Mindfulness for smoking cessation.
Mindfulness-based smoking cessation interventions may aid smoking cessation by teaching individuals to pay attention to, and work mindfully with, negative affective states, cravings, and other symptoms of nicotine withdrawal. Types of mindfulness-based interventions include mindfulness training, which involves training in meditation; acceptance and commitment therapy (ACT); distress tolerance training; and yoga. To assess the efficacy of mindfulness-based interventions for smoking cessation among people who smoke, and whether these interventions have an effect on mental health outcomes. We searched the Cochrane Tobacco Addiction Group's specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, and trial registries to 15 April 2021. We also employed an automated search strategy, developed as part of the Human Behaviour Change Project, using Microsoft Academic. We included randomised controlled trials (RCTs) and cluster-RCTs that compared a mindfulness-based intervention for smoking cessation with another smoking cessation programme or no treatment, and assessed smoking cessation at six months or longer. We excluded studies that solely recruited pregnant women. We followed standard Cochrane methods. We measured smoking cessation at the longest time point, using the most rigorous definition available, on an intention-to-treat basis. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) for smoking cessation for each study, where possible. We grouped eligible studies according to the type of intervention and type of comparator. We carried out meta-analyses where appropriate, using Mantel-Haenszel random-effects models. We summarised mental health outcomes narratively. We included 21 studies, with 8186 participants. Most recruited adults from the community, and the majority (15 studies) were conducted in the USA. We judged four of the studies to be at low risk of bias, nine at unclear risk, and eight at high risk. Mindfulness-based interventions varied considerably in design and content, as did comparators, therefore, we pooled small groups of relatively comparable studies. We did not detect a clear benefit or harm of mindfulness training interventions on quit rates compared with intensity-matched smoking cessation treatment (RR 0.99, 95% CI 0.67 to 1.46; I2 = 0%; 3 studies, 542 participants; low-certainty evidence), less intensive smoking cessation treatment (RR 1.19, 95% CI 0.65 to 2.19; I2 = 60%; 5 studies, 813 participants; very low-certainty evidence), or no treatment (RR 0.81, 95% CI 0.43 to 1.53; 1 study, 325 participants; low-certainty evidence). In each comparison, the 95% CI encompassed benefit (i.e. higher quit rates), harm (i.e. lower quit rates) and no difference. In one study of mindfulness-based relapse prevention, we did not detect a clear benefit or harm of the intervention over no treatment (RR 1.43, 95% CI 0.56 to 3.67; 86 participants; very low-certainty evidence). We did not detect a clear benefit or harm of ACT on quit rates compared with less intensive behavioural treatments, including nicotine replacement therapy alone (RR 1.27, 95% CI 0.53 to 3.02; 1 study, 102 participants; low-certainty evidence), brief advice (RR 1.27, 95% CI 0.59 to 2.75; 1 study, 144 participants; very low-certainty evidence), or less intensive ACT (RR 1.00, 95% CI 0.50 to 2.01; 1 study, 100 participants; low-certainty evidence). There was a high level of heterogeneity (I2 = 82%) across studies comparing ACT with intensity-matched smoking cessation treatments, meaning it was not appropriate to report a pooled result. We did not detect a clear benefit or harm of distress tolerance training on quit rates compared with intensity-matched smoking cessation treatment (RR 0.87, 95% CI 0.26 to 2.98; 1 study, 69 participants; low-certainty evidence) or less intensive smoking cessation treatment (RR 1.63, 95% CI 0.33 to 8.08; 1 study, 49 participants; low-certainty evidence). We did not detect a clear benefit or harm of yoga on quit rates compared with intensity-matched smoking cessation treatment (RR 1.44, 95% CI 0.40 to 5.16; 1 study, 55 participants; very low-certainty evidence). Excluding studies at high risk of bias did not substantially alter the results, nor did using complete case data as opposed to using data from all participants randomised. Nine studies reported on changes in mental health and well-being, including depression, anxiety, perceived stress, and negative and positive affect. Variation in measures and methodological differences between studies meant we could not meta-analyse these data. One study found a greater reduction in perceived stress in participants who received a face-to-face mindfulness training programme versus an intensity-matched programme. However, the remaining eight studies found no clinically meaningful differences in mental health and well-being between participants who received mindfulness-based treatments and participants who received another treatment or no treatment (very low-certainty evidence). We did not detect a clear benefit of mindfulness-based smoking cessation interventions for increasing smoking quit rates or changing mental health and well-being. This was the case when compared with intensity-matched smoking cessation treatment, less intensive smoking cessation treatment, or no treatment. However, the evidence was of low and very low certainty due to risk of bias, inconsistency, and imprecision, meaning future evidence may very likely change our interpretation of the results. Further RCTs of mindfulness-based interventions for smoking cessation compared with active comparators are needed. There is also a need for more consistent reporting of mental health and well-being outcomes in studies of mindfulness-based interventions for smoking cessation.


Anti-glycoprotein D monoclonal antibody protects against herpes simplex virus type 1-induced diseases in mice functionally depleted of selected T-cell subsets or asialo GM1+ cells.
Passive transfer of a monoclonal antibody (MAb) specific for glycoprotein D (gD) is highly effective in preventing the development of herpes simplex virus type 1-induced stromal keratitis. In the present study, we investigated whether animals which had been functionally depleted of T-cell subsets or asialo GM1+ cells would continue to be responsive to MAb therapy. BALB/c mice were depleted of CD4+, CD8+, or asialo GM1+ cells by treatment with anti-L3T4, anti-Lyt 2.2, or anti-asialo GM1 antibodies, respectively. Functional depletion of CD4+ cells was documented by the loss of delayed-type hypersensitivity responsiveness, while CD8+ cell depletion was accompanied by abrogation of cytotoxic lymphocyte activity. Anti-asialo GM1 treatment led to the loss of natural killer cell lytic activity. Mice depleted of the desired cell population and infected on the scarified cornea with herpes simplex virus type 1 uniformly developed necrotizing stromal keratitis by 3 weeks postinfection. A single inoculation of anti-gD MAb (55 micrograms) given intraperitoneally 24 h postinfection strongly protected hosts depleted of CD4+ cells against stromal keratitis. Likewise, antibody treatment in CD8+ or asialo GM1+ cell-depleted hosts was as therapeutically effective as that seen in non-cell-depleted mice. We also observed that in cell-depleted mice, the virus spread into the central nervous system and caused encephalitis. The CD4+ cell-depleted mice were the most severely affected, as 100% developed fatal disease. Anti-gD MAb treatment successfully protected all (32 of 32) CD4+-, CD8+-, or asialo GM1(+)-depleted hosts against encephalitis. We therefore conclude that antibody-mediated prevention of stromal keratitis and encephalitis does not require the obligatory participation of CD4+, CD8+, or asialo GM1+ cells. However, when mice were simultaneously depleted of both CD4+ and CD8+ T-cell subsets, antibody treatment could not prevent fatal encephalitis. Thus, antibody can compensate for the functional loss of one but not two T-lymphocyte subpopulations.


Robust and Efficient Biomolecular Clustering of Tumor Based on ${p}$ -Norm Singular Value Decomposition.
High dimensionality has become a typical feature of biomolecular data. In this paper, a novel dimension reduction method named p-norm singular value decomposition (PSVD) is proposed to seek the low-rank approximation matrix to the biomolecular data. To enhance the robustness to outliers, the Lp-norm is taken as the error function and the Schatten p-norm is used as the regularization function in the optimization model. To evaluate the performance of PSVD, the Kmeans clustering method is then employed for tumor clustering based on the low-rank approximation matrix. Extensive experiments are carried out on five gene expression data sets including two benchmark data sets and three higher dimensional data sets from the cancer genome atlas. The experimental results demonstrate that the PSVD-based method outperforms many existing methods. Especially, it is experimentally proved that the proposed method is more efficient for processing higher dimensional data with good robustness, stability, and superior time performance.


Wireless Neural/EMG Telemetry Systems for Small Freely Moving Animals.
We have developed miniature telemetry systems that capture neural, EMG, and acceleration signals from a freely moving insect or other small animal and transmit the data wirelessly to a remote digital receiver. The systems are based on custom low-power integrated circuits (ICs) that amplify, filter, and digitize four biopotential signals using low-noise circuits. One of the chips also digitizes three acceleration signals from an off-chip microelectromechanical-system accelerometer. All information is transmitted over a wireless ~ 900-MHz telemetry link. The first unit, using a custom chip fabricated in a 0.6- μm BiCMOS process, weighs 0.79 g and runs for two hours on two small batteries. We have used this system to monitor neural and EMG signals in jumping and flying locusts as well as transdermal potentials in weakly swimming electric fish. The second unit, using a custom chip fabricated in a 0.35-μ m complementary metal-oxide semiconductor CMOS process, weighs 0.17 g and runs for five hours on a single 1.5-V battery. This system has been used to monitor neural potentials in untethered perching dragonflies.


The effect of control strategies to reduce social mixing on outcomes of the COVID-19 epidemic in Wuhan, China: a modelling study.
In December, 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, emerged in Wuhan, China. Since then, the city of Wuhan has taken unprecedented measures in response to the outbreak, including extended school and workplace closures. We aimed to estimate the effects of physical distancing measures on the progression of the COVID-19 epidemic, hoping to provide some insights for the rest of the world. To examine how changes in population mixing have affected outbreak progression in Wuhan, we used synthetic location-specific contact patterns in Wuhan and adapted these in the presence of school closures, extended workplace closures, and a reduction in mixing in the general community. Using these matrices and the latest estimates of the epidemiological parameters of the Wuhan outbreak, we simulated the ongoing trajectory of an outbreak in Wuhan using an age-structured susceptible-exposed-infected-removed (SEIR) model for several physical distancing measures. We fitted the latest estimates of epidemic parameters from a transmission model to data on local and internationally exported cases from Wuhan in an age-structured epidemic framework and investigated the age distribution of cases. We also simulated lifting of the control measures by allowing people to return to work in a phased-in way and looked at the effects of returning to work at different stages of the underlying outbreak (at the beginning of March or April). Our projections show that physical distancing measures were most effective if the staggered return to work was at the beginning of April; this reduced the median number of infections by more than 92% (IQR 66-97) and 24% (13-90) in mid-2020 and end-2020, respectively. There are benefits to sustaining these measures until April in terms of delaying and reducing the height of the peak, median epidemic size at end-2020, and affording health-care systems more time to expand and respond. However, the modelled effects of physical distancing measures vary by the duration of infectiousness and the role school children have in the epidemic. Restrictions on activities in Wuhan, if maintained until April, would probably help to delay the epidemic peak. Our projections suggest that premature and sudden lifting of interventions could lead to an earlier secondary peak, which could be flattened by relaxing the interventions gradually. However, there are limitations to our analysis, including large uncertainties around estimates of R0 and the duration of infectiousness. Bill & Melinda Gates Foundation, National Institute for Health Research, Wellcome Trust, and Health Data Research UK.


