Ultrasonographic Evaluation of Cerebral Arterial and Venous Haemodynamics in Multiple Sclerosis: A Case-Control Study

Objective

Although recent studies excluded an association between Chronic Cerebrospinal Venous Insufficiency and Multiple Sclerosis (MS), controversial results account for some cerebrovascular haemodynamic impairment suggesting a dysfunction of cerebral autoregulation mechanisms. The aim of this cross-sectional, case-control study is to evaluate cerebral arterial inflow and venous outflow by means of a non-invasive ultrasound procedure in Relapsing Remitting (RR), Primary Progressive (PP) Multiple Sclerosis and age and sex-matched controls subjects.

Material and Methods

All subjects underwent a complete extra-intracranial arterial and venous ultrasound assessment with a color-coded duplex sonography scanner and a transcranial doppler equipment, in both supine and sitting position by means of a tilting chair. Basal arterial and venous morphology and flow velocities, postural changes in mean flow velocities (MFV) of middle cerebral arteries (MCA), differences between cerebral venous outflow (CVF) in clinostatism and in the seated position (ΔCVF) and non-invasive cerebral perfusion pressure (CPP) were evaluated.

Results

85 RR-MS, 83 PP-MS and 82 healthy controls were included. ΔCVF was negative in 45/85 (52.9%) RR-MS, 63/83 (75.9%) PP-MS (p = 0.01) and 11/82 (13.4%) controls (p<0.001), while MFVs on both MCAs in sitting position were significantly reduced in RR-MS and PP-MS patients than in control, particularly in EDSS≥5 subgroup (respectively, 42/50, 84% vs. 66/131, 50.3%, p<0.01 and 48.3±2 cm/s vs. 54.6±3 cm/s, p = 0.01). No significant differences in CPP were observed within and between groups.

Conclusions

The quantitative evaluation of cerebral blood flow (CBF) and CVF and their postural dependency may be related to a dysfunction of autonomic nervous system that seems to characterize more disabled MS patients. It''s not clear whether the altered postural control of arterial inflow and venous outflow is a specific MS condition or simply an “epiphenomenon” of neurodegenerative events.     

Extrajugular pathways of human cerebral venous blood drainage assessed by duplex ultrasound.

Cerebral venous drainage in humans is thought to be ensured mainly via the internal jugular veins (IJVs). However, anatomic, angiographic, and ultrasound studies suggest that the vertebral venous system serves as an important alternative drainage route. We assessed venous blood volume flow in vertebral veins (VVs) and IJVs of 12 healthy volunteers using duplex ultrasound. Measurements were performed at rest and during a transient bilateral IJV and a circular neck compression. Total venous blood volume flow at rest was 766 +/- 226 ml/min (IJVs: 720 +/- 232, VVs: 47 +/- 33 ml/min). During bilateral IJV compression, VV flow increased to 128 +/- 64 ml/min. Circular neck compression, causing an additional deep cervical vein obstruction, led to a further rise in VV volume flow (186 +/- 70 ml/min). As the observed flow increase did not compensate for IJV flow cessation, other parts of the vertebral venous system, like the intraspinal epidural veins and the deep cervical veins, have to be considered as additional alternative drainage pathways.     

Multiple Sclerosis and CCSVI: A Population-Based Case Control Study

Background

Chronic cerebrospinal venous insufficiency (CCSVI) has been associated to multiple sclerosis (MS).

Objective

To evaluate the possible association between CCSVI and MS, using a population-based control design.

Methods

A random cohort of 148 incident MS patients were enrolled in the study. We have also studied 20 patients with clinically isolated syndrome (CIS), 40 patients with other neurological diseases (OND), and 172 healthy controls. Transcranial (TCC) and Echo Color Doppler (ECD) were carried out in 380 subjects. A subject was considered CCSVI positive if ≥2 venous hemodynamic criteria were fulfilled.

