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Nocturnal enuresis (NE) is a common health problem. Approximately 10% of 7-year-old children wet the bed regularly during sleep. Enuresis can be categorized into monosymptomatic (MEN) and nonmonosymptomatic (NMEN) forms. MEN occurs without any other symptoms of bladder dysfunction. NMEN is associated with dysfunction of the lower urinary tract with or without daytime incontinence. The rate of comorbid gastrointestinal, behavioral, and emotional disorders is elevated depending upon the subtype of NE. A careful clinical history is fundamental to the evaluation of enuresis. Diagnostic procedures include medical history and psychological screening with questionnaires, bladder and bowel diary, physical examination, urinalysis, ultrasound, and examination of residual urine. The mainstay of treatment is urotherapy with information and psychoeducation about normal lower urinary tract function, the underlying cause of MEN, disturbed bladder dysfunction in the child with NMEN and instructions about therapeutic strategies. Alarm therapy and the use of desmopressin have been shown to be effective in randomized trials. Children with NMEN first need treatment of the underlying daytime functional bladder problem before treatment of nocturnal enuresis. In patients with findings of overactive bladder, besides urotherapy, anticholinergic drugs may be useful. [ABSTRACT FROM AUTHOR]

Objective Medical compression stockings are a standard, non-invasive treatment option for all venous and lymphatic diseases. The aim of this consensus document is to provide up-to-date recommendations and evidence grading on the indications for treatment, based on evidence accumulated during the past decade, under the auspices of the International Compression Club. Methods A systematic literature review was conducted and, using PRISMA guidelines, 51 relevant publications were selected for an evidence-based analysis of an initial 2407 unrefined results. Key search terms included: ‘acute', CEAP', ‘chronic', ‘compression stockings', ‘compression therapy', ‘lymph', ‘lymphatic disease', ‘vein' and ‘venous disease'. Evidence extracted from the publications was graded initially by the panel members individually and then refined at the consensus meeting. Results Based on the current evidence, 25 recommendations for chronic and acute venous disorders were made. Of these, 24 recommendations were graded as: Grade 1A (n = 4), 1B (n = 13), 1C (n = 2), 2B (n = 4) and 2C (n = 1). The panel members found moderately robust evidence for medical compression stockings in patients with venous symptoms and prevention and treatment of venous oedema. Robust evidence was found for prevention and treatment of venous leg ulcers. Recommendations for stocking-use after great saphenous vein interventions were limited to the first post-interventional week. No randomised clinical trials are available that document a prophylactic effect of medical compression stockings on the progression of chronic venous disease (CVD). In acute deep vein thrombosis, immediate compression is recommended to reduce pain and swelling. Despite conflicting results from a recent study to prevent post-thrombotic syndrome, medical compression stockings are still recommended. In thromboprophylaxis, the role of stockings in addition to anticoagulation is limited. For the maintenance phase of lymphoedema management, compression stockings are the most important intervention. Conclusion The beneficial value of applying compression stockings in the treatment of venous and lymphatic disease is supported by this document, with 19/25 recommendations rated as Grade 1 evidence. For recommendations rated with Grade 2 level of evidence, further studies are needed. [ABSTRACT FROM AUTHOR]

Objective: Severe hypoglycemic events (SHEs) in type 2 diabetes are associated with subsequent cardiovascular (CV) event risk. We examined whether CV events were associated with subsequent SHE risk.Research Design and Methods: Time-dependent associations between SHEs and a composite CV end point (fatal/nonfatal myocardial infarction or stroke, hospitalization for unstable angina, hospitalization for heart failure [hHF]) were examined post hoc in 14,671 TECOS (Trial Evaluating Cardiovascular Outcomes With Sitagliptin) participants with type 2 diabetes and CV disease followed for a median of 3.0 years.Results: SHEs were uncommon and unassociated with sitagliptin therapy (N = 160 [2.2%], 0.78/100 patient-years vs. N = 143 [1.9%], 0.70/100 patient-years for placebo; hazard ratio [HR] 1.12 [95% CI 0.89, 1.40], P = 0.33). Patients with (versus without) SHEs were older with longer diabetes duration, lower body weight, and lower estimated glomerular filtration rate; were more frequently women, nonwhite, and insulin treated; and more often had microalbuminuria or macroalbuminuria. Analyses adjusted for clinical factors showed SHEs were associated with increased risk of the primary composite CV end point (1.55 [1.06, 2.28], P = 0.025), all-cause death (1.83 [1.22, 2.75], P = 0.004), and CV death (1.72 [1.02, 2.87], P = 0.040). Conversely, nonfatal myocardial infarction (3.02 [1.83, 4.96], P < 0.001), nonfatal stroke (2.77 [1.36, 5.63], P = 0.005), and hHF (3.68 [2.13, 6.36], P < 0.001) were associated with increased risk of SHEs. Fully adjusted models showed no association between SHEs and subsequent CV or hHF events, but the association between CV events and subsequent SHEs remained robust.Conclusions: These findings, showing greater risk of SHEs after CV events and greater risk of CV events after SHEs, suggest a common at-risk type 2 diabetes frail patient phenotype. [ABSTRACT FROM AUTHOR]

Background Lipidapheresis techniques are increasingly used to treat drug-resistant hyperlipidemia but few efficacy studies under routine application are available. In this multicenter observational study we investigated direct adsorption of lipoproteins (DALI) and lipoprotein filtration (MONET) for the short and the long-term effects on lipid-lowering effects. Methods Data of 122 apheresis patients from 11 centers (DALI: n = 78, MONET: n = 44) were prospectively collected for a period of 2 years. Routine lipid measurements were evaluated (2154 DALI and 1297 MONET sessions). It was investigated whether the relative reduction of LDL-C during apheresis session achieves at least 60%. Also relative reduction of total cholesterol, HDL, triglyceride, and Lp(a) were analyzed. Results The relative reduction of LDL-C was at least 60%: DALI: 70.62%, 95% CI = [69.34; 71.90] and MONET: 64.12%, 95% CI = [60.79; 67.46]. Also triglycerides were reduced with both systems: DALI 38.63%, 95% CI = [33.95; 43.30] vs. MONET 57.68%, 95% CI = [51.91; 63.45]. Relative reductions of total cholesterol were in the range of 50% (DALI 95% CI = [46.49; 49.65] MONET 95% CI = [48.93; 55.26]) and of Lp(a) in the range of 65% (DALI 95% CI = [61.92; 65.83] MONET 95% CI = [63.71; 70.30]. HDL reduction was: DALI 15.01%, 95% CI = [13.22; 16.79] and MONET 22.59%, 95% CI = [19.33; 25.84]. For both devices treated patient plasma/blood volume and in case of DALI the use of the larger adsorber configurations (DALI 1000 and DALI 1250) were independent positive predictors of the relative reduction of LDL-C and of Lp(a). Conclusions Both systems effectively improved lipid profile and reduced atherogenic lipids. The results point to the importance of the individualized application of these valuable therapies to achieve clinical targets. [ABSTRACT FROM AUTHOR]

Genetic testing has been propagated as a suitable means to specify individual risks for canine hip dysplasia (CHD). However, the current lack of validation of most genetic CHD tests has left dog owners and breeders in the dark about their practical utility. Therefore, the Society for German Shepherd Dogs (Verein für Deutsche Schäferhunde, SV) initiated a prospective study of 935 animals to assess independently the value of a genetic CHD test (European Patent Specification EP 2 123 777 B1) that was developed by Distl et al. (2009) on the basis of the SV animal stock. Dogs were followed-up for 3 years after birth, classified regarding their CHD phenotype using the scheme of the Fédération Cynologique Internationale, and genotyped for the 17 single nucleotide polymorphisms (SNPs) constituting the CHD test in question. Individual SNP genotypes were combined into animal-specific genomic breeding values (GBVs), calculated as the weighted sum of SNP-wise scores as laid down in the patent specification. Logistic regression analysis revealed that, unexpectedly, the odds ratio for CHD decreased, rather than increased, by a factor of 0.98 per unit increase of the GBV. Nevertheless, since this effect was not statistically significant (95% CI: 0.93–1.03), and the area-under-curve of the test was only 0.523, it must be concluded that the genetic test patented by Distl et al. (2009) is unsuitable for individual CHD risk assessment. [ABSTRACT FROM AUTHOR]