The relationship between lower urinary tract symptoms and health status: the UREPIK study.
To assess the hypothesis that as lower urinary tract symptoms (LUTS) increase in severity, the impact as measured by the BPH impact index (BII) would also increase. The UREPIK survey collected information on this relationship from men and their partners in the Netherlands, Korea, France and the UK. Culturally and linguistically validated versions of three standard questionnaires, the SF-12, the BII and the International Prostate Symptom Score (IPSS) were used to assess the distribution of symptoms and the impact on health status. Stratified random samples of men aged 40-79 years in each community were recruited. Response rates were 72% in Boxmeer, 28% in Auxerre, 60% in Birmingham and 68% in Seoul. Regression analyses were undertaken on total SF-12, BII and IPSS. In all, 4800 index men and 3674 women responded; the BII increased with increasing IPSS. The correlation coefficients were; Boxmeer 0.69, Auxerre 0.56, Birmingham 0.60 and Seoul 0.68. For women, the correlations were slightly lower except in Birmingham, at 0.65 (Boxmeer), 0.44 (Auxerre), 0.71 (Birmingham), 0.57 (Korea). BII scores were higher in women than in men with the same level of IPSS. Adjusting for IPSS there was no association between age and BII. There was an association between IPSS quality-of-life (QoL) score and BII; for men the correlation was 0.62 and for women 0.60. Men and women with the same score on the IPSS QoL reported the same bother. Among those with an IPSS of 20-35 women expressed significantly more bother (P < 0.001). The SF-12 scores decreased as the IPSS and the BII increased in both men and women. Furthermore, the SF-12 mental score decreased with increasing symptoms in the partner. The relationship between the severity of LUTS and BII was similar in all centres. There is a clear association between the BII and the IPSS QoL question in men and women. The BII discriminates between people who are unhappy about their urinary condition compared with those who are pleased. Although designed for use in men with benign prostatic hyperplasia, the index also appears to be a useful among women. The severity of symptoms of LUTS has an adverse effect on the health status of the individual and his/her partner.


Analysis of rabbit pulmonary angiotensin converting enzyme kinetics in vivo.
We investigated the kinetics of pulmonary angiotensin converting enzyme (ACE) in vivo by measuring the hydrolysis of a bolus dose of a synthetic ACE substrate, benzoyl-phenylalanyl-alanyl-proline (BPAP). Estimates of apparent Km and Vmax were calculated by multiple regression analysis using a nonlinear model of enzyme kinetics. A bolus injection of indocyanine green and BPAP was given into the jugular vein of anesthetized rabbits (3-4 kg b. wt.) and serial blood samples were collected at 1-sec intervals from the carotid artery. The concentration of indocyanine green, [3H]BPAP and its metabolite in each sample was used to construct pulmonary venous outflow concentration-time curves and to assess ACE activity. Addition of 0.04 to 2.6 mumol of unlabeled BPAP per kg to the injectate reduced [3H]BPAP metabolism in a dose-dependent manner, with a calculated ID50 of 0.37 mumol/kg at the peak of the outflow curve and 0.58 mumol/kg over the integral. There was a similar correlation between the concentration of BPAP in pulmonary blood, estimated from indocyanine green outflow curves, and the metabolism of [3H] BPAP. For each animal, application of the mathematical model provided statistically significant estimates of the kinetic constants for pulmonary BPAP metabolism in vivo. The apparent Km and Vmax were 9.3 +/- 0.8 and 63.1 +/- 9.5 mumol/sec/organ, respectively; the Vmax/Km was 6.8 +/- 1.0 ml/sec/organ. BPAP did not affect any of the hemodynamic parameters measured. The technique described provides a method for detailed study of the kinetics of pulmonary ACE in vivo and effects of inhibitor drugs or other experimental treatments on the function of this enzyme in the intact animal.


The Tetraspanin CD53 Regulates Early B Cell Development by Promoting IL-7R Signaling.
The tetraspanin CD53 has been implicated in B cell development and function. CD53 is a transcriptional target of EBF1, a critical transcription factor for early B cell development. Further, human deficiency of CD53 results in recurrent infections and reduced serum Igs. Although prior studies have indicated a role for CD53 in regulating mature B cells, its role in early B cell development is not well understood. In this study, we show that CD53 expression, which is minimal on hematopoietic stem and progenitor cells, increases throughout bone marrow B cell maturation, and mice lacking CD53 have significantly decreased bone marrow, splenic, lymphatic, and peripheral B cells. Mixed bone marrow chimeras show that CD53 functions cell autonomously to promote B lymphopoiesis. Cd53-/- mice have reduced surface expression of IL-7Rα and diminished phosphatidylinositol 3 kinase and JAK/STAT signaling in prepro- and pro-B cells. Signaling through these pathways via IL-7R is essential for early B cell survival and transition from the pro-B to pre-B cell developmental stage. Indeed, we find increased apoptosis in developing B cells and an associated reduction in pre-B and immature B cell populations in the absence of CD53. Coimmunoprecipitation and proximity ligation studies demonstrate physical interaction between CD53 and IL-7R. Together, these data, to our knowledge, suggest a novel role for CD53 during IL-7 signaling to promote early B cell differentiation.


Synopsis of recent developments in venomous snake systematics.
Changes to our understanding of venomous snake systematics, and the consequent changes in the nomenclature of these animals, have traditionally been a great source of confusion among biomedical researchers. This paper aims to facilitate access to the taxonomic literature by presenting a synopsis of the changes in venomous snake systematics that have taken place recently (primarily since 1992), together with some comments on the implications of these changes for toxinologists and clinicians. Some long-standing problems in venomous snake taxonomy receive special attention. This includes Asiatic Naja, Asiatic Agkistrodon/Gloydius, Bothrops and related genera, Trimeresurus, Echis, Daboia (including Daboia russellii) and Vipera. It is hoped that this synopsis will result in the use of a more up-to-date and interpretable nomenclature for venomous snakes in the toxinological literature.


Mass detection on mammograms: influence of signal shape uncertainty on human and model observers.
We studied the influence of signal variability on human and model observers for detection tasks with realistic simulated masses superimposed on real patient mammographic backgrounds and synthesized mammographic backgrounds (clustered lumpy backgrounds, CLB). Results under the signal-known-exactly (SKE) paradigm were compared with signal-known-statistically (SKS) tasks for which the observers did not have prior knowledge of the shape or size of the signal. Human observers' performance did not vary significantly when benign masses were superimposed on real images or on CLB. Uncertainty and variability in signal shape did not degrade human performance significantly compared with the SKE task, while variability in signal size did. Implementation of appropriate internal noise components allowed the fit of model observers to human performance.


Low dose phenytoin is an osteogenic agent in the rat.
Long-term use of phenytoin for the treatment of epilepsy has been associated with increased thickness of craniofacial bones. The aim of the present study was to evaluate the possibility that low doses of phenytoin are osteogenic in vivo by measuring the effects of phenytoin administration on serum and bone histomorphometric parameters of bone formation in two rat experiments. In the first experiment, four groups of adult male Sprague-Dawley rats received daily I.P. injections of 0, 5, 50, or 150 mg/kg/day of phenytoin, respectively, for 47 days. Serum alkaline phosphatase (ALP) and osteocalcin were increased by 5 and 50 mg/kg/day phenytoin. The increases in osteocalcin and ALP occurred by day 7 and day 21, respectively. The tibial diaphyseal mineral apposition rate (MAR) at sacrifice (day 48) was significantly increased in rats receiving 5 mg/kg/day phenytoin. At a dose of 150 mg/kg/day, the increase in serum ALP, osteocalcin and MAR was reversed. No significant differences in serum calcium, phosphorus, or 1,25(OH)2D3 levels were seen. In a second experiment, three groups of rats received daily I.P. injection of lower doses of phenytoin (i.e., 0, 1, or 5 mg/kg/day, respectively) for 42 days. Phenytoin also did not affect the growth rate or serum calcium, phosphorus, and 25(OH)D3 levels. Daily injection of 5 mg/kg/day phenytoin significantly increased several measures of bone formation, i.e., serum ALP and osteocalcin bone ALP, periosteal MAR, and trabecular bone volume.(ABSTRACT TRUNCATED AT 250 WORDS)


Graft failure from severe recurrent primary sclerosing cholangitis following orthotopic liver transplantation.
Speculation that primary sclerosing cholangitis (PSC) may recur in the transplanted liver is based on the relative increase in frequency of biliary abnormalities and histologic evidence of periportal fibrosis without other causes. A recent study demonstrated almost 9% of patients undergoing liver transplantation (OLT) for primary sclerosing cholangitis (PSC) develop recurrent sclerosing cholangitis although the patient and graft survival is not different from those in whom recurrence does not develop. Most reports of PSC recurrence post-OLT estimate rates of 1% to 14%, but to date, no center has reported rapidly progressive fibro-obliterative cholangitis leading to graft failure. DV was a 39-year-old white man with ulcerative colitis, since age 21, who developed jaundice and pruritus in 1992. ERCP and liver biopsy were consistent with PSC, and he developed thrombocytopenia and bleeding esophageal varices. He underwent an uneventful OLT in May 1994 with an ABO-compatible organ and normal ischemic times. There was no evidence of postoperative cytomegalovirus infection, hepatic artery thrombosis, or rejection. In October 1994, mild abnormalities of liver function tests (LFTs) led to liver biopsy that revealed inflammatory infiltrate in triad with spillover into lobules and mild periportal fibrosis. LFTs normalized without any treatment, but in February 1995 repeat liver biopsy for increased LFTs revealed moderate periportal fibrosis with inflammatory cells in triads and lobules. Viral shell and CMV titers were negative. No evidence of infectious etiology or rejection was noted. The patient was started on ursodeoxycholic acid at that time and percutaneous transhepatic cholangiogram (PTC) revealed marked narrowing of the intrahepatic ducts. Esophagogastroduodenoscopy (EGD) revealed esophageal varices. Hepatic arteriogram and Doppler ultrasound were negative. He developed progressive graft failure, and died at home while awaiting re-transplant. Although most series report mild recurrence of PSC following OLT, this case illustrates that early, severe recurrence of PSC may occur, leading to graft failure and need for re-transplantation.


