On the development of idiopathic subglottic stenosis.
Idiopathic subglottic stenosis is a fibrotic narrowing of the airway at the level of the cricoid cartilage, which can result in severe dyspnea. There is an overwhelming female preponderance, and treatment usually involves dilation, tracheostomy or resection with reconstruction of the involved portion of the airway. The exact mechanism of action is unknown. Estrogen has been thought to play a role in the pathogenesis of this disease, but estrogen receptors have not been found in tissue specimens taken from afflicted individuals. A careful history taken from the patient often reveals a severe episode of coughing prior to the development of symptoms, and intraoperative examination can reveal impaction of the first tracheal ring within the lumen of the cricoid cartilage. Based on these observations, we surmise that an intermittent telescoping effect of the first tracheal ring within the lumen of the cricoid cartilage can lead to disruption of the local blood supply and trauma to the cricoid mucosa, with consequent mucosal edema, ischemia, and ultimately fibrosis. While estrogen has been shown to play a beneficial role in wound healing, abnormal wound healing may be potentiated by variations in estrogen receptor expression, and could also explain the female preponderance seen in this disease.


ALZHEIMER'S CONGRESS: Further Progress on a.
An experimental vaccine that can reverse Alzheimer's-like symptoms in mice is holding up under continued testing. The treatment appears to improve mental functioning in mice, and despite earlier concerns, is well tolerated by a variety of experimental animals, and by humans as well. Excitement was palpable here at last week's World Alzheimer Congress 2000, but researchers caution against undue optimism given that safety trials in Alzheimer's patients are just beginning and there is currently no evidence that it will help people with the disease.


Sibling dynamics and sport expertise.
Family members are known to be highly influential in the development of sport expertise. To date, much of the research in this area has focused on parents, with less known about sibling influences on expertise. This investigation explored associations between sport expertise, sibling characteristics, and sibling participation in sport and physical activity. Athletes representing three skill levels provided details of sibling characteristics and participation in sport and physical activity via the Developmental History of Athletes Questionnaire. Elite athletes were more likely to be later-born children, while pre-elite and non-elite athletes were more likely to be first-born. Compared with siblings of non-elite athletes, siblings of elite athletes were more likely to have participated in regular physical activity and were more likely to have participated in sport at the pre-elite and elite levels. These results suggest siblings may play a key role in sport expertise development.


Sleep and risk of parkinsonism and Parkinson's disease: a population-based study.
Sleep disturbances may signal presence of prodromal parkinsonism, including Parkinson's disease. Whether general sleep quality or duration in otherwise healthy subjects is related to the risk of parkinsonism remains unclear. We hypothesized that both worse self-reported sleep quality and duration, as well as a longitudinal deterioration in these measures, are associated with the risk of parkinsonism, including Parkinson's disease. In the prospective population-based Rotterdam Study, we assessed sleep quality and duration with the Pittsburgh Sleep Quality Index in 7726 subjects (mean age 65 years, 57% female) between 2002 and 2008, and again in 5450 subjects between 2009 and 2014. Participants were followed until 2015 for a diagnosis of parkinsonism and Parkinson's disease. Outcomes were assessed using multiple modalities: interviews, physical examination, and continuous monitoring of pharmacy records and medical records of general practitioners. We used Cox regression to associate sleep, and changes in sleep over time, with incident parkinsonism and Parkinson's disease, adjusting for age, sex, education and smoking status. Over 64 855 person-years in 13 years of follow-up (mean: 8.4 years), 75 participants developed parkinsonism, of whom 47 developed Parkinson's disease. We showed that within the first 2 years of follow-up, worse sleep quality {hazard ratio (HR) 2.38 per standard deviation increase [95% confidence interval (CI 0.91-6.23)]} and shorter sleep duration [HR 0.61 per standard deviation increase (95% CI 0.31-1.21)] related to a higher risk of parkinsonism. Associations of worse sleep quality [HR 3.86 (95% CI 1.19-12.47)] and shorter sleep duration [HR 0.48 (95% CI 0.23-0.99)] with Parkinson's disease were more pronounced, and statistically significant, compared to parkinsonism. This increased risk disappeared with longer follow-up duration. Worsening of sleep quality [HR 1.76 per standard deviation increase (95% CI 1.12-2.78)], as well as shortening of sleep duration [HR 1.72 per standard deviation decrease (95% CI 1.08-2.72)], were related to Parkinson's disease risk in the subsequent 6 years. Therefore, we argue that in the general population, deterioration of sleep quality and duration are markers of the prodromal phase of parkinsonism, including Parkinson's disease.


Evidence of active microglia in substantia nigra pars compacta of parkinsonian monkeys 1 year after MPTP exposure.
Inflammatory changes have been found in Parkinson's disease, in humans intoxicated with the parkinsonian toxin MPTP, and in animal models of the disease. However, it is still not known whether inflammatory changes are responsible for active nerve cell death or if they have a protective role against neurodegeneration. In this study, we analyzed the glial reaction in the substantia nigra pars compacta (SNpc) and the striatum of monkeys rendered parkinsosian by chronic MPTP injections. At postmortem examination 1 year after the last MPTP injection, the density of astroglial cells and activated microglial cells in the SNpc, but not in the striatum, of MPTP-intoxicated animals was significantly higher than in the two control animals. These data suggest that neurodegeneration was still active despite the absence of the agent triggering cell death and that the glial reaction is associated with long-term neurodegeneration.


Subtrochanteric-intertrochanteric femoral fractures.
Subtrochanteric fractures can be managed effectively with newer techniques and implants. If the proximal fragment is intact and includes the lesser trochanter, an interlocking intramedullary nail is indicated. If there is inter-subtrochanteric comminution, a screw-plate device with bone graft, or a Zickel nail should be used.


Could conductivity be used as a parameter in urinalysis?
Conductivity is a non-linear function of electrolyte concentration in solutions and could be used as an indirect method. The aim of this study was to determine the feasibility of urine conductivity measurement, which is a simple, cheap and not time consuming method, in the evaluation of renal functions. Seventy-two patients whose primary diseases were not taken into consideration were enrolled in this study. First morning urine specimens were obtained from all the patients and evaluated for osmolality, conductivity, pH, specific gravity, protein, creatinine, urea, uric acid, glucose, sodium, potassium, chloride, inorganic phosphate and calcium levels. There was a significant positive relation between osmolality and creatinine, urea, sodium, potassium, chloride, inorganic phosphate, uric acid, conductivity and specific gravity. Conductivity was also determined to be positively related to osmolality (r: 0.390, p < 0.01), sodium (r: 0.326, p < 0.01) and uric acid (r: 0.345, p < 0.01). The patients were grouped as those with a urine osmolality of less or more than 290 m Osm/kg. H2O (group A and B respectively). Urine conductivity was 6.84 +/- 5.35 (0.16-23.2) mScm-1 in group A and 10.6 +/- 5.25 (0.12-192) mScm-1 in group B. The difference was statistically significant (p = 0.005). When the spectrum of conductivity values were evaluated separately in each group, 74% of the patients in group A and 33.9% of the patients in group B were determined to have a conductivity level of less than 7.338 mScm-1. In conclusion, urine conductivity has a positive relation with osmolality. In addition, while osmolality and specific gravity are effected by many non-electrolyte molecules, conductivity is only related to sodium and uric acid concentrations. In addition, urine osmolality and conductivity levels could be used to interpret the concentration of uncharged glucose molecules. These results suggest that conductivity could be used as a parameter in routine urinalysis.


Caffeine fatalities--do sales restrictions prevent intentional intoxications?
Caffeine is widely available in beverages and in different over-the-counter products, including tablets containing 100 mg caffeine. Because intentional fatal intoxications with caffeine occur, the maximum quantity of caffeine tablets that can be bought over the counter in a single purchase was restricted from 250 to 30 in Sweden in the year 2004. The objective of this article was to study the effect of this decision on the number of fatal caffeine intoxications. In Sweden 95% of all cases undergoing forensic autopsy are screened for a number of drugs including caffeine. All cases during January 1993-September 2009 with a caffeine concentration above 80 microg/g blood were recorded. During the study period toxicological investigations were performed in 83,580 forensic autopsies. Caffeine contributed to the fatal outcome in 20 cases (0.02%). Thirteen (65%) of these fatalities occurred before the introduction of the sales restriction. However, no fatal intoxications where caffeine contributed to the cause of death was recorded between May 2007 and September 2009. Overdoses of tablets containing caffeine can be fatal, suicides as well as accidents occur. Restricting the maximum quantity of caffeine tablets available over the counter seemed to be effective in preventing suicides because of caffeine although some time elapsed until the effect was noted. Further monitoring is required to ensure that the observed lower caffeine mortality is a sustained effect.


Conscious Perception: Time for an Update?
Understanding the neural mechanisms underlying conscious perception has become a central endeavor in cognitive neuroscience. In theories of conscious perception, a stimulus gaining conscious access is usually considered as a discrete neuronal event to be characterized in time or space, sometimes referred to as a conscious "episode." Surprisingly, the alternative hypothesis according to which conscious perception is a dynamic process has rarely been considered. Here, we discuss this hypothesis and its implications. We show how it can reconcile inconsistent empirical findings on the timing of the neural correlates of consciousness and make testable predictions. According to this hypothesis, a stimulus is consciously perceived for as long as it is recoded to fit an ongoing stream composed of all other perceived stimuli. We suggest that this "updating" process is governed by at least three factors (1) context, (2) stimulus saliency, and (3) observers' goals. Finally, this framework forces us to reconsider the typical distinction between conscious and unconscious information processing.


A new technique of microlympho-venous anastomoses. Experimental study.
This experimental study in dogs presents a new technique of microlympho-venous anastomosis to improve long-term patency rates and clinical results in lymphedema therapy. Technical points, such as an oval window on the wall of the vein and a few sutures piercing only two lymphatic layers, adventitia and media, outside the lumen for successful results are emphasized. Three methods for assessment of patency of anastomoses were used: (1) observation with operating microscope of dye transit across the anastomotic site; (2) lymphography, and (3) histopathologic examination. Of 23 dogs, five were used to perfect the technique, three died after operation, while the remaining 15 were divided into three groups of five dogs each. In the first group which were explored one month after surgery, all anastomoses were patent (100% patency). In the second group, explored three months after surgery, one anastomosis was obstructed and four were patent (80% patency). In the third group, explored six months after surgery, one anastomosis was obstructed and four were patent (80% patency). The results obtained with this technique and the occurrence of a similar physiological lympho-venous anastomosis suggest that end-to-side anastomosis may be the technique of choice.


