Difficulties in clinical skills evaluation.
A case-specific method of evaluating clinical skills is presented. The instrument is described together with its evaluation based on results from ninety-two medical students. The method involves direct observation, by pairs of teachers, of student encounters with simulated patients. The purpose of this paper is to explore the methodology of assessing clinical competence. Three aspects of this are addressed: reliability between teachers acting as observers, and the relationship of both observations of process measures and self-assessments with the students' understanding of the patient. Three aspects of clinical skills were evaluated; interviewing, problem orientation and physical examination. The results showed the observers to be highly reliable in observing physical examination but to have a wide range of reliability across cases in their observations of the other aspects of clinical skill. There was no correlation between both teachers' observations and the students' self-assessments with the students' understanding of the patient. This is a worrying finding. The implications of this study are that evaluation of the process of clinical skills is difficult methodologically and, added to which, it is not clear what relevance these observations have to clinical competence. Rather than effort being devoted to refining instruments to measure the process of clinical skills it would seem preferable to devote energy to assessing students' abilities in diagnosis and management, at least until we understand what observations of clinical skills are measuring.


A designed beta-hairpin peptide in crystals.
Beta-hairpin structures have been crystallographically characterized only in very short acyclic peptides, in contrast to helices. The structure of the designed beta-hairpin, t-butoxycarbonyl-Leu-Val-Val-D-Pro-Gly-Leu-Val-Val-OMe in crystals is described. The two independent molecules of the octapeptide fold into almost ideal beta-hairpin conformations with the central D-Pro-Gly segment adopting a Type II' beta-turn conformation. The definitive characterization of a beta-hairpin has implications for de novo peptide and protein design, particularly for the development of three- and four-stranded beta-sheets.


Expression and significance of silent information regulator two homolog 1 in the placenta and plasma of patients with pre-eclampsia-a meta-analysis.
This study aimed to collect, organize, and conduct a meta-analysis of the literature on the expression of silent information regulator two homolog 1 (SIRT1) in the placental tissue and plasma of patients with pre-eclampsia. The enrolled patients were divided into two groups: the pre-eclampsia group and the healthy group. This study summarized and analyzed the demographic characteristics of the two groups, including pregnancy age, gestational weeks, parity, gravidity, blood pressure, Body Mass Index, newborn weight, placental weight, and SIRT1 expression in placental tissue and maternal plasma. Eleven studies were included in this research, with 586 cases in the pre-eclampsia group and 479 cases in the control group. Three research studies are reporting immunohistochemistry tests, among which the pre-eclampsia group had a positivity rate of 30.24% (62/205), while the control group had 58.02% (76/131); the two groups have a significant difference (p < 0.05). Two research studies reported the results of ELISA tests, with 107 cases in the pre-eclampsia group and 125 cases in the control group. A comparison of the SIRT1 test results showed a statistically significant difference between the two groups (p < 0.05). Pre-eclampsia group patients had lower gestational weeks, newborn birth weight, and placental weight compared to the healthy control group (all p < 0.05). However, systolic and diastolic blood pressures were higher in the pre-eclampsia group than in the control group (p < 0.05). SIRT1 expression is downregulated in pre-eclampsia patients' plasma and placental tissue. Further research is needed to validate this conclusion.


The weight of patriarchy? Gender obesity gaps in the Middle East and North Africa (MENA).
The worldwide obesity epidemic has impacted women more heavily than men. These gender-based differences are particularly pronounced in the Middle East and North Africa (MENA) region where gender obesity gaps on average exceed 10 percentage points. This paper examines one of the explanations, namely the role of female empowerment on gender gaps in obesity. We study the effect of several measures of female empowerment including female labor market participation on gender obesity gaps over a time span of 41 years (1975-2016) in a sample of 190 countries. We document that after controlling for a number relevant controls, gender obesity gaps are only associated to measures of female empowerment in the MENA region but that this is not true worldwide. We then use an instrumental variable approach in order to illustrate that the causality runs indeed from empowerment, proxy it by both labor market and political participation to gender obesity gaps and not vice versa. Our results reveal that a one percentage point increase in female labor market participation (female MPs in national parliament) predicts a 0.2 (0.09) percentage point decrease in gender gaps in obesity in the MENA region.


Potential biological activity of acacia honey.
Recent advances in functional foods-based research have increasingly become an area of major interest because it affects human health and activities. Functional foods are classes of foods with health promoting and disease preventing properties in addition to multiple nutritional values and of such type is honey. Acacia honey is a type of honey produced by bees (Apis mellifera) fed on Acacia flowers, hence the name. This review focuses on the potential biological activities of Acacia honey which includes quality, antioxidant, immuno-modulatory, antiproliferative and neurological properties at in vitro and in vivo levels. Based on our review, Acacia honey used from various researches is of high purity, contains some bioactive compounds ranging from vitamins, phenolics, flavonoids and fatty acids. It's highly nutritional with strong antioxidant and immuno-modulatory potentials which may therefore be considered a potential candidate for both cancer prevention and treatment. Neurologically, it may be considered as a viable therapeutic agent in the management of Alzheimer's disease.


[Resilience: a new perspective in health promotion?].
This descriptive study deals with some concepts of resilience seeking to understand the concept from the viewpoint of health promotion, one of the basic principles of the Brazilian Family Health Program (FHP). Resilience appeared as a new subject in human sciences and in the health area. In human sciences, resilience means the positive capacity of an individual to construct itself coping with adversities, a dimension more attentive to social conditions. Although there is no consensus with regard to this subject, there seem to be some aspects related with Health Promotion. We emphasize the modern understanding of Health Promotion in order to illustrate some aspects associated with resilience such as the greater capacity of Man to decide about the determinants of his health condition. Given that Health Promotion is one of the attributions of the Family Health Program, we contextualized the program emphasizing the action of the health professionals in this area in relation to the subject, seeking to promote health working with resilience. The multi-professional teams of the Family Health Program represent at the same time a network of support and protection for the families, identifying possible risk factors. The emphasis given to the promotion of resilience however should not substitute the public policies for fighting the social inequality and precarious life conditions of part of the population.


Regulation of the near-IR spectral properties of individually dissolved single-walled carbon nanotubes in aqueous solutions of dsDNA.
Two different single-walled carbon nanotubes (SWNTs), the so-called HiPco and CoMoCAT, have been individually dissolved in aqueous solutions of double-stranded DNA (dsDNA). Atomic force microscopy (AFM) revealed the fine structures of the dsDNA-wrapped SWNTs. The near-IR absorption and photoluminescence (PL) spectra of aqueous solutions of dsDNA-wrapped SWNTs were recorded and, in pure water, we observed only a single two-dimensional PL spot from (6,5) SWNTs for both HiPco and CoMoCAT. In sharp contrast, when Tris-EDTA (TE) buffer was used in place of pure water, the PL-mapping images of the solutions showed chirality indices of (6,5), (7,5), (7,6), (8,4), (9,4), and (10,2) for HiPco-SWNTs, and (6,5) and (7,5) for CoMoCAT-SWNTs. The first semiconducting bands in the near-IR absorption spectra of solutions of dsDNA-wrapped SWNTs are different. To explain the observed differences in the near-IR absorption and PL behavior we conducted several experiments and found that the near-IR optical properties of the SWNTs can be modulated by changing the pH of the solutions. The pH break-points for near-IR absorption bleaching and PL quenching are different and the phenomena are explained by differences in the numbers of holes generated on the SWNTs. These findings are important from both fundamental and applied viewpoints.


Solid-phase microextraction for determining the distribution of sixteen US Environmental Protection Agency polycyclic aromatic hydrocarbons in water samples.
A solid-phase microextraction (SPME) procedure has been developed for the determination of 16 US Environmental Protection Agency promulgated polycyclic aromatic hydrocarbons (PAHs). Five kinds of SPME fibers were used and compared in this study. The extracted sample was analyzed by gas chromatography with flame ionization detection or mass spectrometry. Parameters affecting the sorption of analyte into the fibers, including sampling time, thickness of the fiber coating, and the effect of temperature, have been examined. Moreover, the feasibility of headspace SPME with different working temperatures was evaluated. The method was also applied to real samples. The 85-microm polyacrylate (PA) and 100-microm poly(dimethylsiloxane) (PDMS) fibers were shown to have the highest affinities for the selected PAHs. The PA fiber was more suitable than the PDMS fiber for the determination of low-ring PAHs while high sensitivity of high-ring PAHs was observed when a 100-microm PDMS fiber was used. The method showed good linearity between 0.1 and 100 ng/ml with regression coefficients ranging from 0.94 to 0.999. The reproducibility of the measurements between fibers was found to be very good. The precisions of PA and PDMS fibers were from 3 to 24% and from 3 to 14%, respectively. Headspace SPME is a valid alternative for the determination of two- to five-ring PAHs. A working temperature of 60 degrees C provides significant enhancement in sensitivity of two- to five-ring PAHs having low vapor pressures (>10(-6) mmHg at 25 degrees C) (1 mmHg = 133.3 Pa) and low Henry's constants (>10 atm ml/mol) (1 atm = 1.01 x 10(5) Pa).


Survivorship of Metaphyseal Sleeves in Revision Total Knee Arthroplasty.
Metaphyseal fixation has promising early results in providing component stability and fixation in revision total knee arthroplasty (TKA). However, there are limited studies on midterm results of metaphyseal sleeves. We analyzed complications, rerevisions, and survivorship free of revision for aseptic loosening of metaphyseal sleeves in revision TKA. Two hundred eighty patients with 393 metaphyseal sleeves (144 femoral, 249 tibial) implanted during revision TKA from 2006-2014 were reviewed. Sleeves were most commonly cemented (55% femoral, 72% tibial). Mean follow-up was 3 years, mean age was 66 years, and mean body mass index was 34 kg/m2. Indications for revision TKA included 2-stage reimplantation for deep infection (37%), aseptic loosening of the tibia (14%), femur (12%), or both components (9%), and instability (14%). There was a 12% rate of perioperative complications, most commonly intraoperative fracture (6.5%). Eight sleeves (2.5%) required removal: 6 (2%) during component resection for deep infection (all were well-fixed at removal) as well as 1 (0.8%) femoral sleeve and 1 (0.8%) tibial sleeve for aseptic loosening. Five-year survivorship free of revision for aseptic loosening was 96% and 99.5% for femoral and tibial sleeves, respectively. Level of constraint, bone loss, sleeve and/or stem fixation, and revision indication did not significantly affect outcomes. Metaphyseal sleeve fixation to enhance component stability during revision TKA has a 5-year survivorship free of revision for aseptic loosening of 96% and 99.5% in femoral and tibial sleeves, respectively. Both cemented and cementless sleeve fixation provides reliable durability at intermediate follow-up.


