Epidemiological study on gender bias and low-value practices in primary care: a study protocol.
Evidence shows that gender has a substantial impact on health behaviours, access to and use of health systems and health system responses. This study aims to assess gender bias in patients subjected to low-value practices in the primary care setting and to develop recommendations for reducing adverse events that women experience for this reason. A Delphi study will be performed to reach a consensus on the 'Do Not Do' recommendations with a possible gender bias. A retrospective cohort study in a random selection of medical records will then be carried out to identify the frequency of adverse events that occur when the selected 'Do Not Do' recommendations are ignored. Qualitative research techniques (consensus conference and nominal group) will be carried out to develop recommendations to address any gender bias detected, considering barriers and facilitators in clinical practice. The study was approved by the ethics committee of San Juan de Alicante Hospital (San Juan de Alicante, Spain) Reference N. 21/061. We will disseminate the research findings via peer-reviewed articles, presentations at national and international scientific forums and webinars. The study was registered at ClinicalTrials.gov (NCT05233852) on 10 February 2022.


Influence of a meal on skin temperatures estimated from quantitative IR-thermography.
In young men at 25 degrees C, quantitative IR-thermography showed that fasting values of skin temperatures over suspected areas of brown adipose tissue (BAT) were higher than where no BAT is thought to occur. However, at 30 min and again at 60-90 min after a meal of 2.5 MJ, the magnitude of the increase in skin temperature was similar in areas with or without suspected BAT. In conclusion, either thermography was unable to detect the activation of BAT, or the meal did not stimulate heat production in the sites of suspected BAT.


Increased plasma leptin as a novel predictor for psychopathological depressive symptoms in chronic schizophrenia.
Depressive symptoms are often seen in schizophrenia. The overlap in presentation makes it difficult to distinguish depressive symptoms from the negative symptoms of schizophrenia. The adipokine leptin was found to be altered in both depression and schizophrenia. There are few studies focusing on the prediction of leptin in diagnosis and evaluation of depressive symptoms in schizophrenia. To assess the plasma leptin level in patients with schizophrenia and its relationships with depressive symptoms. Cross-sectional studies were applied to (1) compare the levels of plasma leptin between schizophrenia (n=74) and healthy controls (n=50); and (2) investigate the relationship between plasma leptin levels and depressive subscores. (1) Plasma leptin levels were significantly higher in patients with schizophrenia than in healthy controls. (2) Correlation analysis revealed a significant negative association between leptin levels and the depressed factor scores on the Positive and Negative Syndrome Scale (PANSS). (3) Stepwise multiple regression analyses identified leptin as an influencing factor for depressed factor score on PANSS. Leptin may serve as a predictor for the depressive symptoms of chronic schizophrenia.


Supercycled R-symmetry sequences for robust heteronuclear polarization transfer in solid-state NMR.
Herein, we introduce supercycle of R-symmetry sequences (SR-sequences) and incomplete supercycle schemes of R-symmetry sequences (iSR-I- and iSR-II-sequences) to improve the robustness of PRESTO for heteronuclear polarization transfer in MAS NMR. The constructions of SR- and iSR-I/II- sequences are based on the different phase-inverted supercycles of R-symmetry sequences, and such supercycles can suppress the influence of CSA, resonance offset and RF mismatch when incorporated into the PRESTO method. Moreover, the SR- and iSR-II-sequences are more efficient in suppressing the interference of homonuclear dipolar coupling. The improved robustness of SR-, iSR-I- and iSR-II-PRESTO over the original R-PRESTO has been verified by numerical simulations and NMR experiments on NH4H2PO4 and gamma-alumina at fast MAS conditions. It is also important to note that the SR- and iSR-II-PRESTO can greatly lengthen the transverse relaxation times and lead to much higher polarization transfer efficiency compared to R-PRESTO, thanks to their superior tolerance to RF inhomogeneity and homonuclear dipolar coupling.


Critical shoulder angle: what do radiologists need to know?
The critical shoulder angle (CSA) constitutes a straightforward and highly reproducible tool. Degenerative rotator cuff tears (RCT) are associated with a significantly larger CSA. In this review, the most relevant features of the CSA are summarized: (1) the relationship between the CSA and RCT pathophysiology, (2) accurate measurement of the CSA according to various imaging modalities, (3) the contribution of the CSA in predicting the occurrence of RCT, and (4) RCT recurrence after surgical repair.


Evaluation of the new LCx HIV RNA quantitative assay: comparison with the Cobas Amplicor HIV Monitor assay.
In the present study we evaluated the performance of the new LCx HIV RNA quantitative kit (Abbott Laboratories, Delkenheim, Germany) for the quantitative detection of HIV-1 RNA in human plasma in comparison to the Cobas Amplicor HIV-1 Monitor assay (Roche Diagnostics, Branchburg, N.J.), including samples containing a variety of HIV-1 subtypes. LCx and Cobas were compared using archived EDTA plasma samples collected from HIV-infected patients. Considering the lower limit of the linear range of 50 copies/ml, the detection rate of the LCx was 139 out of 174 (79.9%) versus 131 out of 174 (75.3%) of the Cobas. Overall agreement was 95.4% (166/174) at a cut-off of 50 copies. LCx and Cobas results on clinical samples were found linearly associated (r2 = 0.900) and strongly correlated (r = 0.949). The mean viral load in the 174 frozen patient samples was 3.25 log10 copies/ml by LCx compared to 2.71 log10 copies/ml by Cobas. Considering only samples with a viral load > or =50 copies/ml, the average difference was -0.132 log copy/ml. Using a panel consisting of 9 plasma samples spiked with 9 different HIV-1 cultured isolates (A-H, and O) LCx detected the 9 subtypes with a high degree of precision, i.e., 9-33% coefficient of variation. As expected, the Cobas failed to detect the group O isolates. The results of the remaining samples showed a higher degree of variation (when testing four replicates of the subtype panel) than the LCx of 14.2-40.3%. Nevertheless, the results were comparable with the LCx data.


Targeting the respiratory muscles of fetal sheep for prenatal gene therapy for Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DMD) is a lethal degenerative muscular disease. Fetal gene therapy may correct the primary genetic defect. Our aim was to achieve expression of a reporter gene in the respiratory muscles of early gestation fetal sheep. An adenovirus vector containing the beta-galactosidase reporter gene (AdRSVbetagal) was injected into the thoracic musculature (n = 3) and pleural cavity (n = 6) of fetal sheep (61-67 days' gestation) under ultrasound guidance. Tissues were harvested after 48 hours and site and intensity of beta-galactosidase expression were assessed. Limited transgene expression observed after a single injection was improved by multiple injections, but remained localized. Ultrasound-guided creation of a hydrothorax led to an increase in the intensity of beta-galactosidase expression (ELISA). X-gal staining and immunohistochemistry showed that vector spread was confined to the innermost intercostal musculature. Ultrasound-guided injection can deliver gene therapy vectors to the fetal pleural cavity and achieve transduction of the respiratory muscles.


Nature of collagen in dermatofibrosarcoma protuberans.
The nature of collagen from 2 cases of dermatofibrosarcoma protuberans was studied. For this purpose, the tumor tissue was carefully separated from adjacent normal dermis. The collagen types comprised in the tumor were identified by CM-cellulose chromatographic and SDS-gel electrophoretic analysis of the component alpha-chains. Semiquantitative evaluation of the relative type III content was established by separation of the cyanogen bromide peptides on gels of 12% polyacrylamide in SDS. These studies showed that dermatofibrosarcoma protuberans contains alpha 1(I)-, alpha 2-, and alpha 1(III)-chains as well, and corresponding type I- and type III-related CNBr peptides. Comparing the collagen from dermatofibrosarcoma protuberans to that of normal skin, the relatively increased type III content in the case of dermatofibrosarcoma protuberans becomes apparent.