Metabolism of apoprotein B in cynomolgus monkey: evidence for independent production of low-density lipoprotein apoprotein B.
The catabolism of very-low-density lipoprotein apoprotein B and its conversion to low-density lipoprotein was studied in five chow-fed cynomolgus monkeys following injection of radioiodinated homologous very-low-density lipoproteins. The mean (+/- SD) fractional catabolic rate of very-low-density lipoprotein apoprotein B was 0.97 +/- 0.20 h-1 and the mean (+/- SD) production rate was 0.76 +/- 0.20 mg X kg-1 X h-1. The percent of conversion of very-low-density lipoprotein apoprotein B to low-density lipoprotein ranged from 33 to 59%. In separate studies of low-density lipoprotein apoprotein B turnover performed using homologous radiolabeled low-density lipoprotein in five additional animals, the mean (+/- SD) fractional catabolic rate for low-density lipoprotein apoprotein B was 0.050 +/- 0.017 h-1 and the mean (+/- SD) apoprotein B production rate was 0.70 +/- 0.18 mg X kg-1 X h-1. Comparison of the total low-density lipoprotein apoprotein B production with that derived from very-low-density lipoprotein apoprotein B suggested that a large fraction of plasma low-density lipoprotein apoprotein B was derived from a source exclusive of circulating very-low-density lipoprotein apoprotein B. This was confirmed in two animals by simultaneous injection of radiolabeled very-low-density and low-density lipoproteins. Thus, a significant proportion of cynomolgus monkey low-density lipoproteins are produced either by direct hepatic secretion or by rapid conversion of lower-density lipoproteins before they appear in the peripheral circulation.


[CME: Traumatized Refugees in Family Practice - A Quick Reference Guide].
CME: Traumatized Refugees in Family Practice - A Quick Reference Guide Abstract. Traumatic experiences, flight and life in exile do not constitute an illness per se, but are associated with an increased risk of mental illness. In view of the lack of specialized treatment units, the general practitioner's office often remains the only place of treatment for traumatized refugees. Particularly challenging is the combination of complex complaints, multidimensional psychosocial stress factors and difficult treatment conditions which face managerial and organizational limitations in the dense daily practice routine. In this article, recommendations for working with this heterogeneous group of patients are discussed.


[The features of sleep homeostasis in pregnant rats].
To investigate the effects of short-term sleep deprivation on the sleep pattern during pregnancy, cortical and hippocampal EEG and locomotor activity were recorded within 24-hours in a "disk-over-water" paradigm in 18 Wistar rats. Rats were adapted to experimental situation and were able to move across the rotating disk without falling in water. Then a polysomnogram was recorded for 3 sequential days in the control group 1 (n = 12) without disk rotation. On the next day non-pregnant rats (experimental group 1, n = 6) were subjected to the sleep deprivation procedure with a pre-set program of disk rotation from 11:00 to 14:00 during 3 sequential days. Other 6 rats (experimental group 2) were subjected to sleep deprivation on the 5-7th day of pregnancy. EEG and locomotor activity were also constantly recorded during the sleep deprivation procedure. In control group 2 (n = 6, without sleep deprivation), a polysomnogram was recorded on the 5-7th day of pregnancy. As compared to non-pregnant rats, sleep intensity of pregnant rats increased during the first hours after the deprivation, and a considerable rebound of REM sleep took place. Sleep pattern during the off-light 12 hours remained unchanged. The results suggest that homeostatic compensation of sleep deprivation effects in rats on the first week of pregnancy is more efficient than in control non-pregnant animals.


Lymphoepithelioma-like hepatocellular carcinoma: an uncommon variant of hepatocellular carcinoma with favorable outcome.
Lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is an uncommon variant of HCC with only 22 cases reported in the literature. To better determine the incidence, clinicopathologic features, prognostic significance, and molecular pathogenesis of LEL-HCC, we presented the largest series of LEL-HCC from a 9-year retrospective cohort of patients with HCC undergoing surgical resection. LEL-HCC was identified in 20 patients (4.9%). Compared with patients having HCC without significant tumor-infiltrating lymphocyte (TIL), patients with LEL-HCC had a relatively lower frequency of male sex (P=0.022), tended to present at early-stage disease (80.0% vs. 56.3% as AJCC stage I, P=0.037; 100% vs. 77.3% as BCLC stage 0/A, P=0.010), and all harbored a solitary tumor only (P=0.006). There was no significant difference in the age at presentation, underlying chronic liver disease, cirrhotic background, serum α-fetoprotein level, tumor size, histologic grade, and frequencies of vascular invasion. Most of the TILs in LEL-HCC were cytotoxic T lymphocytes. None of the LEL-HCCs was associated with Epstein-Barr virus. LEL-HCC was associated with better overall (5-y survival: 94.1% vs. 63.9%; P=0.007) and progression-free (5-y survival: 87.8% vs. 46.6%; P=0.002) survivals compared with HCC without significant TIL. The multivariate analysis revealed that LEL-HCC was an independent prognostic factor for overall and progression-free survivals. The adjusted hazard ratio of cancer death and tumor progression for LEL-HCC was 0.12 (P=0.037) and 0.14 (P=0.002), respectively. LEL-HCC did not differ in frequencies of microsatellite instability, BRAF mutation, and DNA hypermethylation. In brief, LEL-HCC is a distinct uncommon variant of HCC characterized by dense cytotoxic T-cell infiltration and favorable prognosis.


Neonatal bisphenol-a exposure alters rat reproductive development and ovarian morphology without impairing activation of gonadotropin-releasing hormone neurons.
Developmental exposure to endocrine-disrupting compounds is hypothesized to adversely affect female reproductive physiology by interfering with the organization of the hypothalamic-pituitary-gonadal axis. Here, we compared the effects of neonatal exposure to two environmentally relevant doses of the plastics component bisphenol-A (BPA; 50 microg/kg and 50 mg/kg) with the ESR1 (formerly known as ERalpha)-selective agonist 4,4',4''-(4-propyl-[(1)H]pyrazole-1,3,5-triyl)trisphenol (PPT; 1 mg/kg) on the development of the female rat hypothalamus and ovary. An oil vehicle and estradiol benzoate (EB; 25 microg) were used as negative and positive controls. Exposure to EB, PPT, or the low dose of BPA advanced pubertal onset. A total of 67% of females exposed to the high BPA dose were acyclic by 15 wk after vaginal opening compared with 14% of those exposed to the low BPA dose, all of the EB- and PPT-treated females, and none of the control animals. Ovaries from the EB-treated females were undersized and showed no evidence of folliculogenesis, whereas ovaries from the PPT-treated females were characterized by large antral-like follicles, which did not appear to support ovulation. Severity of deficits within the BPA-treated groups increased with dose and included large antral-like follicles and lower numbers of corpora lutea. Sexual receptivity, examined after ovariectomy and hormone replacement, was normal in all groups except those neonatally exposed to EB. FOS induction in hypothalamic gonadotropic (GnRH) neurons after hormone priming was impaired in the EB- and PPT-treated groups but neither of the BPA-treated groups. Our data suggest that BPA disrupts ovarian development but not the ability of GnRH neurons to respond to steroid-positive feedback.


Predicting recovery after lumbar spinal stenosis surgery: A protocol for a historical cohort study using data from the Canadian Spine Outcomes Research Network (CSORN).
Background: Symptomatic lumbar spinal stenosis (SLSS) is a condition in which narrowing of the spinal canal results in entrapment and compression of neurovascular structures. Decompressive surgery, with or without spinal fusion, is recommended for those with severe symptoms for whom conservative management has failed. However, significant persistent pain, functional limitations, and narcotic use can affect up to one third of patients postsurgery. Aims: The aim of this study will be to identify predictors of outcomes 1-year post SLSS surgery with a focus on modifiable predictors. Methods: The Canadian Spine Outcomes Research Network (CSORN) is a large database of prospectively collected data on pre- and postsurgical outcomes among surgical patients. We include participants with a primary diagnosis of SLSS undergoing their first spine surgery. Outcomes are measured at 12 months after surgery and include back and leg pain, disability (Oswestry Disability Index, ODI), walking capacity (ODI item 4), health-related quality of life, and an overall recovery composite outcome (clinically important changes in pain, disability, and quality of life). Predictors include demographics (education level, work status, marital status, age, sex, body mass index), physical activity level, smoking status, previous conservative treatments, medication intake, depression, patient expectations, and other comorbidities. A multivariate partial least squares model is used to identify predictors of outcomes. Conclusion: Study results will inform targeted SLSS interventions, either for the selection of best candidates for surgery or the identification of targets for presurgical rehabilitation programs.


Fecal microbiota composition associates with the capacity of human peripheral blood monocytes to differentiate into immunogenic dendritic cells in vitro.
Although promising for active immunization in cancer patients, dendritic cells (DCs) vaccines generated in vitro display high inter-individual variability in their immunogenicity, which mostly limits their therapeutic efficacy. Gut microbiota composition is a key emerging factor affecting individuals' immune responses, but it is unknown how it affects the variability of donors' precursor cells to differentiate into immunogenic DCs in vitro. By analyzing gut microbiota composition in 14 healthy donors, along with the phenotype and cytokines production by monocyte-derived DCs, we found significant correlations between immunogenic properties of DC and microbiota composition. Namely, donors who had higher α-diversity of gut microbiota and higher abundance of short-chain fatty acid (SCFAs) and SCFA-producing bacteria in feces, displayed lower expression of CD1a on immature (im)DC and higher expression of ILT-3, costimulatory molecules (CD86, CD40) proinflammatory cytokines (TNF-α, IL-6, IL-8) and IL-12p70/IL-10 ratio, all of which correlated with their lower maturation potential and immunogenicity upon stimulation with LPS/IFNγ, a well-known Th1 polarizing cocktail. In contrast, imDCs generated from donors with lower α-diversity and higher abundance of Bifidobacterium and Collinsella in feces displayed higher CD1a expression and higher potential to up-regulate CD86 and CD40, increase TNF-α, IL-6, IL-8 production, and IL-12p70/IL-10 ratio upon stimulation. These results emphasize the important role of gut microbiota on the capacity of donor precursor cells to differentiate into immunogenic DCs suitable for cancer therapy, which could be harnessed for improving the actual and future DC-based cancer therapies.


