Miracle-dz/UniFAR-FTUs huggingface dataset:
Influence of CYP2B6 polymorphisms on the persistence of plasma nevirapine concentrations following a single intra-partum dose for the prevention of mother to child transmission in HIV-infected Thai women.

OBJECTIVES To investigate the association of single nucleotide polymorphisms (SNPs) with nevirapine concentrations following intra-partum single-dose nevirapine. METHODS Plasma and DNA samples were obtained from 330 HIV-infected Thai women who received intra-partum single-dose nevirapine in the PHPT-2 clinical trial to prevent perinatal HIV transmission. Nine SNPs within CYP2B6, CYP3A4 and ABCB1 were genotyped by real-time PCR. Nevirapine plasma concentrations were determined by HPLC and used in a population pharmacokinetic analysis. RESULTS Higher nevirapine exposure was observed in women carrying the CYP2B6 516G>T polymorphism, but this did not reach statistical significance (P = 0.054). The TGATC CYP2B6 haplotype (g.3003T, 516G, 785A, g.18492T and g.21563C) was associated with increased nevirapine clearance and lower exposure (P = 0.0029). The median time for nevirapine concentrations to reach 10 ng/mL post-partum (nevirapine IC(50) for HIV-1) was 14 days [interquartile range (IQR, 14-18)] for TGATC homozygotes, 16 days (14-20) for TGATC heterozygotes and 18 days (14-20) for non-TGATC homozygotes (P = 0.020). CONCLUSIONS The CYP2B6 516G>T impact on nevirapine concentrations was less pronounced after intra-partum single-dose nevirapine than reported under steady-state conditions, perhaps due to lack of enzyme auto-induction at the time of dosing. Although the TGATC CYP2B6 haplotype may shorten the persistence of nevirapine post-partum, its practical implications for the prevention of HIV transmission or selection of resistance mutations are likely limited.
Negotiating knowledge: parents' experience of the neuropsychiatric diagnostic process for children with autism.

BACKGROUND Parents often recognize problems in their child's development earlier than health professionals do and there is new emphasis on the importance of involving parents in the diagnostic process. In Gothenburg, Sweden, over 100 children were identified as having an autism spectrum disorder (ASD) in 2009-11 through a general population language and autism screening of 2.5 year olds at the city's child healthcare centres. AIMS To increase understanding of parents' lived experience of the neuropsychiatric diagnostic process, i.e. the period from the initial screening at age 2.5 years to the 2-year follow-up of the ASD diagnosis. METHODS & PROCEDURES A qualitative design, a phenomenological hermeneutic method, was used. Interviews were conducted with parents of 11 children who were diagnosed with ASD 2 years prior. The parents were interviewed about their experiences of the neuropsychiatric diagnostic process, i.e. the time before the screening, the time during the neuropsychiatric multidisciplinary evaluation and the time after diagnosis. The interviews lasted for 45-130 min, and an interview guide with set questions was used. Most of the interviews were conducted at the parents' homes. OUTCOMES & RESULTS The essence that emerged from the data was negotiating knowledge, and the three themes capturing the parents' experiences of going through the process of having their child diagnosed with ASD were seeking knowledge, trusting and challenging experts, and empowered but alone. CONCLUSIONS & IMPLICATIONS The parents expected intervention to start directly after diagnosis but felt they had to fight to obtain the resources their child needed. After the process, they described that they felt empowered but still alone, i.e. although they received useful and important information about their child, they were left to manage the situation by themselves. As for clinical implications, the study points to the necessity of developing routines to support the parents during and after the diagnostic process. Recommended measures include developing a checklist outlining relevant contacts and agencies, establishing a coordinator responsible for each child, dividing the summary meeting at the clinic into two parts, making more than one visit to the preschool, and providing a parental training programme.
Hedgehog Signaling Alters Adipocyte Maturation of Human Mesenchymal Stem Cells

