An account of American Academy of Microbiology reforms and pandemic operations.
Change is an inevitable part of any organization if it wants to adapt and strive in a changing environment. That was what the American Academy of Microbiology (Academy) did from 2019-2023 when it transformed itself into a scientific think tank at ASM while maintaining the high standard of an honorific community of scholars. Here, we report on the recent history of the Academy and the changes that have taken place during this period. With the contribution of many thougtful leaders, the Academy refreshed its commitment to promote excellence and uphold its high values.


The gene expression and immunohistochemical time-course of diphenylcyclopropenone-induced contact allergy in healthy humans following repeated epicutaneous challenges.
The gene expression time-course of repeated challenge of contact allergy (CA) remains largely unknown. Therefore, using diphenylcyclopropenone (DPCP) as model allergen in healthy humans we set out to examine: (i) the monotonous and complex gene expression time-course trajectories following repeated DPCP challenges to find the predominant gene expression pattern, (ii) the time-course of cell infiltration following repeated DPCP challenges and (iii) the transcriptome of a repeated CA exposure model. We obtained punch biopsies from control and DPCP-exposed skin from ten DPCP sensitized individuals at 5-6 monthly elicitation challenges. Biopsies were used for microarray gene expression profiling, histopathology and immunohistochemical staining. Validation of microarray data by qRT-PCR was performed on 15 selected genes. Early gene expression time points were also validated in an independent data set. An increasing and decreasing trend in gene expression followed by a plateau was predominantly observed during repeated DPCP challenges. Immune responses reached a plateau after two challenges histopathologically, immunohistochemically and in the time-course gene expression analysis. Transcriptional responses over time revealed a Th1/Th17 polarization as three upstream regulators (IFN-γ, IL-1 and IL-17) activated most of the top upregulated genes. Of the latter genes, 9 of 10 were the same throughout the time course. Excellent correlations between array and PCR data were observed. The transcriptional responses to DPCP over time followed a monotonous pattern. This response pattern confirms and supports the newly reported clinical time-course observations in de novo-sensitized individuals showing a plateau response, and thus, there is concordance between clinical response, histopathology, immunohistochemistry and microarray gene expression in volunteers de novo-sensitized to DPCP.


The pharmacologic profile of desloratadine: a review.
Desloratadine is a new agent for the treatment of diseases such as seasonal allergic rhinitis and chronic urticaria. The pharmacologic profile of desloratadine offers particular benefits in terms of histamine H1-receptor binding potency and H1 selectivity. Desloratadine has a half-life of 21-24 h, permitting once-daily dosing. No specific cautions are required with respect to administration in renal or hepatic failure, and food or grapefruit juice have no effect on the pharmacologic parameters. No clinically relevant racial or sex variations in the disposition of desloratadine have been noted. In combination with the cytochrome P450 inhibitors, ketoconazole and erythromycin, the AUC and Cmax of desloratadine were increased to a small extent, but no clinically relevant drug accumulation occurred. With high-dose treatment (45 mg/day for 10 days), no significant adverse events were observed, despite the sustained elevation of plasma desloratadine levels. Specifically, desloratadine had no effects on the corrected QT interval (QTc) when administered alone, at high dose, or in combination with ketoconazole or erythromycin. Preclinical studies also show that desloratadine does not interfere with HERG channels or cardiac conduction parameters even at high dose. Desloratadine is nonsedating and free of antimuscarinic/anticholinergic effects in preclinical and clinical studies. Novel antiallergic and anti-inflammatory effects have also been noted with desloratadine, a fact which may be relevant to its clinical efficacy.


Development of the embryonic heat shock response and the impact of repeated thermal stress in early stage lake whitefish (Coregonus clupeaformis) embryos.
Lake whitefish (Coregonus clupeaformis) embryos were exposed to thermal stress (TS) at different developmental stages to determine when the heat shock response (HSR) can be initiated and if it is altered by exposure to repeated TS. First, embryos were subject to one of three different TS temperatures (6, 9, or 12°C above control) at 4 points in development (21, 38, 60 and 70 days post-fertilisation (dpf)) for 2h followed by a 2h recovery to understand the ontogeny of the HSR. A second experiment explored the effects of repeated TS on the HSR in embryos from 15 to 75 dpf. Embryos were subjected to one of two TS regimes; +6°C TS for 1h every 6 days or +9°C TS for 1h every 6 days. Following a 2h recovery, a subset of embryos was sampled. Our results show that embryos could initiate a HSR via upregulation of heat shock protein 70 (hsp70) mRNA at all developmental ages studied, but that this response varied with age and was only observed with a TS of +9 or +12°C. In comparison, when embryos received multiple TS treatments, hsp70 was not induced in response to the 1h TS and 2h recovery, and a downregulation was observed at 39 dpf. Downregulation of hsp47 and hsp90α mRNA was also observed in early age embryos. Collectively, these data suggest that embryos are capable of initiating a HSR at early age and throughout embryogenesis, but that repeated TS can alter the HSR, and may result in either reduced responsiveness or a downregulation of inducible hsps. Our findings warrant further investigation into both the short- and long-term effects of repeated TS on lake whitefish development.


Pyramided QTL underlying tolerance to Phytophthora root rot in mega-environments from soybean cultivars 'Conrad' and 'Hefeng 25'.
Phytophthora root rot (PRR) of soybean (Glycine max (L.) Merr.) is the second most important cause of yield loss by disease in North America, surpassed only by soybean cyst nematode (Wrather et al. in Can J Plant Pathol 23:115-121, 2001). Tolerance can provide economically useful disease control, conditioning partial resistance of soybean to PRR. The aims of this study were to identify new quantitative trait loci (QTL) underlying tolerance to PRR, and to evaluate the effects of pyramided or stacked loci on the level of tolerance. A North American cultivar 'Conrad' (tolerant to PRR) was crossed with a northeastern China cultivar 'Hefeng 25' (tolerant to PRR). Through single-seed descent, 140 F2:5 and F2:6 recombinant inbred lines were advanced. A total of 164 simple sequence repeat (SSR) markers were used to construct a genetic linkage map. The percentage of seedling death was measured over 2 years (2007 and 2008) in the field at four naturally infested locations in Canada and China following additional soil infestation and in the greenhouse following inoculation with Phytophthora sojae isolate. A total of eight QTL underlying tolerance to PRR were identified, located in five linkage groups (F, D1b+w, A2, B1, and C2). The phenotypic variation contributed by the loci ranged from 4.24 to 27.98%. QPRR-1 (anchored in the interval of SSR markers Satt325 and Satt343 of LG F), QPRR-2 (anchored in the interval of Satt005 and Satt600 of LG D1b+w), and QPRR-3 (anchored in the interval of Satt579 and Sat_089 of LG D1b+w) derived their beneficial allele from 'Conrad'. They were located at chromosomal locations known to underlie PRR tolerance in diverse germplasm. Five QTL that derived beneficial alleles from 'Hefeng 25' were identified. The QTL (QPRR-1 to QPRR-7) that were detected across at least three environments were selected for loci stacking and to analyze the relationship between number of tolerance loci and disease loss percentage. The accumulation of tolerance loci was positively correlated with decreases in disease loss percentage. The pyramid of loci underlying tolerance to PRR provided germplasm useful for crop improvement by marker-assisted selection and may provide durable cultivar tolerance against the PRR disease.


Web-based continuing medical education (I): field test of a hybrid computer-mediated instructional delivery system.
The Internet and the World Wide Web (the Web) present exciting new possibilities for distributing educational materials at a distance and facilitating collaborative learning among geographically isolated physicians. This article provides a brief overview of the Web as an instructional delivery platform and discusses its strengths and weaknesses as a potential medium for enhancing distance learning opportunities for rural and remote physicians. It also describes an innovative hybrid instructional delivery model that was field tested by the Telemedicine Centre to determine its efficiency and effectiveness for providing Web-based instruction. A hybrid model merges the Web and CD-ROMs (compact disk read-only memory) to use several of the more valuable instructional components of Web-based education (i.e., multimedia, interactive forms, hypermedia, and computer-mediated communications). The results of the field test indicate that the hybrid delivery model was an efficient means for delivering computer-mediated continuing medical education instruction on dermatologic office procedures to a group of rural physicians in low telecommunication bandwidth regions.


Short-term results of the management of severe bone defects in primary TKA with cement and K-wires.
The aim of this study was to evaluate the results of cement and kirschner wire augmentation in the management of bone defects in primary TKA. Twenty-four patients (10 male, 14 female; mean age: 66 years) with uncontained unilateral medial tibial articular bone defect who underwent TKA between 2010 and 2014 were included in this study. The average follow up time was 33.7 months. Patients were divided to two groups according to the size of the bone defect (Group 1: <20 mm, Group 2: >20 mm). The tibial defect was reconstructed by using cement and K-wires. We used posterior stabilized prosthesis with no tibial stem extension. The preoperative and postoperative lower extremity mechanical axis in Group I was in a mean varus of 15° and mean varus of 3°, respectively (p < 0.001). The preoperative and postoperative lower extremity mechanical axis in Group 2 was in a mean varus of 20° and mean varus of 3° respectively in Group II (p < 0.001). None of the patients neither suffered from failure of K-wires nor loosening. The use of cement and K-wires augmentation appears to be a simple and cost-effective treatment option for the tibial bone defects in primary TKA. Level IV, Therapeutic study.


Primary care physicians and AIDS. Attitudinal and structural barriers to care.
To explore the extent to which primary care physicians are providing health care for people with human immunodeficiency virus (HIV) infection and to document barriers to HIV care giving. National random-sample mailed survey. Population-based random sample of 2004 US general internists, family physicians, and general practitioners in 1990. Response rate was 59%. HIV treatment experience, willingness to treat HIV-infected patients, negative attitudes toward homosexuals and intravenous drug users, fear of contagion of the acquired immunodeficiency syndrome (AIDS), perceived lack of information about AIDS, and time demands of HIV care. Most physicians (75%) had treated one or more patients with HIV infection. A majority (68%) believed that they had a responsibility to treat people with HIV infection, yet half (50%) indicated that they would not, if given a choice. Over 80% of respondents believed that they lacked information about AIDS and that caring for people with AIDS is time consuming. Further, 35% of respondents agreed that they "would feel nervous among a group of homosexuals" and 55% expressed discomfort about having intravenous drug users in their practice. Physicians who had treated 10 or more HIV-infected patients expressed less negativity toward members of these stigmatized groups who are likely to be HIV infected. These data suggest that many primary care physicians are responding professionally to the AIDS epidemic but that attitudinal barriers may be hindering some physicians from providing treatment to HIV-infected patients.


