Higher-order cellular information processing with synthetic RNA devices.
The engineering of biological systems is anticipated to provide effective solutions to challenges that include energy and food production, environmental quality, and health and medicine. Our ability to transmit information to and from living systems, and to process and act on information inside cells, is critical to advancing the scale and complexity at which we can engineer, manipulate, and probe biological systems. We developed a general approach for assembling RNA devices that can execute higher-order cellular information processing operations from standard components. The engineered devices can function as logic gates (AND, NOR, NAND, or OR gates) and signal filters, and exhibit cooperativity. RNA devices process and transmit molecular inputs to targeted protein outputs, linking computation to gene expression and thus the potential to control cellular function.


Surrogate Data Methods Based on a Shuffling of the Trials for Synchrony Detection: The Centering Issue.
We investigate several distribution-free dependence detection procedures, all based on a shuffling of the trials, from a statistical point of view. The mathematical justification of such procedures lies in the bootstrap principle and its approximation properties. In particular, we show that such a shuffling has mainly to be done on centered quantities-that is, quantities with zero mean under independence-to construct correct p-values, meaning that the corresponding tests control their false positive (FP) rate. Thanks to this study, we introduce a method, named permutation UE, which consists of a multiple testing procedure based on permutation of experimental trials and delayed coincidence count. Each involved single test of this procedure achieves the prescribed level, so that the corresponding multiple testing procedure controls the false discovery rate (FDR), and this with as few assumptions as possible on the underneath distribution, except independence and identical distribution across trials. The mathematical meaning of this assumption is discussed, and it is in particular argued that it does not mean what is commonly referred in neuroscience to as cross-trials stationarity. Some simulations show, moreover, that permutation UE outperforms the trial-shuffling of Pipa and Grün ( 2003 ) and the MTGAUE method of Tuleau-Malot et al. ( 2014 ) in terms of single levels and FDR, for a comparable amount of false negatives. Application to real data is also provided.


Percentage tumor necrosis following chemotherapy in neuroblastoma correlates with MYCN status but not survival.
The percentage of chemotherapy-induced necrosis in primary tumors corresponds with outcome in several childhood malignancies, including high-risk metastatic diseases. In this retrospective pilot study, the authors assessed the importance of postchemotherapy necrosis in high-risk neuroblastoma with a histological and case notes review of surgically resected specimens. The authors reviewed all available histology of 31 high-risk neuroblastoma cases treated with COJEC (dose intensive etoposide and vincristine with either cyclophosphamide, cisplatin or carboplatin) or OPEC/OJEC (etoposide, vincristine and cyclophosphamide with alternating cisplatin [OPEC] or carboplatin [OJEC]) induction chemotherapy in 2 Children's Cancer & Leukaemia Group (CCLG) pediatric oncology centers. The percentage of postchemotherapy necrosis was assessed and compared with MYCN amplification status and overall survival. The median percentage of postchemotherapy tumor necrosis was 60%. MYCN status was available for 28 cases, of which 12 were amplified (43%). Survival in cases with ≥ 60% necrosis or ≥ 90% necrosis was not better than those with less necrosis, nor was percentage necrosis associated with survival using Cox regression. However, MYCN-amplified tumors showed a higher percentage of necrosis than non-MYCN-amplified tumors, 71.3% versus 37.2% (P = .006). This effect was not related to prechemotherapy necrosis and did not confer improved overall survival. Postchemotherapy tumor necrosis is higher in patients with MYCN amplification. In this study, postchemotherapy necrosis did not correlate with overall survival and should not lead to modification of postoperative treatment. However, these findings need to be confirmed in a larger prospective study of children with high-risk neuroblastoma.


Daytime noninvasive ventilatory support for patients with ventilatory pump failure: a narrative review.
Over the past three decades, the use of noninvasive ventilation or "NIV" to assuage symptoms of hypoventilation for patients with early onset or mild ventilatory pump failure has been extended to up to the use of continuous noninvasive ventilatory support (CNVS) at full ventilatory support settings as a definitive alternative to tracheostomy mechanical ventilation. NVS, along with mechanical insufflation-exsufflation, now provides a noninvasive option for the management of both chronic and acute respiratory failure for these patients. The most common diagnoses for which these methods are useful include chest wall deformities, neuromuscular diseases, morbid obesity, high level spinal cord injury and idiopathic, primary or secondary disorders of the ventilatory control. Thus, NVS is being used in diverse settings: critical care units, medical wards, at home, and in extended care. The aim of this review is to examine the techniques used for daytime support.


Caregiver characteristics and bereavement needs: Findings from a population study.
Globally, most care for people with life-limiting illnesses is provided by informal caregivers. Identifying characteristics of caregivers that may have unmet needs and negative outcomes can help provide better support to facilitate adjustment. We compared characteristics, expressed unmet needs and outcomes for spousal caregivers, with other caregivers at the end of life, by gender and age. The South Australian Health Omnibus is an annual, random, face-to-face, cross-sectional survey wherein respondents are asked about end-of-life care. Participants were aged over 15 years, resided in households in South Australia and had someone close to them die from a terminal illness in the last 5 years. Of the 1540 respondents who provided hands-on care for someone close at the end of life, 155 were widows/widowers. Bereaved spousal caregivers were more likely to be older, female, better educated, have lower incomes, less full-time work, English as second language, sought help with grief and provided more day-to-day care for longer periods. Spousal caregivers were less likely to be willing to take on caregiving again, less able to 'move on' with life and needed greater emotional support and information about illness and services. The only difference between widows and widowers was older age of spouse in women. Younger spousal caregivers perceived greater unmet emotional needs and were significantly less likely to be able to 'move on'. Spousal caregivers are different from other caregivers, with more intense needs that are not fully met. These have implications for bereavement, health and social services.


[Progress in psychoanalytic treatment].
The author considers psychoanalytic treatment to be most effective when based upon an interactive, intersubjective conception of normal and pathological psychic development. By internalizing pathological and pathogenic relationships during childhood, the person builds up a troubled internal relational pattern; it determines his her choices and ensuing relationships and thus perpetuates his her pathology. When it appears in the psychoanalytic relationship this pathological relational style can be analysed and resolved, while a new relationship, promoted by the psychoanalyst, is begun. It aims at fostering the person's development and mental health. This new, healthier relationship is progressively integrated into the patient's everyday life. Consequently the internal relationship pattern itself, through the person's new experiences, changes. Psychoanalysis comes to an end when the new internal relational pattern is consolidated. Therefore the psychoanalytic cure is seen as a process of transformation; and the psychoanalyst is its agent. Therein, the author maintains that counter transference precedes transference and is the driving force of the curing process. The author states that: precedence and priority should be given to counter-transference.


The mouse homeoprotein mLIM-3 is expressed early in cells derived from the neuroepithelium and persists in adult pituitary.
LIM-homeodomain proteins are important in cell lineage specification and possibly mediate transcriptional processes in eukaryotes. During the screening of a mouse pituitary cDNA library, we isolated a partial cDNA coding for a novel gene product that exhibited a predicted amino-terminal sequence similar to the homeobox of LIM-homeodomain-containing proteins. Reverse transcriptase-polymerase chain reactions (RT-PCR) performed on mouse pituitary mRNA using degenerate oligonucleotides based on the conserved LIM-domain sequences, allowed the extension of the 5' end of the sequence. The composite 2.2-kb cDNA structure predicts a 400-amino-acid-long novel mouse (m) protein, called mLIM-3. This name was chosen since within the 59-amino-acid homeodomain, it exhibits 97% sequence identity to a recently reported Xenopus homologue xLIM-3. The gene coding for mLIM-3 maps to the murine chromosome 2, most probably within the 2B band. Based on sequence characteristics, we suggest that LIM-3 belongs to a distinct subfamily of LIM-containing homeoproteins. Ontogeny studies using in situ hybridization demonstrated that mLIM-3 transcripts can be detected on embryonic day 11 (e11) in the primordium of the hypophysis. Following a maximum between e12 and e14, lower levels persisted into adulthood, where mLIM-3 was expressed primarily in the anterior and intermediate lobes of the pituitary. These results were confirmed by Northern blot analysis in adult mice which revealed a 2.4-kb pituitary mRNA transcript. mLIM-3 transcripts were also detected in pituitary cell lines such as the somatotrophs GH3 and GH4C1, the gonadotroph alpha T3-1, and the corticotroph AtT-20 cells, but not in 20 other cell lines derived from peripheral, endocrine, and neural tissues. Starting from e11, we also observed a transient expression of mLIM-3 in the ventral part of the spinal cord, pons, and medulla oblongata, reaching a maximum at e13 and from p7 onward, the expression of this transcript is no longer detectable. mLIM-3 is also expressed in the pineal gland with high levels observed at e20. These data suggest a potential role for mLIM-3 in the transcriptional regulation of certain genes during morphogenesis and/or maintenance of the differentiated state of the pituitary, motor neurons, and pineal gland.


Low birth weight is associated with altered immune function in rural Bangladeshi children: a birth cohort study.
Low birth weight is generally an outcome of a fetal insult or nutritional insufficiency. Recent studies have shown that such exposure early in life may have long-term implications for later immunocompetence and susceptibility to infectious diseases. We aimed to investigate the effect of birth weight on immune function in preschool-age children. A birth cohort cross-sectional study was conducted in children (n = 132) aged 60.8 +/- 0.32 mo who were born in Matlab, a rural area of Bangladesh, and whose weight and length were measured within 72 h of birth. The outcome measures were thymopoiesis, T cell turnover, acute phase response, and percentage of lymphocytes. Children born with low birth weight (<2500 g; LBW group, n = 66) had significantly higher concentrations of T cell receptor excision circles in peripheral blood mononuclear cells-a biomarker for thymopoiesis-and significantly higher serum bactericidal activity and C-reactive protein concentrations than did children born with normal birth weight (>or=2500 g; NBW group, n = 66) (P < 0.05 for both). The LBW group children had significantly lower concentrations of interleukin 7 in plasma (P = 0.02), shorter telomere length in peripheral blood mononuclear cells (P = 0.02), and a lower percentage of CD3 T cells (P = 0.06) than did the NBW group children. Greater peripheral T cell turnover (shorter telomeres and lower CD3 concentrations) due to immune activation (elevated C-reactive protein concentrations and bactericidal activity) may have resulted in a greater need for replenishment from the thymus (higher T cell receptor excision circles); these events may cause lower immune functional reserve in preschool-age children born with LBW. Thus, LBW has implications for immunocompetence and increased vulnerability to infectious diseases in later life.


