Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3

We describe first cousin sibling pairs with focal epilepsy, one of each pair having focal cortical dysplasia (FCD) IIa. Linkage analysis and whole‐exome sequencing identified a heterozygous germline frameshift mutation in the gene encoding nitrogen permease regulator‐like 3 (NPRL3). NPRL3 is a component of GAP Activity Towards Rags 1, a negative regulator of the mammalian target of rapamycin complex 1 signaling pathway. Immunostaining of resected brain tissue demonstrated mammalian target of rapamycin activation. Screening of 52 unrelated individuals with FCD identified 2 additional patients with FCDIIa and germline NPRL3 mutations. Similar to DEPDC5, NPRL3 mutations may be considered as causal variants in patients with FCD or magnetic resonance imaging–negative focal epilepsy. ANN NEUROL 2016;79:132–137     

Immunization with neurofilament light protein induces spastic paresis and axonal degeneration in Biozzi ABH mice

Axonal damage is the major cause of irreversible neurologic disability in patients with multiple sclerosis. Although axonal damage correlates with antibodies against neurofilament light (NF-L) protein, a major component of the axonal cytoskeleton, the possible pathogenic role of autoimmunity to axonal antigens such as NF-L has so far been ignored. Here we show that Biozzi ABH mice immunized with NF-L protein develop neurologic disease characterized by spastic paresis and paralysis concomitant with axonal degeneration and inflammation primarily in the dorsal column of the spinal cord. The inflammatory central nervous system lesions were dominated by F4/80+ macrophages/microglia and relatively low numbers of CD4+ and CD8+ T-cells. In splenocyte cultures, proliferation to NF-L was observed in CD4+ T-cells accompanied by the production of the proinflammatory cytokine interferon-gamma. Elevated levels of circulating antibodies recognizing recombinant mouse NF-L were present in the serum, and immunoglobulin deposits were observed within axons in spinal cord lesions of mice exhibiting clinical disease. These data provide evidence that autoimmunity to NF-L protein induces axonal degeneration and clinical neurologic disease in mice, indicating that autoimmunity to axonal antigens, as described in multiple sclerosis, may be pathogenic rather than acting merely as a surrogate marker for axonal degeneration.     

The human CMV-UL86 peptide 981-1003 shares a crossreactive T-cell epitope with the encephalitogenic MOG peptide 34-56, but lacks the capacity to induce EAE in rhesus monkeys

Rhesus monkeys immunized with MOG(34-56), a dominant T-cell epitope from myelin/oligodendrocyte glycoprotein, develop an acute neurological disease resembling acute disseminated encephalomyelitis (ADEM) in humans. The typical large demyelinated lesions and mononuclear infiltrates in the monkey brains are caused by MOG(34-56) T-cells. We show that MOG(34-56)-reactive CD4+ and CD8+ T-cells are induced in monkeys immunized with a peptide from the human CMV major capsid protein (UL86; 981-1003), that shares sequence similarity with MOG(34-56). Monkeys sensitized against the viral peptide and subsequently challenged with MOG(34-56) display histological signs of encephalitis, but do not show overt neurological signs.     

Tyrosine phosphorylation / dephosphorylation balance is involved in thrombin-evoked microtubular reorganisation in human platelets

We have investigated the intracellular mechanisms involved in microtubular remodelling by thrombin and its possible involvement in platelet aggregation and secretion. Platelet stimulation with thrombin induces a time- and concentration-dependent regulation of the microtubular content, which was found to be maximally effective at the concentration 0.1 U/ml. Thrombin (0.1 U/ml) evoked an initial decrease in the microtubule content detectable at 5 seconds (sec) and reached a minimum 10 sec after stimulation. The microtubular content then increased, exceeding basal levels again approximately 30 sec after stimulation. Inhibition of tyrosine phosphatases using vanadate abolished thrombin-induced microtubular depolymerisation while inhibition of tyrosine kinases by methyl-2,5-dihydroxycinnamate prevented microtubule polymerisation. Thrombin activates the cytosolic Bruton's tyrosine kinase (Btk) and Src proteins. Inhibition of Btk or Src by LFM-A13 or PP1, respectively, abolished thrombin-induced microtubular polymerisation, while maintaining intact its ability to induce initial depolymerisation. Microtubular disruption by colchicine significantly reduced thrombin-induced platelet aggregation and ATP secretion. Similar results were observed after inhibition of microtubular disassembly by paclitaxel. These findings indicate that thrombin induces microtubular remodelling by modifying the balance between protein tyrosine phosphorylation and dephosphorylation. The former seems to be required for microtubular polymerisation, while tyrosine dephosphorylation is required for microtubular depolymerisation. Both, initial microtubular disassembly and subsequent polymerisation are required for thrombin-induced platelet aggregation and secretion in human platelets.     