The development of bacterial flora of premature neonates.
The sequential acquisition of bacterial flora by premature neonates was studied during a 10 month period. Mean gestational age of the babies was 29.01 weeks and the mean birth weight was 1.728 kg. Escherichia coli and group B streptococci (GBS) colonized the umbilicus of 7 and 6 babies respectively, out of 23 studied, on the first day of life. E. coli and staphylococci were the predominant flora on the 6th day and they colonized 12 and 13 respectively. The oral flora was predominantly Gram-positive cocci, mainly Streptococcus salivarius which was isolated from 17 out of 22 babies on the 6th day, viridans streptococci were isolated from 14 babies, Staphylococcus albus from 16 babies and group D streptococci from 11 babies. Candida spp. also colonized the oral cavities of 17 out of 22 babies on the 6th day. At the end of the first week of life, the faecal flora was predominantly anaerobic represented by Bifidobacterium spp., Bacteroides spp. and Clostridium spp. The commonest facultative faecal flora were E. coli, which was isolated from all the babies, and Strept. faecalis isolated from 20 babies. Early gut colonization by GBS, Bacteroides spp. and Clostridium spp. was noticed in more babies delivered vaginally than by caesarean section where colonization by these bacteria was relatively delayed. The use of prophylactic penicillin plus gentamicin in the special neonatal unit probably prevented systemic spread of any of the potential opportunistic pathogens during the study.


Unexpected N-glycosidation reaction of glycals with 1-amino-anthracene: structure revision and application to the synthesis of new analogues of marmycin A.
An unexpected N-glycosidation reaction of anthracen-1-amine with glycals was identified, and its use in the synthesis of C1' N-linked analogues of natural product marmycin A was explored. The structures of all these products were determined by 1D and 2D NMR, CD spectra, and X-ray crystal analysis. These products were then subjected to Friedel-Crafts acylation, Dess-Martin oxidation and nucleophilic addition leading to novel natural product analogues bearing a quaternary carbon center.


How much do differences in medical schools influence student performance? A longitudinal study employing hierarchical linear modeling.
Medical school curricula have undergone considerable change in the past half century. There is little evidence, however, for the impact of various curricula and educational policies on student learning once incoming performance and the nonrandom nature of students nested within schools has been accounted for. To investigate effects of school variables on United States Medical Licensing Examination (USMLE) Step 1-3 scores over an 11-year period (1994-2004). Using Association of American Medical Colleges and USMLE longitudinal data for 116 medical schools, hierarchical linear modeling was used to study the effects of school variables on Step 1-3. Mean unadjusted between school variance was 14.74%, 10.50%, and 11.25%, for USMLE Step 1-3. When student covariates were included, between-school variation was less than 5%. The variance accounted for in student performance by the student covariates ranged from 27.58% to 36.51% for Step 1,16.37% to 24.48% for Step 2 and 19.22% to 25.32% for Step 3.The proportion of the between-school variance that was accounted for by the student covariates ranged between 81.22% and 88.26% for Step 1, 48.44% and 79.77% for Step 2, and 68.41% and 80.78% for Step 3 [corrected]. School-level variables did not consistently predict for adjusted mean school Step performance. Individual student differences account for most of the variation in USMLE performance with small contributions from between-school variation and even smaller contribution from curriculum and educational policies.


Muscle pH/PCO2 monitoring.
The surface pH of skeletal muscle has been confirmed to be a sensitive indicator of peripheral muscle blood flow, but the development of a better electrode has been required. As a consequence, a unique and minute sensor was developed to measure muscle pH/PCO2. The purpose of this article was to evaluate this new monitoring device experimentally and clinically in order to clarify its effects, usefulness and specificity. Our experimental and clinical results showed that placement and measurements using the muscle pH/PCO2 monitor were easily and quickly accomplished without any complications. This small sensor provided an accurate assessment of vital physiologic functions and gave an early warning of clinical deterioration. The new monitor should be useful in pediatric surgery clinical management.


Differential dopamine release dynamics in the nucleus accumbens core and shell track distinct aspects of goal-directed behavior for sucrose.
Mesolimbic dopamine projections to the nucleus accumbens (NAc) have been implicated in goal-directed behaviors for natural rewards and in learning processes involving cue-reward associations. The NAc has been traditionally subdivided into two anatomically distinct sub-regions with different functional properties: the shell and the core. The aim of the present study was to characterize rapid dopamine transmission across the two NAc sub-regions during cue-signaled operant behavior for a natural (sucrose) reward in rats. Using fast-scan cyclic voltammetry (FSCV) we observed differences in the magnitude and dynamics of dopamine release events between the shell and core. Specifically, although cue-evoked dopamine release was observed in both sub-regions, it was larger and longer lasting in the shell compared with the core. Further, secondary dopamine release events were observed following the lever press response for sucrose in the NAc shell, but not the core. These findings demonstrate that the NAc displays regional specificity in dopamine transmission patterns during cued operant behavior for natural reward.


Cross-sectional associations of total sitting and leisure screen time with cardiometabolic risk in adults. Results from the HUNT Study, Norway.
To examine associations of total sitting time, TV-viewing and leisure-time computer use with cardiometabolic risk biomarkers in adults. Population based cross-sectional study. Waist circumference, BMI, total cholesterol, HDL cholesterol, blood pressure, non-fasting glucose, gamma glutamyltransferase (GGT) and triglycerides were measured in 48,882 adults aged 20 years or older from the Nord-Trøndelag Health Study 2006-2008 (HUNT3). Adjusted multiple regression models were used to test for associations between these biomarkers and self-reported total sitting time, TV-viewing and leisure-time computer use in the whole sample and by cardiometabolic disease status sub-groups. In the whole sample, reporting total sitting time ≥10 h/day was associated with poorer BMI, waist circumference, total cholesterol, HDL cholesterol, diastolic blood pressure, systolic blood pressure, non-fasting glucose, GGT and triglyceride levels compared to those reporting total sitting time <4h/day (all p<0.05). TV-viewing ≥4 h/day was associated with poorer BMI, waist circumference, total cholesterol, HDL cholesterol, systolic blood pressure, GGT and triglycerides compared to TV-viewing <1h/day (all p<0.05). Leisure-time computer use ≥1 h/day was associated with poorer BMI, total cholesterol, diastolic blood pressure, GGT and triglycerides compared with those reporting no leisure-time computing. Sub-group analyses by cardiometabolic disease status showed similar patterns in participants free of cardiometabolic disease, while similar albeit non-significant patterns were observed in those with cardiometabolic disease. Total sitting time, TV-viewing and leisure-time computer use are associated with poorer cardiometabolic risk profiles in adults. Reducing sedentary behaviour throughout the day and limiting TV-viewing and leisure-time computer use may have health benefits.


Using the photo-enhanced barrier effect on electrochemical response for highly sensitive detection of melamine.
Melamine added to milk powder can lead to kidney injury and even death, but rapid detection is still hard due to the strong interference of milk powder solution. Herein, the CC/CeO2/CNPs mesh was constructed to detect melamine by using the photo-enhanced barrier effects on electrochemical response. Schottky barrier was regulated effectively to produce electrochemical response to melamine by photo-induced electrostatic interaction, which exhibited strong resistance to interference in milk powder solution. Sensitivity was enhanced by nearly 5 times and the lowest detection limit was reduced as low as 0.274 nM. The obtained high recovery (100%-104%) and good stability in milk powder solution indicated the good potential for practical applications. It provides a new opportunity for achieving strong resistance to interference by using the photo-enhanced barrier driving effect on electrochemical response.


Simultaneous catecholamine histofluorescence and thymidine autoradiography of the sexually dimorphic nucleus of the preoptic area in the rat.
The sexually dimorphic nucleus of the preoptic area (SDN-POA) in the rat represents a morphological substrate in which the influence of gonadal hormones on the process of sexual differentiation of the brain can be seen. Since the medial preoptic area (MPO) is a region rich in catecholamine (CA) terminals, it is possible that catecholamines may play a role either in the differentiation of the perinatal SDN-POA or in the function of this nucleus in the adult. It is not known whether catecholamine terminals exist within the SDN-POA or whether they can directly influence the activity of SDN-POA neurons. The present study was conducted to determine the extent to which catecholamines innervate this nucleus and further to elucidate the possibility of a potential sexual dimorphism in the innervation pattern. In order to determine which of the neurons in the MPO are within the SDN-POA we have utilized the fact that the SDN-POA has a prolonged period of neurogenesis in comparison to other neurons of the MPO. Thus, tritiated thymidine-labeled neurons can be used as a detection criterion for the SDN-POA. To conduct this experiment, timed pregnant Sprague-Dawley females were given a single injection of [3H]thymidine on Day 18 of gestation. Pups were killed as adults and prepared for fluorescence histochemistry of monoamines. Sections adjacent to those examined for catecholamine fluorescence were treated for autoradiographic localization of [3H]thymidine. Fluorescence innervation patterns were plotted within the boundaries of the nucleus following its identification from Nissl sections as well as from adjacent autoradiograms simultaneously viewed in a comparator bridge microscope with dark-field illumination.(ABSTRACT TRUNCATED AT 250 WORDS)