Nutritional status, metabolic responses to exercise and implications for performance.
Diet can significantly influence exercise performance. Diet alone will not ensure successful performance in sport, but it plays a permissive role in allowing sustained intensive training with limited risk of illness and injury. Diet may also promote adaptations to training by stimulating synthesis and breakdown of the specific proteins that respond to the training stimulus. Protein synthesis and breakdown are both stimulated for some time after exercise, and protein ingestion before, during or immediately after exercise will enhance the fractional synthetic rate. Carbohydrate and fat are key energy substrates during exercise, and acute nutritional manipulation will affect both substrate selection and exercise performance.


Nuchal translucency measurements for first-trimester screening: the 'price' of inaccuracy.
First-trimester aneuploidy screening is in transition from the phase of 'development' to that of 'diffusion.' As with all other technologies, there is risk of diminished performance until newer centers are well experienced. Typically, inexperienced sonographers under-measure nuchal translucency (NT), and experience, training and continual monitoring of data are needed to ensure that measurements do not deviate. Here we assess the impact of systematic under-measurement on abnormality detection. Actual NT measurements from 13,887 normal fetuses, 82 with trisomy 21 (T21) and 61 with other abnormalities (OA) with birth outcome data were mathematically modified to show either a 25% or 0.5-mm decrease in measurement. The impact upon sensitivity and screen-positive rates were assessed. Reducing the NT measurements of T21 and OA cases lowers the sensitivity from 81.7 and 70.5%, respectively, to 67.1 and 62.3% (p < 0.01). If normals are correspondingly lowered, then the screen-positive rates are reduced from 6.9 to 2.0 and 2.5%. To maintain the same screen-positive rates and sensitivity, the risk threshold would have to be increased from 1/300 to 1/556. Minor inaccuracies in NT measurements as small as 25% or 0.5 mm will have very significant negative impacts upon abnormality detection, reducing detection rates by 18% (81.7 to 67.1%). Just as it is completely accepted that laboratory measurements require standardization and quality assurance, NT measurements, because they are used in an algorithm, need to be treated with the same rigor. That way the published data from centers that have developed such screening can be applied by other operators at other sites when counseling their patients.


[Directed immobilization of recognizing elements of biosensor transducers].
Data about the directed immobilisation of recognising structures on metal and silicon surfaces of biosensor transducers are analyzed in the review. Attention is paid to such approaches as pretreatment of surface by silanes, thiol compounds as well as to formation of polyelectrolyte-based layers.


[Observations of movements of lymphy vessels in patients with lymphedema of the limbs].
The authors report own observations on the spontaneous active movements of lymph vessels in man. Two cases of lymphedema of the lower limb are presented in which these movements of lymph vessels were observed during lymphography and after surgical exposure during the operation of a lympho-venous anastomosis.


[Diabetes as a risk factor for tooth loss in the geriatric population].
A comparative study of the level and type of tooth loss, and the use of dental prostheses, was performed on one diabetic sample and another non-diabetic one, taken from elderly people receiving health care at the San Pablo Health Centre, Sevilla, in order to assess the repercussion of diabetes on tooth loss. A descriptive and observational study of a crossover type. Primary care. San Pablo Health Centre, Sevilla. Patients aged > 65 requesting health care for any reason at our PC clinic during March-April 1995. 98 patients, 42 diabetics and 56 non-diabetics, were studied. The percentage of toothlessness was significantly greater in diabetic patients than in non-diabetic ones. None of the patients had kept all their teeth. 52.4% of the diabetic patients wore complete prostheses, percentage which went down to 25% in non-diabetics. 57.1% of diabetics and 44.6% of non-diabetics wore some type of prosthesis. We can consider diabetes as a risk factor in tooth loss among the elderly. Applying buco-dental hygiene measures from the diagnosis of diabetes, along with regular dental check-ups, might significantly lessen diabetics' dental loss over their lives. Opening the elderly person's mouth, whether he/she is diabetic or not, and evaluating oral mucus and dental structure, should be a investigative procedure in primary care.


Prediction of Vertebral Fractures by Trabecular Bone Score in Patients With Ankylosing Spondylitis.
Ankylosing spondylarthritis (AS) is associated falsely increased lumbar spine bone mineral density (BMD). New tool for discrimination of subjects at fracture risk is needed. Vertebral fracture (VF) prediction of routine methods for osteoporosis assessment, BMD and trabecular bone score (TBS), in patients with AS. Cross-sectional study of all AS patients regularly followed at the rheumatology outpatient clinics of two centers. All subjects undergone BMD measurement at lumbar spine (LS), total hip (TH) and femoral neck (FN) using Hologic® Horizon device. TBS at L1-4 in all subjects by TBS InSight® software were assessed. Vertebral fracture assessment (VFA) was performed using the lateral spine imaging IVA™ and graded using Genant semi-quantitative approach. 119 AS subjects (90 males/29 females), mean age 47.6 years were included in the study. In 20 patients 34 VFs were detected, from whom 7 patients had multiple fractures. Subjects with VF were older and had lower FN BMD, TBS in comparison to non-VF subjects. No differences in LS BMD, FN BMD or BASDAI between groups were observed. Among patients with VF only 3 had T-score less than -2.5 but 7 has TBS less than 1.23 which means highly degraded microarchitecture. AS patients with VF have lower TBS and FN BMD in comparison to non-VF subjects. In addition, TBS was able to detect 20 % more VFs than BMD. Therefore, TBS seems promising in VF discrimination among patients with AS.


The mediating role of social ostracism in the effect of social media addiction on loneliness in adolescents.
This study aimed to determine the mediating role of social ostracism in the effect of social media addiction on loneliness in adolescents. This descriptive and cross-sectional study was conducted with 1225 adolescent students attending high school in a province in Eastern Turkey between 30 May 2023 and 01 August 2023. The study data were collected using the "Personal Information Form", "Bergen Social Media Addiction Scale", "UCLA Loneliness Scale-Short Form" and "Ostracism Experience Scale for Adolescents". The analysis of the study data was performed by using SPSS 22.0, AMOS V 24.0, and G*Power 3.1 Statistical package software. It was determined that the model created in line with the determining the mediating role of social ostracism in the effect of social media addiction on loneliness in adolescents was compatible and the model fit indices were within the desired limits x2/df = 4.481, RMSEA = 0.05, CFI = 0.96, GFI = 0.96, AGFI = 0.94, IFI = 0.96. Social media addiction has been found to affect loneliness and social ostracism (p < 0.05). It was found that social ostracism affected the level of loneliness (p < 0.05). It was determined that social ostracism had a mediating role in the effect of social media addiction on loneliness (p < 0.05). As the level of social media addiction increases, the level of loneliness and social ostracism increases. As the level of social ostracism increases, the level of loneliness increases. Longitudinal studies on the factors affecting loneliness are recommended. In order to reduce the loneliness and social ostracism levels of adolescents, their access to social media should be controlled. Programs to reduce social ostracism should be designed.


Anti-Legionella dumoffii activity of Galleria mellonella defensin and apolipophorin III.
The gram-negative bacterium Legionella dumoffii is, beside Legionella pneumophila, an etiological agent of Legionnaires' disease, an atypical form of pneumonia. The aim of this study was to determine the antimicrobial activity of Galleria mellonella defense polypeptides against L. dumoffii. The extract of immune hemolymph, containing a mixture of defense peptides and proteins, exhibited a dose-dependent bactericidal effect on L. dumoffii. The bacterium appeared sensitive to a main component of the hemolymph extract, apolipophorin III, as well as to a defense peptide, Galleria defensin, used at the concentrations 0.4 mg/mL and 40 μg/mL, respectively. L. dumoffii cells cultured in the presence of choline were more susceptible to both defense factors analyzed. A transmission electron microscopy study of bacterial cells demonstrated that Galleria defensin and apolipophorin III induced irreversible cell wall damage and strong intracellular alterations, i.e., increased vacuolization, cytoplasm condensation and the appearance of electron-white spaces in electron micrographs. Our findings suggest that insects, such as G. mellonella, with their great diversity of antimicrobial factors, can serve as a rich source of compounds for the testing of Legionella susceptibility to defense-related peptides and proteins.


Antiproteases in the treatment of acute necrotizing pancreatitis: continuous regional arterial infusion.
Acute necrotizing pancreatitis is still a fatal disease. Pancreatic necrosis might be, in part, a result of infarction due to ischemia with vasospasm and an increase in intravascular coagulability. Synthetic antiproteases have a broad inhibitory action on pancreatic enzymes, the coagulation system, the complement system and the production of proinflammatory cytokines. Therefore, antiproteases have been expected to prevent necrotic changes in the pancreas and to reduce the mortality rate. However, the clinical efficacy of antiproteases is still a matter of controversy. Unfortunately, an antiprotease cannot easily reach the pancreas when administered intravenously because of its pharmacokinetic characteristics and impaired microcirculation. Administration through a catheter placed in one of the arteries which supplies the inflamed area of the pancreas, dramatically increases the concentration of the antiprotease in the pancreas. Clinical studies of continuous regional arterial infusion of a protease inhibitor have been conducted in Japan and have demonstrated the possible therapeutic efficacy of the new treatment in severe acute pancreatitis.


Pineal indoleamine metabolism in the cotton rat, Sigmodon hispidus: studies on norepinephrine, serotonin, N-acetyltransferase activity and melatonin.
The purpose of this study was to examine the levels of norepinephrine (NE), serotonin, melatonin and N-acetyltransferase (NAT) activity in the cotton rat pineal gland in relationship to environmental lighting. In each of two experiments cotton rats were collected from the wild and housed indoors in a 14:10 light:dark (LD) cycle (lights on at 0600) for a period of at least two weeks. Pineal glands were removed from animals in groups of eight at 0800, 1200, 1600, 2000, 2400, 0200 and 0400 hours over a 24 hour period for each experiment. Collection was done under a dim red light during the nighttime hours. In the first experiment pineal melatonin production showed a striking circadian rhythm with nighttime levels 20 times greater than that of daytime levels. In the second experiment pineal NE, serotonin and NAT activity were measured in aliquots from the same gland. NE showed no circadian rhythm whereas serotonin values were significantly depressed at night. The nighttime NAT activity rose to 10 times that of the daytime level. The NAT peak was concurrent with the melatonin peak. These data indicate that the neural and the biochemical control of the cotton rat pineal may be similar to that of other mammalian species.


