Abnormal temporal lobe morphology in asymptomatic relatives of patients with hippocampal sclerosis: A replication study.

We investigated gray and white matter morphology in patients with mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE+HS) and first-degree asymptomatic relatives of patients with mTLE+HS. Using T1-weighted magnetic resonance imaging (MRI), we sought to replicate previously reported findings of structural surface abnormalities of the anterior temporal lobe in asymptomatic relatives of patients with mTLE+HS in an independent cohort. We performed whole-brain MRI in 19 patients with mTLE+HS, 14 first-degree asymptomatic relatives of mTLE+HS patients, and 32 healthy control participants. Structural alterations in patients and relatives compared to controls were assessed using automated hippocampal volumetry and cortical surface-based morphometry. We replicated previously reported cortical surface area contractions in the ipsilateral anterior temporal lobe in both patients and relatives compared to healthy controls, with asymptomatic relatives showing similar but less extensive changes than patients. These findings suggest morphologic abnormality in asymptomatic relatives of mTLE+HS patients, suggesting an inherited brain structure endophenotype

Choice of geographic unit influences socioeconomic inequalities in breast cancer survival

Socioeconomic differences in age-standardised crude survival for women diagnosed with breast cancer during 1991–1999 in England were influenced by the population of the geographic area used to assign the deprivation index, but not by the choice of index

Thromboembolic risk with IVIg: Incidence and risk factors in inflammatory neuropathy patients

Our objective was to evaluate whether IV immunoglobulin (IVIg) increases the risk of thromboembolic events in neurology outpatients with inflammatory neuropathies, as there is conflicting evidence supporting this hypothesis, mainly from non-neurologic cohorts. We investigated this question over 30 months in our cohort of patients with inflammatory neuropathies receiving regular IVIg anOur objective was to evaluate whether IV immunoglobulin (IVIg) increases the risk of thromboembolic events in neurology outpatients with inflammatory neuropathies, as there is conflicting evidence supporting this hypothesis, mainly from non-neurologic cohorts. We investigated this question over 30 months in our cohort of patients with inflammatory neuropathies receiving regular IVIg and found a greater incidence of arterial and venous thromboembolic events than population-based rates determined by hospital admissions data. Vascular risk factors were more common in the event group but there were no IVIg administration factors that contributed to the risk. This study suggests that IVIg may have a small but contributory role in determining thromboembolic risk in the inflammatory neuropathy cohort and more evidence is required before it is clear whether the current primary prevention guidelines are appropriate in this group of patients.d found a greater incidence of arterial and venous thromboembolic events than population-based rates determined by hospital admissions data. Vascular risk factors were more common in the event group but there were no IVIg administration factors that contributed to the risk. This study suggests that IVIg may have a small but contributory role in determining thromboembolic risk in the inflammatory neuropathy cohort and more evidence is required before it is clear whether the current primary prevention guidelines are appropriate in this group of patients

The Energy Landscape, Folding Pathways and the Kinetics of a Knotted Protein

The folding pathway and rate coefficients of the folding of a knotted protein are calculated for a potential energy function with minimal energetic frustration. A kinetic transition network is constructed using the discrete path sampling approach, and the resulting potential energy surface is visualized by constructing disconnectivity graphs. Owing to topological constraints, the low-lying portion of the landscape consists of three distinct regions, corresponding to the native knotted state and to configurations where either the N- or C-terminus is not yet folded into the knot. The fastest folding pathways from denatured states exhibit early formation of the N-terminus portion of the knot and a rate-determining step where the C-terminus is incorporated. The low-lying minima with the N-terminus knotted and the C-terminus free therefore constitute an off-pathway intermediate for this model. The insertion of both the N- and C-termini into the knot occur late in the folding process, creating large energy barriers that are the rate limiting steps in the folding process. When compared to other protein folding proteins of a similar length, this system folds over six orders of magnitude more slowly.Comment: 19 page

