Demystifying Chronic Kidney Disease of Unknown Etiology (CKDu): Computational Interaction Analysis of Pesticides and Metabolites with Vital Renal Enzymes.
Chronic kidney disease of unknown etiology (CKDu) has been recognized as a global non-communicable health issue. There are many proposed risk factors for CKDu and the exact reason is yet to be discovered. Understanding the inhibition or manipulation of vital renal enzymes by pesticides can play a key role in understanding the link between CKDu and pesticides. Even though it is very important to take metabolites into account when investigating the relationship between CKDu and pesticides, there is a lack of insight regarding the effects of pesticide metabolites towards CKDu. In this study, a computational approach was used to study the effects of pesticide metabolites on CKDu. Further, interactions of selected pesticides and their metabolites with renal enzymes were studied using molecular docking and molecular dynamics simulation studies. It was evident that some pesticides and metabolites have affinity to bind at the active site or at regulatory sites of considered renal enzymes. Another important discovery was the potential of some metabolites to have higher binding interactions with considered renal enzymes compared to the parent pesticides. These findings raise the question of whether pesticide metabolites may be a main risk factor towards CKDu.


Cryptococcus gattii: An Emerging Cause of Fungal Disease in North America.
During the latter half of the twentieth century, fungal pathogens such as Cryptococcus neoformans were increasingly recognized as a significant threat to the health of immune compromised populations throughout the world. Until recently, the closely related species C. gattii was considered to be a low-level endemic pathogen that was confined to tropical regions such as Australia. Since 1999, C. gattii has emerged in the Pacific Northwest region of North America and has been responsible for a large disease epidemic among generally healthy individuals. The changing epidemiology of C. gattii infection is likely to be a consequence of alterations in fungal ecology and biology and illustrates its potential to cause serious human disease. This review summarizes selected biological and clinical aspects of C. gattii that are particularly relevant to the recent North American outbreak and compares these to the Australian and South American experience.


Acoustic Performance of 3D Printed Nanocomposite Earmuff.
Hearing protection devices are one of the primary noise reduction tools in developing countries. This study is intended to produce and apply acrylonitrile butadiene styrene (ABS)/clay nanocomposites to fabricate a laboratory single cup earmuffs and then compare it with double cup and single cup pure ABS earmuffs in terms of noise attenuation performance and comfort. In addition, the noise attenuation performance of single cup pure ABS earmuffs is compared with double cup pure ABS earmuffs. ABS/nanoclay filament was fabricated using a twin screw extruder. A three dimensional (3D) printing machine and a 3D model of earcup, designed by solid work software, were applied to print single and double cup earmuffs using ABS/nanoclay composite and pure ABS filaments. Finally, using an acoustic test fixture, objective noise attenuation test was performed on three different types of earmuffs, including with and without nano material and a secondary cup. Moreover, earmuffs weight was measured as a comfort component. Insertion loss and calculated noise reduction rating (NRR) of single cup ABS/nanoclay earmuffs (NRR=19.4 dB) and double cup pure ABS earmuffs (NRR=18.93 dB) were improved in comparison with single cup pure ABS earmuffs (NRR=15.7 dB). Additionally, both single cup earmuffs were significantly lighter than double cup earmuffs. Although single cup nano and double cup earmuffs had nearly the same attenuation performance, single cup nano earmuffs were 74 gr lighter than double cup earmuffs, so with reference to comfort, single cup nano earmuffs will probably be more acceptable. From this survey it might be concluded that, even though single cup ABS/nanoclay earmuffs was lighter than double cup pure ABS earmuffs, it had approximately more attenuation performance in comparison with double cup pure ABS earmuffs. Consequently, users are probably more prone to wear light- weight single cup ABS/nanoclay earmuffs as a result of improved comfort. In short, ABS/nanoclay composite can be considered a good choice in products with the necessity of high acoustic performance and low weight.


Cloning of hamster type XVII collagen cDNA, and pathogenesis of anti-type XVII collagen antibody and complement in hamster bullous pemphigoid.
Bullous pemphigoid is an inflammatory subepidermal blistering skin disease associated with an IgG autoimmune response to the type XVII collagen. The immunopathologic features of bullous pemphigoid can be reproduced in mice by the passive transfer of anti-type XVII collagen antibodies. In this model, it is thought that blister formation depends upon complement activation, neutrophil recruitment, and some proteolytic enzymes. In this study, we cloned hamster type XVII collagen cDNA, which contains a 4296 bp coding region and which is predicted to be a transmembrane protein with an extracellular collagenous domain, residing in type II orientation. Antipeptide antibodies (anti-1191 IgG) were obtained against a segment of hamster type XVII collagen homologous with the human type XVII collagen autoantibody-reactive site. The antipeptide antibodies were passively transferred to neonatal Syrian hamsters. The injected hamsters developed a microscopic subepidermal blister as seen previously in the mice. In order to test whether antigen-antibody complexes and complement initiate the subepidermal blister formation, we carried out experiments in vitro on condition that inflammatory cells were completely eliminated. Complement activation in sera was inhibited either by heating (at 56 degrees C for 30 min) or by preincubating with cobra venom factor. When the hamster skin was incubated with fresh anti-1191 antisera, separation of dermal-epidermal junction was observed. The anti-1191 IgG failed to induce C3 deposition and dermal-epidermal junction separation, however, if the anti-1191 IgG was added alone or complement activation in sera was inhibited. Under these conditions, IgG but not C3 was deposited on the basement membrane. These results strongly suggest that antigen-antibody complexes and complement initiate dermal-epidermal junction separation.


Impact of the COVID-19 pandemic on exercise habits among cancer patients.
Purpose There is limited information on how the COVID-19 pandemic has changed health behaviors among cancer patients. We examined the impact of the pandemic on changes in exercise behaviors and identified characteristics associated with these changes among cancer patients. Methods Cancer patients (n = 1,361) completed a survey from August-September 2020 to assess COVID-19 pandemic-related changes in health behaviors and psychosocial factors. Patients were categorized into 3 groups: exercising less, exercising did not change, and exercising more. Patient characteristics were compared by exercise groups. Results One-third of the patients reported a decreased amount of regular exercise, while 11% reported exercising more during the pandemic. Patients who exercised less were more likely to be unemployed/retired, undergoing active treatment, and had increased pandemic-related alcohol consumption and psychosocial stressors such as loneliness and financial stress (all p < 0.05). In contrast, patients who exercised more were younger, female, full-time employed, did not consume alcohol, and had good health status and more social interactions (all p < 0.05). Patients who were living in rural areas and did not experience changes in daily life, were also more likely not to experience changes in exercise habits (all p < 0.05). Conclusion Our results indicate that a significant proportion of cancer patients experienced changes in exercise habits during the first 6 months of the COVID-19 pandemic. Age, sex, employment status, health status, alcohol consumption, and psychosocial factors were associated with changes in exercise behaviors. Providers should monitor for changes in health behaviors, such as exercise, because of their importance in improving cancer survivorship.


Immune regulation by mesenchymal stem cells derived from adult spleen and thymus.
We show here that human and mouse mesenchymal stem cells (MSCs) can be obtained not only from bone marrow (BM), but also from adult spleen and thymus. In vitro, both human and mouse spleen- and thymus-derived MSCs exhibit immunophenotypic characteristics and differentiation potential completely comparable to BM-MSCs. In addition, they can inhibit immune responses mediated by activated T lymphocytes with efficiency comparable to BM-MSCs. In vivo, mouse MSCs from BM, spleen, and thymus, if injected together with a genetically modified tumor cell vaccine, can equally prevent the onset of an anti-tumor memory immune response, thus leading to tumor growth in normally resistant mice. Our data suggest that not only do spleen and thymus have a stem cell reservoir to build up their stromal architecture, but also contain microenviromental immunoregulatory cells with the same properties of BM-MSCs.


Attosecond pulse extreme-ultraviolet photoionization in a two-color laser field.
Attosecond-pulse extreme-ultraviolet (XUV) photoionization in a two-color laser field is investigated. Attosecond pulse trains with different numbers of pulses are examined, and their strong dependence on photoelectronic spectra is found. Single-color driving-laser-field-assisted attosecond XUV photoionization cannot determine the number of attosecond pulses from the photoelectronic energy spectrum that are detected orthogonally to the beam direction and the electric field vector of the linearly polarized laser field. A two-color-field-assisted XUV photoionization scheme is proposed for directly determining the number of attosecond pulses from a spectrum detected orthogonally.


Disentangling the multifactorial contributions of fibronectin, collagen and cyclic strain on MMP expression and extracellular matrix remodeling by fibroblasts.
Early wound healing is associated with fibroblasts assembling a provisional fibronectin-rich extracellular matrix (ECM), which is subsequently remodeled and interlaced by type I collagen. This exposes fibroblasts to time-variant sets of matrices during different stages of wound healing. Our goal was thus to gain insight into the ECM-driven functional regulation of human foreskin fibroblasts (HFFs) being either anchored to a fibronectin (Fn) or to a collagen-decorated matrix, in the absence or presence of cyclic mechanical strain. While the cells reoriented in response to the onset of uniaxial cyclic strain, cells assembled exogenously added Fn with a preferential Fn-fiber alignment along their new orientation. Exposure of HFFs to exogenous Fn resulted in an increase in matrix metalloproteinase (MMP) expression levels, i.e. MMP-15 (RT-qPCR), and MMP-9 activity (zymography), while subsequent exposure to collagen slightly reduced MMP-15 expression and MMP-9 activity compared to Fn-exposure alone. Cyclic strain upregulated Fn fibrillogenesis and actin stress fiber formation, but had comparatively little effect on MMP activity. We thus propose that the appearance of collagen might start to steer HFFs towards homeostasis, as it decreased both MMP secretion and the tension of Fn matrix fibrils as assessed by Fluorescence Resonance Energy Transfer. These results suggest that HFFs might have a high ECM remodeling or repair capacity in contact with Fn alone (early event), which is reduced in the presence of Col1 (later event), thereby down-tuning HFF activity, a processes which would be required in a tissue repair process to finally reach tissue homeostasis.


