Examining the efficacy of verteporfin photo-dynamic therapy (PDT) at different dose & fluence levels.
Photodynamic therapy (PDT) is a vaso-occlusive treatment for a number of chorioretinal vascular pathologies. We aimed to retrospectively analyse efficiency and safety of PDT for different conditions (central serous retinopathy (CSR), age-related macular degeneration (AMD), macular telangiectasia type 2 and choroidal hemangioma) and with different verteporfin parameters. Clinical parameters were ascertained from the medical records of patients undergoing PDT over a 6-year period. This included indications for PDT, dosing regimens of verteporfin PDT (which includes treatment dose of verteporfin and fluence). Response to treatment was measured by best corrected visual acuity (BCVA) and central foveal thickness (CFT) on ocular coherence tomography. Complications and side effects were recorded. 67.4 % (31/46) of PDT treatments performed over the last six years were for CSR. In the CSR cohort, there were significant improvements in BCVA (0.47 ± 0.24 to 0.29 ± 0.27, p < 0.05) and CFT (350.2μm ± 66.9 μm to 286.1μm ± 60.6 μm. In the AMD cohort, there was no change in BCVA (1.08 ± 0.52 to 1.07 ± 0.53, p = 0.96) but significant improvement in CFT (488.2μm ± 164.6 μm to 348.7μm ± 65.7 μm, p < 0.05). There was no significant difference in BCVA or CFT for macular telangiectasia type 2 and choroidal hemangioma. PDT continues to have a role in the management of medical retina conditions. Our results show PDT is most effective in improving and stabilizing visual acuity in CSR, with earlier intervention resulting in better outcomes.


Quality control in protein biogenesis: thiol-mediated retention monitors the redox state of proteins in the endoplasmic reticulum.
There is accumulating evidence that proteins can be retained in the endoplasmic reticulum by a mechanism that is believed to monitor the oxidation status of one or more cysteines in their sequences. For example, a single cysteine residue critical for retention of secretory IgM assembly intermediates has been mapped to the C-terminal cysteine, Cys575, of the secretory mu chain. Little is known concerning the mechanism responsible for this system of quality control, which has been termed thiolmediated retention. In particular, it is not known if the mechanism monitors the redox state of the important cysteine residue in the secretory mu protein itself or within the context of higher-order IgM complexes. To address this question, we evaluated the fidelity of retention of secretory IgM and determined the redox status of cysteines in secretory mu proteins in polymers and polymer intermediates at various stages of maturation. We demonstrate that all secreting B cells and B cell lines secrete assembly intermediates in addition to completed, covalent pentameric and hexameric IgM polymers. A fraction of assembly intermediates exit the endoplasmic reticulum as individual components, mature through the Golgi without undergoing further assembly, and most, if not all, are secreted. While the majority of IgM assembly intermediates have exposed thiols and are contained within the endoplasmic reticulum where they can be utilized for oligomerization, maturing assembly intermediates found in the Golgi and extracellular space are completely oxidized. Thus, while the retention of unpolymerized IgM is highly efficient, the retention system lacks the ability to distinguish fully oxidized assembly intermediates from fully oxidized completed polymers. The molecular mechanisms that may contribute to this aspect of IgM biogenesis and their implications for the concept of thiolmediated retention are discussed.


Widespread formation of intracellular calcium carbonates by the bloom-forming cyanobacterium Microcystis.
The formation of intracellular amorphous calcium carbonates (iACC) has been recently observed in a few cultured strains of Microcystis, a potentially toxic bloom-forming cyanobacterium found worldwide in freshwater ecosystems. If iACC-forming Microcystis are abundant within blooms, they may represent a significant amount of particulate Ca. Here, we investigate the significance of iACC biomineralization by Microcystis. First, the presence of iACC-forming Microcystis cells has been detected in several eutrophic lakes, indicating that this phenomenon occurs under environmental conditions. Second, some genotypic (presence/absence of ccyA, a marker gene of iACC biomineralization) and phenotypic (presence/absence of iACC) diversity have been detected within a collection of strains isolated from one single lake. This illustrates that this trait is frequent but also variable within Microcystis even at a single locality. Finally, one-third of publicly available genomes of Microcystis were shown to contain the ccyA gene, revealing a wide geographic and phylogenetic distribution within the genus. Overall, the present work shows that the formation of iACC by Microcystis is common under environmental conditions. While its biological function remains undetermined, this process should be further considered regarding the biology of Microcystis and implications on the Ca geochemical cycle in freshwater environments.


Surgeon Preference for Radiologist Interpretation of Deformity Radiographs-A Survey of Lumbar Spine Research Society Membership.
The radiologist interpretation of scoliosis films is non-standardized, with some practitioners providing detailed measurements of the deformity whereas others defer the interpretation of the deformity to the ordering surgeon. For radiologists, the standard of care is not clear, and this creates confusion in terms of how much interpretation is required. However, detailed radiologist reports sometimes conflict with the surgeon's interpretation, which can create confusion for patients who receive the reports, or in extreme cases can lead to insurance denials. Thus, the purpose of this study was to help establish a standard for interpretation of these films by surveying the ordering surgeons and documenting expert opinion about the amount and type of radiologist interpretation that is requested. We designed a SurveyMonkey survey which aimed to look at standard practice for radiologist dictation of scoliosis radiographs. Twelve questions were sent to Lumbar Spine Research Society membership via email with a description of the study. One follow-up email was also sent to non-responders. The rate of completed surveys was 46 out of 185 Lumbar Spine Research Society members (25%). Thirty-seven respondents (80%) worked in academic institutions, 33 were orthopedists (71%), and 13 were neurosurgeons (28%). Fifty percent reported that radiologists' level of detail in dictations was inconsistent at their institution. Detailed numeric reporting was rare (6.5%). When the radiologist did provide numeric measurements, surgeons reported that they often differed from the surgeon's own measurements, with only 4% reporting that the measurements "rarely" differed from the surgeon's; 49% reported that the radiologist's measurements that differed from the surgeon's had led to insurance denials for their patients. The majority of respondents (70%) did not want the radiologist to provide detailed numeric measurements of the deformity, and 91% reported that the radiologist's measurements had no impact on their clinical decision making. Detailed deformity measurements are time consuming for the radiologist, and would seem to have low clinical utility for the responding surgeons in this survey, with significant potential for discrepancies in interpretation to lead to insurance denials. IV.


Prolactin is a survival factor for androgen-deprived rat dorsal and lateral prostate epithelium in organ culture.
PRL is one of several polypeptide factors that regulate growth and differentiation of prostate epithelium besides steroid hormones. This hormone may also participate in the development of pathologic changes of the prostate, as evidenced by marked prostate hyperplasia in hyperprolactinemic mice. We have previously demonstrated expression of PRL receptors and androgen-dependent local production of PRL in rat and human prostate epithelium, suggesting the existence of an autocrine loop. We now show that PRL acts as a survival factor for epithelial cells of rat dorsal and lateral prostate but not ventral prostate, using long-term organ cultures as an in vitro model. Culture of prostate explants in androgen-free medium was associated with a transient surge of apoptosis during the first 2-4 days of culture in rat ventral, dorsal, and lateral prostate tissues, as quantified by either nuclear morphology or in situ DNA fragmentation analysis. PRL significantly inhibited apoptosis in androgen-deprived dorsal and lateral prostate cultures, by 40-60%, as determined by the two methods. The present study has established conditions and methodology for analysis of apoptosis in organ cultures of rat prostate and suggests a physiological role for PRL as a survival factor for prostate epithelium.


Lupus nephropathy and pregnancy. Report of 104 cases in 36 patients.
The reciprocal influence of lupus nephropathy on the outcome of pregnancy and of pregnancy on the course of renal involvement was studied retrospectively in a series of 106 pregnancies observed during the past two decades in 36 patients with lupus nephropathy. The overall incidence of live births, corrected for induced abortions, was 54 (84%) in 64 pregnancies that began before clinical onset of systemic lupus erythematosus (SLE), 20 (87%) in 23 pregnancies that began after onset of SLE, and only four (57%) in seven cases where SLE was first manifested during or after gestation. Relapse or exacerbation of disease activity occurred in 12 (46%) of 26 pregnancies antedated by clinical onset of SLE, more frequently during gestation than post partum, with two cases (8%) of irreversible deterioration of renal function; clinical exacerbation of lupus disease was observed in 11 (66%) of 15 cases where SLE was clinically active at the time of conception, and in only one (9%) of 11 cases where SLE nephritis was in stable clinical remission for at least five months before conception. The data indicate that successful outcome of pregnancy may be expected even in the more severe forms of lupus nephritis if gestation begins after a sustained, complete clinical remission.


Anti-obesity drugs.
Recent discoveries about the metabolic and genetic control systems that govern regulation of body weight and energy expenditure have afforded the opportunity to develop pharmacological agents that can be used as adjunctive treatments for patients with obesity. However, the scarcity of medications available or those that have made it to Phase III trials reflects the difficult challenge of manipulating the biology of appetite regulation. The aim of this study was to inform health professionals about new anti-obesity medications that target neuronal systems within the central nervous system and peripheral humoral proteins that send signals to the central nervous system. A critical review was conducted of information available from the medical literature. An emerging theme is to use combination therapies that are directed towards several targets or leverage existing gastrointestinal satiety hormonal signals. By using combination therapies, it is anticipated that greater weight loss will be achieved compared to monotherapy.


Residual spatial correlation between geographically referenced observations: a Bayesian hierarchical modeling approach.
Analytic methods commonly used in epidemiology do not account for spatial correlation between observations. In regression analyses, this omission can bias parameter estimates and yield incorrect standard error estimates. We present a Bayesian hierarchical model (BHM) approach that accounts for spatial correlation, and illustrate its strengths and weaknesses by applying this modeling approach to data on Wuchereria bancrofti infection in Haiti. A program to eliminate lymphatic filariasis in Haiti assessed prevalence of W. bancrofti infection in 57 schools across Leogane Commune. We analyzed the spatial pattern in the prevalence data using semi-variograms and correlograms. We then modeled the data using (1) standard logistic regression (GLM); (2) non-Bayesian logistic generalized linear mixed models (GLMMs) with school-specific nonspatial random effects; (3) BHMs with school-specific nonspatial random effects; and (4) BHMs with spatial random effects. An exponential semi-variogram with an effective range of 2.15 km best fit the data. GLMM and nonspatial BHM point estimates were comparable and also were generally similar with the marginal GLM point estimates. In contrast, compared with the nonspatial mixed model results, spatial BHM point estimates were markedly attenuated. The clear spatial pattern evident in the Haitian W. bancrofti prevalence data and the observation that point estimates and standard errors differed depending on the modeling approach indicate that it is important to account for residual spatial correlation in analyses of W. bancrofti infection data. Bayesian hierarchical models provide a flexible, readily implementable approach to modeling spatially correlated data. However, our results also illustrate that spatial smoothing must be applied with care.


