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Alzheimer's disease (AD) is a progressive and ultimately fatal condition that causes debilitating memory loss and extensive deterioration of cognitive and functional abilities. Currently available treatments for AD (donepezil, rivastigmine, galantamine and memantine) are symptomatic and do not decelerate or prevent the progression of the disease. These therapies demonstrate modest, but particularly consistent, benefit for cognition, global status and functional ability. The search for disease-modifying interventions has focused largely on compounds targeting the amyloid-β pathway. To date, the treatments targeting this pathway, such as tramiprosate and semagacestat, have been unsuccessful in demonstrating efficacy in clinical stages of testing. At this point, it is likely that not only amyloid-β aggregation but other possible neuronal mechanisms--such as hyperphosphorylated tau, neuro- inflammation and other processes - play important roles in the pathophysiology of this multifactorial disorder. Development of better disease models and biomarkers is essential for the advancement of knowledge of the disease mechanisms. This systematic review critically examines the efficacy and safety data for currently approved drugs and emerging treatments in AD, as well as discussing the present and future directions of innovation in this field. [ABSTRACT FROM AUTHOR]

Evicel® is a fibrin sealant consisting of two components, human clottable protein (predominantly human fibrinogen) and human thrombin. It is indicated as supportive treatment in patients undergoing surgery when control of bleeding by standard surgical techniques is ineffective or impractical. Evicel® is a new formulation of the previously available fibrin sealant Quixil® (in the EU) or Crosseal™ (in the US). Evicel® differs from Quixil®/Crosseal™ in that its fibrinogen component does not contain the antifibrinolytic agent trane- xamic acid, which is potentially neurotoxic, resulting in Quixil®/Crosseal™ being contraindicated for use in neurosurgery. The removal of tranexamic acid did not affect the haemostatic efficacy or longevity of Evicel® fibrin clots and allowed the sealant to be granted an expanded indication. Evicel® and Quixil®/Crosseal™ are easy to use and, since they do not contain synthetic or bovine aprotinin, have a reduced potential for hypersensitivity reactions. This article reviews the pharmacological properties, clinical efficacy and tolerability of Evicel® and its previous formulation as supportive treatment for haemostasis in surgery. In clinical studies, Evicel® and Quixil®/Crosseal™ were generally well tolerated and effective haemostatic agents for adjunctive use in various types of surgeries when conventional methods were impractical or ineffective in controlling bleeding. Two pivotal, randomized studies showed that Evicel® was significantly more effective than manual compression in patients undergoing vascular surgery, and significantly more effective than Surgicel® in patients undergoing retroperitoneal or intra-abdominal surgery, as assessed by the proportion of patients achieving haemostasis. In another similarly designed pivotal study in patients undergoing liver resection, Crosseal™ was significantly more effective than standard haemostatic agents (e.g. Surgicel®), as assessed by the mean time to haemostasis. The incidences of treatment-emergent adverse events in these studies were generally similar between the Evicel® or Crosseal™ groups and the comparator groups. Quixil® was also generally well tolerated and an effective haemostatic agent in endonasal surgeries, and tonsillectomies and/or adenoidectomies, with some benefit of treatment with Evicel® or Quixil® also observed in orthopaedic surgeries. Although additional comparative studies with other haemostatic agents would help to definitively position Evicel® with respect to these agents, current evidence suggests that Evicel® is useful in surgeries for improving haemostasis where standard surgical techniques are insufficient. [ABSTRACT FROM AUTHOR]

Eldecalcitol (1α,25[OH]2-2Ã-(3-hydroxypropyloxy)vitamin D3; ED-71; Edirol®) is an orally administered analogue of active vitamin D (calcitriol) that is available in Japan for the treatment of osteoporosis. Two randomized, double-blind, multicentre trials were conducted in patients with osteoporosis. In a placebo-controlled, dose-ranging trial, eldecalcitol significantly reduced serum bone-specific alkaline phosphatase (BALP) and serum osteocalcin, markers of bone formation, more than placebo. Eldecalcitol ata 1.0 μg/day dosage, but not at lower dosages, also significantly reduced urinary type I collagen N-telopeptide (NTX), a marker of bone résorption, more than placebo. In a comparison with alfacalcidol (a prodrug of calcitriol), eldecalcitol produced significantly greater reductions in serum BALP and urinary NTX, and had a positive effect on CT markers of femoral biomechanical properties. In the comparison with alfacalcidol, eldecalcitol 0.75 μg/day significantly reduced the 3-year incidence of vertebral fractures, with an absolute risk reduction of 4.1% over this period, representing a relative risk reduction of 26%. There was no significant difference in the rate of non-vertebral fractures. In both trials, eldecalcitol treatment was also associated with an increase in bone mineral density, whereas patients who received the comparators generally had a reduction in bone mineral density. Increases in blood calcium (to >2.6mmol/L) and urinary calcium (to >0.1 mmol/L glomerular filtrate) were the most clinically important treatment- emergent adverse events. In the placebo-controlled, dose-ranging trial, 23% and 25% of patients in the eldecalcitol 1 ug/day group had increased blood and urinary calcium compared with 5% and 7%, 7% and 9%, and 0% and 1.9% in the eldecalcitol 0.5 and 0.75 ug/day, and placebo groups, respectively. In the comparison with alfacalcidol, 21.0% and 13.5% of eldecalcitol 0.75 ug/day and alfacalcidol 1.0 ug/day recipients had increased blood calcium, whereas hypercalcaemia (defined as a serum calcium >2.9 mmol/L) occurred in 0.4% and urolithiasis in 1.3% of eldecalcitol recipients over 36 months of treatment. Eldecalcitol is an efficacious treatment for patients with osteoporosis that should be further investigated in head-to-head trials with other recommended first-line pharmacological treatments. [ABSTRACT FROM AUTHOR]

Athletic osteitis pubis is a painful and chronic condition affecting the pubic symphysis and/or parasymphyseal bone that develops after athletic activity. Athletes with osteitis pubis commonly present with anterior and medial groin pain and, in some cases, may have pain centred directly over the pubic symphysis. Pain may also be felt in the adductor region, lower abdominal muscles, perineal region, inguinal region or scrotum. The pain is usually aggravated by running, cutting, hip adduction and flexion against resistance, and loading of the rectus abdominis. The pain can progress such that athletes are unable to sustain athletic activity at high levels. It is postulated that osteitis pubis is an overuse injury caused by biomechanical overloading of the pubic symphysis and adjacent parasymphyseal bone with subsequent bony stress reaction. The differential diagnosis for osteitis pubis is extensive and includes many other syndromes resulting in groin pain. Imaging, particularly in the form of MRI, may be helpful in making the diagnosis. Treatment is variable, but typically begins with conservative measures and may include injections and/or surgical procedures. Prolotherapy injections of dextrose, anti-inflammatory corticosteroids and a variety of surgical procedures have been reported in the literature with varying efficacies. Future studies of athletic osteitis pubis should attempt to define specific and reliable criteria to make the diagnosis of athletic osteitis pubis, empirically define standards of care and reduce the variability of proposed treatment regimens. [ABSTRACT FROM AUTHOR]

