A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome.

Wolfram syndrome (WS) is a rare childhood disease characterized by diabetes mellitus, diabetes insipidus, blindness, deafness, neurodegeneration and eventually early death, due to autosomal recessive mutations in the WFS1 (and WFS2) gene. While it is categorized as a neurodegenerative disease, it is increasingly becoming clear that other cell types besides neurons may be affected and contribute to the pathogenesis. MRI studies in patients and phenotyping studies in WS rodent models indicate white matter/myelin loss, implicating a role for oligodendroglia in WS-associated neurodegeneration. In this study, we sought to determine if oligodendroglia are affected in WS and whether their dysfunction may be the primary cause of the observed optic neuropathy and brain neurodegeneration. We demonstrate that 7.5-month-old Wfs1∆exon8 mice display signs of abnormal myelination and a reduced number of oligodendrocyte precursor cells (OPCs) as well as abnormal axonal conduction in the optic nerve. An MRI study of the brain furthermore revealed grey and white matter loss in the cerebellum, brainstem, and superior colliculus, as is seen in WS patients. To further dissect the role of oligodendroglia in WS, we performed a transcriptomics study of WS patient iPSC-derived OPCs and pre-myelinating oligodendrocytes. Transcriptional changes compared to isogenic control cells were found for genes with a role in ER function. However, a deep phenotyping study of these WS patient iPSC-derived oligodendroglia unveiled normal differentiation, mitochondria-associated endoplasmic reticulum (ER) membrane interactions and mitochondrial function, and no overt signs of ER stress. Overall, the current study indicates that oligodendroglia functions are largely preserved in the WS mouse and patient iPSC-derived models used in this study. These findings do not support a major defect in oligodendroglia function as the primary cause of WS, and warrant further investigation of neurons and neuron-oligodendroglia interactions as a target for future neuroprotective or -restorative treatments for WS.

Carer-supported home-based exercises designed to target physical activity levels and functional mobility after stroke: a scoping review.

PURPOSE: To explore the literature on carer-supported home-based exercise programs for people after stroke, as a form of physical activity. The review focus was to examine the training carers receive, the content of programs, and investigate the physical activity levels and functional mobility of people after stroke. MATERIALS AND METHODS: A scoping review was undertaken, guided by Joanna Briggs Institute methodology. The concept of home-based carer-supported exercise, in people after stroke, was searched across five databases. Outcomes of interest were physical activity levels and functional mobility. RESULTS: We screened 2285 references and included 10 studies: one systematic review, five randomised controlled trials, one trial with non-equivalent control, and four uncontrolled studies. Carer training ranged from one to twelve sessions. Exercise interventions commonly including walking, other whole body functional exercises and balance activities. In eight studies interventions were in addition to standard care. Five studies reported significant between-group differences for functional mobility, favouring the intervention. One study reported physical activity levels. CONCLUSION: There was large variation in the volume and content of training provided to carers. Physical activity levels were infrequently objectively reported. Future studies should include greater details on their protocols to allow for replication and implementation into clinical practice.

Carer-supported home-based exercises may improve functional mobility once home after a stroke.The optimal length, content, and model of delivery of carer training, so carers can provide better targeted home-based exercise support to people after stroke, is not known.Better monitoring of participation in home-based exercise and reporting of short and long-term physical activity is needed.

Unique case of duplex interventricular branching from the left coronary artery.

We report a rare morphological variant of the left coronary artery in this case of a female embalmed cadaver, where in the heart was nourished by double anterior and posterior interventricular arteries. These were branches of the left coronary artery and it was also observed that distribution of right coronary artery was very limited. The deceased may have been without symptoms in her life, but a prior knowledge of this kind of presentation would be very much informative to the interventional cardiologist and cardiothoracic surgeons in their protocol of treatment. This has implications for the coronary angiography and subsequent management of the ischemic heart disease.

Supersonic jet noise source distributions.