Internuclear ophthalmoplegia in systemic lupus erythematosus.
To describe and review internuclear ophthalmoplegia (INO) in systemic lupus erythematosus (SLE). A population of 268 SLE patients was retrospectively studied. INO was clinically defined as palsy of the ipsilateral rectus muscle and failure in contralateral eye adduction with dissociated nystagmus. A systematic review of the literature was made using MEDLINE (Silver-Platter) between 1966 and 1997, and for completeness, earlier references cited in identified articles. Four women with INO were identified. Their mean age at INO diagnosis was 38 years, and mean delay from diagnosis of SLE to INO was 6 years. INO was unilateral in all and coincided with disease activity in three. Cardiovascular risk factors were present in three. Magnetic brain resonance showed multiple and hyperintense (T2) lesions in white matter without correlation with clinical features. Other ancillary tests were not helpful for diagnosis. Corticosteroid therapy resulted in full resolution of INO in three cases. Review of 14 additional cases from the literature showed a similar experience. INO is uncommon in SLE, but it should be suspected in young patients with active disease and impairment of ocular movements. Diagnosis relies largely on clinical grounds. Neuroimaging is of little help. Steroid therapy seems effective in improving eye movements.


Incremental grouping of image elements in vision.
One important task for the visual system is to group image elements that belong to an object and to segregate them from other objects and the background. We here present an incremental grouping theory (IGT) that addresses the role of object-based attention in perceptual grouping at a psychological level and, at the same time, outlines the mechanisms for grouping at the neurophysiological level. The IGT proposes that there are two processes for perceptual grouping. The first process is base grouping and relies on neurons that are tuned to feature conjunctions. Base grouping is fast and occurs in parallel across the visual scene, but not all possible feature conjunctions can be coded as base groupings. If there are no neurons tuned to the relevant feature conjunctions, a second process called incremental grouping comes into play. Incremental grouping is a time-consuming and capacity-limited process that requires the gradual spread of enhanced neuronal activity across the representation of an object in the visual cortex. The spread of enhanced neuronal activity corresponds to the labeling of image elements with object-based attention.


Increased protoporphyrin in erythrocytes in a child with acute intermittent porphyria.
A child is described with acute intermittent porphyria but having an erythropoietic component, with disordered metabolism of porphyrins in bone marrow.


Clinical and pharmacokinetic evaluation of S-ketamine for intravenous general anaesthesia in horses undergoing field castration.
Intravenous anaesthetic drugs are the primary means for producing general anaesthesia in equine practice. The ideal drug for intravenous anaesthesia has high reliability and pharmacokinetic properties indicating short elimination and lack of accumulation when administered for prolonged periods. Induction of general anaesthesia with racemic ketamine preceded by profound sedation has already an established place in the equine field anaesthesia. Due to potential advantages over racemic ketamine, S-ketamine has been employed in horses to induce general anaesthesia, but its optimal dose remains under investigation. The objective of this study was to evaluate whether 2.5 mg/kg S-ketamine could be used as a single intravenous bolus to provide short-term surgical anaesthesia in colts undergoing surgical castration, and to report its pharmacokinetic profile. After premedication with romifidine and L-methadone, the combination of S-ketamine and diazepam allowed reaching surgical anaesthesia in the 28 colts. Induction of anaesthesia as well as recovery were good to excellent in the majority (n = 22 and 24, respectively) of the colts. Seven horses required additional administration of S-ketamine to prolong the duration of surgical anaesthesia. Redosing did not compromise recovery quality. Plasma concentration of S-ketamine decreased rapidly after administration, following a two-compartmental model, leading to the hypothesis of a consistent unchanged elimination of the parent compound into the urine beside its conversion to S-norketamine. The observed plasma concentrations of S-ketamine at the time of first movement were various and did not support the definition of a clear cut-off value to predict the termination of the drug effect. The administration of 2.5 mg/kg IV S-ketamine after adequate premedication provided good quality of induction and recovery and a duration of action similar to what has been reported for racemic ketamine at the dose of 2.2 mg/kg. Until further investigations will be provided, close monitoring to adapt drug delivery is mandatory, particularly once the first 10 minutes after injection are elapsed. Taking into account rapid elimination of S-ketamine, significant inter-individual variability and rapid loss of effect over a narrow range of concentrations a sudden return of consciousness has to be foreseen.


A combined intrapleural administration of dornase alfa and tissue plasminogen activator is safe in children with empyema - A pilot study.
There is still no consensus regarding the treatment of empyema in children. Intrapleural combination of tissue plasminogen activator and dornase alfa is a promising treatment for empyema in adults. The aim of this pilot study was to determine whether this combination is safe and successful in pediatric empyema. Previous well children diagnosed with empyema as classified by the British Thoracic Society. After chest tube insertion, intrapleurally dornase alfa 2.5 mg for 2 days and tissue plasminogen activator 0.15 mg/kg for 3 days was given after which the chest tube was clamped for 4 h. Primary outcome was safety. Ten consecutive children were included (4 boys, aged 3.2 (1.3-15.0) years old). No serious adverse events were seen. One child developed urticaria but additional intervention or cessation of the trial was not needed. There was no bleeding or mortality and no additional procedures were performed. The median hospital stay after intervention was 7.5 days. The intrapleural treatment of dornase alfa and tissue plasminogen activator as treatment of empyema was safe in ten children with empyema. If confirmed in further studies, this combination of intrapleural therapy may improve the management of pediatric empyema.


Prevalence of increased QT interval duration and dispersion in type 2 diabetic patients and its relationship with coronary heart disease: a population-based cohort.
To evaluate the prevalence of prolonged QT interval and dispersion in a population-based cohort of type 2 diabetic patients and their relationship with clinical and metabolic variables. Cross-sectional population-based cohort. Diabetes clinics and general practitioners in Casale Monferrato (Northern Italy). A total of 1357 patients with known type 2 diabetes (70% of the cohort). Albumin excretion rate and coronary heart disease (CHD); a standard supine 12-lead electrocardiogram (ECG) was recorded and coded according to the Minnesota code criteria. QT interval corrected for heart rate (QTc) > 0.44 s and QTc dispersion > 0.080 s were considered abnormally prolonged. Prevalence of increased QTc duration and QTc dispersion were 25.8% (95% CI 23.5-28.3) and 33.1% (95% CI 30.6-35.7), with no sex differences. No metabolic differences were found, apart from fibrinogen and creatinine levels, which were higher in patients with increased QTc dispersion. Patients with CHD had higher mean adjusted values of QTc and QTc dispersion, whereas no association was found with albumin excretion rate (AER) and diabetes treatment. QTc duration and QTc dispersion were significantly correlated (0.17, P < 0.001). In multiple regression analysis, only CHD was independently associated with QTc, after adjustment for age and sex (beta=0.010, P < 0.001, R2=2.5%); as regards QTc dispersion, a similar association with CHD was found (beta=0.20, P < 0.001, R2=4.8%). This population-based study shows a considerably high prevalence of increased QTc and QTc dispersion in type 2 diabetic patients and their association with CHD. These findings have both epidemiological and clinical relevance, as they might be implicated in the excess mortality risk of type 2 diabetic patients.


[Influence of cycle length shortening, atropine and beta-receptor blockage on sinus node recovery time (SRT) in patients with healthy sinus node (author's transl)].
Sinus node recovery time (SRT) was measured in 30 patients with healthy sinus nodes to examine the influence of the increase in atrial frequency, atropine and beta-receptor blockade. The measurements were performed following pacing with 3 atrial frequencies before and after administration of 1 mg atropine i.v. (13 patients) and 0.4 mg prindolol (Visken) i.v. (17 patients). Total group; Increase of frequency alone caused prolongation of the SRT in 17 patients and shortening in 13 patients. Atropine group: Blockade of the parasympathicus alone induced a highly significant reduction in the SRT. Simultaneous increase in frequency and blockade of the parasympathicus led to greater SRT-shortening during low frequency than with high frequency. This interrelationship of frequency and blockade of the parasympathicus influencing the SRT is statistically significant. Visken-group: Blockade of the sympathicus causes a highly significant prolongation of the SRT. Simultaneous increase in frequency and blockade of the sympathicus led to greater SRT-prolongation during low frequency than with high frequency. This interrelationship of frequency and blockade of the sympathicus influencing the SRT has slight statistical significance. The results are discussed in respect to the electrophysiological influences of atrial cycle length shortening, acetylcholine and catecholamines on the sinus node, the perinodal atrial fibres and the atrial working myocardium.


