‐face interviews were conducted, and 1855 respondents were approached to participate in the study by adopting a cluster random sampling method. A 25‐item questionnaire was used to explore public attitudes towards, complications of and preventive measures for depression and delays in seeking help. A total of 1149 (61.94%) showed willingness to participate in the survey. Ethnically, 490 (42.6%) of the respondents who participated in the survey were Malay, while 413 (35.9%) were Chinese, 149 (13%) Indian and 97 (8.4%) from other ethnic minorities. The mean age of the respondents was 30 years (SD ± 11.5). In evaluating public attitudes, the majority (n = 910, 79.2%) agreed with the statement that family and friends can enhance the depression recovery process by providing more care and attention to the patient and this was found to be statistically significant (P ≤0.001). More than one‐third of the respondents (n = 437, 38.0%) perceived depression as a normal medical condition and believed that it subsides automatically. The majority (n = 830, 72.2%) stated that depression results in social problems, while some felt that it can lead to raised blood pressure (n = 518, 45.1%). In terms of prevention, most of the respondents indicated that one can prevent depression by maintaining a good social life. In evaluating the barriers to seeking professional help, the majority (n = 582, 50.7%) stated that they did not believe they were at risk, with the next largest group identifying a lack of awareness regarding the signs and symptoms. However, a positive attitude was observed towards the complications and prevention of depression. Initiatives to increase mental health literacy will

Birth preparedness, complication readiness and other determinants of place of delivery among mothers in Goba District, Bale Zone, South East Ethiopia.

PubMed

Belda, Semere Sileshi; Gebremariam, Mulugeta Betre

2016-04-06

Ethiopia is one of the countries with the highest maternal mortality ratio 676/100,000 LB and the lowest skilled delivery at birth (10%) in 2011. Skilled delivery care and provision of emergency obstetric care prevents many of these deaths. Despite implementation of birth preparedness and complication readiness packages to antenatal care users since 2007 in the study area, yet an overwhelming proportion of births take place at home. The effect of birth preparedness and complication readiness on place of delivery is not well known and studied in this context. A community based case control study preceded by initial census was conducted on a total of 358 sampled respondents (119 cases and 239 controls) who were selected using stratified two stage sampling technique. A pre-tested and standardized questionnaire with a face-to-face interview was used to collect the data, and then data was cleaned, coded and entered in to SPSS version-21 for analysis. Binary logistic regression models were run to identify predictors of place of delivery and Odds ratio with 95% CI was used to assess presence of associations at a 0.05 level of significance. The mean (± Standard Deviation) age of respondents was; 27.41(±5.8) and 28.84(±5.7) years for the cases and the controls respectively. Two third (67.1%) of the childbirths took place in the respondents house while only (32.9%) gave birth in health facilities. Great proportion (79.7%) of the cases and two third (34.0%) of the controls were well-prepared for birth and complication. Maternal education, religion, distance from health facility, knowledge of availability of ambulance transport and history of obstetric complication were significantly associated with place of delivery (P-value <0.01). Birth preparedness and complication readiness practice had an independent effect on place of delivery (AOR =2.55, 95% CI: 1.12, 5.84). The study identified better institutional delivery service utilization by mothers who were well-prepared for

Metabolic memory and chronic diabetes complications: potential role for epigenetic mechanisms.

PubMed

Intine, Robert V; Sarras, Michael P

2012-10-01

Recent estimates indicate that diabetes mellitus currently affects more than 10 % of the world's population. Evidence from both the laboratory and large scale clinical trials has revealed that prolonged hyperglycemia induces chronic complications which persist and progress unimpeded even when glycemic control is pharmaceutically achieved via the phenomenon of metabolic memory. The epigenome is comprised of all chromatin modifications including post translational histone modification, expression control via miRNAs and the methylation of cytosine within DNA. Modifications of these epigenetic marks not only allow cells and organisms to quickly respond to changing environmental stimuli but also confer the ability of the cell to "memorize" these encounters. As such, these processes have gained much attention as potential molecular mechanisms underlying metabolic memory and chronic diabetic complications. Here we present a review of the very recent literature published pertaining to this subject.

Rescue Pharmacotherapy With Duloxetine for Selective Serotonin Reuptake Inhibitor Nonresponders in Late-Life Depression: Outcome and Tolerability

PubMed Central

Karp, Jordan F.; Whyte, Ellen M.; Lenze, Eric J.; Dew, Mary A.; Begley, Amy; Miller, Mark D.; Reynolds, Charles F.

2010-01-01

Background Up to 50% of depressed older adults either do not adequately respond to or are unable to tolerate treatment with a serotonin-specific reuptake inhibitor. On the basis of previous experience with serotonin-norepinephrine reuptake inhibitors, we predicted at least a 50% response rate to open-label treatment with duloxetine in subjects who were resistant to treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram. Method Community-dwelling subjects aged 65 years or older with current nonpsychotic major depressive disorder as established by the Structured Clinical Interview for DSM-IV received escitalopram under protocolized conditions between April 2004 and September 2006. Subjects who failed to meet response criteria or relapsed after achieving an initial response were subsequently switched to open treatment with duloxetine up to 120 mg/day. Side effects were assessed at every visit. Results Subjects (N = 40) switched to duloxetine had a mean (SD) age of 74.4 (7.0) years and a baseline (before escitalopram) 17-item Hamilton Rating Scale for Depression (HAM-D-17) score of 20.0 (3.5) and were predominantly female (65.0%) and white (82.5%). The mean (SD) maximum dose of duloxetine was 93.0 (27.8) mg/day. Subjects received this maximum dose for a median duration of 6.9 weeks. Fifty percent of subjects (N = 20) met criteria for full response, 17.5% (N = 7) were partial responders, and 32.5% (N = 13) did not respond. The median time to response was 12.0 weeks (95% CI = 8.4 to 14.6). Five of the subjects (12.5%) discontinued duloxetine because of intolerable side effects. Discussion These open-label data suggest that duloxetine at doses up to 120 mg/day is a well-tolerated and potentially effective treatment for older adults who fail to respond to an adequate trial of an SSRI. These results are preliminary, and future controlled studies are required to test the efficacy of rescue pharmacotherapy with duloxetine. Trial Registration

Phosphodiesterase inhibitors for persistent pulmonary hypertension of the newborn: a review.

PubMed

Travadi, J N; Patole, S K

2003-12-01

Persistent pulmonary hypertension of the newborn (PPHN) is a complex syndrome with multiple causes, with an incidence of 0.43-6.8/1,000 live births and a mortality of 10-20%. Survivors have high morbidity in the forms of neurodevelopmental and audiological impairment, cognitive delays, hearing loss, and a high rate of rehospitalization. The optimal approach to the management of PPHN remains controversial. Inhaled nitric oxide (iNO) is currently regarded as the gold standard therapy, but with as many as 30% of cases failing to respond, has not proven to be the single magic bullet. Given the complex pathophysiology of the disease, any such magic bullet is unlikely. A number of recent studies have suggested a role for specific phosphodiesterase (PDE) inhibitors in the management of PPHN. Sildenafil, a specific PDE5 inhibitor, appears the most promising of such agents. We aim to review the current status and limitations of iNO and the potential of PDE inhibitors in the management of PPHN. The reasons why caution is warranted before specific PDE5 inhibitors like sildenafil are labelled as potential magic bullets for PPHN will be discussed. The need for randomized-controlled trials to determine the safety, efficacy, and long-term outcome following treatment with sildenafil in PPHN is emphasized. Copyright 2003 Wiley-Liss, Inc.

New associations: INFG and TGFB1 genes and the inhibitor development in severe haemophilia A.

PubMed

de Alencar, J B; Macedo, L C; de Barros, M F; Rodrigues, C; Shinzato, A H; Pelissari, C B; Machado, J; Sell, A M; Visentainer, J E L

2015-07-01

The development of factor VIII (FVIII) inhibitor is the main complication of replacement therapy in patients with haemophilia A (HA). A ratio of 5-7% of individuals HA develops antibodies (inhibitors) against the FVIII infused during the treatment, thereby reducing their pro-coagulant activity. The immunomodulatory cytokine genes have been related to the risk of development of alloantibodies in several studies, mainly in HA with severe form. We investigated the polymorphisms in regulatory regions of cytokine genes (IL1A, IL1B, IL1R, IL1RA, IL4RA, IL12, INFG, TGFB1, TNF, IL2, IL4, IL6, IL10) that could influence the risk of developing inhibitors in patients with severe HA. The genotyping of cytokine genes of 117 patients with HA was performed by polymerase chain reaction with sequence-specific primers (PCR-SSP) using the protocol recommended by the manufacturer (Invitrogen kit Cytokines(®) , Canoga Park, USA) RESULTS: From the cohort of 117 patients with severe HA, 35 developed inhibitors. There was a higher frequency of +874 T allele in INFG and of +869 TT and TG/TG in TGFB1 genes on patients with inhibitors. This suggests that polymorphisms in INFG and in TGFB1 genes are related to risk of developing inhibitor, and could contribute to a genetic profile of the individual HA for the risk of inhibitors development to FVIII. © 2015 John Wiley & Sons Ltd.

Recent developments in antibiotic agents for the treatment of complicated intra-abdominal infections.

PubMed

Lin, Shang-Yi; Huang, Chung-Hao; Ko, Wen-Chien; Chen, Yen-Hsu; Hsueh, Po-Ren

2016-01-01

Treatment of complicated intra-abdominal infections (cIAIs) is becoming increasingly difficult because of the widespread emergence of multidrug-resistant organisms. In this review, we discuss the effectiveness of several new antibiotics for the treatment of cIAIs, including new β-lactamase inhibitor combinations (BLICs) and tetracycline-class drugs, recently developed aminoglycosides and quinolones, and novel lipoglycopeptides and oxazolidinones. Of the new BLICs, ceftolozane/tazobactam is associated with adequate clinical cure rates in patients with cIAIs. Currently, two new β-lactamase inhibitors, namely avibactam and MK-7655, are under development for clinical use in the treatment of cIAIs. Eravacycline, a novel, fully synthetic tetracycline-class drug, has been shown in Phase II and III clinical trials to be more potent than tigecycline against a significant number of multidrug-resistant organisms causing cIAIs. Plazomicin, a next-generation aminoglycoside, is a promising agent for treatment of cIAIs due to multidrug-resistant pathogens. Of the recently developed quinolones, delafloxacin and finafloxacin have been shown to be effective against pathogens that survive and multiply in mildly acidic environments, although further clinical studies examining their clinical utility in the treatment of cIAIs are warranted. Oritavancin, a new semisynthetic lipoglycopeptide agent, has been demonstrated to be a potent antibiotic in the treatment of cIAIs due to drug-resistant Gram-positive organisms. Several other new antibiotics in development also show promise and will hopefully broaden the possibilities for treatment of complicated intra-abdominal infections due to MDR pathogens.

Enhancing Academic Engagement: Providing Opportunities for Responding and Influencing Students to Choose to Respond

ERIC Educational Resources Information Center

Skinner, Christopher H.; Pappas, Danielle N.; Davis, Kai A.

2005-01-01

Although educators often provide opportunities for students to engage in active academic responding, in many situations, students either cannot or will not respond. In the current article, we analyze the reasons students fail to respond. Practical procedures educators can use to prevent "can't do" problems are provided. "Won't do" problems are…

Immunological changes with kinase inhibitor therapy for chronic lymphocytic leukemia.

PubMed

Pleyer, Christopher; Wiestner, Adrian; Sun, Clare

2018-05-15

Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell-cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib. While opportunistic infections and viral reactivations occur with both ibrutinib and idelalisib, these complications are less common and less severe with ibrutinib, especially when used as monotherapy without additional immunosuppressive agents. This review discusses the impact of ibrutinib and idelalisib on the immune system, including infectious and auto-immune complications as well as their specific effects on the B-cell, T-cell, and myeloid compartment.

Efficacy, safety, and patient preference of monoamine oxidase B inhibitors in the treatment of Parkinson's disease.

PubMed

Robottom, Bradley J

2011-01-20

Parkinson's disease (PD) is the second most common neurodegenerative disease and the most treatable. Treatment of PD is symptomatic and generally focuses on the replacement or augmentation of levodopa. A number of options are available for treatment, both in monotherapy of early PD and to treat complications of advanced PD. This review focuses on rasagiline and selegiline, two medications that belong to a class of antiparkinsonian drugs called monoamine oxidase B (MAO-B) inhibitors. Topics covered in the review include mechanism of action, efficacy in early and advanced PD, effects on disability, the controversy regarding disease modification, safety, and patient preference for MAO-B inhibitors.

Inconsistent Responding in a Criminal Forensic Setting: An Evaluation of the VRIN-r and TRIN-r Scales of the MMPI-2-RF.

PubMed

Gu, Wen; Reddy, Hima B; Green, Debbie; Belfi, Brian; Einzig, Shanah

2017-01-01

Criminal forensic evaluations are complicated by the risk that examinees will respond in an unreliable manner. Unreliable responding could occur due to lack of personal investment in the evaluation, severe mental illness, and low cognitive abilities. In this study, 31% of Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF; Ben-Porath & Tellegen, 2008/2011) profiles were invalid due to random or fixed-responding (T score ≥ 80 on the VRIN-r or TRIN-r scales) in a sample of pretrial criminal defendants evaluated in the context of treatment for competency restoration. Hierarchical regression models showed that symptom exaggeration variables, as measured by inconsistently reported psychiatric symptoms, contributed over and above education and intellectual functioning in their prediction of both random responding and fixed responding. Psychopathology variables, as measured by mood disturbance, better predicted fixed responding after controlling for estimates of cognitive abilities, but did not improve the prediction for random responding. These findings suggest that random responding and fixed responding are not only affected by education and intellectual functioning, but also by intentional exaggeration and aspects of psychopathology. Measures of intellectual functioning and effort and response style should be considered for administration in conjunction with self-report personality measures to rule out rival hypotheses of invalid profiles.

Evaluation of respondent-driven sampling.

PubMed

McCreesh, Nicky; Frost, Simon D W; Seeley, Janet; Katongole, Joseph; Tarsh, Matilda N; Ndunguse, Richard; Jichi, Fatima; Lunel, Natasha L; Maher, Dermot; Johnston, Lisa G; Sonnenberg, Pam; Copas, Andrew J; Hayes, Richard J; White, Richard G

2012-01-01

Respondent-driven sampling is a novel variant of link-tracing sampling for estimating the characteristics of hard-to-reach groups, such as HIV prevalence in sex workers. Despite its use by leading health organizations, the performance of this method in realistic situations is still largely unknown. We evaluated respondent-driven sampling by comparing estimates from a respondent-driven sampling survey with total population data. Total population data on age, tribe, religion, socioeconomic status, sexual activity, and HIV status were available on a population of 2402 male household heads from an open cohort in rural Uganda. A respondent-driven sampling (RDS) survey was carried out in this population, using current methods of sampling (RDS sample) and statistical inference (RDS estimates). Analyses were carried out for the full RDS sample and then repeated for the first 250 recruits (small sample). We recruited 927 household heads. Full and small RDS samples were largely representative of the total population, but both samples underrepresented men who were younger, of higher socioeconomic status, and with unknown sexual activity and HIV status. Respondent-driven sampling statistical inference methods failed to reduce these biases. Only 31%-37% (depending on method and sample size) of RDS estimates were closer to the true population proportions than the RDS sample proportions. Only 50%-74% of respondent-driven sampling bootstrap 95% confidence intervals included the population proportion. Respondent-driven sampling produced a generally representative sample of this well-connected nonhidden population. However, current respondent-driven sampling inference methods failed to reduce bias when it occurred. Whether the data required to remove bias and measure precision can be collected in a respondent-driven sampling survey is unresolved. Respondent-driven sampling should be regarded as a (potentially superior) form of convenience sampling method, and caution is required

Evaluation of Respondent-Driven Sampling

PubMed Central

McCreesh, Nicky; Frost, Simon; Seeley, Janet; Katongole, Joseph; Tarsh, Matilda Ndagire; Ndunguse, Richard; Jichi, Fatima; Lunel, Natasha L; Maher, Dermot; Johnston, Lisa G; Sonnenberg, Pam; Copas, Andrew J; Hayes, Richard J; White, Richard G

2012-01-01

Background Respondent-driven sampling is a novel variant of link-tracing sampling for estimating the characteristics of hard-to-reach groups, such as HIV prevalence in sex-workers. Despite its use by leading health organizations, the performance of this method in realistic situations is still largely unknown. We evaluated respondent-driven sampling by comparing estimates from a respondent-driven sampling survey with total-population data. Methods Total-population data on age, tribe, religion, socioeconomic status, sexual activity and HIV status were available on a population of 2402 male household-heads from an open cohort in rural Uganda. A respondent-driven sampling (RDS) survey was carried out in this population, employing current methods of sampling (RDS sample) and statistical inference (RDS estimates). Analyses were carried out for the full RDS sample and then repeated for the first 250 recruits (small sample). Results We recruited 927 household-heads. Full and small RDS samples were largely representative of the total population, but both samples under-represented men who were younger, of higher socioeconomic status, and with unknown sexual activity and HIV status. Respondent-driven-sampling statistical-inference methods failed to reduce these biases. Only 31%-37% (depending on method and sample size) of RDS estimates were closer to the true population proportions than the RDS sample proportions. Only 50%-74% of respondent-driven-sampling bootstrap 95% confidence intervals included the population proportion. Conclusions Respondent-driven sampling produced a generally representative sample of this well-connected non-hidden population. However, current respondent-driven-sampling inference methods failed to reduce bias when it occurred. Whether the data required to remove bias and measure precision can be collected in a respondent-driven sampling survey is unresolved. Respondent-driven sampling should be regarded as a (potentially superior) form of convenience

22 CFR 1006.1000 - Respondent.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 2 2010-04-01 2010-04-01 true Respondent. 1006.1000 Section 1006.1000 Foreign Relations INTER-AMERICAN FOUNDATION GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 1006.1000 Respondent. Respondent means a person against whom an agency has initiated a debarment or...

29 CFR 1471.1000 - Respondent.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 4 2010-07-01 2010-07-01 false Respondent. 1471.1000 Section 1471.1000 Labor Regulations Relating to Labor (Continued) FEDERAL MEDIATION AND CONCILIATION SERVICE GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 1471.1000 Respondent. Respondent means a person against whom an...

22 CFR 1508.1000 - Respondent.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 2 2010-04-01 2010-04-01 true Respondent. 1508.1000 Section 1508.1000 Foreign Relations AFRICAN DEVELOPMENT FOUNDATION GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 1508.1000 Respondent. Respondent means a person against whom an agency has initiated a debarment...

Neurologic complications after allogeneic hematopoietic stem cell transplantation in children: analysis of prognostic factors.

PubMed

Kang, Ji-Man; Kim, Yae-Jean; Kim, Ju Youn; Cho, Eun Joo; Lee, Jee Hun; Lee, Mun Hyang; Lee, Soo-Hyun; Sung, Ki Woong; Koo, Hong Hoe; Yoo, Keon Hee

2015-06-01

Neurologic complications are serious complications after hematopoietic stem cell transplantation (HSCT) and significantly contribute to morbidity and mortality. The purpose of this study was to investigate the clinical features and prognosis in pediatric patients who had neurologic complications after allogeneic HSCT. We retrospectively reviewed the medical records of children and adolescents (19 years old or younger) who underwent allogeneic HSCT at our institution from 2000 to 2012. A total of 383 patients underwent 430 allogeneic transplantations. Among them, 73 episodes of neurologic complications occurred in 70 patients. The cumulative incidence of neurologic complications at day 400 was 20.0%. Almost two thirds of the episodes (63.0%, 46 of 73) occurred within 100 days after transplantation. Calcineurin inhibitor-related neurotoxicity was observed as the most common cause of neurotoxicity (47.9%, 35 of 73) and was significantly associated with earlier onset neurologic complications, seizure, and tremor. It also showed a significant association with lower probability of headache, abnormality of cranial nerve, and neurologic sequelae. In a multivariate analysis, days to neutrophil engraftment after HSCT, extensive chronic graft-versus-host disease (GVHD) and the existence of neurologic sequelae were identified as risk factors for mortality in patients who had neurologic complications (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.02 to 1.15; P = .011; HR, 5.98; 95% CI, 1.71 to 20.90; P = .005; and HR, 4.37; 95% CI, 1.12 to 17.05; P = .034, respectively). However, there was no significant difference in the 5-year overall survival between the patients who had neurologic complications without sequelae and the patients who did not have any neurologic complications (57.3% versus 61.8%, P = .906). In conclusion, we found that the major significant risk factors for mortality in pediatric recipients with neurologic complications were the existence of

GI complications after lung transplantation in patients with cystic fibrosis.

PubMed

Gilljam, Marita; Chaparro, Cecilia; Tullis, Elizabeth; Chan, Charles; Keshavjee, Shaf; Hutcheon, Michael

2003-01-01

Lung transplantation is now available for patients with cystic fibrosis (CF) and end-stage lung disease. While pulmonary graft function is often considered the major priority following transplantation, the nonpulmonary complications of this systemic disease also continue. We examined the GI complications in a cohort of patients who underwent transplantation. This was a retrospective study of all patients with CF who underwent transplantation between March 1988 and December 1998 in Toronto. Medical records were reviewed, and a short questionnaire was mailed to patients who were alive as of December 1998. There were 80 bilateral lung transplants performed in 75 patients. The questionnaire was distributed to 43 patients, of whom 27 patients (63%) responded. Pancreatic insufficiency requiring enzyme intake was evident in 72 of 75 patients (96%) at the time of surgery. Of three pancreatic-sufficient patients (4%), pancreatic insufficiency was diagnosed in two patients later. Biliary cirrhosis was diagnosed in three patients prior to transplantation. Distal intestinal obstruction syndrome (DIOS) was recorded for 15 patients (20%). Ten patients had a single episode, of which eight episodes occurred early in the postoperative period. Five patients had recurrent episodes. All were medically treated, except for two patients who underwent surgery. Other complications included cholecystitis (n = 3), mucocele of the appendix (n = 1), peptic ulcer disease (n = 3), and colonic carcinoma (n = 1). GI complications after lung transplantation are common in patients with CF, and attention should be paid to the risk for DIOS in the early postoperative period. Prevention and early medical treatment are important in order to avoid acute surgery. Close collaboration with the CF clinic, in order to diagnose and treat CF-related complications, is recommended.

Sarcoid-like lung granulomas in a hemodialysis patient treated with a dipeptidyl peptidase-4 inhibitor.

PubMed

Sada, Ken-Ei; Wada, Jun; Morinaga, Hiroshi; Tuchimochi, Shigeyuki; Uka, Mayu; Makino, Hirofumi

2014-04-01

It has been reported that the inhibition of dipeptidyl peptidase-4 (DPP-4)/CD26 on T-cells by DPP-4 enzymatic inhibitors suppresses lymphocyte proliferation and reduces the production of various cytokines, including tumor necrosis factor (TNF)-α. A 72-year-old female with diabetic nephropathy on hemodialysis developed multiple lung nodules following the administration of vildagliptin. A biopsy demonstrated the histology of granulomas without caseous necrosis. The discontinuation of vildagliptin resulted in the disappearance of the granulomas within 4 months. As granulomatosis often develops in patients under anti-TNF-α therapy, the accumulation of DPP-4 inhibitors or its metabolites is possibly linked to unrecognized complications, such as sarcoid-like lung granulomas.

Sarcoid-like lung granulomas in a hemodialysis patient treated with a dipeptidyl peptidase-4 inhibitor

PubMed Central

Sada, Ken-ei; Wada, Jun; Morinaga, Hiroshi; Tuchimochi, Shigeyuki; Uka, Mayu; Makino, Hirofumi

2014-01-01

It has been reported that the inhibition of dipeptidyl peptidase-4 (DPP-4)/CD26 on T-cells by DPP-4 enzymatic inhibitors suppresses lymphocyte proliferation and reduces the production of various cytokines, including tumor necrosis factor (TNF)-α. A 72-year-old female with diabetic nephropathy on hemodialysis developed multiple lung nodules following the administration of vildagliptin. A biopsy demonstrated the histology of granulomas without caseous necrosis. The discontinuation of vildagliptin resulted in the disappearance of the granulomas within 4 months. As granulomatosis often develops in patients under anti-TNF-α therapy, the accumulation of DPP-4 inhibitors or its metabolites is possibly linked to unrecognized complications, such as sarcoid-like lung granulomas. PMID:25852868

Is the Proportion of Carbohydrate Intake Associated with the Incidence of Diabetes Complications?-An Analysis of the Japan Diabetes Complications Study.

PubMed

Horikawa, Chika; Yoshimura, Yukio; Kamada, Chiemi; Tanaka, Shiro; Tanaka, Sachiko; Matsunaga, Satoshi; Hanyu, Osamu; Araki, Atsushi; Ito, Hideki; Tanaka, Akira; Ohashi, Yasuo; Akanuma, Yasuo; Sone, Hirohito

2017-02-06

The appropriate proportions of macronutritional intake have been controversial in medical nutritional therapy for diabetes, and evidence of the effects of carbohydrate consumption on diabetes complications in prospective settings is sparse. We investigated the relationships between proportions of carbohydrate intake as the % of total energy and diabetes complications in a nationwide cohort of Japanese patients with type 2 diabetes aged 40-70 years with hemoglobin A1c ≥6.5%. The analysis was of 1516 responders to a baseline dietary survey assessed by the Food Frequency Questionnaire based on food groups. Primary outcomes were times to overt nephropathy, diabetic retinopathy, and cardiovascular disease (CVD) after 8 years. Hazard ratios (HRs) for proportions of carbohydrate intake were estimated by Cox regression adjusted for confounders. High carbohydrate intake was significantly related to higher intakes of grain, fruits, and sweets/snacks and lower intakes of soybean and soy products, vegetables, seaweed, meat and processed meat, fish and processed fish, eggs, milk and dairy products, oil, and alcoholic beverages. During the eight-year follow-up, there were 81, 275, and 129 events of overt nephropathy, diabetic retinopathy, and CVD, respectively. After adjustment for confounders, HRs for complications in patients with carbohydrate intake in the second or third tertiles (51.0%-56.4% and ≥56.5%, respectively) compared with carbohydrate intake in the first tertile (<50.9%, referent) were analyzed. No significant associations were shown in the second and third tertiles relative to first tertile (overt nephropathy: 1.05 (95% Confidence Interval, 0.54-2.06) and 0.98 (0.40-2.44); diabetic retinopathy: 1.30 (0.90-1.88) and 1.30 (0.78-2.15); and CVD: 0.95 (0.55-1.63) and 1.37 (0.69-2.72)). By exploring potentially nonlinear relationships, trends for the incidence of diabetes complications according to proportions of carbohydrate intake were not clearly shown. Findings

Divergent Gene Expression Responses to Complicated Grief and Non-complicated Grief

PubMed Central

Irwin, Michael R.; Arevalo, Jesusa M. G.; Cole, Steven W.

2014-01-01

The “widowhood effect” (i.e., morbidity/mortality in recently bereaved spouses) may be related to changes in immune function, but little is known about the impact of bereavement on gene transcription in immune cells. This study examined how Complicated Grief and Non-complicated Grief responses to bereavement differentially affect leukocyte gene expression. Genome-wide transcriptional profiling and bioinformatic analyses were completed on 63 older adults. Thirty-six of them had lost their spouse/partner on average 2 years ago, and 27 were nonbereaved, married controls. Twelve of the bereaved participants met criteria for Complicated Grief. Compared to nonbereaved controls, bereavement (both Complicated Grief and Non-complicated Grief) was associated with upregulated expression of genes involved in general immunologic activation and a selective downregulation of genes involved in B lymphocyte responses. However, Complicated Grief and Non-complicated Grief differed markedly in their expression of Type I interferon-related transcripts, with Non-complicated Grief subjects showing substantial upregulation relative to nonbereaved controls and Complicated Grief subjects showing substantial downregulation. Bereavement significantly modulates immune function gene expression. The magnitude of bereavement-related distress (i.e., Complicated Grief vs. Non-complicated Grief) is linked to differential patterns of transcription factor activation and gene expression involved in innate antiviral responses. These findings provide a molecular framework for understanding the health effects of bereavement, as well as new insights into the particular gene modules that are most sensitive to the individual's psychological response to loss. PMID:24380850

Naringin improves zidovudine- and stavudine-induced skeletal muscle complications in rats.

PubMed

Adebiyi, O O; Adebiyi, O A; Owira, Pmo

2016-03-22

Chronic use of nucleoside reverse transcriptase inhibitors (NRTIs) in managing human immunodeficiency virus (HIV) infection has been associated with several complications. Available management options for these complications have yielded controversial results, thus the need to urgently find newer alternatives. Naringin, a plant-derived flavonoid, has been shown to possess antioxidant and antiapoptotic properties which can be exploited in managing NRTI-induced complications. This study therefore investigated the effects of naringin on some NRTI-induced complications. Forty-nine rats (200-250 g) were divided into seven groups and were orally treated with stavudine (d4T)-only, d4T + naringin, d4T + vitamin E, zidovudine (AZT)-only, AZT + naringin, AZT + vitamin E, and distilled water, respectively. Drugs were administered once daily for 56 days, and oral glucose tolerance tests conducted on day 54 of the experiments and rats were thereafter sacrificed on day 56 by halothane overdose. Plasma samples and the left gastrocnemius muscles were stored at -80°C for further analysis. There was significant glucose intolerance, insulin resistance, oxidative stress, and apoptosis in the skeletal muscles of AZT- or d4T-only-treated rats. Naringin, however, significantly reduced fasting blood glucose and fasting plasma insulin concentrations, mitigated glucose intolerance, and insulin resistance in addition to reducing malondialdehyde and carbonyl protein concentrations when coadministered with either NRTIs. Furthermore, naringin improved antioxidant enzyme activities, reduced skeletal muscle BCL-2-associated X protein expression, and improved B-cell lymphoma-2 protein expression compared to AZT- or d4T-only-treated rats. Naringin ameliorated AZT- and d4T-induced complications and therefore should be further investigated as a possible nutritional supplement in managing HIV infection. © The Author(s) 2016.

Carbon dioxide laser ablation of dermatosis papulosa nigra: high satisfaction and few complications in patients with pigmented skin.

PubMed

Ali, Faisal R; Bakkour, Waseem; Ferguson, Janice E; Madan, Vishal

2016-04-01

Dermatosis papulosa nigra (DPN) is a common condition of pigmented skin. Whilst lesions are benign, they may be symptomatic or cosmetically disfiguring. Ablative lasers have previously been reported as a useful therapeutic modality in DPN. We report the largest case series to date of patients with DPN ablated with the carbon dioxide (CO2) laser. A retrospective case note review was conducted of all patients with DPN treated in our laser clinic in the last five years, and a post-treatment telephone survey was undertaken to assess patient satisfaction. Forty-five patients were identified, with a median age of 41 years (range 25-74 years), of whom 37 (82%) were female. The median number of treatments undertaken was three (range 1-10). Of the 18 respondents to the telephone survey, when asked to grade their satisfaction with the procedure out of 10, median response was 9.5 (range 6-10) with nine patients citing the maximum score of 10. All patients replied that their confidence had improved following the procedure and that they would recommend the treatment to other patients. Five respondents (28%) reported recurrence of a few lesions following CO2 laser ablation; the remaining 13 respondents (72%) reported no recurrence of DPN. No respondents reported any other post-procedural complications (including scarring, hypopigmentation and hyperpigmentation). We advocate use of the CO2 laser as a safe, convenient means of treating DPN, with a high degree of patient satisfaction, low recurrence rate and few complications.

29 CFR 98.1000 - Respondent.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 29 Labor 1 2010-07-01 2010-07-01 true Respondent. 98.1000 Section 98.1000 Labor Office of the Secretary of Labor GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 98.1000 Respondent. Respondent means a person against whom an agency has initiated a debarment or suspension action. ...

21 CFR 1404.1000 - Respondent.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Respondent. 1404.1000 Section 1404.1000 Food and Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 1404.1000 Respondent. Respondent means a person against whom an agency has initiated a debarment...

Amitriptyline converts non-responders into responders to low-frequency electroacupuncture-induced analgesia in rats.

PubMed

Fais, Rafael S; Reis, G M; Rossaneis, A C; Silveira, J W S; Dias, Q M; Prado, W A

2012-07-26

The purpose of this study was to examine whether the use of intraperitoneal or intrathecal amitriptyline combined with electroacupuncture modifies the tail-flick reflex and incision pain in rats that normally do not have analgesia to electroacupuncture in the tail-flick test (non-responder rats). Changes in the nociceptive threshold of intraperitoneal or intrathecal saline- or amitriptyline-treated non-responder rats were evaluated using the tail-flick or incision pain tests before, during and after a 20-min period of electroacupuncture, applied at 2 Hz to the Zusanli and Sanynjiao acupoints. Amitriptyline was used at doses of 0.8 mg/kg or 30 μg/kg by intraperitoneal or intrathecal route, respectively. At these doses, amitriptyline has no effect against thermal or incision pain in rats. Rats selected as non-responders to the analgesic effect of electroacupuncture 2 Hz in tail-flick and incision pain tests become responders after an intraperitoneal or intrathecal injection of amitriptyline. Amitriptyline converts non-responder rats to rats that respond to electroacupuncture with analgesia in a model of thermal phasic pain and anti-hyperalgesia in a model of incision pain. Copyright © 2012 Elsevier Inc. All rights reserved.

SGLT2 inhibitors with cardiovascular benefits: Transforming clinical care in Type 2 diabetes mellitus.

PubMed

d'Emden, Michael; Amerena, John; Deed, Gary; Pollock, Carol; Cooper, Mark E

2018-02-01

Cardiovascular risk reduction in individuals with Type 2 diabetes mellitus (T2DM) is a key part of clinical management. Sodium-glucose co-transporter (SGLT2) inhibitors improve glycaemic control, reduce body weight and decrease blood pressure. In addition, the SGLT2 inhibitors empagliflozin and canagliflozin reduced the risk of composite cardiovascular events in high-risk individuals with T2DM in the EMPA-REG OUTCOME trial and the CANVAS Program, respectively. Empagliflozin also reduced cardiovascular deaths and improved renal outcomes. This class of agents should be considered in people with established cardiovascular disease, usually in combination with other glucose lowering medications, when satisfactory glycaemic control has not been achieved. The dose of insulin or sulfonylureas may need to be lowered when used with SGLT2 inhibitors, to reduce the risk of hypoglycaemia. Genitourinary infections can occur with SGLT2 inhibitors in a small proportion of people. In people with osteoporosis or prior amputation, it may be prudent to use empagliflozin rather than canagliflozin, based on the increased risk for bone fractures and amputations observed with canagliflozin in the CANVAS Program. SGLT2 inhibitors have the potential to transform the clinical care of persons with T2DM by not only improving glycaemic control but also reducing blood pressure, body weight and diabetes-related end-organ complications. Copyright © 2017 Elsevier B.V. All rights reserved.

Extraocular Muscle Enlargement and Thyroid Eye Disease-like Orbital Inflammation Associated with Immune Checkpoint Inhibitor Therapy in Cancer Patients.

PubMed

Sagiv, Oded; Kandl, Thomas J; Thakar, Sudip D; Thuro, Bradley A; Busaidy, Naifa L; Cabanillas, Maria; Jimenez, Camilo; Dadu, Ramona; Graham, Paul H; Debnam, J Matthew; Esmaeli, Bita

2018-06-19

To describe thyroid eye disease (TED)-like orbital inflammatory syndrome in 3 cancer patients treated with immune checkpoint inhibitors. All consecutive patients treated by the senior author who were receiving immune checkpoint inhibitors and developed TED-like orbital inflammation were included. Three cancer patients treated with immune checkpoint inhibitors developed orbital inflammation. The first patient was treated with a combination of a cytotoxic T-lymphocyte antigen-4 inhibitor and a programmed cell death protein 1 inhibitor and developed TED-like orbital inflammation with normal thyroid function and antibody levels. The second patient had a previous diagnosis of Graves disease without TED, and developed TED soon after initiating treatment with a programmed cell death protein 1 inhibitor. The third patient developed acute hyperthyroidism with symptomatic TED following treatment with an investigational cytotoxic T-lymphocyte antigen-4 inhibitor agent. All 3 patients were managed with either systemic steroids or observation, with resolution of their symptoms and without the need to halt immune checkpoint inhibitor treatment for their cancer. TED-like orbital inflammation may occur as a side effect of immune checkpoint inhibitor therapy with anti-cytotoxic T-lymphocyte antigen-4 or anti-PD-1 inhibitors. To the best of their knowledge, this is the first reported case of TED as a result of programmed cell death protein 1 inhibitor monotherapy. All 3 patients were treated with systemic steroids and responded quickly while continuing treatment with immune checkpoint inhibitors for their cancer. With increasing use of this class of drugs, clinicians should be familiar with the clinical manifestations and treatments for this adverse reaction.

The significance of interfamilial relationships on birth preparedness and complication readiness in Pakistan.

PubMed

Ghani, Usman; Crowther, Susan; Kamal, Yasir; Wahab, Muhammad

2018-03-29

In the interests of improving maternal health care and survival, the issue of birth preparedness and complication readiness has been much debated and has remained a priority for the international health community. The provision of birth preparedness and complications readiness is determined by a range of different factors. The main aim of this study is to identify and measure the influence of husbands and other family relationships on birth preparedness and complications readiness in the Khyber Pakhtunkhwa province of Pakistan. This study is a cross-sectional exploratory study. Data was collected through a survey questionnaire. Logistic regression and descriptive analysis was used. Analysis indicated that the mother-in-law's role, men's and women's level of education and interfamilial relationships are still the most significant factors influencing birth preparedness and complications readiness. Of the respondents, 86% were receiving antenatal care and 76.5% were planning for the birth to take place in state-run hospitals or private obstetric and gynae clinics. The tendency to take up antenatal care in Khyber Pakhtunkhwa can mainly be credited to a mutual understanding between husband and wife and a good relationship between the woman and her mother-in-law. Highlighting the significance of these relationships has implications for ensuring birth preparedness and complications readiness. Copyright © 2018 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.

Angiotensin-Converting Enzyme Inhibitors and the Risk of Congenital Malformations

PubMed Central

Bateman, Brian T; Patorno, Elisabetta; Desai, Rishi J; Seely, Ellen W; Mogun, Helen; Dejene, Sara Z; Fischer, Michael A; Friedman, Alexander M; Hernandez-Diaz, Sonia; Huybrechts, Krista F

2016-01-01

Objective To examine the association between first-trimester angiotensin-converting enzyme (ACE) inhibitor exposure and the risk for overall major congenital, cardiac, and central nervous system (CNS) malformations. Methods We used a cohort of completed pregnancies linked to liveborn infants derived from Medicaid claims from 2000 to 2010. We examined the risk of malformations associated with first-trimester exposure to an ACE inhibitor. Propensity score based methods were used to control for potential confounders including maternal demographics, medical conditions, exposure to other medications, and measures of health care utilization. Results The cohort included 1,333,624 pregnancies, of which 4,107 (0.31%) were exposed to ACE inhibitors during the first trimester. The prevalence of overall malformations in the ACE inhibitor–exposed was 5.9% versus 3.3% in the unexposed (unadjusted relative risk (RR), 1.82; 95% confidence interval (CI) 1.61 to 2.06), of cardiac malformations was 3.4% versus 1.2% (RR 2.95; 95% CI 2.50 to 3.47), and of CNS malformations was 0.27% versus 0.18% (RR 1.46; 95% CI 0.81 to 2.64). After restricting the cohort to pregnancies complicated by chronic hypertension (both exposed and unexposed) and accounting for other confounding factors, there was no significant increase in the risk for any of the outcomes assessed. Relative risks associated with first-trimester ACE inhibitor exposure were 0.89 (95% CI 0.75 to 1.06) for overall malformations, 0.95 (95% CI 0.75 to 1.21) for cardiac malformations, and 0.54 (95% CI 0.26 to 1.11) for CNS malformations. Conclusions After accounting for confounders, among women with hypertension, exposure to ACE inhibitors during the first trimester was not associated with an increased risk of major congenital malformations. PMID:27926639

Comparative efficacy and safety of tocilizumab, rituximab, abatacept and tofacitinib in patients with active rheumatoid arthritis that inadequately responds to tumor necrosis factor inhibitors: a Bayesian network meta-analysis of randomized controlled trials.

PubMed

Lee, Young Ho; Bae, Sang-Cheol

2016-11-01

This study aimed to assess the relative efficacy and safety of biologics and tofacitinib in patients with rheumatoid arthritis (RA) showing an inadequate response to tumor necrosis factor (TNF) inhibitors. We performed a Bayesian network meta-analysis to combine the direct and indirect evidence from randomized controlled trials (RCTs) examining the efficacy and safety of tocilizumab, rituximab, abatacept and tofacitinib in patients with RA that inadequately responds to TNF inhibitors. Four RCTs including 1796 patients met the inclusion criteria. The tocilizumab 8 mg group showed a significantly higher American College of Rheumatology 20% (ACR20) response rate than the abatacept and tofacitinib groups. Ranking probability based on surface under the cumulative ranking curve (SUCRA) indicated that tocilizumab 8 mg had the highest probability of being the best treatment for achieving the ACR20 response rate (SUCRA = 0.9863), followed by rituximab (SUCRA = 0.6623), abatacept (SUCRA = 0.5428), tocilizumab 4 mg (SUCRA = 0.4956), tofacitinib 10 mg (SUCRA = 0.4715), tofacitinib 5 mg (SUCRA = 0.3415) and placebo (SUCRA = 0). In contrast, the safety based on the number of withdrawals due to adverse events did not differ significantly among the treatment options. Tocilizumab 8 mg was the second-line non-TNF biologic with the highest performance regarding an early good response based on ACR20 response rate and acceptable safety profile, followed by rituximab, abatacept and tofacitinib in patients with RA and an inadequate response to anti-TNF therapy, and none of these treatments were associated with a significant risk of withdrawal due to adverse events. © 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

Emergency responders' critical infrared (ERCI)

NASA Astrophysics Data System (ADS)

Konsin, Larry S.

