Critical Care Management of Patients After Cardiac Arrest: A Scientific Statement From the American Heart Association and Neurocritical Care Society.
The critical care management of patients after cardiac arrest is burdened by a lack of high-quality clinical studies and the resultant lack of high-certainty evidence. This results in limited practice guideline recommendations, which may lead to uncertainty and variability in management. Critical care management is crucial in patients after cardiac arrest and affects outcome. Although guidelines address some relevant topics (including temperature control and neurological prognostication of comatose survivors, 2 topics for which there are more robust clinical studies), many important subject areas have limited or nonexistent clinical studies, leading to the absence of guidelines or low-certainty evidence. The American Heart Association Emergency Cardiovascular Care Committee and the Neurocritical Care Society collaborated to address this gap by organizing an expert consensus panel and conference. Twenty-four experienced practitioners (including physicians, nurses, pharmacists, and a respiratory therapist) from multiple medical specialties, levels, institutions, and countries made up the panel. Topics were identified and prioritized by the panel and arranged by organ system to facilitate discussion, debate, and consensus building. Statements related to postarrest management were generated, and 80% agreement was required to approve a statement. Voting was anonymous and web based. Topics addressed include neurological, cardiac, pulmonary, hematological, infectious, gastrointestinal, endocrine, and general critical care management. Areas of uncertainty, areas for which no consensus was reached, and future research directions are also included. Until high-quality studies that inform practice guidelines in these areas are available, the expert panel consensus statements that are provided can advise clinicians on the critical care management of patients after cardiac arrest.


Laparoscopic sleeve gastrectomy: a novel procedure for weight loss.
Morbid obesity is associated with increased morbidity and mortality. Bariatric surgery offers morbidly obese individuals substantial and sustainable weight loss and reduction in obesity-related comorbidities. Laparoscopic sleeve gastrectomy (LSG) is a new restrictive procedure in bariatric surgery. We aimed to evaluate our experience with LSG with regard to its safety and feasibility and early weight loss. The surgical outcome, complications and early clinical results of all patients who underwent LSG at Singapore General Hospital were studied. 30 patients underwent LSG between December 2008 and October 2010. The mean preoperative weight of the patients was 113.4 (range 91.0-170.0) kg, while the mean body mass index (BMI) was 42.6 (range 33.0-60.0) kg/m². Diabetes mellitus was present in 39 percent of the patients, hypertension in 43 percent, hyperlipidaemia in 35 percent, obstructive sleep apnoea in 30 percent and osteoarthritis in 22 percent. The majority of patients had two or more obesity-related comorbidities (52 percent). Mean operative time was 142 (range 80-220) minutes and median duration of postoperative stay was three days. At two weeks, one, three and six months post operation, the mean BMI was 38.6 kg/m², 37.8 kg/m², 34.5 kg/m² and 30.8 kg/m², the mean percentage of excess weight loss was 17.7 percent, 23.3 percent, 40.9 percent and 56.7 percent, and absolute weight loss was 8.00 kg, 11.52 kg, 18.77 kg and 26.85 kg, respectively. LSG is a promising procedure for surgical treatment of obesity, with good early weight loss and low morbidity.


Relationship between supramaximal flow during cough and mortality in motor neurone disease.
The main function of cough is clearance of intrathoracic airways. A normal cough is characterized by a transient increase in expiratory flow above the maximal flow-volume loop envelope, known as cough "spikes". They may be absent in patients with motor neurone disease. The relationship between cough pattern, pulmonary function and survival was studied. Fifty-three patients were recruited (25 bulbar). Vital capacity, maximal inspiratory and expiratory mouth pressures and cough flow/volume curves were performed on all patients, and the presence or absence of spikes were recorded. The primary endpoints were mortality or initiation of ventilatory support over a period of 18 months. Thirty-five patients died over the 18-month period of the study (including the six who were started on noninvasive ventilation). Twelve of the 24 patients with spikes died compared to 23 out of 29 patients without spikes (p<0.05). Patients without spikes were more likely to be bulbar on clinical grounds (p<0.0001) and had poorer lung function. The results showed an association between the absence of cough spikes and increased mortality. However the main determinants of survival in motor neurone disease are age, vital capacity and inspiratory mouth pressure, and it remains to be shown whether regular monitoring of cough conveys any additional advantage.


A phase I study of pegylated liposomal doxorubicin hydrochloride (Caelyx) in combination with cyclophosphamide and vincristine as second-line treatment of patients with small-cell lung cancer.
The purpose of this study was to determine the recommended phase II dose of liposomal doxorubicin (Caelyx ; Doxil in the United States) in combination with cyclophosphamide and vincristine for previously treated patients with good performance status with relapsed or refractory small-cell lung cancer. Twenty-one eligible patients were enrolled between November 1999 and September 2001 and received liposomal doxorubicin 25-40 mg/m2, cyclophosphamide 750-1000 mg/m2, and vincristine 1.2 mg/m2 intravenously (I.V.) every 21 days. At doses of liposomal doxorubicin 40 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.2 mg/m2 I.V., 1 of 6 patients had dose-limiting neutropenia and fever in cycle 2 and 2 of 6 developed grade 3 hand-foot syndrome during cycle 3. Therefore, the recommended phase II doses are liposomal doxorubicin 35 mg/m2, cyclophosphamide 750 mg/m2, and vincristine 1.2 mg/m2 I.V. every 21 days. Antitumor activity was seen at all dose levels. This combination is well tolerated and has evidence of antitumor activity. A phase II evaluation is ongoing.


Enough skill to kill: intentionality judgments and the moral valence of action.
Extant models of moral judgment assume that an action's intentionality precedes assignments of blame. Knobe (2003b) challenged this fundamental order and proposed instead that the badness or blameworthiness of an action directs (and thus unduly biases) people's intentionality judgments. His and other researchers' studies suggested that blameworthy actions are considered intentional even when the agent lacks skill (e.g., killing somebody with a lucky shot) whereas equivalent neutral actions are not (e.g., luckily hitting a bull's-eye). The present five studies offer an alternative account of these provocative findings. We suggest that people see the morally significant action examined in previous studies (killing) as accomplished by a basic action (pressing the trigger) for which an unskilled agent still has sufficient skill. Studies 1 through 3 show that when this basic action is performed unskillfully or is absent, people are far less likely to view the killing as intentional, demonstrating that intentionality judgments, even about immoral actions, are guided by skill information. Studies 4 and 5 further show that a neutral action such as hitting the bull's-eye is more difficult than killing and that difficult actions are less often judged intentional. When difficulty is held constant, people's intentionality judgments are fully responsive to skill information regardless of moral valence. The present studies thus speak against the hypothesis of a moral evaluation bias in intentionality judgments and instead document people's sensitivity to subtle features of human action.


Effects of glucagon, glucose, adrenaline and insulin infusion on blood glucose level in the common African toad (bufo regularis).
Male toads, weighing 70-123 g, were divided into 13 groups with 8 toad in each group. Animals in each group were fasted overnight before the experiments. Toads in groups 1 to 4 were infused for 30 minutes with adrenaline, 5 ugkg-1 min-1, glucose, 5.5 mg kg-1 min-1; glucagon 2 ugkg-1 min-1; and insulin 2000 uU kg-1 min-1, respectively. Blood samples for blood glucose measurement were taken before, during and after each infusion. The experiment was repeated in groups 5 and 6 using 3.5 mg kg-1 min-1 and 7.5 mg kg-1 min-1 of glucose respectively. Toads in groups 7 to 9 were pretreated with prazosin, 0.2 mg/kg and those in groups 10 to 12 were pretreated with propranolol, 0.5 mg/kg. After pretreatment, glucose, glucagon and insulin infusions were repeated in the alpha-blocked and beta-blocked toads, respectively. Group 13 was infused with 0.7% saline and served as the control. The results showed that infusions of adrenaline, glucose and glucagon resulted in significant hyperglycaemia while insulin caused hypoglycaemia. The hyperglycaemic response to glucose was dose-dependent. The experiments using blockers showed that the glycaemic effects of glucagon and insulin are mediated via beta adrenoceptors, that for glucose is via alpha adrenoceptors and from an earlier study, the glycaemic response of adrenaline is through both alpha and beta adrenoceptors.


In vitro evaluation of the anti-diabetic potential of Helichrysum petiolare Hilliard & B.L. Burtt using HepG2 (C3A) and L6 cell lines.
Background:Helichrysum petiolare Hilliard & B.L. Burtt has been listed in a survey of plants used in traditional medicine for the treatment of type 2 diabetes in the Eastern Cape of South Africa. In this study, the antidiabetic potentials of ethanol, cold aqueous (CAQ) and boiled aqueous (BAQ) extracts of H. petiolare were investigated. Methods: The cytotoxic and glucose utilization effects of the extracts were evaluated using L6 myocytes and HepG2 (C3A) hepatocytes. α-amylase, α-glucosidase and lipase inhibition assays were also carried out. Results: The ethanol extract showed significant cytotoxic effects in the treated cells. Both BAQ and CAQ extracts significantly increased glucose uptake in L6 and C3A cell lines. The CAQ extract enhanced glucose uptake more in the L6 myocytes than in the C3A cell-lines hepatocytes. The BAQ extract showed higher levels of inhibition on α-amylase and α-glucosidase than CAQ. The activities were not significantly different from acarbose. However, BAQ showed lower lipase inhibition than acarbose (p<0.05). Conclusions: The BAQ and CAQ extracts of H. petiolare may, therefore, contain pharmacologically active and relatively non-toxic hypoglycaemic chemicals, which may be effective substitutes in the treatment of diabetes mellitus.


Tailoring of alginate-gelatin microspheres properties for oral Ciprofloxacin-controlled release against Pseudomonas aeruginosa.
Ciprofloxacin (Cip) is a broad spectrum antibiotic frequently used in the treatment of infectious diseases caused by Pseudomonas aeruginosa. Cip oral administration is commonly associated with poor drug biodisponibility, gastrointestinal tract irritation, and toxic undesirable side effects. The aim of this work is to provide an oral biopolymeric system for controlled release of Cip. Alginate-gelatin blend microspheres were crosslinked in the presence of 1,2-propylene glycol, calcium, and glutaraldehyde. Studies of Cip encapsulation and release were performed. Matrix characteristics were studied simultaneously by optical microscopy and Fourier transform infrared spectroscopy (FTIR) using synchrotron light, and by texturometric analysis. Microsphere surface topologies were observed by scanning electron microscopy (SEM), atomic force microscopy (AFM), and epifluorescence microscopy. Microspheres crosslinked with glutaraldehyde showed about 80% Cip encapsulation and less than 10% Cip release under simulated gastric conditions in 15 min, while a controlled release profile was observed at intestinal environment conditions. Antimicrobial activity against P. aeruginosa showed an increasing bacterial growth inhibition in time. Finally, bovine serum albumin (BSA) was used as model protein for binding of macromolecules onto active surface of microspheres, with a consequently modulation of Cip release. The results are indicating that alginate/gelatin matrix crosslinked via Ca(2+) and glutaraldehyde can be tailored by decorating the microsphere surface with biological active molecules useful for targeting, making a potential tool to improve Cip oral administration for infection diseases.