The male sterility locus ms3 is present in a fertility controlling gene cluster in soybean.
Soybean [Glycine max (L.) Merr.] is self-pollinated. To produce large quantities of hybrid seed, insect-mediated cross-pollination is necessary. An efficient nuclear male-sterile system for hybrid seed production would benefit from molecular and/or phenotypic markers linked to male fertility/sterility loci to facilitate early identification of phenotypes. Nuclear male-sterile, female-fertile ms3 mutant is a single recessive gene and displays high outcrossed seed set with pollinators. Our objective was to map the ms3 locus. A segregating population of 150 F(2) plants from Minsoy (PI 27890) x T284H, Ms3ms3 (A00-68), was screened with 231 simple sequence repeat markers. The ms3 locus mapped to molecular linkage group (MLG) D1b (Gm02) and is flanked by markers Satt157 and Satt542, with a distance of 3.7 and 12.3 cM, respectively. Female-partial sterile-1 (Fsp1) and the Midwest Oilseed male-sterile (msMOS) mutants previously were located on MLG D1b. msMOS and Fsp1 are independent genes located very close to each other. All 3 genes are located in close proximity of Satt157. We believe that this is the first report of clustering of fertility-related genes in plants. Characterization of these closely linked genes may help in understanding the evolutionary relationship among them.


Understanding ethnic diversity in open dementia neuroimaging data sets.
Ethnic differences in dementia are increasingly recognized in epidemiological measures and diagnostic biomarkers. Nonetheless, ethnic diversity remains limited in many study populations. Here, we provide insights into ethnic diversity in open-access neuroimaging dementia data sets. Data sets comprising dementia populations with available data on ethnicity were included. Statistical analyses of sample and effect sizes were based on the Cochrane Handbook. Nineteen databases were included, with 17 studies of healthy groups or a combination of diagnostic groups if breakdown was unavailable and 12 of mild cognitive impairment and dementia groups. Combining all studies on dementia patients, the largest ethnic group was Caucasian (20 547 participants), with the next most common being Afro-Caribbean (1958), followed by Asian (1211). The smallest effect size detectable within the Caucasian group was 0.03, compared to Afro-Caribbean (0.1) and Asian (0.13). Our findings quantify the lack of ethnic diversity in openly available dementia data sets. More representative data would facilitate the development and validation of biomarkers relevant across ethnicities.


A self-sustaining ultrahigh-frequency nanoelectromechanical oscillator.
Sensors based on nanoelectromechanical systems vibrating at high and ultrahigh frequencies are capable of levels of performance that surpass those of larger sensors. Nanoelectromechanical devices have achieved unprecedented sensitivity in the detection of displacement, mass, force and charge. To date, these milestones have been achieved with passive devices that require external periodic or impulsive stimuli to excite them into resonance. Here, we demonstrate an autonomous and self-sustaining nanoelectromechanical oscillator that generates continuous ultrahigh-frequency signals when powered by a steady d.c. source. The frequency-determining element in the oscillator is a 428 MHz nanoelectromechanical resonator that is embedded within a tunable electrical feedback network to generate active and stable self-oscillation. Our prototype nanoelectromechanical oscillator exhibits excellent frequency stability, linewidth narrowing and low phase noise performance. Such ultrahigh-frequency oscillators provide a comparatively simple means for implementing a wide variety of practical sensing applications. They also offer intriguing opportunities for nanomechanical frequency control, timing and synchronization.


Crystal structure of 4-(4-chloro-phen-yl)-6-(morpholin-4-yl)pyridazin-3(2H)-one.
In the title compound, C14H14ClN3O2, the morpholine ring adopts a chair conformation, with the exocyclic N-C bond in an equatorial orientation. The 1,6-di-hydro-pyridazine ring is essentially planar, with a maximum deviation of 0.014 (1) Å, and forms a dihedral angle of 40.16 (7)° with the plane of the benzene ring. In the crystal, pairs of centrosymmetrically related mol-ecules are linked into dimers via N-H⋯O hydrogen bonds, forming R 2 (2)(8) ring motifs. The dimers are connected via C-H⋯O and C-H⋯Cl hydrogen bonds, forming a three-dimensional network. Aromatic π-π stacking inter-actions [centroid-centroid distance = 3.6665 (9) Å] are also observed. Semi-empirical mol-ecular orbital calculations were carried out using the AM1 method. The calculated dihedral angles between the pyridizine and benzene rings and between the pyridizine and morpholine (all atoms) rings are 34.49 and 76.96°, respectively·The corresponding values obtained from the X-ray structure determination are 40.16 (7) and 12.97 (9)°, respectively. The morpholine ring of the title compound in the calculated gas-phase seems to have a quite different orientation compared to that indicated by the X-ray structure determination.


Could African swine fever and classical swine fever viruses enter into the United States via swine products carried in air passengers' luggage?
On average 8,000 pork derived products are annually confiscated by Customs and Border Protection at the United States (US) ports of entry such as international airports, harbours or mail offices. These swine products with unknown sanitary status could pose a risk for foreign animal diseases introduction into the US. This study aimed at analysing the risk of African swine fever virus (ASFV) and classical swine fever virus (CSFV) being introduced into the US through prohibited swine products carried by air passengers (PSPAP) and identifying locations and time periods at higher risk where and when preventive and mitigation measures should be implemented. Our results estimated that the risk for CSFV entry was seven times higher and further spread between US airports than for ASFV. Specifically, the overall mean annual probability of ASFV entry was estimated as 0.061 at 95% confidence interval (CI) [0.007, 0.216] while the probability of CSFV entry was estimated as 0.414 (95% CI [0.074, 1]). For both diseases, July and May were the months at highest risk for entry. For ASFV, the origin countries of those PSPAP that represented the highest risk (above 70% of the total risk) were Ghana, Cape Verde, Ethiopia and the Russian Federation, while for CSFV above 90% of the risk at origin was concentrated in the Dominican Republic and Cuba, followed by India, Colombia, Peru, Ecuador and China. These results could be used to implement and feed real time surveillance systems, which could potentially help customs to increase the detection rate of smuggled products, indicating when and where to look for them. Similarly, these systems could be adapted and implemented to other diseases improving the cost-effectiveness of the resources invested in preventing entrance of diseases via air passengers' luggage.


Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer.
Gastric cancer cell lines, particularly those with low levels of ataxia telangiectasia mutated (ATM), a key activator of DNA damage response, are sensitive to the poly (ADP-ribose) polymerase inhibitor olaparib. We compared the efficacy of olaparib plus paclitaxel (olaparib/paclitaxel) with paclitaxel alone in patients with recurrent or metastatic gastric cancer and assessed whether low ATM expression is predictive of improved clinical outcome for olaparib/paclitaxel. In this phase II, double-blind study (Study 39; NCT01063517), patients were randomly assigned to oral olaparib 100 mg twice per day (tablets) plus paclitaxel (80 mg/m(2) per day intravenously on days 1, 8, and 15 of every 28-day cycle) or placebo plus paclitaxel (placebo/paclitaxel), followed by maintenance monotherapy with olaparib (200 mg twice per day) or placebo. The study population was enriched to 50% for patients with low or undetectable ATM levels (ATMlow). Primary end point was progression-free survival (PFS). One hundred twenty-three of 124 randomly assigned patients received treatment (olaparib/paclitaxel, n = 61; placebo/paclitaxel, n = 62). The screening prevalence of ATMlow patients was 14%. Olaparib/paclitaxel did not lead to a significant improvement in PFS versus placebo/paclitaxel (overall population: hazard ratio [HR], 0.80; median PFS, 3.91 v 3.55 months, respectively; ATMlow population: HR, 0.74; median PFS, 5.29 v 3.68 months, respectively). However, olaparib/paclitaxel significantly improved overall survival (OS) versus placebo/paclitaxel in both the overall population (HR, 0.56; 80% CI, 0.41 to 0.75; P = .005; median OS, 13.1 v 8.3 months, respectively) and the ATMlow population (HR, 0.35; 80% CI, 0.22 to 0.56; P = .002; median OS, not reached v 8.2 months, respectively). Olaparib/paclitaxel was generally well tolerated, with no unexpected safety findings. Olaparib/paclitaxel is active in the treatment of patients with metastatic gastric cancer, with a greater OS benefit in ATMlow patients. A phase III trial in this setting is under way.


Ipsenol, Ipsdienol, Ethanol, and α-Pinene: Trap Lure Blend for Cerambycidae and Buprestidae (Coleoptera) in Pine Forests of Eastern North America.
In 2007-2008, we examined the flight responses of wood-boring beetles (Coleoptera: Cerambycidae and Buprestidae) to multiple-funnel traps baited with the pine volatiles, ethanol, and α-pinene [85% (-)], and the bark beetle pheromones, racemic ipsenol and racemic ipsdienol. Experiments were conducted in mature pine stands in Canada (Ontario and New Brunswick) and the United States (Arkansas, Florida, Michigan, New Hampshire, North Carolina, Ohio, Tennessee, and Wisconsin). At each location, traps were deployed in 10 replicate blocks of four traps per block. The trap treatments were: 1) blank control; 2) ipsenol and ipsdienol; 3) ethanol and α-pinene; and 4) a quaternary blend of ipsenol, ipsdienol, ethanol, and α-pinene. Traps baited with the quaternary blend caught the greatest numbers of Acanthocinus nodosus (F.), Acanthocinus obsoletus (Olivier), Acmaeops proteus (Kirby), Astylopsis sexguttata (Say), Rhagium inquisitor (L.) (Cerambycidae), and Buprestis lineata (F.) (Buprestidae). Traps baited with ethanol and α-pinene caught the greatest numbers of Arhopalus rusticus (LeConte), Asemum striatum (L.), Tetropium spp., Xylotrechus sagittatus (Germar) (Cerambycidae), and Buprestis maculipennis Gory (Buprestidae) with minimal interruption by ipsenol and ipsdienol. Our results suggest that multiple-funnel traps baited with the quaternary lure blend of ipsenol, ipsdienol, ethanol, and α-pinene are effective for trapping various species of wood-boring beetles in pine forests of eastern North America, and may have utility in detection programs for adventive species in North America and overseas.


