Insulin resistance, obesity and the metabolic syndrome. Is there a therapeutic role for endothelin-1 antagonists?

There is increasing evidence to suggest that chronic activation of the endothelin-1 system can lead to heterologous desensitization of the glucose-regulatory and mitogenic actions of insulin with subsequent development of glucose intolerance, hyperinsulinemia, impaired endothelial function and exacerbation of cardiovascular disease. Effects are mediated through a variety of mechanisms that include attenuation of key insulin signalling pathways and decreased tyrosine phosphorylation of insulin receptor substrates IRS-1, SHC and G alpha q/11. Other actions involve hemodynamic changes leading to reduced delivery of insulin and glucose to peripheral tissues as well as enhanced hepatic glycogenolysis, decreased glucose-transporter translocation and modulation of various adipokines that regulate insulin action. Overall the data suggest that ET-1 antagonists may provide an effective means of improving cardiac dysfunction and favourably influencing glucose tolerance in obese humans and patients with early insulin sensitivity where there is clear evidence for activation of the ET-1 system. Although most effects of ET-1 that modulate mechanisms leading to glucose intolerance appear to involve the ETA receptor subtype recent data indicates that combined ETA/ETB receptor antagonists may function as effectively as selective ETA blockers. Prospective trials are needed to assess whether ET-1 antagonists, either alone or in combination, are superior to other more conventional therapies such as insulin sensitizers and to evaluate effects of combined treatments on the development of insulin resistance and the progression of diabetes. Early screening of patients at risk for evidence of ET-1 activation would help to identify subjects who may benefit most from such treatment.

The blood-central nervous system barriers actively control immune cell entry into the central nervous system

Before entering the central nervous system (CNS) immune cells have to penetrate any one of its barriers, namely either the endothelial blood-brain barrier, the epithelial blood-cerebrospinal fluid barrier or the tanycytic barrier around the circumventricular organs, all of which maintain homeostasis within the CNS. The presence of these barriers in combination with the lack of lymphatic vessels and the absence of classical MHC-positive antigen presenting cells characterizes the CNS as an immunologically privileged site. In multiple sclerosis a large number of inflammatory cells gains access to the CNS parenchyma. Studies performed in experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis, have enabled us to understand some of the molecular mechanisms involved in immune cell entry into the CNS. In particular, the realization that /alpha4-integrins play a predominant role in leukocyte trafficking to the CNS has led to the development of a novel drug for the treatment of relapsing-remitting multiple sclerosis, which targets /alpha4-integrin mediated immune cell migration to the CNS. At the same time, the involvement of other adhesion and signalling molecules in this process remains to be investigated and novel molecules contributing to immune cell entry into the CNS are still being identified. The entire process of immune cell trafficking into the CNS is strictly controlled by the brain barriers not only under physiological conditions but also during neuroinflammation, when some barrier properties are lost. Thus, immune cell entry into the CNS critically depends on the unique characteristics of the brain barriers maintaining CNS homeostasis.

Effect of the NMDA-receptor antagonist dextromethorphan in infant rat pneumococcal meningitis

Excitatory amino acids (EAA) and particularly glutamate toxicity have been implicated in the pathogenesis of neuronal injury occurring in bacterial meningitis by activating the N-methyl-d aspartate (NMDA) receptor complex. Here, we evaluated the effect of adjuvant treatment with the antitussive drug dextromethorphan (DM), a non-competitive NMDA receptor antagonist with neuroprotective potential, in an infant rat model of pneumococcal meningitis. The experiments were carried out in postnatal day 6 (P6) and 11 (P11) animals. Pharmacokinetics of DM and its major metabolite dextrorphan (DO) were performed for dose finding. In our study, DM did not alter clinical parameters (clinical score, motor activity, incidence of seizures, spontaneous mortality) and cortical neuronal injury but increased the occurrence of ataxia (P<0.0001). When DM treatment was started at the time of infection (DM i.p. 15 mg/kg at 0, 4, 8 and 16 hours (h) post infection) in P11 animals, an aggravation of apoptotic neuronal death in the hippocampal dentate gyrus was found (P<0.05). When treatment was initiated during acute pneumococcal meningitis (DM i.p. 15 mg/kg at 12 and 15 h and 7.5 mg/kg at 18 and 21 h after infection), DM had no effect on the extent of brain injury but reduced the occurrence of seizures (P<0.03). We conclude that in this infant rat model of pneumococcal meningitis interference of the EEA and NMDA pathway using DM causes ataxia, attenuates epileptic seizures and increases hippocampal apoptosis, but is not effective in protecting the brain from injury.

Targeting Myc in pediatric malignancies of the central and peripheral nervous system

Myc family genes are often deregulated in embryonal tumors of childhood including medulloblastoma and neuroblastoma and are frequently associated with aggressive, poorly differentiated tumors. The Myc protein is a transcription factor that regulates a variety of cellular processes including cell growth and proliferation, cell cycle progression, differentiation, apoptosis, and cell motility. Potential strategies that either inhibit the proliferation-promoting effect of Myc and/or activate its pro-apoptotic function are presently being explored. In this review, we will give an overview of Myc activation in embryonal tumors and discuss current strategies aimed at targeting Myc for cancer treatment.

Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies

The association between subclinical thyroid dysfunction and cardiovascular outcomes has been recently clarified with the publication of three individual participant data (IPD) analyses from the Thyroid Studies Collaboration. We identified original cohort studies with a systematic review and pooled individual data from over 70'000 participants to obtain a more precise estimate of the risks of cardiovascular outcomes associated with subclinical thyroid dysfunction. Subclinical hypothyroidism and subclinical hyperthyroidism, defined as normal thyroxine (FT4) levels with increased or decreased Thyroid-Stimulating Hormones (TSH or thyrotropin) respectively, are associated with increased risk of cardiovascular outcomes compared to euthyroid state, particularly in those with a more pronounced thyroid dysfunction. Specifically, subclinical hypothyroidism is associated with an increased risk of coronary heart disease (CHD) events, CHD mortality and heart failure (HF) events in individuals with higher TSH levels, particularly in those with TSH levels ≥10.0 mIU/L. Conversely, subclinical hyperthyroidism is associated with an increased risk of total mortality, CHD mortality, HF and atrial fibrillation, particularly in those with suppressed TSH levels <0.10 mIU/L. Pending ongoing randomized controlled trials, these observational findings allow identifying potential TSH thresholds for thyroid medication initiation based on risk of clinical outcomes, although clinical decision based solely on observational data need caution. The impact of thyroid replacement among the elderly with subclinical hypothyroidism is currently studied in a multicenter international randomized controlled trial (Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial, TRUST trial).

G-CSF induced arteriogenesis in humans: molecular insights into a randomized controlled trial

AIMS Recent data have demonstrated the feasibility of therapeutic induction of coronary collateral growth (arteriogenesis); however, mechanisms of action of such therapeutic collateral stimulation in humans are unknown. The aim of this study was to evaluate potential mechanisms, especially the involvement of arteriogenesis-relevant genes. METHODS AND RESULTS A total of 52 patients were randomized into two groups: subcutaneous G-CSF (10 μg/kg; n=26) or placebo (n=26). Before and after this 2-week treatment, collateral-flow index (CFI) was determined by simultaneous measurement of mean aortic, distal coronary occlusive and central venous pressure. CD34+ endothelial progenitor cells (EPC) and monocytes were quantified before, during and after treatment; gene-expression analysis of monocytes was performed with real-time polymerase chain reaction (RT-PCR). G-CSF lead to a significant increase of EPC and monocytes (4.8 and 2.6 fold, p < 0.05); for both cell types, the extent of increase correlated with CFI increase (r=0.23 and 0.14, p < 0.05). G-CSF also induced a change in gene expression of pro-and anti-arteriogenic genes in monocytes. Among nine assessed genes, three were found to be differentially regulated (IL8, JAK2, and PNPLa4; p < 0.05). CONCLUSIONS The mechanism of induction of collateral growth by G-CSF is related to an increase of EPC and of peripheral monocytes. It also leads to a change toward a pro-arteriogenic gene expression in peripheral monocytes.

Thiazolides, a Novel Class of Anti-Infective Drugs, Effective Against Viruses, Bacteria, Intracellular and Extracellular Protozoan Parasites and Proliferating Mammalian Cells

The thiazolide nitazoxanide (2-acetolyloxy-N-(5-nitro 2-thiazolyl) benzamide; NTZ) is composed of a nitrothiazole- ring and a salicylic acid moiety, which are linked together through an amide bond. NTZ exhibits a broad spectrum of activities against a wide range of helminths, protozoa, enteric bacteria, and viruses infecting animals and humans. Since the first synthesis of the drug, a number of derivatives of NTZ have been produced, which are collectively named thiazolides. These are modified versions of NTZ, which include the replacement of the nitro group with bromo-, chloro-, or other functional groups, and the differential positioning of methyl- and methoxy-groups on the salicylate ring. The presence of a nitro group seems to be the prerequisite for activities against anaerobic or microaerophilic parasites and bacteria. Intracellular parasites and viruses, however, are susceptible to non-nitro-thiazolides with equal or higher effectiveness. Moreover, nitro- and bromo-thiazolides are effective against proliferating mammalian cells. Biochemical and genetic approaches have allowed the identification of respective targets and the molecular basis of resistance formation. Collectively, these studies strongly suggest that NTZ and other thiazolides exhibit multiple mechanisms of action. In microaerophilic bacteria and parasites, the reduction of the nitro group into a toxic intermediate turns out to be the key factor. In proliferating mammalian cells, however, bromo- and nitro-thiazolides trigger apoptosis, which may also explain their activities against intracellular pathogens. The mode of action against helminths may be similar to mammalian cells but has still not been elucidated.