The purpose of this work is to examine the noise source distributions of shock-containing supersonic jets at various pressure ratios corresponding to fully expanded Mach numbers ranging from 1.0 to 1.4 in intervals of 0.2 for various nozzle exit diameters. Source location measurements using a phased array (beamforming), farfield jet noise measurements, and schlieren flow visualization are presented. It is found that supersonic noise source distributions are more complex than those of subsonic jets. The source distributions for supersonic jets can be divided into three different Strouhal regions. At low Strouhal numbers ( fD/U≤0.3), the noise source distributions appear very similar to those of a subsonic jet, as reported in open literature. This Strouhal region is dominated by jet-mixing noise associated with small-scale turbulence mixing. At high Strouhal numbers ( fD/U≥1.0), the noise source distributions are comprised of several repetitive sources at various discrete downstream jet locations that produce noise at all frequencies. The locations of these sources roughly correspond to the shock cells in the jet, and thus, vary with jet Mach number. Another region exists at Strouhal numbers between these two regions ( 0.3

Shared motherhood IVF: high delivery rates in a large study of treatments for lesbian couples using partner-donated eggs.

Shared motherhood IVF treatment is becoming increasingly accepted among assisted reproductive techique practitioners and patients in Europe, although data on its overall efficiency remain scarce. This 6-year retrospective study from a single, private, UK HFEA-regulated centre included consecutive lesbian couples (n = 121) undergoing shared motherhood IVF treatment (141 cycles). Recipients were more parous and had undergone more previous intrauterine insemination and IVF treatments than donor partners, who had slightly higher ovarian reserve markers than recipients. Indications in most cycles (60%) were non-medical. Most (79%) egg-providers were stimulated with gonadotrophin releasing hormone antagonist protocol, and no moderate or severe cases of ovarian hyperstimulation syndrome (OHSS) arose. A total of 172 fresh and vitrified-warmed embryo transfers were carried out: 70% at the blastocyst-stage and 58% involved a single embryo. Cumulative live birth rate per receiver was 60% (72/120), and twin delivery rate was 14% (10/72). Perinatal outcome parameters were better for singleton than twin pregnancies, although the latter also achieved generally favourable outcomes. No significant difference in cumulative outcomes were found between synchronized and non-synchronized cycles. Shared motherhood IVF combines ovarian stimulation with single blastocyst transfer to provide a safe and effective treatment modality offering reassuring obstetrical and perinatal outcomes.

Neonatal and obstetric outcomes of in vitro fertilization (IVF) and natural conception at a Chinese reproductive unit.

In vitro fertilization (lVF) has been associated with an increased risk of preterm delivery, caesarean delivery, low and very low birth-weight infants. The authors investigated the possible high risks of adverse health outcomes in infants conceived using IVF and intracytoplasmic sperm injection (ICSI). The present study includes 443 infants born to 424 women who conceived naturally and 694 infants born to 536 women that had IVF or ICSI. The study was conducted in the Department of Obstetrics at the Yu Huang Ding Hospital from 2008 to 2009. The main outcome measures were:gestational age, birth weight, mode of delivery, multiple pregnancy rates, and baby gender. The results showed significant differences between the neonatal and obstetric outcomes of IVF/ICSI and natural conception pregnancies. When referred to singletons only, there were no major differences seen in the neonatal and obstetric outcomes between the IVF and the control group.When the IVF group was divided into two sub-groups according to the patient's age (< 35 and > or = 35 years), there was no statistically significant difference between the two groups in the observed outcomes.

Omega-3 dietary Fatty Acid status of healthy older adults in Tasmania, Australia: an observational study.

OBJECTIVES: To determine the dietary and supplement intake of omega-3 (n-3) polyunsaturated fatty acids (PUFA) of older Tasmanian adults; their plasma n-3 PUFA status and the relationship between n-3 PUFA intake and plasma status. DESIGN: Cross-sectional study. SETTING: Launceston and surrounding regions, Tasmania, Australia. PARTICIPANTS: Seventy-three community-dwelling older adults: 23 men aged 70 ± 6.1 years and 50 women aged 70 ± 6.7 years. MEASUREMENTS: A validated, semi-quantitative food frequency questionnaire estimated dietary PUFA intake. The plasma phospholipid fraction of venous blood samples was analysed for fatty acid content. Anthropometric data was recorded. RESULTS: Thirty-five participants (48%) regularly ingested a fish oil supplement. Their plasma n-3 PUFA profile contained significantly more eicosapentaenoic acid (EPA) (odds ratio 3.14; 95% CI 1.37% to 7.30%; p<0.05) and docosahexaenoic acid (DHA) (odds ratio 2.64; 95% CI 1.16% to 6.01%; p<0.05) than non-supplement users. Fish and meat were the main dietary sources of n-3 PUFAs. Participants most commonly consumed fish 3-4 times per week. Significant associations of dietary α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA) and DHA with plasma n-3 PUFAs were noted but not always between dietary and plasma counterparts. CONCLUSION: Without the use of fish oil supplements, most study participants were unable to meet the recommended daily intake of 0.5g EPA and DHA combined; however, the plasma n-3 PUFA profile of non-supplement-users was still robust compared to other Australian and overseas studies.

