Review: Transport of maternal cholesterol to the fetal circulation

Data obtained from recent studies in humans, rodents, and cell culture demonstrate that circulating maternal cholesterol can be transported to the fetus. The two major cell types responsible for the transport are trophoblasts and endothelial cells of the fetoplacental vasculature. Maternal lipoprotein-cholesterol is initially taken up by trophoblasts via receptor-mediated and receptor-independent processes, is transported by any number of the sterol transport proteins expressed by cells, and is effluxed or secreted out of the basal side via protein-mediated processes or by aqueous diffusion. This cholesterol is then taken up by the endothelium and effluxed to acceptors within the fetal circulation. The ability to manipulate the mass of maternal cholesterol that is taken up by the placenta and crosses to the fetus could positively impact development of fetuses affected with the Smith-Lemli-Opitz Syndrome (SLOS) that have reduced ability to synthesize cholesterol and possibly impact growth of fetuses unaffected by SLOS but with low birthweights.     

Reduced production of noggin by immune cells of patients with relapsing-remitting multiple sclerosis

Multiple sclerosis (MS) plaques are characterized by neurodegeneration, astrogliolis, the presence of immature oligodendrocytes and infiltrating immune cells. Recent studies revealed a putative role for noggin in both neurogenesis and oligodenrocytes development. In order to study the potential of peripheral immune cells to contribute to neurogenesis in MS, we studied the mRNA expression, protein secretion and regulation profile of noggin in peripheral blood mononuclear cells (PBMCs) of untreated patients with relapsing-remitting MS (RR-MS), interferon-β (IFN-β) treated RR-MS patients compared to matched healthy controls (HC). Basal levels of noggin mRNA expression, determined by quantitative real-time PCR were lower in untreated patients than in HC. No differences were found between untreated patients and IFN-β treated patients. Similarly, the secreted levels of noggin, detected in 24h PBMCs supernatants by ELISA, were decreased in untreated RR-MS patients than in HC. Again no significant differences were found between untreated patients and IFN-β treated patients. Stimulation with anti-CD3/CD28 mAbs increased noggin mRNA expression in untreated patients but not in HC. However, noggin mRNA levels in untreated patients PBMCs stimulated with anti-CD3/CD28 did not reach noggin levels in unstimulated PBMCs of HC. Purification of monocytes (CD14+) and T cells (CD3+ cells) by magnet-activated cell separation has demonstrated that noggin mRNA is predominantly expressed in CD3(+) cells in both HC and in RR-MS patients. This pattern also appeared in protein level of noggin, tested by Western blot. The incubation of the PBMCs with TNF-α increased the expression of noggin only in HC group. In conclusion, T cells possess the potential to participate in the induction of neurogeneration by the production of noggin. This potential seems to be defective in immune cells of RR-MS patients as there is reduced mRNA expression and protein secretion levels of noggin, insufficient stimulatory effect of CD3/CD28 stimulation and unresponsiveness to TNF-α in these patients PBMCs.     

Accuracy of diagnoses delivered by an automated hand-held nerve conduction device in comparison to standard electrophysiological testing in patients with unilateral leg symptoms

Introduction: Automated hand‐held nerve conduction study (NCS) devices are being marketed for use in the diagnosis of lumbosacral radiculopathy (LSR). In this study we compared the specificity and sensitivity of a hand‐held NCS device for the detection of LSR with standard electrodiagnostic study (EDX). Methods: Fifty patients referred to a tertiary referral electromyography (EMG) laboratory for testing of predominantly unilateral leg symptoms (weakness, sensory complaints, and/or pain) were included in the investigation. Twenty‐five normal “control” subjects were later recruited to calculate the specificity of the automated protocol. All patients underwent standard EDX and automated testing. Results: Raw NCS data were comparable for both techniques; however, computer‐generated interpretations delivered by the automated device showed high sensitivity with low specificity (i.e., many false positives) in both symptomatic patients and normal controls. Conclusions: The automated device accurately recorded raw data, but the interpretations provided were overly sensitive and lacked the specificity necessary for a screening or diagnostic examination. Muscle Nerve, 2011     

Pyrimethamine increases β-hexosaminidase A activity in patients with Late Onset Tay Sachs

ObjectiveTo assess whether or not pyrimethamine (PMT) can be used to enhance β-hexosaminidase A activity (HexA) in subjects with Late Onset Tay Sachs (LOTS), we studied the effect of incremental doses of PMT in vivo in 9 LOTS patients carrying the αG269S/c.1278insTACT mutations.MethodsPMT treatment was initiated at a dose of 6.25 mg, increasing gradually up to a maximal allowable dose of 75 mg daily at 4–6 weeks intervals for a total of up 10 months. Mean patients' age was 37.9 ± 16.1 yrs (range 20–67 years).ResultsLymphocyte HexA activity rose in all subjects, peaking at 78 ± 30% over baseline activity (mean ± SD; range 36–114%). The optimal PMT dose varied considerably, averaging at 30 ± 24.1 mg (range—6.25–75 mg, daily). Further increase in PMT beyond the optimal dose was associated with gradual loss of effect on lymphocyte HexA. Improvement in speech was seen within several weeks in 4 out of 9 subjects, mostly paralleling the initial increment in HexA. Mood stabilization was also perceived in 3 subjects, but this was more difficult to assess due to the concomitant use of psychotropic/mood stabilizing agents. Reversible decline in motor activity manifesting predominantly in more frequent falls was seen in 3 subjects when the PMT dose was increased beyond the peak effect generating dose.ConclusionsPMT therapy can increase HexA activity in LOTS in vivo. Optimal doses should be tailored individually to avoid loss of biochemical effects. Clear cut neurological and psychiatric effects are difficult to discern at this time, mostly due to short term study follow up and large inter-individual variability.     