Background: Opioids are critical for managing cancer pain, but may provide inadequate relief and/or unacceptable side effects in some cases. Objective: To assess the analgesic efficacy of adjunctive Sativex (Δ9-tetrahydrocannabinol (27 mg/mL): cannabidiol (25 mg/mL)) in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy. Methods: This report describes two phase 3, double-blind, randomized, placebo-controlled trials. Eligible patients had advanced cancer and average pain numerical rating scale (NRS) scores ≥4 and ≤8 at baseline, despite optimized opioid therapy. In Study-1, patients were randomized to Sativex or placebo, and then self-titrated study medications over a 2-week period per effect and tolerability, followed by a 3-week treatment period. In Study-2, all patients self-titrated Sativex over a 2-week period. Patients with a ≥15% improvement from baseline in pain score were then randomized 1:1 to Sativex or placebo, followed by 5-week treatment period (randomized withdrawal design). Results: The primary efficacy endpoint (percent improvement (Study-1) and mean change (Study-2) in average daily pain NRS scores) was not met in either study. Post hoc analyses of the primary endpoints identified statistically favourable treatment effect for Sativex in US patients <65 years (median treatment difference: 8.8; 95% confidence interval (CI): 0.00-17.95; p = 0.040) that was not observed in patients <65 years from the rest of the world (median treatment difference: 0.2; 95% CI: -5.00 to 7.74; p = 0.794). Treatment effect in favour of Sativex was observed on quality-of-life questionnaires, despite the fact that similar effects were not observed on NRS score. The safety profile of Sativex was consistent with earlier studies, and no evidence of abuse or misuse was identified. Conclusions: Sativex did not demonstrate superiority to placebo in reducing self-reported pain NRS scores in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy, although further exploration of differences between United States and patients from the rest of the world is warranted. [ABSTRACT FROM AUTHOR]

Background: Hypogonadotropic hypogonadism (HH) in men results in insufficient testicular function and deficiencies in testosterone and spermatogenesis. Combinations of human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (recFSH) have been successful in the treatment of HH. Corifollitropin alfa is a long-acting FSH-analog with demonstrated action in women seeking infertility care. The aim of this study was to investigate the efficacy and safety of corifollitropin alfa combined with hCG to increase testicular volume and induce spermatogenesis in men with HH. Methods: This was a Phase III, multi-center, open-label, single-arm trial of corifollitropin alfa in azoospermic men aged 18 to 50 years with HH. After 16 weeks of pretreatment of 23 subjects with hCG alone, 18 subjects with normalized testosterone (T) levels who remained azoospermic entered the 52-week combined treatment phase with hCG twice-weekly and 150 μg corifollitropin alfa every other week. The increase in testicular volume (primary efficacy endpoint) and induction of spermatogenesis resulting in a sperm count ≥1 × 106/mL (key secondary efficacy endpoint) during 52 weeks of combined treatment were assessed. Safety was evaluated by the presence of anti-corifollitropin alfa antibodies and the occurrence of adverse events (AEs). Results: Mean (±SD) testicular volume increased from 8.6 (±6.09) mL to 17.8 (±8.93) mL (geometric mean fold increase, 2.30 [95% CI: 2.03, 2.62]); 14 (77.8%) subjects reached a sperm count ≥1 × 106/mL. No subject developed confirmed anti-corifollitropin alfa antibodies during the trial. Treatment was generally well tolerated. Conclusions: Corifollitropin alfa 150 μg administrated every other week combined with twice-weekly hCG for 52 weeks increased testicular volume significantly, and induced spermatogenesis in >75% of men with HH who had remained azoospermic after hCG treatment alone. [ABSTRACT FROM AUTHOR]

Communication is the act of information transfer between sender and receiver. In rats, vocal communication can be studied through ultrasonic vocalizations (USV). 50-kHz USV occur in appetitive situations, most notably juvenile play, likely expressing the sender׳s positive affective state. Such appetitive 50-kHz USV serve important pro-social communicative functions and elicit social exploratory and approach behavior in the receiver. Emission of 50-kHz USV can be induced pharmacologically by the administration of psychostimulant drugs, such as amphetamine. However, it is unknown whether amphetamine affects the pro-social communicative function of 50-kHz USV in the receiver. We therefore assessed dose-response effects of amphetamine (0.0 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.5 mg/kg, 5.0 mg/kg) on pro-social ultrasonic communication on both, sender and receiver, in juvenile rats. We found an inverted U-shaped effect of amphetamine on 50-kHz USV emission, with 50-kHz USV levels being strongly enhanced by moderate doses, yet less prominent effects were seen following the highest dose. Likewise, amphetamine exerted inverted U-shaped effects on social exploratory and approach behavior induced by playback of appetitive 50-kHz USV. Social approach was enhanced by moderate amphetamine doses, but completely abolished following the highest dose. Amphetamine further dose-dependently promoted the emission of 50-kHz USV following playback of appetitive 50-kHz USV, indicating more vigorous attempts to establish social proximity. Our results support an important role of dopamine in closing a perception-and-action-loop through linking mechanisms relevant for detection and production of social vocalizations. Moreover, our approach possibly provides a new means to study mania-like aberrant social interaction and communication in animal models for bipolar disorder. [ABSTRACT FROM AUTHOR]

Immune senescence as well as disturbed CD8+ T cell differentiation are a hallmark of chronic HIV infection. Here, we investigated to what extent immune senescence is reversible after initiation of anti-retroviral treatment (ART). Peripheral blood mononuclear cells (PBMCs) from a cohort of HIV patients with different disease courses, including untreated viral controllers ( n = 10), viral non-controllers ( n = 16) and patients on ART ( n = 20), were analysed and compared to uninfected controls ( n = 25) by flow cytometry on bulk and HIV-specific major histocompatibility complex (MHC) class I tetramer+ CD8+ T cells for expression of the memory markers CCR7 and CD45RO, as well as the senescence marker CD57 and the differentiation and survival marker CD127. Furthermore, a subset of patients was analysed longitudinally before and after initiation of ART. Frequencies of CD57+CD8+ T cells decreased after initiation of ART in central memory (Tcm) but not in effector memory T cell populations (TemRO and TemRA). The frequency of CD127+CD8+ cells increased in Tcm and TemRO. We observed a reduction of CD127- T cells in Tcm, TemRO and partially in TemRA subsets after initiation of ART. Importantly, HIV-specific CD8+ TemRO cells predominantly displayed a CD127-CD57+ phenotype in untreated HIV-patients, whereas the CD127+CD57- phenotype was under-represented in these patients. The frequency of the CD127+CD57-CD8+ T cell subpopulation correlated strongly with absolute CD4+ counts in HIV-infected patients before and after initiation of ART. These findings can be interpreted as a phenotypical correlate of CD8+ memory T cell differentiation and the premature 'ageing' of the immune system, which was even observed in successfully virally suppressed HIV patients. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate patients with bipolar I disorder (BD-I) who have mania with depressive symptoms and who meet the new "with mixed features" specifier of the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5). Method: This prospective, multinational, naturalistic study surveyed psychiatrists and their patients with BD-I from October 2013 to March 2014. Eligible patients had BD-I, had a (current) manic episode, and had experienced onset of a manic episode within the previous 3 months. Psychiatrists provided patient information on depressive symptoms (DSM-5 criteria); symptoms of anxiety, irritability, and agitation; suicide attempts; and physician satisfaction with treatment response. Data were stratified according to whether patients met the criteria for the BD-I "with mixed features" specifier of DSM-5 ($3 depressive symptoms) or not, and characteristics were compared between the two subgroups. Patients also self-reported on depressive symptoms using the Mini-International Neuropsychiatric Interview module questionnaire. Results: Overall, 34% of 1,035 patients met the criteria for BD-I "with mixed features," exhibiting $3 depressive symptoms during their current manic episode. This correlated with the matched patient self-reports of depressive symptoms. During their current manic episode, BD-I patients "with mixed features" had more severe symptoms of anxiety, irritability, and agitation (average composite severity score of 4.1 vs 3.4), a higher incidence of suicide attempts (38% vs 9%), and more physician dissatisfaction with treatment response (22% vs 14%), compared to patients with 0-2 depressive symptoms (all P,0.05). Conclusion: This study found that patients with BD-I "with mixed features" (ie, $3 depressive symptoms during a manic episode), suffered, on average, from a greater burden of disease than patients with pure mania. Improved identification of these patients may help to optimize treatment outcomes. [ABSTRACT FROM AUTHOR]