Pharmacokinetics and metabolic pattern after intravenous infusion and oral administration to healthy subjects.
Meloxicam [4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H- 1,2-benzothiazine-3-carboxamide-1,1-dioxide] is a new nonsteroidal antiinflammatory drug belonging to the enolic acid group. In a crossover study, 30 mg 14C-labeled meloxicam was administered to four male healthy volunteers as a short-term infusion and as an oral solution. The objectives of the study were to determine the mode of elimination, the excretion balance, the in vivo binding characteristics to serum proteins, and to investigate the metabolic pattern in plasma, urine, and feces. A comparison of plasma concentration measurements of unchanged drug by a specific HPLC assay and total radioactivity by liquid scintillation counting revealed a very close conformity. Over 90% of the plasma radioactivity was represented by unchanged drug. Its terminal and dominant half-life of elimination from plasma, as determined from plasma and urinary data in this study, ranged from 12 to 17 hr in the volunteers. The serum protein binding of the radioactivity from in vivo samples was very high (99.1-99.7%). The excretion balance was complete after 6 days. Average urinary excretion of 14C-radioactivity accounted for 43% of the dose, with the remainder appearing with the feces. Meloxicam was extensively metabolized, with only traces of the drug appearing unchanged in urine and feces. The main metabolites were formed by hydroxylation and further oxidation of the methyl group of the thiazolyl moiety. In addition, two further metabolites were found, particularly in urine. Altogether, > 95% of the dose excreted could be accounted for by the metabolites identified or the parent compound itself.


Early Mother-Child Interaction and Later Quality of Attachment in Infants With an Orofacial Cleft Compared to Infants Without Cleft.
Objective : The main objective of this study was to assess mother-child patterns of interaction in relation to later quality of attachment in a group of children with an orofacial cleft compared with children without cleft. Design : Families were contacted when the child was 2 months old for a direct assessment of mother-child interaction and then at 12 months for a direct assessment of the child's attachment. Data concerning socioeconomical information and posttraumatic stress symptoms in mothers were collected at the first appointment. Participants : Forty families of children with a cleft and 45 families of children without cleft were included in the study. Families were recruited at birth in the University Hospital of Lausanne. Results : Results showed that children with a cleft were more difficult and less cooperative during interaction at 2 months of age with their mother compared with children without a cleft. No significant differences were found in mothers or in dyadic interactive styles. Concerning the child's attachment at 12 months old, no differences were found in attachment security. However, secure children with a cleft were significantly more avoidant with their mother during the reunion episodes than secure children without cleft. Conclusion : Despite the facial disfigurement and the stress engendered by treatment during the first months of the infant's life, children with cleft and their mothers are doing as well as families without cleft with regard to the mothers' mental health, mother-child relationships, and later quality of attachment. A potential contribution for this absence of difference may be the pluridisciplinary support that families of children with cleft benefit from in Lausanne.


Proteomic analysis of mouse brain microsomes: identification and bioinformatic characterization of endoplasmic reticulum proteins in the mammalian central nervous system.
The endoplasmic reticulum (ER) is the main source for the storage and release of intracellular calcium in neurons and, thus, contributes to the functionality of a diverse set of pathways that control critical aspects of central nervous system function including but not limited to gene expression, neurotransmission, learning, and memory. ER-derived proteins obtained after subcellular fractionation of mouse brain homogenate were digested with trypsin and the corresponding peptides fractionated by strong cation exchange chromatography followed by LC-MS/MS analysis on a hybrid linear ion trap--Fourier transform ion cyclotron resonance (FTICR) mass spectrometer. A comprehensive catalogue representing 1914 proteins was generated from this particular proteomic analysis using identification criteria that corresponded to a false positive identification rate of 0.4%. Various molecular functions and biological processes relevant to the ER were identified upon gene ontology (GO)-based analysis including pathways associated with molecular transport, protein trafficking and localization, and cell signaling. Comparison of the 2D-LC-MS/MS results with those obtained from shotgun LC-MS/MS analyses demonstrated that most molecular functions and biological processes were represented via GO analysis using either methodology. Results from this comparison as well as a focused investigation into components of calcium-mediated signaling in the mouse brain ER are also presented.


TumorHoPe: a database of tumor homing peptides.
Cancer is responsible for millions of immature deaths every year and is an economical burden on developing countries. One of the major challenges in the present era is to design drugs that can specifically target tumor cells not normal cells. In this context, tumor homing peptides have drawn much attention. These peptides are playing a vital role in delivering drugs in tumor tissues with high specificity. In order to provide service to scientific community, we have developed a database of tumor homing peptides called TumorHoPe. TumorHoPe is a manually curated database of experimentally validated tumor homing peptides that specifically recognize tumor cells and tumor associated microenvironment, i.e., angiogenesis. These peptides were collected and compiled from published papers, patents and databases. Current release of TumorHoPe contains 744 peptides. Each entry provides comprehensive information of a peptide that includes its sequence, target tumor, target cell, techniques of identification, peptide receptor, etc. In addition, we have derived various types of information from these peptide sequences that include secondary/tertiary structure, amino acid composition, and physicochemical properties of peptides. Peptides in this database have been found to target different types of tumors that include breast, lung, prostate, melanoma, colon, etc. These peptides have some common motifs including RGD (Arg-Gly-Asp) and NGR (Asn-Gly-Arg) motifs, which specifically recognize tumor angiogenic markers. TumorHoPe has been integrated with many web-based tools like simple/complex search, database browsing and peptide mapping. These tools allow a user to search tumor homing peptides based on their amino acid composition, charge, polarity, hydrophobicity, etc. TumorHoPe is a unique database of its kind, which provides comprehensive information about experimentally validated tumor homing peptides and their target cells. This database will be very useful in designing peptide-based drugs and drug-delivery system. It is freely available at http://crdd.osdd.net/raghava/tumorhope/.


Q50, an iron-chelating and zinc-complexing agent, improves cardiac function in rat models of ischemia/reperfusion-induced myocardial injury.
Reperfusion of ischemic myocardium may contribute to substantial cardiac tissue damage, but the addition of iron chelators, zinc or zinc complexes has been shown to prevent heart from reperfusion injury. We investigated the possible beneficial effects of an iron-chelating and zinc-complexing agent, Q50, in rat models of ischemia/reperfusion (I/R)-induced myocardial infarction and on global reversible myocardial I/R injury after heart transplantation. Rats underwent 45-min myocardial ischemia by left anterior descending coronary artery ligation followed by 24h reperfusion. Vehicle or Q50 (10 mg/kg, IV) were given 5 min before reperfusion. In a heart transplantation model, donor rats received vehicle or Q50 (30 mg/kg, IV) 1h before the onset of ischemia. In myocardial infarcted rats, increased left ventricular end-systolic and end-diastolic volumes were significantly decreased by Q50 post treatment as compared with the sham group. Moreover, in I/R rat hearts, the decreased dP/dtmax and load-independent contractility parameters were significantly increased after Q50. However, Q50 treatment did not reduce infarct size or have any effect on increased plasma cardiac troponin-T-levels. In the rat model of heart transplantation, 1h after reperfusion, decreased left ventricular systolic pressure, dP/dt(max), dP/dt(min) and myocardial ATP content were significantly increased and myocardial protein expression of superoxide dismutase-1 was upregulated after Q50 treatment. In 2 experimental models of I/R, administration of Q50 improved myocardial function. Its mechanisms of action implicate in part the restoration of myocardial high-energy phosphates and upregulation of antioxidant enzymes.


Lactation in whales and dolphins: evidence of divergence between baleen- and toothed-species.
Although it has been more than one hundred years since the first publication on the milks of whales and dolphins (Order Cetacea), information on lactation in these species is scattered and fragmentary. Yet the immense size of some cetaceans, and the recent evidence that another group of marine mammals, the true seals, have remarkable rates of secretion of milk fat and energy, make this group of great comparative interest. In this paper information on lactation patterns, milk composition and lactation performance is reviewed. Two very different patterns are evident. Many of the baleen whales (Suborder Mysticeti) have relatively brief lactations (5-7 months) during which they fast or eat relatively little. At mid-lactation they produce milks relatively low in water (40-53%), high in fat (30-50%), and moderately high in protein (9-15%) and ash (1.2-2.1%). From mammary gland weights and postnatal growth rates, it is predicted that their energy outputs in milk are exceptional, reaching on the order of 4000 MJ/ d in the blue whale. This is possible because pregnant females migrate to feeding grounds where they can ingest and deposit great amounts of energy, building up blubber stores prior to parturition. On the other hand, the toothed whales and dolphins (Suborder Odontoceti) have much more extensive lactations typically lasting 1-3 years, during which the mothers feed. At mid-lactation their milks appear to be higher in water (60-77%) and lower in fat (10-30%) and ash (0.6-1.1%), with similar levels of protein (8-11%). At least some odontocetes resemble primates in terms of low predicted rates of energy output and a long period of dependency of the young. However, these hypotheses are based on small numbers of samples for a relatively small number of species. Much of the available data on milk composition is of rather poor quality; for example, it is not possible to determine if milk composition changes over the course of lactation among odontocetes. Additional research on cetacean mammary glands and their secretions is needed to understand the reproductive strategies of these fascinating animals.


