Outcome prediction of head and neck squamous cell carcinoma by MRI radiomic signatures.
Head and neck squamous cell carcinoma (HNSCC) shows a remarkable heterogeneity between tumors, which may be captured by a variety of quantitative features extracted from diagnostic images, termed radiomics. The aim of this study was to develop and validate MRI-based radiomic prognostic models in oral and oropharyngeal cancer. Native T1-weighted images of four independent, retrospective (2005-2013), patient cohorts (n = 102, n = 76, n = 89, and n = 56) were used to delineate primary tumors, and to extract 545 quantitative features from. Subsequently, redundancy filtering and factor analysis were performed to handle collinearity in the data. Next, radiomic prognostic models were trained and validated to predict overall survival (OS) and relapse-free survival (RFS). Radiomic features were compared to and combined with prognostic models based on standard clinical parameters. Performance was assessed by integrated area under the curve (iAUC). In oral cancer, the radiomic model showed an iAUC of 0.69 (OS) and 0.70 (RFS) in the validation cohort, whereas the iAUC in the oropharyngeal cancer validation cohort was 0.71 (OS) and 0.74 (RFS). By integration of radiomic and clinical variables, the most accurate models were defined (iAUC oral cavity, 0.72 (OS) and 0.74 (RFS); iAUC oropharynx, 0.81 (OS) and 0.78 (RFS)), and these combined models outperformed prognostic models based on standard clinical variables only (p < 0.001). MRI radiomics is feasible in HNSCC despite the known variability in MRI vendors and acquisition protocols, and radiomic features added information to prognostic models based on clinical parameters. • MRI radiomics can predict overall survival and relapse-free survival in oral and HPV-negative oropharyngeal cancer. • MRI radiomics provides additional prognostic information to known clinical variables, with the best performance of the combined models. • Variation in MRI vendors and acquisition protocols did not influence performance of radiomic prognostic models.


Go Grrrls: A Randomized Controlled Trial of a Gender-Specific Intervention to Reduce Sexual Risk Factors in Middle School Females.
Adolescent females continue to face health consequences associated with risky sexual behaviors such as unintended pregnancies and sexually transmitted diseases. The purpose of this study was to investigate the efficacy of a gender-specific intervention targeted to early adolescent females. This study used an intent to treat randomized clinical trial comparing a broad-based female empowerment curriculum with a dose-matched science and technology female leadership curriculum. The sample ( N = 801) was recruited from schools and was implemented in community-based settings mostly in an after school context. Assessments were conducted at baseline, postintervention, 6-, and 18-month follow-up time periods. Both groups in the study obtained good implementation and engagement. The average attendance rate was 81% of program sessions. There were significant differences between the two groups favoring the intervention group on measures of sexually transmitted disease knowledge and condom technical skills. On a measure of condom self-efficacy, there was a significant trend. At the postassessment, there was a significant difference on the intentions to reduce sexual risk behaviors. Both the intervention and control groups made gains on the self-assertive behavior scale. Gender-specific programs for early adolescent females can help reduce indicators that are related to sexual risk reduction. More long-term follow-up is needed to assess impact on sexual behaviors. Efforts directed at a younger population of females should continue to be researched for potential in reducing sexual risks.


Progression of gastritis to monoclonal B-cell lymphoma with resolution and recurrence following eradication of Helicobacter pylori.
To follow a patient with Helicobacter pylori-associated gastritis by performing serial endoscopic biopsies to observe the histologic progression of the gastritis to a monoclonal B-cell lymphoma with resolution and subsequent recurrence following eradication of H pylori organisms. A case report of a patient followed over 3 years. Characteristics of the gastric mucosa as determined by histologic and gene rearrangement studies on multiple random biopsies obtained serially before and after the eradication of H pylori organisms. A progression from H pylori-associated gastritis through lymphoid hyperplasia to a monoclonal B-cell lymphoma was observed. With the techniques used, a resolution of the lymphoma was observed on eradication of H pylori organisms, with a subsequent recurrence of the lymphoma 15 months later, despite the absence of H pylori organisms. The observations made of this patient support an association between H pylori and the development of a gastric monoclonal B-cell lymphoma. This lesion appears to develop in the setting of gastritis and progresses through lymphoid hyperplasia followed subsequently by the lymphoma. We speculate that this process is initially antigen driven by the organism and may subsequently become autonomous as genetic damage is accumulated, so that eradication of H pylori organisms will lead to regression of the lesion to the degree that there are autonomously proliferating cells present.


[Links in the histamine metabolism in the brain of rats with sequential exposure to low- and high-pressure oxygen].
Histamine content and diamine oxidase activity in rat brain under hyperbaric oxygenation have been studied. Under 0,3 MPa histamine level decreases in brain of more sensitive rats, but it does not change in brain of more resistant animals in comparison with the control ones. High oxygen pressure (0,7 MPa) causes a significant increase of histamine concentration. Diamine oxidase activity decreases under hyperoxia. Under the consequent action of high and low pressure (0,3 MPa during 1 h and 0,7 MPa) convulsions in rats begin later and alterations of histamine content in brain are less than under 0,7 MPa oxygen action only. The role of histamine at compensate reaction and cause of increasing resistance of animals to hyperoxia are discussed.


The influence of quantal content on the time course of the endplate current in frogs.
The aim of this study was to find out whether control and facilitated endplate current (EPC) of a curarized frog nerve-muscle preparation stimulated with paired impulses decay at the same time constant. The experiments revealed that the decay of the greater second EPC was slower in nearly half of the cases. This half of the results suggests that a larger quantity of the released transmitter and, consequently, a higher density of open channels promote a cooperative effect among them. The end effect can be a longer mean lifetime of open acetylcholine channels. In the other half of the experiments, the mean lifetime of open channels seems to be independent of the agonist concentration.


Mice transgenic for an expanded CAG repeat in the Huntington's disease gene develop diabetes.
The autosomal dominant neurological syndrome of Huntington's disease has been modeled in transgenic mice by the expression of a portion of the human huntingtin gene together with 140 CAG repeats (the R6/2 strain). The mice develop progressive chorea with onset at approximately 9 weeks of age and with death at approximately 13 weeks. Associated symptoms include weight loss and polyuria in the absence of eating or drinking deficits. We have found that these mice have insulin-responsive diabetes. Fasting glucose was 211 + 19 mg/dl in R6/2 mice compared with 93 + 5 mg/dl in C57/B6 controls (n = 12, both groups; P < 0.01). Administration of insulin intraperitoneally led to a reduction in blood glucose. At 12.5 weeks, animals were killed and pancreas weighed and analyzed for insulin and glucagon. Pancreatic mass in R6/2 mice was the same as controls, and islets appeared normal in morphology without lymphocytic infiltration. Immunohistochemical staining showed dramatic reductions in glucagon in the alpha-cells and in insulin in the beta-cells. Direct tissue assays showed glucagon and insulin content were reduced to only 10 and 15% of controls, respectively. Diabetes has been reported as being more common in Huntington's disease and other triplet repeat disorders. The R6/2 mouse should prove useful for elucidating the mechanism of diabetes in these genetic diseases.


Complex urban environments provide Apis mellifera with a richer plant forage than suburban and more rural landscapes.
Growth in the global development of cities, and increasing public interest in beekeeping, has led to increase in the numbers of urban apiaries. Towns and cities can provide an excellent diet for managed bees, with a diverse range of nectar and pollen available throughout a long flowering season, and are often more ecologically diverse than the surrounding rural environments. Accessible urban honeybee hives are a valuable research resource to gain insights into the diet and ecology of wild pollinators in urban settings. We used DNA metabarcoding of the rbcL and ITS2 gene regions to characterize the pollen community in Apis mellifera honey, inferring the floral diet, from 14 hives across an urban gradient around Greater Manchester, UK. We found that the proportion of urban land around a hive is significantly associated with an increase in the diversity of plants foraged and that invasive and non-native plants appear to play a critical role in the sustenance of urban bees, alongside native plant species. The proportion of improved grassland, typical of suburban lawns and livestock farms, is significantly associated with decreases in the diversity of plant pollen found in honey samples. These findings are relevant to urban landscape developers motivated to encourage biodiversity and bee persistence, in line with global bio-food security agendas.


The impact of virtual simulation on the recognition and response to the rapidly deteriorating patient among undergraduate nursing students.
A major patient safety challenge is recognition and response to deteriorating patients since early warning signs are often not detected in a timely manner. Nursing students typically learn the skills for early identification through clinical placement, but clinical placements are not guaranteed to provide exposure to deteriorating patients. Nursing students require practice with emergency scenarios to develop their competency and confidence to act in this area. This study aimed to explore the impact of a virtual simulation intervention on the recognition and response to the rapidly deteriorating patient among undergraduate nursing students. A mixed methods study involving a quasi-experimental pre/post design and focus groups. The participants were third or final year undergraduate nursing students from five university sites across four countries (Canada, England, Scotland and Australia, n = 88). Students were randomly assigned to a treatment or control group. The treatment group received a virtual simulation intervention and participated in a focus group. The virtual simulation intervention had a significant effect on improving nursing student knowledge and clinical self-efficacy in the recognition and response to the rapidly deteriorating patient. Students reported that the virtual simulations decreased anxiety, helped them prioritize, filled gaps in their learning, and encouraged autonomous learning within a safe 'low risk' environment. Virtual simulation is an effective strategy for improving knowledge and confidence in recognizing and responding to the rapidly deteriorating patient among undergraduate nursing students.


Three-Patch Reconstruction of Hourglass Supravalvar Pulmonary Artery Stenosis Mid-Term Results.
Some patients with pulmonary stenosis present with a complex multilevel disease that involves the valve, the leaflets, and the sinotubular junction (STJ) forming an hourglass appearance. We herein report the mid-term results of our experience with the reconstruction of the supravalvar narrowing using three pericardial patches. Retrospective analysis of patient charts and echocardiography studies of patients who underwent three-patch reconstruction of the pulmonary valve (PV) from 2013 to 2022. After PV transection distal to STJ, vertical incisions into the sinuses were performed, and leaflets were trimmed and thinned. The three sinuses were augmented using three pericardial patches. Nineteen patients underwent repair of hourglass supravalvar pulmonary stenosis. Mean weight at surgery was 9.4 kg (median 7.2, range 4.7-35); 16 patients underwent previous catheterization with unsuccessful balloon dilatation of the PV (13 pts.). Preoperative aortic/pulmonary annulus ratio was 1.02 (median 1, range 0.89-1.25). After surgery, gradients across the PV were significantly reduced (94 ± 26 vs 29 ± 9 mm Hg, P = .02). Postoperatively, 14 patients had mild or no pulmonary insufficiency (PI) and five had mild to moderate PI. At a mean follow-up of 71 months (median 78 months, range 8-137), gradients continued to decrease (29 ± 9 vs 15 ± 5 mm Hg, P < .001). The three-patch technique for the repair of supravalvar pulmonary stenosis is simple, reproducible, and achieves excellent and long-standing relief of the right ventricular outflow tract gradient.