In recent years there has been considerable concern that certain classes of drugs, for example antidepressants, may increase the risk of suicide. In this current opinion article, we examine the literature on methodological and statistical approaches to the design and analysis of suicidal event studies. Experimental, ecological and observational studies of the relationship between drugs and suicidal events (thoughts, attempts and completion) are discussed. Areas considered include analysis of spontaneous reporting system data, ecological trends in national and/or small area (e.g. county) suicide rates, meta-analyses of randomized clinical trials, and large-scale medical claims data. New statistical and experimental strategies for investigating possible associations between drugs and suicide are highlighted, and we suggest directions for future statistical/methodological research. To put this into context, we then review the most recent literature on the relationship between drugs (antidepressants, antiepileptics, varenicline, montelukast and antipsychotics) and suicidal events. Overall, there appears to be little evidence that drugs increase the risk of suicide and related behaviour. Numerous lines of evidence in adults clearly demonstrate that inadequate treatment of depression (pharmacotherapy and/or psychotherapy) is associated with increased risk of suicidal behaviour. In children, the results are less clear and further study is required to better delineate which children benefit from treatment and who may be at increased risk as a consequence of treatment. From a statistical and methodological perspective, the field of pharmacoepidemiology is a fertile area for statistical research, both in theory and in application. In general, methods have been adopted from other areas such as general epidemiology, despite the singular nature of many of the problems that are unique to drug safety in general, in particular the study of rare events. Finally, there is considerable debate concerning the communication of risk. For suicide, regulatory action has been taken largely on the basis of evidence suggesting increased risk of suicidal thoughts. However, suicidal thoughts are quite common, particularly among patients with depression, and may have little relationship to suicidal behaviour and/or completion. [ABSTRACT FROM AUTHOR]

Plyometric training (PLY) is a very popular form of physical conditioning of healthy individuals that has been extensively studied over the last 3 decades. In this article, we critically review the available literature related to lower-body PLY and its effects on human neural and musculoskeletal systems, athletic performance and injury prevention. We also considered studies that combined lower-body PLY with other popular training modalities, as well as studies that applied PLY on non-rigid surfaces. The available evidence suggests that PLY, either alone or in combination with other typical training modalities, elicits numerous positive changes in the neural and musculoskeletal systems, muscle function and athletic performance of healthy individuals. Specifically, the studies have shown that long-term PLY (i.e. 3-5 sessions a week for 5-12 months) represents an effective training method for enhancing bone mass in prepubertal/early pubertal children, young women and premenopausal women. Furthermore, short-term PLY (i.e. 2-3 sessions a week for 6-15 weeks) can change the stiffness of various elastic components of the muscle-tendon complex of plantar flexors in both athletes and non-athletes. Short-term PLY also improves the lower-extremity strength, power and stretch-shortening cycle (SSC) muscle function in healthy individuals. These adaptive changes in neuromuscular function are likely the result of (i) an increased neural drive to the agonist muscles; (ii) changes in the muscle activation strategies (i.e. improved intermuscular coordination); (iii) changes in the mechanical characteristics of the muscle-tendon complex of plantar flexors; (iv) changes in muscle size and/or architecture; and (v) changes in single-fibre mechanics. Our results also show that PLY, either alone or in combination with other training modalities, has the potential to (i) enhance a wide range of athletic performance (i.e. jumping, sprinting, agility and endurance performance) in children and young adults of both sexes; and (ii) to reduce the risk of lower-extremity injuries in female athletes. Finally, available evidence suggests that short-term PLY on non-rigid surfaces (i.e. aquatic- or sand-based PLY) could elicit similar increases in jumping and sprinting performance as traditional PLY, but with substantially less muscle soreness. Although many issues related to PLY remain to be resolved, the results of this review allow us to recommend the use of PLY as a safe and effective training modality for improving lower-extremity muscle function and functional performance of healthy individuals. For performance enhancement and injury prevention in competitive sports, we recommend an implementation of PLY into a well designed, sport-specific physical conditioning programme. [ABSTRACT FROM AUTHOR]

lthough electrical discharge machining is essentially a material removal process, efforts have been made in the recent past to use it as a surface treatment method. An additive powder in the dielectric medium affects the sparking action and helps in improving the surface properties. It may melt at the high temperature of the plasma channel and alloy with the machined surface under appropriate machining conditions. Breakdown of the hydrocarbon dielectric contributes carbon to the plasma channel. In this paper, changes in surface properties of oil-hardening non-shrinkable die steel after machining with manganese powder suspended in kerosene dielectric medium have been investigated. Results show improvement in microhardness by 73%, and no microcracks on the machined surface. X-ray diffraction analysis of the machined surfaces reveals the transfer of manganese and carbon from the plasma channel in the form of manganese carbide. Quantitative analysis of chemical composition by optical emission spectrometer confirms significant increase in the percentages of manganese and carbon. [ABSTRACT FROM AUTHOR]

In recent years there have been a number of interesting advances in several topics relating to the diagnosis and treatment of cutaneous lesions with particular applicability to primary and metastatic malignancies of the scalp. In this article we provide a general update of advances in this field, and cover the more salient points relating to a variety of malignant tumors that have been reported to appear on the scalp as primary or metastatic lesions. A search and review of the literature on PubMed was made to identify and discuss relevant points relating to diagnosis and treatment of primary and metastatic tumors of the scalp. We describe the anatomy of the scalp, epidemiology of scalp tumors, theories of field cancerization and field therapy, photodynamic therapy, excisional surgical techniques and reconstruction, lymphoscintigraphy, chemoprevention, as well as details relating to atypical fibroxanthoma, Brooke-Spiegler syndrome, nevus sebaceus, cutaneous lymphoma, and metastatic disease. There is a very broad differential diagnosis for scalp nodules, which includes many different benign and malignant diseases, and treatment should be tailored accordingly. Given the potential for poor prognosis with some of the more aggressive malignancies that can be found in this anatomic area, the importance of a thorough physical examination cannot be emphasized enough, and early detection is critical to provide patients with the best chance for a favorable outcome. [ABSTRACT FROM AUTHOR]

The calcineurin inhibitors ciclosporin (cyclosporine) and tacrolimus are immunosuppressant drugs used for the prevention of organ rejection following transplantation. Both agents are metabolic substrates for cytochrome P450 (CYP) 3A enzymes - in particular, CYP3A4 and CYP3A5 - and are transported out of cells via P-glycoprotein (ABCB1). Several single nucleotide polymorphisms (SNPs) have been identified in the genes encoding for CYP3A4, CYP3A5 and P-glycoprotein, including CYP3A4 -392A>G (rs2740574), CYP3A5 6986A>G (rs776746), ABCB1 3435C>T (rs1045642), ABCB1 1236C>T (rs1128503) and ABCB1 2677G>T/A (rs2032582). The aim of this review is to provide the clinician with an extensive overview of the recent literature on the known effects of these SNPs on the pharmacokinetics of ciclosporin and tacrolimus in solid-organ transplant recipients. Literature searches were performed, and all relevant primary research articles were critiqued and summarized. Influence of the CYP3A4 -392A>G SNP on the pharmacokinetics of either ciclosporin or tacrolimus appears limited. Variability in CYP3A4 expression due to environmental factors is likely to be more important than patient genotype. Influence of the CYP3A5 6986A>G SNP on the pharmacokinetics of ciclosporin is also uncertain and likely to be small. CYP3A4 may play a more dominant role than CYP3A5 in the metabolism of ciclosporin. The CYP3A5 6986A>G SNP has a well established influence on the pharmacokinetics of tacrolimus. Several studies in kidney, heart and liver transplant recipients have reported an approximate halving of tacrolimus dose-adjusted trough concentrations and doubling of tacrolimus dose requirements in heterozygous or homozygous carriers of a CYP3A5*1 wild-type allele compared with homozygous carriers of a CYP3A5*3 variant allele. Carriers of a CYP3A5*1 allele take a longer time to reach target blood tacrolimus concentrations. Influence of ABCB1 3435C>T, 1236C>T and 2677G>T/A SNPs on the pharmacokinetics of ciclosporin and tacrolimus remains uncertain, with inconsistent results. Genetic linkage between the three variant genotypes suggests that the pharmacokinetic effects are complex and not related to any one ABCB1 SNP. It is likely that these polymorphisms exert a small but combined effect, which is additive to the effects of the CYP3A5 6986A>G SNP. In liver transplant patients, recipient and donor liver genotypes may act together in determining overall drug disposition, hence the importance of assessing both. Studies with low patient numbers may account for many inconsistent results to date. Meta-analyses of the current data should help resolve some discrepancies. The majority of studies have only evaluated the effects of individual SNPs; however, multiple polymorphisms may interact to produce a combined effect. Further haplotype analyses are likely to be useful. It is not yet clear whether pharmacogenetic profiling of calcineurin inhibitors will be a useful clinical tool for personalizing immunosuppressant therapy. [ABSTRACT FROM AUTHOR]