Bi-allelic Mutations in NDUFA6 Establish Its Role in Early-Onset Isolated Mitochondrial Complex I Deficiency.
Isolated complex I deficiency is a common biochemical phenotype observed in pediatric mitochondrial disease and often arises as a consequence of pathogenic variants affecting one of the ∼65 genes encoding the complex I structural subunits or assembly factors. Such genetic heterogeneity means that application of next-generation sequencing technologies to undiagnosed cohorts has been a catalyst for genetic diagnosis and gene-disease associations. We describe the clinical and molecular genetic investigations of four unrelated children who presented with neuroradiological findings and/or elevated lactate levels, highly suggestive of an underlying mitochondrial diagnosis. Next-generation sequencing identified bi-allelic variants in NDUFA6, encoding a 15 kDa LYR-motif-containing complex I subunit that forms part of the Q-module. Functional investigations using subjects' fibroblast cell lines demonstrated complex I assembly defects, which were characterized in detail by mass-spectrometry-based complexome profiling. This confirmed a marked reduction in incorporated NDUFA6 and a concomitant reduction in other Q-module subunits, including NDUFAB1, NDUFA7, and NDUFA12. Lentiviral transduction of subjects' fibroblasts showed normalization of complex I. These data also support supercomplex formation, whereby the ∼830 kDa complex I intermediate (consisting of the P- and Q-modules) is in complex with assembled complex III and IV holoenzymes despite lacking the N-module. Interestingly, RNA-sequencing data provided evidence that the consensus RefSeq accession number does not correspond to the predominant transcript in clinically relevant tissues, prompting revision of the NDUFA6 RefSeq transcript and highlighting not only the importance of thorough variant interpretation but also the assessment of appropriate transcripts for analysis.


Coffee Grounds to Multifunctional Quantum Dots: Extreme Nanoenhancers of Polymer Biocomposites.
Central to the design and execution of nanocomposite strategies is the invention of polymer-affinitive and multifunctional nanoreinforcements amenable to economically viable processing. Here, a microwave-assisted approach enabled gram-scale fabrication of polymer-affinitive luminescent quantum dots (QDs) from spent coffee grounds. The ultrasmall dimensions (approaching 20 nm), coupled with richness of diverse oxygen functional groups, conferred the zero-dimensional QDs with proper exfoliation and uniform dispersion in poly(l-lactic acid) (PLLA) matrix. The unique optical properties of QDs were inherited by PLLA nanocomposites, giving intensive luminescence and high visible transparency, as well as nearly 100% UV-blocking ratio in the full-UV region at only 0.5 wt % QDs. The strong anchoring of PLLA chains at the nanoscale surfaces of QDs facilitated PLLA crystallization, which was accompanied by substantial improvements in thermomechanical and tensile properties. With 1 wt % QDs, for example, the storage modulus at 100 °C and tensile strength increased over 2500 and 69% compared to those of pure PLLA (4 and 57.3 MPa), respectively. The QD-enabled energy-dissipating and flexibility-imparting mechanisms upon tensile deformation, including the generation of numerous shear bands, crazing, and nanofibrillation, gave an unusual combination of elasticity and extensibility for PLLA nanocomposites. This paves the way to biowaste-derived nanodots with high affinity to polymer for elegant implementation of distinct light management and extreme nanoreinforcements in an ecofriendly manner.


Vitamin C downregulates interleukin-18 production by increasing reactive oxygen intermediate and mitogen-activated protein kinase signalling in B16F10 murine melanoma cells.
We recently reported that interleukin-18 (IL-18) is highly expressed in malignant skin tumours such as melanomas, and may play a key role in the malignancy of such tumours. This study was designed to investigate the mechanisms of IL-18 regulation by vitamin C in B16F10 murine melanoma cells. Cells were treated with vitamin C, and the expression of IL-18 was measured by reverse transcription-polymerase chain reaction and intracellular flow cytometry analysis. Decreased IL-18 production and a significant reduction in IL-18 mRNA transcript were detected in cells treated with vitamin C. The effect of vitamin C treatment was blocked by the antioxidant N-acetyl-L-cysteine, suggesting that vitamin C affects IL-18 expression by up-regulating intracellular reactive oxygen intermediate (ROI) levels. To investigate whether the mitogen-activated protein kinase (MAPK) signalling pathway is involved in the downregulation of IL-18 production, cells were pretreated with SB203580, an inhibitor of p38 MAPK, prior to the addition of vitamin C. This pretreatment blocked the decrease in IL-18 production. However, vitamin C treatment enhanced the expression of phosphorylated p38 MAPK. Taken together, we conclude that vitamin C increases intracellular ROI levels, and regulates IL-18 production through the MAPK signalling pathway.


DEAD-box protein-103 (DP103, Ddx20) is essential for early embryonic development and modulates ovarian morphology and function.
The DEAD-box helicase DP103 (Ddx20, Gemin3) is a multifunctional protein that interacts with Epstein-Barr virus nuclear proteins (EBNA2/EBNA3) and is a part of the spliceosomal small nuclear ribonucleoproteins complex. DP103 also aggregates with the micro-RNA machinery complex. We have previously shown that DP103 interacts with the nuclear receptor steroidogenic factor-1 (SF-1, NR5A1), a key regulator of reproductive development, and represses its transcriptional activity. To further explore the physiological function of DP103, we disrupted the corresponding gene in mice. Homozygous Dp103-null mice die early in embryonic development before a four-cell stage. Although heterozygous mice are healthy and fertile, analysis of steroidogenic tissues revealed minor abnormalities in mutant females, including larger ovaries, altered estrous cycle, and reduced basal secretion of ACTH. Our data point to diverse functions of murine DP103, with an obligatory role during early embryonic development and also in modulation of steroidogenesis.


Risk factors for multiple myeloma: evidence from the Japan Collaborative Cohort (JACC) study.
This study assessed the association of multiple myeloma (MM) with age, body mass index (BMI, kg/m(2)), physical activity, occupational history, and medical history for a Japanese cohort of 46,157 men and 63,541 women aged 40-79 years followed during 1988-2003 years. Cox proportional hazard model was mainly used to estimate the age and sex adjusted hazard ratio (HR) of MM including 95% confidence interval (CI) for both sexes. Same model, adjusted for age, was also used for each sex. In total, 98 MM deaths (men=49 and women=49) was observed for both sexes. Higher age groups (60-69 and 70-79 years) experienced significantly higher unadjusted HR of MM than the age group of 40-49 years. Men revealed significantly higher age-adjusted MM than women (HR=1.5; 95% CI=1.0-2.2). For both sexes, higher BMI of >or=30 kg/m(2)) (HR=2.8; 95% CI=1.0-7.7), walking <or=30 minutes/day (HR=2.0; 95% CI=1.2-3.4), worried about personal relationship in working place (HR=2.3; 95% CI=1.3-4.2), restricted own pace in working place (HR=1.9; 95% CI=1.0-3.4), and history of peptic ulcer (HR=1.7; 95% CI=1.0-2.7) significantly increased age and sex adjusted MM risk. Some of the above-mentioned significant associations became insignificant for age adjusted sex specific analyses. However, these findings should be validated by further epidemiologic studies in Japan before generalization.


Uremic serum-induced calcification of human aortic smooth muscle cells is a regulated process involving Klotho and RUNX2.
Vascular calcification (VC) is common in subjects with chronic kidney disease (CKD) and is associated with increased cardiovascular risk. It is an active process involving transdifferentiation of arterial smooth muscle cells (SMCs) into osteogenic phenotype. We investigated the ability of serum from CKD subjects to induce calcification in human SMCs in vitro (calcific potential of sera: CP), and associated changes in expression of Runt-related transcription factor 2 (RUNX2), SM22α, and Klotho. Sera from subjects with CKD (18 stage 3, 17 stage 4/5, and 29 stage 5D) and 20 controls were added to human cultured SMCs and CP quantified. The CP of CKD sera was greater (P<0.01) than that of controls, though not influenced by CKD stage. Modification of diet in renal disease estimated glomerular filtration rate (MDRD-4 eGFR) (P<0.001), serum phosphate (P=0.042), receptor activator of nuclear factor κappa-B ligand (RANKL) (P=0.001), parathyroid hormone (PTH) (P=0.014), and high-density lipoprotein (HDL)/cholesterol ratio (P=0.026) were independent predictors of CP accounting for 45% of variation. Adding calcification buffer (CB: calcium chloride [7 mM] and β-glycerophosphate [7 mM]) increased the CP of control sera to approximate that of CKD sera. CP of CKD sera was unchanged. CKD sera increased RUNX2 expression (P<0.01) in human SMCs and decreased SM22α expression (P<0.05). Co-incubating control but not CKD serum with CB further increased RUNX2 expression (P<0.01). Both SM22α and Klotho expression decreased significantly (P<0.01) in the presence of CKD serum, and were virtually abolished with stage 5D sera. These findings support active regulation by CKD serum of in vitro VC by induction of RUNX2 and suppression of SM22α and Klotho.


Melatonin: A Versatile Protector against Oxidative DNA Damage.
Oxidative damage to DNA has important implications for human health and has been identified as a key factor in the onset and development of numerous diseases. Thus, it is evident that preventing DNA from oxidative damage is crucial for humans and for any living organism. Melatonin is an astonishingly versatile molecule in this context. It can offer both direct and indirect protection against a wide variety of damaging agents and through multiple pathways, which may (or may not) take place simultaneously. They include direct antioxidative protection, which is mediated by melatonin's free radical scavenging activity, and also indirect ways of action. The latter include, at least: (i) inhibition of metal-induced DNA damage; (ii) protection against non-radical triggers of oxidative DNA damage; (iii) continuous protection after being metabolized; (iv) activation of antioxidative enzymes; (v) inhibition of pro-oxidative enzymes; and (vi) boosting of the DNA repair machinery. The rather unique capability of melatonin to exhibit multiple neutralizing actions against diverse threatening factors, together with its low toxicity and its ability to cross biological barriers, are all significant to its efficiency for preventing oxidative damage to DNA.


Enhancement of imaging depth of two-photon microscopy using pinholes: analytical simulation and experiments.
Achieving a greater imaging depth with two-photon fluorescence microscopy (TPFM) is mainly limited by out-of-focus fluorescence generated from both ballistic and scattered light excitation. We report on an improved signal-to-noise ratio (SNR) in a highly scattering medium as demonstrated by analytical simulation and experiments for TPFM. Our technique is based on out-of-focus rejection using a confocal pinhole. We improved the SNR by introducing the pinhole in the collection beam path. Using the radiative transfer theory and the ray-optics approach, we analyzed the effects of different sizes of pinholes on the generation of the fluorescent signal in the TPFM system. The analytical simulation was evaluated by comparing its results with the experimental results in a scattering medium. In a combined confocal pinhole and two-photon microscopy system, the imaging depth limit of approximately 5 scattering mean free paths (MFP) was found to have improved to 6.2 MFP.