Preterm birth and intra-uterine growth retardation among children of women with schizophrenia.
There is conflicting evidence about the frequency of adverse pregnancy outcomes among women with schizophrenia. To investigate the risk of preterm birth, low birth weight and intra-uterine growth retardation among women with schizophrenia. A total of 2212 births to 1537 women with schizophrenia in Denmark were compared with a random sample of all deliveries in Denmark in 1973-1993 (122,931 births to 72,742 women). The children of women with schizophrenia were at increased risk of preterm delivery (relative risk = 1.46, 95% CI = 1.19-1.79), low birth weight (relative risk = 1.57, 95% CI = 1.36-1.82) and small for gestational age (relative risk = 1.34, 95% CI = 1.17-1.53). Women with schizophrenia are at increased risk of adverse pregnancy outcome. This may be associated with an increased mortality and general morbidity and risk of schizophrenia in their children.


Potential relevance of pre-operative quality of life questionnaires to identify candidates for surgical treatment of genital prolapse: a pilot study.
To evaluate prolapse-related symptoms, quality of life and sexuality of patients with validated questionnaires before and after surgery for genital prolapse and assess relevance of such an evaluation to select women for surgery. From November 2009 to April 2010, 16 patients operated on for genital prolapse of grade greater than or equal to 2 (POP-Q classification) were evaluated prospectively by three questionnaires of quality of life Pelvic Floor Distress Inventory (PFDI-20), Pelvic Floor Impact Questionnaire (PFIQ-7) and Pelvic Organ Prolaps/Urinary Incontinence Sexual Questionnaire (PISQ-12). Data were collected the day before surgery and 6 weeks postoperatively. Eleven patients had laparoscopic surgery and five vaginal surgery. There was a significant decrease in pelvic heaviness, vaginal discomfort and urinary symptoms after surgery. The score of symptoms of prolapse, the PFDI-20 score was 98.5 preoperatively and 31.8 postoperatively (p < 0.0001). The score for quality of life, the PFIQ-7 score was 54.5 preoperatively and 7.4 postoperatively (p = 0.001). The score of sexuality, the PISQ-12 score was 35.3 preoperatively and 37.5 postoperatively (p = 0.1). Two of the 3 patients with a PFIQ 7 under or equal to 20 were not improved while all the women with a preoperative PFIQ-7 over 20 were improved after surgery. This study suggests that surgery improves quality of life of patients with genital prolapse. Quality of life questionnaires could help select good candidates for surgery. Further studies are required to determine threshold to standardize indications of surgery.


Improved Mortality Prediction in Dialysis Patients Using Specific Clinical and Laboratory Data.
Risk prediction models can be used to inform patients undergoing renal replacement therapy about their survival chances. Easily available predictors such as registry data are most convenient, but their predictive value may be limited. We aimed to improve a simple prediction model based on registry data by incrementally adding sets of clinical and laboratory variables. Our data set includes 1,835 Dutch patients from the Netherlands Cooperative Study on the Adequacy of Dialysis. The potential survival predictors were categorized on availability. The first category includes easily available clinical data. The second set includes laboratory values like albumin. The most laborious category contains glomerular filtration rate (GFR) and Kt/V. Missing values were substituted using multiple imputation. Within 1,225 patients, we recalibrated the registry model and subsequently added parameter sets using multivariate Cox regression analyses with backward selection. On the other 610 patients, calibration and discrimination (C-index, integrated discrimination improvement (IDI) index and net reclassification improvement (NRI) index) were assessed for all models. The recalibrated registry model showed adequate calibration and discrimination (C-index=0.724). Adding easily available parameters resulted in a model with 10 predictors, with similar calibration and improved discrimination (C-index=0.784). The IDI and NRI indices confirmed this, especially for short-term survival. Adding laboratory values resulted in an alternative model with similar discrimination (C-index=0.788), and only the NRI index showed minor improvement. Adding GFR and Kt/V as candidate predictors did not result in a different model. A simple model based on registry data was enhanced by adding easily available clinical parameters.


The pathobiologic features of carcinomas of type II pneumocytes. An immunocytologic study.
Adenocarcinomas of the lung without squamous differentiation or obvious mucus production from 51 patients were studied. Twenty-eight tumors (55%), when stained with rabbit anti-human surfactant apoprotein antiserum by the peroxidase-antiperoxidase method, demonstrated characteristic nuclear inclusions. Most of these tumors could be identified histochemically by the presence of eosinophilic, periodic acid-Schiff (PAS)-positive nuclear inclusions. In patients with apoprotein-immunoreactive tumors there were nine deaths due to tumor (32%) within 5 years of diagnosis. Eight of the nine deaths occurred in patients whose tumors exceeded 3 cm in diameter; an equal number of patients were smokers. The average age of patients with apoprotein-positive tumors was 67.3 years, a figure greater than that for patients with apoprotein-negative tumors (61.4 years). Five of the 23 patients with apoprotein-negative tumors died of their neoplasms; in two of the subjects the tumors exceeded 3 cm in diameter. In that no significant difference in survival was observed in patients with apoprotein-positive and apoprotein-negative tumors, it was concluded that subclassification of adenocarcinomas of the lung as apoprotein-positive, i.e., type II pneumocytic, or as apoprotein-negative, is of no clinical or prognostic significance. Nonetheless, peripheral tumors measuring less than 3 cm in size and showing neither squamous differentiation nor obvious mucus production should be recognized as a prognostically favorable group in comparison with other types of lung carcinomas.


Synaptic plasticity in neural networks needs homeostasis with a fast rate detector.
Hebbian changes of excitatory synapses are driven by and further enhance correlations between pre- and postsynaptic activities. Hence, Hebbian plasticity forms a positive feedback loop that can lead to instability in simulated neural networks. To keep activity at healthy, low levels, plasticity must therefore incorporate homeostatic control mechanisms. We find in numerical simulations of recurrent networks with a realistic triplet-based spike-timing-dependent plasticity rule (triplet STDP) that homeostasis has to detect rate changes on a timescale of seconds to minutes to keep the activity stable. We confirm this result in a generic mean-field formulation of network activity and homeostatic plasticity. Our results strongly suggest the existence of a homeostatic regulatory mechanism that reacts to firing rate changes on the order of seconds to minutes.


Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors.
Genome-wide copy number profiles were characterized in 41 primary bladder tumors using array-based comparative genomic hybridization (array CGH). In addition to previously identified alterations in large chromosomal regions, alterations were identified in many small genomic regions, some with high-level amplifications or homozygous deletions. High-level amplifications were detected for 192 genomic clones, most frequently at 6p22.3 (E2F3), 8p12 (FGFR1), 8q22.2 (CMYC), 11q13 (CCND1, EMS1, INT2), and 19q13.1 (CCNE). Homozygous deletions were detected in 51 genomic clones, with four showing deletions in more than one case: two clones mapping to 9p21.3 (CDKN2A/p16, in nine cases), one at 8p23.1 (three cases), and one at 11p13 (two cases). Significant correlations were observed between copy number gain of clones containing CCNE1 and gain of ERBB2, and between gain of CCND1 and deletion of TP53. In addition, there was a significant complementary association between gain of CCND1 and gain of E2F3. Although there was no significant relationship between copy number changes and tumor stage or grade, the linked behavior among genomic loci suggests that array CGH will be increasingly important in understanding pathways critical to bladder tumor biology.


Linking drugs of abuse in wastewater to contamination of surface and drinking water.
The concentrations of 17 drugs of abuse, including cocaine, several amphetamines, opioid drugs, and 2 metabolites--benzoylecgonine, a metabolite of cocaine, and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine, a metabolite of methadone--were investigated in an urban watershed that is heavily impacted by discharges of municipal wastewater. The artificial sweetener sucralose was also monitored as a persistent tracer of contamination from municipal wastewater. Monitoring was conducted in a municipal wastewater treatment plant (WWTP) and at sites upstream and downstream of the WWTP discharge, as well as in a drinking water treatment plant (DWTP) located 19 km downstream of the WWTP discharge that withdraws raw water from the river. Drug concentrations were monitored with polar organic chemical integrative samplers deployed for 2 wk in the river and in the WWTP and DWTP. Several of the investigated compounds exhibited a decrease in concentration with distance downstream from the wastewater discharge into the river, but there was little attenuation of sucralose, cocaine, benzoylecgonine, morphine, acetylmorphine, acetylcodeine, and oxycodone. Heroin and methadone were not detected at any sample locations. Amphetamine, methamphetamine, 3,4-methylenedioxy-methamphetamine, and 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrolidine were not detected in the samples collected at the drinking water intake. Many of the drugs of abuse were not removed effectively in the DWTP, including cocaine, benzoylecgonine, methylenedioxyamphetamine, ephedrine, and several prescription opioids, most probably because the DWTP was operating at or above its rated treatment capacity. These data indicate that there can be transport of drugs of abuse from wastewater sources into drinking water in urban watersheds.


Carotid stenting using tapered and nontapered stents: associated neurological complications and restenosis rates.
Self-expanding stent design systems for carotid artery stenting (CAS) have morphed from nontapered (NTS) to tapered (TS); however, the impact of this change is unknown. We reviewed the outcomes of CAS with these two broad categories of stents in a single-center retrospective review of 308 CAS procedures from May 2001 to July 2007. Nitinol self-expanding TS or NTS coupled with cerebral embolic protection devices were used to treat extracranial carotid occlusive disease. Data analysis included demographics, procedural records, duplex exams, and conventional arteriography. Mean follow-up was 18 months (range 1-69). Restenosis was defined as >or=80% in-stent carotid artery stenosis by angiography. The mean age of the entire cohort was 71.3 years (75% men, 25% women). Of the 308 cases, 233 were de novo lesions and 75 had a prior ipsilateral carotid endarterectomy (n = 44) or external beam radiation exposure (n = 31). Preprocedure neurological symptoms were present in 30% of patients. TS were used in 156 procedures and NTS in 152 procedures. The 30-day ipsilateral stroke and death rates were 1.3% and 0.3%, respectively. An additional three (1.0%) posterior circulation strokes occurred. There was no statistically significant difference in the 30-day total stroke rates between TS (3.2%, n = 5) and NTS (1.3%, n = 2) (p = 0.5). At midterm follow-up, restenosis or asymptomatic occlusion was detected in eight cases (2.6%). All occurred in arteries treated with NTS, and this was statistically different when compared to arteries treated with TS (p = 0.03). Furthermore, a post-hoc subgroup analysis revealed significant correlation (chi(2) = 0.02) for restenosis in "hostile necks" when separated by TS vs. NTS. Early CAS outcomes between TS and NTS are comparable. In contrast, self-expanding nitinol TS may have a lower incidence of significant restenosis or asymptomatic occlusion when compared to NTS.