A pilot study evaluating a peer led and professional led physical activity intervention with blue-collar employees.
To measure the effect of a physical activity intervention, based on social cognitive theory, delivered by a peer and a professional leader. Quasi-experimental. Three locations at a large Mid-Western railroad. One hundred and forty-eight skilled labor employees participated: one hundred and twenty completed the study. Self-reported energy expenditure, self-efficacy and stages of change. ANOVA and categorical analysis using rates and proportions were used for evaluation. The peer group had a non-significant short-term increase in energy expenditure of 3%, which returned to baseline post intervention. The professional and control groups showed a non-significant decrease in energy expenditure of 5% and 9%, respectively. The peer (p < 0.002) and professional groups (p < 0.004) showed significant increases in average stages scores. The peer group maintained increases over time (p < 0.001). The peer and professional led groups showed a 54% and 24% increase in the number of employees reporting regular physical activity over time, respectively. The peer group also showed positive trends in self-efficacy. The peer intervention enhanced self-efficacy and self-reported physical activity. A job layoff at the professional led site confounded comparisons between locations. Employees reported high energy expenditure and high BMI values, suggesting that a weight management intervention may be more appropriate and appealing in this population.


Identifying Cancer Patients at Risk for Heart Failure Using Machine Learning Methods.
Cardiotoxicity related to cancer therapies has become a serious issue, diminishing cancer treatment outcomes and quality of life. Early detection of cancer patients at risk for cardiotoxicity before cardiotoxic treatments and providing preventive measures are potential solutions to improve cancer patients' quality of life. This study focuses on predicting the development of heart failure in cancer patients after cancer diagnoses using historical electronic health record (EHR) data. We examined four machine learning algorithms using 143,199 cancer patients from the University of Florida Health (UF Health) Integrated Data Repository (IDR). We identified a total number of 1,958 qualified cases and matched them to 15,488 controls by gender, age, race, and major cancer type. Two feature encoding strategies were compared to encode variables as machine learning features. The gradient boosting (GB) based model achieved the best AUC score of 0.9077 (with a sensitivity of 0.8520 and a specificity of 0.8138), outperforming other machine learning methods. We also looked into the subgroup of cancer patients with exposure to chemotherapy drugs and observed a lower specificity score (0.7089). The experimental results show that machine learning methods are able to capture clinical factors that are known to be associated with heart failure and that it is feasible to use machine learning methods to identify cancer patients at risk for cancer therapy-related heart failure.


Knock-in mice with a chimeric human/murine p53 gene develop normally and show wild-type p53 responses to DNA damaging agents: a new biomedical research tool.
The high prevalence and great diversity of p53 tumor suppressor gene mutations in human tumors call for development of therapeutic molecules that rescue function of aberrant p53 protein. P53 mutations also offer new approaches to the study of the origins of mutations in human cancer. An experimental mouse model with a genetically modified but normal functioning p53 gene harboring the human rather than the murine core domain, would be of considerable benefit to research on both cancer therapeutics and etiology; however, it is uncertain whether such mice would permit biological functions of p53 to be retained. Using a Cre/lox P gene-targeting approach, we have constructed a human p53 knock-in (hupki) mouse strain in which exons 4-9 of the endogenous mouse p53 allele were replaced with the homologous, normal human p53 gene sequence. The chimeric p53 allele (p53(KI)) is properly spliced, transcribed in various tissues at levels equivalent to wild-type mice, and yields cDNA with the anticipated sequence, that is, with a core domain matching that of humans. The hupki p53 protein binds to p53 consensus sequences in gel mobility shift assays and accumulates in the nucleus of hupki fibroblasts in response to UV irradiation, as is characteristic of wild-type p53. Induction of various p53-regulated genes in spleen of gamma-irradiated homozygous hupki mice (p53(KI/KI)), and the kinetics of p53-dependent apoptosis in thymocytes are similar to results with wild-type (p53(+/+)) mice, further indicating normal p53 pathway function in the hupki strain. The mice are phenotypically normal and do not develop spontaneous tumors at an early age, in contrast to knock-out (p53(-/-)) strains with a defective p53 gene. The chimeric (p53(KI)) allele thus appears to provide a biological equivalent to the endogenous murine (p53(+)) gene. This strain is a unique tool for examining in vivo spontaneous and induced mutations in human p53 gene sequences for comparison with published human tumor p53 mutation spectra. In addition, the hupki strain paves the way for mouse models in pre-clinical testing of pharmaceuticals designed to modulate DNA-binding activity of human p53.


Potential dopamine prodrug-loaded liposomes: preparation, characterization, and in vitro stability studies.
Dopamine delivery to the central nervous system (CNS) undergoes the permeability limitations of the blood-brain barrier (BBB). Condensation of dopamine with neutral amino acids could afford potential prodrugs able to interact with the BBB endogenous transporters and easily enter the brain. To improve the bioavailability of the dopamine prodrug, 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (DOPH), it was encapsulated in unilamellar liposomes of dimiristoylphosphatidylcholine (DMPC) and cholesterol. Vesicles were characterized by dynamic light scattering in order to evaluate their dimensions and vesicle stability, by zeta-potential measurements, by means of electronic microscopy after freeze-fracture and differential scanning calorimetry. The influence of vesicle composition on DOPH chemical and enzymatic stability was also evaluated. The formulated liposome suspensions were found to be stable, monodisperse systems with a negative zeta potential. From the obtained results, it is possible to conclude that, in studied samples, DOPH inclusion in liposomes offers the possibility of preventing photodegradation and of enhancing in vitro plasma stability. These studies suggest the potential of these formulations as a method to prevent DOPH chemical degradation and enzymatic metabolism.


Structure, dynamics and stability of the smallest and most complex 71 protein knot.
Proteins can spontaneously tie a variety of intricate topological knots through twisting and threading of the polypeptide chains. Recently developed artificial intelligence algorithms have predicted several new classes of topological knotted proteins, but the predictions remain to be authenticated experimentally. Here, we showed by X-ray crystallography and solution state NMR spectroscopy that Q9PR55, an 89-residue protein from Ureaplasma urealyticum, possesses a novel 71 knotted topology that is accurately predicted by AlphaFold 2, except for the flexible N-terminus. Q9PR55 is monomeric in solution, making it the smallest and most complex knotted protein known to date. In addition to its exceptional chemical stability against urea-induced unfolding, Q9PR55 is remarkably robust to resist the mechanical unfolding-coupled proteolysis by a bacterial proteasome, ClpXP. Our results suggest that the mechanical resistance against pulling-induced unfolding is determined by the complexity of the knotted topology rather than the size of the molecule.


Key factors in planning and implementing interprofessional education in health care settings.
Interprofessional education (IPE) is regarded by many health care practitioners (i.e., nurses, occupational therapists, physicians), educators, and policy makers as an important activity to enhance the quality of teamwork and patient care. While the focus on developing an evidence basis for IPE has demonstrated the potential value of IPE for improving collaboration and patient outcomes, exploration of key concepts that underpin IPE has been overlooked. In this commentary, we aim to begin addressing this oversight by identifying and discussing key conceptual factors that are critical for the planning and implementation of IPE. We draw upon our prior IPE curricula development and research experiences, as well as the published literature, to argue that seven interconnecting learner-focused, faculty-focused, and organization-focused factors are key to the successful planning and implementation of IPE. We also argue that IPE planners need to be cognizant of all seven factors and how they interact with one another to help ensure they maximize success in their work.


Organellar genome copy number variation and integrity during moderate maturation of roots and leaves of maize seedlings.
Little information is available about organellar genome copy numbers and integrity in plant roots, although it was reported recently that the plastid and mitochondrial genomes were damaged under light, resulting in non-functional fragments in green seedling leaves in a maize line. In the present study, we investigated organellar genome copy numbers and integrity, after assessing the cellular ploidy, in seedling leaves and roots of two elite maize (Zea mays) cultivars using both long-fragment polymerase chain reaction (long-PCR) and real-time quantitative polymerase chain reaction (qPCR, a type of short-PCR). Since maize leaf and root cells are mainly diploid according to chromosome number counting and the literature, the DNA amount ratio between the organellar genomes and the nuclear genome could be used to estimate average organellar genome copy numbers per cell. In the present study, both long-PCR and qPCR analyses found that green leaves had dramatically more plastid DNA and less mitochondrial DNA than roots had in both cultivars. The similarity in results from long-PCR and qPCR suggests that green leaves and roots during moderate maturation have largely intact plastid and mitochondrial genomes. The high resolution of qPCR led to the detection of an increase in copies in the plastid genome and a decrease in copies in the analyzed mitochondrial sub-genomes during the moderate maturation of seedling leaves and roots. These results suggest that green seedling leaves and roots of these two maize cultivars during moderate maturation had essentially intact organellar genomes, an increased copy number of the plastid genome, and decreased copy numbers of certain mitochondrial sub-genomes.


Dual targeting, a new strategy for novel PARP inhibitor discovery.
As a hallmark for cancer treatment, PARP inhibitors can effectively kill tumor cells with a mechanism termed as synthetic lethality, and are used to treat various cancers including ovarian, breast, prostate, pancreatic and others with DNA repair defects. However, along with the clinical trials progressing, the limitations of PARP-1 inhibitors became apparent such as limited activity and indications. Studies have shown that a molecule that is able to simultaneously restrict two or more targets involving in tumors is more effective in preventing and treating cancers due to the enhancing synergies. In order to make up for the shortcomings of PARP inhibitors, reduce the development cost and overcome the pharmacokinetic defects, multiple works were carried out to construct dual targeting PARP inhibitors for cancer therapy. Herein, they were summarized briefly.


