Lattice stability and formation energies of intrinsic defects in Mg2Si and Mg2Ge via first principles simulations.
We report an ab initio study of the semiconducting Mg(2)X (with X = Si, Ge) compounds and in particular we analyze the formation energies of the different point defects with the aim of understanding the intrinsic doping mechanisms. We find that the formation energy of Mg(2)Ge is 50% larger than that of Mg(2)Si, in agreement with the experimental tendency. From a study of the stability and the electronic properties of the most stable defects, taking into account the growth conditions, we show that the main cause of the n doping in these materials comes from interstitial magnesium defects. Conversely, since other defects acting like acceptors such as Mg vacancies or multivacancies are more stable in Mg(2)Ge than in Mg(2)Si, this explains why Mg(2)Ge can be of n or p type, in contrast to Mg(2)Si. The finding that the most stable defects are different in Mg(2)Si and Mg(2)Ge and depend on the growth conditions is important and must be taken into account in the search for the optimal doping to improve the thermoelectric properties of these materials.


Valley polarized quantum Hall effect and topological insulator phase transitions in silicene.
The electronic properties of silicene are distinct from both the conventional two dimensional electron gas and the famous graphene due to strong spin orbit interaction and the buckled structure. Silicene has the potential to overcome limitations encountered for graphene, in particular the zero band gap and weak spin orbit interaction. We demonstrate a valley polarized quantum Hall effect and topological insulator phase transitions. We use the Kubo formalism to discuss the Hall conductivity and address the longitudinal conductivity for elastic impurity scattering in the first Born approximation. We show that the combination of an electric field with intrinsic spin orbit interaction leads to quantum phase transitions at the charge neutrality point, providing a tool to experimentally tune the topological state. Silicene constitutes a model system for exploring the spin and valley physics not accessible in graphene due to the small spin orbit interaction.


Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in the early period after kidney transplantation.
The role of renin-angiotensin system inhibitors (ACE-inhibitors) or angiotensin receptor blockers (ARB) in the renal transplant recipients (RTRs) is incompletely defined and according to the current guidelines they should be initiated after six months post-transplantation. The aim of the present paper is to evaluate the efficiency and safety of early (within six months post-transplantation) versus late (after six months post-transplantation) initiation of ACE-inhibitors or ARB in RTRs. The study group compromised of 108 RTRs (50 male and 58 female) who received a kidney transplant. Beside other prescribed antihypertensive drugs all of them took and ACE inhibitors or ARB in order to achieve blood pressure control. For this analysis purpose, recipients were stratified into two groups according to the time of ACE inhibitors/ARB initiation into early (within six months post-transplantation) and late (after six months after transplantation) group. For each patient haemoglobin, serum creatinine and potassium levels were analyzed at the beginning of ACE inhibitors/ARB introduction and at the end of the first, third, sixth and twelfth month. In the 54 (50%) of the 108 patients ACE inhibitors/ARB were initiated within six months post-transplantation and in 49 (90.7%) of them within three months (in 29 patients within one month; in 13 within two months; in 7 within 3 months) post-transplantation. In additional 54 (50%) patients ACE inhibitors/ARB were initiated, but after six months post-transplantation. There was no statistically significant difference between the two groups related to age or gender and due to the duration of dialysis treatment before the transplantation. Analyzing the haemoglobin, creatinine and potassium serum levels after initiation of therapy with ACE inhibitors/ARB trough observed period we did not found any statistically significant difference in all measured parameters between the two groups of patients and also within the same group of patients. Therefore, according to experience from our Institution early initiation of ACE inhibitors or ARB appears to be safe in carefully selected recipients with relatively good early graft function.


Supraphysiological Oxygen Levels in Mammalian Cell Culture: Current State and Future Perspectives.
Most conventional incubators used in cell culture do not regulate O2 levels, making the headspace O2 concentration ~18%. In contrast, most human tissues are exposed to 2-6% O2 (physioxia) in vivo. Accumulating evidence has shown that such hyperoxic conditions in standard cell culture practices affect a variety of biological processes. In this review, we discuss how supraphysiological O2 levels affect reactive oxygen species (ROS) metabolism and redox homeostasis, gene expression, replicative lifespan, cellular respiration, and mitochondrial dynamics. Furthermore, we present evidence demonstrating how hyperoxic cell culture conditions fail to recapitulate the physiological and pathological behavior of tissues in vivo, including cases of how O2 alters the cellular response to drugs, hormones, and toxicants. We conclude that maintaining physioxia in cell culture is imperative in order to better replicate in vivo-like tissue physiology and pathology, and to avoid artifacts in research involving cell culture.


Are ictal vocalisations related to the lateralisation of frontal lobe epilepsy?
The purpose was to analyse whether non-speech vocalisations in seizures originating in the frontal lobe do have lateralising value. Patients were included who had undergone presurgical evaluation with ictal video-EEG monitoring at the Epilepsy Centre, had had resective epilepsy surgery involving the frontal lobe, and who had remained seizure free>1 year postoperatively. Twenty seven patients aged 1-42 years (mean 18) met the inclusion criteria. Age at epilepsy onset ranged from 1 month to 41 years (mean 7.1 years). All selected patients had a unilateral MRI detected lesion within the frontal lobe. Fifteen patients had right sided, 12 patients had left sided epileptogenic zones. Seizures recorded during EEG-video monitoring were re-evaluated to identify the occurrence of ictal vocalisations. Pure ictal vocalisations were distinguished from ictal sound productions due to motor or vegetative seizure activity (for example, cloni or respiratory sounds). Pure ictal vocalisation occurred in 11 patients of whom nine had a left frontal epileptogenic zone (p<0.01). It is concluded that ictal vocalisation could be an additional lateralising sign in frontal lobe epilepsy. The results suggest that not only speech, but vocalisation at a subverbal level also shows a left hemispheric dominance in humans.


Intravenous prostaglandin for induction of labour.
Intravenous prostaglandin E2 and F2 alpha can be used to induce labour. The use of intravenous prostaglandins in this context has been limited by perceived unacceptable maternal side effect profiles. This is one of a series of reviews of methods of cervical ripening and labour induction using standardised methodology. To determine the effects of intravenous prostaglandin for third trimester cervical ripening or induction of labour. The Cochrane Pregnancy and Childbirth Group trials register, The Cochrane Controlled Trials Register and bibliographies of relevant papers. The criteria for inclusion included the following: (1) clinical trials comparing intravenous prostaglandin used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods; (2) random allocation to the treatment or control group; (3) adequate allocation concealment; (4) violations of allocated management not sufficient to materially affect conclusions; (5) clinically meaningful outcome measures reported; (6) data available for analysis according to the random allocation; (7) missing data insufficient to materially affect the conclusions. A strategy has been developed to deal with the large volume and complexity of trial data relating to labour induction. This involves a two-stage method of data extraction. The initial data extraction is done centrally, and incorporated into a series of primary reviews arranged by methods of induction of labour, following a standardised methodology. The data will then be extracted from the primary reviews into a series of secondary reviews, arranged by category of woman. To avoid duplication of data in the primary reviews, the labour induction methods have been listed in a specific order, from one to 25. Each primary review includes comparisons between one of the methods (from two to 25) with only those methods above it on the list. Thirteen trials were eligible for inclusion in this review. Two trials (comprising 400 women) compared intravenous prostaglandin E2 to intravenous oxytocin, a further seven trials (comprising 590 women) compared intravenous prostaglandin F2 alpha to intravenous oxytocin. Two trials (comprising 115 women) each randomised women to one of three treatment arms namely intravenous oxytocin or intravenous prostaglandin F2 alpha or prostaglandin E2. One trial reported a comparison of combined oxytocin and prostaglandin F2 alpha and oxytocin alone in 20 women and lastly one trial compared extra amniotic prostaglandin E2 versus intravenous prostaglandin E2 (40 women). The use of intravenous prostaglandin was associated with higher rates of uterine hyperstimulation with changes in the fetal heart rate (relative risk (RR) 6.76, 95% confidence interval (CI) 1.23-37.11) and without (RR 4.25, 95%CI 1.48-12.24) compared to oxytocin. Use of prostaglandins was also associated with significantly more maternal side effects (gastrointestinal, thrombophlebitis and pyrexia, RR 3.75, 95% CI 2.46-5.70) than oxytocin. Prostaglandin was no more likely to result in vaginal delivery than oxytocin (RR 0.85, 95% CI 0.61-1.18). No significant differences emerged from subgroup analysis or from the trials comparing combination oxytocin/prostaglandin F2 alpha and oxytocin or extra amniotic versus intravenous prostaglandin E2. Intravenous prostaglandin is no more efficient than intravenous oxytocin for the induction of labour but its use is associated with higher rates of maternal side effects and uterine hyperstimulation than oxytocin. No conclusions can be drawn form the comparisons of combination of prostaglandin F2 alpha and oxytocin compared to oxytocin alone or extra amniotic and intravenous prostaglandin E2.


Safety evaluation of crosslinked polyacrylic acid polymers (carbomer) as a new food additive.
The EFSA Panel on Food Additives and Flavourings (FAF) provides a scientific opinion on the safety of crosslinked polyacrylic acid polymers (carbomer) proposed for use as food additive in solid and liquid food supplements. Carbomer is formed from the monomer, acrylic acid, which is polymerised and crosslinked with allyl pentaerythritol (APE). The polymers are synthesised in ethyl acetate using ■■■■■ as free-radical polymerisation initiator. In vivo data showed no evidence for systemic availability or biotransformation of carbomer. Carbomer does not raise a concern regarding genotoxicity. Considering the available data set, the Panel derived an acceptable daily intake (ADI) of 190 mg/kg body weight (bw) per day based on a no observed adverse effect level (NOAEL) of 1,500 mg/kg bw per day from a sub-chronic 13-week study in rat, applying a compound specific uncertainty factor (UF) of 8. At the proposed maximum use levels, the exposure estimates ranged at the mean from 1.1 to 90.2 mg/kg bw per day and at the p95 from 12.5 to 237.4 mg/kg bw per day. At the proposed typical use level, the exposure estimates ranged at the mean from 0.7 to 60.2 mg/kg bw per day and at the p95 from 10.3 to 159.5 mg/kg bw per day. The Panel noted that the maximum proposed use levels would result in exposure estimates close to or above the ADI. The Panel also noted that level of exposure to carbomer from its proposed use is likely to be an overestimation. Taking a conservative approach, the Panel considered that exposure to carbomer would not give rise to a safety concern if the proposed maximum use level for solid food supplements is lowered to the typical use level reported by the applicant.