Intractable Blepharospasm Treated with Bilateral Pallidal Deep Brain Stimulation.
Blepharospasm can be present as an isolated dystonia or in conjunction with other forms of cranial dystonia, causing significant disability. We report a case of a 69-year-old male with craniocervical dystonia, manifesting primarily as incapacitating blepharospasm refractory to medical treatments. He underwent bilateral globus pallidus (GP) deep brain stimulation (DBS) with complete resolution of his blepharospasm and sustained benefit at 12 months postoperatively. This case illustrates successful treatment of blepharospasm with pallidal stimulation. GP-DBS should be considered a reasonable therapeutic option for intractable blepharospasm.


Recognizing the value of software: a software citation guide.
Software is as integral as a research paper, monograph, or dataset in terms of facilitating the full understanding and dissemination of research. This article provides broadly applicable guidance on software citation for the communities and institutions publishing academic journals and conference proceedings. We expect those communities and institutions to produce versions of this document with software examples and citation styles that are appropriate for their intended audience. This article (and those community-specific versions) are aimed at authors citing software, including software developed by the authors or by others. We also include brief instructions on how software can be made citable, directing readers to more comprehensive guidance published elsewhere. The guidance presented in this article helps to support proper attribution and credit, reproducibility, collaboration and reuse, and encourages building on the work of others to further research.


Spouse-assisted coping skills training in the management of knee pain in osteoarthritis: long-term followup results.
To evaluate the long-term effects of a spouse-assisted coping skills intervention in patients with osteoarthritis (OA) of the knees, and to evaluate how pre- to posttreatment changes in marital adjustment and self-efficacy relate to long-term improvements in pain, psychological disability, physical disability, pain coping, and pain behavior. A followup study was conducted with 88 OA patients who had been randomly assigned to 1 of 3 treatment conditions: 1) spouse-assisted coping skills training (spouse-assisted CST), 2) a conventional CST intervention with no spouse involvement, and 3) an arthritis education-spousal support (AE-SS) control condition. To evaluate long-term outcome, comprehensive measures of self-efficacy, marital adjustment, pain, psychological disability, physical disability, pain coping, and pain behavior were collected from these individuals at 6 and 12 months posttreatment. Data analysis revealed that, at 6-month followup, patients in the spouse-assisted CST condition scored higher on measures of coping and self-efficacy than those in the AE-SS control group. At 6-month followup, patients who received CST without spouse involvement showed a significantly higher frequency of coping attempts and reported higher levels of marital adjustment than those in the AE-SS control group. At 12-month followup, patients in the spouse-assisted CST condition had significantly higher overall self-efficacy than those in the AE-SS control condition. In addition, patients in both the spouse-assisted CST and CST only conditions tended to show improvements in physical disability at the 12-month followup. Individual differences in outcome were noted at the 12-month followup. Patients in the spouse-assisted CST condition who reported initial (pre- to posttreatment) increases in marital adjustment had lower levels of psychological disability, physical disability, and pain behavior at 12-month followup. However, for patients in the conventional CST and AE-SS control conditions, increases in marital adjustment occurring over the initial phase of treatment were related to increases in pain and decreases in scores on the Pain Control in Rational Thinking factor of the Coping Strategies Questionnaire. Finally, patients in the spouse-assisted CST condition who showed pre- to posttreatment increases in self-efficacy were more likely to show decreases in pain, psychological disability, and physical disability at 12-month followup. These findings suggest that spouse-assisted CST can enhance self-efficacy and improve the coping abilities of OA patients in the long term. Individual differences in the long-term outcome of spouse-assisted CST were noted, with some patients (those showing increases in marital satisfaction and self-efficacy) showing much better outcomes than others.


Distance transform for images represented by quadtrees.
The concept of distance used in binary array representations of images is adapted to a quadtree representation. The chessboard distance metric is shown to be particularly suitable for the quadtree. A chessboard distance transform for a quadtree is defined as the minimum distance in the plane from each BLACK node to the border of a WHiTE node. An algorithm is presented which computes this transform by only examining the BLACK node's adjacent and abutting neighbors and their progeny. However, unlike prior work with quadtrees, computation of the distance transform requires a capability of finding neighbors in the diagonal direction rather than merely in the horizontal and vertical directions. The algorithm's average execution time is proportional to the number of leaf nodes in the quadtree.


Corticotropin-releasing factor and adrenocorticotrophic hormone as potential central mediators of OB effects.
OB (leptin) has been identified as a factor that suppresses appetite and stimulates metabolism. Attention has focused on the hypothalamus as its potential site of action, but OB could also act on other brain regions. In addition, the paradox of high OB levels in obese humans remains unresolved. Here we show in mice that both the long and short form of the OB receptor are expressed not only in the hypothalamus but also in the amygdala and pituitary. Recombinant murine OB elicited the release of corticotropin-releasing factor from superfused brain slice preparations containing hypothalamus or amygdala. Because corticotropin-releasing factor inhibits appetite and stimulates metabolism, it may be a key mediator of central OB effects. Recombinant OB also induced pituitary release of adrenocorticotrophic hormone. Because adrenocorticotrophic hormone-induced elevation of plasma glucocorticoid levels can inhibit corticotropin-releasing factor release via negative feedback, the OB effects on pituitary adrenocorticotrophic hormone release may be pertinent to human obesity, which combines increased plasma glucocorticoid levels with elevated levels of OB. An imbalance between the effects of OB on corticotropin-releasing factor release from the hypothalamus and on adrenocorticotrophic hormone release from the pituitary could contribute to obesity.


Diacylglycerol kinase-ε is S-palmitoylated on cysteine in the cytoplasmic end of its N-terminal transmembrane fragment.
Diacylglycerol kinase-ε (DGKε) catalyzes phosphorylation of diacylglycerol to phosphatidic acid with a unique specificity toward 1-stearoyl-2-arachidonoyl-sn-glycerol which is a backbone of phosphatidylinositol (PI). Owing to this specificity, DGKε is involved in the PI cycle maintaining the cellular level of phosphorylated PI derivatives of signaling activity, and was also found crucial for lipid metabolism. DGKε dysfunction is linked with the development of atypical hemolytic uremic syndrome and possibly other human diseases. Despite the DGKε significance, data on its regulation by co/posttranslational modifications are scarce. Here we report that DGKε is S-palmitoylated at Cys38/40 (mouse/human DGKε) located in the cytoplasmic end of its N-terminal putative transmembrane fragment. The S-palmitoylation of DGKε was revealed by metabolic labeling of cells with a palmitic acid analogue followed by click chemistry, and with acyl-biotin and acyl-PEG exchange assays. The S-acyltransferases zDHHC7 and zDHHC17, and the zDHHC6/16 tandem were found to catalyze DGKε S-palmitoylation which also increased the DGKε abundance. Mouse DGKε-Myc ectopically expressed in HEK293 cells localized to the endoplasmic reticulum where zDHHC6/16 reside and in small amounts also to the Golgi apparatus where zDHHC7 and zDHHC17 are present. The Cys38Ala substitution upregulated while hyperpalmitoylation of wild type DGKε reduced the kinase activity, indicating an inhibitory effect of the Cys38 S-palmitoylation. Additionally, the substitution of neighboring Pro31 with Ala also diminished the activity of DGKε. Taken together, our data indicate that S-palmitoylation can fine-tune DGKε activity in distinct cellular compartments, possibly by affecting the distance between the kinase and its substrate in a membrane.


Dedifferentiated liposarcoma with heterologous rhabdomyosarcomatous differentiation in the bone marrow.
We present a case of advanced well-differentiated liposarcoma transforming to dedifferentiated liposarcoma in the bone marrow.Our patient presented with 5 weeks of worsening flank pain. He was found to have profound leukocytosis, thrombocytopenia, and normocytic anemia. Imaging showed a dominant retrocaval mass concerning for viable disease. Bone marrow biopsy revealed dedifferentiated liposarcoma with heterologous rhabdomyosarcomatous differentiation. He underwent 3 cycles of eribulin and subsequently developed complications of his increasingly aggressive liposarcoma. He was transitioned to hospice care and died 3 months after initial bone marrow biopsy. While exceedingly rare, it is possible for liposarcoma to metastasize to the bone marrow and cause rapid progression to death. In patients with high-grade liposarcoma, new cytopenia, leukocytosis, elevated granulocyte colony stimulating factor, and/or leukoerythroblasosis on peripheral smear should prompt bone marrow biopsy for early detection of this rare disease entity.


The proximate determinants of educational homogamy: the effects of first marriage, marital dissolution, remarriage, and educational upgrading.
This paper adapts the population balancing equation to develop a framework for studying the proximate determinants of educational homogamy. Using data from the National Longitudinal Survey of Youth on a cohort of women born between 1957 and 1964, we decompose the odds of homogamy in prevailing marriages into four proximate determinants: (1) first marriages, (2) first and later marital dissolutions, (3) remarriages, and (4) educational attainment after marriage. The odds of homogamy among new first marriages are lower than among prevailing marriages, but not because of selective marital dissolution, remarriage, and educational attainment after marriage, as has been speculated. Prevailing marriages are more likely to be educationally homogamous than new first marriages because of the accumulation of homogamous first marriages in the stock of marriages. First marriages overwhelmingly account for the odds of homogamy in prevailing marriages in this cohort. Marital dissolutions, remarriages, and educational upgrades after marriage have relatively small and offsetting effects. Our results suggest that, despite the high prevalence of divorce, remarriage, and continued schooling after marriage in the United States, the key to understanding trends in educational homogamy lies primarily in variation in assortative mating into first marriage.