[Pathogenesis and induced virus resistance in tobacco plants affected by tomato spotted wilt virus].
Pathogenecity and virulence of tomato spotted wilt virus isolated from tobacco were studied under the field conditions of the Crimea in the tobacco plants of Immunny 580 variety and Datura stramonium. As to their virulence the obtained 26 isolates were divided into three groups: strongly virulent (severe), middle-virulent and weakly virulent ("mosaic"). It has been shown that strongly virulent isolates interfere with weakly virulent ones and induce the development of nonspecific resistance in tobacco plants, this resistance is also efficient to the tobacco mosaic virus.


[Burnout syndrome: a "true" cardiovascular risk factor].
The burnout syndrome is characterized by emotional exhaustion, depersonalization and reduced personal accomplishment in individuals professionally involved with others. The burnout syndrome is poorly recognized, particularly in France, as a distinct nosology from adaptation troubles, stress, depression, or anxiety. Several tools quantifying burnout and emotional exhaustion exist, the most spread is the questionnaire called Maslach Burnout Inventory. The burnout syndrome alters cardiovascular function and its neuroregulation by autonomic nervous system and is associated with: increased sympathetic tone to heart and vessels after mental stress, lowered physiological post-stress vagal rebound to heart, and lowered arterial baroreflex sensitivity. Job strain as burnout syndrome seems to be a real independent cardiovascular risk factor. Oppositely, training to manage emotions could increase vagal tone to heart and should be cardio-protective.


A Survey of Wireless Sensor Network Based Air Pollution Monitoring Systems.
The air quality in urban areas is a major concern in modern cities due to significant impacts of air pollution on public health, global environment, and worldwide economy. Recent studies reveal the importance of micro-level pollution information, including human personal exposure and acute exposure to air pollutants. A real-time system with high spatio-temporal resolution is essential because of the limited data availability and non-scalability of conventional air pollution monitoring systems. Currently, researchers focus on the concept of The Next Generation Air Pollution Monitoring System (TNGAPMS) and have achieved significant breakthroughs by utilizing the advance sensing technologies, MicroElectroMechanical Systems (MEMS) and Wireless Sensor Network (WSN). However, there exist potential problems of these newly proposed systems, namely the lack of 3D data acquisition ability and the flexibility of the sensor network. In this paper, we classify the existing works into three categories as Static Sensor Network (SSN), Community Sensor Network (CSN) and Vehicle Sensor Network (VSN) based on the carriers of the sensors. Comprehensive reviews and comparisons among these three types of sensor networks were also performed. Last but not least, we discuss the limitations of the existing works and conclude the objectives that we want to achieve in future systems.


Decision-making impairments in patients with Parkinson's disease.
A high percentage of Parkinson's disease (PD) patients show cognitive impairments in addition to the cardinal motor symptoms. These deficits primarily concern executive functions most probably linked to dysfunctions in prefrontal regions due to decreased dopaminergic transmission in fronto-striatal loops. To investigate possible associations between decision-making and executive functions in PD, we examined 20 non-demented PD patients and 20 healthy control subjects with a neuropsychological test battery and the Game of Dice Task. In this computerised decision-making task, the rules for gains and losses and the winning probabilities are obvious and stable. Thus, strategic components besides feedback processing might influence decision-making in this task. We found that PD patients were impaired in the Game of Dice task performance and that the frequency of disadvantageous choices correlated with both executive functions and feedback processing. We suggest that decision-making deficits of PD patients in explicit gambling situations might be associated with dysfunctions in two different fronto-striatal loops: the limbic-orbitofrontal-striatal loop, involved in feedback processing, and the dorsolateral prefrontal-striatal loop, involved in executive functions.


A Case of Male Breast Cancer with a BRCA Gene Mutation.
Male breast cancer (MBC) is an uncommon malignancy with an incidence that accounts for about 1% of all breast cancer cases. It commonly presents as a locally advanced tumor that has already spread to the regional nodal basin. Similar to female breast cancers, MBC gene expression profiling and tumor studies help to detect molecular subtypes of tumors that correlate with clinical outcome and mortality rates. We report a relatively uncommon case of a 64-year-old male with a BRCA1+ gene mutation that is also found to be HER2+ on receptor analysis. Initial diagnostic studies with mammography and ultrasound revealed a left-sided hypoechoic mass measuring 2.3 cm, located at the 11 o'clock position adjacent to the nipple-areolar complex. Whole body positron emission tomography-computed tomography scan revealed a hypermetabolic retroareolar left breast mass and enlarged, hypermetabolic left axillary lymph nodes. Final pathology revealed an infiltrating ductal carcinoma with a Nottingham histologic score of 3 (mitotic count score, 3; nuclear pleomorphism score, 3). Of the 19 lymph nodes examined, 15 had evidence of macrometastatic disease. This report highlights a novel case of MBC with a rare genotypic presentation. A need exists to further explore this disease process because the literature is scant with information regarding the long-term treatment and outcomes of MBC, especially in the genotypic form presented here. Subsequent studies in the long-term outcomes of various MBC cases will need to be pursued to better understand the optimal screening and treatment strategies for this disease.


Epigenetic aging is associated with aberrant neural oscillatory dynamics serving visuospatial processing in people with HIV.
Despite effective antiretroviral therapy, cognitive impairment and other aging-related comorbidities are more prevalent in people with HIV (PWH) than in the general population. Previous research examining DNA methylation has shown PWH exhibit accelerated biological aging. However, it is unclear how accelerated biological aging may affect neural oscillatory activity in virally suppressed PWH, and more broadly how such aberrant neural activity may impact neuropsychological performance. In the present study, participants (n = 134) between the ages of 23 - 72 years underwent a neuropsychological assessment, a blood draw to determine biological age via DNA methylation, and a visuospatial processing task during magnetoencephalography (MEG). Our analyses focused on the relationship between biological age and oscillatory theta (4-8 Hz) and alpha (10 - 16 Hz) activity among PWH (n=65) and seronegative controls (n = 69). PWH had significantly elevated biological age when controlling for chronological age relative to controls. Biological age was differentially associated with theta oscillations in the left posterior cingulate cortex (PCC) and with alpha oscillations in the right medial prefrontal cortex (mPFC) among PWH and seronegative controls. Stronger alpha oscillations in the mPFC were associated with lower CD4 nadir and lower current CD4 counts, suggesting such responses were compensatory. Participants who were on combination antiretroviral therapy for longer had weaker theta oscillations in the PCC. These findings support the concept of interactions between biological aging and HIV status on the neural oscillatory dynamics serving visuospatial processing. Future work should elucidate the long-term trajectory and impact of accelerated aging on neural oscillatory dynamics in PWH.


Pain after microlaparoscopic cholecystectomy. A randomized double-blind controlled study.
Laparoscopic cholecystectomy (LC) is traditionally performed with two 10-mm and two 5-mm trocars. The effect of smaller port incisions on pain has not been established in controlled studies. In a double-blind controlled study, patients were randomized to LC or cholecystectomy with three 2-mm trocars and one 10-mm trocar (micro-LC). All patients received a multimodal analgesic regimen, including incisional local anesthetics at the beginning of surgery, NSAID, and paracetamol. Pain was registered preoperatively, for the first 3 h postoperatively, and daily for the 1st week. The study was discontinued after inclusion of 26 patients because five of the 13 patients (38%) randomized to micro-LC were converted to LC. In the remaining 21 patients, overall pain and incisional pain intensity during the first 3 h postoperatively increased in the LC group (n = 13) compared with preoperative pain levels (p<0.01), whereas pain did not increase in the micro-LC group (n = 8). Micro-LC in combination with a prophylactic multimodal analgesic regimen reduced postoperative pain for the first 3 h postoperatively. However, the micro-LC led to an unacceptable rate of conversion to LC (38%). The micro-LC instruments therefore need further technical development before this surgical technique can be used on a routine basis for laparoscopic cholecystectomy.


Breastfeeding among high-risk inner-city African-American mothers: a risky choice?
This study identified barriers to breastfeeding among high-risk inner-city African-American mothers. We used audiotaped focus groups moderated by an experienced International Board Certified Lactation Consultant, with recruitment supported by the community partner MomsFirst™ (Cleveland Department of Public Health, Cleveland, OH). Institutional Review Board approval and written informed consent were obtained. Notes-based analysis was conducted with use of a prior analytic structure called Factors Influencing Beliefs (FIBs), redefined with inclusion/exclusion criteria to address breastfeeding issues. Three focus groups included 20 high-risk inner-city expectant and delivered mothers. Relevant FIBs domains were as follows: Risk Appraisal, Self Perception, Relationship Issues/Social Support, and Structural/Environmental Factors. Risk Appraisal themes included awareness of benefits, fear of pain, misconceptions, and lack of information. Self Perception themes included low self-efficacy with fear of social isolation and limited expression of positive self-esteem. Relationship Issues/Social Support themes included formula as a cultural norm, worries about breastfeeding in public, and challenging family relationships. Structural/Environmental Factors themes included negative postpartum hospital experiences and lack of support after going home. Several findings have been previously reported, such as fear of pain with breastfeeding, but we identified new themes, including self-esteem and self-efficacy, and new concerns, for example, that large breasts would suffocate a breastfeeding infant. The FIBs analytic framework, as modified for breastfeeding issues, creates a context for future analysis and comparison of related studies and may be a useful tool to improve understanding of barriers to breastfeeding among high-risk inner-city women.


The association of selected cancers with service in the US military in Vietnam. I. Non-Hodgkin's lymphoma. The Selected Cancers Cooperative Study Group.
As part of a series of investigations into the health of Vietnam veterans, we conducted a population-based, case-control study of non-Hodgkin's lymphoma between 1984 and 1988. All men born between 1929 and 1953 and diagnosed as having non-Hodgkin's lymphoma in an area covered by eight cancer registries were considered eligible. Control subjects were identified by random-digit dialing from these same regions and were frequency-matched to men with lymphoma by age. Analyses of 1157 men with pathologically confirmed lymphomas and 1776 control subjects showed that the risk of non-Hodgkin's lymphoma was approximately 50% higher among Vietnam veterans (odds ratio, 1.47; 95% confidence interval, 1.1 to 2.0) compared with men who did not serve in Vietnam. Vietnam veterans were also at higher risk relative to (1) men who had not served in the military, (2) other veterans, and (3) other veterans who served between 1964 and 1972. An analysis of the military histories of the 232 Vietnam veterans suggested that the relative risk (1) increased with length of service in Vietnam (P = .10), and (2) was higher among men in the sea-based Navy than among other veterans (P = .11). Little difference in risk, however, was noted according to dates of service, type of unit, military region, or any other characteristics that may have been associated with the use of Agent Orange. Although the cause remains uncertain, results of this study indicate that the risk of non-Hodgkin's lymphoma is higher among Vietnam veterans than among other men.


