Integrated clinical pharmacy activities into the pediatric kidney graft pathway
The pediatric renal graft pathway is at risk of care discontinuation, even though therapeutic adherence is essential. The objective is to evaluate the integration of clinical pharmacy activities into this care pathway. This feasibility study is divided into three stages: structuring, implementing and evaluation. In pre-transplant, immediate and remote post-transplant, interviews were proposed as well as the pharmaceutical analysis of medication prescriptions. In 8 months duration, 32 patients were included. All patients included in pre-transplant and immediate post-transplant benefited from the activities. At M0, all the prescriptions analyzed resulted in at least one problem detected. Half of the transplanted patients benefited from M1 maintenance, one patient from M3 maintenance and no M6 follow-up could be carried out. This work concludes with the good feasibility and integration of clinical pharmacy activities within the care pathway.


Phenological characterization and temperature requirements of Annona squamosa L. in the Brazilian semiarid region.
The phenological growth stages of various species of monocotyledonous and dicotyledonous plants can be uniformly coded using the Biologische Bundesanstalt, Bundessortenamt, und Chemische Industrie (BBCH) scale. The aim of the present study was to determine the duration of different phenological stages and the temperature requirements of the sugar-apple, Annona squamosa, during two crop cycles in the semiarid region of Brazil. Phenological stages were divided into eight of ten possible principal stages: (0) bud development, (1) leaf development, (3) shoot/branch development, (5) inflorescence emergence, (6) flowering, (7) fruit development, (8) fruit maturity and (9) senescence and the beginning of dormancy. The phenological cycle of the sugar-apple from having closed leaf buds to the fruit ripening stage lasted 149 and 164 days with temperature requirements of 1684.5 and 1786.7 degree days (DD) for the first and second crop cycles, respectively. The results provided important information that will inform the correct timing for crop management practices.


A mathematical model for microRNA in lung cancer.
Lung cancer is the leading cause of cancer-related deaths worldwide. Lack of early detection and limited options for targeted therapies are both contributing factors to the dismal statistics observed in lung cancer. Thus, advances in both of these areas are likely to lead to improved outcomes. MicroRNAs (miRs or miRNAs) represent a class of non-coding RNAs that have the capacity for gene regulation and may serve as both diagnostic and prognostic biomarkers in lung cancer. Abnormal expression patterns for several miRNAs have been identified in lung cancers. Specifically, let-7 and miR-9 are deregulated in both lung cancers and other solid malignancies. In this paper, we construct a mathematical model that integrates let-7 and miR-9 expression into a signaling pathway to generate an in silico model for the process of epithelial mesenchymal transition (EMT). Simulations of the model demonstrate that EGFR and Ras mutations in non-small cell lung cancers (NSCLC), which lead to the process of EMT, result in miR-9 upregulation and let-7 suppression, and this process is somewhat robust against random input into miR-9 and more strongly robust against random input into let-7. We elected to validate our model in vitro by testing the effects of EGFR inhibition on downstream MYC, miR-9 and let-7a expression. Interestingly, in an EGFR mutated lung cancer cell line, treatment with an EGFR inhibitor (Gefitinib) resulted in a concentration specific reduction in c-MYC and miR-9 expression while not changing let-7a expression. Our mathematical model explains the signaling link among EGFR, MYC, and miR-9, but not let-7. However, very little is presently known about factors that regulate let-7. It is quite possible that when such regulating factors become known and integrated into our model, they will further support our mathematical model.


Improving communication among health professionals, avoiding mistakes.
With each shift change or informal handoff during the workday, critical information can be lost or miscommunicated. Good communication helps catch and correct errors, plan future work, and create a culture of collaboration. It also allows team members to teach and learn. Improving handoffs is a National Patient Safety Goal. Facilities that establish formal procedures and processes tend to have fewer handoff communication problems than those that do not.


The triple function of the capsaicin-sensitive sensory neurons: In memoriam János Szolcsányi.
This paper is dedicated to the memory of János Szolcsányi (1938-2018), an outstanding Hungarian scientist. Among analgesics that act on pain receptors, he identified capsaicin as a selective lead molecule. He studied the application of capsaicin and revealed several physiological (pain, thermoregulation) and pathophysiological (inflammation, gastric ulcer) mechanisms. He discovered a new neuroregulatory system without sensory efferent reflex and investigated its pharmacology. The authors of this review are his former Ph.D. students who carried out their doctoral work in Szolcsányi's laboratory between 1985 and 2010 and report on the scientific results obtained under his guidance. His research group provided evidence for the triple function of the peptidergic capsaicin-sensitive sensory neurons including classical afferent function, local efferent responses, and remote, hormone-like anti-inflammatory, and antinociceptive actions. They also proposed somatostatin receptor type 4 as a promising drug target for the treatment of pain and inflammation. They revealed that neonatal capsaicin treatment caused no acute neuronal death but instead long-lasting selective ultrastructural and functional changes in B-type sensory neurons, similar to adult treatment. They described that lipid raft disruption diminished the agonist-induced channel opening of the TRPV1, TRPA1, and TRPM8 receptors in native sensory neurons. Szolcsányi's group has developed new devices for noxious heat threshold measurement: an increasing temperature hot plate and water bath. This novel approach proved suitable for assessing the thermal antinociceptive effects of analgesics as well as for analyzing peripheral mechanisms of thermonociception.


Quality of light and quality of life--the effect of lighting adaptation among people with low vision.
The study has investigated the effect of lighting on the daily activities (ADL) of the visually impaired in their homes by comparison before and after light adjustments were made in the kitchen, hall and bathroom. It has also investigated the additional effects on the quality of life after providing task lighting in the living room. A total of 56 people were consecutively recruited from those receiving lighting adaptation help by the Low Vision Clinic in Göteborg. Ten persons did not complete the study. After medical examinations, lighting standards and psychosocial factors were charted. After lighting improvements were carried out in the kitchen, hall and bathroom, the subjects were randomly divided into two groups, an intervention and a comparison group. The task lighting in the living room was also improved for those included in the intervention group. Follow-up interviews to determine ADL and quality of life were performed 6 months after lighting adaptation. A marked effect on quality of life of the lighting in the living room was found for the intervention group. The effect on ADL of the basic lighting adaptation in kitchen, hall and bathroom for both groups was significant for tasks carried out on the working surface in the kitchen. Other activities in the kitchen and in the bathroom tended to improve but changes were not significant. The results confirm that it is possible to increase quality of life by improving the lighting conditions.


Twelve-month outcomes and predictors of very stable INR control in prevalent warfarin users.
For patients on warfarin therapy an international normalized ratio (INR) recall interval not exceeding 4 weeks has traditionally been recommended. For patients whose INR values are nearly always therapeutic, less frequent INR monitoring may be feasible. To identify patients with stable INRs (INR values exclusively within the INR range) and comparator patients (at least one INR outside the INR range), compare occurrences of thromboembolism, bleeding and death between groups, and identify independent predictors of stable INR control. The study was a retrospective, longitudinal cohort study using data extracted from electronic databases. Patient characteristics and risk factors were entered into multivariate logistic regression models to identify variables that independently predict stable INR status. There were 533 stable and 2555 comparator patients. Bleeding and thromboembolic complications were significantly lower in stable vs. comparator patients (2.1% vs. 4.1% and 0.2% vs. 1.3%, respectively; P < 0.05). Independent predictors of stable INR control were age >70 years, male gender and the absence of heart failure. Stable patients were significantly less likely to have target INR > or =3.0 or chronic diseases. A group of patients with exclusively therapeutic INR values over 12 months is identifiable. In general, these patients are older, have a target INR <3.0, and do not have heart failure and/or other chronic diseases. Our findings suggest that many patients whose INR values remain within the therapeutic range over time could be safely treated with INR recall intervals >4 weeks.


Morphology and phylogenies of two hypotrichous brackish-water ciliates from China, Neourostylopsis orientalis n. sp. and Protogastrostyla sterkii (Wallengren, 1900) n. comb., with establishment of a new genus Neourostylopsis n. gen. (Protista, Ciliophora, Hypotrichia).
This paper investigates the morphology, infraciliature and small-subunit (SSU) rRNA gene sequences of two hypotrichous ciliates, Neourostylopsis orientalis n. sp., and Protogastrostyla sterkii (Wallengren, 1900) n. comb. (basionym Gastrostyla sterkii), collected from coastal waters in southern China. Neourostylopsis orientalis n. sp. is diagnosed mainly by the arrangement of brownish cortical granules, the numbers of adoral membranelles and frontal and transverse cirri and the characteristics of its midventral cirral pairs. The SSU rRNA gene phylogeny strongly supports the establishment of the new genus Neourostylopsis n. gen., which is characterized mainly by the following features: frontal and transverse cirri clearly differentiated, buccal cirri present, two frontoterminal cirri, midventral complex composed of midventral pairs only and not exceeding the halfway point of the cell, more than one row of marginal cirri on each side which derive from individual anlagen within each parental row, caudal cirri lacking. Thus, two new combinations are required: Neourostylopsis songi (Lei et al., 2005) n. comb., and Neourostylopsis flavicana (Wang et al., 2011) n. comb. Additionally, improved diagnoses for both Metaurostylopsis and Apourostylopsis are supplied in this study. Protogastrostyla sterkii (Wallengren, 1900) n. comb. differs from the similar congener Protogastrostyla pulchra mainly in body shape, ratio of buccal field to body length in vivo and molecular data. Based on the present studies, we conclude that the estuarine population of P. pulchra collected by J. Gong and others [Gong et al., J Eukaryot Microbiol (2007) 54, 468-478] is a population of P. sterkii.