Effect of Pitavastatin Compared with Atorvastatin andRosuvastatin on New-Onset Diabetes Mellitus in PatientsWith Acute Myocardial Infarction.
Although statin use in patients with acute myocardial infarction (AMI) is mandatory, it has been suggested to be associated with new-onset diabetes mellitus (NODM). In real world practice, moderate-intensity statin therapy is more commonly used than high-intensity statin therapy. In this study, we investigated the impact of moderate-intensity pitavastatin (2 to 4 mg) compared with moderate-intensity atorvastatin (10 to 20 mg) and rosuvastatin (5 to 10 mg) on the development of NODM during a follow-up period of up to 3years. Between November 2011 and May 2015, 2001 patients with AMI who did not have diabetes mellitus were investigated. The cumulative incidence of NODM was evaluated in all groups. To adjust for potential confounders, multinomial propensity scores were used. Cox proportional hazard models were used to assess the hazard ratio of NODM in the atorvastatin and rosuvastatin groups compared with pitavastatin group. The cumulative incidence of NODM was significantly lower in pitavastatin group compared with the atorvastatin and rosuvastatin groups (3.0% vs 8.4% vs 10.4%, respectively; Log-rank p value = 0.001). After weighting the baseline characteristics of the 3 statin groups by multinomial propensity scores, atorvastatin (hazard ratio: 2.615, 95% confidence interval: 1.163 to 5.879) and rosuvastatin (hazard ratio: 3.906, 95% confidence interval: 1.756 to 8.688) were found to be associated with a higher incidence of NODM compared with pitavastatin therapy on multivariable analysis. Moderate-intensity pitavastatin therapy is associated with a lower incidence of NODM in patients with AMI andhas similar clinical outcomes to moderate-intensity atorvastatin and rosuvastatin therapy.


The transmembrane inner ear (tmie) gene contributes to vestibular and lateral line development and function in the zebrafish (Danio rerio).
The inner ear is a complex organ containing sensory tissue, including hair cells, the development of which is not well understood. Our long-term goal is to discover genes critical for the correct formation and function of the inner ear and its sensory tissue. A novel gene, transmembrane inner ear (Tmie), was found to cause hearing-related disorders when defective in mice and humans. A homologous tmie gene in zebrafish was cloned and its expression characterized between 24 and 51 hours post-fertilization. Embryos injected with morpholinos (MO) directed against tmie exhibited circling swimming behavior (approximately 37%), phenocopying mice with Tmie mutations; semicircular canal formation was disrupted, hair cell numbers were reduced, and maturation of electrically active lateral line neuromasts was delayed. As in the mouse, tmie appears to be required for inner ear development and function in the zebrafish and for hair cell maturation in the vestibular and lateral line systems as well.


COVID-19 - Does This Disease Kill Due to Imbalance of the Renin Angiotensin System (RAS) Caused by Genetic and Gender Differences in the Response to Viral ACE 2 Attack?
Debate continues in the medical literature on the role of the renin angiotensin system (RAS) in Coronavirus disease 2019 (COVID-19) pathophysiology and the implications for the use of cardiovascular drugs acting on the RAS. Could these drugs - which include angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptors blockers (ARBs) - be harmful or potential key therapeutic agents in COVID-19? And, could potentially helpful measures be available and in plain view on the pharmacy shelf?


A cross-sectional and a prospective study of thyroid disorders in lithium-treated patients.
The effects of lithium treatment on the thyroid gland have been demonstrated in a number of studies. Most of this research is based on cross-sectional studies and prospective studies are required to confirm these observations. During our genetic association studies, we recruited 115 males and 159 females suffering with affective disorders who had received lithium treatment. We observed longitudinally 57 of these patients, who attended our clinic for between 1 and 7 years and had no thyroid abnormalities at baseline. We performed regular checks of thyroid antibodies, thyroid function tests and lithium levels. Hypo- and hyperthyroidism, including cases that developed prior to lithium treatment, were more common in women (25.8%) than in men (8.7%) and increased with age. By the age of 65, the risk in women increased to 50%. Hypothyroidism was induced by lithium in 17% women. In the prospective study, 4 out of 33 women developed hypothyroidism (an incidence of 27.4 cases per 1000 years). One woman developed thyrotoxicosis. The risk for hypothyroidism induced by lithium is especially increased in women over the age of 50. Women should be warned of the risks involved when offered lithium treatment. The frequency of lithium-induced thyrotoxicosis is very low.


[Treatment of infections of the deep soft tissues in reconstructive vascular surgery].
After 685 reconstructive vascular operations (1982-1984) on account of arterial occlusive disease in the supra-aortic arteries as well as in the aorto-iliac and femoro-popliteal segments there occurred 9 deep infections (1.31%); most infected by-passes were extra-anatomical type. In 2 cases an aseptic by-pass was performed; in 4 cases an open local treatment was performed (early broad splitting of the soft tissues and laying open the entire infected graft, surgical wound debridement and local application of antiseptic solution); in 3 cases there was no other possibility than to remove the implant and amputate the leg. Each of the 2 methods described has its specific indications: the aseptic by-pass has to be performed in retroperitoneal and inguinal infections; the open local treatment has to be performed in cases of extra-anatomical by-passes and operations in the femoro-popliteal-cruralis or supra-aortic region. The correct use of these 2 treatment modalities, with their specific indications, allows a conservative management of deep tissue infections.


Triton X-100 solubilized bone matrix-induced alkaline phosphatase.
1. Solubilized and membrane-bound alkaline phosphatase showed Michaelis-Menten behavior in a wide range of different substrate concentrations. 2. Membrane-bound alkaline phosphatase has a molecular weight of 130,000 and its minimum active configuration comprises two identical subunits of about 65,000. 3. The two forms of the enzyme behave similarly with respect to NaCl, urea and guanidine HCl. 4. Catalytic groups have pK values of about 8.5 and 9.7 for both membrane-bound and solubilized enzyme.


High concentration of symmetric dimethylarginine is associated with low platelet reactivity and increased bleeding risk in patients with acute coronary syndrome.
Dual antiplatelet therapy (DAPT) prevents ischemic events in patients with acute coronary syndrome (ACS), but is associated with increased risk of bleeding events. Symmetric dimethylarginine (SDMA) is one of nitric oxide (NO)-related pathway metabolites and stands as a promising biomarker of early chronic kidney disease (CKD) and cardiovascular diseases (CVDs). Our study evaluated the role of SDMA in predicting bleeding events in patients after ACS treated with DAPT. We compared plasma concentrations of NO-related pathway metabolites in patients with ACS (n = 291) and investigated the prognostic value of SDMA as a bleeding predictor during 1-year follow-up. We measured the metabolites concentration using ultra performance liquid chromatography. Platelet reactivity was determined using impedance aggregometry. Patients with the highest quartile (4th) of SDMA concentration had significantly lower platelet aggregation compared to those in the 1st-3rd quartiles of SDMA, based on ADP + PGE1-, AA-, and ADP-induced platelet reactivity tests (p = 0.0004, p = 0.002, p = 0.014, respectively). Patients with major or minor bleeding events had significantly higher concentrations of SDMA as compared to those without bleeding events or to those with minimal bleeding events (p = 0.019, p = 0.019, respectively). Higher SDMA concentration is associated with lower platelet reactivity and is associated with major and minor bleeding events in patients with ACS on DAPT. Therefore, SDMA stands as a potential biomarker for individualization of duration and potency of antiplatelet therapies in the ACS population at high risk of bleeding complications.


Searching and generating test inputs for mutation testing.
Mutation testing is usually regarded as an important method towards fault revealing. Despite this advantage, it has proved to be impractical for industrial use because of its expenses. To this extend, automated techniques are needed in order to apply and reduce the method's demands. Whilst there is much evidence that automated test data generation techniques can effectively automate the testing process, there has been little work on applying them in the context of mutation testing. In this paper, search-based testing is used in order to effectively generate test inputs capable of revealing mutants. To this end, a dynamic execution scheme capable of introducing and guiding the search towards the sought mutants is proposed. Experimentation with the proposed approach reveals its superiority from the previously proposed methods. Additionally, the framework's feasibility and practicality of producing mutation based test cases are also demonstrated.