Treatment discontinuation and disease progression with injectable disease-modifying therapies: findings from the north american research committee on multiple sclerosis database.
Injectable first-line disease-modifying therapies (DMTs) for multiple sclerosis (MS) are generally prescribed for continuous use. Accordingly, the various factors that influence patient persistence with treatment and that can lead some patients to switch medications or discontinue treatment may affect clinical outcomes. Using data from the North American Research Committee on Multiple Sclerosis (NARCOMS) database, this study evaluated participants' reasons for discontinuation of injectable DMTs as well as the relationship between staying on therapy and sustained patient-reported disease progression and annualized relapse rates. Participants selected their reason(s) for discontinuation from among 16 possible options covering the categories of efficacy, safety, tolerability, and burden, with multiple responses permitted. Both unadjusted data and data adjusted for baseline age, disease duration, disability, and sex were evaluated. Discontinuation profiles varied among DMTs. Participants on intramuscular interferon beta-1a (IM IFNβ-1a) and glatiramer acetate (GA) reported the fewest discontinuations based on safety concerns, although GA was associated with reports of higher burden and lower efficacy than other therapies. Difficulties with tolerability were more often reported as a reason for discontinuing subcutaneous (SC) IFNβ-1a than as a reason for discontinuing IM IFNβ-1a, GA, or SC IFNβ-1b. In the persistent therapy cohort, less patient-reported disability progression was reported with IM IFNβ-1a treatment than with SC IFNβ-1a, IFNβ-1b, or GA. These findings have relevance to clinical decision making and medication compliance in MS patient care.


Pathogenesis of myasthenia gravis: update on disease types, models, and mechanisms.
Myasthenia gravis is an autoimmune disease of the neuromuscular junction (NMJ) caused by antibodies that attack components of the postsynaptic membrane, impair neuromuscular transmission, and lead to weakness and fatigue of skeletal muscle. This can be generalised or localised to certain muscle groups, and involvement of the bulbar and respiratory muscles can be life threatening. The pathogenesis of myasthenia gravis depends upon the target and isotype of the autoantibodies. Most cases are caused by immunoglobulin (Ig)G1 and IgG3 antibodies to the acetylcholine receptor (AChR). They produce complement-mediated damage and increase the rate of AChR turnover, both mechanisms causing loss of AChR from the postsynaptic membrane. The thymus gland is involved in many patients, and there are experimental and genetic approaches to understand the failure of immune tolerance to the AChR. In a proportion of those patients without AChR antibodies, antibodies to muscle-specific kinase (MuSK), or related proteins such as agrin and low-density lipoprotein receptor-related protein 4 (LRP4), are present. MuSK antibodies are predominantly IgG4 and cause disassembly of the neuromuscular junction by disrupting the physiological function of MuSK in synapse maintenance and adaptation. Here we discuss how knowledge of neuromuscular junction structure and function has fed into understanding the mechanisms of AChR and MuSK antibodies. Myasthenia gravis remains a paradigm for autoantibody-mediated conditions and these observations show how much there is still to learn about synaptic function and pathological mechanisms.


Cellular complexity of the bone marrow hematopoietic stem cell niche.
The skeleton serves as the principal site for hematopoiesis in adult terrestrial vertebrates. The function of the hematopoietic system is to maintain homeostatic levels of all circulating blood cells, including myeloid cells, lymphoid cells, red blood cells, and platelets. This action requires the daily production of more than 500 billion blood cells. The vast majority of these cells are synthesized in the bone marrow, where they arise from a limited number of hematopoietic stem cells (HSCs) that are multipotent and capable of extensive self-renewal. These attributes of HSCs are best demonstrated by marrow transplantation, where even a single HSC can repopulate the entire hematopoietic system. HSCs are therefore adult stem cells capable of multilineage repopulation, poised between cell fate choices which include quiescence, self-renewal, differentiation, and apoptosis. While HSC fate choices are in part determined by multiple stochastic fluctuations of cell autonomous processes, according to the niche hypothesis, signals from the microenvironment are also likely to determine stem cell fate. While it had long been postulated that signals within the bone marrow could provide regulation of hematopoietic cells, it is only in the past decade that advances in flow cytometry and genetic models have allowed for a deeper understanding of the microenvironmental regulation of HSCs. In this review, we will highlight the cellular regulatory components of the HSC niche.


Remote sensing of the ocean contributions from ultraviolet to near-infrared using the shortwave infrared bands: simulations.
In the remote sensing of the ocean near-surface properties, it is essential to derive accurate water-leaving radiance spectra through the process of the atmospheric correction. The atmospheric correction algorithm for Sea-Viewing Wide Field-of-View Sensor (SeaWiFS) and Moderate Resolution Imaging Spectroradiometer (MODIS) uses two near-infrared (NIR) bands at 765 and 865 nm (748 and 869 nm for MODIS) for retrieval of aerosol properties with assumption of the black ocean at the NIR wavelengths. Modifications are implemented to account for some of the NIR ocean contributions for the productive but not very turbid waters. For turbid waters in the coastal regions, however, the ocean could have significant contributions in the NIR, leading to significant errors in the satellite-derived ocean water-leaving radiances. For the shortwave infrared (SWIR) wavelengths (approximately > 1000 nm), water has significantly larger absorption than those for the NIR bands. Thus the black ocean assumption at the SWIR bands is generally valid for turbid waters. In addition, for future sensors, it is also useful to include the UV bands to better quantify the ocean organic and inorganic materials, as well as for help in atmospheric correction. Simulations are carried out to evaluate the performance of atmospheric correction for nonabsorbing and weakly absorbing aerosols using the NIR bands and various combinations of the SWIR bands for deriving the water-leaving radiances at the UV (340 nm) and visible wavelengths. Simulations show that atmospheric correction using the SWIR bands can generally produce results comparable to atmospheric correction using the NIR bands. In particular, the water-leaving radiance at the UV band (340 nm) can also be derived accurately. The results from a sensitivity study for the required sensor noise equivalent reflectance, (NE Delta rho), [or the signal-to-noise ratio (SNR)] for the NIR and SWIR bands are provided and discussed.


Effects of diets rich in monounsaturated fatty acids on plasma lipoproteins--the Jerusalem Nutrition Study: high MUFAs vs high PUFAs.
Twenty-six Yeshiva students were randomly assigned to a 24-wk crossover study of monounsaturated fatty acid (MUFA) vs polyunsaturated fatty acid (PUFA) diets (50% carbohydrate, 32% fat, 18% protein) fed alternately during two 12-wk periods. Total plasma cholesterol (TC) decreased significantly by approximately 10% and approximately 16% on the MUFA and PUFA diets, respectively. Plasma triglyceride response was variable. Low-density-lipoprotein cholesterol (LDL-C) decreased in both groups with an additional significant effect between periods. Concentrations of high-density-lipoprotein cholesterol did not change significantly. LDL-receptor status in fresh monocytes, affinity of LDL towards the LDL receptor in cultured fibroblasts, zonal-centrifugation profiles, and lipoprotein composition were not significantly different between the diets. There was a significantly higher tendency toward lipid peroxidation on the PUFA diet, as ascertained by more thiobarbituric acid-reactive-substances formation on that diet. Dietary PUFA results in somewhat lower TC and LDL-C concentrations whereas with MUFA the susceptibility of LDL to oxidative stress is lower.


An Atlas of Transcription Factors Expressed in Male Pupal Terminalia of Drosophila melanogaster.
During development, transcription factors and signaling molecules govern gene regulatory networks to direct the formation of unique morphologies. As changes in gene regulatory networks are often implicated in morphological evolution, mapping transcription factor landscapes is important, especially in tissues that undergo rapid evolutionary change. The terminalia (genital and anal structures) of Drosophila melanogaster and its close relatives exhibit dramatic changes in morphology between species. While previous studies have identified network components important for patterning the larval genital disc, the networks governing adult structures during pupal development have remained uncharted. Here, we performed RNA-seq in whole Drosophila melanogaster male terminalia followed by in situ hybridization for 100 highly expressed transcription factors during pupal development. We find that the male terminalia are highly patterned during pupal stages and that specific transcription factors mark separate structures and substructures. Our results are housed online in a searchable database (https://flyterminalia.pitt.edu/) as a resource for the community. This work lays a foundation for future investigations into the gene regulatory networks governing the development and evolution of Drosophila terminalia.


Acceptability, reliability, and validity of the Stroke and Aphasia Quality of Life Scale-39 (SAQOL-39) across languages: a systematic review.
This systematic review aimed to explore the acceptability, reliability, and validity of the Stroke and Aphasia Quality of Life-39 (SAQOL-39) scale across languages. We employed a systematic search of the online databases including MEDLINE (Pubmed), Science direct, Web of science, Psychinfo, Scopus, ProQuest, Google Scholar, and Cochrane library published between 2003 and 2016. We used PRISMA guidelines for conducting and reporting this review. Subsequently, screening of the titles and abstracts, extraction of data as well as the appraisal of the quality of relevant studies were carried out. The initial search returned 8185 studies. Subsequent screening and study selection processes narrowed them to 20, needing detailed review. Forward-backward translation scheme was the preferred method for translation of the SAQOL-39 from English to other languages. Mainly, the socio-cultural and linguistic adaptations were performed in the translated versions. Most versions of the SAQOL-39 showed high test-retest reliability and internal consistency. However, several psychometric properties including the validity and responsiveness were seldom reported in these versions. The SAQOL-39 scale showed high acceptability, and reliability across the languages reviewed in this study. Future translations may additionally focus on reporting the validity and responsiveness of the instrument.


Visual field test simulation and error in threshold estimation.
To establish, via computer simulation, the effects of patient response variability and staircase starting level upon the accuracy and repeatability of static full threshold visual field tests. Patient response variability, defined by the standard deviation of the frequency of seeing versus stimulus intensity curve, is varied from 0.5 to 20 dB (in steps of 0.5 dB) with staircase starting levels ranging from 30 dB below to 30 dB above the patient's threshold (in steps of 10 dB). Fifty two threshold estimates are derived for each condition and the error of each estimate calculated (difference between the true threshold and the threshold estimate derived from the staircase procedure). The mean and standard deviation of the errors are then determined for each condition. The results from a simulated quadrantic defect (response variability set to typical values for a patient with glaucoma) are presented using two different algorithms. The first corresponds with that normally used when performing a full threshold examination while the second uses results from an earlier simulated full threshold examination for the staircase starting values. The mean error in threshold estimates was found to be biased towards the staircase starting level. The extent of the bias was dependent upon patient response variability. The standard deviation of the error increased both with response variability and staircase starting level. With the routinely used full threshold strategy the quadrantic defect was found to have a large mean error in estimated threshold values and an increase in the standard deviation of the error along the edge of the defect. When results from an earlier full threshold test are used as staircase starting values this error and increased standard deviation largely disappeared. The staircase procedure widely used in threshold perimetry increased the error and the variability of threshold estimates along the edges of defects. Using earlier data, when available, overcomes this problem and reduces examination time.


