Glucose availability and sensitivity to anoxia of isolated rat peripheral nerve

The contrast between resistance to ischemia and ischemic lesions in peripheral nerves of diabetic patients was explored by in vitro experiments. Isolated and desheathed rat peroneal nerves were incubated in the following solutions with different glucose availability: 1) 25 mM glucose, 2) 2.5 mM glucose, and 3) 2.5 mM glucose plus 10 mM 2-deoxy-D-glucose. Additionally, the buffering power of all of these solutions was modified. Compound nerve action potential (CNAP), extracellular pH, and extracellular potassium activity (aKe) were measured simultaneously before, during, and after a period of 30 min of anoxia. An increase in glucose availability led to a slower decline in CNAP and to a smaller rise in aKe during anoxia. This resistance to anoxia was accompanied by an enhanced extracellular acidosis. Postanoxic recovery of CNAP was always complete in 25 mM HCO3(-)-buffered solutions. In 5 mM HCO3- and in HCO3(-)-free solutions, however, nerves incubated in 25 mM glucose did not recover functionally after anoxia, whereas nerves bathed in solutions 2 or 3 showed a complete restitution of CNAP. We conclude that high glucose availability and low PO2 in the combination with decreased buffering power and/or inhibition of HCO3(-)-dependent pH regulation mechanisms may damage peripheral mammalian nerves due to a pronounced intracellular acidosis

Glutathione accelerates sodium channel inactivation in excised rat axonal membrane patches

The effects of glutathione were studied on the gating behaviour of sodium channels in membrane patches of rat axons. Depolarizing pulses from –120 to –40 mV elicited sodium currents of up to 500 pA, indicating the simultaneous activation of up to 250 sodium channels. Inactivation of these channels in the excised, inside-out configuration was fitted by two time constants ( h1=0.81 ms; h2= 5.03 ms) and open time histograms at 0 mV revealed a biexponential distribution of channel openings ( short=0.28 ms; long=3.68 ms). Both, the slow time constant of inactivation and the long lasting single channel openings disappeared after addition of the reducing agent glutathione (2–5 mM) to the bathing solution. Sodium channels of excised patches with glutathione present on the cytoplasmatic face of the membrane had inactivation kinetics similar to channels recorded in the cell-attached configuration. These observations indicate that redox processes may contribute to the gating of axonal sodium channels

Efficacy and safety of betahistine treatment in patients with Meniere’s disease: primary results of a long term, multicentre, double blind, randomised, placebo controlled, dose defining trial (BEMED trial)

Study question What is the long term efficacy of betahistine dihydrochloride on the incidence of vertigo attacks in patients with Meniere’s disease, compared with placebo? Methods The BEMED trial is a multicentre, double blind, randomised, placebo controlled, three arm, parallel group, phase III, dose defining superiority trial conducted in 14 German tertiary referral centres (for neurology or ear, nose, and throat). Adults aged 21-80 years (mean age 56 years) with definite unilateral or bilateral Meniere’s disease were recruited from March 2008 to November 2012. Participants received placebo (n=74), low dose betahistine (2×24 mg daily, (n=73)), or high dose betahistine (3×48 mg daily, (n=74)) over nine months. The primary outcome was the number of attacks per 30 days, based on patients’ diaries during a three month assessment period at months seven to nine. An internet based randomisation schedule performed a concealed 1:1:1 allocation, stratified by study site. Secondary outcomes included the duration and severity of attacks, change in quality of life scores, and several observer-reported parameters to assess changes in audiological and vestibular function. Study answer and limitations Incidence of attacks related to Meniere’s disease did not differ between the three treatment groups (P=0.759). Compared with placebo, attack rate ratios were 1.036 (95% confidence interval 0.942 to 1.140) and 1.012 (0.919 to 1.114) for low dose and high dose betahistine, respectively. The overall monthly attack rate fell significantly by the factor 0.758 (0.705 to 0.816; P<0.001). The population based, mean monthly incidence averaged over the assessment period was 2.722 (1.304 to 6.309), 3.204 (1.345 to 7.929), and 3.258 (1.685 to 7.266) for the placebo, low dose betahistine, and high dose betahistine groups, respectively. Results were consistent for all secondary outcomes. Treatment was well tolerated with no unexpected safety findings. Without a control group of patients who did not receive any intervention to follow the natural course of the disease, the placebo effect could not be accurately assessed and differentiated from spontaneous remission and fluctuation of symptoms. What this study adds Current evidence is limited as to whether betahistine prevents vertigo attacks caused by Meniere’s disease, compared with placebo. The trial provides information on symptom relief on placebo intervention which is relevant for the design of future studies on potential disease modifying treatments in patients with Meniere’s disease. Funding, competing interests, data sharing Support from the German Federal Ministry of Education and Research (BMBF support code 01KG0708). Potential competing interests have been reported in full at the end of the paper on thebmj.com. Data are available from the corresponding author ([email protected]) or biostatistician ([email protected]). Study registration EudraCT no 2005-000752-32; ISRCTN no ISRCTN44359668