Why good thoughts block better ones: the mechanism of the pernicious Einstellung (set) effect.
The Einstellung (set) effect occurs when the first idea that comes to mind, triggered by familiar features of a problem, prevents a better solution being found. It has been shown to affect both people facing novel problems and experts within their field of expertise. We show that it works by influencing mechanisms that determine what information is attended to. Having found one solution, expert chess players reported that they were looking for a better one. But their eye movements showed that they continued to look at features of the problem related to the solution they had already thought of. The mechanism which allows the first schema activated by familiar aspects of a problem to control the subsequent direction of attention may contribute to a wide range of biases both in everyday and expert thought - from confirmation bias in hypothesis testing to the tendency of scientists to ignore results that do not fit their favoured theories.


App-Controlled Treatment Monitoring and Support for Patients With Head and Neck Cancer Undergoing Radiotherapy: Results From a Prospective Randomized Controlled Trial.
Head and neck cancers (HNCs) are very common malignancies, and treatment often requires multimodal approaches, including radiotherapy and chemotherapy. Patients with HNC often display a high symptom burden, both due to the disease itself and the adverse effects of the multimodal therapy. Close telemonitoring of symptoms and quality of life during the course of treatment may help to identify those patients requiring early medical support. The App-Controlled Treatment Monitoring and Support for Patients With Head and Neck Cancer (APCOT) trial aimed to investigate the feasibility of integrating electronic patient-reported outcomes (ePROs) in the treatment surveillance pathway of patients with HNC during the course of their radiotherapy. Additionally, the influence of app-based ePRO monitoring on global and disease-specific quality of life and patient satisfaction with treatment was assessed. Patients undergoing radiotherapy for histologically proven HNCs at the Department of Radiation Oncology, University Medical Center Freiburg, Germany, were enrolled in this trial and monitored by weekly physician appointments. Patients were randomized between additional ePRO monitoring on each treatment day or standard-of-care monitoring. Feasibility of ePRO monitoring was defined as ≥80% of enrolled patients answering ≥80% of their daily app-based questions. Quality of life and patient satisfaction were assessed by the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30), the head and neck cancer module (H&N35), and the validated Patient Satisfaction Questionnaire Short Form (PSQ-18) at the completion of treatment and compared between trial arms. A total of 100 patients were enrolled in this trial, and 93 patients were evaluable. All patients (100%) in the experimental arm answered ≥80% of the ePRO questions during treatment, reaching the predefined threshold for the feasibility of ePRO monitoring (P<.001 in the binomial test). No clinical or patient-specific factor was found to influence feasibility. Global health and most domains of the general quality of life were comparable between trial arms, but an increased HNC-specific symptom burden was reported by patients undergoing ePRO surveillance. ePRO monitoring resulted in improved patient satisfaction regarding interpersonal manners (P=.01), financial aspects (P=.01), and time spent with a doctor (P=.01). This trial demonstrated the feasibility of incorporating daily app-based ePRO surveillance for patients with HNC undergoing radiotherapy. Our data, for the first time, demonstrate that telemonitoring in this setting led to increased reporting of HNC-specific symptom burden and significantly improved several domains of patient satisfaction. Further analyses are needed to assess whether our findings hold true outside the context of a clinical trial. German Clinical Trials Register DRKS00020491; https://drks.de/search/en/trial/DRKS00020491.


Regional comparisons of child abuse and related variables in the United States.
The objective of this article is to familiarize the health care professional with 1990 national data on child abuse and to review some of the trends reported in the literature. The United States was divided into Northeast, Midwest, South, and West. Data were collected, analyzed, and transformed to calculate the incidence and types of abuse reported by region. Variables of interest were income, marital status, perpetrator, age of victim, and drug use by region. To determine significant differences among regions for each type of abuse and related variable, frequency distributions were calculated and chi-squared tests were used. State data summaries were measured for correlation analysis. The West was highest in reported incidence of child abuse (5.9%) and, specifically, physical abuse (36.7%). California reported 55% of the physical abuse in the West. In all regions, neglect and physical maltreatment were reported more than sexual and emotional abuse. The incidence of neglect in the south (52.8%) was greater than in any other region and did not correlate to income in this region. Early detection of child abuse can aid in preventing fatalities. This information should increase awareness of child abuse and result in an increase in reporting if abuse is suspected.


Prostatodynia in United Nations peacekeeping forces in Haiti.
Prostatodynia is a clinical entity associated with voiding symptoms and pelvic pain suggestive of prostatitis but with a normal prostate examination and without evidence of inflammation or infection in expressed prostatic secretions. The problem tends to be chronic and is vexing in its management. Although thought to be a common condition, prevalence data are generally lacking. From June to October 1995, the U.S. Army's 86th Combat Support Hospital provided medical support to a multinational United Nations peacekeeping force in Haiti. Patients diagnosed with prostatodynia were more common (13 cases) than men with other urologic problems (urolithiasis, 6 cases; urinary tract infection, 6 cases; scrotal abscess/mass, 2 cases; epididymitis, 1 case). Patients tended to be young (mean age 29.8), had multiple visits, failed to respond to multiple courses of antibiotics for presumed "prostatitis," and denied recent sexual relations. Some patients reported having had similar symptoms on prolonged separation from their spouses in the past that resolved with resumption of normal intercourse. Masturbation, however, had no impact on symptoms and was painful in some individuals. Terazosin, an alpha-antagonist, and stress-reduction therapy led to improvement in some patients' symptoms. A discussion of these retrospective findings in light of what is known about the possible etiologies and treatment of prostatodynia is presented. Prostatodynia appears to be a common problem in deployed troops and can lead to frequent use of medical services. Physicians supporting long deployments need to be aware of this entity.


Low-temperature degradation of a Y-TZP ceramic after surface treatments.
The purpose of this study was to evaluate the influence of zirconia surface treatments on low-temperature degradation (LTD). Disc-shaped specimens were subjected to one of four surface treatments, denoted as C (control-no surface treatment), Si (air abrasion with 30 µm silica-modified alumina particles), Al (air abrasion with 30 µm alumina particles), and Gr (grinding with 120 grit diamond discs). Half of the samples were submitted to autoclave treatment for 12 h (127°C, 1.5 bar). Samples were characterized by x-ray diffraction and profilometer analysis and were subjected to biaxial flexural strength test. All of the groups exhibited an increase in the amount of monoclinic phase (m-phase) after LTD. The t→m transformation was remarkable for the specimens from the C group, which also exhibited a significant increase in strength. The Gr group also exhibited an increase in strength but lower initial roughness, which probably suppressed LTD on the zirconia surface. The specimens subjected to air abrasion exhibited higher initial amounts of m-phase and a small increase in m-phase after LTD; the strength was not affected in these groups. The effects of LTD were different with each surface treatment applied. Apparently, LTD may be suppressed by smoother surfaces or the presence of an initial amount of m-phase on zirconia surface.


Feasibility and Utility of a Pilot Peer Education Program to Improve Patient Engagement in Lupus Clinical Trials: Implementation and Evaluation in a Multisite Model Within a Lupus Clinical Trials Network.
To assess outcomes related to Lupus Therapeutics' Patient Advocates for Lupus Studies (LT-PALS), a peer-to-peer lupus clinical trial (LCT) education program designed to improve representation of diverse groups in LCTs. Patients with lupus and clinical trial participation experience were trained as peer educators (PALs) providing trial-agnostic education to trial-naive patients with lupus. We used a two-arm, randomized pretest/posttest study design to evaluate outcomes related to LCT participation: knowledge, attitudes, self-efficacy, and intentions to participate in an LCT. Five academic medical centers piloted the program. The intervention group (IG) individually received peer-to-peer education sessions with trained PALs, primarily via telephone; the control group (CG) received a 3-week waiting period. We conducted within/between-group t-tests and multiple linear regressions with posttest scores as dependent variables and participation in LT-PALS as the exposure variable. The sample (n = 136) included 64 IG and 72 CG participants, with 67.7% identifying as Black. At posttest, IG participants had higher knowledge (P < 0.01) scores than the CG participants. Regression models controlling for participant characteristics showed higher IG posttest scores for knowledge (P < 0.001) and intentions (P < 0.05). From pretest to 3-month follow-up, IG self-efficacy scores increased (P < 0.01). About half (46.9%) of IG participants reported engagement with an LCT at 1-year follow-up. Black and Hispanic participants rated higher overall program satisfaction compared with White (P < 0.01) and non-Hispanic (P < 0.05) participants. Findings demonstrated feasibility of LT-PALS and showed promise in increasing engagement from groups underrepresented in LCTs.


Substrate specificity of the expressed carotenoid 3,4-desaturase from Rubrivivax gelatinosus reveals the detailed reaction sequence to spheroidene and spirilloxanthin.
Carotenoid biosynthesis in the photosynthetic bacterium Rubrivivax gelatinosus leads to the formation of hydroxyspheroidene and spirilloxanthin as the products of a branched pathway. In this study we investigated the role of the desaturase encoded by crtD which catalyses the introduction of C-3,4 double bonds into acyclic carotenoids. The desaturase was expressed in Escherichia coli, and the activity and the substrate specificity of the enzyme were evaluated in vitro by application of structurally different carotenoids. The results indicate that the enzyme is a 3,4-desaturase that converts 1-hydroxy carotenoids. The 3,4-desaturation reaction can only occur with mono-1-hydroxy carotenoids at a psi-end group or with 1,1'-dihydroxy derivatives carrying a 3',4'-double bond. In addition, 1-HO-zeta-carotene could also be converted by the desaturase. Enzyme kinetic studies showed a substrate preference of 1-HO-neurosporene over 1-HO-lycopene. Consequences from the biochemical data for the reaction sequence of hydroxyspheroidene and spirilloxanthin formation and the interconnection of both branches are discussed.