The European Society of Regional Anaesthesia and Pain Therapy and the American Society of Regional Anesthesia and Pain Medicine Joint Committee Practice Advisory on Controversial Topics in Pediatric Regional Anesthesia.
Some topics in the clinical management of regional anesthesia in children remain controversial. To evaluate and come to a consensus regarding some of these topics, The European Society of Regional Anaesthesia and Pain Therapy (ESRA) and the American Society of Regional Anesthesia and Pain Medicine (ASRA) developed a joint committee practice advisory on pediatric regional anesthesia (PRA). Representatives from both ASRA and ESRA comprised the joint committee practice advisory on PRA. Evidence-based recommendations were based on a systematic search of the literature. In cases where no literature was available, expert opinion was elicited. Experts selected controversial topics in PRA. The performance of PRA under general anesthesia or deep sedation is associated with acceptable safety and should be viewed as the standard of care (Evidence B2 and Evidence B3). Because of the difficulty interpreting a negative test dose, the use of test dosing should remain discretionary (Evidence B4). The use of either air-loss of resistance or saline-loss of resistance techniques is supported by expert opinion, but the literature supporting one technique over the other is sparse and controversial; when used appropriately, each technique may be safely used in children. There are no current evidence-based data that the use of RA increases the risk for acute compartment syndrome or delays its diagnosis in children. High-level evidence is not yet available for the topics evaluated, and most recommendations are based on Evidence B studies. The ESRA/ASRA recommendations intend to provide guidance for the safe practice of regional anesthesia in children.


Dihydrotestosterone induces SREBP-1 expression and lipogenesis through the phosphoinositide 3-kinase/Akt pathway in HaCaT cells.
The purpose of this study was to investigate the effects and mechanisms of dihydrotestosterone (DHT)-induced expression of sterol regulatory element binding protein-1 (SREBP-1), and the synthesis and secretion of lipids, in HaCaT cells. HaCaT cells were treated with DHT and either the phosphoinositide 3-kinase inhibitor LY294002 or the extracellular-signal-regulated kinase (ERK) inhibitor PD98059. Real time-PCR, Western blot, Oil Red staining and flow cytometry were employed to examine the mRNA and protein expressions of SREBP-1, the gene transcription of lipid synthesis, and lipid secretion in HaCaT cells. We found that DHT upregulated mRNA and protein expressions of SREBP-1. DHT also significantly upregulated the transcription of lipid synthesis-related genes and increased lipid secretion, which can be inhibited by the addition of LY294002. Collectively, these results indicate that DHT induces SREBP-1 expression and lipogenesis in HaCaT cells via activation of the phosphoinositide 3-kinase/Akt Pathway.


Racial Disparities in Health Behaviors and Conditions Among Lesbian and Bisexual Women: The Role of Internalized Stigma.
There are documented disparities in physical health behaviors and conditions, such as physical activity and obesity, with regard to both race/ethnicity and sexual orientation. However, physical health disparities for lesbian and bisexual (LB) women who are also racial minorities are relatively unexplored. Minority stressors, such as internalized stigma, may account for disparities in such multiply marginalized populations. We sought to (1) characterize inequalities among non-Hispanic white and African American LB women and (2) examine the roles of internalized sexism and homophobia in disparities. Data on health behaviors (diet, physical activity); physical health (hypertension, diabetes, overweight/obesity); internalized sexism; and internalized homophobia were collected via a web-based survey. Recruitment ads were sent electronically to over 200 listservs, online groups, and organizations serving the lesbian, gay, and bisexual community in all 50 U.S. states. The analytic sample consisted of 954 white and 75 African American LB women. African American participants were more likely than white participants to report low fruit/vegetable intake and physical activity, a higher body mass index, and a history of diabetes and hypertension. There were no racial differences in internalized homophobia, but African American women reported higher levels of internalized sexism. Internalized sexism partially mediated racial disparities in physical activity and diabetes, but not in the other outcomes. Findings suggest that African American LB women may be at greater risk than their white counterparts for poor health and that internalized sexism may be a mediator of racial differences for certain behaviors and conditions.


The human immunodeficiency virus Tat proteins specifically associate with TAK in vivo and require the carboxyl-terminal domain of RNA polymerase II for function.
Human immunodeficiency virus types 1 and 2 encode closely related proteins, Tat-1 and Tat-2, that stimulate viral transcription. Previously, we showed that the activation domains of these proteins specifically interact in vitro with a cellular protein kinase named TAK. In vitro, TAK phosphorylates the Tat-2 but not the Tat-1 protein, a 42-kDa polypeptide of unknown identity, and the carboxyl-terminal domain (CTD) of RNA polymerase II (RNAP II). We now show that the 42-kDa substrate of TAK cochromatographs with TAK activity, suggesting that this 42-kDa polypeptide is a subunit of TAK. We also show that the Tat proteins specifically associate with TAK in vivo, since wild-type Tat-1 and Tat-2 proteins expressed in mammalian cells, but not mutant Tat proteins containing a nonfunctional activation domain, can be coimmunoprecipitated with TAK. We also mapped the in vivo phosphorylation sites of Tat-2 to the carboxyl terminus of the protein, but analysis of proteins with mutations at these sites suggests that phosphorylation is not essential for Tat-2 transactivation function. We further investigated whether the CTD of RNAP II is required for Tat function in vivo. Using plasmid constructs that express an alpha-amanitin-resistant RNAP II subunit with a truncated or full-length CTD, we found that an intact CTD is required for Tat function. These observations strengthen the proposal that the mechanism of action of Tat involves the recruitment or activation of TAK, resulting in activated transcription through phosphorylation of the CTD.


Structural Modeling of the SARS-CoV-2 Spike/Human ACE2 Complex Interface can Identify High-Affinity Variants Associated with Increased Transmissibility.
The COVID-19 pandemic has triggered concerns about the emergence of more infectious and pathogenic viral strains. As a public health measure, efficient screening methods are needed to determine the functional effects of new sequence variants. Here we show that structural modeling of SARS-CoV-2 Spike protein binding to the human ACE2 receptor, the first step in host-cell entry, predicts many novel variant combinations with enhanced binding affinities. By focusing on natural variants at the Spike-hACE2 interface and assessing over 700 mutant complexes, our analysis reveals that high-affinity Spike mutations (including N440K, S443A, G476S, E484R, G502P) tend to cluster near known human ACE2 recognition sites (K31 and K353). These Spike regions are structurally flexible, allowing certain mutations to optimize interface interaction energies. Although most human ACE2 variants tend to weaken binding affinity, they can interact with Spike mutations to generate high-affinity double mutant complexes, suggesting variation in individual susceptibility to infection. Applying structural analysis to highly transmissible variants, we find that circulating point mutations S477N, E484K and N501Y form high-affinity complexes (~40% more than wild-type). By combining predicted affinities and available antibody escape data, we show that fast-spreading viral variants exploit combinatorial mutations possessing both enhanced affinity and antibody resistance, including S477N/E484K, E484K/N501Y and K417T/E484K/N501Y. Thus, three-dimensional modeling of the Spike/hACE2 complex predicts changes in structure and binding affinity that correlate with transmissibility and therefore can help inform future intervention strategies.


Teasing apart structural determinants of 'toxicity' and 'adjuvanticity': implications for meningococcal vaccine development.
The use of lipopolysaccharide (LPS) as an adjuvant is limited by its high endotoxic activity. In particular, the fatty-acyl pattern of the lipid A part of LPS has been demonstrated to determine its biological activity. By genetic modification of the lipid A biosynthesis pathway in Neisseria meningitidis, a panel of recombinant strains with specific alterations in the lipid A acylation pattern, as well as a strain completely lacking LPS were isolated. Whereas all variations in the fatty-acyl pattern resulted in reduced endotoxic activity, as measured by TNF-alpha induction in the human macrophage cell line MM6, the adjuvant activity of the modified LPS was, in most cases, barely affected. The in vivo adjuvant properties of N. meningitidis wild-type and mutant LPS was found to correlate with induction of co-stimulatory molecules, in particular CD80 and CD40, and with IL-12 production by LPS-stimulated bone marrow-derived BALB/c dendritic cells in vitro. Our results suggest that the ability of LPS to stimulate pro-inflammatory cytokine induction is not necessarily linked to its adjuvant activity. The availability of this novel set of lipid A variants with improved pharmacological properties will be of great importance for the improvement of future outer membrane vesicle vaccines against N. meningitidis.


Lipid-related genes and myocardial infarction in 4685 cases and 3460 controls: discrepancies between genotype, blood lipid concentrations, and coronary disease risk.
Blood lipid concentrations are causally related to the risk of coronary heart disease (CHD). Various associations between CHD risk and genes that moderately affect plasma lipid levels have been described, but previous studies have typically involved too few 'cases' to assess these associations reliably. The present study involves 4685 cases of myocardial infarction (MI) and 3460 unrelated controls without diagnosed cardiovascular disease. Six polymorphisms of four 'lipid-related' genes were genotyped. For the apolipoprotein E epsilon2/epsilon3/epsilon4 polymorphism, the average increase in the plasma ratio of apolipoprotein B to apolipoprotein A(1) (apoB/apoA(1) ratio) among controls was 0.082 (s.e. 0.007) per stepwise change from epsilon3/epsilon2 to epsilon3/epsilon3 to epsilon3/epsilon4 genotype (trend P < 0.0001). The case-control comparison yielded a risk ratio for MI of 1.16 (95% CI: 1.06, 1.27; P = 0.001) per stepwise change in these genotypes. But, this risk ratio was not as extreme as would have been expected from the corresponding differences in plasma apoB/apoA(1) ratio between genotypes. Hence, following adjustment for the measured level of the plasma apoB/apoA(1) ratio, the direction of the risk ratio per stepwise change reversed to 0.83 (95% CI: 0.74, 0.92; P < 0.001). Similarly, for the apolipoprotein B Asn4311Ser and Thr71Ile polymorphisms, genotypes associated with more adverse plasma apolipoprotein concentrations were associated with significantly lower risk of MI after adjustment for the apoB/apoA(1) ratio. The B2 allele of the cholesteryl ester transfer protein TaqIb polymorphism was associated with a significantly lower plasma apoB/apoA(1) ratio, but with no significant difference in the risk of MI. Finally, the lipoprotein lipase Asn291Ser and T4509C (PvuII) polymorphisms did not produce clear effects on either the plasma apoB/apoA(1) ratio or the risk of MI. It remains unresolved why some of these genetic factors that produce lifelong effects on plasma lipid concentrations have significantly less than the correspondingly expected effects on CHD rates in adult life.