The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease.
Recent studies indicate that oxysterols, which are ligands for the nuclear hormone liver X receptors (LXR), decrease amyloid beta (Abeta) secretion in vitro. The effect was attributed primarily to the ATP-binding cassette transporter A1 (ABCA1) transcriptionally up-regulated by ligand-activated LXRs. We now examined the effect of the synthetic LXR ligand T0901317, which can be used in vivo, on Abeta production in vitro and in APP23 transgenic mice. T0901317 applied to a variety of in vitro models, including immortalized fibroblasts from Tangier patients, and primary embryonic mouse neurons caused a concentration-dependent decrease in Abeta secretion, and this effect was increased by the addition of apolipoprotein A-I. The inhibition of Abeta production by T0901317 was cell-type specific, being more prominent in primary neurons than in non-neuronal cells. Tangier fibroblasts lacking a functional ABCA1 secreted more Abeta than control fibroblasts, thus demonstrating the role of ABCA1 in amyloid precursor protein (APP) processing and Abeta generation. T0901317 treatment of 11-week-old APP23 mice for 6 days showed a significant increase in ABCA1 expression and a decrease in the ratio of soluble APP (sAPP)beta- to sAPPalpha-cleavage products. Most importantly, the treatment caused a statistically significant reduction in the levels of soluble Abeta40 and of Abeta42 in the brain these mice. Our experiments demonstrate that T0901317 decreases amyloidogenic processing of APP in vitro and in vivo, thus supporting the search for potent and specific LXR ligands with properties allowing therapeutic application.


[Bacteriological indications for the choice of antibacterial preparations in the cancer clinic].
Opportunistic microorganisms with multiple drug resistance are the main causative agents of infectious complications in oncological patients. The spectrum of the causative agents and their antibiotic sensitivity change with introduction of new drugs. This requires constant control over the composition of the causative agents and their sensitivity. Such a control provides rational antibacterial therapy when the causative agent is in virtue of some reasons unknown or the bacteriological data are not available. The prophylactic use of antibacterial drugs is of limited value, largely in operations on the gastrointestinal tract and other naturally contaminated cavities.


Lateralization of auditory sensory gating and neuropsychological dysfunction in schizophrenia.
Sensory gating assessed via EEG in a paired-click paradigm has often served as a neurophysiological metric of attentional function in schizophrenia. However, the standard EEG measure of sensory gating using the P50 component at electrode Cz does not foster differential assessment of left and right hemisphere contributions. Magnetoencephalography (MEG) is complementary to EEG, and its analogous M50 component may be better suited for localization and analysis of such lateralized cortical generators. The authors hypothesized that 1) auditory gating would be evident in M50 sources in superior temporal gyrus, demonstrating ratios similar to P50; 2) M50 would resemble P50 in distinguishing gating in comparison subjects and patients with schizophrenia, but M50 would show lateralization of the gating deficit; and 3) P50 and M50 sensory gating ratios would predict neuropsychological measures in patients and comparison subjects, with the MEG identification of left and right hemisphere sources allowing for the evaluation of lateralization in brain-behavior relationships. Event-related EEG and MEG recordings were simultaneously obtained from 20 patients with schizophrenia and 15 comparison subjects. P50 amplitudes, M50 dipole source strengths, and P50 and M50 gating ratios were compared and assessed with respect to scores on neuropsychological performance measures. M50 dipoles localizing to superior temporal gyrus demonstrated gating similar to that of P50. As expected, patients demonstrated less P50 gating than did comparison subjects. Left (but not right) hemisphere M50 gating 1) correlated with EEG gating, 2) differentiated patients and comparison subjects, and 3) correlated with neuropsychological measures of sustained attention and working memory. Converging evidence from EEG, MEG, and neuropsychological measures points to left hemisphere dysfunction as strongly related to the well-established sensory gating deficit in schizophrenia.


Developing and implementing guidelines to promote appropriate use of fluconazole therapy in an AIDS clinic.
A retrospective and concurrent drug use evaluation for fluconazole in an outpatient AIDS clinic is described. Eighty-eight patient charts were reviewed in the evaluation during an 8-week period, and 72 patients were studied in the concurrent evaluation for a period of 5 weeks. A set of preestablished fluconazole usage and dosing guidelines was developed by the clinical pharmacist and the chairman of the antimicrobial subcommittee/chief of infectious disease and approved by the pharmacy and therapeutics committee. Patients who did not meet these guidelines were those being treated for oropharyngeal and esophageal candidiasis. The use of fluconazole was not indicated in 43 of 54 (80%) patients in retrospective evaluation and 31 of 39 (79.5%) patients before clinical pharmacist intervention in concurrent study. If guidelines had been followed during the retrospective evaluation, cost savings would have been $295 per day, which adds up to $16,520 for 8 weeks. In the actual evaluation, the cost savings with pharmacist intervention for 5 weeks was $5,460, which can be extrapolated to annual cost savings of $65,520.


Investigating Temporal Features of Carotid Intima-Media Thickness from Ultrasound Imaging with Recurrent Neural Networks.
Measuring carotid intima-media thickness (cIMT) of the Common Carotid Artery (CCA) via B-mode ultrasound imaging is a non-invasive yet effective way to monitor and assess cardiovascular risk. Recent studies using Convolutional Neural Networks (CNNs) to automate the process have mainly focused on the detection of regions of interest (ROI) in single frame images collected at fixed time points and have not exploited the temporal information captured in ultrasound imaging. This paper presents a novel framework to investigate the temporal features of cIMT, in which Recurrent Neural Networks (RNN) were deployed for ROI detection using consecutive frames from ultrasound imaging. The cIMT time series can be formed from estimates of cIMT in each frame of an ultrasound scan, from which additional information (such as min, max, mean, and frequency) on cIMT time series can be extracted. Results from evaluation show the best performance for ROI detection improved 4.75% by RNN compared to CNN-based methods. Furthermore, the heart rate estimated from the cIMT time series for seven patients was highly correlated with the patient's clinical records, which suggests the potential application of the cIMT time series and related features for clinical studies in the future.Clinical relevance- The temporal features extracted from cIMT time series provide additional information that can be potentially beneficial for clinical studies.


Distal landmarks and hippocampal place cells: effects of relative translation versus rotation.
Hippocampal neurons are selectively active when a rat occupies restricted locations in an environment. These place cells derive their specificity from a multitude of sources, including idiothetic cues and sensory input derived from both distal and local landmarks. Most experiments have attempted to dissociate the relative strengths and roles played by these sources by rotating one set against the other. Few studies have addressed the effects of relative translation of the local cue set versus salient distal landmarks. To address this question, ensembles of place cells were recorded as a rectangular or circular track was moved to different locations in a room with controlled visual landmarks. Place cells primarily maintained their firing fields relative to the track (i.e., occupying new locations relative to the distal landmarks), even though the track could occupy completely nonoverlapping regions of the room. When the distal landmarks were rotated around the circular track, however, the place fields rotated with the landmarks, demonstrating that the cues were perceptible to the rat. These results suggest that, under these conditions, the spatial tuning of place cells may derive from an interaction between local and idiothetic cues, which define the precise firing locations of the cells and the relationships between them, and distal landmarks, which set the orientation of the ensemble representation relative to the external environment.


Anticholinergic Medication Burden-Associated Cognitive Impairment in Schizophrenia.
Many psychotropic medications used to treat schizophrenia have significant anticholinergic properties, which are linked to cognitive impairment and dementia risk in healthy subjects. Clarifying the impact of cognitive impairment attributable to anticholinergic medication burden may help optimize cognitive outcomes in schizophrenia. The aim of this study was to comprehensively characterize how this burden affects functioning across multiple cognitive domains in schizophrenia outpatients. Cross-sectional data were analyzed using inferential statistics and exploratory structural equation modeling to determine the relationship between anticholinergic medication burden and cognition. Patients with a diagnosis of schizophrenia or schizoaffective disorder (N=1,120) were recruited from the community at five U.S. universities as part of the Consortium on the Genetics of Schizophrenia-2. For each participant, prescribed medications were rated and summed according to a modified Anticholinergic Cognitive Burden (ACB) scale. Cognitive functioning was assessed by performance on domains of the Penn Computerized Neurocognitive Battery (PCNB). ACB score was significantly associated with cognitive performance, with higher ACB groups scoring worse than lower ACB groups on all domains tested on the PCNB. Similar effects were seen on other cognitive tests. Effects remained significant after controlling for demographic characteristics and potential proxies of illness severity, including clinical symptoms and chlorpromazine-equivalent antipsychotic dosage. Anticholinergic medication burden in schizophrenia is substantial, common, conferred by multiple medication classes, and associated with cognitive impairments across all cognitive domains. Anticholinergic medication burden from all medication classes-including psychotropics used in usual care-should be considered in treatment decisions and accounted for in studies of cognitive functioning in schizophrenia.