Self-affirmation among the poor: cognitive and behavioral implications.
The poor are universally stigmatized. The stigma of poverty includes being perceived as incompetent and feeling shunned and disrespected. It can lead to cognitive distancing, diminish cognitive performance, and cause the poor to forego beneficial programs. In the present research, we examined how self-affirmation can mitigate the stigma of poverty through randomized field experiments involving low-income individuals at an inner-city soup kitchen. Because of low literacy levels, we used an oral rather than written affirmation procedure, in which participants verbally described a personal experience that made them feel successful or proud. Compared with nonaffirmed participants, affirmed individuals exhibited better executive control, higher fluid intelligence, and a greater willingness to avail themselves of benefits programs. The effects were not driven by elevated positive mood, and the same intervention did not affect the performance of wealthy participants. The findings suggest that self-affirmation can improve the cognitive performance and decisions of the poor, and it may have important policy implications.


The Association Between Adiposity and Inpatient Hospital Costs in the UK Biobank Cohort.
High adiposity is associated with higher risks for a variety of adverse health outcomes, including higher rates of age-adjusted mortality and increased morbidity. This has important implications for the management of healthcare systems, since the endocrinal, cardiometabolic and other changes associated with increased adiposity may be associated with substantial healthcare costs. We studied the association between various measures of adiposity and inpatient hospital costs through record linkage between UK Biobank and records of inpatient care in England and Wales. UK Biobank is a large prospective cohort study that aimed to recruit men and women aged between 40 and 69 from 2006 to 2010. We applied generalised linear models to cost per person year to estimate the marginal effect of adiposity, and average adjusted predicted costs of adiposity. Valid cost and body mass index (BMI) data from 457,689 participants were available for inferential analysis. Some 54.4% of individuals included in the analysis sample had positive inpatient healthcare costs over the period of follow-up. Median hospital costs per person-year of follow-up were £89, compared to mean costs of £481. Mean BMI overall was 27.4 kg/m2 (standard deviation 4.8). The marginal effect of a unit increase in BMI was £13.61 (99% confidence interval £12.60-£14.63) per person-year of follow up. The marginal effect of a standard deviation increase in BMI was £69.20 (99% confidence interval £64.98-£73.42). The marginal effect of becoming obese was £136.35 (99% confidence interval £124.62-£148.08). Average adjusted predicted inpatient hospital costs increased almost linearly when modelled using continuous measure of adiposity. Sensitivity analysis of different scenarios did not substantially change these conclusions, although there was some evidence of attenuation of the effects of adiposity when controlling for waist-hip ratios, and when individuals who self-reported any pre-existing conditions were excluded from analysis. Higher adiposity is associated with higher inpatient hospital costs. Further scrutiny using causal inferential methods is warranted to establish if further public health investments are required to manage the large healthcare costs observationally associated with overweight and obesity.


Child mental health problems as risk factors for victimization.
The current study examines the effects of child internalizing and externalizing symptoms on increases in victimization over a 1-year period. Using longitudinal data from the Developmental Victimization Survey (DVS), analyses are based on a national probability sample of 1,467 children aged 2-17. Results indicate that children with high levels of co-occurring internalizing and externalizing symptoms were particularly likely to experience increased exposure to several forms of victimization, including peer victimization, maltreatment, and sexual victimization, controlling for earlier victimization and adversity. The relationship of symptoms to victimization exposure differed across developmental stage. Elementary school-age children with high levels of symptoms were especially vulnerable to victimization by peers, whereas distressed youth in early adolescence were particularly vulnerable to sexual victimization. Mental health problems in childhood and adolescence appear to represent important risk factors for increased victimization. Future interventions might consider targeting youth with co-occurring internalizing and externalizing symptoms during especially vulnerable developmental stages.


Oestradiol stimulates prolactin secretion in women through oestrogen receptors.
To examine the effects of clomiphene and raloxifene on basal and GnRH-induced prolactin (PRL) secretion in postmenopausal women. Postmenopausal women participated in two experimental procedures a month apart. In one experiment they received raloxifene (180 mg/day) (R-Exp) and in the other clomiphene (150 mg/day) (Cl-Exp). In Group 1, the women (n = 8) received raloxifene or clomiphene for 30 days plus oestradiol via skin patches (100 microg/24 h) for the last 10 days. In Group 2, the women (n = 8) received oestradiol for 30 days plus raloxifene (R-Exp) or clomiphene (Cl-Exp) for the last 10 days. The pituitary response to GnRH (100 microg i.v.) was investigated in all women on days 0, 10, 20 and 30 of each experiment. The study included 16 healthy postmenopausal volunteer women aged 56-60 years. Basal levels of PRL and the area under the curve (AUC) of DeltaPRL response to GnRH were calculated. In Group 1, basal levels of PRL and the area under the curve (AUC) of PRL response to GnRH did not change significantly in both experiments. In Group 2, during both experiments basal levels of PRL and the AUC of PRL increased significantly on days 10 (P < 0.05) and 20 (P < 0.05) as compared to day 0 and then they decreased significantly on day 30 as compared to day 20 (P < 0.05). Our study demonstrates for the first time that raloxifene and clomiphene affect the secretion of PRL in postmenopausal women in a similar manner. It is suggested that oestradiol stimulates the secretion of PRL in women by acting through oestrogen receptors.


Adult allogeneic haematopoietic stem cell transplantation: a single centre experience in Malaysia.
We analysed the outcome of 104 patients from a single institution who underwent allogeneic haematopoietic stem cell transplantation (AHSCT) from their HLA-identical siblings between 1993 and 2006. Sixty-nine percent of patients had peripheral blood stem cell (PBSC) as the stem cell source and the remaining had bone marrow (BM). The majority of patients are Chinese (60%) followed by Malays (24%) and Indians (14%). The median time to reach white cell counts of >1 x 10(9)/L and platelet counts of >30 x 10(9)/L was 13 and 15 days, respectively in patients who had PBSC transplantation compared with 16 and 25 days in patients who had BM transplantation, (p < 0.0001 and p < 0.001). Acute graft-versus-host disease (aGVHD) of grade II to IV was observed in 34% of patients and chronic graft-versus-host disease (cGVHD) in 38% of patients. Although not statistically significant, there was a higher incidence of overall aGVHD in Indian patients (73%) compared to Chinese and Malays (57% and 56% respectively). There was no significant difference in the incidence of aGVHD and cGVHD with the source of stem cells. Overall survival (OS) and disease free survival (DFS) was 50% and 60% at five years respectively. Multivariate analysis showed that patients transplanted in standard risk and those who had limited cGVHD had a significant better OS, (p = 0.05 and p = 0.05). Patients who had cGVHD and transplanted in standard risk had a better DFS, (p = 0.002 and p < 0.001). In summary, AHSCT in standard risk patients is associated with a better outcome than those transplanted in high risk and although not statistically significant, there is a higher incidence of aGVHD in Indian patients.


Investigation between the S377G3 GATA-4 polymorphism and migraine.
Migraine is a common and painful neurological disorder, with genetic and environmental components. Several conditions have been shown to be comorbid with migraine, notably a cardiac malformation affecting the interatrial septum and leading to patent foramen ovale (PFO). Mutations in the development regulatory gene GATA-4, located on human chromosome 8p23.1-p22, have been found to be responsible for some cases of congenital heart defects including PFO. To determine whether the GATA-4 gene is involved in migraine, the present study performed an association analysis of a common GATA-4 variant that results in a change of amino acid (S377G), in a large case/control population (275 unrelated Caucasian migraineurs versus 275 control individuals). The results showed that there was no significant association for this polymorphism between migraine and controls (chi(2) = 0.84, P = 0.66). Thus it appears that the GATA-4 (S377G) mutation does not play a significant role in common migraine susceptibility.


What is the significance of black-white differences in risky sexual behavior?
A sample of African-American and white young adults were classified as having multiple sex partners or one sexual partner. Subjects with multiple sexual partners were more likely to use drugs and practice risky sexual behaviors such as having anal intercourse, having sexual experiences with a prostitute, and having a history of gonorrhea (P < .001) and genital warts (P < .01). Additional analyses were conducted to determine African-American versus white differences in risky sexual behaviors. Results indicated that whites in the multiple partners and single partner groups were more likely to engage in anal and oral sex, while African Americans were more likely to have sex with prostitutes. Attitudes about the use of condoms differed significantly by multiple partner status (P < .004) and gender (P < .007), but not ethnicity. However, angry reactions about the use of condoms occurred more with African Americans (P < .003) and males (P < .05) than with whites or females. While whites reported a greater use of drugs and a significantly higher level of knowledge about HIV/AIDS, African Americans reported a significantly greater perception of risk for being exposed to human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) (P < .01) and significantly more gonorrhea (P < .10), syphilis (P < .05), and HIV/AIDS (P < .05). No whites in our sample were treated for syphilis nor had they tested positive for HIV/AIDS. On the other hand, 4.5% of the total sample of African Americans reported testing positive for HIV/AIDS. Finally, the results from discriminant analysis indicate that a large number of variables significantly discriminate between subjects who engage in risky sexual behaviors and those who do not. Although there is some similarity in the variables for African Americans and whites, there was tremendous variability between the ethnic groups in the factors that predict risky behaviors. These findings are discussed with reference to the need to develop HIV/AIDS prevention programs for African Americans that are based on data derived from African-American populations rather than from black versus white comparison studies.


Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders.
Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders, including childhood autism, atypical autism, and Asperger syndrome, with an estimated prevalence of 1.0-2.5% in the general population. ASDs have a complex multifactorial etiology, with genetic causes being recognized in only 10-20% of cases. Recently, copy-number variants (CNVs) have been shown to contribute to over 10% of ASD cases. We have applied a custom-designed oligonucleotide array comparative genomic hybridization with an exonic coverage of over 1700 genes, including 221 genes known to cause autism and autism candidate genes, in a cohort of 145 patients with ASDs. The patients were classified according to ICD-10 standards and the Childhood Autism Rating Scale protocol into three groups consisting of 45 individuals with and 69 individuals without developmental delay/intellectual disability (DD/ID), and 31 patients, in whom DD/ID could not be excluded. In 12 patients, we have identified 16 copy-number changes, eight (5.5%) of which likely contribute to ASDs. In addition to known recurrent CNVs such as deletions 15q11.2 (BP1-BP2) and 3q13.31 (including DRD3 and ZBTB20), and duplications 15q13.3 and 16p13.11, our analysis revealed two novel genes clinically relevant for ASDs: ARHGAP24 (4q21.23q21.3) and SLC16A7 (12q14.1). Our results further confirm the diagnostic importance of array CGH in detection of CNVs in patients with ASDs and demonstrate that CNVs are an important cause of ASDs as a heterogeneous condition with a variety of contributory genes.