2004-08-01

Emergency Responders (Fire, Police, Medical, and Emergency Management) face a high risk of injury or death. Even before September 11, 2001, public and private organizations have been driven to better protect Emergency Responders through education, training and improved technology. Recent research on Emergency Responder safety, health risks, and personal protective requirements, shows infrared (IR) imaging as a critical need. Today"s Emergency Responders are increasingly challenged to do more, facing demands requiring technological assistance and/or solutions. Since the introduction of Fire Service IR imaging in the mid 1990s, applications have increased. Emergency response IR is no longer just seeing through smoke to find victims or the seat of a fire. Many more mission critical needs now exist across the broad spectrum of emergency response. At the same time, Emergency Responder injuries and deaths are increasing. The Office of Domestic Preparedness (ODP) has also recognized IR imaging as critical in protecting our communities -- and in preventing many of the injuries and deaths of Emergency Responders. Currently, only 25% of all fire departments (or less than 7% of individual firefighters) have IR imaging. Availability to Police, EMS and Emergency Management is even lower. Without ERCI, Emergency Responders and our communities are at risk.

The evolving landscape of RAAS inhibition: from ACE inhibitors to ARBs, to DRIs and beyond.

PubMed

Epstein, Benjamin J; Leonard, Paul T; Shah, Niren K

2012-06-01

Chronic renin-angiotensin-aldosterone system (RAAS) activation has far-reaching effects on cardiometabolic risk and is a substantial contributor to cardiovascular (CV) disease and renal dysfunction. The vascular effects of sustained RAAS activation are associated with hemodynamic imbalances, as well as inflammatory stimulation and prothrombotic processes that lead to fibrosis, endothelial dysfunction and cellular remodeling. RAAS inhibition therapies, which include the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and more recently, direct renin inhibitors, have been used in clinical practice for more than 30 years. Our understanding of how these drugs work, alone and in combination, has contributed to an expanding landscape of treatment options and established RAAS inhibition as essential for reducing the risk of CV and renal disease. This perspective provides a historical overview of how RAAS inhibitors have evolved to their present-day status and will discuss recently discovered functions for components of this complicated and powerful regulatory system.

Exceptional responders in conservation.

PubMed

Post, Gerald; Geldmann, Jonas

2017-08-30

Conservation operates within complex systems with incomplete knowledge of the system and the interventions utilized. This frequently results in the inability to find generally applicable methods to alleviate threats to Earth's vanishing wildlife. One approach used in medicine and the social sciences has been to develop a deeper understanding of positive outliers. Where such outliers share similar characteristics, they may be considered exceptional responders. We devised a 4-step framework for identifying exceptional responders in conservation: identification of the study system, identification of the response structure, identification of the threshold for exceptionalism, and identification of commonalities among outliers. Evaluation of exceptional responders provides additional information that is often ignored in randomized controlled trials and before-after control-intervention experiments. Interrogating the contextual factors that contribute to an exceptional outcome allow exceptional responders to become valuable pieces of information leading to unexpected discoveries and novel hypotheses. © 2017 Society for Conservation Biology.

Medulloblastomas derived from Cxcr6 mutant mice respond to treatment with a smoothened inhibitor.

PubMed

Sasai, Ken; Romer, Justyna T; Kimura, Hiromichi; Eberhart, Derek E; Rice, Dennis S; Curran, Tom

2007-04-15

The sonic hedgehog (Shh) pathway is activated in approximately 30% of human medulloblastoma resulting in increased expression of downstream target genes. In about half of these cases, this has been shown to be a consequence of mutations in regulatory genes within the pathway, including Ptc1, Smo, and Sufu. However, for some tumors, no mutations have been detected in known pathway genes. This suggests that either mutations in other genes promote tumorigenesis or that epigenetic alterations increase pathway activity in these tumors. Here, we report that 3% to 4% of mice lacking either one or both functional copies of Cxcr6 develop medulloblastoma. Although CXCR6 is not known to be involved in Shh signaling, tumors derived from Cxcr6 mutant mice expressed Shh pathway target genes including Gli1, Gli2, Ptc2, and Sfrp1, indicating elevated pathway activity. Interestingly, the level of Ptc1 expression was decreased in tumor cells although two normal copies of Ptc1 were retained. This implies that reduced CXCR6 function leads to suppression of Ptc1 thereby increasing Smoothened function and promoting tumorigenesis. We used a direct transplant model to test the sensitivity of medulloblastoma arising in Cxcr6 mutant mice to a small-molecule inhibitor of Smoothened (HhAntag). We found that transplanted tumors were dramatically inhibited in mice treated for only 4 days with HhAntag. These findings suggest that HhAntag may be effective against tumors lacking mutations in known Shh pathway genes.

Design and development of a personal alarm monitor for use by first responders

NASA Astrophysics Data System (ADS)

Ehntholt, Daniel J.; Louie, Alan S.; Marenchic, Ingrid G.; Forni, Ronald J.

2004-03-01

This paper describes the design and development of a small, portable alarm device that can be used by first responders to an emergency event to warn of the presence of low levels of a toxic nerve gas. The device consists of a rigid reusable portion and a consumable packet that is sensitive to the presence of acetylcholinesterase inhibitors such as the nerve gases Sarin or Soman. The sensitivity level of the alarm is set to be at initial physiological response at the meiosis level, orders of magnitude below lethal concentrations. The AChE enzyme used is specific for nerve-type toxins. A color development reaction is used to demonstrate continued activity of the enzyme over its twelve-hour operational cycle.

Contact lens complications.

PubMed

Suchecki, Jeanine K; Donshik, Peter; Ehlers, William H

2003-09-01

Complications associated with contact lenses range from mild to severe and occur with all lens modalities. Contact lens wear can cause a change in corneal physiology, which can lead to epithelial, stromal, and endothelial compromise. Other complications include lens deposition, allergic conjunctivitis, giant papillary conjunctivitis, peripheral infiltrates, microbial keratitis, and neovascularization. Pre-existing conditions can contribute to these complications, or they can occur in association with contact lens wear and care regimens. Patient-related factors, such as alteration of the recommended wearing or replacement schedules and noncompliance with recommended contact lens care regimens for economic reasons, convenience, or in error, contribute to contact lens-related complications and have led to difficulty in accurate determination of complication rates among the various lens wear modalities. Complications may require discontinuation of contact lenses, topical therapy, and changes in contact lens wearing schedules, materials, and care solutions. On initial lens fitting and follow-up evaluations, practitioners should review contact lens replacement and cleaning regimens with patients and discuss complications. To avoid serious complications, patients should be reminded to remove their contact lenses as soon as ocular irritation occurs, and to call their eye care practitioner immediately if symptoms persist.

POTENTIAL PLACE OF SGLT2 INHIBITORS IN TREATMENT PARADIGMS FOR TYPE 2 DIABETES MELLITUS.

PubMed

Handelsman, Yehuda

2015-09-01

Following the first Food and Drug Administration (FDA) approval in 2013, sodium glucose cotransporter 2 (SGLT2) inhibitors have generated much interest among physicians treating patients with type 2 diabetes mellitus (T2DM). Here, the role in treatment with this drug class is considered in the context of T2DM treatment paradigms. The clinical trials for the SGLT2 inhibitors are examined with a focus on canagliflozin, dapagliflozin, and empagliflozin. Evidence from clinical trials in patients with T2DM supports the use of SGLT2 inhibitors either as monotherapy or in addition to other glucose-lowering treatments as adjuncts to diet and exercise, and we have gained significant clinical experience in a relatively short time. The drugs appear to be useful in a variety of T2DM populations, contingent primarily on renal function. Most obviously, SGLT2 inhibitors appear to be well suited for patients with potential for hypoglycemia or weight gain. In clinical trials, patients treated with SGLT2 inhibitors have experienced moderate weight loss and a low risk of hypoglycemic events except when used in combination with an insulin secretagogue. In addition, SGLT2 inhibitors have been shown to reduce blood pressure, so they may be beneficial in patients with T2DM complicated by hypertension. SGLT2 inhibitors were incorporated into the 2015 American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) position statement on the management of hyperglycemia and received an even more prominent position in the American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) comprehensive diabetes management guidelines and algorithm.

Efficacy, safety, and patient preference of monoamine oxidase B inhibitors in the treatment of Parkinson’s disease

PubMed Central

Robottom, Bradley J

2011-01-01

Parkinson’s disease (PD) is the second most common neurodegenerative disease and the most treatable. Treatment of PD is symptomatic and generally focuses on the replacement or augmentation of levodopa. A number of options are available for treatment, both in monotherapy of early PD and to treat complications of advanced PD. This review focuses on rasagiline and selegiline, two medications that belong to a class of antiparkinsonian drugs called monoamine oxidase B (MAO-B) inhibitors. Topics covered in the review include mechanism of action, efficacy in early and advanced PD, effects on disability, the controversy regarding disease modification, safety, and patient preference for MAO-B inhibitors. PMID:21423589

Majority of symptoms in esophageal reflux PPI non-responders are not related to reflux

PubMed Central

Roman, Sabine; Keefer, Laurie; Imam, Hala; Korrapati, Praneet; Mogni, Benjamin; Eident, Kate; Friesen, Laurel; Kahrilas, Peter J; Martinovich, Zoran; Pandolfino, John

2015-01-01

Background Genesis of persistent gastro-esophageal reflux symptoms despite proton pump inhibitor (PPI) therapy is not fully understood. We aimed at determining reflux patterns on 24-h pH-impedance monitoring performed on PPI and correlating impedance patterns and symptom occurrence in PPI non-responders. Methods 78 PPI non-responder patients underwent 24-h pH-impedance monitoring on PPI. Reflux impedance characterization included gastric and supragastric belches and proximal extent of reflux. Symptoms were considered associated with reflux if occurring within 5 min after a reflux event. Patients were classified into 3 groups: persistent acid reflux (acid esophageal exposure (AET) >5% of time), reflux sensitivity (AET<5%, symptom index (SI) ≥50%), and functional symptoms (AET<5%, SI<50%). Dominant impedance pattern was determined for each patient. Key results 7 patients (9%) had persistent acid reflux, 28 (36%) reflux sensitivity and 43 (55%) functional symptoms. A total of 4,296 reflux events were identified (median per patient 45 (range 4–221)). Although liquid reflux was the most common pattern in all groups, patients with reflux sensitivity and functional symptoms had much more variability in their pattern profile with a large proportion being associated with gastric and supra-gastric belching. Only 417 reflux events (9.7%) were associated with symptoms. Reflux with a supragastric component and proximal extent were more likely to be associated with symptoms. Conclusions & Inferences The impedance reflux profile in PPI non-responders was heterogeneous and the majority of reflux events were not associated with symptoms. Thus, the treatment of PPI non-responders should focus on mechanisms beyond reflux, such as visceral hypersensitivity and hypervigilance. PMID:26337396

Preclinical rationale for PI3K/Akt/mTOR pathway inhibitors as therapy for epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer.

PubMed

Gadgeel, Shirish M; Wozniak, Antoinette

2013-07-01

Mutations in the epidermal growth factor receptor gene (EGFR) are frequently observed in non-small-cell lung cancer (NSCLC), occurring in about 40% to 60% of never-smokers and in about 17% of patients with adenocarcinomas. EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed therapy for patients with EGFR-mutant NSCLC and have proved superior to chemotherapy as first-line treatment for this patient group. Despite these benefits, there are currently 2 key challenges associated with EGFR inhibitor therapy for patients with NSCLC. First, only 85% to 90% of patients with the EGFR mutation derive clinical benefit from EGFR TKIs, with the remainder demonstrating innate resistance to therapy. Second, acquired resistance to EGFR TKIs inevitably occurs in patients who initially respond to therapy, with a median duration of response of about 10 months. Mutant EGFR activates various subcellular signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which demonstrates maintained activity in a variety of TKI-resistant cancers. Given the fundamental role of the PI3K/Akt/mTOR pathway in tumor oncogenesis, proliferation, and survival, PI3K pathway inhibitors have emerged as a possible solution to the problem of EGFR TKI resistance. However resistance to EGFR TKIs is associated with considerable heterogeneity and complexity. Preclinical experiments investigating these phenomena suggest that in some patients, PI3K inhibitors will have to be paired with other targeted agents if they are to be effective. This review discusses the preclinical data supporting PI3K/Akt/mTOR pathway inhibitor combinations in EGFR TKI-resistant NSCLC from the perspective of the various agents currently being investigated in clinical trials. Copyright © 2013 Elsevier Inc. All rights reserved.

Brain Changes in Responders vs. Non-Responders in Chronic Migraine: Markers of Disease Reversal

PubMed Central

Hubbard, Catherine S.; Becerra, Lino; Smith, Jonathan H.; DeLange, Justin M.; Smith, Ryan M.; Black, David F.; Welker, Kirk M.; Burstein, Rami; Cutrer, Fred M.; Borsook, David

2016-01-01

The aim of this study was to identify structural and functional brain changes that accompanied the transition from chronic (CM; ≥15 headache days/month) to episodic (EM; <15 headache days/month) migraine following prophylactic treatment with onabotulinumtoxinA (BoNT-A). Specifically, we examined whether CM patients responsive to prophylaxis (responders; n = 11), as evidenced by a reversal in disease status (defined by at least a 50% reduction in migraine frequency and <15 headache days/month), compared to CM patients whose migraine frequency remained unchanged (non-responders; n = 12), showed differences in cortical thickness using surface-based morphometry. We also investigated whether areas showing group differences in cortical thickness displayed altered resting-state functional connectivity (RS-FC) using seed-to-voxel analyses. Migraine characteristics measured across groups included disease duration, pain intensity and headache frequency. Patient reports of headache frequency over the 4 weeks prior to (pre-treatment) and following (post-treatment) prophylaxis were compared (post minus pre) and this measure served as the clinical endpoint that determined group assignment. All patients were scanned within 2 weeks of the post-treatment visit. Results revealed that responders showed significant cortical thickening in the right primary somatosensory cortex (SI) and anterior insula (aINS), and left superior temporal gyrus (STG) and pars opercularis (ParsOp) compared to non-responders. In addition, disease duration was negatively correlated with cortical thickness in fronto-parietal and temporo-occipital regions in responders but not non-responders, with the exception of the primary motor cortex (MI) that showed the opposite pattern; disease duration was positively associated with MI cortical thickness in responders versus non-responders. Our seed-based RS-FC analyses revealed anti-correlations between the SI seed and lateral occipital (LOC) and dorsomedial

Responding to Patients' Concerns.

ERIC Educational Resources Information Center

Henrich, Ann P.; Bernheim, Kayla F.

1981-01-01

Discusses a staff development program for nurses at an acute care hospital, aimed at responding to patient comments. Elements included (1) listening skills before training, (2) a formula to help nurses respond empathetically, (3) a pre- and posttest, (4) a followup class, and (5) program evaluation. (CT)

ACE inhibitor and angiotensin II type 1 receptor antagonist therapies in elderly patients with diabetes mellitus: are they underutilized?

PubMed

Pappoe, Lamioko Shika; Winkelmayer, Wolfgang C

2010-02-01

Diabetes mellitus is highly prevalent in older adults in the industrialized world. These patients are at high risk of complications from diabetes, including diabetic kidney disease. ACE inhibitors and their newer cousins, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), are powerful medications for the prevention of progression of diabetic renal disease. Unfortunately, among the elderly, these medications have been underutilized. The reasons for this include physician concerns regarding patient age and limited life expectancy and potential complications of ACE inhibitor or ARB use, specifically an increase in creatinine levels and hyperkalaemia. As discussed in this article, there have been several studies that show that the effects of inhibition of the renin-angiotensin system can be beneficial for the treatment of cardiovascular disease and renal disease among elderly patients with diabetes and that the potential risks mentioned above are no greater in this group than in the general population. For these reasons, several professional societies recommend that elderly patients with diabetes and hypertension (systolic blood pressure >or=140 mmHg or diastolic blood pressure >or=90 mmHg) be treated with an ACE inhibitor or ARB (as is recommended for younger diabetics). Use of ACE inhibitors or ARBs is also recommended for those with cardiovascular disease or those who are at risk of cardiovascular disease. Furthermore, in the management of diabetic kidney disease in elderly patients, treatment with ACE inhibitors or ARBs is also recommended to reduce the risk or slow the progression of nephropathy. Renal function and potassium levels should be monitored within the first 12 weeks of initiation of these medications, with each dose increase, and on a yearly basis thereafter. This article summarizes the current guidelines on the use of ACE inhibitors and ARBs in older adults with diabetes, reviews the evidence for their use in the elderly

Towards rational therapy with monoamine oxidase inhibitors.

PubMed

Tyrer, P

1976-04-01

A rational approach to the use of monoamine oxidase inhibitors (MAOIs) is outlined. Patients suitable for treatment cannot be classified adequately using conventional diagnostic labels. They include those with primary symptoms of hypochondriasis, agoraphobia and social phobias, irritability, somatic anxiety and anergia; those with primary depressed mood, guilt, ideas of reference and personality disorders seldom respond. There is great variation in the interval between the first administration of these drugs and clinical response, and this may account for the inconsistencies in published trials. The type of drug and its dose may affect rate of response, as may biochemical factors, including acetylator and monoamine oxidase status. To obtain maximum benefit, a course of therapy with MAOIs should last for several months.

[The Role of GRK2 and Its Potential as a New Therapeutic Target in Diabetic Vascular Complications].

PubMed

Taguchi, Kumiko

2015-01-01

A decrease in nitric oxide (NO) production may induce pathological conditions associated with endothelial dysfunction and diabetes. Although a decrease in NO production caused by impaired Akt/endothelial nitric oxide synthesis (eNOS) signaling has been demonstrated at the aorta in the presence of diabetic vascular complications, little is known regarding the details of the mechanism. We identified G-protein-coupled receptor kinase 2 (GRK2) as a critical factor in diabetic endothelial dysfunction. GRK2 plays a role in many physiological functions including regulation of G-protein-coupled receptors (GPCRs). We found that the vasculature affected by type 2 diabetes expresses high levels of GRK2, which may induce endothelial dysfunction caused by impaired Akt/eNOS signaling. GRK2 activation also induces changes in the subcellular localization of GRK2 and β-arrestin 2, a downstream protein, from the cytosol to membrane. In mouse aorta GRK2 may be, on translocation, a key negative regulator and an important regulator of β-arrestin 2/Akt/eNOS signaling, which has been implicated in diabetic endothelial dysfunction. Furthermore, in the aortic membrane of type 2 diabetic model mice under insulin stimulation, the impaired Akt/eNOS signaling was improved by a selective GRK2 inhibitor. These results suggest that in diabetes the GRK2 inhibitor ameliorates vascular endothelial dysfunction via Akt/eNOS signaling by inhibiting GRK2 activity and enhancing β-arrestin 2 translocation to the membrane under GPCR or non-GPCR stimulation, thereby contributing to blood pressure- and blood glucose-lowering effects. We propose that the GRK2 inhibitor may be a promising therapeutic target for cardiovascular complications in type 2 diabetes.

Transitioning issues in adolescent to young adult hemophilia patients with inhibitors: an approach for a growing population.

PubMed

Young, Guy

2010-09-01

The major adverse effect of factor replacement therapy in patients with hemophilia is the development of neutralizing antibodies termed inhibitors. This complication renders standard factor replacement therapy ineffective resulting in increased morbidity and mortality. Until recently, the population of adults with inhibitors was relatively small due to the death of many of the patients from HIV that they contracted from contaminated factor in the early 1980s. With the advent of factor products with reduced risks for deadly infections in the mid-1980s to early 1990s, a cohort of inhibitor patients is now beginning to enter adulthood thus raising the issues regarding the transition of these patients into adulthood. It is, therefore, expected that adult hematologists will be seeing more inhibitor patients and that pediatric hematologists will be faced with managing this transition process, which may not necessarily include transition to an adult facility or adult hematologist. This review will discuss the various issues ranging from choice of medical provider to a discussion of psychosocial and financial issues facing this specific patient population.

Risk Factors for Inhibitor Formation in Hemophilia: A Prevalent Case-Control Study

PubMed Central

Ragni, Margaret V.; Ojeifo, Oluseyi; Feng, Jinong; Yan, Jin; Hill, Kathleen A.; Sommer, Steve S.; Trucco, Massimo N.; Brambilla, Donald J.

2009-01-01

Background Inhibitor formation is a major complication of hemophilia treatment. Aim In a prevalent case-control study, we evaluated blood product exposure, genotype, and HLA type on hemophilia A inhibitor formation. Methods Product exposure was extracted from medical records. Genotype was determined on stored DNA samples by detection of virtually all mutations-SSCP (DOVAM-S) and subcycling PCR. HLA typing was performed by PCR amplification and exonuclease-released fluorescence. Results Cases experienced higher intensity factor, 455 vs. 200 U per exposure, p<0.005, more frequent central nervous system (CNS) bleeding, 7 of 20 (35.0%) vs. 1 of 57 (1.7%), p=0.001, and more commonly from inhibitor families, 7 of 20 (35.0%) vs. 0 of 57 (0%), p<0.001, and African-American, 12 of 63 (19.0%) vs. 6 of 117 (5.1%), p=0.015. Among the latter, CNS bleeding was more commonly the initial bleed, 60% vs. 0%, p<0.001, and survival was shorter, 14 vs. 38 yr, p=0.025. Inhibitor formation was uncommon in those with missense mutations, 2 of 65 (3.1%) vs. 31 of 119 (26.0%), p=0.008, and unrelated to factor VIII immunogenic epitope, p=0.388, or HLA type, p>0.100. Genotype was not associated with race. Time to immune tolerance was shorter for titers < 120 vs. ≥ 120 BU/ml, 6 vs. 16 months, p<0.01, but unaffected by tolerizing dose regimen, p>0.50. Conclusions Inhibitor formation is associated with high intensity product exposure, CNS bleeding, African-American race, and low frequency of missense mutations. The ideal time to initiate prophylaxis to reduce CNS bleeding and inhibitor formation will require prospective studies. PMID:19563499

Methotrexate Is a JAK/STAT Pathway Inhibitor

PubMed Central

Thomas, Sally; Fisher, Katherine H.; Snowden, John A.; Danson, Sarah J.; Brown, Stephen; Zeidler, Martin P.

2015-01-01

Background The JAK/STAT pathway transduces signals from multiple cytokines and controls haematopoiesis, immunity and inflammation. In addition, pathological activation is seen in multiple malignancies including the myeloproliferative neoplasms (MPNs). Given this, drug development efforts have targeted the pathway with JAK inhibitors such as ruxolitinib. Although effective, high costs and side effects have limited its adoption. Thus, a need for effective low cost treatments remains. Methods & Findings We used the low-complexity Drosophila melanogaster pathway to screen for small molecules that modulate JAK/STAT signalling. This screen identified methotrexate and the closely related aminopterin as potent suppressors of STAT activation. We show that methotrexate suppresses human JAK/STAT signalling without affecting other phosphorylation-dependent pathways. Furthermore, methotrexate significantly reduces STAT5 phosphorylation in cells expressing JAK2 V617F, a mutation associated with most human MPNs. Methotrexate acts independently of dihydrofolate reductase (DHFR) and is comparable to the JAK1/2 inhibitor ruxolitinib. However, cells treated with methotrexate still retain their ability to respond to physiological levels of the ligand erythropoietin. Conclusions Aminopterin and methotrexate represent the first chemotherapy agents developed and act as competitive inhibitors of DHFR. Methotrexate is also widely used at low doses to treat inflammatory and immune-mediated conditions including rheumatoid arthritis. In this low-dose regime, folate supplements are given to mitigate side effects by bypassing the biochemical requirement for DHFR. Although independent of DHFR, the mechanism-of-action underlying the low-dose effects of methotrexate is unknown. Given that multiple pro-inflammatory cytokines signal through the pathway, we suggest that suppression of the JAK/STAT pathway is likely to be the principal anti-inflammatory and immunosuppressive mechanism-of-action of low

Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib.

PubMed

Rothstein, Brooke; Joshipura, Deep; Saraiya, Ami; Abdat, Rana; Ashkar, Huda; Turkowski, Yana; Sheth, Vaneeta; Huang, Victor; Au, Shiu Chung; Kachuk, Courtney; Dumont, Nicole; Gottlieb, Alice B; Rosmarin, David

2017-06-01

Existing therapies for vitiligo are limited in efficacy and can be associated with undesirable side effects. Topical Janus kinase inhibitors may offer a new therapeutic option for vitiligo. We sought to assess the role of topical ruxolitinib 1.5% cream, a Janus kinase inhibitor, in vitiligo treatment. This 20-week, open-label, proof-of-concept trial of twice-daily topical ruxolitinib 1.5% cream was conducted in 12 patients with a minimum of 1% affected body surface area of vitiligo. The primary outcome was percent improvement in Vitiligo Area Scoring Index from baseline to week 20. Of 12 patients screened, 11 were enrolled and 9 completed the study (54.5% men; mean age, 52 years). Four patients with significant facial involvement at baseline had a 76% improvement in facial Vitiligo Area Scoring Index scores at week 20 (95% confidence interval, 53-99%; P = .001). A 23% improvement in overall Vitiligo Area Scoring Index scores was observed in all enrolled patients at week 20 (95% confidence interval, 4-43%; P = .02). Three of 8 patients responded on body surfaces and 1 of 8 patients responded on acral surfaces. Adverse events were minor, including erythema, hyperpigmentation, and transient acne. Limitations of the study include the small sample size and open-label study design. Topical ruxolitinib 1.5% cream provided significant repigmentation in facial vitiligo and may offer a valuable new treatment for vitiligo. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

37 CFR 41.68 - Respondent's brief.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 37 Patents, Trademarks, and Copyrights 1 2010-07-01 2010-07-01 false Respondent's brief. 41.68... Respondent's brief. (a)(1) Respondent(s) in an appeal may once, within the time limit for filing set forth in... title. (2) The brief must be signed by the party, or the party's duly authorized attorney or agent, and...

The selective serotonin reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and spatial reversal learning

PubMed Central

Brown, Holden D.; Amodeo, Dionisio A.; Sweeney, John A.; Ragozzino, Michael E.

2011-01-01

Previous findings indicate treatment with a selective serotonin reuptake inhibitor (SSRI) facilitates behavioral flexibility when conditions require inhibition of a learned response pattern. The present experiment investigated whether acute treatment with the SSRI, escitalopram, affects behavioral flexibility when conditions require inhibition of a naturally-biased response pattern (elevated conflict test) and/or reversal of a learned response pattern (spatial reversal learning). An additional experiment was carried out to determine whether escitalopram, at doses that affected behavioral flexibility, also reduced anxiety as tested in the elevated plus-maze. In each experiment, Long-Evans rats received an intraperitoneal injection of either saline or escitalopram (0.03, 0.3 or 1.0 mg/kg) 30 minutes prior to behavioral testing. Escitalopram, at all doses tested, enhanced acquisition in the elevated conflict test, but did not affect performance in the elevated plus-maze. Escitalopram (0.3 and 1.0 mg/kg) did not alter acquisition of the spatial discrimination, but facilitated reversal learning. In the elevated conflict and spatial reversal learning test, escitalopram enhanced the ability to maintain the relevant strategy after being initially selected. The present findings suggest that enhancing serotonin transmission with a SSRI facilitates inhibitory processes when conditions require a shift away from either a naturally-biased response pattern or a learned choice pattern. PMID:22219222

Generalised pustular psoriasis induced by cyclosporin a withdrawal responding to the tumour necrosis factor alpha inhibitor etanercept.

PubMed

Kamarashev, J; Lor, P; Forster, A; Heinzerling, L; Burg, G; Nestle, F O

2002-01-01

We report a 50-year-old male patient with a 15-year history of psoriasis including mutilating psoriatic arthritis, in whom the withdrawal of cyclosporin A induced a generalised pustular exacerbation and a aggravation of the joint condition. Two weekly injections of 25 mg of the tumour necrosis factor alpha inhibitor etanercept led to a rapid improvement of his psoriatic arthritis, as well as regression of the pustular eruption, while residual erythema was still present. The clinical response was reflected by an increase in circulating interleukin (IL) 10 and a decrease in IL-6 and IL-8 serum levels during treatment. We conclude that etanercept may be a safe and effective therapy not only in severe psoriatic arthritis, but also in cases of pustular rebound after withdrawal of immunosuppressive agents. Copyright 2002 S. Karger AG, Basel

Recombinant factor VIIa (eptacog alfa): a review of its use in congenital hemophilia with inhibitors, acquired hemophilia, and other congenital bleeding disorders.

PubMed

Croom, Katherine F; McCormack, Paul L

2008-01-01

Recombinant factor VIIa (NovoSeven; also known as recombinant activated factor VII or eptacog alfa) is structurally similar to human plasma-derived coagulation factor VIIa, but is manufactured using DNA biotechnology. Recombinant factor VIIa interacts with thrombin-activated platelets to produce a thrombin burst leading to accelerated fibrin clot formation localized to the site of vascular injury. It is approved in many countries for use as an intravenous hemostatic agent in patients with congenital hemophilia with inhibitors, and also for acquired hemophilia, factor VII deficiency, and Glanzmann thrombasthenia in some countries. Studies have shown it to be effective and generally well tolerated when used intravenously to treat bleeding episodes or provide hemostatic cover during surgery in patients with congenital hemophilia with inhibitors, acquired hemophilia, factor VII deficiency or Glanzmann thrombasthenia. Based on available data, its efficacy in terms of patient-assessed response may be similar to that of activated prothrombin complex concentrate (aPCC), but treatment with a single 270 microg/kg dose of recombinant factor VIIa might reduce the need for rescue therapy compared with aPCC. Recombinant factor VIIa is not immunogenic in patients with hemophilia, does not produce an anamnestic response in hemophilia patients with inhibitors, and has very low thrombogenicity. It is recommended in guidelines as the treatment of choice for bleeds in patients with hemophilia B with high-responding inhibitors and for patients with factor VII deficiency, and is also a first-line therapeutic option for high-responder hemophilia A patients with inhibitors and those with acquired hemophilia. Cost data from pharmacoeconomic analyses support its use in hemophilia patients with inhibitors. Thus, recombinant factor VIIa is a valuable treatment option for patients with these rare, but potentially serious, bleeding disorders.

Plasmin-dependent proteolysis of Tissue Factor Pathway Inhibitor in a mouse model of endotoxemia

PubMed Central

Lupu, Cristina; Herlea, Oana; Tang, Haiwang; Lijnen, Roger H.; Lupu, Florea

2012-01-01

Summary Background Development of a procoagulant state in sepsis, due to aberrant expression of tissue factor (TF) and sharp decrease of its major inhibitor tissue factor pathway inhibitor (TFPI), could lead to microthrombotic organ failure. The mechanism for the decline of TFPI activity in the lung could involve plasmin-mediated cleavage of the inhibitor. Objective To investigate the effect of plasmin generation on lung-associated TFPI activity, in normal conditions and during infusion of endotoxin (LPS) in mice. Methods Plasmin generation and TFPI activity were assayed in the lungs of mice deficient of tissue-type plasminogen activator (t-PA) or plasminogen (Plg), at 2-hrs after LPS or saline injection. Results The sharp loss of lung-associated TFPI activity at 2-hrs post LPS paralleled the abrupt increase of plasmin generation. TFPI activity was significantly retained in both t-PA-/- and Plg-/- mice, which are unable to generate plasmin. Conclusion The increased plasmin generation during the early stages of sepsis could cleave/inactivate TFPI and thus lead to thrombotic complications. PMID:23106863

Plasmin-dependent proteolysis of tissue factor pathway inhibitor in a mouse model of endotoxemia.

PubMed

Lupu, C; Herlea, O; Tang, H; Lijnen, R H; Lupu, F

2013-01-01

The development of a procoagulant state in sepsis, owing to aberrant expression of tissue factor (TF) and a sharp decrease in the level of its major inhibitor, TF pathway inhibitor (TFPI), could lead to microthrombotic organ failure. The mechanism for the decline in TFPI activity in the lung could involve plasmin-mediated cleavage of the inhibitor. To investigate the effect of plasmin generation on lung-associated TFPI activity, in normal conditions and during infusion of endotoxin (lipopolysaccharide [LPS]) in mice. Plasmin generation and TFPI activity were assayed in the lungs of mice deficient in tissue-type plasminogen (Plg) activator (t-PA) or Plg, at 2 h after LPS or saline injection. The sharp loss of lung-associated TFPI activity at 2 h after LPS challenge paralleled the abrupt increase in plasmin generation. TFPI activity was significantly retained in both t-PA(-/-) and Plg(-/-) mice, which are unable to generate plasmin. The increased plasmin generation during the early stages of sepsis could cleave/inactivate TFPI and thus lead to thrombotic complications. © 2012 International Society on Thrombosis and Haemostasis.

Understanding and responding the students in learning mathematics through the differentiated instruction

NASA Astrophysics Data System (ADS)

Hapsari, T.; Darhim; Dahlan, J. A.

2018-05-01

This research discusses the differentiated instruction, a mathematic learning which is as expected by the students in connection with the differentiated instruction itself, its implementation, and the students’ responses. This research employs a survey method which involves 62 students as the research respondents. The mathematics learning types required by the students and their responses to the differentiated instruction are examined through questionnaire and interview. The mathematics learning types in orderly required by the students, from the highest frequency cover the easily understood instructions, slowly/not rushing teaching, fun, not complicated, interspersed with humour, various question practices, not too serious, and conducive class atmosphere for the instructions. Implementing the differentiated instruction is not easy. The teacher should be able to constantly assess the students, s/he should have good knowledge of relevant materials and instructions, and properly prepare the instructions, although it is time-consuming. The differentiated instruction is implemented on the instructions of numerical pattern materials. The strategies implemented are flexible grouping, tiered assignment, and compacting. The students positively respond the differentiated learning instruction that they become more motivated and involved in the instruction.

Prevention of inhibitor development in hemophilia A in 2016. A glimpse into the future?

PubMed

Franchini, Massimo; Lippi, Giuseppe

2016-12-01

Thanks to considerable progresses made over the last 30years, hemophilia benefits from the most efficacious and safe treatment among the many monogenic inherited disorders. The most challenging complication of replacement therapy in hemophilia A is the occurrence of alloantibodies against infused factor VIII (FVIII), thus predisposing the patients to increased morbidity and disability. Extensive research in this field has definitively unraveled that development of inhibitors in hemophilia A is a complex and multifactorial process, in which inherited and environmental factors dynamically interact. This narrative review, after providing a concise overview about the main genetic and non-genetic risk factors, is aimed to focus on prediction risk models and preventive strategies for minimizing the risk of developing inhibitors in hemophilia A patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

CBT for childhood anxiety disorders: differential changes in selective attention between treatment responders and non-responders.

PubMed

Legerstee, Jeroen S; Tulen, Joke H M; Dierckx, Bram; Treffers, Philip D A; Verhulst, Frank C; Utens, Elisabeth M W J

2010-02-01

This study examined whether treatment response to stepped-care cognitive-behavioural treatment (CBT) is associated with changes in threat-related selective attention and its specific components in a large clinical sample of anxiety-disordered children. Ninety-one children with an anxiety disorder were included in the present study. Children received a standardized stepped-care CBT. Three treatment response groups were distinguished: initial responders (anxiety disorder free after phase one: child-focused CBT), secondary responders (anxiety disorder free after phase two: child-parent-focused CBT), and treatment non-responders. Treatment response was determined using a semi-structured clinical interview. Children performed a pictorial dot-probe task before and after stepped-care CBT (i.e., before phase one and after phase two CBT). Changes in selective attention to severely threatening pictures, but not to mildly threatening pictures, were significantly associated with treatment success. At pre-treatment assessment, initial responders selectively attended away from severely threatening pictures, whereas secondary responders selectively attended toward severely threatening pictures. After stepped-care CBT, initial and secondary responders did not show any selectivity in the attentional processing of severely threatening pictures. Treatment non-responders did not show any changes in selective attention due to CBT. Initial and secondary treatment responders showed a reduction of their predisposition to selectively attend away or toward severely threatening pictures, respectively. Treatment non-responders did not show any changes in selective attention. The pictorial dot-probe task can be considered a potentially valuable tool in assigning children to appropriate treatment formats as well as for monitoring changes in selective attention during the course of CBT.

Hepatotoxicity of nucleoside reverse transcriptase inhibitors.

PubMed

Montessori, Valentina; Harris, Marianne; Montaner, Julio S G

2003-05-01

Hepatotoxicity is an adverse effect of all available classes of antiretrovirals, including nucleoside reverse transcriptase inhibitors (NRTI). A syndrome of hepatic steatosis and lactic acidosis has been recognized as a rare, potentially fatal complication since the advent of NRTI monotherapy in the early 1990s. Today, NRTI remain the backbone of antiretroviral combination regimens, and, with the success of current treatment strategies, exposure to two or more of these agents may occur over a number of years. Hepatic steatosis and lactic acidosis are accordingly being observed more frequently, along with a more recently recognized syndrome of chronic hyperlactatemia. These as well as other adverse effects of NRTI are mediated by inhibition of human DNA polymerase gamma, resulting in mitochondrial dysfunction in the liver and other tissues. Early recognition and intervention are essential to avert serious outcomes.

The influence of lunar phases and zodiac sign 'Leo' on perioperative complications and outcome in elective spine surgery.

PubMed

Joswig, Holger; Stienen, Martin N; Hock, Carolin; Hildebrandt, Gerhard; Surbeck, Werner

2016-06-01

Many people believe that the moon has an influence on daily life, and some even request elective surgery dates depending on the moon calendar. The aim of this study was to assess the influence of 'unfavorable' lunar or zodiac constellations on perioperative complications and outcome in elective surgery for degenerative disc disease. Retrospective database analysis including 924 patients. Using uni- and multivariate logistic regression, the likelihood for intraoperative complications and re-do surgeries as well as the clinical outcomes at 4 weeks was analyzed for surgeries performed during the waxing moon, full moon, and dates when the moon passed through the zodiac sign 'Leo.' In multivariate analysis, patients operated on during the waxing moon were 1.54 times as likely as patients who were operated on during the waning moon to suffer from an intraoperative complication (OR 1.54, 95 % CI 1.07-2.21, p = 0.019). In contrast, there was a trend toward fewer re-do surgeries for surgery during the waxing moon (OR 0.51, 95 % CI 0.23-1.16, p = 0.109), while the 4-week responder status was similar (OR 0.73, 95 % CI 0.47-1.14, p = 0.169). A full moon and the zodiac sign Leo did not increase the likelihood for complications, re-do surgeries or unfavorable outcomes. We found no influence of 'unfavorable' lunar or zodiac constellations on the 4-week responder status or the revision rate that would justify a moon calendar-based selection approach to elective spine surgery dates. However, the fact that patients undergoing surgery during the waxing moon were more likely to suffer from an intraoperative complication is a surprising curiosity and defies our ability to find a rational explanation.

Empathy-related responding and prosocial behaviour.

PubMed

Eisenberg, Nancy

2007-01-01

In this paper I differentiate among empathy, sympathy and personal distress and discuss the central role of empathy-related responding in positive (including moral) development. Empathy-related responding, especially sympathy, is likely an important source of prosocial, other-oriented motivation. In fact, empathy-related responding, especially sympathy, has been associated with prosocial behaviour (voluntary behaviour intended to benefit another, e.g. helping, sharing); this relation has been obtained for both specific instances of empathy-related responding and for dispositional sympathy. In addition, sympathy (or sometimes empathy) has been linked to relatively high levels of moral reasoning and social competence, and to low levels of aggression and antisocial behaviour. In my talk, I will review research on the relation of empathy-related responding to prosocial behaviour, the consistency of costly prosocial behaviour over time and the possible role of sympathy in its consistency, and the relation of empathy-related responding to moral reasoning, antisocial behaviour and social competence. Examples of research, including longitudinal research in our laboratory, are provided to illustrate these relations. Because of its close relations to social and prosocial responding, an understanding of empathy-related responding contributes to efforts to promote children's moral development.

[Characteristics of central nervous system activity in patients with complications of arterial hypertension and dependence on psychomotor status and treatment].

PubMed

Usenko, A G; Velichko, N P; Usenko, G A; Nishcheta, O V; Kozyreva, T Iu; Demin, A A

2013-01-01

Changes in certain CNS characteristics were used as indicators of the efficacy of antihypertensive therapy (AHT) both targeted (T-AHT) and empirical (E-AHT) designed to suppress activity of the sympathetic component of vegetative nervous system (VNS) and renin-angiotensin-aldosterone system (RAAS) in patients of different psychic status and AH. A group of 835 men (mean age 54.2+-1.8yr) was divided into cholerics, sanguinics, melancholics and phlegmatics with a high and low anxiety level (HA and LA). 416 healthy men served as controls. The following parameters were estimated: mobility of cortical processes, balance between sympathetic and parasympathetic activities, blood corrisol and aldosterone levels, oxygen utilization coefficient, resistance to breath holding, severity of dyscirculatory encephalopathy and the fraction of patients with AH complications during 12 month T-AHT for the suppression of sympathetic activity in cholerics and sanguinics by beta-adrenoblockers and PAA C- ACE inhibitors in phlegmatics and melancholics and during E-AHT (ACE inhibitors in cholerics and sanguinics, BAB in phlegmatics and melancholics). The functional activity of CNS in phlegmatics and melancholics before and during AHT was lower and severity of encephalopathy and the number ofAH complications higher than in cholerics and sanguinics. . The changes wiere more pronounced in patients with HA than in those with LA. Unlike E-AHT T-AHT (anxiolytics for cholerics and sanguinics with HA, antidepressants for phlegmatics and melancholics with HA) normalized the study parameters and decreased the frequency of complications by 2-3 times.

Molecular mechanisms for vascular complications of targeted cancer therapies.

PubMed

Gopal, Srila; Miller, Kenneth B; Jaffe, Iris Z

2016-10-01

Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Intrahepatic bilioenteric anastomosis after biliary complications of liver transplantation: operative rescue of surgical failures.