Heritability of lung disease severity in cystic fibrosis.
Obstructive lung disease, the major cause of mortality in cystic fibrosis (CF), is poorly correlated with mutations in the disease-causing gene, indicating that other factors determine severity of lung disease. To quantify the contribution of modifier genes to variation in CF lung disease severity. Pulmonary function data from patients with CF living with their affected twin or sibling were converted into reference values based on both healthy and CF populations. The best measure of FEV(1) within the last year was used for cross-sectional analysis. FEV(1) measures collected over at least 4 years were used for longitudinal analysis. Genetic contribution to disease variation (i.e., heritability) was estimated in two ways: by comparing similarity of lung function in monozygous (MZ) twins (approximately 100% gene sharing) with that of dizygous (DZ) twins/siblings (approximately 50% gene sharing), and by comparing similarity of lung function measures for related siblings to similarity for all study subjects. Forty-seven MZ twin pairs, 10 DZ twin pairs, and 231 sibling pairs (of a total of 526 patients) with CF were studied. Correlations for all measures of lung function for MZ twins (0.82-0.91, p < 0.0001) were higher than for DZ twins and siblings (0.50-0.64, p < 0.001). Heritability estimates from both methods were consistent for each measure of lung function and ranged from 0.54 to 1.0. Heritability estimates generally increased after adjustment for differences in nutritional status (measured as body mass index z-score). Our heritability estimates indicate substantial genetic control of variation in CF lung disease severity, independent of CFTR genotype.


Phosphorylase re-expression, increase in the force of contraction and decreased fatigue following notexin-induced muscle damage and regeneration in the ovine model of McArdle disease.
McArdle disease is caused by a deficiency of myophosphorylase and currently a satisfactory treatment is not available. The injection of notexin into, or the layering of notexin onto, the muscles of affected sheep resulted in necrosis followed by regeneration of muscle fibres with the expression of both non-muscle isoforms of phosphorylase within the fibres and a reduction of the amount of glycogen in the muscle with an increase in the strength of contraction and a decrease in fatiguability in the muscle fibres. The sustained re-expression of both the brain and liver isoforms of phosphorylase within the muscle fibres provides further emphasis that strategies to enhance the re-expression of these isoforms should be investigated as a possible treatment for McArdle disease.


The NIMA-related kinase 2, Nek2, is expressed in specific stages of the meiotic cell cycle and associates with meiotic chromosomes.
The Aspergillus nimA gene encodes a Ser/Thr protein kinase which is required for mitosis, in addition to Cdc2, and which has been suggested to have a role in chromosomal condensation. In this study, we isolated a potential murine homologue of nimA, Nek2, which was shown to be expressed most abundantly in the testis of the adult tissues examined. Its expression in the testis was restricted to the germ cells, with highest levels detected in spermatocytes at pachytene and diplotene stages. Immunohistochemical analysis revealed that Nek2 localized to nuclei, exhibiting a non-uniform distribution within the nucleus. Nek2 appeared to be associated with meiotic chromosomes, an association that was better defined by immunolocalization to hypotonically dispersed meiotic chromosomes. This localization was more apparent in regions of dense chromatin, including the sex vesicle, and was also obvious at some of the chromosome ends. The presence of Nek2 protein was not unique to male germ cells, as it was found in meiotic pachytene stage oocytes as well. Furthermore, in an in vitro experimental setting in which meiotic chromosome condensation was induced with okadaic acid, a concomitant induction of Nek2 kinase activity was observed. The expression of Nek2 in meiotic prophase is consistent with the hypothesis that in vivo, Nek2 is involved in the G2/M phase transition of the cell cycle. Our results further provide evidence that in vivo, mouse Nek2 is involved in events of meiosis, including but not limited to chromosomal condensation.


[Effects of Chinese herbs for replenishing qi and resolving stagnation on transforming growth factor-beta1 of skin ulcers in rats with diabetes].
To explore the effects of Yiqi Huayu Recipe, a compound traditional Chinese herbal medicine for replenishing qi and resolving stagnation, on transforming growth factor-beta1(TGF-beta1) of skin ulcers in rats with diabetes. Sixty rats were randomly divided into six groups, Yiqi Huayu Recipe-treated group, Yiqi (replenishing qi) Recipe-treated group, Huayu (resolving stagnation) Recipe-treated group, basic fibroblast growth factor (bFGF) treated group, untreated group and normal control group. Diabetes was induced by peritoneal injection of streptozotocin and skin ulcers were made by surgery method in rats except for the normal control group. Then the rats were administered with different drugs respectively, and the expression of TGF-beta1 in granulation tissue of the skin ulcers was detected with the methods of Western blotting, image analysis and immunohistochemistry. The level of TGF-beta1 expression in the untreated group was lower than that in the normal control group (P<0.01); and the level of TGF-beta1 expression in the drug-treated groups was higher than that in the untreated group (P<0.01); and the TGF-beta1 expression in the Yiqi Huayu Recipe-treated group was higher than that in the Yiqi Recipe-treated group, Huayu Recipe-treated group and bFGF-treated group (P<0.05). The replenishing qi and resolving stagnation therapy can control the secretion of TGF-beta1 of the wound in the process of wound healing in the levels of gene and molecule.


Night eating syndrome in patients with eating disorders: Is night eating syndrome distinct from bulimia nervosa?
Night eating syndrome (NES) is a diagnosis newly introduced in the fifth version of the Diagnostic and Statistical Manual of Mental Disorders. This study investigated the characteristics of NES in individuals with eating disorders and the clinical significance of NES in individuals with bulimia nervosa (BN). We recruited participants with eating problems at psychiatric outpatient clinics and from Internet referrals and age, sex, and educational level-comparable controls from September 2013 to April 2017. All participants received in-face structured clinical interviews to establish their eating disorder and NES diagnoses and completed questionnaires assessing NES, eating attitudes/behaviors, depression, sleep disturbances, morningness/eveningness preference, and functional impairment. Comparisons of measurements were made across patients with eating disorder subtypes and across patients with NES-only, BN-only, comorbid BN and NES, and controls. NES was identified in 10.3%, 34.9%, and 51.7% of the individuals with anorexia nervosa, BN, and binge-eating disorder, respectively. NES-only group had more frequent binge-eating, higher degrees of eating pathology, depression, sleep disturbances, and functional impairment compared to controls; however, NES-only group shared similar levels of disordered eating, depression, sleep disturbances, and functional impairment with BN-only group. BN-NES group had no difference from BN-only group on most eating pathology, psychopathology, and functional impairment, except for the presence of greater eating and weight concerns. NES has its clinical significance; however, it overlaps with BN in several dimensions of psychopathology. Presence of night eating in a BN group may not contribute clinically meaningful psychopathology.


Assessment of dietary determinants of nonheme-iron absorption in humans and rats.
Prior investigations have shown that rats are less sensitive than humans to dietary factors that influence the absorption of nonheme iron. This investigation was undertaken to determine whether this disparity is due to differences in the methods used to measure absorption in the two species. By use of identical methodology and test meals, absorption studies were performed in rats and humans to compare the effect of known dietary enhancers (ascorbic acid and meat) and inhibitors (tea, bran, and soy protein) on nonheme-iron absorption. Meat and tea had a marked effect on absorption in humans but did not influence absorption in rats. Although the effect of ascorbic acid, soy protein, and bran on absorption was statistically significant in rats, the absorptive response was far less than it was in humans. Our studies indicate that rodents cannot be used to assess the quantitative importance of dietary factors in human iron nutrition.


C5a mutants are potent antagonists of the C5a receptor (CD88) and of C5L2: position 69 is the locus that determines agonism or antagonism.
The anaphylatoxin C5a exerts a plethora of biologic activities critical in the pathogenesis of systemic inflammatory diseases. Recently, we reported on a C5a mutant, jun/fos-A8, as a potent antagonist for the human and mouse C5a receptor (CD88). Addressing the molecular mechanism accounting for CD88 receptor antagonism by site-directed mutagenesis, we found that a positively charged amino acid at position 69 is crucial. Replacements by either hydrophobic or negatively charged amino acids switched the CD88 antagonist jun/fos-A8 to a CD88 agonist. In addition to CD88, the seven-transmembrane receptor C5L2 has recently been found to provide high affinity binding sites for C5a and its desarginated form, C5adesArg74. A jun/fos-A8 mutant in which the jun/ fos moieties and amino acids at positions 71-73 were deleted, A8Delta71-73, blocked C5a and C5adesArg74 binding to CD88 and C5L2. In contrast, the cyclic C5a C-terminal analog peptide AcF-[OP-d-ChaWR] inhibited binding of the two anaphylatoxins to CD88 but not to C5L2, suggesting that the C5a core segment is important for high affinity binding to C5L2. Both receptors are coexpressed on human monocytes and the human mast cell line HMC-1; however, C5L2 expression on monocytes is weaker as compared with HMC-1 cells and highly variable. In contrast, no C5L2 expression was found on human neutrophils. A8Delta71-73 is the first antagonist that blocks C5a and C5adesArg74 binding to both C5a receptors, CD88 and C5L2, making it a valuable tool for studying C5L2 functions and for blocking the biological activities of C5a and C5adesArg74 in mice and humans.


Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis.
The co-occurrence of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation. In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double-negative (anti-cyclic citrullinated peptide [anti-CCP]-/RF-), anti-CCP+/RF-, anti-CCP-/RF+, or double-positive (anti-CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM-RF, and tumor necrosis factor α production measured as a readout of macrophage activation. Compared with the double-negative subgroup (as well as each single-positive subgroup), the double-positive subgroup exhibited higher disease activity as well as higher levels of C-reactive protein and inflammatory cytokines (all P < 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM-RF significantly increased macrophage tumor necrosis factor α production (P = 0.003 versus ACPA ICs alone). The combined presence of ACPAs and IgM-RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM-RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA.


Applying a Pedestrian Level of Service in the Context of Social Distancing: The Case of the City of Madrid.
During the COVID-19 pandemic, there has been a lot of discussion about keeping interpersonal distance to prevent the virus from spreading. To keep this interpersonal distance, authorities at different levels have taken measures to reduce people's interactions, such as reducing capacities, curfews, pop-up cycle lanes, temporary pedestrianisation, and lockdowns. Many of these temporary measures have been perceived from a static view. Nevertheless, in a scenario of "new normality" or in the face of a possible new pandemic, the amount of data (big data) generated by different sources, such as sensors, in large cities has extraordinary potential to be used together with tactical urbanism for quick adaptation. The aim of this study was to gain insight into the aforementioned issues by analysing spatio-temporal patterns of pedestrian mobility and developing a variation of the pedestrian level of service measure; the pandemic pedestrian level of service (P-PLOS). This measure provides a dynamic view of pavement capacities according to the interpersonal distance recommendations during the pandemic. P-PLOS was tested in the city of Madrid based on the pedestrian counter data that was provided by the local government through its open data website. We found that the application of P-PLOS, together with street design, allows for knowing where and when it is necessary to take tactical urbanism measures in order to maintain or improve the level of service, as well as where it is necessary to take measures to reduce pedestrian flow.