Results

CCSVI was present in 28 (18.9%) of the MS patients, in 2 (10%) of CIS patients, in 11 (6.4%) of the controls, and in 2 (5%) of the OND patients. A significant association between MS and CCSVI was found with an odds ratio of 3.41 (95% confidence interval 1.63–7.13; p = 0.001). CCSVI was significantly more frequent among MS subjects with a disease duration longer than 144 months (26.1% versus 12.6% of patients with duration shorter than 144 months; p = 0.03) and among patients with secondary progressive (SP) and primary progressive (PP) forms (30.2% and 29.4, respectively) than in patients with relapsing remitting (RR) MS (14.3%). A stronger association was found considering SP and PP forms (age adjusted OR = 4.7; 95% CI 1.83–12.0, p = 0.001); the association was weaker with the RR patients (age adjusted OR = 2.58; 95%CI 1.12–5.92; p = 0.02) or not significant in CIS group (age adjusted OR = 2.04; 95%CI 0.40–10.3; p = 0.4).

Conclusions

A higher frequency of CCSVI has been found in MS patients; it was more evident in patients with advanced MS, suggesting that CCSVI could be related to MS disability.     

Effect of CCR5-Δ32 heterozygosity on HIV-1 susceptibility: a meta-analysis

Background

So far, many studies have investigated the distribution of CCR5 genotype between HIV-1 infected patients and uninfected people. However, no definite results have been put forward about whether heterozygosity for a 32-basepair deletion in CCR5 gene (CCR5-Δ32) can affect HIV-1 susceptibility.

Methods

We performed a meta-analysis of 18 studies including more than 12000 subjects for whom the CCR5-Δ32 polymorphism was genotyped. Odds ratio (OR) with 95% confidence interval (CI) were employed to assess the association of CCR5-Δ32 polymorphism with HIV-1 susceptibility.

Results

Compared with the wild-type CCR5 homozygotes, the pooled OR for CCR5-Δ32 heterozygotes was 1.02 (95%CI, 0.88–1.19) for healthy controls (HC) and 0.95 (95%CI, 0.71–1.26) for exposed uninfected (EU) controls. Similar results were found in stratified analysis by ethnicity, sample size and method of CCR5-Δ32 genotyping.

Conclusions

The meta-analysis indicated that HIV-1 susceptibility is not significantly affected by heterozygosity for CCR5-Δ32.     

MRI Evidence for Altered Venous Drainage and Intracranial Compliance in Mild Traumatic Brain Injury

Purpose

To compare venous drainage patterns and associated intracranial hydrodynamics between subjects who experienced mild traumatic brain injury (mTBI) and age- and gender-matched controls.

Methods

Thirty adult subjects (15 with mTBI and 15 age- and gender-matched controls) were investigated using a 3T MR scanner. Time since trauma was 0.5 to 29 years (mean 11.4 years). A 2D-time-of-flight MR-venography of the upper neck was performed to visualize the cervical venous vasculature. Cerebral venous drainage through primary and secondary channels, and intracranial compliance index and pressure were derived using cine-phase contrast imaging of the cerebral arterial inflow, venous outflow, and the craniospinal CSF flow. The intracranial compliance index is the defined as the ratio of maximal intracranial volume and pressure changes during the cardiac cycle. MR estimated ICP was then obtained through the inverse relationship between compliance and ICP.

Results

Compared to the controls, subjects with mTBI demonstrated a significantly smaller percentage of venous outflow through internal jugular veins (60.9±21% vs. controls: 76.8±10%; p = 0.01) compensated by an increased drainage through secondary veins (12.3±10.9% vs. 5.5±3.3%; p<0.03). Mean intracranial compliance index was significantly lower in the mTBI cohort (5.8±1.4 vs. controls 8.4±1.9; p<0.0007). Consequently, MR estimate of intracranial pressure was significantly higher in the mTBI cohort (12.5±2.9 mmHg vs. 8.8±2.0 mmHg; p<0.0007).

Conclusions

mTBI is associated with increased venous drainage through secondary pathways. This reflects higher outflow impedance, which may explain the finding of reduced intracranial compliance. These results suggest that hemodynamic and hydrodynamic changes following mTBI persist even in the absence of clinical symptoms and abnormal findings in conventional MR imaging.     

Correlation of circulating omentin-1 with bone mineral density in multiple sclerosis: the crosstalk between bone and adipose tissue

Background

Patients with multiple sclerosis (MS) are at increased risk of osteoporosis and fractures. Adipose tissue-derived adipokines may play important roles in the osteoimmunology of MS. In order to determine whether omentin-1 and vaspin may be related to bone health in MS patients, we compared circulating levels of these recently identified adipokines, between MS patients and healthy controls.