Current perspectives on supercharging reagents in electrospray ionization mass spectrometry.
In electrospray ionization mass spectrometry (ESI-MS), analytes are introduced into the mass spectrometer in typically aqueous-organic solvent mixtures, including pH modifiers. One mechanism for improving the signal intensity and simultaneously increasing the generation of higher charge-state ions is the inclusion of small amounts (approx. <0.5% v/v mobile phase solution) of charge-inducing or supercharging reagents, such as m-nitrobenzyl alcohol, o-nitrobenzyl alcohol, m-nitrobenzonitrile, m-(trifluoromethyl)-benzyl alcohol and sulfolane. We explore the direct and indirect (colligative properties) that have been proposed as responsible for their modes of action during ESI. Of the many theorized mechanisms of ESI, we re-visit the three most popular and highlight how they are impacted by supercharging observations on small ions to large molecules including proteins. We then provide a comprehensive list of 34 supercharging reagents that have been demonstrated in ESI experiments. We include an additional 19 potential candidate isomers as supercharging reagents and comment on their broad physico-chemical properties. It is becoming increasingly obvious that advances in technology and improved ion source design, analyzers e.g. the use of ion mobility, ion trap, circular dichroism (CD) spectroscopy, together with computer modeling are increasing the knowledge base and, together with the untested isomers and yet-to-be unearthed ones, offer opportunities for further research and application in other areas of polymer research.


Shotgun pellet embolus to the middle cerebral artery.
A 24-year-old man had a massive right cerebral infarction after occlusion of the middle cerebral artery trunk by a shotgun pellet that embolized from the heart during external cardiac massage for cardiac arrest. The cerebral infarct was followed by massive edema, uncal herniation, and death.


The lability of the products of mitochondrial protein synthesis in Saccharomyces cerevisiae. A novel method for protein half-life determination.
A method for the determination of the half-life of mitochondrial translation products in yeast in vivo is proposed. The method uses inhibitors of cytoplasmic and mitochondrial protein synthesis and is based on double-labelling pulse-chase techniques, the second label being used to estimate 'post-incorporation' during the 'chase'. For the first time the difference between post-incroporation and the widely known recycling of the label is considered. These studies show that, in the turnover of mitochondrial translation products, the problem is of post-incorporation into mitochondria (especially from the cell sap) is predominant. The results obtained with this procedure indicate that the half-life of the products of mitochondrial protein synthesis in yeast at the late-exponential phase is about 60 min. The results suggest that mitochondrial transplantation products are subject to proteolysis to acid-soluble forms.


Fatty acid and lipidomic data in normal and tumor colon tissues of rats fed diets with and without fish oil.
Data is provided to show the detailed fatty acid and lipidomic composition of normal and tumor rat colon tissues. Rats were fed either a Western fat diet or a fish oil diet, and half the rats from each diet group were treated with chemical carcinogens that induce colon cancer (azoxymethane and dextran sodium sulfate). The data show total fatty acid profiles of sera and of all the colon tissues, namely normal tissue from control rats and both normal and tumor tissues from carcinogen-treated rats, as obtained by gas chromatography with mass spectral detection. Data from lipidomic analyses of a representative subset of the colon tissue samples is also shown in heat maps generated from hierarchical cluster analysis. These data display the utility lipidomic analyses to enhance the interpretation of dietary feeding studies aimed at cancer prevention and support the findings published in the companion paper (Effects of fish oil supplementation on prostaglandins in normal and tumor colon tissue: modulation by the lipogenic phenotype of colon tumors, Djuric et al., 2017 [1]).


Association of 25-hydroxyvitamin D with prevalent osteoarthritis of the hip in elderly men: the osteoporotic fractures in men study.
To examine the cross-sectional association of serum levels of 25-hydroxyvitamin D, or 25(OH)D, with prevalent radiographic hip osteoarthritis (OA) in elderly men. In a cohort of 1,104 elderly men from the Osteoporotic Fractures in Men Study, 25(OH)D serum levels were determined by mass spectrometry, followed by pelvic radiographs approximately 4.6 years later. Categories of vitamin D levels were defined as follows: deficiency as < or =15 ng/ml, insufficiency as 15.1-30 ng/ml, and sufficiency as >30 ng/ml. Radiographs were assessed for severity of hip OA using a summary grade of 0-4 for individual features of hip OA. Logistic regression was used to assess associations of serum 25(OH)D levels with prevalent radiographic hip OA; covariates included age, clinic site, season at the time of blood withdrawal, self-reported hip pain for >30 days, timed 6-meter walk, presence of at least 1 coexisting condition, and self-rated health status. Men with radiographic hip OA had a slower 6-meter walking time (P < 0.0001), reported more hip pain (P = 0.0001), had a lower vitamin D level (P = 0.0002), and had a higher prevalence of vitamin D insufficiency (P = 0.002) and vitamin D deficiency (P = 0.012) compared with controls. Higher 25(OH)D levels were associated with a lower prevalence of radiographic hip OA (odds ratio [OR] 1.39 per 1 SD decrease in 25[OH]D, 95% confidence interval [95% CI] 1.11-1.74) after adjusting for age, season, and clinic site. Men with vitamin D insufficiency had an increased likelihood of prevalent radiographic hip OA (OR 2.19, 95% CI 1.21-3.97) compared with men with sufficient levels of 25(OH)D, and in men with vitamin D deficiency, there was a tendency toward an increased likelihood of radiographic hip OA (OR 1.99, 95% CI 0.83-4.74). Men with vitamin D deficiencies are twice as likely to have prevalent radiographic hip OA, and therefore vitamin D therapy to augment skeletal health in the elderly is warranted.


NLRP3/IL-1β mediates denervation during bladder outlet obstruction in rats.
Denervation of the bladder is a detrimental consequence of bladder outlet obstruction (BOO). We have previously shown that, during BOO, inflammation triggered by the NLRP3 inflammasome in the urothelia mediates physiological bladder dysfunction and downstream fibrosis in rats. The aim of this study was to assess the effect of NLRP3-mediated inflammation on bladder denervation during BOO. There were five groups of rats: (i) Control (no surgery); (ii) Sham-operated; (iii) BOO rats given vehicle; (iv) BOO rats given the NLRP3 inhibitor glyburide; and (v) BOO rats given the IL-1 receptor antagonist anakinra. BOO was constructed by ligating the urethra over a 1 mm catheter and removing the catheter. Medications were given prior to surgery and once daily for 12 days. Bladder sections were stained for PGP9.5, a pan-neuronal marker. Whole transverse sections were used to identify and count nerves while assessing cross-sectional area. For in vitro studies, pelvic ganglion neurons were isolated and treated with IL-1β. After a 48 h incubation apoptosis, neurite length and branching were assessed. In obstructed bladders, the number of nerves decreased while total area increased, indicating a loss of cell number and/or branching. The decrease in nerve density was blocked by glyburide or anakinra, clearly implicating the NLRP3 pathway in denervation. In vitro analysis demonstrated that IL-1β, a product of the inflammasome, induced apoptosis in pelvic ganglion neurons, suggesting one mechanism of BOO-induced denervation is NLRP3/IL-1β triggered apoptosis. The NLRP3/IL-1β-mediated inflammation pathway plays a significant role in denervation during BOO.


Transmission of viruses via contact in ahousehold setting: experiments using bacteriophage straight phiX174 as a model virus.
Contamination of the environment with pathogens is the prerequisite for contact infections. The aim of this study was to elucidate how viruses can be transmitted from a primary contact person to further individuals. Bacteriophage straight phiX174 was chosen as a model virus. In its stability straight phiX174 is comparable with the most resistant human pathogenic viruses, e.g. polio- or parvoviruses. About 10(7)pfu were applied to exposed contact points such as door handles or the hands of volunteers. After touching of these handles and common social contacts like hand shaking, re-isolation rates were determined from the hands of our test persons. Contaminated door handles and skin surfaces were found to be efficient sources for potential infection. At least 14 persons could be contaminated by horizontal spread, one after the other by touching the same door handle. Successive transmission from one person to another could be followed up to the sixth contact person. These results were confirmed under everyday life conditions in a flat shared by four students. The transmission could not be prevented by the usual standards of hand hygiene, practised in this household. straight phiX174 could be reisolated after 24h from the hands of all persons tested even after normal use and cleaning of their hands. This might be improved by the use of liquid soap dispensers.


The use of counterflow centrifugal elutriation for the depletion of T cells from unrelated donor bone marrow.
Transplantation of marrow from unrelated donors is associated with an increased incidence and severity of graft-versus-host disease (GVHD). In an attempt to minimize GVHD without compromising engraftment, unrelated donor marrow was depleted of lymphocytes by counterflow centrifugal elutriation (CCE), and a fixed dose of 0.5 x 10(6) CD3+ T cells/kg, as measured in real time by flow cytometry, was added back to the graft. Patients received cyclosporine (CYA) and corticosteroids for GVHD prophylaxis and to facilitate engraftment. In the first cohort (study I), 7 patients received busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (CY) and one patient received CY (200 mg/kg) + 1260 cGy fractionated TBI. Of 6 who were evaluable for both engraftment and rejection, 4 rejected their graft. The study was terminated, and the protocol was modified (study II) by the addition of antithymocyte globulin (ATG) to the pre-BMT and post-BMT therapy. Twelve patients received CY + TBI as above plus ATG given pre-BMT and post-BMT. Ten of twelve who received ATG engrafted. Twelve patients from studies I and II were evaluable for acute GVHD. Two developed grade I acute GVHD. Two patients developed grade II acute GVHD, 2 patients developed grade III GVHD, and 1 patient developed grade IV acute GVHD. Two of three cases of acute GVHD (> grade II) occurred later than day 100 after BMT concomitant with reduction of immunosuppressive therapy. The rate of engraftment was significantly higher in study II (p = .054). In numbers of CD34+ cells infused, numbers of CFU-GM infused, and numbers of nucleated cells did not correlate with engraftment. We conclude that (a) in contrast to the results seen in recipients of marrow from HLA-matched sibling donors, the depletion of unrelated donor marrow of all but 0.5 x 10(6) CD34+ cells/kg together with CYA + corticosteroids was not sufficient to facilitate engraftment. The use of a more immunosuppressive regimen containing TBI and ATG appeared to improve engraftment. (b) The reduction of the graft T cell dose to 0.5 x 10(6) CD34+ cells/kg resulted in a higher incidence of acute GVHD than that seen in recipients of marrow from genotypically identical donors whose marrow was similarly processed.