Studies on corneal wound healing. Effect of fucose on iodine vapor-burnt rabbit corneas.
Corneal wound healing often leads to the development of scar tissue with loss of transparency. Reconstitution of transparent corneal stroma depends on the regulation of the biosynthetic activities of postlesional keratocytes and also to a large extent on the limitation of matrix degradation, attributed essentially to the upregulation of matrix metalloproteases and especially MMP-9. Using a standardized method for the production of reproducible corneal lesions by burning with iodine vapors, we could show that the local application of 0.5 mg/ml L-fucose reduced significantly MMP-9 upregulation and accelerated the recovery of the epithelial layer of the cornea. The iodine vapor used in the experiments produces a rapid loss of epithelium with no or slight effect below the basement membrane. A relatively rapid regrowth of epithelium was observed. The speed of this reepithelialization was stimulated by the local application of fucose. At 48 h after burn, there was a difference between fucose-treated and control corneas (epithelial thickness was about 50 mum for fucose-treated corneas and 37 microm for control corneas). Culture media of in vivo fucose-treated corneas showed an important decrease of MMP-9 activity (-51%, n = 6, p < 0.01). It appears that the in vivo fucose treatment reduced the MMP-9 activity released in the media. This effect is significant 24 h after iodine vapor burn. In order to study the effect of fucose on normal corneas, it was added to rabbit as well as human cornea explant cultures, and the production and release of MMP-9 was determined by zymography. Fucose at a concentration of 0.5 mg/ml produced a 70% decrease of MMP-9 activity released in the medium by corneal explant cultures. Other mono- and oligosaccharides were also tested. Besides lactose, fucose-rich oligosaccharides also produced significant inhibition. Galactose, melibiose, mannose and glucose were inactive. These results justify the use of fucose for the local treatment of corneal wounds.


Model-based learning of local image features for unsupervised texture segmentation.
Features that capture well the textural patterns of a certain class of images are crucial for the performance of texture segmentation methods. The manual selection of features or designing new ones can be a tedious task. Therefore, it is desirable to automatically adapt the features to a certain image or class of images. Typically, this requires a large set of training images with similar textures and ground truth segmentation. In this work, we propose a framework to learn features for texture segmentation when no such training data is available. The cost function for our learning process is constructed to match a commonly used segmentation model, the piecewise constant Mumford-Shah model. This means that the features are learned such that they provide an approximately piecewise constant feature image with a small jump set. Based on this idea, we develop a two-stage algorithm which first learns suitable convolutional features and then performs a segmentation. We note that the features can be learned from a small set of images, from a single image, or even from image patches. The proposed method achieves a competitive rank in the Prague texture segmentation benchmark, and it is effective for segmenting histological images.


Thoracic splenosis twenty-nine years after traumatic splenectomy mimicking intrathoracic neoplasm.
Thoracic splenosis refers to a condition of ectopic splenic tissue in the thoracic cavity. It is usually a consequence of splenic tissue seeding in the pleural cavity after thoracoabdominal trauma. A rare case of thoracic splenosis, in a 62-year-old man who had had a traumatic splenectomy due to thoracoabdominal trauma 29 years earlier, is reported. The patient, a heavy smoker, was admitted for evaluation of a left-side thoracic lesion discovered on a plain chest film. Bronchoscopy, CT scan and needle biopsy proved inconclusive for the diagnosis. Exploratory thoracotomy was necessary to establish the diagnosis. During the operation, a thoracic splenosis was confirmed. To date, only 28 cases of thoracic splenosis have been reported in the literature. The purpose of this report is to present a new case of splenosis of the thoracic cavity simulating intrathoracic neoplasm.


Transit time dispersion in the pulmonary arterial tree.
Knowledge of the contributions of arterial and venous transit time dispersion to the pulmonary vascular transit time distribution is important for understanding lung function and for interpreting various kinds of data containing information about pulmonary function. Thus, to determine the dispersion of blood transit times occurring within the pulmonary arterial and venous trees, images of a bolus of contrast medium passing through the vasculature of pump-perfused dog lung lobes were acquired by using an X-ray microfocal angiography system. Time-absorbance curves from the lobar artery and vein and from selected locations within the intrapulmonary arterial tree were measured from the images. Overall dispersion within the lung lobe was determined from the difference in the first and second moments (mean transit time and variance, respectively) of the inlet arterial and outlet venous time-absorbance curves. Moments at selected locations within the arterial tree were also calculated and compared with those of the lobar artery curve. Transit times for the arterial pathways upstream from the smallest measured arteries (200-micron diameter) were less than approximately 20% of the total lung lobe mean transit time. Transit time variance among these arterial pathways (interpathway dispersion) was less than approximately 5% of the total variance imparted on the bolus as it passed through the lung lobe. On average, the dispersion that occurred along a given pathway (intrapathway dispersion) was negligible. Similar results were obtained for the venous tree. Taken together, the results suggest that most of the variation in transit time in the intrapulmonary vasculature occurs within the pulmonary capillary bed rather than in conducting arteries or veins.


Follistatin is induced by ionizing radiation and potentially predictive of radiosensitivity in radiation-induced fibrosis patient derived fibroblasts.
Follistatin is a potent regulator of the inflammatory response and binds to and inhibits activin A action. Activin A is a member of the TGFβ protein superfamily which has regulatory roles in the inflammatory response and in the fibrotic process. Fibrosis can occur following cell injury and cell death induced by agents such as ionizing radiation (IR). IR is used to treat cancer and marked fibrotic response is a normal tissue (non-tumour) consequence in a fraction of patients under the current dose regimes. The discovery and development of a therapeutic to abate fibrosis in these radiosensitive patients would be a major advance for cancer radiotherapy. Likewise, prediction of which patients are susceptible to fibrosis would enable individualization of treatment and provide an opportunity for pre-emptive fibrosis control and better tumour treatment outcomes. The levels of activin A and follistatin were measured in fibroblasts derived from patients who developed severe radiation-induced fibrosis following radiotherapy and compared to fibroblasts from patients who did not. Both follistatin and activin A gene expression levels were increased following IR and the follistatin gene expression level was lower in the fibroblasts from fibrosis patients compared to controls at both basal levels and after IR. The major follistatin transcript variants were found to have a similar response to IR and both were reduced in fibrosis patients. Levels of follistatin and activin A secreted in the fibroblast culture medium also increased in response to IR and the relative follistatin protein levels were significantly lower in the samples derived from fibrosis patients. The decrease in the follistatin levels can lead to an increased bioactivity of activin A and hence may provide a useful measurement to identify patients at risk of a severe fibrotic response to IR. Additionally, follistatin, by its ability to neutralise the actions of activin A may be of value as an anti-fibrotic for radiation induced fibrosis.


The control of iron absorption by the gastrointestinal mucosal cell.
Gastrointestinal mucosal factors controlling rates of iron absorption were studied utilizing an in vivo closed duodenal loop technique. Cellular distribution of newly absorbed radioiron was identified by molecular sieve and iron-exchange chromatography of the mucosal cell supernate. In the normal animal, iron rapidly appeared in ferritin, and this fraction accounted for greater than 90% of mucosal supernatant radioactivity after 60 min absorption time. The nonferritin radioiron appeared to be unbound iron salts. In the presence of increased iron absorption induced by iron depletion or hemolysis, the major difference from the normal distribution pattern was an increase in the proportion and quantity of the free iron salts. Incorporation of newly absorbed iron into ferritin did not correlate with the rate of iron absorption. No evidence was found for a specific soluble iron-chelating molecule within the mucosal cell. The nonheme iron content of the mucosal supernates from iron-deficient and hemolyzing animals were significantly lower than in the normal animal.The data are consistent with hypotheses which suggest that iron absorption rates may be controlled in part by the rate of initial iron uptake by the mucosal cell and that a membrane transport mechanism exists which is modulated by the nonheme iron content of the mucosal cell or some portion thereof.


Immune response to a mammary adenocarcinoma. V. Sera from tumor-bearing rats contain multiple factors blocking cell-mediated cytotoxicity.
Sera from Fischer rats 3 to 13 days after i.p. injection of syngeneic 13762A mammary adenocarcinoma contain three factors specifically blocking cell-mediated cytotoxicity (CMC). The major blocking factor is a 160,000-dalton IgG that combines specifically to cytolytic lymphocytes but not to tumor cells or tumor antigen, and that is not dissociated after treatment with 8 M urea. The other factors have been putatively identified as tumor antigen (less than 70,000 daltons) and as soluble antigen-antibody complexes (greater than 200,000 daltons). Injecting the tumor antigen into tumor-free rats induced spleen cells specifically cytotoxic to the 13762A tumor and provided partial protection to challenge with live tumor cells. Treating soluble antigen-antibody complexes with 8 M urea decreased the size of the blocking activity from greater than 200,000 to less than 70,000 daltons. Although the IgG fraction dissociated from the complex did not block CMC, it did recombine with the tumor antigen fraction to transfer activity to the greater than 200,000-dalton fraction. In contrast, mixing tumor antigen with the IgG fraction that did block CMC did not alter the size of the blocking activities.


A prospective randomized controlled study of Aurolab aqueous drainage implant versus Ahmed glaucoma valve in refractory glaucoma: A pilot study.
To study the efficacy of the Aurolab aqueous drainage implant (AADI) compared to Ahmed glaucoma valve (AGV) in patients with refractory glaucoma. This was a prospective, randomized controlled trial. Thirty-eight adult patients (>18 years) scheduled for a glaucoma drainage device (GDD) were randomized into two groups to receive either AGV or AADI. Primary outcome measures: intraocular pressure (IOP) control and requirement of antiglaucoma medications; secondary outcome measures: final best correct visual acuity (log MAR), visual field (Visual field index [VFI], mean deviation [MD] and pattern standard deviation [PSD]), postoperative complications and additional interventions. Complete success was defined as IOP ≥5-≤18 mmHg without antiglaucoma medications/laser/additional glaucoma surgery or any vision threatening complications. There were 19 age and sex-matched patients in each group. Both groups had comparable IOP before surgery (P = 0.61). The AGV group had significantly lower IOP compared to AADI group (7.05 ± 4.22 mmHg vs 17.90 ± 10.32 mmHg, P = <0.001) at 1 week. The mean postoperative IOP at 6 months was not significantly different in the two groups (13.3 ± 4.2 and 11.4 ± 6.8 mmHg respectively; P = 0.48). At 6 months, complete success rate according to antiglaucoma medication criteria was 78.94% in AADI and 47.36% in AGV groups. AGV group required 1.83 times more number of topical medications than AADI group. There was no significant difference in early (P = 0.75) and late (P = 0.71) postoperative complications in the AADI and AGV group. The complete success rate was higher in AADI group (68.42%) than AGV group (26.31%) (P = 0.034). In this study, AADI appears to have comparable efficacy versus AGV implant with higher complete success rate at 6 months follow-up.