PubMed

Mercado, Miguel Angel; Vilatobá, Mario; Chan, Carlos; Domínguez, Ismael; Leal, Rafael Paulino; Olivera, Marco Antonio

2009-03-01

Biliary complications after orthotopic liver transplantation (OLT) are multifactorial in origin. In most series, the frequency of such complications ranges from 5-20%. Most can be treated by endoscopy and/or interventional radiology. For cases in which this option is not successful, surgical approach is indicated. We report the results of reoperation using an intrahepatic bilioenteric anastomosis. The medical charts of patients with biliary complications after OLT during a 10-year period (1997-2007), who failed to respond to nonsurgical treatment and were surgically treated, were reviewed. Roux-en-Y hepatojejunostomy was performed. Segments IV and V were partially removed after cutting the hilar plate, thus obtaining healthy ducts without ischemic or inflammatory reaction and allowing a wide hepatojejunostomy. Five cases (8.4%) with biliary complications after duct-to-duct anastomosis not amenable to further endoscopic management or interventional radiology were identified. Hepaticojejunostomy was achieved in all cases (wide, tension-free, nonischemic, fine hydrolyzable sutures), and segments IV and V were partially removed. No cholangitis, jaundice, and liver function test abnormalities were present in the postoperative. Mean follow-up was 24 months. Only one patient died of causes not related to bile duct reconstruction during follow-up. Intrahepatic hepatojejunostomy with partial resection of segments IV and V offers an excellent therapeutic alternative for biliary complications that require a surgical approach after OLT.

24 CFR 103.202 - Notification of respondent; joinder of additional or substitute respondents.

Code of Federal Regulations, 2013 CFR

2013-04-01

....42, the Assistant Secretary will serve a notice on each respondent by certified mail or by personal service. A person who is not named as a respondent in a complaint, but who is identified in the course of... Regulations Relating to Housing and Urban Development OFFICE OF ASSISTANT SECRETARY FOR EQUAL OPPORTUNITY...

24 CFR 103.202 - Notification of respondent; joinder of additional or substitute respondents.

Code of Federal Regulations, 2012 CFR

2012-04-01

....42, the Assistant Secretary will serve a notice on each respondent by certified mail or by personal service. A person who is not named as a respondent in a complaint, but who is identified in the course of... Regulations Relating to Housing and Urban Development OFFICE OF ASSISTANT SECRETARY FOR EQUAL OPPORTUNITY...

24 CFR 103.202 - Notification of respondent; joinder of additional or substitute respondents.

Code of Federal Regulations, 2010 CFR

2010-04-01

....42, the Assistant Secretary will serve a notice on each respondent by certified mail or by personal service. A person who is not named as a respondent in a complaint, but who is identified in the course of... Regulations Relating to Housing and Urban Development OFFICE OF ASSISTANT SECRETARY FOR EQUAL OPPORTUNITY...

24 CFR 103.202 - Notification of respondent; joinder of additional or substitute respondents.

Code of Federal Regulations, 2014 CFR

2014-04-01

....42, the Assistant Secretary will serve a notice on each respondent by certified mail or by personal service. A person who is not named as a respondent in a complaint, but who is identified in the course of... Regulations Relating to Housing and Urban Development OFFICE OF ASSISTANT SECRETARY FOR EQUAL OPPORTUNITY...

24 CFR 103.202 - Notification of respondent; joinder of additional or substitute respondents.

Code of Federal Regulations, 2011 CFR

2011-04-01

....42, the Assistant Secretary will serve a notice on each respondent by certified mail or by personal service. A person who is not named as a respondent in a complaint, but who is identified in the course of... Regulations Relating to Housing and Urban Development OFFICE OF ASSISTANT SECRETARY FOR EQUAL OPPORTUNITY...

The dopamine β-hydroxylase inhibitor, nepicastat, suppresses chocolate self-administration and reinstatement of chocolate seeking in rats.

PubMed

Zaru, Alessandro; Maccioni, Paola; Colombo, Giancarlo; Gessa, Gian Luigi

2013-10-01

Craving for chocolate is a common phenomenon, which may evolve to an addictive-like behaviour and contribute to obesity. Nepicastat is a selective dopamine β-hydroxylase (DBH) inhibitor that suppresses cocaine-primed reinstatement of cocaine seeking in rats. We verified whether nepicastat was able to modify the reinforcing and motivational properties of a chocolate solution and to prevent the reinstatement of chocolate seeking in rats. Nepicastat (25, 50 and 100 mg/kg, intraperitoneal) produced a dose-related inhibition of operant self-administration of the chocolate solution in rats under fixed-ratio 10 (FR10) and progressive-ratio schedules of reinforcement, measures of the reinforcing and motivational properties of the chocolate solution, respectively. The effect of nepicastat on the reinstatement of chocolate seeking was studied in rats in which lever-responding had been extinguished by removing the chocolate solution for approximately 8 d. Nepicastat dose-dependently suppressed the reinstatement of lever-responding triggered by a 'priming' of the chocolate solution together with cues previously associated with the availability of the reward. In a separate group of food-restricted rats trained to lever-respond for regular food pellets, nepicastat reduced FR10 lever-responding with the same potency as for the chocolate solution. Spontaneous locomotor activity was not modified by nepicastat doses that reduced self-administration of the chocolate solution and regular food pellets and suppressed the reinstatement of chocolate seeking. The results indicate that nepicastat reduces motivation to food consumption sustained by appetite or palatability. Moreover, the results suggest that DBH inhibitors may be a new class of pharmacological agents potentially useful in the prevention of relapse to food seeking in human dieters.

Newer treatments of psoriasis regarding IL-23 inhibitors, phosphodiesterase 4 inhibitors, and Janus kinase inhibitors.

PubMed

Wcisło-Dziadecka, Dominika; Zbiciak-Nylec, Martyna; Brzezińska-Wcisło, Ligia; Bebenek, Katarzyna; Kaźmierczak, Agata

2017-11-01

The rapid progress of genetic engineering furthermore opens up new prospects in the therapy of this difficult-to-treat disease. IL-23 inhibitors, phosphodiesterase 4 (PDE4) inhibitors, and Janus kinase (JAK) inhibitors are currently encouraging further research. Two drugs which are IL-23 inhibitors are now in phase III of clinical trials. The aim of the action of both drugs is selective IL-23 inhibition by targeting the p19 subunit. Guselkumab is a fully human monoclonal antibody. Tildrakizumab is a humanized monoclonal antibody, which also belongs to IgG class and is targeted to subunit p19 of interleukin 23 (IL-23). Phosphodiesterase inhibitors exert an anti-inflammatory action and their most common group is the PDE4 family. PDE4 inhibits cAMP, which reduces the inflammatory response of the pathway of Th helper lymphocytes, Th17, and type 1 interferon which modulates the production of anti-inflammatory cytokines such as IL-10 interleukins. The Janus kinase (JAK) signaling pathway plays an important role in the immunopathogenesis of psoriasis. Tofacitinib suppresses the expression of IL-23, IL-17A, IL-17F, and IL-22 receptors during the stimulation of lymphocytes. Ruxolitinib is a selective inhibitor of JAK1 and JAK2 kinases and the JAK-STAT signaling pathway. This article is a review of the aforementioned drugs as described in the latest available literature. © 2017 Wiley Periodicals, Inc.

Repeated daclizumab administration to delay the introduction of calcineurin inhibitors in heart transplant patients with postoperative renal dysfunction.

PubMed

Sánchez Lázaro, Ignacio J; Almenar Bonet, Luis; Martínez Dolz, Luis; Buendía Fuentes, Francisco; Navarro Manchón, Josep; Agüero Ramón-Llin, Jaime; Vicente Sánchez, José Luis; Salvador Sanz, Antonio

2011-03-01

Daclizumab is an interleukin-2 receptor antagonist which is used for induction therapy in heart transplant patients. It has few side effects and is associated with a low infection rate. Postoperative renal failure after heart transplantation is common and potentially fatal. The administration of calcineurin inhibitors in the postoperative period can aggravate the situation. We report the cases of six patients who underwent heart transplantation and developed acute renal failure in the immediate postoperative period. All were administered daclizumab weekly to avoid the introduction of calcineurin inhibitors and to facilitate recovery of renal function. Calcineurin inhibitors were introduced only once renal function had improved. Renal function recovered in all cases and there was a low complication rate. The administration of repeated doses of daclizumab to patients who experience acute postoperative renal failure after heart transplantation may provide an alternative therapeutic approach that enables calcineurin inhibitors to be avoided and, consequently, renal function to recover. Copyright © 2010 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.

Proton pump inhibitors and symptomatic hypomagnesemic hypoparathyroidism.

PubMed

Fatuzzo, P; Portale, G; Scollo, V; Zanoli, L; Granata, Antonio

2017-04-01

Hypomagnesemia is a common but often overlooked problem in hospitalized patients. Unrecognized hypomagnesemia can cause serious complications. The association of hypokalemia and hypocalcemia is strongly evocative of a magnesium deficiency. Research into the causes of hypomagnesemia is imperative, as it will definitely change the approach, treatment and prognosis. We report the case of a 65-year-old man with chronic hypocalcemia and hypokalemia associated with cerebellar syndrome, a solitary seizure and cerebellar hyperintensities on magnetic resonance imaging. After the detection and treatment of hypomagnesemia with oral supplements of magnesium and the replacement of pantoprazole with ranitidine, we observed immediate relief of the symptoms. In conclusion, in clinical practice, magnesium depletion should be investigated in elderly patients with hypocalcemia treated with proton pump inhibitors for many years, in particular in the presence of neurological disorders.

Complications of wrist arthroscopy.

PubMed

Ahsan, Zahab S; Yao, Jeffrey

2012-06-01

The purpose of this systematic review was to address the incidence of complications associated with wrist arthroscopy. Given the paucity of information published on this topic, an all-inclusive review of published wrist arthroscopy complications was sought. Two independent reviewers performed a literature search using PubMed, Google Scholar, EBSCO, and Academic Megasearch using the terms "wrist arthroscopy complications," "complications of wrist arthroscopy," "wrist arthroscopy injury," and "wrist arthroscopy." Inclusion criteria were (1) Levels I to V evidence, (2) "complication" defined as an adverse outcome directly related to the operative procedure, and (3) explicit description of operative complications in the study. Eleven multiple-patient studies addressing complications of wrist arthroscopy from 1994 to 2010 were identified, with 42 complications reported from 895 wrist arthroscopy procedures, a 4.7% complication rate. Four case reports were also found, identifying injury to the dorsal sensory branch of the ulnar nerve, injury to the posterior interosseous nerve, and extensor tendon sheath fistula formation. This systematic review suggests that the previously documented rate of wrist arthroscopy complications may be underestimating the true incidence. The report of various complications provides insight to surgeons for improving future surgical techniques. Level IV, systematic review of Levels I-V studies. Copyright © 2012 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Patients undergoing PCI from the femoral route by default radial operators are at high risk of vascular access-site complications.

PubMed

Rafie, Ihsan M; Uddin, Muez M; Ossei-Gerning, Nicholas; Anderson, Richard A; Kinnaird, Timothy D

2014-02-01

Radial artery (RA) access for PCI has a lower incidence of vascular access-site (VAS) complications than the femoral artery (FA) approach. However, even for default radial operators certain patients are intervened upon from the FA. We examined the demographics and incidence of VAS complications when default radial operators resort to the FA for PCI. The demographics and VAS complications were compared by access site retrospectively for all PCI cases performed by default radial operators (n=1,392). A modified ACUITY trial definition of major VAS complication was used. FA puncture occurred in 25.2% (351/1,392) of cases. Patients were more likely to be female, older and weigh less than patients undergoing PCI from the RA. The FA procedure was likely to be more complex with larger sheaths, more left main stem, graft and multivessel intervention, and there was a greater proportion of emergency cases. Despite increased case complexity, glycoprotein inhibitors were used less frequently in femoral cases (26.5% vs. 36.8%, p<0.001). A VAS complication occurred in 12.5% (44/351) of cases. The risk factors for access-site bleeding are disproportionately high in the population requiring FA puncture by default radial operators, and as a result such patients have a high rate of vascular access-site complications.

Severe facial dermatitis as a late complication of aesthetic rhinoplasty; a case report

PubMed Central

Rajabian, Mohammad Hossain; Sodaify, Manoochehr; Aghaei, Shahin

2004-01-01

Background Contact dermatitis, as a cutaneous complication after rhinoplasty, is of early onset, limited and transient. The cause of this dermatitis is irritant or allergic. Late onset skin complications are rare and non-inflammatory. Case presentation We are reporting an unexpected, severe allergic contact dermatitis of the face, in a young female, appearing one month following aesthetic rhinoplasty. She failed to respond to ordinary treatments for dermatitis. We did standard battery – including nitrofurazone, tincture of benzoin and hydrocortisone – patch test for the patient that showed sensitivity to benzoin and corticosteroid. Conclusions In summary we report a case of a severe allergic contact dermatitis of the face, in a 21-year-old girl who underwent corrective aesthetic rhinoplasty, appearing one month following surgical operation. We were unable to find a similar report in the medical literature. PMID:15056395

NOX2 As a Target for Drug Development: Indications, Possible Complications, and Progress

PubMed Central

Diebold, Becky A.; Smith, Susan M.E.; Li, Yang

2015-01-01

Abstract Significance: NOX2 is important for host defense, and yet is implicated in a large number of diseases in which inflammation plays a role in pathogenesis. These include acute and chronic lung inflammatory diseases, stroke, traumatic brain injury, and neurodegenerative diseases, including Alzheimer's and Parkinson's Diseases. Recent Advances: Recent drug development programs have targeted several NOX isoforms that are implicated in a variety of diseases. The focus has been primarily on NOX4 and NOX1 rather than on NOX2, due, in part, to concerns about possible immunosuppressive side effects. Nevertheless, NOX2 clearly contributes to the pathogenesis of many inflammatory diseases, and its inhibition is predicted to provide a novel therapeutic approach. Critical Issues: Possible side effects that might arise from targeting NOX2 are discussed, including the possibility that such inhibition will contribute to increased infections and/or autoimmune disorders. The state of the field with regard to existing NOX2 inhibitors and targeted development of novel inhibitors is also summarized. Future Directions: NOX2 inhibitors show particular promise for the treatment of inflammatory diseases, both acute and chronic. Theoretical side effects include pro-inflammatory and autoimmune complications and should be considered in any therapeutic program, but in our opinion, available data do not indicate that they are sufficiently likely to eliminate NOX2 as a drug target, particularly when weighed against the seriousness of many NOX2-related indications. Model studies demonstrating efficacy with minimal side effects are needed to encourage future development of NOX2 inhibitors as therapeutic agents. Antioxid. Redox Signal. 23, 375–405. PMID:24512192

Complications of immobilization and bed rest. Part 1: Musculoskeletal and cardiovascular complications.

PubMed Central

Dittmer, D. K.; Teasell, R.

1993-01-01

Prolonged bed rest and immobilization inevitably lead to complications. Such complications are much easier to prevent than to treat. Musculoskeletal complications include loss of muscle strength and endurance, contractures and soft tissue changes, disuse osteoporosis, and degenerative joint disease. Cardiovascular complications include an increased heart rate, decreased cardiac reserve, orthostatic hypotension, and venous thromboembolism. Images Figures 1-2 Figures 3-4 PMID:8324411

Discovery of a BTK/MNK dual inhibitor for lymphoma and leukemia.

PubMed

Wu, H; Hu, C; Wang, A; Weisberg, E L; Chen, Y; Yun, C-H; Wang, W; Liu, Y; Liu, X; Tian, B; Wang, J; Zhao, Z; Liang, Y; Li, B; Wang, L; Wang, B; Chen, C; Buhrlage, S J; Qi, Z; Zou, F; Nonami, A; Li, Y; Fernandes, S M; Adamia, S; Stone, R M; Galinsky, I A; Wang, X; Yang, G; Griffin, J D; Brown, J R; Eck, M J; Liu, J; Gray, N S; Liu, Q

2016-01-01

Bruton's tyrosine kinase (BTK) kinase is a member of the TEC kinase family and is a key regulator of the B-cell receptor (BCR)-mediated signaling pathway. It is important for B-cell maturation, proliferation, survival and metastasis. Pharmacological inhibition of BTK is clinically effective against a variety of B-cell malignances, such as mantle cell lymphoma, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and activated B-cell-diffuse large B-cell lymphoma. MNK kinase is one of the key downstream regulators in the RAF-MEK-ERK signaling pathway and controls protein synthesis via regulating the activity of eIF4E. Inhibition of MNK activity has been observed to moderately inhibit the proliferation of AML cells. Through a structure-based drug-design approach, we have discovered a selective and potent BTK/MNK dual kinase inhibitor (QL-X-138), which exhibits covalent binding to BTK and noncovalent binding to MNK. Compared with the BTK kinase inhibitor (PCI-32765) and the MNK kinase inhibitor (cercosporamide), QL-X-138 enhanced the antiproliferative efficacies in vitro against a variety of B-cell cancer cell lines, as well as AML and CLL primary patient cells, which respond moderately to BTK inhibitor in vitro. The agent can effectively arrest the growth of lymphoma and leukemia cells at the G0-G1 stage and can induce strong apoptotic cell death. These primary results demonstrate that simultaneous inhibition of BTK and MNK kinase activity might be a new therapeutic strategy for B-cell malignances.

Development and testing of responder : phase III.

DOT National Transportation Integrated Search

2017-06-28

This report documents the research project Development and Testing of Responder Phase III. Under previous research, a Responder system has been developed to provide relevant and timely information to first responders, allow responders to provid...

On complicity theory.

PubMed

Kline, A David

2006-04-01

The received account of whistleblowing, developed over the last quarter century, is identified with the work of Norman Bowie and Richard DeGeorge. Michael Davis has detailed three anomalies for the received view: the paradoxes of burden, missing harm and failure. In addition, he has proposed an alternative account of whistleblowing, viz., the Complicity Theory. This paper examines the Complicity Theory. The supposed anomalies rest on misunderstandings of the received view or misreadings of model cases of whistleblowing, for example, the Challenger disaster and the Ford Pinto. Nevertheless, the Complicity Theory is important for as in science the contrast with alternative competing accounts often helps us better understand the received view. Several aspects of the received view are reviewed and strengthened through comparison with Complicity Theory, including why whistleblowing needs moral justification. Complicity Theory is also critiqued. The fundamental failure of Complicity Theory is its failure to explain why government and the public encourage and protect whistleblowers despite the possibility of considerable harm to the relevant company in reputation, lost jobs, and lost shareholder value.

Coprescribing proton-pump inhibitors with nonsteroidal anti-inflammatory drugs: risks versus benefits

PubMed Central

Gwee, Kok Ann; Goh, Vernadine; Lima, Graca

2018-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often coadministered with proton-pump inhibitors (PPIs) to reduce NSAID-induced gastrointestinal (GI) adverse events. This coadministration is generally regarded as safe, and is included in many of the guidelines on NSAID prescription. However, recent evidence indicates that the GI risks associated with NSAIDs can be potentiated when they are combined with PPIs. This review discusses the GI effects and complications of NSAIDs and how PPIs may potentiate these effects, options for prevention of GI side effects, and appropriate use of PPIs in combination with NSAIDs. PMID:29491719

Coprescribing proton-pump inhibitors with nonsteroidal anti-inflammatory drugs: risks versus benefits.

PubMed

Gwee, Kok Ann; Goh, Vernadine; Lima, Graca; Setia, Sajita

2018-01-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often coadministered with proton-pump inhibitors (PPIs) to reduce NSAID-induced gastrointestinal (GI) adverse events. This coadministration is generally regarded as safe, and is included in many of the guidelines on NSAID prescription. However, recent evidence indicates that the GI risks associated with NSAIDs can be potentiated when they are combined with PPIs. This review discusses the GI effects and complications of NSAIDs and how PPIs may potentiate these effects, options for prevention of GI side effects, and appropriate use of PPIs in combination with NSAIDs.

Difference in blood pressure response to ACE-Inhibitor monotherapy between black and white adults with arterial hypertension: a meta-analysis of 13 clinical trials.

PubMed

Peck, Robert N; Smart, Luke R; Beier, Rita; Liwa, Anthony C; Grosskurth, Heiner; Fitzgerald, Daniel W; Schmidt, Bernhard M W

2013-09-26

Among African-Americans adults, arterial hypertension is both more prevalent and associated with more complications than among white adults. Hypertension is also epidemic among black adults in sub-Saharan Africa. The treatment of hypertension among black adults may be complicated by lesser response to certain classes of anti-hypertensive agents. We systematically searched literature for clinical trials of ACE-inhibitors among hypertensive adults comparing blood pressure response between whites and blacks. Meta-analysis was performed to determine the difference in systolic and diastolic blood pressure response. Further analysis including meta-regressions, funnel plots, and one-study-removed analyses were performed to investigate possible sources of heterogeneity or bias. In a meta-analysis of 13 trials providing 17 different patient groups for evaluation, black race was associated with a lesser reduction in systolic (mean difference: 4.6 mmHg (95% CI 3.5-5.7)) and diastolic (mean difference: 2.8 mmHg (95% CI 2.2-3.5)) blood pressure response to ACE-inhibitors, with little heterogeneity. Meta-regression revealed only ACE-inhibitor dosage as a significant source of heterogeneity. There was little evidence of publication bias. Black race is consistently associated with a clinically significant lesser reduction in both systolic and diastolic blood pressure to ACE-inhibitor therapy in clinical trials in the USA and Europe. In black adults requiring monotherapy for uncomplicated hypertension, drugs other than ACE-inhibitors may be preferred, though the proven benefits of ACE-inhibitors in some sub-groups and the large overlap of response between blacks and whites must be remembered. These data are particularly important for interpretation of clinical drug trials for hypertensive black adults in sub-Saharan Africa and for the development of treatment recommendations in this population.

Label-free LC-MS analysis of HER2+ breast cancer cell line response to HER2 inhibitor treatment.

PubMed

Di Luca, Alessio; Henry, Michael; Meleady, Paula; O'Connor, Robert

2015-08-04

Human epidermal growth-factor receptor (HER)-2 is overexpressed in 25 % of breast-cancers and is associated with an aggressive form of the disease with significantly shortened disease free and overall survival. In recent years, the use of HER2-targeted therapies, monoclonal-antibodies and small molecule tyrosine-kinase inhibitors has significantly improved the clinical outcome for HER2-positive breast-cancer patients. However, only a fraction of HER2-amplified patients will respond to therapy and the use of these treatments is often limited by tumour drug insensitivity or resistance and drug toxicities. Currently there is no way to identify likely responders or rational combinations with the potential to improve HER2-focussed treatment outcome. In order to further understand the molecular mechanisms of treatment-response with HER2-inhibitors, we used a highly-optimised and reproducible quantitative label-free LC-MS strategy to characterize the proteomes of HER2-overexpressing breast-cancer cell-lines (SKBR3, BT474 and HCC1954) in response to drug-treatment with HER2-inhibitors (lapatinib, neratinib or afatinib). Following 12 ours treatment with different HER2-inhibitors in the BT474 cell-line; compared to the untreated cells, 16 proteins changed significantly in abundance following lapatinib treatment (1 μM), 21 proteins changed significantly following neratinib treatment (150 nM) and 38 proteins changed significantly following afatinib treatment (150 nM). Whereas following 24 hours treatment with neratinib (200 nM) 46 proteins changed significantly in abundance in the HCC1954 cell-line and 23 proteins in the SKBR3 cell-line compared to the untreated cells. Analysing the data we found that, proteins like trifunctional-enzyme subunit-alpha, mitochondrial; heterogeneous nuclear ribonucleoprotein-R and lamina-associated polypeptide 2, isoform alpha were up-regulated whereas heat shock cognate 71 kDa protein was down-regulated in 3 or more comparisons. This proteomic

What Respondents Really Expect from Researchers

ERIC Educational Resources Information Center

Kolar, Tomaz; Kolar, Iztok

2008-01-01

This article addresses the issue of falling response rates in telephone surveys. To better understand and maintain respondent goodwill, concepts of psychological contract and respondent expectations are introduced and explored. Results of the qualitative study show that respondent expectations are not only socially contingent but also…

Dual trigger of triptorelin and HCG optimizes clinical outcome for high ovarian responder in GnRH-antagonist protocols.

PubMed

Li, Saijiao; Zhou, Danni; Yin, Tailang; Xu, Wangming; Xie, Qingzhen; Cheng, Dan; Yang, Jing

2018-01-12

In this paper, a retrospective cohort study was conducted to the high ovarian responders in GnRH-antagonist protocols of IVF/ICSI cycles. The purpose of the study is to investigate whether dual triggering of final oocyte maturation with a combination of gonadotropin-releasing hormone (GnRH) agonist and human chorionic gonadotropin (HCG) can improve the clinical outcome compared with traditional dose (10000IU) HCG trigger and low-dose (8000IU) HCG trigger for high ovarian responders in GnRH-antagonist in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) cycles. Our study included 226 couples with high ovarian responders in GnRH-antagonist protocols of IVF/ICSI cycles. Standard dosage of HCG trigger (10000 IU of recombinant HCG) versus dual trigger (0.2 mg of triptorelin and 2000 IU of recombinant HCG) and low-dose HCG trigger (8000IU of recombinant HCG) were used for final oocyte maturation. Our main outcome measures were high quality embryo rate, the number of usable embryos, the risk of OHSS, duration of hospitalization and incidence rate of complications. Our evidence demonstrated that dual trigger is capable of preventing severe OHSS while still maintaining excellent high quality embryo rate in in high ovarian responders of GnRH-antagonist protocols.

Redding Responder Field Test - UTC

DOT National Transportation Integrated Search

2008-10-30

This UTC project facilitated field testing and evaluation of the "Responder" system between Phases 1 and 2 of the Redding Responder Project, sponsored by the California Department of Transportation. A pilot system, with hardware purchased by Caltrans...

Streptococcal toxic shock syndrome complicating a peritonsillar abscess.

PubMed

Aalling, Mathilde; Klug, Tejs Ehlers

2015-02-01

A 68-year-old man was admitted to hospital in an acute confusional state with a 2-week history of fever, influenza-like illness and sore throat. He quickly developed coagulation disturbances, hypotension and renal function impairment. Despite broad-spectrum antibiotic therapy, he deteriorated. Group A streptococcus (GAS) was recovered from blood cultures, which gave the diagnosis streptococcal toxic shock syndrome (STSS). A computed tomography scan showed a right-sided peritonsillar abscess (PTA). Acute tonsillectomy was carried out and the patient recovered. STSS complicating PTA has not previously been described in the literature, but GAS is a common pathogen in PTA. Clinicians should be aware that STSS can develop secondary to tonsillar infections and that abscess development should be suspected in STSS patients who do not respond to antibiotic treatment.

[Sacrospinous colpopexy complications].

PubMed

Estrade, J-P; Agostini, A; Roger, V; Dallay, D; Blanc, B; Cravello, L

2004-10-01

To evaluate complications of sacrospinous ligament fixation. Monocentric retrospective study. Department of Obstetrics & Gynecology, La Conception University Hospital, Marcella. Between January 1991 and September 2002, 277 women (mean age 64.9 years, range 37 to 92 years) underwent a sacrospinous ligament fixation; 91% had a menopausal status, and 15.5% used hormone replacement therapy. 33.2% of the patients had prior hysterectomy, 28.9% had a history of surgery for prolapse, and 18.8% had associated symptoms of stress urinary incontinence. In all cases, sacrospinous ligament fixation was performed under visual control using conventional stitch. Sacrospinous ligament fixation was combined with the following procedures: anterior vaginal repair (N =137), additional incontinence surgery (N =31), vaginal hysterectomy (N =137), levator myorraphy (N =203). Intraoperative complications, postoperative complications, long-term painful symptoms. Intraoperative complications were represented by 1 case of vascular wound and four rectal injuries. Main postoperative complications were vaginal haematomas (N =6) and abscesses (N =2). Long-term symptoms were perineal pain, sciatic neuralgia, and dyspareunia. There was no surgical mortality, and we noted low rates of major complications. Sacrospinous ligament fixation assumes high priority in our therapeutic regimen.

Propranolol in Treatment of Huge and Complicated Infantile Hemangiomas in Egyptian Children

PubMed Central

Hassan, Basheir A.; Shreef, Khalid S.

2014-01-01

Background. Infantile hemangiomas (IHs) are the most common benign tumours of infancy. Propranolol has recently been reported to be a highly effective treatment for IHs. This study aimed to evaluate the efficacy and side effects of propranolol for treatment of complicated cases of IHs. Patients and Methods. This prospective clinical study included 30 children with huge or complicated IHs; their ages ranged from 2 months to 1 year. They were treated by oral propranolol. Treatment outcomes were clinically evaluated. Results. Superficial cutaneous hemangiomas began to respond to propranolol therapy within one to two weeks after the onset of treatment. The mean treatment period that was needed for the occurrence of complete resolution was 9.4 months. Treatment with propranolol was well tolerated and had few side effects. No rebound growth of the tumors was noted when propranolol dosing stopped except in one case. Conclusion. Propranolol is a promising treatment for IHs without obvious side effects. However, further studies with longer follow-up periods are needed. PMID:24899888

Propranolol in treatment of huge and complicated infantile hemangiomas in egyptian children.

PubMed

Hassan, Basheir A; Shreef, Khalid S

2014-01-01

Background. Infantile hemangiomas (IHs) are the most common benign tumours of infancy. Propranolol has recently been reported to be a highly effective treatment for IHs. This study aimed to evaluate the efficacy and side effects of propranolol for treatment of complicated cases of IHs. Patients and Methods. This prospective clinical study included 30 children with huge or complicated IHs; their ages ranged from 2 months to 1 year. They were treated by oral propranolol. Treatment outcomes were clinically evaluated. Results. Superficial cutaneous hemangiomas began to respond to propranolol therapy within one to two weeks after the onset of treatment. The mean treatment period that was needed for the occurrence of complete resolution was 9.4 months. Treatment with propranolol was well tolerated and had few side effects. No rebound growth of the tumors was noted when propranolol dosing stopped except in one case. Conclusion. Propranolol is a promising treatment for IHs without obvious side effects. However, further studies with longer follow-up periods are needed.

Death by request in Switzerland: posttraumatic stress disorder and complicated grief after witnessing assisted suicide.

PubMed

Wagner, B; Müller, J; Maercker, A

2012-10-01

Despite continuing political, legal and moral debate on the subject, assisted suicide is permitted in only a few countries worldwide. However, few studies have examined the impact that witnessing assisted suicide has on the mental health of family members or close friends. A cross-sectional survey of 85 family members or close friends who were present at an assisted suicide was conducted in December 2007. Full or partial Post-Traumatic Distress Disorder (PTSD; Impact of Event Scale-Revised), depression and anxiety symptoms (Brief Symptom Inventory) and complicated grief (Inventory of Complicated Grief) were assessed at 14 to 24 months post-loss. Of the 85 participants, 13% met the criteria for full PTSD (cut-off≥35), 6.5% met the criteria for subthreshold PTSD (cut-off≥25), and 4.9% met the criteria for complicated grief. The prevalence of depression was 16%; the prevalence of anxiety was 6%. A higher prevalence of PTSD and depression was found in the present sample than has been reported for the Swiss population in general. However, the prevalence of complicated grief in the sample was comparable to that reported for the general Swiss population. Therefore, although there seemed to be no complications in the grief process, about 20% of respondents experienced full or subthreshold PTSD related to the loss of a close person through assisted suicide. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Review article: relationship between the metabolism and efficacy of proton pump inhibitors--focus on rabeprazole.

PubMed

Horn, J

2004-11-01

Proton pump inhibitors are now considered the mainstay of treatment for acid-related disease. Although all proton pump inhibitors are highly effective, the antisecretory effects of different drugs in this class are not completely consistent across patients. One reason for this is the acid-suppressing effect of Helicobacter pylori infection, which may augment the actions of proton pump inhibitors. A second important reason for interpatient variability of the effects of proton pump inhibitors on acid secretion involves genetically determined differences in the metabolism of these drugs. This article focuses on the impact of genetic polymorphism of cytochrome P450 (CYP)2C19 on the pharmacokinetics and pharmacodynamics of proton pump inhibitors, particularly rabeprazole. Results reviewed indicate that the metabolism and pharmacokinetics of rabeprazole differ significantly from those of other proton pump inhibitors. Most importantly, the clearance of rabeprazole is largely nonenzymatic and less dependent on CYP2C19 than other drugs in its class. This results in greater consistency of pharmacokinetics for rabeprazole across a wide range of patients with acid-related disease, particularly those with different CYP2C19 genotypes. The pharmacodynamic profile for rabeprazole is also characterized by more rapid suppression of gastric acid secretion than with other proton pump inhibitors, which is also independent of CYP2C19 genotype. The favourable pharmacokinetic/pharmacodynamic profile for rabeprazole has been shown to result in high eradication rates for H. pylori in both normal and poor metabolizers. Pharmacodynamic results have also suggested that rabeprazole may be better suited than omeprazole as on-demand therapy for symptomatic gastro-oesophageal reflux disease. Finally, the use of rabeprazole is not complicated by clinically significant drug-drug interactions of the type that have been reported for omeprazole.

Exceptional Responders Initial Feasibility Results

Cancer.gov

A pilot study evaluating identification of cancer patients who respond to treatment that is ineffective in at least 90 percent of patients found that it was indeed able to confirm a majority of proposed patients as exceptional responders based on clinical

Hypomagnesaemia associated with long-term use of proton pump inhibitors

PubMed Central

Toh, James Wei Tatt; Ong, Evonne; Wilson, Robert

2015-01-01

Hypomagnesaemia and associated hypocalcaemia and hypoparathyroidism have been increasingly recognised as rare long-term side-effects of proton pump inhibitors (PPIs). The PPIs may inhibit active magnesium (Mg) absorption by interfering with transcellular transient receptor potential melastatin-6 and -7 (TRPM 6 and 7) channels. More recent cell culture studies have suggested concomitant inhibition of passive Mg absorption by omeprazole. After being treated with a range of PPIs, the four patients in our case series developed hypomagnesaemia, which responded to withdrawal of therapy and initiation of Mg replacement. Their clinical course and management demonstrate key aspects of hypomagnesaemia associated with long-term use of PPIs. PMID:25138239

Discovery of natural mouse serum derived HIV-1 entry inhibitor(s).

PubMed

Wei, M; Chen, Y; Xi, J; Ru, S; Ji, M; Zhang, D; Fang, Q; Tang, B

Among rationally designed human immunodeficiency virus 1 (HIV-1) inhibitors, diverse natural factors have showed as potent anti-HIV activity in human blood. We have discovered that the boiled supernatant of healthy mouse serum could suppress HIV-1 entry, and exhibited reduced inhibitory activity after trypsin digestion. Further analysis demonstrated that only the fraction containing 10-25 K proteins could inhibit HIV-1 mediated cell-cell fusion. These results suggest that the 10-25 K protein(s) is novel natural HIV-1 entry inhibitor(s). Our findings provide important information about novel natural HIV entry inhibitors in mouse serum.

Sociodemographic factors influence use of proton pump inhibitors among users of nonsteroidal anti-inflammatory drugs.

PubMed

van Boxel, Ofke S; Hagenaars, Matthijs P; Smout, André J P M; Siersema, Peter D

2009-08-01

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs. Although adequate gastroprotection is indicated in individuals at high risk for upper gastrointestinal complications, underutilization of preventive strategies has been demonstrated. We investigated the utilization of proton pump inhibitors (PPIs) in high risk, short term users of NSAIDs and assessed the association between sociodemographic factors and the rates at which PPIs are prescribed. A retrospective study was conducted using data from 2.8 million individuals. Short term use was defined as an isolated period of NSAID use between 7 to 30 days. Logistic regression was performed to determine sociodemographic factors associated with PPI inhibitor use. A total of 155,825 short term users of NSAID were identified. Of these, 52,842 subjects (33.9%) had 1 or more risk factors; 56.1% of these subjects did not receive PPIs. Utilization was associated with sociodemographic factors of patients (such as older age [odds ratio (OR), 1.80; 95% confidence interval (CI), 1.64-1.99], female gender [OR, 1.14; 95% CI, 1.10-1.18], risk factors for upper gastrointestinal complications [OR, 3.72; 95% CI, 3.45-4.00]) and physicians (such as female gender [OR, 1.09; 95% CI, 1.03-1.14], practice in a deprived area [OR, 0.57; 95% CI, 0.53-0.61], or an urban area [OR, 0.86; 95% CI, 0.82-0.90]). Adequate gastroprotection is not provided to more than 50% of short term users of NSAIDs who are at an increased risk for upper gastrointestinal complications. Utilization is associated with sociodemographic factors of patients and physicians.

ROMK inhibitor actions in the nephron probed with diuretics

PubMed Central

Kharade, Sujay V.; Flores, Daniel; Lindsley, Craig W.; Satlin, Lisa M.

2015-01-01

Diuretics acting on specific nephron segments to inhibit Na+ reabsorption have been used clinically for decades; however, drug interactions, tolerance, and derangements in serum K+ complicate their use to achieve target blood pressure. ROMK is an attractive diuretic target, in part, because its inhibition is postulated to indirectly inhibit the bumetanide-sensitive Na+-K+-2Cl− cotransporter (NKCC2) and the amiloride- and benzamil-sensitive epithelial Na+ channel (ENaC). The development of small-molecule ROMK inhibitors has created opportunities for exploring the physiological responses to ROMK inhibition. The present study evaluated how inhibition of ROMK alone or in combination with NKCC2, ENaC, or the hydrochlorothiazide (HCTZ) target NCC alter fluid and electrolyte transport in the nephron. The ROMK inhibitor VU591 failed to induce diuresis when administered orally to rats. However, another ROMK inhibitor, termed compound A, induced a robust natriuretic diuresis without kaliuresis. Compound A produced additive effects on urine output and Na+ excretion when combined with HCTZ, amiloride, or benzamil, but not when coadministered with bumetanide, suggesting that the major diuretic target site is the thick ascending limb (TAL). Interestingly, compound A inhibited the kaliuretic response induced by bumetanide and HCTZ, an effect we attribute to inhibition of ROMK-mediated K+ secretion in the TAL and CD. Compound A had no effect on heterologously expressed flow-sensitive large-conductance Ca2+-activated K+ channels (Slo1/β1). In conclusion, compound A represents an important new pharmacological tool for investigating the renal consequences of ROMK inhibition and therapeutic potential of ROMK as a diuretic target. PMID:26661652

A multicentre case control study on complicated coeliac disease: two different patterns of natural history, two different prognoses

PubMed Central

2014-01-01

Background Coeliac disease is a common enteropathy characterized by an increased mortality mainly due to its complications. The natural history of complicated coeliac disease is characterised by two different types of course: patients with a new diagnosis of coeliac disease that do not improve despite a strict gluten-free diet (type A cases) and previously diagnosed coeliac patients that initially improved on a gluten-free diet but then relapsed despite a strict diet (type B cases). Our aim was to study the prognosis and survival of A and B cases. Methods Clinical and laboratory data from coeliac patients who later developed complications (A and B cases) and sex- and age-matched coeliac patients who normally responded to a gluten-free diet (controls) were collected among 11 Italian centres. Results 87 cases and 136 controls were enrolled. Complications tended to occur rapidly after the diagnosis of coeliac disease and cumulative survival dropped in the first months after diagnosis of complicated coeliac disease. Thirty-seven cases died (30/59 in group A, 7/28 in group B). Type B cases presented an increased survival rate compared to A cases. Conclusions Complicated coeliac disease is an extremely serious condition with a high mortality and a short survival. Survival depends on the type of natural history. PMID:25103857

A multicentre case control study on complicated coeliac disease: two different patterns of natural history, two different prognoses.

PubMed

Biagi, Federico; Marchese, Alessandra; Ferretti, Francesca; Ciccocioppo, Rachele; Schiepatti, Annalisa; Volta, Umberto; Caio, Giacomo; Ciacci, Carolina; Zingone, Fabiana; D'Odorico, Anna; Carroccio, Antonio; Ambrosiano, Giuseppe; Mansueto, Pasquale; Gasbarrini, Antonio; Piscaglia, Anna Chiara; Andrealli, Alida; Astegiano, Marco; Segato, Sergio; Neri, Matteo; Meggio, Alberto; de Pretis, Giovanni; De Vitis, Italo; Gobbi, Paolo; Corazza, Gino Roberto

2014-08-07

Coeliac disease is a common enteropathy characterized by an increased mortality mainly due to its complications. The natural history of complicated coeliac disease is characterised by two different types of course: patients with a new diagnosis of coeliac disease that do not improve despite a strict gluten-free diet (type A cases) and previously diagnosed coeliac patients that initially improved on a gluten-free diet but then relapsed despite a strict diet (type B cases). Our aim was to study the prognosis and survival of A and B cases. Clinical and laboratory data from coeliac patients who later developed complications (A and B cases) and sex- and age-matched coeliac patients who normally responded to a gluten-free diet (controls) were collected among 11 Italian centres. 87 cases and 136 controls were enrolled. Complications tended to occur rapidly after the diagnosis of coeliac disease and cumulative survival dropped in the first months after diagnosis of complicated coeliac disease. Thirty-seven cases died (30/59 in group A, 7/28 in group B). Type B cases presented an increased survival rate compared to A cases. Complicated coeliac disease is an extremely serious condition with a high mortality and a short survival. Survival depends on the type of natural history.

7 CFR 3017.1000 - Respondent.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 15 2010-01-01 2010-01-01 false Respondent. 3017.1000 Section 3017.1000 Agriculture Regulations of the Department of Agriculture (Continued) OFFICE OF THE CHIEF FINANCIAL OFFICER, DEPARTMENT OF AGRICULTURE GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 3017.1000 Respondent...

A case of adult onset Still's disease complicated with cryptogenic organizing pneumonia.