Human stem cells are powerful tools by which to investigate molecular mechanisms of cell growth and differentiation under normal and pathological conditions. Hedgehog signaling, the dysregulation of which causes several pathologies, such as congenital defects and cancer, is involved in several cell differentiation processes and interferes with adipocyte differentiation of rodent cells. The present study was aimed at investigating the effect of Hedgehog pathway modulation on adipocyte phenotype using different sources of human mesenchymal cells, such as bone marrow stromal cells and human multipotent adipose‐derived stem cells. We bring evidence that Hedgehog signaling decreases during human adipocyte differentiation. Inhibition of this pathway is not sufficient to trigger adipogenesis, but activation of Hedgehog pathway alters adipocyte morphology as well as insulin sensitivity. Analysis of glycerol‐3‐phosphate dehydrogenase activity and expression of adipocyte marker genes indicate that activation of Hedgehog signaling by purmorphamine impairs adipogenesis. In sharp contrast to reports in rodent cells, the maturation process, but not the early steps of human mesenchymal stem cell differentiation, is affected by Hedgehog activation. Hedgehog interferes with adipocyte differentiation by targeting CCAAT enhancer‐binding protein α and peroxisome proliferator‐activated receptor (PPAR) γ2 expression, whereas PPARγ1 level remains unaffected. Although Hedgehog pathway stimulation does not modify the total number of adipocytes, adipogenesis appears dramatically impaired, with reduced lipid accumulation, a decrease in adipocyte‐specific markers, and acquisition of an insulin‐resistant phenotype. This study indicates that a decrease in Hedgehog signaling is necessary but not sufficient to trigger adipocyte differentiation and unveils a striking difference in the adipocyte differentiation process between rodent and human mesenchymal stem cells.
Neurochemical identification of stereotypic burst‐firing neurons in the rat dorsal raphe nucleus using juxtacellular labelling methods

Recent electrophysiological studies have discovered evidence of heterogeneity of 5‐hydroxytryptamine (5‐HT) neurons in the mesencephalic raphe nuclei. Of particular interest is a subpopulation of putative 5‐HT neurons that display many of the electrophysiological properties of presumed 5‐HT‐containing neurons (regular and slow firing of single spikes with a broad waveform) but fire spikes in short, stereotyped bursts. In the present study we investigated the chemical identity of these neurons in rats utilizing in vivo juxtacellular labelling methods. Of ten dorsal raphe nucleus (DRN) neurons firing short stereotyped bursts within an otherwise regular firing pattern, all exhibited immunoreactivity for either 5‐HT (n = 6) or the 5‐HT synthesizing enzyme, tryptophan hydroxylase (TRH; n = 2) or both (n = 2). Supporting pharmacological experiments demonstrated that the burst firing DRN neurons demonstrated equal sensitivity to 5‐HT1A agonism and α1‐adrenoceptor antagonism to single spiking DRN neurons that we have previously identified as 5‐HT‐containing. Collectively these data provide direct evidence that DRN neurons that exhibit stereotyped burst firing activity are 5‐HT containing. The presence of multiple types of electrophysiologically distinct midbrain 5‐HT neurons is discussed.
A simple and reliable liquid chromatography-tandem mass spectrometry method for the determination of aflatoxin B1 in feed

A chromatographic method is proposed for the analysis of aflatoxin B1 in cereal-based feed, particularly targeted to dairy animals. The method is based on a solid–liquid extraction followed by a Mycosep 226 clean-up. Accuracy and precision were established at the LOQ (1 µg kg−1) with a spiked sample as well as with two other different naturally contaminated reference materials. The mean overall recovery (n = 18) was 100.8%, with a confidence interval of 2.7% and a CV% of 5.5%. The performance of the proposed method was compared with the AOAC method based on the use of immunoaffinity chromatography columns, proving that it could be considered a valid alternative. Moreover, the sample preparation is very simple and straightforward, potentially being applicable as a high-throughput method. On account of its simplicity and low cost, the method may be applied to the analysis of a large number of samples in the occasion of outbreaks of large-scale contamination.
Amphiphilic block copolymers for drug delivery.