Association of plasma neurofilament light chain with disease activity in chronic inflammatory demyelinating polyradiculoneuropathy

BACKGROUND AND PURPOSE: This study was undertaken to explore associations between plasma neurofilament light chain (pNfL) concentration (pg/ml) and disease activity in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and examine the usefulness of pNfL concentrations in determining disease remission. METHODS: We examined pNfL concentrations in treatment-naïve CIDP patients (n = 10) before and after intravenous immunoglobulin (IVIg) induction treatment, in pNfL concentrations in patients on maintenance IVIg treatment who had stable (n = 15) versus unstable disease (n = 9), and in clinically stable IVIg-treated patients (n = 10) in whom we suspended IVIg to determine disease activity and ongoing need for maintenance IVIg. pNfL concentrations in an age-matched healthy control group were measured for comparison. RESULTS: Among treatment-naïve patients, pNfL concentration was higher in patients before IVIg treatment than healthy controls and subsequently reduced to be comparable to control group values after IVIg induction. Among CIDP patients on IVIg treatment, pNfL concentration was significantly higher in unstable patients than stable patients. A pNFL concentration > 16.6 pg/ml distinguished unstable treated CIDP from stable treated CIDP (sensitivity = 86.7%, specificity = 66.7%, area under receiver operating characteristic curve = 0.73). Among the treatment withdrawal group, there was a statistically significant correlation between pNfL concentration at time of IVIg withdrawal and the likelihood of relapse (r = 0.72, p < 0.05), suggesting an association of higher pNfL concentration with active disease. CONCLUSIONS: pNfL concentrations may be a sensitive, clinically useful biomarker in assessing subclinical disease activity

Routine blood monitoring in maintenance immunoglobulin treatment of inflammatory neuropathy: Is it clinically relevant?

Background: Pre-treatment screening for IgA deficiency and close monitoring of full blood count(FBC) and renal function is recommended with intravenous immunoglobulin(IVIg) therapy in neurological diseases. / Aims: To examine the frequency of biochemically defined and clinically significant episodes of treatment associated haemolysis, neutropenia, thrombocytopenia and acute kidney injury(AKI) in a cohort of patients on maintenance Immunoglobulin(Ig) therapy for inflammatory neuropathy. / Methods: A retrospective review of routine blood monitoring in patients from two UK specialist peripheral nerve centres. Accepted definitions for clinically and biochemically significant haemolysis, neutropenia, thrombocytopenia and AKI were used. / Results: 1919 infusion episodes in 90 patients were analysed. Age(mean(S.D)) = 58.09(14.4)years, 63% male, 72% CIDP(28% MMN), 97% IVIg(3% SCIg). Dose = 1.57(0.79)g/kg/month or 97.1(37.3)g/infusion, frequency:3.9(1.4) weeks. Relative IgA deficiency was noted in 2 individuals (prevalence:2.2%, 95%C.I.:0–5.2) who received a combined total of 38 infusions(3800 g IVIg) without adverse event. No clinically significant episodes of haemolysis, neutropenia, thrombocytopenia or AKI occurred in relation to treatment. An asymptomatic drop>10 g/L haemoglobin(Hb) occurred in 3.5%(95%CI:2.7–4.3) of treatment episodes in 38 individuals, mean reduction:17.7(7.4)g/L; lowest Hb:86 g/L. Lower pre-treatment haemoglobin correlated with risk of recurrent Ig-related drop(p:0.007). Two patients with chronic renal failure(stage 1 and 3) received 28(IV) and 104(SC) infusions respectively(6416 g) without impact on estimated glomerular filtration rate(eGFR). / Conclusions: No clinically significant Ig-related episodes of haemolysis or AKI were identified in this representative cohort. This suggests that routine monitoring is not essential in long-term Ig use but should be considered when clinically indicated

Diabetes is a Risk Factor for Pulmonary Tuberculosis: A Case-Control Study from Mwanza, Tanzania.