Objective: The first oxycodone once daily (OOD) has been developed and after successful pharmacokinetic characterization, therapeutic efficacy and safety were compared to an established oxycodone twice daily (OTD: Oxygesic/OxyContin, Mundipharma). Design and methods: A randomized, double-blind, multicenter, cross-over, non-inferiority study was conducted in patients (n = 68) with chronic malignant or non-malignant pain. The new OOD was compared to OTD at identical total daily doses (TDD: 40–120 mg/day) employing intensive, five times daily current pain (0–100 mm visual analog scale, VAS) and twice daily 12 h recalled pain assessments as well as safety parameters such as nausea and sedation (VAS) over 5 days for each treatment (after a 5 day run-in phase). Results: There was no significant difference in analgesic potency detected between the two treatments based on 95% CI for difference in the daily mean current pain (−2.09 mm VAS) over 5 days, determined as −5.09 to 0.91 mm VAS. A difference ≤12 mm VAS indicated non-inferiority of OOD, i.e. lack of clinically relevant difference in analgesia. Intake of rescue medication had no effect on study results as evaluated by ANCOVA. The difference in adverse events (AEs) between the two treatments did not reach significance, as 19.1% and 23.5% of patients experienced treatment-related AEs while on OOD and OTD, respectively. Advantages for OOD regarding consistency of analgesia (i.e. use of rescue medication, current and recalled pain) and sedation did not reach statistical significance in this limited study population. Conclusion: Despite the small number of patients and short study duration, the results support the conclusion that new OOD is (at least) equivalent to established OTD regarding safety and efficacy. [ABSTRACT FROM AUTHOR]

Highlights: [•] HIV-1 viremia significantly increases Ki-67, CD57, and CD95 expressions in CD4+ CD31+ naïve T cells. [•] 37.5% of IR fail to restored the numbers of CD4+ CD31+ naïve T cells. [•] CD57 and CD95 expressions are significantly associated with reconstitution failure of CD4+ CD31+ naïve T cells in IR. [ABSTRACT FROM AUTHOR]

The article discusses the comprehensive evaluations undertaken by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) on the safety of incretin-based drugs on patients with pancreatitis or pancreatic cancer. Topics discussed include a description of the drug incretin, the FDA's study with the drug exenatide on rats with diabetes, and results of two cardiovascular outcome trials. A list of approved incretin-based drugs by FDA and EMA is also provided.

Abstract: Testosterone is an essential part of all regimens for hormonal male contraception tested to date. Initial efficacy trials revealed that the half-life of the testosterone preparations available at that time was too short to be used for male contraception. The ensuing search for long-acting preparations yielded testosterone buciclate and undecanoate as well as 7α-methyl-19-nortestosterone (MENT). Following description of the principle of male hormonal contraception and the efficacy trials performed to date, the systematic development of MENT for substitution of male hypogonadism and use in male contraception by the Population Council is reviewed here. [Copyright &y& Elsevier]

Background: Water displacement leg volumetry is a highly reproducible method, allowing the confirmation of efficacy of vasoactive substances. Nevertheless errors of its execution and the selection of unsuitable patients are likely to negatively affect the outcome of clinical studies in chronic venous insufficiency (CVI). Discussion: Placebo controlled double-blind drug studies in CVI were searched (Cochrane Review 2005, MedLine Search until December 2007) and assessed with regard to efficacy (volume reduction of the leg), patient characteristics, and potential methodological error sources. Almost every second study reported only small drug effects (= 30 mL volume reduction). As the most relevant error source the conduct of volumetry was identified. Because the practical use of available equipment varies, volume differences of more than 300 mL - which is a multifold of a potential treatment effect - have been reported between consecutive measurements. Other potential error sources were insufficient patient guidance or difficulties with the transition from the Widmer CVI classification to the CEAP (Clinical Etiological Anatomical Pathophysiological) grading. Summary: Patients should be properly diagnosed with CVI and selected for stable oedema and further clinical symptoms relevant for the specific study. Centres require a thorough training on the use of the volumeter and on patient guidance. Volumetry should be performed under constant conditions. The reproducibility of short term repeat measurements has to be ensured. [ABSTRACT FROM AUTHOR]

Introduction: Teaching of biomedical knowledge lays the foundations for the understanding and treatment of diseases. However, the representation of pathophysiological explanations in the management of clinical cases differs for various levels of medical expertise and different theories have been proposed to explain this phenomenon. The present study investigated for the first time how biomedical knowledge is used in clinical reasoning in dental medicine. Materials and methods: In an experimental study 20 experts in the field of Periodontology and 61 students of different levels of training produced written pathophysiological explanations after having studied three different clinical cases. By comparing the written protocols to a visualised expert-made ‘canonical’ explanation the concepts used in the pathophysiological explanation were counted and classified as well as the links between concepts. Results: The statistical analysis by MANOVA showed significant differences between third- and fourth-year students, students of intermediate expertise level (fifth-year) and experts for various parameters qualifying concepts or links of the written pathophysiological explanations. The participants of intermediate expertise level produced a high rate of concepts and links; however, characteristic findings for knowledge encapsulation in the different levels of expertise were not evident. The analysis showed that the design of the clinical cases and of the canonical explanations significantly influenced the outcomes. Conclusion: The present study demonstrated the pathophysiological representations of clinical cases in dental students and experts to be different from other medical disciplines. It could be assumed that this observation is based on different contents for teaching of practical skills and diagnostic procedures in dental compared with medical education. [ABSTRACT FROM AUTHOR]

Delirium is a common problem in ICU patients, resulting in prolonged ICU stay and increased mortality. A cholinergic deficiency in the central nervous system is supposed to be a relevant pathophysiologic process in delirium. Acetylcholine is a major transmitter of the parasympathetic nervous system influencing several organs (e.g., heart and kidneys) and the inflammatory response too. This perception might explain that delirium is not an individual symptom, but rather a part of a symptom complex with various disorders of the whole organism. The cholinergic deficiency could not be quantified up to now. Using the possibility of bedside determination of the acetylcholinesterase activity (AChE activity), we assumed to objectify the cholinergic homeostasis within minutes. As reported here, the postoperative delirium was accompanied by a massive hemodynamic and renal deterioration of unclear genesis. We identified the altered AChE activity as a plausible pathophysiological mechanism. The pharmacological intervention with the indirect parasympathomimetic physostigmine led to a quick and lasting improvement of the patient’s cognitive, hemodynamic, and renal status. In summary, severe delirium is not always an attendant phenomenon of critical illness. It might be causal for multiple organ deterioration if it is based on cholinergic deficiency and has to be treated at his pathophysiological roots whenever possible. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hormone replacement therapy (HRT) has been suggested to prevent cardiovascular disease, while some intervention studies have shed doubt on this concept. Thus, uncertainty remains whether current HRT use is beneficial as to cardiovascular disease or may even be harmful. Objectives: This research investigates the association of hormone replacement therapy, risk factors and lifestyle characteristics with the manifestation of coronary heart disease in current HRT users versus never users. Design: The coronary risk factors for atherosclerosis in women study (CORA-study) provide clinical and biochemical parameters and data on lifestyle in 200 consecutive pre- and postmenopausal women with incident coronary heart disease compared to 255 age-matched population-based controls, of which 87.9% were postmenopausal. Results: Significantly more controls than cases used currently HRT for a median of 9.5 years (32.9% versus 20.2%), while 50.0% of cases and 42.5% of controls had never used HRT (p <0.02). Compared to women who never used HRT, current users ate less meat and sausage, had a significantly lower BMI and waist-to-hip ratio and a lower prevalence of hypertension, insulin resistance and diabetes. However, current users among cases were often smokers and smoked significantly more cigarettes than never users. In a multivariate analysis the risk of current HRT users for coronary artery disease was 57% lower than the risk of never users (odds ratio 0.428, CI 0.206–0.860, p <0.02). Adjustment for conventional and dietary risk factors revealed neither current HRT use, nor HRT use combined with smoking as independent risk factors. Conclusions: These data from the CORA-study are not compatible with an adverse impact of hormone replacement therapy on cardiovascular disease, rather support the notion of beneficial effects of HRT on weight, central adiposity, insulin sensitivity and blood pressure. Yet, the data do not support the presumption of a general healthy user effect in women on HRT either. Rather, in some women adverse lifestyle habits, especially intense smoking, appear to counteract possible beneficial effects of HRT. [Copyright &y& Elsevier]