The expression of dystrophin, alpha-sarcoglycan, and beta-dystroglycan during skeletal muscle regeneration: immunohistochemical and western blot studies.
We evaluated re-expression of dystrophin, alpha-sarcoglycan and beta-dystroglycan in regenerating skeletal muscles of rats after cardiotoxin-induced myonecrosis in order to understand the dynamic behaviour of these proteins during the regeneration process. Immunohistochemical staining of these proteins almost disappeared in the sarcolemma of necrotic fibers on the 1st day, and was obscured due to non-specific staining on the 3rd day. Dystrophin was labeled faintly at the sarcolemma of regenerating muscle fibers on the 5th day. From the 5th day to the 10th day, levels of immunostaining of dystrophin increased. After the 14th day, dystrophin was stained conspicuously. alpha-Sarcoglycan was labeled weakly at the sarcolemma of small regenerating muscle fibers on the 5th day and was labeled conspicuously after the 7th day. beta-Dystroglycan was labeled moderately at the sarcolemma of regenerating muscle fibers on the 5th day and was labeled conspicuously after the 7th day. In western blot analysis, beta-dystroglycan persisted throughout the entire cycle of myonecrosis and regeneration, and re-expression of alpha-sarcoglycan progressed faster than that of dystrophin. We speculate that regeneration advances from the basement membrane side to the subsarcolemmal side, and that proteins at the basement membrane side resist disruption and have a high capacity for regeneration.


Association between the estrogen receptor α gene polymorphisms rs2234693 and rs9340799 and severe and mild pre-eclampsia: a meta-analysis.
This meta-analysis was performed in order to determine the associations between the estrogen receptor α (ESR1) gene PvuII site (-397T/C, rs2234693) and XbaI site (-351A/G, rs9340799) polymorphisms with severe and mild pre-eclampsia. Eligible studies were identified by searching PubMed, Medline, Embase, China National Knowledge Infrastructure (CNKI), and WanFang databases until May 2018. The pooled odds ratio (OR) and 95% confidence interval (CI) were used to calculate the associations. Six articles (consisting of seven studies; one article was considered as two separate studies with two different subpopulations) investigated the ESR1 gene PvuII -397T/C and XbaI -351A/G polymorphisms in severe and mild pre-eclampsia patients and included controls. The pooled results indicated an increased risk of severe pre-eclampsia for the XbaI -351A/G polymorphism (OR = 1.67, 95% CI = 1.10-2.25, P=0.017 for GG compared with AA+GA; OR = 1.81, 95% CI = 1.17-2.82, P=0.008 for GG compared with GA). The GG genotype of the ESR1 XbaI polymorphism could be a genetic risk factor for severe pre-eclampsia susceptibility. However, the ESR1 gene PvuII -397T/C polymorphism was not significantly associated with the risk of severe pre-eclampsia, and there was no association between mild pre-eclampsia and the ESR1 gene PvuII -397T/C and XbaI -351A/G polymorphisms separately. The current meta-analysis indicates that the ESR1 XbaI genetic polymorphism may be associated with severe pre-eclampsia. However, there was no association of the ESR1 gene PvuII and XbaI polymorphisms with the risk of mild pre-eclampsia. Owing to the low statistical power, the results may not be sufficiently robust and this conclusion should be interpreted cautiously, which highlights the requirement for large-scale and high-quality studies in this field.


Engineering Heterogeneous Tumor Models for Biomedical Applications.
Tumor tissue engineering holds great promise for replicating the physiological and behavioral characteristics of tumors in vitro. Advances in this field have led to new opportunities for studying the tumor microenvironment and exploring potential anti-cancer therapeutics. However, the main obstacle to the widespread adoption of tumor models is the poor understanding and insufficient reconstruction of tumor heterogeneity. In this review, the current progress of engineering heterogeneous tumor models is discussed. First, the major components of tumor heterogeneity are summarized, which encompasses various signaling pathways, cell proliferations, and spatial configurations. Then, contemporary approaches are elucidated in tumor engineering that are guided by fundamental principles of tumor biology, and the potential of a bottom-up approach in tumor engineering is highlighted. Additionally, the characterization approaches and biomedical applications of tumor models are discussed, emphasizing the significant role of engineered tumor models in scientific research and clinical trials. Lastly, the challenges of heterogeneous tumor models in promoting oncology research and tumor therapy are described and key directions for future research are provided.


Effect of inter-phase gap on the sensitivity of cochlear implant users to electrical stimulation.
Human behavioral thresholds for trains of biphasic pulses applied to a single channel of Nucleus CI24 and LAURA cochlear implants were measured as a function of inter-phase gap (IPG). Experiment 1 used bipolar stimulation, a 100-pps pulse rate, and a 400-ms stimulus duration. In one condition, the two phases of each pulse had opposite polarity. Thresholds continued to drop by 9-10 dB as IPG was increased from near zero to the longest value tested (2900 micros for CI24, 4900 micros for LAURA). This time course is much longer than reported for single-cell recordings from animals. In a second condition, the two phases of each pulse had the same polarity, which alternated from pulse to pulse. Thresholds were independent of IPG, and similar to those in condition 1 at IPG=4900 micros. Experiment 2 used monopolar stimulation. One condition was similar to condition 1 of experiment 1, and thresholds also dropped up to the longest IPG studied (2900 micros). This also happened when the pulse rate was reduced to 20 pps, and when only a single pulse was presented on each trial. Keeping IPG constant at 8 micros and adding an extra biphasic pulse x ms into each period produced thresholds that were roughly independent of x, indicating that the effect of IPG in the other conditions was not due to a release from refractoriness at sites central to the auditory nerve. Experiment 3 measured thresholds at three IPGs, which were less than, equal to, and more than one half of the interval between successive pulses. Thresholds were lowest at the intermediate IPG. The results of all experiments could be fit by a linear model consisting of a lowpass filter based on the function relating threshold to the frequency of sinusoidal electrical stimulation. The data and model have implications for reducing the power consumption of cochlear implants.


[Isotopic effect in enzymatic oxidation of methane].
The isotopic effect during oxidation of methane and deuteromethane by a suspension of Methylomonas rubrum cells, for which methane is the only source of carbon, was observed. The rate of CH4 oxidation is 12.5 times higher than that of CH4 oxidation. It is demonstrated that CD4 is a competitive inhibitor of CH4 oxidation. The results obtained suggest that the disruption of the C-H bond is the limiting step of enzymatic oxidation of methane.


Unusual plastic deformation behavior of nanotwinned Cu/high entropy alloy FeCoCrNi nanolaminates.
Compared with coarse-grained FeCoCrNi-based high entropy alloys (HEAs), their nanocrystalline (NC) siblings with ultra-high strength often suffer from notably reduced deformability. Here, to enhance the deformability of these NC HEAs without losing their high strength, we design equal layered nanotwinned (NT) Cu/HEA (HEA = FeCoCrNi) crystalline/crystalline nanolaminates (C/CNLs) with coherent crystalline/crystalline interfaces (CCIs). In contrast to the tenet that in conventional bimetal C/CNLs, the soft/ductile phase plays the dominant major role, we discover that in NT Cu/HEA C/CNLs, the hard HEA phase unusually makes more contribution to the plastic deformation. The underlying reason is that the soft NT Cu layers without dislocation pile-up serve as the dislocation donator and export abundant dislocations that transmit across the coherent CCIs into the hard HEA accepter, and thus trigger their great deformability. The size-dependent hardness was explained based on dislocation-based models considering the stability of extremely small nanotwins with thickness less than ∼10 nm. These findings provide a new pathway to achieve great deformability of strong alloys with high lattice friction stresses in ultra-strong metallic composites: control the size of NT soft phases to suppress dislocation pile-up in conjunction with coherent CCIs to facilitate continuity of dislocation slip.


How Do You Touch an Impossible Thing?
How, and how much, physiotherapists should touch in practice is once again being debated by the profession. COVID-19 and people's enforced social isolation, combined with the growth of virtual technologies, and the profession's own turn away from so-called "passive" therapies, has placed therapeutic touch once again in an uncertain position. The situation is more ambiguous and uncertain because, despite its historical importance to the profession, physiotherapists have never articulated a comprehensive philosophy of touch, taking-for-granted its seeming obviousness as either a bio-physical or inter-subjective phenomenon. But both of these approaches are limited, with one failing to account for the existential and socio-cultural significance of touch, and the other rejecting the reality of the physical body altogether. And both are narrowly humanistic. Since touch occurs between all entities throughout the cosmos, and human touch makes up only an infinitesimally small part of this, physiotherapy's approach to touch seems paradoxically to be at the same time both highly reductive and ontologically vague. Given physiotherapists' much vaunted claim to be experts in therapeutic touch, it would seem timely to theorize how touch operates and when touch becomes therapeutic. In this paper I draw on Gilles Deleuze's machine ontology as a new way to think about touch. Critiquing existing approaches, I argue that machine ontology provides a more robust and inclusive philosophy of touch, pointing to some radical new possibilities for the physical therapies.


Structure and comparison of the oxytocin and vasopressin genes from rat.
The gene encoding the precursor protein to the hormone oxytocin and its associated neurophysin has been isolated from a rat genomic library, and its sequence has been determined. The small gene (approximately equal to 850 base pairs) predicts a mRNA of approximately equal to 500 bases [without the poly(A) tail]. The exon-intron organization is similar to that of the vasopressin gene, with two splice sites in the protein-coding region. The first exon (A) comprises the 5' noncoding promoter region, a putative signal peptide, the nonapeptide hormone oxytocin, and the NH2-terminal, variable region of neurophysin. The second exon (B) encodes the central, conserved region of neurophysin, and the third exon (C) encodes the remaining COOH terminus of neurophysin, with an additional arginine residue at its end, presumably cleaved off during post-translational processing. A stretch of 143 nucleotides within exon B, except for a single base change, is entirely homologous to the equivalent part of the rat vasopressin gene, offering support for a gene conversion event having recently affected the two genes.