The impact of Drinking in the Dark (DID) procedural manipulations on ethanol intake in High Drinking in the Dark (HDID) mice.
The High Drinking in the Dark mouse lines (HDID-1 and HDID-2) were selectively bred to achieve high blood ethanol concentrations (BECs) in the Drinking in the Dark (DID) task, a widely used model of binge-like intake of 20% ethanol. There are several components that differentiate DID from other animal models of ethanol intake: time of day of testing, length of ethanol access, single-bottle access, and individual housing. Here, we sought to determine how some of these individual factors contribute to the high ethanol intake observed in HDID mice. HDID-1, HDID-2, and non-selected HS/NPT mice were tested in a series of DID experiments where one of the following factors was manipulated: length of ethanol access, fluid choice, number of ethanol bottles, and housing condition. We observed that 1) HDID mice achieve intoxicating BECs in DID, even when they are group-housed; 2) HDID mice continue to show elevated ethanol intake relative to HS/NPT mice during an extended access session, but this is most apparent during the first 4 h of access; and 3) offering a water choice during DID prevents elevated intake in the HDID-1 mice, but not necessarily in HDID-2 mice. Together, these results suggest that the lack of choice in the DID paradigm, together with the length of ethanol access, are important factors contributing to elevated ethanol intake in the HDID mice. These results further suggest important differences between the HDID lines in response to procedural manipulations of housing condition and ethanol bottle number in the DID paradigm, highlighting the distinct characteristics that each of these lines possess, despite being selectively bred for the same phenotype.


Early work as a source of developmental discontinuity during the transition to adulthood.
From a developmental perspective, work has been considered as both a deleterious and salutary experience. According to one prominent view, part-time work places adolescents at risk because it limits participation in more developmentally beneficial activities and confronts them with stressors for which they are not yet ready. If this were the case, teenage part-time work would be "stress sensitizing," lowering thresholds of reactivity to subsequent stressors and increasing the risk of poor young-adult mental health. As a result, early work experience could interfere with adequate preparation for adulthood. A more optimistic perspective, shared by some social scientists and most parents, is that employment for the young person signifies progress in moving toward adulthood and promotes adaptation to the work environment. Challenges at work are considered to be "steeling," fostering coping resources that alleviate the detrimental effects of subsequent stressors, especially those encountered in the workplace. These processes would promote resilience and psychological well-being in early adulthood. This research examines these alternatives, using data from the Youth Development Study (1988--2000) covering the period from adolescence (age 14-15) to early adulthood (age 26-27). The analysis indicates that the character of their teenage work experience is a source of resilience as young adults make the transition from school to work.


Results of a phase 2, multicenter, single-arm, open-label study of lenalidomide in pediatric patients with relapsed or refractory acute myeloid leukemia.
Outcomes after relapse remain poor in pediatric patients with acute myeloid leukemia (AML), and new therapeutic approaches are needed. Lenalidomide has demonstrated activity in adults with lower risk myelodysplastic syndromes and older adults with relapsed or refractory (R/R) AML. In this phase 2 study (NCT02538965), pediatric patients with R/R AML who received two or more prior therapies were treated with lenalidomide (starting dose 2 mg/kg/day on days 1-21 of each 28-day cycle) for a maximum of 12 cycles. The primary endpoint was rate of complete response (CR) and CR with incomplete blood count recovery (CRi) within the first four cycles. Seventeen patients enrolled and received one or more dose of lenalidomide. Median age was 12 years (range 5-18 years), median white blood cell count was 3.7 × 109 /L, and median peripheral blood blast count was 1.0 × 109 /L. One patient (5.9%) with a complex karyotype including del(5q) achieved CRi after two cycles of lenalidomide. This responder proceeded to a second hematopoietic stem cell transplantation and has remained without evidence of disease for 3 years. All patients experienced one or more of grades 3-4 treatment-emergent adverse event (TEAE). The most common grades 3-4 TEAEs were thrombocytopenia (58.8%), febrile neutropenia (47.1%), anemia (41.2%), and hypokalemia (41.2%). In this population of pediatric patients with R/R AML, safety data were consistent with the known safety profile of lenalidomide. As only one patient responded, further evaluation of lenalidomide at the dose and schedule studied is not warranted in pediatric AML, with the possible exception of patients with del(5q).


A constructivist-based proposal for bioinformatics teaching practices during lockdown.
The Coronavirus Disease 2019 (COVID-19) outbreaks have caused universities all across the globe to close their campuses and forced them to initiate online teaching. This article reviews the pedagogical foundations for developing effective distance education practices, starting from the assumption that promoting autonomous thinking is an essential element to guarantee full citizenship in a democracy and for moral decision-making in situations of rapid change, which has become a pressing need in the context of a pandemic. In addition, the main obstacles related to this new context are identified, and solutions are proposed according to the existing bibliography in learning sciences.


How do non-physician clinicians respond to advanced cancer patients' negative expressions of emotions?
Patients with advanced cancer often experience negative emotion; clinicians' empathic responses can alleviate patient distress. Much is known about how physicians respond to patient emotion; less is known about non-physician clinicians. Given that oncology care is increasingly provided by an interdisciplinary team, it is important to know more about how patients with advanced cancer express emotions to non-physician clinicians (NPCs) and how NPCs respond to those empathic opportunities. We audio recorded conversations between non-physician clinicians and patients with advanced cancer. We analyzed 45 conversations between patients and oncology physician assistants, nurse practitioners, and nurse clinicians in which patients or their loved ones expressed at least one negative emotion to the NPC (i.e., an empathic opportunity). Empathic opportunities were coded three ways: type of emotion (anger, sadness, or fear), severity of emotion (least, moderate, or most severe), and NPC response to emotion (not empathic, on-topic medical response, and empathic response). We identified 103 empathic opportunities presented to 25 different NPCs during 45 visits. Approximately half of the empathic opportunities contained anger (53%), followed by sadness (25%) and fear (21%). The majority of emotions expressed were moderately severe (73%), followed by most severe (16%), and least severe (12%). The severity of emotions presented was not found to be statistically different between types of NPCs. NPCs responded to empathic opportunities with empathic statements 30% of the time. Additionally, 40% of the time, NPCs responded to empathic opportunities with on-topic, medical explanations and 30% of the responses were not empathic. Patients expressed emotional concerns to NPCs typically in the form of anger; most emotions were moderately severe, with no statistical differences among types of NPC. On average, NPCs responded to patient emotion with empathic language only 30% of the time. A better understanding of NPC-patient interactions can contribute to improved communication training for NPCs and, ultimately, to higher quality patient care in cancer.


Use of a monoclonal antibody (GA3) to demonstrate lineage restricted O-glycosylation on leukosialin during terminal erythroid differentiation.
A murine monoclonal antibody (GA3) obtained by immunizing mice with cells of the human erythroleukemic cell line K562 is shown to define a 105 kilodalton (kd) membrane antigen on K562 cells that is restricted within the hematopoietic system to the erythroid lineage and to a minor population of CD3, CD4 positive T lymphocytes. Cocapping studies and immunoprecipitation experiments performed with GA3 and L10, an anti-sialophorin monoclonal antibody reacting with leukosialin (Gp 105) on K562 cells, demonstrate that the antigen detected by GA3 on K562 cells is identical to leukosialin. Neuraminidase treatment but not tunicamycin treatment of K562 cells abolishes the expression of the GA3-epitope without affecting the L10-epitope thus providing evidence that terminal sialic acid present on O-linked oligosaccharide chains on Gp 105 is essential for the expression of the GA3-epitope. Further analysis by flow cytometry and immune panning experiments performed on bone marrow cells with GA3 or L10 demonstrate that, in contrast to L10, which reacts with all types of hematopoietic progenitors, the epitope recognized by GA3 is restricted to the erythroid lineage, and appears during erythroid differentiation before glycophorin A on the earliest morphologically recognizable erythroid precursor, the proerythroblast. Our results therefore suggest that O-linked oligosaccharides on leukosialin express lineage restricted and even maturation restricted antigenic structures that might serve as cell lineage specific markers.


Racial and ethnic variations in waiting times for emergency department visits related to nontraumatic dental conditions in the United States.
Researchers have documented an association between waiting times in emergency departments (EDs) and quality of care for medical conditions, but little is known about trends and factors associated with waiting times for ED visits related to nontraumatic dental conditions (NTDCs). The authors examined trends in waiting time and associated factors for NTDC-related ED visits in the United States. The authors analyzed data from the National Hospital Ambulatory Medical Care survey for 1997 to 2007, excluding 2001 and 2002 owing to lack of information about waiting times. The authors used a survey-weighted linear regression of log-transformed waiting-time model to determine the waiting time for NTDC-related visits. The geometric mean (standard error) waiting times for NTDC- and non-NTDC-related visits were 29 (1.0) and 25 (0.6) minutes, respectively (P < .01). The geometric mean waiting time for NTDC-related visits increased by 6 percent annually and from 20 minutes in 1997 to 37 minutes in 2007. Compared with whites, Hispanics and African Americans had significantly longer waiting times for NTDC-related visits (adjusted fold-difference [R] = 1.2, 95 percent confidence interval [CI] = 1.13-1.31) and [R] = 1.3, [CI] = 1.29-1.38). Age, payer type, reason for visit and triage category were significant predictors of waiting time (R = 2.3 and 2.4 for NTDC-related visits in the triage categories of more than one to two hours and more than two to 24 hours, respectively). Nationally, waiting times in EDs for NTDC-related visits increased over time. Compared with whites, Hispanics and blacks waited longer to receive care for NTDCs in EDs. Prolonged waiting times associated with NTDC-related ED visits reinforce the need for dental professionals to continue to advise patients regarding the need to implement oral health preventive strategies and to avoid the use of the ED for preventable common dental conditions.


Fluoride content of toothpastes available in South Africa.
A high dental caries burden coupled with a lack of water or salt fluoridation make it imperative that toothpastes available to the South African consumer demonstrate adequate potential for caries control and contain between 1000ppm and 1500ppm total fluoride (TF), with at least 1000ppm F in free available/soluble form. The objective was to determine TF, total soluble fluoride (TSF) and insoluble fluoride (IF) concentrations in 22 fluoride toothpastes commercially available in South Africa. Samples were purchased from a major pharmaceutical and food retailer located in the two metropolitan areas in South Africa. TF and TSF concentrations were determined potentiometrically, in quadruplicate, following acid hydrolysis of the samples using a calibrated Combination Fluoride Ion Selective Electrode. IF was calculated by subtracting TSF from TF. Although TF content was found to be statistically significantly lower than manufacturer declaration (3.2x10-⁷; p≤0.05), 77.3% of the samples still contained adequate free, available/soluble F levels. Relative mean TSF content for toothpastes formulated with a calcium-based abrasive was 85% (sd ±14.5; n=6) as opposed to 98.6% (sd ±2.6; n=16) for those containing silica. The total fluoride concentration of all the toothpastes was lower than that declared by the manufacturers, with one in four having TSF concentrations of less than 1000ppm F. The relative TSF concentrations for the calcium-containing toothpastes were lower than for the silica-based products, reducing their preventive and protective potential. The results call for strengthened regulation and quality control of fluoride toothpastes in South Africa, as well as international efforts to improve related norms.