Mental Health and Behavior of College Students During the COVID-19 Pandemic: Longitudinal Mobile Smartphone and Ecological Momentary Assessment Study, Part II.
Since late 2019, the lives of people across the globe have been disrupted by COVID-19. Millions of people have become infected with the disease, while billions of people have been continually asked or required by local and national governments to change their behavioral patterns. Previous research on the COVID-19 pandemic suggests that it is associated with large-scale behavioral and mental health changes; however, few studies have been able to track these changes with frequent, near real-time sampling or compare these changes to previous years of data for the same individuals. By combining mobile phone sensing and self-reported mental health data in a cohort of college-aged students enrolled in a longitudinal study, we seek to understand the behavioral and mental health impacts associated with the COVID-19 pandemic, measured by interest across the United States in the search terms coronavirus and COVID fatigue. Behaviors such as the number of locations visited, distance traveled, duration of phone use, number of phone unlocks, sleep duration, and sedentary time were measured using the StudentLife mobile smartphone sensing app. Depression and anxiety were assessed using weekly self-reported ecological momentary assessments, including the Patient Health Questionnaire-4. The participants were 217 undergraduate students. Differences in behaviors and self-reported mental health collected during the Spring 2020 term, as compared to previous terms in the same cohort, were modeled using mixed linear models. Linear mixed models demonstrated differences in phone use, sleep, sedentary time and number of locations visited associated with the COVID-19 pandemic. In further models, these behaviors were strongly associated with increased interest in COVID fatigue. When mental health metrics (eg, depression and anxiety) were added to the previous measures (week of term, number of locations visited, phone use, sedentary time), both anxiety and depression (P<.001) were significantly associated with interest in COVID fatigue. Notably, these behavioral and mental health changes are consistent with those observed around the initial implementation of COVID-19 lockdowns in the spring of 2020. In the initial lockdown phase of the COVID-19 pandemic, people spent more time on their phones, were more sedentary, visited fewer locations, and exhibited increased symptoms of anxiety and depression. As the pandemic persisted through the spring, people continued to exhibit very similar changes in both mental health and behaviors. Although these large-scale shifts in mental health and behaviors are unsurprising, understanding them is critical in disrupting the negative consequences to mental health during the ongoing pandemic.


Predictors and outcomes of pacemaker implantation in patients with cardiac amyloidosis.
We sought to investigate prevalence, incidence and prognostic implications of permanent pacemaker (PPM) implantation in patients with cardiac amyloidosis (CA), thereby identifying the predictors of time to PPM implantation. Seven hundred eighty-seven patients with CA (602 men, median age 74 years, 571 transthyretin amyloidosis (ATTR), 216 light-chain amyloidosis (AL)) evaluated at two European referral centres were retrospectively included. Clinical, laboratory and instrumental data were analysed. The associations between PPM implantation and mortality, heart failure (HF) or a composite endpoint of mortality, cardiac transplantation and HF were analysed. 81 (10.3%) patients had a PPM before initial evaluation. Over a median follow-up time of 21.7 months (IQR 9.6-45.2), 81 (10.3%) additional patients (18 with AL (22.2%) and 63 with ATTR (77.8%)) underwent PPM implantation with a median time to implantation of 15.6 months (IQR 4.2-40), complete atrioventricular block was the most common indication (49.4%). Independent predictors of PPM implantation were QRS duration (HR 1.03, 95% CI 1.02 to 1.03, p<0.001) and interventricular septum (IVS) thickness (HR 1.1, 95% CI 1.03 to 1.17, p=0.003). The model to estimate the probability of PPM at 12 months and containing both factors showed a C-statistic of 0.71 and a calibration of slope of 0.98. Conduction system disease requiring PPM is a common complication in CA that affects up to 20.6% of patients. QRS duration and IVS thickness are independently associated with PPM implantation. A PPM implantation at 12 months model was devised and validated to identify patients with CA at higher risk of requiring a PPM and who require closer follow-up.


[Immune defense is both stimulated and inhibited by physical activity].
Physical exercise may enhance some and depress other immune functions. The biological importance of these changes is not fully elucidated. Acute endurance exercise results in a relatively large redistribution of leukocytes between circulating blood and other tissues, as well as an increase in circulating cytokines. Some of these changes have been related to energy metabolism. A temporal correlation has been observed between altered immune functions and resistance to infections. A post-exercise infection can be either the result of a pre-exercise, sub-clinical infection amplified by the performed work or a novel infection, acquired during a period of decreased immune function shortly after exercise. Animal experiments have demonstrated that the susceptibility to infections after exercise depends on exercise intensity and duration, type of pathogen and time of inoculation. Exercise before inoculation with some bacterial agents can enhance resistance to infection, while exercise during an ongoing viral or bacterial infection worsens symptoms and enhances the risk for complications. Most studies demonstrate a deleterious effect of physical exercise in conjunction with infectious episodes.


Jaundice in the emergency department: meeting the challenges of diagnosis and treatment.
There are approximately 52,000 visits a year to emergency departments for patients presenting with jaundice. While many of these patients will not have immediately life-threatening pathology, it is essential that the emergency clinician understands the pathophysiology of jaundice, as this will guide the appropriate workup to detect critical diagnoses. Patients who present with jaundice could require intravenous antibiotics, emergent surgery, and, in severe cases, organ transplantation. This issue will focus on the challenge of evaluating and treating the jaundiced patient in the ED using the best available evidence from the literature.


Proton circulation in Vibrio costicola.
The importance of proton movements was assessed in the moderate halophile Vibrio costicola. When anaerobic cells in acidic buffer (pH 6.5) were given an O2 pulse, protons were extruded regardless of the presence of Na+. At pH 8.5, however, V. costicola produced an acidic response to an O2 pulse in the absence of Na+ and an alkaline response when Na+ was present. An Na+/H+ antiport activity was confirmed at pH 8.5. All of these effects were prevented by protonophores or butanol treatment. Growth in complex medium at pH 8.5 was prevented by a high concentration (50 microM) of carbonyl cyanide m-chlorophenyl-hydrazone (CCCP) or a low concentration (5 microM) of another protonophore, 3,3',4',5-tetrachlorosalicylanilide (TCS). The relative ineffectiveness of the former protonophore was caused by the proteose peptone and tryptone ingredients of the complex medium, since 5 microM completely prevented growth in their absence. The results are explained by a primary respiratory-linked proton efflux coupled to a secondary Na+/H+ antiport operating at alkaline pH. Evidence was seen for a role of Na+ in stimulating proton influx at alkaline pH, presumably via the pH homeostasis mechanism.


Associations between genetic variants in the TGF-β signaling pathway and breast cancer risk among Hispanic and non-Hispanic white women.
The TGF-β signaling pathway has a significant role in breast cancer initiation and promotion by regulating various cellular processes. We evaluated whether genetic variation in eight genes (TGF-β1, TGF-β2, TGF-βR1, TGF-βR2, TGF-βR3, RUNX1, RUNX2, and RUNX3) is associated with breast cancer risk in women from the Breast Cancer Health Disparities Study. A total of 3,524 cases (1,431 non-Hispanic whites (NHW); 2,093 Hispanics/Native Americans(NA)) and 4,209 population-based controls (1,599 NHWs; 2,610 Hispanics/NAs) were included in analyses. Genotypes for 47 single nucleotide polymorphisms (SNPs) were determined. Additionally, 104 ancestral informative markers estimated proportion of NA ancestry. Associations with breast cancer risk overall, by menopausal status, NA ancestry, and estrogen receptor (ER)/progesterone receptor tumor phenotype were evaluated. After adjustment for multiple comparisons, two SNPs were significantly associated with breast cancer risk: RUNX3 (rs906296 ORCG/GG = 1.15 95 % CI 1.04-1.26) and TGF-β1 (rs4803455 ORCA/AA = 0.89 95 % CI 0.81-0.98). RUNX3 (rs906296) and TGF-βR2 (rs3773644) were associated with risk in pre-menopausal women (p adj = 0.002 and 0.02, respectively) and in those with intermediate to high NA ancestry (p adj = 0.04 and 0.01, respectively). Self-reported race was strongly correlated with NA ancestry (r = 0.86). There was a significant interaction between NA ancestry and RUNX1 (rs7279383, p adj = 0.04). Four RUNX SNPs were associated with increased risk of ER- tumors. Results provide evidence that genetic variation in TGF-β and RUNX genes are associated with breast cancer risk. This is the first report of significant associations between genetic variants in TGF-β and RUNX genes and breast cancer risk among women of NA ancestry.


Characteristics of borderline personality disorder: a Canadian study.
This study presents data on a Canadian sample of inpatients with the diagnosis of Borderline Personality Disorder (BPD). Inpatients with BPD were compared to inpatients with borderline traits. The results indicate that the BPD inpatients have a chronic severe disorder, which onsets in adolescence, and are likely to have suffered early deprivation or abuse.


