Conditional BDNF release under pathological conditions improves Huntington's disease pathology by delaying neuronal dysfunction

Background Brain-Derived Neurotrophic Factor (BDNF) is the main candidate for neuroprotective therapy for Huntington's disease (HD), but its conditional administration is one of its most challenging problems. Results Here we used transgenic mice that over-express BDNF under the control of the Glial Fibrillary Acidic Protein (GFAP) promoter (pGFAP-BDNF mice) to test whether up-regulation and release of BDNF, dependent on astrogliosis, could be protective in HD. Thus, we cross-mated pGFAP-BDNF mice with R6/2 mice to generate a double-mutant mouse with mutant huntingtin protein and with a conditional over-expression of BDNF, only under pathological conditions. In these R6/2:pGFAP-BDNF animals, the decrease in striatal BDNF levels induced by mutant huntingtin was prevented in comparison to R6/2 animals at 12 weeks of age. The recovery of the neurotrophin levels in R6/2:pGFAP-BDNF mice correlated with an improvement in several motor coordination tasks and with a significant delay in anxiety and clasping alterations. Therefore, we next examined a possible improvement in cortico-striatal connectivity in R62:pGFAP-BDNF mice. Interestingly, we found that the over-expression of BDNF prevented the decrease of cortico-striatal presynaptic (VGLUT1) and postsynaptic (PSD-95) markers in the R6/2:pGFAP-BDNF striatum. Electrophysiological studies also showed that basal synaptic transmission and synaptic fatigue both improved in R6/2:pGAP-BDNF mice. Conclusions These results indicate that the conditional administration of BDNF under the GFAP promoter could become a therapeutic strategy for HD due to its positive effects on synaptic plasticity.

Effect of a whey-predominant starter formula containing LCPUFAs and oligosaccharides (FOS/GOS) on gastrointestinal comfort in infants.

Development of new infant formulas aims to replicate the benefits of breast milk. One benefit of breast milk over infant formulas is greater gastrointestinal comfort. We compared indicators of gastrointestinal comfort in infants fed a whey-predominant formula containing long-chain polyunsaturated fatty acids, galacto-oligo-saccharides and fructo-oligosaccharides, and infants fed a control casein-predominant formula without additional ingredients. The single-centre, prospective, double-blind, controlled trial randomly assigned healthy, full-term infants (n=144) to receive exclusively either experimental or control formula from 30 days to 4 months of age. A group of exclusively breast-fed infants served as reference (n=80). At 1, 2, 3, and 4 months, infants' growth parameters were measured and their health assessed. Parents recorded frequency and physical characteristics of infants' stool, frequency of regurgitation, vomiting, crying and colic. At 2-months, gastric emptying (ultrasound) and intestinal transit time (H2 breath test) were measured, and stool samples collected for bacterial analysis. Compared to the control (n=69), fewer of the experimental group (n=67) had hard stools (0.7 vs 7.5%, p<0.001) and more had soft stools (90.8 vs 82.3%, p<0.05). Also compared to the control, the experimental group's stool microbiota composition (mean % bifidobacteria: 78.1 (experimental, n=17), 63.7 (control, n=16), 74.3 (breast-fed, n=20), gastric transit times (59.6 (experimental, n=53), 61.4 (control, n=62), 55.9 (breast-fed, n=67) minutes) and intestinal transit times (data not shown) were closer to that of the breast-fed group. Growth parameter values were similar for all groups. The data suggest that, in infants, the prebiotic-containing whey-based formula provides superior gastrointestinal comfort than a control formula.

Respiratory chain dysfunction associated with multiple mitochondrial DNA deletions in antiretroviral therapy-related lipodystrophy.

Highly-active antiretroviral therapy (HAART) can induce a characteristic lipodystrophy syndrome characterized by peripheral fat wasting and central adiposity, usually associated with hyperlipidaemia and insulin resistance [1,2]. Indirect data have led some authors to propose that mitochondrial dysfunction could play a role in this syndrome [3,4].To date, as recently outlined by Kakuda et al. [5] in this journal, HIV-infected patients developing lipodystrophy have not been studied for mitochondrial changes or respiratory chain capacity...

Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients.

The paradoxical coexistence of spontaneous tumor antigen-specific immune responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction. In patients with advanced melanoma, we have previously shown that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1-specific CD8(+) T cells that up-regulate PD-1 expression. We also observed that PD-1 regulates NY-ESO-1-specific CD8(+) T cell expansion upon chronic antigen stimulation. In the present study, we show that a fraction of PD-1(+) NY-ESO-1-specific CD8(+) T cells in patients with advanced melanoma up-regulates Tim-3 expression and that Tim-3(+)PD-1(+) NY-ESO-1-specific CD8(+) T cells are more dysfunctional than Tim-3(-)PD-1(+) and Tim-3(-)PD-1(-) NY-ESO-1-specific CD8(+) T cells, producing less IFN-γ, TNF, and IL-2. Tim-3-Tim-3L blockade enhanced cytokine production by NY-ESO-1-specific CD8(+) T cells upon short ex vivo stimulation with cognate peptide, thus enhancing their functional capacity. In addition, Tim-3-Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1-specific CD8(+) T cells upon prolonged antigen stimulation and acted in synergy with PD-1-PD-L1 blockade. Collectively, our findings support the use of Tim-3-Tim-3L blockade together with PD-1-PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.