New methods and devices for pursuing performance enhancement through altitude training were developed in Scandinavia and the USA in the early l990s. At present, several forms of hypoxic training and/or altitude exposure exist: traditional 'live high-train high' (LHTH), contemporary 'live high-train low' (LHTL), intermittent hypoxic exposure during rest (IHE) and intermittent hypoxic exposure during continuous session (IHT). Although substantial differences exist between these methods of hypoxic training and/ or exposure, all have the same goal: to induce an improvement in athletic performance at sea level. They are also used for preparation for competition at altitude and/or for the acclimatization of mountaineers. The underlying mechanisms behind the effects of hypoxic training are widely debated. Although the popular view is that altitude training may lead to an increase in haematological capacity, this may not be the main, or the only, factor involved in the improvement of performance. Other central (such as ventilatory, haemodynamic or neural adaptation) or peripheral (such as muscle buffering capacity or economy) factors play an important role. LHTL was shown to be an efficient method. The optimal altitude for living high has been defined as being 2200-2500 m to provide an optimal erythropoietic effect and up to 3100 m for non-haematological parameters. The optimal duration at altitude appears to be 4 weeks for inducing accelerated erythropoiesis whereas <3 weeks (i.e. 18 days) are long enough for beneficial changes in economy, muscle buffering capacity, the hypoxic ventilatory response or Na+/K+-ATPase activity. One critical point is the daily dose of altitude. A natural altitude of 2500 m for 20-22 h/day (in fact, travelling down to the valley only for training) appears sufficient to increase erythropoiesis and improve sea-level performance. 'Longer is better' as regards haematological changes since additional benefits have been shown as hypoxic exposure increases beyond 16 h/day. The minimum daily dose for stimulating erythropoiesis seems to be 12 hlday. For non-haematological changes, the implementation of a much shorter duration of exposure seems possible. Athletes could take advantage of IHT, which seems more beneficial than IHE in performance enhancement. The intensity of hypoxic exercise might play a role on adaptations at the molecular level in skeletal muscle tissue. There is clear evidence that intense exercise at high altitude stimulates to a greater extent muscle adaptations for both aerobic and anaerobic exercises and limits the decrease in power. So although IHT induces no increase in VO2max due to the low 'altitude dose', improvement in athletic performance is likely to happen with high-intensity exercise (i.e. above the ventilatory threshold) due to an increase in mitochondrial efficiency and pH/lactate regulation. We propose a new combination of hypoxic method (which we suggest naming Living High-Training Low and High, interspersed; LHTLHi) combining LHTL (five nights at 3000 m and two nights at sea level) with training at sea level except for a few (2.3 per week) IHT sessions of supra-threshold training. This review also provides a rationale on how to combine the different hypoxic methods and suggests advances in both their implementation and their periodization during the yearly training programme of athletes competing in endurance, glycolytic or intermittent sports. [ABSTRACT FROM AUTHOR]

It is estimated that knee injuries account for up to 60% of all sport injuries, with the anterior cruciate ligament (ACL) accounting for almost half of these knee injuries. These knee injuries can result in high healthcare costs, as an ACL injury is often associated with surgery, long and costly rehabilitation, differing degrees of impairment and potential long-term consequences such as osteoarthritis. The interest in ACL injury prevention has been extensive for the past decade. Over this period, many ACL (intrinsic and extrinsic) injury risk factors have been identified and investigated by numerous researchers. Although prevention programmes have shown potential in decreasing knee ligament injuries, several researchers have suggested that no conclusive evidence has been presented in reducing the rate and/or severity of ACL injuries during sporting competition. Knee braces have been available for the last 30 years and have been used to assist individuals with ACL-deficient and ACL-reconstructed knees. However, research is limited on the use of knee braces (prophylactic and functional) to potentially prevent knee ligament injury in the non-injured population. One possible explanation for the limited research could be that the use of these devices has raised concerns of decreased or impaired athletic performance. In summary, the review of subjective and some objective publications suggests that a functional knee brace may offer stability to an ACL-deficient knee joint; however, research is limited on the use of a knee brace for prophylactic use in non-injured athletes. The limited research could be a result of fear of performance hindrance that has led to poor knee brace compliance. [ABSTRACT FROM AUTHOR]

The isotherms of sorption of ornithine, lysine, arginine, and histidine by an MK-40 membrane were obtained by the method of variable concentrations. The influence of the geometric parameters of side groups in the basic amino acids and pH on the degree of their absorption by the membrane was studied. The formation of doubly charged amino acid cations in the membrane phase when membranes in the H+ form were used was substantiated IR spectroscopically. The distribution coefficient was found to depend linearly on the size of amino acid side groups. The dependence of interphase surface tension at the membrane-solution interface on the degree of membrane filling was indicative of the formation of sorbate associates in the membrane phase. [ABSTRACT FROM AUTHOR]

This paper describes an annotation model of digital design representations which aims to provide the design actors with a way to communicate more clearly in asynchronous situations. Our objective is to develop a model that improves design communication through the elicitation of knowledge related to the context of design. We present a case study based on our observations in an industrial vehicle company where we observed and analysed annotation practices during design reviews. The speech act theory is used in order to propose a model based on the concept of locutionary and illocutionary annotation acts, and annotation categories are drawn from cognitive approaches of design. An annotation scenario is then developed on the basis of the case study as an illustration of our model. [ABSTRACT FROM AUTHOR]

Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor that has demonstrated substantial antitumour activity in patients with metastatic renal cell carcinoma. The more common grade 3 or 4 adverse effects of sunitinib include hypertension, fatigue, hand-foot syndrome, elevated lipase and lymphopenia. We report the case of a 69-year-old patient with metastatic renal clear-cell carcinoma, treated with nephrectomy and three lines of therapy (interleukin-2 plus interferon-a2a, vinorelbine plus gemcitabine, and capecitabine), who started a fourth-line therapy with oral sunitinib because of disease progression. At the end of his fifth cycle of sunitinib therapy, the patient complained of the development of abnormally large mammary glands associated with pain and peri-areolar erythema. After 2 weeks' off therapy, a partial reduction in mammary gland enlargement, local pain and erythema was observed. However, re-initiation of sunitinib treatment was followed by bilateral breast enlargement again. The mechanism by which sunitinib induces gynaecomastia is thought to be associated with an unknown direct action on breast hormonal receptors. To the best of our knowledge, this is the first report of an association between sunitinib and gynaecomastia. [ABSTRACT FROM AUTHOR]