Postoperative complications and surgical outcomes of robotic versus conventional nipple-sparing mastectomy in breast cancer: meta-analysis.
Breast cancer is the most common cancer worldwide, with remarkable advances in early diagnosis, systemic treatments, and surgical techniques. Robotic nipple-sparing mastectomy has been trialled; however, the complication rates, surgical outcomes, and oncological safety of this approach remain obscure. A systematic search of the literature was conducted from conception until September 2022. Studies examining complications and operative variables where robotic nipple-sparing mastectomy was compared with conventional nipple-sparing mastectomy were included. Primary study outcomes were complications (Clavien-Dindo grade III complications, skin or nipple necrosis, seroma, haematoma, infection, implant loss, and wound dehiscence) and oncological safety (recurrence and positive margins). The secondary outcomes included operative variables, length of stay, cost-effectiveness, learning curve, and aesthetic outcome. A total of seven studies of overall fair quality, involving 1674 patients, were included in the systematic review and meta-analysis. Grade 3 complications were reduced in robotic nipple-sparing mastectomy without statistical significance (OR 0.60 (95 per cent c.i. 0.35 to 1.05)). Nipple necrosis was significantly reduced in robotic nipple-sparing mastectomy (OR 0.54 (95 per cent c.i. 0.30 to 0.96); P = 0.03; I2 = 15 per cent). Operating time (mean difference +58.81 min (95 per cent c.i. +28.19 to +89.44 min); P = 0.0002) and length of stay (mean difference +1.23 days (95 per cent c.i. +0.64 to +1.81 days); P < 0.0001) were significantly increased in robotic nipple-sparing mastectomy, whereas the opposite was true for blood loss (mean difference -53.18 ml (95 per cent c.i. -71.78 to -34.58 ml); P < 0.0001). Whilst still in its infancy, robotic breast surgery may become a viable option in breast surgery. Nonetheless, the oncological safety of this approach requires robust assessment.


Retrograde seeding of malignant cells during hysteroscopy in presumed early endometrial cancer.
The aim of this study was to determine the effect that preoperative hysteroscopy has on the frequency of positive cytology at the time of definitive surgical management in endometrial cancer. Charts of 222 patients with endometrial cancer were reviewed. Patients were divided according to whether (n = 64) or not (n = 158) they had hysteroscopy with saline infusion. Each group was stratified into low or high risk for positive peritoneal cytology. Logistic regression analysis was used to compare the prevalence of positive peritoneal cytology with and without hysteroscopy, before and after the stratification, adjusting for the confounding risk factors. After adjusting for confounding variables there was a statistical difference in the frequency of positive peritoneal cytology in those who had hysteroscopy versus those who did not (odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.02-6.63, P = 0.05). Even after stratifying patients into a low-risk group (OR = 2.12, 95% CI = 0.13-35.9, P = 0.6) and a high-risk group (OR = 3.46, 95% CI = 1.3-9.12, P = 0.01) the difference in the high-risk group was statistically significant. Hysteroscopy seems to affect the prevalence of positive peritoneal cytology, especially in those patients with high-risk cell types. Its use in patients with suspicion of endometrial cancer should be reconsidered.


Nicotinic 123I-5IA-85380 single photon emission computed tomography as a predictor of cognitive progression in Alzheimer's disease and dementia with Lewy bodies.
To investigate normalized I-5-Iodo-3-[2(S)-2-azetidinylmethoxy] pyridine (5IA-85380) single photon emission computed tomography (SPECT) imaging, a marker for the alpha4beta2 nicotinic receptor, as a predictor of cognitive progression in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Thirty-one patients with dementia (16 patients with AD and 15 patients with DLB) underwent I-5IA-85380 SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM2), which involved spatial preprocessing of scans to standard Montreal Neurological Institute space and intensity normalization of each image to its mean global brain activity. Regression analysis revealed that reduced normalized I-5IA-85380 uptake in left superior, middle, and inferior frontal gyri and prepost central and anterior cingulate regions significantly correlated with decline in executive function in a pooled group comprising AD and DLB. The findings, although preliminary, suggest that the cholinergic system may be more involved in neurodegenerative processes affecting some cognitive processes more than others, as such, this procedure may be useful for increased understanding of the pathophysiological mechanisms responsible for neurodegeneration.


Evidence of impaired longitudinal strain in pre-Fontan palliation in functional single left ventricle.
We evaluated two-dimensional speckle-tracking echocardiography longitudinal strain (L2DSE) in functionally single left ventricles (LV). We retrospectively analyzed 21 patients with functionally single LV. We divided patients into two groups according to pre-Fontan cardiac catheterization data: group 1, adequate data for Fontan procedure and group 2, inadequate data. LV strain correlated with predicted pressure in the Fontan system (r = 0.64; P = 0.003), pressure in the Glenn system (r = 0.57; P = 0.010), and transpulmonary gradient (r = 0.59; P = 0.008), but not with left atrial pressure (r = 0.292; P = 0.226) or ejection fraction (r = 0.254; P = 0.294). In multiple regression analysis, four-chamber LV strain was correlated with predicted pressure in the Fontan (β = 0.642: P = 0.003), whereas no association was found with LV ejection fraction (β = 0.254; P = 0.294), or time from Glenn palliation (β = 0.082; P = 0.893). When dividing the population into two groups according to catheterization data, significantly lower four-chamber longitudinal 2DSE (-25.8 ± 3.2 vs.-19.5 ± 5.1; P = 0.004) was found to be not suitable for the Fontan procedure, as compared with those who underwent successful Fontan completion. Regardless of ejection fraction, four-chamber L2DSE is associated with high predicted pressure in the Fontan system. Patients with hemodynamic data unsuitable for Fontan operation have significantly lower mean longitudinal strain parameters. 2DSE may represent a valuable tool in assessing patients with single LV physiology and might provide useful pre-Fontan information.


Medical Reasons for Marijuana Use, Forms of Use, and Patient Perception of Physician Attitudes Among the US Population.
The use of marijuana for medical purposes is increasing in parallel with expanding legalization and decreased public perception of harm. Despite this increase in use, it is unclear which medical conditions patients are attempting to treat with marijuana and whether they are communicating with medical providers about their use. To understand the medical reasons for marijuana use, forms of marijuana used for medical purposes, and disclosure of use to physicians. National, probability-based online survey. The USA, 2017. 16,280 US adults. Proportion of US adults who agreed with a statement. A total of 9003 participants completed the survey (55% response rate). Five hundred ninety-one (7% of US adults) reported using marijuana for medical purposes. The most common medical reasons for marijuana use were anxiety (49%), insomnia (47%), chronic pain (42%), and depression (39%). The most common forms of use for all medical conditions were smoking and edibles, followed by vaping, concentrate, and topical. We found women were more likely to use marijuana for posttraumatic stress disorder, sleep, anxiety, and migraines. We did not find substantial variation in medical reasons for marijuana use by race. Among those using marijuana for medical purposes, 21% did not have a doctor. Among those with doctors, 33% did not inform them, 28% reported their doctor was neutral on their use, 32% reported their doctor was supportive, and 8% reported their doctor was not supportive. Those who lived in states where medical marijuana was illegal were less likely to disclose use to their doctor. The online format of the survey may have caused selection bias. Wording of the questions may have affected interpretation. Doctors were not queried directly, rather participants were asked about their perception of doctor attitudes. Americans are using marijuana to treat medical conditions despite lack of evidence of efficacy.


Fatigue is a systemic extraintestinal disease manifestation largely independent of disease activity, chronicity, and nutritional deficiencies in inflammatory bowel disease on biologics.
Fatigue is a common symptom reported by patients with chronic immunoinflammatory diseases and with profound negative implications on health-related quality of life. This study aimed to delineate underlying components contributing to fatigue in patients with inflammatory bowel disease (IBD) receiving biologic therapy. Cross-sectional questionnaire study of all patients with IBD receiving any biologic therapy at a tertiary IBD center. Fatigue was assessed by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F). Disease activity and quality of life were evaluated by generic questionnaires. Principal component analysis (PCA) was used to identify components of variables explaining fatigue. Three hundred patients with IBD were included. Moderate-to-severe fatigue defined as FACIT-F ≤ 39 was present in half of the included patients. PCA condensed variables associated with fatigue into three main components contributing to 49% of observed fatigue. The first component, explaining 21% of fatigue, included factors related to disease chronicity, e.g., long disease duration, high number of previously used biologic therapies, presence of previous intestinal surgery, and increasing age. The second component explained 14% of fatigue and comprised disease activity-related aspects, e.g., disease activity indices and C-reactive protein. The third explained 14% of fatigue and comprised various nutritional deficiencies. Fatigue can partly be explained by chronicity, disease activity, and nutritional deficits. However, the cause of fatigue is unexplained in approximately half of the patients with IBD supporting that fatigue can be an independent, systemic extraintestinal disease manifestation in IBD.


Evaluation of eight commercial Zika virus IgM and IgG serology assays for diagnostics and research.
Several commercial Zika virus (ZIKV) serology assays have been developed since the recognition of ZIKV outbreaks as a Public Health Emergency of International Concern in 2016. However, test interpretation for ZIKV serology can be challenging due to antibody cross-reactivity with other flaviviruses like dengue virus (DENV). Therefore, we sought to evaluate the performance of eight commercially available ZIKV IgM and IgG assays across three testing platforms, namely, immunochromatographic tests (ICT), ELISAs and immunofluorescence tests (IIFT). The test panel comprised of 278 samples, including acute and convalescent sera or plasma from ZIKV-confirmed, DENV-confirmed, non-ZIKV and non-DENV patients, and residual sera from healthy blood donors. The ZIKV IgM and IgG serology assays yielded higher test sensitivities of 23.5% - 97.1% among ZIKV convalescent samples as compared to 5.6% - 27.8% among ZIKV acute samples; the test specificities were 63.3% - 100% among acute and convalescent DENV, non-DENV samples. Among the ELISAs and IIFTs, the Diapro ZIKV IgM ELISA demonstrated high test sensitivity (96%) and specificity (80%) when tested on early convalescent samples, while the Euroimmun ZIKV IgG ELISA yielded the highest test specificity of 97% - 100% on samples from non-ZIKV patients and healthy blood donors. For rapid ICTs, the LumiQuick IgM rapid ICT yielded low test sensitivity, suggesting its limited utility. We showed that commercial ZIKV IgM and IgG serology assays have differing test performances, with some having moderate to high test sensitivities and specificities when used in a dengue endemic setting, although there were limitations in IgG serology.