Amphiphilic block copolymers (ABCs) have been used extensively in pharmaceutical applications ranging from sustained-release technologies to gene delivery. The utility of ABCs for delivery of therapeutic agents results from their unique chemical composition, which is characterized by a hydrophilic block that is chemically tethered to a hydrophobic block. In aqueous solution, polymeric micelles are formed via the association of ABCs into nanoscopic core/shell structures at or above the critical micelle concentration. Upon micellization, the hydrophobic core regions serve as reservoirs for hydrophobic drugs, which may be loaded by chemical, physical, or electrostatic means, depending on the specific functionalities of the core-forming block and the solubilizate. Although the Pluronics, composed of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide), are the most widely studied ABC system, copolymers containing poly(L-amino acid) and poly(ester) hydrophobic blocks have also shown great promise in delivery applications. Because each ABC has unique advantages with respect to drug delivery, it may be possible to choose appropriate block copolymers for specific purposes, such as prolonging circulation time, introduction of targeting moieties, and modification of the drug-release profile. ABCs have been used for numerous pharmaceutical applications including drug solubilization/stabilization, alteration of the pharmacokinetic profile of encapsulated substances, and suppression of multidrug resistance. The purpose of this minireview is to provide a concise, yet detailed, introduction to the use of ABCs and polymeric micelles as delivery agents as well as to highlight current and past work in this area.
Radiological and functional assessment of radiation-induced pulmonary damage following breast irradiation

Purpose. The purpose of this study was to compare late radiation-induced radiological abnormalities of the lung with spirometric observations. Radiological abnormalities were also related to theoretical calculations, in order to predict late effects based on dose-volume histograms. Patients and methods. Sixty-one breast cancer patients who had received postoperative radiotherapy were included. During a follow-up examination 3 years or more after start of radiotherapy, computed tomography (CT) scans and pulmonary function tests were performed. Grading of radiological abnormalities (fibrosis) was performed based on CT images. Based on the dose volume histograms of the lung, effective dose was calculated. Results. There was a positive correlation between the effective radiation dose and the fraction of patients that developed radiation induced fibrosis. No significant association was found between the normalized forced vital capacity (FVC) and the radiological abnormality score or the effective radiation dose. Conclusion. In this study we found no correlation between local radiation-induced changes in the lung tissue and overall lung function. The effective dose was a better predictive factor for radiation induced fibrosis than for overall lung function.
Reversible Phosphorylation as a Molecular Switch to Regulate Plasma Membrane Targeting of Acylated SH4 Domain Proteins

Acylated SH4 domains represent N‐terminal targeting signals that anchor peripheral membrane proteins such as Src kinases in the inner leaflet of plasma membranes. Here we provide evidence for a novel regulatory mechanism that may control the levels of SH4 proteins being associated with plasma membranes. Using a fusion protein of the SH4 domain of Leishmania HASPB and GFP as a model system, we demonstrate that threonine 6 is a substrate for phosphorylation. Substitution of threonine 6 by glutamate (to mimic a phosphothreonine residue) resulted in a dramatic redistribution from plasma membranes to intracellular sites with a particular accumulation in a perinuclear region. As shown by both pharmacological inhibition and RNAi‐mediated down‐regulation of the threonine/ serine‐specific phosphatases PP1 and PP2A, recycling back to the plasma membrane required dephosphorylation of threonine 6. We provide evidence that a cycle of phosphorylation and dephosphorylation may also be involved in intracellular targeting of other SH4 proteins such as the Src kinase Yes.
Taeniases and cysticercosis in Indonesia: past and present situations

SUMMARY The main aim of this study is to overview the past and present situations of human taeniases and cysticercosis in Indonesia and including future perspectives. Through joint projects from 1996, we have confirmed the occurrence of Taenia saginata (beef tapeworm) in Bali, of Taenia solium (pork tapeworm) mainly in Papua and sporadically in Bali, and of Taenia asiatica in North Sumatra. These taeniases were caused through eating uncooked pork and pig viscera for T. solium and T. asiatica, respectively, and beef for T. saginata. The distribution of these tapeworms in Indonesia is basically highly restricted by the traditional cultural and religious backgrounds in each island. T. saginata is relatively common in Bali although people consume pork ‘lawar’ more than beef ‘lawar’. Taeniases due to T. saginata or T. asiatica and T. solium and cysticercosis due to T. solium have also been sporadically reported in some other islands. Among these species, T. solium is exceptional since humans can be infected not only by larval stages (cysticerci) in pork but also by eggs released from human tapeworm carriers. Cysticercosis has been confirmed in Indonesia in humans, pigs and even dogs.
Epidemiological patterns of scoliosis in a spinal center in Saudi Arabia.