A hazards-model analysis of the covariates of infant and child mortality in Sri Lanka.
The purpose of this paper is twofold: (a) to provide a complete self-contained exposition of estimating life tables with covariates through the use of hazards models, and (b) to illustrate this technique with a substantive analysis of child mortality in Sri Lanka, thereby demonstrating that World Fertility Survey data are a valuable source for the study of child mortality. We show that life tables with covariates can be easily estimated with standard computer packages designed for analysis of contingency tables. The substantive analysis confirms and supplements an earlier study of infant and child mortality in Sri Lanka by Meegama. Those factors found to be strongly associated with mortality are mother's and father's education, time period of birth, urban/rural/estate residence, ethnicity, sex, birth order, age of the mother at the birth, and type of toilet facility.


Effect of yoga and aerobics exercise on sleep quality in women with Type 2 diabetes: a randomized controlled trial.
The aim of this study was investigating the effect of 12 weeks of yoga and aerobic exercise (running on a treadmill) on the sleep quality in women with Type 2 diabetes. 39 diabetic women were selected from Semnan city with the mean age of 46.85±3.35 years, weight of 69.79±17.18 kg, height of 155.03±5.00, BMI of 29.64±5.00 kg/m2 who had a background of diabetes for 6.46±2.69 years. They were then randomly divided into yoga exercise (n=15), aerobic exercise (n=13), and control group (n=11). The exercise program was performed for 12 weeks, three sessions per each week. In order to measure the sleep quality, the Pittsburgh Sleep Quality Index (PSQI) was used. The data were analyzed by non-parametric wilcoxon and Kruskal-Wallis Test at significance level of p<0.05. Overall score of sleep quality improved after six (p=0.001) and 12 (p=0.001) weeks of yoga exercise. Also, significant effect was observed after 6 weeks of aerobic exercise (p=0.039). However, the positive effect was diminished to under significant levels after 12 weeks of aerobic exercise (p=0.154). Kruskal-Wallis Test showed significant differences between yoga and aerobic groups after 12 weeks of exercise (p=0.002). No significant differences were observed in control groups in all situation. It can be concluded that yoga exercise is more effective in improving the sleep quality in comparison with the same course of aerobic exercise in women suffering from diabetes Type 2. Thus, yoga exercise can be suggested to these patients.


Low glycemic index diet restrains epileptogenesis in a gender-specific fashion.
Dietary restriction, such as low glycemic index diet (LGID), have been successfully used to treat drug-resistant epilepsy. However, if such diet could also counteract antiepileptogenesis is still unclear. Here, we investigated whether the administration of LGID during the latent pre-epileptic period, prevents or delays the appearance of the overt epileptic phenotype. To this aim, we used the Synapsin II knockout (SynIIKO) mouse, a model of temporal lobe epilepsy in which seizures manifest 2-3 months after birth, offering a temporal window in which LGID may affect epileptogenesis. Pregnant SynIIKO mice were fed with either LGID or standard diet during gestation and lactation. Both diets were maintained in weaned mice up to 5 months of age. LGID delayed the seizure onset and induced a reduction of seizures severity only in female SynIIKO mice. In parallel with the epileptic phenotype, high-density multielectrode array recordings revealed a reduction of frequency, amplitude, duration, velocity of propagation and spread of interictal events by LGID in the hippocampus of SynIIKO females, but not mutant males, confirming the gender-specific effect. ELISA-based analysis revealed that LGID increased cortico-hippocampal allopregnanolone (ALLO) levels only in females, while it was unable to affect ALLO plasma concentrations in either sex. The results indicate that the gender-specific interference of LGID with the epileptogenic process can be ascribed to a gender-specific increase in cortical ALLO, a neurosteroid known to strengthen GABAergic transmission. The study highlights the possibility of developing a personalized gender-based therapy for temporal lobe epilepsy.


Curing of an Escherichia coli episome by rifampicin (acridine orange-F + -F - -Hfr-lac).
Low doses of rifampicin, an antibiotic that specifically inhibits RNA polymerase, cure F(+) cells from the episome. An E. coli mutant, whose RNA polymerase is resistant to rifampicin, does not show the curing. The growth of Hfr strains, which replicate the chromosome by the F-replication system, is inhibited by low doses of the antibiotic.


Factors Associated with Length of Stay in Psychiatric Inpatient Services in London, UK.
The purpose of this research was to identify factors associated with lengthy stays in psychiatric hospital in a UK mental health trust. A multiple regression using a multiple imputation method to deal with missing data was performed on inpatient admissions data over a four-year period for 7653 individuals. Factors associated with a longer length of stay included gender (being male), ethnicity (being Asian/Asian British, Black/Black British, or having a mixed background compared to being White/White British), accommodation status (being homeless, or in accommodation with support), primary diagnostic group of psychosis (F20-29), and number of care coordinators. Marital status was not found to be associated with length of stay in this sample. Length of stay is likely to be multifactorially determined, and more similar studies examining factors associated with length of hospital stay are needed to understand the operation of psychiatric services.


Plasma-protein binding of tricyclic antidepressants.
The tricyclic and related antidepressants are strongly bound to plasma proteins and interindividual differences in the free (unbound) fraction of drug may be important. However, there are serious methodological problems with the determination of protein-binding and misleading results may sometimes be obtained so the use of more than one technique is recommended. Other plasma proteins apart from albumin may be involved in the binding process and may be influenced by the presence of other disease states. The observed 4-fold interindividual differences in the binding of these drugs represents an additional source of variability in drug response, but are relatively less important than the 20- to 30-fold interindividual differences in total drug plasma concentrations that are commonly observed.


Modulation of the inwardly rectifying potassium channel Kir4.1 by the pro-invasive miR-5096 in glioblastoma cells.
Inwardly rectifying potassium channels (Kir), and especially the barium-sensitive Kir4.1 encoded by KCNJ10, are key regulators of glial functions. A lower expression or mislocation of Kir4.1 is detected in human brain tumors. MicroRNAs participate in the regulation of ionic channels and associated neurologic disorders. Here, we analyze effects of miR-5096 on the Kir4.1 expression and function in two glioblastoma cell lines, U87 and U251. Using whole-cell patch-clamp and western-blot analysis, we show that cell loading with miR-5096 decreases the Kir4.1 protein level and associated K+ current. Cell treatment with barium, a Kir4.1 blocker, or cell loading of miR-5096 both increase the outgrowth of filopodia in glioma cells, as observed by time-lapse microscopy. Knocking-down Kir4.1 expression by siRNA transfection similarly increased both filopodia formation and invasiveness of glioma cells as observed in Boyden chamber assay. MiR-5096 also promotes the release of extracellular vesicles by which it increases its own transfer to surrounding cells, in a Kir4.1-dependent manner in U251 but not in U87. Altogether, our results validate Kir4.1 as a miR-5096 target to promote invasion of glioblastoma cells. Our data highlight the complexity of microRNA effects and the role of K+ channels in cancer.


[Effect of nucleophilic compounds on sarcolysine-3H and DMNA-14C binding with DNA].
The authors have studied the effect of adenine, adenosine, guanosine, cytidine and cysteine on sarcolysine-3H binding to DNA in vivo (rat liver) an in vitro and DMNA-14C binding in vivo. It was shown that among the compounds under test adenine, adenosine and guanosine rendered a marked protective effect with relation to DNA alkylation, which is likely to be due to their nucleophilic properties.


Binding of alpha2-laminins by pathogenic and non-pathogenic mycobacteria and adherence to Schwann cells.
The ability of Mycobacterium leprae to specifically bind alpha2-laminins of Schwann cells has been described recently as being an important property of the leprosy bacillus, which could explain the neural tropism of M. leprae. Therefore, the extent of the expression of alpha2-laminin-binding properties among mycobacteria was investigated. In an ELISA-based assay, all three species of Mycobacterium tested (M. tuberculosis, M. chelonae and M. smegmatis) expressed laminin-binding capacity, suggesting that the ability to bind alpha2-laminins is conserved within the genus Mycobacterium. This report also demonstrated that not only M. leprae but all the mycobacterial species tested readily interacted with the ST88-14 cells, a human schwannoma cell line, and that the addition of soluble alpha2-laminins significantly increased their adherence to these cells. These results failed to demonstrate the presence in M. leprae of a unique system based on alpha2-laminins for adherence to Schwann cells.


Role of alveolar phospholipids in bleomycin-induced pulmonary fibrosis in the rat.
The events leading to the onset of the experimental bleomycin-induced pulmonary fibrosis are so far unknown, though recent observations emphasize the crucial role played by lung phospholipids and by alveolar macrophages. In an attempt to verify this point, a series of studies were undertaken by treating rats (CD-COBS) with intratracheal instillation of a single dose of bleomycin (1.5 U). At the same time a group of animals was pretreated with ambroxol (which is known to be a powerful inducer of surfactant production both in fetal and adult type II pneumocytes), 4 mg/kg body weight/day per os, 5 days before the treatment with bleomycin and up to the sacrifice of the animals at the 1st, 3rd, 7th, 14th or 28th day from the instillation. In our experimental model, the 14th day from the treatment with bleomycin seems to be a crucial time since it histologically corresponds to the proliferation of type II pneumocytes; furthermore, an increase of total lecithins in the alveolar spaces was observed, together with an increase of macrophage membrane fluidity. In the ambroxol-pretreated group a partial reduction of the rate of interstitial fibrosis was observed. At the 14th day from treatment the alteration of phospholipid levels was much less pronounced and the microviscosity of alveolar macrophages was similar to that of control animals. These data suggest that the onset of bleomycin-induced pulmonary fibrosis in the rat is characterized by an increase of alveolar lecithins and that this fact could modify the physico-chemical peculiarities of alveolar macrophages. Ambroxol shows a partially protective effect, perhaps by modulating the activity of type II pneumocytes.