A technique for the rapid selection of drug-sensitive and auxotrophic mutants of Phycomyces blakesleeanus.
An auxotroph enrichment procedure has been developed for Phycomyces blakesleeanus which has proven useful in obtaining both auxotrophs and drug-sensitive mutants. The technique is based on the differential heat sensitivity between ungerminated auxotrophic spores and germinated prototrophic spores. Germinated spores and mycelia die when left at temperatures higher than about 35 degrees C for 16 to 24 h but ungerminated spores survive this treatment and subsequently germinate if transferred to complete medium. With the dwarf colonial strain, replica plating permits the rapid characterization of these newly selected auxotrophs.


Prevalence and Time Trend of SARS-CoV-2 Infection in Puducherry, India, August-October 2020.
We conducted 3 population-based cross-sectional surveys, at 1-month intervals, to estimate the prevalence and time-trend of severe acute respiratory syndrome coronavirus 2 infection in Puducherry, India. Seropositivity rate increased from 4.9% to 34.5% over 2 months and was 20-fold higher than the number of diagnosed cases of infection.


Nonenzymatic polyubiquitination of expressed proteins.
Ubiquitination is one of the most ubiquitous posttranslational modifications in eukaryotes and is involved in various cellular events such as proteasomal degradation and DNA repair. The overwhelming majority of studies aiming to understand ubiquitination and deubiquitination have employed unanchored ubiquitin chains and mono-ubiquitinated proteins. To shed light on these processes at the molecular level, it is crucial to have facile access to ubiquitin chains linked to protein substrates. Such conjugates are highly difficult to prepare homogenously and in workable quantities using the enzymatic machinery. To address this formidable challenge we developed new chemical approaches to covalently attach ubiquitin chains to a protein substrate through its Cys residue. A key aspect of this approach is the installation of acyl hydrazide functionality at the C-terminus of the proximal Ub, which allows, after ubiquitin chain assembly, the introduction of various reactive electrophiles for protein conjugation. Employing α-globin as a model substrate, we demonstrate the facile conjugation to K48-linked ubiquitin chains, bearing up to four ubiquitins, through disulfide and thioether linkages. These bioconjugates were examined for their behavior with the USP2 enzyme, which was found to cleave the ubiquitin chain in a similar manner to unanchored ones. Furthermore, proteasomal degradation study showed that di-ubiquitinated α-globin is rapidly degraded in contrast to the mono-ubiquitinated counterpart, highlighting the importance of the chain lengths on proteasomal degradation. The present work opens unprecedented opportunities in studying the ubiquitin signal by enabling access to site-specifically polyubiquitinated proteins with an increased size and complexity.


Multi-actuation and PI control: a simple recipe for high-speed and large-range atomic force microscopy.
High speed atomic force microscopy enables observation of dynamic nano-scale processes. However, maintaining a minimal interaction force between the sample and the probe is challenging at high speed specially when using conventional piezo-tubes. While rigid AFM scanners are operational at high speeds with the drawback of reduced tracking range, multi-actuation schemes have shown potential for high-speed and large-range imaging. Here we present a method to seamlessly incorporate additional actuators into conventional AFMs. The equivalent behavior of the resulting multi-actuated setup resembles that of a single high-speed and large-range actuator with maximally flat frequency response. To achieve this, the dynamics of the individual actuators and their couplings are treated through a simple control scheme. Upon the implementation of the proposed technique, commonly used PI controllers are able to meet the requirements of high-speed imaging. This forms an ideal platform for retroactive enhancement of existing AFMs with minimal cost and without compromise on the tracking range. A conventional AFM with tube scanner is retroactively enhanced through the proposed method and shows an order of magnitude improvement in closed loop bandwidth performance while maintaining large range. The effectiveness of the method is demonstrated on various types of samples imaged in contact and tapping modes, in air and in liquid.


Interactions of mitochondrial inhibitors with methylmercury on spontaneous quantal release of acetylcholine.
The interaction of methylmercury (MeHg) with various inhibitors of mitochondrial function (dinitrophenol, 50 microM; dicoumarol, 100 microM; valinomycin, 20 microM; and ruthenium red, 20 microM) on spontaneous quantal release of acetylcholine was tested at the neuromuscular junction of the rat. The objective was to determine whether these mitochondrial inhibitors blocked the MeHg-induced increase of spontaneous release of acetylcholine, an effect measured electrophysiologically as increased miniature endplate potential (MEPP) frequency. MEPPs were recorded from myofibers of the rat hemidiaphragm using conventional, intracellular microelectrode recording techniques. When given alone, all four inhibitors increased MEPP frequency from resting levels of 1-2/sec (Hz) to approximately 10-60 Hz after a latency which ranged from 5 to 30 min. MEPP frequency subsequently returned to control levels. Subsequent concomitant application of MeHg (100 microM) with dinitrophenol, dicoumarol, or valinomycin increased MEPP frequency sharply to peak values of 40-60 Hz after 15-20 min. MEPP frequency subsided to pre-MeHg levels 10 min later. The time course and peak MEPP frequency elicited by MeHg after pretreatment with these uncouplers were similar to results obtained in preparations treated with MeHg alone. Ruthenium red, a putative specific inhibitor of the Ca2+ uptake uniporter in mitochondria, increased MEPP frequency to 12 Hz after 8.5 min when given alone. MEPP frequency returned to control levels approximately 10 min later. Subsequent application of MeHg and ruthenium red for up to 80 min failed to increase MEPP frequency. The inability of MeHg to increase MEPP frequency in ruthenium red-treated preparations was not due to depletion of acetylcholine nor to block of postjunctional receptors by ruthenium red since subsequent treatment with La3+ (2 mM) increased MEPP frequency to 12.5 Hz within 10 min. Thus, ruthenium red blocked the stimulatory effect of MeHg on MEPP frequency while uncouplers of oxidative phosphorylation and a K+ ionophore did not. The results with ruthenium red are consistent with the proposal that MeHg may block mitochondrial uptake of Ca2+ or promote its release, leading to an increased free cytosolic Ca2+ concentration which in turn stimulates spontaneous release of acetylcholine.


Three dimensional printed degradable and conductive polymer scaffolds promote chondrogenic differentiation of chondroprogenitor cells.
Conductive polymers have been used for various biomedical applications including biosensors, tissue engineering and regenerative medicine. However, the poor processability and brittleness of these polymers hinder the fabrication of three-dimensional structures with desirable geometries. Moreover, their application in tissue engineering and regenerative medicine has been so far limited to excitable cells such as neurons and muscle cells. To enable their wider adoption in tissue engineering and regenerative medicine, new materials and formulations that overcome current limitations are required. Herein, a biodegradable conductive block copolymer, tetraaniline-b-polycaprolactone-b-tetraaniline (TPT), is synthesised and 3D printed for the first time into porous scaffolds with defined geometries. Inks are formulated by combining TPT with PCL in solutions which are then directly 3D printed to generate porous scaffolds. TPT and PCL are both biodegradable. The combination of TPT with PCL increases the flexibility of the hybrid material compared to pure TPT, which is critical for applications that need mechanical robustness of the scaffolds. The highest TPT content shows the lowest tensile failure strain. Moreover, the absorption of a cell adhesion-promoting protein (fibronectin) and chondrogenic differentiation of chondroprogenitor cells are found to be dependent on the amount of TPT in the blends. Higher content of TPT in the blends increases both fibronectin adsorption and chondrogenic differentiation, though the highest concentration of TPT in the blends is limited by its solubility in the ink. Despite the contradicting effects of TPT concentration on flexibility and chondrogenic differentiation, a concentration that strikes a balance between the two factors is still available. It is worth noting that the effect on chondrogenic differentiation is found in scaffolds without external electric stimulation. Our work demonstrates the possibility of 3D printing flexible conductive and biodegradable scaffolds and their potential use in cartilage tissue regeneration, and opens up future opportunities in using electric stimulation to control chondrogenesis in these scaffolds.


Source analysis of event-related cortical activity during visuo-spatial attention.
Recordings of event-related potentials (ERPs) were combined with structural and functional magnetic resonance imaging (fMRI) to study the spatio-temporal patterns of cortical activity that underlie visual-spatial attention. Small checkerboard stimuli were flashed in random order to the four quadrants of the visual field at a rapid rate while subjects attended to stimuli in one quadrant at a time. Attended stimuli elicited enhanced ERP components in the latency range 80-200 ms that were co-localized with fMRI activations in multiple extrastriate cortical regions. The earliest ERP component (C1 at 50-90 ms) was unaffected by attention and was localized by dipole modeling to calcarine cortex. A longer latency deflection in the 150-225 ms range that was accounted for by this same calcarine source, however, did show consistent modulation with attention. This late attention effect, like the C1, inverted in polarity for upper versus lower field stimuli, consistent with a neural generator in primary visual cortex (area V1). These results provide support to current hypotheses that spatial attention in humans is associated with delayed feedback to area V1 from higher extrastriate areas that may have the function of improving the salience of stimuli at attended locations.


Cuspal movement related to different polymerization protocols.
The aim of this study to investigate the effects of different polymerization protocols on the cuspal movement in class II composite restorations. Human premolar teeth were prepared with class II cavities and then restored with composite and three-step and two-step etch-and-rinse adhesive systems under different curing techniques (n = 10). It was used a light- emitting-diode curing unit and the mode of polymerization were: standard (exposure for 40 seconds at 700 mW/cm(2)), pulse-delay (initial exposure for 6 seconds at 350 mW/cm(2) followed by a resting period of 3 minutes and a final exposure of 37 seconds at 700 mW/cm(2)) and soft-start curing (exposure 10 seconds at 350 mW/cm(2) and 35 seconds at 700 mW/cm(2)). The cuspal distance (μm) was measured before and after the restorative procedure and the difference was recorded as cuspal movement. The data were submitted to two-way ANOVA and Bonferroni test (p < 0.05). The type of adhesive system did not influenced the cuspal movement for all the curing methods. Standard protocol showed the highest values of cuspal movement and was statistically different from the pulse-delay and soft-start curing modes. Although the cuspal displacement was not completely avoided, alternative methods of photocuring should be considered to minimize the clinical consequences of composites contraction stress.