Induction of apoptosis by EGF receptor in rat mammary adenocarcinoma cells coincides with enhanced spontaneous tumour metastasis.
The low metastatic MTC (13762NF) rat mammary adenocarcinoma cell line is devoid of epidermal growth factor receptor (EGFR). To test for a link between expression of EGFR and the ability of tumour cells to metastasise from their orthotopic site (spontaneous metastasis), stable subclones of this line (S+) that had been retrovirally transduced to express an ectopic full length HER1 were established and characterised. Proliferation, survival, and response to TGF-alpha were investigated and related to the tumorigenic growth and metastatic properties of the cells. S+ clones responded in vitro to ligand stimulation by growth inhibition and apoptosis. Upon orthotopic inoculation into the mammary fat pad of nude (nu/nu) mice, S+ clones showed retarded growth and apoptosed in situ, while MTC cells or neoR control cells showed no signs of apoptosis. Yet, S+ cells exhibited more spontaneous metastasis than the MTC parental cells or neoR control cells. Spontaneous metastasis requires cellular detachment (primary site) as well as attachment (secondary site) and growth in target organs. Neither the HER1 mediated increased ECM adhesion nor its negative effect on growth potential explains the observed effect. This is the first direct demonstration of the potential of EGFR to promote spontaneous metastasis of mammary adenocarcinoma cells from their orthotopic site.


Development and validation of synchronous spectrofluorimetric method for the simultaneous determination of duvelisib and moxifloxacin: greenness metric assessment and application to a pharmacokinetic study in rats.
Duvelisib (DUV) is a potent anticancer drug whereas Moxifloxacin (MOX) is an antimicrobial drug with anti-proliferative potency against cancerous cells, which is empirically administered in cancer treatment. DUV and MOX combination is commonly prescribed to combat infections in patients while they are under chemotherapy treatment. This study describes, for the first time, the development of a simple and green synchronous spectrofluorimetric (SSF) method for the simultaneous estimation of DUV and MOX in plasma. DUV and MOX were quantified at 273 and 362 nm, respectively without interference between each other at Δλof 120 nm. The experimental variables influencing fluorescence intensities were thoroughly investigated and the optimum conditions were established. At pH 3.5, the optimum synchronous fluorescence intensity (SFI) was achieved in water solvent by using sodium acetate buffer solution. Calibration curves for DUV and MOX, correlating the SFI with the corresponding drug concentration, were linear in the range of 50-1000 ng mL-1for both drugs, with good correlation coefficients. The method was extremely sensitive, with limits of detection of 24 and 22 ng mL-1, and limits of quantitation of 40 and 45 ngmL-1for DUV and MOX, respectively. The SSF method was validated according to the Food and Drug Administration (FDA) guidelines for validation of analytical procedures, and the validation parameters were acceptable. The proposed SSF method was applied to the pharmacokinetic and bioavailability studies in rats' plasma after single concurrent oral administration of both drugs. The results of the study revealed that caution should be taken with DUV dose when concurrently administered with MOX. The greenness of SSF method was assessed by three different metric tools namely Analytical Eco-scale, Green Analytical Procedure Index, and Analytical Greenness Calculator. The results confirmed that SSF method is an eco-friendly and green analytical approach. In conclusion, the proposed SSF method is a valuable tool for pharmacokinetic/bioavailability studies and therapeutic drug monitoring of simultaneously administered DUV and MOX.


Using laboratory selection for desiccation resistance to examine the relationship between respiratory pattern and water loss in insects.
We conducted concurrent measurements of rates of CO2 and H2O release from individual fruit flies Drosophila melanogaster taken from populations subjected to three different selective regimes: (1) populations selected for resistance to desiccation (D flies); (2) populations maintained as their controls (C flies); and (3) the ancestral populations of the D and C populations (O flies). In the D flies, water loss rates were significantly reduced, the standard error of the regression (SER) of the CO2 release pattern measured over the survival period of the flies was increased, and the ratio of CO2 loss to H2O loss (VCO2/VH2O) was increased. Correlations across all 15 populations from the three selection treatments indicate that survival time was negatively correlated with water loss rate, positively correlated with the SER of CO2 release and positively correlated with the VCO2/VH2O ratio. We did not, however, find a significant correlation between the SER of CO2 release and rates of water loss or the VCO2/VH2O ratio.


[Interferon-gamma and IgG antibodies to M. tuberculosis in the serum of patients with active pulmonary tuberculosis].
The above parameters in the sera from patients with active tuberculosis (n = 20) and healthy individuals (n = 16) were studied in parallel to examine the relationship and mutual effects of interferon-gamma (IFN-gamma) and IgG antibodies to Mycobacterium tuberculosis, as well as their relationship with some clinical and immunological features of tuberculous infection. The relative and absolute counts of CD4 and CD16 cells were additionally measured in these patients' peripheral blood. Patients with active tuberculosis were found to have significantly elevated serum levels of IFN-gamma, IgG antibodies and CD16 cells with the decreased count of CD4 cells as compared with the similar parameters in healthy individuals. There was no relationship of the serum level of IFN-gamma to the clinical features of tuberculosis. The serum level of IFN-gamma is likely to determine the interferonogenic activity of the causative agent itself.


Contributors to the substantial variation in on-treatment testosterone levels in men receiving transdermal testosterone gels in randomized trials.
There is substantial inter-individual variability in serum testosterone levels in hypogonadal men treated with testosterone gels. We aimed to elucidate participant-level factors that contribute to inter-individual variability in testosterone levels during testosterone therapy. An exploratory aim was to determine whether polymorphisms in genes encoding testosterone-metabolizing enzymes could explain the variation in on-treatment testosterone concentrations in men who were randomized to testosterone arm in TOM Trial. We used data from three randomized trials that used 1% transdermal testosterone gels and had testosterone levels measured 2-4 weeks after randomization for dose adjustment: Testosterone in Older Men with Mobility Limitation (TOM), Effects of Testosterone on Pain Perception (TAP), and Effects of Testosterone on Atherosclerosis Progression (TEAAM). Forty-seven percent, 38%, and 9% of participants in TAP, TEAAM, and TOM trials, respectively, failed to raise testosterone levels >400 ng/dL; 6, 8, and 30% of participants had on-treatment testosterone levels >1000 ng/dL. Even after dose adjustment, there was substantial variation in on-treatment levels at subsequent study visits. Baseline characteristics (age, height, weight, baseline testosterone, SHBG, hematocrit, and creatinine) accounted for only a small fraction of the variance (<8%). Polymorphisms in SHBG and AKR1C3 genes were suggestively associated with on-treatment testosterone levels. To conclude, baseline participant characteristics account for only a small fraction of the variance in on-treatment testosterone levels investigated. Multiple dose titrations are needed to maintain on-treatment testosterone levels in the target range. The role of SHBG and AKR3C1 polymorphisms as contributors to variations in on-treatment testosterone levels should be investigated.


Quality assurance in the United Kingdom.
In short, quality assurance in UK healthcare has developed since the mid-1980s driven by a series of national policy initiatives in the NHS, by increasing determination of the clinical professions to maintain standards, and by a general consumer movement to know more about public and professional services. Much has been achieved but there remains substantial debate about quality assurance leadership, coordination, funding and evaluation--or even what to call it.


Efficient laser based on CaF(2)-SrF(2)-YbF(3) nanoceramics.
CaF(2)-SrF(2)-YbF(3) fluoride ceramics of high optical quality was prepared, and its absorption, fluorescence, and laser oscillation properties were investigated. Oscillation slope efficiency that was only a few percent lower than that for a single crystal of similar composition was demonstrated under diode pumping.


The Cardiorespiratory fitness of children and adolescents in Tibet at altitudes over 3,500 meters.
Cardiorespiratory fitness (CRF) is the core element of health-related physical fitness evaluation. High pressure and low oxygen in Tibet (over 3,500 m above sea level) may negatively impact the residents' CRF. The 20-m shuttle run test (20mSRT) is the most popular field-based assessment and estimate of CRF in children and adolescents worldwide. However, normative CRF data for the children and adolescents residing in China's plateau region are unavailable, which prevents comparability among those living at high-altitudes around the world. To measure the CRF of Chinese children and adolescents aged 9-18 years living in Tibet at altitudes exceeding 3,500 m, and to identify correlations between this metric and demographic characteristics (age, sex, and ethnicity). These data were then compared with those generated in the lowland (Shanghai, China) and various global regions. 20mSRT performance (number of completed laps) and predicted peak oxygen consumption (VO2peak) were used as indicators of CRF. We measured the CRF of 1,717 healthy children and adolescents aged 9-18 years living in Tibet. The CRF data from school-age subjects in Shanghai (2,437 boys and 2,396 girls) and worldwide (1,142,026 students from 50 countries/regions in Africa, Asia, Europe, Latin America, North America, and Oceania) were collated from published papers. The average CRF of the participants from Tibet was 39.8 mL/kg/min. The male subjects (n = 876; 41.1 ± 4.42 mL/kg/min) had a higher average CRF than their female counterparts (n = 841; 37.8 ± 5.40 mL/kg/min). CRF decreased with age in both sexes at statistical significance (F = 1249.9, p for trend 0.05). The indigenous Tibetans (n = 1289; 40.1 ± 3.71 mL/kg/min) had a significant higher average CRF than those of Han descent (n = 394; 38.9 ± 4.70 mL/kg/min) (p < 0.05). Children and adolescents aged 7-18 years residing above 3,500 m in Tibet displayed lower CRF traits compared with their counterparts from the plains area and other high altitude places. CRF varied according to age, sex, and ethnic group. Given the importance of CRF in children and adolescents, effective intervention strategies should be implemented to improve CRF in children and adolescents on the plateau.


Do sociodemographic variables moderate effects of an internet intervention for mild to moderate depressive symptoms? An exploratory analysis of a randomised controlled trial (EVIDENT) including 1013 participants.
To explore the moderating effects of sociodemographic variables on treatment benefits received from participating in an internet intervention for depression. Randomised, assessor-blind, controlled trial. Online intervention, with participant recruitment using multiple settings, including inpatient and outpatient medical and psychological clinics, depression online forums, health insurance companies and the media (eg, newspaper, radio). The EVIDENT trial included 1013 participants with mild to moderate depressive symptoms. The intervention group subjects (n=509) received an online intervention (Deprexis) in addition to care as usual (CAU), while 504 participants received CAU alone. To explore subgroup differences, moderating effects were investigated using linear regression models based on intention-to-treat analyses. Moderating effects included sex, age, educational attainment, employment status, relationship status and lifetime frequency of episodes. The primary endpoint was change in self-rated depression severity measured by the Patient Health Questionnaire-9 (PHQ-9), comparing baseline versus 12-week post-test assessment. Secondary outcome measures were the Hamilton Rating Scale for Depression and the Quick Inventory of Depressive Symptoms each at 12 weeks and at 6 and 12 months, and PHQ-9 at 6 and 12 months, respectively. In this article, we focus on the primary outcome measure only. Between-group differences were observed in post-test scores, indicating the effectiveness of Deprexis. While the effects of the intervention could be demonstrated across all subgroups, some showed larger between-group differences than others. However, after exploring the moderating effects based on linear regression models, none of the selected variables was found to be moderating treatment outcomes. Our findings suggest that Deprexis is equally beneficial to a wide range of people; that is, participant characteristics were not associated with treatment benefits. Therefore, participant recruitment into web-based psychotherapeutic interventions should be broad, while special attention may be paid to those currently under-represented in these interventions. NCT01636752.