Local compartment changes and regulatory landscape alterations in histone H1-depleted cells.
Linker histone H1 is a core chromatin component that binds to nucleosome core particles and the linker DNA between nucleosomes. It has been implicated in chromatin compaction and gene regulation and is anticipated to play a role in higher-order genome structure. Here we have used a combination of genome-wide approaches including DNA methylation, histone modification and DNase I hypersensitivity profiling as well as Hi-C to investigate the impact of reduced cellular levels of histone H1 in embryonic stem cells on chromatin folding and function. We find that depletion of histone H1 changes the epigenetic signature of thousands of potential regulatory sites across the genome. Many of them show cooperative loss or gain of multiple chromatin marks. Epigenetic alterations cluster to gene-dense topologically associating domains (TADs) that already showed a high density of corresponding chromatin features. Genome organization at the three-dimensional level is largely intact, but we find changes in the structural segmentation of chromosomes specifically for the epigenetically most modified TADs. Our data show that cells require normal histone H1 levels to expose their proper regulatory landscape. Reducing the levels of histone H1 results in massive epigenetic changes and altered topological organization particularly at the most active chromosomal domains. Changes in TAD configuration coincide with epigenetic landscape changes but not with transcriptional output changes, supporting the emerging concept that transcriptional control and nuclear positioning of TADs are not causally related but independently controlled by the locally associated trans-acting factors.


17beta-estradiol inhibits apoptosis of endothelial cells.
Endothelial cells provide an antithrombotic and anti-inflammatory barrier for the normal vessel wall. Dysfunction of endothelial cells has been shown to promote atherosclerosis, and normalization of previously dysfunctional endothelial cells can inhibit the genesis of atheroma. In normal arteries, endothelial cells are remarkably quiescent. Acceleration of the turnover rate of endothelial cells can lead to their dysfunction. Apoptosis is a physiological process that contributes to vessel homeostasis, by eliminating damaged cells from the vessel wall. However, increased endothelial cell turnover mediated through accelerated apoptosis may alter the function of the endothelium and therefore, promote atherosclerosis. Apoptotic endothelial cells can be detected on the luminal surface of atherosclerotic coronary vessels, but not in normal vessels. This finding links endothelial cell apoptosis and the process of atherosclerosis, although a causative role for apoptosis in this process remains hypothetical. Estrogen metabolites have been shown to be among the most potent anti-atherogenic agents available to date for post-menopausal women. The mechanism of estrogen's protective effect is currently incompletely characterized. Here we show that 17beta-estradiol, a key estrogen metabolite, inhibits apoptosis in cultured endothelial cells. Our data support the hypothesis that 17beta-estradiol's anti-apoptotic effect may be mediated via improved endothelial cell interaction with the substratum, increased tyrosine phosphorylation of pp125 focal adhesion kinase, and a subsequent reduction in programmed cell death of endothelial cells. Inhibition of apoptosis by estrogens may account for some of the anti-atherogenic properties of these compounds.


Does the Use of Mobile Phone Affect Male Fertility? A Mini-Review.
Presently, there is a rise in the use of mobile phones, laptops, and wireless internet technologies such as Wi-Fi and 5G routers/modems across the globe; these devices emit a considerable amount of electromagnetic radiation (EMR) which could interact with the male reproductive system either by thermal or nonthermal mechanisms. The aim of this review was to examine the effects of mobile phone use on male fertility. Related studies that reported on the effects of EMR from mobile phones on male fertility from 2003 to 2020 were evaluated. PubMed database was used. The Medical Subject Heading system was used to extract relevant research studies from PubMed. Based on the outcomes of both human and animal studies analyzed in this review, animal and human spermatozoa exposed to EMR emitted by mobile phones had reduced motility, structural anomalies, and increased oxidative stress due to overproduction of reactive oxygen species. Scrotal hyperthermia and increased oxidative stress might be the key mechanisms through which EMR affects male fertility. However, these negative effects appear to be associated with the duration of mobile phone use.


The role of vertebral body collapse in the management of malignant spinal cord compression.
The management of malignant spinal cord compression has been reviewed recently and attention drawn to the adverse effects of laminectomy. Data from that review suggested that the presence of vertebral body collapse could have an important negative effect on the outcome of laminectomy. However, there was only scant evidence available in the literature to support that conclusion. Eighty consecutive patients with thoracic spinal cord compression due to a single metastasis treated by laminectomy are reported here. It is seen that the presence of vertebral collapse signified: a much reduced chance of regaining the ability to walk; a much greater possibility of further neurological deterioration; and a major increase in the incidence of post-operative spinal instability. The role of laminectomy in the management of such patients needs to be further questioned and alternative therapeutic measures such as radiotherapy, posterior spinal instrumentation or anterior surgery should be strongly considered in the presence of vertebral body collapse.


Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis.
Hemophagocytic lymphohistiocytosis (HLH) is an inborn disorder of immune regulation caused by mutations affecting perforin-dependent cytotoxicity. Defects in this pathway impair negative feedback between cytotoxic lymphocytes and APCs, leading to prolonged and pathologic activation of T cells. Etoposide, a widely used chemotherapeutic drug that inhibits topoisomerase II, is the mainstay of treatment for HLH, although its therapeutic mechanism remains unknown. We used a murine model of HLH, involving lymphocytic choriomeningitis virus infection of perforin-deficient mice, to study the activity and mechanism of etoposide for treating HLH and found that it substantially alleviated all symptoms of murine HLH and allowed prolonged survival. This therapeutic effect was relatively unique among chemotherapeutic agents tested, suggesting distinctive effects on the immune response. We found that the therapeutic mechanism of etoposide in this model system involved potent deletion of activated T cells and efficient suppression of inflammatory cytokine production. This effect was remarkably selective; etoposide did not exert a direct anti-inflammatory effect on macrophages or dendritic cells, and it did not cause deletion of quiescent naive or memory T cells. Finally, etoposide's immunomodulatory effects were similar in wild-type and perforin-deficient animals. Thus, etoposide treats HLH by selectively eliminating pathologic, activated T cells and may have usefulness as a novel immune modulator in a broad array of immunopathologic disorders.


Long Tandem Arrays of Cassandra Retroelements and Their Role in Genome Dynamics in Plants.
Retrotransposable elements are widely distributed and diverse in eukaryotes. Their copy number increases through reverse-transcription-mediated propagation, while they can be lost through recombinational processes, generating genomic rearrangements. We previously identified extensive structurally uniform retrotransposon groups in which no member contains the gag, pol, or env internal domains. Because of the lack of protein-coding capacity, these groups are non-autonomous in replication, even if transcriptionally active. The Cassandra element belongs to the non-autonomous group called terminal-repeat retrotransposons in miniature (TRIM). It carries 5S RNA sequences with conserved RNA polymerase (pol) III promoters and terminators in its long terminal repeats (LTRs). Here, we identified multiple extended tandem arrays of Cassandra retrotransposons within different plant species, including ferns. At least 12 copies of repeated LTRs (as the tandem unit) and internal domain (as a spacer), giving a pattern that resembles the cellular 5S rRNA genes, were identified. A cytogenetic analysis revealed the specific chromosomal pattern of the Cassandra retrotransposon with prominent clustering at and around 5S rDNA loci. The secondary structure of the Cassandra retroelement RNA is predicted to form super-loops, in which the two LTRs are complementary to each other and can initiate local recombination, leading to the tandem arrays of Cassandra elements. The array structures are conserved for Cassandra retroelements of different species. We speculate that recombination events similar to those of 5S rRNA genes may explain the wide variation in Cassandra copy number. Likewise, the organization of 5S rRNA gene sequences is very variable in flowering plants; part of what is taken for 5S gene copy variation may be variation in Cassandra number. The role of the Cassandra 5S sequences remains to be established.


Secular trends in prevalence of overweight and obesity from 2006 to 2009 in urban asian Indian adolescents aged 14-17 years.
The present study examines the secular trends in prevalence of overweight and obesity among urban Asian Indian adolescents in New Delhi (North India). The data were derived from cross-sectional sampling of children, 3493 in year 2006 and 4908 in year 2009, aged 14-17 years studying in privately-funded and government-funded schools. Age, gender and Asian Indian-specific cut offs of body mass index (BMI) were used to define overweight and obesity. The prevalence of obesity increased significantly from 9.8% in 2006 to 11.7% in 2009 (p<0.01), whereas underweight decreased from 11.3% to 3.9% (p<0.001). There was a significantly higher risk of being overweight (OR 1.28; 95% CI, 1.15-1.42) and obese (OR 1.44; 95% CI, 1.24-1.66) in year 2009 than 2006, after adjusting for age, gender and type of school. Males and privately-funded school children had significantly higher increase in prevalence and risk of being overweight and obese over the three years. In conclusion, this study showed an increasing trend in prevalence of overweight and obesity in urban Asian Indian adolescents. More specifically, the study showed the association of this increasing trend of overweight and obesity prevalence with male gender and high socio-economic status, calling for an urgent need for immediate and targeted preventive measures.