OBJECTIVE To study the patterns of scoliosis seen in a major Spinal Unit in Saudi Arabia. METHODS Medical records of 192 Saudi patients with scoliosis seen between 1992 and 1997 at the Spinal Unit of the Riyadh Medical Complex (which is a major spinal unit in the Kingdom) were studied and analyzed and epidemiological data was collected. RESULTS Fifty nine percent of all cases of scoliosis were idiopathic, 7% were secondary to poliomyelitis and 17% were congenital scoliosis. The mean age of discovery of idiopathic scoliosis was 12.5 years and at presentation was 16 years. The mean Cobb's angle at presentation was 58 degrees C. Adolescent type constituted 74% of idiopathic curves with a male to female ratio of 1:3.8. Thoracic curves were the most common followed by the double major curves. Half of the curves were right sided. Infantile idiopathic scoliosis constituted 8% with male to female ratio of 4:1 and here left thoracic curves formed 50%. The juvenile type constituted the remaining 18% with male to female ratio of 1:1.5. CONCLUSION The pattern of scoliosis in our study is comparable in many aspects with other studies carried out elsewhere, with the exception of delay in patients age at referral. We believe that our data could reflect a possible pattern of the epidemiology of scoliosis in Saudi Arabia, given the fact that there is no National Registry. To avoid delay in management, community education will help in the early detection of cases.
Clinical trial of lamivudine in children with chronic hepatitis B.

BACKGROUND Lamivudine therapy is effective for chronic hepatitis B infection in adults. We evaluated the efficacy and tolerability of lamivudine as a treatment for chronic infection with hepatitis B virus (HBV) in children. METHODS Children with chronic hepatitis B were randomly assigned in a 2:1 ratio to receive either oral lamivudine (3 mg per kilogram of body weight; maximum, 100 mg) or placebo once daily for 52 weeks. The primary end point was virologic response (defined by the absence of serum hepatitis B e antigen and serum HBV DNA) at week 52 of treatment. RESULTS Of the 403 children screened, 191 were randomly assigned to receive lamivudine and 97 to receive placebo. The rate of virologic response at week 52 was higher among children who received lamivudine than among those who received placebo (23 percent vs. 13 percent, P=0.04). Lamivudine therapy was well tolerated and was also associated with higher rates of seroconversion from hepatitis B e antigen to hepatitis B e antibody, normalization of alanine aminotransferase levels, and suppression of HBV DNA. CONCLUSIONS In children with chronic hepatitis B, 52 weeks of treatment with lamivudine was associated with a significantly higher rate of virologic response than was placebo.
Inflammatory and neurodegeneration markers during asymptomatic HSV-1 reactivation.

BACKGROUND Currently, it is unclear whether asymptomatic recurrent reactivations of herpes simplex virus type 1 (HSV-1) occur in the central nervous systems of infected people, and if these events could lead to a progressive deterioration of neuronal function. In this context, HSV-1 constitutes an important candidate to be included among the risk factors for the development of neuropathies associated with chronic neuroinflammation. OBJECTIVE The aim of this study was to assess in vivo inflammatory and neurodegenerative markers in the brain during productive and latent HSV-1 infection using a mouse model of herpes simplex encephalitis. METHODS Neuroinflammation and neurodegeneration markers were evaluated in mice trigeminal ganglia and cerebral cortex during HSV-1 infection, by immunohistochemistry, western blot, and RT-PCR. RESULTS Neuronal ICP4 viral antigen expression indicative of a reactivation episode during asymptomatic latency of HSV-1 infection in mice was accompanied by upregulation of neuroinflammatory (toll-like receptor-4, interferon α/β, and p-IRF3) and early neurodegenerative markers (phospho-tau and TauC3). CONCLUSIONS HSV-1 reactivation from latency induced neuroinflammatory and neurodegenerative markers in the brain of asymptomatic mice suggesting that recurrent reactivations could be associated with cumulative neuronal dysfunctions.
Neuroactive Sulphur Amino Acids Evoke a Calcium‐Dependent Transmitter Release from Cultured Neurones That Is Sensitive to Excitatory Amino Acid Receptor Antagonists