The impact of muscle relaxation techniques on the quality of life of cancer patients, as measured by the FACT-G questionnaire.
Patients with cancer frequently suffer from emotional distress, characterized by psychological symptoms such as anxiety or depression. The presence of psychological symptoms combined with the complex nature of oncology processes can negatively impact patients' quality of life. We aimed to determine the impact of a relaxation protocol on improving quality of life in a sample of oncological patients treated in the Spanish National Public Health System. We conducted a multicenter interventional study without a control group. In total, 272 patients with different oncologic pathologies and showing symptoms of anxiety were recruited from 10 Spanish public hospitals. The intervention comprised abbreviated progressive muscle relaxation training, according to Bernstein and Borkovec. This was followed by weekly telephone calls to each patient over a 1-month period. We collected sociodemographic variables related to the disease process, including information about mental health and the intervention. Patients' quality of life was assessed using the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire. Bivariate and univariate analyses were performed, along with an analysis of multiple correspondences to identify subgroups of patients with similar variations on the FACT-G. Patients showed statistically significant improvements on the FACT-G overall score (W = 16806; p<0.001), with an initial mean score of 55.33±10.42 and a final mean score of 64.49±7.70. We also found significant improvements for all subscales: emotional wellbeing (W = 13118; p<0.001), functional wellbeing (W = 16155.5; p<0.001), physical wellbeing (W = 8885.5; p<0.001), and social and family context (W = -1840; p = 0.037). Patients with cancer who learned and practiced abbreviated progressive muscle relaxation experienced improvement in their perceived quality of life as measured by the FACT-G. Our findings support a previous assumption that complementary techniques (including relaxation techniques) are effective in improving the quality of life of patients with cancer.


Exploiting the biomolecular corona: pre-coating of nanoparticles enables controlled cellular interactions.
Formation of the biomolecular corona ultimately determines the successful application of nanoparticles in vivo. Adsorption of biomolecules such as proteins is an inevitable process that takes place instantaneously upon contact with physiological fluid (e.g. blood). Therefore, strategies are needed to control this process in order to improve the properties of the nanoparticles and to allow targeted drug delivery. Here, we show that the design of the protein corona by a pre-formed protein corona with tailored properties enables targeted cellular interactions. Nanoparticles were pre-coated with immunoglobulin depleted plasma to create and design a protein corona that reduces cellular uptake by immune cells. It was proven that a pre-formed protein corona remains stable even after nanoparticles were re-introduced to plasma. This opens up the great potential to exploit protein corona formation, which will significantly influence the development of novel nanomaterials.


Pre-diagnosis body mass index and survival after breast cancer in the After Breast Cancer Pooling Project.
Obese and underweight women who develop breast cancer may have poorer survival compared with normal-weight women. However, the optimal weight for best prognosis is still under study. We conducted a prospective investigation of pre-diagnosis body mass index (BMI) and mortality among 14,948 breast cancer patients in the After Breast Cancer Pooling Project. Breast cancer patients diagnosed from 1990 to 2006 with AJCC Stage I-III breast tumors were drawn from four prospective cohorts. Hazard ratios (HR) and 95% confidence intervals (CI) representing the associations of BMI categories (World Health Organization international classifications) with recurrence and mortality were estimated using delayed entry Cox proportional hazards models. Obese (30 to < 35 kg/m(2)), severely obese (35 to < 40 kg/m(2)), and morbidly obese (≥ 40 kg/m(2)) were examined. After a mean follow-up of 7.8 years, 2,140 deaths and 2,065 recurrences were documented. Both underweight (HR = 1.59; 95% CI: 1.18, 2.13) and morbidly obese women (HR = 1.81; 95% CI: 1.42, 2.32) had the greatest risk of overall mortality compared with normal weight (18.5-24.9 kg/m(2)) women. Severe obesity (HR = 1.09; 95% CI: 0.88, 1.36) and obesity (HR = 1.11; 95% CI: 0.97, 1.27) were related to small non-significant increased risks. Overweight (25.0-29.9 kg/m(2)) was not associated with any excess risk compared with normal weight. Similar associations were found for breast cancer death and non-breast cancer death but not recurrence. Women who were underweight and morbidly obese before breast cancer diagnosis were at the greatest risk of all-cause mortality. Morbidly obese women were also at increased risk of death from breast cancer. These results suggest that degree of obesity confers differential risk on survival.


Indirect effects of COVID-19 on maternal, neonatal, child, sexual and reproductive health services in Kampala, Uganda.
COVID-19 impacted global maternal, neonatal and child health outcomes. We hypothesised that the early, strict lockdown that restricted individuals' movements in Uganda limited access to services. An observational study, using routinely collected data from Electronic Medical Records, was carried out, in Kawempe district, Kampala. An interrupted time series analysis assessed the impact on maternal, neonatal, child, sexual and reproductive health services from July 2019 to December 2020. Descriptive statistics summarised the main outcomes before (July 2019-March 2020), during (April 2020-June 2020) and after the national lockdown (July 2020-December 2020). Between 1 July 2019 and 31 December 2020, there were 14 401 antenatal clinic, 33 499 deliveries, 111 658 childhood service and 57 174 sexual health attendances. All antenatal and vaccination services ceased in lockdown for 4 weeks.During the 3-month lockdown, the number of antenatal attendances significantly decreased and remain below pre-COVID levels (370 fewer/month). Attendances for prevention of mother-to-child transmission of HIV dropped then stabilised. Increases during lockdown and immediately postlockdown included the number of women treated for high blood pressure, eclampsia and pre-eclampsia (218 more/month), adverse pregnancy outcomes (stillbirths, low-birth-weight and premature infant births), the rate of neonatal unit admissions, neonatal deaths and abortions. Maternal mortality remained stable. Immunisation clinic attendance declined while neonatal death rate rose (from 39 to 49/1000 livebirths). The number of children treated for pneumonia, diarrhoea and malaria decreased during lockdown. The Ugandan response to COVID-19 negatively impacted maternal, child and neonatal health, with an increase seen in pregnancy complications and fetal and infant outcomes, likely due to delayed care-seeking behaviour. Decreased vaccination clinic attendance leaves a cohort of infants unprotected, affecting all vaccine-preventable diseases. Future pandemic responses must consider impacts of movement restrictions and access to preventative services to protect maternal and child health.


Anti-β-amyloid immunotherapy for Alzheimer's disease: focus on bapineuzumab.
Recent advances in our understanding of the neurobiology of Alzheimer's disease (AD) have led to the development of putative disease-modifying treatments. The most revolutionary of these approaches consists in the removal of brain β-amyloid (Aβ) via anti-Aβ antibodies. Brain imaging and neuropathological studies have shown the ability of both active and passive anti-Aβ immunotherapies of clearing Aβ deposits from the brain of the AD patients. An active anti-Aβ vaccine preparation, AN1792, has been used in AD patients with some clues of clinical efficacy but causing meningoencephalitis in about 6% of patients and it has been abandoned. Several second-generation active Aβ vaccines and passive Aβ immunotherapies have been developed and are under clinical investigation with the aim of accelerating Aβ clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Aβ monoclonal antibodies, that has been tested in two Phase II trials, demonstrating to reduce Aβ burden in the brain of AD patients. However, the preliminary cognitive efficacy of bapineuzumab appears uncertain. The occurrence of vasogenic edema, especially in apolipoprotein E 4 carriers, may limit its clinical use and have led to abandon the highest dose of the drug (2 mg/kg). The results of four ongoing large Phase III trials on bapineuzumab will tell us if passive anti-Aβ immunization is able to alter the course if this devastating disease.


Development of birth weight estimation model for Ethiopian population from sonographic evaluation.
Fetal birth weight (FBW) estimation involves predicting the weight of a fetus prior to delivery. This prediction serves as a crucial input for ensuring effective, accurate, and appropriate obstetric planning, management, and decision-making. Typically, there are two methods used to estimate FBW: the clinical method (which involves measuring fundal height and performing abdominal palpation) or sonographic evaluation. The accuracy of clinical method estimation relies heavily on the experience of the clinician. Sonographic evaluation involves utilizing various mathematical models to estimate FBW, primarily relying on fetal biometry. However, these models often demonstrate estimation errors that exceed acceptable levels, which can result in inadequate labor and delivery management planning. One source of this estimation error is sociodemographic variations between population groups in different countries. Additionally, inter- and intra-observer variability during fetal biometry measurement also contributes to errors in FBW estimation. In this research, a novel mathematical model was proposed through multiple regression analysis to predict FBW with an accepted level of estimation error. To develop the model, population data consisting of fetal biometry, fetal ultrasound images, obstetric variables, and maternal sociodemographic factors (age, marital status, ethnicity, educational status, occupational status, income, etc.) of the mother were collected. Two approaches were used to develop the mathematical model. The first method was based on fetal biometry data measured by a physician and the second used fetal biometry data measured using an image processing algorithm. The image processing algorithm comprises preprocessing, segmentation, feature extraction, and fetal biometry measurement. The model developed using the two approaches were tested to assess their performance in estimating FBW, and they achieved mean percentage errors of 7.53% and 5.89%, respectively. Based on these results, the second model was chosen as the final model. The findings indicate that the developed model can estimate FBW with an acceptable level of error for the Ethiopian population. Furthermore, this model outperforms existing models for FBW estimation. The proposed approach has the potential to reduce infant and maternal mortality rates by providing accurate fetal birth weight estimates for informed obstetric planning.