Different Effects of BORIS/CTCFL on Stemness Gene Expression, Sphere Formation and Cell Survival in Epithelial Cancer Stem Cells.
Cancer stem cells are cancer cells characterized by stem cell properties and represent a small population of tumor cells that drives tumor development, progression, metastasis and drug resistance. To date, the molecular mechanisms that generate and regulate cancer stem cells are not well defined. BORIS (Brother of Regulator of Imprinted Sites) or CTCFL (CTCF-like) is a DNA-binding protein that is expressed in normal tissues only in germ cells and is re-activated in tumors. Recent evidences have highlighted the correlation of BORIS/CTCFL expression with poor overall survival of different cancer patients. We have previously shown an association of BORIS-expressing cells with stemness gene expression in embryonic cancer cells. Here, we studied the role of BORIS in epithelial tumor cells. Using BORIS-molecular beacon that was already validated, we were able to show the presence of BORIS mRNA in cancer stem cell-enriched populations (side population and spheres) of cervical, colon and breast tumor cells. BORIS silencing studies showed a decrease of sphere formation capacity in breast and colon tumor cells. Importantly, BORIS-silencing led to down-regulation of hTERT, stem cell (NANOG, OCT4, SOX2 and BMI1) and cancer stem cell markers (ABCG2, CD44 and ALDH1) genes. Conversely, BORIS-induction led to up-regulation of the same genes. These phenotypes were observed in cervical, colon and invasive breast tumor cells. However, a completely different behavior was observed in the non-invasive breast tumor cells (MCF7). Indeed, these cells acquired an epithelial mesenchymal transition phenotype after BORIS silencing. Our results demonstrate that BORIS is associated with cancer stem cell-enriched populations of several epithelial tumor cells and the different phenotypes depend on the origin of tumor cells.


First case of chronic wasting disease in Europe in a Norwegian free-ranging reindeer.
Chronic wasting disease (CWD) is a fatal contagious prion disease in cervids that is enzootic in some areas in North America. The disease has been found in deer, elk and moose in the USA and Canada, and in South Korea following the importation of infected animals. Here we report the first case of CWD in Europe, in a Norwegian free-ranging reindeer in Southern Norway. The origin of the disease is unknown. Until now a low number of cervids, and among them a few reindeer, have been tested for CWD in Norway. Therefore the prevalence of CWD is unknown.


The lymphocyte transformation test for diagnosis of drug-induced occupational allergy.
Twenty-five workers with clinically diagnosed or suspected occupational hypersensitivity caused by contact with bacampicillin, alprenolol, and/or quinidine were studied by the lymphocyte transformation test and by skin tests. Ten healthy exposed workers, 16 job applicants, and seven healthy nonexposed laboratory workers served as control subjects. Lymphocyte transformation was measured by 3H-thymidine uptake into DNA and by counting of lymphoblasts on cell smears. Lymphocytes from workers with contact eczema or with eczema in combination with conjunctivitis and rhinitis responded to offending drugs in vitro as demonstrated by an increased 3H-thymidine incorporation and by the presence of lymphoblasts in the cultures. In vitro proliferative responses were reproduced during a 4-year period. Drug-specific allergy was confirmed by positive patch test in most workers with eczema. In addition, bacampicillin-specific lymphocyte proliferation was also observed in workers with suspected bacampicillin hypersensitivity but with negative skin tests. They suffered mostly from eczema in combination with conjunctivitis and rhinitis or from conjunctivitis/rhinitis only. Lymphocytes from most control subjects did not respond in vitro to bacampicillin, alprenolol, or quinidine. Weak proliferative responses to bacampicillin were observed in two of the 16 job applicants. The exquisite specificity of drug-induced lymphocyte responses is demonstrated. Thus, lymphocytes from a quinidine-sensitive worker did not respond in vitro to the quinidine stereoisomer, quinine. Furthermore, lymphocytes from a bacampicillin-sensitive worker responded to some penicillins, such as pivampicillin and ampicillin, but not to others, such as benzylpenicillin or pivmecillinam. These data suggest the role of N-acylamido side chain in the sensitization of lymphocytes from this particular donor. In conclusion, lymphocyte transformation test can be used for the detection of offending agents in occupationally sensitized workers. Furthermore, lymphocytes from such individuals may serve as a model for study of specificity of cellular reactions underlying drug-induced hypersensitivity.


School-based Sexuality Education Experiences across Three Generations of Sexual Minority People.
Sexual minority people face greater risk for compromised sexual health than their heterosexual peers, yet school-based sexuality education often excludes them. Little is known about whether or how sexual minority people's sexuality education experiences have varied across sociohistorical contexts of rapid social change in both sexuality education and sexual minority visibility. Semi-structured qualitative interviews were conducted among 191 sexual minority people from three distinct sociohistorical generations (ages 18-25, 34-41, and 52-59, respectively) and four geographic regions of the United States. Data were analyzed using thematic content analysis following a consensual qualitative protocol. Fifty-one participants (i.e., 27%) discussed school-based sexuality education experiences despite the lack of an explicit question in the interview protocol prompting them to do so. Four distinct yet overlapping themes emerged in participants' experiences of sexuality education: 1) Silence; 2) The profound influence of HIV/AIDS; 3) Stigma manifest through fear, shame, and prejudice; and, 4) Comparing school-based experiences to sexuality education outside of school. The presence of themes varied across groups defined by sociohistorical generation. The implications of sexuality education experiences for the wellbeing of sexual minority people are discussed.


Multi-Disease Detection Using a Prism-Based Surface Plasmon Resonance Sensor: A TMM and FEM Approach.
This research introduces a surface plasmon resonance (SPR)-based biosensor with multilayered structures for telecommunication wavelength in order to detect multiple diseases. Malaria and chikungunya viruses are taken into account, and the presence of these viruses is determined by examining several blood components in healthy and affected phases. Here, two distinct configurations (Al-BTO-Al-MoS2 and Cu-BTO-Cu-MoS2) are proposed and contrasted for the detection of numerous viruses. The performance characteristics of this work have been analyzed using Transfer Matrix Method (TMM) method and Finite Element Method (FEM) method under the angle interrogation technique. From the TMM and FEM solutions, it is evident that the Al-BTO-Al-MoS2 structure provides the highest sensitivities of ~270 deg./RIU for malaria and ~262 deg./RIU for chikungunya viruses, with the satisfactory detection accuracy of ~1.10 for malaria, ~1.64 for chikungunya, and quality factor of ~204.40 for malaria, ~208.20 for chikungunya. In addition, the Cu-BTO-Cu MoS2 structure offers the highest sensitivities of ~310 deg./RIU for malaria and ~298 deg./RIU for chikungunya, with a satisfactory detection accuracy of ~0.40 for malaria, ~0.58 for chikungunya, and quality factor of ~89.85 for malaria, ~86.38 for chikungunya viruses. Therefore, the performance of the proposed sensors is analyzed using two distinct methods and gives around similar results. In sum, this research could be utilized as a theoretical foundation and the first step in the development of a real sensor.


[Participation in cardiac rehabilitation after coronary bypass surgery: good news, bad news].
Cardiac rehabilitation programs have the potential to decrease morbidity and mortality and increase quality of life after acute coronary events and coronary bypass surgery (CABG). Unfortunately, the proportion of eligible patients that participate in cardiac rehabilitation remains low, despite coverage of such programs by the Israeli National Health Insurance. A low participation rate is especially prominent in women, elderly, minorities and low socioeconomic classes. In this edition of Harefuah, Gendler et at conducted an interventional study aimed at increasing the participation of patients in cardiac rehabilitation programs after CABG in 5 cardiothoracic wards across Israel. They interviewed 489 patients in the intervention arm and 472 patients in the control arm before surgery and a year later. The intervention included dissemination of information on cardiac rehabilitation to the medical staff and patients. Following the intervention, cardiac rehabilitation increased almost twofold in veteran-Israeli males and females. Although it increased significantly in USSR-born male immigrants, their absolute rate of participation remained low (13.6%). No USSR-born female participated in rehabilitation, either before or after the intervention. The good news is that a simple, inexpensive intervention can increase participation in cardiac rehabilitation after CABG surgery. The bad news is that this potentially lifesaving activity remains unattended by most USSR-born immigrants, and particularly by females. Additional research is required to explore the cultural, social and economic barriers of this phenomenon.


Safety and efficacy of switching to alternative nucleoside analogues following symptomatic hyperlactatemia and lactic acidosis.
To evaluate the safety and efficacy of rechallenging patients who have recovered from nucleoside reverse transcriptase inhibitor (NRTI)-induced symptomatic hyperlactatemia or lactic acidosis with alternative NRTI-containing regimens. Data in this case series was collected from patients followed at the UCSD Owen Clinic from July 1998 through September 2002. Cases of symptomatic hyperlactatemia were HIV-infected adults receiving NRTI who had symptoms compatible with hyperlactatemia and two lactates > 2 times the upper normal limit. Lactic acidosis was defined as lactate > 5 mmol/l with bicarbonate < 20 mmol/l. The suspected offending NRTI in the prior regimen were replaced with other NRTI thought to have equivalent antiviral potency but less mitochondrial toxicity. Ten patients diagnosed with symptomatic hyperlactatemia and two with lactic acidosis were later restarted on antiretrovirals that included new NRTI. The NRTI that patients were receiving when symptomatic hyperlactatemia or lactic acidosis was diagnosed included stavudine and lamivudine (n = 6), stavudine and didanosine (n = 4), and stavudine and abacavir (n = 2). The median (range) peak lactate was 5.4 (4.7-19.1) mmol/l. Five patients were rechallenged with abacavir and lamivudine, five with zidovudine, abacavir and lamivudine, and two with zidovudine and lamivudine. Among the 12 patients contributing over 22 years of cumulative reexposure to NRTI-containing therapy, one developed symptomatic hyperlactatemia again yielding a recurrence rate of 45.5 cases/1000 patient-years. Virologic control was maintained in all patients. This data supports the strategy that in cases of symptomatic hyperlactatemia or lactic acidosis in which the toxicity is associated with stavudine, didanosine or both, it is safe and efficacious to reintroduce NRTI that are less potent inhibitors of mitochondria.