Word position and stress effects in consonant cluster perception and production.
The aim of the present study was to investigate whether the saliency effect for word beginnings reported in children with dyslexia (Marshall & Van der Lely, 2009) can be found also in typically developing children. Thirty-four typically developing Italian children aged 8-10 years completed two specifically designed tasks: a production task and a perception task. Both tasks used nonwords containing clusters consisting of plosive plus liquid (e.g. pl). Clusters could be either in a stressed or in an unstressed syllable and could be either in initial position (first syllable) or in medial position (second syllable). In the production task, children were asked to repeat the nonwords. In the perception task, the children were asked to discriminate between two nonwords differing in one phoneme belonging to a cluster by reporting whether two repetitions were the same or different. Results from the production task showed that children are more accurate in repeating stressed than unstressed syllables, but there was no difference with respect to position of the cluster. Results from the perception task showed that children performed more accurately when discriminating word initial contrasts than when discriminating word medial contrasts, especially if the cluster was unstressed. Implications of this finding for clinical assessments are discussed.


piRNA-30473 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in DLBCL.
The initiation and progression of diffuse large B-cell lymphoma (DLBCL) is governed by genetic and epigenetic aberrations. As the most abundant eukaryotic messenger RNA (mRNA) modification, N6-methyladenosine (m6A) is known to influence various fundamental bioprocesses by regulating the target gene; however, the function of m6A modifications in DLBCL is unclear. PIWI-interacting RNAs (piRNAs) have been indicated to be epigenetic effectors in cancer. Here, we show that high expression of piRNA-30473 supports the aggressive phenotype of DLBCL, and piRNA-30473 depletion decreases proliferation and induces cell cycle arrest in DLBCL cells. In xenograft DLBCL models, piRNA-30473 inhibition reduces tumor growth. Moreover, piRNA-30473 is significantly associated with overall survival in a univariate analysis and is statistically significant after adjusting for the National Comprehensive Cancer Network-International Prognostic Index in the multivariate analysis. Additional studies demonstrate that piRNA-30473 exerts its oncogenic role through a mechanism involving the upregulation of WTAP, an m6A mRNA methylase, and thus enhances the global m6A level. Integrating transcriptome and m6A-sequencing analyses reveals that WTAP increases the expression of its critical target gene, hexokinase 2 (HK2), by enhancing the HK2 m6A level, thereby promoting the progression of DLBCL. Together, the piRNA-30473/WTAP/HK2 axis contributes to tumorigenesis by regulating m6A RNA methylation in DLBCL. Furthermore, by comprehensively analyzing our clinical data and data sets, we discover that the m6A regulatory genes piRNA-30473 and WTAP improve survival prediction in DLBCL patients. Our study highlights the functional importance of the m6A modification in DLBCL and might assist in the development of a prognostic stratification and therapeutic approach for DLBCL.


Maximal inhibition of intestinal first-pass metabolism as a pragmatic indicator of intestinal contribution to the drug-drug interactions for CYP3A4 cleared drugs.
For certain CYP3A4 substrates intestinal first-pass metabolism makes a substantial contribution to low oral bioavailability and extent of drug-drug interactions (DDI). In order to include the contribution of enzyme inhibition in the gut wall in the assessment of DDI potential, the ratio of the intestinal wall availability in the presence and absence of an inhibitor (F(G)(') and F(G), respectively) has been incorporated into a prediction equation based on hepatic enzyme interactions. This approach has been applied for both reversible and irreversible DDIs, involving 36 different inhibitors and 11 CYP3A4 substrates. The aim was to investigate the use of maximal (complete) inhibition of intestinal CYP3A4 (F(G)(')=1) as a pragmatic measure of the intestinal enzyme interaction and to compare this approach with observed in vivo values (where available) and predicted F(G) ratios from an intestinal model. The latter was obtained from the decrease in the intestinal intrinsic clearance in the presence of an inhibitor, using an estimated inhibitor concentration in the intestinal wall during absorption phase (I(G)) and an in vitro obtained K(i). In addition, the impact of variability in the enterocytic blood flow on the estimated I(G) and subsequently the model predicted F(G) ratio was investigated. The maximal F(G) ratios for the 11 CYP3A4 substrates investigated ranged from 1.06-7.14 for alprazolam and tacrolimus, respectively. In 91% of the studies investigated the model predicted F(G) ratio was within 40% of the maximal value. Maximal F(G) ratio is proposed as an initial indicator of the magnitude of intestinal enzyme interaction; the implications for drug elimination involving substrates cleared either by metabolism or by a combination of metabolism and efflux transporters are discussed.


Fluorescent chemodosimeter for Cys/Hcy with a large absorption shift and imaging in living cells.
A novel molecule T1 with efficient intramolecular charge transfer was designed as a fluorescent chemodosimeter for cysteine (Cys) and homocysteine (Hcy). Upon addition of Cys/Hcy, T1 exhibited greatly enhanced fluorescence intensity as well as a large absorption peak shift (70 nm), and can be used for bioimaging of Cys/Hcy in living cells and detection in human plasma by visual color change. The detection mechanism was proved by (1)H NMR, mass spectrometry analysis and Gaussian calculations.


Associations between psychosocial factors and antiretroviral therapy outcomes differ by gender and sexual orientation among people living with HIV in British Columbia, Canada.
Little is known about how the co-occurrence of psychosocial factors affect sub-populations of people living with HIV (PLWH). We used cross-sectional data from 999 PLWH, aged ≥19, accessing antiretroviral therapy (ART) in British Columbia, Canada (2007-2010) to examine associations between psychosocial factors and ART-related outcomes separately for trans/cis inclusive women; heterosexual men; and gay, bisexual, and other men who have sex with men (gbMSM). Multivariable logistic regression examined associations between psychosocial factors (0-3): any violence in the past 6 months, depressive symptoms in the past week, and current street drug use (heroin, crack, meth or speedball) with sub-optimal adherence (outcome 1: average annual ART adherence <95% from interview until end of follow-up, death, or December 31st, 2018) and ever viral rebound (outcome 2) adjusting for potential confounders. Of 999 PLWH (264 women, 382 heterosexual men, and 353 gbMSM), women and heterosexual men had significantly higher median counts than gbMSM. Overall, higher counts were associated with sub-optimal adherence (adjusted odds ratio [aOR] = 1.26/1-unit increase, 95%CI = 1.07-1.49). All effect estimates were of a greater magnitude among gbMSM, but not significant for women or heterosexual men, highlighting the need for population (e.g., gender and sexual orientation)-centered care and research.


Genomic and non-genomic pathways are both crucial for peak induction of neurite outgrowth by retinoids.
Retinoic acid (RA) is the active metabolite of vitamin A and essential for many physiological processes, particularly the induction of cell differentiation. In addition to regulating genomic transcriptional activity via RA receptors (RARs) and retinoid X receptors (RXRs), non-genomic mechanisms of RA have been described, including the regulation of ERK1/2 kinase phosphorylation, but are poorly characterised. In this study, we test the hypothesis that genomic and non-genomic mechanisms of RA are regulated independently with respect to the involvement of ligand-dependent RA receptors. A panel of 28 retinoids (compounds with vitamin A-like activity) showed a marked disparity in genomic (gene expression) versus non-genomic (ERK1/2 phosphorylation) assays. These results demonstrate that the capacity of a compound to activate gene transcription does not necessarily correlate with its ability to regulate a non-genomic activity such as ERK 1/2 phosphorylation. Furthermore, a neurite outgrowth assay indicated that retinoids that could only induce either genomic, or non-genomic activities, were not strong promoters of neurite outgrowth, and that activities with respect to both transcriptional regulation and ERK1/2 phosphorylation produced maximum neurite outgrowth. These results suggest that the development of effective retinoids for clinical use will depend on the selection of compounds which have maximal activity in non-genomic as well as genomic assays.


Level I to III craniofacial approaches based on Barrow classification for treatment of skull base meningiomas: surgical technique, microsurgical anatomy, and case illustrations.
Although craniofacial approaches to the midline skull base have been defined and surgical results have been published, clear descriptions of these complex approaches in a step-wise manner are lacking. The objective of this study is to demonstrate the surgical technique of craniofacial approaches based on Barrow classification (Levels I-III) and to study the microsurgical anatomy pertinent to these complex craniofacial approaches. Ten adult cadaveric heads perfused with colored silicone and 24 dry human skulls were used to study the microsurgical anatomy and to demonstrate craniofacial approaches in a step-wise manner. In addition to cadaveric studies, case illustrations of anterior skull base meningiomas were presented to demonstrate the clinical application of the first 3 (Levels I-III) approaches. Cadaveric head dissection was performed in 10 heads using craniofacial approaches. Ethmoid and sphenoid sinuses, cribriform plate, orbit, planum sphenoidale, clivus, sellar, and parasellar regions were shown at Levels I, II, and III. In 24 human dry skulls (48 sides), a supraorbital notch (85.4%) was observed more frequently than the supraorbital foramen (14.6%). The mean distance between the supraorbital foramen notch to the midline was 21.9 mm on the right side and 21.8 mm on the left. By accepting the middle point of the nasofrontal suture as a landmark, the mean distances to the anterior ethmoidal foramen from the middle point of this suture were 32 mm on the right side and 34 mm on the left. The mean distance between the anterior and posterior ethmoidal foramina was 12.3 mm on both sides; the mean distance between the posterior ethmoidal foramen and distal opening of the optic canal was 7.1 mm on the right side and 7.3 mm on the left. Barrow classification is a simple and stepwise system to better understand the surgical anatomy and refine the techniques in performing these complex craniofacial approaches. On the other hand, thorough anatomical knowledge of the midline skull base and variations of the neurovascular structures is crucial to perform successful craniofacial approaches.