Three novel transcription factors involved in cannabinoid biosynthesis in Cannabis sativa L.
Three novel transcription factors were successfully identified and shown to interact with the trichome-specific THCAS promoter regulatory region. Cannabinoids are important secondary metabolites present in Cannabis sativa L. (cannabis). One cannabinoid that has received considerable attention, 9-tetrahydrocannabinol (THC), is derived from Delta-9-Tetrahydrocannabinolic acid (THCA) and responsible for the mood-altering and pain-relieving effects of cannabis. A detailed understanding of transcriptional control of THCA synthase (THCAS) is currently lacking. The primary site of cannabinoid biosynthesis is the glandular trichomes that form on female flowers. Transcription factors (TFs) have been shown to play an important role in secondary-metabolite biosynthesis and glandular trichome formation in Artemisia annua, Solanum lycopersicum and Humulus lupulus. However, analogous information is not available for cannabis. Here, we characterize a 548 bp fragment of the THCAS promoter and regulatory region that drives trichome-specific expression. Using this promoter fragment in a yeast-one-hybrid screen, we identified 3 novel TFs (CsAP2L1, CsWRKY1 and CsMYB1) and provided evidence that these 3 TFs regulate the THCAS promoter in planta. The O-Box element within the proximal region of the THCAS promoter is necessary for CsAP2L1-induced transcriptional activation of THCAS promoter. Similar to THCAS, the genes for all three TFs have trichome-specific expression, and subcellular localization of the TFs indicates that all three proteins are in the nucleus. CsAP2L1 and THCAS exhibit a similar temporal, spatial and strain-specific gene expression profiles, while those expression patterns of CsWRKY1 and CsMYB1 are opposite from THCAS. Our results identify CsAP2L1 playing a positive role in the regulation of THCAS expression, while CsWRKY1 and CsMYB1 may serve as negative regulators of THCAS expression.


Process improvement for semipurified oleosomes on a pilot-plant scale.
Semipurified oleosomes were isolated on a pilot-plant scale using improved-process extraction conditions. The improved process consisted of continuous centrifugation in a three-phase decanter with recirculation of slurry until most of the oleosomes were recovered. Oleosome fractionation, oleosin identification, and isoflavone and saponin mass distributions and recoveries were investigated. The improved pilot-plant oleosome extraction process was achieved in 8 h. A total of 91%± 1% of soybean oil was recovered as intact oleosomes. The oil content of the aqueous supernatant and the residue fractions were low at 2% and 3%, respectively. The aqueous supernatant fraction contained 40% total soybean protein. About 76% of the proteins present in the oleosome fraction were soybean storage proteins. Washing the semipurified oleosomes with a 0.1 M Tris-HCl, pH 8.6 containing 0.4 M sucrose, and 0.5 M NaCl resulted in the recovery of the associated storage proteins. The recovery of these proteins in addition to the protein in aqueous supernatant accounted for 79% of the total soybean storage proteins fractionated by this process. Oleosins were detected at 17 and 18 kDa. Isoflavones and saponins partitioned into the oleosome, aqueous supernatant, and residue fractions at different ratios with the majority, about 82 and 63 mole%, respectively, in oleosome and aqueous supernatant fractions, making these fractions an attractive source for phytochemicals.


THE KINETICS OF EXOSMOSIS OF WATER FROM LIVING CELLS.
1. The rate of exosmosis of water was studied in unfertilized Arbacia eggs, in order to bring out possible differences between the kinetics of exosmosis and endosmosis. 2. Exosmosis, like endosmosis, is found to follow the equation See PDF for Equation, in which a is the total volume of water that will leave the cell before osmotic equilibrium is attained, x is the volume that has already left the cell at time t, and k is the velocity constant. 3. The velocity constants of the two processes are equal, provided the salt concentration of the medium is the same. 4. The temperature characteristic of exosmosis, as of endomosis, is high. 5. It is concluded that the kinetics of exosmosis and endosmosis of water in these cells are identical, the only difference in the processes being in the direction of the driving force of osmotic pressure.


Monocytic cell activation by Nonendotoxic glycoprotein from Prevotella intermedia ATCC 25611 is mediated by toll-like receptor 2.
Lipopolysaccharide (LPS) preparations from gram-negative black-pigmented bacteria such as Porphyromonas gingivalis and Prevotella intermedia activate cells from non-LPS-responsive C3H/HeJ mice, but it is still unclear whether this activity is due to the unique structure of LPS or to a minor component(s) responsible for the activity in the preparation. A nonendotoxic glycoprotein with bioactivity against cells from C3H/HeJ mice was purified from a hot phenol-water extract of P. intermedia ATCC 25611 and designated Prevotella glycoprotein (PGP). Treatment of human monocytic THP-1 cells with 22-oxyacalcitriol (OCT) induced maturation and marked expression of CD14 on the cells, but the cells constitutively expressed Toll-like receptor 2 (TLR2) and TLR4 on the cells irrespective of the treatment. PGP induced a high level of interleukin-8 production at doses of 100 ng/ml and higher in OCT-treated THP-1 cells compared with Salmonella LPS, and the production was significantly inhibited by anti-CD14 and anti-TLR2 but not anti-TLR4 antibodies. Consistent with this, TLR2-deficient murine macrophages did not respond to PGP. It was also shown that PGP activity on the THP-1 cells was LPS-binding protein dependent and was inhibited by a synthetic lipid A precursor IV(A). These results indicate that PGP activates monocytic cells in a CD14- and TLR2-dependent manner.


Chondrocyte cluster formation in agarose cultures as a functional assay to identify genes expressed in osteoarthritis.
Understanding altered gene expression in osteoarthritic cartilage can lead to new targets for drug intervention. We established a functional assay based on chondrocyte cluster formation, a phenotype associated with osteoarthritis (OA), to screen an OA cartilage gene library. Previous reports have demonstrated that normal chondrocytes grown in suspension culture maintain their chondrocytic phenotype, however, certain growth factors such as basic fibroblast growth factor (bFGF) will induce the cells to proliferate in tight clusters similar to those seen in osteoarthritic cartilage. In this study we validate that overexpression of bFGF by retrovirally transduced normal chondrocytes would similarly induce the proliferation of tight cell clusters. We then used this approach as a basis to set up a functional screen where an entire OA cartilage cDNA library was tranduced into normal chondrocytes to search for other genes that would also induce cluster formation. Seven potential genes were isolated from the OA gene library, including BPOZ, IL-17 receptor C, NADH ubiquinone oxidoreductase, COMP, Soluble carrier 16 (MCT 3), C1r, and bFGF itself. None of the identified genes were upregulated by bFGF, however, all of them upregulated the expression of bFGF suggesting a common pathway. Although cluster formation is not considered to be destructive in OA cartilage, it is consistent with the disease and could yield answers to the altered phenotype. Further studies are needed to elucidate how these genes are linked to the disease state.


Atrial natriuretic peptide differentially modulates T- and L-type calcium channels.
Atrial natriuretic peptide (ANP) inhibits the secretion of aldosterone stimulated by any of these major physiological agonists: angiotensin II, adrenocorticotropic hormone, or K+. The stimulatory actions of each of these agonists depend on calcium influx through voltage-dependent calcium channels. Because two types of calcium channels have been previously described in bovine glomerulosa cells (T- and L-type), the patch-clamp technique was used to evaluate the effect of ANP on each voltage-dependent calcium channel type. ANP was found to differentially modulate these two channel types, stimulating L-current while inhibiting T-current. Inhibition of T-current resulted from a shift in the voltage dependence of inactivation to more negative potentials within the physiological range. These results indicate that the ANP-induced inhibition of aldosterone secretion may be partially mediated via a reduction of the calcium current through T-type channels.


Lifestyle Intervention in Pregnant Women With Obesity Impacts Cord Blood DNA Methylation, Which Associates With Body Composition in the Offspring.
Maternal obesity may lead to epigenetic alterations in the offspring and might thereby contribute to disease later in life. We investigated whether a lifestyle intervention in pregnant women with obesity is associated with epigenetic variation in cord blood and body composition in the offspring. Genome-wide DNA methylation was analyzed in cord blood from 208 offspring from the Treatment of Obese Pregnant women (TOP)-study, which includes pregnant women with obesity randomized to lifestyle interventions comprised of physical activity with or without dietary advice versus control subjects (standard of care). DNA methylation was altered at 379 sites, annotated to 370 genes, in cord blood from offspring of mothers following a lifestyle intervention versus control subjects (false discovery rate [FDR] <5%) when using the Houseman reference-free method to correct for cell composition, and three of these sites were significant based on Bonferroni correction. These 370 genes are overrepresented in gene ontology terms, including response to fatty acids and adipose tissue development. Offspring of mothers included in a lifestyle intervention were born with more lean mass compared with control subjects. Methylation at 17 sites, annotated to, for example, DISC1, GBX2, HERC2, and HUWE1, partially mediates the effect of the lifestyle intervention on lean mass in the offspring (FDR <5%). Moreover, 22 methylation sites were associated with offspring BMI z scores during the first 3 years of life (P < 0.05). Overall, lifestyle interventions in pregnant women with obesity are associated with epigenetic changes in offspring, potentially influencing the offspring's lean mass and early growth.


Principles and methods for transferring polygenic risk scores across global populations.
Polygenic risk scores (PRSs) summarize the genetic predisposition of a complex human trait or disease and may become a valuable tool for advancing precision medicine. However, PRSs that are developed in populations of predominantly European genetic ancestries can increase health disparities due to poor predictive performance in individuals of diverse and complex genetic ancestries. We describe genetic and modifiable risk factors that limit the transferability of PRSs across populations and review the strengths and weaknesses of existing PRS construction methods for diverse ancestries. Developing PRSs that benefit global populations in research and clinical settings provides an opportunity for innovation and is essential for health equity.


Pressure ulcer development and vasopressor agents in adult critical care patients: a literature review.
Critical care units provide technologically sophisticated care to the sickest patients in the healthcare system. The contribution of iatrogenic factors, including administration of pharmacologic agents such as vasopressors, to pressure ulcer (PU) development in adult critical care patients is understudied, thus less understood, but may be an important PU risk factor to consider in the critical care population. Vasopressor agents are potent vasoconstrictors commonly administered to critical care patients to elevate mean arterial pressure to counteract the effects of inadequate tissue perfusion and hypoxia; they have reemerged over the past decade in contemporary intensive care units as important first-line drugs in the treatment of shock states. A comprehensive review of the literature was undertaken in order to determine the level of evidence regarding the relationship between vasopressor agents (norepinephrine, epinephrine, phenylephrine, vasopressin, and dopamine) and PU development in adult critical care patients. Computerized databases of EBSCOCINAHL and OVID MEDLINE were searched for English-language publications from 2000 to the present using the following terms: pressure ulcer, vasopressor, norepinephrine, epinephrine, vasopressin, dopamine, phenylephrine, critical care and pressure ulcers; intensive care and pressure ulcers; and pressure ulcer risk factors. Ten studies were identified that met the inclusion/exclusion criteria. Statistically significant associations were reported between the broad category of vasopressor agents and PU development in seven studies. Of those, two identified a specific vasopressor agent (norepinephrine) as a significant predictor of PU development in this population. Empirical support for the broad category of vasopressors as a PU risk factor is increasing, and a small body of evidence is emerging to support the role of one specific vasopressor (norepinephrine) in PU development. Increased vigilance regarding PU risk in critical care patients receiving vasopressor agents may be warranted. However, studies are needed to examine the effects of individual vasopressor agents and dosage and duration thresholds, as well as empirical investigation regarding the synergistic effect of multiple vasopressor agents administered simultaneously, on PU development in this population. Finally, research is needed to further elucidate vasopressor use as an independent risk factor for PU development in this population.