Decreased Phase-Amplitude Coupling Between the mPFC and BLA During Exploratory Behaviour in Chronic Unpredictable Mild Stress-Induced Depression Model of Rats.
Depression is a common neuropsychiatric illness observed worldwide, and reduced interest in exploration is one of its symptoms. The control of dysregulated medial prefrontal cortex (mPFC) over the basolateral amygdala (BLA) is related to depression. However, the oscillation interaction in the mPFC-BLA circuit has remained elusive. Therefore, this study used phase-amplitude coupling (PAC), which provides complicated forms of information transmission by the phase of low-frequency rhythm, modulating the amplitude of high-frequency rhythm, and has a potential application for the treatment of neurological disease. The chronic unpredictable mild stress (CUMS) was used to prepare the rat models of depression. Moreover, multichannel in vivo recording was applied to obtain the local field potentials (LFPs) of the mPFC, the BLA in rats in control, and CUMS groups, while they explored the open field. The results showed prominent coupling between the phase of theta oscillation (4-12 Hz) in the mPFC and the amplitude of high-gamma oscillation (70-120 Hz) in the BLA. Compared to the control group, this theta-gamma PAC was significantly decreased in the CUMS group, which was accompanied by the diminished exploratory behaviour. The results indicate that the coupling between the phase of theta in the mPFC and the amplitude of gamma in the BLA is involved in exploratory behaviour, and this decreased coupling may inhibit exploratory behaviour of rats exposed to CUMS.


Study on the production of biodiesel by magnetic cell biocatalyst based on lipase-producing Bacillus subtilis.
Production of biodiesel from waste cooking oils by a magnetic cell biocatalyst (MCB) immobilized in hydrophobic magnetic polymicrosphere is studied here. The cells of lipase-producing Bacillus subtilis were encapsulated within the net of hydrophobic carrier with magnetic particles (Fe(3)O(4)), and the secreted lipase can be conjugated with carboxyl at the magnetic polymicrosphere surface. Environmental scanning electron microscope, transmission electron microscope, and vibrating magnetometer, and so on were used to characterize the MCB. The MCB was proved to be superparamagnetic; and could be recovered by magnetic separation; moreover it could be regenerated under 48 h of cultivation. When methanolysis is carried out using MCB with waste cooking oils under stepwise additions of methanol, the methyl esters in the reaction mixture reaches about 90% after 72 h reaction in a solvent-free system. The process presented here is environmentally friendly and simple without purification and immobilized process required by the current lipase-catalyzed process. Therefore, the process is very promising for development of biodiesel fuel industry.


Usage of cadavers in surgical training and research in Japan over the past decade.
The "Guidelines for Cadaver Dissection in Education and Research of Clinical Medicine" drafted by the Japan Surgical Society (JSS) and the Japanese Association of Anatomists in 2012 helped dispel legal concerns over cadaver surgical training (CST) and the usage of donated human bodies for research and development (R&D) in the country. Subsequently, in the fiscal year 2018, the Ministry of Health, Labour and Welfare increased the funding for CST, prompting its wider implementation. This study analyzed data obtained in 2012-2021 through the reporting system of the JSS-CST Promotion Committee to map the usage of cadavers for clinical purposes, specifically education and R&D, in Japan. We found that the number of medical universities using cadavers for CST and R&D programs was just 5 in 2012, and it reached 38 for the decade. Thus, about half of Japan's medical universities implemented such programs over the period. Meanwhile, the total number of programs was 1,173. In the clinical field, the highest number of programs were implemented in orthopedics (27%), followed by surgery (21%), and neurosurgery (12%). Based on the purpose, the most common objective of the programs (approximately 70%) was acquiring advanced surgical techniques. Further, the highest number of programs and participants were recorded in 2019 (295 programs, 6,537 participants). Thus, the guidelines helped expand cadaver usage for clinical purposes in Japan. To further promote the clinical usage of cadavers in medical and dental universities throughout Japan, sharing know-how on operating cadaver laboratories and building understanding among the general public is recommended.


Binaphthyl-based chiral ligands: design, synthesis and evaluation of their performance in enantioselective addition of diethylzinc to aromatic aldehydes.
The design strategy and the performance of binaphthyl-based chiral ligands were evaluated with computation and enantioselective addition of diethylzinc to aromatic aldehydes. Under optimized conditions, enantioselective addition of diethylzinc to aromatic aldehydes provided the desired optically active secondary alcohols in high isolated yields (up to 91%) and excellent enantiomeric excesses (up to 98% ee).


Optimal age at sexual maturity of sympatric and experimentally allopatric cutthroat trout and Dolly Varden charr.
Reproductive potentials of transplanted curthroat trout (Salmo clarki) and Dolly Varden charr (Salvelinus malma) and of their donor stocks were estimated from life history data. We found good agreement between observed and predicted age at maturity in all populations, and cannot reject the hypothesis that the fish matured at the age maximizing the overall lifetime reproductive potential ([Formula: see text]). Our estimates were insensitive to probable variations in female fecundity, adult mortalityrate and maximum body length. Small changes in either juvenile mortality-rate or individual growth-rate had marked effects on the estimations, as did changes in the Malthusian parameter (r). Three alternative mechanistic explanations of how age at maturity is determined could be rejected. We suggest that fish are able to adjust the maturity age non-genetically to changes in growth-rate, and that temporal variations in juvenile survival-rate allow coexistence of genotypes coding for different ages at maturity at the same growth-rate.


Novel validity evidence of the Psychopathy Checklist- Revised (PCL-R) in a representative sample of Spanish inmates.
Psychopathy Checklist-Revised (PCL-R) validation studies have been conducted mainly in non representative samples of North American adult male serious offenders. Research in other samples is needed to test the generalizability of PCL-R construct validity. PCL-R psychometric properties and construct validity were evaluated in a representative sample of 204 Spanish sentenced inmates. These inmates had served at least 6 months of their sentence at Pereiro de Aguiar prison. This sample was heterogeneous with respect to type of official charges and was representative, as all offenders who met the inclusion and exclusion criteria were invited to participate. Classical test theory indexes of reliability, correlations between PCL-R items, factors and facets, external correlations, and factor structure analysis demonstrated that PCL-R affective, interpersonal and lifestyle dimensions were more reliable and valid for the psychopathy than the antisocial construct in this Southern European sample.


Estimation of cell DNA synthesis rate from flow-cytometric histograms.
The rate of DNA synthesis along S-phase can be estimated on the basis of a simple model of a cell population, from a single FCM histogram under conditions of balanced exponential growth, and from two histograms suitably spaced in time under conditions of locally exponential S-phase influx. An algorithm that constructs a piecewise constant approximation of the synthesis rate and estimates the phase fractions from a single histogram is presented. The results of the application of the algorithm to a set of computer generated histograms in balanced exponential growth are reported.


Modulation of picryl chloride-induced contact hypersensitivity reaction in mice by nitric oxide.
We have studied the possible involvement of nitric oxide (NO) in the contact hypersensitivity reaction. A biphasic response of ear swelling was observed at 2 h (early phase) and 24 h (late phase) after application of the antigen to picryl chloride (PC1)-sensitized CBA/J mice. Intravenous injection of NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), at the time of PC1 challenge, inhibited in a concentration-dependent fashion the antigen-induced contact hypersensitivity reaction. Low-dose (1 mg/kg) L-NAME inhibited the early-phase reaction but not the late-phase reaction. High-dose (250 mg/kg) L-NAME inhibited both early- and late-phase reactions. D-NAME (enantiomer of L-NAME) did not inhibit the antigen-induced ear swelling. High-dose (250 mg/kg) L-arginine increased both early and late phase reactions. D-Arginine (enantiomer of L-arginine) did no increase the antigen-induced ear swelling. L-NAME injection, however, did not suppress phenol-induce irritant inflammation. Treatment of mice undergoing PC1-induced contact hypersensitivity reaction with L-NAME reduced the production of interleukin-2 and interferon-gamma by draining lymph node cells. Treatment with L-arginine, on the other hand increased the production of interleukin-2 and interferon-gamma. These results suggest that NO plays a modulating role in contact hypersensitivity reaction.