Heterogeneous Dose-Response Analyses of Alcohol Abuse and Dependence.
Survey-based estimates of the prevalence of alcohol abuse, dependence, and disorders in the United States rely upon self-reports of drinking patterns (e.g., binge drinking), social problems (e.g., trouble at work), physiological responses to use (e.g., tolerance), and desistance from use (e.g., withdrawal). Diagnostic criteria derived from these reports enable prevalence estimates of abuse and dependence, but moderating structural relationships among symptom groups may lead some light and moderate drinkers to appear to exhibit an alcohol use disorder (AUD). A dynamic model of drinking and problems predicts that symptoms of dependence will moderate relationships between drinking measures and symptoms of abuse. Wave 1 National Epidemiologic Survey on Alcohol and Related Conditions data on DSM-IV diagnoses of abuse and dependence were used to test predictions from this model and assess whether moderating effects were observed among lighter and heavier drinkers (those who drink 1 to 3 vs. 4 or more drinks on average). A dose-response model that accounts for other known sources of risk heterogeneity related to drinking and problems enabled us to test these predictions. As expected from previous work, symptoms of abuse and dependence and dependence criteria were nonlinearly related to drinking patterns; more symptom reports appeared and criteria were met among less frequent drinkers who drank more on each occasion and this pattern of dose-response was substantially moderated among heavier drinkers. Controlling for these effects, relationships between drinking and symptoms of abuse were moderated among respondents who met more dependence criteria. These effects were observed among both lighter and heavier drinkers. Moderating relationships observed between measures of drinking, abuse, and dependence criteria among lighter and heavier drinkers suggest that the same etiologic forces are at play among all drinking groups. Greater symptoms of dependence among lighter drinkers may lead to greater reports of symptoms of abuse and an AUD diagnosis.


Kinetics of influenza A virus infection in humans.
Currently, little is known about the viral kinetics of influenza A during infection within an individual. We utilize a series of mathematical models of increasing complexity, which incorporate target cell limitation and the innate interferon response, to examine influenza A virus kinetics in the upper respiratory tracts of experimentally infected adults. The models were fit to data from an experimental H1N1 influenza A/Hong Kong/123/77 infection and suggest that it is important to include the eclipse phase of the viral life cycle in viral dynamic models. Doing so, we estimate that after a delay of approximately 6 h, infected cells begin producing influenza virus and continue to do so for approximately 5 h. The average lifetime of infected cells is approximately 11 h, and the half-life of free infectious virus is approximately 3 h. We calculated the basic reproductive number, R(0), which indicated that a single infected cell could produce approximately 22 new productive infections. This suggests that antiviral treatments have a large hurdle to overcome in moderating symptoms and limiting infectiousness and that treatment has to be initiated as early as possible. For about 50% of patients, the curve of viral titer versus time has two peaks. This bimodal behavior can be explained by incorporating the antiviral effects of interferon into the model. Our model also compared well to an additional data set on viral titer after experimental infection and treatment with the neuraminidase inhibitor zanamivir, which suggests that such models may prove useful in estimating the efficacies of different antiviral therapies for influenza A infection.


DIVERSITY: Parity as a Goal Sparks Bitter Battle.
A small group of contrarian scholars believes that the main reason for the dearth of women in engineering and physical sciences is that females by nature are more interested in people-oriented professions. And they don't see this as a problem that needs fixing. Mainstream activists acknowledge the differences but attribute them to cultural factors.


A dominant function of p38 mitogen-activated protein kinase signaling in receptor activator of nuclear factor-kappaB ligand expression and osteoclastogenesis induction by Aggregatibacter actinomycetemcomitans and Escherichia coli lipopolysaccharide.
Lipopolysaccharide from gram-negative bacteria is one of the microbial-associated molecular patterns that initiate the immune/inflammatory response, leading to the tissue destruction observed in periodontitis. The aim of this study was to evaluate the role of the p38 mitogen-activated protein kinase (MAPK) signaling pathway in lipopolysaccharide-induced receptor activator of nuclear factor-kappaB ligand (RANKL) expression by murine periodontal ligament cells. Expression of RANKL and osteoprotegerin mRNA was studied by reverse transcription-polymerase chain reaction upon stimulation with lipopolysaccharide from Escherichia coli and Aggregatibacter actinomycetemcomitans. The biochemical inhibitor SB203580 was used to evaluate the contribution of the p38 MAPK signaling pathway to lipopolysaccharide-induced RANKL and osteoprotegerin expression. Stable cell lines expressing dominant-negative forms of MAPK kinase (MKK)-3 and MKK6 were generated to confirm the role of the p38 MAPK pathway. An osteoclastogenesis assay using a coculture model of the murine monocytic cell line RAW 264.7 was used to determine if osteoclast differentiation induced by lipopolysaccharide-stimulated periodontal ligament was correlated with RANKL expression. Inhibiting p38 MAPK prior to lipopolysaccharide stimulation resulted in a significant decrease of RANKL mRNA expression. Osteoprotegerin mRNA expression was not affected by lipopolysaccharide or p38 MAPK. Lipopolysaccharide-stimulated periodontal ligament cells increased osteoclast differentiation, an effect that was completely blocked by osteoprotegerin and significantly decreased by inhibition of MKK3 and MKK6, upstream activators of p38 MAPK. Conditioned medium from murine periodontal ligament cultures did not increase osteoclast differentiation, indicating that periodontal ligament cells produced membrane-bound RANKL. Lipopolysaccharide resulted in a significant increase of RANKL in periodontal ligament cells. The p38 MAPK pathway is required for lipopolysaccharide-induced membrane-bound RANKL expression in these cells.


Familial contribution to adolescent subjective well-being.
The purpose of this study was to obtain a more complete understanding of which familial factors contribute to adolescent satisfaction and ill-being, the latter term originally developed by Alexander Grob. Semistructured interviews were conducted with 19 non-clinical adolescents from the 7th and 9th grades. The data were analysed using qualitative content analysis. Six themes concerning satisfaction arose from the analysis. Teenagers described familial contribution to their satisfaction in terms of experiences of a comfortable home, emotionally warm atmosphere, open communication, familial involvement, possibilities for external relations and a sense of personal significance in the family. Three themes related to ill-being emerged: familial hostility, ill-being or death of a family member, as well as excessive dependency. The findings expand our understanding of the diversity of familial contribution to adolescent life and subjective well-being. They challenge nurses to focus on the adolescent's self-perception of familial effects on well-being and on promotion of familial factors in adolescent health issues.


Modulation of Rab7a-mediated growth factor receptor trafficking inhibits islet beta cell apoptosis and autophagy under conditions of metabolic stress.
Regenerative medicine approaches to enhancing beta cell growth and survival represent potential treatments for diabetes. It is known that growth factors such as insulin, IGF-1 and HGF support beta cell growth and survival, but in people with type 2 diabetes the destructive effects of metabolic stress predominate and beta cell death or dysfunction occurs. In this study we explore the novel hypothesis that regulation of growth factor receptor trafficking can be used to promote islet beta cell survival. Growth factor signalling is dependent on the presence of cell surface receptors. Endosomal trafficking and subsequent recycling or degradation of these receptors is controlled by the Rab GTPase family of proteins. We show that Rab7a siRNA inhibition enhances IGF-1 and HGF signalling in beta cells and increases expression of the growth factor receptors IGF-1R and c-Met. Furthermore, Rab7a inhibition promotes beta cell growth and islet survival, and protects against activation of apoptosis and autophagy pathways under conditions of metabolic stress. This study therefore demonstrates that Rab7a-mediated trafficking of growth factor receptors controls beta cell survival. Pharmaceutical Rab7a inhibition may provide a means to promote beta cell survival in the context of metabolic stress and prevent the onset of type 2 diabetes.


Structural Revision of Wentiquinone C and Related Congeners from Anthraquinones to Xanthones Using Chemical Derivatization and NMR Analysis.
Wentiquinone C, which was previously isolated from the marine brown alga-derived endophytic fungus Aspergillus wentii EN-48, was found to be a potent antioxidant against α,α-diphenyl-picrylhydrazyl (DPPH) radical. The structure of wentiquinone C was originally assigned as an anthraquinone derivative (1,10-dihydroxy-3-(hydroxymethyl)-8-methoxydibenzo [b,e]oxepine-6,11-dione, 1) by 1D and 2D NMR experiments. However, the minor differences of the chemical shifts between xanthones and anthraquinones were queried, leading to the structure of 1 to be revised as a xanthone analog (8-hydroxy-6-(hydroxymethyl)-3-methoxy-9-oxo-9H-xanthene-1-carboxylic acid, 2) on the basis of a methylation and subsequent NMR measurements, and was confirmed by X-ray crystallographic analysis. The method established in this paper could be applied to the structural re-examination or revision for some of the reported seco-anthraquinone derivatives.


Pancreatic extract lung sensitivity.
Seven patients with respiratory tract sensitivity to powdered pig pancreatic extract were studied with regard to their atropic status and the immunological nature of this sensitivity. The results confirmed the role of allergen specific antibodies to pig pancreatic extract in this sensitization and underlined susceptibility of atopic subjects to develop respiratory sensitivity to allergens to which they are exposed.


IMPORTANCE SAMPLING AND THE TWO-LOCUS MODEL WITH SUBDIVIDED POPULATION STRUCTURE.
The diffusion-generator approximation technique developed by De Iorio and Griffiths (2004a) is a very useful method of constructing importance sampling proposal distributions. Being based on general mathematical principles, the method can be applied to various models in population genetics. In this paper we extend the technique to the neutral coalescent model with recombination, thus obtaining novel sampling distributions for the two-locus model. We consider the case with subdivided population structure, as well as the classic case with only a single population. In the latter case we also consider the importance sampling proposal distributions suggested by Fearnhead and Donnelly (2001), and show that their two-locus distributions generally differ from ours. In the case of the infinitely-many-alleles model, our approximate sampling distributions are shown to be generally closer to the true distributions than are Fearnhead and Donnelly's.