Ultrasonic Doppler technique for imaging blood vessels.
Present ultrasonic Doppler flow detectors that use the Doppler effect on waves scattered from moving blood have provided useful information when directed by hand to trace the circulation of animals and man. By scanning with a highly directive flow detector, the areas of flow can be localized. Images can be formed of the interior of blood vessels. These images have the appearance of arteriograms and venograms made by dye contrast radiography, but have none of its hazards. The resolution appears adequate for useful images.


Genomic microarrays in the spotlight.
Microarray-based comparative genomic hybridization (array-CGH) has emerged as a revolutionary platform, enabling the high-resolution detection of DNA copy number aberrations. In this article we outline the use and limitations of genomic clones, cDNA clones and PCR products as targets for genomic microarray construction. Furthermore, the applications and future aspects of these arrays for DNA copy number analysis in research and diagnostics, epigenetic profiling and gene annotation are discussed. These recent developments of genomic microarrays mark only the beginning of a new generation of high-resolution and high-throughput tools for genetic analysis.


ETV6/RUNX1 fusion lacking prognostic effect in pediatric patients with acute lymphoblastic leukemia.
A Brazilian sample of 58 patients with acute lymphoblastic leukemia has been prospectively followed up with the objective of evaluating evolution of disease. Age ranged from 6 months to 16 years. Of the 58 patients, 11 were positive and 47 were negative for the ETV6/RUNX1 fusion (previously known as TEL/AML1). After a minimum follow-up period of 57 months, 2 of the ETV6/RUNX1(+) patients had died and 11 of the ETV6/RUNX1(-), for an overall survival of 77.6%. Among the 11 ETV6/RUNX1(+) patients (age range, 2 years to 13 years 7 months), all achieved a complete remission; the average overall survival was 64.2 months and the average event-free survival was 61.7 months. Among the 47 ETV6/RUNX1(-) patients, 4 did not have a complete remission; the average overall survival was of 60.8 months and the average event-free survival was 57.2 months. No significant difference was observed between overall survival and event-free survival, nor in any of the other data comparatively analyzed. The patients had a cure rate similar to that described in literature. In this small sample population, the presence of the ETV6/RUNX1 fusion did not identify statistical difference in prognosis.


Cardiac risk in patients aged >75 years with asymptomatic, severe aortic stenosis undergoing noncardiac surgery.
Severe aortic stenosis (AS) is a known predictor of cardiac risk during noncardiac surgery. However, for patients with asymptomatic AS, it is unclear whether aortic valve surgery should precede noncardiac surgery. We studied 30 patients with asymptomatic, severe AS with a mean age of 78 + or - 9 years, an aortic valve area of 0.77 + or - 0.16 cm(2), a mean gradient of 50.1 + or - 9.5 mm Hg, and a peak gradient of 84 + or - 22 mm Hg. They were compared to 60 age-matched (within 2 years) and gender-matched (ratio of 1:2) patients with mild-to-moderate AS (controls). The primary end point of the study was a composite of death, myocardial infarction, heart failure, ventricular arrhythmias before dismissal, and intraoperative hypotension requiring vasopressor administration. Most patients (>75%) and controls underwent intermediate-risk surgical procedures that were similar with respect to the nature of the surgery, type of anesthesia used, and preoperative risk assessment. Combined postoperative events were more common for the patients (n = 10; 33%) than for the controls (n = 14; 23%), but the difference was not statistically significant (p = 0.06). Intraoperative hypotension requiring vasopressor use was more likely for the patients (n = 9; 30%) than for the controls (n = 10; 17%; odds ratio 2.5; p = 0.11). The perioperative myocardial infarction rates were similar for both groups (3%; p = 0.74). No deaths, heart failure events, or ventricular arrhythmias occurred in the patients and 1 death and 1 ventricular arrhythmia episode occurred in the controls. In conclusion, intermediate-to-low-risk noncardiac surgery for patients with severe, asymptomatic AS can be performed relatively safely. Intraoperative hypotension was frequent and required prompt and aggressive treatment.


Real-time extracellular measurement of neurotransmitters in conscious sheep.
Measurements of neurotransmitters in conscious animals have been restrictive in real-time. The use of specific enzymes within an amperometric probe, based upon a microdialysis membrane, may overcome some of these problems. I report the use of such a probe, with different perfusions of enzymes, to allow real-time measurement of glutamate, catecholamines and indoleamines, in conscious animals. At an adjacent site microdialysis sample collections were made concurrently and neurotransmitters measured in the dialysate. Both probes were positioned within the somatosensory cortex. Values obtained by amperometric probes were similar to those in dialysate samples for glutamate, catecholamines and indoleamines during basal and stimuli related collections. Amperometric measurements showed higher peak concentrations and better time resolution than dialysate sampling. This reflects sampling differences. Application of external stimuli increased extracellular concentrations of glutamate, catecholamines and indoleamines, in both forms of sampling. Dopamine measurements did not correlate well between the two forms of sampling. This may reflect the non-specificity of the enzyme (dopamine-beta-hydroxylase) used in the amperometric probe. This combination, of microdialysis and amperometry, offers a useful tool for real-time neurotransmitter studies in vivo.


Body Mass Index, masculinities and moral worth: men's critical understandings of 'appropriate' weight-for-height.
Based on the Body Mass Index (BMI, kg/m(2)), most men in nations such as the UK and USA are reportedly overweight or obese. This is authoritatively defined as a massive and growing problem. Drawing from embodied sociology, critical obesity literature and qualitative data generated during an Economic and Social Research Council funded project on masculinities and weight-related issues, this paper offers a critical realist contribution to the obesity debate. Rather than endorsing the institutionalised war on fat, and correcting so-called 'laymen' who dismiss medicalized weight-for-height recommendations, the following presents and honours men's justificatory accounts for levels of body mass that medicine labels too heavy (implicitly or explicitly too fat). Men's critical understandings, which are connected to their displays of moral worth, are considered under three headings: the compatibility of heaviness, healthiness and physical fitness; looking and feeling ill at a supposedly 'healthy' BMI; and resisting irrational standardisation. By empirically 'bringing in' men's meanings, sensibilities and culturally informed aesthetics, this paper casts a different light on medicalized measures that support potentially corrosive obesity epidemic psychology.


Cancer rates not explained by smoking: a county-level analysis.
Debates over the importance of "lifestyle" versus "environment" contributions to cancer have been going on for over 40 years. While it is clear that cigarette smoking is the most significant cancer risk factor, the contributions of occupational and environmental carcinogens in air, water and food remain controversial. In practice, most cancer prevention messaging focuses on reducing cigarette smoking and changing other personal behaviors with little mention of environmental chemicals, despite widespread exposure to many known carcinogens. To inform decision-making on cancer prevention priorities, we evaluated the potential impact of smoking cessation on cancer rates. Using cancer incidence data from 612 counties in the SEER database, and county-level smoking prevalences, we investigated the impact of smoking cessation on incidence for 12 smoking-related cancer types, 2006-2016. A multilevel mixed-effects regression model quantified the association between county-level smoking prevalence and cancer incidence, adjusting for age, gender and variability over time and among counties. We simulated complete smoking cessation and estimated the effects on county-level cancer rates. Regression models showed the expected strong association between smoking prevalence and cancer incidence. Simulating complete smoking cessation, the incidence of the 12 smoking-related cancer types fell by 39.8% (54.9% for airways cancers; 28.9% for non-airways cancers). And, while the actual rates of smoking-related cancers from 2006 to 2016 declined (annual percent change (APC) = - 0.8, 95% CI = - 1.0 to - 0.5%), under the scenario of smoking elimination, the trend in cancer incidence at these sites was not declining (APC = - 0.1, 95% CI = - 0.4 to + 0.1%). Not all counties were predicted to benefit equally from smoking elimination, and cancer rates would fall less than 10% in some counties. Smoking prevention has produced dramatic reductions in cancer in the US for 12 major types. However, we estimate that eliminating smoking completely would not affect about 60% of cancer cases of the 12 smoking-related types, leaving no improvement in the incidence trend from 2006 to 2016. We conclude that cancer prevention strategies should focus not only on lifestyle changes but also the likely contributions of the full range of risk factors, including environmental/occupational carcinogens.


When "the Cure" Is the Risk: Understanding How Substance Use Affects HIV and HCV in a Layered Risk Environment in San Juan, Puerto Rico.
Substance use, particularly injection drug use, continues to fuel the HIV/HCV (hepatitis C virus) epidemics in San Juan, Puerto Rico (PR). This article examines individual and sociostructural factors that affect HIV/HCV risk among people who use drugs (PWUD) living with or at risk for HIV/HCV in San Juan, PR. Findings were used to inform a community-level intervention to enhance HIV care access and retention for this population. A rapid ethnographic assessment in collaboration with a community-based organization was conducted. Data collection took place between June and December 2013 and included field observations, 49 unstructured interviews with PWUD, and 19 key informant interviews with community stakeholders. Fieldnotes, photographs, and interview transcripts were analyzed for recurrent themes and to address the intervention-planning needs. Study results are presented as fieldnote excerpts, direct quotes from interviews, and photographs. Findings suggest that PWUD in PR face myriad challenges that affect HIV/HCV risk and hinder linkage to and retention in care. Results describe a layered risk environment where PWUD encounter many barriers to prevention, care, and treatment such as transience, social isolation, stigma, limited housing options, and inadequate medical and substance use disorder treatment services. These observed circumstances provide an empirical basis for the development and evaluation of comprehensive interventions that may serve to reduce barriers to care and link individuals to other supportive services. New approaches and comprehensive interventions are needed to break the structures that perpetuate risk and lack of engagement and retention in HIV care and substance use disorder treatment in San Juan.