Methods

A total of 35 ambulatory MS patients with relapsing-remitting courses were compared with 38 age- and sex-matched healthy controls. Bone mineral density (BMD) was determined for the lumbar spine (L2–L4) and the proximal femur using dual-energy x-ray absorptiometry. Circulating omentin-1, vaspin, osteocalcin, osteopontin, osteoprotegerin, the receptor activator of nuclear factor-κB ligand, matrix metalloproteinase 9, C-reactive protein and 25-hydroxy vitamin D levels were evaluated by highly specific enzyme-linked immunosorbent assay methods.

Results

There was no significant difference between the two groups regarding bone-related cytokines, adipocytokines, and the BMD measurements of patients with MS and the healthy controls. However, in multiple regression analysis, serum omentin-1 levels were positively correlated with BMD at the femoral neck (β = 0.49, p = 0.016), total hip (β = 0.42, p = 0.035), osteopontin (β = 0.42, p = 0.030) and osteocalcin (β = 0.53, p = 0.004) in MS patients. No correlations were found between vaspin, biochemical, and BMD measures in both groups.

Conclusions

Elevated omentin-1 serum levels are correlated with BMD at the femoral neck and the serum levels of osteocalcin and osteopontin in MS patients. Therefore, there is crosstalk between adipose tissue and bone in MS.     

FADS2 function loss at the cancer hotspot 11q13 locus diverts lipid signaling precursor synthesis to unusual eicosanoid fatty acids

Background

Genes coding for the fatty acid desaturases (FADS1, 2, 3) localized at the cancer genomic hotspot 11q13 locus are required for the biosynthesis of 20 carbon polyunsaturated fatty acids (PUFA) that are direct eicosanoid precursors. In several cancer cell lines, FADS2 encoded Δ6 and Δ8 desaturation is not functional.

Methodology/Principal Findings

Analyzing MCF7 cell fatty acids with detailed structural mass spectrometry, we show that in the absence of FADS2 activity, the FADS1 product Δ5-desaturase operates to produce 5,11,14–20∶3 and 5,11,14,17–20∶4. These PUFA are missing the 8–9 double bond of the eicosanoid signaling precursors arachidonic acid (5,8,11,14–20∶4) and eicosapentaenoic acid (5,8,11,14,17–20∶5). Heterologous expression of FADS2 restores Δ6 and Δ8-desaturase activity and normal eicosanoid precursor synthesis.

Conclusions/Significance

The loss of FADS2-encoded activities in cancer cells shuts down normal PUFA biosynthesis, deleting the endogenous supply of eicosanoid and downstream docosanoid precursors, and replacing them with unusual butylene-interrupted fatty acids. If recapitulated in vivo, the normal eicosanoid and docosanoid cell signaling milieu would be depleted and altered due to reduction and substitution of normal substrates with unusual substrates, with unpredictable consequences for cellular communication.     

Mitochondrial membrane potential in human neutrophils is maintained by complex III activity in the absence of supercomplex organisation

Background

Neutrophils depend mainly on glycolysis for their energy provision. Their mitochondria maintain a membrane potential (Δψ_m), which is usually generated by the respiratory chain complexes. We investigated the source of Δψ_m in neutrophils, as compared to peripheral blood mononuclear leukocytes and HL-60 cells, and whether neutrophils can still utilise this Δψ_m for the generation of ATP.

Methods and Principal Findings

Individual activity of the oxidative phosphorylation complexes was significantly reduced in neutrophils, except for complex II and V, but Δψ_m was still decreased by inhibition of complex III, confirming the role of the respiratory chain in maintaining Δψ_m. Complex V did not maintain Δψ_m by consumption of ATP, as has previously been suggested for eosinophils. We show that complex III in neutrophil mitochondria can receive electrons from glycolysis via the glycerol-3-phosphate shuttle. Furthermore, respiratory supercomplexes, which contribute to efficient coupling of the respiratory chain to ATP synthesis, were lacking in neutrophil mitochondria. When HL-60 cells were differentiated to neutrophil-like cells, they lost mitochondrial supercomplex organisation while gaining increased aerobic glycolysis, just like neutrophils.

Conclusions

We show that neutrophils can maintain Δψ_m via the glycerol-3-phosphate shuttle, whereby their mitochondria play an important role in the regulation of aerobic glycolysis, rather than producing energy themselves. This peculiar mitochondrial phenotype is acquired during differentiation from myeloid precursors.     