Specific cleavage of tRNA by nuclease S1.
Nuclease S1 specifically hydrolizes tRNAs in their anticodon loops, forming new 5' phosphate and 3' OH ends. Some single-stranded regions are not cut by nuclease S1. The strong preference of nuclease S1 for the anticodon region can be used for rapid identification of an anticodon-containing oligonucleotide and subsequent identification of the probable amino acid specificity of tRNA.


Generational Differences in Food Consumption among Chinese Adults of Different Ages.
Limited knowledge currently exists regarding the dynamics of generational shifts in food consumption among adult residents in China. This study aimed to investigate the generational differences in dietary status among different generations of Chinese adult residents aged 20 years and older. Survey participants from four waves (1991, 2000, 2009, and 2018) of the China Health and Nutrition Survey (CHNS) cohort were included in the study (N = 40,704), providing three-day 24 h dietary data. Participants were categorized into six age groups (20-29, 30-39, 40-49, 50-59, 60-69, and ≥70 years old), each corresponding to specific generations (Gen 10, 20, 30, 40, 50, 60, 70, 80, and 90) based on their age at the time of the survey. This study examined generational differences in the intake of cereals, animal-based foods, vegetables, fruits, dairy, energy, and the contribution of macronutrients to energy using chi-square tests and Kruskal-Wallis tests. All analyses were stratified by gender. Our findings revealed that younger generations exhibited lower daily intake of cereals, vegetables, energy, and contribution of carbohydrates to energy, compared to their older counterparts, regardless of gender. Conversely, regardless of male or female, younger generations showed higher daily consumption of animal-based foods, average fruit and dairy intake, fruit and dairy consumption rates, as well as contributions of protein and fat to energy, compared to older generations. The magnitude of generational differences in food consumption varied by age and gender. In addition, cereal and vegetable intake, energy intake, and contribution of carbohydrates to energy declined with age across all generations, while average dairy intake, fruit and dairy consumption rates, and the contribution of fat to energy tended to increase, regardless of gender. In conclusion, generational differences in food consumption were evident among different generations of Chinese adult residents, characterized by an increase in animal-based food intake and the contribution of fat to energy among generations. Attention should be directed towards addressing the eating behavior of younger generations.


[Recent progress in pediatric stem cell transplantation].
Pediatric hematopoietic stem cell transplantation (SCT) has been well established. Recent advances in the transplantation conditioning regimens and in the stem cell sources allow us to increase the candidates for transplantation, but the actual number of pediatric SCTs has been decreased because of the decline in the pediatric population and the progress of various chemotherapies and molecular targeted therapies. Pediatric SCT has become rather sophisticated. Cord blood (CB) stem cell transplantation has the problem of rejection and high relapse rate in the advanced malignant diseases. To overcome the rejection and relapse, it is important to select CB with a large number of the cells and the HLA-mismatched CB. Reduced intensity preparative regimens are increasingly adopted to reduce the early and late transplantation-related complications. In the pediatric setting, reduced intensity transplantation is still under investigation. Late complications for pediatric SCT, growth failure and secondary malignancies should be considered for the increasing number of long-term survivors.


Feasibility of an HIV self-testing intervention: a formative qualitative study among individuals, community leaders, and HIV testing experts in northern Tanzania.
Achieving the 95-95-95 global targets by 2030, innovative HIV testing models, such as HIV self-testing are needed for people, who are unaware of their HIV status. We aimed to explore key informants, mountain climbing porters, and female bar workers' attitudes, perceived norms, and personal agency related to HIV self-testing. This was a formative qualitative study to inform the design of an HIV self-testing intervention in Northern Tanzania. Informed by the Integrated Behaviour Model, we conducted four focus group discussions, and 18 in-depth interviews with purposively selected participants. Data were analyzed using the framework method. We recruited 55 participants. Most participants had positive attitudes towards HIVST, in that they anticipated positive consequences related to the introduction and uptake of HIVST. These included privacy and convenience, avoidance of long queues at health facilities, reduced counselor workload, and reduced indirect costs (given that transport to health facilities might not be required). Participants expressed the belief that significant people in their social environment, such as parents and peers, would approve their uptake of HIVST, and that they would accept HIVST. Additionally, features of HIVST that might facilitate its uptake were that it could be performed in private and would obviate visits to health facilities. Most participants were confident in their capacity to use HIVST kits, while a few were less confident about self-testing while alone. Strategies to maximize beliefs about personal agency and facilitate uptake included supplying the self-test kits in a way that was easy to access, and advocacy. Perceived potential constraints to the uptake of HIVST were the cost of buying the self-test kits, poverty, illiteracy, poor eyesight, fear of knowing one's HIV status, lack of policy/ guidelines for HIVST, and the absence of strategies for linkage to HIV care, treatment, and support. The findings suggest that HIVST may be feasible to implement in this study setting, with the majority of participants reporting positive attitudes, supportive perceived norms, and self-efficacy. Hence, future HIVST interventions should address the negative beliefs, and perceived barriers towards HIVST to increase HIV testing among the target population in Northern Tanzania.


Cytokinesis in plant and animal cells: endosomes 'shut the door'.
For many years, cytokinesis in eukaryotic cells was considered to be a process that took a variety of forms. This is rather surprising in the face of an apparently conservative mitosis. Animal cytokinesis was described as a process based on an actomyosin-based contractile ring, assembling, and acting at the cell periphery. In contrast, cytokinesis of plant cells was viewed as the centrifugal generation of a new cell wall by fusion of Golgi apparatus-derived vesicles. However, recent advances in animal and plant cell biology have revealed that many features formerly considered as plant-specific are, in fact, valid also for cytokinetic animal cells. For example, vesicular trafficking has turned out to be important not only for plant but also for animal cytokinesis. Moreover, the terminal phase of animal cytokinesis based on midbody microtubule activity resembles plant cytokinesis in that interdigitating microtubules play a decisive role in the recruitment of cytokinetic vesicles and directing them towards the cytokinetic spaces which need to be plugged by fusing endosomes. Presently, we are approaching another turning point which brings cytokinesis in plant and animal cells even closer. As an unexpected twist, new studies reveal that both plant and animal cytokinesis is driven not so much by Golgi-derived vesicles but rather by homotypically and heterotypically fusing endosomes. These are generated from cytokinetic cortical sites defined by preprophase microtubules and contractile actomyosin ring, which induce local endocytosis of both the plasma membrane and cell wall material. Finally, plant and animal cytokinesis meet together at the physical separation of daughter cells despite obvious differences in their preparatory events.


A Novel Intramedullary Locked Fixation Device for Treatment of Clavicle Shaft Fractures.
An intramedullary nail (the Sonoma CRx) with a unique flexible anatomical design and locking system is a viable alternative for treatment of displaced and shortened clavicle shaft fractures. Place the patient in the beach-chair position and drape the arm free so that you can obtain an exaggerated anteroposterior and an axial fluoroscopic view of the clavicle by manipulating the position of the arm. The surgical technique necessitates opening the fracture site in order to implant the device. The preparation of the medial fragment is of utmost importance as the intramedullary Sonoma CRx nail should be placed as far as possible into the medial fragment of the clavicle, to provide the highest level of stability and the lowest risk of device failure. Preparation of the lateral fragment is more challenging than preparation of the medial fragment because of its relative immobility and shorter medullary canal. Use the longest possible intramedullary nail that the clavicle can accommodate and insert the nail as far medially as possible into the medullary canal of the clavicle bone. Lock the device at its medial end with distally deployed grippers and laterally with a locking screw placed through a jig. Comminuted fractures are not a contraindication to the use of the intramedullary device as they can be reduced by the nail and secured by using cerclage sutures. Protect the affected shoulder in a shoulder immobilizer for six weeks. In our original study, forty-seven consecutive patients with a displaced and shortened clavicle shaft fracture were treated with open reduction and internal fixation using the Sonoma CRx device.


Post-COVID-19 fatigue: the contribution of cognitive and neuropsychiatric symptoms.
Fatigue in its many forms of physical, mental, and psychosocial exhaustion is a common symptom of post-COVID-19 condition, also known as "Long COVID." Persistent fatigue in COVID-19 patients is frequently accompanied by cognitive dysfunction and neuropsychiatric symptoms; however, less is known about the relationships between these components of post-COVID-19 condition and fatigue itself. Consequently, the present study sought to (1) distinguish the types of fatigue experienced by participants, and (2) investigate whether cognitive deficits across various domains and neuropsychiatric conditions predicted these different types of fatigue. The study included 136 COVID-19 patients referred for neuropsychological evaluation due to cognitive complaints 8 months on average after SARS-CoV-2 infection. Measures included self-reported fatigue (physical, cognitive, and psychosocial), neuropsychiatric questionnaires (assessing symptoms of depression, anxiety, apathy, and executive functioning), a comprehensive neuropsychological assessment, and self-reported quality of life and everyday functioning. Results showed that reports of clinical significant fatigue were pervasive in our sample (82.3% of participants), with physical fatigue rated highest on average relative to the subscale maximum. Elevated levels of apathy, anxiety, and executive dysfunction in neuropsychiatric measures along with executive and attentional difficulties on cognitive tests were found to be consistently important predictors among different types of fatigue. This implicates both cognitive and neuropsychiatric symptoms as predictors of fatigue in post-COVID-19 condition, and stresses the importance of a holistic approach in assessing and considering potential treatment for COVID-19 patients experiencing fatigue.