Surgical Management of Lower Extremity Pyoderma Gangrenosum With Viable Cryopreserved Umbilical Tissue: A Case Series.
Pyoderma gangrenosum (PG) is a rare skin disease that often presents as a uniquely painful and necrotic ulceration of the lower extremity. Pyoderma gangrenosum is often misdiagnosed and can have deleterious consequences to the patient, as there is no gold standard treatment and it can be difficult to manage. Surgery for these wounds is controversial, as pathergy can develop, worsening the ulceration. Advanced wound care products such as cellular- and/or tissue-based products (CTPs) are effective in helping stagnant chronic wounds reach full closure. Amnion/chorion-based skin substitutes that have been cryopreserved and contain viable cells have been shown to promote more cell recruitment and reduce inflammation. This case series presents evidence of using a cryopreserved umbilical cord tissue with living cells in adjunctive treatment of wounds associated with PG. This report presents 3 different clinical scenarios of lower extremity PG treated surgically with viable cryopreserved umbilical tissue (vCUT). All 3 patients were successfully treated with vCUT and resulted in complete healing. To the best of the authors' knowledge, this is the first case series demonstrating the ability of vCUT to heal these difficult-to-treat ulcers. In addition, it may be an effective modality to adjunctive management of PG.


A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3.
Among the various coats involved in vesicular transport, the clathrin associated coats that contain the adaptor complexes AP-1 and AP-2 are the most extensively characterized. The function of the recently described adaptor complex AP-3, which is similar to AP-1 and AP-2 in protein composition but does not associate with clathrin, is not known. By monitoring surface plasmon resonance we observed that AP-3 is able to interact with the tail of the lysosomal integral membrane protein LIMP-II and that this binding depends on a DEXXXLI sequence in the LIMP-II tail. Furthermore, AP-3 bound to the cytoplasmic tail of the melanosome-associated protein tyrosinase which contains a related EEXXXLL sequence. The tails of LIMP-II and tyrosinase either did not interact, or only interacted poorly, with AP-1 or AP-2. In contrast, the cytoplasmic tails of other membrane proteins containing di-leucine and/or tyrosine-based sorting signals did not bind AP-3, but AP-1 and/or AP-2. This points to a function of AP-3 in intracellular sorting to lysosomes and melanosomes of a subset of cargo proteins via di-leucine-based sorting motifs.


Social network diversity and risks of ischemic heart disease and total mortality: findings from the Copenhagen City Heart Study.
Measures of various types of social contacts were used as predictors of ischemic heart disease events and total mortality in an age-stratified random sample of 9,573 adults enrolled in the Copenhagen City Heart Study (Copenhagen, Denmark). Baseline examinations were conducted in 1991-1994, and participants were followed until the end of 1997. Contacts with parents, children, family members, and friends were associated with better health. The presence of a spouse or partner was protective for men. Contacts with neighbors showed a trend toward a reversed pattern, and the effects of contacts with work colleagues and children differed by gender. Most types of contacts that occurred at least monthly were just as protective as those occurring more frequently. An index of intimate social contact diversity with family and friends had graded relations with both outcomes. Comparisons of persons reporting three or more types of contacts with those reporting fewer types yielded age- and gender-adjusted hazard ratios of 0.73 (95% confidence interval (CI): 0.64, 0.82) for mortality and 0.75 (95% CI: 0.61, 0.91) for ischemic heart disease. Comparable fully adjusted hazard ratios were 0.83 (95% CI: 0.73, 0.95) and 0.82 (95% CI: 0.67, 1.00). These data suggest that health benefits are derived from the diversity of social roles, especially those involving intimate relationships.


Dietary protein intake and all-cause and cause-specific mortality: results from the Rotterdam Study and a meta-analysis of prospective cohort studies.
Evidence for associations between long-term protein intake with mortality is not consistent. We aimed to examine associations of dietary protein from different sources with all-cause and cause-specific mortality. We followed 7786 participants from three sub-cohorts of the Rotterdam Study, a population-based cohort in the Netherlands. Dietary data were collected using food-frequency questionnaires at baseline (1989-1993, 2000-2001, 2006-2008). Deaths were followed until 2018. Associations were examined using Cox regression. Additionally, we performed a highest versus lowest meta-analysis and a dose-response meta-analysis to summarize results from the Rotterdam Study and previous prospective cohorts. During a median follow-up of 13.0 years, 3589 deaths were documented in the Rotterdam Study. In this cohort, after multivariable adjustment, higher total protein intake was associated with higher all-cause mortality [e.g. highest versus lowest quartile of total protein intake as percentage of energy (Q4 versus Q1), HR = 1.12 (1.01, 1.25)]; mainly explained by higher animal protein intake and CVD mortality [Q4 versus Q1, CVD mortality: 1.28 (1.03, 1.60)]. The association of animal protein intake and CVD was mainly contributed to by protein from meat and dairy. Total plant protein intake was not associated with all-cause or cause-specific mortality, mainly explained by null associations for protein from grains and potatoes; but higher intake of protein from legumes, nuts, vegetables, and fruits was associated with lower risk of all-cause and cause-specific mortality. Findings for total and animal protein intake were corroborated in a meta-analysis of eleven prospective cohort studies including the Rotterdam Study (total 64,306 deaths among 350,452 participants): higher total protein intake was associated with higher all-cause mortality [pooled RR for highest versus lowest quantile 1.05 (1.01, 1.10)]; and for dose-response per 5 energy percent (E%) increment, 1.02 (1.004, 1.04); again mainly driven by an association between animal protein and CVD mortality [highest versus lowest, 1.09 (1.01, 1.18); per 5 E% increment, 1.05 (1.02, 1.09)]. Furthermore, in the meta-analysis a higher plant protein intake was associated with lower all-cause and CVD mortality [e.g. for all-cause mortality, highest versus lowest, 0.93 (0.87, 0.99); per 5 E% increment, 0.87 (0.78, 0.98), for CVD mortality, highest versus lowest 0.86 (0.73, 1.00)]. Evidence from prospective cohort studies to date suggests that total protein intake is positively associated with all-cause mortality, mainly driven by a harmful association of animal protein with CVD mortality. Plant protein intake is inversely associated with all-cause and CVD mortality. Our findings support current dietary recommendations to increase intake of plant protein in place of animal protein.Clinical trial registry number and website NTR6831, https://www.trialregister.nl/trial/6645.


Sodium arsenite disturbs mitosis and induces chromosome loss in human fibroblasts.
Arsenite, a unique human carcinogen, induces many types of cytogenetic alterations, such as sister chromatid exchanges, chromosome aberrations, and endoreduplication in a variety of in vivo and in vitro systems. Cytogenetic alterations are frequently associated with cancer development. The purpose of this study was to explore how arsenite induces cytogenetic alterations in human skin fibroblasts (HFW). The present results show that treatment of G2-enriched HFW cells with 5 microM arsenite results in significant delay of cell cycle progression, accumulation of mitotic cells, and prolongation of mitosis. Arsenite-induced G2 and mitotic delay are accompanied by accumulation of cyclin B1 and hyperphosphorylation of cdc2 and Mos proteins. In addition to mitotic delay and prolongation, arsenite treatment also induced out-of-phase centromere separation and alterations of chromosome segregation, such as the appearance of c-metaphase, ball-metaphase, and lagged chromosomes. Unlike spindle poisons, arsenite at the dose range used did not inhibit the spindle fiber formation but conceivably deranges the spindle apparatus. By analyzing the karyotype of established subclones surviving arsenite injury, 18% (8 of 44) showed one chromosome loss, whereas all 26 subclones derived from the untreated cultures were diploid. Furthermore, most arsenite-treated clones manifest prolonged life span (86 +/- 18 population doublings) as compared to those derived from the untreated cultures (44 +/- 11 population doublings). Unfortunately, none became immortal. Collectively, treatment of the G2-enriched HFW cells with arsenite can disturb the mitotic events and subsequently induce chromosome loss.


Number of teeth is related to atherosclerotic plaque in the carotid arteries in an elderly population.
Periodontal disease has been associated with cardiovascular disorders with an atherosclerotic background, and number of teeth (NT) has been suggested as a possible risk indicator for cardiovascular disease. The objective of this study is to investigate whether NT was related to the intima-media thickness (IMT) and to atherosclerotic plaque in carotid arteries in an elderly population. In a population-based study including 1,016 participants aged 70 years, the NT was self-reported by 947 of the participants. Carotid artery IMT was evaluated by ultrasound. The occurrence of plaque was also measured. Logistic regression was used to analyze the associations between NT and the number of carotid arteries with plaque. A significant inverse relationship was found between the NT and the number of carotid arteries with plaque after adjustment for age, sex, smoking, body mass index, waist/hip ratio, blood glucose, triglycerides, cholesterol, C-reactive protein, leukocyte count, blood pressure, and Framingham risk score, with odds ratio of 0.89, 95% confidence interval of 0.82 to 0.98, and P = 0.016. The relationship was fairly linear, suggesting a dose-response relationship. When NT was divided into quintiles using the first one as referent, the relationship persisted for all quintiles except for the second one. However, no relationship to IMT was seen. The present study further emphasizes that tooth loss could be an easily obtained risk indicator for atherosclerosis.


The ARO4 gene of Candida albicans encodes a tyrosine-sensitive DAHP synthase: evolution, functional conservation and phenotype of Aro3p-, Aro4p-deficient mutants.
The enzyme 3-deoxy-D-arabinoheptulosonate-7-phosphate (DAHP) synthase catalyses the first step in aromatic amino acid biosynthesis in prokaryotes, plants and fungi. Cells of Saccharomyces cerevisiae contain two catalytically redundant DAHP synthases, encoded by the genes ARO3 and ARO4, whose activities are feedback-inhibited by phenylalanine and tyrosine, respectively. ARO3/4 gene transcription is controlled by GCN4. The authors previously cloned an ARO3 gene orthologue from Candida albicans and found that: (1) it can complement an aro3 aro4 double mutation in S. cerevisiae, an effect inhibited by excess phenylalanine, and (2) a homozygous aro3-deletion mutant of C. albicans is phenotypically Aro(+), suggesting the existence of another isozyme(s). They now report the identification and functional characterization of the C. albicans orthologue of S. cerevisiae Aro4p. The two Aro4p enzymes share 68% amino acid identity. Phylogenetic analysis places the fungal DAHP synthases in a cluster separate from prokaryotic orthologues and suggests that ARO3 and ARO4 arose from a single gene via a gene duplication event early in fungal evolution. C. albicans ARO4 mRNA is elevated upon amino acid starvation, consistent with the presence of three putative Gcn4p-responsive elements (GCREs) in the gene promoter sequence. C. albicans ARO4 complements an aro3 aro4 double mutation in S. cerevisiae, an effect inhibited by excess tyrosine. The authors engineered Deltaaro3/Deltaaro3 Deltaaro4/MET3p::ARO4 cells of C. albicans (with one wild-type copy of ARO4 placed under control of the repressible MET3 promoter) and found that they fail to grow in the absence of aromatic amino acids when ARO4 expression is repressed, and that this growth defect can be partially rescued by aromatic amino acids and certain aromatic amino acid pathway intermediates. It is concluded that, like S. cerevisiae, C. albicans contains two DAHP synthases required for the first step in the aromatic amino acid biosynthetic pathway.