[Characteristics of the action of the influenza virus on the microcirculatory vessels in an experiment].
The dynamic light-optic and electron microscopic examination of the organs of experimental animals with the influenza infection have revealed the most pronounced pathology in vessels of the lung and brain microcirculation. The early developing perivascular edema around capillaries which is induced by an increase in the transcellular transport without a disturbance of the dense contact integrity is observed in the brain tissue. Variations in the lung microvessels manifested in a rise of the pinocytosis activity of endothelial cells, in a change of the luminal surface profile and damage of the supermembrane layer. A reversible aggregation of plate and erythrocytes was observed in the lung and brain microvessel lumen at early periods. The revealed changes, including the main of them--microvessel permeability disturbance, are associated with the dynamics of the concentration of the influenza virus and its complexes with antibodies in the organs under study.


Aldose reductase structures: implications for mechanism and inhibition.
During chronic hyperglycaemia, elevated vascular glucose level causes increased flux through the polyol pathway, which induces functional and morphological changes associated with secondary diabetic complications. Inhibitors of aldose reductase (ARIs) have been widely investigated as potential therapeutic agents, but to date only epalrestat is successfully marketed for treatment of diabetic neuropathy, in Japan. Promising compounds during in vitro studies or in trials with animal models have failed to proceed beyond clinical trials and to everyday use, due to a lack of efficacy or adverse side effects attributed to lack of inhibitor specificity and likely inhibition of the related aldehyde reductase (ALR1). Knowledge of the catalytic mechanism and structures of the current inhibitors complexed with ALR2 are means by which more specific and tightly bound inhibitors can be discovered. This review will provide an overview of the proposed catalytic mechanism and the current state of structure-based drug design.


Information: the ultimate frontier.
Although long-term forecasting is best left to science fiction writers, scientists can illumine basic technological trends, as in the 100-year scenario presented here. Computers will continue the "small is beautiful" trend, but they are not likely to follow the semilog trail because extrapolation from the current base would lead to absurdities such as a computer cost of 3/100 of a cent. To achieve inexpensive high speed and Lilliputian size, new techniques are likely to replace silicon technology. The ultimate computer might be biological and patterned on DNA. Future computers will reacquire information when needed rather than store it, and we will see personalized products at mass production prices. Light wave communication will broaden communications exchange, but software that is more friendly to human users will be needed. By taking over knowledge distribution, electronic information systems will let universities concentrate on new knowledge. More importantly, they will expand everyone's right to information and free expression through the existing media system and to protection from misuse of information by others.


Robotic assisted radical prostatectomy in morbidly obese patients: how to create a cost-effective adequate optical trocar.
Obesity is a major health issue in modern society, and with the progressive widespread employment of robotic assisted radical prostatectomy (RALP), the urologist-robotic surgeon is increasingly involved in the treatment of obese patients. However, the vast majority of urological departments are not equipped with a complete set of bariatric instruments. One of the potential difficulties of robotic surgery on the morbidly obese patient is the relatively short length of the optical trocar sheath, as the optical robotic arm requires some very valuable centimeters of the sheath to hang onto. This condition may make it impossible to properly reach the peritoneal cavity with the optical trocar during the RALP procedure. We present a series of four morbidly obese patients (BMI ranging from 42.1 to 46.2) with localized prostate cancer treated with RALP. We have developed an effective and "easy-to-implement" solution to the problem of properly elongating the sheath of the optical trocar which involves the use of the plastic cylindrical transparent protective tube of a disposable 26-Ch Amplatz sheath. The Amplatz sheath, with an internal diameter of 13 mm and length of 25 cm, perfectly fits outside of the 13-mm trocar usually employed for the optical trocar. Additionally, the cylindrical tube perfectly fits and hangs onto the robotic optical arm system. Mean operative time was 202.5 min (range 185-220 min). Mean blood loss was 284 mL (range 185-380 mL). Catheterization time and hospital stay were 5 and 6 days, respectively, in all patients. All procedures were safely completed, and no minor or major complications were reported. The optical trocar lengthening technique allowed us to properly perform RALP procedures even in severely morbidly obese patients in an urological setting not equipped for bariatric minimally invasive surgery.


Behavioral Effects of Neurofeedback Compared to Stimulants and Physical Activity in Attention-Deficit/Hyperactivity Disorder: A Randomized Controlled Trial.
The efficacy of neurofeedback as a treatment for attention-deficit/hyperactivity disorder (ADHD), and whether neurofeedback is a viable alternative for stimulant medication, is still an intensely debated subject. The current randomized controlled trial compared neurofeedback to (1) optimally titrated methylphenidate and (2) a semi-active control intervention, physical activity, to account for nonspecific effects. A multicenter 3-way parallel-group study with balanced randomization was conducted. Children with a DSM-IV-TR diagnosis of ADHD, aged 7-13 years, were randomly allocated to receive neurofeedback (n = 39), methylphenidate (n = 36), or physical activity (n = 37) over a period of 10-12 weeks. Neurofeedback comprised theta/beta training on the vertex (Cz). Physical activity consisted of moderate to vigorous intensity exercises. Neurofeedback and physical activity were balanced in terms of number (~30) and duration of sessions. A double-blind pseudorandomized placebo-controlled crossover titration procedure was used to determine an optimal dose in the methylphenidate intervention. Parent and teacher ratings on the Strengths and Difficulties Questionnaire (SDQ) and Strengths and Weaknesses of ADHD Symptoms and Normal Behavior (SWAN) were used to assess intervention outcomes. Data collection took place between September 2010 and March 2014. Intention-to-treat analyses revealed an improvement in parent-reported behavior on the SDQ and the SWAN Hyperactivity/Impulsivity scale, irrespective of received intervention (ηp² = 0.21-0.22, P ≤ .001), whereas the SWAN Inattention scale revealed more improvement in children who received methylphenidate than neurofeedback and physical activity (ηp² = 0.13, P ≤ .001). Teachers reported a decrease of ADHD symptoms on all measures for methylphenidate, but not for neurofeedback or physical activity (range of ηp² = 0.14-0.29, P < .001). The current study found that optimally titrated methylphenidate is superior to neurofeedback and physical activity in decreasing ADHD symptoms in children with ADHD. ClinicalTrials.gov identifier: NCT01363544.


Patterns of readmission and reoperation within 90 days after Roux-en-Y gastric bypass.
Health insurance payors harbor concerns regarding the cost of bariatric procedures that are chiefly related to early readmissions and reoperations. We have attempted to identify the avoidable causes of readmission. We retrospectively reviewed the indications for short-term (<90-d) emergency department (ED) visits, readmissions, and reoperations from August 2004 through May 2007 for patients undergoing primary Roux-en-Y gastric bypass (RYGB) for morbid obesity at a tertiary care teaching hospital. The electronic medical record of the primary hospital was reviewed, as well as the electronic medical records of 9 local hospitals serving the area, allowing the incorporation of data from 35 locoregional hospitals. A total of 1222 consecutive patients underwent RYGB, 1051 laparoscopically. Of these 1222 patients, 173 had 252 ED visits, readmissions, and/or reoperations; 147 (58%) visits were to the primary institution and 105 (42%) occurred at a local or regional hospital. No age difference was found between the patients who underwent ED visits, hospital readmissions, or reoperations and those who did not (mean age 43 yr for both groups, P > .05). Patients who were seen in the ED, readmitted to the hospital, or underwent reoperation had had a greater body mass index (50 kg/m(2) versus 48 kg/m(2), P = .001). On average, the readmissions occurred 27.3 days (range 2-88) postoperatively, and the mean hospital length of stay for readmitted patients was 3.3 days (range 1-16). Patients who presented for ED visits, readmission, or reoperations were more likely to have undergone open RYGB than laparoscopic RYGB (P = .002). The <90-day all-cause ED visit, readmission, and reoperation rate was 21% (n = 252). Considering all 1222 patients, the incidence of nausea, vomiting, and dehydration, abdominal pain, and wound issues was 5% (n = 65), 4% (n = 50), and 2% (n = 21), respectively. Considering only the 173 patients with ED visits, readmissions, or reoperations (n = 252), the admitting diagnosis was nausea, vomiting, and dehydration in 26%, abdominal pain in 20%, and wound issues in 8%. The unemployed, disabled, or retired were more likely to have been seen in the ED or readmitted compared with the employed, nondisabled, or not retired (P = .01). A considerable number of patients are affected by nausea, vomiting, and dehydration, abdominal pain, and wound issues <90 days postoperatively. Socioeconomic and functional status might have an effect on the rate of ED visits and readmissions. By ensuring that the appropriate outpatient mechanisms for management of these problems are available, early ED visits and readmission rates should significantly decrease.


A comparative analysis for anti-viral drugs: Their efficiency against SARS-CoV-2.
Coronavirus, known as the coronavirus pandemic, is continuing its spread across the world, with over 42 million confirmed cases in 189 countries and more than 1.15 million deaths. Although, scientists focus on the finding novel drugs and vaccine for SARS-CoV-2, there is no certain treatment for it. Antiviral drugs such as; oseltamivir, favipiravir, umifenovir, lopinavir, remdesivir, hydroxychloroquine, chloroquine, azithromycin, ascorbic acid, corticosteroids, are mostly used for patients. They prevent cytokine storm that is the main reason of deaths related to SARS-CoV-2. In addition, anti-inflammatory agents have critical roles to inhibit the lung injury and multisystem organ dysfunction. The combination with anti-viral drugs with other drugs displays high synergistic effects. In the present study, the drugs used for Covid-19 are analyzed and compare the efficiency for the Covid-19 patients from the different continents including USA, South Korea, Italy, Spain, Germany, Russia, Brazil, Turkey, and China. Nowadays, all countries tried to find vaccine and new drug candidates for SARS-CoV-2, but anti-viral drugs may be the best candidates for the treatment of Covid-19 before finding novel anti-Covid drug.


5-J 1.8-microsec pulse 10-pps dye laser for combustion applications.
A 5-J/pulse 1.8-microsec pulse width 10-Hz flashlamp-pumped tunable dye laser system has been built for performing spontaneous Raman scattering experiments in combusting media at the Combustion Research Facility, Sandia National Laboratories, Livermore. Details of construction, including a microprocessor-based diagnostic and control system, are described, and performance of the system in terms of various operating parameters is noted.