The influence of sleep onset on the diurnal variation in cardiac activity and cardiac control.
Heart rate (HR), blood pressure (BP) and autonomic nervous system (ANS) activity vary diurnally, with a reduction in HR and BP, and a shift to vagal dominance during the dark phase. However, the cause of these changes, particularly the relative influence of sleep and circadian mechanisms, remains uncertain. The present study assessed the effect of sleep onset on HR, BP, high frequency (HF) component of heart rate variability (HRV), low frequency/high frequency (LF/HF) ratio and pre-ejection period (PEP). Sleep onset was dissociated from circadian influences by having subjects go to sleep at two different circadian phases, their normal time of sleep onset (normal sleep onset, NSO), and after a delay of 3 h (delayed sleep onset, DSO). The assumption was that changes caused by sleep onset would occur in association with sleep onset, irrespective of its timing, while circadian effects would have a consistent circadian phase and be independent of when sleep onset occurred. Thirteen and 17 subjects were run in the NSO and DSO conditions, respectively. Following a 1-h adaptation period, data collection began 2 h before subjects' normal time of sleep onset and continued until morning awakening. The lights were turned out after 2 h in the NSO condition and 5 h in the DSO condition. Subjects were required to maintain a supine position throughout the experimental sessions. The night-time decrease in HR was found to be due to both sleep onset and a circadian influence, with the circadian component being more prominent. In contrast, the fall in BP was largely due to a sleep onset effect. Increased vagal activity, as reflected in the HF component and a shift to vagal dominance in the LF/HF ratio, appeared to be primarily a function of the sleep system, while sympathetic activity, as assessed by PEP, reflected a circadian influence.


Reconstructing cone-beam CT with spatially varying qualities for adaptive radiotherapy: a proof-of-principle study.
With the aim of maximally reducing imaging dose while meeting requirements for adaptive radiation therapy (ART), we propose in this paper a new cone beam CT (CBCT) acquisition and reconstruction method that delivers images with a low noise level inside a region of interest (ROI) and a relatively high noise level outside the ROI. The acquired projection images include two groups: densely sampled projections at a low exposure with a large field of view (FOV) and sparsely sampled projections at a high exposure with a small FOV corresponding to the ROI. A new algorithm combining the conventional filtered back-projection algorithm and the tight-frame iterative reconstruction algorithm is also designed to reconstruct the CBCT based on these projection data. We have validated our method on a simulated head-and-neck (HN) patient case, a semi-real experiment conducted on a HN cancer patient under a full-fan scan mode, as well as a Catphan phantom under a half-fan scan mode. Relative root-mean-square errors (RRMSEs) of less than 3% for the entire image and ~1% within the ROI compared to the ground truth have been observed. These numbers demonstrate the ability of our proposed method to reconstruct high-quality images inside the ROI. As for the part outside ROI, although the images are relatively noisy, it can still provide sufficient information for radiation dose calculations in ART. Dose distributions calculated on our CBCT image and on a standard CBCT image are in agreement, with a mean relative difference of 0.082% inside the ROI and 0.038% outside the ROI. Compared with the standard clinical CBCT scheme, an imaging dose reduction of approximately 3-6 times inside the ROI was achieved, as well as an 8 times outside the ROI. Regarding computational efficiency, it takes 1-3 min to reconstruct a CBCT image depending on the number of projections used. These results indicate that the proposed method has the potential for application in ART.


Association of neurofilament proteins with neuronal Cdk5 activator.
Cdk5 exists in brain extracts in multiple forms, one of which is a macromolecular protein complex comprising Cdk5, neuron-specific Cdk5 activator p35nck5a and other protein components (Lee, K.-Y., Rosales, J. L., Tang, D., and Wang, J.H. (1996) J. Biol. Chem. 271, 1538-1543). The yeast two-hybrid system was employed to identify p35nck5a-interacting proteins from a human brain cDNA library. One of the isolated clones encodes a fragment of glial fibrillary acidic protein, which is a glial-specific protein. Sequence alignment revealed significant homology between the p35nck5a-binding fragment of glial fibrillary acidic protein and corresponding regions in neurofilaments. The association between p35nck5a and neurofilament medium molecular weight subunit (NF-M) was confirmed by both the yeast two-hybrid assay and direct binding of the bacteria-expressed proteins. The p35nck5a binding site on NF-M was mapped to a carboxyl-terminal region of the rod domain, in close proximity to the putative Cdk5 phosphorylation sites in NF-M. A region immediately amino-terminal to the kinase-activating domain in p35nck5a is required for its binding with NF-M. In in vitro binding assays, NF-M binds both monomeric p35nck5a and the Cdk5/p35nck5a complex. The binding of NF-M has no effect on the kinase activity of Cdk5/p35nck5a.


Dry heat inactivation of Bacillus subtilis var. niger spores as a function of relative humidity.
Dry heat sterilization of Bacillus subtilis var. niger spores at 105 C is enhanced in the relative humidity range 0.03 to 0.2%. D-values of 115 and 125 C are predicted by a kinetic model with parameters set from 105 C data. These predictions are compared to observations.


Hemodynamic performance of the Fontan circulation compared with a normal biventricular circulation: a computational model study.
The physiological limitations of the Fontan circulation have been extensively addressed in the literature. Many studies emphasized the importance of pulmonary vascular resistance in determining cardiac output (CO) but gave little attention to other cardiovascular properties that may play considerable roles as well. The present study was aimed to systemically investigate the effects of various cardiovascular properties on clinically relevant hemodynamic variables (e.g., CO and central venous pressure). To this aim, a computational modeling method was employed. The constructed models provided a useful tool for quantifying the hemodynamic effects of any cardiovascular property of interest by varying the corresponding model parameters in model-based simulations. Herein, the Fontan circulation was studied compared with a normal biventricular circulation so as to highlight the unique characteristics of the Fontan circulation. Based on a series of numerical experiments, it was found that 1) pulmonary vascular resistance, ventricular diastolic function, and systemic vascular compliance play a major role, while heart rate, ventricular contractility, and systemic vascular resistance play a secondary role in the regulation of CO in the Fontan circulation; 2) CO is nonlinearly related to any single cardiovascular property, with their relationship being simultaneously influenced by other cardiovascular properties; and 3) the stability of central venous pressure is significantly reduced in the Fontan circulation. The findings suggest that the hemodynamic performance of the Fontan circulation is codetermined by various cardiovascular properties and hence a full understanding of patient-specific cardiovascular conditions is necessary to optimize the treatment of Fontan patients.


Ambient temperature and stillbirth: Risks associated with chronic extreme temperature and acute temperature change.
Ambient temperature events are increasing in frequency and intensity. Our prior work in a U.S. nationwide study suggests a strong association between both chronic and acute temperature extremes and stillbirth risk. We attempted to replicate our prior study by assessing stillbirth risk associated with average whole-pregnancy temperatures and acute ambient temperature changes in a low-risk U.S. Singleton deliveries in the NICHD Consecutive Pregnancies Study (Utah, 2002-2010; n = 112,005) were identified using electronic medical records. Ambient temperature was derived from the Weather Research and Forecasting model. Binary logistic regression determined the adjusted odds ratio (aOR) and 95% confidence interval (95% CI) for stillbirth associated with whole-pregnancy exposure to extreme cold (<10th percentile) and hot (>90th percentile) versus moderate (10th-90th percentiles) average temperature, adjusting for maternal demographics, season of conception, hypertensive disorders of pregnancy, and gestational diabetes. In a case-crossover analysis, we estimated the stillbirth aOR and 95% CI for each 1° Celsius increase during the week prior to delivery using conditional logistic regression. In both models, we adjusted for relative humidity, ozone, and fine particulates. We observed 500 stillbirth cases among 498 mothers. Compared to moderate temperatures, whole-pregnancy exposure to extreme cold (aOR: 4.42, 95% CI:3.43, 5.69) and hot (aOR: 5.06, 95% CI: 3.34, 7.68) temperatures were associated with stillbirth risk. Case-crossover models observed a 7% increased odds (95% CI: 1.04, 1.10) associated with each 1° Celsius increase during the week prior to delivery. Both chronic and acute ambient temperature were associated with odds of stillbirth in this low-risk population, similar to our prior nationwide findings. Future increases in temperature extremes are likely and the observed risk in a low-risk population suggests this association merits attention.


Phosphatase of regenerating liver 2 (PRL2) is essential for placental development by down-regulating PTEN (Phosphatase and Tensin Homologue Deleted on Chromosome 10) and activating Akt protein.
The PRL (phosphatase of regenerating liver) phosphatases are implicated in the control of cell proliferation and invasion. Aberrant PRL expression is associated with progression and metastasis of multiple cancers. However, the specific in vivo function of the PRLs remains elusive. Here we show that deletion of PRL2, the most ubiquitously expressed PRL family member, leads to impaired placental development and retarded growth at both embryonic and adult stages. Ablation of PRL2 inactivates Akt and blocks glycogen cell proliferation, resulting in reduced spongiotrophoblast and decidual layers in the placenta. These structural defects cause placental hypotrophy and insufficiency, leading to fetal growth retardation. We demonstrate that the tumor suppressor PTEN is elevated in PRL2-deficient placenta. Biochemical analyses indicate that PRL2 promotes Akt activation by down-regulating PTEN through the proteasome pathway. This study provides the first evidence that PRL2 is required for extra-embryonic development and associates the oncogenic properties of PRL2 with its ability to negatively regulate PTEN, thereby activating the PI3K-Akt pathway.


Cellular oxygen sensing by mitochondria: old questions, new insight.
Hypoxia elicits a variety of adaptive responses at the tissue level, at the cellular level, and at the molecular level. A physiological response to hypoxia requires the existence of an O(2) sensor coupled to a signal transduction system, which in turn activates the functional response. Although much has been learned about the signaling systems activated by hypoxia, no consensus exists regarding the nature of the underlying O(2) sensor or whether multiple sensors exist. Among previously considered mechanisms, heme proteins have been suggested to undergo allosteric modification in response to O(2) binding or release at different PO(2) levels. Other studies suggest that ion channels may change conductance as a function of PO(2), allowing them to signal the onset of hypoxia. Still other studies suggest that NADPH oxidase may decrease its generation of reactive O(2) species (ROS) during hypoxia. Recent data suggest that mitochondria may function as O(2) sensors by increasing their generation of ROS during hypoxia. These oxidant signals appear to act as second messengers in the adaptive responses to hypoxia in a variety of cell types. Such observations contribute to a growing awareness that mitochondria do more than just generate ATP, in that they initiate signaling cascades involved in adaptive responses to hypoxia and that they participate in the control of cell death pathways.