Simultaneous Visualization of Enzymatic Activity in the Cytoplasm and at Polyphosphate Inclusions in Beggiatoa sp. Strain 35Flor Incubated with 18O-Labeled Water.
Here we report on a new nanoscale secondary ion mass spectrometry (nanoSIMS) approach based on enzyme-mediated oxygen isotope exchange, which combines the visualization of general metabolic activity in the cytoplasm with insights into the activity of enzymes related to polyphosphate (polyP) inclusions. The polyP-accumulating strain of the large sulfur bacterium Beggiatoa was used as a model organism. Beggiatoa cultures were grown under oxic and anoxic conditions when exposed to either low- or high-sulfide conditions, which are known to influence polyP metabolism in this strain. Subsequent incubation with 18O-labeled water led to high 18O enrichments above the natural background in the cytoplasm and polyP granules derived from enzymatically mediated oxygen isotope exchange. The relative importance of polyP under the different sulfide regimes became evident by an apparent continued metabolic activity at polyP inclusions under stressfully high sulfide concentrations, in contrast to a decreased general metabolic activity in the cytoplasm. This finding confirms the role of polyP as a critical component in bacterial stress response and maintenance of a survival metabolism.IMPORTANCE Microbial organisms exert a large influence on the environment as they directly affect the turnover of essential elements. This is particularly true for polyphosphate-accumulating large sulfur bacteria, which can either accumulate phosphate as polyphosphate or degrade it and release phosphate into the environment, depending on environmental conditions. This study presents a new approach to simultaneously visualize general metabolic activity and enzymatic activity at polyphosphate granules by incubation with 18O-labeled water as the only stable isotope tracer. For this purpose, the well-studied Beggiatoa sp. strain 35Flor was used as a model organism and was exposed to different stress regimes. General metabolic activity was strongly impaired during high-stress regimes. In contrast, intense intracellular polyP cycling was not restricted to favorable or stressful conditions, highlighting the importance of polyP for general cell physiology, especially during hostile conditions. The nanoSIMS approach adds a new tool to study microorganisms involved in phosphorus cycling in the environment together with the identification of general metabolic activity.


The structure and function of the pericellular matrix of articular cartilage.
Chondrocytes in articular cartilage are surrounded by a narrow pericellular matrix (PCM) that is both biochemically and biomechanically distinct from the extracellular matrix (ECM) of the tissue. While the PCM was first observed nearly a century ago, its role is still under investigation. In support of early hypotheses regarding its function, increasing evidence indicates that the PCM serves as a transducer of biochemical and biomechanical signals to the chondrocyte. Work over the past two decades has established that the PCM in adult tissue is defined biochemically by several molecular components, including type VI collagen and perlecan. On the other hand, the biomechanical properties of this structure have only recently been measured. Techniques such as micropipette aspiration, in situ imaging, computational modeling, and atomic force microscopy have determined that the PCM exhibits distinct mechanical properties as compared to the ECM, and that these properties are influenced by specific PCM components as well as disease state. Importantly, the unique relationships among the mechanical properties of the chondrocyte, PCM, and ECM in different zones of cartilage suggest that this region significantly influences the stress-strain environment of the chondrocyte. In this review, we discuss recent advances in the measurement of PCM mechanical properties and structure that further increase our understanding of PCM function. Taken together, these studies suggest that the PCM plays a critical role in controlling the mechanical environment and mechanobiology of cells in cartilage and other cartilaginous tissues, such as the meniscus or intervertebral disc.


[The use of the plasmid pTH10 for isolating the donor strains of Pseudomonas mallei].
The plasmid pTH10 was transfered by conjugation into the Pseudomonas mallei strains. An attempt to construct the donor strains using the widely known technique employing the homology between the plasmid and chromosome due to the transposon Tn1 carried by the plasmid was unsuccessful. Among the clones resistant to bacteriophage PRD1 the variants were selected with the supposed integration of the plasmid into the chromosome. The latter clones required the ability to transfer the auxotrophic chromosomal markers in conjugation after the repeated conjugational transfer of the plasmid pTH10 into them.


Experience with risperidone long-acting injection: results of a naturalistic observation study.
Typical antipsychotics are effective in the management of schizophrenia, but are associated with troublesome adverse effects which may lead to treatment discontinuation and relapse. Long-acting depot formulations of these drugs improve patient compliance, but do not reduce the incidence of adverse effects. There is evidence to suggest that newer atypical antipsychotic drugs have a reduced propensity to induce movement disorders and are associated with a modest reduction in relapse rates. The introduction of risperidone long-acting injection (RLAI) provided clinicians with the first long-acting formulation of an atypical antipsychotic. Objective. The aim of this study was to investigate the outcomes of patients from an acute mental health trust who received RLAI during the 18-month period following its licensing in the UK in order to examine measures of clinical effectiveness, and reasons for treatment discontinuation. Methods. Data were collected retrospectively from medical notes. Results. Fifty-nine patients were included in the study, and at the time of data collection 32 (54%) had discontinued treatment. The most common reason for discontinuation was lack of effectiveness, although all of the patients who discontinued due to lack of response were treatment resistant. RLAI appeared to be well tolerated, with only 12% of patients discontinuing due to adverse effects. Thirty-eight percent of the patients treated with RLAI showed a good response as measured by discharge from inpatient setting, and of the 22 outpatients at time of data collection, five had one re-hospitalisation during the study period. Conclusion. This study concludes that RLAI appears to be well tolerated, and shows some effectiveness in the treatment of schizophrenia, but may not be effective for patients who are treatment resistant.


[Immunity in the fetus and the newborn infant: a swine model].
An efficient placental barrier protects the pig fetus from all exogenous antigenic stimulation. The results of studies on different subpopulations of lymphocytes, histological localization, and stimulation as well as immunization in utero with allogeneic lymphocytes have confirmed that the pig fetus becomes immunocompetent at around 80 days of fetal life (total length of gestation: 115 days). Because the newborn piglet has had no "immunological experience" in utero, it can only elaborate a primary response which is often advantageous to pathogenic microorganisms. Under natural conditions, immune protection is provided by the mother in the form of colostrum. This colostrum provides systemic immunity and is followed by milk which insures local immunity in the piglet gastrointestinal tract. However, the great disadvantage of maternal antibodies is that they suppress the active synthesis of new antibodies in young pig. Thus, the beginning of active immunity in the piglet is a function of the ratio of maternal antibody level to the level of antigenic stimulation.


Evaluation of surgical treatment for ruptured Achilles tendon in 31 athletes.
In the past few decades, the incidence of Achilles tendon rupture has increased in parallel with increased sports participation. Although the optimal treatment remains controversial, there is a trend towards surgical treatment in athletes. Surgical repair of ruptured Achilles tendon in athlete results in good functional and objective recovery, irrespective of the type of surgery performed. Subsidiarily, are the results different between percutaneous surgery (PS) and standard open surgery (OS)? This was a cross-sectional study of 31 patients who presented with a ruptured Achilles tendon that occurred during sports participation. Percutaneous surgery was performed in 16 patients and open surgery in 15 patients between 2005 and 2009. The objective recovery status was evaluated by open chain goniometry, measurement of leg muscle atrophy and assessment of isokinetic strength. The functional analysis was based on the delay, level of sports upon return, AOFAS and VAS for pain. Our series of Achilles tendon rupture patients consisted of 88% men and 12% women, with an average age of 38 years. In 71% of cases, the rupture occurred during eccentric loading. After a follow-up of 15 months, the muscle atrophy was 13 mm after PS and 24 mm after OS (P=0.01). A strength deficit of 19% in the plantar flexors was found in the two groups. No patient experienced a rerupture. The return to sports occurred at 130 days after PS and 178 days after OS (P=0.005). The average AOFAS score was 94 and the VAS was 0.5. There were no differences in ankle range of motion between the two groups. The majority (77%) of patients had returned to their preinjury level of sports activity. The return to activities of daily living was slower in our study than in studies based in Anglo-Saxon countries; this can be explained by the different sick leave coverage systems. Percutaneous surgery resulted in a faster return to sports (about 130 days) and less muscle atrophy than open surgery. Our results for return to sports and return to preinjury levels were similar to published results for athletes and were independent of the type of surgery performed. The AOFAS score was comparable to published studies. We found no difference in muscle strength between the two surgery groups 15 months after the procedure. Apart from venous thrombosis typically described after lower-limb immobilization, secondary postoperative complications mostly consisted of sural paresthesia, which had resolved at the 15-month postoperative follow-up evaluation. The results of surgical treatment for ruptured Achilles tendon are good overall. By combining the simplicity of conservative treatment and the reliability of standard surgical treatment, percutaneous surgery is the treatment of choice to achieve excellent results. The return to sports occurred earlier, the muscle atrophy was less and the functional score was better in our patients treated by percutaneous surgery. Level IV.


Molecular organization and expression of the genetic locus glued in Drosophila melanogaster.
The Glued locus of Drosophila melanogaster is genetically defined as the functional unit which is affected by the dominant Glued mutation Gl. Genomic DNA was cloned from the region of the Glued locus, at 70C2 on chromosome 3, by using a P element insertion in the region as a molecular marker. Three genes encoding polyadenylated transcripts were detected within a 30-kilobase span of the cloned DNA. The gene nearest the P element insertion site was identified as a Glued gene on the basis of alterations in its DNA and encoded transcript associated with the Gl mutation and with reversions of Gl which eliminate the dominant effect by inactivation of the mutant allele. Expression of the wild-type Gl+ gene is temporally regulated during development; the amount of the encoded transcript is highest in the embryonic stage, decreasing in the first and second larval instars, and then increasing in the third instar and pupal stages. There is a maternal contribution of the Gl+ transcript to the embryo, which probably accounts for the maternal lethal effect of Glued mutations on early development. In situ hybridizations of Gl+ DNA to RNA in tissue sections showed that the Gl+ transcript is present in virtually all tissues of the embryo, late larva, and pupa. The general distribution of this transcript is consistent with genetic evidence indicating that the Glued locus controls a generally essential cell function (P. J. Harte and D. R. Kankel, Genetics 101:477-501, 1982). Different Glued mutations produce distinct phenotypic effects, including adults with severe visual defects, larvae lacking imaginal discs, and early lethality. These diverse mutant phenotypes are discussed in terms of quantitative changes in the Glued function. Closely adjacent to Gl+ is another gene which is transcribed in a divergent direction and expressed coordinately with Gl+ throughout Drosophila development. It remains to be determined whether this gene is also involved with the Glued function.


