Vagus Nerve Stimulation in Refractory Epilepsy: Effects on Pro- and Anti-Inflammatory Cytokines in Peripheral Blood

Objective: The vagus nerve has important immunological functions that may be relevant for its anticonvulsive action. We postulate that this anticonvulsive action is activated by a shift in the immune system resulting in a reduction of neurotoxic and an increase of neuroprotective tryptophan metabolites. Methods: Eleven patients with refractory epilepsy and 11 controls matched for age and gender were included in this study. The primary outcome measure was a 50% seizure reduction. Other variables were pro-inflammatory cytokines IL-6 and TNF-alpha, anti-inflammatory cytokine IL-10, cortisol, and the tryptophan metabolites 3-hydroxykynurenine (3-OH-KYN), kynurenic acid (KYNA), kynurenine, serotonin (5-HT) and 5-hydroxyindol acetic acid (5-HIAA). Blood samples were scheduled during baseline, and in week 28 of add-on treatment. Results: IL-6 levels were higher in the responders than in the control group, and decreased after vagus nerve stimulation (VNS), whereas IL-10 was low and increased after VNS. In nonresponders, VNS resulted in an increase of IL-6 plasma levels and in a decrease of IL-10. Cortisol concentrations are higher in the epilepsy group than in the control group. After VNS, these concentrations decreased. The concentrations of the tryptophan metabolites were lower in the epilepsy group than in the control group. The KYNA ratios are defined as the ratio of neuroprotective KYNA versus neurotoxic 3-OH-KYN and KYNA versus neurotoxic kynurenine: these ratios were lower in epilepsy patients than in controls, and they both moderately increased after VNS. Conclusion: The outcome of this preliminary study indicates that VNS causes a rebalancing of the immune system. This results in: (1) a reduction of neurotoxic and an increase of neuroprotective kynurenine metabolites and (2) in the normalization of cortisol levels. Copyright (C) 2010 S. Karger AG, Base

Effect of introduced species and habitat alteration on the occurrence and distribution of euryhaline fishes in fresh- and brackish-water habitats on Aruba, Bonaire and Curaçao (South Caribbean)

We conducted an ichthyological survey during the dry season of 2006 on the semi-arid islands of Aruba, Bonaire and Curaçao to provide information on species composition, richness and distribution in natural and non-natural aquatic habitats. The dry season species assemblages (N = 9 species) comprised less species than the wet seasons, and these data refine our knowledge of the indigenous fish fauna and its refuge localities during phases of drought and ensuing high salinity. A hierarchical cluster analysis reveals that the three islands have different species compositions with Curaçao being the most diverse, probably due to its having the most habitats and freshwaters present throughout the year. Species richness was unrelated to salinity and species diversity was highest in canalised streams. In the dry season fewer amphidromous species are present than in the wet season. We found no significant effect of human-induced changes on the presence or absence of fish species in the Netherlands Antilles. The presence of exotic species (including Xiphophorus helleri on Aruba, a first record for this island, and Oreochromis mossambicus and Poecilia reticulata occurring on all three islands) did not have a clear effect on the presence of indigenous species, nor did human alteration of the habitats have an influence on the occurrence of fish species

Low profile vascular plug for transarterial occlusion of patent ductus arteriosus in small dogs