[IgA and its different molecular forms in the mesenteric, portal and peripheral venous blood in man].
The aim of this study was to assess the role of mesenteric blood in polymeric IgA (p-IgA) and IgA2-transport from the intestinal mucosa into plasma and the role of the liver in the clearance of these molecular forms of IgA. The concentrations of IgA, p-IgA and IgA2 were measured in mesenteric, splenic, portal, and hepatic veins of 7 control subjects without liver disease and in portal and peripheral veins of 4 patients with alcoholic cirrhosis. In control subjects, the concentration of the different molecular forms of IgA were not significantly different in mesenteric and in splenic vein. No significant decrease of IgA concentrations was observed in hepatic vein, as compared with portal vein. In cirrhotic patients IgA concentrations were significantly higher than in control subjects, but concentrations of IgA, p-IgA and IgA2 were not different in portal and peripheral blood. These results show that mesenteric vein is not a major way for p-IgA and IgA2 from the gut lamina propria to plasma, and suggest that the origin of a significant part of these molecular forms of IgA could be peripheral lymph-nodes more than gut-associated-lymphoid-tissue. The absence of significant clearance of p-IgA by the liver in normal subjects suggests that abnormalities of hepato-biliary transport of p-IgA is not responsible for the increased IgA levels observed in cirrhotic patients.


Locally low-rank denoising in transform domains.
To develop an extension to locally low rank (LLR) denoising techniques based on transform domain processing that reduces the number of images required in the MR image series for high-quality denoising. LLR methods with random matrix theory-based thresholds are successfully used in the denoising of MR image series in a number of applications. The performance of these methods depend on how well the LLR assumption is satisfied, which deteriorates with few numbers of images, as is commonly encountered in quantitative MRI applications. We propose a transform-domain approach for denoising of MR image series to represent the underlying signal with higher fidelity when using a locally low rank approximation. The efficacy of the method is demonstrated for fully-sampled k-space, undersampled k-space, DICOM images, and complex-valued SENSE-1 images in quantitative MRI applications with as few as 4 images. For both MSK and brain applications, the transform domain denoising preserves local subtle variability, whereas the quantitative maps based on image domain LLR methods tend to be locally more homogeneous. A transform domain extension to LLR denoising produces high quality images and is compatible with both raw k-space data and vendor reconstructed data. This allows for improved imaging and more accurate quantitative analyses and parameters obtained therefrom.


Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells.
Vascular adhesion protein-1 (VAP-1) is an amine oxidase and adhesion receptor that is expressed by endothelium in the human liver. The hepatic sinusoids are perfused by blood at low flow rates, and sinusoidal endothelium lacks selectin expression and has low levels of CD31, suggesting that VAP-1 may play a specific role in lymphocyte recruitment to the liver. In support of this we now report the constitutive expression of VAP-1 on human hepatic sinusoidal endothelial cells (HSEC) in vitro and demonstrate that VAP-1 supports adhesion and transmigration of lymphocytes across these cells under physiological shear stress. These are the first studies to report the function of VAP-1 on primary human endothelial cells. Under static conditions lymphocyte adhesion to unstimulated HSEC was dependent on VAP-1 and ICAM-2, whereas adhesion to TNF-alpha-stimulated HSEC was dependent on ICAM-1, VCAM-1, and VAP-1. Under conditions of flow, blocking VAP-1 reduced lymphocyte adhesion to TNF-alpha-treated HSEC by 50% and significantly reduced the proportion of adherent lymphocytes that transmigrated across cytokine or LPS-activated endothelium. In addition, inhibition of the amine oxidase activity of VAP-1 reduced both adhesion and transmigration of lymphocytes to a level similar to that seen with VAP-1 Ab. Thus, VAP-1 can support transendothelial migration as well as adhesion, and both functions are dependent on its enzymatic activity. In the absence of selectins and CD31, VAP-1 may play a specific role in lymphocyte recruitment via hepatic sinusoidal endothelium. Moreover, since VAP-1 is induced on nonhepatic endothelium in response to inflammation, its ability to support lymphocyte transendothelial migration may be an important systemic function of VAP-1.


Impaired autophagy in Lafora disease.
Lafora disease (LD) is a progressive, lethal, autosomal recessive, neurodegenerative disorder that manifests with myoclonus epilepsy. LD is characterized by the presence of intracellular inclusion bodies called Lafora bodies (LB), in brain, spinal cord and other tissues. More than 50 percent of LD is caused by mutations in EPM2A that encodes laforin. Here we review our recent findings that revealed that laforin regulates autophagy. We consider how autophagy compromise may predispose to LB formation and neurodegeneration in LD, and discuss future investigations suggested by our data.


Tonsillar cytokine expression between patients with tonsillar hypertrophy and recurrent tonsillitis.
Tonsils provide an innovative in vivo model for investigating immune response to infections and allergens. However, data are scarce on the differences in tonsillar virus infections and immune responses between patients with tonsillar hypertrophy or recurrent tonsillitis. We investigated the differences in virus detection and T cell and interferon gene expression in patients undergoing tonsillectomy due to tonsillar hypertrophy or recurrent tonsillitis. Tonsils of 89 surgical patients with tonsillar hypertrophy (n = 47) or recurrent tonsillitis (n = 42) were analysed. Patients were carefully characterized clinically. Standard questionnaire was used to asses preceding and allergy symptoms. Respiratory viruses were analysed in tonsils and nasopharynx by PCR. Quantitative real-time PCR was used to analyse intratonsillar gene expressions of IFN-α, IFN-β, IFN-γ, IL-10, IL-13, IL-17, IL-28, IL-29, IL-37, TGF-β, FOXP3, GATA3, RORC2 and Tbet. Median age of the subjects was 15 years (range 2-60). Patients with tonsillar hypertrophy were younger, smoked less often, had less pollen allergy and had more adenovirus, bocavirus-1, coronavirus and rhinovirus in nasopharynx (all P < 0.05). Only bocavirus-1 was more often detected in hypertrophic tonsils (P < 0.05). In age-adjusted analysis, tonsillar hypertrophy was associated with higher mRNA expressions of IL-37 (P < 0.05). Intratonsillar T cell and interferon gene expressions appeared to be relatively stable for both tonsillar hypertrophy and recurrent tonsillitis. Of the studied cytokines, only newly discovered anti-inflammatory cytokine IL-37, was independently associated with tonsillar hypertrophy showing slightly stronger anti-inflammatory response in these patients.


Regulation of DNA methylation activity through Dnmt3L promoter methylation by Dnmt3 enzymes in embryonic development.
The genomic DNA is methylated by de novo methyltransferases Dnmt3a and Dnmt3b during early embryonic development. The establishment of appropriate methylation patterns depends on a fine regulation of the methyltransferase activity. The activity of both enzymes increases in the presence of Dnmt3L, a Dnmt3a/3b-like protein. However, it is unclear how the function of Dnmt3L is regulated. We found here that the expression of Dnmt3L is controlled via its promoter methylation during embryonic development. Genetic studies showed that Dnmt3a, Dnmt3b and Dnmt3L are all involved in the methylation of the Dnmt3L promoter. Disruption of both Dnmt3a and Dnmt3b genes in mouse rendered the Dnmt3L promoter devoid of methylation, causing incomplete repression of the Dnmt3L transcription in embryonic stem cells and embryos. Disruption of either Dnmt3a or Dnmt3b led to reduced methylation and increased transcription of Dnmt3L, but severe hypomethylation occurred only when Dnmt3b was deficient. Consistent with the major contribution of Dnmt3b in the Dnmt3L promoter methylation, methylation of Dnmt3L was significantly reduced in mouse models of the human ICF syndrome carrying point mutations in Dnmt3b. Interestingly, Dnmt3L also contributes to the methylation of its own promoter in embryonic development. We thus propose an auto-regulatory mechanism for the control of DNA methylation activity whereby the activity of the Dnmt3L promoter is epigenetically modulated by the methylation machinery including Dnmt3L itself. Insufficient methylation of the DNMT3L promoter during embryonic development due to deficiency in DNMT3B might be implicated in the pathogenesis of the ICF syndrome.


Osteosarcoma enters a post genomic era with in silico opportunities: Generation of the High Dimensional Database for facilitating sarcoma biology research: A report from the Children's Oncology Group and the QuadW Foundation.
The prospective banking of osteosarcoma tissue samples to promote research endeavors has been realized through the establishment of a nationally centralized biospecimen repository, the Children's Oncology Group (COG) biospecimen bank located at the Biopathology Center (BPC)/Nationwide Children's Hospital in Columbus, Ohio. Although the physical inventory of osteosarcoma biospecimens is substantive (>15,000 sample specimens), the nature of these resources remains exhaustible. Despite judicious allocation of these high-value biospecimens for conducting sarcoma-related research, a deeper understanding of osteosarcoma biology, in particular metastases, remains unrealized. In addition the identification and development of novel diagnostics and effective therapeutics remain elusive. The QuadW-COG Childhood Sarcoma Biostatistics and Annotation Office (CSBAO) has developed the High Dimensional Data (HDD) platform to complement the existing physical inventory and to promote in silico hypothesis testing in sarcoma biology. The HDD is a relational biologic database derived from matched osteosarcoma biospecimens in which diverse experimental readouts have been generated and digitally deposited. As proof-of-concept, we demonstrate that the HDD platform can be utilized to address previously unrealized biologic questions though the systematic juxtaposition of diverse datasets derived from shared biospecimens. The continued population of the HDD platform with high-value, high-throughput and mineable datasets allows a shared and reusable resource for researchers, both experimentalists and bioinformatics investigators, to propose and answer questions in silico that advance our understanding of osteosarcoma biology.