Background and objectives: Few and mainly cross-sectional studies of glucose homeostasis are available in HIV-infected children treated with highly active antiretroviral therapy (HAART). The aim of the present study was to describe a 4-year course of glucose homeostasis in a cohort of HAART-treated children and adolescents, using glucose and insulin levels during an oral glucose tolerance test (OGTT) as outcome measures. In addition, we investigated possible risk factors, both related and unrelated to antiretroviral therapy, associated with insulin resistance. Methods: We assessed glucose metabolism yearly for 4 consecutive years in 37 HIV-infected children receiving a protease inhibitor (PI)-based HAART regimen containing lamivudine/stavudine plus indinavir or ritonavir or nelfinavir or a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based HAART regimen containing lamivudine/tenofovir/efavirenz. Generalized estimating equations were used to evaluate the relationship between the loge-transformed area under the serum concentration-time curve (AUC) of insulin during OGIT and antiretroviral therapy, controlling for time, sex, baseline age, puberty, body mass index and CD4+ T cells percentage. Results: Ritonavir-unboosted PI-based HAART regimens were administered to most children at baseline; however, their use decreased during follow-up in favour of an NNRTI-based regimen. The nelfinavir/lamivudine/stavudine (regression coefficient = -0.69, p < 0.05) and efavirenz/lamivudine/tenofovir (regression coefficient = -0.93, p < 0.05) regimens, but not the ritonavir/lamivudine/stavudine regimen, were negatively associated with loge-transformed insulin AUC compared with indinavir/lamivudine/stavudine. Puberty was positively associated with loge-transformed insulin AUC. Conclusions; This 4-year prospective study of HAART-treated HTV-infected children shows that; (i) the nelfinavir/lamivudine/stavudine and the efavirenz/ lamivudine/tenofovir regimens but not the ritonavir/lamivudine/stavudine regimen were associated with higher insulin sensivity, i.e. lower insulin AUC, compared with indinavir/lamivudine/stavudine; (ii) the treatment switched substantially in favour of NNRTI from the third year on and this change was associated with an improvement in insulin sensitivity compared with the previous HAART-based regimens; and (iii) puberty is a primary determinant of insulin sensitivity. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) remains the leading cause of morbidity and premature mortality in both women and men in most industrialized countries, and has for some time also established a prominent role in developing nations. In fact, obesity, diabetes mellitus and hypertension are now commonplace even in children and youths. Regular exercise is rapidly gaining widespread advocacy as a preventative measure in schools, medical circles and in the popular media. There is overwhelming evidence garnered from a number of sources, including epidemiological. prospective cohort and intervention studies, suggesting that CVD is largely a disease associated with physical inactivity. A rapidly advancing body of human and animal data confirms an important beneficial role for exercise in the prevention and treatment of CVD. In Part 1 of this review we discuss the impact of exercise on CVD. and we highlight the effects of exercise on (i) endothelial function by regulation of endothelial genes mediating oxidative metabolism, inflammation, apoptosis. cellular growth and proliferation, increased Superoxide dismutase (SOD)-l. down-regulation of p67phox changes in intracellular calcium level, increased vascular endothelial nitric oxide synthase (eNOS), expression and eNOS Ser-II77 phosphorylation; (ii) vascular smooth muscle function by either an increased affinity of the Ca2+ extrusion mechanism or an augmented Ca2+ buffering system by the superficial sarcoplasmic reticulum to increase Ca2+ sequestration, increase in K+ channel activity and/or expression, and increase in L-type Ca2+ current density; (iii) antioxidant systems by elevation of Mn-SOD, Cu/Zn-SOD and catalase. increases in glutathione peroxidase activity and activation of vascular nicotinamide adenine dinucleotide phosphate [(NAD(P)H] oxidase and p22phox expression; (iv) heat shock protein (HSP) expression by stimulating HSP70 expression in myocardium, skeletal muscle and even in human leucocytes, probably through heal shock transcription factor I activity; (v) inflammation by reducing serum infiammatory cytokines such as high-sensitivity C-reactive protein (hCRP). interleukin (IL)-6, IL-18 and tumour necrosis factor-a and by regulating Toll-like receptor 4 pathway. Exercise also alters vascular remodelling, which involves two forms of vessel growth including angiogenesis and arteriogenesis. Angiogenesis refers to the formation of new capillary networks. Arteriogenesis refers to the growth of pre-existent collateral arterioies leading to formation of large conductance arteries that are well capable to compensate for the loss of function of occluded arteries. Another aim of this review is to focus on exercise-related cardiovascular protection against CVD and associated risk factors such as aging, coronary heart disease, hypertension, heart failure, diabetes mellitus and peripheral arterial diseases mediated by vascular remodelling. Lastly, this review examines the benefits of exercise in mitigating pre-eclampsia during pregnancy by mechanisms that include improved blood flow, reduced blood pressure, enhanced placental growth and vascularity, increased activity of antioxidant enzymes, reduced oxidative stress and restored vascular endothelial dysfunction. [ABSTRACT FROM AUTHOR]

We report here our studies on the clinical efficacy of courses of magnetophoresis of glutamic acid and magnesium sulfate in the complex rehabilitation treatment of preschool children with spastic types of cerebral palsy. Clinical-neurophysiological investigations were performed in 40 children aged 1–7 years. Treatment was significantly more effective when use of running pulsed magnetic fields was combined with medicinal agents as compared with magnetotherapy using the same regime. [ABSTRACT FROM AUTHOR]

Objective: The pharmacokinetics of mycophenolic acid (MPA) were compared in renal transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). Methods: MPA concentration-time profiles were included from EC-MPS- (n = 208) and MMF-treated (n = 184) patients 4-257 months after renal transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling (NONMEM®). A two-compartment model with first-order absorption and elimination was used to describe the data. Results: No differences were detected in MPA clearance, intercompartmental clearance, or the central or peripheral volume of distribution. Respective values and interindividual variability (IIV) were 16 L/h (39%), 22 L/h (78%), 40 L ( 100%) and 518 L (490%). EC-MPS was absorbed more slowly than MMF with respective absorption rate constant values of 3.0 h-1 and 4.1 h-l (p<0.001) [IIV 187%]. A mixture model was used for the change-point parameter lag-time (tiag) in order to describe IIV in this parameter adequately for EC-MPS. Following the morning dose of EC-MPS, the tlag values were 0.95, 1.88 and 4.83 h for 51%, 32% and 17% of the population (IIV 8%), respectively. The morning tlag following EC-MPS administration was significantly different from both the tlag following MMF administration (0.30 h; p < 0.001 [IIV 11%]) and the tlag following the evening dose of EC-MPS (9.04 h; p < 0.001 [IIV 40%J). Post hoc analysis showed that the tlag was longer and more variable following EC-MPS administration (morning median 2.0 h [0.9-5.5 h], evening median 8.9 h [5.4-12.3 h]) than following MMF administration (median 0.30 h [0.26-0.34 h]; p < 0.001). The morning MPA predose concentrations were higher and more variable following EC-MPS administration than following MMF administration, with respective values of 2.6 mg/L (0.4-24.4 mg/L) and 1.6 mg/L (0.2-7.6 mg/L). The correlation between predose concentrations and the area under the plasma concentration-time curve (AUC) was lower in EC-MPS-treated patients (r² = 0.02) than in MMF-treated patients (r² = 0.48). Conclusion: Absorption of MPA was delayed and also slower following EC-MPS administration than following MMF administration. Furthermore, the tiag varied more In EC-M PS-treated patients. MPA predose concentrations were poorly correlated with the MPA AUC in both MMF- and EC-MPS-treated patients. [ABSTRACT FROM AUTHOR]