The entire organization of transcription units on the Bacillus subtilis genome.
In the post-genomic era, comprehension of cellular processes and systems requires global and non-targeted approaches to handle vast amounts of biological information. The present study predicts transcription units (TUs) in Bacillus subtilis, based on an integrated approach involving DNA sequence and transcriptome analyses. First, co-expressed gene clusters are predicted by calculating the Pearson correlation coefficients of adjacent genes for all the genes in a series that are transcribed in the same direction with no intervening gene transcribed in the opposite direction. Transcription factor (TF) binding sites are then predicted by detecting statistically significant TF binding sequences on the genome using a position weight matrix. This matrix is a convenient way to identify sites that are more highly conserved than others in the entire genome because any sequence that differs from a consensus sequence has a lower score. We identify genes regulated by each of the TFs by comparing gene expression between wild-type and TF mutants using a one-sided test. By applying the integrated approach to 11 sigma factors and 17 TFs of B. subtilis, we are able to identify fewer candidates for genes regulated by the TFs than were identified using any single approach, and also detect the known TUs efficiently. This integrated approach is, therefore, an efficient tool for narrowing searches for candidate genes regulated by TFs, identifying TUs, and estimating roles of the sigma factors and TFs in cellular processes and functions of genes composing the TUs.


In vivo exposure of young adult male rats to methoxychlor reduces serum testosterone levels and ex vivo Leydig cell testosterone formation and cholesterol side-chain cleavage activity.
Methoxychlor (MC) was developed as a replacement for the banned pesticide DDT. After in vivo administration, it is metabolized in the liver to 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), which is proposed to be the active agent. Both MC and HPTE have been shown to exhibit weak estrogenic and antiandrogenic activities, and they are thought to exert their effects through estrogen and androgen receptors, respectively. Although in vitro studies using cultured rat Leydig cells have reported that HPTE inhibits both basal and hCG-stimulated testosterone formation, the response of circulating testosterone levels to in vivo MC has been more variable. Therefore, the current studies evaluated whether the daily in vivo administration of MC (0, 5, 40 and 200 mg/kg body weight) for a short duration (days 54-60 of age) by gavage altered serum testosterone levels and ex vivo Leydig cell testosterone formation in young adult male rats. These results demonstrate that both fluid-retained and fluid-expressed seminal vesicle weights declined to 44 and 60% of control, respectively, in the 200 mg/kg MC-exposed animals. Similarly, serum testosterone and dehydroepiandrosterone levels declined to 41 and 45% of control, respectively, in the 200 mg/kg MC-exposed animals; however, serum LH and FSH levels were unaffected. Ex vivo Leydig cell basal testosterone formation over 4h declined to 49% of control in animals exposed to 200 mg/kg MC, and ex vivo Leydig cell P450 cholesterol side-chain cleavage activity declined to 79 and 50% of control in animals exposed to 40 and 200 mg/kg of MC, respectively, supporting previous in vitro studies which demonstrated the sensitivity of this step to MC.


From WSN towards WoT: Open API Scheme Based on oneM2M Platforms.
Conventional computing systems have been able to be integrated into daily objects and connected to each other due to advances in computing and network technologies, such as wireless sensor networks (WSNs), forming a global network infrastructure, called the Internet of Things (IoT). To support the interconnection and interoperability between heterogeneous IoT systems, the availability of standardized, open application programming interfaces (APIs) is one of the key features of common software platforms for IoT devices, gateways, and servers. In this paper, we present a standardized way of extending previously-existing WSNs towards IoT systems, building the world of the Web of Things (WoT). Based on the oneM2M software platforms developed in the previous project, we introduce a well-designed open API scheme and device-specific thing adaptation software (TAS) enabling WSN elements, such as a wireless sensor node, to be accessed in a standardized way on a global scale. Three pilot services are implemented (i.e., a WiFi-enabled smart flowerpot, voice-based control for ZigBee-connected home appliances, and WiFi-connected AR.Drone control) to demonstrate the practical usability of the open API scheme and TAS modules. Full details on the method of integrating WSN elements into three example systems are described at the programming code level, which is expected to help future researchers in integrating their WSN systems in IoT platforms, such as oneM2M. We hope that the flexibly-deployable, easily-reusable common open API scheme and TAS-based integration method working with the oneM2M platforms will help the conventional WSNs in diverse industries evolve into the emerging WoT solutions.


Enhanced photocatalytic degradation of Amaranth dye on mesoporous anatase TiO2: evidence of C-N, N[double bond, length as m-dash]N bond cleavage and identification of new intermediates.
The photocatalytic degradation mechanism of Amaranth, a recalcitrant carcinogenic azo dye, was investigated using mesoporous anatase TiO2 under sunlight. Mesoporous anatase TiO2 of a high photocatalytic activity has been synthesized using a sol-gel method and its photocatalytic activity for the degradation of Amaranth dye has been evaluated with respect to Degussa P25. The effect of bi-dentate complexing agents like oxalic acid, ethylene glycol and urea on the surface properties of TiO2 catalyst has been investigated using TG-DTA, FTIR, HR-TEM, SAED, PXRD, EDS, UV-DRS, PL, BET N2 adsorption-desorption isotherm studies and BJH analysis. The influence of catalyst properties such as the mesoporous network, pore volume and surface area on the kinetics of degradation of Amaranth as a function of irradiation time under natural sunlight has been monitored using UV-Vis spectroscopy. The highest rate constant value of 0.069 min-1 was obtained for the photocatalytic degradation of Amaranth using TiO2 synthesized via a urea assisted sol-gel synthesis method. The effect of the reaction conditions such as pH, TiO2 concentration and Amaranth concentration on the photodegradation rate has been investigated. The enhanced photocatalytic activity of synthesized TiO2 in comparison with P25 is attributed to the mesoporous nature of the catalyst leading to increased pore diameter, pore volume, surface area and enhanced charge carrier separation efficiency. New intermediates of photocatalytic degradation of Amaranth, namely, sodium-3-hydroxynaphthalene-2,7-disulphonate, 3-hydroxynaphthalene, sodium-4-aminonaphthalenesulphonate and sodium-4-aminobenzenesulphonate have been identified using LC-ESI-MS for the very first time, providing direct evidence for simultaneous bond cleavage pathways (-C-N-) and (-N[double bond, length as m-dash]N-). A new plausible mechanism of TiO2 catalysed photodegradation of Amaranth along with the comparison of its toxicity to that of its degradation intermediates and products is proposed.


The evolution of protein interaction networks in regulatory proteins.
Interactions between proteins are essential for intracellular communication. They form complex networks which have become an important source for functional analysis of proteins. Combining phylogenies with network analysis, we investigate the evolutionary history of interaction networks from the bHLH, NR and bZIP transcription-factor families. The bHLH and NR networks show a hub-like structure with varying gamma values. Mutation and gene duplication play an important role in adding and removing interactions. We conclude that in several of the protein families that we have studied, networks have primarily arisen by the development of heterodimerizing transcription factors, from an ancestral gene which interacts with any of the newly emerging proteins but also homodimerizes.


Phylogenetic and functional marker genes to study ammonia-oxidizing microorganisms (AOM) in the environment.
The oxidation of ammonia plays a significant role in the transformation of fixed nitrogen in the global nitrogen cycle. Autotrophic ammonia oxidation is known in three groups of microorganisms. Aerobic ammonia-oxidizing bacteria and archaea convert ammonia into nitrite during nitrification. Anaerobic ammonia-oxidizing bacteria (anammox) oxidize ammonia using nitrite as electron acceptor and producing atmospheric dinitrogen. The isolation and cultivation of all three groups in the laboratory are quite problematic due to their slow growth rates, poor growth yields, unpredictable lag phases, and sensitivity to certain organic compounds. Culture-independent approaches have contributed importantly to our understanding of the diversity and distribution of these microorganisms in the environment. In this review, we present an overview of approaches that have been used for the molecular study of ammonia oxidizers and discuss their application in different environments.


Colloidal membranes of hard rods: unified theory of free edge structure and twist walls.
Monodisperse suspensions of rod like chiral fd viruses are condensed into a rod-length thick colloidal monolayers of aligned rods by depletion forces. Twist deformations of the molecules are expelled to the monolayer edge as in a chiral smectic A liquid crystal, and a cholesteric band forms at the edge. Coalescence of two such isolated membranes results in a twist wall sandwiched between two regions of aligned rods, dubbed π-walls. By modeling the membrane as a binary fluid of coexisting cholesteric and chiral smectic A liquid-crystalline regions, we develop a unified theory of the π-walls and the monolayer edge. The mean-field analysis of our model yields the molecular tilt profiles, the local thickness change, and the crossover from smectic to cholesteric behavior at the monolayer edge and across the π-wall. Furthermore, we calculate the line tension associated with the formation of these interfaces. Our model offers insights regarding the stability and the detailed structure of the π-wall and the monolayer edge.


Complications of HIV infection: a systems-based approach.
Patients with human immunodeficiency virus (HIV) infection often develop multiple complications and comorbidities. Opportunistic infections should always be considered in the evaluation of symptomatic patients with advanced HIV/AIDS, although the overall incidence of these infections has decreased. Primary care of HIV infection includes the early detection of some complications through screening at-risk and symptomatic patients with routine laboratory monitoring (e.g., comprehensive metabolic and lipid panels) and validated tools (e.g., the HIV Dementia Scale). Treatment of many chronic complications is similar for patients with HIV infection and those without infection; however, combination antiretroviral therapy has shown benefit for some conditions, such as HIV-associated nephropathy. For other complications, such as cardiovascular disease and lipoatrophy, management may include switching antiretroviral regimens to reduce exposure to HIV medications known to cause toxicity.


Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis.
Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks by identifying all the interactomic shortest paths linking Xk and chorein to the corresponding set of proteins whose tyrosine phosphorylation was altered in patients. These networks include the most likely paths of functional influence of Xk and chorein on phosphorylated proteins. We further refined the analysis by extracting restricted sets of highly interacting signaling proteins representing a common molecular background bridging the generation of acanthocytes in MLS and ChAc. The final analysis pointed to a novel, very restricted, signaling module of 14 highly interconnected kinases, whose alteration is possibly involved in generation of acanthocytes in MLS and ChAc.


Anaplasma phagocytophilum evolves in geographical and biotic niches of vertebrates and ticks.
Anaplasma phagocytophilum is currently regarded as a single species. However, molecular studies indicate that it can be subdivided into ecotypes, each with distinct but overlapping transmission cycle. Here, we evaluate the interactions between and within clusters of haplotypes of the bacterium isolated from vertebrates and ticks, using phylogenetic and network-based methods. The presence of A. phagocytophilum DNA was determined in ticks and vertebrate tissue samples. A fragment of the groEl gene was amplified and sequenced from qPCR-positive lysates. Additional groEl sequences from ticks and vertebrate reservoirs were obtained from GenBank and through literature searches, resulting in a dataset consisting of 1623 A. phagocytophilum field isolates. Phylogenetic analyses were used to infer clusters of haplotypes and to assess phylogenetic clustering of A. phagocytophilum in vertebrates or ticks. Network-based methods were used to resolve host-vector interactions and their relative importance in the segregating communities of haplotypes. Phylogenetic analyses resulted in 199 haplotypes within eight network-derived clusters, which were allocated to four ecotypes. The interactions of haplotypes between ticks, vertebrates and geographical origin, were visualized and quantified from networks. A high number of haplotypes were recorded in the tick Ixodes ricinus. Communities of A. phagocytophilum recorded from Korea, Japan, Far Eastern Russia, as well as those associated with rodents had no links with the larger set of isolates associated with I. ricinus, suggesting different evolutionary pressures. Rodents appeared to have a range of haplotypes associated with either Ixodes trianguliceps or Ixodes persulcatus and Ixodes pavlovskyi. Haplotypes found in rodents in Russia had low similarities with those recorded in rodents in other regions and shaped separate communities. The groEl gene fragment of A. phagocytophilum provides information about spatial segregation and associations of haplotypes to particular vector-host interactions. Further research is needed to understand the circulation of this bacterium in the gap between Europe and Asia before the overview of the speciation features of this bacterium is complete. Environmental traits may also play a role in the evolution of A. phagocytophilum in ecotypes through yet unknown relationships.


Saccharomyces boulardii prevents oral-poliovirus vaccine-induced IgA nephropathy in mice.
Immunoglobulin A nephropathy (IgAN) is associated with mucosal IgA defect. Probiotics regulate specific and innate immunity. We evaluated the effect of Saccharomyces boulardii on experimental IgAN in mice. Four groups of BALB/c mice (eight for each) were formed. Group 1 was immunized by oral poliovirus vaccine (OPV) at 0, 14, and 28 days. Group 2 was also given S. boulardii in addition to OPV. Group 3 was given only S. boulardii, whereas group 4 received no treatment. At week 6, after urine and serum samples were obtained for urinalysis and serum creatinine and IgA measurements, all animals were sacrificed to get their kidneys for histopathological evaluation. Urinalysis and serum creatinine levels were normal in all groups. Serum IgA level was increased only in group 1. Whereas group 1 had mesangial proliferation, histology was normal in the other groups. Predominant IgA deposition was universal in group 1, whereas it was either not present or minimal in other groups. Three mice in group 1 also had C3 deposition, which was absent in other groups. Electron microscopy revealed mesangial proliferation, matrix expansion, focal glomerular basement membrane thickening and electron-dense deposits in group 1 only, whereas the other groups were normal. In conclusion, enteral S. boulardii prevented OPV-induced IgAN in mice.


Molecular basis of Sindbis virus neurovirulence in mice.
We examined a variety of strains of Sindbis virus for the genetic changes responsible for differences in neurovirulence in mice. SV1A (a low passage of the AR339 strain of Sindbis virus), a neuroadapted Sindbis virus (NSV), and two laboratory strains of Sindbis virus (HRSP and Toto1101) were examined. NSV causes severe encephalomyelitis with hind-limb paralysis and high mortality after intracerebral inoculation in weanling mice. In contrast, SV1A causes only mild, nonfatal disease in weanling mice; however, in suckling mice, SV1A causes a fatal encephalomyelitis after either intracerebral or subcutaneous inoculation. The two laboratory strains used have a greatly reduced neurovirulence for suckling mice and are avirulent for weanling mice. The nucleotide sequences and encoded amino acid sequences of the structural glycoproteins of these four strains were compared. Hybrid genomes were constructed by replacing restriction fragments in a full-length cDNA clone of Sindbis virus, from which infectious RNA can be transcribed in vitro, with fragments from cDNA clones of the various strains. These recombinant viruses allowed us to test the importance of each amino acid difference between the various strains for neurovirulence in weanling and suckling mice. Glycoproteins E2 and E1 were of paramount importance for neurovirulence in adult mice. Recombinant viruses containing the nonstructural protein region and the capsid protein region from an avirulent strain and the E1 and E2 glycoprotein regions from NSV were virulent, although they were less virulent than NSV. Furthermore, changes in either E2 (His-55 in NSV to Gln in SV1A) or E1 (Ala-72 in NSV to Val in SV1A and Asp-313 in NSV to Gly in SV1A) reduced virulence. For virulence in suckling mice, we found that a number of changes in E2 and E1 can lead to decreased virulence and that in fact, a gradient of virulence exists.


PEDF-derived synthetic peptides exhibit antitumor activity in an orthotopic model of human osteosarcoma.
Pigment epithelium-derived factor (PEDF) is one of the most potent inhibitors of angiogenesis, and has recently been demonstrated to have an important multifunctional role in tumor growth, invasion, and metastasis. However, relatively little is known of mechanisms through which PEDF exerts its antitumor activity. Therefore, with the aim of identifying potential functional epitopes specifically against osteosarcoma, we evaluated the bioactivity of four 25-mer synthetic PEDF-derived peptides (termed StVOrth-1, -2 -3, and -4) against a human osteosarcoma cell line, SaOS-2. We found that StVOrth-2 (residues 78-102) predominantly inhibited tumor cell proliferation, while StVOrth-3 (residues 90-114) markedly increased cellular adhesion to collagen type-1, with StVOrth-4 (residues 387-411) demonstrating most significant inhibition of Matrigel invasion. Furthermore, we show that StVOrth-1 (residues 40-64), -2 and -3 induce osteoblastic differentiation, evidenced by increased mineralized nodule formation. Interestingly, although no peptide inhibited angiogenesis in the tube formation assay, StVOrth-3 and -4 markedly suppressed VEGF expression. We further tested the activity of StVOrth-2 and StVOrth-3 in vivo, in an orthotopic model of osteosarcoma and found that both peptides significantly inhibited primary tumor growth and the development of pulmonary metastases. Together these results provide greater insight into the potential mechanisms through which PEDF exerts its antitumor function. Furthermore, this raises the possibility of developing short PEDF fragments as lead compounds for the treatment of osteosarcoma.


Effect of chronic treatment with clozapine and haloperidol on 5-HT(2A and 2C) receptor mRNA expression in the rat brain.
This study examined regional changes of 5-HT(2A and 2C) receptor mRNA expression in the rat brain after chronic administration of clozapine (1.5 mg/kg/day) and haloperidol (2.0 mg/kg/day) for 36 days. 5-HT(2A and 2C) receptor mRNA expression and distributions were detected by in situ hybridization after rats were sacrificed either 2 or 48 h after the last drug administration to examine both immediate and delayed effects following drug withdrawal. Following 2 h of drug withdrawal, it showed that clozapine administration significantly decreased 5-HT(2A) receptor mRNA, predominantly in the nucleus accumbens (65%), hippocampus (80%), lasteral septal nucleus (61%) and striatum (68%) compared to controls, whilst rebound increases were observed in most of these regions 48 h later. In contrast, no change in 5-HT(2A) receptor mRNA expression was found in the haloperidol treated groups either 2 h or 48 h after drug withdrawal. Clozapine also decreased 5-HT(2C) receptor mRNA expression in the posteromedial cortical amygdala (32%) and substantia nigra (35%) 2 h after the last drug administration, while rebound effects were also observed 48 h later. 5-HT(2C) receptor mRNA was only decreased in the substantia nigra at both 2 h (42%) and 48 h (54%) after the last haloperidol administration. Alterations in serotonin receptor expression in limbic system region such as the nucleus accumbens, hippocampus and lateral septal nucleus as well as the striatum may represent the specific regional targets that mediate the clinical effects of antipsychotics via the serotonin system.


How and why are communities of practice established in the healthcare sector? A systematic review of the literature.
Communities of Practice (CoPs) are promoted in the healthcare sector as a means of generating and sharing knowledge and improving organisational performance. However CoPs vary considerably in the way they are structured and operate in the sector. If CoPs are to be cultivated to benefit healthcare organisations, there is a need to examine and understand their application to date. To this end, a systematic review of the literature on CoPs was conducted, to examine how and why CoPs have been established and whether they have been shown to improve healthcare practice. Peer-reviewed empirical research papers on CoPs in the healthcare sector were identified by searching electronic health-databases. Information on the purpose of establishing CoPs, their composition, methods by which members communicate and share information or knowledge, and research methods used to examine effectiveness was extracted and reviewed. Also examined was evidence of whether or not CoPs led to a change in healthcare practice. Thirty-one primary research papers and two systematic reviews were identified and reviewed in detail. There was a trend from descriptive to evaluative research. The focus of CoPs in earlier publications was on learning and exchanging information and knowledge, whereas in more recently published research, CoPs were used more as a tool to improve clinical practice and to facilitate the implementation of evidence-based practice. Means by which members communicated with each other varied, but in none of the primary research studies was the method of communication examined in terms of the CoP achieving its objectives. Researchers are increasing their efforts to assess the effectiveness of CoPs in healthcare, however the interventions have been complex and multifaceted, making it difficult to directly attribute the change to the CoP. In keeping with Wenger and colleagues' description, CoPs in the healthcare sector vary in form and purpose. While researchers are increasing their efforts to examine the impact of CoPs in healthcare, cultivating CoPs to improve healthcare performance requires a greater understanding of how to establish and support CoPs to maximise their potential to improve healthcare.