PubMed

Sato, Hiroshi; Yokoe, Isamu; Nishio, Shinya; Onishi, Tsubasa; Takao, Tadashi; Kobayashi, Yasuyuki; Haraoka, Hitomi

2011-01-01

Only a few pathologic reports exist describing adult onset Still's disease (AOSD) with pulmonary involvement. We report this very rare case of AOSD complicated with cryptogenic organizing pneumonia (COP). A 32-year-old woman was referred with high spiking fever, salmon-pink rash in her arms and legs, and polyarthralgia. The laboratory data showed marked increases in white blood cell count, an erythrocyte sedimentation rate, and C reactive protein, ferritin, and liver dysfunction. All cultures remained negative, as were autoantibodies and rheumatoid factor. The patient was strongly suspected of AOSD according to specific diagnostic criteria. However, chest X ray disclosed an infiltrative shadow accompanied by air bronchogram in the upper lobe of the right lung and therapy with antibiotics was initiated. As the patient did not respond to antibiotics and a remittent fever of over 38°C, a flexible bronchoscopy was performed. Organizing pneumonia was diagnosed by transbronchial lung biopsy (TBLB) histology and radiologically, and the lesions were thought to be due to pulmonary involvement of AOSD. Therefore, she was diagnosed with AOSD complicated with COP. Oral treatment with prednisolone (30 mg/day) resulted in rapid disappearance of the infiltrative shadow. Symptoms and markers of inflammation also improved. Clinicians should be aware that COP can be a complication of AOSD.

Treatment of selective mutism: focus on selective serotonin reuptake inhibitors.

PubMed

Kaakeh, Yaman; Stumpf, Janice L

2008-02-01

Abstract Selective mutism is a pediatric psychiatric disorder that occurs when a child consistently fails to speak in specific situations in which speaking is expected, such as at school and social gatherings, but speaks appropriately in other settings. Selective mutism often is diagnosed when a child starts school and does not talk to teachers or peers, but talks to family members at home; the condition is frequently accompanied by anxiety and shyness. Although the underlying etiology of the condition remains unclear, psychotherapy is the preferred initial treatment, with the support of parents and teachers. If the child does not respond to psychotherapy, addition of pharmacologic treatment should be considered, depending on the severity of symptoms and presence of other illnesses. Although data are limited to case reports and trials with small patient populations and short follow-up periods, some patients with selective mutism respond to therapy with selective serotonin reuptake inhibitors (SSRIs). Fluoxetine is the most studied SSRI as treatment for the condition, although further investigation is required to determine the optimal dosage and duration of therapy.

How Roots Perceive and Respond to Gravity.

ERIC Educational Resources Information Center

Moore, Randy

1984-01-01

Discusses graviperception and gravitropism by plant roots. Indicates that graviperception occurs via sedimentation of amyloplasts in columella cells of the root cap and that the minimal graviresponsiveness of lateral roots may be due to the intensity of their caps to establish a concentration gradient of inhibitor(s) sufficient to affect…

Emergency medicine tools to manage smallpox (vaccinia) vaccination complications: clinical practice guideline and policies and procedures.

PubMed

Thorne, Craig D; Hirshon, Jon Mark; Himes, Carrie D; McDiarmid, Melissa A

2003-11-01

In December 2002, the federal government began a program to immunize approximately 500000 civilian public health and health care workers with smallpox (vaccinia) vaccine as a part of our pre-event defense against bioterrorism. First responders will likely follow, and the general US population might be offered vaccination in the next 1 to 2 years. Recent reports that suggest the possible association of the vaccine to adverse cardiac events (including deaths), liability concerns for hospitals, and the availability of compensation for workers with vaccine complications have significantly reduced voluntary participation. Vaccinees might experience robust primary takes or serious adverse events, including viral or even bacterial cellulitides, encephalitis, progressive skin destruction, and other life-threatening complications. With the increasing prevalence of immune suppression from both diseases and immunosuppressive medications, complications might be seen in higher frequency than previously reported. Emergency medicine providers and staff must become familiar with clinical presentations and management of vaccine complications. In addition, policies and procedures must be developed to prevent unimmunized providers from inadvertently contacting the active vaccination sites of their patients and, if the providers themselves have active vaccination sites, to protect their patients and their own families.

Design checkpoint kinase 2 inhibitors by pharmacophore modeling and virtual screening techniques.

PubMed

Wang, Yen-Ling; Lin, Chun-Yuan; Shih, Kuei-Chung; Huang, Jui-Wen; Tang, Chuan-Yi

2013-12-01

Damage to DNA is caused by ionizing radiation, genotoxic chemicals or collapsed replication forks. When DNA is damaged or cells fail to respond, a mutation that is associated with breast or ovarian cancer may occur. Mammalian cells control and stabilize the genome using a cell cycle checkpoint to prevent damage to DNA or to repair damaged DNA. Checkpoint kinase 2 (Chk2) is one of the important kinases, which strongly affects DNA-damage and plays an important role in the response to the breakage of DNA double-strands and related lesions. Therefore, this study concerns Chk2. Its purpose is to find potential inhibitors using the pharmacophore hypotheses (PhModels) and virtual screening techniques. PhModels can identify inhibitors with high biological activities and virtual screening techniques are used to screen the database of the National Cancer Institute (NCI) to retrieve compounds that exhibit all of the pharmacophoric features of potential inhibitors with high interaction energy. Ten PhModels were generated using the HypoGen best algorithm. The established PhModel, Hypo01, was evaluated by performing a cost function analysis of its correlation coefficient (r), root mean square deviation (RMSD), cost difference, and configuration cost, with the values 0.955, 1.28, 192.51, and 16.07, respectively. The result of Fischer's cross-validation test for the Hypo01 model yielded a 95% confidence level, and the correlation coefficient of the testing set (rtest) had a best value of 0.81. The potential inhibitors were then chosen from the NCI database by Hypo01 model screening and molecular docking using the cdocker docking program. Finally, the selected compounds exhibited the identified pharmacophoric features and had a high interaction energy between the ligand and the receptor. Eighty-three potential inhibitors for Chk2 are retrieved for further study. Copyright © 2013 Elsevier Ltd. All rights reserved.

Predictors of Complicated Grief and Depression in Bereaved Caregivers: A Nationwide Prospective Cohort Study.

PubMed

Nielsen, Mette Kjaergaard; Neergaard, Mette Asbjoern; Jensen, Anders Bonde; Vedsted, Peter; Bro, Flemming; Guldin, Mai-Britt

2017-03-01

Complicated grief and depressive symptoms in bereaved caregivers have been associated with female gender, spousal relation, and preloss psychological distress, but population-based, prospective studies are scarce. We aimed to investigate whether severe preloss grief and depressive symptoms, caregiver burden, preparedness for death, communication about dying, and socioeconomic factors predicted complicated grief and postloss depressive symptoms. We conducted a population-based, prospective Danish survey of caregivers. Questionnaires for their closest caregiver were mailed to patients registered with drug reimbursement for terminal illness. Of the 3635 (38%) responding caregivers, 2420 were bereaved within six months. Of these, 2215 (88%) completed a postloss follow-up questionnaire. Associations between complicated grief (Prolonged Grief-13), postloss depressive symptoms (Beck Depression Inventory-II), and predictive factors were analyzed with mutually adjusted multivariable logistic regression models. At six-month follow-up, 7.6% reported complicated grief and 12.1% reported postloss depressive symptoms, whereas the levels of grief and depressive symptoms were higher preloss. Complicated grief and postloss depressive symptoms were predicted by severe preloss grief symptoms (adjusted odds ratio [OR] = 3.8, 95% CI: 2.4-6.1), preloss depressive symptoms (adjusted OR = 5.6, 95% CI: 3.5-9.0), being a partner (adjusted OR = 2.2, 95% CI: 1.2-3.7), and low educational level (adjusted OR = 2.0, 95% CI: 1.2-3.7). Complicated grief was not predicted by age and gender, whereas postloss depressive symptoms were predicted by young age, female gender, and low preparedness for death. Severe preloss grief and depressive symptoms were key predictors of postloss complicated grief and depressive symptoms. Systematic assessment may identify caregivers with a high risk profile who need targeted support. Copyright © 2016 American Academy of Hospice and Palliative Medicine

Severe cardiorespiratory complications derived from propofol sedation monitored by an endoscopist.

PubMed

Maestro Antolín, Sergio; Moreira Da Silva, Bruno Antonio; Santos Santamarta, Fernando; Germade, Arantza; Pérez Citores, Laura; Santamaría, Ana; Bonoso Criado, Rocío; Madrigal, Rosa Eva; Saracibar, Esther; Barcenilla Laguna, Javier; Igea Arisqueta, Francisco; Pérez-Millán, Antonio Germán

2018-04-01

deep sedation with propofol monitored by an endoscopist in different endoscopy units is a controversial subject and the source of conflicts of interest between the various scientific societies of Anesthesiology and Gastroenterology. Many studies have already demonstrated the efficacy, efficiency and low incidence of complications associated with sedation when under the control of a trained endoscopist vs an anesthesiologist. the rate of severe cardiorespiratory complications during various endoscopic examinations (gastroscopy, colonoscopy, endoscopic retrograde cholangiopancreatography [ERCP] and endoscopic ultrasound [EUS]) where sedation was controlled by an endoscopist within our unit, from 2011 to 2016, was reviewed. during the study period, 33,195 examinations were analyzed. The rate of cardiorespiratory complications was 0.13% and the majority were severe desaturations. Most cases responded to an opening in the airway associated with the interruption of drug infusion and an ambu bag was required in a few cases. There were no statistically significant differences between the different groups, except for mean age, risk by type of examination and ASA risk, where the difference between ERCP and the rest of examinations was statistically significant. there is a high level of evidence in the scientific literature suggesting that sedation controlled by a trained endoscopist is safe, effective and efficient. However, further prospective studies are required in order to confirm this conclusion due to the fact that the majority of studies to date are retrospective.

Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results

PubMed Central

Hughes, Timothy; Deininger, Michael; Hochhaus, Andreas; Branford, Susan; Radich, Jerald; Kaeda, Jaspal; Baccarani, Michele; Cortes, Jorge; Cross, Nicholas C. P.; Druker, Brian J.; Gabert, Jean; Grimwade, David; Hehlmann, Rüdiger; Kamel-Reid, Suzanne; Lipton, Jeffrey H.; Longtine, Janina; Martinelli, Giovanni; Saglio, Giuseppe; Soverini, Simona; Stock, Wendy; Goldman, John M.

2006-01-01

The introduction in 1998 of imatinib mesylate (IM) revolutionized management of patients with chronic myeloid leukemia (CML) and the second generation of tyrosine kinase inhibitors may prove superior to IM. Real-time quantitative polymerase chain reaction (RQ-PCR) provides an accurate measure of the total leukemiacell mass and the degree to which BCR-ABL transcripts are reduced by therapy correlates with progression-free survival. Because a rising level of BCR-ABL is an early indication of loss of response and thus the need to reassess therapeutic strategy, regular molecular monitoring of individual patients is clearly desirable. Here we summarize the results of a consensus meeting that took place at the National Institutes of Health (NIH) in Bethesda in October 2005. We make suggestions for (1) harmonizing the differing methodologies for measuring BCR-ABL transcripts in patients with CML undergoing treatment and using a conversion factor whereby individual laboratories can express BCR-ABL transcript levels on an internationally agreed scale; (2) using serial RQ-PCR results rather than bone marrow cytogenetics or fluorescence in situ hybridization (FISH) for the BCR-ABL gene to monitor individual patients responding to treatment; and (3) detecting and reporting Philadelphia (Ph) chromosome-positive subpopulations bearing BCR-ABL kinase domain mutations. We recognize that our recommendations are provisional and will require revision as new evidence emerges. (Blood. 2006;108:28-37) PMID:16522812

Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications

PubMed Central

Kumar VR, Santhosh; Darisipudi, Murthy N.; Steiger, Stefanie; Devarapu, Satish Kumar; Tato, Maia; Kukarni, Onkar P.; Mulay, Shrikant R.; Thomasova, Dana; Popper, Bastian; Demleitner, Jana; Zuchtriegel, Gabriele; Reichel, Christoph; Cohen, Clemens D.; Lindenmeyer, Maja T.; Liapis, Helen; Moll, Solange; Reid, Emma; Stitt, Alan W.; Schott, Brigitte; Gruner, Sabine; Haap, Wolfgang; Ebeling, Martin; Hartmann, Guido

2016-01-01

Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role for intrinsic Cat-S/PAR2 in ischemia–induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impaired the integrity and barrier function of glomerular endothelial cells selectively through PAR2. In human and mouse type 2 diabetic nephropathy, only CD68+ intrarenal monocytes expressed Cat-S mRNA, whereas Cat-S protein was present along endothelial cells and inside proximal tubular epithelial cells also. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Delayed treatment of type 2 diabetic db/db mice with Cat-S or PAR2 inhibitors attenuated albuminuria and glomerulosclerosis (indicators of diabetic nephropathy) and attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy. These data identify Cat-S as a monocyte/macrophage–derived circulating PAR2 agonist and mediator of endothelial dysfunction–related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases. PMID:26567242

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors from Natural Products: Discovery of Next-Generation Antihyperglycemic Agents.

PubMed

Choi, Chang-Ik

2016-08-27

Diabetes mellitus is a chronic condition associated with the metabolic impairment of insulin actions, leading to the development of life-threatening complications. Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, weight gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium-glucose cotransporter 2 (SGLT2) for glucose homeostasis in the kidney were recently elucidated, pharmacological inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes. Since the discovery of the first natural SGLT2 inhibitor, phlorizin, several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing. This review introduces the history of research on the development of early-generation SGLT2 inhibitors, and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine.

PARP-1 inhibition alleviates diabetic cardiac complications in experimental animals.

PubMed

Zakaria, Esraa M; El-Bassossy, Hany M; El-Maraghy, Nabila N; Ahmed, Ahmed F; Ali, Abdelmoneim A

2016-11-15

Cardiovascular complications are the major causes of mortality among diabetic population. Poly(ADP-ribose) polymerase-1 enzyme (PARP-1) is activated by oxidative stress leading to cellular damage. We investigated the implication of PARP-1 in diabetic cardiac complications. Type 2 diabetes was induced in rats by high fructose-high fat diet and low streptozotocin dose. PARP inhibitor 4-aminobenzamide (4-AB) was administered daily for ten weeks after diabetes induction. At the end of study, surface ECG, blood pressure and vascular reactivity were studied. PARP-1 activity, reduced glutathione (GSH) and nitrite contents were assessed in heart muscle. Fasting glucose, fructosamine, insulin, and tumor necrosis factor alpha (TNF-α) levels were measured in serum. Finally, histological examination and collagen deposition detection in rat ventricular and aortic sections were carried out. Hearts isolated from diabetic animals showed increased PARP-1 enzyme activity compared to control animals while significantly reduced by 4-AB administration. PARP-1 inhibition by 4-AB alleviated cardiac ischemia in diabetic animals as indicated by ECG changes. PARP-1 inhibition also reduced cardiac inflammation in diabetic animals as evidenced by histopathological changes. In addition, 4-AB administration improved the elevated blood pressure and the associated exaggerated vascular contractility, endothelial destruction and vascular inflammation seen in diabetic animals. Moreover, PARP-1 inhibition decreased serum levels of TNF-α and cardiac nitrite but increased cardiac GSH contents in diabetic animals. However, PARP-1 inhibition did not significantly affect the developed hyperglycemia. Our findings prove that PARP-1 enzyme plays an important role in diabetic cardiac complications through combining inflammation, oxidative stress, and fibrosis mechanisms. Copyright © 2016. Published by Elsevier B.V.

Structural basis for decreased induction of class IB PI3-kinases expression by MIF inhibitors

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

Singh, Abhay Kumar; Pantouris, Georgios; Borosch, Sebastian

Macrophage migration inhibitory factor (MIF) is a master regulator of proinflammatory cytokines and plays pathological roles when not properly regulated in rheumatoid arthritis, lupus, atherosclerosis, asthma and cancer. Unlike canonical cytokines, MIF has vestigial keto-enol tautomerase activity. Most of the current MIF inhibitors were screened for the inhibition of this enzymatic activity. However, only some of the enzymatic inhibitors inhibit receptor-mediated biological functions of MIF, such as cell recruitment, through an unknown molecular mechanism. The goal of this study was to understand the molecular basis underlying the pharmacological inhibition of biological functions of MIF. Here, we demonstrate how the structuralmore » changes caused upon inhibitor binding translate into the alteration of MIF-induced downstream signalling. Macrophage migration inhibitory factor activates phosphoinositide 3-kinases (PI3Ks) that play a pivotal role in immune cell recruitment in health and disease. There are several different PI3K isoforms, but little is known about how they respond to MIF. We demonstrate that MIF up-regulates the expression of Class IB PI3Ks in leucocytes. We also demonstrate that MIF tautomerase active site inhibitors down-regulate the expression of Class IB PI3Ks as well as leucocyte recruitment in vitro and in vivo. Finally, based on our MIF:inhibitor complex crystal structures, we hypothesize that the reduction in Class IB PI3K expression occurs because of the displacement of Pro1 towards the second loop of MIF upon inhibitor binding, which results in increased flexibility of the loop 2 and sub-optimal MIF binding to its receptors. These results will provide molecular insights for fine-tuning the biological functions of MIF.« less

Effects of repeated administration of the monoamine oxidase inhibitor phenelzine on the discriminability of d-lysergic acid diethylamide (LSD) and 1-(m-trifluoromethylphenyl) piperazine (TFMPP).

PubMed

Cunningham, K A; Carroll, B A; Appel, J B

1986-01-01

Rats trained to discriminate d-lysergic acid diethylamide (LSD; 0.08 mg/kg) or 1-(m-trifluoromethylphenyl) piperazine (TFMPP; 0.8 mg/kg) were treated with the monoamine oxidase inhibitor (MAOI) phenelzine (10 mg/kg/day) for 7 days. After a 24 h "washout" period, they were challenged with the training drug (and dose) or saline, during extinction test sessions. Following 0.08 mg/kg LSD, LSD-trained rats responded primarily on the saline lever (29% drug-appropriate responding) while, after TFMPP (0.8 mg/kg), TFMPP-trained animals responded on the drug lever (75% drug-appropriate responding). These preliminary data suggest that, if serotonin receptors are involved in the behavioral effects of TFMPP, these receptors differ from those involved in the effects of LSD.

An unusual case of calcineurine inhibitor pain syndrome.

PubMed

Nickavar, Azar; Mehrazma, Mitra; Hallaji, Farideh

2014-09-01

Cyclosporine induced pain syndrome (CIPS) is a newly diagnosed complication of calcineurine inhibitors, mainly observed in solid organ and hematopoetic transplantations. The present case is a male child with steroid resistant nephrotic syndrome on low therapeutic level cyclosporine treatment. He presented with intractable and debilitating leg pain, with no reported history of previous injury or trauma. The pain was reluctant to antimicrobial and sedative treatment. MRI revealed bone marrow and soft tissue edema in the mid shaft of patient's right leg. Inspite of unusual manifestations, CIPS was suggested and cyclosporine discontinued. However, the pain did not improve and was resistant to calcium blocker. Subsequently, core decompression was performed as an unusual treatment of CIPS, revealing normal bone morphology. The pain improved rapidly and the patient was discharged a few days later.

Enzyme Assay Guided Isolation of an α-Amylase Inhibitor Flavonoid from Vaccinium arctostaphylos Leaves

PubMed Central

Nickavar, Bahman; Amin, Gholamreza

2011-01-01

The management of postprandial hyperglycemia is an important strategy in the control of diabetes mellitus and complications associated with the disease, especially in the diabetes type 2. Therefore, inhibitors of carbohydrate hydrolyzing enzymes can be useful in the treatment of diabetes and medicinal plants can offer an attractive strategy for the purpose. Vaccinium arctostaphylos leaves are considered useful for the treatment of diabetes mellitus in some countries. In our research for antidiabetic compounds from natural sources, we found that the methanol extract of the leaves of V. arctostaphylos displayed a potent inhibitory activity on pancreatic α-amylase activity (IC50 = 0.53 (0.53 – 0.54) mg/mL). The bioassay-guided fractionation of the extract resulted in the isolation of quercetin as an active α-amylase inhibitor. Quercetin showed a dose-dependent inhibitory effect with IC50 value 0.17 (0.16 – 0.17) mM. PMID:24250422

Birth preparedness and complication readiness among rural women of reproductive age in Abeshige district, Guraghe zone, SNNPR, Ethiopia

PubMed Central

Zepre, Kebebush; Kaba, Mirgissa

2017-01-01

Background Birth preparedness and complication readiness (BPCR) is a strategy that helps women to consider all available maternal health care services during pregnancy and prepare for potential complications. Federal Ministry of Health in Ethiopia has taken steps to roll out the strategy at community level. Yet, women in rural communities still do not make use of available services to avoid complications in connection to pregnancy and delivery. Objective This study aims to assess the current BPCR practice and determine associated factors among rural women of reproductive age in Abeshige district, Guraghe zone, SNNPR, Ethiopia. Methods A community-based cross-sectional study was carried out from February to March 2015. A total of 454 women were randomly selected and interviewed using pretested structured questionnaires, while opinion leaders, health extension workers, and selected women in the community were engaged in in-depth interviews and focus group discussions, using checklists prepared to guide the interviews. Data from different sources were analyzed, triangulated, and interpreted to respond to the objectives. Results Thirty-seven percent of the respondents were found to have prepared for birth and its complications. BPCR was higher among women who lived within a 1-hour walk from a health center (adjusted odds ratio [AOR] =3.51, 95% confidence interval [CI]: 1.78, 36.79) and who were aware of the danger signs of pregnancy (AOR =1.72, 95% CI: 1.78, 2.94) and postpartum complications (AOR =2.32, 95% CI: 1.32, 4.21). A major source of information was found to be health extension workers and one-to-five women networks (AOR =2.81, 95% CI: 1.34, 6.21) and (AOR =2.52, 95% CI: 1.17, 5.54), respectively. Qualitative finding revealed that lack of transportation and concern over cost of services are key barriers to BPCR. Conclusion BPCR in Abeshige was found to be relatively low, calling for more interventions beyond mere awareness. Availing transportation services and

Birth preparedness and complication readiness among rural women of reproductive age in Abeshige district, Guraghe zone, SNNPR, Ethiopia.

PubMed

Zepre, Kebebush; Kaba, Mirgissa

2017-01-01

Birth preparedness and complication readiness (BPCR) is a strategy that helps women to consider all available maternal health care services during pregnancy and prepare for potential complications. Federal Ministry of Health in Ethiopia has taken steps to roll out the strategy at community level. Yet, women in rural communities still do not make use of available services to avoid complications in connection to pregnancy and delivery. This study aims to assess the current BPCR practice and determine associated factors among rural women of reproductive age in Abeshige district, Guraghe zone, SNNPR, Ethiopia. A community-based cross-sectional study was carried out from February to March 2015. A total of 454 women were randomly selected and interviewed using pretested structured questionnaires, while opinion leaders, health extension workers, and selected women in the community were engaged in in-depth interviews and focus group discussions, using checklists prepared to guide the interviews. Data from different sources were analyzed, triangulated, and interpreted to respond to the objectives. Thirty-seven percent of the respondents were found to have prepared for birth and its complications. BPCR was higher among women who lived within a 1-hour walk from a health center (adjusted odds ratio [AOR] =3.51, 95% confidence interval [CI]: 1.78, 36.79) and who were aware of the danger signs of pregnancy (AOR =1.72, 95% CI: 1.78, 2.94) and postpartum complications (AOR =2.32, 95% CI: 1.32, 4.21). A major source of information was found to be health extension workers and one-to-five women networks (AOR =2.81, 95% CI: 1.34, 6.21) and (AOR =2.52, 95% CI: 1.17, 5.54), respectively. Qualitative finding revealed that lack of transportation and concern over cost of services are key barriers to BPCR. BPCR in Abeshige was found to be relatively low, calling for more interventions beyond mere awareness. Availing transportation services and ensuring services free of charge would help in

A Phosphoproteomic Comparison of B-RAFV600E and MKK1/2 Inhibitors in Melanoma Cells.

PubMed

Stuart, Scott A; Houel, Stephane; Lee, Thomas; Wang, Nan; Old, William M; Ahn, Natalie G

2015-06-01

Inhibitors of oncogenic B-RAF(V600E) and MKK1/2 have yielded remarkable responses in B-RAF(V600E)-positive melanoma patients. However, the efficacy of these inhibitors is limited by the inevitable onset of resistance. Despite the fact that these inhibitors target the same pathway, combination treatment with B-RAF(V600E) and MKK1/2 inhibitors has been shown to improve both response rates and progression-free survival in B-RAF(V600E) melanoma patients. To provide insight into the molecular nature of the combinatorial response, we used quantitative mass spectrometry to characterize the inhibitor-dependent phosphoproteome of human melanoma cells treated with the B-RAF(V600E) inhibitor PLX4032 (vemurafenib) or the MKK1/2 inhibitor AZD6244 (selumetinib). In three replicate experiments, we quantified changes at a total of 23,986 phosphosites on 4784 proteins. This included 1317 phosphosites that reproducibly decreased in response to at least one inhibitor. Phosphosites that responded to both inhibitors grouped into networks that included the nuclear pore complex, growth factor signaling, and transcriptional regulators. Although the majority of phosphosites were responsive to both inhibitors, we identified 16 sites that decreased only in response to PLX4032, suggesting rare instances where oncogenic B-RAF signaling occurs in an MKK1/2-independent manner. Only two phosphosites were identified that appeared to be uniquely responsive to AZD6244. When cells were treated with the combination of AZD6244 and PLX4032 at subsaturating concentrations (30 nm), responses at nearly all phosphosites were additive. We conclude that AZD6244 does not substantially widen the range of phosphosites inhibited by PLX4032 and that the benefit of the drug combination is best explained by their additive effects on suppressing ERK1/2 signaling. Comparison of our results to another recent ERK1/2 phosphoproteomics study revealed a surprising degree of variability in the sensitivity of phosphosites to

Responder Technology Alert (February 2015)

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

Upton, Jaki F.; Stein, Steven L.

2015-04-10

As part of technology foraging for the Responder Technology Alliance, established by the Department of Homeland Science and Technologies First Responders Group, this report summarizes technologies that are relevant in the area of “wearables,” with the potential for use by first responders. The content was collected over the previous month(s) and reproduced from a general Internet search using the term wearables. Additional information is available at the websites provided. This report is not meant to be an exhaustive list nor an endorsement of any technology described herein. Rather, it is meant to provide useful information about current developments in themore » areas wearable technology.« less

The Role of the Kidney and SGLT2 Inhibitors in Type 2 Diabetes.

PubMed

Katz, Pamela M; Leiter, Lawrence A

2015-12-01

Effective glycemic control reduces the risk for diabetes-related complications. However, the majority of patients with type 2 diabetes still do not achieve glycemic targets. Beyond metformin therapy, current practice guidelines for the management of type 2 diabetes recommend individualized treatment based on patient and agent characteristics. The sodium glucose cotransporter type 2 (SGLT2) inhibitors represent a novel treatment strategy, independent of impaired beta-cell function and insulin resistance. SGLT2 inhibitors decrease renal glucose reabsorption, thereby increasing urinary glucose excretion with subsequent reduction in plasma glucose levels and glycosylated hemoglobin concentrations. Current evidence suggests that they are effective as monotherapy or as add-ons to metformin either alone, or in combination with other oral glucose-lowering agents or insulin. They are generally well tolerated, though rates of lower urinary tract and genital mycotic infections are slightly increased. The advantages of this class include modest reductions in body weight and blood pressure, and low risk for hypoglycemia. Long-term safety data and results of ongoing cardiovascular outcome studies are awaited so we can fully understand the role that SGLT2 inhibitors will play in the comprehensive management of type 2 diabetes. Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

The gefitinib long-term responder (LTR)--a cancer stem-like cell story? Insights from molecular analyses of German long-term responders treated in the IRESSA expanded access program (EAP).

PubMed

Gottschling, Sandra; Herpel, Esther; Eberhardt, Wilfried E E; Heigener, David F; Fischer, Jürgen R; Köhne, Claus-Henning; Kortsik, Cornelius; Kuhnt, Thomas; Muley, Thomas; Meister, Michael; Bischoff, Helge G; Klein, Peter; Moldenhauer, Ines; Schnabel, Philipp A; Thomas, Michael; Penzel, Roland

2012-07-01

In selected patients with advanced non-small cell lung cancer (NSCLC) the EGFR (epidermal growth factor receptor) tyrosine kinase inhibitor (TKI) gefitinib (IRESSA) shows response rates of ≥ 70% and a significant prolongation of progression free survival (PFS). However, cogent biomarkers predicting long-term response to EGFR-TKIs are yet lacking. Cancer stem-like cells (CSC) are thought to play a pivotal role in tumor regeneration and appear to be influenced by the EGFR-pathway. This makes them a promising candidate for predicting long-term response to EGFR-TKIs. We analyzed pre-therapeutic tissue specimens of a rare and specific subset of previously treated German patients with advanced NSCLC who experienced ≥ 3 year response to gefitinib within the International IRESSA EAP. 11/20 identified long-term responders (LTRs) had appropriate tissue specimens available. Those were analyzed for EGFR and k-ras (Kirsten rat sarcoma) mutations, EGFR and c-met (met proto-oncogene) amplifications and protein expression of EGFR, E-cadherin/vimentin and the CSC antigens CD133 and BCRP1 (breast cancer resistance protein 1). The results were compared to primary resistant patients (RPs) and intermediate responders (IRs) showing a median response of 8.6 months. Each group consisted of 6 women and 5 men, with 1 squamous cell carcinoma (SCC) and 10 adenocarcinoma (AC). Along the LTRs, all but the SCC had EGFR mutations, whereas the RPs had no EGFR, but k-ras mutations in 5/11 cases. 8/11 IRs had EGFR and 3/11 k-ras mutations, of which 2 occurred concomitantly. One patient of each group had an EGFR and/or c-met amplification. EGFR and E-cadherin/vimentin expression was not different between the groups, whereas CD133 was expressed only in 4/10 LTRs and BCRP1 predominantly in responders. The LTRs showed a substantially longer mean PFS to previous therapies, a substantially lower number of metastatic sites and almost exclusively pulmonary or pleural metastasis. LTRs display established

Treating Complicated Grief

PubMed Central

Simon, Naomi M.

2015-01-01

IMPORTANCE The death of a loved one is one of life’s greatest, universal stressors to which most bereaved individuals successfully adapt without clinical intervention. For a minority of bereaved individuals, grief is complicated by superimposed problems and healing does not occur. The resulting syndrome of complicated grief causes substantial distress and functional impairment even years after a loss, yet knowing when and how to intervene can be a challenge. OBJECTIVE To discuss the differential diagnosis, risk factors for and management of complicated grief based on available evidence and clinical observations. EVIDENCE REVIEW MEDLINE was searched from January 1990 to October 2012. Additional citations were procured from references of select research and review articles. Available treatment studies targeting complicated grief were included. RESULTS A strong research literature led to inclusion of complicated grief in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (termed persistent complex bereavement disorder as a subtype of other specified trauma and stressor-related disorders), although it is a condition for which more research is formally recommended, and there is still ongoing discussion about the optimal name and diagnostic criteria for the disorder. Reliable screening instruments are available, and the estimated prevalence rate is 7% of bereaved people. Randomized controlled data support the efficacy of a targeted psychotherapy including elements that foster resolution of complicating problems and facilitate the natural healing process. Preliminary studies suggest antidepressant medications may be helpful. CONCLUSION AND RELEVANCE Individuals with complicated grief have greater risk of adverse health outcomes, should be diagnosed and assessed for suicide risk and comorbid conditions such as depression and posttraumatic stress disorder, and should be considered for treatment. PMID:23917292

Irreversible pan-ErbB tyrosine kinase inhibitors and breast cancer: current status and future directions.

PubMed

Ocaña, Alberto; Amir, Eitan

2009-12-01

Aberrant activation of HER2 through overexpression has been shown to play an important role in some breast cancers. Therapies against this receptor including the monoclonal antibody, trastuzumab, or the small tyrosine kinase inhibitor, lapatinib have shown to improve the prognosis of such patients. Despite overexpressing HER2, some patients do not respond to these targeted treatments or progress after a short period of time. Irreversible tyrosine kinase inhibitors have been developed to bypass several pathways that could be involved in this resistance. In vitro, these agents have been shown to be more potent and to prolong target inhibition. Clinical development of these agents is ongoing and early results are promising. This review will describe the biologic rationale that justifies the development of these agents in breast cancer focusing on the current status and future directions.

Complications Following Pediatric Tracheotomy.

PubMed

D'Souza, Jill N; Levi, Jessica R; Park, David; Shah, Udayan K

2016-05-01

Pediatric tracheotomy is a complex procedure with significant postoperative complications. Wound-related complications are increasingly reported and can have considerable impact on clinical course and health care costs to tracheotomy-dependent children. The primary objective of this study was to identify the type and rate of complications arising from pediatric tracheotomy. A retrospective review of medical records of 302 children who underwent tracheotomy between December 1, 2000, and February 28, 2014, at a tertiary care pediatric referral center. Records were reviewed for preoperative diagnoses, gestational age, age at tracheotomy, tracheotomy technique, and incidence of complication. Main outcome measures included incidence, type, and timing of complications. Secondary measures included medical diagnoses and surgical technique. Of the 302 children who underwent tracheotomy, the median (SD) age at time of tracheotomy was 5 months (64 months) and the range was birth to 21 years. The most frequent diagnosis associated with performance of a tracheotomy was ventilator-associated respiratory failure (61.9%), followed by airway anomaly or underdevelopment (25.2%), such as subglottic or tracheal stenosis, laryngotracheomalacia, or bronchopulmonary dysplasia. The remaining indications for tracheotomy included airway obstruction (11.6% [35 of 302]) and vocal fold dysfunction (1.3% [4 of 302]). No statistical significance was found associated with diagnosis and incidence of complications. Sixty children (19.9%) had a tracheotomy-related complication. Major complications, such as accidental decannulation (1.0% [3 of 302]). There were no deaths associated with tracheotomy. Minor complications, such as peristomal wound breakdown or granuloma (12.9% [39 of 302]) and bleeding from stoma (1.7% [5 of 302]), were more common. Of all complications, 70% (42 of 60) occurred early (≤7 days postoperatively) and 20% (12 of 60) were late (>7 days postoperatively). Pediatric

Pregnancy Complications: Anemia

MedlinePlus

... online community Home > Complications & Loss > Pregnancy complications > Anemia Anemia E-mail to a friend Please fill in ... anemia at a prenatal care visit . What causes anemia? Usually, a woman becomes anemic (has anemia) because ...

Complications in Hip Arthroscopy

PubMed Central

Nakano, Naoki; Khanduja, Vikas

2016-01-01

Summary Background Recent developments in hip arthroscopic techniques and technology have made it possible in many cases to avoid open surgical dislocation for treating a variety of pathology in the hip. Although early reports suggest favourable results’ using hip arthroscopy and it has been shown to be a relatively safe procedure, complications do exist and can sometimes lead to significant morbidity. Methods This is a review article. The aim of this manuscript is to present the most frequent and/or serious complications that could occur at or following hip arthroscopy and some guidelines to avoid these complications. Conclusion Most complications of hip arthroscopy are minor or transient but serious complications can occur as well. A lot of complication e.g. acetabular labral puncture go unreported. Appropriate education and training, precise and meticulous surgical technique with correct instrumentation, the right indication in the right patient and adherence to advice from mentors and experienced colleagues are all essential factors for a successful outcome. Level of evidence: V. PMID:28066747

Protease inhibitors: changing the way AIDS case management does business.

PubMed

Merithew, M A; Davis-Satterla, L

2000-09-01

The purpose of the qualitative evaluation study discussed in this article was to examine the AIDS case management model under which five nonprofit AIDS service organizations (ASOs) in Midcity were operating. The study was organized around 40 qualitative interviews with executive directors, directors, and case managers. The finding was that AIDS case management is evolving to accommodate the changing environmental/contextual conditions that have resulted from combination drug therapies (protease inhibitors) introduced in 1996. The agencies are responding to the changes individually rather than as a network, and responses vary among the agencies. Institutional theory, an examination of the interconnectedness of clients, the ASOs, and their environmental context guided the analysis of the findings.

Recreational Use of Phosphodiesterase 5 Inhibitors and Its Associated Factors among Undergraduate Male Students in an Ethiopian University: A Cross-Sectional Study.

PubMed

Gebreyohannes, Eyob Alemayehu; Bhagavathula, Akshaya Srikanth; Gebresillassie, Begashaw Melaku; Tefera, Yonas Getaye; Belachew, Sewunet Admasu; Erku, Daniel Asfaw

2016-12-01

To assess the prevalence of phosphodiesterase 5 (PDE5) inhibitor use and associated factors among University of Gondar undergraduate students. An institution-based, cross-sectional study, using a survey questionnaire, was conducted from October to December 2015 to assess PDE5 inhibitor use and associated factors among male students at the University of Gondar. A Self-Esteem and Relationship questionnaire (14 items), an International Index of Erectile Function questionnaire (15 items) and a questionnaire on PDE5 inhibitor use (14 items) were included in the survey. Across all respondents (age, 21.9±1.88 years), more than half (55.7%, n=233) had heard about PDE5 inhibitors, but only 23 men (5.5%) reported trying a PDE5 inhibitor drug at least once. Older students were more likely to use PDE5 inhibitors compared to younger students (adjusted odds ratio [AOR], 1.40; 95% confidence interval [CI], 1.109~1.768). Those students who were smokers were 5.15 times more likely to use PDE5 inhibitors as compared to their non-smoking counterparts (AOR, 5.15; 95% CI, 2.096~12.687). In addition, multivariate logistic regression showed that being in a relationship, alcohol use, greater number of cigarettes smoked per day, and more sexual partners were significantly associated with PDE5 inhibitor use. The prevalence of PDE5 inhibitor use among undergraduate students was 5.5%. Cigarette smoking and other substance use, older age, and greater number of sexual partners were significantly associated factors for PDE5 inhibitor use. These findings suggest that restricting access to PDE5 inhibitor drugs is essential to curtailing misuse among university students.

Practice and perception of first aid among lay first responders in a southern district of India.

PubMed

Pallavisarji, Uthkarsh; Gururaj, Gopalkrishna; Girish, Rao Nagaraja

2013-01-01

Injuries rank among the leading causes of morbidity and mortality worldwide, and are steadily increasing in developing countries like India. However, it is often possible to minimize injury and crash consequences by providing effective pre-hospital services promptly. In most low-and middle-income countries (LMICs), transportation of road traffic victims, is usually provided by relatives, taxi drivers, truck drivers, police officers and other motorists who are often untrained. The current study was conducted to understand the current practice and perception of first aid among lay first responders in a rural southern district of India. The current cross sectional descriptive study was conducted in the southern district of Tumkur in India within three months from January to March 2011 and covered the population including all police, ambulance personnel, taxi drivers, bus and auto drivers, and primary and middle school teachers within the study area. Nearly 60% of the responders had witnessed more than two emergencies in the previous six months and 55% had actively participated in helping the injured person. The nature of the help was mainly by calling for an ambulance (41.5%), transporting the injured (19.7%) and consoling the victim (14.9%). Majority (78.1%) of the responders informed that they had run to the victim (42.4%) or had called for an ambulance. The predominant reason for not providing help was often the 'fear of legal complications' (30%) that would follow later. Significant number (81.4%) of respondents reported that they did not have adequate skills to manage an emergency and were willing to acquire knowledge and skills in first aid to help victims. Regular and periodical community-based first aid training programs for first care responders will help to provide care and improve outcomes for injured persons.

Experience with DPP-4 inhibitors in the management of patients with type 2 diabetes fasting during Ramadan

PubMed Central

Schweizer, Anja; Halimi, Serge; Dejager, Sylvie

2014-01-01

A large proportion of Muslim patients with type 2 diabetes mellitus (T2DM) elect to fast during the holy month of Ramadan. For these patients hypo- and hyperglycemia constitute two major complications associated with the profound changes in food pattern during the Ramadan fast, and efficacious treatment options with a low risk of hypoglycemia are therefore needed to manage their T2DM as effectively and safely as possible. Dipeptidyl peptidase-4 (DPP-4) inhibitors modulate insulin and glucagon secretion in a glucose-dependent manner, and consequently a low propensity of hypoglycemia has consistently been reported across different patient populations with these agents. Promising data with DPP-4 inhibitors have now also started to emerge in patients with T2DM fasting during Ramadan. The objective of this review is to provide a comprehensive overview of the currently available evidence and potential role of DPP-4 inhibitors in the management of patients with T2DM fasting during Ramadan whose diabetes is treated with oral antidiabetic drugs, and to discuss the mechanistic basis for their beneficial effects in this setting. PMID:24391442

Combined effects of EGFR tyrosine kinase inhibitors and vATPase inhibitors in NSCLC cells

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

Jin, Hyeon-Ok; Hong, Sung-Eun; Kim, Chang Soon

2015-08-15

Despite excellent initial clinical responses of non-small cell lung cancer (NSCLC) patients to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), many patients eventually develop resistance. According to a recent report, vacuolar H + ATPase (vATPase) is overexpressed and is associated with chemotherapy drug resistance in NSCLC. We investigated the combined effects of EGFR TKIs and vATPase inhibitors and their underlying mechanisms in the regulation of NSCLC cell death. We found that combined treatment with EGFR TKIs (erlotinib, gefitinib, or lapatinib) and vATPase inhibitors (bafilomycin A1 or concanamycin A) enhanced synergistic cell death compared to treatments with each drugmore » alone. Treatment with bafilomycin A1 or concanamycin A led to the induction of Bnip3 expression in an Hif-1α dependent manner. Knock-down of Hif-1α or Bnip3 by siRNA further enhanced cell death induced by bafilomycin A1, suggesting that Hif-1α/Bnip3 induction promoted resistance to cell death induced by the vATPase inhibitors. EGFR TKIs suppressed Hif-1α and Bnip3 expression induced by the vATPase inhibitors, suggesting that they enhanced the sensitivity of the cells to these inhibitors by decreasing Hif-1α/Bnip3 expression. Taken together, we conclude that EGFR TKIs enhance the sensitivity of NSCLC cells to vATPase inhibitors by decreasing Hif-1α/Bnip3 expression. We suggest that combined treatment with EGFR TKIs and vATPase inhibitors is potentially effective for the treatment of NSCLC. - Highlights: • Co-treatment with EGFR TKIs and vATPase inhibitors induces synergistic cell death • EGFR TKIs enhance cell sensitivity to vATPase inhibitors via Hif-1α downregulation • Co-treatment of these inhibitors is potentially effective for the treatment of NSCLC.« less

ROS inhibitor N-acetyl-L-cysteine antagonizes the activity of proteasome inhibitors.