Persistent elevation of central pulse pressure during postural stress in patients with type 2 diabetes mellitus.

An abnormal increase or decrease in blood pressure (BP) in response to postural stress is associated with increased risk of developing hypertension and stroke. However, the haemodynamic responses contributing to changes in central BP with postural stress are not well characterised. We aimed to determine this in controls compared to patients with type 2 diabetes mellitus (T2DM), whom we hypothesised would have an abnormal postural response. 41 participants (20 control, 21 T2DM) underwent measurement of brachial and central BP (by radial tonometry), with simultaneous bioimpedance cardiography (to determine stroke volume (SV) and cardiac output (CO)) and heart rate variability in seated and standing postures. Systemic vascular resistance (SVR; mean arterial pressure/CO), and arterial elastance (EA; end systolic pressure/SV) were calculated. Postural changes were defined as seated minus standing values. Central pulse pressure (PP) was higher in patients with T2DM and did not change from seated-to-standing positions, whereas there was a significant decrease upon standing in controls (P<0.05). The change in central systolic BP (SBP) correlated with change in SVR and EA in controls (r=0.67 and 0.68, P<0.05, respectively), but not in patients with T2DM (r=-0.05 and r=0.03, P>0.05, respectively). SV was the only significant correlate of change in central SBP in T2DM patients (r=0.62, P<0.05) and this was not observed in controls (r=-0.08 P>0.05). We conclude that central haemodynamic responses to postural stress are altered in patients with T2DM and result in persistent elevation of central PP while standing. This may contribute to increased cardiovascular risk associated with T2DM.

Postprandial platelet aggregation: effects of different meals and glycemic index.

BACKGROUND/OBJECTIVES: Hyperglycaemia is associated with increased platelet aggregation that increases the risk of thrombosis in people with type-2 diabetes and cardiovascular disease. Low glycemic index (GI) meals high in carbohydrate or moderately high in protein have been shown to acutely reduce postprandial excursions of plasma glucose and insulin compared with high carbohydrate high GI meals. However, it is not known whether these differences in glucose and insulin profile also impact on postprandial platelet aggregation. This study aimed to investigate the acute effects of three iso-energetic meals, on measures of postprandial platelet aggregation, in healthy individuals. SUBJECTS/METHODS: A randomised cross-over study compared the acute effects of a high GI high carbohydrate (HGI-HC), a low GI high carbohydrate (LGI-HC) and a low GI moderately high in protein and fat (LGI-MPF) meal on postprandial platelet aggregation, glucose, insulin and triglyceride concentrations. Comparisons were made at fasting, 60 and 120 min postprandially. RESULTS: A total of 32 volunteers (mean ± s.d.; age 59.9 ± 11.7 years, BMI 27.1 ± 3.7 kg/m(2)) participated in the study. Results showed significant reductions in maximum platelet aggregation postprandially with nonsignificant differences (all P > 0.29) between the three meals. Glucose and insulin were significantly (both P < 0.001) higher at 60 min postprandially on the HGI-HC meal compared with both LGI-HC and LGI-MPF meals. Triglycerides were not significantly different (all P > 0.25) between the three test meals. CONCLUSION: In healthy individuals platelet aggregation is reduced postprandially but this decrease is similar between meals of different GI that induce different glucose and insulin responses.

Loss of WT1 expression in the endometrium of infertile PCOS patients: a hyperandrogenic effect?