Background: Minimally invasive transcatheter occlusion using Amplatz canine duct occluder (ACDO) is the treatment of choice for dogs with left-to-right shunting patent ductus arteriosus (PDA). However, in small dogs the femoral artery diameter is often too small to accommodate the guiding catheter required for ACDO deployment. Objective: Describe the effectiveness of transarterial implantation of Amplatzer Vascular Plug 4 (AVP-4), the only self-expandable nitinol mesh occlusion device which can be implanted through a 4 French diagnostic catheter, in small dogs with left-to-right shunting PDA. Animals: Seven client-owned dogs. Methods: Descriptive case series. Dogs with hemodynamically relevant left-to-right shunting PDA and a femoral artery diameter less than 2.0 mm measured preoperatively with ultrasonography were prospectively enrolled. Results: Angiography after releasing the device showed complete immediate PDA closure in 5 dogs, where the manufacturers' recommendation were strictly followed (30%-50% device oversizing of the ductal ampulla's diameter). Trivial residual flow on angiography in the 6th dog, whose device was slightly undersized, had resolved on echocardiography within 2 hours after placement. Marked device undersizing in the 7th dog resulted in severe residual shunting, which necessitated the addition of a coil. In this dog, the AVP-4 embolized into the pulmonary artery within 2 weeks after placement. Conclusions and Clinical Importance: Transarterial implantation of AVP-4 is a safe, effective and technically easy procedure for PDA occlusion in small dogs and offers a valuable alternative to coil implantation. Accurate PDA measurement and device sizing is essential to prevent residual shunting, inadvertent device embolization, and protrusion of the device into the aorta

Doppler Ultrasonographic Assessment of Abdominal Aortic Flow to Evaluate the Hemodynamic Relevance of Left-to-Right Shunting Patent Ductus Arteriosus in Dogs

In this multicenter, prospective, observational study, abdominal aortic flow was examined with pulsed-wave Doppler ultrasound in dogs with a left-to-right shunting patent ductus arteriosus (PDA) and in apparently healthy dogs. Forty-eight dogs with a PDA and 35 controls were included. In the dogs with a PDA, 37/48 had hemodynamically significant PDAs (hsPDAs) while 11/48 had non-hsPDAs, based on the presence or absence of echocardiographic signs of left-sided volume overload, respectively. In 12 dogs (4/35 control dogs, 7/37 dogs with an hsPDA and 1/11 dogs with a non-hsPDA), the diastole was too short to visualize the end-diastolic flow. Antegrade end-diastolic flow was observed in 30/35 controls and 6/11 dogs with a non-hsPDA. Absent end-diastolic flow was observed in 1/35 control dogs and 3/11 dogs with a non-hsPDA. Retrograde end-diastolic flow was observed in 30/37 dogs with an hsPDA and 1/11 dogs with a non-hsPDA. Twenty-one dogs (15 with an hsPDA and 6 with a non-hsPDA) were reassessed after PDA closure, and, in 19/21, end-diastolic flow was visualized: 17/19 showed an antegrade flow, 1/19 an absent flow and 1/19 a retrograde flow. Sensitivity and specificity of retrograde end-diastolic flow for detection of hsPDAs were 100% and 90%, respectively. In conclusion, ultrasonographic assessment of abdominal aortic flow was feasible in dogs with PDA. However, end-diastolic flow was not always visualized. The presence of a retrograde end-diastolic flow was an accurate finding for discriminating hsPDAs and non-hsPDAs

Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity

BACKGROUND: The major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants. OBJECTIVE: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD. METHODS: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members. RESULTS: All affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities. CONCLUSION: We hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family

USP15 deubiquitinase safeguards hematopoiesis and genome integrity in hematopoietic stem cells and leukemia cells

Altering ubiquitination by disruption of individual deubiquitinating enzymes (DUBs) has proven to affect hematopoietic stem cell (HSC) maintenance. However, comprehensive knowledge of DUB function during hematopoiesis in vivo is lacking. To accomplish this goal, we systematically inactivated DUBs in mouse hematopoietic progenitors using in vivo small hairpin RNAs (shRNAs) screens. We found that multiple DUBs may be individually required for hematopoiesis and that the ubiquitin-specific protease 15 (USP15) is particularly important for the maintenance of murine hematopoietic stem and progenitor cells in vitro and in vivo. Consistently, Usp15 knockout mice exhibited a reduced HSC pool. The defect was intrinsic to HSCs, as demonstrated by competitive repopulation assays. Importantly, USP15 is highly expressed in normal human hematopoietic cells and leukemias, and USP15 depletion in murine early progenitors and myeloid leukemia cells impaired in vitro expansion and increased genotoxic stress. Our study underscores the importance of DUBs in preserving normal hematopoiesis and uncovers USP15 as a critical DUB in safeguarding genome integrity in HSC and in leukemia cells