PubMed

Halasi, Marianna; Wang, Ming; Chavan, Tanmay S; Gaponenko, Vadim; Hay, Nissim; Gartel, Andrei L

2013-09-01

NAC (N-acetyl-L-cysteine) is commonly used to identify and test ROS (reactive oxygen species) inducers, and to inhibit ROS. In the present study, we identified inhibition of proteasome inhibitors as a novel activity of NAC. Both NAC and catalase, another known scavenger of ROS, similarly inhibited ROS levels and apoptosis associated with H₂O₂. However, only NAC, and not catalase or another ROS scavenger Trolox, was able to prevent effects linked to proteasome inhibition, such as protein stabilization, apoptosis and accumulation of ubiquitin conjugates. These observations suggest that NAC has a dual activity as an inhibitor of ROS and proteasome inhibitors. Recently, NAC was used as a ROS inhibitor to functionally characterize a novel anticancer compound, piperlongumine, leading to its description as a ROS inducer. In contrast, our own experiments showed that this compound depicts features of proteasome inhibitors including suppression of FOXM1 (Forkhead box protein M1), stabilization of cellular proteins, induction of ROS-independent apoptosis and enhanced accumulation of ubiquitin conjugates. In addition, NAC, but not catalase or Trolox, interfered with the activity of piperlongumine, further supporting that piperlongumine is a proteasome inhibitor. Most importantly, we showed that NAC, but not other ROS scavengers, directly binds to proteasome inhibitors. To our knowledge, NAC is the first known compound that directly interacts with and antagonizes the activity of proteasome inhibitors. Taken together, the findings of the present study suggest that, as a result of the dual nature of NAC, data interpretation might not be straightforward when NAC is utilized as an antioxidant to demonstrate ROS involvement in drug-induced apoptosis.

SGLT2 Inhibitors: Glucotoxicity and Tumorigenesis Downstream the Renal Proximal Tubule?

PubMed

Bertinat, Romina; Nualart, Francisco; Yáñez, Alejandro J

2016-08-01

At present, diabetes mellitus is the main cause of end-stage renal disease. Effective glycaemic management is the most powerful tool to delay the establishment of diabetic complications, such as diabetic kidney disease. Together with reducing blood glucose levels, new anti-diabetic agents are expected not only to control the progression but also to restore known defects of the diabetic kidney. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are promising anti-diabetic agents that reduce hyperglycaemia by impairing glucose reabsorption in proximal tubule of the kidney and increasing glucosuria. SGLT2 inhibitors have shown to reduce glucotoxicity in isolated proximal tubule cells and also to attenuate expression of markers of overall kidney damage in experimental animal models of diabetes, but the actual renoprotective effect for downstream nephron segments is still unknown and deserves further attention. Here, we briefly discuss possible undesired effects of enhanced glucosuria and albuminuria in nephron segments beyond the proximal tubule after SGLT2 inhibitor treatment, offering new lines of research to further understand the renoprotective action of these anti-diabetic agents. Strategies blocking glucose reabsorption by renal proximal tubule epithelial cells (RPTEC) may be protective for RPTEC, but downstream nephron segments will still be exposed to high glucose and albumin levels through the luminal face. The actual effect of constant enhanced glucosuria over distal nephron segments remains to be established. J. Cell. Physiol. 231: 1635-1637, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

ROMK inhibitor actions in the nephron probed with diuretics.

PubMed

Kharade, Sujay V; Flores, Daniel; Lindsley, Craig W; Satlin, Lisa M; Denton, Jerod S

2016-04-15

Diuretics acting on specific nephron segments to inhibit Na + reabsorption have been used clinically for decades; however, drug interactions, tolerance, and derangements in serum K + complicate their use to achieve target blood pressure. ROMK is an attractive diuretic target, in part, because its inhibition is postulated to indirectly inhibit the bumetanide-sensitive Na + -K + -2Cl - cotransporter (NKCC2) and the amiloride- and benzamil-sensitive epithelial Na + channel (ENaC). The development of small-molecule ROMK inhibitors has created opportunities for exploring the physiological responses to ROMK inhibition. The present study evaluated how inhibition of ROMK alone or in combination with NKCC2, ENaC, or the hydrochlorothiazide (HCTZ) target NCC alter fluid and electrolyte transport in the nephron. The ROMK inhibitor VU591 failed to induce diuresis when administered orally to rats. However, another ROMK inhibitor, termed compound A, induced a robust natriuretic diuresis without kaliuresis. Compound A produced additive effects on urine output and Na + excretion when combined with HCTZ, amiloride, or benzamil, but not when coadministered with bumetanide, suggesting that the major diuretic target site is the thick ascending limb (TAL). Interestingly, compound A inhibited the kaliuretic response induced by bumetanide and HCTZ, an effect we attribute to inhibition of ROMK-mediated K + secretion in the TAL and CD. Compound A had no effect on heterologously expressed flow-sensitive large-conductance Ca 2+ -activated K + channels (Slo1/β1). In conclusion, compound A represents an important new pharmacological tool for investigating the renal consequences of ROMK inhibition and therapeutic potential of ROMK as a diuretic target. Copyright © 2016 the American Physiological Society.

Rotigotine in Combination with the MAO-B Inhibitor Selegiline in Early Parkinson's Disease: A Post Hoc Analysis.

PubMed

Giladi, Nir; Asgharnejad, Mahnaz; Bauer, Lars; Grieger, Frank; Boroojerdi, Babak

2016-04-02

Monoamine oxidase B (MAO-B) inhibitors and dopamine receptor agonists are common first-line treatment options in early Parkinson's disease (PD). To evaluate the efficacy and safety of rotigotine transdermal patch as an add-on therapy to an MAO-B inhibitor in patients with early-PD. In two Phase III, randomized, double-blind, placebo-controlled studies in early-PD (SP512, SP513), patients were randomized to rotigotine (titrated to optimal dose ≤8 mg/24 h) or placebo, and maintained for 24 (SP512) or 33 (SP513) weeks. Post hoc analyses were performed on pooled data for patients receiving an MAO-B inhibitor (selegiline) at a stable dose at randomization and throughout the studies, with groups defined as "Selegiline+Rotigotine" and "Selegiline+Placebo". Outcome measures included change from baseline in Unified Parkinson's Disease Rating Scale (UPDRS) II (activities of daily living), III (motor), UPDRS II+III and responders (patients achieving ≥20%, ≥25% or ≥30% decrease in UPDRS II+III). As post hoc analyses, p-values are exploratory. 130 patients were evaluable for efficacy analyses ("Selegiline+Rotigotine": 84, "Selegiline+Placebo": 46). Combined treatment with rotigotine and selegiline improved UPDRS III and UPDRS II+III scores versus selegiline alone (LS-mean [95% CI] treatment difference for UPDRS III: -4.89 [-7.87 to -1.91], p = 0.0015; for UPDRS II+III: -5.76 [-9.71 to -1.82], p = 0.0045). Higher proportion of patients in the "Selegiline+Rotigotine" group were classified as ≥20%, ≥25% or ≥30% responders (all p < 0.001). Combined treatment appeared more effective in patients aged ≤65 years versus > 65 years (although patient numbers in the subgroups were low). Adverse event profile was consistent with the known safety profile of rotigotine. In these post hoc analyses, adjunctive treatment with rotigotine in patients already receiving an MAO-B inhibitor improved UPDRS II+III score; this appeared to be largely driven by

The probability of reinforcement per trial affects posttrial responding and subsequent extinction but not within-trial responding.

PubMed

Harris, Justin A; Kwok, Dorothy W S

2018-01-01

During magazine approach conditioning, rats do not discriminate between a conditional stimulus (CS) that is consistently reinforced with food and a CS that is occasionally (partially) reinforced, as long as the CSs have the same overall reinforcement rate per second. This implies that rats are indifferent to the probability of reinforcement per trial. However, in the same rats, the per-trial reinforcement rate will affect subsequent extinction-responding extinguishes more rapidly for a CS that was consistently reinforced than for a partially reinforced CS. Here, we trained rats with consistently and partially reinforced CSs that were matched for overall reinforcement rate per second. We measured conditioned responding both during and immediately after the CSs. Differences in the per-trial probability of reinforcement did not affect the acquisition of responding during the CS but did affect subsequent extinction of that responding, and also affected the post-CS response rates during conditioning. Indeed, CSs with the same probability of reinforcement per trial evoked the same amount of post-CS responding even when they differed in overall reinforcement rate and thus evoked different amounts of responding during the CS. We conclude that reinforcement rate per second controls rats' acquisition of responding during the CS, but at the same time, rats also learn specifically about the probability of reinforcement per trial. The latter learning affects the rats' expectation of reinforcement as an outcome of the trial, which influences their ability to detect retrospectively that an opportunity for reinforcement was missed, and, in turn, drives extinction. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Targeted vs. systematic early antiviral treatment against A(H1N1)v influenza with neuraminidase inhibitors in patients with influenza-like symptoms: Clinical and economic impact

PubMed Central

Deuffic-Burban, Sylvie; Lenne, Xavier; Dervaux, Benoit; Julien Poissy; Lemaire, Xavier; Sloan, Caroline; Carrat, Fabrice; Desenclos, Jean-Claude; Delfraissy, Jean-Francois; Yazdanpanah, Yazdan

2009-01-01

Capitalizing on available data, we used a decision model to estimate the clinical and economic outcomes associated with early initiation of treatment with neuraminidase inhibitors in all patients with influenza-like illnesses ( ILI ) (systematic strategy) vs. only those at high risk of complications (targeted strategy). Systematic treatment of ILI during an A(H1N1)v influenza epidemic wave is both effective and cost-effective. Patients who present to care with ILI during an A(H1N1)v influenza epidemic wave should initiate treatment with neuraminidase inhibitors, regardless of risk status. Administering neuraminidase inhibitors between epidemic waves, when the probability of influenza is low, is less effective and cost-effective. PMID:20029659

Pregnancy Complicated by Obesity Induces Global Transcript Expression Alterations in Visceral and Subcutaneous Fat

PubMed Central

Bashiri, Asher; Heo, Hye J.; Ben-Avraham, Danny; Mazor, Moshe; Budagov, Temuri; Einstein, Francine H.; Atzmon, Gil

2014-01-01

Maternal obesity is a significant risk factor for development of both maternal and fetal metabolic complications. Increase in visceral fat and insulin resistance is a metabolic hallmark of pregnancy, yet little is known how obesity alters adipose cellular function and how this may contribute to pregnancy morbidities. We sought to identify alterations in genome-wide transcription expression in both visceral (omental) and abdominal subcutaneous fat deposits in pregnancy complicated by obesity. Visceral and abdominal subcutaneous fat deposits were collected from normal weight and obese pregnant women (n=4/group) at time of scheduled uncomplicated cesarean section. A genome-wide expression array (Affymetrix Human Exon 1.0 st platform), validated by quantitative real-time PCR, was utilized to establish the gene transcript expression profile in both visceral and abdominal subcutaneous fat in normal weight and obese pregnant women. Global alteration in gene expression was identified in pregnancy complicated by obesity. These regions of variations lead to identification of indolethylamine N-methyltransferase (INMT), tissue factor pathway inhibitor-2 (TFPI-2), and ephrin type-B receptor 6 (EPHB6), not previously associated with fat metabolism during pregnancy. In addition, subcutaneous fat of obese pregnant women demonstrated increased coding protein transcripts associated with apoptosis compared to lean counterparts. Global alteration of gene expression in adipose tissue may contribute to adverse pregnancy outcomes associated with obesity. PMID:24696292

Neurological Complications Associated With Anti-Programmed Death 1 (PD-1) Antibodies.

PubMed

Kao, Justin C; Liao, Bing; Markovic, Svetomir N; Klein, Christopher J; Naddaf, Elie; Staff, Nathan P; Liewluck, Teerin; Hammack, Julie E; Sandroni, Paola; Finnes, Heidi; Mauermann, Michelle L

2017-10-01

Neurological complications are an increasingly recognized consequence of the use of anti-programmed death 1 (PD-1) antibodies in the treatment of solid-organ tumors, with an estimated frequency of 4.2%. To date, the clinical spectrum and optimum treatment approach are not established. To investigate the frequency, clinical spectrum, and optimum treatment approach to neurological complications associated with anti-PD-1 therapy. This single-center, retrospective cohort study was conducted from either September or December 2014 (the approval dates of the study drugs by the US Food and Drug Administration) to May 19, 2016. All patients receiving anti-PD-1 monoclonal antibodies were identified using the Mayo Cancer Pharmacy Database. Patients with development of neurological symptoms within 12 months of anti-PD-1 therapy were included. Patients with neurological complications directly attributable to metastatic disease or other concurrent cancer-related treatments were excluded. Clinical and pathological characteristics, time to development of neurological symptoms, and modified Rankin Scale (mRS) score. Among 347 patients treated with anti-PD1 monoclonal antibodies (pembrolizumab or nivolumab), 10 (2.9%) developed subacute onset of neurological complications. Seven patients were receiving pembrolizumab, and 3 patients were receiving nivolumab. The patients included 8 men and 2 women. Their median age was 71 years (age range, 31-78 years). Neurological complications occurred after a median of 5.5 (range, 1-20) cycles of anti-PD-1 inhibitors. Complications included myopathy (n = 2), varied neuropathies (n = 4), cerebellar ataxia (n = 1), autoimmune retinopathy (n = 1), bilateral internuclear ophthalmoplegia (n = 1), and headache (n = 1). Peripheral neuropathies included axonal and demyelinating polyradiculoneuropathies (n = 2), length-dependent neuropathies (n = 1), and asymmetric vasculitic neuropathy (n = 1). The time to maximum

Polyphenol oxidase inhibitor(s) from German cockroach (Blattella germanica) extract

USDA-ARS?s Scientific Manuscript database

An extract from German cockroach appears effective in inhibiting browning on apples and potatoes. Successful identification of inhibitor(s) of PPO from German cockroach would be useful to the fruit and vegetable segments of the food industry, due to the losses they incur from enzymatic browning. Ide...

The role played by serine proteases in the development and worsening of vascular complications in type 1 diabetes mellitus.

PubMed

Finotti, Paola

2006-08-01

Much attention has been given to the role played by serine proteases in the development and worsening of vascular complications in Type 1 diabetes mellitus. A generalized increase in proteolytic activity, either due to a true increase in concentration of specific proteases or defects of their protease inhibitors, represents an early marker of diabetes. However, the precise molecular mechanism whereby an unopposed proteolytic activity leads to overt vascular alterations has not fully been elucidated as yet. The picture is further complicated by the fact that, although sharing the same function, serine proteases constitute a structurally heterogeneous class of molecules. Besides classical proteases, for most part belonging to coagulative and fibrinolytic systems, other unrelated molecules exhibit serine-like protease activity and are capable of triggering both inflammatory and immune reactions. The specific role of these non classical serine proteases in the complex pathogenesis of diabetes and its vascular complications is attracting a new investigative interest, as these molecules may represent additional therapeutic targets. This review will focus on most recent acquisitions on this issue relevant to Type 1 diabetes.

Development of a small-molecule screening method for inhibitors of cellular response to myostatin and activin A.

PubMed

Cash, Jennifer N; Angerman, Elizabeth B; Kirby, R Jason; Merck, Lisa; Seibel, William L; Wortman, Matthew D; Papoian, Ruben; Nelson, Sandra; Thompson, Thomas B

2013-08-01

Myostatin, a member of the transforming growth factor (TGF)-β family of secreted ligands, is a strong negative regulator of muscle growth. As such, therapeutic inhibitors of myostatin are actively being investigated for their potential in the treatment of muscle-wasting diseases such as muscular dystrophy and sarcopenia. Here, we sought to develop a high-throughput screening (HTS) method for small-molecule inhibitors that target myostatin. We created a HEK293 stable cell line that expresses the (CAGA)12-luciferase reporter construct and robustly responds to signaling of certain classes of TGF-β family ligands. After optimization and miniaturization of the assay to a 384-well format, we successfully screened a library of compounds for inhibition of myostatin and the closely related activin A. Selection of some of the tested compounds was directed by in silico screening against myostatin, which led to an enrichment of target hits as compared with random selection. Altogether, we present an HTS method that will be useful for screening potential inhibitors of not only myostatin but also many other ligands of the TGF-β family.

Dental Implant Complications.

PubMed

Liaw, Kevin; Delfini, Ronald H; Abrahams, James J

2015-10-01

Dental implants have increased in the last few decades thus increasing the number of complications. Since many of these complications are easily diagnosed on postsurgical images, it is important for radiologists to be familiar with them and to be able to recognize and diagnose them. Radiologists should also have a basic understanding of their treatment. In a pictorial fashion, this article will present the basic complications of dental implants which we have divided into three general categories: biomechanical overload, infection or inflammation, and other causes. Examples of implant fracture, loosening, infection, inflammation from subgingival cement, failure of bone and soft tissue preservation, injury to surround structures, and other complications will be discussed as well as their common imaging appearances and treatment. Lastly, we will review pertinent dental anatomy and important structures that are vital for radiologists to evaluate in postoperative oral cavity imaging. Copyright © 2015 Elsevier Inc. All rights reserved.

Do "placebo responders" exist?

PubMed

Kaptchuk, Ted J; Kelley, John M; Deykin, Aaron; Wayne, Peter M; Lasagna, Louis C; Epstein, Ingrid O; Kirsch, Irving; Wechsler, Michael E

2008-07-01

The placebo effect has been the subject of much controversy. For a scientific investigation of placebo effects to advance it is important to establish whether a placebo response in any particular illness is reliable - i.e., if there is a response to a single placebo administration there will also be a placebo response to the repeated administration of a similar placebo in similar conditions. A positive answer would allow more sophisticated clinical trial designs and more precise basic research experiments on the placebo effect. This article reviews experiments that used multiple administrations of placebo to answer the question "do reliable placebo responders exist?" This paper also examines the evidence for the existence of a consistent placebo responder, i.e. a person who responds to placebo in one situation will respond in another condition or using a different type of placebo ritual. Much of the existing evidence for these two questions was performed before 1967. This early evidence is contradictory, methodologically weak and is sufficiently old to be considered medical history. Since 1969, at least eight experiments exposed asthma patients to multiple administrations of placebo given with deceptive suggestions that the "treatment" was an active medication. While the results of this research are not unequivocal, and may not be equivalent to non-deceptive conditions, this line of inquiry suggests that if a reliable and consistent placebo response exists it could be detected within this population. Finally, this paper proposes one model to rigorously investigate the stability of placebo responses.

Placenta associated pregnancy complications in pregnancies complicated with placenta previa.

PubMed

Baumfeld, Yael; Herskovitz, Reli; Niv, Zehavi Bar; Mastrolia, Salvatore Andrea; Weintraub, Adi Y

2017-06-01

The purpose of our study was to examine the hypothesis that pregnancies complicated with placenta previa have an increased risk of placental insufficiency associated pregnancy complications (IUGR, preeclampsia, placental abruption and perinatal mortality). Our study included all deliveries that occurred at Soroka University Medical Center (Beer Sheva, Israel) between January 1998 and December 2013. Of them 1,249 were complicated by placenta previa and represented our study group. A composite outcome was created to include conditions associated with placental insufficiency. It included hypertensive disorders (i.e. gestational hypertension, mild and severe preeclampsia, HELLP and eclampsia), small for gestational age neonates and placental abruption. Patients with pregnancy complicated by placenta previa had significantly different obstetrical characteristics including bad obstetric history (8% vs. 4%, p < 0.001), recurrent abortions (11% vs. 5%, p < 0.001). Patients with placenta previa had higher rates of vaginal bleeding in the second half of pregnancy (3% vs. 0%, p < 0.001), gestational diabetes (8% vs. 5.5%, p < 0.001), placental abruption (10% vs. 1%, p < 0.001), adherent placenta (4% vs. 0.5%, p < 0.001), preterm delivery (52% vs. 8%, p < 0.001), with a median gestational age of 36 vs. 39 weeks, p < 0.001. The composite outcome was significantly more prevalent in the placenta previa group (21% vs. 13%, p < 0,001). Our study demonstrated an increased rate of placental insufficiency associated complications in women with placenta previa. This is of clinical relevance and suggests that a careful surveillance for women with placenta previa may help in minimizing maternal, fetal and neonatal complications. Copyright © 2017. Published by Elsevier B.V.

The Place of Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes Therapeutics: A “Me Too” or “the Special One” Antidiabetic Class?

PubMed Central

Godinho, Ricardo; Carvalho, Eugénia; Teixeira, Frederico

2015-01-01

Incretin-based therapies, the most recent therapeutic options for type 2 diabetes mellitus (T2DM) management, can modify various elements of the disease, including hypersecretion of glucagon, abnormal gastric emptying, postprandial hyperglycaemia, and, possibly, pancreatic β cell dysfunction. Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) increase glucagon-like peptide-1 (GLP-1) availability and correct the “incretin defect” seen in T2DM patients. Clinical studies have shown good glycaemic control with minimal risk of hypoglycaemia or any other adverse effects, despite the reports of pancreatitis, whose association remains to be proved. Recent studies have been focusing on the putative ability of DPP-4 inhibitors to preserve pancreas function, in particular due to the inhibition of apoptotic pathways and stimulation of β cell proliferation. In addition, other cytoprotective effects on other organs/tissues that are involved in serious T2DM complications, including the heart, kidney, and retina, have been increasingly reported. This review outlines the therapeutic potential of DPP-4 inhibitors for the treatment of T2DM, focusing on their main features, clinical applications, and risks, and discusses the major challenges for the future, in particular the possibility of becoming the preferred therapy for T2DM due to their ability to modify the natural history of the disease and ameliorate nephropathy, retinopathy, and cardiovascular complications. PMID:26075286

Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema.

PubMed

Brown, Nancy J; Byiers, Stuart; Carr, David; Maldonado, Mario; Warner, Barbara Ann

2009-09-01

Dipeptidyl peptidase-IV (DPP-IV) inhibitors decrease degradation of the incretins. DPP-IV inhibitors also decrease degradation of peptides, such as substance P, that may be involved in the pathogenesis of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. This study tested the hypothesis that DPP-IV inhibition affects risk of clinical angioedema, by comparing the incidence of angioedema in patients treated with the DPP-IV inhibitor vildagliptin versus those treated with comparator in Phase III randomized clinical trials. Prospectively defined angioedema-related events were adjudicated in a blinded fashion by an internal medicine adjudication committee and expert reviewer. Concurrent ACE inhibitor or angiotensin receptor blocker exposure was ascertained from case report forms. Study drug exposure was ascertained from unblinded data from phase III studies. Odds ratios and 95% confidence intervals comparing angioedema risk in vildagliptin-treated and comparator-treated patients were calculated for the overall population and for patients taking ACE inhibitors or angiotensin receptor blockers, using both an analysis of pooled data and a meta-analysis (Peto method). Overall, there was no association between vildagliptin use and angioedema. Among individuals taking an ACE inhibitor, however, vildagliptin use was associated with an increased risk of angioedema (14 confirmed cases among 2754 vildagliptin users versus 1 case among 1819 comparator users: odds ratio 4.57 [95% confidence interval 1.57 to 13.28]) in the meta-analysis. Vildagliptin use may be associated with increased risk of angioedema among patients taking ACE inhibitors, although absolute risk is small. Physicians confronted with angioedema in a patient taking an ACE inhibitor and DPP-IV inhibitor should consider this possible drug-drug interaction.

Intratemporal complications of otitis media.

PubMed

Maranhão, André Souza de Albuquerque; Andrade, José Santos Cruz de; Godofredo, Valéria Romero; Matos, Rafaella Caruso; Penido, Norma de Oliveira

2013-01-01

Otitis media (OM) is considered a potentially severe disease due to the risk of complications. To establish the annual incidence of intratemporal complications (ITC) resulting from OM and to prospectively assess patients for epidemiological and clinical factors. This prospective cohort study included patients admitted during one year at a university hospital diagnosed with intratemporal complications of OM. Patients were analyzed for age, gender, type of intratemporal complication, treatment, and clinical outcome. The overall incidence of complications and the specific incidence rates of each type of complication were determined. 1,816 patients were diagnosed with OM; 592 (33%) had chronic OM; 1224 (67%) had acute OM. Fifteen patients were diagnosed with OM ITC, adding up to an annual incidence of 0.8%. Nineteen diagnoses of ITC were made in 15 patients. Seven (36.8%) patients were diagnosed with labyrinthine fistula, five (26.3%) with mastoiditis, four (21.1%) with peripheral facial palsy, and three (15.8%) with labyrinthitis. The incidence of intratemporal complications remains significant when compared to the rates seen in developed countries. Chronic cholesteatomatous otitis media is the most frequent etiology of intratemporal complications. Labyrinthine fistula is the most common intratemporal complication.

ACE Phenotyping as a Guide Toward Personalized Therapy With ACE Inhibitors.

PubMed

Danilov, Sergei M; Tovsky, Stan I; Schwartz, David E; Dull, Randal O

2017-07-01

Angiotensin-converting enzyme (ACE) inhibitors (ACEI) are widely used in the management of cardiovascular diseases but with significant interindividual variability in the patient's response. To investigate whether interindividual variability in the response to ACE inhibitors is explained by the "ACE phenotype"-for example, variability in plasma ACE concentration, activity, and conformation and/or the degree of ACE inhibition in each individual. The ACE phenotype was determined in plasma of 14 patients with hypertension treated chronically for 4 weeks with 40 mg enalapril (E) or 20 mg E + 16 mg candesartan (EC) and in 20 patients with hypertension treated acutely with a single dose (20 mg) of E with or without pretreatment with hydrochlorothiazide. The ACE phenotyping included (1) plasma ACE concentration; (2) ACE activity (with 2 substrates: Hip-His-Leu and Z-Phe-His-Leu and calculation of their ratio); (3) detection of ACE inhibitors in patient's blood (indicator of patient compliance) and the degree of ACE inhibition (ie, adherence); and (4) ACE conformation. Enalapril reduced systolic and diastolic blood pressure in most patients; however, 20% of patients were considered nonresponders. Chronic treatment results in 40% increase in serum ACE concentrations, with the exception of 1 patient. There was a trend toward better response to ACEI among patients who had a higher plasma ACE concentration. Due to the fact that "20% of patients do not respond to ACEI by blood pressure drop," the initial blood ACE level could not be a predictor of blood pressure reduction in an individual patient. However, ACE phenotyping provides important information about conformational and kinetic changes in ACE of individual patients, and this could be a reason for resistance to ACE inhibitors in some nonresponders.

Effect of counseling quality on anxiety, grief, and coping after second-trimester abortion for pregnancy complications.

PubMed

Kerns, Jennifer L; Mengesha, Biftu; McNamara, Blair C; Cassidy, Arianna; Pearlson, Geffan; Kuppermann, Miriam

2018-06-01

We sought to explore the relationship between counseling quality, measured by shared decision making and decision satisfaction, and psychological outcomes (anxiety, grief, and posttraumatic stress) after second-trimester abortion for pregnancy complications. We conducted a cross-sectional study of women who underwent second-trimester abortion for complications. We recruited participants from Facebook and online support groups and surveyed them about counseling experiences and psychosocial issues. We used multivariate linear regression to evaluate relationships between counseling quality and psychological outcomes. We analyzed data from 145 respondents. Shared decision making and decision satisfaction scores were positively and strongly correlated in bivariate analysis (r=0.7, p<.0001), as were posttraumatic stress and grief scores (r=0.7, p<.0001). In the adjusted analysis, higher decision satisfaction was associated with lower grief and posttraumatic stress scores (p=.02 and p=.01, respectively) and higher shared decision making was associated with lower posttraumatic stress scores (p=.01). Decision satisfaction and shared decision making have a positive effect on psychological outcomes after second-trimester abortion for pregnancy complications. Counseling quality may be especially important in this setting given the sensitive nature of decisions regarding pregnancy termination for complications. These results highlight the importance of patient-centered counseling for women seeking pregnancy termination. Copyright © 2018. Published by Elsevier Inc.

Sulfonylureas as Concomitant Insulin Secretagogues and NLRP3 Inflammasome Inhibitors.

PubMed

Hill, James R; Coll, Rebecca C; Sue, Nancy; Reid, Janet C; Dou, Jennifer; Holley, Caroline L; Pelingon, Ruby; Dickinson, Joshua B; Biden, Trevor J; Schroder, Kate; Cooper, Matthew A; Robertson, Avril A B

2017-09-07

Insulin-secretory sulfonylureas are widely used, cost-effective treatments for type 2 diabetes (T2D). However, pancreatic β-cells are continually depleted as T2D progresses, thereby rendering the sulfonylurea drug class ineffective in controlling glycaemia. Dysregulation of the innate immune system via activation of the NLRP3 inflammasome, and the consequent production of interleukin-1β, has been linked to pancreatic β-cell death and multiple inflammatory complications of T2D disease. One proposed strategy for treating T2D is the use of sulfonylurea insulin secretagogues that are also NLRP3 inhibitors. We report the synthesis and biological evaluation of nine sulfonylureas that inhibit NLRP3 activation in murine bone-marrow- derived macrophages in a potent, dose-dependent manner. Six of these compounds inhibited NLRP3 at nanomolar concentrations and can also stimulate insulin secretion from a murine pancreatic cell line (MIN6). These novel compounds possess unprecedented dual modes of action, paving the way for a new generation of sulfonylureas that may be useful as therapeutic candidates and/or tool compounds in T2D and its associated inflammatory complications. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Removal of inhibitor(s) of the polymerase chain reaction from formalin fixed, paraffin wax embedded tissues.

PubMed

An, S F; Fleming, K A

1991-11-01

A problem associated with use of the polymerase chain reaction to amplify specific DNA fragments from formalin fixed, paraffin wax embedded tissues is the not infrequent failure of amplification. One possible reason for this could be the presence of inhibitor(s), which interfere with the activity of the reaction. It has been shown that such inhibitor(s) exist when amplifying the human beta globin gene (which exists in human genomic DNA as a single copy gene) from routine clinical samples. A variety of methods to remove such inhibitor(s) were investigated. The results indicate that inhibitor(s) are removed by proteinase K digestion, followed by purification with phenol/chloroform, and centrifugation through a Centricon-30 membrane (30,000 molecular weight cut off). Other factors, including the length and concentration of the DNA sequence to be amplified, can also affect amplification.

Plasma oxytocin changes and anti-obsessive response during serotonin reuptake inhibitor treatment: a placebo controlled study.

PubMed

Humble, Mats B; Uvnäs-Moberg, Kerstin; Engström, Ingemar; Bejerot, Susanne

2013-12-23

The drug treatments of choice for obsessive-compulsive disorder (OCD) are serotonin reuptake inhibitors (SRIs). However, a correlation between the neuropeptide oxytocin in cerebrospinal fluid and the severity of OCD has previously been shown, and oxytocin and serotonin are interconnected within the brain. Few studies have investigated whether SRIs have any effect on oxytocin; thus, our aim was to explore the possibility that oxytocinergic mechanisms contribute to the anti-obsessive effect of SRIs. In a randomized, double-blind trial, comparing SRIs (clomipramine and paroxetine) with placebo in 36 adults with OCD (characterized for subtypes), plasma oxytocin was measured with radioimmunoassay after plasma extraction, at baseline, after 1 week, and after 4 weeks of treatment, and related to baseline severity and clinical response after 12 weeks, as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Baseline oxytocin levels correlated positively with baseline Y-BOCS ratings, but only among the future SRI responders. Patients with early onset of OCD had higher baseline oxytocin. During treatment, plasma oxytocin did not differ between SRI and placebo treatment. In SRI responders, plasma oxytocin first decreased and then increased; in non-responders (to SRI as well as to placebo), the reverse was the case. After 4 weeks, treatment responders had attained higher oxytocin levels compared to non-responders. The intra-individual range (i.e., the variability) of plasma oxytocin between measurements was the measure that best differentiated responders from non-responders. This range was higher in responders than non-responders, and lower in patients with autistic traits. SRIs have highly variable effects on plasma oxytocin between individuals. The associations between baseline oxytocin and OCD severity and between oxytocin changes and treatment response support the notions that oxytocin is involved in OCD pathophysiology, and that the anti-obsessive effects of

The influence of scale inhibitors on calcium oxalate

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

Gill, J.S.

1999-11-01

Precipitation of calcium oxalate is a common occurrence in mammalian urinary tract deposits and in various industrial processes such as paper making, brewery fermentation, sugar evaporation, and tannin concentration. Between pH 3.5 to 4.5 the driving force for calcium oxalate precipitation increases almost by three fold. It is a complicated process to predict both the nature of a deposit and at which stage of a multi-effect evaporator a particular mineral will deposit, as this depends on temperature, pH, total solids, and kinetics of mineralization. It is quite a challenge to inhibit calcium oxalate precipitation in the pH range of 4--6.more » Al{sup 3+} ions provide excellent threshold inhibition in this pH range and can be used to augment traditional inhibitors such as polyphosphates and polycarboxylates.« less

[Complications of induced abortion].

PubMed

Kretowicz, J

1984-03-26

The abortion problem has been a major topic of debate for many years. Polish legislation permitting abortion has both supporters and opponents. It appears that both groups fail to fully recognize the risks of the various medical complications of induced abortion. A literature review of the complications of abortion shows that these complications are often underestimated by the public and the medical community. The review clearly demonstrates that abortion adversely affects women's health. Inflammation of the genital system is the most frequent complication. The ocurrence of complications increases as the term of the pregnancy advances. It is concluded that the public is not fully aware of the immediate danger and aftereffects of induced abortion. Wider popularization of the extensive body of scientific information regarding the risks of induced abortion might change current perceptions about the "safety" of abortion.

Case series: Two cases of eyeball tattoos with short-term complications.

PubMed

Duarte, Gonzalo; Cheja, Rashel; Pachón, Diana; Ramírez, Carolina; Arellanes, Lourdes

2017-04-01

To report two cases of eyeball tattoos with short-term post procedural complications. Case 1 is a 26-year-old Mexican man that developed orbital cellulitis and posterior scleritis 2 h after an eyeball tattoo. Patient responded satisfactorily to systemic antibiotic and corticosteroid treatment. Case 2 is a 17-year-old Mexican man that developed two sub-episcleral nodules in the ink injection sites immediately after the procedure. Eyeball tattoos are performed by non-ophthalmic trained personnel. There are a substantial number of short-term risks associated with this procedure. Long-term effects on the eyes and vision are still unknown, but in a worst case scenario could include loss of vision or permanent damage to the eyes.

[Surgical complications of colostomies].

PubMed

Ben Ameur, Hazem; Affes, Nejmeddine; Rejab, Haitham; Abid, Bassem; Boujelbene, Salah; Mzali, Rafik; Beyrouti, Mohamed Issam

2014-07-01

The colostomy may be terminal or lateral, temporary or permanent. It may have psychological, medical or surgical complications. reporting the incidence of surgical complications of colostomies, their therapeutic management and trying to identify risk factors for their occurrence. A retrospective study for a period of 5 years in general surgery department, Habib Bourguiba hospital, Sfax, including all patients operated with confection of a colostomy. Were then studied patients reoperated for stoma complication. Among the 268 patients who have had a colostomy, 19 patients (7%) developed surgical stoma complications. They had a mean age of 59 years, a sex ratio of 5.3 and a 1-ASA score in 42% of cases. It was a prolapse in 9 cases (reconfection of the colostomy: 6 cases, restoration of digestive continuity: 3 cases), a necrosis in 5 cases (reconfection of the colostomy), a plicature in 2 cases (reconfection of the colostomy) a peristomal abscess in 2 cases (reconfection of the colostomy: 1 case, restoration of digestive continuity: 1 case) and a strangulated parastomal hernia in 1 case (herniorrhaphy). The elective incision and the perineal disease were risk factors for the occurrence of prolapse stomial. Surgical complications of colostomies remain a rare event. Prolapse is the most common complication, and it is mainly related to elective approach. Reoperation is often required especially in cases of early complications, with usually uneventful postoperative course.

Two antagonistic gustatory receptor neurons responding to sweet-salty and bitter taste in Drosophila.

PubMed

Hiroi, Makoto; Meunier, Nicolas; Marion-Poll, Frédéric; Tanimura, Teiichi

2004-12-01

In Drosophila, gustatory receptor neurons (GRNs) occur within hair-like structures called sensilla. Most taste sensilla house four GRNs, which have been named according to their preferred sensitivity to basic stimuli: water (W cell), sugars (S cell), salt at low concentration (L1 cell), and salt at high concentration (L2 cell). Labellar taste sensilla are classified into three types, l-, s-, and i-type, according to their length and location. Of these, l- and s-type labellar sensilla possess these four cells, but most i-type sensilla house only two GRNs. In i-type sensilla, we demonstrate here that the first GRN responds to sugar and to low concentrations of salt (10-50 mM NaCl). The second GRN detects a range of bitter compounds, among which strychnine is the most potent; and also to salt at high concentrations (over 400 mM NaCl). Neither type of GRN responds to water. The detection of feeding stimulants in i-type sensilla appears to be performed by one GRN with the combined properties of S+L1 cells, while the other GRN detects feeding inhibitors in a similar manner to bitter-sensitive L2 cells on the legs. These sensilla thus house two GRNs having an antagonistic effect on behavior, suggesting that the expression of taste receptors is segregated across them accordingly. copyright (c) 2004 Wiley Periodicals, Inc.

The characteristics of non-respondents and respondents of a mental health survey among evacuees in a disaster: The Fukushima Health Management Survey

PubMed Central

Horikoshi, Naoko; Iwasa, Hajime; Yasumura, Seiji; Maeda, Masaharu

2017-01-01

Abstract The Fukushima Medical University conducted a mental health care program for evacuees after the Fukushima Daiichi nuclear power plant accident. However, the mental health status of non-respondents has not been considered for surveys using questionnaires. Therefore, the aim of this study was to clarify the characteristics of non-respondents and respondents. The target population of the survey (FY2011-2013) is people living in the nationally designated evacuation zone of Fukushima prefecture. Among these, the participants were 967 people (20 years or older). We examined factors that affected the difference between the groups of participants (i.e., non-respondents and respondents) using multivariate logistic regression analysis. Employment was higher in non-respondents (p=0.022) and they were also more socially isolated (p=0.047) when compared to respondents; non-respondents had a higher proportional risk of psychological distress compared to respondents (p<0.033). The results of the multivariate logistic regression analysis showed that, within the participants there was a significant association between employment status (OR=1.99, 95% confidence interval [CI]:1.12-3.51) and psychological distress (OR=2.17, 95% CI: 1.01-4.66). We found that non-respondents had a significantly higher proportion of psychological distress compared to the respondents. Although the non-respondents were the high-risk group, it is not possible to grasp the complexity of the situation by simply using questionnaire surveys. Therefore, in the future it is necessary to direct our efforts towards the mental health of non-respondents and respondents alike. PMID:29237989

The characteristics of non-respondents and respondents of a mental health survey among evacuees in a disaster: The Fukushima Health Management Survey.

PubMed

Horikoshi, Naoko; Iwasa, Hajime; Yasumura, Seiji; Maeda, Masaharu

2017-12-19

The Fukushima Medical University conducted a mental health care program for evacuees after the Fukushima Daiichi nuclear power plant accident. However, the mental health status of non-respondents has not been considered for surveys using questionnaires. Therefore, the aim of this study was to clarify the characteristics of non-respondents and respondents. The target population of the survey (FY2011-2013) is people living in the nationally designated evacuation zone of Fukushima prefecture. Among these, the participants were 967 people (20 years or older). We examined factors that affected the difference between the groups of participants (i.e., non-respondents and respondents) using multivariate logistic regression analysis. Employment was higher in non-respondents (p=0.022) and they were also more socially isolated (p=0.047) when compared to respondents; non-respondents had a higher proportional risk of psychological distress compared to respondents (p<0.033). The results of the multivariate logistic regression analysis showed that, within the participants there was a significant association between employment status (OR=1.99, 95% confidence interval [CI]:1.12-3.51) and psychological distress (OR=2.17, 95% CI:1.01-4.66). We found that non-respondents had a significantly higher proportion of psychological distress compared to the respondents. Although the non-respondents were the high-risk group, it is not possible to grasp the complexity of the situation by simply using questionnaire surveys. Therefore, in the future it is necessary to direct our efforts towards the mental health of non-respondents and respondents alike.

Platelet glycoprotein IIb/IIIa inhibitors in acute ischemic stroke.

PubMed

Kumar, Sudhir; Rajshekher, G; Prabhakar, Subhashini

2008-01-01

Acute ischemic stroke (AIS) is a common cause of morbidity and mortality worldwide. Thrombolytic therapy with tissue plasminogen activator, the only approved treatment for AIS, is received by less than 2% of patients. Moreover, there is a slight increase in hemorrhagic complications with thrombolysis. Therefore, there is a need for newer therapeutic modalities in AIS, which could be used in window periods beyond 3-6 h after stroke onset with fewer hemorrhagic complications. Glycoprotein IIb/IIIa inhibitors (GPI), after their initial success in patients with acute coronary syndromes, promised much in patients with AIS over the past decade or so. However, their exact role in patients with AIS, including the window periods and type of strokes, and the risk of symptomatic or asymptomatic hemorrhage are unclear at the moment. The current review focuses on the literature concerning the use of GPI in AIS and looks at the available evidence regarding their use. Abciximab thought to be safe and effective in initial case series and early trials, has not been shown to improve outcomes in AIS, and is associated with higher rates of hemorrhage. Tirofiban appears to be safe and effective in initial trials and there is a need to conduct further trials to establish its role in AIS.