Taller height as a risk factor for venous thromboembolism: a Mendelian randomization meta-analysis.
Essentials Observational data suggest taller people have a higher risk of venous thromboembolism (VTE). We used Mendelian randomization techniques to further explore this association in three studies. Risk of VTE increased by 30-40% for each 10 cm increment in height. Height was more strongly associated with deep vein thrombosis than with pulmonary embolism. Background Taller height is associated with a greater risk of venous thromboembolism (VTE). Objectives To use instrumental variable (IV) techniques (Mendelian randomization) to further explore this relationship. Methods Participants of European ancestry were included from two cohort studies (Atherosclerosis Risk in Communities [ARIC] study and Cardiovascular Health Study [CHS]) and one case-control study (Mayo Clinic VTE Study [Mayo]). We created two weighted genetic risk scores (GRSs) for height; the full GRS included 668 single-nucleotide polymorphisms (SNPs) from a previously published meta-analysis, and the restricted GRS included a subset of 362 SNPs not associated with weight independently of height. Standard logistic regression and IV models were used to estimate odds ratios (ORs) for VTE per 10-cm increment in height. ORs were pooled across the three studies by the use of inverse variance-weighted random effects meta-analysis. Results Among 9143 ARIC and 3180 CHS participants free of VTE at baseline, there were 367 and 109 incident VTE events. There were 1143 VTE cases and 1292 controls included from Mayo. The pooled ORs from non-IV models and models using the full and restricted GRSs as IVs were 1.27 (95% confidence interval [CI] 1.11-1.46), 1.34 (95% CI 1.04-1.73) and 1.45 (95% CI 1.04-2.01) per 10-cm greater height, respectively. Conclusions Taller height is associated with an increased risk of VTE in adults of European ancestry. Possible explanations for this association, including taller people having a greater venous surface area, a higher number of venous valves, or greater hydrostatic pressure, need to be explored further.


Enhanced expression of miR-204 attenuates LPS stimulated inflammatory injury through inhibiting the Wnt/β-catenin pathway via targeting CCND2.
One of the most common bacterial diseases of the reproductive system in dairy cows is endometritis, which will cause huge economic loss. Here, we investigate the mechanisms of miR-204 on LPS-stimulated endometritis in vitro and in vivo. Experiments displayed that the expression of miR-204 was lower in bovine uterine tissue samples or bovine endometrial epithelial cell line (BEND) that stimulated by LPS. Compared with the negative group, miR-204 treatment significantly suppressed the production of proinflammatory factors and the Wnt/β-catenin pathway activation. Additionally, the result of the dual luciferase assay showed that miR-204 targeted cyclin D2. More importantly, up-regulation of miR-204 alleviated LPS induced uterine injury was confirmed in vivo studies. Molecular experiments indicated that the expression level of tight junctional proteins Claudin3 and cadherin1 were both enchanced by miR-204 treatment. Accordingly, miR-204 may serve as a new measure to prevent and treat endometritis caused by LPS.


Lipid peroxidation and antioxidant capacity of G6PD-deficient patients with A-(202G>A) mutation.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an enzymopathy in which reduced NADPH concentrations are not maintained, resulting in oxidative damage. We evaluated G6PD activity, oxidative stress levels and Trolox equivalent antioxidant capacity in individuals with the A-(202G>A) mutation for G6PD deficiency. Five hundred and forty-four peripheral blood samples were screened for G6PD deficiency; we also analyzed lipid peroxidation products measured as thiobarbituric acid reactive species and Trolox equivalent antioxidant capacity. Men with the A-(202G>A) mutation had lower G6PD activity than women with the same mutation. Individuals with the A-(202G>A) mutation also differed in mean Trolox equivalent antioxidant capacity values but not for thiobarbituric acid reactive species values. We concluded that A-(202G>A) mutation is associated with reduced G6PD activity and increased Trolox equivalent antioxidant capacity.


Effect of aqueous leaves extract of Costus afer Ker Gawl (Zingiberaceae) on the liver and kidney of male albino Wistar rat.
The use of medicinal plants in Nigeria has significantly increased over recent years as it is easily accessible, cheap and the strong belief that herbal remedies are natural and therefore non toxic. This study aims to investigate the sub-chronic toxicity (28-day) of the aqueous extract of Costus afer Ker Gawl leaves on the liver and kidney of male albino Wistar rats. A total of 20 male albino Wistar rats (113-205 g) divided into four groups of five weight-matched animals each, were used for the study. Group 1 received standard feed and water ad libitium and served as the control. Group 2, 3 and 4 received 375, 750 and 1125 mg/kg of aqueous extract of C. afer leaves respectively. The animals were sacrificed under ether anesthesia and the organs were harvested, weighed and histopathological studies carried out. The effect of C. afer on the hepatic biomarkers aspartate aminotransferase (AST), alanine aminotransferase (ALT); alkaline phosphatase (ALP); triglyceride (TG); total bilirubin (TB); conjugated bilirubin (CB); albumin (ALB) and kidney biomarkers urea, creatinine, sodium, potassium and bicarbonate were investigated. Data were evaluated using Mann Whitney. If P ≤ 0.05 groups were considered to be significantly different. C. afer contained alkaloids, saponins, flavonoids, anthraquinones, cardiac glycosides, terpenoids, phenolic compounds and tannins. The average body, organ, relative weights, feed and fluid intake showed no significant changes (P > 0.05) when compared to the control. The liver function tests (ALT, ALP, AST, CB, TB and ALB) showed significant differences (P < 0.05) in the test groups when compared with the control while TG showed no statistical difference (P > 0.05). The kidney function tests (urea, creatinine, sodium, potassium and bicarbonate) showed no significant differences (P > 0.05) in the test groups when compared to the control. Costus afer may be hepatotoxic but non-toxic to the kidney.


Type I collagen exists as a distribution of nanoscale morphologies in teeth, bones, and tendons.
This study demonstrates that collagen, the most abundant protein in animals, exists as a distribution of nanoscale morphologies in teeth, bones, and tendons. This fundamental characteristic of Type I collagen has not previously been reported and provides a new understanding of the nanoscale architecture of this ubiquitous and important biological nanomaterial. Dentin, bone, and tendon tissue samples were chosen for their differences in cellular origin and function, as well as to compare mineralized tissues with a tissue that lacks mineral in a normal physiological setting. A distribution of morphologies was present in all three tissues, confirming that this characteristic is fundamental to Type I collagen regardless of the presence of mineral, cellular origin of the collagen (osteoblast versus odontoblast versus fibroblast), anatomical location, or mechanical function of the tissue.


[Infrared sweat secretion stimulation as a means of homeostatic correction in patients with kidney dysfunction].
The clinical and laboratory investigation was done on 40 patients with kidney disfunction (glomerulonefritis), treated by standard medicines with regulary infrared total body heating (from 15-20 to 40 min) daily during 10 days. Control group of 37 patients, was treated only by standard medicines. The thermochambers construction forces the possibility of normal temperature air breathing under the radial skin heating to 50-60 degrees C. It was shown, that hypertensions, dropsy manifestation and nitrogen contents in blood significantly decreased in comperison with the control group of patients. The positive effects in laboratory dates was shown in 65%; the subjective reports--in 100% patients. These data may be conformed to widley using infrared chamber procedures for combinative drugs and thermal treating patients with kidney disfunction.


Hyperbaric oxygen treatment of retinal artery occlusion.
Five patients with a one- to 12-day history of symptoms secondary to retinal artery occlusion (RAO) were treated with hyperbaric oxygen therapy (HBO2) for one hour at 1.5 ATA. Four patients had been diagnosed with branch retinal artery occlusion (BRAO) and one patient with a cilioretinal artery occlusion. The three patients with macular sparing occlusions had experienced a loss of visual field, and the remaining two patients with macular involvement had marked loss of central visual acuity. All patients improved following HBO2 treatment. There were no complications. HBO2 may be a safe and effective treatment for patients with RAO.


Pornography Use and Sexual Objectification of Others.
Researchers have demonstrated associations between use of pornography and sexual objectification of women. We examine whether self-reported preference for degrading pornography moderated the relation between use frequency and sexual objectification of others. Participants were 1,342 heterosexual women and men residing in the United States. In women and men, pornography use frequency was associated with the sexual objectification of others, even after controlling for interest in generally explicit content. In men, interest in degrading pornography content significantly predicted sexual objectification of women. Our results suggest greater pornography use is associated with greater sexual objectification of others, across a variety of content categories.


The Rise and Fall of a Local SARS-CoV-2 Variant with the Spike Protein Mutation L452R.
Emerging SARS-CoV-2 variants may threaten global vaccination efforts and the awaited reduction in outbreak burden. In this study, we report a novel variant carrying the L452R mutation that emerged from a local B.1.362 lineage, B.1.362+L452R. The L452R mutation is associated with the Delta and Epsilon variants and was shown to cause increased infection and reduction in neutralization in pseudoviruses. Indeed, the B.1.362+L452R variant demonstrated a X4-fold reduction in neutralization capacity of sera from BNT162b2-vaccinated individuals compared to a wild-type strain. The variant infected 270 individuals in Israel between December 2020 and March 2021, until diminishing due to the gain in dominance of the Alpha variant in February 2021. This study demonstrates an independent, local emergence of a variant carrying a critical mutation, L452R, which may have the potential of becoming a variant of concern and emphasizes the importance of routine surveillance and detection of novel variants among efforts undertaken to prevent further disease spread.


Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans.
Delta-9-tetrahydrocannabinol (THC) is known to modulate immune response in peripheral blood cells. The mechanisms of THC's effects on gene expression in human immune cells remains poorly understood. Combining a within-subject design with single cell transcriptome mapping, we report that THC acutely alters gene expression in 15,973 blood cells. We identified 294 transcriptome-wide significant genes among eight cell types including 69 common genes and 225 cell-type-specific genes affected by THC administration, including those genes involving in immune response, cytokine production, cell proliferation and apoptosis. We revealed distinct transcriptomic sub-clusters affected by THC in major immune cell types where THC perturbed cell-type-specific intracellular gene expression correlations. Gene set enrichment analysis further supports the findings of THC's common and cell-type-specific effects on immune response and cell toxicity. This comprehensive single-cell transcriptomic profiling provides important insights into THC's acute effects on immune function that may have important medical implications.


The changing epidemiology of Staphylococcus aureus?
Strains of methicillin-resistant Staphylococcus aureus (MRSA), which had been largely confined to hospitals and long-term care facilities, are emerging in the community. The changing epidemiology of MRSA bears striking similarity to the emergence of penicillinase-mediated resistance in S. aureus decades ago. Even though the origin (hospital or the community) of the emerging MRSA strains is not known, the prevalence of these strains in the community seems likely to increase substantially.


[Solubility of the polyene antibiotics nystatin and levorin in water-organic mixtures].
Solubility of the polyenic antibiotics levorin and nystatin in water-alcohol mixtures and in the water-acetone system was studied. Methanol, ethanol, n-propanol, isopropanol and n-butanol were used as alcohols. It was shown that the water-n-propanol system had the maximum dissolving properties with respect to levorin and nystatin. In the water-acetone system nystatin and levorin were maximally dissolved under 40 per cent of water and 60 per cent of acetone and 30 per cent of water and 70 per cent of acetone, respectively.