Exploring anterograde associative memory in London taxi drivers

London taxi drivers are renowned for their navigation ability, spending a number of years acquiring 'The Knowledge' of London's complex layout and having to pass stringent examinations to obtain an operating licence. In several studies, this navigation skill has been associated with increased posterior but also decreased anterior hippocampal grey matter volume. Neuropsychologically, gain and loss has also been documented in taxi drivers; while very skilled at navigation in London, they are significantly poorer than controls at learning and recalling new object-location associations. Here we tested a group of London taxi drivers and matched control participants on this object-location associations task, while also subjecting them to a battery of challenging anterograde associative memory tests involving verbal, visual and auditory material both within and across modalities. Our aim was to assess whether their difficulty in previous studies reflected a general problem with associative memory, or was restricted to the spatial domain. We replicated previous findings of poor learning and memory of object-location associations. By contrast, their performance on the other anterograde associative memory tasks was comparable with controls. This resolves an outstanding question in the memory profile of London taxi drivers following hippocampal plasticity, and underlines the close relationship between space and the hippocampus.     

Pegylated interferon alfa and ribavirin for children with chronic hepatitis C

AIM:To study current treatment options for pediatric hepatitis C infection and their associated success rates.METHODS:We retrospectively reviewed charts of thirty children who had been treated with combination therapy of pegylated interferon alfa plus ribavirin for chronic hepatitis C infection.Patients had been treated with ribavirin(15 mg/kg per day) and either pegylated interferon alfa 2a(180 mg/m 2 once weekly) or pegylated interferon alfa 2b(1.5 mg/kg once weekly).Patients’ follow-up included subjective assessment of complaints,physical examination including weight and height,as well as laboratory evaluations for viral load [before treatment,at 12 wk,and 6 mo following treatment completion,as determined by sustained viral response(SVR)],complete blood count,liver enzymes,alkaline phosphatase,bilirubin,renal function tests,and thyroid function tests.For patients not achieving a two log decrease in viral load at treatment week 12,treatment was discontinued and the patient was considered a treatment non-responder.RESULTS:Thirty children aged 3-18 years were included in the study.Twenty patients(11 males,9 females) received pegylated interferon alfa 2b and ten patients(6 males,4 females) received pegylated interferon alfa 2a.Twenty-three patients were infected with genotype 1,six patients were infected with genotype 3,and one patient was infected with genotype 2.Twenty patients(67%) achieved SVR.Treatment success rates were 90% with pegylated interferon alfa 2a vs 55% with pegylated interferon alfa 2b.Although a trend was noted for improved outcomes in the group receiving pegylated interferon alfa 2a,there were no statistically significant outcome differences between the two treatment groups(P = 0.1).Treatment success was 56.5% for patients infected with genotype 1 virus,compared to 100% for patients infected with other genotypes(P = 0.064).There was no difference in treatment response between males and females.A cut-off age of twelve years was used to dichotomize younger vs older participants;however,no diff     

Effects of azadirachtin on the development and mortality of Lutzomyia longipalpis larvae (Diptera: Psychodidae: Phlebotominae)

The effects of azadirachtin A added to the standard diet on the development, mortality, and metamorphosis of Lutzomyia longipalpis Lutz & Neiva, 1912 were studied. Concentrations of 0.1, 1.0, and 10.0 microg of azadirachtin/mg of diet significantly increased larval mortality in comparison with nontreated insects. Concentrations 0.1 and 1.0 microg blocked the molt of larvae, which remained as third instars until the end of the experiment. The 10 microg/mg concentration resulted in greater molt inhibition. In this group, all insects stopped their development as second instars. Simultaneous addition of ecdysone (1 microg/mg) to the standard diet containing azadirachtin counteracted the effects of azadirachtin on mortality and inhibition of ecdysis. These results indicate that azadirachtin is a potent growth inhibitor of L. longipalpis.     

Pediatric Early Warning Systems aid in triage to intermediate versus intensive care for pediatric oncology patients in resource‐limited hospitals

Pediatric oncology patients hospitalized in resource‐limited settings are at high risk for clinical deterioration resulting in mortality. Intermediate care units (IMCUs) provide a cost‐effective alternative to pediatric intensive care units (PICUs). Inappropriate IMCU triage, however, can lead to poor outcomes and suboptimal resource utilization. In this study, we sought to characterize patients with clinical deterioration requiring unplanned transfer to the IMCU in a resource‐limited pediatric oncology hospital. Patients requiring subsequent early PICU transfer had longer PICU length of stay. PEWS results prior to IMCU transfer were higher in patients requiring early PICU transfer, suggesting PEWS can aid in triage between IMCU and PICU care.