Recreational Use of Phosphodiesterase 5 Inhibitors and Its Associated Factors among Undergraduate Male Students in an Ethiopian University: A Cross-Sectional Study

PubMed Central

Bhagavathula, Akshaya Srikanth; Gebresillassie, Begashaw Melaku; Tefera, Yonas Getaye; Belachew, Sewunet Admasu; Erku, Daniel Asfaw

2016-01-01

Purpose To assess the prevalence of phosphodiesterase 5 (PDE5) inhibitor use and associated factors among University of Gondar undergraduate students. Materials and Methods An institution-based, cross-sectional study, using a survey questionnaire, was conducted from October to December 2015 to assess PDE5 inhibitor use and associated factors among male students at the University of Gondar. A Self-Esteem and Relationship questionnaire (14 items), an International Index of Erectile Function questionnaire (15 items) and a questionnaire on PDE5 inhibitor use (14 items) were included in the survey. Results Across all respondents (age, 21.9±1.88 years), more than half (55.7%, n=233) had heard about PDE5 inhibitors, but only 23 men (5.5%) reported trying a PDE5 inhibitor drug at least once. Older students were more likely to use PDE5 inhibitors compared to younger students (adjusted odds ratio [AOR], 1.40; 95% confidence interval [CI], 1.109~1.768). Those students who were smokers were 5.15 times more likely to use PDE5 inhibitors as compared to their non-smoking counterparts (AOR, 5.15; 95% CI, 2.096~12.687). In addition, multivariate logistic regression showed that being in a relationship, alcohol use, greater number of cigarettes smoked per day, and more sexual partners were significantly associated with PDE5 inhibitor use. Conclusions The prevalence of PDE5 inhibitor use among undergraduate students was 5.5%. Cigarette smoking and other substance use, older age, and greater number of sexual partners were significantly associated factors for PDE5 inhibitor use. These findings suggest that restricting access to PDE5 inhibitor drugs is essential to curtailing misuse among university students. PMID:28053948

Carboxylesterase inhibitors

PubMed Central

Hatfield, M. Jason; Potter, Philip M.

2011-01-01

Introduction Carboxylesterases play major roles in the hydrolysis of numerous therapeutically active compounds. This is, in part, due to the prevalence of the ester moiety in these small molecules. However, the impact these enzymes may play on drug stability and pharmacokinetics is rarely considered prior to molecule development. Therefore, the application of selective inhibitors of this class of proteins may have utility in modulating the metabolism, distribution and toxicity of agents that are subjected to enzyme hydrolysis. Areas covered This review details the development of all such compounds dating back to 1986, but principally focuses on the very recent identification of selective human carboxylesterases inhibitors. Expert opinion The implementation of carboxylesterase inhibitors may significantly revolutionize drug discovery. Such molecules may allow for improved efficacy of compounds inactivated by this class of enzymes and/or reduce the toxicity of agents that are activated by these proteins. Furthermore, since lack of carboxylesterase activity appears to have no obvious biological consequence, these compounds could be applied in combination with virtually any esterified drug. Therefore, inhibitors of these proteins may have utility in altering drug hydrolysis and distribution in vivo. The characteristics, chemical and biological properties, and potential uses of such agents, are discussed here. PMID:21609191

[Complications in pediatric anesthesia].

PubMed

Becke, K

2014-07-01

As in adult anesthesia, morbidity and mortality could be significantly reduced in pediatric anesthesia in recent decades. This fact cannot conceal the fact that the incidence of anesthetic complications in children is still much more common than in adults and sometimes with a severe outcome. Newborns and infants in particular but also children with emergency interventions and severe comorbidities are at increased risk of potential complications. Typical complications in pediatric anesthesia are respiratory problems, medication errors, difficulties with the intravenous puncture and pulmonal aspiration. In the postoperative setting, nausea and vomiting, pain, and emergence delirium can be mentioned as typical complications. In addition to the systematic prevention of complications in pediatric anesthesia, it is important to quickly recognize disturbances of homeostasis and treat them promptly and appropriately. In addition to the expertise of the performing anesthesia team, the institutional structure in particular can improve quality and safety in pediatric anesthesia.

Lisinopril. A review of its pharmacology and use in the management of the complications of diabetes mellitus.

PubMed

Goa, K L; Haria, M; Wilde, M I

1997-06-01

Lisinopril, like other ACE inhibitors, lowers blood pressure and preserves renal function in hypertensive patients with non-insulin-dependent or insulin-dependent diabetes mellitus (NIDDM or IDDM) and early or overt nephropathy, without adversely affecting glycaemic control or lipid profiles. On available evidence, renoprotective effects appear to be greater with lisinopril than with comparator calcium channel blockers, diuretics and beta-blockers, despite similar antihypertensive efficacy. As shown by the EUCLID (EUrodiab Controlled trial of Lisinopril in Insulin-Dependent Diabetes) trial, lisinopril is also renoprotective in normotensive patients with IDDM and microalbuminuria. The effect in normotensive patients with normoalbuminuria was smaller than in those with microalbuminuria, and no conclusions can yet be made about its use in patients with normoalbuminuria. In complications other than nephropathy, lisinopril has shown some benefit. Progression to retinopathy was slowed during 2 years' lisinopril therapy in the EUCLID study. Although not yet fully published, these results provide the most convincing evidence to date for an effect of an ACE inhibitor in retinopathy. The drug may also improve neurological function, but this finding is preliminary. Lastly, post hoc analysis of the GISSI-3 trial indicates that lisinopril reduces 6-week mortality rates in diabetic patients when begun as early treatment after an acute myocardial infarction. The tolerability profile of lisinopril is typical of ACE inhibitors and appears to be similar in diabetic and nondiabetic individuals. Hypoglycaemia has occurred at a similar frequency with lisinopril and placebo, as shown in the EUCLID trial. In addition, the GISSI-3 study indicates that the incidence of persistent hypotension and renal dysfunction is increased with lisinopril in general, but the presence of diabetes does not appear to confer additional risk of these events in diabetic patients with acute myocardial

Reduced tyrosine kinase inhibitor dose is predicted to be as effective as standard dose in chronic myeloid leukemia: A simulation study based on phase 3 trial data.

PubMed

Fassoni, Artur C; Baldow, Christoph; Roeder, Ingo; Glauche, Ingmar

2018-06-28

Continuing tyrosine kinase inhibitor mediated targeting of the BCR-ABL1 oncoprotein is the standard therapy for chronic myeloid leukemia and allows for a sustained disease control in the majority of patients. While therapy cessation for patients appeared as a safe option for about half of the optimally responding patients, a systematic assessment of long-term tyrosine kinase inhibitor dose de-escalation is missing. We use a mathematical model to analyze and consistently describe biphasic treatment responses from tyrosine kinase inhibitor treated patients from two independent clinical phase-3 trials. Scale estimates reveal that drug efficiency determines the initial response while the long-term behavior is limited by the rare activation of leukemic stem cells. We use this mathematical framework to investigate the influence of different dosing regimens on the treatment outcome. We provide strong evidence suggesting that tyrosine kinase inhibitor dose de-escalation (at least 50%) does not lead to a reduction of long-term treatment efficiency for most patients, which have already achieved sustained remission, and maintains the secondary decline of BCR-ABL1 levels. We demonstrate that continuous BCR-ABL1 monitoring provides patient-specific predictions of an optimal reduced dose not decreasing the anti-leukemic effect on residual leukemic stem cells. Our results are consistent with the interim results of the DESTINY trial and provide clinically testable predictions. Our results suggest that dose halving should be considered as a long-term treatment option for well-responding chronic myeloid leukemia patients under continuing maintenance therapy with tyrosine kinase inhibitors. We emphasize the clinical potential of this approach to reduce treatment-related side-effects and therapy costs. Copyright © 2018, Ferrata Storti Foundation.

A novel association of acquired ADAMTS13 inhibitor and acute dengue virus infection

PubMed Central

Rossi, Fernanda C.; Angerami, Rodrigo N.; de Paula, Erich V.; Orsi, Fernanda L.; Shang, Dezhi; del Guercio, Vânia M.; Resende, Mariângela R.; Annichino-Bizzacchi, Joyce M.; da Silva, Luiz J.; Zheng, X. Long; Castro, Vagner

2011-01-01

BACKGROUND Dengue is a mosquito-borne viral disease with an increasing incidence worldwide. Thrombocytopenia is a common finding in dengue virus (DV) infection; however, the underlying mechanisms remain unknown. CASE REPORT Here we provide the first evidence of a case of antibody formation against ADAMTS13 (ADAMTS13 inhibitor) in the course of a severe acute DV infection resulting in thrombotic microangiopathy (TMA). The patient presented with classical dengue symptoms (positive epidemiology, high fever, myalgia, predominantly in the lower limbs and lumbar region for 1 week) and, after 11 days of initial symptoms, developed TMA. Clinical and laboratorial investigation of dengue and TMA was performed. RESULTS The patient presented with ADAMTS13 inhibitor (IgG) during the acute phase of the disease, without anti-platelet antibodies detectable. Dengue infection had laboratorial confirmation. There were excellent clinical and laboratory responses to 11 serial plasma exchanges. Anti-ADAMTS13 inhibitor disappeared after remission of TMA and dengue resolution. No recurrence of TMA symptoms was observed after 2-year follow-up. CONCLUSIONS Although the real incidence of dengue-related TMA is unknown, this case provides the basis for future epidemiologic studies on acquired ADAMTS13 deficiency in DV infection. The prompt clinical recognition of this complication and early installment of specific therapy with plasma exchange are likely to improve the outcome of severe cases of dengue. PMID:19788513

A novel association of acquired ADAMTS13 inhibitor and acute dengue virus infection.

PubMed

Rossi, Fernanda C; Angerami, Rodrigo N; de Paula, Erich V; Orsi, Fernanda L; Shang, Dezhi; del Guercio, Vânia M; Resende, Mariângela R; Annichino-Bizzacchi, Joyce M; da Silva, Luiz J; Zheng, X Long; Castro, Vagner

2010-01-01

Dengue is a mosquito-borne viral disease with an increasing incidence worldwide. Thrombocytopenia is a common finding in dengue virus (DV) infection; however, the underlying mechanisms remain unknown. Here we provide the first evidence of a case of antibody formation against ADAMTS13 (ADAMTS13 inhibitor) in the course of a severe acute DV infection resulting in thrombotic microangiopathy (TMA). The patient presented with classical dengue symptoms (positive epidemiology, high fever, myalgia, predominantly in the lower limbs and lumbar region for 1 week) and, after 11 days of initial symptoms, developed TMA. Clinical and laboratorial investigation of dengue and TMA was performed. The patient presented with ADAMTS13 inhibitor (IgG) during the acute phase of the disease, without anti-platelet antibodies detectable. Dengue infection had laboratorial confirmation. There were excellent clinical and laboratory responses to 11 serial plasma exchanges. Anti-ADAMTS13 inhibitor disappeared after remission of TMA and dengue resolution. No recurrence of TMA symptoms was observed after 2-year follow-up. Although the real incidence of dengue-related TMA is unknown, this case provides the basis for future epidemiologic studies on acquired ADAMTS13 deficiency in DV infection. The prompt clinical recognition of this complication and early installment of specific therapy with plasma exchange are likely to improve the outcome of severe cases of dengue.

Insulin resistance in clomiphene responders and non-responders with polycystic ovarian disease and therapeutic effects of metformin.

PubMed

Parsanezhad, M E; Alborzi, S; Zarei, A; Dehbashi, S; Omrani, G

2001-10-01

To evaluate the clinical features, endocrine and metabolic profiles in clomiphene (CC) responders and non-responders with polycystic ovarian disease (PCOD), and to examine the effects of metformin (MTF) on the above parameters of CC resistance. A prospective clinical trial was undertaken at the infertility division of a university teaching hospital. Forty-one CC responders were selected and their hormonal and clinical features were determined. Forty-one CC-resistant PCOD women were also selected and clinical features; metabolic and hormonal profiles before and after treatment with MTF 1500 mg/day for 6-8 weeks were evaluated. Women who failed to conceive were treated by CC while continuing to take MTF. CC responders had higher insulin levels while non-responders were hyperinsulinemic. Menstrual irregularities improved in 30%. Mean+/-S.D. area under curve of insulin decreased from 297.58+/-191.33 to 206+/-0.1 mIU/ml per min (P=0.005). Only 39.39% ovulated and 24.24% conceived. PCOD is associated with insulin resistance (IR) particularly in CC-resistant women. Insulin resistance and androgen levels are significantly higher in obese patients. MTF therapy improved hyperandrogenemia, IR, and pregnancy rate.

Fast-responder: Rapid mobile-phone access to recent remote sensing imagery for first responders

NASA Astrophysics Data System (ADS)

Talbot, L. M.; Talbot, B. G.

We introduce Fast-Responder, a novel prototype data-dissemination application and architecture concept to rapidly deliver remote sensing imagery to smartphones to enable situational awareness. The architecture implements a Fast-Earth image caching system on the phone and interacts with a Fast-Earth server. Prototype evaluation successfully demonstrated that National Guard users could select a location, download multiple remote sensing images, and flicker between images, all in less than a minute on a 3G mobile commercial link. The Fast-Responder architecture is a significant advance that is designed to meet the needs of mobile users, such as National Guard response units, to rapidly access information during a crisis, such as a natural or man-made disaster. This paper focuses on the architecture design and advanced user interface concepts for small-screens for highly active mobile users. Novel Fast-Responder concepts can also enable rapid dissemination and evaluation of imagery on the desktop, opening new technology horizons for both desktop and mobile users.

Complications in reverse shoulder arthroplasty

PubMed Central

Barco, Raul; Savvidou, Olga D.; Sperling, John W.; Sanchez-Sotelo, Joaquín; Cofield, Robert H.

2016-01-01

The reported rate of complications of reverse shoulder arthroplasty (RSA) seems to be higher than the complication rate of anatomical total shoulder arthroplasty. The reported overall complication rate of primary RSA is approximately 15%; when RSA is used in the revision setting, the complication rate may approach 40%. The most common complications of RSA include instability, infection, notching, loosening, nerve injury, acromial and scapular spine fractures, intra-operative fractures and component disengagement. Careful attention to implant design and surgical technique, including implantation of components in the correct version and height, selection of the best glenosphere-humeral bearing match, avoidance of impingement, and adequate management of the soft tissues will hopefully translate in a decreasing number of complications in the future. Cite this article: Barco R, Savvidou OD, Sperling JW, Sanchez-Sotelo J, Cofield RH. Complications in reverse shoulder arthroplasty. EFORT Open Rev 2016;1:72-80. DOI: 10.1302/2058-5241.1.160003. PMID:28461931

Complications in reverse shoulder arthroplasty.

PubMed

Barco, Raul; Savvidou, Olga D; Sperling, John W; Sanchez-Sotelo, Joaquín; Cofield, Robert H

2016-03-01

The reported rate of complications of reverse shoulder arthroplasty (RSA) seems to be higher than the complication rate of anatomical total shoulder arthroplasty.The reported overall complication rate of primary RSA is approximately 15%; when RSA is used in the revision setting, the complication rate may approach 40%.The most common complications of RSA include instability, infection, notching, loosening, nerve injury, acromial and scapular spine fractures, intra-operative fractures and component disengagement.Careful attention to implant design and surgical technique, including implantation of components in the correct version and height, selection of the best glenosphere-humeral bearing match, avoidance of impingement, and adequate management of the soft tissues will hopefully translate in a decreasing number of complications in the future. Cite this article: Barco R, Savvidou OD, Sperling JW, Sanchez-Sotelo J, Cofield RH. Complications in reverse shoulder arthroplasty. EFORT Open Rev 2016;1:72-80. DOI: 10.1302/2058-5241.1.160003.

Risk evaluation and mitigation strategies: a focus on the mammalian target of rapamycin inhibitors.

PubMed

Gabardi, Steven

2013-03-01

To review the history of risk evaluation and mitigation strategies (REMS) with the mammalian target of rapamycin (mToR) inhibitors, evaluate their required REMS elements, and delineate the reasons for them being released from their REMS requirements. Articles were identified through a literature search of MEDLINE and EMBASE (January 2007-July 2012) using the search terms: risk evaluation and mitigation strategies, REMS, everolimus, sirolimus and organ transplant (individual organs also were searched). Information from the Federal Register, the Food and Drug Administration, and the manufacturers of the mToR inhibitors was also evaluated. REMS are strategies implemented to manage known or potential risks associated with medications and to ensure ongoing pharmacovigilance throughout the life of a pharmaceutical product. The mToR inhibitors have been associated with several potential risks, including proteinuria, graft thrombosis, and wound-healing complications. The Food and Drug Administration approved REMS programs for both sirolimus and everolimus. The manufacturers of both medications complied with the components of their approved REMS, but after less than 2 years, both medications have been relieved of their REMS obligations. The only element of the sirolimus REMS was a medication guide, whereas the everolimus REMS consisted of a medication guide and a communication plan. The sirolimus REMS was implemented more than 10 years after its initial approval by the Food and Drug Administration, but was released from its REMS requirement within 7 months of its implementation. The everolimus REMS was instituted upon initial approval and was removed approximately 2 years later. Both medications' REMS were always intended to educate health care providers and patients about the potential risks associated with this transplant immunosuppressant. Transplant practitioners should be familiar with the mToR inhibitors' associated risks and properly educate patients regarding the

Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus.

PubMed

Hemmingsen, Bianca; Sonne, David P; Metzendorf, Maria-Inti; Richter, Bernd

2017-05-10

The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether dipeptidyl-peptidase (DPP)-4 inhibitors or glucagon-like peptide (GLP)-1 analogues are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown. To assess the effects of DPP-4 inhibitors and GLP-1 analogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. We searched the Cochrane Central Register of Controlled Trials; MEDLINE; PubMed; Embase; ClinicalTrials.gov; the World Health Organization (WHO) International Clinical Trials Registry Platform; and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was January 2017. We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing DPP-4 inhibitors and GLP-1 analogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these. Two review authors read all abstracts and full-text articles and records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses, we planned to use a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We assessed the

Understanding Quality of Life in Adults with Spinal Cord Injury Via SCI-Related Needs and Secondary Complications.

PubMed

Sweet, Shane N; Noreau, Luc; Leblond, Jean; Dumont, Frédéric S

2014-01-01

Understanding the factors that can predict greater quality of life (QoL) is important for adults with spinal cord injury (SCI), given that they report lower levels of QoL than the general population. To build a conceptual model linking SCI-related needs, secondary complications, and QoL in adults with SCI. Prior to testing the conceptual model, we aimed to develop and evaluate the factor structure for both SCI-related needs and secondary complications. Individuals with a traumatic SCI (N = 1,137) responded to an online survey measuring 13 SCI-related needs, 13 secondary complications, and the Life Satisfaction Questionnaire to assess QoL. The SCI-related needs and secondary complications were conceptualized into factors, tested with a confirmatory factor analysis, and subsequently evaluated in a structural equation model to predict QoL. The confirmatory factor analysis supported a 2-factor model for SCI related needs, χ(2)(61, N = 1,137) = 250.40, P <.001, comparative fit index (CFI) = .93, root mean square error of approximation (RMSEA) = .05, standardized root mean square residual (SRMR) = .04, and for 11 of the 13 secondary complications, χ(2)(44, N = 1,137) = 305.67, P < .001, CFI = .91, RMSEA = .060, SRMR = .033. The final 2 secondary complications were kept as observed constructs. In the structural model, both vital and personal development unmet SCI-related needs (β = -.22 and -.20, P < .05, respectively) and the neuro-physiological systems factor (β = -.45, P < .05) were negatively related with QoL. Identifying unmet SCI-related needs of individuals with SCI and preventing or managing secondary complications are essential to their QoL.

Discovery of novel aldose reductase inhibitors using a protein structure-based approach: 3D-database search followed by design and synthesis.

PubMed

Iwata, Y; Arisawa, M; Hamada, R; Kita, Y; Mizutani, M Y; Tomioka, N; Itai, A; Miyamoto, S

2001-05-24

Aldose reductase (AR) has been implicated in the etiology of diabetic complications. Due to the limited number of currently available drugs for the treatment of diabetic complications, we have carried out structure-based drug design and synthesis in an attempt to find new types of AR inhibitors. With the ADAM&EVE program, a three-dimensional database (ACD3D) was searched using the ligand binding site of the AR crystal structure. Out of 179 compounds selected through this search followed by visual inspection, 36 compounds were purchased and subjected to a biological assay. Ten compounds showed more than 40% inhibition of AR at a 15 microg/mL concentration. In a subsequent lead optimization, a series of analogues of the most active compound were synthesized based on the docking mode derived by ADAM&EVE. Many of these congeners exhibited higher activities compared to the mother compound. Indeed, the most potent, synthesized compound showed an approximately 20-fold increase in inhibitory activity (IC(50) = 0.21 vs 4.3 microM). Furthermore, a hydrophobic subsite was newly inferred, which would be useful for the design of inhibitors with improved affinity for AR.

Complications of infective endocarditis.

PubMed

Mocchegiani, R; Nataloni, M

2009-12-01

Infective endocarditis (IE) is a lethal disease if not promptly treated with antibiotics, either in association with surgery or not. The incidence of disease has not decreased over the last decades due to the change of risk conditions. Complications of IE may involve cardiac structures when the infection spreads within the heart, or extra cardiac ones when the cause is usually from embolic origin; they may also be due to medical treatment or to the septic condition itself. A variety of complications may occur in most of patients. The literature reports one complication of IE in 57%, two in 26% and three or more in about 14% of patients examined. The frequency of specific complications depends on variables as the infecting pathogen, duration of disease before therapy and type of treatment. However it is often difficult to assess the true incidence of complications because the published reviews in literature are frequently based on retrospective chart reviews and different diagnostic criteria are used. The decision over either indication or timing of surgery should be individualized and based on a multidisciplinary approach involving at least cardiologists and cardiac surgeons. Congestive heart failure (CHF) is the most important complication of IE, which has the greatest impact on prognosis. Periannular abscesses are a relatively common complication of IE (42% to 85% of cases during surgery or at autopsy respectively), associated with a higher morbidity and mortality. Systemic embolization occurs in 22% to 50% of cases; emboli may involve major arteries, mostly affecting the central nervous system, but also other organs. Splenic abscess is a rare complication of IE, due to direct seeding of spleen by an embolus or bacterial seeding of a bland infarction. Neurological complications develop in 20% to 40% of patients with IE and represent a dangerous subset of complications. Mycotic aneurysms are rare, resulting from diffusion of infection to the vessel wall. Actually

Cellular death, reactive oxygen species (ROS) and diabetic complications.

PubMed

Volpe, Caroline Maria Oliveira; Villar-Delfino, Pedro Henrique; Dos Anjos, Paula Martins Ferreira; Nogueira-Machado, José Augusto

2018-01-25

Chronic or intermittent hyperglycemia is associated with the development of diabetic complications. Several signaling pathways can be altered by having hyperglycemia in different tissues, producing oxidative stress, the formation of advanced glycation end products (AGEs), as well as the secretion of the pro-inflammatory cytokines and cellular death (pathological autophagy and/or apoptosis). However, the signaling pathways that are directly triggered by hyperglycemia appear to have a pivotal role in diabetic complications due to the production of reactive oxygen species (ROS), oxidative stress, and cellular death. The present review will discuss the role of cellular death in diabetic complications, and it will suggest the cause and the consequences between the hyperglycemia-induced signaling pathways and cell death. The signaling pathways discussed in this review are to be described step-by-step, together with their respective inhibitors. They involve diacylglycerol, the activation of protein kinase C (PKC) and NADPH-oxidase system, and the consequent production of ROS. This was initially entitled the "dangerous metabolic route in diabetes". The historical usages and the recent advancement of new drugs in controlling possible therapeutical targets have been highlighted, in order to evaluate the evolution of knowledge in this sensitive area. It has recently been shown that the metabolic responses to stimuli (i.e., hyperglycemia) involve an integrated network of signaling pathways, in order to define the exact responses. Certain new drugs have been experimentally tested-or suggested and proposed-for their ability to modulate the possible biochemical therapeutical targets for the downregulation of retinopathy, nephropathy, neuropathy, heart disease, angiogenesis, oxidative stress, and cellular death. The aim of this study was to critically and didactically evaluate the exact steps of these signaling pathways and hence mark the indicated sites for the actions of such

Complicated grief associated with hurricane Katrina.

PubMed

Shear, M Katherine; McLaughlin, Katie A; Ghesquiere, Angela; Gruber, Michael J; Sampson, Nancy A; Kessler, Ronald C

2011-08-01

Although losses are important consequences of disasters, few epidemiological studies of disasters have assessed complicated grief (CG) and none assessed CG associated with losses other than death of loved one. Data come from the baseline survey of the Hurricane Katrina Community Advisory Group, a representative sample of 3,088 residents of the areas directly affected by Hurricane Katrina. A brief screen for CG was included containing four items consistent with the proposed DSM-V criteria for a diagnosis of bereavement-related adjustment disorder. Fifty-eight and half percent of respondents reported a significant hurricane-related loss: Most-severe losses were 29.0% tangible, 9.5% interpersonal, 8.1% intangible, 4.2% work/financial, and 3.7% death of loved one. Twenty-six point one percent respondents with significant loss had possible CG and 7.0% moderate-to-severe CG. Death of loved one was associated with the highest conditional probability of moderate-to-severe CG (18.5%, compared to 1.1-10.5% conditional probabilities for other losses), but accounted for only 16.5% of moderate-to-severe CG due to its comparatively low prevalence. Most moderate-to-severe CG was due to tangible (52.9%) or interpersonal (24.0%) losses. Significant predictors of CG were mostly unique to either bereavement (racial-ethnic minority status, social support) or other losses (prehurricane history of psychopathology, social competence.). Nonbereavement losses accounted for the vast majority of hurricane-related possible CG despite risk of CG being much higher in response to bereavement than to other losses. This result argues for expansion of research on CG beyond bereavement and alerts clinicians to the need to address postdisaster grief associated with a wide range of losses. © 2011 Wiley-Liss, Inc.

Complicated grief associated with Hurricane Katrina

PubMed Central

Shear, M. Katherine; McLaughlin, Katie A.; Ghesquiere, Angela; Gruber, Michael J.; Sampson, Nancy A.; Kessler, Ronald C.

2011-01-01

Background Although losses are important consequences of disasters, few epidemiological studies of disasters have assessed complicated grief (CG) and none assessed CG associated with losses other than death of loved one. Methods Data come from the baseline survey of the Hurricane Katrina Community Advisory Group (CAG), a representative sample of 3,088 residents of the areas directly affected by Hurricane Katrina. A brief screen for CG was included containing four items consistent with the proposed DSM 5 criteria for a diagnosis of bereavement-related adjustment disorder. Results 58.5% of respondents reported a significant hurricane-related loss: Most-severe losses were 29.0% tangible, 9.5% interpersonal, 8.1% intangible, 4.2% work-financial, and 3.7% death of loved one. 26.1% of respondents with significant loss had possible CG and 7.0% moderate-severe CG. Death of loved one was associated with the highest conditional probability of moderate-severe CG (18.5%, compared to 1.1–10.5% conditional probabilities for other losses) but accounted for only 16.5% of moderate-severe CG due to its comparatively low prevalence. Most moderate-severe CG was due to tangible (52.9%) or interpersonal (24.0%) losses. Significant predictors of CG were mostly unique to either bereavement (racial-ethnic minority status, social support) or other losses (pre-hurricane history of psychopathology, social competence.). Conclusions Non-bereavement losses accounted for the vast majority of hurricane-related possible CG despite risk of CG being much higher in response to bereavement than to other losses. This result argues for expansion of research on CG beyond bereavement and alerts clinicians to the need to address post-disaster grief associated with a wide range of losses. PMID:21796740

Vascular Access System for Continuous Arterial Infusion of a Protease Inhibitor in Acute Necrotizing Pancreatitis

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

Ganaha, Fumikiyo; Yamada, Tetsuhisa; Yorozu, Naoya

1999-09-15

We used a vascular access system (VAS) for continuous arterial infusion (CAI) of a protease inhibitor in two patients with acute necrotizing pancreatitis. The infusion catheter was placed into the dorsal pancreatic artery in the first patient and into the gastroduodenal artery in the second, via a femoral artery approach. An implantable port was then connected to the catheter and was secured in a subcutaneous pocket prepared in the right lower abdomen. No complications related to the VAS were encountered. This system provided safe and uncontaminated vascular access for successful CAI for acute pancreatitis.

Successful treatment of lymphoproliferative disease complicating primary immunodeficiency/immunodysregulatory disorders with reduced-intensity allogeneic stem-cell transplantation.

PubMed

Cohen, Jonathan M; Sebire, Neil J; Harvey, Julia; Gaspar, H Bobby; Cathy, Cale; Jones, Alison; Rao, Kanchan; Cubitt, David; Amrolia, Persis J; Davies, E Graham; Veys, Paul

2007-09-15

Lymphoproliferative disease (LPD) is a recognized complication of primary immunodeficiency (PID) and immunodysregulatory syndromes. Historically, it has a very poor outcome. For patients surviving LPD, myeloablative hematopoietic stem cell transplantation (SCT) was the only cure for the underlying PID, with a high risk of developing posttransplantation complications, including recurrent lymphoproliferative disease. We describe 8 patients with a range of PID and immunodysregulatory syndromes complicated by LPD. After initial treatment of the LPD (including the use of anti-CD20 monoclonal antibody, rituximab, in 6 of the patients), all patients underwent reduced-intensity conditioning (RIC) SCT with prospective monitoring for Epstein-Barr virus (EBV) viremia. After transplantation, 3 patients received rituximab, and 3 patients received prophylactic EBV-specific cytotoxic T-lymphocytes. Only 1 patient developed recurrent LPD posttransplantation, which responded to rituximab. All patients who underwent transplantation survive free of LPD and are cured of their PID at a median follow-up of 4 years (range, 1-7 years). With careful monitoring and pre-emptive therapy, we advocate this RIC SCT approach to patients with PID who have pre-existing EBV-LPD.

Association between baseline impedance values and response proton pump inhibitors in patients with heartburn.

PubMed

de Bortoli, Nicola; Martinucci, Irene; Savarino, Edoardo; Tutuian, Radu; Frazzoni, Marzio; Piaggi, Paolo; Bertani, Lorenzo; Furnari, Manuele; Franchi, Riccardo; Russo, Salvatore; Bellini, Massimo; Savarino, Vincenzo; Marchi, Santino

2015-06-01

Esophageal impedance measurements have been proposed to indicate the status of the esophageal mucosa, and might be used to study the roles of the impaired mucosal integrity and increased acid sensitivity in patients with heartburn. We compared baseline impedance levels among patients with heartburn who did and did not respond to proton pump inhibitor (PPI) therapy, along with the pathophysiological characteristics of functional heartburn (FH). In a case-control study, we collected data from January to December 2013 on patients with heartburn and normal findings from endoscopy who were not receiving PPI therapy and underwent impedance pH testing at hospitals in Italy. Patients with negative test results were placed on an 8-week course of PPI therapy (84 patients received esomeprazole and 36 patients received pantoprazole). Patients with more than 50% symptom improvement were classified as FH/PPI responders and patients with less than 50% symptom improvement were classified as FH/PPI nonresponders. Patients with hypersensitive esophagus and healthy volunteers served as controls. In all patients and controls, we measured acid exposure time, number of reflux events, baseline impedance, and swallow-induced peristaltic wave indices. FH/PPI responders had higher acid exposure times, numbers of reflux events, and acid refluxes compared with FH/PPI nonresponders (P < .05). Patients with hypersensitive esophagus had mean acid exposure times and numbers of reflux events similar to those of FH/PPI responders. Baseline impedance levels were lower in FH/PPI responders and patients with hypersensitive esophagus, compared with FH/PPI nonresponders and healthy volunteers (P < .001). Swallow-induced peristaltic wave indices were similar between FH/PPI responders and patients with hypersensitive esophagus. Patients with FH who respond to PPI therapy have impedance pH features similar to those of patients with hypersensitive esophagus. Baseline impedance measurements might allow for

Neurologic complications of vaccinations.

PubMed

Miravalle, Augusto A; Schreiner, Teri

2014-01-01

This chapter reviews the most common neurologic disorders associated with common vaccines, evaluates the data linking the disorder with the vaccine, and discusses the potential mechanism of disease. A literature search was conducted in PubMed using a combination of the following terms: vaccines, vaccination, immunization, and neurologic complications. Data were also gathered from publications of the American Academy of Pediatrics Committee on Infectious Diseases, the World Health Organization, the US Centers for Disease Control and Prevention, and the Vaccine Adverse Event Reporting System. Neurologic complications of vaccination are rare. Many associations have been asserted without objective data to support a causal relationship. Rarely, patients with a neurologic complication will have a poor outcome. However, most patients recover fully from the neurologic complication. Vaccinations have altered the landscape of infectious disease. However, perception of risk associated with vaccinations has limited the success of disease eradication measures. Neurologic complications can be severe, and can provoke fear in potential vaccines. Evaluating whether there is causal link between neurologic disorders and vaccinations, not just temporal association, is critical to addressing public misperception of risk of vaccination. Among the vaccines available today, the cost-benefit analysis of vaccinations and complications strongly argues in favor of vaccination. © 2014 Elsevier B.V. All rights reserved.

Complications of Guillain-Barré syndrome.

PubMed

Wang, Ying; Zhang, Hong-Liang; Wu, Xiujuan; Zhu, Jie

2016-01-01

Guillain-Barré syndrome (GBS) is an immune-mediated disorder in the peripheral nervous system with a wide spectrum of complications. A good understanding of the complications of GBS assists clinicians to recognize and manage the complications properly thereby reducing the mortality and morbidity of GBS patients. Herein, we systemically review the literature on complications of GBS, including short-term complications and long-term complications. We summarize the frequency, severity, clinical manifestations, managements and possible mechanisms of different kinds of complications, and point out the flaws of current studies as well as demonstrate the further investigations needed.

Treatment of Visual Hallucinations in Schizophrenia by Acetylcholinesterase Inhibitors: a case report

PubMed Central

Abad, Nazir Hashemi; Doulatabad, Najafi Shala; Mohammadi, Ali

2011-01-01

Schizophrenia and various neurological disorders have some signs and symptoms. Visual hallucinations are one of such disorders. The related studies in some diseases for example Parkinson Disease and Lewy Body Dementia indicate that Acetylcholine (Ach) plays a significant role in neuropsychiatric manifestation and its association with visual hallucination; therefore, visual hallucinations occur due to the depletion of Ach. Drug therapies such as Cholinesterase inhibitors (ChEIs) for increasing Ach level may be beneficial in treating visual hallucination. AchEI's have been used in the treatment of visual hallucinations in Dementia and Parkinson's Disease. We thought that a similar Ach depletion may cause visual hallucinations in patients with schizophrenia and may provide a target for drug treatment. We had a patient with schizophrenia whose psychotic symptoms responded to the treatment plan, but her visual hallucination did not. However, the patient's visual hallucination successfully responded to Rivastigmine (AchEI). This case illustrates the use of an AchEI in the treatment of refractory visual hallucinations in a patient with schizophrenia. PMID:22952543

Complication Rates among Trauma Centers

PubMed Central

Ang, Darwin N; Rivara, Frederick P; Nathens, Avery; Jurkovich, Gregory J; Maier, Ronald V; Wang, Jin; MacKenzie, Ellen J

2009-01-01

Background To examine the association between patient complications and admission to level 1 trauma centers (TC) compared to non-trauma centers (NTC). Study Design A retrospective cohort study of data derived from the National Study on the Costs and Outcomes of Trauma (NSCOT). Patients were recruited from 18 level 1 TC and 51 NTC in 15 regions encompassing 14 states. Trained study nurses, using standardized forms, abstracted the medical records of the patients. The overall number of complications per patient was identified as well as the presence or absence of 13 specific complications. Results Patients treated in TC were more likely to have any complication compared to NTC with an adjusted relative risk (RR) of 1.34 (95% CI 1.03, 1.74). For individual complications, only urinary tract infection RR 1.94 (95% CI 1.07, 3.17) was significantly higher in TC. TC patients were more likely to have three or more complications, RR 1.83 (95% CI 1.16, 2.90). Treatment variables that are surrogates for markers of injury severity, such as use of pulmonary artery catheters, multiple operations, massive transfusions (> 2,500mL packed red blood cells), and invasive brain catheters, occurred significantly more often in TC. Conclusions Trauma centers have a slightly higher incidence rate of complications even after adjusting for patient case mix. Aggressive treatment may account for a significant portion of TC-associated complications. PA catheter use and intubation had the most influence on overall TC complication rates. Further study is needed to provide accurate benchmark measures of complication rates and to determine their causes. PMID:19854399

Urological complications of coitus.

PubMed

Eke, N

2002-02-01

To ascertain the urological complications of coitus, as the proximity of the lower urinary tract to the organs of coitus exposes the tract to coital trauma. Medline was searched from 1966 to 2000 to identify reports on coital injuries. Publications and relevant references were retrieved. Those reporting urological complications were selected for analysis. In all, 1454 cases of reported coital injuries were reviewed; 790 occurred in men while 664 occurred in women, mainly in the genital area. Physical urological complications were more common in men than in women. The injuries were often sustained during voluntary coitus, but one penile fracture was sustained during an attempted rape. The presentations included penile swellings and deviations, haemorrhage, erectile dysfunction and urinary incontinence. Complications included vesicovaginal fistulae, bladder and cavernosal ruptures, and urinary tract infections. Rare complications included isolated rupture of the penile vasculature. Major risk factors included penovaginal disproportion, excessive force at coitus, urethral coitus, fellatio and anal intercourse. Urethral injuries were the commonest complications; in men these were associated with 10-38% of penile fractures. The treatments included cold compress and anti-inflammatory agents in contusions, repairs of lacerations, closure of fistulae and urethral and vaginal reconstruction. The results of treatment were essentially good. Recurrent penile fractures were reported. Coitus, although pleasurable, may be risky. The complications have been termed 'faux pas' implying that they are preventable. While the ultimate prevention is abstinence, this is an unrealistic prescription. Therefore, efforts are necessary to identify risk factors to enable preventive strategies.

Ocular complications of diabetes mellitus

PubMed Central

Sayin, Nihat; Kara, Necip; Pekel, Gökhan

2015-01-01

Diabetes mellitus (DM) is a important health problem that induces ernestful complications and it causes significant morbidity owing to specific microvascular complications such as, retinopathy, nephropathy and neuropathy, and macrovascular complications such as, ischaemic heart disease, and peripheral vasculopathy. It can affect children, young people and adults and is becoming more common. Ocular complications associated with DM are progressive and rapidly becoming the world’s most significant cause of morbidity and are preventable with early detection and timely treatment. This review provides an overview of five main ocular complications associated with DM, diabetic retinopathy and papillopathy, cataract, glaucoma, and ocular surface diseases. PMID:25685281

Chemotherapeutics-resistance "arms" race: An update on mechanisms involved in resistance limiting EGFR inhibitors in lung cancer.

PubMed

Singh, Pankaj Kumar; Silakari, Om

2017-10-01

Clinical reports suggest that EGFR-mutated lung cancer usually respond significantly towards small molecule tyrosine kinase inhibitors. Same studies also report the eventual development of acquired resistance within a median time interval of 9 to 14months. One of the major mechanisms involved in this acquired resistance was found to be a secondary point mutation at gate-keeper residue, EGFR T790M. However, there are other recent studies which disclose the role of few other novel key players such as, ZEB1, TOPK etc., in the development of tolerance towards the EGFR TKI's, along with other commonly known mechanisms, such as amplification of signalling pathways such as, c-MET, Erbb2, AXL, additional acquired secondary mutations (PIK3CA, BRAF), or phenotypic transformation (small cell or epithelial to mesenchymal transitions). Interestingly, a recent study showed development of resistance via another point mutation, C797S, in case of tumors which were previously resistant and were administered agents capable of overcoming T790M gatekeeper mutation based resistance. Thus, raising serious concern over the direction of drug development involving tyrosine kinases such as EGFR. Current approaches focussing on development of third generation inhibitors, dual inhibitors or inhibitors of HSP90 have shown significant activity but do not answer the long term question of resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Antitumor activity of pan-HER inhibitors in HER2-positive gastric cancer.

PubMed

Yoshioka, Takahiro; Shien, Kazuhiko; Namba, Kei; Torigoe, Hidejiro; Sato, Hiroki; Tomida, Shuta; Yamamoto, Hiromasa; Asano, Hiroaki; Soh, Junichi; Tsukuda, Kazunori; Nagasaka, Takeshi; Fujiwara, Toshiyoshi; Toyooka, Shinichi

2018-04-01

Molecularly targeted therapy has enabled outstanding advances in cancer treatment. Whereas various anti-human epidermal growth factor receptor 2 (HER2) drugs have been developed, trastuzumab is still the only anti-HER2 drug presently available for gastric cancer. In this study, we propose novel treatment options for patients with HER2-positive gastric cancer. First, we determined the molecular profiles of 12 gastric cancer cell lines, and examined the antitumor effect of the pan-HER inhibitors afatinib and neratinib in those cell lines. Additionally, we analyzed HER2 alteration in 123 primary gastric cancers resected from Japanese patients to clarify possible candidates with the potential to respond to these drugs. In the drug sensitivity analysis, both afatinib and neratinib produced an antitumor effect in most of the HER2-amplified cell lines. However, some cells were not sensitive to the drugs. When the molecular profiles of the cells were compared based on the drug sensitivities, we found that cancer cells with lower mRNA expression levels of IGFBP7, a tumor suppressor gene that inhibits the activation of insulin-like growth factor-1 receptor (IGF-1R), were less sensitive to pan-HER inhibitors. A combination therapy consisting of pan-HER inhibitors and an IGF-1R inhibitor, picropodophyllin, showed a notable synergistic effect. Among 123 clinical samples, we found 19 cases of HER2 amplification and three cases of oncogenic mutations. In conclusion, afatinib and neratinib are promising therapeutic options for the treatment of HER2-amplified gastric cancer. In addition to HER2 amplification, IGFBP7 might be a biomarker of sensitivity to these drugs, and IGF-1R-targeting therapy can overcome drug insensitiveness in HER2-amplified gastric cancer. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Appraisal of the Operation Respond Emergency Information System (OREIS)

DOT National Transportation Integrated Search

1998-04-01

The Operation Respond Institute has been instrumental in developing the Operation Respond Emergency Information System (OREIS) for first responders to hazardous material incidents in transportation. The Operation Respond system aims to facilitate rap...