A history of spike-timing-dependent plasticity.
How learning and memory is achieved in the brain is a central question in neuroscience. Key to today's research into information storage in the brain is the concept of synaptic plasticity, a notion that has been heavily influenced by Hebb's (1949) postulate. Hebb conjectured that repeatedly and persistently co-active cells should increase connective strength among populations of interconnected neurons as a means of storing a memory trace, also known as an engram. Hebb certainly was not the first to make such a conjecture, as we show in this history. Nevertheless, literally thousands of studies into the classical frequency-dependent paradigm of cellular learning rules were directly inspired by the Hebbian postulate. But in more recent years, a novel concept in cellular learning has emerged, where temporal order instead of frequency is emphasized. This new learning paradigm - known as spike-timing-dependent plasticity (STDP) - has rapidly gained tremendous interest, perhaps because of its combination of elegant simplicity, biological plausibility, and computational power. But what are the roots of today's STDP concept? Here, we discuss several centuries of diverse thinking, beginning with philosophers such as Aristotle, Locke, and Ribot, traversing, e.g., Lugaro's plasticità and Rosenblatt's perceptron, and culminating with the discovery of STDP. We highlight interactions between theoretical and experimental fields, showing how discoveries sometimes occurred in parallel, seemingly without much knowledge of the other field, and sometimes via concrete back-and-forth communication. We point out where the future directions may lie, which includes interneuron STDP, the functional impact of STDP, its mechanisms and its neuromodulatory regulation, and the linking of STDP to the developmental formation and continuous plasticity of neuronal networks.


[Histological study on the surviving processes of the free grafted tendon sheath].
This article reports the histological study on the surviving processes of the free grafted tendon sheath. The results showed that there were three phases in the surviving processes: inflammation phase, adaptation phase and function phase. The inflammation phase was from the first day to about the 10th day postoperatively and characterised by inflammatory changes in the grafted sheath. The adaptation phase was from about the 10th day to the fourth week. During this period, the grafted sheath formed solid healing with surrounding tissues, and adapts its nutritional supplies. The function phase began at the end of the fourth week. The grafted sheath restores the normal functions. The possible nutritional sources for maintaining the survival of the grafted sheath are discussed.


Pancreato-jejunostomy versus hand-sewn closure of the pancreatic stump to prevent pancreatic fistula after distal pancreatectomy: a retrospective analysis.
Different methods of pancreatic stump closure after distal pancreatectomy (DP) have been described to decrease the incidence of pancreatic fistula (PF) which still represents one of the most common complications in pancreatic surgery. We retrospectively compared the pancreato-jejunostomy technique with the hand-sewn closure of the pancreatic stump after DP, and analyzed clinical outcomes between the two groups, focusing on PF rate. Thirty-six patients undergoing open DP at our institution between May 2005 and December 2011 were included. They were divided in two groups depending on pancreatic remnant management: in 24 cases the stump was closed by hand-sewn suture (Group A), while in 12 earlier cases a pancreato-jejunostomy was performed (Group B). We analyzed postoperative data in terms of mortality, morbidity and length of hospital stay between the two groups. PF occurred in 7 of 24 (29.1%) cases of group A (control group) compared to zero fistula rate in group B (anastomosis group) (p=0.005). Operative time was significantly higher in the anastomosis group (p=0.024). Mortality rate was 0% in both groups. Other postoperative outcomes such as hemorrhages, infections, medical complications and length of hospital stay were not significant between the two groups. Despite a higher operative time, the pancreato-jejunostomy after DP seems to be related to a lower incidence of PF compared to the hand-sewn closure of the pancreatic remnant.


New tools and novel approaches in treating locally advanced pancreatic adenocarcinoma.
Pancreatic adenocarcinoma is one of the most aggressive malignant tumors and represents the fourth leading cause of cancer-related death. The median survival of locally advanced pancreatic carcinoma is ten to thirteen months. In this year's American Society of Clinical Oncology (ASCO) Annual Meeting, several studies were presented with novel approaches towards treating locally advanced pancreatic cancer. Wild et al. (Abstract #4055) explored a novel tool of selective delivery of TNF-alpha intratumoral injection. This approach limited the systemic toxicity, and suggested survival benefit in only the subgroup of patients with locally advanced pancreatic adenocarcinoma with stage T1-T3. Two studies were presented which were designed to assess the use of two novel agents, targeting signaling pathways, in addition to gemcitabine. Van Laethem et al. (Abstract #4050) are testing the MEK inhibitor, BAY 86-9766 in combination with gemcitabine. However, treatment related toxicity is still of concern. In the other study, Evans et al. (Abstract #TPS4134) are testing the combination of dasatinib and gemcitabine. This is a placebo-controlled, randomized, double blind phase II study. However, results are not available. Stereotactic body radiotherapy (SBRT) is an emerging technology with the comparative efficacy of single fraction radiotherapy (as is used in radiosurgery) vs. fractionated SBRT still unknown. Herman et al. (Abstract #4045) examined the role of fractionated SBRT in locally advanced pancreatic cancer. The phase II results showed a median overall survival of 15.9 months, suggesting that SBRT may be an emerging tool in the multi-modality treatment of locally advanced pancreatic cancer.


Mapping viral DNA specificity to the central region of integrase by using functional human immunodeficiency virus type 1/visna virus chimeric proteins.
We previously described the construction and analysis of the first set of functional chimeric lentivirus integrases, involving exchange of the N-terminal, central, and C-terminal regions of the human immunodeficiency virus type 1 (HIV-1) and visna virus integrase (IN) proteins. Based on those results, additional HIV-1/visna virus chimeric integrases were designed and purified. Each of the chimeric enzymes was functional in at least one oligonucleotide-based IN assay. Of a total of 12 chimeric IN proteins, 3 exhibit specific viral DNA processing, 9 catalyze insertion of viral DNA ends, 12 can reverse that reaction, and 11 are active for nonspecific alcoholysis. Functional data obtained with the processing assay indicate that the central region of the protein is responsible for viral DNA specificity. Target site selection for nonspecific alcoholysis again mapped to the central domain of IN, confirming our previous data indicating that this region can position nonviral DNA for nucleophilic attack. However, the chimeric proteins created patterns of viral DNA insertion distinct from that of either wild-type IN, suggesting that interactions between regions of IN influence target site selection for viral DNA integration. The results support a new model for the functional organization of IN in which viral DNA initially binds nonspecifically to the C-terminal portion of IN but the catalytic central region of the enzyme has a prominent role both in specific recognition of viral DNA ends and in positioning the host DNA for viral DNA integration.


Working conditions in primary health care in the COVID-19 pandemic: an overview of Brazil and Portugal.
The COVID-19 pandemic has put pressure on public health systems worldwide since 2020. This article aims to discuss working conditions in Primary Health Care (PHC) in Brazil, while dialoguing with primary health care (CSP, Cuidados de Saúde Primários) in Portugal in the pandemic scenario. For that purpose, data from the study "Working conditions of health professionals in the context of COVID-19 in Brazil" are presented, for further discussion with the report produced by "Family Health Units - National Association (USF-AN, Unidades de Saúde Familiar - Associação Nacional)" on the CSP in Portugal. In Brazil, regarding the sample of 3,895 PHC health professionals, it was observed: multiple employment relationships, lack of institutional support and specific training, living with fake news and the lack of political cohesion between health authorities, with significant changes in these workers' mental health. In Portugal, the increase in the workload and the presence of Burnout Syndrome among FHU professionals was emphasized. The pandemic had a significant impact on the health and daily work of health professionals in PHC and CSP. However, the Brazilian context was more adverse due to fake news and divergences regarding conducts related to the fight against the pandemic, due to the actions and denialism by the federal government.


A best evidence systematic review of interprofessional education: BEME Guide no. 9.
BACKGROUND AND REVIEW CONTEXT: Evidence to support the proposition that learning together will help practitioners and agencies work better together remains limited and thinly spread. This review identified, collated, analysed and synthesised the best available contemporary evidence from 21 of the strongest evaluations of IPE to inform the above proposition. In this way we sought to help shape future interprofessional education and maximize the potential for interprofessional learning to contribute to collaborative practice and better care. To identify and review the strongest evaluations of IPE. To classify the outcomes of IPE and note the influence of context on particular outcomes. To develop a narrative about the mechanisms that underpin and inform positive and negative outcomes of IPE. Bibliographic database searches as follows: Medline 1966-2003, CINAHL 1982-2001, BEI 1964-2001, ASSIA 1990-2003 which produced 10,495 abstracts. Subsequently, 884 full papers were obtained and scrutinized. In addition, hand searching (2003-5 issues) of 21 journals known to have published two or more higher quality studies from a previous review. Peer-reviewed papers and reports included in the review had to be formal educational initiatives attended by at least two of the many professional groups from health and social care, with the objective of improving care; and learning with, from and about each other. Standard systematic review procedures were applied for sifting abstracts, scrutinizing full papers and abstracting data. Two members of the team checked each abstract to decide whether the full paper should be read. A third member was consulted over any discrepancies. Similarly, each full paper was read by at least two members of the team and agreement sought before passing it to one member of the team (SR) for data abstraction. Other members of the team checked 10% of the abstraction records. Coding into a Statistical Package for Social Scientists (SPSS) data base led to collection of different outcome measures used in the primary studies via the common metric of an adapted Kirkpatrick's four-level model of educational outcomes. Additionally, a narrative synthesis was built after analysis of primary data with the 3-P model (presage-process-product) of education development and delivery. Government calls for enhanced collaboration amongst practitioners frequently leads to IPE that is then developed and delivered by educators, practitioners or service managers. Staff development is a key influence on the effectiveness of IPE for learners who all have unique values about themselves and others. Authenticity and customization of IPE are important mechanisms for positive outcomes of IPE. Interprofessional education is generally well received, enabling knowledge and skills necessary for collaborative working to be learnt; it is less able to positively influence attitudes and perceptions towards others in the service delivery team. In the context of quality improvement initiatives interprofessional education is frequently used as a mechanism to enhance the development of practice and improvement of services.


Secular decrease of wind power potential in India associated with warming in the Indian Ocean.
The Indian government has set an ambitious target for future renewable power generation, including 60 GW of cumulative wind power capacity by 2022. However, the benefits of these substantial investments are vulnerable to the changing climate. On the basis of hourly wind data from an assimilated meteorology reanalysis dataset covering the 1980-2016 period, we show that wind power potential may have declined secularly over this interval, particularly in western India. Surface temperature data confirm that significant warming occurred in the Indian Ocean over the study period, leading to modulation of high pressure over the ocean. A multivariable linear regression model incorporating the pressure gradient between the Indian Ocean and the Indian subcontinent can account for the interannual variability of wind power. A series of numerical sensitivity experiments confirm that warming in the Indian Ocean contributes to subsidence and dampening of upward motion over the Indian continent, resulting potentially in weakening of the monsoonal circulation and wind speeds over India.