CONTEXT: In fertile patients the endometrial Wilms tumor suppressor gene (WT1) is expressed during the window of implantation. Polycystic ovary syndrome (PCOS) patients suffer from hyperandrogenemia and infertility and have elevated endometrial androgen receptor (AR) expression. WT1 is known to be down-regulated by AR. Therefore, the expression of WT1 and its targets may be altered in PCOS endometrium. OBJECTIVE: The objective of the study was to assess the expression and regulation of WT1 and selected downstream targets in secretory endometrium from ovulatory PCOS (ovPCOS) and fertile women. DESIGN AND PATIENTS: Endometrial samples were obtained from 25 ovPCOS and 25 fertile patients. MAIN OUTCOME MEASURE: Endometrial expression of WT1 and selected downstream targets were assessed by immunohistochemistry and RT-PCR. The androgen effect on WT1 expression was determined in vitro by immunoblots and RT-PCR. The expression of WT1 and its targets was quantified in fertile and ovPCOS stromal cells in the presence of androgens by RT-PCR. Caspase-3/7 activity was measured to evaluate sensitivity to drug-induced apoptosis. RESULTS: WT1 expression was down-regulated in secretory-phase ovPCOS endometrium. Stromal expression of Bcl-2 and p27 was higher, and epidermal growth factor receptor was lower in ovPCOS than in fertile patients. Endometrial stromal expression of WT1, Bcl-2, Bcl-2-associated X protein, and ß-catenin was regulated by androgens. Apoptosis levels were reduced in ovPCOS samples and androgen-treated fertile samples. CONCLUSION: WT1 expression is down-regulated in ovPCOS endometrium during the window of implantation. Androgens regulate the expression of WT1 and its targets during endometrial decidualization. The altered balance between WT1 and AR in the endometrium of PCOS patients may jeopardize the success of decidualization and endometrial receptivity.

Functional antibody deficiency in a patient with type I Gaucher disease.

Gaucher disease (GD), the most common lysosomal storage disorder, demonstrates an autosomal recessive pattern of inheritance. The genetic defect in GD leads to decreased production of the lysosomal enzyme glucosylceramide hydrolase, thereby resulting in the deposition of glucosylceramide sphingolipids within multiple organ systems. Although the precise mechanisms remain unclear, GD is usually associated with chronic antigenic stimulation and hyperimmunoglobulinaemia. We report a novel case of type I GD coexisting with relatively low serum immunoglobulins, impaired antibody production, and recurrent bacterial infections in a 62-year-old male. The patient had been diagnosed with GD 30 years previously and had subsequently started enzyme replacement therapy. Since being diagnosed with GD, the patient had suffered from repeated episodes of acute bronchitis and a recent severe bout of community-acquired pneumonia that required a lengthy hospitalization. On our initial evaluation, the patient had laboratory testing that demonstrated: decreased serum IgG, IgG2, and IgA levels; reduced absolute CD3(+)/CD4(+), CD3(+)/CD8(+), and lymphocyte counts; low IgG titres to pneumococcal polysaccharide vaccine; and decreased anti-tetanus antibodies. Lymphocyte function analysis demonstrated a normal response to phytohaemagglutinin, and decreased responses to concanavalin A and pokeweed mitogen. Repeat testing after 6 months revealed normal serum immunoglobulin levels and mitogenic responses. Although the explanation for our observed transient hypogammaglobulinaemia remains unclear, this patient's clinical constellation (i.e. repeated infections, hypogammaglobulinaemia and lymphopenia, decreased post-vaccination titres, and impaired responses to some mitogens) shares overlapping features with common variable immunodeficiency (CVID).

The effect of 4-week chilli supplementation on metabolic and arterial function in humans.

OBJECTIVE: To investigate the effects of regular chilli ingestion on some indicators of metabolic and vascular function. DESIGN: A randomized cross-over dietary intervention study. SETTING: Launceston, Australia. SUBJECTS: Healthy free-living individuals. INTERVENTION: Thirty-six participants (22 women and 14 men), aged 46+/-12 (mean+/-s.d.) years; BMI 26.4+/-4.8 kg/m(2), consumed 30 g/day of a chilli blend (55% cayenne chilli) with their normal diet (chilli diet), and a bland diet (chilli-free) for 4 weeks each. Metabolic and vascular parameters, including plasma glucose, serum lipids and lipoproteins, insulin, basal metabolic rate, blood pressure, heart rate, augmentation index (AIx; an indicator of arterial stiffness), and subendocardial-viability ratio (SEVR; a measure of myocardial perfusion), were measured at the end of each diet. In a sub-study, during week 3 of each dietary period, the vascular responses of 15 subjects to glyceryl-trinitrate (GTN) and salbutamol were also studied. RESULTS: For the whole group, there were no significant differences between any of the measured parameters when compared at the end of the two dietary periods. When analysed separately, men had a lower resting heart rate (P=0.02) and higher SEVR (P=0.05) at the end of the chilli diet than the bland diet. In the sub-study, baseline AIx on the chilli diet was lower (P<0.001) than on the bland diet, but there was no difference in the effects of GTN and salbutamol between the two diets. CONCLUSION: Four weeks of regular chilli consumption has no obvious beneficial or harmful effects on metabolic parameters but may reduce resting heart rate and increase effective myocardial perfusion pressure time in men.