Brain viscoelasticity alteration in chronic-progressive multiple sclerosis

Introduction

Viscoelastic properties indicate structural alterations in biological tissues at multiple scales with high sensitivity. Magnetic Resonance Elastography (MRE) is a novel technique that directly visualizes and quantitatively measures biomechanical tissue properties in vivo. MRE recently revealed that early relapsing-remitting multiple sclerosis (MS) is associated with a global decrease of the cerebral mechanical integrity. This study addresses MRE and MR volumetry in chronic-progressive disease courses of MS.

Methods

We determined viscoelastic parameters of the brain parenchyma in 23 MS patients with primary or secondary chronic progressive disease course in comparison to 38 age- and gender-matched healthy individuals by multifrequency MRE, and correlated the results with clinical data, T2 lesion load and brain volume. Two viscoelastic parameters, the shear elasticity μ and the powerlaw exponent α, were deduced according to the springpot model and compared to literature values of relapsing-remitting MS.

Results

In chronic-progressive MS patients, μ and α were reduced by 20.5% and 6.1%, respectively, compared to healthy controls. MR volumetry yielded a weaker correlation: Total brain volume loss in MS patients was in the range of 7.5% and 1.7% considering the brain parenchymal fraction. All findings were significant (P<0.001).

Conclusions

Chronic-progressive MS disease courses show a pronounced reduction of the cerebral shear elasticity compared to early relapsing-remitting disease. The powerlaw exponent α decreased only in the chronic-progressive stage of MS, suggesting an alteration in the geometry of the cerebral mechanical network due to chronic neuroinflammation.     

Induction of Bcl-2 expression by hepatitis B virus pre-S2 mutant large surface protein resistance to 5-fluorouracil treatment in Huh-7 cells

Background

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with poor prognosis due to resistance to conventional chemotherapy and limited efficacy of radiotherapy. Our previous studies have indicated that expression of Hepatitis B virus pre-S2 large mutant surface antigen (HBV pre-S2Δ) is associated with a significant risk of developing HCC. However, the relationship between HBV pre-S2Δ protein and the resistance of chemotherapeutic drug treatment is still unclear.

Methodology/Principal Findings

Here, we show that the expression of HBV pre-S2Δ mutant surface protein in Huh-7 cell significantly promoted cell growth and colony formation. Furthermore, HBV pre-S2Δ protein increased both mRNA (2.7±0.5-fold vs. vehicle, p = 0.05) and protein (3.2±0.3-fold vs. vehicle, p = 0.01) levels of Bcl-2 in Huh-7 cells. HBV pre-S2Δ protein also enhances Bcl-2 family, Bcl-xL and Mcl-1, expression in Huh-7 cells. Meanwhile, induction of NF-κB p65, ERK, and Akt phosphorylation, and GRP78 expression, an unfolded protein response chaperone, were observed in HBV pre-S2Δ and HBV pre-S-expressing cells. Induction of Bcl-2 expression by HBV pre-S2Δ protein resulted in resistance to 5-fluorouracil treatment in colony formation, caspase-3 assay, and cell apoptosis, and can enhance cell death by co-incubation with Bcl-2 inhibitor. Similarly, transgenic mice showed higher expression of Bcl-2 in liver tissue expressing HBV pre-S2Δ large surface protein in vivo.

Conclusion/Significance

Our result demonstrates that HBV pre-S2Δ increased Bcl-2 expression which plays an important role in resistance to 5-fluorouracil-caused cell death. Therefore, these data provide an important chemotherapeutic strategy in HBV pre-S2Δ-associated tumor.     

CCR5Δ32 genotype leads to a Th2 type directed immune response in ESRD patients

Background

In patients with end stage renal disease (ESRD) we observed protection from inflammation-associated mortality in CCR5Δ32 carriers, leading to CCR5 deficiency, suggesting impact of CCR5Δ32 on inflammatory processes. Animal studies have shown that CCR5 deficiency is associated with a more pronounced Th2 type immune response, suggesting that in human CCR5Δ32 carriers the immune response may be more Th2 type directed. So, in the present study we determined the Th1-Th2 type directed immune response in ESRD patients carrying and not carrying the CCR5Δ32 genetic variant after stimulation.