Out of the shade and into the light.
Plants reach for the sun by avoiding the shade and by directly growing towards the light. Two studies now suggest that the polar relocation of PIN3, a transporter directing the flow of the plant hormone auxin, drives both growth processes. PIN3 repolarization occurs downstream of shade perception through phytochrome photoreceptors, whereas blue light perceived by phototropin initiates polar recycling of PIN3 and growth towards the light.


Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D.
The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.


Changes in intestinal microbiota and humoral immune response following probiotic administration in brown trout (Salmo trutta).
We studied the effect of several lactic acid bacteria (LAB) on the humoral response of brown trout (Salmo trutta). LAB groups (Lactococcus (Lc.) lactis ssp. lactis, Lactobacillus (Lb.) sakei and Leuconostoc (Leu.) mesenteroides) were administered orally at 10(6) colony-forming units/g feed to brown trout for 2 weeks, after which fish were switched to an unsupplemented feed. Blood and intestinal samples were taken from the onset of feeding supplemented diets at 1, 2, 3 and 4 weeks. During the LAB-feeding period, Lc. lactis ssp. lactis, Lb. sakei and Leu. mesenteroides persisted in the fish intestines, but the number of LAB slowly decreased in the intestines after changing to the unsupplemented diet. Only Lb. lactis ssp. lactis and Leu. mesenteroides were detected at levels above 1 x 10(2) colony-forming units/g at the end of the fourth week. In comparison to untreated control fish, the alternative complement activity in the serum was found to be significantly greater in all LAB groups at the end of the second week. Groups supplemented with Lc. lactis ssp. lactis and Leu. mesenteroides exhibited an elevated level of lysozyme activity at the end of the third week, but the group supplemented with Lb. sakei did not exhibit any significant change in lysozyme activity. Serum immunoglobulin levels were higher compared with the control group, but there was no significant difference between the LAB and control groups.


The Worrying Trend of Diabetes Mellitus in Saudi Arabia: An Urgent Call to Action.
From last few years, the pervasiveness of diabetes mellitus (DM), in Saudi Arabia, is growing at a frightening rate. Overall, one-fourth of the adult population is affected by DM, which is further predicted to rise to more than double by the year 2030. The most alarming is possibly the escalation propensity of diabetes, in recent years, where a nearly ten-fold increase has been witnessed over the past thirty years in Saudi Arabia. However, the number of research arbitrations on the prevalence and incidence of DM is woefully inadequate, as compared to developed countries. Apart from this, most of the existing research data carried out in Saudi Arabia is cross-sectional, with small sample sizes, which most often involve only certain parts of the country. Consequently, the present scenario demands more multidimensional and multisectoral research to strengthen the evidence base and to accumulate greater knowledge as a basis for measures and programmes to confront diabetes and its complications. Thus, the present report makes an attempt to depict the current trend of diabetes as well as intends to put forward essential measures for controlling diabetes in Saudi Arabia.


Phylogenomic species delimitation in microendemic frogs of the Brazilian Atlantic Forest.
The advent of next-generation sequencing allows researchers to use large-scale datasets for species delimitation analyses, yet one can envision an inflection point where the added accuracy of including more loci does not offset the increased computational burden. One alternative to including all loci could be to prioritize the analysis of loci for which there is an expectation of high informativeness. Here, we explore the issue of species delimitation and locus selection with montane species from two anuran genera that have been isolated in sky islands across the southern Brazilian Atlantic Forest: Melanophryniscus (Bufonidae) and Brachycephalus (Brachycephalidae). To delimit species, we obtained genetic data using target enrichment of ultraconserved elements from 32 populations (13 for Melanophryniscus and 19 for Brachycephalus), and we were able to create datasets that included over 800 loci with no missing data. We ranked loci according to their number of parsimony-informative sites, and we performed species delimitation analyses using BPP with the most informative 10, 20, 40, 80, 160, 320, and 640 loci. We identified three types of phylogenetic node: nodes with either consistently high or low support regardless of the number of loci or their informativeness and nodes that were initially poorly supported where support became stronger as we included more data. When viewed across all sensitivity analyses, our results suggest that the current species richness in both genera is likely underestimated. In addition, our results show the effects of different sampling strategies on species delimitation using phylogenomic datasets.


Type I interferon-dependent CCL4 is induced by a cGAS/STING pathway that bypasses viral inhibition and protects infected tissue, independent of viral burden.
Type I interferons (T1-IFN) are critical in the innate immune response, acting upon infected and uninfected cells to initiate an antiviral state by expressing genes that inhibit multiple stages of the lifecycle of many viruses. T1-IFN triggers the production of Interferon-Stimulated Genes (ISGs), activating an antiviral program that reduces virus replication. The importance of the T1-IFN response is highlighted by the evolution of viral evasion strategies to inhibit the production or action of T1-IFN in virus-infected cells. T1-IFN is produced via activation of pathogen sensors within infected cells, a process that is targeted by virus-encoded immunomodulatory molecules. This is probably best exemplified by the prototypic poxvirus, Vaccinia virus (VACV), which uses at least 6 different mechanisms to completely block the production of T1-IFN within infected cells in vitro. Yet, mice lacking aspects of T1-IFN signaling are often more susceptible to infection with many viruses, including VACV, than wild-type mice. How can these opposing findings be rationalized? The cytosolic DNA sensor cGAS has been implicated in immunity to VACV, but has yet to be linked to the production of T1-IFN in response to VACV infection. Indeed, there are two VACV-encoded proteins that effectively prevent cGAS-mediated activation of T1-IFN. We find that the majority of VACV-infected cells in vivo do not produce T1-IFN, but that a small subset of VACV-infected cells in vivo utilize cGAS to sense VACV and produce T1-IFN to protect infected mice. The protective effect of T1-IFN is not mediated via ISG-mediated control of virus replication. Rather, T1-IFN drives increased expression of CCL4, which recruits inflammatory monocytes that constrain the VACV lesion in a virus replication-independent manner by limiting spread within the tissue. Our findings have broad implications in our understanding of pathogen detection and viral evasion in vivo, and highlight a novel immune strategy to protect infected tissue.


[Fungal contamination in a University building].
It is recognized that airborne fungi can cause illnesses in humans but data on environmental exposure are still poor. The aim of this study was to evaluate the fungal airborne contamination in a university building. The study was performed in February and May 2018; air samples were collected, before activity (on Monday) and during activity, (on Friday), both through active (CFU/m3) and passive (Index of microbial air contamination, IMA) method. Fungi were identified by using the scotch test. In February the median fungal contamination value decreased from 14 CFU/m3 before activity to 7 CFU/m3 during activity, while IMA median remains 0. Instead in May both increased during activity (from 87 to 140 CFU/m3; from 5.5 to 7.5 IMA). Overall values increased in May compared to February. Aspergillus spp., Penicillium spp., Cladosporium spp. Absidia spp. were the genera most frequently isolated in both months, while in May Chaetomium spp. e Ulocladium spp. were recovered too. Seasonal trend in the levels of fungal contamination of the air was observed, with a statistically significant increase in May. This study represents the first step of a wider study aimed at enhancing knowledge about air fungal contamination.


Uptake and release of bilirubin by skin.
1. Skin epithelium of albino rat, mouse and guinea pig was shown to accumulate bilirubin from a medium containing free or bound bilirubin. 2. The K(m) values for bound bilirubin were 2.22x10(-3), 1.33x10(-3) and 9.5x10(-4)m for rat, mouse and guinea pig respectively and the corresponding K(m) values for free bilirubin were 5.2x10(-4), 4.0x10(-4), 1.8x10(-4)m; the V(max.) values of bound and free bilirubin were unchanged. 3. The uptake showed saturation kinetics. Bound bilirubin was released together with serum proteins. Free bilirubin bound to skin was not released into the medium. 4. Freezing and thawing of skin epithelium did not cause any significant lowering of the uptake of bilirubin but heat-denatured skin epidermis took up only 50% of the bound bilirubin or free bilirubin taken up by control unheated skin epithelium. 5. The uptake of free and bound bilirubin was prevented by HgCl(2) but not by sodium arsenate, NaCN, NaF, cycloheximide, 2,4-dinitrophenol or iodoacetate. 6. Most of the free bilirubin was bound to the lipids or lipoprotein fraction of skin epithelium and could be extracted by solvents. 7. Rat skin showed the highest accumulation and efflux of bilirubin.


Is cardioplegia system pressure the optimal measure of coronary perfusion during antegrade cardioplegia delivery? A critical review of pressure measurements for optimal antegrade delivery.
Antegrade cardioplegia is routinely given during cardiac surgery. The delivery of antegrade cardioplegia from the cardiopulmonary bypass machine has many variables. Many perfusionists rely exclusively on cardioplegia system pressure to ensure safe antegrade delivery. Our group reviewed antegrade cardioplegia delivery in 50 patients undergoing coronary artery bypass graft. The data collected included the cardioplegia system pressure and the patient's direct aortic root pressure. The analysis of the data found weak correlation between the two pressures with a large mean difference and a wide standard deviation. The results suggest the direct measurement of aortic root pressure as guidance to antegrade cardioplegia instead of relying solely on cardioplegia system pressure.