Characterization and lysine control of expression of the lys1 gene of Penicillium chrysogenum encoding homocitrate synthase.
A 2071-bp DNA fragment, containing a gene (lys1) encoding a protein that showed 71.1% identical amino acids with the Yarrowia lipolytica homocitrate synthase and 71.7% identity with the Saccharomyces cerevisiae homologous enzyme, was cloned from a genomic library of Penicillium chrysogenum. The lys1 gene contained three introns and encoded a protein of 474 amino acids with a deduced molecular mass of 52kDa. lys1 was located in chromosome II (9.6Mb) in the wild-type P. chrysogenum NRRL 1951, whereas it hybridized with chromosome III (7.5Mb) in the high penicillin production strain AS-P-78. The lys1 gene is transcribed as a monocistronic transcript of 2.0kb. Levels of the lys1 transcript were high in P. chrysogenum Wis 54-1255 cultures in defined penicillin production medium at 24 and 48h, coinciding with the rapid growth phase, but clearly decreased during the penicillin production phase, suggesting that alpha-aminoadipic acid formation for penicillin biosynthesis may be limited at the homocitrate synthase level. Expression of lys1 was partially repressed by high concentrations of lysine in the culture medium, but lysine repression seems to be a weak mechanism of control of the lysine pathway as compared to lysine inhibition of homocitrate synthase.


Murine neurotropic retrovirus spongiform polioencephalomyelopathy: acceleration of disease by virus inoculum concentration.
A 10-fold reduction in the incubation period of murine neurotropic retrovirus spongiform polioencephalomyelopathy was effected by a 1,000-fold concentration of the cloned virus inoculum.


Noncontrast Pediatric Brain Perfusion: Arterial Spin Labeling and Intravoxel Incoherent Motion.
Noncontrast magnetic resonance imaging techniques for measuring brain perfusion include arterial spin labeling (ASL) and intravoxel incoherent motion (IVIM). These techniques provide noninvasive and repeatable assessment of cerebral blood flow or cerebral blood volume without the need for intravenous contrast. This article discusses the technical aspects of ASL and IVIM with a focus on normal physiologic variations, technical parameters, and artifacts. Multiple pediatric clinical applications are presented, including tumors, stroke, vasculopathy, vascular malformations, epilepsy, migraine, trauma, and inflammation.


Pressure-induced molten globule state of cholinesterase.
The denaturing effect of pressure on the structure of human butyrylcholinesterase was examined by gel electrophoresis under pressure and by 8-anilino-1-naphthalene sulfonate (ANS) binding. It was found that the fluorescence intensity of bound ANS is increased by pressure between 0.5 and 1.5 kbar and that the hydrodynamic volume of the enzyme swells when pressures around 1.5 kbar are applied. These findings indicate that pressure denaturation of butyrylcholinesterase is a multi-step process and that the observed transient pressure-denatured states have characteristics of molten globules.


Spatiotemporal distribution, ecological risk assessment and source analysis of legacy and emerging Per- and Polyfluoroalkyl Substances in the Bohai Bay, China.
The Bohai Sea is one of the most polluted hotspots by per- and Polyfluoroalkyl substances (PFASs) in the world and studies on the vertical distribution of PFASs at different water layers and phase partitioning between water and suspended particulate matter (SPM) were still limited. 23 legacy and emerging PFASs were investigated in seawater and SPM throughout the Bay in this study. The average concentrations of ∑PFASs in seawater were 48.21 ng/L and 52.71 ng/L during the periods of wet and normal water, respectively. In general, the concentrations of ∑PFASs in surface water were higher than that in deep water. Legacy PFASs in seawater were dominated by PFOA and short-chain PFASs, while the emerging alternative HFPO-DA was detected in the whole water layer of the Bohai Bay with an average concentration of 1.09 ng/L. The spatial distribution showed that ∑PFASs were higher nearshore than inside the bay and higher in the south than that in the north of the bay. The average concentration of ∑PFASs in SPM was 9.02 ng/g. Long-chain PFASs and the emerging alternative 6:2 Cl-PFESA accounted for the major contaminants. The partition coefficients log Kd and φspm-w showed a linear positive correlation with carbon chain length. Preliminary risk assessments revealed that the ecological risk of common PFASs in the Bohai Bay was low, while PFOA was at moderate risk. The principal component analysis demonstrated that the production process of traditional fluorochemical factories, fire-fighting and emerging electroplating industries were the main sources of PFASs. This was the first comprehensive survey of emerging PFASs in different water depths and in SPM of the Bohai Bay during different seasons, which provided important scientific data for studying the ecological risks and pollution prevention of PFASs.


External sources of vancomycin-resistant enterococci for intensive care units.
The incidence of colonization and infection with vancomycin-resistant enterococci (VRE) has increased dramatically in the last 5 yrs, especially in intensive care units (ICUs). We studied VRE-colonization in patients on admission to a medical ICU (MICU) where VRE colonization is endemic. Prospective, descriptive analysis. An MICU of a public hospital. Three hundred and one consecutively admitted patients. Rectal swabs were obtained on admission from all patients. VRE isolates from all colonized patients were genetically fingerprinted by pulsed-field gel-electrophoresis (PFGE). Forty-three (14%) of 301 patients were colonized with VRE on MICU admission. Three (7%) of these 43 patients were admitted directly from the community without prior hospital contact. Risk of colonization on admission was related to the length of stay in the hospital before MICU-admission (odds ratio 4.65 for patients with a stay of at least 3 days) and previous in-hospital use of antibiotics. Of 22 VRE PFGE strain types recognized in the MICU during the study period, four (18%) were introduced by patients admitted directly from the community and ten (45%) were introduced by patients admitted from other hospital wards. These results show that although ICUs are considered epicenters for antibiotic resistance, sources extraneous to our MICU (e.g., other wards) contributed the majority of VRE strain types in the unit.


Insight into High-Hydrostatic Pressure Extraction of Polyphenols from Tomato Peel Waste.
In this paper, high-hydrostatic pressure extraction (HHPE) as an emerging food processing and preservation technique constitutes an alternative to conventional thermal treatment that has been used for extraction of polyphenols from tomato peel waste generated by the canning industry. The impact of time (5 and 10 min), temperature (25, 35, 45 and 55 °C) and solvents (water, 1% HCl, 50 and 70% methanol with and without addition of HCl, and 50 and 70% ethanol), at a constant pressure of 600 MPa, has been evaluated in this paper with respect to polyphenols' yields. The results showed a significant (p < 0.05) variation in the contents of a great number of phenolic compounds in respect of the applied temperatures and solvents. On the other hand, the time invested in HHPE had no effect on polyphenols' yields. Among phenolic compounds, the p-coumaric acid (p-CA) and chlorogenic acid derivative (ChA der) are predominant, i.e., 0.57 to 67.41 mg/kg and 1.29 to 58.57 mg/kg, respectively, depending on the solvents and temperatures used. In particular, methanol (50 and 70%) at temperatures of 45 and 55 °C enhanced the recovery of polyphenols in comparison to other utilised solvents. In conclusion, this paper puts forth the theory that by applying HHPE with minimal expenditure of time, it is possible to achieve efficient production of polyphenols from low-cost tomato peel waste, generating income both for producers and agri-food industries.


[Hospital disinfection challenges due to multiresistant pathogens in surgery].
The number of antibiotic-resistant pathogens is increasing continuously while the development of new, effective antibiotics cannot be expected in the near future. Postoperative infections represent most of the nosocomial infections by now. Based on this, hygienic strategies regain importance, since a sustainable control of nosocomial infections will not succeed without the implementation of such strategies. In this article, the most important preventive strategies for prevention of infections with MRSA and 3- and 4-fold resistant gram-negative bacteria on the basis of current recommendations of the Commission for Hospital Hygiene and Infection Prevention (KRINKO) are presented.