Notch2 is required for progression of pancreatic intraepithelial neoplasia and development of pancreatic ductal adenocarcinoma.
Pancreatic cancer is one of the most fatal malignancies lacking effective therapies. Notch signaling is a key regulator of cell fate specification and pancreatic cancer development; however, the role of individual Notch receptors and downstream signaling is largely unknown. Here, we show that Notch2 is predominantly expressed in ductal cells and pancreatic intraepithelial neoplasia (PanIN) lesions. Using genetically engineered mice, we demonstrate the effect of conditional Notch receptor ablation in KrasG12D-driven pancreatic carcinogenesis. Deficiency of Notch2 but not Notch1 stops PanIN progression, prolongs survival, and leads to a phenotypical switch toward anaplastic pancreatic cancer with epithelial-mesenchymal transition. By expression profiling, we identified increased Myc signaling regulated by Notch2 during tumor development, placing Notch2 as a central regulator of PanIN progression and malignant transformation. Our study supports the concept of distinctive roles of individual Notch receptors in cancer development.


NPY and cardiac diseases.
Hypertension-induced left ventricular hypertrophy (LVH), along with ischemic heart disease, result in LV remodeling as part of a continuum that often leads to congestive heart failure. The neurohormonal model has been used to underpin many treatment strategies, but optimal outcomes have not been achieved. Neuropeptide Y (NPY) has emerged as an additional therapeutic target, ever since it was recognised as an important mediator released from sympathetic nerves in the heart, affecting coronary artery constriction and myocardial contraction. More recent interest has focused on the mitogenic and hypertrophic effects that are observed in endothelial and vascular smooth muscle cells, and cardiac myocytes. Of the six identified NPY receptor subtypes, Y(1), Y(2) and Y(5) appear to mediate the main functional responses in the heart. Plasma levels of NPY become elevated due to the increased sympathetic activation present in stress-related cardiac conditions. Also, NPY and Y receptor polymorphisms have been identified that may predispose individuals to increased risk of hypertension and cardiac complications. This review examines what understanding exists regarding the likely contribution of NPY to cardiac pathology. It appears that NPY may play a part in compensatory or detrimental remodeling of myocardial tissue subsequent to hemodynamic overload or myocardial infarction, and in angiogenic processes to regenerate myocardium after ischemic injury. However, greater mechanistic information is required in order to truly assess the potential for treatment of cardiac diseases using NPY-based drugs.


Pathophysiology of cardiac extracorporeal membrane oxygenation.
The treatment of cardiogenic shock using inotropic agents and vascular volume expansion places an added burden on the heart. The resultant increase in cardiac work may cause myocardial ischemia and lead to cardiac arrest. Extracorporeal membrane oxygenation (ECMO) may be used to treat cardiogenic shock. It supports systemic circulation, assures diastolic perfusion of the myocardium, and reduces cardiac workload. The rise in blood pressure associated with restoring systemic circulation afterloads the heart and can cause left atrial hypertension and pulmonary edema. ECMO does not automatically reduce cardiac work, especially in the presence of residual shunts. Left atrial drainage or decompression may be essential in certain patients both to avert pulmonary edema and to reduce cardiac work.


Hyponatraemia associated with pneumonia or bacterial meningitis.
Serum sodium concentrations were measured in 93 children with pneumonia or bacterial meningitis on their admission to hospital. Hyponatraemia (sodium value 134 mmol/l or less) was present in 33 (45%) of the 73 children with pneumonia, and in 10 (50%) of the 20 children with bacterial meningitis. Increased secretion of antidiuretic hormone is common in children with pneumonia, as well as in children with meningitis. The maintenance fluid requirement in these children is usually about 50 ml/kg/per day, and children with hyponatraemia caused by water overload need even lower fluid intakes. In developing countries, most children with pneumonia and meningitis should be managed without intravenous fluid treatment.


Effectiveness of out-patient based acute heart failure care: a pilot randomised controlled trial.
Acute heart failure (AHF) hospitalisation is associated with 10% mortality. Outpatient based management (OPM) of AHF appeared effective in observational studies. We conducted a pilot randomised controlled trial (RCT) comparing OPM with standard inpatient care (IPM). We randomised patients with AHF, considered to need IV diuretic treatment for ≥2 days, to IPM or OPM. We recorded all-cause mortality, and the number of days alive and out-of-hospital (DAOH). Quality of life, mental well-being and Hope scores were assessed. Mean NHS cost savings and 95% central range (CR) were calculated from bootstrap analysis. Follow-up: 60 days. Eleven patients were randomised to IPM and 13 to OPM. There was no statistically significant difference in all-cause mortality during the index episode (1/11 vs 0/13) and up to 60 days follow-up (2/11 vs 2/13) [p = .86]. The OPM group accrued more DAOH {47 [36,51] vs 59 [41,60], p = .13}. Two patients randomised to IPM (vs 6 OPM) were readmitted [p = .31]. Hope scores increased more with OPM within 30 days but dropped to lower levels than IPM by 60 days. More out-patients had increased total well-being scores by 60 days (p = .04). OPM was associated with mean cost savings of £2658 (95% CR 460-4857) per patient. Patients with acute HF randomised to OPM accrued more days alive out of hospital (albeit not statistically significantly in this small pilot study). OPM is favoured by patients and carers and is associated with improved mental well-being and cost savings.


Critical transition between cohesive and population-dividing responses to change.
Globalization and global climate change will probably be accompanied by rapid social and biophysical changes that may be caused by external forcing or internal nonlinear dynamics. These changes often subject residing populations (human or otherwise) to harsh environments and force them to respond. Research efforts have mostly focused on the underlying mechanisms that drive these changes and the characteristics of new equilibria towards which populations would adapt. However, the transient dynamics of how populations respond under these new regimes is equally, if not more, important, and systematic analysis of such dynamics has received less attention. Here, we investigate this problem under the framework of replicator dynamics with fixed reward kernels. We show that at least two types of population responses are possible--cohesive and population-dividing transitions--and demonstrate that the critical transition between the two, as well as other important properties, can be expressed in simple relationships between the shape of reward structure, shift magnitude and initial strategy diversity. Importantly, these relationships are derived from a simple, yet powerful and versatile, method. As many important phenomena, from political polarization to the evolution of distinct ecological traits, may be cast in terms of division of populations, we expect our findings and method to be useful and applicable for understanding population responses to change in a wide range of contexts.


Generative modeling of living cells with SO(3)-equivariant implicit neural representations.
Data-driven cell tracking and segmentation methods in biomedical imaging require diverse and information-rich training data. In cases where the number of training samples is limited, synthetic computer-generated data sets can be used to improve these methods. This requires the synthesis of cell shapes as well as corresponding microscopy images using generative models. To synthesize realistic living cell shapes, the shape representation used by the generative model should be able to accurately represent fine details and changes in topology, which are common in cells. These requirements are not met by 3D voxel masks, which are restricted in resolution, and polygon meshes, which do not easily model processes like cell growth and mitosis. In this work, we propose to represent living cell shapes as level sets of signed distance functions (SDFs) which are estimated by neural networks. We optimize a fully-connected neural network to provide an implicit representation of the SDF value at any point in a 3D+time domain, conditioned on a learned latent code that is disentangled from the rotation of the cell shape. We demonstrate the effectiveness of this approach on cells that exhibit rapid deformations (Platynereis dumerilii), cells that grow and divide (C. elegans), and cells that have growing and branching filopodial protrusions (A549 human lung carcinoma cells). A quantitative evaluation using shape features and Dice similarity coefficients of real and synthetic cell shapes shows that our model can generate topologically plausible complex cell shapes in 3D+time with high similarity to real living cell shapes. Finally, we show how microscopy images of living cells that correspond to our generated cell shapes can be synthesized using an image-to-image model.


Refining measures of alcohol problems for general population surveys.
There is a need to improve classification of alcohol use disorders (AUDs) in general population surveys. We developed and tested follow-up questions for 2 commonly reported symptom domains (withdrawal and larger/longer) to assess effects on Diagnostic and Statistical Manual-5 AUD classification. Telephone interviews recontacted a selective follow-up sample of respondents under age 46 from the 2010 National Alcohol Survey with at least 1 lifetime AUD symptom (n = 244). Items included detailed questions about past-year AUD symptoms. Three items (vomiting, sweating, irritability) were recoded as acute intoxication rather than withdrawal if they most recently occurred within 8 hours of stopping drinking. The larger/longer criterion was recoded as socially motivated if respondents endorsed "got caught up in drinking with a group of friends" and not "feel compelled to drink and just can't stop" as a reason for drinking more than intended. Of 225 current drinkers, 11% reported past-year withdrawal, with 28% of those reporting acute intoxication instead of physical withdrawal. Adjusting past-year withdrawal classification reduced AUD prevalence by 6%. A minority (12%) reported the past-year larger/longer criterion. Of those, 50% indicated social reasons for drinking more than intended, rather than compulsion to drink. Adjusting the past-year larger/longer criterion reduced AUD prevalence by 8%. Accounting for both adjustments reduced AUD prevalence by 13%. Cases that met AUD criteria after both adjustments were substantially heavier drinkers than those that were reclassified. Follow-up items could be implemented in epidemiologic studies with minimal response burden and may help reduce misclassification of AUD.


An update on the use and investigation of probiotics in health and disease.
Probiotics are derived from traditional fermented foods, from beneficial commensals or from the environment. They act through diverse mechanisms affecting the composition or function of the commensal microbiota and by altering host epithelial and immunological responses. Certain probiotic interventions have shown promise in selected clinical conditions where aberrant microbiota have been reported, such as atopic dermatitis, necrotising enterocolitis, pouchitis and possibly irritable bowel syndrome. However, no studies have been conducted that can causally link clinical improvements to probiotic-induced microbiota changes. Whether a disease-prone microbiota pattern can be remodelled to a more robust, resilient and disease-free state by probiotic administration remains a key unanswered question. Progress in this area will be facilitated by: optimising strain, dose and product formulations, including protective commensal species; matching these formulations with selectively responsive subpopulations; and identifying ways to manipulate diet to modify bacterial profiles and metabolism.