[Video endoscopy of the residual cavity in hydatidectomy of the liver].
Results of treatment of 162 patients with echinococcosis of the liver were analyzed. Traditional surgical treatment of these patients was followed by endovideoscopy of the residual cavity of the liver. During endovideoscopy of the residual cavities the remnants of the chitinous membranes and small daughter vesicles not noticed during the open stage of the operation were removed in 7.4% of the patients, in 25.9% of the patients cystobiliary fistulas were detected. The endovideoscopy considerably improves revision of the residual cavities of the liver and facilitates liquidation of cystobiliary fistulas which gives better results of the treatment of such patients.


Identification of Immunopotentiating Lactic Acid Bacteria that Induce Antibody Production by in vitro Stimulated Human Peripheral Blood Mononuclear Cells.
L-leucyl-L-leucine methyl ester (LLME) is known to remove lysosome-rich cells from human peripheral blood mononuclear cells (PBMCs). To evaluate the immunopotentiating ability of lactic acid bacteria (LAB), we adopted the in vitro stimulation protocol of LLME-treated PBMCs as a model assay system and monitored the level of antibody produced by stimulated PBMCs. The results indicated that several LAB strains have immunopotentiating ability against PBMCs, as evidenced by the enhanced antibody production and increased number of antigen-specific B cells. Next, we identified T cells as the direct target cells of the immunopotentiating LAB strain L32, suggesting that L32 induced antibody production by PBMCs through T-cell activation. Finally, we tested the immunopotentiating ability of ligands for Toll-like receptor 2 (TLR2), which is known to mediate the LAB signal, and observed that both L32 and one of the TLR2 ligands, LTA-BS, induced antigen-specific antibody production by in vitro stimulated PBMC. This suggests that L32 and LTA-BS can be used as an adjuvant for stimulating immune reaction in PBMCs.


Fulvestrant for advanced breast cancer: a meta-analysis.
Fulvestrant is an endocrine agent which degrades the estrogen receptor, thereby downregulating its signaling. Trials of fulvestrant are limited by inconsistent study populations and drug dosing. The optimal use of fulvestrant in advanced breast cancer is therefore unclear. A systematic review of electronic databases was conducted to identify randomized trials of fulvestrant versus other endocrine therapy. The hazard ratios (HR) for time to progression (TTP) and the odds ratios (OR) for serious adverse events (SAEs), discontinuation of treatment due to toxicity and commonly reported toxicities (hot flashes, venous thrombosis, gastrointestinal disturbance, arthralgia, and asthenia) were pooled in a meta-analysis. Meta-regression explored heterogeneity in study population and fulvestrant dosing. Eight studies were included in the analysis. Overall, there was no difference in TTP between fulvestrant and control groups (HR: 0.94, p=0.18). On meta-regression, fulvestrant showed reduced hazards for TTP compared to aromatase inhibitors (AI) if used in first line, in studies where fewer patients received adjuvant endocrine therapy and at higher doses. Rates of SAEs and treatment discontinuation were similar for fulvestrant and control groups, but fulvestrant monotherapy was associated with significantly less arthralgia (OR: 0.73, p=0.02). The addition of fulvestrant to AI was not associated with improved TTP, but led to increased toxicity. In unselected patients, fulvestrant monotherapy is associated with similar efficacy, but reduced arthralgia compared with other endocrine therapy options. Use of high dose fulvestrant monotherapy in first line or in patients with limited prior exposure to adjuvant endocrine therapy may delay progression compared with AI.


Pegfilgrastim: using pegylation technology to improve neutropenia support in cancer patients.
Pegylation of a protein can improve not only its formulation properties, but also both its pharmacokinetic and pharmacodynamic performance. Pegfilgrastim was made by linking a 20-kDa polyethylene glycol molecule to filgrastim, producing a long-acting cytokine requiring less frequent dosing than its parent drug. This review describes the clinical development of pegfilgrastim, and discusses its potential benefits to patients and caregivers in the prophylaxis of chemotherapy-induced neutropenia. Pegfilgrastim has a longer half-life and slower elimination rate than filgrastim, resulting in an increased serum concentration over time. Serum levels of pegfilgrastim are maintained until after a chemotherapy-induced neutrophil nadir and then decline rapidly as the neutrophil count recovers, consistent with a neutrophil-mediated clearance mechanism. In two pivotal phase III studies of women receiving chemotherapy for breast cancer, a single injection of pegfilgrastim per chemotherapy cycle, dosed either by body weight (100 microg/kg) or as a fixed dose (6 mg), was comparable to daily filgrastim (5 microg/kg) for all efficacy parameters, including duration of severe neutropenia and depth of neutrophil nadir. Analysis of pooled data from these studies showed a significantly lower incidence of febrile neutropenia in patients receiving pegfilgrastim compared with filgrastim (11 versus 19%, p<0.05), and a trend towards a lower risk of hospitalization and use of i.v. anti-infectives. The safety profiles of pegfilgrastim and filgrastim were similar. Pegfilgrastim given once per chemotherapy cycle is as effective and well tolerated as daily injections of filgrastim. With its more convenient dosing regimen, pegfilgrastim has the potential to improve quality of life and compliance in patients, and to be more cost effective.


Early experience in transoral robotic surgery (TORS) for non-oropharyngeal head and neck malignancies: a review of functional and oncologic outcomes.
To review and summarize functional and oncologic outcomes after transoral robotic surgery (TORS) for non-oropharyngeal head and neck malignancies. The MEDLINE database and bibliographies of relevant studies were searched through December 2014. Search strategy was ((transoral) AND surgery) AND robotics) OR TORS. Abstracts and titles were screened for relevance and full articles of the selected records were evaluated and critically appraised after inclusion. Data concerning functional and oncologic outcomes as well as adverse effects were collected. 22 records were eventually included in the review. For TORS in the treatment of glottic, hypopharyngeal ands supraglottic cancer we retained 3 case series (26 patients), 5 case series (36 patients) and 6 case series (67 patients) respectively. 8 case reports/series (14 patients) assessing safety and feasibility of TORS for tumours in the parapharyngeal space, nasopharynx and skull base were also evaluated. In general, treatment of laryngeal and hypopharyngeal cancer by means of TORS seems to be feasible and safe with satisfying functional and short-term oncologic results. For treatment of malignant tumours in the parapharyngeal space, nasopharynx and skull base, the benefits of TORS, when compared to classic surgical techniques, are still uncertain and are particularly based on theoretical advantages. TORS offers an interesting new approach for treating non-oropharyngeal head and neck malignancies. However, long-term results are still not reported and TORS should be directly compared to existing therapeutic options in randomized controlled trials. Until then, its use should be subject to critical appraisal.


Heating affects the content and distribution profile of isoflavones in steamed black soybeans and black soybean koji.
Steamed black soybeans and black soybean koji, a potentially functional food additive, were subjected to heating at 40-100 degrees C for 30 min. It was found that steamed black soybeans and black soybean koji after heating at 80 degrees C or higher generally showed reduced contents of malonylglucoside, acetylglucoside, and aglycone isoflavone and an increased content of beta-glucoside. A lower reduction in malonylglucoside and acetylglucoside isoflavone but greater reduction in aglycone content was noted in steamed black soybeans compared to black soybean koji after a similar heat treatment. After 30 min of heating at 100 degrees C, steamed black soybean retained ca. 90.3 and 83.8%, respectively, of its original malonylglucoside and acetylglucoside isoflavone, compared to lower residuals of 80.9 and 78.8%, respectively, for black soybean koji. In contrast, the heated black soybeans showed an aglycone residual of 68.0%, which is less than the 80.0% noted with the heated black soybean koji.


Flexible co-data learning for high-dimensional prediction.
Clinical research often focuses on complex traits in which many variables play a role in mechanisms driving, or curing, diseases. Clinical prediction is hard when data is high-dimensional, but additional information, like domain knowledge and previously published studies, may be helpful to improve predictions. Such complementary data, or co-data, provide information on the covariates, such as genomic location or P-values from external studies. We use multiple and various co-data to define possibly overlapping or hierarchically structured groups of covariates. These are then used to estimate adaptive multi-group ridge penalties for generalized linear and Cox models. Available group adaptive methods primarily target for settings with few groups, and therefore likely overfit for non-informative, correlated or many groups, and do not account for known structure on group level. To handle these issues, our method combines empirical Bayes estimation of the hyperparameters with an extra level of flexible shrinkage. This renders a uniquely flexible framework as any type of shrinkage can be used on the group level. We describe various types of co-data and propose suitable forms of hypershrinkage. The method is very versatile, as it allows for integration and weighting of multiple co-data sets, inclusion of unpenalized covariates and posterior variable selection. For three cancer genomics applications we demonstrate improvements compared to other models in terms of performance, variable selection stability and validation.


Nitric oxide-releasing drugs: a novel class of effective and safe therapeutic agents.
Nitric oxide (NO) deficiency has been implicated in many pathologic processes, thus providing a solid biological basis for the use of NO replacement therapy. Exogenous NO sources constitute a powerful way to supplement NO when the body cannot generate sufficient NO for normal biological functions. This theory has opened up the possibility of designing new drugs that are capable of delivering NO into tissues and the bloodstream in a sustained and controlled manner. This objective has been achieved by grafting an organic nitrate structure onto existing drugs through chemical spacers, such as aliphatic, aromatic, or a heterocyclic chain. The approach has led to the synthesis of several new chemical entities whose pharmacologic profile challenges the parent drug, not only on the basis of new properties, but also with respect to a better safety profile. In this article, a specific class of NO donors is reviewed, the nitric oxide-releasing non-steroidal antiinflammatory drugs, NO-NSAIDs. Recently discovered compounds, whose action depends on the combined properties of both the known drug and NO release, are illustrated. Two examples are described in detail: (1) nitric oxide-releasing aspirin, which has demonstrable innovative properties for treatment of vascular disorders and cancer; (2) nitro-derivatives of flurbiprofen that have shown encouraging results in models of Alzheimer's disease.


Urbanization Impact on Regional Climate and Extreme Weather: Current Understanding, Uncertainties, and Future Research Directions.
Urban environments lie at the confluence of social, cultural, and economic activities and have unique biophysical characteristics due to continued infrastructure development that generally replaces natural landscapes with built-up structures. The vast majority of studies on urban perturbation of local weather and climate have been centered on the urban heat island (UHI) effect, referring to the higher temperature in cities compared to their natural surroundings. Besides the UHI effect and heat waves, urbanization also impacts atmospheric moisture, wind, boundary layer structure, cloud formation, dispersion of air pollutants, precipitation, and storms. In this review article, we first introduce the datasets and methods used in studying urban areas and their impacts through both observation and modeling and then summarize the scientific insights on the impact of urbanization on various aspects of regional climate and extreme weather based on more than 500 studies. We also highlight the major research gaps and challenges in our understanding of the impacts of urbanization and provide our perspective and recommendations for future research priorities and directions.