Psychological impact of self-image dissatisfaction after orthognathic surgery: a case report.
The number of patients who need treatment for dentofacial abnormalities has increased over the past 30 years. Facial alterations can influence both the patient's self-confidence and his interpersonal relationships, possibly generating emotional or physical handicaps. This qualitative study discusses a patient's psychological dissatisfaction with a postoperative outcome, despite the esthetic and functional success of the treatment. The Oral Health Status Questionnaire, Post Surgical Satisfaction Questionnaire, Illness Behavior Questionnaire, and a clinical interview were used for the research methodology. Oral surgeons are encouraged to identify, presurgery, the patient's true motivation. An efficacious behavioral model is proposed that might help the patient transition through the consequences stages of the psychosocial changes associated with facial reconstructive surgery. Orthognathic surgery involves more than the correction of a physical problem. The psychological needs of the patient must be recognized and acknowledged, and communication between surgeons and patients is essential. It is important to understand that any surgical treatment that modifies body image could generate psychological disorders for some patients. Early surgical intervention and a referral for psychological counseling may reduce long-term morbidity. This case report should alert attending surgeons and orthodontists to possible unfavorable psychological sequelae.


COVID-19-associated mucormycosis - "The Black fungus" with associated invasive aspergillosis and actinomycosis infection: Series of 5 cases in the Indian scenario.
COVID-19 caused by SARS-CoV-2 has been studied and reported widely since November 2019, after its first case was detected in Wuhan, China. It has proven to be a fatal disease worldwide. COVID-19 causes severe disease in patients with immunosuppression and has always been associated with high mortality in such patients. Immunocompromised patients are always at a higher risk of getting co-infections too, and the same is true with COVID-19. It predisposes to the development of many fungal infections of which, mucormycosis is one of the most common ones, especially in the Indian population where a large group of the population is predisposed to diabetes mellitus. India has the world's largest population of diabetic patients; therefore, the prevalence of COVID-19-associated mucormycosis (CAM) is also the highest in India. Also, the use of corticosteroids over a long duration of time predisposes the patients to the development of mucormycosis owing to immunosuppression. Hypoxia, low total leukocyte count, and high ferritin are the other predisposing factors that lead to the growth of mucormycosis associated with COVID-19. Here, we present five cases within a span of 2 months, of mucormycosis-associated COVID-19 with mixed infections of aspergillosis and actinomycetes. Four cases had mucormycosis with aspergillosis and one with mucormycosis with Actinomyces. Three patients recovered fully after being treated with intravenous amphotericin B; however, unfortunately, two of our patients could not be saved.


Zebrafish embryo, a tool to study tumor angiogenesis.
Zebrafish (Danio rerio) represents a powerful model system in cancer research. Recent observations have shown the possibility to exploit zebrafish to investigate tumor angiogenesis, a pivotal step in cancer progression and target for anti-tumor therapies. Experimental models have been established in zebrafish adults, juveniles, and embryos, each one with its own advantages and disadvantages. Novel genetic tools and high resolution in vivo imaging techniques are also becoming available in zebrafish. It is anticipated that zebrafish will represent an important tool for chemical discovery and gene targeting in tumor angiogenesis. This review focuses on the recently developed tumor angiogenesis models in zebrafish, with particular emphasis to tumor engrafting in zebrafish embryos.


Non-coordinate expression of closely linked mouse casein genes.
Expression levels of five mouse casein genes were analysed in the mammary gland of virgin, pregnant and lactating mice. We have already shown that the five murine casein genes are arranged in the order, alpha-beta-gamma-epsilon-kappa in a tandem array, very close to each other in a 250 kb DNA fragment of mouse genome. Northern blot analysis showed that, of the calcium-sensitive casein genes, the epsilon casein gene is expressed only during lactation unlike the alpha, beta and gamma casein genes which are expressed during pregnancy and lactation. Even though the alpha, beta and gamma genes exhibited a co-ordinated expression pattern from mid to the later stages of pregnancy, the mRNA levels varied considerably (60, 90 and 100% respectively) by the onset of lactation. The mRNA level of the calcium-insensitive kappa casein gene increased from mid-pregnancy but at a lower rate and reached approximately 60% by the first day of lactation. Considering the locations and closeness of the casein genes, a non-coordinate expression profile is exhibited by the mouse casein genes, particularly the epsilon casein gene.


Estrogen receptor alpha mediates estrogen's immune protection in autoimmune disease.
Estrogens are known to influence a variety of autoimmune diseases, but it is not known whether their actions are mediated through classic estrogen receptor alpha (ERalpha). The presence of a functional ER was demonstrated in secondary lymphoid tissues, then ERalpha expression was shown at both the RNA and protein levels in these tissues. Use of ERalpha knockout mice revealed that both the estrogen-induced disease protection and the estrogen-induced reduction in proinflammatory cytokines were dependent upon ERalpha in the prototypic Th1-mediated autoimmune disease experimental autoimmune encephalomyelitis. These findings are central to the design of selective ER modifiers which aim to target biologic responses in specific organ systems.


Perceptual and response-dependent profiles of attention in children with ADHD.
Attention-deficit hyperactivity disorder (ADHD) is a complex developmental neuropsychiatric disorder, characterized by inattentiveness, impulsivity, and hyperactivity. Recent literature suggests a potential core deficit underlying these behaviors may involve inefficient processing when contextual stimulation is low. In order to specify this inefficiency, the aim of the present study was to disentangle perceptual and response-based deficits of attention by supplementing classic reaction time (RT) measures with an accuracy-only test. Moreover, it was explored whether ADHD symptom severity was systematically related to perceptual and response-based processes. We applied an RT-independent paradigm (Bundesen, 1990) and a sustained attention task (Dockree et al., 2006) to test visual attention in 24 recently diagnosed, medication-naïve children with ADHD, 14 clinical controls with pervasive developmental disorder, and 57 healthy controls. Outcome measures included perceptual processing speed, capacity of visual short-term memory, and errors of commission and omission. Children with ADHD processed information abnormally slow (d = 0.92), and performed poorly on RT variability and response stability (d's ranging from 0.60 to 1.08). In the ADHD group only, slowed visual processing speed was significantly related to response lapses (omission errors). This correlation was not explained by behavioral ratings of ADHD severity. Based on combined assessment of perceptual and response-dependent variables of attention, the present study demonstrates a specific cognitive profile in children with ADHD. This profile distinguishes the disorder at a basic level of attentional functioning, and may define subgroups of children with ADHD in a way that is more sensitive than clinical rating scales. (PsycINFO Database Record


Understanding Ring Puckering in Small Molecules and Cyclic Peptides.
The geometry of a molecule plays a significant role in determining its physical and chemical properties. Despite its importance, there are relatively few studies on ring puckering and conformations, often focused on small cycloalkanes, 5- and 6-membered carbohydrate rings, and specific macrocycle families. We lack a general understanding of the puckering preferences of medium-sized rings and macrocycles. To address this, we provide an extensive conformational analysis of a diverse set of rings. We used Cremer-Pople puckering coordinates to study the trends of the ring conformation across a set of 140 000 diverse small molecules, including small rings, macrocycles, and cyclic peptides. By standardizing using key atoms, we show that the ring conformations can be classified into relatively few conformational clusters, based on their canonical forms. The number of such canonical clusters increases slowly with ring size. Ring puckering motions, especially pseudo-rotations, are generally restricted and differ between clusters. More importantly, we propose models to map puckering preferences to torsion space, which allows us to understand the inter-related changes in torsion angles during pseudo-rotation and other puckering motions. Beyond ring puckers, our models also explain the change in substituent orientation upon puckering. We also present a novel knowledge-based sampling method using the puckering preferences and coupled substituent motion to generate ring conformations efficiently. In summary, this work provides an improved understanding of general ring puckering preferences, which will in turn accelerate the identification of low-energy ring conformations for applications from polymeric materials to drug binding.


[Comparative analysis of dimephosphon, ionol, and xydiphone effects on indomethacin-induced gastric lesions in rats].
Gastroprotective activity of dimephosphon, xydiphone, and ionol and their effects on the lipid peroxidation (LPO) indices and the activity of antioxidant enzymes in blood and organ tissues were studied on the model of indomethacin-induced gastric lesions in white rats. The indomethacin-induced gastropathy leads to increased concentration of LPO products in blood plasma and tissues. Dimephosphon and ionol reduced the number of gastric lesions and prevented LPO activation. In contrast, xydiphone administration had no effect on indometacin-induced gastric lesions and was accompanied by increased concentration of LPO products in the blood, liver, kidneys, spleen and stomachs of rats.


In situ/Operando studies of electrocatalysts using hard X-ray spectroscopy.
This review focuses on the use of X-ray absorption and emission spectroscopy techniques using hard X-rays to study electrocatalysts under in situ/operando conditions. We describe the importance and the versatility of methods in the study of electrodes in contact with the electrolytes, when being cycled through the catalytic potentials during the progress of the oxygen-evolution, oxygen reduction and hydrogen evolution reactions. The catalytic oxygen evolution reaction is illustrated with examples using Co, Ni and Mn oxides, and Mo and Co sulfides are used as an example for the hydrogen evolution reaction. A bimetallic, bifunctional oxygen evolving and oxygen reducing Ni/Mn oxide is also presented. The various advantages and constraints in the use of these techniques and the future outlook are discussed.


A genome-wide association study identifies a breast cancer risk variant in ERBB4 at 2q34: results from the Seoul Breast Cancer Study.
Although approximately 25 common genetic susceptibility loci have been identified to be independently associated with breast cancer risk through genome-wide association studies (GWAS), the genetic risk variants reported to date only explain a small fraction of the heritability of breast cancer. Furthermore, GWAS-identified loci were primarily identified in women of European descent. To evaluate previously identified loci in Korean women and to identify additional novel breast cancer susceptibility variants, we conducted a three-stage GWAS that included 6,322 cases and 5,897 controls. In the validation study using Stage I of the 2,273 cases and 2,052 controls, seven GWAS-identified loci [5q11.2/MAP3K1 (rs889312 and rs16886165), 5p15.2/ROPN1L (rs1092913), 5q12/MRPS30 (rs7716600), 6q25.1/ESR1 (rs2046210 and rs3734802), 8q24.21 (rs1562430), 10q26.13/FGFR2 (rs10736303), and 16q12.1/TOX3 (rs4784227 and rs3803662)] were significantly associated with breast cancer risk in Korean women (Ptrend < 0.05). To identify additional genetic risk variants, we selected the most promising 17 SNPs in Stage I and replicated these SNPs in 2,052 cases and 2,169 controls (Stage II). Four SNPs were further evaluated in 1,997 cases and 1,676 controls (Stage III). SNP rs13393577 at chromosome 2q34, located in the Epidermal Growth Factor Receptor 4 (ERBB4) gene, showed a consistent association with breast cancer risk with combined odds ratios (95% CI) of 1.53 (1.37-1.70) (combined P for trend = 8.8 × 10-14). This study shows that seven breast cancer susceptibility loci, which were previously identified in European and/or Chinese populations, could be directly replicated in Korean women. Furthermore, this study provides strong evidence implicating rs13393577 at 2q34 as a new risk variant for breast cancer.