Methodology/Principal Findings

We tested this hypothesis by determining the levels of IFN-γ and IL-4 and the distribution of Th1, Th2 and Th17 directed circulating CD4+ and CD8+ T cells and regulatory T cells (Tregs) after stimulation in ESRD patients with (n = 10) and without (n = 9) the CCR5Δ32 genotype. The extracellular levels of IFN-γ and IL-4 did not differ between CCR5Δ32 carriers and non carriers. However, based on their intracellular cytokine profile the percentages IL-4 secreting CD4+ and CD8+ T cells carrying the CCR5Δ32 genotype were significantly increased (p = 0.02, respectively p = 0.02) compared to non carriers, indicating a more Th2 type directed response. Based on their intracellular cytokine profile the percentages IFN-γ and IL-17 secreting T cells did not differ between carriers and non-carriers nor did the percentage Tregs, indicating that the Th1, Th17 and T regulatory response was not affected by the CCR5Δ32 genotype.

Conclusions/Significance

This first, functional human study shows a more pronounced Th2 type immune response in CCR5Δ32 carriers compared to non carriers. These differences may be involved in the previously observed protection from inflammation-associated mortality in ESRD patients carrying CCR5Δ32.     

How yield relates to ash content, ��13C and ��18O in maize grown under different water regimes

Background and Aims

Stable isotopes have proved a valuable phenotyping tool when breeding for yield potential and drought adaptation; however, the cost and technical skills involved in isotope analysis limit its large-scale application in breeding programmes. This is particularly so for Δ¹⁸O despite the potential relevance of this trait in C₄ crops. The accumulation of minerals (measured as ash content) has been proposed as an inexpensive way to evaluate drought adaptation and yield in C₃ cereals, but little is known of the usefulness of this measure in C₄ cereals such as maize (Zea mays). The present study investigates how yield relates to ash content, Δ¹³C and Δ¹⁸O, and evaluates the use of ash content as an alternative or complementary criterion to stable isotopes in assessing yield potential and drought resistance in maize.

Methods

A set of tropical maize hybrids developed by CIMMYT were subjected to different water availabilities, in order to induce water stress during the reproductive stages under field conditions. Ash content and Δ¹³C were determined in leaves and kernels. In addition, Δ¹⁸O was measured in kernels.

Key Results

Water regime significantly affected yield, ash content and stable isotopes. The results revealed a close relationship between ash content in leaves and the traits informing about plant water status. Ash content in kernels appeared to reflect differences in sink–source balance. Genotypic variation in grain yield was mainly explained by the combination of ash content and Δ¹⁸O, whilst Δ¹³C did not explain a significant percentage of such variation.

Conclusions

Ash content in leaves and kernels proved a useful alternative or complementary criterion to Δ¹⁸O in kernels for assessing yield performance in maize grown under drought conditions.     

Food composition of the diet in relation to changes in waist circumference adjusted for body mass index

Background

Dietary factors such as low energy density and low glycemic index were associated with a lower gain in abdominal adiposity. A better understanding of which food groups/items contribute to these associations is necessary.

Objective

To ascertain the association of food groups/items consumption on prospective annual changes in “waist circumference for a given BMI” (WC_BMI), a proxy for abdominal adiposity.

Design

We analyzed data from 48,631 men and women from 5 countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Anthropometric measurements were obtained at baseline and after a median follow-up time of 5.5 years. WC_BMI was defined as the residuals of waist circumference regressed on BMI, and annual change in WC_BMI (ΔWC_BMI, cm/y) was defined as the difference between residuals at follow-up and baseline, divided by follow-up time. The association between food groups/items and ΔWC_BMI was modelled using centre-specific adjusted linear regression, and random-effects meta-analyses to obtain pooled estimates.

Results

Higher fruit and dairy products consumption was associated with a lower gain in WC_BMI whereas the consumption of white bread, processed meat, margarine, and soft drinks was positively associated with ΔWC_BMI. When these six food groups/items were analyzed in combination using a summary score, those in the highest quartile of the score – indicating a more favourable dietary pattern –showed a ΔWC_BMI of −0.11 (95% CI −0.09 to −0.14) cm/y compared to those in the lowest quartile.

Conclusion

A dietary pattern high in fruit and dairy and low in white bread, processed meat, margarine, and soft drinks may help to prevent abdominal fat accumulation.     