Toward Improving Interventions Against Toxoplasmosis by Identifying Routes of Transmission Using Sporozoite-specific Serological Tools.
Horizontal transmission of Toxoplasma gondii occurs primarily via ingestion of environmental oocysts or consumption of undercooked/raw meat containing cyst-stage bradyzoites. The relative importance of these 2 transmission routes remains unclear. Oocyst infection can be distinguished from bradyzoite infection by identification of immunoglobulin G (IgG) antibodies against T. gondii embryogenesis-related protein (TgERP). These antibodies are, however, thought to persist for only 6-8 months in human sera, limiting the use of TgERP serology to only those patients recently exposed to T. gondii. Yet recent serological survey data indicate a more sustained persistence of anti-TgERP antibodies. Elucidating the duration of anti-TgERP IgG will help to determine whether TgERP serology has epidemiological utility for quantifying the relative importance of different routes of T. gondii transmission. We developed a serocatalytic mathematical model to capture the change in seroprevalence of non-stage-specific IgG and anti-TgERP IgG antibodies with human age. The model was fitted to published datasets collected in an endemic region of Brazil to estimate the duration of anti-TgERP IgG antibodies, accounting for variable age-force of infection profiles and uncertainty in the diagnostic performance of TgERP serology. We found that anti-TgERP IgG persists for substantially longer than previously recognized, with estimates ranging from 8.3 to 41.1 years. The Brazilian datasets were consistent with oocysts being the predominant transmission route in these settings. The longer than previously recognized duration of anti-TgERP antibodies indicates that anti-TgERP serology could be a useful tool for delineating T. gondii transmission routes in human populations. TgERP serology may therefore be an important epidemiological tool for informing the design of tailored, setting-specific public health information campaigns and interventions.


[Pharmacology of local anesthetics and clinical aspects of segmental blocking. II. Spinal anesthesia].
Clinical picture of development of segmental blocking after subarachnoidal injection of hyperbaric solutions of 0.75% bupivacaine, 5% ultracaine, and isobaric 0.5% bupivacaine is studied. A total of 152 patients operated on the lower part of the body and the lower limbs were examined under conditions of single, prolonged subarachnoidal, and combined spinal epidural anesthesia. Ultracaine and bupivacaine in different concentrations with different barism provided anesthesia equivalent by the efficacy, depth, and dissemination of sensory block. Segmental blocking with 5% ultracaine was characterized by the shortest latent period (3.14 +/- 0.16 min, p < 0.05) but was no shorter (124.1 +/- 3.37 min) than operative analgesia with 0.75% hyperbaric bupivacaine (120.0 +/- 5.10 min). Isobaric bupivacaine provided the longest effective analgesia (215.0 +/- 45.0 min, p < 0.05). Microcatheter technique improved the safety and control of subarachnoidal anesthesia in comparison with a single injection, and combined spinal epidural anesthesia shortened the latent period of segmental blocking and ensured intraoperative anesthesia and postoperative analgesia at the expense of the epidural component.


Does adherence to treatment targets in children with severe traumatic brain injury avoid brain hypoxia? A brain tissue oxygenation study.
Most physicians rely on conventional treatment targets for intracranial pressure, cerebral perfusion pressure, systemic oxygenation, and hemoglobin to direct management of traumatic brain injury (TBI) in children. In this study, we used brain tissue oxygen tension (PbtO2) monitoring to examine the association between PbtO2 values and outcome in pediatric severe TBI and to determine the incidence of compromised PbtO2 in patients for whom acceptable treatment targets had been achieved. In this prospective observational study, 26 children with severe TBI and a median postresuscitation Glasgow Coma Scale score of 5 were managed with continuous PbtO2 monitoring. The relationships between outcome and the 6-hour period of lowest PbtO2 values and the length of time that PbtO2 was less than 20, 15, 10, and 5 mmHg were examined. The incidence of reduced PbtO2 for each threshold was evaluated where the following targets were met: intracranial pressure less than 20 mmHg, cerebral perfusion pressure greater than 50 mmHg, arterial oxygen tension greater than 60 mmHg (and peripheral oxygen saturation > 90%), and hemoglobin greater than 8 g/dl. There was a significant association between poor outcome and the 6-hour period of lowest PbtO2 and length of time that PbtO2 was less than 15 and 10 mmHg. Multiple logistic regression analysis showed that low PbtO2 had an independent association with poor outcome. Despite achieving the management targets described above, 80% of patients experienced one or more episodes of compromised PbtO2 (< 20 mmHg), and almost one-third experienced episodes of brain hypoxia (PbtO2 < 10 mmHg). Reduced PbtO2 is associated with poor outcome in pediatric severe TBI. In addition, many patients experience episodes of compromised PbtO2 despite achieving acceptable treatment targets.


Factors Associated with Adherence Rates for Oral and Intravenous Anticancer Therapy in Commercially Insured Patients with Metastatic Colon Cancer.
Over the past decade, oncology therapies have trended toward orally administered regimens, and there has been growing attention on evaluation of factors that affect adherence. There has not been a rigorous investigation of factors associated with adherence to intravenous (i.v.) and oral anticancer drugs in the setting of metastatic colorectal cancer (mCRC). To (a) assess potential patient-specific factors related to adherence to mCRC chemotherapy regimens and (b) compare adherence with IV versus oral dosage forms. A retrospective analysis was performed using the Optum Oncology Management claims database. Patients aged 18 years and older diagnosed with mCRC between July 1, 2004, and December 31, 2010, who were insured by a commercial health plan were included in the study. Adherence to i.v. and oral chemotherapy regimens was assessed using the National Comprehensive Cancer Network (NCCN) guidelines as the standard for expected cycle/regimen duration. The most commonly prescribed chemotherapy regimens were assessed. Adherence was evaluated using the medication possession ratio (MPR), calculated as the number of days a patient was covered by their chemotherapy regimen, according to NCCN guidelines, divided by the number of days elapsed from the first to the last infusion of that regimen. For most analyses, the MPR was considered a continuous variable that could take on values between 0 and 1. In other analyses, a dichotomous categorical variable designated if the MPR was at least 0.8 versus less than 0.8. The Wilcoxon rank sum, Kruskal-Wallis, and Student's t-test were used to detect differences in continuous measures between patients receiving oral capecitabine therapy versus i.v. chemotherapy. The chi square test (X(2) test) or Fisher's exact test was used to assess differences in the dichotomous MPR variable. Generalized estimating equation (GEE) models were used for regimen-level analyses to account for correlated responses within individuals. A total of 6,780 patients were included in the analysis, virtually all (98%) with commercial insurance coverage and the remaining (2%) with Medicare Advantage. Patients with mCRC received 17,095 regimens of chemotherapy, including 2,252 regimens of oral capecitabine. Of the 17,095 regimens, 6,780 (40%) were first-line regimens (i.e., the first time mCRC was treated for a given patient). The most common chemotherapy regimen, regardless of line of therapy, was FOLFOX (2,991 regimens, 17.5% of all regimens used). FOLFOX-based therapies with or without bevacizumab were the most common regimens for first- and second-line chemotherapy, while oral capecitabine treatment was the most commonly prescribed regimen for patients in third- or fourth-line therapy. Overall, medication adherence across all regimens was relatively high, with a mean MPR of 0.87 (SD = 0.17). Evaluation of the distribution of i.v. and oral capecitabine regimens revealed that 28% of all regimens were associated with an MPR of less than 0.8. The average MPR was clinically similar, but statistically higher for i.v. chemotherapy regimens (0.881) compared with oral capecitabine regimens (0.799; P < 0.0001). In the multivariable GEE model, lung or liver metastases were associated with a higher MPR, while lower Charlson Comorbidity Index and oral anticancer therapy were associated with lower MPR. Furthermore, as line of therapy increased, the difference in MPR between patients receiving oral capecitabine and i.v. chemotherapy increased. This analysis determined that adherence with i.v. chemotherapy regimens was clinically similar, but statistically higher, compared to oral capecitabine therapy. The difference in adherence rates between the 2 routes of administration increased as the line of anticancer regimen increased. These results suggest that there should be an increased focus on improving adherence rates in patients receiving oral capecitabine.


Recent progress on the total syntheses of macrocyclic diamine alkaloids.
Covering: 2006 to 2019Macrocyclic diamine alkaloids derived from 3-alkyldihydropyridine dimers comprise a diverse and highly complex family of natural products. The macrocyclic and caged structural features of these alkaloids have inspired many creative solutions from the synthetic organic community over the past 30 years. This review will cover the successful synthetic campaigns over the past decade, with a focus on (1) key bond disconnections and advances and (2) remaining challenges and opportunities for innovation within this natural product class.


Reduction in estimated stroke risk associated with practice-based stroke-risk assessment and awareness in a large, representative population of hypertensive patients: results from the ForLife study in Italy.
A previous analysis of the ForLife study demonstrated a high estimated risk of stroke, poor blood pressure control and higher cardiovascular risk. Data from a subsequent visit within 6 months, to evaluate the impact of systematic stroke risk assessment, are reported. Between February and July 2003, 1800 general practitioners (GPs) recruited a total of 12,792 (7512 untreated and 5280 treated) patients with hypertension. Blood pressure values were assessed in the whole study population, and for different demographic and clinical features in two visits within 6 months. The data were recorded into a Framingham-based stroke risk score and computed using a risk calculator. Between the two visits the percentage of patients with controlled blood pressure (< 140/90 mmHg) increased substantially in all subgroups, being greater in patients who were not treated at baseline. Among initially treated patients, the greater control of blood pressure involved both diastolic and systolic values. The percentage of patients with diabetes whose blood pressure levels were less than 130/80 mmHg also increased at the second visit. Between the two visits the estimated stroke risk score showed a reduction, with a significant shift of patients from high to intermediate and low-risk categories. This reduction involved all subgroups, including patients with diabetes and left ventricular hypertrophy. The present large-scale observational study demonstrates that the assessment of stroke risk and increased awareness of stroke risk factors by GPs is associated with improved blood pressure control, reduced cardiovascular risk profile and a prompt reduction in the 10-year estimated risk of stroke.


Food and Drug Administration proposed testing guidelines for developmental toxicity studies. Revision Committee. FDA Guidelines for Developmental Toxicity and Reproduction, Food and Drug Administration.
The Food and Drug Administration (FDA) is the agency responsible for ensuring that the direct food additives and color additives used in food in the United States are safe for all consumers. In 1982, in an effort to provide guidance concerning appropriate tests, the FDA issued Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food, commonly known as the Redbook. The Redbook included detailed guidelines for testing the effects of direct and indirect food and color additives on mothers and their developing fetuses. Based on refinements in safety assessment and risk evaluation as well as expansion of knowledge concerning the metabolism and pharmacokinetics of food and color additives, the need to revise and update the 1982 document became apparent. In 1993, Redbook II in draft form was made available for public comment. Since then, test end points and developmental landmarks have been refined. The latest proposed guidelines for developmental toxicity studies are provided here.