Interferon γ (IFNγ) controls hepatitis B virus replication. As systemic application may cause severe adverse effects, approaches of liver-directed IFNγ gene therapy may represent an attractive alternative for treatment of chronic viral hepatitis B and thus needs testing in vivo in suitable animal models. Methods: We therefore crossbred Alb-1HBV transgenic mice overexpressing the large HBV surface protein (LHBs) in their livers and developing LHBs storage disease and ground glass hepatocyte appearance with SAP-IFNγ transgenic animals previously shown to exhibit constitutive hepatic IFNγ expression, and analyzed the resulting double-transgenic offspring. Results: We found that IFNγ coexpression significantly reduced hepatic LHBs expression and thereby inhibited hepatocellular LHBs storage disease and ground glass hepatocyte appearance. The beneficial antiviral IFNγ effects as observed in Alb1-HBV SAP-IFNγ double-transgenic livers were associated with significantly elevated serum ALT concentrations, massive mononuclear cell infiltrates, appearance of Councilman bodies, and increased α-PARP (poly(ADP-ribose) polymerase cleavage). Conclusions: Exacerbation of hepatic necroinflammation and increased hepatocellular apoptosis rate in IFNγ-expressing Alb1-HBV transgenic livers suggest that special precautions be taken for testing approaches of liver-specific IFNγ expression in patients with chronic hepatitis B. [ABSTRACT FROM AUTHOR]

The forward bending test according to Adams and rib hump quantification by scoliometer are common clinical examination techniques in idiopathic scoliosis, although precise data about the change of axial surface rotation in forward bending posture are not available. In a pilot study the influence of leg length inequalities on the back shape of five normal subjects was clarified. Then 91 patients with idiopathic scoliosis with Cobb-angles between 20° and 82° were examined by rasterstereography, a 3D back surface analysis system. The axial back surface rotation in standing posture was compared with that in forward bending posture and additionally with a scoliometer measurement in forward bending posture. The changes of back shape in forward bending posture were correlated with the Cobb-angle, the level of the apex of the scoliotic primary curve and the age of the patient. Averaged over all patients, the back surface rotation amplitude increased from 23.1° in standing to 26.3° in forward bending posture. The standard deviation of this difference was high (6.1°). The correlation of back surface rotation amplitude in standing with that in forward bending posture was poor ( R 2=0.41) as was the correlation of back surface rotation in standing posture with the scoliometer in forward bending posture measured rotation ( R 2=0.35). No significant correlation could be found between the change of back shape in forward bending and the degree of deformity ( R 2=0.07), likewise no correlation with the height of the apex of the scoliosis ( R 2=0.005) and the age of the patient ( R 2=0.001). Before forward bending test leg length inequalities have to be compensated accurately. Compared to the standing posture, forward bending changes back surface rotation. However, this change varies greatly between patients, and is independent of the type and degree of scoliosis. Furthermore remarkable differences were found between scoliometer measurement of the rib hump and rasterstereographic measurement of the vertebral rotation. Therefore the forward bending test and the identification of idiopathic scoliosis rotation by scoliometer can be markedly different compared to rasterstereographic surface measurement in the standing posture. [ABSTRACT FROM AUTHOR]

Abstract: Background:: Gastroesophageal reflux disease (GERD) is a chronic disorder,and although effective short-term treatment strategies are known, the rate of relapse within 1 year is as high as 90% despite successful acute treatment. Consequently, most patients with GERD require an effective long-term management strategy to achieve adequate symptom control and maintain mucosal healing. Objective:: The present study was undertaken to compare the control ofGERD symptoms during long-term (24-week) treatment with pantoprazole 20 mg used on-demand or continuously in patients with mild GERD after complete relief of acute GERD symptoms. Methods:: Patients with endoscopically confirmed Savary/Miller grade 0(normal mucosa) or I (patchy red lesions without white coating or with central white coating) GERD were enrolled in this multinational, multicenter study comprising 2 phases. In the first phase, which was open label, patients were treated with pantoprazole 20 mg QD for 4 weeks. The presence and intensity of the symptoms of heartburn, acid regurgitation, and pain on swallowing were assessed. In the second phase, which was an open-label, 24-week, randomized design, only patients completely free of GERD symptoms after acute treatment were included. During this phase, on-demand treatment with pantoprazole 20 mg was directly compared with continuous treatment. The rate of failure to control GERD symptoms after 24 weeks of treatment was estimated using the Kaplan-Meier method. Subsequently, the difference between treatments (on-demand minus continuous) and its 95% CI were calculated, and the on-demand treatment was tested for noninferiority using a predefined noninferiority margin of 20%. The mean daily symptom loads were compared between the treatment groups using the 1-sided Wilcoxon rank sum test on a 5% α level. The point estimate of the difference was determined using the Hodges-Lehman estimator and the 1-sided 95% CI according to Moses. The number of patients unwilling to continue due to insufficient control of heartburn, acid regurgitation, and pain on swallowing was analyzed using the Kaplan-Meier (time-to-event) analysis. Analysis was performed in the same manner as for the rate of failure to control GERD symptoms, but the 95% CI was interpreted for statistical superiority. Results:: A total of 558 patients were enrolled in this study. At the end of theacute phase, 82.1% of patients in the per-protocol (PP) population and 79.1% in the intent-to-treat (ITT) population were relieved of all GERD symptoms, and subsequently entered the long-term phase. After 24 weeks of treatment, analysis of the failure rates revealed that on-demand treatment was noninferior to continuous treatment because the 95% CI was completely below 20% (ITT, 12.1% difference [95% CI, −∞ to 18.9%]; PP, 10.1% difference [95% CI, −∞ to 17.7%]). The higher perceived mean (SD) daily symptom load in the on-demand group (ITT, 1.26 [1.491 vs 0.82 [1.341) was balanced by the reduced tablet intake in that group (PP, 0.51 [0.31 ] vs 0.97 [0.11 ] tablets/d; P < 0.001). With respect to the rate of patients unwilling to continue treatment, no statistically significant difference was observed between the on-demand and continuous groups (ITT/PP, 0.95/1.13 vs 0.95/1.26). Conclusions:: In this study of pantoprazole 20 mg tablets in patients withmild GERD, patients receiving on-demand treatment benefited despite their higher symptom load. The similar rates of unwillingness to continue treatment in both groups might suggest that patients were satisfied with the on-demand treatment strategy. On-demand treatment with pantoprazole 20 mg was found to be noninferior compared with continuous therapy with regard to symptom control. Both on-demand and continuous treatments were well tolerated. [Copyright &y& Elsevier]

Objective: The different speech sounds are formed by the primary voice signal and by the shape of the articulation tract. With this mechanism, specific overtones, the formants, are generated for each vowel. The objective of this study was to investigate the fundamental frequency (F0) of the voice signal and the first three formants (F1–F3) as a parameter of the articulation in prelingually deafened children at different timepoints after cochlear implantation (CI) compared with children with normal speech development. Methods: Using the Kay CSL 4300B, the fundamental frequency and the formants F1–F3 of the Swiss–German vowel /a/ were investigated at different timepoints after CI in 20 prelingually deafened children aged 3.8–10.2 years by means of spectrographic and linear predictive coding (LPC) analysis. Results: Children who had been operated before their fourth birthday showed no significant deviation in their fundamental frequency from age- and sex-matched peers, whereas a significant difference was documented in children who were older at the time of implantation. The first formant was very stable in every child and showed only discrete deviations from the normal range. The second and third formants, however, developed a broader scatter, but there was no systematic deviation of these formants to higher or lower values. The F1:F2 ratio was normal in children who were implanted at the age of up to 4 years and more centralized in children who were older at the time of implantation, as is known from the hearing impaired. Conclusions: Our results indicate that prelingually deaf children who receive a cochlear implant before their fourth birthday attain a better acoustic control over their speech, normalizing their fundamental frequencies and improving their articulatory skills. [Copyright &y& Elsevier]