Hypermethylation of the Wilms' tumor suppressor gene CpG island in human breast carcinomas.
CpG island hypermethylation is known to be associated with transcriptional silencing of tumor suppressor genes in neoplasia. We have previously detected aberrantly methylated sites in the first intron of the Wilms' tumor suppressor (WT1) gene in breast cancer. In the present study, we extended the investigation to a CpG island located in the promoter and first exon regions of WT1. Methylation of this CpG island was found to be extensive in MCF-7 and MDA-MB-231 breast cancer cells, as well as in 25% (five of 20 patients) of primary breast tumors. While levels of the known 3.0-kb WT1 mRNAs were decreased or not detected in these cell lines, the expression could be partially restored following treatment with a demethylation agent, 5-aza-2'-deoxycytidine. Surprisingly, a novel 2.5-kb WT1 transcript was expressed at high levels in both untreated and treated MDA-MB-231 cells. This novel transcript was likely a WT1 variant missing the first exon, and therefore escaped the methylation control present in the normal transcript. Our study implicates the future need to investigate the significance of this aberrant transcript as well as the role of WT1 CpG island hypermethylation in breast neoplasia.


Innate Lymphoid Cells and Intestinal Inflammatory Disorders.
Innate lymphoid cells (ILCs) are a population of lymphoid cells that do not express T cell or B cell antigen-specific receptors. They are largely tissue-resident and enriched at mucosal sites to play a protective role against pathogens. ILCs mimic the functions of CD4 T helper (Th) subsets. Type 1 innate lymphoid cells (ILC1s) are defined by the expression of signature cytokine IFN-γ and the master transcription factor T-bet, involving in the type 1 immune response; ILC2s are characterized by the expression of signature cytokine IL-5/IL-13 and the master transcription factor GATA3, participating in the type 2 immune response; ILC3s are RORγt-expressing cells and are capable of producing IL-22 and IL-17 to maintain intestinal homeostasis. The discovery and investigation of ILCs over the past decades extends our knowledge beyond classical adaptive and innate immunology. In this review, we will focus on the roles of ILCs in intestinal inflammation and related disorders.


Nitric oxide and cardiobiology-methods for intact hearts and isolated myocytes.
The cross talk between reactive oxygen species (ROS) and reactive nitrogen species (RNS) plays a pivotal role in the regulation of myocardial and vascular function. Both nitric oxide and redox-based signaling involve the posttranslational modification of proteins through S-nitrosylation and oxidation of specific cysteine residues. Disruption of this cross talk between ROS and RNS contributes to the pathogenesis of heart failure. Therefore, the elucidation of these complex chemical interactions may improve our understanding of cardiovascular pathophysiology. This chapter discusses the significant role of spatial confinement of nitric oxide synthases, NADPH oxidase, and xanthine oxidoreductase in the regulation of myocardial excitation-contraction coupling. This chapter describes techniques for assessing oxidative and nitrosative stress. A variety of assays have been developed that quantify S-nitrosylated proteins. Among them, the biotin-switch method directly evaluates endogenously nitrosylated proteins in a reproducible way. Identification of the biotinylated or S-nitrosylated proteins subjected to the biotin-switch assay are described and evaluated with a one-dimensional gel (Western blot) or with the newly developed two-dimensional fluorescence difference gel electrophoresis proteomic analysis. Quantifying the number of free thiols with the monobromobimane assay in a protein of interest allows estimation of cysteine oxidation and, in turn, the state of nitroso-redox balance of effector molecules. In summary, this chapter reviews the biochemical methods that assess the impact of nitroso/redox signaling in the cardiovascular system.


Drosophila DNase I footprint database: a systematic genome annotation of transcription factor binding sites in the fruitfly, Drosophila melanogaster.
Despite increasing numbers of computational tools developed to predict cis-regulatory sequences, the availability of high-quality datasets of transcription factor binding sites limits advances in the bioinformatics of gene regulation. Here we present such a dataset based on a systematic literature curation and genome annotation of DNase I footprints for the fruitfly, Drosophila melanogaster. Using the experimental results of 201 primary references, we annotated 1367 binding sites from 87 transcription factors and 101 target genes in the D.melanogaster genome sequence. These data will provide a rich resource for future bioinformatics analyses of transcriptional regulation in Drosophila such as constructing motif models, training cis-regulatory module detectors, benchmarking alignment tools and continued text mining of the extensive literature on transcriptional regulation in this important model organism. http://www.flyreg.org/ email@example.com.


Cigarette smoking, alcohol consumption, and risk of hip fracture in women.
Previous studies regarding the impact of cigarette smoking on the risk of hip fracture in postmenopausal women have been inconsistent, suggesting different effects in different groups. The effect of alcohol intake on fracture risk is puzzling: moderate alcohol intake appears to increase bone density, and its association with hip fracture is not clear. To assess the associations of cigarette smoking and alcohol consumption with hip fracture risk among postmenopausal women, we conducted an analysis of a population-based case-control study from Sweden. Cases were postmenopausal women, aged 50 to 81 years, who sustained a hip fracture after minor trauma between October 1, 1993, and February 28, 1995; controls were randomly selected from a population-based register during the same period. A mailed questionnaire requesting information on lifestyle habits and medical history was used 3 months after the hip fracture for cases and simultaneously for controls. Age-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were computed by means of logistic regression. Of those eligible, 1328 cases (82.5%) and 3312 controls (81.6%) responded. Compared with never smokers, current smokers had an increased risk of hip fracture (age-adjusted OR, 1.66; 95% CI, 1.41-1.95). Duration of smoking-particularly postmenopausal smoking-was more important than the amount smoked. Former smokers had a small increase in risk (age-adjusted OR, 1.15; 95% CI, 0.97-1.37) that decreased with the duration of cessation. The age-adjusted OR for women consuming alcohol was 0.80 (95% CI, 0.69-0.93). Cigarette smoking is a risk factor for hip fracture among postmenopausal women; risk decreases after cessation. Alcohol consumption has a weak inverse association with risk.


Photophysical properties of the excited states of bacteriochlorophyll f in solvents and in chlorosomes.
Bacteriochlorophyll f (BChl f) is a photosynthetic pigment predicted nearly 40 years ago as a fourth potential member of the Chlorobium chlorophyll family (BChl c, d, and e). However, this pigment still has not been found in a naturally occurring organism. BChl c, d, and e are utilized by anoxygenic green photosynthetic bacteria for assembly of chlorosomes--large light-harvesting complexes that allow those organisms to survive in habitats with extremely low light intensities. Recently, using genetic methods on two different strains of Chlorobaculum limnaeum that naturally produce BChl e, two research groups produced mutants that synthesize BChl f and assemble it into chlorosomes. In this study, we present detailed investigations on spectral and dynamic characteristics of singlet excited and triplet states of BChl f with the application of ultrafast time-resolved absorption and fluorescence spectroscopies. The studies were performed on isolated BChl f in various solvents, at different temperatures, and on BChl f-containing chlorosomes in order to uncover any unusual or unfavorable properties that stand behind the lack of appearance of this pigment in natural environments.


Structure dependent antioxidant capacity of phlorotannins from Icelandic Fucus vesiculosus by UHPLC-DAD-ECD-QTOFMS.
Brown algae are rich in polyphenolic compounds, phlorotannins, which have been found to possess high in vitro antioxidant capacity, especially DPPH radical scavenging activity, due to the high number of hydroxyl groups. Whereas, the overall antioxidant capacity of brown algae extracts has been widely studied, the antioxidant capacity of individual phlorotannins has been rarely explored. The aim of this study was to determine the structure dependant antioxidant capacity of phlorotannins from Icelandic brown algae, Fucus vesiculosus. The antioxidant capacity of individual phlorotannins was determined by an on-line method using liquid chromatography and an electrochemical detector followed by quadrupole Time of Flight mass spectrometry (UHPLC-DAD-ECD-QTOFMS). Tentative structural elucidation of 13 phlorotannin isomers from EAF was obtained by LC-DAD-QTOFMS, ranging from 374 to 870Da. On-line determination of antioxidant capacity of the individual phlorotannins generally showed that low molecular phlorotannins exhibited higher antioxidant capacity and that the capacity decreased with polymerisation.


Disposition and metabolism of [14C]-galunisertib, a TGF-βRI kinase/ALK5 inhibitor, following oral administration in healthy subjects and mechanistic prediction of the effect of itraconazole on galunisertib pharmacokinetics.
1. The disposition and metabolism of galunisertib (LY2157299 monohydrate, a TGF-βRI Kinase/ALK5 Inhibitor) was characterized following a single oral dose of 150 mg of [14C]-galunisertib (100 µCi) to six healthy human subjects. 2. The galunisertib plasma half-life was 8.6 h, while the 14C half-life was 10.0 h. Galunisertib was abundant in circulation (40.3% of the 14C AUC024 h), with 7 additional metabolites detected in plasma. Two metabolites LSN3199597 (M5, mono-oxidation), and M4 (glucuronide of M3) were the most abundant circulating metabolites (10.7 and 9.0% of the 14C AUC024 h respectively). The pharmacological activity of LSN3199597 was tested and found to be significantly less potent than galunisertib. 3. The dose was recovered in feces (64.5%) and in urine (36.8%). Galunisertib was cleared primarily by metabolism, based on low recovery of parent in excreta (13.0% of dose). Due to the slow in vitro metabolism of galunisertib in suspended hepatocytes, a long term hepatocyte system was used to model the human excretion profile. 4. Expressed cytochromes P450 and hepatocytes indicated clearance was primarily CYP3A4-mediated. Mechanistic static modeling that incorporated small non-CYP-mediated metabolic clearance and renal clearance components predicted an AUC ratio of 4.7 for the effect of itraconazole, a strong CYP3A4 inhibitor, on galunisertib.