[112-POS] : Increased post-partum prevalence of hypertension and renal dysfunction after preeclampsia

OBJECTIVES: Women with a history of preeclampsia (PE) are at increased risk of long term cardiovascular and end-stage renal diseases. However, follow up of preeclamptic women is often omitted, mainly due to a weakness of knowledge of maternal caregivers and lack of comprehensive guidelines. The aim of this study was to define the prevalence of albuminuria, high blood pressure, and renal dysfunction 6 weeks after a preeclampsia. METHODS: This is a prospective case-control study comparing women presenting with preeclampsia to an unmatched control group of women with no hypertensive disorders of pregnancy. A complete medical assessment was performed at 6 weeks post-partum. Recruitment started in June 2010. RESULTS: 324 women were included in the PE group and 50 in the control one. Characteristics of both groups and results of the medical work-up at 6 weeks post-partum are presented in Table 1. Women with preeclampsia presented with a higher BMI, higher prevalence of office high blood pressure, pathological albuminuria and renal hyper-filtration than women in the control group. CONCLUSIONS: Prevalence of post-partum hypertension, and renal dysfunction is higher in women with PE than in uncomplicated pregnancies. Systematic assessment of renal risk factors 6 weeks after preeclampsia allows identification of high-risk women and early implementation of preventive and therapeutic strategies. DISCLOSURES: A. Ditisheim: None. B. Ponte: None. G. Wuerzner: None. M. Burnier: None. M. Boulvain: None. A. Pechère-Bertschi: None.

Systemic and pulmonary vascular dysfunction in children conceived by assisted reproductive technologies.

BACKGROUND: Assisted reproductive technology (ART) involves the manipulation of early embryos at a time when they may be particularly vulnerable to external disturbances. Environmental influences during the embryonic and fetal development influence the individual's susceptibility to cardiovascular disease, raising concerns about the potential consequences of ART on the long-term health of the offspring. METHODS AND RESULTS: We assessed systemic (flow-mediated dilation of the brachial artery, pulse-wave velocity, and carotid intima-media thickness) and pulmonary (pulmonary artery pressure at high altitude by Doppler echocardiography) vascular function in 65 healthy children born after ART and 57 control children. Flow-mediated dilation of the brachial artery was 25% smaller in ART than in control children (6.7±1.6% versus 8.6±1.7%; P<0.0001), whereas endothelium-independent vasodilation was similar in the 2 groups. Carotid-femoral pulse-wave velocity was significantly (P<0.001) faster and carotid intima-media thickness was significantly (P<0.0001) greater in children conceived by ART than in control children. The systolic pulmonary artery pressure at high altitude (3450 m) was 30% higher (P<0.001) in ART than in control children. Vascular function was normal in children conceived naturally during hormonal stimulation of ovulation and in siblings of ART children who were conceived naturally. CONCLUSIONS: Healthy children conceived by ART display generalized vascular dysfunction. This problem does not appear to be related to parental factors but to the ART procedure itself. CLINICAL TRIAL REGISTRATION: URL: www.clinicaltrials.gov. Unique identifier: NCT00837642.

Douteur testiculaire, un défi diagnostique [Testicular pain, a diagnostic challenge?].

Scrotal pain is frequently encountered in practice, as it affects 4 men in 1000, with a peak of incidence between the ages of 45 and 50. After excluding an urological or gastrointestinal cause, referred pain of musculoskeletal origin should be considered, even in the absence of back pain. Described by Dr. Robert Maigne, this referred pain originates from a minor intervertebral dysfunction of the thoracolumbar junction. Imaging of the spine is not helpful. Rather, the diagnosis is made by seeking pain triggered by the mobilization of the lumbar vertebrae; the pinch and roll skin manoeuvre will highlight this referred pain. Treatment is symptomatic, though manual therapies by spine specialists are also recommended.

Unusual fatal petrositis presenting as myofascial pain and dysfunction of the temporal muscle.

Petrositis is a rare and severe complication of acute otitis media and mastoiditis. Although the extension of the inflammatory process from the petrous apex to the adjacent Meckel cave can lead to trigeminal pain, an irritation of the trigeminal nerve roots resulting in acute or chronic hyperactivity of masticatory muscles has never been reported. We report here the unusual case of an 86-year-old man who presented with a handicapping myofascial pain and dysfunction syndrome of the right temporal muscle as a heralding manifestation of an unusual form of petrositis. The patient progressively developed a retropharyngeal abscess, a right sphenoid sinusitis, and fatal meningitis. This case demonstrated that (1) myofascial pain and dysfunction syndrome that does not respond to conventional treatments may suggest an unusual etiology and warrant further medical investigations and a detailed medical history and that (2) petrositis can manifest itself with atypical clinical symptoms and radiologic signs. (Quintessence Int 2011;42:419-422).