[Prevalence of latex hypersensitivity in operating room workers of the University of Chile Clinical Hospital].
Health care workers (HCW) are a high risk group for developing natural rubber latex (NRL) hypersensitivity and allergy. Some studies showed a correlation between time and frequency of exposure to NRL gloves and hypersensitivity, but a recent meta-analysis showed no clear evidences for such assumption. To determine the prevalence of NRL hypersensitivity and allergy in a group of HCW at the University of Chile Clinical Hospital. Ninety five HCW (aged 37+/-10 years, 59 females) were interviewed about time of exposure, atopic diseases and latex-related allergy symptoms. Different NRL extracts and seven NRL gloves brands were tested by the prick test method. Twenty four workers (25%, 95% CI = 16.9%-35.2%) were sensitized. No gender differences were found. No symptomatic cases were found in the sensitized group. In the workplace, six and two non sensitized subjects had respiratory symptoms or contact urticaria, respectively. Sensitivity to bananas, avocadoes, kiwi and chestnut was not significantly more common among latex sensitive individuals. No differences between sensitized and non sensitized subjects were observed for the presence of atopic diseases or the mean number of years at the workplace. The sensitization rate to NRL increased along with years of work, from 18.6% in patients working less than 10 years, to 28.1% in the group between 10 and 20 years and to 35% in those working more than 21 years (p=0.693). Sensitization was also related to the weekly hours of exposure: 1-10 hours, 17%; 11-20 hours, 23.5%; 21-30 hours, 50% and 31-40 hours, 28.5% (p=0.036). Sensitization increased proportionally to the years and weekly hours wearing NLR gloves. We did not find symptomatic patients in the sensitized group.


A Rickettsiella Endosymbiont Is a Potential Source of Essential B-Vitamins for the Poultry Red Mite, Dermanyssus gallinae.
Many obligate blood-sucking arthropods rely on symbiotic bacteria to provision essential B vitamins that are either missing or at sub-optimal levels in their nutritionally challenging blood diet. The poultry red mite Dermanyssus gallinae, an obligate blood-feeding ectoparasite, is a serious threat to the hen egg industry. Poultry red mite infestation has a major impact on hen health and welfare and causes a significant reduction in both egg quality and production. Thus far, the identity and biological role of nutrient provisioning bacterial mutualists from D. gallinae are little understood. Here, we demonstrate that an obligate intracellular bacterium of the Rickettsiella genus is detected in D. gallinae mites collected from 63 sites (from 15 countries) across Europe. In addition, we report the genome sequence of Rickettsiella from D. gallinae (Rickettsiella - D. gallinae endosymbiont; Rickettsiella DGE). Rickettsiella DGE has a circular 1.89Mbp genome that encodes 1,973 proteins. Phylogenetic analysis confirms the placement of Rickettsiella DGE within the Rickettsiella genus, related to a facultative endosymbiont from the pea aphid and Coxiella-like endosymbionts (CLEs) from blood feeding ticks. Analysis of the Rickettsiella DGE genome reveals that many protein-coding sequences are either pseudogenized or lost, but Rickettsiella DGE has retained several B vitamin biosynthesis pathways, suggesting the importance of these pathways in evolution of a nutritional symbiosis with D. gallinae. In silico metabolic pathway reconstruction revealed that Rickettsiella DGE is unable to synthesize protein amino acids and, therefore, amino acids are potentially provisioned by the host. In contrast, Rickettsiella DGE retains biosynthetic pathways for B vitamins: thiamine (vitamin B1) via the salvage pathway; riboflavin (vitamin B2) and pyridoxine (vitamin B6) and the cofactors: flavin adenine dinucleotide (FAD) and coenzyme A (CoA) that likely provision these nutrients to the host.


Maternal and paternal attachment in high-risk adolescents: Unique and interactive associations with anxiety and depressive symptoms.
Anxiety and depressive symptoms are common, comorbid, and consequential for adolescents. Attachment theory suggests that styles of relationships with parents, developed from patterns of interactions over time, contribute to risk for these internalizing symptoms. This may be especially relevant for high-risk, clinically severe adolescents. However, most research focuses primarily on attachment relationships to mothers. Some theoretical perspectives also suggest that attachment to other caregivers (such as fathers) may not only be uniquely important for understanding internalizing symptoms but may also interact with maternal attachment. Therefore, it is important to examine these attachment relationships in tandem. The present study examines associations between attachment and internalizing symptoms in a sample of 1,141 youth (12-20 years old; 54.0% female, 96.5% White) from a multisite residential treatment facility. Youth reported on attachment anxiety and avoidance with both parents, as well as anxiety and depressive symptoms. Response surface analyses were used to examine curvilinear, interactive, and fit effects using a model comparison approach. Overall, for patterns of anxious attachment, the best-fitting models reflected simple additive and linear effects. For avoidant attachment, best-fitting models included interactions and fit patterns, suggesting the meaning of maternal attachment was dependent on paternal and vice versa. After accounting for covariates, however, maternal attachment was the sole predictor in most models except attachment avoidance predicting depressive symptoms. These results have implications for attachment theory and research, and further work untangling these complex effects may inform clinical practice for high-risk adolescents. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Construction of a highly stable artificial glutathione peroxidase on a protein nanoring.
Stable Protein One (SP1) is a boiling-stable oligomeric protein. The unique characteristics of SP1 offer a scaffold to design artificial enzymes against extreme temperature. Here, an efficient antioxidase is successfully constructed on the ring-shaped SP1 homododecamer. By means of computational design and genetic engineering, the active center of glutathione peroxidase (GPx), selenocysteine (Sec), is introduced to the SP1 monomer surface, and the self-assembly properties of the protein monomer lead to a ring-shaped SP1 with homododecamer catalytic selenium centers. This artificial selenoenzyme exhibits high GPx catalytic activity and shows a typical ping-pong kinetic mechanism. Moreover, it has a significantly broader temperature range and high thermostability. Owing to having multi-GPx active centers on a SP1 oligomer, this selenium-containing biomacromolecule exerts an excellent capability to protect cells from oxidative damage at the mitochondrial level. This strategy represents a new way to develop thermostable artificial nanoenzymes for some specific applications.


PARP inhibition causes premature loss of cohesion in cancer cells.
Poly(ADP-ribose) polymerases (PARPs) regulate various aspects of cellular function including mitotic progression. Although PARP inhibitors have been undergoing various clinical trials and the PARP1/2 inhibitor olaparib was approved as monotherapy for BRCA-mutated ovarian cancer, their mode of action in killing tumour cells is not fully understood. We investigated the effect of PARP inhibition on mitosis in cancerous (cervical, ovary, breast and osteosarcoma) and non-cancerous cells by live-cell imaging. The clinically relevant inhibitor olaparib induced strong perturbations in mitosis, including problems with chromosome alignment at the metaphase plate, anaphase delay, and premature loss of cohesion (cohesion fatigue) after a prolonged metaphase arrest, resulting in sister chromatid scattering. PARP1 and PARP2 depletion suppressed the phenotype while PARP2 overexpression enhanced it, suggesting that olaparib-bound PARP1 and PARP2 rather than the lack of catalytic activity causes this phenotype. Olaparib-induced mitotic chromatid scattering was observed in various cancer cell lines with increased protein levels of PARP1 and PARP2, but not in non-cancer or cancer cell lines that expressed lower levels of PARP1 or PARP2. Interestingly, the sister chromatid scattering phenotype occurred only when olaparib was added during the S-phase preceding mitosis, suggesting that PARP1 and PARP2 entrapment at replication forks impairs sister chromatid cohesion. Clinically relevant DNA-damaging agents that impair replication progression such as topoisomerase inhibitors and cisplatin were also found to induce sister chromatid scattering and metaphase plate alignment problems, suggesting that these mitotic phenotypes are a common outcome of replication perturbation.


Undergraduate students' motivations for the consumption of legal drugs.
This qualitative research aimed at identifying conceptions held by undergraduate students regarding the term motivation, and motives leading them to the consumption of legal drugs. Data were collected through a questionnaire with four open questions, applied to 15 students of a public university in the central region of Mexico. In order to perform the data analysis, answers were classified in two categories: a) Undergraduate students' conceptions regarding the term motivation and b) Undergraduate students' conceptions regarding the motives for consumption. Such analysis indicated that students identify two types of motivations: external and internal. The external motivation includes family, mass media and friends; whereas internal motivation includes personal characteristics, need of belonging, curiosity, pleasure and idleness.


Conspiracy in Paris, November 1938: medical fraud as pretext for the Kristallnacht pogrom.
This medical history essay claims that a medical fraud was committed by the authorities and was used as a pretext for the November 1938 anti-jewish Kristallnacht pogrom throughout the Third Reich. The suggested conspiracy covered up the real cause of death of the German Embassy's secretary in Paris. Baron Ernst vom Rath had been shot by a Jewish teenager who was frantic because of the plight of his family. A surgical analysis of the victim's injuries, and of the medical attention he received, suggests the likelihood of medical malpractice which led to his preventable demise.