Prenatal cocaine exposure alters alpha2 receptor expression in adolescent rats

BACKGROUND: Prenatal cocaine exposure produces attentional deficits which to persist through early childhood. Given the role of norepinephrine (NE) in attentional processes, we examined the forebrain NE systems from prenatal cocaine exposed rats. Cocaine was administered during pregnancy via the clinically relevant intravenous route of administration. Specifically, we measured α(2)-adrenergic receptor (α(2)-AR) density in adolescent (35-days-old) rats, using [(3)H]RX821002 (5 nM). RESULTS: Sex-specific alterations of α(2)-AR were found in the hippocampus and amygdala of the cocaine-exposed animals, as well as an upregulation of α(2)-AR in parietal cortex. CONCLUSION: These data suggest that prenatal cocaine exposure results in a persistent alteration in forebrain NE systems as indicated by alterations in receptor density. These neurochemical changes may underlie behavioral abnormalities observed in offspring attentional processes following prenatal exposure to cocaine

Diagnostic criteria for persistent postural-perceptual dizziness (PPPD): Consensus document of the committee for the Classification of Vestibular Disorders of the Barany Society

This paper presents diagnostic criteria for persistent postural-perceptual dizziness (PPPD) to be included in the International Classification of Vestibular Disorders (ICVD). The term PPPD is new, but the disorder is not. Its diagnostic criteria were derived by expert consensus from an exhaustive review of 30 years of research on phobic postural vertigo, space-motion discomfort, visual vertigo, and chronic subjective dizziness. PPPD manifests with one or more symptoms of dizziness, unsteadiness, or non-spinning vertigo that are present on most days for three months or more and are exacerbated by upright posture, active or passive movement, and exposure to moving or complex visual stimuli. PPPD may be precipitated by conditions that disrupt balance or cause vertigo, unsteadiness, or dizziness, including peripheral or central vestibular disorders, other medical illnesses, or psychological distress. PPPD may be present alone or co-exist with other conditions. Possible subtypes await future identification and validation. The pathophysiologic processes underlying PPPD are not fully known. Emerging research suggests that it may arise from functional changes in postural control mechanisms, multi-sensory information processing, or cortical integration of spatial orientation and threat assessment. Thus, PPPD is classified as a chronic functional vestibular disorder. It is not a structural or psychiatric condition

A master protocol to investigate a novel therapy acetyl-L-leucine for three ultra-rare neurodegenerative diseases: Niemann-Pick type C, the GM2 gangliosidoses, and ataxia telangiectasia.