Intrathecal catheterisation after observed accidental dural puncture in labouring women: update of a meta-analysis and a trial-sequential analysis.
Our meta-analysis from 2013 showed that inserting a catheter intrathecally after an observed accidental dural puncture can reduce the need for epidural blood patch in labouring women requesting epidural analgesia. We updated our conventional meta-analysis and added a trial-sequential analysis (TSA). A systematic literature search was conducted to identify studies that compared inserting the catheter intrathecally with an epidural catheter re-site or with no intervention. The extracted data were pooled and the risk ratio (RR) and 95% confidence interval (95%CI) for the incidence of post-dural puncture headache (PDPH) was calculated, using the random effects model. A contour-enhanced funnel plot was constructed. A TSA was performed and the cumulative Z score, monitoring and futility boundaries were constructed. Our search identified 13 studies, reporting on 1653 patients, with a low risk of bias. The RR for the incidence of PDPH was 0.82 (95%CI 0.71 to 0.95) and the RR for the need for epidural blood patch was 0.62 (95%CI 0.49 to 0.79); heterogeneity of both analyses was high. The TSA showed that the monitoring or futility boundaries were not crossed, indicating insufficient data to exclude a type I error of statistical analysis. Contour-enhanced funnel plots were symmetric, suggesting no publication bias. Conventional meta-analyses showed for the first time that intrathecal catheterisation can reduce the incidence of PDPH. However, TSA did not corroborate this finding. Despite increasing use in clinical practice there is no firm evidence on which to base a definite conclusion.


Change in ascorbate radical production in an irradiated experimental tumor with increased tumor size.
We have reported that ascorbate radical (Asc.-) could serve as an indicator of the amount of hydroxyl radical and superoxide produced by irradiation in vivo. Using this method, we investigated the relationship between tumor size and Asc.- production after irradiation (10 Gy) and between tumor size and the radical-scavenging ability of WR-2721 (300 mg/kg). Asc.- was measured in normal muscle and SCC-VII tumors transplanted into mice (n = 6). In tumors, the increase in Asc.- significantly decreased with increasing tumor size (r = -0.483; P < 0.05). The increase in Asc.- production after irradiation was more inhibited by WR-2721 in normal muscle tissue than in tumor tissue at various sizes. In tumors, the increase in Asc.- was less inhibited by WR-2721 with increasing tumor size. These results demonstrate that the increase in radical production after irradiation and drug distribution decreased with increasing tumor size and that WR-2721 has excellent differential protection. This method is expected to measure changes in the amounts of local hydroxyl radical and superoxide modified by a change of tumor environment or drug administration.


An initial radiation safety needs assessment of Costa Rica: the South Texas Chapter of the Health Physics Society's strategic planning appraisal for participation in the "Radiation Safety Without Borders" initiative.
In response to the Health Physics Society's recent 'radiation safety without borders" initiative, the South Texas Chapter of the Health Physics Society selected Costa Rica as its partner country of choice. To develop an understanding of the radiation safety needs of this country, the fall 2001 University of Texas Health Science Center at Houston School of Public Health Environmental Radiation and Radioactivity class was tasked with the assignment of assessing the possible radiation safety needs and concerns for this country. The assignment culminated in a class presentation to the membership of the South Texas Chapter during its annual fall meeting. Using library and web based resources, tile students reviewed a number of public health and radiation-related topics. Life expectancies were found to be equivalent to the United States, even though significant differences in per capita health expenditures were noted. Costa Rica exhibited lower population mortality rates from major causes such as cardiovascular diseases, neoplasms, and external sources. Maternal and infant mortality rates were found to be much higher in Costa Rica than in the United States. Naturally occurring radiation sources such as uranium deposits were not identified as apparent major radiation issues of concern, although ultraviolet radiation exposures are consistently high. Several recent events in the country and the region involving patient overexposures suggest that concerns are likely focused on ensuring the proper use and maintenance of healing arts radiation equipment. The lack of available information on radioactive waste disposal suggests that waste handling also may be an issue warranting attention. The exercise proved to be very educational for the students, and the information gathered will serve to focus the Chapter's efforts when technical exchanges are initiated. The importance of linking this initiative to other existing programs within the country is also discussed.


Estimating the Impact of Necrotizing Soft Tissue Infections in the United States: Incidence and Re-Admissions.
Background: Previous estimates of the incidence of necrotizing soft tissue infections (NSTI) in the United States have substantial limitations and underestimate its occurrence. Improvements in hospital mortality after NSTI have increased the number of survivors at risk for long-term sequelae. This study estimates the incidence of NSTI and the burden of re-admission and associated healthcare spending in patients who survived admission for NSTI. Methods: Index admissions for NSTI were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes combined with either Current Procedural Technology (CPT) or diagnosis-related group codes to increase specificity. Two separate datasets were used to provide primary and secondary estimates of the annual incidence of NSTIs in the United States: the National Inpatient Sample (NIS) for the years 2012-2016 and the Watson Health dataset for 2009-2013, respectively, and extrapolated to estimate the incidence for 2018. The Nationwide Readmissions Database (NRD) from 2013-2015 was used to estimate of the risk for re-admission, cost of re-admissions, and to compare 90-day re-admission rates for NSTI to common medical conditions. Results: National Inpatient Sample and Watson Health datasets demonstrated an increasing annual incidence and estimated 33,600 and 28,500 cases in 2018, respectively. The estimated annual incidences in the United States in 2018 were 10.3 and 8.7 per 100,000 persons, respectively. Risk of 90-day re-admission ranged from 24%-29% over the 3 years, 89% of which were unplanned. Of those re-admitted, 90% had one or more comorbidities, the most common diagnoses associated with re-admission were infection in 65%, acute kidney injury in 22%, and shock in 10%. The median re-admission length of stay was seven days (interquartile range [IQR]: 4-13 days) with a median cost of re-admission of $13,590 (IQR: $7186-$27440). Conclusion: The incidence of NSTI is more common than generally reported. Re-admission within 90 days is common, occurring in more than one in four survivors resulting in high healthcare costs.


Differences in adaptations to 1 year of aerobic endurance training: individual patterns of nonresponse.
Lacking responses to endurance training (ET) have been observed for several variables. However, detailed analyses of individuals' responses are scarce. To learn more about the variability of ET adaptations, patterns of response were analyzed for each subject in a 1-year ET study. Eighteen participants [42 ± 5 years, body mass index: 24 ± 3 kg/m(2), maximal oxygen uptake (VO(2max) ): 38 ± 5 mL/min/kg] completed a 1-year jogging/walking program on 3 days/week, 45 min/session at 60% heart rate (HR) reserve. VO(2max), resting HR (rHR), exercise HR (eHR) and individual anaerobic threshold (IAT) were determined by treadmill and cycling ergometry respectively. Intraindividual coefficients of variation were extracted from the literature to distinguish random changes from training responses. Eight participants showed improvements in all variables. In 10 participants, one or two variables did not improve (VO(2max), rHR, eHR and IAT remained unchanged in four, four, three and one cases, respectively). At least one variable improved in each subject. Data indicate that ET adaptations might be detected in each individual using multiple variables of different adaptation levels and intensity domains. Nonresponse seems to occur frequently and might affect all variables. Further studies should investigate whether nonresponders improve with altered training. Furthermore, associations between patterns of nonresponse and health benefits from ET are worth considering.


Evaluation of two commercially available media for detection of bacteremia.
Analysis of the results of 13,162 blood cultures during a 9-month interval has shown that Pseudomonas aeruginosa statistically was recovered more frequently from Trypticase soy broth (TSB) than from Thioglycollate-135C and that contaminants, including Staphylococcus epidermidis and aerobic and anaerobic Corynebacterium species, were isolated with statistically greater frequency from Thioglycollate-135C than from TSB. No other statistically significant differences were found.


[Evaluation of on-the-job noise exposure in the case of bartenders].
In places associated with the entertainment industry in which music is performed or played, sounds with high sound pressure levels may occur. Such exposure is a threat to both people spending their free time at concerts, in discos or pubs, as well as employees in these places. The aim of the research conducted in 2017 was to assess on-the-job noise exposure in the case of bartenders at various premises of the entertainment industry. The measurements included 15 entertainment venues in Łódź, out of which 3 were selected: a music club, disco and pub. The exposure measurements were taken together for 4 work stations for bartenders using individual dosimetry in accordance with the PN-EN ISO 9612: 2011 standard. A total of 64 measurements were carried out, which showed that the equivalent sound levels A at the bartenders' workplaces vary considerably depending on the type of premises and the day of the week and the range of 67.6-108.7 dB. The highest sound levels occurred during the weekend (Fridays and Saturdays). The determined daily noise exposure levels exceeded the threshold of preventive action (80 dB) in 95% of the analyzed cases. Exceeding the maximum permissible noise level (NDN = 85 dB) was found in 66% of cases. It has been found that on-the-job noise levels in the case of bartenders significantly exceed the acceptable values of exposure levels and pose a risk of hearing damage. Med Pr 2018;69(6):633-641.


Trends in PM2.5 emissions, concentrations and apportionments in Detroit and Chicago.
PM2.5 concentrations throughout much of the U.S. have decreased over the last 15 years, but emissions and concentration trends can vary by location and source type. Such trends should be understood to inform air quality management and policies. This work examines trends in emissions, concentrations and source apportionments in two large Midwest U.S. cities, Detroit, Michigan, and Chicago, Illinois. Annual and seasonal trends were investigated using National Emission Inventory (NEI) data for 2002 to 2011, speciated ambient PM2.5 data from 2001 to 2014, apportionments from positive matrix factorization (PMF) receptor modeling, and quantile regression. Over the study period, county-wide data suggest emissions from point sources decreased (Detroit) or held constant (Chicago), while emissions from on-road mobile sources were constant (Detroit) or increased (Chicago), however changes in methodology limit the interpretation of inventory trends. Ambient concentration data also suggest source and apportionment trends, e.g., annual median concentrations of PM2.5 in the two cities declined by 3.2 to 3.6 %/yr (faster than national trends), and sulfate concentrations (due to coal-fired facilities and other point source emissions) declined even faster; in contrast, organic and elemental carbon (tracers of gasoline and diesel vehicle exhaust) declined more slowly or held constant. The PMF models identified nine sources in Detroit and eight in Chicago, the most important being secondary sulfate, secondary nitrate and vehicle emissions. A minor crustal dust source, metals sources, and a biomass source also were present in both cities. These apportionments showed that the median relative contributions from secondary sulfate sources decreased by 4.2 to 5.5% per year in Detroit and Chicago, while contributions from metals sources, biomass sources, and vehicles increased from 1.3 to 9.2% per year. This first application of quantile regression to trend analyses of speciated PM2.5 data reveals that source contributions to PM2.5 varied as PM2.5 concentrations decreased, and that the fraction of PM2.5 due to emissions from vehicles and other local emissions has increased. Each data source has uncertainties, but emissions, monitoring and PMF data provide complementary information that can help to discern trends and identify contributing sources. Study results emphasize the need to target specific sources in policies and regulations aimed at decreasing PM2.5 concentrations in urban areas.