The initial clinical experience of 1819 physicians in maintaining anesthesia with propofol: characteristics associated with prolonged time to awakening.
In October 1989, propofol underwent Phase IV Food and Drug Administration testing that involved 25,981 patients, 1722 institutions, and 1819 anesthesiologists. Participants were 18-80 yr of age and ASA physical status I-III; they could not have a continuing pregnancy or prior adverse anesthetic experience. Anesthesiologists completed detailed forms to describe their use of propofol in this three-step study: propofol for induction only (Step 1), for induction and then maintenance by intermittent bolus injection (Step 2), or for continuous infusion (Step 3). In early 1992, our group of anesthesiologists and epidemiologists analyzed the resulting data base. We evaluated data from 14,882 patients (8095 given bolus injections and 6787 given continuous infusion) to determine factors predicting prolonged time (> 15 min after cessation of all anesthesia) to awakening, one measure of recovery from anesthesia. The incidence of prolonged awakening was 6.8% (1016 patients); the median and mean (+/- SD) times to awakening were, respectively, 5 min and 7.2 +/- 7.3 min. The following variables were associated (P < 0.05) with prolonged awakening from propofol maintenance anesthesia: a total dose of propofol > 8 mg/kg, male gender, endotracheal intubation, age > 65 yr, abdominal surgery, continuous infusion of propofol, and concomitant use of isoflurane or benzodiazepines. These results support the clinical impression that recovery from propofol anesthesia is remarkably rapid; although the vast majority of physicians participating in this study were using propofol for maintenance for the first time, only 6.8% of patients had awakening times exceeding 15 min.


[Animal experiment studies on CO2 laser stapedotomy].
Experiments were performed in guinea pigs to clarify which, if any, of the CO2 lasers used can damage the inner ear on application of the laser parameters required for stapedotomy. A further aim was to determine their application safety. The basal convolution of the guinea-pig cochlea was chosen as the application site, since its thickness is similar to that of the human stapes base. We examined the laser effect in connection with perforation of the basal convolution and subsequent application in the open cochlea. Acoustic evoked potentials (compound action potentials [CAP]) yielded information on inner-ear function. Animals without laser treatment were used as controls. Perforation of the basal convolution and laser applications in the open cochlea with the same parameters did not lead to a measurable CAP alteration with the CO2 cw laser (power: 8 W, pulse duration: 50 ms, power density: 3200 W/cm2). An increase of the laser power to 15 W (power density: 6000 W/cm2) and of the pulse duration to 200 and 500 ms (energy: 3 J and 7.5 J) caused partly irreversible CAP alterations; finally, no potential could be recorded any more at a maximal laser power and pulse duration (15 W and 500 ms). Examination of high power densities (40,000 and 60,000 W/cm2) through reduction of the laser beam diameter to 180 microns yielded comparable results.(ABSTRACT TRUNCATED AT 250 WORDS)


Incremental Value of Transesophageal Echocardiography Integrated with Transthoracic Echocardiography in the Assessment of Aortic Stenosis Severity.
Transthoracic echocardiography (TTE) is the standard method for evaluating the severity of aortic stenosis (AS), while transesophageal echocardiography (TEE) is useful for morphologic characterization. The study aim was to assess the impact of complementary TEE to TTE in refining hemodynamic assessment of AS severity. A retrospective analysis was conducted of sequential TTE and TEE studies performed in 100 patients with moderate or severe AS confirmed on prior TTE. The left ventricular outflow tract (LVOT) velocity-time-integral (VTI1) and the aortic valve velocity-time integral (VTI2) were measured for both modalities. The highest values of VTI1 and VTI2 and mean gradients and peak velocities were selected from the sequential TTE/TEE study for indexed aortic valve area (AVAi) calculation and AS severity determination through an integrated assessment. AVAi determined by TTE was not significantly different from that determined by TEE (mean difference -0.008 cm2; p = 0.38). The dimensionless velocity index (DVI) was higher when assessed by TTE than by TEE (mean difference 0.0126 ± 0.04; p = 0.003). Using the integrated AS assessment, six of 13 patients with a TTE-based diagnosis of moderate AS were re-classified as severe AS. A slight lowering of the recommended TTE-derived DVI threshold for severe AS, from 0.25 to 0.24, improved the ability to discriminate moderate versus severe AS, as determined by the integrated assessment. TEE integrated with TTE may improve the detection of severe AS, particularly in patients with moderate AS criteria assessed by TTE, but with a DVI ratio ≤0.24.


A segmentation algorithm for automated tracking of fast swimming unlabelled cells in three dimensions.
Recent advances in microscopy and cytolabelling methods enable the real time imaging of cells as they move and interact in their real physiological environment. Scenarios in which multiple cells move autonomously in all directions are not uncommon in biology. A remarkable example is the swimming of marine spermatozoa in search of the conspecific oocyte. Imaging cells in these scenarios, particularly when they move fast and are poorly labelled or even unlabelled requires very fast three-dimensional time-lapse (3D+t) imaging. This 3D+t imaging poses challenges not only to the acquisition systems but also to the image analysis algorithms. It is in this context that this work describes an original automated multiparticle segmentation method to analyse motile translucent cells in 3D microscopical volumes. The proposed segmentation technique takes advantage of the way the cell appearance changes with the distance to the focal plane position. The cells translucent properties and their interaction with light produce a specific pattern: when the cell is within or close to the focal plane, its two-dimensional (2D) appearance matches a bright spot surrounded by a dark ring, whereas when it is farther from the focal plane the cell contrast is inverted looking like a dark spot surrounded by a bright ring. The proposed method analyses the acquired video sequence frame-by-frame taking advantage of 2D image segmentation algorithms to identify and select candidate cellular sections. The crux of the method is in the sequential filtering of the candidate sections, first by template matching of the in-focus and out-of-focus templates and second by considering adjacent candidates sections in 3D. These sequential filters effectively narrow down the number of segmented candidate sections making the automatic tracking of cells in three dimensions a straightforward operation.


Fas ligand is constitutively secreted by prostate cancer cells in vitro.
LNCaP, DU145, and PC3 prostate carcinoma cells secrete the 27-kDa soluble Fas ligand (sFasL) into their local environment. sFasL arises from the 40-kDa membrane-bound form (mFasL), which can be found on the cell surface in the LNCaP line, as demonstrated by monoclonal antibody staining. mFasL was also found in extracts of all three cell lines, as demonstrated by Western blotting. FasL mRNA was detected not only in the cell lines, but in the normal prostate as well. sFasL protein could also be detected immunohistochemically in prostate secretions and in human semen. Cleavage of mFasL to sFasL could be inhibited by several matrix metalloprotease inhibitors without a change in the cellular levels of FasL. Prostate-derived sFasL is biologically active, as demonstrated by its induction of apoptosis in Fas-positive Ramos cells, which was detected by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. Mitoxantrone induces cellular apoptosis in all three prostate cancer cell lines. Mitoxantrone treatment and doxorubicin treatment also cause up-regulation of Fas, the cell surface receptor for FasL, in LNCaP cells, but not in DU145 or PC3 cells. Furthermore, the up-regulation of Fas expression by mitoxantrone at a high concentration was potentiated by hydrocortisone. When FasL interacts with its Fas, the Fas-bearing cell undergoes apoptosis. When LNCaP cells were treated with mitoxantrone and incubated with an anti-FasL monoclonal antibody, apoptosis was partially blocked. This not only further suggests that the sFasL is biologically active, but that the up-regulation of Fas in the presence of sFasL accounts, in part, for the cytotoxicity of mitoxantrone.


Model of Structured Emulsion Droplet Stability and Reconfigurability.
A model of internally structured emulsion droplets is presented that accounts for the traction forces generated by interfacial tension and the von Mises yield criterion of the internal supporting network. For symmetric droplets, the method calculates the total stress acting on a droplet locally, allowing droplet stability and location of failure to be predicted. It is not regions of high interfacial curvature that prompt droplet reconfiguration, rather regions transitioning from high to low curvature. The model enables the design of emulsion droplet response and reconfigurability to external triggers such as changes in surface tension (surfactant concentration) and temperature.


Recent developments of oleogel utilizations in bakery products.
Available evidence from clinical trials suggests the replacement of saturated fatty acids with polyunsaturated fatty acids as well as with essential fatty acids to reduce the risk of coronary heart disease. Thus, the importance of limiting of saturated fatty acid intake as well as the removal of trans-fatty acids from the diet have also emphasized. Conversely, recent studies have questioned the simple explanation of the relationship of dietary saturated fats and of individual saturated fatty acids to cardiovascular disease. Although, controversies continue to exist, current recommendations have highlighted that the importance of a critical look at the evaluation of scientific understanding about dietary fats and health. Therefore, manufacturers and scientists have focused on seeking alternative ways to modify or structure liquid oil without the use of saturated and trans-fats and hence to offer the functionality of fats to food products without changing the nutritional profile of liquid oil. However, since shortening as the essential component of bakery products affects dough structure and the desired final product attributes, the replacement of shortening creates a big challenge in bakery problems. The aim of this study was to provide an overview of the functions of shortening in bakery products and of the field of oleogels with special importance on the updates from recent years and their possible applications in bakery products. With the incorporation of oleogels or oleogel/shortening blends, rheological properties of dough/batters as well as physicochemical properties of resulted products may be resembled to those made with shortening. Conversely, the application of this technique had a role on retaining solid-like properties while possesses a healthier fatty acid profile. Very recent study indicated that gradual replacement of shortening with oleogels have potential for partial reduction of saturated fat without chancing physical properties of gluten free aerated products. Thus, the applications of oleogels may also present more alternatives for celiac sufferers' diet.