The Drosophila TGF-alpha-like protein Gurken: expression and cellular localization during Drosophila oogenesis.
The establishment of anterior-posterior and dorsal-ventral polarity of the Drosophila egg and embryo depends on the function of the genes gurken, cornichon and Egfr (Drosophila epidermal growth factor receptor homolog). These genes encode components of a signal transduction pathway that transmits information between the germline cells and the somatic follicle cells of the ovary. gurken encodes a transforming growth factor-alpha-like protein and is a putative germline ligand of the Egfr present on the follicle cells. In mid-oogenesis the gurken transcript becomes spatially localized to the future dorsal-anterior cortex of the oocyte. To analyze the distribution pattern of Gurken protein we prepared antibodies against Gurken. We describe here the distribution pattern of the Gurken protein in wild-type ovaries and in ovaries from a number of dorsal-ventral patterning mutants. By immunoblotting we detect one major form of the Gurken protein, which likely corresponds to the unprocessed protein.


Armoured brain of unknown etiology.
Armoured brain is a rare condition where dense calcification occurs over the brain. It can result in mass effect and raised intracranial pressure. Most often, it happens due to trauma, subdural effusion, infection, or after VP shunt. There is controversy in its treatment. Most published literature does not support removing the calcification. We describe a rare case of idiopathic chronic calcified subdural hematoma with relatively short history which was successfully treated by microsurgical removal of calcification over the brain. This resulted in complete expansion of the brain with relief in symptoms.


Synthesis and antibacterial activities of acylide derivatives bearing an aryl-tetrazolyl chain.
Seventeen acylides bearing an aryl-tetrazolyl alkyl-substituted side chain were synthesized, starting from clarithromycin, via several reactions including hydrolysis, acetylating, esterification, carbamylation, and Michael addition. The structures of all new compounds were confirmed by (1)H nuclear magnetic resonance spectroscopy, (13)C nuclear magnetic resonance spectroscopy, and mass spectrometry. All these synthesized acylides were evaluated for in vitro antimicrobial activities against gram-positive pathogens (Staphylococcus aureus, Staphylococcus epidermidis) and gram-negative pathogens (Pseudomonas aeruginosa, Escherichia coli), using the broth microdilution method. Results showed that compounds 10 e, 10 f, 10 g, 10 h, 10 o have good antibacterial activities.


The future of taxonomy.
Microbial systematics has always been a misunderstood scientific discipline. It is readily assumed that systematists use antiquated techniques to examine the molecular, morphological, physiological, and biochemical properties of microorganisms. It is also believed that the circumscription of novel taxa is not essential let alone a requirement and it is due to this that systematics has become a dying art. It is rarely appreciated that systematics is a discipline that is essential to all sciences and that without the use of current techniques, descriptions of novel species or higher taxa cannot be correctly published. Since Woese and colleagues first publicized the use of the small subunit ribosomal RNA as a molecular tool, phylogenetic analysis of 16S rRNA gene sequences has become an essential step in the polyphasic approach of microbial systematics. However, this molecular technique has limitations which have become apparent, and therefore it is evident that full genome comparisons are soon going to be a requirement for the full circumscription of novel taxa. The next generation of sequencing technology has enabled more information to be incorporated into the full systematic picture and that is immense as it is only the start of the genomic era. It is hoped that high-throughput sequencing will compliment polyphasic data rather than throwing a different light on it and thus soon become an essential minimal standard for taxonomic descriptions.


Gut bitter taste receptor signalling induces ABCB1 through a mechanism involving CCK.
T2Rs (bitter taste-sensing type 2 receptors) are expressed in the oral cavity to prevent ingestion of dietary toxins through taste avoidance. They are also expressed in other cell types, including gut enteroendocrine cells, where their physiological role is enigmatic. Previously, we proposed that T2R-dependent CCK (cholecystokinin) secretion from enteroendocrine cells limits absorption of dietary toxins, but an active mechanism was lacking. In the present study we show that T2R signalling activates ABCB1 (ATP-binding cassette B1) in intestinal cells through a CCK signalling mechanism. PTC (phenylthiocarbamide), an agonist for the T2R38 bitter receptor, increased ABCB1 expression in both intestinal cells and mouse intestine. PTC induction of ABCB1 was decreased by either T2R38 siRNA (small interfering RNA) or treatment with YM022, a gastrin receptor antagonist. Thus gut ABCB1 is regulated through signalling by CCK/gastrin released in response to PTC stimulation of T2R38 on enteroendocrine cells. We also show that PTC increases the efflux activity of ABCB1, suggesting that T2R signalling limits the absorption of bitter tasting/toxic substances through modulation of gut efflux membrane transporters.


[Injuries to myocardium in infectious endocarditis].
Clinical and morphological characteristics of myocardium in infectious endocarditis (IE) are described as exemplified by pathological changes in the vascular bed, stroma, and myofibrils. Multiple sclerotic changes in myocardium in the form of "sheath sclerosis" were revealed. It is shown that progress of cardiac insufficiency in IE may be due to specific changes in the heart muscle. The necessity of early diagnostics of myocardial lesions is discussed with reference to revision of antibiotic therapy and modern surgical treatment of lE.


The stereochemical structure of disodium DL-glycerol 3-phosphate hexahydrate, the D isomer of which is an inhibitor of triose phosphate isomerase.
The stereochemistry of dl-glycerol 3-phosphate was studied by X-ray-crystallographic techniques. All the bond lengths and angles are within normally accepted limits except the ester bond, which is one of the largest yet noted, being 0.1637nm. The conformation of the molecule is such that an intramolecular hydrogen bond is formed between the hydroxyl group on the beta-carbon atom and the phosphate group. The crystal, which was grown by alcohol diffusion into an aqueous solution, is held together by sodium co-ordination and a complex system of hydrogen bonds. A table of the observed and calculated structure factors, F(obs.) and F(calc.), has been deposited as Supplementary Publication 50010 at the National Lending Library for Science and Technology, Boston Spa, Yorks. LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1972) 126, 5.


An 80 Kb P1 clone from chromosome 3p21.3 suppresses tumor growth in vivo.
High frequencies of allelic loss on the short arm of chromosome 3 in small cell lung cancer (SCLC) and a number of other tumors suggest the existence of a tumor suppressor gene(s) within the deleted regions. Two small cell lung cancer lines, NCI H740 and GLC20, have been described which have homozygous deletions in the region 3p21.3. The deleted region overlaps with a 2 Mb fragment of human DNA present in the interspecies hybrid HA(3)BB9F, that suppresses tumor formation by mouse A9 fibrosarcoma cells. Human sequences from this cell hybrid were isolated using inter Alu PCR. From this starting point, a P1 contig was developed for the region of 450 Kb that is common to the homozygous deletions seen in the SCLC lines NCI H740 and GLC20 and is also present in HA(3)BB9F, the suppressed A9 hybrid. Individual P1 clones were assayed for their ability to suppress the tumorigenicity of the mouse fibrosarcoma cell line A9 as assayed by injection of transfected A9 cells into athymic nude mice. The introduction of one of the P1 clones into A9 cells resulted in suppression of tumor growth whereas two other P1 clones from the contig failed to suppress tumor formation in athymic nude mice. These data functionally delimit a tumor suppressor locus to a region of 80 kb within a P1 clone at 3p21.3.


In vitro migration of mononuclear cells towards synovial fluid and plasma from rheumatoid arthritis patients correlates to RANTES synovial fluid levels and to clinical pain parameters.
To evaluate in vitro migration of mononuclear cells towards synovial fluid (SF) and plasma in relation to RANTES synovial fluid levels and clinical disease activity. 31 RA patients with synovitis in one knee were included. Modified Boyden chamber technique was used to determine a migratory index defined as: 'In vitro migrating cells towards SF' divided by 'In vitro migrating cells towards plasma'. RANTES was quantified by ELISA. Disease activity was assessed by the swollen joint count, the Ritchie articular index (RAI), global assessment, pain on VAS, HAQ, ESR and CRP. A positive significant correlation was found between the migratory index and the RANTES levels in SF (r=0.48, p=0.006), the RAI (r=0.56, p=0.0001) and pain on VAS (r=0.43, p=0.04). The in vitro migration could be inhibited in 3 of 4 SF samples by neutralising antibodies towards RANTES (12-18%). The migratory index correlate to SF levels of RANTES and parameters for joint pain.


Time course for arm and chest muscle thickness changes following bench press training.
The purpose of this study was to investigate the time course of hypertrophic adaptations in both the upper arm and trunk muscles following high-intensity bench press training. Seven previously untrained young men (aged 25 ± 3 years) performed free-weight bench press training 3 days (Monday, Wednesday and Friday) per week for 24 weeks. Training intensity and volume were set at 75% of one repetition maximum (1-RM) and 30 repetitions (3 sets of 10 repetitions, with 2-3 min of rest between sets), respectively. Muscle thickness (MTH) was measured using B-mode ultrasound at three sites: the biceps and triceps brachii and the pectoralis major. Measurements were taken a week prior to the start of training, before the training session on every Monday and 3 days after the final training session. Pairwise comparisons from baseline revealed that pectoralis major MTH significantly increased after week-1 (p = 0.002), triceps MTH increased after week-5 (p = 0.001) and 1-RM strength increased after week-3 (p = 0.001) while no changes were observed in the biceps MTH from baseline. Significant muscle hypertrophy was observed earlier in the chest compared to that of the triceps. Our results indicate that the time course of the muscle hypertrophic response differs between the upper arm and chest.


Retroviral recombination and reverse transcription.
Recombination occurs at a high rate in retroviral replication, and its observation requires a virion containing two different RNA molecules (heterodimeric particles). Analysis of retroviral recombinants formed after a single round of replication revealed that (i) the nonselected markers changed more frequently than expected from the rate of recombination of selected markers; (ii) the transfer of the initially synthesized minus strand strong stop DNA was either intramolecular or intermolecular; (iii) the transfer of the first synthesized plus strand strong stop DNA was always intramolecular; and (iv) there was a strong correlation between the type of transfer of the minus strand strong stop DNA and the number of template switches observed. These data suggest that retroviral recombination is ordered and occurs during the synthesis of both minus and plus strand DNA.