Renal, gastrointestinal, and hepatic late effects in survivors of childhood acute myeloid leukemia treated with chemotherapy only--a NOPHO-AML study.
We investigated the spectrum, frequency, and risk factors for renal, gastrointestinal, and hepatic late adverse effects in survivors of childhood acute myeloid leukemia (AML) without relapse treated with chemotherapy alone according to three consecutive AML trials by the Nordic Society of Pediatric Hematology and Oncology (NOPHO). A population-based cohort of children treated for AML according to the NOPHO-AML-84, -88, and -93 trials included 138 eligible survivors of whom 102 (74%) completed a questionnaire and 104 (75%) had a clinical examination and blood sampling performed. Eighty-five of 94 (90%) eligible sibling controls completed a similar questionnaire. Siblings had no clinical examination or blood sampling performed. At a median of 11 years (range 4-25) after diagnosis, renal, gastrointestinal, and hepatic disorders were rare both in survivors of childhood AML and in sibling controls, with no significant differences. Ferritin was elevated in 21 (21%) AML survivors but none had biochemical signs of liver damage. Viral hepatitis was present in three and cholelithiasis in two AML survivors. One adult survivor had hypertension, two had slightly elevated systolic blood pressure, and eight survivors had slightly elevated diastolic blood pressure. These persons all had normal creatinine and cystatin C levels. Marginal abnormalities in potassium, magnesium, calcium, or bicarbonate levels were found in 34 survivors. Survivors of childhood AML treated with chemotherapy only experienced few renal, gastrointestinal, and hepatic late effects.


First-Order Dynamic Modeling and Control of Soft Robots.
Modeling of soft robots is typically performed at the static level or at a second-order fully dynamic level. Controllers developed upon these models have several advantages and disadvantages. Static controllers, based on the kinematic relations tend to be the easiest to develop, but by sacrificing accuracy, efficiency and the natural dynamics. Controllers developed using second-order dynamic models tend to be computationally expensive, but allow optimal control. Here we propose that the dynamic model of a soft robot can be reduced to first-order dynamical equation owing to their high damping and low inertial properties, as typically observed in nature, with minimal loss in accuracy. This paper investigates the validity of this assumption and the advantages it provides to the modeling and control of soft robots. Our results demonstrate that this model approximation is a powerful tool for developing closed-loop task-space dynamic controllers for soft robots by simplifying the planning and sensory feedback process with minimal effects on the controller accuracy.


Inhibition of HBV targeted ribonuclease enhanced by introduction of linker.
To construct human eosinophil-derived neurotoxin(hEDN) and HBV core protein (HBVc) eukaryotic fusion expression vector with a linker (Gly(4)Ser) (3) between them to optimize the molecule folding, which will be used to inhibit HBV replication in vitro. Previously constructed pcDNA3.1(-)/TR was used as a template. Linker sequence was synthesized and annealed to form dslinker, and cloned into pcDNA3.1(-)/TR to produce plasmid pcDNA3.1(-)/HBc-linker. Then the hEDN fragment was PCR amplified and inserted into pcDNA3.1(-)/HBc-linker to form pcDNA3.1(-)/TNL in which the effector molecule and the target molecule were separated by a linker sequence. pcDNA3.1(-)/TNL expression was identified by indirect immunofluorescence staining. Radioimmunoassay was used to analyse anti-HBV activity of pcDNA3.1(-)/TNL. Meanwhile, metabolism of cells was evaluated by MTT colorimetry. hEDN and HBVc eukaryotic fusion expression vector with a linker (Gly(4)Ser)(3) between them was successfully constructed. pcDNA3.1(-)/TNL was expressed in HepG2.2.15 cells efficiently. A significant decrease of HBsAg concentration from pcDNA3.1(-)/TNL transfectant was observed compared to pcDNA3.1(-)/TR (P=0.036, P<0.05). MTT assay suggested that there were no significant differences between groups (P=0.08, P>0.05). Linker introduction enhances the inhibitory effect of HBV targeted ribonuclease significantly.


Risk Factors for Early Reoperation After Operative Treatment of Acetabular Fractures.
To identify the risk factors for early reoperation after operative fixation of acetabular fractures. Retrospective evaluation. Level I Trauma Center. Seven hundred ninety-one patients with displaced acetabular fractures treated with open reduction and internal fixation (ORIF) from 2006 to 2015. Average follow-up was 52 weeks. Early reoperation after acetabular ORIF, defined as secondary procedure for infection or revision within 3 years of initial operation. Fifty-six (7%) patients underwent irrigation and debridement for infection and wound complications. Four associated risk factors identified were length of stay in the intensive care unit, pelvic embolization, operative time, and time delay between injury and surgical fixation. Sixty-two (8%) patients underwent early revision, including 45 conversions to total hip arthroplasty, 10 revision ORIF, 6 fixation device removals because of concern for joint penetration (2 acutely and 4 > 6 months after surgery), and 1 stabilization procedure. Three risk factors associated with early revision were hip dislocation, articular comminution, and concomitant femoral head or neck injury. Combined injuries to the pelvic ring and acetabulum, fracture pattern, marginal impaction, and body mass index had no significant effect on early revision surgery. Risk factors for early reoperation after operative fixation of acetabular fractures differed based on the reason for return to the operating room. Infection was more likely to occur in patients who had prolonged stays in the intensive care unit, had prolonged operative times, were embolized, or experienced delay in time to fixation. Revision was more likely with hip dislocation, articular comminution, femoral head or neck fracture, and advancing age. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Should COVID-19 be branded to viral thrombotic fever?
Coronaviruses can cause a diverse array of clinical manifestations, from fever with symptoms of the common cold to highly lethal severe acute respiratory syndrome (SARS) and middle east respiratory syndrome (MERS). SARS-CoV-2, the coronavirus discovered in Hubei province, China, at the end of 2019, became known worldwide for causing coronavirus disease 2019 (COVID-19). Over one year's time period, the scientific community has produced a large bulk of knowledge about this disease and countless reports about its immune-pathological aspects. This knowledge, including data obtained in postmortem studies, points unequivocally to a hypercoagulability state. However, the name COVID-19 tells us very little about the true meaning of the disease. Our proposal is more comprehensive; it intends to frame COVID-19 in more clinical terminology, making an analogy to viral haemorrhagic fever (VHF). Thus, we found irrefutable evidence in the current literature that COVID-19 is the first viral disease that can be branded as a viral thrombotic fever. This manuscript points out that SARS-CoV-2 goes far beyond pneumonia or SARS. COVID-19 infections promote remarkable interactions among the endothelium, coagulation, and immune response, building up a background capable of promoting a "thrombotic storm," much more than a "cytokine storm." The importance of a viral protease called main protease (Mpro) is highlighted as a critical component for its replication in the host cell. A deeper analysis of this protease and its importance on the coagulation system is also discussed for the first time, mainly because of its similarity with the thrombin and factor Xa molecules, as recently pointed out by structural comparison crystallographic structures.


Incidental finding of severe hypertriglyceridemia in children. Role of multiple rare variants in genes affecting plasma triglyceride.
The incidental finding of severe hypertriglyceridemia (HyperTG) in a child may suggest the diagnosis of familial chylomicronemia syndrome (FCS), a recessive disorder of the intravascular hydrolysis of triglyceride (TG)-rich lipoproteins. FCS may be due to pathogenic variants in lipoprotein lipase (LPL), as well as in other proteins, such as apolipoprotein C-II and apolipoprotein A-V (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface) and LMF1 (a factor required for intracellular formation of active LPL). Molecular characterization of 5 subjects in whom HyperTG was an incidental finding during infancy/childhood. We performed the parallel sequencing of 20 plasma TG-related genes. Three children with severe HyperTG were found to be compound heterozygous for rare pathogenic LPL variants (2 nonsense, 3 missense, and 1 splicing variant). Another child was found to be homozygous for a nonsense variant of APOA5, which was also found in homozygous state in his father with longstanding HyperTG. The fifth patient with a less severe HyperTG was found to be heterozygous for a frameshift variant in LIPC resulting in a truncated Hepatic Lipase. In addition, 1 of the patients with LPL deficiency and the patient with APOA-V deficiency were also heterozygous carriers of a pathogenic variant in LIPC and LPL gene, respectively, whereas the patient with LIPC variant was also a carrier of a rare APOB missense variant. Targeted parallel sequencing of TG-related genes is recommended to define the molecular defect in children presenting with an incidental finding of HyperTG.


A machine learning and experimental-based model for prediction of soil sorption capacity toward phenanthrene.
Sorption by soil is the fundamental basis for environment fate of hydrophobic organic contaminants (HOCs), which varies significantly depending on diverse properties of soils. Therefore, a generalized approach to predict HOC sorption by soils is required. In this study, 488 data points were extracted from references and adopted to develop models for estimating the sorption capacities of phenanthrene in soils using six different machine learning (ML) approaches. The extreme gradient boosting (XGBT) model demonstrated the most favorable performance, achieving a coefficient of determination of 0.91 and root-mean-square errors of 0.24 for the testing dataset. The XGBT model's performance was further demonstrated by comparing with experimental data from batch sorption tests conducted on 20 soil samples collected from 17 provinces of China. The differences between the predicted values and the experimental values were statistically equal to zero (p = 0.14). Leveraging the XBGT model together with soil properties from the Harmonized World Soil Database, the distribution of sorption capacities in Chinese soils was successfully depicted on a national scale. This research is expected to contribute to a deeper understanding of the migration of persistent organic pollutants in terrestrial system. Furthermore, the established model holds implications for more precise and scientific soil environmental management.


An upgraded method of high-throughput chromosome conformation capture (Hi-C 3.0) in cotton (Gossypium spp.).
High-throughput chromosome conformation capture (Hi-C) technology has been applied to explore the chromatin interactions and shed light on the biological functions of three-dimensional genomic features. However, it remains challenging to guarantee the high quality of Hi-C library in plants and hence the reliable capture of chromatin structures, especially loops, due to insufficient fragmentation and low efficiency of proximity ligations. To overcome these deficiencies, we optimized the parameters of the Hi-C protocol, principally the cross-linking agents and endonuclease fragmentation strategy. The double cross-linkers (FA+DSG) and double restriction enzymes (DpnII+DdeI) were utilized. Thus, a systematic in situ Hi-C protocol was designed using plant tissues embedded with comprehensive quality controls to monitor the library construction. This upgraded method, termed Hi-C 3.0, was applied to cotton leaves for trial. In comparison with the conventional Hi-C 2.0, Hi-C 3.0 can obtain more than 50% valid contacts at a given sequencing depth to improve the signal-to-noise ratio. Hi-C 3.0 can furthermore enhance the capturing of loops almost as twice as that of Hi-C 2.0. In addition, Hi-C 3.0 showed higher efficiency of compartment detection and identified compartmentalization more accurately. In general, Hi-C 3.0 contributes to the advancement of the Hi-C method in plants by promoting its capability on decoding the chromatin organization.