Diabetes and TB are associated, and diabetes is increasingly common in low-income countries where tuberculosis (TB) is highly endemic. However, the role of diabetes for TB has not been assessed in populations where HIV is prevalent. A case-control study was conducted in an urban population in Tanzania among culture-confirmed pulmonary TB patients and non-TB neighbourhood controls. Participants were tested for diabetes according to WHO guidelines and serum concentrations of acute phase reactants were measured. The association between diabetes and TB, and the role of HIV as an effect modifier, were examined using logistic regression. Since blood glucose levels increase during the acute phase response, we adjusted for elevated serum acute phase reactants. Among 803 cases and 350 controls the mean (SD) age was 34.8 (11.9) and 33.8 (12.0) years, and the prevalence of diabetes was 16.7% (95% CI: 14.2; 19.4) and 9.4% (6.6; 13.0), respectively. Diabetes was associated with TB (OR 2.2, 95% CI: 1.5; 3.4, p<0.001). However, the association depended on HIV status (interaction, p = 0.01) due to a stronger association among HIV uninfected (OR 4.2, 95% CI: 1.5; 11.6, p = 0.01) compared to HIV infected (OR 0.1, 95% CI: 0.01; 1.8, p = 0.13) after adjusting for age, sex, demographic factors and elevated serum acute phase reactants. Diabetes is a risk factor for TB in HIV uninfected, whereas the association in HIV infected patients needs further study. The increasing diabetes prevalence may be a threat to TB control

The cometary composition of a protoplanetary disk as revealed by complex cyanides

Observations of comets and asteroids show that the Solar Nebula that spawned our planetary system was rich in water and organic molecules. Bombardment brought these organics to the young Earth's surface, seeding its early chemistry. Unlike asteroids, comets preserve a nearly pristine record of the Solar Nebula composition. The presence of cyanides in comets, including 0.01% of methyl cyanide (CH3CN) with respect to water, is of special interest because of the importance of C-N bonds for abiotic amino acid synthesis. Comet-like compositions of simple and complex volatiles are found in protostars, and can be readily explained by a combination of gas-phase chemistry to form e.g. HCN and an active ice-phase chemistry on grain surfaces that advances complexity[3]. Simple volatiles, including water and HCN, have been detected previously in Solar Nebula analogues - protoplanetary disks around young stars - indicating that they survive disk formation or are reformed in situ. It has been hitherto unclear whether the same holds for more complex organic molecules outside of the Solar Nebula, since recent observations show a dramatic change in the chemistry at the boundary between nascent envelopes and young disks due to accretion shocks[8]. Here we report the detection of CH3CN (and HCN and HC3N) in the protoplanetary disk around the young star MWC 480. We find abundance ratios of these N-bearing organics in the gas-phase similar to comets, which suggests an even higher relative abundance of complex cyanides in the disk ice. This implies that complex organics accompany simpler volatiles in protoplanetary disks, and that the rich organic chemistry of the Solar Nebula was not unique.Comment: Definitive version of the manuscript is published in Nature, 520, 7546, 198, 2015. This is the author's versio

Loneliness, social support and cardiovascular reactivity to laboratory stress

Self-reported or explicit loneliness and social support have been inconsistently associated with cardiovascular reactivity (CVR) to stress. The present study aimed to adapt an implicit measure of loneliness, and use it alongside the measures of explicit loneliness and social support, to investigate their correlations with CVR to laboratory stress. Twenty-five female volunteers aged between 18 and 39 years completed self-reported measures of loneliness and social support, and an Implicit Association Test (IAT) of loneliness. The systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) reactivity indices were measured in response to psychosocial stress induced in the laboratory. Functional support indices of social support were significantly correlated with CVR reactivity to stress. Interestingly, implicit, but not explicit, loneliness was significantly correlated with DBP reactivity after one of the stressors. No associations were found between structural support and CVR indices. Results are discussed in terms of validity of implicit versus explicit measures and possible factors that affect physiological outcomes