Hyperoxia affects the lung tissue: A porcine histopathological and metabolite study using five hours of apneic oxygenation.
Oxygen is a liberally dosed medicine; however, too much oxygen can be harmful. In certain situations, treatment with high oxygen concentration is necessary, e.g. after cardiopulmonary resuscitation. The amount of oxygen and duration of hyperoxia causing pulmonary damage is not fully elucidated. The aim of this study was to investigate pathophysiological and metabolite changes in lung tissue during hyperoxia while the lungs were kept open under constant low pressure. Seven pigs were exposed to 100% oxygen for five hours, using an apneic oxygenation technique with one long uninterrupted inspiration, while carbon dioxide was removed with an interventional lung assist. Arterial blood samples were collected every 30 minutes. Lung biopsies were obtained before and after hyperoxia. Microscopy and high-resolution magic angle spinning nuclear magnetic resonance spectroscopy were used to detect possible pathological and metabolite changes, respectively. Unsupervised multivariate analysis of variance and paired sample tests were performed. A two-tailed p-value ≤ 0.05 was considered significant. No significant changes in arterial pH, and partial pressure of carbon dioxide, and no clear histopathological changes were observed after hyperoxia. While blood glucose and lactate levels changed to a minor degree, their levels dropped significantly in the lung after hyperoxia (p ≤ 0.04). Reduced levels of antioxidants (p ≤ 0.05), tricarboxylic acid cycle and energy (p ≤ 0.04) metabolites and increased levels of several amino acids (p ≤ 0.05) were also detected. Despite no histological changes, tissue metabolites were altered, indicating that exposure to hyperoxia affects lung tissue matrix on a molecular basis.


Expression and regulation of chemerin during rat pregnancy.
Chemerin is an adipocytokine that is expressed in different fat deposits and has been shown to play an important role in adaptive and innate immunity due to its activity as a chemoattractant. Chemerin acts as a ligand for the G protein-coupled receptor chemokine-like receptor 1 (CMKLR1). Chemerin has been shown to regulate the development and metabolic function of adipocytes, liver and muscle tissue. There is evidence indicating that several adipocytokines play an important role in placenta. This study aimed to investigate the regulation of chemerin in rat and human placentas throughout gestation. Chemerin was examined in rat and human placentas using immunohistochemistry. The chemerin expression pattern in the placenta and adipose tissue of female Sprague Dawley rats on days 12, 16, 19 and 21 of gestation (each of these days represents a group of 12 rats) was determined using TaqMan probe-based quantitative real-time PCR. Rat chemerin serum levels were analyzed with ELISA on days 8, 12, 16, 19 and 21 and compared to virgin controls. Chemerin expression was detected in the cytoplasm of rat placental trophoblastic cells and third trimester human placental cytotrophoblast and Hofbauer's cells. The serum chemerin levels of rats decreased significantly as gestation progressed. Furthermore, placental chemerin mRNA levels rose significantly at day 16 of gestation and decreased significantly towards the end of the gestation period. Taken together, this data suggests that chemerin may be an important regulator of maternal-fetal metabolism and metabolic homeostasis during pregnancy.


An uncommon clinical presentation of relapsing dilated cardiomyopathy with identification of sequence variations in MYNPC3, KCNH2 and mitochondrial tRNA cysteine.
We describe a young girl with dilated cardiomyopathy, long QT syndrome, and possible energy deficiency. Two major sequence changes were identified by whole exome sequencing (WES) and mitochondrial DNA analysis that were interpreted as potentially causative. Changes were identified in the KCNH2 gene and mitochondrial tRNA for cysteine. A variation was also seen in MYPBC3. Since the launch of WES as a clinically available technology in 2010, there has been concern regarding the identification of variants unrelated to the patient's phenotype. However, in cases where targeted sequencing fails to explain the clinical presentation, the underlying etiology could be more complex than anticipated. In this situation, the extensive reach of this tool helped explain both her phenotype and family history.


Presence of a specific uridine 5'-monophosphate pyrophosphorylase in baker's yeast.
Uridine 5'-monophosphate pyrophosphorylase was found to be present in baker's yeast. The enzyme preparation, purified about 30-fold, shows a strict specificity toward uracil and requires Mg++ for its activity.


Exercise effects on muscle quality in older adults: a systematic review and meta-analysis.
To systematically review and analyse the effects of exercise on morphological and neuromuscular muscle quality (MQ) outcomes in older adults and assess a range of possible moderators that may affect the impact of exercise on MQ outcomes. Using PRISMA guidelines, randomised controlled trials were searched in CINAHL, EMBASE, LILACS, PubMed, SciELO, Web of Science, MedNar, OpenGrey and OpenThesis databases. Eligible trials examined the effects of exercise interventions on morphological and neuromuscular MQ in older adults (≥ 60 years). Twenty-one trials (n = 973 participants) were included. Exercise significantly improved morphological MQ (effect size (ES) = 0.32, 95% CI 0.13-0.51, P < 0.001) with significant results maintained for studies assessing muscle density and intermuscular adipose tissue (ES = 0.45-0.52, P < 0.05). For neuromuscular MQ, exercise provided significant positive effects (ES = 0.49, 95% CI 0.29-0.69, P < 0.001) but only maintained for physically healthy participants (ES = 0.43, P < 0.001), resistance exercise interventions (ES = 0.64, P < 0.001), or studies assessing 1-RM or knee extensor isokinetic muscle strength relative to leg lean mass (ES = 0.48-0.62, P = 0.001). Associations between exercise duration and changes in MQ measures were not observed (P > 0.05). Supervised exercise interventions significantly improved different measures of MQ regardless of exercise duration, although these effects were small-to-moderate and not supported across all population-, exercise-, and methods-related features.


Shared Sensitivity to Physical Pain and Social Evaluation.
Many studies have demonstrated a link between experiences of physical pain and those of social rejection, both of which can trigger cognitive processes involved in detecting, orienting toward, or reacting to potentially threatening events. This study tested the hypothesis that healthy individuals who are more sensitive to physical pain are also more sensitive to social rejection. We recruited participants with high or low pain-sensitivity (HPS and LPS), as assessed by scores on a pain-sensitivity questionnaire and confirmed by experimental pain-sensitivity assessment. A modified social-judgment task was adopted in which participants first provided expectations about being liked/disliked by "peers", and then received "peers" feedback indicating acceptance or rejection. While both groups rated rejection as more unpleasant than acceptance, this difference was greater in the HPS group. Electroencephalographic results showed that only participants in the HPS group exhibited greater early delta/theta-oscillations (δ/θ-oscillations) in response to rejection than to acceptance, regardless of whether the feedback was expected or unexpected. However, both groups consistently exhibited greater late δ/θ-oscillations in response to rejection when the feedback was unexpected. These results suggest that participants in the HPS group were more sensitive to social cues signaling acceptance or rejection at early stages of information processing. Furthermore, neither early nor late δ/θ-oscillations following nonsocial feedback (correct or incorrect time-estimation) differed between groups. Altogether, these results supported the idea of shared sensitivity in detecting potentially physical and social threats in the environment. PERSPECTIVES: This study showed the greater emotional reactions and early-latency δ/θ-oscillations in response to social evaluation among healthy individuals with high pain sensitivity. It supports the idea of shared sensitivity to physical pain and social evaluation, which could be governed by a common system for detecting and monitoring potentially environmental threats.


Neutrophils promote venular thrombosis by shaping the rheological environment for platelet aggregation.
In advanced inflammatory disease, microvascular thrombosis leads to the interruption of blood supply and provokes ischemic tissue injury. Recently, intravascularly adherent leukocytes have been reported to shape the blood flow in their immediate vascular environment. Whether these rheological effects are relevant for microvascular thrombogenesis remains elusive. Employing multi-channel in vivo microscopy, analyses in microfluidic devices, and computational modeling, we identified a previously unanticipated role of leukocytes for microvascular clot formation in inflamed tissue. For this purpose, neutrophils adhere at distinct sites in the microvasculature where these immune cells effectively promote thrombosis by shaping the rheological environment for platelet aggregation. In contrast to larger (lower-shear) vessels, this process in high-shear microvessels does not require fibrin generation or extracellular trap formation, but involves GPIbα-vWF and CD40-CD40L-dependent platelet interactions. Conversely, interference with these cellular interactions substantially compromises microvascular clotting. Thus, leukocytes shape the rheological environment in the inflamed venular microvasculature for platelet aggregation thereby effectively promoting the formation of blood clots. Targeting this specific crosstalk between the immune system and the hemostatic system might be instrumental for the prevention and treatment of microvascular thromboembolic pathologies, which are inaccessible to invasive revascularization strategies.