BACKGROUND The lack of approved treatments for the majority of rare diseases is reflective of the unique challenges of orphan drug development. Novel methodologies, including new functionally relevant endpoints, are needed to render the development process more feasible and appropriate for these rare populations and thereby expedite the approval of promising treatments to address patients' high unmet medical need. Here, we describe the development of an innovative master protocol and primary outcome assessment to investigate the modified amino acid N-acetyl-L-leucine (Sponsor Code: IB1001) in three separate, multinational, phase II trials for three ultra-rare, autosomal-recessive, neurodegenerative disorders: Niemann-Pick disease type C (NPC), GM2 gangliosidoses (Tay-Sachs and Sandhoff disease; "GM2"), and ataxia telangiectasia (A-T). METHODS/DESIGN The innovative IB1001 master protocol and novel CI-CS primary endpoints were developed through a close collaboration between the Industry Sponsor, Key Opinion Leaders, representatives of the Patient Communities, and National Regulatory Authorities. As a result, the open-label, rater-blinded study design is considerate of the practical limitations of recruitment and retention of subjects in these ultra-orphan populations. The novel primary endpoint, the Clinical Impression of Change in Severity© (CI-CS), accommodates the heterogenous clinical presentation of NPC, GM2, and A-T: at screening, the principal investigator appoints for each patient a primary anchor test (either the 8-m walk test (8MWT) or 9-hole peg test of the dominant hand (9HPT-D)) based on his/her unique clinical symptoms. The anchor tests are videoed in a standardized manner at each visit to capture all aspects related to the patient's functional performance. The CI-CS assessment is ultimately performed by independent, blinded raters who compare videos of the primary anchor test from three periods: baseline, the end of treatment, and the end of a post-treatment washout. Blinded to the time point of each video, the raters make an objective comparison scored on a 7-point Likert scale of the change in the severity of the patient's neurological signs and symptoms from video A to video B. To investigate both the symptomatic and disease-modifying effects of treatment, N-acetyl-L-leucine is assessed during two treatment sequences: a 6-week parent study and 1-year extension phase. DISCUSSION The novel CI-CS assessment, developed through a collaboration of all stakeholders, is advantageous in that it better ensures the primary endpoint is functionally relevant for each patient, is able to capture small but meaningful clinical changes critical to the patients' quality of life (fine-motor skills; gait), and blinds the primary outcome assessment. The results of these three trials will inform whether N-acetyl-L-leucine is an effective treatment for NPC, GM2, and A-T and can also serve as a new therapeutic paradigm for the development of future treatments for other orphan diseases. TRIAL REGISTRATION The three trials (IB1001-201 for Niemann-Pick disease type C (NPC), IB1001-202 for GM2 gangliosidoses (Tay-Sachs and Sandhoff), IB1001-203 for ataxia telangiectasia (A-T)) have been registered at www.clinicaltrials.gov (NCT03759639; NCT03759665; NCT03759678), www.clinicaltrialsregister.eu (EudraCT: 2018-004331-71; 2018-004406-25; 2018-004407-39), and https://www.germanctr.de (DR KS-ID: DRKS00016567; DRKS00017539; DRKS00020511)

Platelet counts and haemorrhagic diathesis in patients with myelodysplastic syndromes.

Most patients with myelodysplastic syndromes (MDS) present with single or multiple lineage cytopenias in peripheral blood despite a hypercellular bone marrow. Thrombocytopenia, attributable to ineffective platelet production by dysfunctional megakaryocytes, has been estimated to occur in 40-65% of patients. However, there are hardly any studies on the clinical relevance of low platelet counts in MDS. We retrospectively analysed data from 2900 patients in the Duesseldorf MDS Registry who were diagnosed at our laboratory between 1982 and 2007. At the time of diagnosis, 43% of the patients had a platelet count lower than 100 000/microL. Platelets were lower than 20 000/microL in 7% of the patients, especially in those with advanced stages of MDS, who showed a higher frequency of thrombocytopenia and platelet transfusion dependency. On multivariate analysis, platelet anisometry, hypocellularity of megakaryopoiesis, maturational defects of megakaryocytes and platelets &lt;20 000/microL were independent variables showing a statistically significant correlation (P &lt; 0.05) with clinical signs of bleeding. Platelets lower than 100 000/microL were associated with significantly shortened survival (P &lt; 0.00005), because of an increased risk of progression to acute myeloid leukaemia (AML) (30% vs. 21%) (P &lt; 0.02) and bleeding (16% vs. 8%) (P = 0.0005). Thrombocytopenia is a strong predictor of short survival, with or without haemorrhagic complications