Mortality in the United States, 2014.
This report presents 2014 U.S. final mortality data on deaths and death rates by demographic and medical characteristics. These data provide information on mortality patterns among U.S. residents by such variables as sex, race and ethnicity, and cause of death. Information on mortality patterns is key to understanding changes in the health and well-being of the U.S. population. Life expectancy estimates, age-adjusted death rates by race and ethnicity and sex, the 10 leading causes of death, and the 10 leading causes of infant death were analyzed by comparing 2014 final data with 2013 final data.


Longitudinal study of Staphylococcus aureus genotypes isolated from bovine clinical mastitis.
Bovine clinical mastitis is an important problem for the dairy industry, and Staphylococcus aureus is a common mastitis-causing pathogen in many countries. Detailed knowledge on genetic variation of Staph. aureus strains within the bovine population, including changes over time, can be useful for mastitis control programs, because severity of disease and effects on milk production are at least partly strain-associated. Therefore, the major aim of this study was to compare sequence types of Staph. aureus isolated from cases of bovine clinical mastitis from 2002 to 2003 with sequence types of a more recent set of isolates collected from 2013 to 2018, using core genome multi-locus sequence typing (cgMLST). We also wanted to compare antibiotic resistance genes of isolates from the 2 sets, to identify changes that may have occurred over time in the Staph. aureus population. A total of 157 isolates of Staph. aureus, almost equally distributed between the 2 time periods, were subjected to high-throughput sequencing and cgMLST. The results showed that the most prevalent sequence types found among the 2002 to 2003 isolates belonged to the clonal complexes CC97, CC133, and CC151, and that those complexes still dominated among the isolates from 2013 to 2018. However, a population shift from CC133 to CC97 and CC151 over time was observed. Likewise, no important differences in prevalence of antibiotic resistance genes were found between the 2 sets of isolates. As expected, genes belonging to the major facilitator superfamily of transporter proteins, and multidrug and toxic compound extrusion transporters, were very common. Moreover, several genes and mutations conferring resistance to fosfomycin were present, but not in CC97 isolates. The β-lactamase gene blaZ was found in only 3 out of 81 isolates from 2002 to 2003 and 1 out of 76 isolates in 2013 to 2018. In conclusion, the results indicate that mastitis-associated Staph. aureus strains circulating among dairy cows in Sweden exhibit a remarkable genotypic persistence over a time frame of close to 15 yr.


Werner Syndrome-specific induced pluripotent stem cells: recovery of telomere function by reprogramming.
Werner syndrome (WS) is a rare human autosomal recessive premature aging disorder characterized by early onset of aging-associated diseases, chromosomal instability, and cancer predisposition. The function of the DNA helicase encoded by WRN, the gene responsible for WS, has been studied extensively. WRN helicase is involved in the maintenance of chromosome integrity through DNA replication, repair, and recombination by interacting with a variety of proteins associated with DNA repair and telomere maintenance. The accelerated aging associated with WS is reportedly caused by telomere dysfunction, and the underlying mechanism of the disease is yet to be elucidated. Although it was reported that the life expectancy for patients with WS has improved over the last two decades, definitive therapy for these patients has not seen much development. Severe symptoms of the disease, such as leg ulcers, cause a significant decline in the quality of life in patients with WS. Therefore, the establishment of new therapeutic strategies for the disease is of utmost importance. Induced pluripotent stem cells (iPSCs) can be established by the introduction of several pluripotency genes, including Oct3/4, Sox2, Klf4, and c-myc into differentiated cells. iPSCs have the potential to differentiate into a variety of cell types that constitute the human body, and possess infinite proliferative capacity. Recent studies have reported the generation of iPSCs from the cells of patients with WS, and they have concluded that reprogramming represses premature senescence phenotypes in these cells. In this review, we summarize the findings of WS patient-specific iPSCs (WS iPSCs) and focus on the roles of telomere and telomerase in the maintenance of these cells. Finally, we discuss the potential use of WS iPSCs for clinical applications.


Effect of different onlay systems on fracture resistance and failure pattern of endodontically treated mandibular molars restored with and without glass fiber posts.
To investigate the relationship between post and core build-up materials on the fracture resistance of endodontically treated teeth restored with different onlay restorations. 60 mandibular molars were endodontically treated and divided into three experimental groups that received one of the following onlay restorations: gold onlays, glass ceramic onlays (Empress I), or resin composite onlays (Gradia). Half of the specimens in each group received a fiber post (n=10). Two controls groups (n=10) were included: one group composed of sound mandibular molars, and the second group was composed of endodontically treated unrestored molars. Fracture tests were carried out by applying axial load using a universal loading machine until fracture. All fractured specimens were fractographically examined using a scanning electron microscope (SEM). Data were analyzed using two-way ANOVA and Tukey multiple comparison tests (alpha=0.05). Statistical analysis showed that restoration of endodontically treated teeth with gold onlays improved fracture resistance when compared to glass ceramic or resin composite onlays. The presence of a fiber post significantly improved (P<0.045) fracture resistance of gold onlays from 2271 to 2874N while it did not influence the performance of the other two groups. Fractographic analyses revealed that the presence of fiber post resulted in more restorable fractures due to better stress distribution of the applied load. All onlay systems resulted in significant improvement of the fracture resistance compared to unrestored teeth (711N) but neither of them resulted in restoring the fracture resistance to match that of sound teeth (3212 N).


Specific ethanol withdrawal seizures in genetically selected mice.
We are selectively breeding mice prone (WSP) and resistant (WSR) to ethanol withdrawal seizures assessed by handling induced convulsions (HIC). The possibility that differences between the lines in HIC scores are a result of differences in general CNS excitability not specific to ethanol withdrawal was examined. Using treatments which produce generalized seizures (electroconvulsive shock, strychnine, and flurothyl) and gamma amino-butyric acid (GABA) antagonists (picrotoxin, bicuculline, and pentylentetrazol), the ED50 for seizures was determined in the selected lines. In addition, the sensitivity of WSP and WSR mice to the anticonvulsant actions of ethanol against each treatment was determined. Neither the convulsant amperage 50 (CA50) for ECS nor the ED50 for any drug treatment differed for the selected lines. When ethanol (1.5 g/kg) was administered prior to ECS, there was a dramatic differential suppression of ECS in the lines: the CA50 of WSR mice was elevated 5-fold, whereas the CA50 of WSP mice increased only two fold. Ethanol pretreatment also elevated the ED50 for strychnine and flurothyl in WSR mice significantly more than WSP mice, but the line difference was smaller than for the anticonvulsant effect against ECS. The ED50s for the GABA antagonists were not different between the WSR and WSP lines after ethanol pretreatment. We conclude that genetic selection is producing lines of mice that differ specifically in the degree of seizure severity caused by withdrawal from ethanol physical dependence and not in generalized CNS excitability. An increased sensitivity to the anticonvulsant effects of ethanol against some convulsant treatments has appeared as a correlated response to selection in the WSR line.


Evaluation of long acting GLP1R/GCGR agonist in a DIO and biopsy-confirmed mouse model of NASH suggest a beneficial role of GLP-1/glucagon agonism in NASH patients.
The metabolic benefits of GLP-1 receptor (GLP-1R) agonists on glycemic and weight control are well established as therapy for type 2 diabetes and obesity. Glucagon's ability to increase energy expenditure is well described, and the combination of these mechanisms-of-actions has the potential to further lower hepatic steatosis in metabolic disorders and could therefore be attractive for the treatment for non-alcoholic steatohepatitis (NASH). Here, we have investigated the effects of a dual GLP-1/glucagon receptor agonist NN1177 on hepatic steatosis, fibrosis, and inflammation in a preclinical mouse model of NASH. Having observed strong effects on body weight loss in a pilot study with NN1177, we hypothesized that direct engagement of the hepatic glucagon receptor (GCGR) would result in a superior effect on steatosis and other liver related parameters as compared to the GLP-1R agonist semaglutide at equal body weight. Male C57Bl/6 mice were fed a diet high in trans-fat, fructose, and cholesterol (Diet-Induced Obese (DIO)-NASH) for 36 weeks. Following randomization based on the degree of fibrosis at baseline, mice were treated once daily with subcutaneous administration of a vehicle or three different doses of NN1177 or semaglutide for 8 weeks. Hepatic steatosis, inflammation and fibrosis were assessed by immunohistochemistry and morphometric analyses. Plasma levels of lipids and liver enzymes were determined, and hepatic gene expression was analyzed by RNA sequencing. NN1177 dose-dependently reduced body weight up to 22% compared to vehicle treatment. Plasma levels of ALT, a measure of liver injury, were reduced in all treatment groups with body weight loss. The dual agonist reduced hepatic steatosis to a greater extent than semaglutide at equal body weight loss, as demonstrated by three independent methods. Both the co-agonist and semaglutide significantly decreased histological markers of inflammation such as CD11b and Galectin-3, in addition to markers of hepatic stellate activation (αSMA) and fibrosis (Collagen I). Interestingly, the maximal beneficial effects on above mentioned clinically relevant endpoints of NN1177 treatment on hepatic health appear to be achieved with the middle dose tested. Administering the highest dose resulted in a further reduction of liver fat and accompanied by a massive induction in genes involved in oxidative phosphorylation and resulted in exaggerated body weight loss and a downregulation of a module of co-expressed genes involved in steroid hormone biology, bile secretion, and retinol and linoleic acid metabolism that are also downregulated due to NASH itself. These results indicate that, in a setting of overnutrition, the liver health benefits of activating the fasting-related metabolic pathways controlled by the glucagon receptor displays a bell-shaped curve. This observation is of interest to the scientific community, due to the high number of ongoing clinical trials attempting to leverage the positive effects of glucagon biology to improve metabolic health.