Transcutaneous treatment with vetdrop(®) sustains the adjacent cartilage in a microfracturing joint defect model in sheep

The significance of the adjacent cartilage in cartilage defect healing is not yet completely understood. Furthermore, it is unknown if the adjacent cartilage can somehow be influenced into responding after cartilage damage. The present study was undertaken to investigate whether the adjacent cartilage can be better sustained after microfracturing in a cartilage defect model in the stifle joint of sheep using a transcutaneous treatment concept (Vetdrop(®)). Carprofen and chito-oligosaccharids were added either as single components or as a mixture to a vehicle suspension consisting of a herbal carrier oil in a water-in-oil phase. This mixture was administered onto the skin with the aid of a specific applicator during 6 weeks in 28 sheep, allocated into 6 different groups, that underwent microfracturing surgery either on the left or the right medial femoral condyle. Two groups served as control and were either treated intravenously or sham treated with oxygen only. Sheep were sacrificed and their medial condyle histologically evaluated qualitatively and semi-quantitatively according to 4 different scoring systems (Mankin, ICRS, Little and O'Driscoll). The adjacent cartilage of animals of group 4 treated transcutaneously with vehicle, chito-oligosaccharids and carprofen had better histological scores compared to all the other groups (Mankin 3.3±0.8, ICRS 15.7±0.7, Little 9.0±1.4). Complete defect filling was absent from the transcutaneous treatment groups. The experiment suggests that the adjacent cartilage is susceptible to treatment and that the combination of vehicle, chitooligosaccharids and carprofen may sustain the adjacent cartilage during the recovery period.

Effects of exercise on anxiety and depression disorders: Review of meta-analyses and neurobiological mechanisms

Anxiety and depression are the most frequently diagnosed psychological diseases showing a high co-morbidity. They have a severe impact on the lives of the persons concerned. Many meta-analytical studies suggested a positive anxiolytic and depression reducing effect of exercise programs. The aim of the present article is to synthesize metaanalyses on the effects of exercise on anxiety and depression and to describe average effect sizes. For this purpose 37 meta-analyses were included reporting 50 effect sizes for anxiety scores of 42,264 participants and depression scores of 48,207 persons. The average documented anxiolytic effect of exercise in these reviews was small, 0.34. In contrast, the effect of exercise on depression was significantly higher and at a moderate level, 0.56. Data of randomized controlled trials suggest higher sizes for the effect of exercise on anxiety and depression leading to increases up to moderate and large effects, respectively. Additionally, exercise seems to be more beneficial for patients compared to participants within a nonclinical, normal range of psychological disease. Especially for the effect of exercise on anxiety, more high quality meta-analyses of randomized controlled trials are needed. Finally, possible neurobiological explanations are suggested for the positive effect of exercise on psychological disorders like anxiety and depression.

Effects of physical and psychological stressors on adolescents’ cortisol levels and self-perceived stress in school

Both, psychosocial stress and exercise in the past have been used as stressors to elevate saliva cortisol and change state anxiety levels. In the present study, high-school students at the age of 14 were randomly assigned to three experimental groups: (1) an exercise group (n = 18), that was running 15 minutes at a medium intensity level of 65-75% HRmax, (2) a psychosocial stress group (n = 19), and (3) a control group (n = 18). The psychosocial stress was induced to the students by completing a standardized intelligence test under the assumption that their IQ scores would be made public in class. Results display that only psychosocial stress but not exercise was able to significantly increase cortisol levels but decreased cognitive state anxiety in adolescents. The psychosocial stress protocol applied here is proposed for use in future stress studies with children or adolescents in group settings, e.g., in school.

Measurement of Neutrino Oscillation Parameters from Muon Neutrino Disappearance with an Off-Axis Beam

The T2K collaboration reports a precision measurement of muon neutrino disappearance with an off-axis neutrino beam with a peak energy of 0.6 GeV. Near detector measurements are used to constrain the neutrino flux and cross section parameters. The Super-Kamiokande far detector, which is 295 km downstream of the neutrino production target, collected data corresponding to 3.01×1020 protons on target. In the absence of neutrino oscillations, 205±17 (syst.) events are expected to be detected and only 58 muon neutrino event candidates are observed. A fit to the neutrino rate and energy spectrum assuming three neutrino flavors, normal mass hierarchy and θ23≤π/4 yields a best-fit mixing angle sin2(2θ23)=1.000 and mass splitting |Δm232|=2.44×10−3 eV2/c4. If θ23≥π/4 is assumed, the best-fit mixing angle changes to sin2(2θ23)=0.999 and the mass splitting remains unchanged.

Observation of Electron Neutrino Appearance in a Muon Neutrino Beam

The T2K experiment has observed electron neutrino appearance in a muon neutrino beam produced 295 km from the Super-Kamiokande detector with a peak energy of 0.6 GeV. A total of 28 electron neutrino events were detected with an energy distribution consistent with an appearance signal, corresponding to a significance of 7.3σ when compared to 4.92 ± 0.55 expected background events. In the PMNS mixing model, the electron neutrino appearance signal depends on several parameters including three mixing angles θ12, θ23, θ13, a mass difference Δm232 and a CP violating phase δCP. In this neutrino oscillation scenario, assuming |Δm232|=2.4×10−3 eV2, sin2θ23=0.5, δCP=0, and Δm232>0 (Δm232<0), a best-fit value of sin22θ13 = 0.140+0.038−0.032 (0.170+0.045−0.037) is obtained.