Myocardial tagging by cardiovascular magnetic resonance: evolution of techniques--pulse sequences, analysis algorithms, and applications.
Cardiovascular magnetic resonance (CMR) tagging has been established as an essential technique for measuring regional myocardial function. It allows quantification of local intramyocardial motion measures, e.g. strain and strain rate. The invention of CMR tagging came in the late eighties, where the technique allowed for the first time for visualizing transmural myocardial movement without having to implant physical markers. This new idea opened the door for a series of developments and improvements that continue up to the present time. Different tagging techniques are currently available that are more extensive, improved, and sophisticated than they were twenty years ago. Each of these techniques has different versions for improved resolution, signal-to-noise ratio (SNR), scan time, anatomical coverage, three-dimensional capability, and image quality. The tagging techniques covered in this article can be broadly divided into two main categories: 1) Basic techniques, which include magnetization saturation, spatial modulation of magnetization (SPAMM), delay alternating with nutations for tailored excitation (DANTE), and complementary SPAMM (CSPAMM); and 2) Advanced techniques, which include harmonic phase (HARP), displacement encoding with stimulated echoes (DENSE), and strain encoding (SENC). Although most of these techniques were developed by separate groups and evolved from different backgrounds, they are in fact closely related to each other, and they can be interpreted from more than one perspective. Some of these techniques even followed parallel paths of developments, as illustrated in the article. As each technique has its own advantages, some efforts have been made to combine different techniques together for improved image quality or composite information acquisition. In this review, different developments in pulse sequences and related image processing techniques are described along with the necessities that led to their invention, which makes this article easy to read and the covered techniques easy to follow. Major studies that applied CMR tagging for studying myocardial mechanics are also summarized. Finally, the current article includes a plethora of ideas and techniques with over 300 references that motivate the reader to think about the future of CMR tagging.


Purification and characterization of a rat brain aldehyde dehydrogenase able to metabolize gamma-aminobutyraldehyde to gamma-aminobutyric acid.
An enzyme which catalyses dehydrogenation of gamma-aminobutyraldehyde (ABAL) to gamma-aminobutyric acid (GABA) was purified to homogeneity from rat brain tissues by using DEAE-cellulose and affinity chromatography on 5'-AMP-Sepharose, phosphocellulose and Blue Agarose, followed by gel filtration. Such an enzyme was first purified from mammalian brain tissues, and was identified as an isoenzyme of aldehyde dehydrogenase. It has an Mr of 210,000 determined by polyacrylamide-gradient-gel electrophoresis, and appeared to be composed of subunits of Mr 50,000. The close similarity of substrate specificity toward acetaldehyde, propionaldehyde and glycolaldehyde between the enzyme and other aldehyde dehydrogenases previously reported was observed. But substrate specificity of the enzyme toward ABAL was higher than those of aldehyde dehydrogenases from human liver (E1 and E2), and was lower than those of ABAL dehydrogenases from human liver (E3), Escherichia coli and Pseudomonas species. The Mr and relative amino acid composition of the enzyme are also similar to those of E1 and E2. The existence of this enzyme in mammalian brain seems to be related to a glutamate decarboxylase-independent pathway (alternative pathway) for GABA synthesis from putrescine.


Homodimerization driven self-assembly of glycoluril molecular clips with covalently immobilized poly(ε-caprolactone).
We present an unexpected self-assembly of a glycoluril clip-poly(ε-caprolactone) conjugate in chloroform. The conjugate forms homodimer aggregates due to supramolecular interactions between glycoluril moieties, which was confirmed with MALDI-TOF-ms and 1H NMR. TEM revealed the formation of multilayered nanosized prism-shaped objects resembling tree bark in nature.


Computed tomography of post-traumatic extracerebral hematomas: comparison to pathophysiology and responses to therapy.
One hundred nine head-injured patients with epidural and acute and chronic subdural hematomas were evaluated by computed tomography (CT). Eighty-two patients had subsequent CT examinations in order to evaluate postoperative changes and responses to therapy. Results seen on CT studies were compared to patients' neurologic status at the time of scanning. The rapid return of the appearance of the brain and the patients' neurologic status to normal soon after evacuation of an uncomplicated epidural hematoma reflect the lack of parenchymal damage. In contrast, acute subdurals are usually produced by associated contusions or cortical lacerations. The mass effect of these parenchymal lesions is responsible for a degree of ventricular shift out of proportion to the usual small size of the acute subdural. Small acute subdurals managed medically and residual collections found after evacuation resolved spontaneously. No acute subdurals progressed to a chronic subdural. The latter are infrequently associated with cerebral parenchymal injury and their symptoms are due to the size of the collections. Deformity of the underlying brain by the chronic process and slow re-expansion of the brain account for the common finding of a slowly resorbing, residual fluid collection following surgical evacuation.


β-Arrestin-2 Counters CXCR7-Mediated EGFR Transactivation and Proliferation.
The atypical 7-transmembrane chemokine receptor, CXCR7, transactivates the EGFR leading to increased tumor growth in several tumor types. However, the molecular mechanism of CXCR7 ligand-independent EGFR transactivation is unknown. We used cDNA knock-in, RNAi and analysis of mitogenic signaling components in both normal prostate epithelial cells and prostate cancer cells to decipher the proliferation-inducing mechanism of the CXCR7-EGFR interaction. The data demonstrate that CXCR7-induced EGFR transactivation is independent of both the release of cryptic EGFR ligands (e.g., AREG/amphiregulin) and G-protein-coupled receptor signaling. An alternate signaling mechanism involving β-arrestin-2 (ARRB2/β-AR2) was examined by manipulating the levels of β-AR2 and analyzing changes in LNCaP cell growth and phosphorylation of EGFR, ERK1/2, Src, and Akt. Depletion of β-AR2 in LNCaP cells increased proliferation/colony formation and significantly increased activation of Src, phosphorylation of EGFR at Tyr-1110, and phosphorylation/activation of ERK1/2 compared with that with control shRNA. Moreover, β-AR2 depletion downregulated the proliferation suppressor p21. Stimulation of β-AR2-expressing cells with EGF resulted in rapid nuclear translocation of phosphorylated/activated EGFR. Downregulation of β-AR2 enhanced this nuclear translocation. These results demonstrate that β-AR2 is a negative regulator of CXCR7/Src/EGFR-mediated mitogenic signaling. This study reveals that β-AR2 functions as a tumor suppressor, underscoring its clinical importance in regulating CXCR7/EGFR-mediated tumor cell proliferation. Mol Cancer Res; 14(5); 493-503. ©2016 AACR.


The relation between outcome expectation, therapeutic alliance, and outcome among depressed patients in group cognitive-behavioral therapy.
Although patients' expectation for improvement correlates with their treatment outcome, there remains limited information regarding the mechanisms through which outcome expectation influences outcome. Although several studies have revealed alliance as a mediator of the expectancy-outcome relation, most have focused on individual psychotherapy only. More research is needed examining mediators, including alliance quality, of the outcome expectation-outcome relation in group therapy. This study focused on such associative chains among 91 depressed outpatients who completed 10 weeks of group cognitive-behavioral therapy. We conducted simple and multiple mediation analyses, accounting for the nested data structure. As predicted, we found: (i) The relations between baseline outcome expectation and both posttreatment anxiety and depression were mediated by alliance quality; (ii) the early therapy outcome expectation-posttreatment anxiety relation was mediated by mid-treatment alliance; (iii) the relation between early alliance and posttreatment interpersonal problems was mediated by during-therapy outcome expectation; and (iv) the relation between baseline outcome expectation and posttreatment interpersonal problems was mediated by two variables acting in turn, early alliance and during-therapy outcome expectation. All other tested models were not significant. Results suggest that bidirectional relations between outcome expectation and alliance, with both directions influencing outcome. Clinical and empirical implications are discussed.


Near-independent capacities and highly constrained output orders in the simultaneous free recall of auditory-verbal and visuo-spatial stimuli.
Three experiments examined the immediate free recall (IFR) of auditory-verbal and visuospatial materials from single-modality and dual-modality lists. In Experiment 1, we presented participants with between 1 and 16 spoken words, with between 1 and 16 visuospatial dot locations, or with between 1 and 16 words and dots with synchronized onsets. We found that for dual-modality lists (a) overall performance, initial recalls, and serial position curves were largely determined by the within-modality list lengths, (b) there was only a small degree of dual-task trade-off (that was limited to the visuospatial items), and (c) there were strongly constrained output orders: participants tended to alternate between words and dots from equivalent or neighboring serial positions. In Experiments 2 and 3, we compared lists of 6 single-modality items with dual-modality lists of 6 words and 6 dots with synchronous or alternating onsets (Experiment 2), or random but asynchronous onsets (Experiment 3). In all 3 dual-modality conditions, we again found only a small trade-off in visuospatial (but not verbal) IFR performance. There were similarly highly constrained output orders with the synchronous and alternating onsets, and these patterns were present but attenuated with the randomized onsets. We propose that both auditory-verbal and visuospatial list items are associated with a common temporal episodic context that is used to guide cross-modal retrieval, and we speculate that the limited, asymmetric interference could arise because the less variable representations of the dots share only a relatively small subset of features with the more variable representations of the words. (PsycINFO Database Record


Structure-activity relationship of nerve-highlighting fluorophores.
Nerve damage is a major morbidity associated with numerous surgical interventions. Yet, nerve visualization continues to challenge even the most experienced surgeons. A nerve-specific fluorescent contrast agent, especially one with near-infrared (NIR) absorption and emission, would be of immediate benefit to patients and surgeons. Currently, there are only three classes of small molecule organic fluorophores that penetrate the blood nerve barrier and bind to nerve tissue when administered systemically. Of these three classes, the distyrylbenzenes (DSBs) are particularly attractive for further study. Although not presently in the NIR range, DSB fluorophores highlight all nerve tissue in mice, rats, and pigs after intravenous administration. The purpose of the current study was to define the pharmacophore responsible for nerve-specific uptake and retention, which would enable future molecules to be optimized for NIR optical properties. Structural analogs of the DSB class of small molecules were synthesized using combinatorial solid phase synthesis and commercially available building blocks, which yielded more than 200 unique DSB fluorophores. The nerve-specific properties of all DSB analogs were quantified using an ex vivo nerve-specific fluorescence assay on pig and human sciatic nerve. Results were used to perform quantitative structure-activity relationship (QSAR) modeling and to define the nerve-specific pharmacophore. All DSB analogs with positive ex vivo fluorescence were tested for in vivo nerve specificity in mice to assess the effect of biodistribution and clearance on nerve fluorescence signal. Two new DSB fluorophores with the highest nerve to muscle ratio were tested in pigs to confirm scalability.