Dietary supplementation with chickpeas for at least 5 weeks results in small but significant reductions in serum total and low-density lipoprotein cholesterols in adult women and men.

AIM: To compare the effects of a chickpea-supplemented diet and those of a wheat-supplemented diet on human serum lipids and lipoproteins. METHODS: Forty-seven free-living adults participated in a randomized crossover weight maintenance dietary intervention involving two dietary periods, chickpea-supplemented and wheat-supplemented diets, each of at least 5 weeks duration. RESULTS: The serum total cholesterol and low-density lipoprotein cholesterol levels were significantly lower (both p < 0.01) by 3.9 and 4.6%, respectively, after the chickpea-supplemented diet as compared with the wheat-supplemented diet. Protein (0.9% of energy, p = 0.01) and monounsaturated fat (3.3% of total fat, p < 0.001) intakes were slightly but significantly lower and the carbohydrate intake significantly higher (1.7% of energy, p < 0.001) on the chickpea-supplemented diet as compared with the wheat-supplemented diet. Multivariate analyses suggested that the differences in serum lipids were mainly due to small differences in polyunsaturated fatty acid and dietary fibre contents between the two intervention diets. CONCLUSIONS: Inclusion of chickpeas in an intervention diet results in lower serum total and low-density lipoprotein cholesterol levels as compared with a wheat-supplemented diet.

Advanced oocyte cryopreservation will not undermine the practice of ethical egg sharing.

The fear that the ethics and practice of egg sharing will be undermined by the growing success of oocyte cryopreservation is not based on published evidence. Separate contracts and directed counselling of donors and recipients as required by law in the UK provide protection against potential pitfalls with egg sharing. The cost and waiting time for egg donation might even fall should oocyte cryopreservation become a practicable procedure.

Minimizing risk in anonymous egg donation.

Assisted conception carries with it known and putative medical and surgical risks. Exposing healthy women to these risks in order to harvest eggs for donation when a safer alternative exists is morally and ethically unacceptable. Egg sharing minimizes risk and provides a source of eggs for donation. Anonymity protects all parties involved and should not be removed.

Effects of a high monounsaturated fat, tomato-rich diet on serum levels of lycopene.

OBJECTIVE: To compare the effect of a modified fat, monounsaturated-fat-enriched diet and a high-carbohydrate low-fat diet with high lycopene content on the serum concentration of lycopene and other carotenoids. DESIGN: A randomised crossover dietary intervention study. SETTING: Melbourne, Australia--Healthy free-living men. SUBJECTS: A total of 13 healthy males between the age of 20 and 70 y, recruited via advertisements in newspapers and university newsletter. INTERVENTION: A randomised dietary intervention with two diets of 14 days each. The two diets were--(1) high-fat monounsaturated-fat-enriched (MUFA) and (2) high-carbohydrate low-fat (HCLF). Both the diets contained the same basic foods and a controlled carotenoid content high in lycopene. RESULTS: A significant increase in serum total lycopene occurred, by 126% on the MUFA diet (P <0.001) and 108% on the HCLF diet (P=0.001). A reduction in serum cryptoxanthin (27% on MUFA diet and 25% on HCLF) and alpha-carotene (43% on the MUFA diet and 25% on the HCLF diet) was observed. No change was observed for the other carotenoids. Comparing the end of the two diets, no statistically significant difference was observed for lycopene or the other carotenoids. CONCLUSION: In all, 15% of energy from fat or 38% of energy from fat (predominantly monounsaturated fat) in the diet does not have a significant differential effect on serum lycopene. SPONSORSHIP: The study was partially funded by the Grains Research Development Corporation, Canberra and Meadow Lea Foods Ltd, Mascot, Australia. HJ Heinz, Melbourne, Australia provided the tomato products and some funds for their carotenoid analysis.

Should non-patient volunteers donate eggs?

Egg donation is associated with medical and surgical risks regardless of the source of eggs, be it through commercial, altruistic or more recent egg-share donors. Egg sharing is the only system that does not turn a healthy woman (the donor) into a patient. Using carefully selected egg-share donors, pregnancy rates for both donor and recipient are as good as any egg-donation programme, with one cohort of eggs being used with more efficiency. We propose that anonymous egg sharing, as licensed by the Human Fertilisation and Embryology Authority (HFEA), minimizes risk, is ethically sound and should be considered as the only acceptable form of anonymous egg donation.