Abstract: A dose‐dependent, saturable, and calcium‐dependent release of γ‐[3H]aminobutyrate ([3H]GABA) from cortical neurones and D‐[3H]aspartate from cerebellar granule cells following stimulation by a range of l‐enantiomers of neuroactive acidic sulphur amino acids has been demonstrated. Moreover, the sulphur amino acid‐evoked release of the transmitter amino acids was found to be sensitive to the presence of both selective N‐methyl‐D‐aspartate and quisqualate/kainate receptor antagonists. Following the recent demonstration of an endogenous location for several of the acidic sulphur amino acids and their excitotoxic involvement in several neuropathological states and coupled with the knowledge that many important CNS connections are still undefined as far as their excitatory transmitter or transmitters are concerned, the present findings are of immediate importance in the continued search for endogenous excitatory amino acid agonists in addition to glutamate and aspartate.
The digestion of fibre by pigs

1. The effects of the amount and the type of dietary fibre on the apparent digestibility (AD) by growing pigs of neutral-detergent fibre (NDF) and NDF components, on nitrogen balance and on the rate of passage of digesta were studied using a semi-purified basal diet and fibre in the forms of soya-bean hulls, lupin (Lupinus sp.) hulls, pea (Pisum sativum) hulls, wheat bran, maize hulls, maize cobs, oat hulls and lucerne (Medicago sativa) stems. 2. Both the amount and the type of dietary fibre significantly influenced the AD of dietary dry matter, N and energy. The AD of NDF and of NDF components was markedly affected by the type and the amount of fibre in the diet. The proportion of NDF digested ranged from 0.016 to 0.905, of cellulose from 0.026 to 0.931 and of hemicellulose from 0.010 to 0.999. 3. N retention by the pigs ranged from 12.9 to 25.8 g/d and with some fibres there was a tendency towards increased N retention with increasing intakes of NDF. 4. Rate of passage of digesta, expressed as the 50 and 95% excretion times of stained feed particles, ranged from 22.2 to 85.1 h and 40.0 to 117.1 h respectively. Large individual variations in rate of passage occurred but, in general, the rate of passage tended to increase with increasing intakes of NDF. No strong associations between the rate of passage of digesta and apparent digestibility of NDF components were observed. 5. The results suggest that the extent of fibre digestibility depends predominantly on the origin of the fibre and to a lesser extent on the amount of fibre in the diet.
Subchronic pulmonary inflammation and fibrosis induced by silica in rats are attenuated by amiodarone.

A previous study demonstrated that the acute phase of silica-induced lung injury in rats can be attenuated by concomitant administration of amiodarone, a cationic amphiphilic drug that inhibits phospholipase activity in the lungs. The purpose of the present study was to determine whether continued amiodarone administration could inhibit subchronic silica-induced lung injury and fibrosis. Male Fischer-344 rats were administered amiodarone (150 mg/kg, p.o., 5 days/week) for 14 days and were then instilled with silica (100 mg/kg) intratracheally. Amiodarone treatment then continued for 60 days. Injury was evaluated by parameters in bronchoalveolar lavage fluid and fibrosis was assessed by lung hydroxyproline content and trichrome staining of collagen. Within the bronchoalveolar lavage fluid, amiodarone treatment resulted in significant decreases in silica-induced elevations in albumin levels, lactate dehydrogenase activity, beta-glucuronidase activity, and neutrophil influx. Amiodarone treatment resulted in significant reductions in silica-induced increases in lung weight and hydroxyproline levels; the diminution of fibrosis due to amiodarone treatment was confirmed histologically. These results indicate that subchronic pulmonary inflammation and fibrosis induced by silica in the rat can be attenuated by the concomitant administration of amiodarone.