Cost savings associated with US hospital palliative care consultation programs.
Hospital palliative care consultation teams have been shown to improve care for adults with serious illness. This study examined the effect of palliative care teams on hospital costs. We analyzed administrative data from 8 hospitals with established palliative care programs for the years 2002 through 2004. Patients receiving palliative care were matched by propensity score to patients receiving usual care. Generalized linear models were estimated for costs per admission and per hospital day. Of the 2966 palliative care patients who were discharged alive, 2630 palliative care patients (89%) were matched to 18,427 usual care patients, and of the 2388 palliative care patients who died, 2278 (95%) were matched to 2124 usual care patients. The palliative care patients who were discharged alive had an adjusted net savings of $1696 in direct costs per admission (P = .004) and $279 in direct costs per day (P < .001) including significant reductions in laboratory and intensive care unit costs compared with usual care patients. The palliative care patients who died had an adjusted net savings of $4908 in direct costs per admission (P = .003) and $374 in direct costs per day (P < .001) including significant reductions in pharmacy, laboratory, and intensive care unit costs compared with usual care patients. Two confirmatory analyses were performed. Including mean costs per day before palliative care and before a comparable reference day for usual care patients in the propensity score models resulted in similar results. Estimating costs for palliative care patients assuming that they did not receive palliative care resulted in projected costs that were not significantly different from usual care costs. Hospital palliative care consultation teams are associated with significant hospital cost savings.


Molecular-dynamics simulation for the characterization of liquid chromatographic stationary phase: effect of temperature.
The influence of temperature on the surface structure of the octadecylsilica (ODS) bonded phase was investigated with a molecular dynamics (MD) simulation. The MD simulation was applied to a molecular model consisting of three parts: amorphous silica base, dimethyloctadecylsilyl ligands and n-hexane as a mobile phase solvent. More detailed information on the effect of temperature was obtained at the low temperature region than that reported in our previous study. The motion of ODS ligands could be estimated by the mean square displacement (MSD) of the terminal carbon atoms of ODS ligands. The gauche fraction in the ODS ligand conformation can also be estimated to obtain the ligand conformation for each simulation condition in detail. It can be seen that an elevated temperature induced the more bent ligand conformation. The trend has a good agreement to that of the results experimentally observed by using various spectroscopic techniques such as nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), and Raman spectroscopy.


Activity of psyllium hydrophilic colloid for reducing serum cholesterol in sea quail fed a diet supplemented with cholesterol.
Groups of six SEA quail were fed a 0.5% cholesterol supplemented diet to which was added 3, 6, and 10% microcrystalline cellulose (controls) or the same concentrations of psyllium hydrophilic colloid for a period of 14 days. Total serum cholesterol was measured enzymically on each animal at the end of the treatment period. Cellulose control cholesterol values averaged approximately 1500 mg/dl overall. Psyllium hydrophilic colloid had no significant effect on total serum cholesterol at either 3% or 6% in the diet but did reduce cholesterol significantly by 52% at the 10% dietary level. These results demonstrate that SEA quail appear to be less sensitive to the hypocholesterolemic action of psyllium than are chickens.


Antibody-targeted liposomes in cancer therapy and imaging.
Targeted liposomes can be broadly defined as liposomes that are engineered to interact with a particular population of cells with the objective of delivering a payload or increasing their retention within the targeted cell population by means of a chemical interaction with cell-surface molecules or other tissue-specific ligands. The authors review recent advances in the field with an emphasis on pre-clinical studies and place them in the context of historical developments. The review focuses on immunoliposomes (antibody-mediated targeting) as these constructs are presently the most prevalent. The field has advanced in tandem with advances in liposome design and antibody and protein engineering. Targeted liposomes have been used in diagnosis to deliver magnetic resonance contrast agents and radionuclides for magnetic resonance and nuclear medicine imaging, respectively. They have been used in gene therapy to deliver a variety of gene expression modifiers, including plasmids, anti-sense oligonucleotides and short interfering RNA. Targeted liposomes provide a delivery advantage over untargeted liposomes not because of increased localization to tumor sites but because of increased interaction with the target cell population once localized to the tumor site. The increased interaction can take on the form of fusion with the cellular membrane or internalization by endocytosis. To the extent that the spatial distribution of targeted liposomes within a solid tumor may become more non-uniform than has been found for untargeted liposomes, this may be a drawback. However, systematic comparisons of the spatial distribution in tumors of targeted versus untargeted liposomes have yet to be performed. The majority of reported studies have been in the area of chemotherapy delivery. Their use in radionuclide and chemo- and radiosensitizer delivery is just emerging. Multifunctional liposomes containing 'layered functionalities' could potentially be the future direction in targeted liposome-based therapy.


Intracellular pathways underlying the effects of lithium.
This is a short overview focusing on the biochemical interactions underlying the protective effects of lithium at the neuronal level. These include lithium modulation of autophagy, growth factors, excitotoxicity, and a variety of mechanisms underlying cell death, neurogenesis, and neuronal differentiation. All these effects represent the result of a multifaceted pharmacology, which is becoming more and more complex. Nonetheless, when trying to dissect the various mechanisms of action of lithium, two primary targets emerge: glycogen synthase kinase 3beta and phosphatidylinositol phosphatase. The numerous lithium effects on biochemical systems are placed downstream of these two main mechanisms. At several steps, these mechanisms interconnect to each other, thus making it difficult to keep distinct the biochemical cascades promoted by lithium. In this way, it is not surprising that, despite being described as different phenomena at the behavioral level, molecular mechanisms underlying the effects of lithium on mood, motor activity, and sensitization overlap with those responsible for neuroprotection and neurorestoration. It is likely that the ancestral role of this ion as a modulator of cell survival, cell growth, movement, and mood is the consequence of a few molecular mechanisms operating in different neuronal networks, where a variety of cascade events take place. This review is an attempt to elucidate the primary effects of lithium to interconnect the simpler targets to the most complex pharmacological effects.


Opioid substitution treatment reduces substance use equivalently in patients with and without posttraumatic stress disorder.
The purpose of this study was to determine whether opioid-dependent patients with diagnosed posttraumatic stress disorder (PTSD) have poorer long-term outcomes in opioid substitution treatment than do patients without PTSD. This prospective observational study examined outcomes of 255 opioid-dependent patients (men = 248) entering opioid substitution treatment at eight clinics in the Veterans Health Administration (VHA). Subjects were interviewed at treatment entry, 6 months, and 1 year about substance use and related problems, health status, treatment satisfaction, and non-VHA health care utilization. Medical records were reviewed to obtain toxicology results, health care utilization data, and diagnoses. Medical record review identified a diagnosis of PTSD in 71 (28%) patients. Substance-use and mental-health outcomes and health care utilization in the first year following treatment entry were compared between patients with and without a diagnosis of PTSD. Patients with and without PTSD had similar treatment responses. Although patients with PTSD had longer histories of drug use at intake, at 1-year follow-up they showed reductions in heroin, cocaine, and alcohol use, comparable to patients without the disorder. PTSD patients received higher doses of opiate medication, attended more psychosocial treatment sessions for substance-use disorder, and had better treatment retention. Psychiatric symptoms for patients with PTSD were more severe at intake and showed little improvement throughout treatment. Opioid substitution therapy is as effective at reducing substance use in PTSD patients as it is in patients without the disorder, but additional services are needed for treatment of psychological problems that are largely unchanged by treatment for addiction.


Three-dimensional wavelet transform video coding using symmetric codebook vector quantization.
A new vector quantizer codebook design for video compression is described. This uses the notion that symmetries in the data, which are seldom captured exactly in any training dataset, are important perceptually and lead to a more robust codebook. The method is illustrated using three-dimensional (3-D) wavelet transformed video sequences.


An early transition state for folding of the P4-P6 RNA domain.
Tertiary folding of the 160-nt P4-P6 domain of the Tetrahymena group I intron RNA involves burying of substantial surface area, providing a model for the folding of other large RNA domains involved in catalysis. Stopped-flow fluorescence was used to monitor the Mg2+-induced tertiary folding of pyrene-labeled P4-P6. At 35 degrees C with [Mg2+] approximately 10 mM, P4-P6 folds on the tens of milliseconds timescale with k(obs) = 15-31 s(-1). From these values, an activation free energy deltaG(double dagger) of approximately 8-16 kcal/mol is calculated, where the large range for deltaG(double dagger) arises from uncertainty in the pre-exponential factor relating k(obs) and delta G(double dagger). The folding rates of six mutant P4-P6 RNAs were measured and found to be similar to that of the wild-type RNA, in spite of significant thermodynamic destabilization or stabilization. The ratios of the kinetic and thermodynamic free energy changes phi = delta deltaG(double dagger)/delta deltaG(o') are approximately 0, implying a folding transition state in which most of the native-state tertiary contacts are not yet formed (an early folding transition state). The k(obs) depends on the Mg2+ concentration, and the initial slope of k(obs) versus [Mg2+] suggests that only approximately 1 Mg2+ ion is bound in the rate-limiting folding step. This is consistent with an early folding transition state, because folded P4-P6 binds many Mg2+ ions. The observation of a substantial deltaG(double dagger) despite an early folding transition state suggests that a simple two-state folding diagram for Mg2+-induced P4-P6 folding is incomplete. Our kinetic data are some of the first to provide quantitative values for an activation barrier and location of a transition state for tertiary folding of an RNA domain.


Interplay between Endoplasmic Reticulum (ER) Stress and Autophagy Induces Mutant p53H273 Degradation.
The unfolded protein response (UPR) is an adaptive response to intrinsic and external stressors, and it is mainly activated by the accumulation of misfolded proteins at the endoplasmic reticulum (ER) lumen producing ER stress. The UPR signaling network is interconnected with autophagy, the proteolytic machinery specifically devoted to clearing misfolded proteins in order to survive bioenergetic stress and/or induce cell death. Oncosuppressor TP53 may undergo inactivation following missense mutations within the DNA-binding domain (DBD), and mutant p53 (mutp53) proteins may acquire a misfolded conformation, often due to the loss of the DBD-bound zinc ion, leading to accumulation of hyperstable mutp53 proteins that correlates with more aggressive tumors, resistance to therapies, and poorer outcomes. We previously showed that zinc supplementation induces mutp53 protein degradation by autophagy. Here, we show that mutp53 (i.e., Arg273) degradation following zinc supplementation is correlated with activation of ER stress and of the IRE1α/XBPI arm of the UPR. ER stress inhibition with chemical chaperone 4-phenyl butyrate (PBA) impaired mutp53 downregulation, which is similar to IRE1α/XBPI specific inhibition, reducing cancer cell death. Knockdown of mutp53 failed to induce UPR/autophagy activation indicating that the effect of zinc on mutp53 folding was likely the key event occurring in ER stress activation. Recently discovered small molecules targeting components of the UPR show promise as a novel anticancer therapeutic intervention. However, our findings showing UPR activation during mutp53 degradation indicate that caution is necessary in the design of therapies that inhibit UPR components.