Impact of prophylaxis with cytogam alone on the incidence of CMV viremia in CMV-seropositive lung transplant recipients.
Cytomegalovirus (CMV) infection remains a serious problem after lung transplantation. The purpose of this study was to evaluate the efficacy of CytoGam, a CMV hyperimmune globulin (CMV-IGIV), as CMV prophylaxis after lung transplantation. This prospective, randomized, open-label study compared prophylaxis with CMV-IGIV and no prophylaxis in 44 CMV-seropositive lung transplant recipients. The primary end-point was development of CMV viremia during the first year after transplantation. Cytomegalovirus viremia was detected in 13 of 22 recipients without prophylaxis and in 16 of 22 recipients with CMV-IGIV prophylaxis (p = 0.19). Cytomegalovirus pneumonitis developed in 8 controls vs in 11 CMV-IGIV recipients (p = 0.54). We found no significant difference between the groups in the incidence of positive shell vial assays (6.8% +/- 6.5% without vs 11.2% +/- 10.1% with prophylaxis, p = 0.09) or in the attack rate of CMV pneumonitis (0.41 +/- 0.59 episodes/patient without vs 0.86 +/- 0.99 episodes/patient with prophylaxis, p = 0.07). Similarly, no difference was apparent in the time to onset of CMV viremia, to detection of CMV DNA in peripheral blood leukocytes by polymerase chain reaction, or to development of CMV pneumonitis. The incidence of acute rejection and bronchiolitis obliterans syndrome and the survival rate during the first post-transplant year did not differ between the groups. Prophylaxis with CMV-IGIV alone did not decrease CMV viremia or pneumonitis, did not decrease the incidence of acute rejection or bronchiolitis obliterans syndrome, and did not affect 1-year survival of CMV-seropositive lung transplant recipients at our center.


Nocardioides vastitatis sp. nov., isolated from Taklamakan desert soil.
A Gram-stain-positive, aerobic, non-motile, rod-shaped actinobacterium, designated strain 21Sc5-5T, was isolated from a soil sample collected in the Taklamakan desert in Xinjiang Uygur Autonomous Region, PR China and investigated by using a polyphasic approach. Strain 21Sc5-5T grew at 10-37 °C (optimum, 28-30 °C), pH 6.0-9.0 (optimum, pH 7.0) and in the presence of 0-3 % (w/v) NaCl (optimum, 0 %). Phylogenetic analysis based on 16S rRNA gene sequences suggested that strain 21Sc5-5T formed a distinct lineage within the genus Nocardioides and had the highest similarity to Nocardioides albidus THG-S11.7T (97.30 %), followed by Nocardioides kongjuensis A2-4T (97.22 %), Nocardioides nitrophenolicus NSP 41T (97.15 %) and Nocardioides caeni MN8T (97.15 %). The results of chemotaxonomic analyses showed that the isolate possessed ll-diaminopimelic acid as the diagnostic diamino acid of the peptidoglycan and MK-8(H4) as the predominant menaquinone. The polar lipids comprised diphosphatidylglycerol, phosphatidylglycerol, phosphatidylinositol, an unidentified phospholipid and three unidentified lipids. The major fatty acids were iso-C16 : 0 and 10-methyl C18 : 0. The genome length of strain 21Sc5-5T was 4.67 Mb containing 372 contigs and with a DNA G+C content of 70.4 mol%. On the basis of data from phylogenetic, phenotypic and chemotaxonomic analyses, strain 21Sc5-5T represents a novel species of the genus Nocardioides, for which the name Nocardioides vastitatis sp. nov. is proposed. The type strain is 21Sc5-5T (=JCM 33365T=CGMCC 4.7608T).


Effect of titanium dioxide nanoparticle reinforcement on flexural strength of denture base resin: A systematic review and meta-analysis.
The study was designed to assess the change in flexural strength of unmodified heat cure denture base polymer resin on reinforcement with titanium dioxide nanoparticles in different concentrations. In vitro, randomized control trials reporting flexural strength of titanium dioxide nanoparticle reinforced resin were selected. The review was formulated based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses- Protocol (PRISMA-P) guidelines. Quality assessment was performed according to Consolidated Standards Of Reporting Trials (CONSORT) guidelines and risk of bias Cochrane tool. Six articles in the category of 1%, 3%, 5% weight fractions of titanium dioxide nanoparticles were subjected to a meta-analysis. A meta-analysis was performed using random-effects at a 95% confidence interval. Within the limitations of the study, it can be assumed that there is no precise conformity on the ideal titanium dioxide nanoparticle concentration required to improve the flexural strength of the polymer. Stringent use of standard ISO guidelines may help in obtaining consistent results.


Increasing complexity in small-angle X-ray and neutron scattering experiments: from biological membrane mimics to live cells.
Small-angle X-ray and neutron scattering are well-established, non-invasive experimental techniques to interrogate global structural properties of biological membrane mimicking systems under physiologically relevant conditions. Recent developments, both in bottom-up sample preparation techniques for increasingly complex model systems, and in data analysis techniques have opened the path toward addressing long standing issues of biological membrane remodelling processes. These efforts also include emerging quantitative scattering studies on live cells, thus enabling a bridging of molecular to cellular length scales. Here, we review recent progress in devising compositional models for joint small-angle X-ray and neutron scattering studies on diverse membrane mimics - with a specific focus on membrane structural coupling to amphiphatic peptides and integral proteins - and live Escherichia coli. In particular, we outline the present state-of-the-art in small-angle scattering methods applied to complex membrane systems, highlighting how increasing system complexity must be followed by an advance in compositional modelling and data-analysis tools.


Diagnostic Accuracy of Cardiac Magnetic Resonance Versus Fractional Flow Reserve: A Systematic Review and Meta-Analysis.
Fractional flow reserve (FFR) is considered the gold standard for diagnosis of coronary artery disease (CAD). Stress Cardiac magnetic resonance (SCMR) has been recently gaining traction as a non-invasive alternative to FFR. Studies comparing the diagnostic accuracy of SCMR versus FFR were identified and analyzed using Review Manager (RevMan) 5.3 and Stata software. A total of 28 studies, comprising 2,387 patients, were included. The pooled sensitivity and specificity for SCMR were 86% and 86% at the patient level, and 82% and 88% at the vessel level, respectively. When the patient-level data were stratified based on the FFR thresholds, higher sensitivity and specificity (both 90%) were noted with the higher cutoff (0.75) and lower cutoff (0.8), respectively. At the vessel level, sensitivity and specificity at the lower FFR threshold were significantly higher at 88% and 89%, compared to the corresponding values for higher cutoff at 0.75. Similarly, meta-regression analysis of SCMR at higher (3T) resolution showed a higher sensitivity of 87% at the patient level and higher specificity of 90% at the vessel level. The highest sensitivity and specificity of SCMR (92% and 94%, respectively) were noted in studies with CAD prevalence greater than 60%. SCMR has high diagnostic accuracy for CAD comparable to FFR at a spatial resolution of 3T and an FFR cut-off of 0.80. An increase in CAD prevalence further improved the specificity of SCMR.


HTLV-III antibody and T-cell subset ratios in haemophiliacs and their spouses.
44% of 63 British patients with either haemophilia A or B were HTLV-III antibody positive (HTLV-VIII+). HTLV-III+ was more frequent in high factor VIII concentrate users and 75% of severely affected haemophilia A patients were HTLV-III+. All eight patients who were exposed to factor IX concentrate were HTLV-III-. 17 haemophilia A patients who received only British made factor VIII concentrate (average 12,000 units/year) were HTLV-III-. Two of 63 patients had evidence of a pre-AIDS type symptom complex and both were HTLV-III+. Information from a cohort of 21 Liverpool haemophiliacs suggests that HTLV-III was first introduced into this country in 1981. OKT4/T8 ratios were abnormal in 52% of 21 patients studied but this finding was not confined to either HTLV-III+ or HTLV-III- individuals. The spouses of 14 HTLV-III+ haemophiliacs were all HTLV-III-.


Military Sexual Assault in Transgender Veterans: Results From a Nationwide Survey.
There is limited understanding about the frequency of military sexual assault (MSA) in transgender veterans, characteristics associated with MSA, or subsequent mental and behavioral health problems. To address this gap, we used an online national survey of 221 transgender veterans to identify prevalence of MSA and to assess its association with demographic characteristics, past history of sexual victimization, and stigma-related factors. We also evaluated the association between MSA and several mental and behavioral health problems. Overall, 17.2% of transgender veterans experienced MSA, but rates differed significantly between transgender women (15.2%) and transgender men (30.0%). Using adjusted regression models, MSA was associated with adult sexual assault prior to military service, odds ratio (OR) = 4.05, 95% CI [1.62, 10.08], and distal minority stress during military service, OR = 2.98, 95% CI [1.28, 6.91]. With respect to health outcomes, MSA was associated with past-month posttraumatic stress disorder (PTSD) symptom severity, B = 10.18, 95% CI [3.45, 16.91]; current depression symptom severity, B = 3.71, 95% CI [1.11, 6.30]; and past-year drug use, OR = 3.17, 95% CI [1.36, 7.40]. Results highlight the vulnerability of transgender veterans to MSA, and the need for military prevention programs that acknowledge transgender individuals' heightened risk. Furthermore, clinicians should consider clinical screening for PTSD, depression, and drug use in transgender veterans who have a history of MSA.


Characterization of translocation of silver nanoparticles and effects on whole-genome gene expression using an in vitro intestinal epithelium coculture model.
Applications of nanoparticles in the food sector are eminent. Silver nanoparticles are among the most frequently used, making consumer exposure to silver nanoparticles inevitable. Information about uptake through the intestines and possible toxic effects of silver nanoparticles is therefore very important but still lacking. In the present study, we used an in vitro model for the human intestinal epithelium consisting of Caco-2 and M-cells to study the passage of silver nanoparticles and their ionic equivalents and to assess their effects on whole-genome mRNA expression. This in vitro intestine model was exposed to four sizes of silver nanoparticles for 4 h. Exposure to silver ions was included as a control since 6-17% of the silver nanoparticles were found to be dissociated into silver ions. The amount of silver ions that passed the Caco-2 cell barrier was equal for the silver ion and nanoparticle exposures. The nanoparticles induced clear changes in gene expression in a range of stress responses including oxidative stress, endoplasmatic stress response, and apoptosis. The gene expression response to silver nanoparticles, however, was very similar to that of AgNO(3). Therefore, the observed effects of the silver nanoparticles are likely exerted by the silver ions that are released from the nanoparticles.