The review discusses available data on asymmetric Diels-Alder reactions of cyclopentadiene, which were published in the past decade. Both noncatalytic and catalytic (in the presence of achiral and chiral catalysts) versions of these reactions are considered. Effects of various factors on the chemical and optical yields, stereoselectivity, and optical purity of the Diels-Alder adducts are analyzed. Prospects in the development of this field of organic chemistry are examined. [ABSTRACT FROM AUTHOR]

Trastuzumab is a monoclonal antibody that targets the human epidermal growth factor receptor tyrosine kinase HER2/ErbB2. This agent has shown a highly significant antitumour effect for patients with HER2-positive breast cancer, and is now considered part of the standard regimens for the treatment of this disease in both the metastatic and adjuvant setting. Cardiotoxicity has been associated with trastuzumab, and this issue has now been studied and documented in a number of adjuvant trials for which data have now been released. Cardiotoxicity has been shown to be potentiated when the agent is used concurrently or sequentially with an anthracycline, and this has limited the use of trastuzumab in some patients. Determining the overall impact of trastuzumab is further complicated by the administration of other cardiotoxic agents such as the taxanes and cyclophosphamide as well as by pre-existing cardiac disease. The incidence of severe congestive heart failure (New York Heart Association class III or IV) was 0-3.9% in the trastuzumab arms versus 0-1.3% in the control arms in the five major randomized adjuvant trials. Only one cardiac death was related to trastuzumab whereas two cardiac deaths occurred in the control arms. Ejection fraction decline of >or=10% or 15% was reported in 3-34% of trastuzumab recipients in these trials. Patients affected by trastuzumab-related cardiotoxicity do not exhibit the cellular death and distinctive ultrastructural myocardial changes seen on electron microscopy with anthracycline-induced cardiotoxicity. The cardiotoxicity of trastuzumab also differs from traditional chemotherapy-induced cardiotoxicity in that it appears to be at least partially reversible, not related to the cumulative dose, and re-challenge is generally tolerated. There remain a number of uncertainties regarding the diagnosis and management of trastuzumab-related cardiotoxicity. While no formal guidelines or consensus statements exist at present regarding cardiac monitoring during use of trastuzumab, proposed recommendations include a careful assessment of ejection fraction prior to initiating trastuzumab, avoidance of concurrent administration of trastuzumab with anthracyclines, and regular monitoring of symptoms and cardiac function during and for several years after therapy. Increased vigilance is appropriate for higher risk patients. [ABSTRACT FROM AUTHOR]

Abstract  A medium access control (MAC) protocol (NULLHOC) for ad hoc networks of nodes with antenna arrays is presented. The antenna array is used for transmit and receive beamforming with the purpose of increasing spatial reuse by directing nulls at active transmitters and receivers in the neighborhood. In contrast to previous work with directional antennas, our approach is applicable to multipath channels, such as occur indoors or in other rich scattering environments. The MAC protocol is designed to support the control information exchange needed to direct nulls toward other users involved in existing communication sessions. Knowledge of the channel coefficients between a transmitter or receiver and its neighbors is used to design transmit or receive beamformer weights that implement the requisite nulling. Simulations are used to demonstrate the improvements in throughput and transmit powers that are obtained in this approach relative to the IEEE 802.11 MAC protocol. We also analyze the effects of channel estimation errors on our protocol and propose a simple modification of the basic (NULLHOC) protocol to minimize their impact. [ABSTRACT FROM AUTHOR]

Aliskiren (Tekturna®) is an orally active, nonpeptidic inhibitor of renin, the enzyme involved in the initial and rate-limiting step of the renin-angiotensin system (RAS). In the US, aliskiren is approved for the treatment of hypertension and may be used alone or in combination with other antihypertensive agents. Monotherapy with aliskiren 150-300mg once daily was effective in lowering blood pressure (BP) and providing 24-hour BP control; it was getter ally well tolerated when administered for up to 1 year to patients with mild to moderate hypertension. In the short term (1-3 months), the BP-lowering effect of aliskiren 150-300mg once daily was significantly greater than that of hydrochlorothiazide (HCTZ) 12.5-25mg once daily and noninferior to, or significantly greater than, that of ramipril 5-10mg once daily. It was similar to that of valsartan 160-320mg once daily and losartan 100mg once daily, and similar to, or significantly greater than, that of irbesartan 150mg once daily. Aliskiren provided significant additional BP-lowenng effects when combined with HCTZ 12.5-25 mg/day. ramipril 5-10 mg/day, amlodipine 5mg once daily or valsartan 160-320 mg/day; combination therapy was well tolerated. Long-term administration of aliskiren-based therapy was superior to HCTZ- and ramipril-hased therapies in lowering BP after 6 months, and was similarly well tolerated. The ultimate role of aliskiren will be determined by the results of target organ protection studies, which are ongoing, and a cardiovascular outcome trial, which is planned. Nonetheless, by offering a new approach to the blockade of the RAS, aliskiren provides a useful addition to the therapeutic options available to treat patients with mild to moderate hypertension. [ABSTRACT FROM AUTHOR]

This review summarises the present knowledge of infliximab therapy in children with inflammatory bowel disease (IBD) based on the available published literature. Infliximab, the chimeric monoclonal IgG1 antibody to tumour necrosis factor a, is indicated for medically refractory luminal and fistulising paediatric Crohn's disease. Recently. ulcerative colitis case series in children and adolescents suggested that infliximab might also be effective for treatment of ulcerative colitis resistant to standard medical therapy. Induction therapy with infliximab 5 mg/kg at weeks 0, 2 and 6 is routinely used. Since the majority of patients will relapse if not re-treated, a long-term approach with systematic re-treatment with 5 mg/kg every 8-12 weeks is recommended. Maintenance therapy every 8 weeks was superior to 12 weeks' administration in maintaining response and remission in the largest-to-date paediatric randomised trial. Concomitant immunosuppressive therapy reduces the risk of infliximab antibody formation and infusion reactions, and prolongs the duration of treatment success. Severe reactions may not be an absolute contraindication to future infliximab therapy. Premedication does not prevent the development of infusion reactions; however, it is indicated for prevention of subsequent infusion reactions. Adverse events and safety findings in children are comparable to those observed in adults. Latent tuberculosis needs to be screened for. Malignancy rates in paediatric patients treated with infliximab do not seem to be increased. However, newly reported cases of hepatosplenic T-cell lymphoma in young patients with IBD treated with infliximab and mercaptopurine therapy raise concern, and Long-term follow-up studies are necessary to determine the true malignancy risk. [ABSTRACT FROM AUTHOR]