Distal embolization after angioplasty in degenerated saphenous vein grafts (SVGs) results in high rates of periprocedural myonecrosis and mortality. Temporary protection of the distal microcirculation with aspiration of dislodged debris may improve the safety of SVG intervention. To evaluate the feasibility, safety, and efficacy of distal protection using the PercuSurge GuardWire Occlusion and Aspiration System, 103 consecutive patients undergoing planned stenting of 105 SVG lesions were prospectively enrolled in a multinational, multicenter study. Before angioplasty, protection of the distal circulation was achieved with the PercuSurge GuardWire distal balloon occlusion system, followed by stenting and debris aspiration. Quality assurance measures in the study included independent on-site data monitoring, clinical event adjudication, data analysis, and use of multiple core laboratories. Mean graft age was 8.9 ± 4.0 years. The duration of distal balloon inflation was 5.4 ± 3.7 minutes; premature balloon deflation for ischemia was not required in any patient. Macroscopically visible red and/or yellow debris was extracted in 91% of patients. By core lab analysis, postprocedural Thrombolysis In Myocardial Infarction-III flow was present in 98.9% of grafts (vs 83.5% before intervention). No patient developed angiographic evidence of no reflow or distal embolization. Postprocedural creatine phosphokinase MB isozyme levels were elevated to >3 × normal in only 5 patients (5%), and 97 patients (94%) were free of major adverse events at 30 days. We conclude that the GuardWire distal balloon occlusion and aspiration system is an effective and safe method for protecting distal microcirculation from the adverse consequences of embolization during mechanical intervention of degenerated SVGs. [Copyright &y& Elsevier]

W. Eberhard, Symposium: Multimodal approaches to oligometastatic disease: state-of-the-art in NSCLC SP-0737: Systemic treatment for OM-NSCLC: which, when, how much?. [Extracted from the article]

Based on cardiovascular (CV) outcome trials (CVOTs) being available on the brink of the 2020ies, CV safety assessed by major adverse CV event outcomes has been established for the classes of glucagon-like-peptide-1 receptor agonists (GLP1 RAs), sodium-glucose-co-transporter-2 inhibitors (SGLT2-is), and dipeptidyl-peptidase-4 inhibitors (DPP4is) in patients at very high CV risk. This should be relevant to the whole population with diabetes in general as well as the fact that no new serious and unexpected side effects have emerged within these trials. At the same time, treatment paradigm shifting CV benefit has been confirmed for two classes of diabetes medications (SGLT2is & GLP1 RAs), with important additional benefit of SGLT2is reducing heart failure and hard renal endpoints, both in patients with such diseases, but also in patients being in primary prevention. Moreover, the "soft" renal outcome of albuminurea progression seems to be attenuated by all three classes of drugs discussed in this overview. Still ongoing CVOTs are not expected to essentially change the current notions, with the potential of some differentiation regarding subgroups of primary heart failure populations in relation to treatment with SGLT2is. [ABSTRACT FROM AUTHOR]

Context: Prior Phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain.Objectives: To assess adjunctive nabiximols (Sativex®), an extract of Cannabis sativa containing two potentially therapeutic cannabinoids (Δ9-tetrahydrocannabinol [27 mg/mL] and cannabidiol [25 mg/mL]), in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy.Methods: Phase 3, double-blind, randomized, placebo-controlled trial in patients with advanced cancer and average pain Numerical Rating Scale scores ≥4 and ≤8 despite optimized opioid therapy. Patients randomized to nabiximols (n = 199) or placebo (n = 198) self-titrated study medications over a two-week period, followed by a three-week treatment period at the titrated dose.Results: Median percent improvements in average pain Numerical Rating Scale score from baseline to end of treatment in the nabiximols and placebo groups were 10.7% vs. 4.5% (P = 0.0854) in the intention-to-treat population (primary variable) and 15.5% vs. 6.3% (P = 0.0378) in the per-protocol population. Nabiximols was statistically superior to placebo on two of three quality-of-life instruments at Week 3 and on all three at Week 5. In exploratory post hoc analyses, U.S. patients, but not patients from the rest of the world, experienced significant benefits from nabiximols on multiple secondary endpoints. Possible contributing factors to differences in nabiximols efficacy include: 1) the U.S. participants received lower doses of opioids at baseline than the rest of the world and 2) the subgroups had different distribution of cancer pain types, which may have been related to differences in pathophysiology of pain. The safety profile of nabiximols was consistent with earlier studies.Conclusions: Although not superior to placebo on the primary efficacy endpoint, nabiximols had benefits on multiple secondary endpoints, particularly in the U.S.Patients: Nabiximols might have utility in patients with advanced cancer who receive a lower opioid dose, such as individuals with early intolerance to opioid therapy. [ABSTRACT FROM AUTHOR]

A response from the author of the article "Embolization is not essential in the treatment of leg varices due to pelvic venous insufficiency" that was published in the previous issue is presented.

To compare the safety and efficacy between Woven EndoBridge (WEB) embolization and conventional coiling for treatment of unruptured intracranial aneurysms using a propensity score-matched analysis. Consecutive patients treated with the WEB at 3 German neurovascular centers and with coiling at a single center during 2011 and 2018 were analyzed. Procedure-related complications, clinical outcome, and angiographic results were retrospectively evaluated and compared. Sixty-seven patients treated by coiling and 56 patients treated with the WEB were identified. Significant differences between the 2 groups were observed in patient age (P = 0.048), aneurysm location (P < 0.01), aneurysm size (P = 0.02), and neck width (P < 0.01). The overall complication rate was comparable between the coil group (9.0%) and the WEB group (8.9%, P = 1.0). Favorable outcome (modified Rankin Scale ≤2) was obtained in 98.5% after coiling and 98.2% after WEB treatment. At last available angiographic follow-up, WEB yielded a higher complete aneurysm occlusion rate (87.2%) than coiling (60.8%, P < 0.01). Nine patients in the coil cohort (17.6%) and 2 patients in the WEB cohort (4.3%) underwent retreatment (P = 0.05). After 1:1 propensity score matching, there were no significant differences in complication (P = 1.0) and morbidity rates (P = 1.0), whereas there was a trend toward a higher complete aneurysm occlusion rate after WEB treatment (P = 0.08). Treatment of unruptured aneurysms with the WEB provides potentially higher aneurysm occlusion rates than conventional coiling while having similar complication rates and no additional morbidity. [ABSTRACT FROM AUTHOR]

Blood pressure lowering has clear beneficial effects in terms of reducing the risk of stroke, cardiovascular events and cardiovascular mortality in the general population, but it is unclear whether treating hypertension in individuals aged >80 years is beneficial. This Practice Point commentary discusses a recent randomized, prospective study by Beckett et al., which found that antihypertensive therapy with indapamide--with or without perindopril--was associated with significant decreases in the rate of death from stroke, rate of heart failure and risk of all-cause mortality in individuals aged 80 years or older. These results indicate that treating hypertension in individuals in this age-group is no longer contraindicated because of a lack of evidence. [ABSTRACT FROM AUTHOR]

Introduction: To investigate the effect of acupuncture on different ocular blood flow (OBF) parameters in patients with primary open-angle glaucoma (POAG). Patients and methods: In a prospective, randomized study, 56 POAG patients were randomly assigned either to an eye-specific acupuncture (group I, n=28) or to an eye-unspecific acupuncture treatment (group II, n=28). Blood flow parameters were measured before and 10 minutes after treatment. Parapapillary retinal blood flow was determined by the Heidelberg retina flowmeter. Retinal vessel diameters were measured by the dynamic vessel analyzer. Pulsatile ocular blood flow, ocular pulse amplitude, and IOP were investigated by the Langham OBF system. Systemic blood pressure was obtained additionally. Results: Pulsatile ocular blood flow increased significantly after the eye-specific acupuncture treatment from 5.6±4.3 to 6.7±4.9 μL/min (P=0.014). There was no significant change in parapapillary retinal blood flow, retinal vessel diameter, systemic blood pressure, or IOP after treatment in neither of the two groups. Conclusion: An eye-specific acupuncture treatment may affect OBF in POAG patients. [ABSTRACT FROM AUTHOR]