Comparison between low flow sevoflurane anesthesia and total intravenous anesthesia during intermediate-duration surgery: effects on renal and hepatic toxicity.
Renal and hepatic dysfunction or injury might be involved by ether based anesthetic and intravenous anesthetic drug or surgical stress. The purpose of this study is to compare the effect of moderate duration low-flow sevoflurane versus total intravenous anesthesia on renal and hepatic functions. Eighty (80) patients between the ages of 25-70 scheduled for elective lumbar disc herniotomy, with an expected operation time of 120-240 min, were enrolled in the study. Anesthesia was induced using remifentanil, propofol and atracurium. Patients were randomly divided into two groups. After intubation, Group S (n=40) received sevoflurane and Group T (n=40) received total intravenous anesthesia with propofol in oxygen and air with a fresh gas flow of 5 L min(?1). Ten minutes after induction the fresh gas flow was decreased to 1L min(?1) in both groups. Serum BUN, creatinine, ALT, AST, LDH and 24 hours excretion of glucose, protein, and creatinine in urine were measured preoperatively and the first three postoperative days. Serum BUN at 48 hours, creatinine at 24, 48. hours, and urine glucose at 24, and 48 hours were significantly higher from the preoperative values in Group S (p<0.05). However, serum BUN and creatinin, urine glucose were within the normal range. There were no significant differences in the renal and hepatic function tests between the groups. These results show that the renal and hepatic effect of moderate duration low-flow sevoflurane and total intravenous anesthesia is similar.


High sensitivity and fast response solution processed polymer photodetectors with polyethylenimine ethoxylated (PEIE) modified ITO electrode.
Most organic photodetectors utilize a bulk heterojunction (BHJ) photo-active film due to its high exciton dissociation efficiency. However, the low dark current density, a key role in determining the overall performance of photodetectors, is hardly achieved in the BHJ structure since both the donor and acceptor domains are in contact with the same electrode. The most popular strategy to overcome this problem is by fabricating bilayer or multilayer devices. However, the complicated fabrication process is a challenge for printing electronics. In this work, we demonstrate a solution processed polymer photodetector based on a poly (3-hexylthiophene) (P3HT): (phenyl-C61-butyric-acid-methyl-ester) (PC61BM) blend film with polyethylenimine ethoxylated (PEIE) modified ITO electrode. The transparent PEIE efficiently blocks the unnecessary electronic charge injection between the active film and the electrode, which dramatically decrease the dark current. Under illumination, the photoexcited charges accumulated in the PEIE modified ITO region finally can tunnel through the barrier with the help of the applied reverse bias, leading to a large photocurrent. Therefore, the resulting polymer photodetector shows a 2.48 × 104 signal-to-noise ratio (SNR) under -0.3 V bias and an 11.4 MHz bandwidth across the visible spectra under a small reverse bias of 0.5 V. The maximum EQE of 3250% in the visible wavelength is obtained for the polymer photodetector at -1 V under 370 nm (3.07 μW/cm2) illumination. This solution processed polymer photodetector manufacturing is highly compatible with the flexible, low-cost, and large area organic electronic technologies.


[Changes in occupational morbidity among workers of petroleum, oil-processing and petroleum chemical industries over 40 years].
Analysis covered 3784 cases of occupational diseases diagnosed first in Research Institute for Industrial Medicine and Human Ecology in Ufa from 1960 till 2000. Locomotory and peripheral nervous system disorders appeared to predominate in structure of occupational morbidity. The authors failed to reveal direct correlation between occupational morbidity level and work conditions jeopardy class.


Computational characterization of flow and hemolytic performance of the UltraMag blood pump for circulatory support.
The Levitronix UltraMag blood pump is a next generation, magnetically suspended centrifugal pump and is designed to provide circulatory support for pediatric and adult patients. The aim of this study is to investigate the hemodynamic and hemolytic characteristics of this pump using the computational fluid dynamics (CFD) approach. The computational domain for CFD analysis was constructed from the three-dimensional geometry (3D) of the UltraMag blood pump and meshed into 3D tetrahedral/hybrid elements. The governing equations of fluid flow were computationally solved to obtain a blood flow through the blood pump. Further, hemolytic blood damage was calculated by solving a scalar transport equation where the scalar variable and the source term were obtained utilizing an empirical power-law correlation between the fluid dynamic variables and hemolysis. To obtain mesh independent flow solution, a comparative examination of vector fields, hydrodynamic performance, and hemolysis predictions were carried out. Different sizes of tetrahedral and tetrahedral/hexahedral mixed hybrid models were considered. The mesh independent solutions were obtained by a hybrid model. Laminar and SST κ-ω turbulence flow models were used for different operating conditions. In order to pinpoint the most significant hemolytic region, the flow field analysis was coupled to the hemolysis predictions. In summary, computational characterization of the device was satisfactorily carried out within the targeted operating conditions of the device, and it was observed that the UltraMag blood pump can be safely operated for its intended use to create a circulatory support for both pediatric and adult-sized patients.


Molecular dynamics simulation of adsorption and separation of xylene isomers by Cu-HKUST-1.
Metal-organic frameworks (MOFs) are widely used in the adsorption separation of various gases. A fundamental understanding of the effective separation of xylene isomers helps improve aromatic products' separation efficiency and reduce industrial separation costs. Grand Canonical Monte Carlo (GCMC) simulations combined with Molecular Science is widely used to predict gas adsorption and diffusion in single crystals with metal-organic frameworks. We performed a GCMC + MD combined approach to study xylene isomers' adsorption and separation in Cu-HKUST-1 to predict the permeability and selectivity of the ternary gas mixture in the MOF with the adsorption and diffusion usage data. Most current studies take into account the computational cost and difficulty. Most recent research models are limited to the adsorption of a single or specific molecule, such as hydrogen, methane, carbon dioxide, etc. For this reason, we report an attempt to study the adsorption separation of aromatic gases (p-xylene/o-xylene/m-xylene) based on Cu-HKUST-1 single-crystal materials based on some previous research methods with an appropriate increase in computational cost. To predict the adsorption selectivity and permeability of the ternary mixture of xylene isomers on the MOF surface, the model simulation calculates key parameters of gas adsorption, including gas adsorption volume (N), the heat of adsorption (Q st), Henry coefficient (K), and diffusion coefficient (D).


Hybrid forum or network? The social and political construction of an international 'technical consultation': male circumcision and HIV prevention.
The technical consultation in Montreux, organised by World Health Organization and UNAIDS in 2007, recommended male circumcision as a method for preventing HIV transmission. This consultation came out of a long process of releasing reports and holding international and regional conferences, a process steered by an informal network. This network's relations with other parties is analysed along with its way of working and the exchanges during the technical consultation that led up to the formal adoption of a recommendation. Conducted in relation to the concepts of a 'hybrid forum' and 'network', this article shows that the decision was based on the formation and consolidation of a network of persons. They were active in all phases of this process, ranging from studies of the recommendation's efficacy, feasibility and acceptability to its adoption and implementation. In this sense, this consultation cannot be described as the constitution of a 'hybrid forum', which is characterised by its openness to a debate as well as a plurality of issues formulated by the actors and of resources used by them. On the contrary, little room was allowed for contradictory discussions, as if the decision had already been made before the Montreux consultation.


Prolongation of fibroblast life span associated with epithelial rat tumor development.
We have examined the proliferative behavior in culture of stromal cells of fibroblast morphology taken from various stages in the development of experimentally induced epithelial tumors in the rat thyroid. In this model long-term stimulation by an elevated level of serum thyroid stimulating hormone leads first to hyperplasia, then to multiple benign, and finally malignant tumors. Fibroblasts from hyperplastic glands, despite having already undergone more divisions in vivo, consistently showed a longer life span than normal fibroblasts in culture, averaging 16 compared with six divisions before senescing. In the three tumor bearing glands studied, all cultures have undergone more than 40 divisions (in one case over 70) and none has yet shown signs of senescence. We conclude that the life span of thyroid fibroblasts observed in culture has been reset to a higher limit by growth stimulation in vivo and furthermore that this limit may be lost altogether in fibroblasts associated with epithelial tumors.


Repairs of partial oblique tendon injuries: a biomechanical evaluation.
This study evaluated the tensile properties of oblique partial tendon lacerations and the effects of peripheral sutures on their strength. Seventy-four fresh pig flexor digitorum profundus tendons were divided into eight groups and were transected across 90% of their diameter. The lacerations in the tendons of five of the groups were at 0 degrees, 15 degrees, 30 degrees, 45 degrees, and 60 degrees to their transverse cross-section, respectively. In the other three groups the lacerations were 0 degrees, 45 degrees, and 60 degrees to the cross-section and were repaired with running peripheral sutures. The tendons were subjected to load-to-failure tests in a tensile testing machine to determine the initial, 1 and 2mm gap formation forces, and the ultimate strength. Obliquity of tendon lacerations affected the strength of partially lacerated tendons. The tendons with 45 degrees and 60 degrees oblique lacerations had a significantly lower ultimate strengths than those with transverse (0 degrees), or 15 degrees or 30 degrees oblique lacerations. Running peripheral sutures significantly increased both the gap formation forces and the ultimate strength of the tendons with oblique partial lacerations.


[Use of standard for quantitation of adhesion of polynuclear neutrophils by flow cytometry].
Adherence receptors are essential for heterotypic (endothelial cell, platelet) polymorphonuclear neutrophil (PMN) interaction. Determination of their expression level give information about activation state and functionality of PMN. Use of flow cytometry associated with an immunolabeling standard, represented by beads coated by a determined amount of immunoglobulins (Qifikit, Dako), allows analysis of specific antibody binding capacity and gives information about antigen density. Using this methodology, the exploration of surface adherence receptors, L-selectin (CD62L) and b2-integrins (CD11a-c/CD18) from PMN unstimulated and incubated with pro-inflammatory stimuli, formyl-methionyl-leucyl-phenylalanine (fMLP) and tumor necrosis factor a (TNFa), allows, on the one hand, the establishment of basal expression values on resting PNN and on the other hand, the study of PNN reactivity. This method of quantification can be applied to clinical studies as adherence receptor deficiency syndromes or inflammatory, infectious and vascular diseases.


Gepirone Extended-Release: First Approval.
Gepirone HCL extended-release (gepirone ER; EXXUA™), an oral, selective serotonin (5HT)1A receptor agonist formulated for once-daily administration, has been developed by Fabre-Kramer Pharmaceuticals, Inc. for the treatment of psychiatric disorders, including major depressive disorder (MDD). In September 2023, gepirone ER was approved in the USA for the treatment of adults with MDD. This article summarizes the milestones in the development of gepirone ER leading to this first approval for the treatment of adults with MDD.