Impaired thymic selection and abnormal antigen-specific T cell responses in Foxn1(Δ/Δ) mutant mice

Background

Foxn1^Δ/Δ mutant mice have a specific defect in thymic development, characterized by a block in TEC differentiation at an intermediate progenitor stage, and blocks in thymocyte development at both the DN1 and DP cell stages, resulting in the production of abnormally functioning T cells that develop from an atypical progenitor population. In the current study, we tested the effects of these defects on thymic selection.

Methodology/Principal Findings

We used Foxn1^Δ/Δ; DO11 Tg and Foxn1^Δ/Δ; OT1 Tg mice as positive selection and Foxn1^Δ/Δ; MHCII I-E mice as negative selection models. We also used an in vivo system of antigen-specific reactivity to test the function of peripheral T cells. Our data show that the capacity for positive and negative selection of both CD4 and CD8 SP thymocytes was reduced in Foxn1^Δ/Δ mutants compared to Foxn1^+/Δ control mice. These defects were associated with reduction of both MHC Class I and Class II expression, although the resulting peripheral T cells have a broad TCR Vβ repertoire. In this deficient thymic environment, immature CD4 and CD8 SP thymocytes emigrate from the thymus into the periphery. These T cells had an incompletely activated profile under stimulation of the TCR signal in vitro, and were either hypersensitive or hyporesponsive to antigen-specific stimulation in vivo. These cell-autonomous defects were compounded by the hypocellular peripheral environment caused by low thymic output.

Conclusions/Significance

These data show that a primary defect in the thymic microenvironment can cause both direct defects in selection which can in turn cause indirect effects on the periphery, exacerbating functional defects in T cells.     

Risk of all-cause mortality in HIV infected patients is associated with clinical, immunologic predictors and the CCR5 Δ32 deletion

Objective

Investigation of the interplay between the CCR5 Δ32/wt genotype and demographic, epidemiological, clinical and immunological factors associated with mortality in the cART era.

Design

Longitudinal data from 507 HIV-infected patients following the Δ32 allele detection were analyzed.

Methods

Cumulative 15 years mortality was calculated using Kaplan-Meyer methodology. Hazard ratios were estimated using univariate Cox models. Basing on Akakie information criteria and statistical significance multivariate Cox model was constructed and effect plots presenting adjusted hazard ratio time-dependency were drawn. Analysis of the association of all-cause mortality and CCR5 Δ32/wt genotype prior to the antiretroviral treatment (cART) initiation (n = 507) and on the therapy (n = 422) was also performed.

Results

A mortality rate of 2.66 (CI 2.57–3.19) per 100 person-years was observed. Univariate analysis factors modifying the risk of death included the CCR5 genotype, gender, history of cART, AIDS diagnosis and also CD4 lymphocyte nadir, zenith, the latest CD4 count and stable levels >500 cells/µl. For multivariate analysis the following predictors were selected: CCR5 genotype (HR for wt/wt 2.53, CI 1.16–5.53, p = 0.02), gender (HR for males 1.91, 95%CI 1.1–3.36, p = 0.023), introduction of combined antiretroviral treatment (HR 4.85, CI 3.0–7.89, if untreated or treated <1 month, p<0.0001) CD4 count of 500 cells/µl for six months or more (HR 4.16, CI 1.95–8.88 if not achieved, p = 0.028), the latest CD4 count (HR 5.44, CI 3.39–8.74 for <100 cells/µl, p<0.0001) and history of AIDS (HR 1.69, CI 1.03–2.79, p = 0.039). Among untreated individuals the Δ32/wt genotype was associated with notably better survival (p = 0.026), while among cART treated individuals the Δ32 mutation did not correlate significantly with higher survival rates (p = 0.23).

Conclusions

The Δ32 CCR5 allele is associated with a reduction of the risk of all-cause mortality in HIV (+) patients alongside clinical and immunologic predictors such as AIDS, history of cART, lymphocyte CD4 cell count and gender.     

Obesity impact on the attentional cost for controlling posture

Background

This study investigated the effects of obesity on attentional resources allocated to postural control in seating and unipedal standing.