Deficient guanine nucleotide regulatory unit activity in cultured fibroblast membranes from patients with pseudohypoparathyroidism type I. a cause of impaired synthesis of 3',5'-cyclic AMP by intact and broken cells.
Deficient activity of the guanine nucleotide regulatory protein (G unit), an integral component of the membrane-bound adenylate cyclase complex, has been implicated as the biochemical lesion in many patients with pseudohypoparathyroidism (PHP) type I. In addition to renal resistance to parathyroid hormone in this disorder, there is decreased responsiveness of diverse tissues to hormones that act via 3',5'-cyclic AMP (cAMP). To assess whether a deficiency of G units could account for impaired adenylate cyclase activity, we studied cAMP production in intact cultured fibroblasts and fibroblast plasma membranes from five patients with PHP in response to several activators of adenylate cyclase. The number of G units in PHP fibroblast membranes, measured by cholera toxin-dependent [(32)P]ADP ribosylation of G-unit peptides, as well as the G-unit activity, determined by the ability of detergent extracts to reconstitute adenylate cyclase activity in G-unit-deficient S49 CYC(-) membranes, were found to be markedly reduced compared with control membranes (43 and 40%, respectively), The activation of fibroblast membrane adenylate cyclase by effectors that act directly through the G unit (guanosine triphosphate, guanosine 5'-0-[3-thiotriphosphate] [GTP-gamma-S], NaF) was significantly greater in control membranes than in membranes from patients with PHP. Moreover, we found that hormone (prostaglandin E(1)) stimulated adenylate cyclase activity was also greater in control membranes than in PHP membranes. Neither the apparent affinity of membrane adenylate cyclase for GTP-gamma-S (apparent K(m) =5 X 10(-8) M) nor the rate of enzyme activation by GTP-gamma-S was significantly different in fibroblast membranes from control subjects and patients with PHP. In contrast to the notable differences in hormone and G-unit-activated adenylate cyclase shown in fibroblast membranes from PHP patients and control subjects, the intrinsic catalytic activity of membranes, as determined by forskolin-stimulated adenylate cyclase, was not significantly different in the two groups. Intact fibroblasts derived from patients with PHP accumulated significantly (P 0.001) less cAMP (46+/-21 pmol cAMP/mcg DNA, n = 5) than cells from normal individuals (170+/-51 pmol cAMP/mcg DNA, n = 11) when stimulated with PGE(1). PGE(1)-stimulated accumulation of cAMP by intact fibroblast monolayers correlated closely with PGE(1) plus GTP-activated membrane adenylate cyclase activity in both patients and controls (r = 0.97, P < 0.001). Our data show that, in patients with PHP, (a) fibroblast membranes show a decreased complement of G units, (b) membrane catalytic activity is normal, but adenylate cyclase activity is reduced when stimulated by hormone or by effectors which activate the G unit, (c) the ability of cells to accumulate cAMP in response to hormone stimulation is reduced, and (d) reduced membrane adenylate cyclase activity correlates well with impaired cellular cAMP synthesis. These results, taken together, indicate that a deficiency of G-unit activity can impair synthesis of cAMP by both intact and broken cells, and may explain the resistance of multiple tissues to hormones that act via cAMP observed in PHP.


Vitamin D and ageing: neurological issues.
Vitamin D has been shown to have multiple biological targets mediated by the vitamin D receptor present in many cells. Specific actions on the central nervous system (CNS) have been described. The objective of this review was to describe the relationship between vitamin D and the nervous system throughout the different stages of life. A bibliographical search was performed in the MedLine and Cochrane library databases. The keywords used were: 'vitamin D' and 'nervous system' and/or 'central nervous system' and/or 'nervous system diseases' and/or 'psychological tests' and/or 'neuropsychological tests' and/or 'mental disorders'. The search period ranged from 01/01/1988 to 31/10/2009. Two hundred and ninety-five abstracts were first identified after screening. A final selection of 127 articles was used for the purpose of this review. The studies published over the past 20 years provide an increasing number of arguments in favor of a life-long role of vitamin D on the nervous system as a whole, and in particular on the CNS. During cerebral development, vitamin D may act like a neurosteroid hormone in the areas of neurotransmission, neuroprotection, and neuroimmunomodulation. Moreover, vitamin D deficiency has been associated with neurological and psychiatric disorders. In older adults, hypovitaminosis D has been associated with neuromuscular disorders, dementia, and Parkinson's disease. Thus, vitamin D supplementation might have a protective effect against these neurological disorders. Vitamin D has been associated with many neurological functions and its deficiency with dysfunction. Low serum 25-hydroxyvitamin D concentrations can potentially be reversed. This simple and low-cost correction might contribute to the primo-secondary prevention of various neuropsychiatric disorders.


A set probability technique for detecting relative time order across multiple neurons.
With the development of multielectrode recording techniques, it is possible to measure the cell firing patterns of multiple neurons simultaneously, generating a large quantity of data. Identification of the firing patterns within these large groups of cells is an important and a challenging problem in data analysis. Here, we consider the problem of measuring the significance of a repeat in the cell firing sequence across arbitrary numbers of cells. In particular, we consider the question, given a ranked order of cells numbered 1 to N, what is the probability that another sequence of length n contains j consecutive increasing elements? Assuming each element of the sequence is drawn with replacement from the numbers 1 through N, we derive a recursive formula for the probability of the sequence of length j or more. For n<2j, a closed-form solution is derived. For n>or=2j, we obtain upper and lower bounds for these probabilities for various combinations of parameter values. These can be computed very quickly. For a typical case with small N (<10) and large n (<3000), sequences of 7 and 8 are statistically very unlikely. A potential application of this technique is in the detection of repeats in hippocampal place cell order during sleep. Unlike most previous articles on increasing runs in random lists, we use a probability approach based on sets of overlapping sequences.


Allopurinol initiation and all-cause mortality in the general population.
Allopurinol is the most commonly used urate-lowering therapy, with rare but potentially fatal adverse effects. However, its impact on overall mortality remains largely unknown. In this study, we evaluated the impact of allopurinol initiation on the risk of mortality among individuals with hyperuricaemia and among those with gout in the general population. We conducted an incident user cohort study with propensity score matching using a UK general population database. The study population included individuals aged ≥40 years who had a record of hyperuricaemia (serum urate level >357 μmol/L for women and >416 μmol/L for men) between January 2000 and May 2010. To closely account for potential confounders of allopurinol use and risk of death, we constructed propensity score matched cohorts of allopurinol initiators and comparators (non-initiators) within 6-month cohort accrual blocks. Of 5927 allopurinol initiators and 5927 matched comparators, 654 and 718, respectively, died during the follow-up (mean=2.9 years). The baseline characteristics were well balanced in the two groups, including the prevalence of gout in each group (84%). Allopurinol initiation was associated with a lower risk of all-cause mortality (matched HR 0.89 (95% CI 0.80 to 0.99)). When we limited the analysis to those with gout, the corresponding HR was 0.81 (95% CI 0.70 to 0.92). In this general population study, allopurinol initiation was associated with a modestly reduced risk of death in patients with hyperuricaemia and patients with gout. The overall benefit of allopurinol on survival may outweigh the impact of rare serious adverse effects.


Validation of electronic health record phenotyping of bipolar disorder cases and controls.
The study was designed to validate use of electronic health records (EHRs) for diagnosing bipolar disorder and classifying control subjects. EHR data were obtained from a health care system of more than 4.6 million patients spanning more than 20 years. Experienced clinicians reviewed charts to identify text features and coded data consistent or inconsistent with a diagnosis of bipolar disorder. Natural language processing was used to train a diagnostic algorithm with 95% specificity for classifying bipolar disorder. Filtered coded data were used to derive three additional classification rules for case subjects and one for control subjects. The positive predictive value (PPV) of EHR-based bipolar disorder and subphenotype diagnoses was calculated against diagnoses from direct semistructured interviews of 190 patients by trained clinicians blind to EHR diagnosis. The PPV of bipolar disorder defined by natural language processing was 0.85. Coded classification based on strict filtering achieved a value of 0.79, but classifications based on less stringent criteria performed less well. No EHR-classified control subject received a diagnosis of bipolar disorder on the basis of direct interview (PPV=1.0). For most subphenotypes, values exceeded 0.80. The EHR-based classifications were used to accrue 4,500 bipolar disorder cases and 5,000 controls for genetic analyses. Semiautomated mining of EHRs can be used to ascertain bipolar disorder patients and control subjects with high specificity and predictive value compared with diagnostic interviews. EHRs provide a powerful resource for high-throughput phenotyping for genetic and clinical research.


Connectivity-based parcellation increases network detection sensitivity in resting state fMRI: An investigation into the cingulate cortex in autism.
Although resting state fMRI (RS-fMRI) is increasingly used to generate biomarkers of psychiatric illnesses, analytical choices such as seed size and placement can lead to variable findings. Seed placement especially impacts on RS-fMRI studies of Autism Spectrum Disorder (ASD), because individuals with ASD are known to possess more variable network topographies. Here, we present a novel pipeline for analysing RS-fMRI in ASD using the cingulate cortex as an exemplar anatomical region of interest. Rather than using seeds based on previous literature, or gross morphology, we used a combination of structural information, task-independent (RS-fMRI) and task-dependent functional connectivity (Meta-Analytic Connectivity Modeling) to partition the cingulate cortex into six subregions with unique connectivity fingerprints and diverse behavioural profiles. This parcellation was consistent between groups and highly replicable across individuals (up to 93% detection) suggesting that the organisation of cortico-cingulo connections is highly similar between groups. However, our results showed an age-related increase in connectivity between the anterior middle cingulate cortex and right lateral prefrontal cortex in ASD, whilst this connectivity decreased in controls. There was also a Group × Grey Matter (GM) interaction, showing increased connectivity between the anterior cingulate cortex and the rectal gyrus in concert with increasing rectal gyrus GM in controls. By comparing our approach to previously established methods we revealed that our approach improves network detection in both groups, and that the ability to detect group differences using 4 mm radius spheres varies greatly with seed placement. Using our multi-modal approach we find disrupted cortico-cingulo circuits that, based on task-dependent information, may contribute to ASD deficits in attention and social interaction. Moreover, we highlight how more sensitive approaches to RS-fMRI are crucial for establishing robust and reproducible connectivity-based biomarkers in psychiatric disorders.


Towards the optimization of the preparation procedures of PMMA bone cement.
The mechanical properties and thermal history of polymethyl-methacrylate bone cement vary significantly with the preparation procedure used. Because the polymerization reaction is exothermic, many researchers have attempted to minimize thermal osteonecrosis due to heat generation by altering procedures in the preparation of the cement. In most previous studies, only one or two aspects of the preparation procedure were controlled, and there has been little research that comprehensively examines the effects of preparation on the cure kinetics and resulting properties of bone cement. In this study, cement viscosity, cement layer thickness, initial cement temperature, initial metal component temperature, and mixing method were varied to assess the effects on the cement. Maximum temperature, polymerization time, necrosis index, bending strength, and porosity were chosen to evaluate the different preparation procedures, where an optimal procedure would minimize necrosis, reduce cement cure time, and maximize bending strength. Design of Experiments (DOE) was used to examine the main effects and interactions of preparation techniques. Among the most prominent results, it was found that the cure kinetics and the related quantities are primarily controlled by the initial metal component temperature and that the bending strength is most dependent on the mixing method. For the two formulations studied, the optimum preparation procedures should keep cement and metal components at room temperature prior to mixing with a vacuum mixing system. Reducing cement mantle thickness may also be advantageous, as it reduces the maximum temperature and the risk of tissue damage. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:915-923, 2016.