A brief history of work expectations for welfare mothers.
The best known of the nation's welfare programs, Aid to Families with Dependent Children (AFDC), has from its inception reflected a tension between the desire to support children in poor, lone-parent families and the belief that parents should be held responsible for providing for themselves and their children. Against that backdrop, this article reviews the history of the AFDC program and traces the emergence of policies and programs intended to encourage employment of the parents (almost exclusively mothers) who receive benefits. The article examines in detail the Work Incentive Program (WIN) launched in 1967 and the Family Support Act of 1988, comparing these to each other and to the outlines of welfare reform signed into law in 1996. The article emphasizes the importance of sustained attention to the implementation of policy goals in concrete programs and shows that the merits of those early programs have not been fully tested because they were never funded or implemented at the scale intended. The article also outlines ways in which welfare-to-work programs can be used to assist children as well as parents, and urges that children's well-being remain the core purpose of welfare policy.


The intergenerational impact of the African orphans crisis: a cohort study from an HIV/AIDS affected area.
In sub-Saharan Africa, the prevalence of orphanhood among children has been greatly exacerbated by the HIV/AIDS pandemic. If orphanhood harms a child's development and these effects perpetuate into adult life, then the African orphan crisis could seriously jeopardize the continent's future generations. Whether or not there exists an adverse, causal and intergenerational effect of HIV/AIDS on development is of crucial importance for setting medical priorities. This study is the first to empirically investigate the impact of orphanhood on health and schooling using long-term longitudinal data following children into adulthood. We examined a cohort of 718 children interviewed in the early 1990s and again in 2004. Detailed survey questionnaires and anthropometric measurements were administered at baseline and during a follow-up survey. Final attained height and education (at adulthood) between children who lost a parent before the age of 15 and those who did not were compared. On average, children who lose their mother before the age of 15 suffer a deficit of around 2 cm in final attained height (mean 1.96; 95% CI 0.06-3.77) and 1 year of final attained schooling (mean 1.01; 95% CI 0.39-1.81). This effect is permanent and the hypothesis that it is causal cannot be rejected by our study. Although father's death is a predictor of lower height and schooling as well, we reject the hypothesis of a causal link. The African orphan crisis, exacerbated by the HIV/AIDS epidemic will have important negative intergenerational effects.


Competition for a unique response element mediates retinoic acid inhibition of vitamin D3-stimulated transcription.
We have identified a novel steroid hormone response element in the avian beta3 integrin promoter. This sequence, comprising three hexameric direct repeat half-sites separated by nine and three nucleotides binds vitamin D receptor (VDR)-retinoid X receptor (RXR) and retinoic acid receptor (RAR)-RXR heterodimers. VDR-RXR binds direct repeats separated by three base pairs, and RAR-RXR recognizes half-sites separated by nine bases, whereas the central half-site interacts with both heterodimers. Retinoic acid and 1, 25-dihydroxyvitamin D3 activate both a genomic fragment including the transcriptional start site and an oligonucleotide containing the three repeats, linked to a heterologous promoter. Co-addition of the steroids produces neither synergy nor an additive effect; rather the result equals that for retinoic acid alone. Scatchard analysis demonstrates that RAR-RXR has greater affinity than VDR-RXR for the composite element. Based on these findings we propose a model in which there is specific, polarity-defined binding of VDR-RXR and RAR-RXR to three half-sites, which form two overlapping steroid response elements, with the central half-site common to both. Our results identify a novel mechanism by which one steroid hormone can modulate the activity of a second, by competing for a shared half-site in a composite response element.


Factors associated with the use of uterine cervical cancer screening services in korean elderly women.
The Papanicolaou (Pap) smear test is an effective screening test for the early detection of uterine cervical cancer. The Pap test still plays an important role in Korean elderly women, as uterine cervical cancer remains a frequent form of cancer and an important cause of death. However, the participation rate and other factors related to the Pap test in Korean elderly women have been studied insufficiently. This study included 654 individuals aged 65 and over who completed a cervical cancer screening questionnaire from the Third Korean National Health and Nutrition Examination Survey 2005. Using multiple logistic regression, odds ratios and confidence intervals for the association between attendance of the Pap test and sociodemographic or health-related factors were calculated. One hundred and eleven individuals (17.0%) of the study population showed compliance with Pap testing within the previous 2 years. We recognized that the most elderly women (75 years and over) or those with lower levels of education were less likely to have had the test. Primary health care providers need to make efforts to improve attendance rates of Pap smear screening in Korean elderly women, individually taking into account previous Pap results, life expectancy, risk factors for cervical cancer, and preferences. More attention will especially be needed among the eldest elderly or less educated elderly women.


Direct access testing in the clinical laboratory: should laboratories offer testing services directly to the consumer?
This article outlines the author's views on the many issues to consider if a laboratory plans to initiate a program to offer clinical laboratory testing directly to the public. Direct access testing and why is it important are discussed in detail. The regulatory issues are outlined with some alternatives for laboratories in states with restrictive regulations. To illustrate many of the operational issues to consider, the author describes the Personal Diagnostic Center (PDC) in Kansas City. Finally, some of the key business issues are mentioned, including several approaches to promote this type of testing program.


Recent Advances in Green Synthesis of Ag NPs for Extenuating Antimicrobial Resistance.
Combating antimicrobial resistance (AMR) is an on-going global grand challenge, as recognized by several UN Sustainable Development Goals. Silver nanoparticles (Ag NPs) are well-known for their efficacy against antimicrobial resistance, and a plethora of green synthesis methodologies now exist in the literature. Herein, this review evaluates recent advances in biological approaches for Ag NPs, and their antimicrobial potential of Ag NPs with mechanisms of action are explored deeply. Moreover, short and long-term potential toxic effects of Ag NPs on animals, the environment, and human health are briefly discussed. Finally, we also provide a summary of the current state of the research and future challenges on a biologically mediated Ag-nanostructures-based effective platform for alleviating AMR.


Microgravity and Hypergravity Induced by Parabolic Flight Differently Affect Lumbar Spinal Stiffness.
The objective of this study was to determine the response of the lumbar spinal motor control in different gravitational conditions. This was accomplished by measuring indicators of lumbar motor control, specifically lumbar spinal stiffness, activity of lumbar extensor and flexor muscles and lumbar curvature, in hypergravity and microgravity during parabolic flights. Three female and five male subjects participated in this study. The mean age was 35.5 years (standard deviation: 8.5 years). Spinal stiffness of the L3 vertebra was measured using impulse response; activity of the erector spinae, multifidi, transversus abdominis, and psoas muscles was recorded using surface electromyography; and lumbar curvature was measured using distance sensors mounted on the back-plate of a full-body harness. An effect of gravity condition on spinal stiffness, activity of all muscles assessed and lumbar curvature (p's < 0.007) was observed (Friedman tests). Post hoc analysis showed a significant reduction in stiffness during hypergravity (p < 0.001) and an increase in stiffness during microgravity (p < 0.001). Activity in all muscles significantly increased during hypergravity (p's < 0.001). During microgravity, the multifidi (p < 0.002) and transversus abdominis (p < 0.001) increased significantly in muscle activity while no significant difference was found for the psoas (p = 0.850) and erector spinae muscles (p = 0.813). Lumbar curvature flattened in hypergravity as well as microgravity, albeit in different ways: during hypergravity, the distance to the skin decreased for the upper (p = 0.016) and the lower sensor (p = 0.036). During microgravity, the upper sensor showed a significant increase (p = 0.016), and the lower showed a decrease (p = 0.005) in distance. This study emphasizes the role of spinal motor control adaptations in changing gravity conditions. Both hypergravity and microgravity lead to changes in spinal motor control. The decrease in spinal stiffness during hypergravity is interpreted as a shift of the axial load from the spine to the pelvis and thoracic cage. In microgravity, activity of the multifidi and of the psoas muscles seems to ensure the integrity of the spine. Swiss (BASEC-NR: 2018-00051)/French "EST-III" (Nr-ID-RCB: 2018-A011294-51/Nr-CPP: 18.06.09).


Correlates of Prescription Opioid Legitimacy Judgments Among Community Pharmacists.
Community pharmacists are legally required to evaluate and confirm the legitimacy of prescription opioids (POs) prior to dispensing. Yet, previous research has indicated community pharmacists perceive nearly 50% of dispensed POs to be issued lacking a legitimate medical purpose. To analyze correlates of PO legitimacy judgments across pharmacist and pharmacy setting characteristics. A cross-sectional study of 2000 Tennessee pharmacists was conducted during October and November of 2012. Community pharmacists' self-reported attitudes, beliefs, and behaviors specific to PO legitimacy were elicited. Step-wise multinomial logistic regression techniques were used to model correlates of PO legitimacy across low, moderate and high PO legitimacy estimations. Being female, practicing in a chain or independent practice setting, fear of employer disciplinary action if PO legitimacy is questioned, and self-confidence in one's ability to detect PO abuse increased the odds of low (vs. high) PO legitimacy estimation (p < 0.05). Employment in chain and independent pharmacies, having POs as a greater percent of total prescriptions filled, and having the perception of PO abuse as a problem in the practice setting were significant positive correlates of moderate (vs high) PO legitimacy estimation (p < 0.05). Both modifiable and non-modifiable correlates were statistically significantly associated with PO legitimacy judgments. Distinct correlates were noted across low and moderate as compared to high estimations of PO legitimacy. Legitimacy judgments can inform theoretical exploration of PO dispensing behaviors and inform intervention development targeted at reducing and preventing prescription drug abuse.


Gimme 5 fruit and vegetables for fun and health: process evaluation.
Gimme 5 (Georgia) was a school-based nutrition education effectiveness trial to help fourth- and fifth-grade students eat more fruit, 100% juice, and vegetables (FJV). Process evaluation assessed fidelity of implementation, reach, and use of intervention materials and environmental mediators: teacher training, curriculum delivery, participation in family activities, attendance at evening point-of-purchase grocery store activities, and availability and accessibility of FJV at home. Approximately half of the curriculum activities were implemented in fourth and fifth grades. The lowest proportion completed were those most pertinent to behavior change. Eighty-seven percent of parents reported participating in homework activities with their fourth grader, 66% with fifth graders. Sixty-five percent of parents reported viewing a video with their child in both grades. Ten percent attended evening point-of-purchase grocery store activities. The low level of implementation and modest level of participation in family activities suggest that higher levels of behavior change may have occurred if exposure to the intervention had been higher.


Baboon syndrome and segmental vitiligo coexistence.
The baboon syndrome is a form of systemic contact dermatitis with skin eruptions in the area of the buttocks and major flexures. Inhalation of mercury vapor causes this rare but distinctive eruption. Broken thermometers are the usual sources of exposure. We hereby present a 14-year-old boy diagnosed with baboon syndrome coexistence with vitiligo, due to broken thermometers. In our case, it was interesting that erythematous eruptions were more evident on the vitiliginous side of the trunk. To our knowledge, there have been no reports in the literature of baboon syndrome and vitiligo coexistence.