A critical review of currently used single-dose rodenticides.
The introduction of the anticoagulants in the early 1950s, with their much greater safety to nontarget animals, resulted in a general decline in the use of single-dose rodenticides. However, the appearance of rodent resistance to the anticoagulants, first in the United Kingdom, later elsewhere in Europe, and still more recently in the USA, has revived interest in the use of single-dose rodenticides. Unfortunately, owing to their danger to nontarget mammals, the use of several of these compounds must be restricted; others, despite their long use, are now recognized to be unsatisfactory because of their poor acceptance or reacceptance by rats and mice. Thus, only very few compounds of this type are available for unrestricted use and there is an urgent need for the development of effective alternatives.


Waveguide lasers with intracavity electrooptic modulators: misalignment loss.
Coupling from the EH(11) fundamental mode of a square, hollow bore waveguide laser to a square electrooptic modulator is treated. The misalignment loss that results from coupling of the laser fundamental mode into higher order modulator modes is calculated. Results are presented for loss from transverse displacement, angular tilt, and axial separation of the two elements. From these results, the alignment tolerances required to minimize loss for an intracavity modulator are found.


The operations of quantum logic gates with pure and mixed initial states.
The implementations of quantum logic gates realized by the rovibrational states of a C(12)O(16) molecule in the X((1)Σ(+)) electronic ground state are investigated. Optimal laser fields are obtained by using the modified multitarget optimal theory (MTOCT) which combines the maxima of the cost functional and the fidelity for state and quantum process. The projection operator technique together with modified MTOCT is used to get optimal laser fields. If initial states of the quantum gate are pure states, states at target time approach well to ideal target states. However, if the initial states are mixed states, the target states do not approach well to ideal ones. The process fidelity is introduced to investigate the reliability of the quantum gate operation driven by the optimal laser field. We found that the quantum gates operate reliably whether the initial states are pure or mixed.


The mode of action of bacilysin and anticapsin and biochemical properties of bacilysin-resistant mutants.
Bacilysin is hydrolysed to L-alanine and anticapsin by suspensions of a bacilysin-sensitive strain of Staphylococcus aureus but not by those of a resistant strain derived from it. In contrast, it is hydrolysed by extracts of both strains. Anticapsin is a powerful inhibitor of glucosamine synthetase in extracts of both the bacilysin-sensitive and -resistant strains of Staph. aureus. Bacilysin, by comparison, is a relatively poor inhibitor of glucosamine synthetase in crude extracts when its hydrolysis is inhibited by EDTA. A phenylalanine auxotroph of Staph. aureus readily uses L-analyl-L-phenylalanine for growth, but a bacilysin-resistant mutant of this strain does not. It is suggested that the antibacterial activity of bacilysin depends on its transport into the organism, its hydrolysis to anticapsin and on inhibition by the latter of glucosamine synthetase, and that bacilysin-resistant mutants are defective in a transport system.


[Epidural anesthesia: step by step to success].
Besides pain management in obstetric patients epidural anaesthesia plays a major role in the perioperative setting. Especially the technique of thoracic epidural anaesthesia (TEA) provides better postoperative analgesia when compared with systemic pain therapy. TEA is associated with improved outcome in high-risk patients and patients undergoing extensive surgery. An acute pain management service is required to guarantee high effectiveness and a low complication rate. TEA is an important part of a multimodal perioperative concept, especially in fast-track surgery, which means advantages for patients outcome and hospitals economics.


Dual-crosslinked methylcellulose hydrogels for 3D bioprinting applications.
Thermo-sensitive methylcellulose (MC) hydrogel has been widely used as a scaffold material for biomedical applications. However, due to its poor mechanical properties, the MC-based hydrogel has rarely been employed in 3D bioprinting for tissue engineering scaffolds. In this study, the dual crosslinkable tyramine-modified MC (MC-Tyr) conjugate was prepared via a two-step synthesis, and its hydrogel showed excellent mechanical properties and printability for 3D bioprinting applications. The MC-Tyr conjugate formed a dual-crosslinked hydrogel by modulating the temperature and/or visible light. A combination of reversible physical crosslinking (thermal crosslinking) and irreversible chemical crosslinking (photocrosslinking) was used in this dual crosslinked hydrogel. Also, the photocrosslinking of MC-Tyr solution was facilitated by visible light exposure in the presence of biocompatible photoinitiators (riboflavin, RF and riboflavin 5'-monophophate, RFp). The RF and RFp were used to compare the cytotoxicity and salting-out effect of MC-Tyr hydrogel, as well as the initiation ability, based on the difference in chemical structure. Also, the influence of the printing parameters on the printed MC hydrogel was investigated. Finally, the cell-laden MC-Tyr bioink was successfully extruded into stable 3D hydrogel constructs with high resolution via a dual crosslinking strategy. Furthermore, the MC-Tyr scaffolds showed excellent cell viability and proliferation.


Effect of vasopressors on organ blood flow during endotoxin shock in pigs.
A volume-resuscitated porcine endotoxin shock model was used to evaluate the effect on organ blood flow of increasing systemic arterial blood pressure with vasopressors. Administration of 0.05-0.2 mg/kg of Escherichia coli endotoxin (E) reduced mean arterial blood pressure (MAP) to 50 mmHg, decreased systemic vascular resistance to 50% of control, and did not change cardiac output or heart rate. Blood flow to brain, kidney, spleen, and skeletal muscle was reduced during endotoxin shock, but blood flow to left ventricle, small and large intestine, and stomach remained at pre-endotoxin levels throughout the study period. Four groups of animals were used to evaluate the effect of vasopressor therapy. A control group received E and no vasopressor, whereas the other three groups received either norepinephrine, dopamine, or phenylephrine. Vasopressors were administered starting 60 min after E exposure, and the dose of each was titrated to increase MAP to 75 mmHg. Despite the increase in MAP, brain blood flow did not increase in any group. Norepinephrine alone increased blood flow to the left ventricle. Kidney, splanchnic, and skeletal muscle blood flow did not change with vasopressor administration. The dose of norepinephrine required to increase MAP by 20-25 mmHg during E shock was 30 times the dose required for a similar increase in MAP in animals not receiving E. We conclude that hypotension in the fluid resuscitated porcine E shock model is primarily the result of peripheral vasodilatation, that the vascular response to vasoconstrictors in this model is markedly attenuated following E administration, that blood pressure elevation with norepinephrine, dopamine, and phenylephrine neither decreases blood flow to any organ nor increases blood flow to organs with reduced flow, and that norepinephrine, dopamine, and phenylephrine affect regional blood flow similarly in this model.


Characteristic Curve and Its Use in Determining the Compressive Strength of Concrete by the Rebound Hammer Test.
During the construction of concrete structures, it is often useful to know compressive strength at an early age. This is an amount of strength required for the safe removal of formwork, also known as stripping strength. It is certainly helpful to determine this strength non-destructively, i.e., without any invasive steps that would damage the structure. Second only to the ultrasonic pulse velocity test, the rebound hammer test is the most common NDT method currently used for this purpose. However, estimating compressive strength using general regression models can often yield inaccurate results. The experiment results show that the compressive strength of any concrete can be estimated using one's own newly created regression model. A traditionally constructed regression model can predict the strength value with 50% reliability, or when two-sided confidence bands are used, with 95% reliability. However, civil engineers usually work with the so-called characteristic value defined as a 5% quantile. Therefore, it appears suitable to adjust conventional methods in order to achieve a regression model with 95% one-sided reliability. This paper describes a simple construction of such a characteristic curve. The results show that the characteristic curve created for the concrete in question could be a useful tool even outside of practical applications.


Safety and efficiency of SGLT2 inhibitor combining with insulin in subjects with diabetes: Systematic review and meta-analysis of randomized controlled trials.
We aimed to assess the safety and efficiency of the novel sodium glucose co-transporter 2 (SGLT2) inhibitor in combinations with insulin for type 1 and type 2 diabetes mellitus (T1DM and T2DM). We searched Medline, Pubmed, Embase, and the Cochrane Collaboration Library from January 2010 to December 2016 without restriction of language. FDA data and Clinical Trials (http://www.clinicaltrials.gov) were also searched. Study selection, data extraction, and evaluation of risk of bias were performed by 2 persons independently. The risk of bias was assessed by Cochrance System Evaluate Method and Q test was used to evaluate the heterogeneity between studies. We used random effect model to analyze the results by Revman 5.3. This meta-analysis has been registered at online public registry PROSPERO (registration number is: CRD42017054718). Nine trials including 3069 patients were analyzed. Compared with control group, SGLT2 inhibitor produced absolute reduction in glycosylated hemoglobin A1c (HbA1c) (MD -1.35%, 95% confidence interval [CI] [-2.36 to -0.34], P = .009), fasting plasma glucose (FPG) (MD -1.01 mmol/L, 95%CI [-1.98 to 0.04], P = .04), insulin dosage (MD -4.85 U/24 hours, 95%CI [-7.42 to -2.29], P = .002), and body weight (MD -2.30 kg, 95%CI [-3.09 to -1.50], P < .00001). But the risk of hypoglycemia (OR 1.18, 95%CI [0.86, 1.61], P = . 30) and urinary tract infection (UTI) (OR 1.34, 95%CI [0.79, 2.27], P = .28) were proved as no difference and genital tract infection (GTI) with SGLT2 inhibitors was higher than control group (OR 2.96, 95%CI [1.05, 8.37], P = .04), in which cases were mild and responded to the therapy. According to the subgroup analysis, SGLT2 inhibitors had a similar effect in effective factors of both T1DM and T2DM, but the risk of GTI mainly increased in T2DM versus T1DM (T1DM OR 0.27 [0.01, 7.19], P = .43 vs T2DM OR 4.28 [2.00, 9.16], P = .0002). SGLT2 inhibitors have improved the HbA1c, FPG, and body weight when combined with insulin and decreased the dose of insulin without increasing the risk of hypoglycemia. However, SGLT2 inhibitor was proved to be related to the events of GTI, despite SGLT2 inhibitors appeared to be well tolerated. We suggest that more monitoring should be done to prevent the events of GTI, and more randomized controlled trials should be planned next step.