Background: Few studies have investigated the drug utilization patterns and factors predicting drug use in pregnant women with migraine. This longitudinal drug utilization study aimed to describe patterns of analgesic use in a sample of Norwegian pregnant women according to their migraine history, and to identify predictors for analgesic use among these women.Methods: Pregnant women giving birth at Akershus University Hospital between 2008 and 2010 were recruited at ultrasound examination in gestational week 17. Data were collected by questionnaires in gestational weeks 17 and 32, and at 8 weeks postpartum, and linked to birth records. Women were grouped into four categories according to migraine history: no migraine history, previous migraine history, recent migraine history (within 1 year prior to pregnancy) and migraine in pregnancy. Patterns of use of analgesics were analyzed descriptively. Multivariable logistic regression was used to identify factors predicting analgesic use.Results: Out of 1981 women, 5.0% reported having migraine in pregnancy, 13.2% had a recent history of migraine, 11.5% had a previous history of migraine, and 68.8% reported no history of migraine. Analgesic use declined during pregnancy. Many women switched from triptans and non-steroidal anti-inflammatory drugs to paracetamol, which constituted most of the analgesic use. Factors associated with analgesic use included recent migraine history (OR 1.6, 95% CI 1.2-2.2), more severe headache intensity (OR 1.3, 95% CI 1.3-1.4), smoking (OR 1.9, 95% CI 1.1-3.3) and multiparity (OR 1.4, 95% CI 1.1-1.7).Conclusions: Women with migraine stop or switch medications during pregnancy. Analgesic use in pregnancy is affected by migraine characteristics and intensity, and also by socio-demographic factors. Clinicians should bear this in mind when giving advice on adequate management of migraine in pregnancy and safe analgesic use. [ABSTRACT FROM AUTHOR]

The time-resolved uptake of 17 nonionic and ionic polar compounds (logD ≤ 2) with a diversity of functional groups into zebrafish embryos (ZFE) was studied over 96 h of exposure. Among them were pharmaceuticals, pesticides and plant active ingredients. Uptake rates for the diffusion controlled passive uptake through the ZFE membrane ranged from 0.02 to 24 h-1 for the nonionic compounds and were slower for ionic compounds (<0.008-0.08 h-1). The study compounds did not enrich much in the ZFE (median bioconcentration factor of 1, max. 7). Biotransformation significantly influenced the internal concentration of some of the test compounds over time (benzocaine, phenacetin, metribuzin, phenytoin, thiacloprid, valproic acid). For benzocaine, valproic acid and phenacetin several transformation products (TPs) were observed by LC-MS already at early life-stages (before 28 hpf); for benzocaine the TPs comprised >90% of the initial amount taken up into the ZFE. For six compounds internal concentrations remained very low (rel. int. conc. < 0.2). Besides biotransformation (sulfamethoxazole), poor membrane permeability (cimetidine, colchicine) and also affinity to efflux transporters (atropine and chloramphenicol) are the likely reasons for these low internal concentrations. This study outlines that the uptake of polar compounds into ZFE is influenced by their physicochemical properties. However, biological processes, biotransformation and, likely, efflux can strongly affect the internal concentrations already in early developmental stages of the ZFE. This should be considered in future toxicokinetic modeling. The evaluation of the toxicity of chemicals by ZFE requires toxicokinetic studies of the test compounds and their TPs to increase comparability to effects in fish. [ABSTRACT FROM AUTHOR]

Editorial. Discusses the implications of the study on renal angioplasty for lowering blood pressure by van Jaarsveld et al in the April 6, 2000 issue of the 'New England Journal of Medicine.' Agreement that treatment of antihypertensive drugs is as effective as angioplasty; Strengths and weaknesses of the study; Questions raised by the study, including whether renal angioplasty should be considered for treating patients with atherosclerotic renal-artery stenosis; Patients who might benefit from the surgery.

Counteracting progression of renal disease: A look into the future. It is always risky to predict the future. It is the very nature of research, including medical research, that truly novel results are not predictable. Nevertheless, some predictions concerning the understanding and management of progression of renal disease are plausible. It is very likely that in the future, exploding health budgets will force authorities and nephrologists to more effectively apply existing knowledge in this field to patients with early renal disease, particularly diabetics. We hope that this optimistic note is justified, although experience admittedly indicates that it is very much against human nature to behave rationally. With the powerful methodological tools available today, it is safe to predict that insight into the mechanisms underlying progression will also increase. Although pharmacological blockade of the renin-angiotensin system has been one of the great success stories of the past two decades, in many patients, progression is seen despite administration of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers. Fortunately, additional targets for intervention, such as endothelin-1, inflammatory cascades, chemokines, etc., are on the horizon. A particularly fertile target for prevention of progression will be kidney grafts, since it has become increasingly clear that factors unrelated to allo-immunity play an important role in chronic allograft nephropathy. [ABSTRACT FROM AUTHOR]

Background: The cardiotonic steroid marinobufagenin (MBG) is increasingly suggested to be responsible for some of the cardiovascular injury that has been previously attributed to aldosterone. We examined the clinical correlates of circulating MBG concentrations in hypertensive patients and tested the hypothesis that MBG serves as a reliable diagnostic tool for detecting primary aldosteronism (PA). Methods: Plasma MBG concentrations (mean: 0.51 ± 0.25 nmol/l) were measured in the morning fasting samples in 20 patients with PA and 20 essential hypertensive (EH) controls matched for age, sex, body mass index, renal function, urinary sodium and intake of antihypertensive medication (mean age: 51.6 years; 52.2% women). Results: Overall, plasma MBG was directly correlated with plasma aldosterone, aldosterone to active renin ratio (AARR), diastolic blood pressure, mean carotid intima-media thickness, serum sodium, urinary protein to creatinine ratio and inversely with serum potassium levels. Plasma MBG levels were significantly higher in patients with PA compared to EH (mean: 0.68 ± 0.12 versus 0.35 ± 0.24 nmol/l; p < 0.001). ROC analysis yielded a greater AUC for plasma MBG compared to the AARR, PAC and serum potassium levels for detecting PA. Youden's Index analyses yielded the optimal plasma MBG cut-off score for diagnosing PA at > 0.49 nmol/l with specificity and sensitivity values of 0.85 and 0.95, respectively, which were higher than those at the optimum AARR cut-off at > 3.32 ng/dl/µU/ml. Conclusions: In a well-characterized cohort, values of plasma MBG were significantly related to clinical correlates of cardiovascular and renal disease. Plasma MBG emerged as a valuable alternative to the AARR for screening of PA. [ABSTRACT FROM AUTHOR]

Aims The rare association of flupirtine with liver injury is most likely caused by reactive quinone diimines and their oxidative formation may be influenced by the activities of N-acetyltransferases ( NAT) that conjugate the less toxic metabolite D13223, and by glucuronosyltransferases ( UGT) and glutathione S-transferases ( GST) that generate stable terminal glucuronides and mercapturic acid derivatives, respectively. The influence of genetic polymorphisms of NAT2, UGT1A1 and GSTP1 on generation of the terminal mercapturic acid derivatives and analgesic effects was evaluated to identify potential genetic risk factors for hepatotoxicity of flupirtine. Methods Metabolic disposition of flupirtine was measured after intravenous administration (100 mg), after swallowing an immediate-release ( IR) tablet (100 mg) and after repeated administration of modified release ( MR) tablets (400 mg once daily 8 days) in 36 selected healthy subjects. Analgesic effects were measured using pain models (delayed onset of muscle soreness, electric pain). Results Flupirtine IR was rapidly but incompletely absorbed (∼72%). Repeated administration of flupirtine MR showed lower bioavailability (∼60%). Approximately 12% of bioavailable flupirtine IR and 8% of bioavailable flupiritine MR was eliminated as mercapturic acid derivatives into the urine independent of the UGT1A1, NAT2 and GSTP1 genotype. Carriers of variant GSTP1 alleles showed lower bioavailability but increased intestinal secretion of flupirtine and increased efficiency in experimental pain. Flupirtine was not a substrate for ABCB1 and ABCC2. Conclusions Formation of mercapturic acid derivatives is a major elimination route for flupirtine in man. However, the theoretically toxic pathway is not influenced by the frequent polymorphisms of UGT1A1, NAT2 and GSTP1. [ABSTRACT FROM AUTHOR]