Postoperative Cognitive Dysfunction (POCD) and Inflammatory Markers in Elderly Patients

Introduction: Particularly in elderly patients, the brain responds to a systemic inflammatory response with an increased production of inflammatory mediators. This has hypothetically been linked to the development of postoperative cognitive dysfunction (POCD). Methods: We investigated 31 patients aged >65 yrs undergoing elective major surgery under standardized general anaesthesia (thiopental, sevoflurane, fentanyl, atracurium). Cognitive function was measured preoperatively and 7 days postoperatively using the extended version of the Consortium to Establish a Registry for Alzheimer's Disease - Neuropsychological Assessment Battery (CERAD-NAB, validated German version) for which we developed a diagnostic cut-off in healthy elderly volunteers. Systemic C-reactive protein (CRP) and interleukin 6 (IL-6) were measured preoperatively, 2 days postoperatively, and 7 days postoperatively. Values for CRP, IL-6, operative characteristics and hospital length of stay in patients with POCD and without POCD were compared using the Mann- Whitney U test and are shown as median [range]. Results: Fourteen patients (45%) developed POCD. Values for CRP were not statistically different in patients with POCD and without POCD but tended to be higher in patients with POCD 2 days postoperatively. Patients with POCD had significantly higher IL-6 values on postoperative days 2 and 7 (table 1). These patients also had a significantly longer duration of anaesthesia (305 [195-620] vs.190 [150-560] min, p = 0.034), larger intraoperative blood loss (425 [0-1600] vs. 100 [0-1500] ml, p = 0.018) and longer hospital stays (15 [8-45] vs. 8 [4-40] days, p = 0.008). Table 1 POCD (n = 14) No POCD (n = 17) p value CRP (mg/dl) preop. 4.0 [1.0-245] 4.2 [0.3-36.2] 0.6 2 days postop. 223 [20-318] 98 [4.5-384] 0.07 7 days postop. 58 [15-147] 44 [11-148] 0.2 IL-6 (U/ml) preop. 2[2-28.1] 2 [2-7.3] 0.8 2 days postop. 56 [17-315] 20 [2-123] 0.009 7 days postop. 9[2-77] 4 [2-16] 0.03 Interpretation: In this small group of patients, high IL-6 values postoperatively were associated with POCD supporting a role for systemic inflammation in the development of POCD. In patients with POCD, duration of anaesthesia was significantly longer, and intraoperative blood losses were larger. These risk factors will need to be confirmed in a larger group of patients. The difference in length of stay may be indicative of postoperative complications, which have been linked to POCD earlier.

The cyclophilin inhibitor alisporivir prevents hepatitis C virus-mediated mitochondrial dysfunction.

Alisporivir (Debio-025) is an analogue of cyclosporine A and represents the prototype of a new class of non-immunosuppressive cyclophilin inhibitors. In vitro and in vivo studies have shown that alisporivir inhibits hepatitis C virus (HCV) replication, and ongoing clinical trials are exploring its therapeutic potential in patients with chronic hepatitis C. Recent data suggest that the antiviral effect is mediated by inhibition of cyclophilin A, which is an essential host factor in the HCV life cycle. However, alisporivir also inhibits mitochondrial permeability transition by binding to cyclophilin D. Because HCV is known to affect mitochondrial function, we explored the effect of alisporivir on HCV protein-mediated mitochondrial dysfunction. Through the use of inducible cell lines, which allow to investigate the effects of HCV polyprotein expression independent from viral RNA replication and which recapitulate the major alterations of mitochondrial bioenergetics observed in infectious cell systems, we show that alisporivir prevents HCV protein-mediated decrease of cell respiration, collapse of mitochondrial membrane potential, overproduction of reactive oxygen species and mitochondrial calcium overload. Strikingly, some of the HCV-mediated mitochondrial dysfunctions could even be rescued by alisporivir. Conclusion: These observations provide new insights into the pathogenesis of HCV-related liver disease and reveal an additional mechanism of action of alisporivir that is likely beneficial in the treatment of chronic hepatitis C. (HEPATOLOGY 2012).

Pulmonary and systemic vascular dysfunction in young offspring of mothers with preeclampsia.

BACKGROUND: Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. METHODS AND RESULTS: We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean+/-SD, 32.1+/-5.6 versus 25.3+/-4.7 mm Hg; P<0.001) and flow-mediated dilation was 30% smaller (6.3+/-1.2% versus 8.3+/-1.4%; P<0.0001) in offspring of mothers with preeclampsia than in control subjects. A strong inverse relationship existed between flow-mediated dilation and pulmonary artery pressure (r=-0.61, P<0.001). The vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after a normal pregnancy had normal vascular function. Augmented oxidative stress may represent an underlying mechanism because thiobarbituric acid-reactive substances plasma concentration was increased in offspring of mothers with preeclampsia. CONCLUSIONS: Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life.