Can mental illness be prevented under managed care?
Ideally, managed care should force a focus on all the issues involved in prevention and treatment. Unfortunately, the decisions in managed care are based on costs, along with the intervention techniques, as the most important criteria in choice of treatment. Medical treatment accounts for only 10 percent of health. To find a solution means working together, making the goal "healthy people in a healthy community." Programs such as the Healthy Cities initiative, not managed care, are more likely to realize this goal.


Icariin induces developmental toxicity via thyroid hormone disruption in zebrafish larvae.
Icariin (ICA) is a natural flavonoid isolated from the traditional Chinese medicinal herb, Epimedium brevicornu Maxim. Although previous studies have reported that ICA exhibits various pharmacological activities, little is known about its toxicology. Herein, zebrafish embryos were exposed to ICA at 0, 2.5, 10, and 40 μM. In developmental analysis, reduced hatching rates, decreased body length, and abnormal swim bladder were found after treatment with 10 and 40 μM ICA. In addition, the ability of locomotor behavior was impaired by ICA. Two important thyroid hormones (THs), triiodothyronine (T3) and thyroxine (T4), were tested. The exposure resulted in a remarkable alteration of T4 level and a significant decrease of the T3/T4 ratio in the 40 μM, indicating thyroid endocrine disruption. Furthermore, gene transcription analysis showed that genes involved in thyroid development (nkx2.1) and THs synthesis (tg) were up-regulated after ICA exposure. Significant down-regulation of iodothyronine deiodinase (dio1) was also observed in the 10 and 40 μM groups compared to the control. Taken together, our study first demonstrated that ICA caused developmental toxicity possibly through disrupting thyroid development and hormone synthesis. These results show that it is necessary to perform risk assessments of ICA in clinical practice.


Tailored educational intervention for primary care to improve the management of dementia: the EVIDEM-ED cluster randomized controlled trial.
Early diagnosis of dementia is important because this allows those with dementia and their families to engage support and plan ahead. However, dementia remains underdetected and suboptimally managed in general practice. Our objective was to test the effect of a workplace-based tailored educational intervention developed for general practice on the clinical management of people with dementia. The tailored educational intervention was tested in an unblinded cluster randomized controlled trial with a pre/post-intervention design, with two arms: usual/normal care control versus educational intervention. The primary outcome measure was an increase in the proportion of patients with dementia who received at least two documented dementia-specific management reviews per year. Case identification was a secondary outcome measure. 23 practices in South-East England participated. A total of 1,072 patients with dementia (intervention: 512, control: 560) had information in their medical records showing the number of reviews within 12 months (or a proportion of) before intervention or randomization and within 12 months (or a proportion of) after. The mean total number of dementia management reviews after the educational intervention for people with dementia was 0.89 (SD 1.09; minimum 0; median 1; maximum 8) compared with 0.89 (SD 0.92; minimum 0; median 1; maximum 4) before intervention. In the control group prior to randomization the mean total number of dementia management reviews was 1.66 (SD 1.87; minimum 0; median 1; maximum 12) and in the period after randomization it was 1.56 (SD 1.79; minimum 0; median 1; maximum 11). Case detection rates were unaffected. The estimated incidence rate ratio for intervention versus control group was 1.03 (P = 0.927, 95% CI 0.57 to 1.86). The trial was timely, coinciding with financial incentives for dementia management in general practice (through the Quality Outcomes Framework); legal imperatives (in the form of the Mental Capacity Act 2005); policy pressure (The National Dementia Strategy 2009); and new resources (such as dementia advisors) that increased the salience of dementia for general practitioners. Despite this the intervention did not alter the documentation of clinical management of patients with dementia in volunteer practices, nor did it increase case identification. NCT00866099/Clinical Trials.


Sudanese mucosal leishmaniasis: epidemiology, clinical features, diagnosis, immune responses and treatment.
The epidemiology, clinical features, pathology, immune responses, diagnosis and treatment of 14 patients with mucosal leishmaniasis in the Sudan are described. The condition occurred mainly in adult males, particularly in certain closely related tribes from the western Sudan. It affected the mucosa of the upper respiratory tract and/or the oral mucosa and sometimes followed treated kala azar. The parasites were sometimes confined to the mucosa, sometimes spread to the lymph nodes, and rarely infected the bone marrow and spleen. One of the 2 patients with both visceral and mucosal leishmaniasis differed from classical kala azar cases; his infection was longer lasting, he was leishmanin positive, and his peripheral mononuclear cells proliferated in response to leishmanial antigens. Mucosal leishmaniasis following treated kala azar is a similar phenomenon to post-kala azar dermal leishmaniasis and post-kala azar uveitis. Post-kala azar mucosal leishmaniasis can therefore be added to the other post-kala azar leishmanial infections. Using the polymerase chain reaction, Southern blot analysis with specific probes, and isoenzyme characterization, the causative parasite was identified as Leishmania donovani in 4 patients and as L. major in one. Unlike American mucocutaneous leishmaniasis, mucosal leishmaniasis in the Sudan was not preceded or accompanied by cutaneous lesions and the response to pentavalent antimony or ketoconazole was good.


Computer tracking of objects moving in space.
A method is developed to represent movement of convex blocks in three-dimensional space from a sequence of two-dimensional camera images. The goals are to determine the objects' movement toward or away from the camera as well as left/right and up/down movement in the image plane and to build models of the blocks. The movement information is used as part of a hierarchical matching process that determines the correspondence of blocks between scenes.


Vitamin D and Fracture Risk in Early Childhood: A Case-Control Study.
The objective of this study was to evaluate the association of vitamin D intake and serum levels with fracture risk in children under 6 years of age. A case-control study was conducted in Toronto, Ontario, Canada. Cases were recruited from the fracture clinic at the Hospital for Sick Children, and matched controls were obtained from the TARGet Kids! primary-care research network. Controls were matched to cases on age, sex, height, and season. Fracture risk was estimated from conditional logistic regression, with adjustment for skin type, fracture history, waist circumference, outdoor free play, neighborhood income, soda consumption, and child's birth weight. A total of 206 cases were recruited during May 2009-April 2013 and matched to 343 controls. Serum 25-hydroxyvitamin D concentration (per 10-nmol/L increment: adjusted odds ratio (aOR) = 0.95, 95% confidence interval (CI): 0.88, 1.03) and intake of cow's milk (<2 cups/day vs. 2 cups/day: aOR = 0.95 (95% CI: 0.60, 1.52); >2 cups/day vs. 2 cups/day: aOR = 1.39 (95% CI: 0.85, 2.23)) were not significantly associated with reduced odds of fracture. A statistically significant association was observed between child use of vitamin D supplements and decreased odds of fracture (yes vs. no: aOR = 0.42, 95% CI: 0.25, 0.69). Vitamin D supplementation, but not serum 25-hydroxyvitamin D level or milk intake, was associated with reduced fracture risk among these healthy young children.


Trabecular microfracture and the influence of pyridinium and non-enzymatic glycation-mediated collagen cross-links.
The propensity of individual trabeculae to fracture (microfracture) may be important clinically since it could be indicative of bone fragility. Whether or not an overloaded trabecula fractures is determined in part by its structural ductility, a mechanical property that describes how much deformation a trabecula can sustain. The overall goal of this study was to determine the structural ductility of individual trabeculae and the degree to which it is influenced by pyridinium and non-enzymatic collagen cross-links. Vertically oriented rodlike trabeculae were taken from the thoracic vertebral bodies of 32 cadavers (16 male and 16 female, 54 - 94 years of age). A total of 221 trabeculae (4 - 9 per donor) were tested to failure in tension using a micro-tensile loading device. A subset of 76 samples was analyzed to determine the concentration of hydroxylysyl-pyridinoline (HP) and lysyl-pyridinoline (LP) cross-links as well as pentosidine, a marker of non-enzymatic glycation. Structural ductility (defined as the ultimate strain of the whole trabecula) ranged from 1.8% to 20.2% strain (8.8 +/- 3.7%, mean +/- SD) and did not depend on age (P = 0.39), sex (P = 0.57), or thickness of the sample at the point of failure (P = 0.36). Pentosidine was the only marker of collagen cross-linking measured that was found to be correlated with structural ductility (P = 0.01) and explained about 9% of the observed variance. We conclude that the ductility of individual trabeculae varies tremendously, can be substantial, and is weakly influenced by non-enzymatic glycation.


Polarity of Tn5 insertion mutations in Escherichia coli.
We assessed the effect of insertions of the kanamycin resistance transposon Tn5 in the lac operon of Escherichia coli on the expression of distal genes lacY and lacA (melibiose fermentation at 41 degrees C and thiogalactoside transacetylase synthesis, respectively). Every insertion mutation tested (41 in lacZ and 23 in lacY) was strongly polar. However, approximately one-third of the insertion mutants expressed distal genes at low levels due to a promoter associated with Tn5. To localize this promoter, we (i) reversed the orientation of Tn5 at several sites and (ii) replaced wild-type Tn5 with several substitution derivatives which lack Tn5's central region. Neither alteration changed the expression of distal genes. Thus, in contrast to transposons IS2 and TnA. Tn5's ability to turn on distal gene expression is not due to a promoter in its central region and therefore is not dependent on the overall orientation of Tn5 in the operon. Our results suggest that the promoter is within 186 base pairs of the ends of Tn5. It is possible that the promoter is detected in only a fraction of insertions because it overlaps Tn5-target sequence boundary.


Looking back on "causal thinking in the health sciences".
It has now been over a quarter of a century since the publication of Mervyn Susser's Causal Thinking in the Health Sciences (1973, Oxford University Press), the first book-length treatment of causal reasoning and inference in our field. Major contributions of this work were its holistic focus on the origins of health outcomes in the context of ecologic systems and its invigoration of the literature on causal criteria in epidemiology. Although a recent resurgence of interest in social context has revivified many points made by Susser, a formal basis for causal analysis consistent with this ecologic perspective has failed to emerge in public health research. Susser's discussion of causal criteria, on the other hand, helped spur a vigorous dialogue that has persisted unabated to the present day. Although the basic outline of the criteria has evolved little, their applications, interrelations, and relative contributions to causal judgments have been the subject of continued and sometimes contentious debate.