Population pharmacokinetic-pharmacodynamic modelling of liquid and controlled-release formulations of oxycodone in healthy volunteers.
Oral controlled-release formulations are playing an ever-increasing role in opioid therapy; however, little is known about their influence on the relationship between pharmacokinetics and pharmacodynamics. The study aim was to characterize the pharmacokinetic-pharmacodynamics of two controlled-release tablet formulations and a liquid formulation of oxycodone in healthy, opioid-naïve volunteers, which can serve as a reference for future patient studies. A semi-double-blinded, three-way crossover study was conducted, with fifteen healthy volunteers receiving two differently designed 20 mg monophasic controlled-release oxycodone tablets and 10 mg oral solution oxycodone in a randomized order. Venous plasma concentrations and pupil diameter were determined pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.33, 2.66, 3, 3.33, 3.66, 4, 5, 6, 8, 12 and 24 hour post-dose. Oxycodone pharmacokinetics was best described by a two-compartment model with first-order absorption. The controlled-release formulations had an absorption lag of 0.23 hour and a slower absorption rate constant (kaCR = 0.19 hour-1 ) compared to the oral solution (kaSOL = 0.94 hour-1 ). Effects on pupil diameter were delayed relative to plasma (14 minutes half-life) for all formulations and were best described by a proportional Emax model. The plasma concentration of oxycodone at half-maximum effect was lower in males (31.1 μg/L) compared to females (52.8 μg/L; P < .001). The absorption profile of controlled-release oxycodone formulations provided a prolonged onset and offset of action compared to oral solution oxycodone. The controlled-release formulations showed no differences in pharmacokinetic and pharmacodynamic parameters suggesting that both may be used interchangeably in human beings with normal gastrointestinal function.


Behavior therapy techniques applied to eating, exercise, and diet modification in childhood obesity.
Behavior therapy techniques are receiving increasing attention in the treatment of childhood obesity. This paper provides a selective review of experimental studies of childhood obesity that have utilized behavior therapy techniques with preadolescent populations. It further defines and describes specific behavior therapy techniques utilized in the modification of eating, exercise, and diet patterns in childhood obesity, including stimulus control, stimulus and response generalization, prompting, positive reinforcement, shaping, contingency contracting, and generalization and maintenance strategies.


[Detection and differentiation of autoantibodies to extractable nuclear antigens with immunoenzyme tests].
Nuclear antigens were extracted from calf thymus with phosphate-buffered saline The 60-80% ammonium sulfate fraction (ASF) of thymus extract contained SS-B-, the 30-60% ASF Sm- and U1-RNP-, and the chromatographically purified 30-60% ASF only Sm antigen. With these fractions enzyme immunoassays were developed for quantitative determination of Sm-, U1-RNP-, and SS-B autoantibodies. Out of 144 sera with antinuclear antibodies 85% were positive in the enzyme immunoassays, 41% in immunofluorescence tests on liver sections (12% speckled, 29% homogeneous immunofluorescence pattern), and 10% in Ouchterlony tests. 26% of the sera were positive in enzyme immunoassays and immunofluorescence tests. All antibody specificities detected by immunodiffusion could be confirmed by enzyme immunoassay. The enzyme immunoassay is far more sensitive then immunodiffusion and in contrast to immunofluorescence allows antibody specificities to be determined. Enzyme immunoassays are recommended for the diagnosis of rheumatic diseases.


The ends of a large RNA molecule are necessarily close.
We show on general theoretical grounds that the two ends of single-stranded (ss) RNA molecules (consisting of roughly equal proportions of A, C, G and U) are necessarily close together, largely independent of their length and sequence. This is demonstrated to be a direct consequence of two generic properties of the equilibrium secondary structures, namely that the average proportion of bases in pairs is ∼60% and that the average duplex length is ∼4. Based on mfold and Vienna computations on large numbers of ssRNAs of various lengths (1000-10 000 nt) and sequences (both random and biological), we find that the 5'-3' distance-defined as the sum of H-bond and covalent (ss) links separating the ends of the RNA chain-is small, averaging 15-20 for each set of viral sequences tested. For random sequences this distance is ∼12, consistent with the theory. We discuss the relevance of these results to evolved sequence complementarity and specific protein binding effects that are known to be important for keeping the two ends of viral and messenger RNAs in close proximity. Finally we speculate on how our conclusions imply indistinguishability in size and shape of equilibrated forms of linear and covalently circularized ssRNA molecules.


Mutations of NOTCH3 in childhood pulmonary arterial hypertension.
Mutations of BMPR2 and other TGF-β superfamily genes have been reported in pulmonary arterial hypertension (PAH). However, 60-90% of idiopathic PAH cases have no mutations in these genes. Recently, the expression of NOTCH3 was shown to be increased in the pulmonary artery smooth muscle cells of PAH patients. We sought to investigate NOTCH3 and its target genes in PAH patients and clarify the role of NOTCH3 signaling. We screened for mutations in NOTCH3, HES1, and HES5 in 41 PAH patients who had no mutations in BMPR2, ALK1, endoglin, SMAD1/4/8, BMPR1B, or Caveolin-1. Two novel missense mutations (c.2519 G>A p.G840E, c.2698 A>C p.T900P) in NOTCH3 were identified in two PAH patients. We performed functional analysis using stable cell lines expressing either wild-type or mutant NOTCH3. The protein-folding chaperone GRP78/BiP was colocalized with wild-type NOTCH3 in the endoplasmic reticulum, whereas the majority of GRP78/BiP was translocated into the nuclei of cells expressing mutant NOTCH3. Cell proliferation and viability were higher for cells expressing mutant NOTCH3 than for those expressing wild-type NOTCH3. We identified novel NOTCH3 mutations in PAH patients and revealed that these mutations were involved in cell proliferation and viability. NOTCH3 mutants induced an impairment in NOTCH3-HES5 signaling. The results may contribute to the elucidation of PAH pathogenesis.


Minimally Invasive Treatment for Appendiceal Mass Formed After Acute Perforated Appendicitis.
The optimal treatment for appendiceal mass formed after appendiceal rupture due to acute appendicitis is surrounded with controversy. The treatment strategy ranges from open surgery (emergency or interval appendectomy), laparoscopic appendectomy, and image-guided drainage, to conservative treatment with or without antibiotics. Nonsurgical treatment (including conservative and drainage treatment), followed by interval appendectomy to prevent recurrence, is the traditional management of these patients. The need for interval appendectomy after a successful conservative or/and image-guided drainage treatment, has recently been questioned as the risk of recurrence is relatively small. Several authors consider that even in cases involving only ambulatory follow-up observation, without interval surgery after conservative management, the recurrence rate and risks of missing underlying pathologies were not high. This article evaluates the minimally invasive treatment modalities in the management of appendiceal mass, risk of undetected serious disease, and the need for interval appendectomy to prevent recurrence.


Longitudinal development of gross motor function among Dutch children and young adults with cerebral palsy: an investigation of motor growth curves.
The aim of this study was to describe patterns for gross motor development by level of severity in a Dutch population of individuals with cerebral palsy (CP). This longitudinal study included 423 individuals (260 males, 163 females) with CP. The mean age at baseline was 9 years 6 months (SD 6y 2mo, range 1-22y). The level of severity of CP among participants, according to the Gross Motor Function Classification System (GMFCS), was 50% level I, 13% level II, 14% level III, 13% level IV, and 10% level V. Participants had been assessed up to four times with the Gross Motor Function Measure (GMFM-66) at 1- or 2-year intervals between 2002 and 2009. Data were analysed using non-linear mixed effects modelling. For each GMFCS level, patterns were created by contrasting a stable limit model (SLM) with a peak and decline model (PDM), followed by estimating limits and rates of gross motor development. The SLM showed a better fit for all GMFCS levels than the PDM. Within the SLM, significant differences between GMFCS levels were found for both the limits (higher values for lower GMFCS levels) and the rates (higher values for GMFCS levels I-II vs level IV and for GMFCS levels I-IV vs level V) of gross motor development. The results validate the existence of five distinct patterns for gross motor development by level of severity of CP.


Cerium oxide nanoparticles: influence of the high-Z component revealed on radioresistant 9L cell survival under X-ray irradiation.
This article pioneers a study into the influence of the high-Z component of nanoparticles on the efficacy of radioprotection some nanoparticles offer to exposed cells irradiated with X-rays. We reveal a significant decrease in the radioprotection efficacy for cells exposed to CeO2 nanoparticles and irradiated with 10 MV and 150 kVp X-rays. In addition, analysis of the 150 kVp survival curve data indicates a change in radiation quality, becoming more lethal for irradiated cells exposed to CeO2 nanoparticles. We attribute the change in efficacy to an increase in high linear energy transfer Auger electron production at 150 kVp which counterbalances the CeO2 nanoparticle radioprotection capability and locally changes the radiation quality. This study highlights an interesting phenomenon that must be considered if radiation protection drugs for use in radiotherapy are developed based on CeO2 nanoparticles. CeO2 nanoparticles are thought to offer radioprotection; however, this study reveals significant decrease in the radioprotection efficacy for cells exposed to CeO2 nanoparticles and irradiated with 10 MV and 150 kVp X-rays. This phenomenon must be considered when developing radiation protection drugs based on CeO2 nanoparticles.


Different binding sites for the neuropeptide Y Y1 antagonists 1229U91 and J-104870 on human Y1 receptors.
The peptidic Y1 antagonist 1229U91 and the non-peptidic antagonist J-104870 have high binding affinities for the human Y1 receptor. These Y1 antagonists show anorexigenic effects on NPY-induced feeding in rats, although they have completely different structures and molecular sizes. To identify the binding sites of these ligands, we substituted amino acid residues of the human Y1 receptor with alanine and examined the abilities of the mutant receptors to bind the radio-labeled ligands. Alanine substitutions, F98A, D104A, T125A, D200A, D205A, L215A, Q219A, L279A, F282A, F286A, W288A and H298A, in the human Y1 receptor lost their affinity for the peptide agonist PYY, but not for 1229U91 and J-104870, while L303A and F173A lost affinity for 1229U91 and J-104870, respectively. N283A retained its affinity for 1229U91, but not for PYY and J-104870. Y47A and N299A retained their affinity for J-104870, but not for PYY and 1229U91. W163A and D287A showed no affinity for any of the three ligands. Taken together, these data indicate that the binding sites of 1229U91 are widely located in the shallow region of the transmembrane (TM) domain of the receptor, especially TM1, TM6 and TM7. In contrast, J-104870 recognized the pocket formed by TM4, TM5 and TM6, based on the molecular modeling of the Y1 receptor and J-104870 complex. In conclusion, 1229U91 and J-104870 have high affinities for Y1 receptors using basically different binding sites. D287 of the common binding site in the TM6 domain could be crucial for the binding of Y1 antagonists.