Responder Technology Alert Monthly (January 2015)

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

Upton, Jaki F.; Stein, Steven L.

As part of technology foraging for the Responder Technology Alliance, established by the Department of Homeland Science and Technologies First Responders Group, this report summarizes technologies that are relevant in the area of “wearables,” with the potential for use by first responders. The content was collected over the previous month(s) and reproduced from a general Internet search using the term wearables. Additional information is available at the websites provided. This report is not meant to be an exhaustive list nor an endorsement of any technology described herein. Rather, it is meant to provide useful information about current developments in themore » areas wearable technology.« less

An Automated, Gravity-driven CSF Drainage System Decreases Complications and Lowers Costs

PubMed Central

Lieberson, Robert E; Meyer, William; Trang, Tung

2017-01-01

Background: FlowSafeTM (BeckerSmith Medical, Irvine, CA, USA) is a novel, robotic, external lumbar drainage (ELD) system, which was designed to control cerebrospinal fluid (CSF) drainage, reduce complications, and decrease treatment costs. Methods: Forty-seven consecutive neurosurgical patients requiring ELD were treated using the FlowSafe system. Results: In 39 of 40 patients with traumatic and surgical dural openings, potential CSF leaks were avoided. In seven patients with suspected normal pressure hydrocephalus, post-infectious ventriculomegaly, or pseudotumor cerebrum, we were able to assess the likelihood of improvement with shunting. The system, therefore, produced what we considered to be the “desired result” in 46 of 47 patients (98%). Our one treatment failure (2%) involved a patient with unrecognized hydrocephalus who, following a Chiari repair with a dural patch graft, was drained for six days. A persistent CSF leak eventually required a reoperation. Two patients (4%) described low-pressure headaches during treatment. Both responded to temporarily suspending or reducing the drainage rate. We saw no complications. Required nursing interventions were minimal.  Conclusions: The FlowSafe system was safe and effective. In our experience, there were fewer complications compared to currently available ELD systems. The FlowSafe was well tolerated by our patients. The near elimination of nursing interventions should allow lumbar drainage to be delivered in less costly, non-intensive care unit settings. Larger trials will be needed. PMID:28331772

KIDFamMap: a database of kinase-inhibitor-disease family maps for kinase inhibitor selectivity and binding mechanisms

PubMed Central

Chiu, Yi-Yuan; Lin, Chih-Ta; Huang, Jhang-Wei; Hsu, Kai-Cheng; Tseng, Jen-Hu; You, Syuan-Ren; Yang, Jinn-Moon

2013-01-01

Kinases play central roles in signaling pathways and are promising therapeutic targets for many diseases. Designing selective kinase inhibitors is an emergent and challenging task, because kinases share an evolutionary conserved ATP-binding site. KIDFamMap (http://gemdock.life.nctu.edu.tw/KIDFamMap/) is the first database to explore kinase-inhibitor families (KIFs) and kinase-inhibitor-disease (KID) relationships for kinase inhibitor selectivity and mechanisms. This database includes 1208 KIFs, 962 KIDs, 55 603 kinase-inhibitor interactions (KIIs), 35 788 kinase inhibitors, 399 human protein kinases, 339 diseases and 638 disease allelic variants. Here, a KIF can be defined as follows: (i) the kinases in the KIF with significant sequence similarity, (ii) the inhibitors in the KIF with significant topology similarity and (iii) the KIIs in the KIF with significant interaction similarity. The KIIs within a KIF are often conserved on some consensus KIDFamMap anchors, which represent conserved interactions between the kinase subsites and consensus moieties of their inhibitors. Our experimental results reveal that the members of a KIF often possess similar inhibition profiles. The KIDFamMap anchors can reflect kinase conformations types, kinase functions and kinase inhibitor selectivity. We believe that KIDFamMap provides biological insights into kinase inhibitor selectivity and binding mechanisms. PMID:23193279

Unsweetening the Heart: Possible Pleiotropic Effects of SGLT2 Inhibitors on Cardio and Cerebrovascular Alterations in Resistant Hypertensive Subjects.

PubMed

Pioli, Mariana R; Ritter, Alessandra M V; Modolo, Rodrigo

2018-02-09

Resistant hypertension (RH) is a multifactorial disease associated with several target organ damage, such as microalbuminuria, left ventricular hypertrophy, and arterial stiffness. These subjects have high cardiovascular complications, especially when associated with diabetes condition. Sodium glucose cotransporter 2 (SGLT-2) inhibitors represent a new class of oral antidiabetic drugs that have shown positive effects in diabetics and even hypertensives subjects. Several studies demonstrated positive outcomes related to blood pressure levels, body weight, and glycemic control. Also found a reduction on microalbuminuria, cardiac and arterial remodeling process, and decrease in hospitalization care due heart failure. Despite these positive effects, the outcomes found for stroke were conflicted and tend neutral effect. Based on this, we sought to assess the pleiotropic effects of SGLT-2 inhibitors and the possible impact in RH subjects. In order to analyze the prospects of SGLT-2 inhibitors as a possible medication to complement the therapy manage of this high-risk class of patients. © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Complications of shoulder arthroscopy.

PubMed

Moen, Todd C; Rudolph, Glen H; Caswell, Kyle; Espinoza, Christopher; Burkhead, Wayne Z; Krishnan, Sumant G

2014-07-01

Over the past 20 to 30 years, arthroscopic shoulder techniques have become increasingly popular. Although these techniques have several advantages over open surgery, surgical complications are no less prevalent or devastating than those associated with open techniques. Some of the complications associated with arthroscopic shoulder surgery include recurrent instability, soft-tissue injury, and neurapraxia. These complications can be minimized with thoughtful consideration of the surgical indications, careful patient selection and positioning, and a thorough knowledge of the shoulder anatomy. Deep infection following arthroscopic shoulder surgery is rare; however, the shoulder is particularly susceptible to Propionibacterium acnes infection, which is mildly virulent and has a benign presentation. The surgeon must maintain a high index of suspicion for this infection. Thromboemoblic complications associated with arthroscopic shoulder techniques are also rare, and studies have shown that pharmacologic prophylaxis has minimal efficacy in preventing these complications. Because high-quality studies on the subject are lacking, minimal evidence is available to suggest strategies for prevention. Copyright 2014 by the American Academy of Orthopaedic Surgeons.

Diabetic ketoacidosis in acromegaly; a rare complication precipitated by corticosteroid use.

PubMed

Weiss, Jeremy; Wood, Anna J; Zajac, Jeffrey D; Grossmann, Mathis; Andrikopoulos, Sofianos; Ekinci, Elif I

2017-12-01

Diabetic ketoacidosis has been described in the literature as a rare possible initial presentation of acromegaly before a diagnosis of acromegaly is eventually made. Indeed, diabetic ketoacidosis is a recognised complication of acromegaly. There are a number of factors that can predispose patients with acromegaly to diabetes as well as to diabetic ketoacidosis. These include high levels of growth hormone and insulin-like growth factor 1 in acromegaly and the effect on glycaemia by medications used in the management of acromegaly. Ketoacidosis has been described in patients with acromegaly even without the presence of an underlying autoimmune diabetes. Patients with acromegaly and ketoacidosis often respond to treatment and may not require long-term insulin. Copyright © 2017. Published by Elsevier B.V.

Ophthalmologic complications after intraoral local anesthesia.

PubMed

von Arx, Thomas; Lozanoff, Scott; Zinkernagel, Martin

2014-01-01

The first ophthalmologic complication in conjunction with a dental anesthesia was reported in 1936. The objective of the present study was a detailed analysis of case reports about that topic. After conducting a literature search in PubMed this study analyzed 108 ophthalmologic complications following intraoral local anesthesia in 65 case reports with respect to patient-, anesthesia-, and complication- related factors. The mean age of the patients was 33.8 years and females predominated (72.3%). The most commonly reported complication was diplopia (39.8%), mostly resulting from paralysis of the lateral rectus muscle. Other relatively frequent complications included ptosis (16.7%), mydriasis (14.8%) and amaurosis (13%). Ophthalmologic complications were mainly associated with block anesthesia of the inferior alveolar nerve (45.8%) or the posterior superior alveolar nerve (40.3%). Typically, the ophthalmologic complications in conjunction with intraoral local anesthesia had an immediate to short onset, and disappeared as the anesthesia subsided. The increased number of ophthalmologic complications after intraoral local anesthesia in females may suggest a gender effect. Double vision (diplopia) is the most frequently described complication, which is usually completely reversible like the other reported ophthalmologic complications.

Complicated infective endocarditis: a case series.

PubMed

Kim, Joo Seop; Kang, Min-Kyung; Cho, A Jin; Seo, Yu Bin; Kim, Kun Il

2017-05-08

Infective endocarditis is associated with not only cardiac complications but also neurologic, renal, musculoskeletal, and systemic complications related to the infection, such as embolization, metastatic infection, and mycotic aneurysm. We report three cases (the first patient is Chinese and the other two are Koreans) of complicated infective endocarditis; two of the cases were associated with a mycotic aneurysm, and one case was associated with a splenic abscess. One case of a patient with prosthetic valve endocarditis was complicated by intracerebral hemorrhage caused by mycotic aneurysm rupture. A second case of a patient with right-sided valve endocarditis associated with a central catheter was complicated by an abdominal aortic mycotic aneurysm. The third patient had a splenic infarction and abscess associated with infected cardiac thrombi. Complicated infective endocarditis is rare and is associated with cardiac, neurologic, renal, musculoskeletal, and systemic complications related to infection, such as embolization, metastatic infection, and mycotic aneurysm. Infective endocarditis caused by Staphylococcus aureus is more frequently associated with complications. Because the mortality rate increases when complications develop, aggressive antibiotic therapy and surgery, combined with specific treatments for the complications, are necessary.

Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors

PubMed Central

Chia, Puey Ling; Mitchell, Paul; Dobrovic, Alexander; John, Thomas

2014-01-01

Improved understanding of molecular drivers of carcinogenesis has led to significant progress in the management of lung cancer. Patients with non-small-cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) gene rearrangements constitute about 4%–5% of all NSCLC patients. ALK+ NSCLC cells respond well to small molecule ALK inhibitors such as crizotinib; however, resistance invariably develops after several months of treatment. There are now several newer ALK inhibitors, with the next generation of agents targeting resistance mutations. In this review, we will discuss the prevalence and clinical characteristics of ALK+ lung cancer, current treatment options, and future directions in the management of this subset of NSCLC patients. PMID:25429239

Clinical Response of Carcinomas Harboring the BRD4-NUT Oncoprotein to the Targeted Bromodomain Inhibitor OTX015/MK-8628

PubMed Central

Stathis, Anastasios; Zucca, Emanuele; Bekradda, Mohamed; Gomez-Roca, Carlos; Delord, Jean-Pierre; de La Motte Rouge, Thibault; Uro-Coste, Emmanuelle; de Braud, Filippo; Pelosi, Giuseppe; French, Christopher A.

2016-01-01

The anti-neoplastic, pro-differentiative effects of bromodomain and extra-terminal (BET) bromodomain (BRD) inhibitors were initially discovered in NUT midline carcinoma (NMC), an aggressive subtype of squamous cancer driven by the BRD4-NUT fusion oncoprotein. BRD4-NUT blocks differentiation and maintains tumor growth through a potent chromatin modifying mechanism. OTX015/MK-8628, a novel oral BET inhibitor, targets BRD2/3/4/T with preclinical activity in NMC and several other tumor types, and is currently in clinical development. Antitumor activity was evaluated in four advanced stage NMC patients with confirmed BRD4-NUT fusions who were treated with 80 mg OTX015/MK-8628 once daily in a compassionate-use context. Two patients responded rapidly with tumor regression and symptomatic relief, and a third had meaningful disease stabilization with a minor metabolic response. The main side effects were mild to moderate gastrointestinal toxicity and fatigue, and reversible grade 3 thrombocytopenia. This is the first proof-of-concept evidence of clinical activity of a bromodomain inhibitor in targeting BRD4-NUT. PMID:26976114

Skin Complications of IBD

MedlinePlus

... Home > Resources > Skin Complications of IBD Go Back Skin Complications of IBD Email Print + Share After arthritis, ... about 5% of people with inflammatory bowel disease. SKIN DISORDERS COMMONLY SEEN IN IBD ERHTHEMA NODOSUM The ...

[Combination therapy of metformin vs dipeptidulpeptidase inhibitors and sulfonylureas in type 2 diabetes: clinical and economic impact].

PubMed

Sicras-Mainar, Antoni; Navarro-Artieda, Ruth

2014-01-01

Determine the clinical repurcussions of adherence, metabolic control, hypoglycemia and cardiovascular events (CVE) and economics (resources and costs) in the combination therapy of metformin vs DPP-4 (dipeptidyl peptidase-4) inhibitors and sulfonylureas in patients with type 2 diabetes. Materials and methods. Observational-multicenter and retrospective design. We evaluated patients ≥ 30 years of age in treatment with metformin and who started a second oral antidiabetic treatment during 2008-2009. 2 study groups were established: a) metformin + DPP-4 inhibitors, and b) metformin + sulfonylurea. comorbidity, metabolic control (HbA1c <7%), compliance and complications (hypoglycemia, CVE). Follow up was conducted over two years. The cost model differentiated between direct healthcare costs (primary/ specialty care), and indirect costs (labor productivity). logistic regression and ANCOVA models. Results. 1,405 patients were recruited (average age 67.1 years old; 56.2% male). 37.0% started a second treatment with DPP-4 inhibitors, and 63.0% with sulfonylureas. After two years of follow up, patients treated with DPP-4 inhibitors showed greater treatment adherence (70.3% vs. 60.6%; p <0.001); better metabolic control (64.3% vs. 60.6%; p<0.001), and a lower proportion of hypoglycemia (13.9% vs. 40.4%; p <0.001, respectively). The average/unit of adjusted total costs was € 2,341 vs. € 2,512; p = 0.038. CVE and renal failure rates were 3.7% vs. 6.4%; p = 0.027. Vildagliptin was the most used drug among DPP-4 inhibitors. Conclusions. Sulfonylureas were the most used drug for diabetes treatment. Patients treated with DPP-4 inhibitors had higher adherence and control of diabetes, with lower rates of hypoglycemia and CVE, resulting in lower healthcare costs.

Natural product-based amyloid inhibitors.

PubMed

Velander, Paul; Wu, Ling; Henderson, Frances; Zhang, Shijun; Bevan, David R; Xu, Bin

2017-09-01

Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned. Copyright © 2017 Elsevier Inc. All rights reserved.

Natural product-based amyloid inhibitors

PubMed Central

Velander, Paul; Wu, Ling; Henderson, Frances; Zhang, Shijun; Bevan, David R.; Xu, Bin

2018-01-01

Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned. PMID:28390938

The role of the pharmacist in the selection and use of over-the-counter proton-pump inhibitors.

PubMed

Boardman, Helen F; Heeley, Gordon

2015-10-01

Heartburn and other symptoms of gastro-oesophageal reflux occur in ~30% of survey respondents in multiple countries worldwide. Heartburn and acid regurgitation are common complaints in the pharmacy, where patients frequently seek relief through medication and advice. The growing number of proton-pump inhibitors available in the over-the-counter setting provides an efficacious choice to patients experiencing frequent heartburn. Pharmacists can assist patients in their treatment decisions whilst inquiring about alarm symptoms that should prompt a physician referral. Aim of the review Provide pharmacists with a review of current clinical research and expert guidelines on use of over-the-counter proton-pump inhibitors. This narrative review was conducted to identify publications relevant to the following themes: overview of available treatments for frequent episodes of heartburn/acid regurgitation; treatment algorithms providing guidance on when to use over-the-counter proton-pump inhibitors; and the role of the pharmacist in the use of over-the-counter proton-pump inhibitors. Frequent symptoms of acid reflux, such as heartburn and acid regurgitation, can interfere substantially with daily life activities. Proton-pump inhibitors are the most efficacious treatment for frequent reflux symptoms and are recommended as an appropriate initial treatment in uncomplicated cases. Proton-pump inhibitors have varying pharmacokinetics and pharmacodynamics across the class; 20 mg esomeprazole has higher bioavailability and exposure than over-the-counter omeprazole, for example. However, differences in clinical efficacy for symptom relief have not been demonstrated. The safety and tolerability of proton-pump inhibitors have been well established in clinical trial and post-marketing settings, and use of a short regimen is associated with a very low likelihood of missing a more serious condition. Pharmacists can assist patients with accurate self-diagnosis by asking short, simple

Optimizing study design for interobserver reliability: IUGA-ICS classification of complications of prostheses and graft insertion.

PubMed

Haylen, Bernard T; Lee, Joseph; Maher, Chris; Deprest, Jan; Freeman, Robert

2014-06-01

Results of interobserver reliability studies for the International Urogynecological Association-International Continence Society (IUGA-ICS) Complication Classification coding can be greatly influenced by study design factors such as participant instruction, motivation, and test-question clarity. We attempted to optimize these factors. After a 15-min instructional lecture with eight clinical case examples (including images) and with classification/coding charts available, those clinicians attending an IUGA Surgical Complications workshop were presented with eight similar-style test cases over 10 min and asked to code them using the Category, Time and Site classification. Answers were compared to predetermined correct codes obtained by five instigators of the IUGA-ICS prostheses and grafts complications classification. Prelecture and postquiz participant confidence levels using a five-step Likert scale were assessed. Complete sets of answers to the questions (24 codings) were provided by 34 respondents, only three of whom reported prior use of the charts. Average score [n (%)] out of eight, as well as median score (range) for each coding category were: (i) Category: 7.3 (91 %); 7 (4-8); (ii) Time: 7.8 (98 %); 7 (6-8); (iii) Site: 7.2 (90 %); 7 (5-8). Overall, the equivalent calculations (out of 24) were 22.3 (93 %) and 22 (18-24). Mean prelecture confidence was 1.37 (out of 5), rising to 3.85 postquiz. Urogynecologists had the highest correlation with correct coding, followed closely by fellows and general gynecologists. Optimizing training and study design can lead to excellent results for interobserver reliability of the IUGA-ICS Complication Classification coding, with increased participant confidence in complication-coding ability.

SGLT2 inhibitors.

PubMed

Dardi, I; Kouvatsos, T; Jabbour, S A

2016-02-01

Diabetes mellitus is a serious health issue and an economic burden, rising in epidemic proportions over the last few decades worldwide. Although several treatment options are available, only half of the global diabetic population achieves the recommended or individualized glycemic targets. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with a novel insulin-independent action. SGLT2 is a transporter found in the proximal renal tubules, responsible for the reabsorption of most of the glucose filtered by the kidney. Inhibition of SGLT2 lowers the blood glucose level by promoting the urinary excretion of excess glucose. Due to their insulin-independent action, SGLT2 inhibitors can be used with any degree of beta-cell dysfunction or insulin resistance, related to a very low risk of hypoglycemia. In addition to improving glycemic control, SGLT2 inhibitors have been associated with a reduction in weight and blood pressure when used as monotherapy or in combination with other antidiabetic agents in patients with type 2 diabetes mellitus (T2DM). Treatment with SGLT2 inhibitors is usually well tolerated; however, they have been associated with an increased incidence of urinary tract and genital infections, although these infections are usually mild and easy to treat. SGLT2 inhibitors are a promising new option in the armamentarium of drugs for patients with T2DM. Copyright © 2015 Elsevier Inc. All rights reserved.

Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors.

PubMed

Philip, Charles-André; Laskov, Ido; Beauchamp, Marie-Claude; Marques, Maud; Amin, Oreekha; Bitharas, Joanna; Kessous, Roy; Kogan, Liron; Baloch, Tahira; Gotlieb, Walter H; Yasmeen, Amber

2017-09-08

Phosphatase and Tensin homolog (PTEN) is a tumor suppressor gene. Loss of its function is the most frequent genetic alteration in endometrioid endometrial cancers (70-80%) and high grade tumors (90%). We assessed the sensitivity of endometrial cancer cell lines to PARP inhibitors (olaparib and BMN-673) and a PI3K inhibitor (BKM-120), alone or in combination, in the context of their PTEN mutation status. We also highlighted a direct pathway linking PTEN to DNA repair. Using endometrial cancer cellular models with known PTEN status, we evaluated their homologous recombination (HR) functionality by RAD51 foci formation assay. The 50% Inhibitory concentration (IC50) of PI3K and PARP inhibitors in these cells was assessed, and western blotting was performed to determine the expression of proteins involved in the PI3K/mTOR pathway. Moreover, we explored the interaction between RAD51 and PI3K/mTOR by immunofluorescence. Next, the combination effect of PI3K and PARP inhibitors on cell proliferation was evaluated by a clonogenic assay. Cells with mutated PTEN showed over-activation of the PI3K/mTOR pathway. These cells were more sensitive to PARP inhibition compared to PTEN wild-type cells. In addition, PI3K inhibitor treatment reduced RAD51 foci formation in PTEN mutated cells, and sensitized these cells to PARP inhibitor. Targeting both PARP and PI3K might lead to improved personalized therapeutic approaches in endometrial cancer patients with PTEN mutations. Understanding the complex interaction of PTEN mutations with DNA repair in endometrial cancer will help to better select patients that are likely to respond to some of the new and costly targeted therapies.

Interactions between scopolamine and muscarinic cholinergic agonists or cholinesterase inhibitors on spatial alternation performance in rats.

PubMed

Shannon, H E; Bemis, K G; Hendrix, J C; Ward, J S

1990-12-01

The effects on working memory of the muscarinic cholinergic agonists oxotremorine, arecoline, RS86 and pilocarpine, and the cholinesterase inhibitors physostigmine and tetrahydroaminoacadine were investigated in male F344 rats. Working memory was assessed by behavior maintained under a spatial alternation schedule of food presentation in which the interval between trials was varied from 2 to 32 sec. Under control conditions the percentage of correct responses decreased as the retention interval was varied from 2 to 32 sec. Administered alone the cholinergic agonists oxotremorine (0.01-0.1 mg/kg), arecoline (3-30 mg/kg), RS86 (0.3-3 mg/kg) and pilocarpine (0.3-3.0 mg/kg), and the cholinesterase inhibitors physostigmine (0.01-0.1 mg/kg) and tetrahydroaminoacridine (0.3-3.0 mg/kg) either had no effect on or produced dose-related deficits in working memory and decreases in response rates. The muscarinic antagonist scopolamine (0.1 mg/kg) produced retention interval-dependent decreases in the percentage of correct responding and rates of responding. The cholinergic agonists and tetrahydroaminoacridine failed to reverse the effects of scopolamine. However, physostigmine produced a dose-dependent reversal of the working-memory deficits and response-rate decreasing effects of scopolamine. The present results are consistent with the interpretation that drugs which primarily enhance M2 muscarinic cholinergic transmission are ineffective in enhancing working memory or in reversing scopolamine-induced deficits in working memory.

Combined treatment with MAO-A inhibitor and MAO-B inhibitor increases extracellular noradrenaline levels more than MAO-A inhibitor alone through increases in beta-phenylethylamine.

PubMed

Kitaichi, Yuji; Inoue, Takeshi; Nakagawa, Shin; Boku, Shuken; Izumi, Takeshi; Koyama, Tsukasa

2010-07-10

Monoamine oxidase inhibitors (MAO inhibitors) have been widely used as antidepressants. However, it remains unclear whether a difference exists between non-selective MAO inhibitors and selective MAO-A inhibitors in terms of their antidepressant effects. Using in vivo microdialysis methods, we measured extracellular noradrenaline and serotonin levels following administration of Ro 41-1049, a reversible MAO-A inhibitor and/or lazabemide, a reversible MAO-B inhibitor in the medial prefrontal cortex (mPFC) of rats. We examined the effect of local infusion of beta-phenylethylamine to the mPFC of rats on extracellular noradrenaline and serotonin levels. Furthermore, the concentrations of beta-phenylethylamine in the tissue of the mPFC after combined treatment with Ro 41-1049 and lazabemide were measured. The Ro 41-1049 alone and the combined treatment significantly increased extracellular noradrenaline levels compared with vehicle and lazabemide alone. Furthermore, the combined treatment increased noradrenaline levels significantly more than Ro 41-1049 alone did. The Ro 41-1049 alone and the combined treatment significantly increased extracellular serotonin levels compared with vehicle and lazabemide alone, but no difference in serotonin levels was found between the combined treatment group and the Ro 41-1049 group. Local infusion of low-dose beta-phenylethylamine increased extracellular noradrenaline levels, but not that of serotonin. Only the combined treatment significantly increased beta-phenylethylamine levels in tissues of the mPFC. Our results suggest that the combined treatment with a MAO-A inhibitor and a MAO-B inhibitor strengthens antidepressant effects because the combined treatment increases extracellular noradrenaline levels more than a MAO-A inhibitor alone through increases in beta-phenylethylamine. Copyright 2010 Elsevier B.V. All rights reserved.

The quantified EEG characteristics of responders and non-responders to long-term treatment with atomoxetine in children with attention deficit hyperactivity disorders.

PubMed

Chiarenza, Giuseppe Augusto; Chabot, Robert; Isenhart, Robert; Montaldi, Luciano; Chiarenza, Marco Paolo; Torto, Maria Grazia Lo; Prichep, Leslie S

2016-06-01

The aim of our study is to examine quantitative Electroencephalogram (QEEG) differences between ADHD patients that are responders and non-responders to long-term treatment with Atomoxetine at baseline and after 6 and 12months of treatment. Patients with attention deficit hyperactivity disorder (ADHD) received atomoxetine titrated, over 7days, from 0.5 to 1.2mg/kg/day. QEEG and Swanson, Nolan, and Pelham-IV Questionnaire (SNAP-IV) scores were recorded before treatment and after therapy. Twenty minutes of eyes closed resting EEG was recorded from 19 electrodes referenced to linked earlobes. Full frequency and narrow band spectra of two minutes of artifact-free EEG were computed as well as source localization using Variable Resolution Electrical Tomography (VARETA). Abnormalities were identified using Z-spectra relative to normative values. Patients were classified as responders, non-responders and partial responders based upon the SNAP-IV findings. At baseline, the responders showed increased absolute power in alpha and delta in frontal and temporal regions, whereas, non-responders showed increased absolute power in all frequency bands that was widely distributed. With treatment responders' absolute power values moved toward normal values, whereas, non-responders remained at baseline values. Patients with increased power in the alpha band with no evidence of alterations in the beta or theta range, might be responders to treatment with atomoxetine. Increased power in the beta band coupled with increased alpha seems to be related to non-responders and one should consider atomoxetine withdrawal, especially if there is persistence of increased alpha and beta accompanied by an increase of theta. Copyright © 2016 Elsevier B.V. All rights reserved.

Improving Situational Awareness for First Responders via Mobile Computing

NASA Technical Reports Server (NTRS)

Betts, Bradley J.; Mah, Robert W.; Papasin, Richard; Del Mundo, Rommel; McIntosh, Dawn M.; Jorgensen, Charles

2005-01-01

This project looks to improve first responder situational awareness using tools and techniques of mobile computing. The prototype system combines wireless communication, real-time location determination, digital imaging, and three-dimensional graphics. Responder locations are tracked in an outdoor environment via GPS and uploaded to a central server via GPRS or an 802.11 network. Responders can also wirelessly share digital images and text reports, both with other responders and with the incident commander. A pre-built three dimensional graphics model of a particular emergency scene is used to visualize responder and report locations. Responders have a choice of information end points, ranging from programmable cellular phones to tablet computers. The system also employs location-aware computing to make responders aware of particular hazards as they approach them. The prototype was developed in conjunction with the NASA Ames Disaster Assistance and Rescue Team and has undergone field testing during responder exercise at NASA Ames.

Improving Situational Awareness for First Responders via Mobile Computing

NASA Technical Reports Server (NTRS)

Betts, Bradley J.; Mah, Robert W.; Papasin, Richard; Del Mundo, Rommel; McIntosh, Dawn M.; Jorgensen, Charles

2006-01-01

This project looks to improve first responder incident command, and an appropriately managed flow of situational awareness using mobile computing techniques. The prototype system combines wireless communication, real-time location determination, digital imaging, and three-dimensional graphics. Responder locations are tracked in an outdoor environment via GPS and uploaded to a central server via GPRS or an 802. II network. Responders can also wireless share digital images and text reports, both with other responders and with the incident commander. A pre-built three dimensional graphics model of the emergency scene is used to visualize responder and report locations. Responders have a choice of information end points, ranging from programmable cellular phones to tablet computers. The system also employs location-aware computing to make responders aware of particular hazards as they approach them. The prototype was developed in conjunction with the NASA Ames Disaster Assistance and Rescue Team and has undergone field testing during responder exercises at NASA Ames.

Responding to Tragedy

ERIC Educational Resources Information Center

Coopman, J. T.

2009-01-01

In this article, the author, a superintendent of Clark-Pleasant School Corporation in Whiteland, Indiana, relates how she and the school community responded to a car accident that killed two students. The author stresses the need to develop a comprehensive crisis plan. It is also important to be sensitive to the needs of family members who are…

Cerebrovascular Complications After Heart Transplantation

PubMed Central

Alejaldre, Aída; Delgado-Mederos, Raquel; Santos, Miguel Ángel; Martí-Fàbregas, Joan

2010-01-01

Neurological complications in orthotopic heart transplantation represent a major cause of morbidity and mortality despite successful transplantation. The most frequent perioperative neurological complications are delirium or encephalopathy. In this period cerebrovascular complication ranges between 5-11%. After the perioperative period, the 5-year stroke risk after cardiac transplantation is 4.1%. In a retrospective study conducted with 314 patients who underwent cardiac transplantation, it was found that 20% of cerebrovascular complications occurred within the first two weeks after transplantation, while 80% occurred in the late postoperative phase. Of these, ischemic stroke is the most common subtype. In the perioperative periode, hemodynamic instability, cardiac arrest, extracorporeal circulation over 2 hours, prior history of stroke, and carotid stenosis greater than 50% have been reported to be risk factors for the occurrence of cerebrovascular complications. Perioperative cerebrovascular complications are associated with higher mortality and poor functional outcome at one year follow-up. After the perioperative period, the only factor that has been significantly associated with an increased risk of cerebrovascular complications is a history of prior stroke, either ischemic or hemorrhagic. Other associated factors include unknown atrial fibrillation, septic emboli from endocarditis, cardiac catheterization and perioperative hemodynamic shock. According to the TOAST etiologic classification, the most prevalent etiologic subtype of ischemic stroke is undetermined cause. PMID:21804780

[Complications in brachial plexus surgery].

PubMed

Martínez, Fernando; Pinazzo, Samantha; Moragues, Rodrigo; Suarez, Elizabeth

2015-01-01

Although traumatic brachial plexus injuries are relatively rare in trauma patients, their effects on the functionality of the upper limb can be very disabling. The authors' objective was to assess the complications in a series of patients operated for brachial plexus injuries. This was a retrospective evaluation of patients operated on by the authors between August 2009 and March 2013. We performed 36 surgeries on 33 patients. The incidence of complications was 27.7%. Of these, only 1 (2.7%) was considered serious and associated with the procedure (iatrogenic injury of brachial artery). There was another serious complication (hypoxia in patients with airway injury) but it was not directly related to the surgical procedure. All other complications were considered minor (wound dehiscence, hematoma, infection). There was no mortality in our series. The complications in our series are similar to those reported in the literature. Serious complications (vascular, neural) are rare and represent less than 5% in all the different series. Given the rate of surgical complications and the poor functional perspective for a brachial plexus injury without surgery, we believe that surgery should be the treatment of choice. Copyright © 2013 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.

Plasma oxytocin changes and anti-obsessive response during serotonin reuptake inhibitor treatment: a placebo controlled study

PubMed Central

2013-01-01

Background The drug treatments of choice for obsessive-compulsive disorder (OCD) are serotonin reuptake inhibitors (SRIs). However, a correlation between the neuropeptide oxytocin in cerebrospinal fluid and the severity of OCD has previously been shown, and oxytocin and serotonin are interconnected within the brain. Few studies have investigated whether SRIs have any effect on oxytocin; thus, our aim was to explore the possibility that oxytocinergic mechanisms contribute to the anti-obsessive effect of SRIs. Method In a randomized, double-blind trial, comparing SRIs (clomipramine and paroxetine) with placebo in 36 adults with OCD (characterized for subtypes), plasma oxytocin was measured with radioimmunoassay after plasma extraction, at baseline, after 1 week, and after 4 weeks of treatment, and related to baseline severity and clinical response after 12 weeks, as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Results Baseline oxytocin levels correlated positively with baseline Y-BOCS ratings, but only among the future SRI responders. Patients with early onset of OCD had higher baseline oxytocin. During treatment, plasma oxytocin did not differ between SRI and placebo treatment. In SRI responders, plasma oxytocin first decreased and then increased; in non-responders (to SRI as well as to placebo), the reverse was the case. After 4 weeks, treatment responders had attained higher oxytocin levels compared to non-responders. The intra-individual range (i.e. the variability) of plasma oxytocin between measurements was the measure that best differentiated responders from non-responders. This range was higher in responders than non-responders, and lower in patients with autistic traits. Conclusions SRIs have highly variable effects on plasma oxytocin between individuals. The associations between baseline oxytocin and OCD severity and between oxytocin changes and treatment response support the notions that oxytocin is involved in OCD pathophysiology

Non-genetic risk factors in haemophilia A inhibitor management - the danger theory and the use of animal models.

PubMed

Lövgren, K M; Søndergaard, H; Skov, S; Wiinberg, B

2016-09-01

In haemophilia A (HA) management, antidrug antibodies, or inhibitors, are a serious complication that renders factor VIII (FVIII) replacement therapy ineffective, increases morbidity and reduces quality of life for affected patients. Inhibitor development aetiology is multifactorial and covers both genetic and therapy related risk factors. Many therapy-related risk factors have proven difficult to confirm due to several confounding factors and the small study populations available. However, clinical studies indicate that e.g. on-demand treatment and surgery affect inhibitor development, and explanations for this association are being investigated. A potential explanation is the danger signal effect, where the immune response is activated by endogenous or exogenous danger or damage signals present at the time and site of FVIII administration. The danger theory explains how alarm signals from stressed, injured or dying cells can activate an immune reaction, without the involvement of foreign antigens. Bleeds, trauma, surgery or concomitant infection could be events initiating danger signalling in HA patients, resulting in an immune reaction towards administered FVIII that otherwise would pass unnoticed. This role of danger in HA inhibitor formation has previously been suggested, but a thorough discussion of this subject is lacking. The present review will discuss the potential role of danger signals in haemophilia and inhibitor development, with focus on treatment related risk factors with a suspected danger signal aetiology; on-demand treatment, treatment during major bleeds or surgery, and treatment during infection or vaccination. Clinical studies as well as animal experiments addressing these factors will be reviewed. © 2016 John Wiley & Sons Ltd.

Targeted therapy of chronic liver diseases with the inhibitors of angiogenesis.

PubMed

Srivastava, Ankita; Shukla, Vanistha; Tiwari, Deepika; Gupta, Jaya; Kumar, Sunil; Kumar, Awanish

2018-05-30

Angiogenesis appears to be intrinsically associated with the progression of chronic liver diseases, which eventually leads to the development of cirrhosis and related complications, including hepatocellular carcinoma. Several studies have suggested that this association is relevant for chronic liver disease (CLD) progression, with angiogenesis. The fact that angiogenesis plays a pivotal role in CLDs gives rise to new opportunities for treating CLDs. Inhibitor of angiogenesis has proved effective for the treatment of patients suffering from CLD. However, it is limited in diagnosis. The last decade has witnessed a plethora of publications which elucidate the potential of angiogenesis inhibitors for the therapy of CLD. The close relationship between the progression of CLDs and angiogenesis emphasizes the need for anti-angiogenic therapy to block/slow down CLD progression. The present review summarizes all these discussions, the results of the related studies carried out to date and the future prospects in this field. We discuss liver angiogenesis in normal and pathophysiologic conditions with a focus on the role and future use of angiogenic factors as second-line treatment of CLD. This review compiles relevant findings and offers opinions that have emerged in last few years relating liver angiogenesis and its treatment using anti-angiogenic factors. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

78 FR 53124 - First Responder Network Authority Filing

Federal Register 2010, 2011, 2012, 2013, 2014

2013-08-28

...-229; and WT Docket No. 06-150; DA 13-1775] First Responder Network Authority Filing AGENCY: Federal... public comment on a filing submitted by the First Responder Network Authority (FirstNet) on August 2... Commission provides seven days for public comment on matters raised by the First Responder Network Authority...

28 CFR 115.64 - Staff first responder duties.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Staff first responder duties. 115.64....64 Staff first responder duties. (a) Upon learning of an allegation that an inmate was sexually abused, the first security staff member to respond to the report shall be required to: (1) Separate the...

28 CFR 115.364 - Staff first responder duties.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Staff first responder duties. 115.364....364 Staff first responder duties. (a) Upon learning of an allegation that a resident was sexually abused, the first staff member to respond to the report shall be required to: (1) Separate the alleged...

28 CFR 115.64 - Staff first responder duties.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Staff first responder duties. 115.64....64 Staff first responder duties. (a) Upon learning of an allegation that an inmate was sexually abused, the first security staff member to respond to the report shall be required to: (1) Separate the...

28 CFR 115.64 - Staff first responder duties.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Staff first responder duties. 115.64....64 Staff first responder duties. (a) Upon learning of an allegation that an inmate was sexually abused, the first security staff member to respond to the report shall be required to: (1) Separate the...

28 CFR 115.364 - Staff first responder duties.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Staff first responder duties. 115.364....364 Staff first responder duties. (a) Upon learning of an allegation that a resident was sexually abused, the first staff member to respond to the report shall be required to: (1) Separate the alleged...

28 CFR 115.364 - Staff first responder duties.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Staff first responder duties. 115.364....364 Staff first responder duties. (a) Upon learning of an allegation that a resident was sexually abused, the first staff member to respond to the report shall be required to: (1) Separate the alleged...

Peptidase inhibitors in tick physiology.

PubMed

Parizi, L F; Ali, A; Tirloni, L; Oldiges, D P; Sabadin, G A; Coutinho, M L; Seixas, A; Logullo, C; Termignoni, C; DA Silva Vaz, I

2018-06-01

Peptidase inhibitors regulate a wide range of physiological processes involved in the interaction between hematophagous parasites and their hosts, including tissue remodeling, the immune response and blood coagulation. In tick physiology, peptidase inhibitors have a crucial role in adaptation to improve parasitism mechanisms, facilitating blood feeding by interfering with defense-related host peptidases. Recently, a larger number of studies on this topic led to the description of several new tick inhibitors displaying interesting novel features, for example a role in pathogen transmission to the host. A comprehensive review discussing these emerging concepts can therefore shed light on peptidase inhibitor functions, their relevance to tick physiology and their potential applications. Here, we summarize and examine the general characteristics, functional diversity and action of tick peptidase inhibitors with known physiological roles in the tick-host-pathogen interaction. © 2017 The Royal Entomological Society.

Inside HDAC with HDAC inhibitors.

PubMed

Bertrand, Philippe

2010-06-01

Histone deacetylase inhibitors are a large group of diverse molecules intrinsically able to inhibit cell proliferation in various cancer cell lines. Their apoptotic effects have been linked to the modulation in the expression of several regulatory tumor suppressor genes caused by the modified status of histone acetylation, a key event in chromatin remodelling. As the initial histone deacetylase activity of HDAC has been extended to other proteins, the possible other biological mechanisms modified by HDAC inhibitor treatments are still to be clarified. The need for HDAC isoform selective inhibitors is an important issue to serve this goal. This review discusses the approaches proposed by several research groups working on the synthesis of HDAC inhibitors, based on modelling studies and the way these findings were used to obtain new HDAC inhibitors with possible isoform selectivity. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Safety of Resuming Tumor Necrosis Factor Inhibitors in Ankylosing Spondylitis Patients Concomitant with the Treatment of Active Tuberculosis: A Retrospective Nationwide Registry of the Korean Society of Spondyloarthritis Research

PubMed Central

Kim, Hye Won; Kwon, Seong Ryul; Jung, Kyong-Hee; Kim, Seong-Kyu; Baek, Han Joo; Seo, Mi Ryung; Bang, So-Young; Lee, Hye-Soon; Suh, Chang-Hee; Jung, Ju Yang; Son, Chang-Nam; Shim, Seung Cheol; Lee, Sang-Hoon; Lee, Seung-Geun; Lee, Yeon-Ah; Lee, Eun Young; Kim, Tae-Hwan

2016-01-01

Backgrounds Patients who develop an active tuberculosis infection during tumor necrosis factor (TNF) inhibitor treatment typically discontinue TNF inhibitor and receive standard anti-tuberculosis treatment. However, there is currently insufficient information on patient outcomes following resumption of TNF inhibitor treatment during ongoing anti- tuberculosis treatment. Our study was designed to investigate the safety of resuming TNF inhibitors in ankylosing spondylitis (AS) patients who developed tuberculosis as a complication of the use of TNF inhibitors. Methods Through the nationwide registry of the Korean Society of Spondyloarthritis Research, 3929 AS patients who were prescribed TNF inhibitors were recruited between June 2003 and June 2014 at fourteen referral hospitals. Clinical information was analyzed about the patients who experienced tuberculosis after exposure to TNF inhibitors. The clinical features of resumers and non-resumers of TNF inhibitors were compared and the outcomes of tuberculosis were surveyed individually. Findings Fifty-six AS patients were treated for tuberculosis associated with TNF inhibitors. Among them, 23 patients resumed TNF inhibitors, and these patients were found to be exposed to TNF inhibitors for a longer period of time and experienced more frequent disease flare-up after discontinuation of TNF inhibitors compared with those who did not resume. Fifteen patients resumed TNF inhibitors during anti-tuberculosis treatment (early resumers) and 8 after completion of anti-tuberculosis treatment (late resumers). Median time to resuming TNF inhibitor from tuberculosis was 3.3 and 9.0 months in the early and late resumers, respectively. Tuberculosis was treated successfully in all resumers and did not relapse in any of them during follow-up (median 33.8 [IQR; 20.8–66.7] months). Conclusions Instances of tuberculosis were treated successfully in our AS patients, even when given concomitantly with TNF inhibitors. We suggest that early

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics

PubMed Central

Corsino, Patrick E.; Narayan, Satya

2015-01-01

Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATP-competitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non–ATP-competitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non–ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer. PMID:26018905

Oral health-related complications of breast cancer treatment: assessing dental hygienists' knowledge and professional practice.