From the discovery of FHV-1 integrase (IN) inhibitors using enzyme-based assays in 1992, it has taken 15 years to achieve success in human clinical trials. Currently available antiretroviral drugs set high clinical standards in efficacy and long-term safety for upcoming novel HIV/AIDS therapeutic agents. The results from advanced stages of human clinical trials with IN inhibitors indicate a promising future for these compounds as a novel class of antiretroviral drugs. Success and failure of previously discovered antiretroviral drugs have taught us that there are no magic bullets in eradicating HIV. However, approval of drugs selectively targeting IN has long been awaited. There is once again a surge of interest in the field focusing on clinical development of IN inhibitors. Here, we summarise the current status of IN inhibitors under clinical development. These agents include S-1360, GSK-364735, L-870,810, L-870,812, MK-0518, GS-9137, L-900564, GS-9224, and BMS-707035. Promising antiviral activity has already been achieved with MK-0518 and GS-9137 in late-stage clinical studies. [ABSTRACT FROM AUTHOR]

Anterior cruciate ligament (ACL) rupture is a common sporting injury, often managed surgically with patella-tendon or hamstrings-gracilis autograft. Some people who sustain the injury, request information about their prognosis if they choose to forgo surgery and opt for conservative management. Numerous studies provide data on the prognosis of conservatively managed ACL injuries. These studies have not been systematically reviewed. Thus, the aims of this systematic review are to describe the natural history and clinical course of function and proprioception in the conservatively managed ACL-deficient knee, and to identify prognostic factors. We searched MEDLINE, CINAHL, EMBASE, SportDiscus, PEDro and the Cochrane Central Register of Clinical Trials without language restrictions from the earliest record available up to July 2006. We also searched the Science Citation Index, and iteratively searched bibliographies for prospective studies of outcomes (>6 months follow-up) of conservatively managed complete ACL tears. Six criteria were used to assess the methodological quality of included studies. The main outcome measures were self-reported measures of knee function, activity level, performance in functional tasks and knee proprioception. Fifteen studies of variable methodological quality were included in the review. On average, patients with mixed or isolated ACL-deficient knees reported good knee function (87/100 Lysholm knee scale) at follow-up duration of 12-66 months. On average, functional performance assessed with the hop-for-distance test, was in the normal range. From pre-injury to follow-up there was a reduction in Tegner activity level of 21.3%. According to the methods used in the assessed studies, conservatively managed ACL-deficient knees have a good short-to mid-term prognosis in terms of self-reported knee function and functional performance. However, subjects reduced their activity levels on average by 21% following injury. [ABSTRACT FROM AUTHOR]

Satraplatin [BMS 182751, BMY 45594, JM 216] belongs to a series of orally-active platinum compounds with anticancer activity. It was jointly originated by Bristol-Myers Squibb, Johnson Matthey and the Institute of Cancer Research in the UK; however, Johnson Matthey has since ceased involvement with drug development. Subsequently, the agent has been licensed to and is under development with GPC Biotech, Pharmion and Spectrum Pharmaceuticals. Clinical trials are underway to evaluate satraplatin among patients with different tumour types, including prostate, breast, cervical and lung cancers. The compound is under regulatory review with the US FDA for the treatment of hormone-refractory prostate cancer. NeoTherapeutics (now Spectrum Pharmaceuticals) granted GPC Biotech an exclusive worldwide licence to develop and market satraplatin in October 2002. Under the terms of the agreement, GPC Biotech is fully funding development costs and commercialisation requirements for the drug. The deal also involves GPC Biotech paying a signing fee, milestone and royalty payments. Spectrum is a member of a joint development committee headed by GPC Biotech to govern development of satraplatin. Previously in October 2001, NeoOncoRx (Spectrum Pharmaceuticals) gained the rights to develop and market the compound worldwide. In December 2005, GPC Biotech and Pharmion Corporation entered into a codevelopment and license agreement for satraplatin. Under the agreement terms, Pharmion has exclusive commercialisation rights for Europe, Turkey, the Middle East, Australia and New Zealand, while GPC Biotech retains rights to North America and all other territories. Pharmion made an upfront payment of $US37. 1 million to GPC Biotech, which included reimbursement for past clinical development costs plus funding for ongoing and certain clinical development activities to be jointly conducted by the companies. In addition, both parties will pursue a joint development plan for satraplatin in a variety of tumour types and will share global development costs, for which Pharmion has made an additional commitment of $US22.2 million. GPC Biotech could also receive up to $US270 million in milestone payments and royalties on sales. Both companies will manage regulatory and commercial activities in their respective territories. A registrational phase III study is ongoing among 950 patients with I-IRPC. This global, multicentre, randomised study, called SPARC (Satraplatin and Prednisone Against Refractory Cancer), is assessing satraplatin plus prednisone versus prednisone alone as second-line therapy in HRPC patients. Top-line results from the trial showed that patients who received satraplatin plus prednisone had a 40% reduction in the risk of progression compared with patients who received prednisone plus placebo. In accordance with the recommendation of the independent Data Monitoring Board for the SPARC trial, patients who have not progressed will continue to be treated and all patients will be followed for overall survival. The company expects to have final overall survival results in the fall of 2007. The company intends to complete the NDA filing with the FDA before the end of 2006. In February 2006, GPC Biotech raised &3x20AC;36.2 million from a private placement of shares; the funds will be used in the commercialisation of satraplatin in the US. GBC Biotech received a Scientific Advice letter from the EMEA in January 2004, enabling the company to use the SPARC trial for registrational plans in both Europe and the US. Data from the pivotal phase III trial are expected in the second half of 2006. If positive, the findings will form the basis of a MAA filing with the EMEA for satraplatin as a second-line therapy of HRPC.… [ABSTRACT FROM AUTHOR]

There are many surveillance systems of congenital defects all over the world; several of them have developed specific approaches to generate and test selected hypotheses regarding human teratogens. However, to the best of our knowledge, none of them have a permanent and systematised programme for the study of the risk and safety of drugs. The aim of this article is to describe the research programme on the potential effects of drugs in pregnancy followed by the Spanish Collaborative Study of Congenital Malformations (ECEMC), which is a permanent ongoing case-control study and surveillance system. The programme to analyse drugs includes a continuous and systematic study on the potential effects of medicines used during pregnancy. This programme has several characteristics that make it different from other current systems: (i) the collection of numerous datapoints (up to 312 per infant) in a case-control design; (ii) the use of a versatile and specific coding of birth defects; (iii) a specific programme for the continuous analysis of the potential effects of each type of drugs used during pregnancy that has been developed specifically for the ECEMC methodology, including its dysmorphological coding system. The description of the ECEMC's approach to surveillance of the effects of drug use during pregnancy may help researches in this area, particularly those using data from birth defects registries. [ABSTRACT FROM AUTHOR]

Sitagliptin, an oral dipeptidyl peptidase-4 (DPP-4) inhibitor, improves glycaemic control by inhibiting DPP-4 inactivation of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. This increases active incretin and insulin levels, and decreases glucagon levels and post-glucose-load glucose excursion. In large, well designed phase III trials in patients with type 2 diabetes mellitus, sitagliptin 100 or 200mg once daily alone or in combination with other antihyperglycaemics was associated with significant improvements relative to placebo in overall glycaemic control and indices for insulin response and beta-cell function. Improvements from baseline in mean glycosylated haemoglobin (HbA(1c)) were significantly greater with sitagliptin monotherapy than with placebo in patients with type 2 diabetes. As add-on therapy in patients with suboptimal glycaemic control despite oral antihyperglycaemic treatment, sitagliptin improved HbA(1c) to a significantly greater extent than placebo when added to metformin or pioglitazone and was noninferior to glipizide when added to metformin.black triangle Sitagliptin was well tolerated when administered alone or in combination with other antihyperglycaemics, with an adverse event profile similar to that shown with placebo. The incidence of hypoglycaemia with sitagliptin was similar to that with placebo and, in combination with metformin, lower than that with glipizide. Sitagliptin had a generally neutral effect on bodyweight. [ABSTRACT FROM AUTHOR]