Single-ring suspended fiber for Bragg grating based hydrostatic pressure sensing.
We present a novel optical fiber composed of a suspended core, a supporting ring and an outer ring. To establish a large holey region, a germanium-doped core is suspended by a silica ring and the entire structure is enclosed by another silica ring. By monitoring the Bragg wavelength shift of an FBG written in such a fiber with an air filling fraction of 65%, a hydrostatic pressure sensitivity of -43.6 pm/MPa was achieved experimentally. The high-pressure sensitivity is in good agreement with the numerically calculated value of ~40 pm/MPa. Due to the significant impact of the fiber core suspended in the large holey region inside the fiber, the pressure sensitivity improved by approximately eleven times compared to a Bragg grating inscribed in a standard single-mode fiber. To the best of our knowledge, it is the highest pressure sensitivity obtained for a FBG-based sensor experimentally, when compared to other FBG-based pressure sensors reported up to date. The large air hole region and the suspended core in the center of the fiber not only make the proposed fiber sensor a good candidate for pressure measurements, especially in the oil industry where space is at a premium, but also allow the detection of substances, by exploiting interaction of light with liquids or gases.


Rapid, multiplexed detection of biomolecules using electrically distinct hydrogel beads.
Rapid, low-cost, and multiplexed biomolecule detection is an important goal in the development of effective molecular diagnostics. Our recent work has demonstrated a microfluidic biochip device that can electrically quantitate a protein target with high sensitivity. This platform detects and quantifies a target analyte by counting and capturing micron-sized beads in response to an immunoassay on the bead surface. Existing microparticles limit the technique to the detection of a single protein target and lack the magnetic properties required for separation of the microparticles for direct measurements from whole blood. Here, we report new precisely engineered microparticles that achieve electrical multiplexing and adapt this platform for low-cost and label-free multiplexed electrical detection of biomolecules. Droplet microfluidic synthesis yielded highly-monodisperse populations of magnetic hydrogel beads (MHBs) with the necessary properties for multiplexing the electrical Coulter counting on chip. Each bead population was designed to contain a different amount of the hydrogel material, resulting in a unique electrical impedance signature during Coulter counting, thereby enabling unique identification of each bead. These monodisperse bead populations span a narrow range of sizes ensuring that all can be captured sensitively and selectively under simultaneously flow. Incorporating these newly synthesized beads, we demonstrate versatile and multiplexed biomolecule detection of proteins or DNA targets. This development of multiplexed beads for the electrical detection of biomolecules, provides a critical advancement towards multiplexing the Coulter counting approach and the development of a low cost point-of-care diagnostic sensor.


Can we expect vasodilator therapy to prolong life in patients with congestive heart failure?
Recent evidence from the Veterans Administration Vasodilator Heart Failure Trial supports the prophylactic use of a combination of hydralazine and isosorbide dinitrate to prolong life in patients with congestive heart failure. The clinical utility of such a combination vasodilator regimen may be limited, however, by its high frequency of adverse reactions, the lack of evidence that such a regimen enhances exercise tolerance, the inconvenience of taking a large number of tablets daily for a prophylactic indication, and the dearth of clinical experience combining hydralazine-nitrate with agents that may be clinically indicated to produce long-term symptomatic benefits (i.e., converting-enzyme inhibitors). Controlled evidence in animals and uncontrolled evidence in humans suggest that converting-enzyme inhibitors may also favorably modify prognosis, perhaps by antagonizing the deleterious actions of endogenous neurohormonal systems. Trials (presently in progress) are designed to evaluate the hypothesis that converting-enzyme inhibitors exert beneficial effects on the survival of patients with congestive heart failure comparable to those reported with hydralazine and isosorbide dinitrate.


p53 Protein accumulation as a prognostic marker of preoperative radiotherapy and/or chemotherapy in advanced squamous cell esophageal carcinoma--preliminary report.
The correlation between immunohistochemical detection (IH) of p53 protein and tumor response to preoperative chemotherapy and/or radiotherapy in advanced esophageal squamous cell carcinoma was evaluated. Fifty-six patients with advanced esophageal squamous cell carcinoma were included in the study. All patients were staged and diagnosed microscopically before treatment. Patients were divided into three groups: 17 patients treated with chemotherapy and radiotherapy preoperatively (group I) (cisplatin and 5-fluorouracil, cobalt-60 therapy; total dose 3000 Gy); 19 patients treated with chemotherapy only (group II); and 20 patients who did not receive preoperative therapy (group III). The response of the tumor tissue to preoperative treatment was evaluated macroscopically and microscopically in operated specimens according to the classification: CR, complete response; PR1, major partial response with regression of at least 50% of initial tumor mass; PR2, minor partial response with regression of less than 50% of initial tumor mass. In all 56 patients immunohistochemistry was used to detect anti-p53 antibody (Dako, DO-7) in normal mucosa and cancer tissue. The response of the tumor was similar in both group I and group II. p53 protein was not expressed in the normal esophageal mucosa. A high level of p53 in operated specimens was associated with unfavorable tumor response to preoperative treatment. Therefore, immunohistochemical detection of p53 protein can be considered to predict the outcome of preoperative therapy.


An evaluation of involving family caregivers in the self-care of heart failure patients on hospital readmission: Randomised controlled trial (the FAMILY study).
The prevalence of heart failure is increasing in Lebanon but to date there is no systematic evaluation of a disease management intervention. The aim of this study was to evaluate the effect of involving family caregivers in the self-care of patients with heart failure on the risk of hospital readmission. A multi-site, block randomised controlled trial. The study was conducted over a 13-month period in three tertiary medical centres in Beirut and Mount Lebanon, Lebanon. Adult patients presenting for an exacerbation of heart failure to one of the study centres were included. Patients with limited life expectancy or physical functionality, planned cardiac bypass or valve replacement surgery, living alone or in nursing homes, or aged less than 18 years were excluded. Patients allocated to the intervention group and their family caregivers were provided with a comprehensive, culturally appropriate, educational session on self-care maintenance and symptom management along with self-care resources. The usual care group received the self-care resources only. Follow-up phone calls were conducted 30days following discharge by a research assistant blinded to treatment assignment. The primary outcome was hospital readmission and the secondary outcomes were self-care, quality of life, major vascular events and healthcare utilization. The final sample included 256 patients hospitalized for heart failure randomised into control (130 patients) and intervention (126 patients) groups. The mean age was 67 (SD=8)years, and the majority (55%) were male. Readmission at 30days was significantly lower in the intervention group compared to the control group (n=10, 9% vs. n=20, 19% respectively, OR=0.40, 95% CI=0.02, 0.10, p=0.02). Self-care scores improved in both groups at 30days, with a significantly larger improvement in the intervention group than the control group in the maintenance and confidence sub-scales, but not in the self-care management sub-scale. No differences were seen in quality of life scores or emergency department presentations between the groups. More patients in the control group than in the intervention group visited health care facilities (n=24, 23% vs. n=12, 11% respectively, OR=0.39, 95% CI=0.18, 0.83, p=0.01). The trial results confirmed the potential of the family-centred self-care educational intervention under evaluation to reduce the risk of readmission in Lebanese patients suffering from exacerbated heart failure. Further research is needed to validate these findings with longer periods of follow-up and to identify the intervention components and intensity required to induce sustained benefits on patients' self-care management and quality of life.


Do comprehensive schools reduce social mobility?
This paper investigates the claim that the shift from a selective to a comprehensive school system had a deleterious effect on social mobility in Great Britain. Using data from the National Child Development Study, we compare the chances, for both class and income mobility, of those who attended different kinds of school. Where media attention focuses exclusively on the chances for upward mobility of those children from lowly origins who were (or would have been) judged worthy of selection into a grammar school, we offer more rounded analyses. We match respondents in a way that helps us to distinguish those inequalities in mobility chances that are due to differences between children from those due to differences between the schools they attended; we look at the effects of the school system on the mobility chances of all children, not merely those from less advantaged origins; and we compare comprehensive- and selective-system schools, not merely comprehensive and grammar schools. After matching, we find, first, that going to a grammar school rather than a comprehensive does not make low-origin children more likely to be upwardly mobile but it helps them move further if they are; second, that grammar schools do not benefit working-class children, in terms of class mobility, more than they benefit service-class children, but, in terms of income mobility, such schools benefit low-income children somewhat more than they benefit higher-income children - that benefit relating only to rather modest and limited movements within the income distribution. Finally, however, the selective system as a whole yields no mobility advantage of any kind to children from any particular origins: any assistance to low-origin children provided by grammar schools is cancelled out by the hindrance suffered by those who attended secondary moderns. Overall, our findings suggest that comprehensive schools were as good for mobility as the selective schools they replaced.


Vasopressin receptor-mediated endocytosis: current view.
A number of peptide hormones have been shown to undergo receptor-mediated endocytosis (RME). RME involves the internalization of receptor-ligand complexes followed by delivery to an intracellular compartment, the endosome, from which ligands or receptors can be delivered to lysosomes or other cellular destinations. Vasopressin, a peptide hormone that plays a role in kidney and vascular physiology, has recently been demonstrated to undergo RME in LLC-PK1 and A10 cells, which express V2- and V1-type vasopressin receptors, respectively. Fluorescent vasopressin analogues are internalized by RME from the basolateral surface of polarized LLC-PK1 cells. The precise role of RME in vasopressin action is uncertain, but it is likely that it is involved in the desensitization of target cells by altering the number of cell surface vasopressin receptors. Alterations in the rate of RME may alter the response of the cell to vasopressin. Fluorescent and biotinylated vasopressins are useful tools for the study of this process.