PubMed

Taichman, L Susan; Gomez, Grace; Inglehart, Marita Rohr

2014-04-01

Approximately 200,000 women are diagnosed with breast cancer in the U.S. every year. These patients commonly suffer from oral complications of their cancer therapy. The purpose of this study was to assess dental hygienists' knowledge and professional practice related to providing care for breast cancer patients. A pre-tested 43-item survey was mailed to a random sample of 10% of all licensed dental hygienists in the state of Michigan (n=962). The survey assessed the respondents' knowledge of potential oral complications of breast cancer treatments as well as their professional practices when treating patients with breast cancer. After 2 mailings, the response rate was 37% (n=331). Descriptive and inferential analyses were conducted using SAS. Many dental hygienists were unaware of the recommended clinical guidelines for treating breast cancer patients and lacked specific knowledge concerning the commonly prescribed anti-estrogen medications for pre-and postmenopausal breast cancer patients. Over 70% of the respondents indicated they were unfamiliar with the AI class of medications. Only 13% of dental hygienists correctly identified the mechanism of action of anti-estrogen therapy. Dental hygienists reported increased gingival inflammation, gingival bleeding, periodontal pocketing, xerostomia and burning tissues in patients receiving anti-estrogen therapies. Less than 10% believed that their knowledge of breast cancer treatments and the potential oral side effects is up to date. Results indicate a need for more education about the oral effects of breast cancer therapies and about providing the best possible care for patients undergoing breast cancer treatment.

Oral Health-Related Complications of Breast Cancer Treatment: Assessing Dental Hygienists' Knowledge and Professional Practice.

PubMed

Taichman, L Susan; Gomez, Grace; Inglehart, Marita Rohr

2015-06-01

Approximately 200,000 women are diagnosed with breast cancer in the U.S. every year. These patients commonly suffer from oral complications of their cancer therapy. The purpose of this study was to assess dental hygienists' knowledge and professional practice related to providing care for breast cancer patients. A pre-tested 43-item survey was mailed to a random sample of 10% of all licensed dental hygienists in the state of Michigan (n=962). The survey assessed the respondents' knowledge of potential oral complications of breast cancer treatments as well as their professional practices when treating patients with breast cancer. After 2 mailings, the response rate was 37% (n=331). Descriptive and inferential analyses were conducted using SAS. Many dental hygienists were unaware of the recommended clinical guidelines for treating breast cancer patients and lacked specific knowledge concerning the commonly prescribed anti-estrogen medications for pre-and postmenopausal breast cancer patients. Over 70% of the respondents indicated they were unfamiliar with the AI class of medications. Only 13% of dental hygienists correctly identified the mechanism of action of anti-estrogen therapy. Dental hygienists reported increased gingival inflammation, gingival bleeding, periodontal pocketing, xerostomia and burning tissues in patients receiving anti-estrogen therapies. Less than 10% believed that their knowledge of breast cancer treatments and the potential oral side effects is up to date. Results indicate a need for more education about the oral effects of breast cancer therapies and about providing the best possible care for patients undergoing breast cancer treatment. Copyright © 2015 The American Dental Hygienists’ Association.

28 CFR 115.264 - Staff first responder duties.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Staff first responder duties. 115.264... Report § 115.264 Staff first responder duties. (a) Upon learning of an allegation that a resident was sexually abused, the first security staff member to respond to the report shall be required to: (1...

28 CFR 115.264 - Staff first responder duties.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Staff first responder duties. 115.264... Report § 115.264 Staff first responder duties. (a) Upon learning of an allegation that a resident was sexually abused, the first security staff member to respond to the report shall be required to: (1...

28 CFR 115.264 - Staff first responder duties.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Staff first responder duties. 115.264... Report § 115.264 Staff first responder duties. (a) Upon learning of an allegation that a resident was sexually abused, the first security staff member to respond to the report shall be required to: (1...

Syk inhibitors.

PubMed

Chihara, Kazuyasu; Kimura, Yukihiro; Honjo, Chisato; Takeuchi, Kenji; Sada, Kiyonao

2013-01-01

Non-receptor type of protein-tyrosine kinase Syk (spleen tyrosine kinase) was isolated in University of Fukui in 1991. Syk is most highly expressed by haemopoietic cells and known to play crucial roles in the signal transduction through various immunoreceptors of the adaptive immune response. However, recent reports demonstrate that Syk also mediates other biological functions, such as innate immune response, osteoclast maturation, platelet activation and cellular adhesion. Moreover, ectopic expression of Syk by epigenetic changes is reported to cause retinoblastoma. Because of its critical roles on the cellular functions, the development of Syk inhibitors for clinical use has been desired. Although many candidate compounds were produced, none of them had progressed to clinical trials. However, novel Syk inhibitors were finally developed and its usefulness has been evaluated in the treatment of allergic rhinitis, rheumatoid arthritis and idiopathic thrombocytopenic purpura. In this review, we will summarize the history, structure and function of Syk, and then the novel Syk inhibitors and their current status. In addition, we will introduce our research focused on the functions of Syk on Dectin-1-mediated mast cell activation.

Targeting KRAS-mutant non-small cell lung cancer with the Hsp90 inhibitor ganetespib.

PubMed

Acquaviva, Jaime; Smith, Donald L; Sang, Jim; Friedland, Julie C; He, Suqin; Sequeira, Manuel; Zhang, Chaohua; Wada, Yumiko; Proia, David A

2012-12-01

Mutant KRAS is a feature of more than 25% of non-small cell lung cancers (NSCLC) and represents one of the most prevalent oncogenic drivers in this disease. NSCLC tumors with oncogenic KRAS respond poorly to current therapies, necessitating the pursuit of new treatment strategies. Targeted inhibition of the molecular chaperone Hsp90 results in the coordinated blockade of multiple oncogenic signaling pathways in tumor cells and has thus emerged as an attractive avenue for therapeutic intervention in human malignancies. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90 currently in clinical trials for NSCLCs in a panel of lung cancer cell lines harboring a diverse spectrum of KRAS mutations. In vitro, ganetespib was potently cytotoxic in all lines, with concomitant destabilization of KRAS signaling effectors. Combinations of low-dose ganetespib with MEK or PI3K/mTOR inhibitors resulted in superior cytotoxic activity than single agents alone in a subset of mutant KRAS cells, and the antitumor efficacy of ganetespib was potentiated by cotreatment with the PI3K/mTOR inhibitor BEZ235 in A549 xenografts in vivo. At the molecular level, ganetespib suppressed activating feedback signaling loops that occurred in response to MEK and PI3K/mTOR inhibition, although this activity was not the sole determinant of combinatorial benefit. In addition, ganetespib sensitized mutant KRAS NSCLC cells to standard-of-care chemotherapeutics of the antimitotic, topoisomerase inhibitor, and alkylating agent classes. Taken together, these data underscore the promise of ganetespib as a single-agent or combination treatment in KRAS-driven lung tumors.

A comparison of physical and psychological features of responders and non-responders to cervical facet blocks in chronic whiplash

PubMed Central

2013-01-01

Background Cervical facet block (FB) procedures are often used as a diagnostic precursor to radiofrequency neurotomies (RFN) in the management of chronic whiplash associated disorders (WAD). Some individuals will respond to the FB procedures and others will not respond. Such responders and non-responders provided a sample of convenience to question whether there were differences in their physical and psychological features. This information may inform future predictive studies and ultimately the clinical selection of patients for FB procedures. Methods This cross-sectional study involved 58 individuals with chronic WAD who responded to cervical FB procedures (WAD_R); 32 who did not respond (WAD_NR) and 30 Healthy Controls (HC)s. Measures included: quantitative sensory tests (pressure; thermal pain thresholds; brachial plexus provocation test); nociceptive flexion reflex (NFR); motor function (cervical range of movement (ROM); activity of the superficial neck flexors during the cranio-cervical flexion test (CCFT). Self-reported measures were gained from the following questionnaires: neuropathic pain (s-LANSS); psychological distress (General Health Questionnaire-28), post-traumatic stress (PDS) and pain catastrophization (PCS). Individuals with chronic whiplash attended the laboratory once the effects of the blocks had abated and symptoms had returned. Results Following FB procedures, both WAD groups demonstrated generalized hypersensitivity to all sensory tests, decreased neck ROM and increased superficial muscle activity with the CCFT compared to controls (p < 0.05). There were no significant differences between WAD groups (all p > 0.05). Both WAD groups demonstrated psychological distress (GHQ-28; p < 0.05), moderate post-traumatic stress symptoms and pain catastrophization. The WAD_NR group also demonstrated increased medication intake and elevated PCS scores compared to the WAD_R group (p < 0.05). Conclusions Chronic WAD responders and non-responders to FB

Facilitators and inhibitors in developing professional values in nursing students.

PubMed

Shafakhah, Mahnaz; Molazem, Zahra; Khademi, Mojgan; Sharif, Farkhondeh

2018-03-01

Values are the basis of nursing practice, especially in making decisions about complicated ethical issues. Despite their key role in nursing, little information exists on the factors affecting their development and manifestation in nursing students. This study identifies and describes the facilitators and inhibitors of the development and manifestation of professional values based on the experiences of nursing students and instructors and nurses. Data were collected through 29 semi-structured interviews and two focus group interviews in 2013-2015 and were analyzed using the conventional content analysis method of Elo and Kyngäs. Participants and research context: In total, 18 nursing undergraduates, five nursing instructors, and five nurses from Shiraz University of Medical Sciences and one of the teaching hospitals in Shiraz were selected through purposive sampling. Ethical considerations: The research was approved by the Ethics Committee of Shiraz University of Medical Sciences and the teaching hospital examined. The findings consisted of two categories: personal and environmental factors. Personal factors consisted of the two subcategories of personal stimuli (work experience and past relationships, inner beliefs and acting on values, belief in God and a divine worldview) and personal inhibitors (the lack of professional motivation and enthusiasm, negative emotions). Environmental factors consisted of the two subcategories of environmental stimuli (cooperation, order and discipline) and environmental inhibitors (unfavorable work environment, society's negative attitude toward nursing, the violation of rights). Given the impact of personal and environmental factors on the development and manifestation of professional values in nursing students, it is upon the education authorities to take account of them in their planning, and nursing managers are also recommended to further address these factors in their development of a proper work environment, provision of

Angiogenesis inhibitors and symptomatic anal ulcers in metastatic colorectal cancer patients *.

PubMed

Bergamo, Francesca; Lonardi, Sara; Salmaso, Beatrice; Lacognata, Carmelo; Battaglin, Francesca; Cavallin, Francesco; Saadeh, Luca; Murgioni, Sabina; Caruso, Antonino; Aliberti, Camillo; Zagonel, Vittorina; Castoro, Carlo; Scarpa, Marco

2018-03-01

Angiogenesis inhibitors are a standard first-line treatment for metastatic colorectal cancer. Anal canal pain is a common adverse event, but its cause has never been described. The aim of the study was to evaluate the association between the use of angiogenesis inhibitors and symptomatic anal ulcer development. This retrospective cohort study included all 601 consecutive metastatic colorectal cancer patients undergoing first line treatment from January 2010 to June 2016 at the Veneto Institute of Oncology. Details about patient characteristics, treatment and proctology reports were retrieved and compared. Vascularization of the anal canal was evaluated with contrast MRI. Fifty out of 601 patients reported perianal complaints during treatment and underwent proctologic evaluation. Among those, 16 were found to have an anal ulcer. Symptomatic anal ulcers occurred only in patients receiving bevacizumab (4.2% vs. 0% with other regimens, p = .009). The peak incidence was 4-8 weeks after treatment start. Vascularization of anal canal was significantly lower in patients treated with bevacizumab (p = .03). Hypertension and hemorrhoids were associated with a lower risk of anal ulcer occurrence (p = .009 and p = .036). Pain intensity was severe. All attempts at symptomatic treatment only led to transient benefit. The absence of symptomatic ulcers was protective against earlier permanent discontinuation of treatment (HR = .22, 95%CI: 0.04-0.62). The development of symptomatic anal ulcers in patients receiving angiogenesis inhibitor is a common adverse event which can compromise the continuation of cancer therapy. We recommend an early proctologic evaluation in case of anal symptoms with the aim to prevent and timely manage such complication.

The effects of residual platelets in plasma on plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays.

PubMed

Pieters, Marlien; Barnard, Sunelle A; Loots, Du Toit; Rijken, Dingeman C

2017-01-01

Due to controversial evidence in the literature pertaining to the activity of plasminogen activator inhibitor-1 in platelets, we examined the effects of residual platelets present in plasma (a potential pre-analytical variable) on various plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays. Blood samples were collected from 151 individuals and centrifuged at 352 and 1500 g to obtain plasma with varying numbers of platelet. In a follow-up study, blood samples were collected from an additional 23 individuals, from whom platelet-poor (2000 g), platelet-containing (352 g) and platelet-rich plasma (200 g) were prepared and analysed as fresh-frozen and after five defrost-refreeze cycles (to determine the contribution of in vitro platelet degradation). Plasminogen activator inhibitor-1 activity, plasminogen activator inhibitor-1 antigen, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasma clot lysis time, β-thromboglobulin and plasma platelet count were analysed. Platelet α-granule release (plasma β-thromboglobulin) showed a significant association with plasminogen activator inhibitor-1 antigen levels but weak associations with plasminogen activator inhibitor-1 activity and a functional marker of fibrinolysis, clot lysis time. Upon dividing the study population into quartiles based on β-thromboglobulin levels, plasminogen activator inhibitor-1 antigen increased significantly across the quartiles while plasminogen activator inhibitor-1 activity and clot lysis time tended to increase in the 4th quartile only. In the follow-up study, plasma plasminogen activator inhibitor-1 antigen was also significantly influenced by platelet count in a concentration-dependent manner. Plasma plasminogen activator inhibitor-1 antigen levels increased further after complete platelet degradation. Residual platelets in plasma significantly influence plasma plasminogen activator inhibitor-1 antigen levels mainly through release of

Comparison of MicroRNAs Mediated in Reactivation of the γ-Globin in β-Thalassemia Patients, Responders and Non-Responders to Hydroxyurea.

PubMed

Hojjati, Mohammad T; Azarkeivan, Azita; Pourfathollah, Ali A; Amirizadeh, Naser

2017-03-01

Drug induction of Hb F seems to be an ideal therapy for patients with hemoglobin (Hb) disorders, and many efforts have been made to reveal the mechanism behind it. Thus, we examined in vivo expression of some microRNAs (miRNAs) that are thought to be involved in this process. Among β-thalassemia (β-thal) patients who were undergoing hydroxyurea (HU) therapy in the past 3 months and five healthy individuals, five responders and five non-responders, were also included in the study. Erythroid progenitors were isolated by magnetic activated cell sorting (MACS) and miRNA expression analyzed using reverse transcription-polymerase chain reaction (RT-PCR). We showed that γ-globin, miR-210 and miR-486-3p had higher levels in the responders than the non-responders group. Moreover, miR-150 and miR-320 had higher levels in the healthy group than both non-responders and responders groups, but the expression of miR-96 did not show any significant difference between the study groups. To the best of our knowledge, this is the first study proposing that 'induction of cellular hypoxic condition by Hb F inducing agents' could be the milestone of possible mechanisms that explain why responders are able to reactivate γ-globin genes and subsequently, more production of Hb F, in response to these agents in comparison to non-responders. However, further investigations need to be performed to verify this hypothesis.

Community first responders and responder schemes in the United Kingdom: systematic scoping review.

PubMed

Phung, Viet-Hai; Trueman, Ian; Togher, Fiona; Orner, Roderick; Siriwardena, A Niroshan

2017-06-19

Community First Responder (CFR) schemes support lay people to respond to medical emergencies, working closely with ambulance services. They operate widely in the UK. There has been no previous review of UK literature on these schemes. This is the first systematic scoping review of UK literature on CFR schemes, which identifies the reasons for becoming a CFR, requirements for training and feedback and confusion between the CFR role and that of ambulance service staff. This study also reveals gaps in the evidence base for CFR schemes. We conducted a systematic scoping review of the published literature, in the English language from 2000 onwards using specific search terms in six databases. Narrative synthesis was used to analyse article content. Nine articles remained from the initial search of 15,969 articles after removing duplicates, title and abstract and then full text review. People were motivated to become CFRs through an altruistic desire to help others. They generally felt rewarded by their work but recognised that the help they provided was limited by their training compared with ambulance staff. There were concerns about the possible emotional impact on CFRs responding to incidents. CFRs felt that better feedback would enhance their learning. Ongoing training and support were viewed as essential to enable CFRs to progress. They perceived that public recognition of the CFR role was low, patients sometimes confusing them with ambulance staff. Relationships with the ambulance service were sometimes ambivalent due to confusion over roles. There was support for local autonomy of CFR schemes but with greater sharing of best practice. Most studies dated from 2005 and were descriptive rather than analytical. In the UK and Australia CFRs are usually lay volunteers equipped with basic skills for responding to medical emergencies, whereas in the US they include other emergency staff as well as lay people. Opportunities for future research include exploring

Crystal Structures of MEK1 Binary and Ternary Complexes with Nucleotides and Inhibitors

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

Fischmann, Thierry O.; Smith, Catherine K.; Mayhood, Todd W.

MEK1 is a member of the MAPK signal transduction pathway that responds to growth factors and cytokines. We have determined that the kinase domain spans residues 35-382 by proteolytic cleavage. The complete kinase domain has been crystallized and its X-ray crystal structure as a complex with magnesium and ATP-{gamma}S determined at 2.1 {angstrom}. Unlike crystals of a truncated kinase domain previously published, the crystals of the intact domain can be grown either as a binary complex with a nucleotide or as a ternary complex with a nucleotide and one of a multitude of allosteric inhibitors. Further, the crystals allow formore » the determination of costructures with ATP competitive inhibitors. We describe the structures of nonphosphorylated MEK1 (npMEK1) binary complexes with ADP and K252a, an ATP-competitive inhibitor (see Table 1), at 1.9 and 2.7 {angstrom} resolution, respectively. Ternary complexes have also been solved between npMEK1, a nucleotide, and an allosteric non-ATP competitive inhibitor: ATP-{gamma}S with compound 1 and ADP with either U0126 or the MEK1 clinical candidate PD325089 at 1.8, 2.0, and 2.5 {angstrom}, respectively. Compound 1 is structurally similar to PD325901. These structures illustrate fundamental differences among various mechanisms of inhibition at the molecular level. Residues 44-51 have previously been shown to play a negative regulatory role in MEK1 activity. The crystal structure of the integral kinase domain provides a structural rationale for the role of these residues. They form helix A and repress enzymatic activity by stabilizing an inactive conformation in which helix C is displaced from its active state position. Finally, the structure provides for the first time a molecular rationale that explains how mutations in MEK may lead to the cardio-facio-cutaneous syndrome.« less

Neurologic Complications After Cardiac Transplant.

PubMed

Öcal, Ruhsen; Kibaroğlu, Seda; Derle, Eda; Tanoğlu, Ceyda; Camkıran, Aynur; Pirat, Arash; Can, Ufuk; Sezgin, Atilla

2016-06-15

Cardiac transplant is the best available therapy for patients with end-stage heart failure. Neurologic complications occur at a rate of 30% to 70% in patients undergoing cardiac transplant, and they affect mortality and morbidity of these patients. Risk factors for neurologic complications include immunosuppressive medication toxicity, infections, brain lesions, and metabolic disorders. The aim of our study was to determine the incidence of neurologic complications in adult patients undergoing cardiac transplant. We retrospectively evaluated the medical records of 70 patients who underwent cardiac transplant between 2004 and April 2016. We recorded the demographic data, neurologic symptoms, neurologic examination findings, laboratory test results, brain imaging study results, and treatments received of the patients. Of the 70 patients enrolled, 55 were male and 15 were female patients. The age range was 18 to 63 years, and the mean age was 42.4 years. Twelve patients had encephalopathy, 4 had neuropathic pain, 3 had tremor, 2 had ischemic cerebrovascular accident, 7 had posterior reversible encephalopathy syndrome, and 1 had drop foot. Encephalopathy usually developed secondary to other neurologic disorders. The incidence of neurologic complications in adult patients undergoing cardiac transplant was 30%. Neurologic complications are common after cardiac transplant. We observed an incidence of 30% for neurologic complications in our clinic, with encephalopathy being the most common complication. Encephalopathy most commonly developed secondary to posterior reversible encephalopathy syndrome.

Risk Factors for Complications of Traumatic Injuries.

PubMed

de Aguiar Júnior, Wagner; Saleh, Carmen Mohamad Rida; Whitaker, Iveth Yamaguchi

2016-01-01

Complications in hospitalized trauma patients are major causes of morbidity and mortality. The aims of this study were to identify the in-hospital trauma patients' complications and identify the risk factors for complications in this population. A retrospective analysis was conducted in a sample from a Brazilian hospital. The sample consisted of 407 patients, 194 (47.66%) of whom had records of complications. The most common complications were infections (41.80%). The risk factors related to the complications were age, length of hospital stay, external causes, and injury severity. The complications were frequent in this sample, and the risk for complications was characterized by multiple factors.

Synthesis of Lysine Methyltransferase Inhibitors

NASA Astrophysics Data System (ADS)

Ye, Tao; Hui, Chunngai

2015-07-01

Lysine methyltransferase which catalyze methylation of histone and nonhistone proteins, play a crucial role in diverse biological processes and has emerged as a promising target for the development of various human diseases, including cancer, inflammation, and psychiatric disorders. However, inhibiting Lysine methyltransferases selectively has presented many challenges to medicinal chemists. During the past decade, lysine methyltransferase inhibitors covering many different structural classes have been designed and developed. In this review, we describe the development of selective, small-molecule inhibitors of lysine methyltransferases with an emphasis on their discovery and chemical synthesis. We highlight the current state of lysine methyltransferase inhibitors and discuss future directions and opportunities for lysine methyltransferase inhibitor discovery.

Birth preparedness and complication readiness among pregnant women in Tehulederie district, Northeast Ethiopia: a community-based cross-sectional study.

PubMed

Endeshaw, Demlie Belete; Gezie, Lema Derseh; Yeshita, Hedija Yenus

2018-01-01

Motherhood is a time of anticipation of joy for a woman, her family, and her community. In spite of this fact, it is not as enjoyable as it should be because of numerous reasons. Insufficiency or lack of birth preparedness and complication readiness is the most common reason. The aim of this study was to assess the practice of birth preparedness and complication readiness and associated factors among pregnant women in Tehuledere district, northeast Ethiopia. A community-based cross-sectional study was conducted in Tehuledere district, northeast Ethiopia. Participants were selected using the multistage sampling technique, and data were analyzed both descriptively and analytically using the binary logistic regression. Out of the total 507 samples, 500 (response rate 98.6%) pregnant women participated in the study. Less than half (44.6%) and (43.4%) of the respondents had knowledge and practice on birth preparedness and complication readiness, respectively. In the multivariate analysis, knowledge of birth preparedness and complication readiness (AOR = 1.648, 95%CI: 1.073, 2.531), knowledge of danger signs during pregnancy (AOR = 2.802, 95% CI: 1.637, 4.793), gestational age (AOR = 3.379, 95% CI: 2.114, 5.401), and antenatal care follow up starting time (AOR = 2.841, 95% CI: 1.330, 6.068) were significantly associated with the practice of birth preparedness and complication readiness, but pregnant women in rural areas (AOR = 0.442, 95% CI:0.244, 0.803) were less associated with birth preparedness and complication readiness compared to women in urban settlements. This study identified that poor knowledge, inadequate birth preparedness, and complication readiness were prevalent among mothers in the study area. Government officials, partners, and health care providers working in the areas of maternal and child health should operate together to maximize birth preparedness and complication readiness practices.

Incidence and Clinical Features of Early Stent Thrombosis in the Era of New P2y12 Inhibitors (PLATIS-2)

PubMed Central

Asher, Elad; Abu-Much, Arsalan; Goldenberg, Ilan; Segev, Amit; Sabbag, Avi; Mazin, Israel; Shlezinger, Meital; Atar, Shaul; Zahger, Doron; Polak, Arthur; Beigel, Roy; Matetzky, Shlomi

2016-01-01

Early stent thrombosis (EST) (≤ 30 days after stent implantation) is a relatively rare but deleterious complication of percutaneous coronary intervention (PCI). Administration of newer P2Y12 inhibitors (prasugrel and ticagrelor) combined with aspirin has been shown to reduce the incidence of sub-acute and late stent thrombosis, compared with clopidogrel. We investigated the “real life” incidence of EST in patients from a large acute coronary syndrome (ACS) national registry, where newer P2Y12 inhibitors are widely used. Patients were derived from the ACS Israeli Survey (ACSIS), conducted during 2006, 2008, 2010 and 2013. Major adverse cardiac events (MACE) at 30days were defined as all-cause death, recurrent ACS, EST and stroke.Of the 4717 ACS patients who underwent PCI and stenting, 83% received clopidogrel and 17% newer P2Y12 inhibitors. The rate of EST was similar in both groups (1.7% in the newer P2Y12 inhibitor group vs. 1.4% in the clopidogrel-treated patients, p = 0.42). Results were consistent after multivariate analysis (adjusted HR = 1.06 [p = 0.89]). MACE occurred in 6.4% in the newer P2Y12 inhibitor group compared with 9.2% in the clopidogrel group (P<0.01). However, multivariate logistic regression modeling showed that treatment with newer P2Y12 inhibitors was not significantly associated with the secondary endpoint of MACE when compared with clopidogrel therapy [OR = 1.26 95%CI (0.93–1.73), P = 0.136]. The incidence of "real life" EST at 1month is relatively low, and appears to be similar in patients who receive newer P2Y12 inhibitors as well as in those who receive clopidogrel. PMID:27310147

Incidence and Clinical Features of Early Stent Thrombosis in the Era of New P2y12 Inhibitors (PLATIS-2).

PubMed

Asher, Elad; Abu-Much, Arsalan; Goldenberg, Ilan; Segev, Amit; Sabbag, Avi; Mazin, Israel; Shlezinger, Meital; Atar, Shaul; Zahger, Doron; Polak, Arthur; Beigel, Roy; Matetzky, Shlomi

2016-01-01

Early stent thrombosis (EST) (≤ 30 days after stent implantation) is a relatively rare but deleterious complication of percutaneous coronary intervention (PCI). Administration of newer P2Y12 inhibitors (prasugrel and ticagrelor) combined with aspirin has been shown to reduce the incidence of sub-acute and late stent thrombosis, compared with clopidogrel. We investigated the "real life" incidence of EST in patients from a large acute coronary syndrome (ACS) national registry, where newer P2Y12 inhibitors are widely used. Patients were derived from the ACS Israeli Survey (ACSIS), conducted during 2006, 2008, 2010 and 2013. Major adverse cardiac events (MACE) at 30days were defined as all-cause death, recurrent ACS, EST and stroke.Of the 4717 ACS patients who underwent PCI and stenting, 83% received clopidogrel and 17% newer P2Y12 inhibitors. The rate of EST was similar in both groups (1.7% in the newer P2Y12 inhibitor group vs. 1.4% in the clopidogrel-treated patients, p = 0.42). Results were consistent after multivariate analysis (adjusted HR = 1.06 [p = 0.89]). MACE occurred in 6.4% in the newer P2Y12 inhibitor group compared with 9.2% in the clopidogrel group (P<0.01). However, multivariate logistic regression modeling showed that treatment with newer P2Y12 inhibitors was not significantly associated with the secondary endpoint of MACE when compared with clopidogrel therapy [OR = 1.26 95%CI (0.93-1.73), P = 0.136]. The incidence of "real life" EST at 1month is relatively low, and appears to be similar in patients who receive newer P2Y12 inhibitors as well as in those who receive clopidogrel.

Low-intensity extracorporeal shock wave therapy--a novel effective treatment for erectile dysfunction in severe ED patients who respond poorly to PDE5 inhibitor therapy.

PubMed

Gruenwald, Ilan; Appel, Boaz; Vardi, Yoram

2012-01-01

Low-intensity shock wave therapy (LI-ESWT) has been reported as an effective treatment in men with mild and moderate erectile dysfunction (ED). The aim of this study is to determine the efficacy of LI-ESWT in severe ED patients who were poor responders to phosphodiesterase type 5 inhibitor (PDE5i) therapy. This was an open-label single-arm prospective study on ED patients with an erection hardness score (EHS) ≤ 2 at baseline. The protocol comprised two treatment sessions per week for 3 weeks, which were repeated after a 3-week no-treatment interval. Patients were followed at 1 month (FU1), and only then an active PDE5i medication was provided for an additional month until final follow-up visit (FU2). At each treatment session, LI-ESWT was applied on the penile shaft and crus at five different anatomical sites (300 shocks, 0.09 mJ/mm(2) intensity at 120 shocks/min). Each subject underwent a full baseline assessment of erectile function using validated questionnaires and objective penile hemodynamic testing before and after LI-ESWT. Outcome measures used are changes in the International Index of Erectile Function-erectile function domain (IIEF-ED) scores, the EHS measurement, and the three parameters of penile hemodynamics and endothelial function. Twenty-nine men (mean age of 61.3) completed the study. Their mean IIEF-ED scores increased from 8.8 ± 1 (baseline) to 12.3 ± 1 at FU1 (P = 0.035). At FU2 (on active PDE5i treatment), their IIEF-ED further increased to 18.8 ± 1 (P < 0.0001), and 72.4% (P < 0.0001) reached an EHS of ≥ 3 (allowing full sexual intercourse). A significant improvement (P = 0.0001) in penile hemodynamics was detected after treatment and this improvement significantly correlated with increases in the IIEF-ED (P < 0.05). No noteworthy adverse events were reported. Penile LI-ESWT is a new modality that has the potential to treat a subgroup of severe ED patients. These preliminary data need to be reconfirmed by multicenter sham control

HOW PEOPLE RESPOND TO CONTINGENT VALUATION QUESTIONS

EPA Science Inventory

The purpose of the project is to understand better how individuals interpret and respond to contingent valuation (CV) questions. The research will address three issues: the reliability of the referendum questions format, the importance of reminding respondents about subst...

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics.

PubMed

Law, Mary E; Corsino, Patrick E; Narayan, Satya; Law, Brian K

2015-11-01

Cyclin-dependent kinases (CDKs) have been considered promising drug targets for a number of years, but most CDK inhibitors have failed rigorous clinical testing. Recent studies demonstrating clear anticancer efficacy and reduced toxicity of CDK4/6 inhibitors such as palbociclib and multi-CDK inhibitors such as dinaciclib have rejuvenated the field. Favorable results with palbociclib and its recent U.S. Food and Drug Administration approval demonstrate that CDK inhibitors with narrow selectivity profiles can have clinical utility for therapy based on individual tumor genetics. A brief overview of results obtained with ATP-competitive inhibitors such as palbociclib and dinaciclib is presented, followed by a compilation of new avenues that have been pursued toward the development of novel, non-ATP-competitive CDK inhibitors. These creative ways to develop CDK inhibitors are presented along with crystal structures of these agents complexed with CDK2 to highlight differences in their binding sites and mechanisms of action. The recent successes of CDK inhibitors in the clinic, combined with the potential for structure-based routes to the development of non-ATP-competitive CDK inhibitors, and evidence that CDK inhibitors may have use in suppressing chromosomal instability and in synthetic lethal drug combinations inspire optimism that CDK inhibitors will become important weapons in the fight against cancer. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Ledipasvir plus sofosbuvir as salvage therapy for HCV genotype 1 failures to prior NS5A inhibitors regimens.

PubMed

Akuta, Norio; Sezaki, Hitomi; Suzuki, Fumitaka; Fujiyama, Shunichiro; Kawamura, Yusuke; Hosaka, Tetsuya; Kobayashi, Masahiro; Kobayashi, Mariko; Saitoh, Satoshi; Suzuki, Yoshiyuki; Arase, Yasuji; Ikeda, Kenji; Kumada, Hiromitsu

2017-07-01

There is little information on retreatment efficacy and predictors of the combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) for patients who fail to respond to NS5A inhibitors. NS5A resistance variants are known to persist for long periods after such treatment. Here, we evaluated 54 patients with chronic HCV genotype 1b infection, free of decompensated cirrhosis, and hepatocellular carcinoma, for sustained virological response after 12 weeks (SVR12) of once-daily treatment with 90 mg ledipasvir and 400 mg sofosbuvir. Intention-to-treat analysis showed SVR12 of 70%. Using ultra-deep sequencing, non-responder to ledipasvir/sofosbuvir showed no change in the rates of detection of NS5A and NS5B resistant-variants at re-elevation of viral loads, relative to baseline. According to response to prior treatment, SVR12 rates were 18, 69, 94, and 100% in non response, viral breakthrough, relapse, and discontinuation due to adverse events, respectively. SVR12 rates in non response were significantly lower than those of the others. Multivariate analysis identified response to previous treatment (failure except for non response) and FIB4 index (<3.25) as significant determinants of SVR12. The SVR12 rates were significantly lower in patients with FIB4 index of ≥3.25 and had not responded to prior treatment, relative to others. The specificity, and positive- and negative-predictive values were high for prediction of poor response based on the combination of two predictors. In conclusion, our study indicated that ledipasvir/sofosbuvir is a potentially useful salvage treatment for patients who fail prior NS5A inhibitors-based therapy. Response to prior treatment was an important predictor of retreatment efficacy. © 2017 Wiley Periodicals, Inc.

Management of Labour and Delivery in a Patient With Acquired Factor VII Deficiency With Inhibitor: A Case Report.

PubMed

Matei, Anca; Dolan, Sean; Andrews, James; Rivard, Georges-Étienne

2016-02-01

Acquired factor VII (FVII) deficiency with inhibitor increases the risk of hemorrhage during pregnancy. However, there are no published reports guiding its management in the peripartum period. A 24-year-old woman with inhibitory antibodies to FVII delivered at 34 weeks of gestation. The patient was administered recombinant factor VIIa (rFVIIa) and tranexamic acid. There were no bleeding-related complications; however, the FVII level was supratherapeutic. The patient returned during a second pregnancy. A reduced dose of rFVIIa was administered. The delivery was complicated by postpartum hemorrhage, which resolved with the addition of uterotonic agents. Recombinant FVIIa and tranexamic acid offer an effective peripartum treatment in women with inhibitory antibody to FVII. Further research should delineate the optimal time of administration. Copyright © 2016 Society of Obstetricians and Gynaecologists of Canada. Published by Elsevier Inc. All rights reserved.

Using DFT methodology for more reliable predictive models: Design of inhibitors of Golgi α-Mannosidase II.

PubMed

Bobovská, Adela; Tvaroška, Igor; Kóňa, Juraj

2016-05-01

Human Golgi α-mannosidase II (GMII), a zinc ion co-factor dependent glycoside hydrolase (E.C.3.2.1.114), is a pharmaceutical target for the design of inhibitors with anti-cancer activity. The discovery of an effective inhibitor is complicated by the fact that all known potent inhibitors of GMII are involved in unwanted co-inhibition with lysosomal α-mannosidase (LMan, E.C.3.2.1.24), a relative to GMII. Routine empirical QSAR models for both GMII and LMan did not work with a required accuracy. Therefore, we have developed a fast computational protocol to build predictive models combining interaction energy descriptors from an empirical docking scoring function (Glide-Schrödinger), Linear Interaction Energy (LIE) method, and quantum mechanical density functional theory (QM-DFT) calculations. The QSAR models were built and validated with a library of structurally diverse GMII and LMan inhibitors and non-active compounds. A critical role of QM-DFT descriptors for the more accurate prediction abilities of the models is demonstrated. The predictive ability of the models was significantly improved when going from the empirical docking scoring function to mixed empirical-QM-DFT QSAR models (Q(2)=0.78-0.86 when cross-validation procedures were carried out; and R(2)=0.81-0.83 for a testing set). The average error for the predicted ΔGbind decreased to 0.8-1.1kcalmol(-1). Also, 76-80% of non-active compounds were successfully filtered out from GMII and LMan inhibitors. The QSAR models with the fragmented QM-DFT descriptors may find a useful application in structure-based drug design where pure empirical and force field methods reached their limits and where quantum mechanics effects are critical for ligand-receptor interactions. The optimized models will apply in lead optimization processes for GMII drug developments. Copyright © 2016 Elsevier Inc. All rights reserved.

Responding to Mechanical Antigravity

NASA Technical Reports Server (NTRS)

Millis, Marc G.; Thomas, Nicholas E.

2006-01-01

Based on the experiences of the NASA Breakthrough Propulsion Physics Project, suggestions are offered for constructively responding to proposals that purport breakthrough propulsion using mechanical devices. Because of the relatively large number of unsolicited submissions received (about 1 per workday) and because many of these involve similar concepts, this report is offered to help the would-be submitters make genuine progress as well as to help reviewers respond to such submissions. Devices that use oscillating masses or gyroscope falsely appear to create net thrust through differential friction or by misinterpreting torques as linear forces. To cover both the possibility of an errant claim and a genuine discovery, reviews should require that submitters meet minimal thresholds of proof before engaging in further correspondence; such as achieving sustained deflection of a level-platform pendulum in the case of mechanical thrusters.

Complications of shoulder dystocia.

PubMed

Dajani, Nafisa K; Magann, Everett F

2014-06-01

Complications of shoulder dystocia are divided into fetal and maternal. Fetal brachial plexus injury (BPI) is the most common fetal complication occurring in 4-40% of cases. BPI has also been reported in abdominal deliveries and in deliveries not complicated by shoulder dystocia. Fractures of the fetal humerus and clavicle occur in about 10.6% of cases of shoulder dystocia and usually heal with no sequel. Hypoxic ischemic brain injury is reported in 0.5-23% of cases of shoulder dystocia. The risk correlates with the duration of head-to-body delivery and is especially increased when the duration is >5 min. Fetal death is rare and is reported in 0.4% of cases. Maternal complications of shoulder dystocia include post-partum hemorrhage, vaginal lacerations, anal tears, and uterine rupture. The psychological stress impact of shoulder dystocia is under-recognized and deserves counseling prior to home discharge. Copyright © 2014 Elsevier Inc. All rights reserved.

Neurologic complications of alcoholism.

PubMed

Noble, James M; Weimer, Louis H

2014-06-01

This review serves as an overview of neurologic conditions associated with alcohol abuse or withdrawal, including epidemiology, clinical symptoms, diagnostic approach, and treatment. Frequent alcohol abuse and frank alcoholism are very common among adults in the United States. Although rates decline with each decade, as many as 10% of the elderly drink excessively. Given the ubiquitous nature of alcoholism in society, its complications have been clinically recognized for generations, with recent advances focusing on improved understanding of ethanol's biochemical targets and the pathophysiology of its complications. The chronic effects of alcohol abuse are myriad and include neurologic complications through both direct and indirect effects on the central and peripheral nervous systems. These disorders include several encephalopathic states related to alcohol intoxication, withdrawal, and related nutritional deficiencies; acute and chronic toxic and nutritional peripheral neuropathies; and myopathy. Although prevention of alcoholism and its neurologic complications is the optimal strategy, this article reviews the specific treatment algorithms for alcohol withdrawal and its related nutritional deficiency states.

Treatment of complicated grief.

PubMed

Rosner, Rita; Pfoh, Gabriele; Kotoučová, Michaela

2011-01-01

Following the death of a loved one, a small group of grievers develop an abnormal grieving style, termed complicated or prolonged grief. In the effort to establish complicated grief as a disorder in DSM and ICD, several attempts have been made over the past two decades to establish symptom criteria for this form of grieving. Complicated grief is different from depression and PTSD yet often comorbid with other psychological disorders. Meta-analyses of grief interventions show small to medium effect sizes, with only few studies yielding large effect sizes. In this article, an integrative cognitive behavioral treatment manual for complicated grief disorder (CG-CBT) of 25 individual sessions is described. Three treatment phases, each entailing several treatment strategies, allow patients to stabilize, explore, and confront the most painful aspects of the loss, and finally to integrate and transform their grief. Core aspects are cognitive restructuring and confrontation. Special attention is given to practical exercises. This article includes the case report of a woman whose daughter committed suicide.

First responder and physician liability during an emergency.

PubMed

Eddy, Amanda

2013-01-01

First responders, especially emergency medical technicians and paramedics, along with physicians, will be expected to render care during a mass casualty event. It is highly likely that these medical first responders and physicians will be rendering care in suboptimal conditions due to the mass casualty event. Furthermore, these individuals are expected to shift their focus from individually based care to community- or population-based care when assisting disaster response. As a result, patients may feel they have not received adequate care and may seek to hold the medical first responder or physician liable, even if they did everything they could given the emergency circumstances. Therefore, it is important to protect medical first responders and physicians rendering care during a mass casualty event so that their efforts are not unnecessarily impeded by concerns about civil liability. In this article, the author looks at the standard of care for medical first responders and physicians and describes the current framework of laws limiting liability for these persons during an emergency. The author concludes that the standard of care and current laws fail to offer adequate liability protection for medical first responders and physicians, especially those in the private sector, and recommends that states adopt clear laws offering liability protection for all medical first responders and physicians who render assistance during a mass casualty event.

Tube Thoracostomy: Complications and Its Management