Renal transplantation in diabetics nephropathy.
Forty diabetics who had developed end-stage renal failure from diabetic nephropathy and underwent renal transplantation have been followed up from one to six years. After one and two years 63% and 42% survived (45% and 33% respectively with functioning kidneys). Older patients, those with coronary and peripheral vascular disease, and those with severe neuropathy are prone to higher postoperative morbidity and mortality. The presence of advanced retinopathy, on the other hand, does not appear to influence the outcome.


Thromboelastographic changes in liver and pancreatic cancer surgery: hypercoagulability, hypocoagulability or normocoagulability?
Despite clinical and laboratory evidence of perioperative hypercoagulability, alterations in haemostasis after potentially haemorrhagic oncologic surgery are difficult to predict. This study aims to evaluate the entity, the extent and the duration of perioperative coagulative alterations following pancreas and liver oncologic surgery, by the use of both routine tests and thromboelastogram (TEG). Fifty-six patients undergoing liver (n = 38) and pancreatic (n = 18) surgery were studied. The coagulation profile was evaluated by platelet count, prothrombin time-international normalized ratio, activated partial thromboplastin time, antithrombin III and TEG at the beginning, at the end of the operation and on postoperative days 1, 3, 5 and 10. All preoperative coagulative screening and TEG traces were normal before incision. In the postoperative period of the liver and pancreas groups, despite an increase in prothrombin time-international normalized ratio, a reduction in antithrombin III and platelet count and normal activated partial thromboplastin time and fibrinogen, TEG evidenced a normocoagulability in the liver group, with a major tendency towards hypocoagulability in the pancreas group, as evidenced by a transient increase in R-time and K-time between postoperative days 1 and 3. During the study period, four cases of pulmonary embolism, resolved with heparin infusion, were recorded, in the absence of laboratory and thromboelastographic evidence of hypercoagulability. Despite laboratory tests evidencing hypocoagulability in both groups, TEG traces showed a normocoagulability in liver resections, whereas a transient thromboelastographic hypocoagulability was evident in patients undergoing pancreas surgery. The discrepancy between laboratory values and thromboelastographic variables was even more evident in patients undergoing major liver resections compared with minor ones. Our study supports the role of thromboelastography, despite its limitations, as a valuable tool for the evaluation of the perioperative whole coagulation process and hypercoagulability changes and to increase patient safety through better management of antithrombotic therapy.


Nebulin regulates actin filament lengths by a stabilization mechanism.
Efficient muscle contraction requires regulation of actin filament lengths. In one highly cited model, the giant protein nebulin has been proposed to function as a molecular ruler specifying filament lengths. We directly challenged this hypothesis by constructing a unique, small version of nebulin (mini-nebulin). When endogenous nebulin was replaced with mini-nebulin in skeletal myocytes, thin filaments extended beyond the end of mini-nebulin, an observation which is inconsistent with a strict ruler function. However, under conditions that promote actin filament depolymerization, filaments associated with mini-nebulin were remarkably maintained at lengths either matching or longer than mini-nebulin. This indicates that mini-nebulin is able to stabilize portions of the filament it has no contact with. Knockdown of nebulin also resulted in more dynamic populations of thin filament components, whereas expression of mini-nebulin decreased the dynamics at both filament ends (i.e., recovered loss of endogenous nebulin). Thus, nebulin regulates thin filament architecture by a mechanism that includes stabilizing the filaments and preventing actin depolymerization.


Spatial Representativeness Error in the Ground-Level Observation Networks for Black Carbon Radiation Absorption.
There is high uncertainty in the direct radiative forcing of black carbon (BC), an aerosol that strongly absorbs solar radiation. The observation-constrained estimate, which is several times larger than the bottom-up estimate, is influenced by the spatial representativeness error due to the mesoscale inhomogeneity of the aerosol fields and the relatively low resolution of global chemistry-transport models. Here we evaluated the spatial representativeness error for two widely used observational networks (AErosol RObotic NETwork and Global Atmosphere Watch) by downscaling the geospatial grid in a global model of BC aerosol absorption optical depth to 0.1° × 0.1°. Comparing the models at a spatial resolution of 2° × 2° with BC aerosol absorption at AErosol RObotic NETwork sites (which are commonly located near emission hot spots) tends to cause a global spatial representativeness error of 30%, as a positive bias for the current top-down estimate of global BC direct radiative forcing. By contrast, the global spatial representativeness error will be 7% for the Global Atmosphere Watch network, because the sites are located in such a way that there are almost an equal number of sites with positive or negative representativeness error.


Critical factors in the biology of human cancer metastasis: twenty-eighth G.H.A. Clowes memorial award lecture.
The process of metastasis is not random. Rather, it consists of a series of linked, sequential steps that must be completed by tumor cells if a metastasis is to develop. Although some of the steps in this process contain stochastic elements, as a whole, metastasis favors the survival and growth of a few subpopulations of cells that preexist within the parent neoplasm. Moreover, metastases can have a clonal origin, and different metastases can originate from the proliferation of single cells. The outcome of metastasis depends on the interaction of metastatic cells with different organ environments. Organ-specific metastases have been demonstrated in a variety of experimental tumor systems. Moreover, we have found tumor growth that is specific to a particular site within one organ. Whether the same conclusions can be reached for human cancers remained unanswered until very recently. Studies from our laboratory and from others have shown that the implantation of human cancer cells derived from surgical specimens into correct anatomical sites of nude mice can provide a suitable model of metastasis of human tumors. Clonal analysis of a human renal carcinoma, colon carcinomas, and melanomas has revealed that these tumors are indeed heterogeneous for metastatic properties, an observation made only after orthotopic implantation. Thus, growth in the environment of specific organs can be selective and the environment per se influences this process. While it is clear that vascularity and local immunity can facilitate or retard tumor growth, we have concentrated on understanding how damage to an organ and the subsequent repair process can facilitate tumor cell proliferation. Accelerated growth of human colon cancer cells was found in hepatectomized nude mice, whereas accelerated growth of human renal cancer cells was found in nephrectomized nude mice. These data suggest that systemic physiological signals can be recognized by neoplastic cells presumably by mechanisms similar to those shared by their normal cell counterparts. In summary, the critical factors that regulate metastasis are the intrinsic properties of metastatic cells and host factors involved in homeostasis. The recent increase in our understanding of metastasis should provide important leads for developing more effective approaches to the treatment of disseminated cancer.


Generating insights in uncharted territories: real-time learning from data in critically ill patients-an implementer report.
Introduction In the current situation, clinical patient data are often siloed in multiple hospital information systems. Especially in the intensive care unit (ICU), large volumes of clinical data are routinely collected through continuous patient monitoring. Although these data often contain useful information for clinical decision making, they are not frequently used to improve quality of care. During, but also after, pressing times, data-driven methods can be used to mine treatment patterns from clinical data to determine the best treatment options from a hospitals own clinical data.Methods In this implementer report, we describe how we implemented a data infrastructure that enabled us to learn in real time from consecutive COVID-19 ICU admissions. In addition, we explain our step-by-step multidisciplinary approach to establish such a data infrastructure.Conclusion By sharing our steps and approach, we aim to inspire others, in and outside ICU walls, to make more efficient use of data at hand, now and in the future.


Growth response and phytoextraction of copper at different levels in soils by Elsholtzia splendens.
Phytoremediation is a promising approach for cleaning up soils contaminated with heavy metals. Information is needed to understand growth response and uptake mechanisms of heavy metals by some plant species with exceptional capability in absorbing and superaccumulating metals from soils. Greenhouse study, field trial, and old mined area survey were conducted to evaluate growth response and Cu phytoextraction of Elsholtzia splendens in contaminated soils, which has been recently identified to be tolerant to high Cu concentration and have great potential in remediating contaminated soils. The results from this study indicate that the plant exhibited high tolerance to Cu toxicity in the soils, and normal growth was attained up to 80 mg kg(-1) available soil Cu (the NH4OAc extractable Cu) or 1000 mg kg(-1) total Cu. Under the field conditions, a biomass yield of 9 ton ha(-1) was recorded at the soil available Cu level of 77 mg kg(-1), as estimated by the NH4OAc extraction method. Concentration-dependent uptake of Cu by the plant occurred mainly at the early growth stage, and at the late stage, there is no difference in shoot Cu concentrations grown at different extractable soil Cu levels. The extractability of Cu from the highly polluted soil is much greater by the roots than that by the shoots. The NH4OAc extractable Cu level in the polluted soil was reduced from 78 to 55 mg kg(-1) in the soil after phytoextraction and removal of Cu by the plant species for one growth season. The depletion of extractable Cu level in the rhizosphere was noted grown in the mined area, even at high Cu levels, the NH4OAc extractable Cu in the rhizosphere was 30% lower than that in the bulk soil. These results indicate that phytoextraction of E. splendens can effectively reduce the plant-available Cu level in the polluted soils.


Charting No-Man's Land in d(0) Transition Metal Six-Coordination: Structure Predictions for the Complexes
Unusual structures between octahedral and trigonal-prismatic are found by density functional calculations for the "simple" six-coordinate d(0) title complexes. While a distorted octahedron is still slightly lower in energy than a prismatic structure for [WCl(5)CH(3)], intermediate structures start to appear for [WCl(4)(CH(3))(2)] (see picture). In the case of [WCl(3)(CH(3))(3)], prismatic arrangements are already more favorable. These and many related compounds should be accessible experimentally.