The role of osteoblasts in peri-prosthetic osteolysis.
Peri-prosthetic osteolysis and subsequent aseptic loosening is the most common reason for revising total hip replacements. Wear particles originating from the prosthetic components interact with multiple cell types in the peri-prosthetic region resulting in an inflammatory process that ultimately leads to peri-prosthetic bone loss. These cells include macrophages, osteoclasts, osteoblasts and fibroblasts. The majority of research in peri-prosthetic osteolysis has concentrated on the role played by osteoclasts and macrophages. The purpose of this review is to assess the role of the osteoblast in peri-prosthetic osteolysis. In peri-prosthetic osteolysis, wear particles may affect osteoblasts and contribute to the osteolytic process by two mechanisms. First, particles and metallic ions have been shown to inhibit the osteoblast in terms of its ability to secrete mineralised bone matrix, by reducing calcium deposition, alkaline phosphatase activity and its ability to proliferate. Secondly, particles and metallic ions have been shown to stimulate osteoblasts to produce pro inflammatory mediators in vitro. In vivo, these mediators have the potential to attract pro-inflammatory cells to the peri-prosthetic area and stimulate osteoclasts to absorb bone. Further research is needed to fully define the role of the osteoblast in peri-prosthetic osteolysis and to explore its potential role as a therapeutic target in this condition.


A Summary of the Inaugural WHO Classification of Pediatric Tumors: Transitioning from the Optical into the Molecular Era.
Pediatric tumors are uncommon, yet are the leading cause of cancer-related death in childhood. Tumor types, molecular characteristics, and pathogenesis are unique, often originating from a single genetic driver event. The specific diagnostic challenges of childhood tumors led to the development of the first World Health Organization (WHO) Classification of Pediatric Tumors. The classification is rooted in a multilayered approach, incorporating morphology, IHC, and molecular characteristics. The volume is organized according to organ sites and provides a single, state-of-the-art compendium of pediatric tumor types. A special emphasis was placed on "blastomas," which variably recapitulate the morphologic maturation of organs from which they originate. SIGNIFICANCE: In this review, we briefly summarize the main features and updates of each chapter of the inaugural WHO Classification of Pediatric Tumors, including its rapid transition from a mostly microscopic into a molecularly driven classification systematically taking recent discoveries in pediatric tumor genomics into account.


Characterization of two alkane hydroxylase genes from the marine hydrocarbonoclastic bacterium Alcanivorax borkumensis.
The marine gamma-Proteobacterium Alcanivorax borkumensis is highly specialized in the assimilation of aliphatic hydrocarbons, and makes up a large part of the biomass in oil-polluted marine environments. In addition to the previously identified alkane hydroxylase AlkB1, a second alkane hydroxylase (AlkB2) showing 65% identity to the Pseudomonas aeruginosa AlkB2 alkane hydroxylase was identified. Unlike alkB1, alkB2 is not flanked by genes involved in alkane metabolism. Heterologous expression of the A. borkumensis AP1 alkB1 and alkB2 genes showed that they encode functional alkane hydroxylases with substrate ranges similar to those of their P. putida and P. aeruginosa homologues. The transcription initiation sites and levels of the alkB1, alkB2 and alkS mRNA transcripts were determined. Expression of both alkB1 and alkB2 was induced by alkanes, but transcripts corresponding to alkB1 were much more abundant than those of alkB2. An inverted repeat similar to the binding site for the P. putida GPo1 transcriptional activator AlkS was present upstream of the promoters for alkB1 and alkB2, although that of alkB2 was less well conserved, and only the transcriptional fusion of promoter PalkB1 to the reporter gene lacZ efficiently responded to n-octane. Contrary to what has been found for the P. putida GPo1 alkane degradation pathway, expression of the A. borkumensis AP1 alkS gene was not induced by alkanes, and an AlkS binding site was not present upstream of the promoter for alkS. This indicates that, in spite of the clear similarities, the A. borkumensis alk-genes are regulated by a strategy different from that of the P. putida GPo1 alk genes.


Evaluation of pain in patients with oral squamous cell carcinoma.
In this study we have developed and tested a novel pain questionnaire to measure the pain experienced by patients with oral squamous cell carcinoma. The questionnaire consisted of 8 questions rated by the patient on a visual analog scale. Patients completed the questionnaire at the time of initial presentation before surgical treatment. None of the patients were taking analgesics. The responses were then scored and compiled with patient data and pathology reports. Of the 15 completed questionnaires, 14 patients reported some level of functional restriction from pain (mean, 46.6 +/- 25.2, scale of 0 to 100 mm). On average, patients experienced significantly higher function-related, rather than spontaneous, pain intensity and sharpness. Men (n = 8) had a significantly higher level of function-related pain intensity and sharpness than women had (n = 7). There was a strong correlation between nodal disease and increased levels of spontaneous intensity, sharpness, throbbing, and overall functional restriction. The results of this study indicate the heterogeneous nature and function dependence of oral cancer pain. The questionnaire we have developed in this study will allow for correlations between pain parameters and specific tumor biology in future studies.


Supporting evidence for PCB pollution threatening global killer whale population.
A recent Science report predicted the global killer whale population to collapse due to PCB pollution. Here we present empirical evidence, which supports and extends the reports' statement. In 2016, a neonate male killer whale stranded on the German island of Sylt. Neonatal attributes indicated an age of at least 3 days. The stomach contained ∼20 mL milk residue and no pathologies explaining the cause of death could be detected. Blubber samples presenting low lipid concentrations were analysed for persistent organic pollutants. Skin samples were collected for genotyping of the mitochondrial control region. The blubber PCB concentrations were very high [SPCBs, 225 mg/kg lipid weight (lw)], largely exceeding the PCB toxicity thresholds reported for the onset of immunosuppression [9 mg/kg lw ∑PCB] and for severe reproductive impairment [41 mg/kg lw ∑PCB] reported for marine mammals. Additionally, this individual showed equally high concentrations in p,p'-DDE [226 mg/kg lw], PBDEs [5 mg/kg lw] and liver mercury levels [1.1 μg/g dry weight dw]. These results suggest a high placental transfer of pollutants from mother to foetus. Consequently, blubber and plasma PCB concentrations and calf mortality rates are both high in primiparous females. With such high pollutant levels, this neonate had poor prerequisites for survival. The neonate belonged to Ecotype I (generalist feeder) and carried the mitochondrial haplotype 35 present in about 16% of the North Atlantic killer whale from or close to the North Sea. The relevance of this data becomes apparent in the UK West Coast Community, the UK's only residentorca population, which is currently composed of only eight individuals (each four males and females) and no calves have been reported over the last 19 years.Despite worldwide regulations, PCBs persist in the environment and remain a severe concern for killer whale populations, placing calves at high risk due to the mother-offspring PCB-transfer resulting in a high toxicological burden of the neonates.


An Efficient Capsule-based Network for 2D Left Ventricle Segmentation in Echocardiography Images.
The segmentation of cardiac chambers is essential for the clinical diagnosis and treatment of cardiovascular diseases. It is demonstrated that in cardiac disease, the left ventricle (LV) is extensively involved. Therefore, segmentation of the LV in echocardiographic images is critical for the precise evaluation of factors that influence cardiac function such as LV volume, ejection fraction, and LV mass. Although these measurements could be obtained by manual segmentation of the LV, it would be time-consuming and inaccurate because of the poor quality and low contrast of these images. Convolutional neural networks, commonly referred to as CNNs, have emerged as a highly favored deep learning technique for medical image segmentation. Despite their popularity, the pooling layers in CNNs ignore the spatial information and do not consider the part-whole hierarchy relationships. Furthermore, they require a large training dataset and a large number of parameters. Therefore, Capsule Networks are proposed to address the CNNs limitations. In this study, for the first time, an optimized capsule-based network for object segmentation called SegCaps is proposed to achieve accurate LV segmentation on echocardiography images applied to the CAMUS dataset. The result was compared against the standard 2D-UNet. The modified SegCaps and 2D-UNet achieved an average Dice similarity coefficient (DSC) of 84.48% and 83.28% on LV segmentation, respectively. The capabilities of the CapsNet led to an improvement of 1.44% in DSC with 92.77% fewer parameters than the U-Net. The results indicate that the proposed method leads to accurate and efficient LV segmentation.Clinical Relevance- From a clinical point of view, our findings lead to more precise evaluations of critical cardiac parameters, including ejection fraction as well as left ventricle volume at end-diastole and end-systole.


Dynamic chromatin accessibility landscapes of osteoblast differentiation and mineralization.
Bone acts as a self-healing organ, which undergoes continuous regeneration process that is tightly regulated by the cooperation of osteoclasts with the capability of bone resorption and osteoblasts with the capability of bone formation. Generally, bone marrow derived mesenchymal stem cells (BMSCs) differentiated to final osteoblasts have been considered as critical role in bone remodeling. In this regard, several transcription factors (TFs) whose binding sites are initially hidden deep within accessible chromatin that participate in modulating osteoblast differentiation and bone matrix mineralization. Then, it is necessary to explore further the dynamic changes about the epigenetic transcription machinery during osteoblastogenesis. Here, we performed the chromatin accessibility and transcriptomic landscape of osteoblast differentiation and mineralization by using transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-Seq). Our data found that global chromatin accessibility during osteoblastogenesis was extensively improved. Above this, it is shown that key target genes including Col6a3, Serpina3n, Ms4a4d, Lyz2, Phf11b and Grin3a were enriched in differential loci RNA-seq and ATAC-Seq peaks with continuous changed tendency during osteoblasts differentiation and mineralization. In addition, Analysis of Motif Enrichment (AME) was used to elucidate TFs which modulated these target genes. In this study, it was shown for the first time that these important TFs including MEF2A, PRRX1, Shox2 and HOXB13 could alter promoter accessibility of target genes during osteoblastogenesis. This helps us understand how TF binding motif accessibility influences osteoblast differentiation. In addition, it also suggests that modulating the chromatin accessibility of osteogenesis could be developed as the promising strategies to regulate bone regeneration.


[Can outpatient measures prevent inpatient admission?].
During the last decades the focus of psychiatric care has shifted from hospital to the "community". As the philosophy of deinstitutionalisation implies that community mental health care is preferable to hospital care and that treatment functions may be performed equally well or even better outside a hospital, one of the main objectives of community-based care consisted in preventing hospital readmission. Despite many objections readmission data and length of stay become most popular as outcome criteria in the evaluation of treatment measures. However, until today evaluative research has failed to demonstrate the overall effectiveness in preventing inpatient treatment. This is mainly due to the fact that the complexity of the research topic could not be adequately modelled and controlled in observational studies as the main source of information.