MIREyA: a computational approach to detect miRNA-directed gene activation.
Emerging studies demonstrate the ability of microRNAs (miRNAs) to activate genes via different mechanisms. Specifically, miRNAs may trigger an enhancer promoting chromatin remodelling in the enhancer region, thus activating the enhancer and its target genes. Here we present MIREyA, a pipeline developed to predict such miRNA-gene-enhancer trios based on an expression dataset which obviates the need to write custom scripts. We applied our pipeline to primary murine macrophages infected by Mycobacterium tuberculosis (HN878 strain) and detected Mir22, Mir221, Mir222, Mir155 and Mir1956, which could up-regulate genes related to immune responses. We believe that MIREyA is a useful tool for detecting putative miRNA-directed gene activation cases. MIREyA is available from: https://github.com/veania/MIREyA.


Evaluation of rescue oral glucocorticoid therapy during inpatient cystic fibrosis exacerbations.
An acute pulmonary exacerbation (APE) in cystic fibrosis (CF) is characterized by increased pulmonary symptoms attributed to bacterial colonization, neutrophil recruitment, and inflammation. Antimicrobials, airway clearance, and nutrition are the mainstay of therapy. However, when patients fail to improve, corticosteroids have been added to therapy. We retrospectively examined the use of rescue steroids in a children's hospital from 2013 to 2017 during CF APE treatment following at least 1 week of inpatient therapy without expected clinical improvement. In total, 106 encounters of 53 unique patients, aged 6-20 years, who had FEV1 percent predicted (FEV1pp) data at baseline, admission, midpoint, and discharge, and had admission duration of at least 12 days were studied. Encounters treated with steroids had less improvement at midpoint percent change from admission in FEV1pp (4.9 ± 11.3) than nonsteroid group change in FEV1pp (20.1 ± 24.6; p < .001). Failure to improve as expected was the rationale for steroid use. At discharge, there was no difference in mean FEV1pp (p = .76). Delays in steroid therapy by waiting until the end of the second week increased the total length of stay (LOS). Propensity matching, comparing outcomes in patients without midpoint improvement in FEV1pp, was also evaluated. There was no difference in admission or discharge FEV1pp between groups. Equally, no difference in FEV1pp at follow-up visit or in time until the next APE was detected. Secondary analysis for associations including gender, genotype, fungal colonization, or inhaled antimicrobials was nonsignificant. These data suggest rescue use of corticosteroids during APE does not predictably impact important outcome measures during CF APE treatment.


Image-Guided Deployment and Monitoring of a Novel Tungsten Nanoparticle-Infused Radiopaque Absorbable Inferior Vena Cava Filter in a Swine Model.
To improve radiopacity of radiolucent absorbable poly-p-dioxanone (PPDO) inferior vena cava filters (IVCFs) and demostrate their effectiveness in clot-trapping ability. Tungsten nanoparticles (WNPs) were incorporated along with polyhydroxybutyrate (PHB), polycaprolactone (PCL), and polyvinylpyrrolidone (PVP) polymers to increase the surface adsorption of WNPs. The physicochemical and in vitro and in vivo imaging properties of PPDO IVCFs with WNPs with single-polymer PHB (W-P) were compared with those of WNPs with polymer blends consisting of PHB, PCL, and PVP (W-PB). In vitro analyses using PPDO sutures showed enhanced radiopacity with either W-P or W-PB coating, without compromising the inherent physicomechanical properties of the PPDO sutures. W-P- and W-PB-coated IVCFs were deployed successfully into the inferior vena cava of pig models with monitoring by fluoroscopy. At the time of deployment, W-PB-coated IVCFs showed a 2-fold increase in radiopacity compared to W-P-coated IVCFs. Longitudinal monitoring of in vivo IVCFs over a 12-week period showed a drastic decrease in radiopacity at Week 3 for both filters. The results highlight the utility of nanoparticles (NPs) and polymers for enhancing radiopacity of medical devices. Different methods of incorporating NPs and polymers can still be explored to improve the effectiveness, safety, and quality of absorbable IVCFs.


Trabeculotomy in late onset congenital glaucoma.
All eyes of children above the age of 1 year referred because of glaucoma were treated with trabeculotomy as the primary procedure. The surgery was modified by the excision of a rectangle of tissue in the deep scleral bed under the scleral flap instead of the classical radial incision. This serves to exteriorise Schlemm's canal while thinning the scleral tissue, without, however, entering the anterior chamber. A total of 7 eyes in 5 children between the ages of 1 and 9 years were operated upon. In 6 of the 7 eyes intraocular pressure has remained under 20 mmHg without treatment after follow-up of between 18 months and 4 years. In the seventh eye intraocular pressure was controlled for 2 years but has since required epinephrine drops twice daily for the maintenance of pressure below 20 mmHg. In 4 of the 7 eyes flat, diffuse conjunctival filtering blebs are present, but no complications have been encountered. We consider that trabeculotomy may be recommended for children with late-onset congenital glaucoma.


Electronic modulation of composite electrocatalysts derived from layered NiFeMn triple hydroxide nanosheets for boosted overall water splitting.
Herein, we report the synthesis of Fe and Mn co-doped Ni3S2 nanosheet arrays (FM-NS NSAs) as well as layered NiFeMn triple hydroxide (NiFeMn-LTH)/FM-NS hybrid NSAs (HNSAs) via an easily controllable sulfidation method with NiFeMn-LTH NSAs as the precursor, which can be employed as coupled oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) electrodes to achieve boosted overall water splitting performance. It is discovered that the incorporation of the dual Fe and Mn cations can simultaneously modulate the morphology and optimize the electron density of the obtained catalysts. As a result, the full sulfidation product of FM-NS NSAs display a much-enhanced activity for the OER at a current density of 10 mA cm-2 with an overpotential of 188 mV. The NiFeMn-LTH/FM-NS HNSAs obtained from partial sulfidation demonstrate an enhanced HER activity with a lower overpotential of 110 mV at 10 mA cm-2. The FM-NS NSA anode and the NiFeMn-LTH/FM-NS HNSA cathode were coupled in an alkaline medium for overall water splitting and exhibited a much lower cell voltage of 1.48 V at 10 mA cm-2, superior to most of the reported noble-metal-free electrocatalysts. Additionally, a battery-assisted electrolyzer (1.5 V) was assembled to explore the feasibility for practical energy-efficient water splitting.


Secondary myelodysplastic syndromes and leukemias.
Although therapy-related (secondary) myelodysplastic syndromes and acute nonlymphocytic leukemias are most frequently observed following therapy of Hodgkin's disease and non-Hodgkin's lymphoma, the therapy of acute lymphocytic leukemia, multiple myeloma, polycythemia vera, cancers of breast, lung, ovary, gastrointestinal tract, testis, and soft tissues is also associated with subsequent development of leukemia. A preceding myelodysplastic syndrome is observed in over 70% of patients who develop therapy-related leukemia, in contrast to patients with de novo leukemia in whom approximately 20% of patients have similar prodromal syndromes. Chemotherapeutic drugs--including alkylating agents, platinum analogs, and epipodophyllotoxins--and ionizing radiation have both been implicated in the etiology of secondary tumors. The median duration from time of chemotherapy or radiation therapy, or both, to diagnosis of secondary leukemia is 3 to 4 years. The risk for development of secondary leukemia is highest between 24 and 72 months following cytotoxic therapy, with a steady decline in incidence thereafter. Of those people who will develop secondary leukemia, approximately 6% of patients do so within the 1st year, whereas 15% of patients will not do so until more than 7 years from commencement of mutagenic therapy. We review here selected recent publications on clinical and therapeutic data in therapy-induced myelodysplasia and acute leukemia.


Post-cholecystectomy alkaline reactive gastritis: a randomized trial comparing sucralfate versus rabeprazole or no treatment.
At present there are no well-established pharmacological approaches in the management of post-cholecystectomy alkaline reactive gastritis. The aim of this study was to assess the effect of sucralfate versus rabeprazole or no treatment on dyspeptic symptoms and endoscopic/histological signs in a population of patients with a history of cholecystectomy and evidence of alkaline reactive gastritis. Sixty dyspeptic patients fulfilling the following criteria of inclusion took part in this study: (1) a history of cholecystectomy; (2) no use of anti-inflammatory steroidal and non-steroidal drugs, or abuse of alcohol; (3) evidence of abundant gastric bile reflux at endoscopy; (4) endoscopic signs of chronic gastritis; (5) histological signs of chronic gastritis; and (6) absence of Helicobacter pylori infection. Dyspeptic symptoms were evaluated by means of a self-administered validated questionnaire. Patients included in the study were randomly assigned to one of three treatment groups for 3 months: sucralfate, rabeprazole, observation. Patients were re-evaluated at the end of the treatment. Sucralfate and rabeprazole therapies were both able to significantly reduce epigastric pain, heartburn, bloating and halitosis. Endoscopic/histological signs were lower in both treatment groups compared to the observation group. Both sucralfate and rabeprazole therapies are effective treatment options in the patients with alkaline gastritis when compared with observation.


Multicenter investigation on the influence of climate in penile prosthesis infection.
The purpose of this study is to investigate the relationship between inflatable penile prosthesis (IPP) infection, time of year, climate, temperature and humidity. This is a retrospective IRB-approved analysis of 211 patients at 25 institutions who underwent salvage procedure or device explant between 2001 and 2016. Patient data were compiled after an extensive review of all aspects of their electronic medical records. Climate data were compiled from monthly norms based on location, as well as specific data regarding temperature, dew point, and humidity from dates of surgery. Rigorous statistical analysis was performed. We found that penile prosthesis infections occurred more commonly in June (n = 24) and less frequently during the winter months (n = 39), with the lowest number occurring in March (n = 11). One-hundred thirty-nine infections occurred at average daily temperatures greater than 55 °F, compared to 72 infections at less than 55 °F. The incidence rate ratio for this trend was 1.93, with a p-value of <0.001. Humidity results were similar, and fungal infections correlate with daily humidity. Infected implants performed in the fall and summer were over 3 and 2.3 times, respectively, more likely to grow Gram-positive bacteria compared to implants performed in spring (p = 0.004; p = 0.039). This was consistent across geographic location, including in the Southern hemisphere. We found trends between climate factors and IPP infection like those seen and proven in other surgical literature. To our knowledge these data represent the first exploration of the relationship between temperature and infection in prosthetic urology.