Establishment and characterization of a patient-derived solitary fibrous tumor/hemangiopericytoma cell line model.
Solitary fibrous tumor/Hemangiopericytoma (SFT/HPC) is a rare subtype of soft tissue sarcoma harboring NAB2-STAT6 gene fusions. Mechanistic studies and therapeutic development on SFT/HPC are impeded by scarcity and lack of system models. In this study, we established and characterized a novel SFT/HPC patient-derived cell line (PDC), SFT-S1, and screened for potential drug candidates that could be repurposed for the treatment of SFT/HPC. Immunohistochemistry profiles of the PDC was consistent with the patient's tumor sample (CD99+/CD34+/desmin-). RNA sequencing, followed by Sanger sequencing confirmed the pathognomonic NAB2exon3-STAT6exon18 fusion in both the PDC and the original tumor. Transcriptomic data showed strong enrichment for oncogenic pathways (epithelial-mesenchymal transition, FGF, EGR1 and TGFβ signaling pathways) in the tumor. Whole genome sequencing identified potentially pathogenic somatic variants such as MAGEA10 and ABCA2. Among a panel of 14 targeted agents screened, dasatinib was identified to be the most potent small molecule inhibitor against the PDC (IC50, 473 nM), followed by osimertinib (IC50, 730 nM) and sunitinib (IC50, 1765 nM). Methylation profiling of the tumor suggests that this specific variant of SFT/HPC could lead to genome-wide hypomethylation. In conclusion, we established a novel PDC model of SFT/HPC with comprehensive characterization of its genomic, epigenomic and transcriptomic landscape, which can facilitate future preclinical studies of SFT/HPC, such as in vitro drug screening and in vivo drug testing.


Dose-Response Relationship Between Intracoronary Acetylcholine and Minimal Lumen Diameter in Coronary Endothelial Function Testing of Women and Men With Angina and No Obstructive Coronary Artery Disease.
Intracoronary acetylcholine (Ach) provocation testing is the gold standard for assessing coronary endothelial function. However, dosing regimens of Ach are quite varied in the literature, and there are limited data evaluating the optimal dose. We evaluated the dose-response relationship between Ach and minimal lumen diameter (MLD) by sex and studied whether incremental intracoronary Ach doses given during endothelial function testing improve its diagnostic utility. We evaluated 65 men and 212 women with angina and no obstructive coronary artery disease who underwent endothelial function testing using the highest tolerable dose of intracoronary Ach, up to 200 μg. Epicardial endothelial dysfunction was defined as a decrease in MLD >20% after intracoronary Ach by quantitative coronary angiography. We used a linear mixed effects model to evaluate the dose-response relationship. Deming regression analysis was done to compare the %MLD constriction after incremental doses of intracoronary Ach. The mean age was 53.5 years. Endothelial dysfunction was present in 186 (68.1%). Among men with endothelial dysfunction, there was a significant decrease in MLD/10 µg of Ach at doses above 50 μg and 100 µg, while this decrease in MLD was not observed in women (P<0.001). The %MLD constriction at 20 μg versus 50 μg and 50 μg versus 100 μg were not equivalent while the %MLD constriction at 100 μg versus 200 μg were equivalent. Women and men appear to have different responses to Ach during endothelial function testing. In addition to having a greater response to intracoronary Ach at all doses, men also demonstrate an Ach-MLD dose-response relationship with doses up to 200 μg, while women have minimal change in MLD with doses above 50 µg. An incremental dosing regimen during endothelial function testing appears to improve the diagnostic utility of the test and should be adjusted based on the sex of the patient.


Curling for Confidence: Psychophysical Benefits of Curling for Older Adults.
While physical activity is increasingly promoted for older adults, there is a paucity of sport promotion, which has distinct benefits from exercise and remains stereotypically associated with younger age. Curling is a moderately intense and safe sport that continues to gain popularity; however, no research has investigated psychophysical benefits of curling for older adults. The present study compares high-experience (20+ years; n = 63) and low-experience (<20 years; n = 53) curlers (aged 60+ years) with older adult noncurlers (n = 44) on measures of daily functionality, balance confidence, and perceptions of the aging process. While no significant differences were found between high- and low-experience curlers, any level of experience reported significantly better functionality, physical confidence, and aging attitudes compared to noncurlers (p ≤ .05). Although further research is necessary, the results suggest that any level of curling experience can enhance older adult psychophysical well-being, and warrants consideration for physical activity promotion and falls prevention programs.


Limiting deoxynucleoside triphosphate concentrations emphasize the processivity defect of lamivudine-resistant variants of human immunodeficiency virus type 1 reverse transcriptase.
The nucleoside drug lamivudine (3TC) triggers the selection of resistant forms of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) with a substitution of amino acid 184Met. The 3TC-resistant RT enzymes 184Val and 184Ile exhibit a processivity defect in in vitro assays that correlates with reduced replication of the corresponding virus variants in primary cells. However, no replication defect is apparent for these two mutants in the transformed T-cell line SupT1. One obvious difference between the two cell types is the intracellular deoxynucleoside triphosphate (dNTP) level. Primary cells have a much smaller dNTP pool, and this cellular condition may emphasize the processivity defect of the codon 184 RT variants. Alternatively, cell-specific cofactors that influence the process of reverse transcription may exist. Such accessory factors may be packaged into the virion to exert an effect on the RT enzyme. To discriminate between these possibilities we performed additional assays with the wild-type and mutant RT enzymes. The RT proteins were either isolated from virions produced by primary and transformed cell types or expressed as recombinant protein. We also performed infection assays with cells treated with a drug that reduces the intracellular dNTP pool. Furthermore, reverse transcription was studied within virus particles in the endogenous assay, which allows for the manipulation of the dNTP level. The combined results indicate that the enzymatic defect of the 3TC-resistant HIV-1 variants is stressed at low dNTP concentrations.


FunGene: the functional gene pipeline and repository.
Ribosomal RNA genes have become the standard molecular markers for microbial community analysis for good reasons, including universal occurrence in cellular organisms, availability of large databases, and ease of rRNA gene region amplification and analysis. As markers, however, rRNA genes have some significant limitations. The rRNA genes are often present in multiple copies, unlike most protein-coding genes. The slow rate of change in rRNA genes means that multiple species sometimes share identical 16S rRNA gene sequences, while many more species share identical sequences in the short 16S rRNA regions commonly analyzed. In addition, the genes involved in many important processes are not distributed in a phylogenetically coherent manner, potentially due to gene loss or horizontal gene transfer. While rRNA genes remain the most commonly used markers, key genes in ecologically important pathways, e.g., those involved in carbon and nitrogen cycling, can provide important insights into community composition and function not obtainable through rRNA analysis. However, working with ecofunctional gene data requires some tools beyond those required for rRNA analysis. To address this, our Functional Gene Pipeline and Repository (FunGene; http://fungene.cme.msu.edu/) offers databases of many common ecofunctional genes and proteins, as well as integrated tools that allow researchers to browse these collections and choose subsets for further analysis, build phylogenetic trees, test primers and probes for coverage, and download aligned sequences. Additional FunGene tools are specialized to process coding gene amplicon data. For example, FrameBot produces frameshift-corrected protein and DNA sequences from raw reads while finding the most closely related protein reference sequence. These tools can help provide better insight into microbial communities by directly studying key genes involved in important ecological processes.


The Unique Role of Peer Support: Exploring the Effects of Various Sources of Social Support on the Mental Health of Unaccompanied Children in China under Residential Education.
This study investigates the impact of various sources of social support on the mental health of unaccompanied children under residential education in China. Unaccompanied children refer to those whose parents are still alive but unable to raise them due to various reasons. The study utilized self-reported questionnaires administered at two time waves, with the first wave (T1) evaluating family support, teacher support, and peer support, and the second wave (T2) evaluating depression, subjective well-being, and resilience. A total of 202 participants completed both surveys. To examine the predictive effect of different sources of social support on the mental health of these children, the study used the structural equation model with depression and subjective well-being as indicators. The results show that neither family support nor teacher support (T1) had a significant effect on the mental health (T2) of the children. However, peer support (T1) had a significant positive predictive effect on mental health (T2), indicating the unique role of peer support in promoting the mental health of unaccompanied children. The study also explored the mediating role of resilience between social support and well-being, revealing that though the direct effect of teacher support (T1) on mental health (T2) was not significant, the indirect mediating effect of resilience on the relationship between teacher support and mental health was significant. Both the direct and indirect effect of family support (T1) on mental health (T2) were not significant. These findings highlight the importance of creating a positive peer environment for unaccompanied children to promote their mental health. This study has important practical implications for the development of effective intervention programs aimed at improving the mental health of this population.


Genomic comparison of Escherichia coli K1 strains isolated from the cerebrospinal fluid of patients with meningitis.
Escherichia coli is a major cause of enteric/diarrheal diseases, urinary tract infections, and sepsis. E. coli K1 is the leading gram-negative organism causing neonatal meningitis, but the microbial basis of E. coli K1 meningitis is incompletely understood. Here we employed comparative genomic hybridization to investigate 11 strains of E. coli K1 isolated from the cerebrospinal fluid (CSF) of patients with meningitis. These 11 strains cover the majority of common O serotypes in E. coli K1 isolates from CSF. Our data demonstrated that these 11 strains of E. coli K1 can be categorized into two groups based on their profile for putative virulence factors, lipoproteins, proteases, and outer membrane proteins. Of interest, we showed that some open reading frames (ORFs) encoding the type III secretion system apparatus were found in group 2 strains but not in group 1 strains, while ORFs encoding the general secretory pathway are predominant in group 1 strains. These findings suggest that E. coli K1 strains isolated from CSF can be divided into two groups and these two groups of E. coli K1 may utilize different mechanisms to induce meningitis.


Some vagaries of the medial epicondyle.
Roentgenographic data on the maturing epiphysis of the medial epicondyle of the humerus are prone to misinterpretation for the following reasons. First, fractures of the medial epicondyle may not be associated with joint effusion or metaphyseal avulsion fragments. Second, in the medial epicondyle the center of ossification, which lies posteromedial to the distal end of the humerus and is the last of the elbow epiphyses to unite with the humerus, may be quite distant from the humeral metaphysis, and differentiation of this normal characteristic from minimum avulsion is necessary. Also, multicentric ossification, although uncommon, will give the epiphysis a fragmented appearance. Finally, just before ossification of the medial epicondylar epiphysis, on its metaphyseal surface on the distal end of the humerus a sharp, straight sclerotic edge develops.