Telemedicine is facing multiple challenges to be established on a broad basis. To overcome these barriers strategies have to be developed with respect to current and future market drivers and restraints. Against the background of the promising revenue forecast for the European market of euro 900 million by 2011, telemedicine is a very promising field for all health care providers. In cardiology, solutions for 'pHealth' and 'eHealth' are already very sophisticated using the outcome of the 'MyHeart' project. As an enabler for 'eHealth' an advanced IT infrastructure such as the German electronic health card is essential. To fulfill the growth promises telemedicine has to pay attention to the auxiliary areas of telemetric, medical information, health research service, content and IT telematic infrastructure. The development of telemedicine will remain a highly interesting and a challenging field. [ABSTRACT FROM AUTHOR]

The tropical diabetic hand syndrome (TDHS) is a complication affecting patients with diabetes mellitus in the tropics. The syndrome encompasses a localized cellulitis with variable swelling and ulceration of the hands, to progressive, fulminant hand sepsis, and gangrene affecting the entire limb. TDHS is less well recognized than foot infections and not generally classified as a specific diabetes complication. Hand infection was first described in Nigeria in 1984. Since then, the majority of cases have been reported in the African continent and more recently in India. There is often a history of antecedent minor hand trauma (e.g. scratches or insect bites). Presentation to hospital is often delayed due to the patients’ unawareness of the potential risks, lack of concern because the initiating trauma might have been trivial, or decision to seek initial help from traditional healers. The first analytic study was done in Dar es Salaam, Tanzania, to characterize the epidemiology, clinical characteristics and risk factors of TDHS. Independent risk factors for TDHS include poorly controlled diabetes, neuropathy, insulin treatment or malnutrition. Clinicians should be aware of these complications and be prepared to immediately admit TDHS patients to hospital for aggressive surgical intervention (i.e. debridement, pus drainage or amputation) and high-dose, intravenous, broad-spectrum antibacterial therapy that includes anti-anaerobic activity. Without prompt, aggressive treatment TDHS can lead to permanent disability, limb amputation (13% of TDHS patients require major upper limb amputation), or death. Prevention strategies include patient and staff education that focuses on proper hand care, nutrition, and the importance of seeking medical attention immediately following hand trauma regardless of the severity of the injury, or at the earliest onset of hand-related symptoms, such as redness or swelling. Prevention of permanent disability and death due to TDHS will require improved management of glycemic levels in resource-limited countries, and surgical intervention during less severe stages of the condition. [ABSTRACT FROM AUTHOR]

As psoriasis and psoriatic arthritis are chronic in nature, ideal treatment should have sustained efficacy, with minimal short- and long-term toxicities to allow lifelong treatment. Traditional therapies used for psoriatic arthritis or psoriasis, including phototherapies and systemic agents, do not satisfy these criteria. Ninety percent of patients surveyed in 1998 by The National Psoriasis Foundation were not satisfied with their treatment options. Several observations have supported the introduction of the tumor necrosis factor (TNF) antagonist etanercept as a treatment for psoriatic disease, including the failure of traditional therapies to meet patient needs, evidence that TNF plays a fundamental role in the inflammatory processes underlying psoriatic arthritis and psoriasis, and the safety and efficacy of this agent in other inflammatory, immune-mediated diseases, such as rheumatoid arthritis (RA). Etanercept prevents initiation of the proinflammatory cascade by competitively binding TNF. First indicated for RA, etanercept is also approved for the treatment of psoriatic arthritis, juvenile RA, ankylosing spondylitis, and most recently psoriasis. Etanercept provides dermatologists with a safe, effective, and convenient treatment option for patients with psoriatic arthritis and psoriasis, which can be used continuously with or without traditional therapies. The self-administered injections provide a distinct advantage over traditional therapies that often require frequent office visits and laboratory monitoring, and other biologic agents that require administration in the doctor’s office. Dermatologists should be aware of the ongoing research with etanercept in psoriasis and other dermatologic conditions. [ABSTRACT FROM AUTHOR]

These are the abstracts presented during the 2004 International Society of Pharmacovigilance. A study about the frequency of hypertension induced by cyclosporine A in renal transplant patients. A cross-sectional survey about spontaneous reporting of adverse drug reactions associated with herbal medicines. A case crossover study about the risk of upper gastrointestinal bleeding with non-steroidal anti-inflammatory drugs in children. A case about serotonin syndrome induced by mirtazapine monotherapy. A report on the organization of regional centers of pharmacovigilance in Sicily, Italy.

Pemetrexed inhibits several folate-dependent enzymes, thereby inhibiting both thymidine synthesis and purine nucleotide synthesis. The median survival time of patients with NSCLC treated with pemetrexed 500 mg/m² monotherapy every 21 days versus docetaxel 75 mg/m² every 21 days in a second-line setting was 8.3 and 7.9 months (hazard ratio = 0.99, 95% CI 0.82-1.20, with a preset 95% CI upper limit of <1.11) in a phase III randomized, nonblind, multicenter trial (n = 571). In a phase III randomized, single-blind, multicenter trial (n = 448) in chemotherapy-naive patients with malignant pleural mesothelioma (MPM), pemetrexed 500 mg/m² plus cisplatin 75 mg/m² every 21 days was better in terms of median survival time (12.1 vs 9.3 months; hazard ratio 0.77, p < 0.05) and tumor response rates (41.3% vs 16.7%, p < 0.001) than cisplatin 75 mg/m² every 21 days. During the MPM trial, a protocol change required all patients to receive supplementation with oral folic acid daily and intravenous cyanocobalamin once every 9 weeks (i.e. supplementation) because of pemetrexed toxicity. Pemetrexed was generally well tolerated as monotherapy in patients with advanced NSCLC and as combination therapy in patients with MPM if supplemented. In patients with NSCLC, neutropenia, alopecia, and fatigue were the most common adverse events, whereas in patients with MPM they were neutropenia, leukopenia, nausea, and vomiting. Severe toxicities in pemetrexed recipients in the NSCLC trial were infrequent. [ABSTRACT FROM AUTHOR]