Identification and analysis of evolutionary selection pressures acting at the molecular level in five forkhead subfamilies.
Members of the forkhead gene family act as transcription regulators in biological processes including development and metabolism. The evolution of forkhead genes has not been widely examined and selection pressures at the molecular level influencing subfamily evolution and differentiation have not been explored. Here, in silico methods were used to examine selection pressures acting on the coding sequence of five multi-species FOX protein subfamily clusters; FoxA, FoxD, FoxI, FoxO and FoxP. Application of site models, which estimate overall selection pressures on individual codons throughout the phylogeny, showed that the amino acid changes observed were either neutral or under negative selection. Branch-site models, which allow estimated selection pressures along specified lineages to vary as compared to the remaining phylogeny, identified positive selection along branches leading to the FoxA3 and Protostomia clades in the FoxA cluster and the branch leading to the FoxO3 clade in the FoxO cluster. Residues that may differentiate paralogs were identified in the FoxA and FoxO clusters and residues that differentiate orthologs were identified in the FoxA cluster. Neutral amino acid changes were identified in the forkhead domain of the FoxA, FoxD and FoxP clusters while positive selection was identified in the forkhead domain of the Protostomia lineage of the FoxA cluster. A series of residues under strong negative selection adjacent to the N- and C-termini of the forkhead domain were identified in all clusters analyzed suggesting a new method for refinement of domain boundaries. Extrapolation of domains among cluster members in conjunction with selection pressure information allowed prediction of residue function in the FoxA, FoxO and FoxP clusters and exclusion of known domain function in residues of the FoxA and FoxI clusters. Consideration of selection pressures observed in conjunction with known functional information allowed prediction of residue function and refinement of domain boundaries. Identification of residues that differentiate orthologs and paralogs provided insight into the development and functional consequences of paralogs and forkhead subfamily composition differences among species. Overall we found that after gene duplication of forkhead family members, rapid differentiation and subsequent fixation of amino acid changes through negative selection has occurred.


Health and economic implications of HPV vaccination in the United States.
The cost-effectiveness of prophylactic vaccination against human papillomavirus types 16 (HPV-16) and 18 (HPV-18) is an important consideration for guidelines for immunization in the United States. We synthesized epidemiologic and demographic data using models of HPV-16 and HPV-18 transmission and cervical carcinogenesis to compare the health and economic outcomes of vaccinating preadolescent girls (at 12 years of age) and vaccinating older girls and women in catch-up programs (to 18, 21, or 26 years of age). We examined the health benefits of averting other HPV-16-related and HPV-18-related cancers, the prevention of HPV-6-related and HPV-11-related genital warts and juvenile-onset recurrent respiratory papillomatosis by means of the quadrivalent vaccine, the duration of immunity, and future screening practices. On the assumption that the vaccine provided lifelong immunity, the cost-effectiveness ratio of vaccination of 12-year-old girls was $43,600 per quality-adjusted life-year (QALY) gained, as compared with the current screening practice. Under baseline assumptions, the cost-effectiveness ratio for extending a temporary catch-up program for girls to 18 years of age was $97,300 per QALY; the cost of extending vaccination of girls and women to the age of 21 years was $120,400 per QALY, and the cost for extension to the age of 26 years was $152,700 per QALY. The results were sensitive to the duration of vaccine-induced immunity; if immunity waned after 10 years, the cost of vaccination of preadolescent girls exceeded $140,000 per QALY, and catch-up strategies were less cost-effective than screening alone. The cost-effectiveness ratios for vaccination strategies were more favorable if the benefits of averting other health conditions were included or if screening was delayed and performed at less frequent intervals and with more sensitive tests; they were less favorable if vaccinated girls were preferentially screened more frequently in adulthood. The cost-effectiveness of HPV vaccination will depend on the duration of vaccine immunity and will be optimized by achieving high coverage in preadolescent girls, targeting initial catch-up efforts to women up to 18 or 21 years of age, and revising screening policies.


Association between symptoms and subtypes of attention-deficit hyperactivity disorder and sleep problems/disorders.
This study aimed to investigate the association between attention-deficit hyperactivity disorder (ADHD) symptoms and subtypes, and sleep schedules, daytime inadvertent napping, and sleep problems/disorders in children and adolescents with and without ADHD. The sample included 325 patients with ADHD, aged 10-17 years [male: 81.5%; combined type (ADHD-C): 174; predominantly inattentive type (ADHD-I): 130; predominantly hyperactive-impulsive type (ADHD-HI): 21], and 257 children and adolescents without lifetime ADHD (non-ADHD). We conducted psychiatric interviews with the participants and their mothers before making the diagnoses of ADHD, other psychiatric disorders, and sleep problems or disorders. We also collected the medication treatment data and parent and teacher reports of ADHD symptoms. Multi-level models were used for data analyses controlling for sex, age, psychiatric comorbidities, and treatment with methylphenidate. The ADHD-C and ADHD-I groups had more daytime inadvertent napping. In general, the three subtypes were associated with increased rates of sleep problems/disorders. Specifically, ADHD-C rather than ADHD-I was associated with circadian rhythm problems, sleep-talking, nightmares (also ADHD-HI), and ADHD-I was associated with hypersomnia. The most-related sleep schedules and problems for inattention and hyperactivity-impulsivity were earlier bedtime, later rise time, longer nocturnal sleep, more frequent daytime napping, insomnia, sleep terrors, sleep-talking, snoring, and bruxism across informants. The findings imply that in addition to the dichotomous approach of ADHD and considering the psychiatric comorbid conditions, ADHD subtypes and symptom dimensions need to be considered in clinical practice and in the research regarding the association between ADHD and sleep problems/disorders.


Knockdown of Indian hedgehog protein induces an inhibition of cell growth and differentiation in osteoblast MC3T3‑E1 cells.
Indian hedgehog protein (Ihh) is evolutionarily conserved and serves important roles in controlling the differentiation of progenitor cells into osteoblasts. Ihh null mutant mice exhibit a failure of osteoblast development in endochondral bone. Although studies have demonstrated that Ihh signaling is a potent local factor that regulates osteoblast differentiation, the specific transcription factors that determine osteoblast differentiation remain unclear. Further studies are required to determine the precise mechanism through which Ihh regulates osteoblast differentiation. In the present study, Ihh was knocked down in osteoblast MC3T3‑E1 cells using short hairpin RNA, to investigate the function of Ihh in osteoblast proliferation and differentiation and to examine the potential mechanism through which Ihh induces osteoblast apoptosis and cell cycle arrest. It was observed that the knockdown of Ihh induced a marked inhibition of cell growth and increased the apoptosis rate compared with the negative control osteoblasts. Downregulation of Ihh resulted in a cell cycle arrest at the G1 to S phase boundary in osteoblasts. In addition, the knockdown of Ihh decreased the alkaline phosphatase activity and mineral deposition of osteoblasts. The inhibitory roles of Ihh downregulation in osteoblast growth and differentiation may be associated with the transforming growth factor‑β/mothers against decapentaplegic homolog and tumor necrosis factor receptor superfamily member 11B/tumor necrosis factor ligand superfamily member 11 signaling pathways. Manipulating either Ihh expression or its signaling components may be of benefit for the treatment of skeletal diseases.


[Transmission of Pneumocystis infection in humans].
Is Pneumocystis pneumonia (PcP) a transmissible fungal disease? Does nosocomial PcP occur? Is there Pneumocystis transmission in the community? These questions, which could not be tackled before the 2000s, may at present be approached using either noninvasive detection methods or experimental transmission models. Represented by a unique entity (P. carinii) for almost one century, the Pneumocystis genus was shown to contain several species, being P. jirovecii the sole species identified in humans hitherto. Molecular methods combined with cross infection experiments revealed strong host specificity that precludes Pneumocystis inter-species transmission. In contrast, respiratory transmission between mammals of a same species is usually highly active, even between immunocompetent hosts. Other transmission ways could also exist. New data show that human being is the unique P. jirovecii reservoir; it would constitute the sole infection source in both hospital and community.


Italian guidelines for therapy of atopic dermatitis-Adapted from consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis).
Atopic dermatitis (AD) therapeutic approach calls for a long-term treatment. Treatment options for AD have recently undergone a revolutionary change by the introduction of the first biologic drug. Availability in daily practice of the last version of international AD guidelines, taking peculiarities of the country into account, can contribute to good clinical practice in Italy. To adapt European Dermatology Forum (EDF) guidelines for AD to the Italian medical-legal context, the EDF guidelines were assessed independently by two independent Italian renowned experts in the field and further integrated with articles published and systematically reviewed before May 2019. The first draft was collegially corrected and updated by the members of the SIDEMAST, ADOI, and SIDAPA. Recommendation levels (A; B; C; D) were graded based on the evidence levels (1-4). The adapted guidelines presented here focus on topical and systemic therapies in AD patients, both children and adults. As opposed to previous Italian guidelines, they include indications about biologics. New relevant evidence available from very recent literature and peculiarities of the Italian medical and legal context have been integrated in the revision process. If compared to general guidelines for AD not adapted to a specific national and cultural context, a revision for specific Italian needs is now available: It comprises the option of implementing the new biologic treatments and is likely to provide an important contribution to the improvement of clinical practice in Italy. Cooperation between patients, dermatologists, allergologists, and pediatricians remains mandatory in AD management. The authors of the present revision recommend an update of the Italian guidelines to be performed at least every second year.


Human behavior state profile mapping based on recalibrated speech affective space model.
People typically associate health with only physical health. However, health is also interconnected to mental and emotional health. People who are emotionally healthy are in control of their behaviors and experience better quality of life. Hence, understanding human behavior is very important in ensuring the complete understanding of one's holistic health. In this paper, we attempt to map human behavior state (HBS) profiles onto recalibrated speech affective space model (rSASM). Such an approach is derived from hypotheses that: 1) Behavior is influenced by emotion, 2) Emotion can be quantified through speech, 3) Emotion is dynamic and changes over time and 4) the emotion conveyance is conditioned by culture. Empirical results illustrated that the proposed approach can complement other types of behavior analysis in such a way that it offers more explanatory components from the perspective of emotion primitives (valence and arousal). Four different driving HBS; namely: distracted, laughing, sleepy and normal are profiled onto the rSASM to visualize the correlation between HBS and emotion. This approach can be incorporated in the future behavior analysis to envisage better performance.