Preferred provider organizations: antitrust aspects and implications for the hospital industry.
The hospital industry is currently undergoing a substantial transformation as a result of changes in third party reimbursement mechanisms and a tendency toward a more competitive economic environment. Hospital administrators will have to demonstrate substantial flexibility in considering and implementing innovative institutional arrangements to ensure survival in this time of austerity. The Preferred Provider Organization (PPO) is a recent development in the health care industry involving the selective contracting for health care services. This Article examines the role of section 1 of the Sherman Antitrust Act in scrutinizing the PPO for anticompetitive effects, considering the divergent requisites for competition in the health care sector. The Article also proposes a modified Rule of Reason for application to the PPO and other innovative cost containment arrangements in the industry and considers the implications of such flexible application of conventional antitrust principles for the future of the hospital industry.


Surgical outcome in occipital lobe epilepsy: implications for pathophysiology.
Medically refractory occipital lobe epilepsies are increasingly treated with surgery, but outcome and its relationship to etiology, pathological substrate, occipital lobe location, surgical approach, and electroclinical features have not been systematically investigated in a substantial group of patients. Thirty-five patients who underwent surgery for intractable occipital lobe seizures were retrospectively evaluated. Outcome and occipital lobe location were analyzed with respect to surgical procedure, pathology, clinical seizure characteristics, seizure onset and termination locations, and localization of interictal spikes. Most patients had developmental abnormalities (14) or tumors (13, all gliomas). Developmental abnormalities consisted of focal cortical dysplasia (5), heterotopia (2), hamartoma (3), cortical duplication (1), polymicrogyria (1), Sturge-Weber syndrome (1), and tuberous sclerosis (1). There was 1 patient with a vascular abnormality, 1 with chronic inflammatory changes, 4 with gliosis, 1 with cerebral ossification, and 1 with normal pathology. Developmental abnormalities had significantly worse outcome (45% excellent/good) than tumors (85% excellent/good). In the developmental group, low-grade focal cortical dysplasias had better outcome than heterotopia and hamartoma regardless of type of surgical procedure. Pathological groups did not significantly differ with respect to location within the occipital lobe (overall medial [50%] or lateral [38%]); clinical seizure characteristics referable to specific lobe (occipital [14%], temporal [34%], frontal [23%], more than one type [29%]); electroencephalographic localization (to occipital [17%], temporal [27%], or other/multifocal locations [56%]); or intracranial ictal onset or termination location. Electroclinical variables were also unrelated to the occipital lobe location of abnormality. Surgical outcome was not predicted by surgical approach (lesion excision with margins or lobectomy). The main pathological substrates of uncontrolled occipital lobe epilepsy are gliomas and developmental abnormalities. Whereas resection of occipital lobe tumors associated with chronic epilepsy produces nearly uniform seizure control, outcome after resection of occipital lobe developmental abnormalities is less uniform.


Utility of the theory of planned behavior to predict nursing staff blood pressure monitoring behaviours.
To evaluate constructs from the theory of planned behavior (TPB, Ajzen 2002) - attitudes, sense of control, subjective norms and intentions - as predictors of accuracy in blood pressure monitoring. Despite numerous initiatives aimed at teaching blood pressure measurement techniques, many healthcare providers measure blood pressures incorrectly. Descriptive, cohort design. Medical assistants and licensed practical nurses were asked to complete a questionnaire on TPB variables. These nursing staff's patients had their blood pressures measured and completed a survey about techniques used to measure their blood pressure. We correlated nursing staff's responses on the TBP questionnaire with their intention to measure an accurate blood pressure and with the difference between their actual blood pressure measurement and a second measurement taken by a researcher immediately after the clinic visit. Patients' perceptions of MAs' and LPNs' blood pressure measurement techniques were examined descriptively. Perceived control and social norm predicted intention to measure an accurate blood pressure, with a negative relationship between knowledge and intention. Consistent with the TPB, intention was the only significant predictor of blood pressure measurement accuracy. Theory of planned behavior constructs predicted the healthcare providers' intention to measure blood pressure accurately and intention predicted the actual accuracy of systolic blood pressure measurement. However, participants' knowledge about blood pressure measurement had an unexpected negative relationship with their intentions. These findings have important implications for nursing education departments and organisations which traditionally invest significant time and effort in annual competency training focused on knowledge enhancement by staff. This study suggests that a better strategy might involve efforts to enhance providers' intention to change, particularly by changing social norms or increasing perceived control of the behaviour by nursing staff.


Prion protein expression in different species: analysis with a panel of new mAbs.
By immunizing prion knockout mice (Prnp-/-) with recombinant murine prion protein (PrPc), we obtained a panel of mAbs specific for murine PrPc. These mAbs can be applied to immunoblotting, cell surface immunofluorescent staining, and immunohistochemistry at light and electron microscopy. These mAbs recognize both the normal (PrPc) and protease-resistant (PrPres) isoforms of PrP. Some mAbs are species restricted, while others react with PrP from a broad range of mammals including mice, humans, monkeys, cows, sheep, squirrels, and hamsters. Moreover, some of the mAbs selectively recognize different PrP glycoforms as well as the metabolic fragments of PrPc. These newly generated PrPc antibodies will help to explore the biology of PrPc and to establish the diagnosis of prion diseases in both humans and animals.


How diverse is Mitopus morio? Integrative taxonomy detects cryptic species in a small-scale sample of a widespread harvestman.
Mitopus morio is a widespread harvestman species occurring in most of Europe and in moderate and cold-moderate zones of Asia and North America. The species is characterized by extreme variability in body size and leg length. As leg length is correlated with habitat temperature, M. morio has been considered as an example of Allen's rule. Recently, observations for a single location in Tyrol, Austria, indicated the absence of mating between short- and long-legged individuals. This study examines for signs of putative cryptic species in M. morio using an integrative approach that combines mating trials, amplified fragment length polymorphism whole-genome scans, mitochondrial sequences and morphometrics. The mating trials did not corroborate the initial hypothesis of a reproductive barrier associated with leg size. Both types of genetic data revealed the existence of three distinct groups, in line with the mating results but largely unrelated to leg morphology and geographical origin of specimens. Morphometric characters supporting the findings of the other disciplines were identified using a supervised approach. We infer from all data together the existence of strongly diverged cryptic lineages among the analysed individuals, cautiously interpret them as three sympatric species and conclude that in these harvestmen Allen's rule applies at different levels. Due to the unexpected amount of differentiation found within a geographical scale very small compared with the distribution of M. morio, we suggest a thorough revision of the genus prior to formal taxonomic changes. Our case study underlines the general applicability of the integrative taxonomic protocol used and highlights the relevance of several rationales implemented in the protocol.


AIP4/Itch regulates Notch receptor degradation in the absence of ligand.
The regulation of Notch signaling heavily relies on ubiquitination events. Drosophila Su(dx), a member of the HECT family of ubiquitin-ligases, has been described as a negative regulator of Notch signaling, acting on the post-endocytic sorting of Notch. The mammalian ortholog of Su(dx), Itch/AIP4, has been shown to have multiple substrates, including Notch, but the precise events regulated by Itch/AIP4 in the Notch pathway have not been identified yet. Using Itch-/- fibroblasts expressing the Notch1 receptor, we show that Itch is not necessary for Notch activation, but rather for controlling the degradation of Notch in the absence of ligand. Itch is indeed required after the early steps of Notch endocytosis to target it to the lysosomes where it is degraded. Furthermore Itch/AIP4 catalyzes Notch polyubiquitination through unusual K29-linked chains. We also demonstrate that although Notch is associated with Itch/AIP4 in cells, their interaction is not detectable in vitro and thus requires either a post-translational modification, or a bridging factor that remains to be identified. Taken together our results identify a specific step of Notch regulation in the absence of any activation and underline differences between mammalian and Drosophila Notch pathways.


A 2-to-2' 18-to-18' doubly linked Ni(ii) norcorrole dimer: an effectively conjugated antiaromatic dyad.
The synthesis and properties of a 2-to-2' 18-to-18' doubly linked Ni(ii) norcorrole dimer are described. It adopts a highly planar structure, resulting in effective electronic interactions between the constituent norcorrole units. Nevertheless, each norcorrole unit exhibits substantial antiaromaticity, which stands in sharp contrast to stacked norcorrole dimers.


The interface chemistry between chalcogenide clusters and open framework chalcogenides.
One of the most exciting recent developments concerning molecular architectures is the emerging field of crystalline chalcogenide superlattices that bridges two traditional but distinct areas of research: chalcogenide clusters and porous materials. By combining synthetic and structural concepts in these two areas, many crystalline solids containing spatially organized chalcogenide clusters have been created that exhibit varied properties ranging from microporosity, fast ion conductivity, and photoluminescence to narrow and tunable electronic band gaps. The potential applications of these materials extend beyond traditional areas such as acid catalysis or adsorption-based separation to include shape- or size-selective photocatalysis, solid-state ionics, and electrochemistry.


HIF1alpha synergizes with glucocorticoids to promote BFU-E progenitor self-renewal.
With the aim of finding small molecules that stimulate erythropoiesis earlier than erythropoietin and that enhance erythroid colony-forming unit (CFU-E) production, we studied the mechanism by which glucocorticoids increase CFU-E formation. Using erythroid burst-forming unit (BFU-E) and CFU-E progenitors purified by a new technique, we demonstrate that glucocorticoids stimulate the earliest (BFU-E) progenitors to undergo limited self-renewal, which increases formation of CFU-E cells > 20-fold. Interestingly, glucocorticoids induce expression of genes in BFU-E cells that contain promoter regions highly enriched for hypoxia-induced factor 1α (HIF1α) binding sites. This suggests activation of HIF1α may enhance or replace the effect of glucocorticoids on BFU-E self-renewal. Indeed, HIF1α activation by a prolyl hydroxylase inhibitor (PHI) synergizes with glucocorticoids and enhances production of CFU-Es 170-fold. Because PHIs are able to increase erythroblast production at very low concentrations of glucocorticoids, PHI-induced stimulation of BFU-E progenitors thus represents a conceptually new therapeutic window for treating erythropoietin-resistant anemia.