Purpose To investigate the effect of flavonoid-rich dark chocolate and non-flavonoid-rich white chocolate on retinal vessel diameter in glaucoma patients and age-matched controls. Methods Thirty glaucoma patients and 30 age-matched subjects were assigned to dark or white chocolate by randomization with forced equal distribution. The number in each of the four groups was 15. Measured parameters included systemic blood pressure ( BP), blood glucose levels, static retinal vessel analysis, as measured by central retinal artery equivalent ( CRAE) (which relates to the diameter of the central retinal artery), central retinal vein equivalent ( CRVE) (which relates to the diameter of central retinal vein) and the arterio-venous ratio ( AVR), which represents the CRAE/ CRVE ratio, dynamic retinal vessel analysis as measured by the change in vessel diameter in response to flicker light stimulation. Three recording cycles from each were averaged. Results Blood pressure parameters (systolic BP, diastolic BP and pulse), IOP and blood glucose levels did not differ significantly between both groups before and after consumption of white or dark chocolate. Static vessel analysis did not show any significant changes in CRAE, CRVE or AVR before and after dark or white chocolate in both groups (p > 0.05). Mean dilatation of the venules in the control group was 3.2 ± 0.9 % before dark chocolate and 4.2 ± 1.4 % after dark chocolate intake, which was statistically significantly different (p = 0.01). Mean dilatation of the arterioles in the control group was 2.8 ± 1.8 % before dark chocolate and 3.5 ± 1.8 % after dark chocolate intake with a trend to statistical significance (p = 0.14), but not reaching the significance level. Mean diameter changes in the glaucoma group did not show any significant differences after dark chocolate consumption. Conclusion The present study showed a significant improvement of venous vasodilatation 2 hr after dark chocolate intake in the control group, but not in the glaucoma group. This effect might be indicative of an increased bioavailability of nitric oxide ( NO) after dark chocolate consumption. The lack of finding a significant venous response after dark chocolate in the glaucoma group might be related to the already impaired endothelial function in these patients. [ABSTRACT FROM AUTHOR]

Background: Substance dependence poses a critical health problem. Sadly, its neurobiological mechanisms are still unclear, and this lack of real understanding is reflected in insufficient treatment options. It has been hypothesized that alcohol effects are due to an imbalance between neuroexcitatory and neuroinhibitory amino acids. However, glutamate and GABA interact with other neurotransmitters, which form a complicated network whose functioning evades intuition and should be investigated systemically with methods of biomedical systems analysis. Methods and Results: We present a heuristic model of neurotransmitters that combines a neurochemical interaction matrix at the biochemical level with a mobile describing the balances between pairs of neurotransmitters at the physiological and behavioral level. We investigate the effects of alcohol on the integrated neurotransmitter systems at both levels. The model simulation results are consistent with clinical and experimental observations. The model demonstrates that the drug diazepam for symptoms of alcohol withdrawal effectively reduces the imbalances between neurotransmitters. Moreover, the acetylcholine signal is suggested as a novel target for treatment of symptoms associated with alcohol withdrawal. Conclusions: Efficient means of integrating clinical symptoms across multiple levels are still scarce and difficult to establish. We present a heuristic model of systemic neurotransmitter functionality that permits the assessment of genetic, biochemical, and pharmacological perturbations. The model can serve as a tool to represent clinical and biological observations and explore various scenarios associated with alcohol dependence and its treatments. It also is very well suited for educational purposes. [ABSTRACT FROM AUTHOR]

Background and Purpose: Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. With the present studies we synthesized and characterized new organic nitrate hybrid molecules. Compounds CLC-1265 (valsartan mononitrate) and CLC-1280 (valsartan dinitrate) are derivatives of the angiotensin receptor blocker valsartan, with CLC-1265 containing a single organic nitrate linker and CLC-1280 also containing a second, different linker. Compounds CLC-2000 (cilostazol mononitrate) and CLC-2100 (cilostazol dinitrate) are nitrate derivatives of the phosphodiesterase III inhibitor cilostazol. All compounds are designed as hybrid molecules, potentially combining the NO-donating properties of organic nitrates with the AT1-blocking activity of valsartan or the phosphodiesterase-III-inhibiting effect of cilostazol. Experimental Approach: The properties of new drugs were assessed by isometric tension recording, inhibition of platelet aggregation and formation of mitochondrial reactive oxygen and nitrogen species. Key Results: In this report, all new nitrate compounds are shown, in vitro, to induce vasodilation in the range of other, classical organic nitrates, without inducing oxidative stress or classical nitrate tolerance. In addition, the new hybrid nitrate molecules displayed superior antiaggregatory properties over classical mono- and dinitrates. Conclusions and Implications: Our results demonstrate that organic nitrates can be successfully linked to existing therapeutic molecules to create a new class of molecular entities with a potential dual mechanism of action via combining the established pharmacological properties of valsartan or cilostazol with the vasodilating properties of organic nitrates. Future experimental studies have to demonstrate whether the combined action of these compounds translates to superior therapeutic effects. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Although statin treatment is generally well tolerated, it is estimated that 5% to 10% of patients develop muscle-related side effects (MRSEs), resulting in less effective nonstatin alternatives or cessation of lipid-lowering therapy completely. This study was designed to assess the efficacy and tolerability of extended-release fluvastatin (fluvastatin XL) and ezetimibe alone or in combination in patients with previous MRSEs with other statins. This was a double-blinded, double-dummy trial of 199 mostly moderate- or high-risk dyslipidemic patients randomized to fluvastatin XL 80 mg/day (n = 69), ezetimibe 10 mg/day (n = 66), or fluvastatin XL 80 mg/day plus ezetimibe 10 mg/day (n = 64) for 12 weeks. Fluvastatin XL lowered low-density lipoprotein (LDL) cholesterol by 32.8% compared with 15.6% with ezetimibe (between-group difference −17.1%, 95% confidence interval −23.6 to −10.7, p <0.0001); the fluvastatin XL/ezetimibe combination lowered LDL cholesterol by 46.1% (between-group difference vs ezetimibe −30.4%, 95% confidence interval −37.0 to −23.8, p <0.0001). Proportions of patients achieving their National Cholesterol Education Program Adult Treatment Panel III target LDL cholesterol were 84% with the fluvastatin XL/ezetimibe combination, 59% with fluvastatin XL, and 29% with ezetimibe (p <0.001 for fluvastatin XL monotherapy or combination therapy vs ezetimibe monotherapy). Incidences of MRSEs were 24% in the ezetimibe group, 17% in the fluvastatin XL group, and 14% in the combination group. There were no instances of creatine kinase increases ≥10 times upper limit of normal. In conclusion, in patients with a history of statin-associated MRSEs, fluvastatin XL alone or in combination with ezetimibe offers an effective and well-tolerated lipid-lowering option. [Copyright &y& Elsevier]

Objectives: This study sought to study stent thrombosis with the paclitaxel-eluting Taxus stent. Background: The incidence and timing of stent thrombosis after drug-eluting stent placement compared with bare-metal stent implantation remain unsettled, with consequent uncertainty about risk stratification and long-term recommendations for antiplatelet medications. Methods: This study used a patient-based meta-analysis using the 4 principal TAXUS randomized trials (3,445 patients) with a follow-up duration of ≥1 year. Results: Cumulative stent thrombosis occurred in 1.28% ± 0.31% in the Taxus group and 0.76% ± 0.23% in the bare-metal stent group at 3 years (hazard ratio 1.51 [95% confidence interval 0.73 to 3.14], p = 0.26). Hazard ratios (per 100 patients per 6 months) were similar between the Taxus stent group (0.59 [95% confidence interval 0.22 to 0.95]) and the bare-metal stent group (0.64 [95% confidence interval 0.26 to 1.02]) through 6 months during the prescribed clopidogrel period. However, from 6 months to 3 years there were more stent thromboses in the Taxus group (hazard ratio 0.19 [95% confidence interval 0.06 to 0.32] vs. 0.02 [95% confidence interval 0.00 to 0.07], p = 0.049). Of 8 patients with Taxus-related thrombosis after 6 months, 0 were taking clopidogrel and 2 were not taking aspirin consistently. No Taxus-related stent thrombosis occurred after 2 years (922 patients thus far followed up for 3 years). Independent correlates of stent thrombosis were nonuse of clopidogrel, male gender, smoking, and possibly use of multiple nonoverlapping stents. Conclusions: Approximately 0.8% of Taxus patients have stent thrombosis in the first 6 months after stent implantation, similar to bare-metal stents. However, a modest increase in risk is present with Taxus stents beyond 6 months, possibly because of inadequate antiplatelet drug therapy. [Copyright &y& Elsevier]