Videolaryngoscopy versus direct laryngoscopy for adult patients requiring tracheal intubation: a Cochrane Systematic Review.
Difficulties with tracheal intubation commonly arise and impact patient safety. This systematic review evaluates whether videolaryngoscopes reduce intubation failure and complications compared with direct laryngoscopy in adults. We searched CENTRAL, MEDLINE, Embase and clinicaltrials.gov up to February 2015, and conducted forward and backward citation tracking. We included randomized controlled trials that compared adult patients undergoing laryngoscopy with videolaryngoscopy or Macintosh laryngoscopy. We did not primarily intend to compare individual videolaryngoscopes. Sixty-four studies (7044 participants) were included. Moderate quality evidence showed that videolaryngoscopy reduced failed intubations (Odds Ratio (OR) 0.35, 95% Confidence Interval (CI) 0.19-0.65) including in participants with anticipated difficult airways (OR 0.28, 95% CI 0.15-0.55). There was no evidence of reduction in hypoxia or mortality, but few studies reported these outcomes. Videolaryngoscopes reduced laryngeal/airway trauma (OR 0.68, 95% CI 0.48-0.96) and hoarseness (OR 0.57, 95% CI 0.36-0.88). Videolaryngoscopy increased easy laryngeal views (OR 6.77, 95% CI 4.17-10.98) and reduced difficult views (OR 0.18, 95% CI 0.13-0.27) and intubation difficulty, typically using an 'intubation difficulty score' (OR 7.13, 95% CI 3.12-16.31). Failed intubations were reduced with experienced operators (OR 0.32, 95% CI 0.13-0.75) but not with inexperienced users. We identified no difference in number of first attempts and incidence of sore throat. Heterogeneity around time for intubation data prevented meta-analysis. We found evidence of differential performance between different videolaryngoscope designs. Lack of data prevented analysis of impact of obesity or clinical location on failed intubation rates. Videolaryngoscopes may reduce the number of failed intubations, particularly among patients presenting with a difficult airway. They improve the glottic view and may reduce laryngeal/airway trauma. Currently, no evidence indicates that use of a videolaryngoscope reduces the number of intubation attempts or the incidence of hypoxia or respiratory complications, and no evidence indicates that use of a videolaryngoscope affects time required for intubation.


FGF23 Induction of O-Linked N-Acetylglucosamine Regulates IL-6 Secretion in Human Bronchial Epithelial Cells.
The hexosamine biosynthetic pathway (HBP) generates the substrate for the O-linked β-N-acetylglucosamine (O-GlcNAc) modification of proteins. The HBP also serves as a stress sensor and has been reported to be involved with nuclear factor of activated T-cells (NFAT) activation, which can contribute to multiple cellular processes including cell metabolism, proliferation, and inflammation. In our previously published report, Fibroblast Growth Factor (FGF) 23, an important endocrine pro-inflammatory mediator, was shown to activate the FGFR4/phospholipase Cγ (PLCγ)/nuclear factor of activated T-cells (NFAT) signaling in chronic inflammatory airway diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Here, we demonstrate that FGF23 increased the O-GlcNAc modification of proteins in HBECs. Furthermore, the increase in O-GlcNAc levels by FGF23 stimulation resulted in the downstream activation of NFAT and secretion of interleukin-6 (IL-6). Conversely, inhibition of FGF23 signaling and/or O-GlcNAc transferase (OGT)/O-GlcNAc reversed these effects. Collectively, these data suggest that FGF23 induced IL-6 upregulation and secretion is, at least, partially mediated via the activation of the HBP and O-GlcNAc levels in HBECs. These findings identify a novel link whereby FGF23 and the augmentation of O-GlcNAc levels regulate airway inflammation through NFAT activation and IL-6 upregulation in HBECs. The crosstalk between these signaling pathways may contribute to the pathogenesis of chronic inflammatory airway diseases such as COPD and CF as well as metabolic syndromes, including diabetes.


Renal cortical accumulation of phenobarbital in rats and rabbits: lack of correlation with induction of renal microsomal monooxygenases.
Subchronic treatment with phenobarbital induces renal cortical microsomal monooxygenase activities (e.g., ethoxycoumarin O-deethylase, benzphetamine N-demethylase and arylhydrocarbon hydroxylase) and cytochrome P-450 content in rabbits but not in rats. The mechanism responsible for this species-specific difference in renal cortical enzyme induction remains unknown, but may be the result of differences in the renal cortical accumulation of phenobarbital by these two species. Rabbit kidneys may be capable of accumulating more phenobarbital than rat kidneys. In the present study, accumulation of phenobarbital by renal cortical slices and the disposition of phenobarbital in vivo were determined. Both rat and rabbit renal cortical accumulation of phenobarbital was partially energy-dependent and inhibited by SKF-525A. Renal cortical accumulation of phenobarbital in rats was also inhibited by piperonyl butoxide. Accumulation of phenobarbital in rabbit renal cortical slices was not greater than that in rat renal cortical slices. Furthermore, rabbit renal cortex did not accumulate more phenobarbital in vivo than rat renal cortex. These results suggest that the different enzyme inducing effects of phenobarbital in rat and rabbit kidneys is not due to quantitative differences in accumulation of phenobarbital in renal cortex.


Synthesis of cell wall microfibrils in vitro by a "soluble" chitin synthetase from Mucor rouxii.
A "soluble" form of chitin synthetase was separated from a membrane-rich fraction by exposure to the enzyme substrate (uridine diphosphate N-acetyl-D-glucosamine) and activator (N-acetyl- D-glucosamine). The solubilized enzyme catalyzed the synthesis of chitin microfibrils similar, if not identical, to those formed in vivo by the fungus. Cell wall microfibrils were thus abundantly formed in the absence of a living cell or its membranes.


[Cardiovascular manifestations in mixed connective tissue disease in adults].
Twenty two patients with mixed connective tissue disease (MCTD) were studied with noninvasive cardiovascular techniques. Fifty percent of the cases presented cardiovascular abnormalities which in order of importance were: pericarditis with effusion (28%), myocarditis (14%) and one case; myocardial infarction. Complications of less importance were: supraventricular and ventricular premature beats, enlargement of left and right cardiac chambers, septal hypertrophy and type A paradoxical septal movement. We consider that patients with MCTD should have a routine cardiological evaluation.


Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness.
Hereditary deafness affects about 1 in 2000 children and mutations in the GJB2 gene are the major cause in various ethnic groups. GJB2 encodes connexin26, a putative channel component in cochlear gap junction. However, the pathogenesis of hearing loss caused by the GJB2 mutations remains obscure. The generation of a mouse model to study the function of connexin26 during hearing has been hampered by the fact that Gjb2 knockout mice are embryonic lethal. To establish viable model mice we generated transgenic mice expressing a mutant connexin26 with R75W mutation that was identified in a deaf family with autosomal-dominant inheritance. The previous expression analysis revealed that the R75W connexin26 inhibited the gap channel function of the co-expressed normal connexin26 in a dominant-negative fashion. We established two lines of transgenic mice that showed severe to profound hearing loss, deformity of supporting cells, failure in the formation of the tunnel of Corti and degeneration of sensory hair cells. Despite robust expression of the transgene, no obvious structural change was observed in the stria vascularis or spiral ligament that is rich in connexin26 and generates the endolymph. The high resting potential in cochlear endolymph essential for hair cell excitation was normally sustained. These results suggest that the GJB2 mutation disturbs homeostasis of cortilymph, an extracellular space surrounding the sensory hair cells, due to impaired K(+) transport by supporting cells, resulting in degradation of the organ of Corti, rather than affecting endolymph homeostasis in mice and probably in humans.


Assessing the Pregnancy Protective Impact of Scheduled Nonadherence to a Novel Progestin-Only Pill: Protocol for a Prospective, Multicenter, Randomized, Crossover Study.
Progestin-only contraceptive pills (POP) are commonly reserved for women with medical comorbidities but in actuality, POPs can be safely used by anyone wanting to prevent pregnancy. This wide safety profile makes them an ideal candidate for being available over the counter without a prescription, but adherence issues may be more common with over-the-counter use. We need a better understanding of the ability of POPs to prevent pregnancy when adherence issues occur in the form of a missed or delayed pill. This study aims to determine cervical mucus characteristics following a 6-hour delayed pill intake or after one missed pill as compared to typical daily use of norgestrel 75 mcg. This prospective, multicenter, randomized, crossover study assesses the effect of norgestrel 75 mcg (Opill) on cervical mucus and ovarian activity during reported compliant daily use, after a 6-hour delayed intake mid cycle, and after a mid-cycle missed pill. Subject participation will last approximately 4.5 months. We will recruit at 2 US sites: Oregon Health & Science University, Portland, Oregon and University of California Davis Health, Sacramento, California. Reproductive-aged subjects with regular menstrual cycles (21-35 days), BMI <32 kg/m2, and proven ovulation (screening luteal phase progesterone >3 ng/mL [>10 nmol/L]) are eligible to enroll. Participants cannot be at risk for pregnancy during the study period and not use other hormonal methods. Norgestrel 75 mcg will be taken at the same time daily except for one day in each of treatment periods 2 and 3, when the pill will be taken either 6 hours late (delayed pill) or omitted completely (missed pill). Every 3-4 days, we will monitor subjects for follicular activity with transvaginal ultrasound (TVUS) examination, cervical mucus, and blood sampling for ovarian hormones and gonadotropins. Subjects will undergo serial cervical mucus sampling on the days with missed and delayed pill intake at 8 hours after pill intake on the day before the delayed or missed pill, 3 hours following the scheduled time of pill intake if intake was delayed, 6 hours after the scheduled time if intake was omitted, and on the next day 30 minutes before the time of scheduled pill intake. The primary objective of the study is to determine the effect of a delayed or omitted pill intake on cervical mucus characteristics based on a modified Insler score compared to reported daily use. Our protocol was successfully approved by a central institutional review board (Advarra, Columbia, MD), received ethical approval on March 23, 2018, and was registered with ClinicalTrials.gov (NCT03585712). As of January 2020, the study completed enrollment of 52 subjects. Analyses are pending. Our protocol was approved by a central review board, and study procedures were successfully executed with completed proposed enrollment. ClinicalTrials.gov NCT03585712; https://clinicaltrials.gov/ct2/show/NCT03585712. DERR1-10.2196/29208.