Malrotation and volvulus in infancy and childhood.
The subject of malrotation and midgut volvulus in infancy and childhood is reviewed from the perspective of experience with 138 patients evaluated in a published series and a further 82 cases seen since. Embryology, historical aspects, clinical presentation, investigation, surgery, and outcome are discussed. The diagnosis of malrotation and volvulus should always be kept in mind when assessing any infant or child with symptoms of vomiting and pain, particularly when the vomiting is bile-stained. The diagnosis cannot be excluded if diarrhea is present, when clinical findings are bland, or even with normal abdominal radiographs. A contrast meal and follow-through should be done and, if correctly interpreted, should be diagnostic. Ultrasound examination may be helpful but is not secure enough to exclude the diagnosis. Laparotomy or laparoscopy is the only way to be sure. Malrotation with its propensity for volvulus is truly a time bomb lying within.


Six-minute walk distance in healthy Singaporean adults cannot be predicted using reference equations derived from Caucasian populations.
The 6-min walk test (6MWT) is commonly used to assess the functional exercise capacity of individuals with cardiopulmonary disease. Recent studies have established regression equations to predict the 6-min walk distance (6MWD) in healthy Caucasian populations; however, regression equations have yet to be established for the Singaporean population. The aim of this study was to determine 6MWD in healthy Singaporeans and identify contributors to 6MWD in this population. We also compared measured 6MWD with predicted 6MWD from two regression equations derived in Caucasian subjects. Thirty-five healthy subjects (32 Chinese, 16 men) aged between 45 and 85 years performed three walking tests using a standardized protocol. 6MWD was defined as the greatest distance achieved from the three tests. Heart rate (HR) was recorded each minute during the 6MWT. Other measurements included age, height, leg length, smoking history and self-reported physical activity. 6MWD was 560 +/- 105 m and was not significantly different between men and women (P = 0.19). 6MWD was related to age (r = -0.36, P = 0.03), height (r = 0.35, P = 0.04), leg length (r = 0.38, P = 0.02) and the maximum HR achieved on the 6MWT when expressed as a percentage of the predicted maximum HR (%predHRmax, r = 0.73, P < 0.001). Stepwise multiple regression analysis showed that age, height, weight and %predHRmax were independent contributors (P < 0.01) to 6MWD, explaining 78% of the variance. Predicted 6MWD using regression equations derived from Caucasian subjects exceeded measured 6MWD by more than 75 m (P < 0.001). This is the first study to report 6MWD for healthy Singaporeans aged 45-85 years. The regression equation developed in this study explained 78% of the variance in 6MWD. Published equations derived from Caucasian subjects overestimate 6MWD in Singaporean Chinese.


Synthesis, structure, magnetic properties and biological activity of supramolecular copper(II) and nickel(II) complexes with a Schiff base ligand derived from vitamin B6.
Three new complexes of Cu(II) and Ni(II), [Cu(II)(H(2)pydmedpt)](2+)·2Cl(-) (1), [Ni(II)(H(2)pydmedpt)](2+)·2Cl(-) (2) and [Ni(II)(pydmedpt)(OH)](-)·K(+) (3) of the Schiff base ligand [H(2)pydmedpt](2+)·2Cl(-) were synthesized by the in situ reaction of pyridoxal (pyd), a vitamer of vitamin B(6), N,N-bis[3-aminopropyl]methylamine (medpt) and copper(II) acetate or nickel(II) acetate, respectively. The molecular structures of 1 and 2 were determined by single crystal X-ray diffraction studies. The structure of 3 in the solid state was inferred by elemental analysis, diffuse reflectance spectrum, variable temperature magnetic moment studies and DFT calculations. The binding of the Schiff base ligand to the metal centers involves two phenolato oxygens, two imine nitrogens and one amine nitrogen. The coordination geometry around Cu in 1 is distorted square pyramidal and that around the Ni atom in 2 is intermediate between square-pyramidal and trigonal-bipyramidal. In the crystals the compounds form supramolecular one dimensional chain structures stabilized by hydrogen bonding and π-π stacking interactions. Variable temperature magnetic moment data of 2 indicate the presence of a momomeric high spin Ni(II) centre in the complex. The solid state diffuse reflectance spectrum, conductance and elemental analysis suggest that 3 is a Ni(II) complex with a tetragonally distorted octahedral field, the sixth position being occupied by the oxygen atom of a hydroxyl group. The variable temperature magnetic moment of 3 indicates the presence of a ferromagnetic dinuclear species (29.2%) along with the major monomeric species, the intra-dimer exchange term J value being 14.3 cm(-1). The competitive binding of 1 and 2 with DNA was studied in the concentration range 40 to 400 μM, the apparent binding constants being K = 2.9 × 10(3) and 6.7 × 10(3) M(-1), respectively. Human Serum Albumin (HSA) binding studies were carried out at concentrations of 800-1000 μM and 400-500 μM for the complexes and HSA, respectively, in PBS buffer at pH 7.4. Complex 1 binds to HSA, while no binding is observed in case of 2, instead, the complex hydrolyses under the experimental conditions used and the resulting Ni(2+) ions bind with HSA.


[Molecular biological bases for adenovirus-induced syntheses in cells].
The latest data from literature concerning the peculiarities of the molecular structure of adenoviruseses and their reproduction in a cell are summarized. Analysis of experimental materials gives evidence that the regulation of adenovirus-induced syntheses in the infected cell takes place at the transcription and translation level; adenoviruses themselves can be used as a model for studying molecular mechanisms for reproduction of DNA-containing viruses.


[Optimization of method for detecting the activation of potassium channels in rat cardiac muscle cells].
To detect the phosphorylation of potassium channel protein (Kv1.2 and Kv1.5) in rat cardiac muscle cells accurately, we applied the combined method of immunoprecipitation and Western blot in this study. Compared with using Western blot alone, the combination of immunoprecipitation and Western blot displayed high sensitivity to detect the activation of potassium channel proteins. Because of its simplicity, quickness and reproducibility, we find that this method was promising for detecting the phosphorylation of Kv1.2 and Kv1.5 proteins or other potassium channel proteins in rat cardiac muscle cells.


Bioengineering a Single-Protein Junction.
Bioelectronics moves toward designing nanoscale electronic platforms that allow in vivo determinations. Such devices require interfacing complex biomolecular moieties as the sensing units to an electronic platform for signal transduction. Inevitably, a systematic design goes through a bottom-up understanding of the structurally related electrical signatures of the biomolecular circuit, which will ultimately lead us to tailor its electrical properties. Toward this aim, we show here the first example of bioengineered charge transport in a single-protein electrical contact. The results reveal that a single point-site mutation at the docking hydrophobic patch of a Cu-azurin causes minor structural distortion of the protein blue Cu site and a dramatic change in the charge transport regime of the single-protein contact, which goes from the classical Cu-mediated two-step transport in this system to a direct coherent tunneling. Our extensive spectroscopic studies and molecular-dynamics simulations show that the proteins' folding structures are preserved in the single-protein junction. The DFT-computed frontier orbital of the relevant protein segments suggests that the Cu center participation in each protein variant accounts for the different observed charge transport behavior. This work is a direct evidence of charge transport control in a protein backbone through external mutagenesis and a unique nanoscale platform to study structurally related biological electron transfer.


Reporting bias related to an environmental hazard.
During spring 1984, second and fifth grade schoolchildren living in three Haifa Bay areas on the eastern Mediterranean coast, with different levels of air pollution, were studied. The parents of these children filled out ATS-NHLI (American Thoracic Society and the National Heart and Lung Institute) health questionnaires and the children performed PFT (Pulmonary Function Tests). A trend of higher prevalence of most reported respiratory symptoms was found for schoolchildren growing up in the medium and high polluted areas as compared with the low pollution area. Logistic models fitted for the respiratory conditions that differed significantly among the three residential areas also included background variables that could be responsible for these differences. Relative risks for respiratory conditions calculated from these models were in the range of 1.38 and 1.81 for children from the polluted area as compared to 1.00 for the low polluted area. All the measured values of PFT were within the normal range, with no consistent reduction in PFT for any residential area. During spring 1989, seventh graders (second graders in 1984) were reexamined and a new cohort of fifth grade children was studied, using the same techniques as in 1984. A very significant rise in the prevalence of most reported respiratory symptoms and diseases was observed among both fifth and seventh grade schoolchildren in 1989 compared to 1984, especially in the low and medium polluted areas and less in the polluted area. Changes over time in PFT in the older cohort were similar in the three areas. PFT of fifth graders in 1984 and in 1989 were very similar. The most significant factor in logistic models fitted for the prevalence of respiratory conditions among the studied schoolchildren in 1989, was the subjective attitude of their parents towards the deleterious effects of air pollution on their children's health, and the subjective estimate of their children's exposure to pollution rather than measured exposure. A huge campaign carried out during the survey against the main polluters in the Haifa Bay area caused both public concern and apparently reporting bias.


Targeting glutamine dependence with DRP-104 inhibits proliferation and tumor growth of castration-resistant prostate cancer.
Prostate cancer (PCa) continues to be one of the leading causes of cancer deaths in men. While androgen deprivation therapy is initially effective, castration-resistant PCa (CRPC) often recurs and has limited treatment options. Our previous study identified glutamine metabolism to be critical for CRPC growth. The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON) blocks both carbon and nitrogen pathways but has dose-limiting toxicity. The prodrug DRP-104 is expected to be preferentially converted to DON in tumor cells to inhibit glutamine utilization with minimal toxicity. However, CRPC cells' susceptibility to DRP-104 remains unclear. Human PCa cell lines (LNCaP, LAPC4, C4-2/MDVR, PC-3, 22RV1, NCI-H660) were treated with DRP-104, and effects on proliferation and cell death were assessed. Unbiased metabolic profiling and isotope tracing evaluated the effects of DRP-104 on glutamine pathways. Efficacy of DRP-104 in vivo was evaluated in a mouse xenograft model of neuroendocrine PCa, NCI-H660. DRP-104 inhibited proliferation and induced apoptosis in CRPC cell lines. Metabolite profiling showed decreases in the tricarboxylic acid cycle and nucleotide synthesis metabolites. Glutamine isotope tracing confirmed the blockade of both carbon pathway and nitrogen pathways. DRP-104 treated CRPC cells were rescued by the addition of nucleosides. DRP-104 inhibited neuroendocrine PCa xenograft growth without detectable toxicity. The prodrug DRP-104 blocks glutamine carbon and nitrogen utilization, thereby inhibiting CRPC growth and inducing apoptosis. Targeting glutamine metabolism pathways with DRP-104 represents a promising therapeutic strategy for CRPC.