Methods

Ten non obese adults (BMI = 22.4±1.3, age = 42.4±15.1) and 10 obese adult patients (BMI = 35.2±2.8, age = 46.2±19.6) maintained postural stability on a force platform in two postural tasks (seated and unipedal). The two postural tasks were performed (1) alone and (2) in a dual-task paradigm in combination with an auditory reaction time task (RT). Performing the RT task together with the postural one was supposed to require some attentional resources that allowed estimating the attentional cost of postural control. 4 trials were performed in each condition for a total of 16 trials.

Findings

(1) Whereas seated non obese and obese patients exhibited similar centre of foot pressure oscillations (CoP), in the unipedal stance only obese patients strongly increased their CoP sway in comparison to controls. (2) Whatever the postural task, the additional RT task did not affect postural stability. (3) Seated, RT did not differ between the two groups. (4) RT strongly increased between the two postural conditions in the obese patients only, suggesting that body schema and the use of internal models was altered with obesity.

Interpretation

Obese patients needed more attentional resources to control postural stability during unipedal stance than non obese participants. This was not the case in a more simple posture such as seating. To reduce the risk of fall as indicated by the critical values of CoP displacement, obese patients must dedicate a strong large part of their attentional resources to postural control, to the detriment of non-postural events. Obese patients were not able to easily perform multitasking as healthy adults do, reflecting weakened psycho-motor abilities.     

SPL7013 Gel (VivaGel?) Retains Potent HIV-1 and HSV-2 Inhibitory Activity following Vaginal Administration in Humans

SPL7013 Gel (VivaGel^®) is a microbicide in development for prevention of HIV and HSV. This clinical study assessed retention and duration of antiviral activity following vaginal administration of 3% SPL7013 Gel in healthy women. Participants received 5 single doses of product with ≥5 days between doses. A cervicovaginal fluid (CVF) sample was collected using a SoftCup™ pre-dose, and immediately, or 1, 3, 12 or 24 h post-dose. HIV-1 and HSV-2 antiviral activities of CVF samples were determined in cell culture assays. Antiviral activity in the presence of seminal plasma was also tested. Mass and concentration of SPL7013 in CVF samples was determined. Safety was assessed by reporting of adverse events. Statistical analysis was performed using the Wilcoxon signed-rank test with Bonferroni adjustment; p≤0.003 was significant. Eleven participants completed the study. Inhibition of HIV-1 and HSV-2 by pre-dose CVF samples was negligible. CVF samples obtained immediately after dosing almost completely inhibited (median, interquartile range) HIV-1 [96% (95,97)] and HSV-2 [86% (85,94)], and activity was maintained in all women at 3 h (HIV-1 [96% (95,98), p = 0.9]; HSV-2 [94% (91,97), p = 0.005]). At 24 h, >90% of initial HIV-1 and HSV-2 inhibition was maintained in 6/11 women. SPL7013 was recovered in CVF samples obtained at baseline (46% of 105 mg dose). At 3 and 24 h, 22 mg and 4 mg SPL7013, respectively, were recovered. More than 70% inhibition of HIV-1 and HSV-2 was observed if there was >0.5 mg SPL7013 in CVF samples. High levels of antiviral activity were retained in the presence of seminal plasma. VivaGel was well tolerated with no signs or symptoms of vaginal, vulvar or cervical irritation reported. Potent antiviral activity was observed against HIV-1 and HSV-2 immediately following vaginal administration of VivaGel, with activity maintained for at least 3 h post-dose. The data provide evidence of antiviral activity in a clinical setting, and suggest VivaGel could be administered up to 3 h before coitus.

Trial Registration

The study is registered at ClinicalTrials.gov under identifier: {"type":"clinical-trial","attrs":{"text":"NCT00740584","term_id":"NCT00740584"}}NCT00740584     

First-borns carry a higher metabolic risk in early adulthood: evidence from a prospective cohort study

Background

Birth order has been associated with early growth variability and subsequent increased adiposity, but the consequent effects of increased fat mass on metabolic risk during adulthood have not been assessed. We aimed to quantify the metabolic risk in young adulthood of being first-born relative to those born second or subsequently.