Non-randomized, prospective, multi-centre evaluation of the ABSOLUTE .035 peripheral self-expanding stent system for occluded or stenotic superficial femoral or proximal popliteal arteries (ASSESS Trial): acute and 30-day results

AIM: The aim of the paper was to investigate the performance of the ABSOLUTE .035 Peripheral Self-Expanding Stent System in preventing restenosis of superficial femoral or proximal popliteal arteries. Due to a lack of large controlled trials proving its long-term durability femoropopliteal artery stenting is still a matter of debate. In this paper we report the study design, the acute and short-term results of a prospective European registry on the treatment of TASC B and C femoropopliteal lesions with the use of the ABSOLUTE stent. METHODS: This prospective, non-randomized, multi-centre study enrolled 122 patients with symptomatic peripheral occlusive disease at 14 sites in Europe. Patients were included with obstructed femoropopliteal arteries. Key inclusion criteria were de novo lesions > or = 4.0 mm and < or = 7.0 mm in diameter, and > or = 40 mm and < or = 200 mm in length. Single target vessel treatment had to be performed with a maximum of three stents. RESULTS: Mean target lesion length was 108 +/- 44 mm (range 22.2 to 200 mm) and mean reference vessel diameter 4.6 +/- 0.8 mm by quantitative angiography; 71% of the lesions analyzable by quantitative angiography (QA) had total occlusions. A total of 227 stents were implanted, 224 of which were deployed successfully (98.7%). Mean percentage of diameter stenosis was reduced from 90.9 +/- 15.5 % (range 41.3 to 100) to 19.0 +/- 8.4% (range 2.3 to 41.5). Device and procedural success were 83.6% each whereas technical success reached 100%. Sixteen lesions had a > or = 30% residual stenosis post-procedure, 6 of them (37.5%) rated as being calcified. Eleven patients experienced major complications (9.1%) and 6 patients experienced minor complications (5%) within 30 days. Duplex ultrasound based 1-month restenosis rate was 9.3%. Target lesion revascularization (TLR) and target vessel revascularization (TVR) rates were 0.8% and 1.7%, respectively and amputation rate was 0.8%. Mean ankle-brachial index (ABI) at rest and after exercise increased significantly from baseline to 30 days follow-up by 0.63 +/- 0.20 to 0.94 +/- 0.17 and from 0.44 +/- 0.23 to 0.85 +/- 0.21, respectively (P<0.001 each). CONCLUSION: The treatment of TASC B and C femoro-popliteal lesions with use of the ABSOLUTE stent is safe and feasible. Short-term follow-up documents persistent improvement of hemodynamics. The 6- and 12-month data have to be awaited for further conclusions:     

Obstructive sleep apnea has little impact on quality of life in the elderly

Study objectiveTo analyze the impact of the number of respiratory sleep disorders or clinically related conditions (especially excessive daytime sleepiness [EDS]), on health related quality of life (HRQoL) in subjects over 65 years of age, as compared to younger subjects and the general population.MethodsTwo hundred and twelve adult patients with obstructive sleep apnea (OSA, AHI ? 10) divided into two age groups, over 65 (n = 109, mean age 74.6 [6, 8] years, and 65 or under (n = 103, mean age 51.7, [6, 5] years).General, anthropometric and clinical data related to OSA (epworth sleepiness score [ESS]), comorbidities (Charlson comorbidity index [CCI]), HRQoL (SF-36 questionnaire), use of psychotropic medications and habitual polygraphic/polysomnographic parameters were recorded and compared between the two age groups. The HRQoL values in each age group were compared with the values in the general population, adjusted for age and gender.ResultsIn patients 65 and under, both the presence of OSA as well as the presence of EDS (ESS > 11) were associated with an important deterioration in HRQoL as compared to normal reference values. The principal determinants of HRQoL were the presence of EDS (p < 0.04), body mass index (p < 0.03) and the apnea–hypopnea index (AHI) (p < 0.04). Nevertheless, in subjects over 65 years of age, the presence of OSA or EDS had only a slight impact on HRQoL, relative to normal values. In this age group, the principal determinants of HRQoL were the presence of comorbidities (CCI, p < 0.01), age (p < 0.01), oxygen desaturation parameters (p < 0.04) and the use of psychotropic medications (p < 0.04).ConclusionIn elders, the presence of OSA with or without EDS has little impact on HRQoL measures.     

HLA-G regulators in cancer medicine: an outline of key requirements

HLA-G is unique among the class I human leukocyte antigens. It plays a pivotal role in immune tolerance and a paradoxical role in therapies. Indeed, HLA-G expression is associated with a good prognosis in organ transplantation and an ominous prognosis in cancer. Recent progress has been made in HLA-G regulation identification, especially on human cell lines; however, little is known about their role in cancer therapy. Based on the role of HLA-G expression in cancer, we investigated the potential impact of the regulation of this expression on the outcome of some cancers. In this communication, we emphasize the importance of screening for HLA-G expression after cancer therapy. Future clinical trials could lead to a better understanding of the implication of HLA-G expression in cancer and lead to a better knowledge of cancer monitoring and recurrence. These studies could also implicate HLA-G as a therapeutic target in cancer therapy.