Randomized, double-blind trial of midazolam and diazepam for endoscopic sedation in children.
We performed a prospective, randomized, double-blind study of 41 children (6-18 years of age) who were undergoing esophagogastroduodenoscopy (EGD) to compare the efficacy of diazepam and midazolam with respect to quality of sedation and amnesia. The endoscopist assessed the patients for control of salivation, gag reflex, vomiting and cooperation after intravenous injection of either 0.1-0.15 mg/kg of midazolam or 0.2-0.4 mg/kg of diazepam. The patients answered a questionnaire at 1 and 24 h after the procedure to assess recall of procedure details, pain and/or discomfort, and their medication choice for future procedures. Vital signs were monitored for 1 h after injection. Although midazolam caused greater mean maximum increase in heart rate than diazepam (30 vs. 14/min), no difference was found between the two treatment groups with respect to other vital signs. There was also no difference in physician's assessment or patient recall of specific events during the procedure. However, significantly fewer patients recalled pain or discomfort with midazolam at both 1 and 24 h following the procedure (p = 0.02). In addition, more patients receiving midazolam indicated preference for the same sedation for future procedures. We conclude that midazolam may provide better amnesia in children undergoing endoscopic procedures.


Suitability of some selected maize hybrids from Serbia for the production of bioethanol and dried distillers' grains with solubles.
Bioethanol is mostly produced from starchy parts of the corn grain kernel leaving significant amounts of valuable by-products such as dried distillers' grains with solubles (DDGS) which can be used as a substitute for traditional feedstuff. The suitability of six maize hybrids from Serbia was investigated for bioethanol and DDGS production. The correlation between physical and chemical characteristics of the grain, bioethanol yield and quality of the corresponding DDGS was assessed. All hybrids had very different chemical composition and physical characteristics which could allow various applications. The highest bioethanol yield (94.5% of theoretical) and volumetric productivity (2.01 g l(-1) h(-1)) were obtained with hybrid ZP 434 and the lowest with ZP 611k. Regarding chemical composition, all DDGS samples manifested good properties as feed components. Their protein content was higher compared to the kernel. In addition, the samples showed high digestibility and high mineral content, especially of calcium and phosphorus. A hybrid ZP 434 was selected as the most promising bioethanol producer. This property is attributed to the highest level of soft endosperm which is more susceptible to starch-hydrolysing enzymes. A high yield potential per hectare makes it the best candidate for commercial bioethanol production.


Knowledge and dispensing practice of community pharmacists towards antipsychotic medicines in a Nigerian metropolitan city - a cross-sectional study.
Antipsychotic drugs are prescription-only-medications which require valid prescriptions before it can be obtained from a pharmacy. On the other hand, community pharmacists in developing countries have sometimes been implicated in over-the-counter dispensing of prescription-only-medications. This study investigated the accessibility of antipsychotic drugs without prescriptions from community pharmacies, and the factors responsible for the over-the-counter dispensing of antipsychotics by community pharmacists. An exploratory cross-sectional mixed method survey design using pretested structured questionnaires among 119 community pharmacists, simulated patients in 119 community pharmacies, and one-on-one in-depth interview among eleven (11) community pharmacist-owners/superintendent pharmacists were utilized for data collection. The knowledge of the pharmacists on antipsychotics including classification, side effects, and dispensing practices were explored. Qualitative data was analyzed with thematic analysis, while quantitative data was analyzed using descriptive statistics. Majority of the community pharmacists (87.4%) showed good knowledge of antipsychotics as it relates to the different classes and the side effects peculiar to each class. Antipsychotic medications were dispensed by 85 (71.4%) of community pharmacists without a prescription. One-on-one in-depth interview sessions with community pharmacist owners/superintendent pharmacists demonstrated that community pharmacists are knowledgeable about antipsychotics and their side effects. Reasons given for dispensing this class of drugs without prescription included emergencies, and knowledge of the person as being on the drugs long-term. About 4% pharmacists were adamant on dispensing only with prescription. Community pharmacists in Ibadan metropolis readily dispense antipsychotics without valid prescriptions despite having an optimal knowledge about the negative implications of doing so. This could be due to weak legislation and regulation of drug laws. There is a need for more stringent regulations as well as adequate sensitization about the negative effects of inappropriate dispensing of prescription-only-medications.


State-of-the-art behavioral and pharmacological treatments for alcohol use disorder.
Alcohol use disorder (AUD) and its associated consequences remain significant public health concerns. Given that AUD represents a spectrum of severity, treatment options represent a continuum of care, ranging from single-session brief interventions to more intensive, prolonged, and specialized treatment modalities. This qualitative literature review seeks to describe the best practices for AUD by placing a particular emphasis on identifying those practices which have received the most empirical support. This review summarizes psychological and pharmacological intervention options for AUD treatment, with a focus on the relapse prevention phase of recovery. Psychological and pharmacological treatments are summarized in terms of the empirical evidence favoring each approach and the level of AUD severity for which they are most indicated. One of the broad assertions from this review is that while AUD is highly prevalent, seeking treatment for AUD is not. There are a myriad of behavioral and pharmacological treatments that have shown compelling evidence of efficacy for the treatment of AUD. In the behavioral treatment literature, cognitive behavioral therapy has received the most consistent support. Opioid antagonism (via naltrexone) has been the most widely studied pharmacotherapy and has produced moderate effect sizes. While none of the treatments reviewed herein represents a so-called silver bullet for AUD, they each have the potential to significantly improve the odds of recovery. Precision medicine, or the identification of best treatment matches for individual patients, looms as an important overarching goal for the field, although specific matches are not yet sufficiently reliable in their empirical evidence to warrant clinical dissemination.


Theory and Practice of Integrating Machine Learning and Conventional Statistics in Medical Data Analysis.
The practice of medical decision making is changing rapidly with the development of innovative computing technologies. The growing interest of data analysis with improvements in big data computer processing methods raises the question of whether machine learning can be integrated with conventional statistics in health research. To help address this knowledge gap, this paper presents a review on the conceptual integration between conventional statistics and machine learning, focusing on the health research. The similarities and differences between the two are compared using mathematical concepts and algorithms. The comparison between conventional statistics and machine learning methods indicates that conventional statistics are the fundamental basis of machine learning, where the black box algorithms are derived from basic mathematics, but are advanced in terms of automated analysis, handling big data and providing interactive visualizations. While the nature of both these methods are different, they are conceptually similar. Based on our review, we conclude that conventional statistics and machine learning are best to be integrated to develop automated data analysis tools. We also strongly believe that machine learning could be explored by health researchers to enhance conventional statistics in decision making for added reliable validation measures.


Effect of curing method and thermocycling on flexural strength and microhardness of a new composite resin with alkaline filler.
Cention N has been introduced as an alternative material for amalgam. The purpose was to investigate the flexural strength and microhardness of this material in self-cure and dual-cure modes before and after thermocycling. In this experimental study, 40 samples of Cention N were prepared in order to determine and compare the microhardness. Half of the samples were set by self-cure method and the other half with dual-cure method. The Vickers microhardness test was performed once after 24 h and again after 10000 thermocyclings. Three-point flexural test was used to determine and compare the flexural strength of 52 rod-shaped samples. Half of the samples were set by self-cure method and the other half with dual-cure method. Among 26 samples in each group, 13 samples were randomly selected and three-point flexural test was performed after 24 h and for another 13 samples after 10,000 thermocyclings. Data were analyzed using two-way ANOVA and paired samples t-test (P < 0.05). There was a statistically significant difference between the mean of microhardness values in two curing methods (P < 0.001) and in two storage conditions (P < 0.001). The mean of dual-cure microhardness (100.99 ± 7.22) was higher than that of self-cure (64.61 ± 12.51) and the mean value associated with pre-thermocycling (89.75 ± 15.84) was higher than that of the post-thermocycling (76.44 ± 23.56). There was no statistically significant difference between the mean flexural strength in the two curing methods (self-cure [72.85 ± 16.26], dual cure [79.87 ± 23.07]; [P > 0.05]). However, the mean flexural strength without thermocycling (85.98 ± 21.74) was higher than that of the thermocycled group (64.24 ± 6.40) (P < 0.001). The microhardness of Cention N in dual-cure mode was higher than that of self-cure mode, but the flexural strength of dual-cure was not significantly different from that of self-cure. Thermocycling had a significant effect on the microhardness and flexural strength.


[Vegetotropic therapy and hypobaric hypoxic adaptation in gallbladder motor dysmotility].
The study of 67 chronic biliary patients (36 - gallbladder dysfunction, 25 acalculuous cholecystitis, 6 - cholelithiasis) was revealed their functional dysadaptation characterized by gallbladder dysmotility and autonomic dysfunction. Vegetotropic therapy (Propranolol, Metoclopramid, Atropine) according to the autonomic regulation activity has advantages in correction of the gallbladder dysmotility in comparison to the routine pharmacotherapy. Hypobaric hypoxic adaptation results in the increase of gallbladder emptying that opens perspectives for the non-pharmacological correction of the gallbladder hypokinetic dyskinesia.


Crystal structures for HIV-1 reverse transcriptase in complexes with three pyridinone derivatives: a new class of non-nucleoside inhibitors effective against a broad range of drug-resistant strains.
In the treatment of AIDS, the efficacy of all drugs, including non-nucleoside inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT), has been limited by the rapid appearance of drug-resistant viruses. Lys103Asn, Tyr181Cys, and Tyr188Leu are some of the most common RT mutations that cause resistance to NNRTIs in the clinic. We report X-ray crystal structures for RT complexed with three different pyridinone derivatives, R157208, R165481, and R221239, at 2.95, 2.9, and 2.43 A resolution, respectively. All three ligands exhibit nanomolar or subnanomolar inhibitory activity against wild-type RT, but varying activities against drug-resistant mutants. R165481 and R221239 differ from most NNRTIs in that binding does not involve significant contacts with Tyr181. These compounds strongly inhibit wild-type HIV-1 RT and drug-resistant variants, including Tyr181Cys and Lys103Asn RT. These properties result in part from an iodine atom on the pyridinone ring of both inhibitors that interacts with the main-chain carbonyl oxygen of Tyr188. An acrylonitrile substituent on R165481 substantially improves the activity of the compound against wild-type RT (and several mutants) and provides a way to generate novel inhibitors that could interact with conserved elements of HIV-1 RT at the polymerase catalytic site. In R221239, there is a flexible linker to a furan ring that permits interactions with Val106, Phe227, and Pro236. These contacts appear to enhance the inhibitory activity of R221239 against the HIV-1 strains that carry the Val106Ala, Tyr188Leu, and Phe227Cys mutations.