Background: The treatment of Parkinson's disease (PD) is complex and highly individual. The choice between available treatment options depends on clinical characteristics such as the patient's age, disease severity and presence of comorbidities, lifestyle characteristics and preferences, costs of different medications and awareness and perception of available treatment options, and education of the treating physician. The impact of PD treatment regimens on patients' health-related quality of life (QOL) is also an important healthcare feature. The objective of the present study was to assess treatment options, treatment satisfaction and opinions about treatment improvements in patients with PD and neurologists treating the disease. Methods: Two surveys using face-to-face interviews and an additional phone survey were carried out in the US and five European countries (France, Germany. Italy, Spain and the UK). Patients with early and advanced stages of PD were included. To participate in the neurologist survey, neurologists were required to personally treat ten or more PD patients per month, including both early and advanced stage patients. Interviews consisted of a mix of closed and open-ended questions; some of these questions involved show cards. Results: Of the 500 patients who were surveyed, 49% had early and 51% had advanced PD. Early-stage PD patients, both in the US and Europe, take a mean of 3.2 tablets daily of PD-medication. In contrast, the mean daily tablet load of PD medication is much higher for advanced-stage patients (9.9 and 8.4 tablets in the US and Europe, respectively). Tablet load was perceived as a major problem; the majority of patients wished to see improvements regarding daily medication intake and expressed interest in other delivery systems such as patches. Overall, patients rated their treatment with a score of 6.6 points (6.7 for early-stage and 6.6 for advanced-stage patients) [scale of 1-10; l0 being highest]. Physicians (n = 592) were satisfied with a number of current PD medications and assumed they improve the QOL of the patients. They regarded efficacy and safety as the most important features for the improvement of PD medication. Conclusion: Further research is needed into PD treatment options not only for symptom alleviation but for better delivery systems that could improve compliance and QOL for patients with PD. Treatment guidelines need to incorporate QOL aspects and general communication between the health professional and the patient. [ABSTRACT FROM AUTHOR]

Although clinical experience influences psychotropic drug treatment world-wide, it has been underutilized because it has not been systematically gathered and widely disseminated. An international survey was conducted to help remedy this situation. One of the major objectives was to develop a representative body of expert judgment and opinion on the clinical use of benzodiazepines in relation to other psychotherapeutic medications that might be used for the same purposes. A select international panel of psychiatric experts on the pharmacotherapy of the anxiety and depressive disorders (N = 73) was constituted on the basis of progressive peer nominations. The peer selection process began with primary nominators from 44 countries. Judgments and opinions about psychotherapeutic medications were elicited from the Expert Panel via a self-administered questionnaire. Completion rate: 90 per cent (66/73). Outcomes bear directly on current therapeutic and regulatory concerns. Topics addressed include: special Indications for use, abuse liability, dependence potential, duration of treatment, high-risk treatments, and adverse effects. Although sometimes divided, agreement was generally high and indicative of a good benefit to risk ratio for the benzodiazepines. Expert judgments were more positive than would have been anticipated from media reports, public concern, and recent regulatory postures. The following inferences can be drawn from this body of expert judgment and opinion: (I) qualitative differences in abuse liability among the benzodiazepines are minimal; (2) physical dependence at therapeutic doses is not a major clinical problem; (3) when physical dependence occurs, it can be readily managed clinically by the treating physician; (4) the relative abuse liability of the benzodiazepines as a class is low. These expert evaluations do not support or justify the imposition of stronger or differential restrictions on the benzodiazepines. [ABSTRACT FROM AUTHOR]

Background: In this series from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG), the authors examined longitudinal outcomes of patients with a second recurrence of retroperitoneal sarcoma (RPS) after complete resection of a first local recurrence (LR). Methods: Data from patients undergoing resection of a first LR from January 2002 to December 2011were collected from 22 sarcoma centers. The primary outcome was overall survival (OS) after second recurrence. Results: Second recurrences occurred in 400 of 567 patients (70.5%) after an R0/R1 resection of a first locally recurrent RPS. Patterns of disease recurrence were LR in 323 patients (80.75%), distant metastases (DM) in 55 patients (13.75%), and both LR and DM in 22 patients (5.5%). The main subtype among the LR group was liposarcoma (77%), whereas DM mainly were leiomyosarcomas (43.6%). In patients with a second LR only, a total of 200 patients underwent re‐resection (61.9%). The 5‐year OS rate varied significantly based on the pattern of failure (P <.001): 45.6% for the LR group, 25.5% for the DM group, and 0% for the group with LR and DM. The only factors found to be associated with improved OS on multivariable analysis were both time between second surgery and the development of the second recurrence (32 months vs 8 months: hazard ratio, 0.44 [P <.001]) and surgery for second recurrence (yes vs no: hazard ratio, 3.25 [P <.001]). The 5‐year OS rate for patients undergoing surgery for a second LR was 59% versus 18% in the patients not deemed suitable for surgical resection. Conclusions: Survival rates after second recurrence of RPS varied based on patterns of disease recurrence and treatment. Durable disease‐free survivors were identified after surgery for second LR in patients selected for this intervention. The current series, derived from 22 sarcoma centers from the Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) collaborative, describes the outcomes of patients experiencing a second recurrence of retroperitoneal sarcoma. Second recurrences are reported in approximately 70.5% of patients, with a 5‐year overall survival rate of between 0% and 45%, but durable disease‐free survivors are identified after surgery for second local recurrence among selected patients. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer is a devastating disease with a dismal prognosis. Despite profound medical advances in systemic therapies for other types of aggressive tumours during recent years, a diagnosis of pancreatic cancer is still often synonymous with a fatal outcome. The term periampullary cancer includes pancreatic cancer and applies to the group of tumours found in proximity to the ampulla of Vater. Molecular events and immune response in the host during chemotherapy remain largely unexplored in this group of tumours. Therefore, the "Chemotherapy, Host Response and Molecular Dynamics in Periampullary Cancer (CHAMP)" study aims to monitor these processes to gain new insight into this perplexing disease.Methods: The CHAMP study is a prospective, single-arm observational study. All patients diagnosed with pancreatic or other periampullary adenocarcinoma undergoing adjuvant or palliative chemotherapy treatment in the Department of Oncology, Skåne University Hospital, are invited to participate. Clinical and pathological data will be compiled at study entry. A single tissue microarray (TMA) block is constructed for each patient with a resected tumour and blood samples are drawn before, during and after chemotherapy in order to sample peripheral blood mononuclear cells (PBMC), cytokines and circulating tumour DNA (ctDNA). Next generation sequencing will be performed on tumour tissue and ctDNA to detect changes in the clonal landscape over space and time.Discussion: Despite the recent emergence of some promising biomarkers for periampullary cancer, there has been a lack of success in clinical implementation. Cancer cells continuously adapt and become resistant to treatment during chemotherapy. To be able to keep pace with and hopefully overtake this rapid evolution we must, with the help of new diagnostic tools, be ready to adapt and alter treatment accordingly. It seems to us that the only way forward is to gain a better understanding of the dynamics of the disease during treatment. With insights gained from the CHAMP study we hope to find answers to key questions in this largely unexplored territory.Trial Registration: This study has been registered 30th October 2018 at clinicaltrials.gov as NCT03724994. [ABSTRACT FROM AUTHOR]

Fibromyalgia is a chronic illness characterized by pain and fatigue. Persons with fibromyalgia experience increased the risk for poor mental and physical health-related quality of life, which may be dependent on multiple factors, including health beliefs, such as confidence in physicians and the health-care system, and health behaviors, such as treatment adherence. Respondents with fibromyalgia (n = 409) were recruited nationally, via support organizations, and completed self-report measures: Multidimensional Health Profile – Health Functioning Index (MHP-H), Short-Form-36 Health Survey (SF-36v2), and Medical Outcomes Study (MOS) Measure of Patient Adherence – General Adherence Items. In mediation models, belief in the healthcare system and health-care personnel, and health efficacy exerted an indirect effect through treatment adherence on mental and physical quality of life. Adaptive health beliefs and attitudes were related to greater treatment adherence and, in turn, to a better quality of life. Maladaptive health beliefs and mistrusting attitudes about physician-level and systemic-level healthcare provision are negatively related to both treatment adherence and consequent physical and mental health-related quality of life in persons with fibromyalgia. Future randomized controlled trials are needed to determine if therapeutic strategies to alter health values might improve adherence and self-rated health. [ABSTRACT FROM AUTHOR]

• The same disease and an individual's responses to drugs can vary considerably. • The central reason for these differences is the complexity of the human body. • The differences in responses pose severe challenges for personalized medicine. • Computational systems biology is a powerful tool for addressing these challenges. • Different modeling modalities can support and aid rational personalized medicine. The complexity of the human body is a major roadblock to diagnosis and treatment of disease. Individuals may be diagnosed with the same disease but exhibit different biomarker profiles or physiological changes and, importantly, they may respond differently to the same risk factors and the same treatment. There is no doubt that computational methods of data analysis and interpretation must be developed for medicine to evolve from the traditional population-based approaches to personalized treatment strategies. We discuss how computational systems biology is contributing to this current evolution. [ABSTRACT FROM AUTHOR]