Objective: Optimal [13C]-urea breath test (UBT) conditions for diagnosis of Helicobacter pylori infection are still being fine-tuned. In the present study we investigated the impact of delaying gastric emptying by different meal substrates or L-DOPA, a drug known to induce gastric stasis, on the performance of the [13C]-UBT. Methods: A total of 115 patients participated in the study. On two consecutive days, participants ingested [13C]-urea (100 mg) 10 min after either 270 ml of a mixed formula meal (1 Kcal/ml) or an equivalent amount of tap water. In 11 participants two additional tests were performed with or without oral 500 mg L-DOPA given 30 min before [13C]-urea load. The 13C/12C ratio in a basal breath sample was compared with ratios in samples collected 30 and 60 min after [13C]-urea. Histological assessment of H. pylori presence in antral biopsy served as reference standard. Results: Formula UBT showed excellent specificity (100% at 30 and 60 min) and good sensitivity (97% at both time intervals), whereas water UBT had the same specificity but slightly lower sensitivity (94% at 30 min and 73% at 60 min). In formula UBT, 13C/12C ratios were higher at 60 min than at 30 min (21.7 ± 2 vs 17.7 ± 1.8‰ respectively.; p < 0.01, whereas in water UBT 13C/12C ratios were higher at 30 min than at 60 min (13.9 ± 1.5 vs 8.4 ± 0.09‰ respectively, p < 0.01). Pretreatment with L-DOPA did not modify either the sensitivity or the specificity of the UBT. Conclusions: The performance of the [13C]-urea with a formula meal may not be improved by pharmacologically delaying gastric emptying. A short, water-based test may be a sensible approach to worldwide standardization of the [13C]-UBT for H. pylori infection. [ABSTRACT FROM AUTHOR]

We study approximations of functions from the sets $$\hat L_\beta ^\psi \mathfrak{N}$$ , which are determined by convolutions of the following form: where η is a fixed subset of functions with locally integrable pth powers ( p≥1). As approximating aggregates, we use the so-called Fourier operators, which are entire functions of exponential type ≤ σ. These functions turn into trigonometric polynomials if the function ϕ(·) is periodic (in particular, they may be the Fourier sums of the function approximated). The approximations are studied in the spaces L determined by local integral norms ∥·∥. Analogs of the Lebesgue and Favard inequalities, wellknown in the periodic case, are obtained and used for finding estimates of the corresponding best approximations which are exact in order. On the basis of these inequalities, we also establish estimates of approximations by Fourier operators, which are exact in order and, in some important cases, exact with respect to the constants of the principal terms of these estimates. [ABSTRACT FROM AUTHOR]

In this paper, a novel raised p−n junction formation technique is presented. The technique makes use of in- situ doped, selectively deposited SiGe as a solid diffusion source. In this study, the films were deposited in a tungsten halogen lamp heated cold-walled rapid thermal processor using SiClH, GeH, and BH. The microstructure of the SiGe layer resembles that of a heavily defected epitaxial layer with a high density of misfit dislocations, micro-twins, and stacking faults. Conventional furnace annealing or rapid thermal annealing were used to drive the boron from the in- situ doped SiGe source into silicon to form ultra-shallow p−n junctions. Segregation at the SiGe/Si interface was observed resulting in an approximately 3:1 boron concentration discontinuity at the interface. Junction profiles as shallow as a few hundred angstroms were formed at a background concentration of 10 cm. [ABSTRACT FROM AUTHOR]

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Let M be a compact riemannian manifold, h an odd function such that h(r)/r is non-decreasing with limit 0 at 0. Let f(r)=h(r)-γr and assume there exist non-negative constants A and B and a real p>1 such that f(r)> Ar -B. We prove that any non-negative solution u of u +Δu=f(u) on M x ℝ satisfying Dirichlet or Neumann boundary conditions on ϖ M converges to a (stationary) solution of ΔΦ= f(Φ) on M with exponential decay of | u-Φ| C (M). For solutions with non-constant sign, we prove an homogenisation result for sufficiently small λ; further, we show that for every λ the map ( u(0,·), u (0,·))→( u(t,·), u (t,·)) defines a dynamical system on W ( M)⊂ C(M)× L ( M) which possesses a compact maximal attractor. [ABSTRACT FROM AUTHOR]

The evolving manufacturing environment is characterized by a drive toward increasing flexibility. One possible manifestation of flexibility within an FMS is in the form of routing flexibility. Providing this typically is an expensive proposition, and system designers therefore aim to provide only the required levels commensurate with a given set of operating conditions. This paper presents a framework based on a Taguchi experimental design for studying the nature of the impact of varying levels of routing flexibility on the performance of an FMS. Simulation results indicate that increases in routing flexibility, when made available at the cost of an associated penalty on operation processing time, is not always beneficial. There is an optimal flexibility level, beyond which system performance deteriorates, as judged by the makespan measure of performance. It is suggested that the proposed methodology can be used in practice for not only setting priorities on specific design and control factors but also for highlighting likely factor level combinations that could yield near-optimal shop performance. [ABSTRACT FROM AUTHOR]

After administration of purified l-C-3-methoxytyrosine ( l-C-3-MTO) to rats, the fractions of labelled amino acids, catecholamines and phenolcarboxylic acids of urine and brain have been separated by column chromatography. Prior to performing the quantitative determinations, the individual metabolites of each urinary fraction and of the cerebral catecholamine fraction were isolated by paper chromatography using different systems. Susbtantial amounts of C-3,4-dihydroxyphenylacetic acid (C-DOPAC) as well as some C-3,4-dihydroxyphenylalanine (C-DOPA) and traces of dopamine (DA) appeared in the urine. Furthermore, small amounts of C-DA and C-norepinephrine were found in the brain with two different chromatographic systems. The urinary excretion of C-DOPAC and C-DA was increased by pretreatment with dopacetamide, an inhibitor of catechol-3-O-methyl-transferase. A possible contamination of the l-C-3-MTO with traces of l-C-DOPA as a major source of the dihydroxylated metabolites has been ruled out. It is concluded that part of l-3-MTO undergoes demethylation in vivo and that the finding of DA in brain and urine after administration of l-3-MTO is not an artifact. [ABSTRACT FROM AUTHOR]

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Mice were given L-DOPA i.p. in doses ranging from 7.8 to 500 mg/kg with and without previous administration of MK 485, a compound capable of inhibiting extracerebral dopa decarboxylase. In addition, dexchlorpheniramine together with MK 485 was given before L-DOPA to some of the animals. Spontaneous locomotor activity of the animals was measured and some preliminary biochemical determinations were performed of dopamine, noradrenaline and 5-hydroxytryptamine levels in brain. It was found, that L-DOPA had both depressant and excitatory effects on locomotor activity depending on dose, and that MK 485 caused a potentiation of both these effects, together with an increased dopamine production in the brain. Dexchlorpheniramine caused a further potentiation of the effects on activity, evidently without affecting the total dopamine level in the brain. On the basis of these data, it was concluded that even the depressant effects on motility, seen after administration of L-DOPA, are probably mediated at least in part centrally. Apparently MK 485 potentiates L-DOPA effects on activity, simply by letting more of the DOPA injected pass through the blood-brain barrier and form dopamine intracerebrally. Further investigations are required to obtain information on the mechanism of the DOPA-potentiating action of dexchlorpheniramine. [ABSTRACT FROM AUTHOR]

Rat irises exposed to DOPA in vitro and subsequently treated with the histochemical technique of Falck and Hillarp for catecholamines show accumulation of a fluorescent formaldehyde condensation product within the capillary endothelial cells. A similar accumulation was observed when rat irises were exposed to 5-OH-Tryptophan and α-methyl-dopa but not after exposure to the corresponding amines. Fluorescent products were also observed in the same cells when control irises were treated with the trihydroxyindole histochemical reaction. It is concluded that certain catechol and indole amino acids accumulate within the endothelial cells of the rat iris capillaries in a manner similar to that observed in brain capillaries. Furthermore, small amounts of DOPA are probably present within these cells normally. [ABSTRACT FROM AUTHOR]