Methodology and Principal Findings

Body composition and metabolic risk were assessed in 2,249 men, aged 17–19 years, from a birth cohort in southern Brazil. Metabolic risk was assessed using a composite z-score integrating standardized measurements of blood pressure, total cholesterol, high density lipoprotein, triglycerides and fat mass. First-borns had lower birth weight z-score (Δ = −0.25, 95%CI −0.35, −0.15,p<0.001) but showed greater weight gain during infancy (change in weight z-score from birth to 20 months: Δ = 0.39, 95%CI 0.28–0.50, p<0.0001) and had greater mean height (Δ = 1.2 cm, 95%CI: 0.7–1.6, p<0.0001) and weight (Δ = 0.34 kg, 95%CI: 0.13–0.55, p<0.002) at 43 months. This greater weight and height tracked into early adulthood, with first-borns being significantly taller, heavier and with significantly higher fat mass than later-borns. The metabolic risk z-score was significantly higher in first-borns.

Conclusions/Significance

First-born status is associated with significantly elevated adiposity and metabolic risk in young adult men in Brazil. Our results, linking cardiovascular risk with life history variables, suggest that metabolic risk may be associated with the worldwide trend to smaller family size and it may interact with changes in behavioural or environmental risk factors.     

Universal stress proteins are important for oxidative and acid stress resistance and growth of Listeria monocytogenes EGD-e in vitro and in vivo

Background

Pathogenic bacteria maintain a multifaceted apparatus to resist damage caused by external stimuli. As part of this, the universal stress protein A (UspA) and its homologues, initially discovered in Escherichia coli K-12 were shown to possess an important role in stress resistance and growth in several bacterial species.

Methods and Findings

We conducted a study to assess the role of three homologous proteins containing the UspA domain in the facultative intracellular human pathogen Listeria monocytogenes under different stress conditions. The growth properties of three UspA deletion mutants (Δlmo0515, Δlmo1580 and Δlmo2673) were examined either following challenge with a sublethal concentration of hydrogen peroxide or under acidic conditions. We also examined their ability for intracellular survival within murine macrophages. Virulence and growth of usp mutants were further characterized in invertebrate and vertebrate infection models.Tolerance to acidic stress was clearly reduced in Δlmo1580 and Δlmo0515, while oxidative stress dramatically diminished growth in all mutants. Survival within macrophages was significantly decreased in Δlmo1580 and Δlmo2673 as compared to the wild-type strain. Viability of infected Galleria mellonella larvae was markedly higher when injected with Δlmo1580 or Δlmo2673 as compared to wild-type strain inoculation, indicating impaired virulence of bacteria lacking these usp genes. Finally, we observed severely restricted growth of all chromosomal deletion mutants in mice livers and spleens as compared to the load of wild-type bacteria following infection.

Conclusion

This work provides distinct evidence that universal stress proteins are strongly involved in listerial stress response and survival under both in vitro and in vivo growth conditions.     

Chronic cerebrospinal vascular insufficiency is not associated with HLA DRB1*1501 status in multiple sclerosis patients

Background

Chronic cerebrospinal venous insufficiency (CCSVI) was described as a vascular condition characterized by anomalies of veins outside the skull was reported to be associated with multiple sclerosis (MS). The objective was to assess the associations between HLA DRB1*1501 status and the occurrence of CCSVI in MS patients.

Methodology/Principal Findings

This study included 423 of 499 subjects enrolled in the Combined Transcranial and Extracranial Venous Doppler Evaluation (CTEVD) study. The HLA DRB1*1501 status was obtained in 268 MS patients and 155 controls by genotyping rs3135005, a SNP associated with DRB1*1501 status. All subjects underwent a clinical examination and Doppler scan of the head and neck. The frequency of CCSVI was higher (OR = 4.52, p<0.001) in the MS group 56.0% vs. 21.9% in the controls group and also higher in the progressive MS group 69.8% vs. 49.5% in the non-progressive MS group. The 51.9% frequency of HLA DRB1*1501 positivity (HLA⁺) in MS was higher compared (OR = 2.33, p<0.001) to 31.6% to controls. The HLA⁺ frequency in the non-progressive (51.6%) and progressive MS groups (52.3%) was similar. The frequency of HLA⁺ CCSVI⁺ was 40.7% in progressive MS, 27.5% in non-progressive MS and 8.4% in controls. The presence of CCSVI was independent of HLA DRB1*1501 status in MS patients.

Conclusions/Significance

The lack of strong associations of CCSVI with HLA DRB1*1501 suggests that the role of the underlying associations of CCSVI in MS should be interpreted with caution. Further longitudinal studies should determine whether interactions between these factors can contribute to disease progression in MS.