Effect of dietary ribonucleic acid on bacterial translocationand survival following blood transfusion and thermal injury.
Ribonucleic acid (RNA) has been shown to have a key role in the maintenance of normal cellular function and host resistance to infection. The effect of experimental diets containing RNA on microbial translocation, killing of translocated bacteria and the survival rate of the host was studied in a burn animal model which included immunosuppression. Balb/c mice were fed for 10 days with an RNA supplemented diet (AIN/76A). Control groups were fed with two commercial diets: AIN-76A or Purina chow 5001 (chow). After 10 days of feeding, all animals received an allogenic transfusion. On day 15 the animals were gavaged with 10(10)(14)C radiolabeled or unlabeled Escherichia coli, and given a 20% total body surface area (TBSA) burn injury. Animals gavaged with unlabeled bacteria were observed for survival (n = 60) and animals gavaged with labeled bacteria were sacrificed 4 h post-burn (n = 30) and the mesenteric lymph nodes, liver and spleen were harvested. Slightly less translocation was observed in the liver and spleen of animals fed on RNA diet. Bacterial counts were measured and the percentages of translocated organisms that survived in the tissues were calculated and showed no statistical differences between the three groups. Survival was 45% in RNA group versus 55% in the non-supplemented AIN-76A and 50% in the chow group. It is concluded that a diet enriched in RNA slightly affects bacterial translocation but does not affect survival after severe injury.


Inhibition of retinoic acid receptor-mediated signalling alters positional identity in the developing hindbrain.
Retinoids regulate gene expression via nuclear retinoic acid receptors, the RARs and RXRs. To investigate the functions of retinoid receptors during early neural development, we expressed a dominant negative RARbeta in early Xenopus embryos. We obtained evidence that dominant negative RARbeta specifically inhibits RAR/RXR heterodimer-mediated, but not RXR homodimer-mediated, transactivation. Both all-trans- and 9-cis-RA-induced teratogenesis were, however, efficiently opposed by ectopic expression of dominant negative RARbeta, indicating that only RAR/RXR transactivation is required for retinoid teratogenesis by each of these ligands. Experiments with two RXR-selective ligands confirmed that activation of RXR homodimers does not cause retinoid teratogenesis. Dominant negative RARbeta thus specifically interferes with the retinoid signalling pathway that is responsible for retinoid teratogenesis. Dominant negative RARbeta-expressing embryos had a specific developmental phenotype leading to disorganization of the hindbrain. Mauthner cell multiplications in the posterior hindbrain, and (both anteriorly and posteriorly) expanded Krox-20 expression domains indicated (partial) transformation of a large part of the hindbrain into (at least partial) rhombomere 3, 4 and/or 5 identity. In contrast, the fore- and midbrain and spinal cord appeared to be less affected. These data indicate that RARs play a role in patterning the hindbrain.


Comparable response of wild rodent gut microbiome to anthropogenic habitat contamination.
Species identity is thought to dominate over environment in shaping wild rodent gut microbiota, but it remains unknown whether the responses of host gut microbiota to shared anthropogenic habitat impacts are species-specific or if the general gut microbiota response is similar across host species. Here, we compare the influence of exposure to radionuclide contamination on the gut microbiota of four wild mouse species: Apodemus flavicollis, A. sylvaticus, A. speciosus and A. argenteus. Building on the evidence that radiation impacts bank vole (Myodes glareolus) gut microbiota, we hypothesized that radiation exposure has a general impact on rodent gut microbiota. Because we sampled (n = 288) two species pairs of Apodemus mice that occur in sympatry in habitats affected by the Chernobyl and Fukushima nuclear accidents, these comparisons provide an opportunity for a general assessment of the effects of exposure to environmental contamination (radionuclides) on gut microbiota across host phylogeny and geographical areas. In general agreement with our hypothesis, analyses of bacterial 16S rRNA gene sequences revealed that radiation exposure alters the gut microbiota composition and structure in three of the four species of Apodemus mice. The notable lack of an association between the gut microbiota and soil radionuclide contamination in one mouse species from Fukushima (A. argenteus) probably reflects host "radiation escape" through its unique tree-dwelling lifestyle. The finding that host ecology can modulate effects of radiation exposure offers an interesting counterpoint for future analyses into effects of radiation or any other toxic exposure on host and its associated microbiota. Our data show that exposure to radionuclide contamination is linked to comparable gut microbiota responses across multiple species of rodents.


The Enigmatic PE/PPE Multigene Family of Mycobacteria and Tuberculosis Vaccination.
The genome of Mycobacterium tuberculosis, the bacterium responsible for the disease tuberculosis, contains an unusual family of abundant antigens (PE/PPEs). To date, certain members of this multigene family occur only in mycobacteria that cause disease. It is possible that the numerous proteins encoded by these mycobacterial genes dictate the immune pathogenesis of this bacterial pathogen. There is also evidence that some of these antigens are present at the cell surface and that they affect the pathology and immunology of the organism in many ways. Also, they elicit both antibodies and T cells, they may be involved in antigenic variation, and they may be good candidates for vaccines and drugs. However, since they are plentiful and extremely homologous, these PE/PPEs are very challenging to study, and it is difficult to be certain what role(s) they have in the pathogenesis of tuberculosis. Consequently, how to develop treatments like vaccines using these antigens as candidates is complex.


Classification of lunge biomechanics with multiple and individual inertial measurement units.
Lunges are a common, compound lower limb resistance exercise. If completed with aberrant technique, the increased stress on the joints used may increase risk of injury. This study sought to first investigate the ability of inertial measurement units (IMUs), when used in isolation and combination, to (a) classify acceptable and aberrant lunge technique (b) classify exact deviations in lunge technique. We then sought to investigate the most important features and establish the minimum number of top-ranked features and decision trees that are needed to maintain maximal system classification efficacy. Eighty volunteers performed the lunge with acceptable form and 11 deviations. Five IMUs positioned on the lumbar spine, thighs, and shanks recorded these movements. Time and frequency domain features were extracted from the IMU data and used to train and test a variety of classifiers. A single-IMU system achieved 83% accuracy, 62% sensitivity, and 90% specificity in binary classification and a five-IMU system achieved 90% accuracy, 80% sensitivity, and 92% specificity. A five-IMU set-up can also detect specific deviations with 70% accuracy. System efficiency was improved and classification quality was maintained when using only 20% of the top-ranked features for training and testing classifiers.


Synthesis of plus strands of retroviral DNA in cells infected with avian sarcoma virus and mouse mammary tumor virus.
The vast majority of plus strands synthesized in quail cells acutely infected with avian sarcoma virus were subgenomic in size, generally less than 3 kilobases (kb). A series of discrete species could be identified after agarose gel electrophoresis by annealing with various complementary DNAs, indicating specificity in the initiation and termination of plus strands. The first plus strand to appear (within 2 h postinfection) was similar in length to the long redundancy at the ends of linear DNA (0.35 kb), and it annealed with complementary DNAs specific for the 3' and 5' termini of viral RNA (Varmus et al., J. Mol. Biol. 120:50-82, 1978). Several subgenomic plus-strand fragments (0.94, 1.38, 2.3, and 3.4 kb) annealed with these reagents. At least the 0.94- and 1.38-kb strands were located at the same end of linear DNA as the 0.35-kb strand, indicating that multiple specific sites for initiation were employed to generate strands which overlapped on the structural map. We were unable to detect RNA liked to plus strands isolated as early as 2.5 h postinfection; thus, the primers must be short (fewer than 50 to 100 nucleotides), rapidly removed, or not composed of RNA. To determine whether multiple priming events are a general property of retroviral DNA synthesis in vivo, we also examined plus strands of mouse mammary tumor virus DNA in chronically infected rat cells after induction of RNA and subsequent DNA synthesis with dexamethasone. In this case, multiple, discrete subgenomic DNA plus strands were not found when the same methods applied to avian sarcoma virus DNA were used; instead, the plus strands present in the linear DNA of mouse mammary tumor virus fell mainly into two classes: (i) strands of ca. 1.3 kb which appeared early in synthesis and were similar in size and genetic content to the terminally repeated sequence in linear DNA; and (ii) plus strands of the same length as linear DNA. A heterogeneous population of other strands diminished with time, was not found in completed molecules, and was probably composed of strands undergoing elongation. These two retroviruses thus appear to differ with respect to both the number of priming sites used for the synthesis of plus strands and the abundance of full-length plus strands. On the other hand the major subgenomic plus strand of mouse mammary tumor virus DNA (1.3 kb) is probably the functional homolog of a major subgenomic plus strand of avian sarcoma virus DNA (0.35 kb). The significance of this plus strand species is discussed in the context of current models which hold that it is used as a template for the completion of the minus strand, thereby generating the long terminal redundancy.


Race in a genome: long read sequencing, ethnicity-specific reference genomes and the shifting horizon of race.
The sequencing of the human genome at the turn of the 21st century was hailed as revealing the overwhelming genetic similarity of human groups. Scholars of genomics have critiqued the subsequent persistence of race-based genetic science, but were reassured that the wide availability of gene sequencing would end the use of race as a proxy for genetic difference. Once an individual's whole gene sequence could be read, they hoped, their ethnoracial classification would become redundant. At the same time, genome science was recognising that the differences between human genomes went beyond the genome sequence to the structure of the genome itself. 'Structural variation' between genomes, including insertions, deletions, translocations, inversions, and copy number variations, mean that the 'universal' reference genome used for genome sequencing is not so universal. As conventional, 'short-read' sequencing wrongly assumes that all genomes have the same structure, significant genetic variation can be missed. This paper examines the twin phenomena that have been posed as a solution to the biases of short-read sequencing: 'long-read' sequencing and 'ethnicity-specific reference genomes'. Long-read sequencing is a method of generating a genome sequence that can be assembled de novo rather than relying on the reference genome. In recent years, a number of countries including China, Korea, and Denmark have used long-read sequencing and de novo assembly to develop 'national' reference genomes. Our analysis of one ethnicity-specific reference genome project, the Korean Reference Genome (KOREF), finds that it unduly emphasises the importance of population structural variation, framed in nationalist terms, and discounts the importance of individual structural variation. We argue that the intellectual labour required to make a Korean reference genome a coherent concept works to extend the horizon of race, prolonging the temporality of the 'meantime' in which race remains a seemingly valid concept in genomic science.