Nonalcoholic fatty liver disease in HIV-infected patients referred to a metabolic clinic: prevalence, characteristics, and predictors.
The prevalence and predictors of nonalcoholic fatty liver disease (NAFLD) in human immunodeficiency virus (HIV)-infected highly active antiretroviral therapy-experienced patients and the association of NAFLD with risk of cardiovascular disease and subclinical atherosclerosis are unknown. We performed a cross-sectional observational study. NAFLD was defined by liver-spleen attenuation values of <1.1 on computed tomography in persons who had neither evidence of chronic viral hepatitis nor a significant history of alcohol consumption. We enrolled 225 patients; 163 (72.4%) were men. Mean (+/-SD) HIV infection duration was 145 +/- 60 months, and mean (+/-SD) body mass index (calculated as weight in kilograms divided by the square of height in meters) was 23.75 +/- 3.59. NAFLD was diagnosed in 83 patients (36.9% of the total cohort). The following variables were significantly associated with NAFLD in univariate analyses: sex, waist circumference, body mass index, cumulative exposure to nucleoside reverse-transcriptase inhibitors, visceral adipose tissue, homeostasis model assessment of insulin resistance index, serum alanine and aspartate aminotransferase levels, and ratios of total serum cholesterol to high-density lipoprotein cholesterol. Coronary artery calcium scores and a diagnosis of diabetes were not associated with NAFLD. In multivariable logistic regression analyses, factors associated (P<0.001) with NAFLD were higher serum alanine to aspartate ratio (odds ratio, 4.59; 95% confidence interval, 2.09-10.08), male sex (odds ratio, 2.49; 95% confidence interval, 1.07-5.81), greater waist circumference (odds ratio, 1.07; 95% confidence interval, 1.03-1.11), and longer nucleoside reverse-transcriptase inhibitor exposure (odds ratio, 1.12 per year of exposure; 95% confidence interval, 1.03-1.22). NAFLD is common among HIV-infected persons who have the traditional risk factors for NAFLD (elevations in serum alanine level, male sex, and increased waist circumference) apparent. Exposure to nucleoside reverse-transcriptase inhibitors was an independent risk factor for NAFLD, with an 11% increase in the odds ratio for each year of use.


Specific alterations in the levels of N-acetyl-aspartyl-glutamate in the nervous system of the dystrophic mouse.
Determinations of N-acetyl-aspartate (NAA) and N-acetyl-aspartyl-glutamate (NAAG) levels were obtained by ion-exchange HPLC from 10 regions of the male dystrophic mouse brain as well as from those of non-dystrophic littermate controls. Similar to previous studies in the rat, NAA levels in control mice were distributed rather uniformly while NAAG levels exhibited a pronounced rostrocaudal gradient, with highest levels found in the lumbar spinal cord. Contrary to a recent report, we found no significant alterations in gross brain or spinal cord levels of NAA. In contrast, levels of NAAG were substantially and differentially reduced in several regions of the dystrophic mouse nervous system. These results demonstrate a pathological dissociation between NAA and NAAG, whose levels are known to display differential regional, ontogenetic and phylogenetic patterns. In addition, they may represent an ability of neural tissue to differentially regulate their steady-state levels, if indeed they can be shown to be biosynthetically related. The pronounced and non-uniform NAAG reductions observed in the dystrophic CNS underscores recent suggestions of a role for the neuropeptide in central systems involved in the control of motor function.


Vulnerable and strong--lesbian women encountering maternity care.
This paper is a report of a study to describe the maternity care experiences narrated by a sample of lesbian couples. Pregnant and labouring women are dependent on the professional skill and caring ability of the healthcare provider. Studies show that lesbian women who reveal their sexual identity are exposed to homophobic prejudice and discrimination in midwifery care. A phenomenological hermeneutical study inspired by the French philosopher Paul Ricoeur was conducted. Six lesbian couples were recruited in Norway by a snowball method, reporting a total of eight children conceived by donor insemination. Joint interviews were performed in January 2006, and the participants were encouraged to share narratives about important events in their maternity care experiences. The fundamental life conditions of vulnerability, responsibility and caring permeated the narratives, and were related with the couples' decisions to be open about their sexual identity. Being exposed, they experienced under- and over-focusing on sexuality. They felt responsible for having the right attitude in interactions, which meant being open, but not over-assertive. They described genuinely caring situations as well as being content with less genuine care, and demonstrated that in addition to receiving care, they provided care in the encounters. Lesbian women are a vulnerable group when encountering maternity care. They took responsibility in caring situations because of healthcare providers' uncertainty and anxiety. Existential needs, such as being seen, being cared for and communicated with, should be considered equally important for lesbian women and heterosexual women in labour.


Image deconvolution with multi-stage convex relaxation and its perceptual evaluation.
This paper proposes a new image deconvolution method using multi-stage convex relaxation, and presents a metric for perceptual evaluation of deconvolution results. Recent work in image deconvolution addresses the deconvolution problem via minimization with non-convex regularization. Since all regularization terms in the objective function are non-convex, this problem can be well modeled and solved by multi-stage convex relaxation. This method, adopted from machine learning, iteratively refines the convex relaxation formulation using concave duality. The newly proposed deconvolution method has outstanding performance in noise removal and artifact control. A new metric, transduced contrast-to-distortion ratio (TCDR), is proposed based on a human vision system (HVS) model that simulates human responses to visual contrasts. It is sensitive to ringing and boundary artifacts, and very efficient to compute. We conduct comprehensive perceptual evaluation of image deconvolution using visual signal-to-noise ratio (VSNR) and TCDR. Experimental results of both synthetic and real data demonstrate that our method indeed improves the visual quality of deconvolution results with low distortions and artifacts.


Initial experience with intracorporeal continuous ow LVAD in pediatric patients in Poland.
The aim of the study is to present the initial experience with continuous flow left ventricle assist device (CF-LVAD) in pediatric patients with BSA below 1.5 m2. Between 2016 and 2017, CF-LVAD (the Heartware System) have been implanted in three pediatric patients in the Department of Pediatric Cardiac Surgery, Jagiellonian University, Krakow, Poland. The indications for initiating CF-LVAD were end-stage congestive heart failure due to dilated cardiomyopathy in all children. Implanted patients have had BSA of 1.09, 1.42, 1.2 m2, and 37, 34, 34 kg of body weight and the age 12, 11, 12 years, respectively. The time of support was 550 days in two patients and 127 in another one, and is ongoing. The main complication has been driveline infection. The outcomes from our single-center experience using the HeartWare CF-LVAD have been excellent with a low incidence of complication and no necessity to reoperation in our patients. Children could be successfully and safely discharged home.


Agouti-related protein (AGRP) has a central inhibitory action on the hypothalamic-pituitary-thyroid (HPT) axis; comparisons between the effect of AGRP and neuropeptide Y on energy homeostasis and the HPT axis.
Because alpha-MSH has a potent stimulatory action on hypophysiotropic TRH synthesizing neurons in the hypothalamic paraventricular nucleus (PVN), preventing the effects of fasting on the gene expression of the TRH prohormone (proTRH), we hypothesized that agouti-related protein (AGRP), a melanocortin receptor antagonist, may exert a central inhibitory action on these neurons. To test the hypothesis, the effects of intracerebroventricularly administered AGRP on circulating thyroid hormone levels and proTRH mRNA in the hypothalamic paraventricular nucleus (PVN) were compared with the effects of the recently described central inhibitor of the HPT axis, neuropeptide Y (NPY). AGRP administration increased food consumption and weight gain, suppressed circulating levels of thyroid hormones (T(3) and T(4)), and resulted in an inappropriately normal TSH. These alterations were associated with a significant suppression of proTRH mRNA in the PVN, indicating that AGRP infusion resulted in a state of central hypothyroidism. While similar observations were made in the NPY-infused animals, AGRP-treated animals had higher feeding efficiency, higher T(4) levels, and lower type 2 iodothyronine deiodinase levels in brown adipose tissue than NPY-infused animals. These data demonstrate that AGRP and NPY have a similarly potent inhibitory action on the proTRH gene expression of hypophysiotropic neurons, indicating that both AGRP and NPY may play a major role in the inhibition of the HPT axis during fasting.


Minimizing surgical blood loss at cesarean hysterectomy for placenta previa with evidence of placenta increta or placenta percreta: the state of play in 2020.
The evolution of multidisciplinary team-based care for women with placenta accreta spectrum disorder has delivered stepwise improvements in clinical outcomes. Central to this overall goal is the ability to limit blood loss at surgery. Placement of inflatable balloons within the pelvic arteries, most commonly in the anterior divisions of the internal iliac arteries, became popular in many centers, at the expense of prolonging surgical care and with attendant risks of vascular injury. In tandem, the need to expose pelvic sidewall anatomy to safely identify the course of the ureters re-popularized the alternative strategy of ligating the same anterior divisions of the internal iliac arteries. With incremental gains in surgical expertise, described in 5 steps in this review, our teams have witnessed a steady decline in surgical blood loss. Nevertheless, a subset of women has the most severe form of placenta accreta spectrum, namely placenta previa-percreta. Such women are at risk of major hemorrhage during surgery from vessels arising outside the territories of the internal iliac arteries. These additional blood supplies, mostly from the external iliac arteries, pose significant risks of major blood loss even in experienced hands. To address this risk, some centers, principally in China, have adopted an approach of routinely placing an infrarenal aortic balloon, with both impressively low rates of blood loss and an ability to conserve the uterus by resecting the placenta with the affected portion of the uterine wall. We review these literature developments in the context of safely performing elective cesarean hysterectomy for placenta previa-percreta, the most severe placenta accreta spectrum disorder.