Fruit cuticle lipid composition and water loss in a diverse collection of pepper (Capsicum).
Pepper (Capsicum spp.) fruits are covered by a relatively thick coating of cuticle that limits fruit water loss, a trait previously associated with maintenance of postharvest fruit quality during commercial marketing. To shed light on the chemical-compositional diversity of cuticles in pepper, the fruit cuticles from 50 diverse pepper genotypes from a world collection were screened for both wax and cutin monomer amount and composition. These same genotypes were also screened for fruit water loss rate and this was tested for associations with cuticle composition. Our results revealed an unexpectedly large amount of variation for the fruit cuticle lipids, with a more than 14-fold range for total wax amounts and a more than 16-fold range for cutin monomer amounts between the most extreme accessions. Within the major wax constituents fatty acids varied from 1 to 46%, primary alcohols from 2 to 19%, n-alkanes from 13 to 74% and triterpenoids and sterols from 10 to 77%. Within the cutin monomers, total hexadecanoic acids ranged from 54 to 87%, total octadecanoic acids ranged from 10 to 38% and coumaric acids ranged from 0.2 to 8% of the total. We also observed considerable differences in water loss among the accessions, and unique correlations between water loss and cuticle constituents. The resources described here will be valuable for future studies of the physiological function of fruit cuticle, for the identification of genes and QTLs associated with fruit cuticle synthesis in pepper fruit, and as a starting point for breeding improved fruit quality in pepper.


[Use of the cultural variants of Coxsackie A viruses in virological practice].
Coxsackie A viruses belong to the enteroviruses, the isolation of which from infectious materials and further cultivation are possible only when laboratory animals are infected. The authors could adapt the strains of 17 of 23 serotypes of these viruses to RD cell culture. The strains of 8 serotypes were additionally adapted to Vero cell culture. The cultural variants of Coxsackle A viruses were used to prepare immune sera. The Bacterial and Viral Agents Enterprise, M. P. Chumakov Institute of Poliomyelitis and Virus Encephalitides, Russian Academy of Medical Sciences, has set up the production of bacterial and viral drugs based on the cultural variants of 5 Coxsackie A virus serotypes. The cultural variants of 14 Coxsackie A virus serotypes were used to carry out a virus neutralization test. Examination of more than 600 children from Moscow and the Moscow Region showed the wide circulation of individual Coxsackie A virus serotypes. It also demonstrated a drastic reduction in Coxsackie A-7 virus circulation in the past 50 years.


Superposition Principle in Auger Recombination of Charged and Neutral Multicarrier States in Semiconductor Quantum Dots.
Application of colloidal semiconductor quantum dots (QDs) in optical and optoelectronic devices is often complicated by unintentional generation of extra charges, which opens fast nonradiative Auger recombination pathways whereby the recombination energy of an exciton is quickly transferred to the extra carrier(s) and ultimately dissipated as heat. Previous studies of Auger recombination have primarily focused on neutral and, more recently, negatively charged multicarrier states. Auger dynamics of positively charged species remains more poorly explored due to difficulties in creating, stabilizing, and detecting excess holes in the QDs. Here we apply photochemical doping to prepare both negatively and positively charged CdSe/CdS QDs with two distinct core/shell interfacial profiles ("sharp" versus "smooth"). Using neutral and charged QD samples we evaluate Auger lifetimes of biexcitons, negative and positive trions (an exciton with an extra electron or a hole, respectively), and multiply negatively charged excitons. Using these measurements, we demonstrate that Auger decay of both neutral and charged multicarrier states can be presented as a superposition of independent elementary three-particle Auger events. As one of the manifestations of the superposition principle, we observe that the biexciton Auger decay rate can be presented as a sum of the Auger rates for independent negative and positive trion pathways. By comparing the measurements on the QDs with the "sharp" versus "smooth" interfaces, we also find that while affecting the absolute values of Auger lifetimes, manipulation of the shape of the confinement potential does not lead to violation of the superposition principle, which still allows us to accurately predict the biexciton Auger lifetimes based on the measured negative and positive trion dynamics. These findings indicate considerable robustness of the superposition principle as applied to Auger decay of charged and neutral multicarrier states, suggesting its generality to quantum-confined nanocrystals of arbitrary compositions and complexities.


Nandrolone decreases mu opioid receptor expression in SH-SY5Y human neuroblastoma cells.
Nandrolone and other anabolic androgenic steroids alter the expression and function of neurotransmitter systems and contribute to drug dependence. Nandrolone treatment (10-10 M) caused a time-dependent and concentration-dependent downregulation of mu opioid receptor (MOPr) transcripts in SH-SY5Y human neuroblastoma cells. This effect was prevented by the androgen receptor antagonist hydroxyflutamide. Receptor binding assays confirmed a decrease in MOPr of approximately 40% in nandrolone-treated cells. Treatment with actinomycin D (10 (-5)M), a transcription inhibitor, revealed that nandrolone might regulate MOPr mRNA stability. In SH-SY5Y cells transfected with a human MOPr luciferase promoter/reporter construct, nandrolone did not alter the rate of gene transcription. These results suggest that nandrolone may regulate MOPr expression through posttranscriptional mechanisms requiring the androgen receptor.


Isolation of a type IV collagen binding protein from human platelets.
In order to study the molecular basis of platelet interaction with collagen IV of the basement membrane separating the arterial endothelium from the underlying subendothelial connective tissue, the possibility of presence of platelet membrane protein with affinity to type IV collagen was examined by subjecting the platelet membrane extract to affinity chromatography on collagen IV-sepharose. Urea (4 M) eluate was found to contain a protein with an apparent mol. wt of 68 kDa. The radioiodinated protein was isolated and used to test its specificity. By dot blot assay on nitrocellulose disks and solid-phase assays, the 68 kDa protein was found to bind with high affinity to collagen IV. Lack of significant binding to fibronectin and laminin when compared to albumin control indicated its high specificity for collagen. The radioiodinated protein was inserted into egg yolk lecithin liposomes. While these liposomes attached to microtitre plates coated with collagen IV, there was no significant binding to fibronectin or laminin coated wells, suggesting the membrane associated character of the protein as well as its specificity for collagen. These results indicate that presence of a 68 kDa protein in platelet membrane which interacts with very high specificity to collagen IV.


Calcium-modulated S100 protein-phospholipid interactions. An NMR study of calbindin D9k and DPC.
The cellular functions of several S100 proteins involve specific interactions with phospholipids and the cell membrane. The interactions between calbindin D(9k) (S100D) and the detergent dodecyl phosphocholine (DPC) were studied using NMR spectroscopy. In the absence of Ca(2+), the protein associates with DPC micelles. The micelle-associated state has intact helical secondary structures but no apparent tertiary fold. At neutral pH, Ca(2+)-loaded calbindin D(9k) does not associate with DPC micelles. However, a specific interaction is observed with individual DPC molecules at a site close to the linker between the two EF-hands. Binding to this site occurs only when Ca(2+) is bound to the protein. A reduction in pH in the absence of Ca(2+) increases the stability of the micelle-associated state. This along with the corresponding reduction in Ca(2+) affinity causes a transition to the micelle-associated state also in the presence of Ca(2+) when the pH is lowered. Site-specific analysis of the data indicates that calbindin D(9k) has a core of three tightly packed helices (A, B, and D), with a dynamic fourth helix (C) more loosely associated. Evidence is presented that the Ca(2+)-binding characteristics of the two EF-hands are distinctly different in a micelle environment. The role of calbindin D(9k) in the cell is discussed, along with the broader implications for the function of the S100 protein family.


Research Progresses on the Function and Detection Methods of Insect Gut Microbes.
The insect gut is home to an extensive array of microbes that play a crucial role in the digestion and absorption of nutrients, as well as in the protection against pathogenic microorganisms. The variety of these gut microbes is impacted by factors such as age, diet, pesticides, antibiotics, sex, and caste. Increasing evidence indicates that disturbances in the gut microbiota can lead to compromised insect health, and that its diversity has a far-reaching impact on the host's health. In recent years, the use of molecular biology techniques to conduct rapid, qualitative, and quantitative research on the host intestinal microbial diversity has become a major focus, thanks to the advancement of metagenomics and bioinformatics technologies. This paper reviews the main functions, influencing factors, and detection methods of insect gut microbes, in order to provide a reference and theoretical basis for better research utilization of gut microbes and management of harmful insects.


Human chitotriosidase-catalyzed hydrolysis of chitosan.
Chitotriosidase (HCHT) is one of two family 18 chitinases produced by humans, the other being acidic mammalian chitinase (AMCase). The enzyme is thought to be part of the human defense mechanism against fungal parasites, but its precise role and the details of its enzymatic properties have not yet been fully unraveled. We have studied the properties of HCHT by analyzing how the enzyme acts on high-molecular weight chitosans, soluble copolymers of β-1,4-linked N-acetylglucosamine (GlcNAc, A), and glucosamine (GlcN, D). Using methods for in-depth studies of the chitinolytic machinery of bacterial family 18 enzymes, we show that HCHT degrades chitosan primarily via an endoprocessive mechanism, as would be expected on the basis of the structural features of its substrate-binding cleft. The preferences of HCHT subsites for acetylated versus nonacetylated sugars were assessed by sequence analysis of obtained oligomeric products showing a very strong, absolute, and a relative weak preference for an acetylated unit in the -2, -1, and +1 subsites, respectively. The latter information is important for the design of inhibitors that are specific for the human chitinases and also provides insight into what kind of products may be formed in vivo upon administration of chitosan-containing medicines or food products.