Effect of varying salt and fat levels on the sensory and physiochemical quality of frankfurters.
The sensory and physiochemical properties of frankfurters with varying fat and salt levels were investigated. Twenty frankfurter formulations were produced with varying concentrations of fat (10%, 15%, 20%, 25% w/w) and salt (1%, 1.5%, 2%, 2.5%, 3% w/w). Frankfurters were assessed instrumentally for colour, moisture, fat, cooking loss and texture profile analysis. Consumers (n=25) evaluated each product in duplicate for colour, coarseness, tenderness, juiciness, salt taste, meat flavour, off-flavour and overall acceptability using a hedonic scale. Salt levels below 1.5% were shown to have a negative effect on consumer acceptability, with 2.5% salt concentration being the most accepted (P<0.001) by consumers. However, frankfurters containing the lower fat levels 10% and 15% fat with higher salt levels (2.5-3%) were significantly the most acceptable variants to consumers. Samples containing less fat and salt were found to be tougher, less juicy and had greater cooking losses. Thus salt perception is very important for consumer acceptability, but fat levels can be potentially reduced without significantly affecting overall acceptability.


Gestational Weight Gain and Pregnancy Complications in a High-Risk, Racially and Ethnically Diverse Population.
Evidence used to guide the current Institute of Medicine (IOM) gestational weight gain (GWG) recommendations is largely derived from studies of European descent, and as such the guidelines are the same for all races and ethnicities. The guidelines are also the same for prepregnancy obesity classes I through III. Considering these literature gaps, we aim to (1) determine the association between the IOM GWG guidelines and three common pregnancy complications: preeclampsia, gestational diabetes mellitus, and cesarean delivery in a racially and ethnically diverse population; and (2) assess whether the association between GWG and pregnancy complications differs by race/ethnicity or prepregnancy body mass index (BMI) categories, particularly obesity classes I through III. To address these aims, we analyzed data from the Boston Birth Cohort. We calculated GWG using data from electronic medical records or, when missing, from a postdelivery questionnaire. We examined GWG continuously and categorically using the IOM formula. Of the 5,568 women included, 54.5% met the IOM criterion for excessive GWG. Compared to women who had adequate GWG, women who gained excessive weight had 1.65 (95% confidence interval [CI] 1.27-2.14) times greater odds of preeclampsia; 1.68 (95% CI 1.15-2.46) times greater odds of gestational diabetes; and no significant change in odds of cesarean delivery (odds ratio [OR] = 1.14, 95% CI 0.99-1.31). Associations did not differ by race, ethnicity, or prepregnancy BMI categories including comparisons of obesity class I versus II or III (all p-values for interaction >0.05). In this racially and ethnically diverse population, excessive GWG was associated with higher odds of preeclampsia, gestational diabetes, and nonsignificantly, with cesarean delivery. Associations did not differ appreciably by race, ethnicity, or prepregnancy BMI categories. Our results support the relevance of the IOM GWG recommendations in racially and ethnically diverse populations, and in women in the higher prepregnancy obesity classes.


[Acute fatty liver of pregnancy. Report of a case and review of the literature].
Acute Fatty Liver of Pregnancy. The acute fatty liver of pregnancy (AFLP) is an uncommon entity, potentially fatal, which affects women during the last quarter of pregnancy. It is characterized by a prodromic period of symptoms followed by jaundice, hepatic failure, clotting disorders and fatty infiltration of the liver, evident through hepatic biopsy. The incidence ranks from 1 to 20 thousand births, and it is more frequent among women with multiple pregnancies. We report the case of a 29-year-old patient, with multiple pregnancy 33 to 34 weeks of gestation, blood pressure values of 140/90 mmHg, 160,000/dL platelets, PT 25.6 seconds, TPT 64.7 seconds, blood glucose 52 mL/dL, creatinine 2.1 mg/dL, uric acid 11.9 mg/dL, lactic dihydrogenase 1063 U/l, GPT 220 U/l, AF 1172 U/l, total bilirubin 8.4 mg/dL, proteinuria 30 mg/dL. A cesarean section was practiced after correcting the coagulation disorders. The first twin was a male with birth weight of 2,070 g, APGAR 8-9; the second twin was a female fetal death weighting 2,050 g. Hepatic biopsy confirmed the diagnosis. The cause of AFLP is unknown. The frequency among multiple pregnancies is higher. Almost half of the cases have hypertension and proteinuria. There are also high levels of both transaminases, phosphatase and bilirubins and hypoglycemia. The prothrombin time is enlarged. The differential diagnostic between pre-eclampsia and AFLP is not crucial since the obstetric management is the same. The main treatment is promptly deliverance and general measures. The obstetrician must be aware of this hepatic disease.


Assessment of the topoisomerase I gene copy number as a predictive biomarker of objective response to irinotecan in metastatic colorectal cancer.
DNA topoisomerase I is a putative biomarker of irinotecan efficacy with clinical associations previously demonstrated at the protein level. The purpose of the present study was to perform the first clinical investigation of the association between the DNA topoisomerase I gene (TOP1) copy number and objective response following irinotecan treatment in patients with metastatic colorectal cancer. Formalin-fixed, paraffin-embedded tumor samples from 78 patients, who received irinotecan monotherapy in second line, were included. TOP1 was assessed by fluorescence in situ hybridization using a technically validated dual-probe combination that hybridizes to TOP1, located at 20q12-q13.1, and to the centromere region of chromosome 20 (CEN-20). In univariate logistic regression models, the TOP1 signal count per cell and the TOP1/CEN-20 ratio were associated with objective response, which was evaluated according to RECIST v.1.1. Gain of TOP1 was identified in 52.6% and 37.2% using the following cutoff values: TOP1 signal count per cell ≥3.6 and TOP1/CEN-20 ≥1.5, respectively. A borderline significant association (Odds ratio (OR): 1.62; p = 0.07) between a stepwise increase in the TOP1 signal count and objective response was demonstrated. In relation to the applied cutoff values, nonsignificant associations with objective response were identified for the TOP1 signal count (OR: 2.41; p = 0.23) and for the TOP1/CEN-20 ratio (OR: 2.05; p = 0.30). Despite limitations of the study the positive associations between TOP1 and objective response suggest that further analysis in larger tumor material, preferably in a randomized setting, is highly warranted.


Methyl-TWAS: A powerful method for in silico transcriptome-wide association studies (TWAS) using long-range DNA methylation.
In silico transcriptome-wide association studies (TWAS) are commonly used to test whether expression of specific genes is linked to a complex trait. However, genotype-based in silico TWAS such as PrediXcan, exhibit low prediction accuracy for a majority of genes because genotypic data lack tissue- and disease-specificity and are not affected by the environment. Because methylation is tissue-specific and, like gene expression, can be modified by environment or disease status, methylation should predict gene expression with more accuracy than SNPs. Therefore, we propose Methyl-TWAS, the first approach that utilizes long-range methylation markers to impute gene expression for in silico TWAS through penalized regression. Methyl-TWAS 1) predicts epigenetically regulated/associated expression (eGReX), which incorporates tissue-specific expression and both genetically- (GReX) and environmentally-regulated expression to identify differentially expressed genes (DEGs) that could not be identified by genotype-based methods; and 2) incorporates both cis- and trans- CpGs, including various regulatory regions to identify DEGs that would be missed using cis -methylation only. Methyl-TWAS outperforms PrediXcan and two other methods in imputing gene expression in the nasal epithelium, particularly for immunity-related genes and DEGs in atopic asthma. Methyl-TWAS identified 3,681 (85.2%) of the 4,316 DEGs identified in a previous TWAS of atopic asthma using measured expression, while PrediXcan could not identify any gene. Methyl-TWAS also outperforms PrediXcan for expression imputation as well as in silico TWAS in white blood cells. Methyl-TWAS is a valuable tool for in silico TWAS, leveraging a growing body of publicly available genome-wide DNA methylation data for a variety of human tissues.


Photonic generation and independent steering of multiple RF signals for software defined radars.
As the improvement of radar systems claims for digital approaches, photonics is becoming a solution for software defined high frequency and high stability signal generation. We report on our recent activities on the photonic generation of flexible wideband RF signals, extending the proposed architecture to the independent optical beamforming of multiple signals. The scheme has been tested generating two wideband signals at 10 GHz and 40 GHz, and controlling their independent delays at two antenna elements. Thanks to the multiple functionalities, the proposed scheme allows to improve the effectiveness of the photonic approach, reducing its cost and allowing flexibility, extremely wide bandwidth, and high stability.


Alpha1-antichymotrypsin in rheumatoid arthritis.
Serum alpha1-antichymotrypsin (alpha1-ACT) of the patient with rheumatoid arthritis was studied by means of single radial immunodiffusion method. There was a significant elevation of the alpha1-ACT concentration in the patients with rheumatoid arthritis, and positive relationships were observed between the concentrations of alpha1-ACT and of other glycoproteins such as alpha1-acid glycoprotein and alpha1-antitrypsin in individual patients, and between C-reactive protein (CRP) rates and the (CRP) rates and the alpha1-ACT concentrations in individual specimens. These facts suggest that alpha1-ACT belongs to a group of acute phase proteins like alpha1-antitrypsin or CRP. An inverse proportional correlation was revealed between alpha1-ACT and fibrinolytic activity. No influences were observed on the alpha1-ACT concentration, activity index or articular index by the oral administration of alpha-chymotrypsin in patients with rheumatoid arthritis.


The significance of time factors in cerebral palsy litigation.
to demonstrate the significance of the lengths of time taken to initiate and conclude litigation concerning cerebral palsy. documentary analysis of 142 closed legal files (92 Scottish; 50 English) relating to births from 1980-1996. Claim outcome, and the dates of birth, legal notification and conclusion of the claim, were analysed using Microsoft Excel. health service legal offices in Scotland and England. successful claims were raised more quickly (on average two years compared with 3.6 years for unsuccessful claims). They also took longer to be decided (six years compared with three years). On average the children of successful and unsuccessful litigants were, respectively, 7.8 and 6.6 years old by the time the claim was decided. Over the period studied there was a steady reduction in the length of time taken to initiate litigation, although successful claims were on average raised more quickly. Overall success rate was 27%. most cerebral palsy claims do not satisfy the requirements of the law of medical negligence. Lengthy periods of time are involved irrespective of outcome: while successful litigants continue to sue more quickly, their claims take longer to be resolved. The extensive period from birth to closure of claim, and uncertainty over the legal outcome, may cause significant distress for practitioners and parents of children with cerebral palsy. Knowledge of the likely duration of the legal process can help practitioners and the families involved to come to terms with this important feature of litigation. Health service claims managers may also be helped in terms of understanding the more likely duration (and therefore cost implications) of cerebral palsy claims. For successful litigants there are questions about the justice of having to wait, on average, nearly eight years for compensation.