On modeling the vibrational spectra of 14-s-cis retinal conformers in bacteriorhodopsin.
The vibrational properties of 13-cis, 14-s-trans and 13-cis, 14-s-cis protonated retinal Schiff base model compounds are explored with MNDO calculations. In particular, the effect of isomerization about the C14-C15 single bond on the vibrational properties of the deuterium in-plane rocking vibrations has been examined. Our MNDO calculations, using a variety of lysine models, lysine conformations and Schiff base charge environments, demonstrate that the C14-D and C15-D in-plane rocking vibrations in the 14,15-dideuterio retinal protonated Schiff base are strongly coupled in 13-cis, 14-s-cis molecules producing a splitting of ca. 80 cm-1 between the symmetric and antisymmetric rocking mode combinations but that these modes are only weakly coupled in 14-s-trans molecules. This analysis demonstrates that the 14,15-dideuterio labeling method developed earlier for determining C14-C15 conformation (S.P.A. Fodor, W. T. Pollard, R. Gebhard, E. M. M. van den Berg, J. Lugtenburg and R. A. Mathies, Proc. Natl. Acad. Sci. USA, 85, (1988) 2156-2160) is valid, and hence that the structure of the retinal chromophore in bacteriorhodopsin's L550 intermediate is 13-cis, 14-s-trans. The reasons for the misleading conclusions derived from MNDO calculations performed earlier by Schulten and Tavan are discussed.


Pharmacokinetics of L-carnitine.
L-Carnitine is a naturally occurring compound that facilitates the transport of fatty acids into mitochondria for beta-oxidation. Exogenous L-carnitine is used clinically for the treatment of carnitine deficiency disorders and a range of other conditions. In humans, the endogenous carnitine pool, which comprises free L-carnitine and a range of short-, medium- and long-chain esters, is maintained by absorption of L-carnitine from dietary sources, biosynthesis within the body and extensive renal tubular reabsorption from glomerular filtrate. In addition, carrier-mediated transport ensures high tissue-to-plasma concentration ratios in tissues that depend critically on fatty acid oxidation. The absorption of L-carnitine after oral administration occurs partly via carrier-mediated transport and partly by passive diffusion. After oral doses of 1-6g, the absolute bioavailability is 5-18%. In contrast, the bioavailability of dietary L-carnitine may be as high as 75%. Therefore, pharmacological or supplemental doses of L-carnitine are absorbed less efficiently than the relatively smaller amounts present within a normal diet.L-Carnitine and its short-chain esters do not bind to plasma proteins and, although blood cells contain L-carnitine, the rate of distribution between erythrocytes and plasma is extremely slow in whole blood. After intravenous administration, the initial distribution volume of L-carnitine is typically about 0.2-0.3 L/kg, which corresponds to extracellular fluid volume. There are at least three distinct pharmacokinetic compartments for L-carnitine, with the slowest equilibrating pool comprising skeletal and cardiac muscle.L-Carnitine is eliminated from the body mainly via urinary excretion. Under baseline conditions, the renal clearance of L-carnitine (1-3 mL/min) is substantially less than glomerular filtration rate (GFR), indicating extensive (98-99%) tubular reabsorption. The threshold concentration for tubular reabsorption (above which the fractional reabsorption begins to decline) is about 40-60 micromol/L, which is similar to the endogenous plasma L-carnitine level. Therefore, the renal clearance of L-carnitine increases after exogenous administration, approaching GFR after high intravenous doses. Patients with primary carnitine deficiency display alterations in the renal handling of L-carnitine and/or the transport of the compound into muscle tissue. Similarly, many forms of secondary carnitine deficiency, including some drug-induced disorders, arise from impaired renal tubular reabsorption. Patients with end-stage renal disease undergoing dialysis can develop a secondary carnitine deficiency due to the unrestricted loss of L-carnitine through the dialyser, and L-carnitine has been used for treatment of some patients during long-term haemodialysis. Recent studies have started to shed light on the pharmacokinetics of L-carnitine when used in haemodialysis patients.


The metabolism of pyrimidines by proteolytic clostridia.
Uracil was used by growing cultures of Clostridium sporogenes, and by proteolytic strains of C. botulinum types A and B. Uracil was not used by C. bifermentans; C. botulinum, type B (non-proteolytic); C. botulinum, type F (non-proteolytic); C. botulinum, type E; C. butyricum; C. cochlearium; C. difficile; C. histolyticum; C. oedematiens, type A; C. paraputrificum; C. scatologenes; C. specticum; C. sordellii; C. sticklandii; C. tertium; C. tetani; C. tetanomorphum; C. welchii, types A, B, C, E and 4 untyped strains. The growth of C. sporogenes was not increased by uracil; it was reduced to dihydrouracil. Experiments with washed cells of C. sporogenes showed that the uracil-reducing system was inducible. Washed cell suspensions incubated under hydrogen with uracil, thymine, iso-barbituric acid, 5-amino uracil and cytosine consumed 1 mole H2/mole pyrimidine. The reduction product of cytosine was dihydrouracil indicating that it was deaminated before reduction. The reduction products of the remaining pyrimidines were the corresponding dihydro derivatives. Extracts of C. sporogenes reduced uracil in the presence of NADPH2 but not NADH2.


Pharmacokinetics of enprofylline in healthy elderly subjects.
The pharmacokinetics of enprofylline, a new potent antiasthmatic, has been studied in 20 healthy, elderly subjects, aged 65 to 81 years, and in 7 young adult controls, aged 23 to 37 years. The dose of 1 mg/kg body weight was given as an i.v. infusion. Plasma levels of enprofylline were followed for about 7 h and urine levels for 24 h. Both groups eliminated the major portion of the dose (about 83%) by renal excretion. As expected the mean creatinine clearance (92.5 ml X min-1 X 1.73 m-2) was moderately decreased in the elderly subjects. The total clearance of enprofylline was 0.16 l X h-1 X kg-1 and the renal clearance was 0.13 l X h-1 X kg-1, which was significantly lower than that in the young controls (0.28 and 0.22 l X h-1 X kg-1) respectively. Thus, the enprofylline clearance had fallen relatively more (about 40%) than the decrease in creatinine clearance (about 20%) with age. The half-life of enprofylline in old age was 2.5 h, which was significantly longer than in the younger adults (1.8 h). It is concluded that the pharmacokinetics of enprofylline was significantly influenced by advanced age, mainly due to reduced renal excretion. This reduction was more pronounced than anticipated from the age-dependent decline in creatinine clearance.


Uptake of noradrenaline in high altitude native's heart.
Uptake of 3H-noradrenaline by the heart was studied with sections of isolated atria obtained from high or lowlanders. In native highlanders, affinity for 3H-noradrenaline by human atria is more significant than in lowlanders. Furthermore, the Michaelis Menten constant is lower in high altitude native's heart.


Phenological patterns of Spodoptera Guenée, 1852 (Lepidoptera: Noctuidae) is more affected by ENSO than seasonal factors and host plant availability in a Brazilian Savanna.
The identification of factors responsible for the population dynamics is fundamental for pest management, since losses can reach 18% of annual production. Besides regular seasonal environmental factors and crop managements, additional supra-annual meteorological phenomena can also affect population dynamics, although its relevance has been rarely investigated. Among crop pests, Spodoptera stands out due to its worldwide distribution, high degree of polyphagy, thus causing damages in several crops in the world. Aiming to distinguish the relevance of different factors shaping population dynamics of Spodoptera in an ecosystem constituted of dry and rainy seasons, the current study used circular statistics to identify phenological patterns and test if its population fluctuation is driven by El Niño-Southern Oscillation (ENSO) effect, seasonal meteorological parameters, and/or host plant availability. Samplings were done in an intercropping system, in the Brazilian Savanna, during the new moon cycles between July/2013 and June/2016. Species were recorded all year round, but demonstrated differently non-uniform distribution, being concentrated in different seasons of the year. Population fluctuations were mostly affected by the ENSO intensity, despite the contrasting seasonal meteorological variation or host plant availability in a 400-m radius. Studies involving the observation of supra-annual phenomena, although rare, reach similar conclusions in relation to Neotropical insect fauna. Therefore, it is paramount to have long-term sampling studies to obtain a more precise response of the pest populations towards the agroecosystem conditions.


Lead levels in circumpulpal dentine of children from different geographic areas.
Lead pollution can produce a variety of effects on the human body. Shed deciduous teeth were collected from primary school children in urban, suburban and rural areas in South Africa. The lead content was determined through atomic-absorption spectrophotometry. The average circumpulpal dentine lead levels in the urban, suburban and rural samples are 74.5, 44.3 and 26.5 parts/10(6) respectively. From the results it is clear that this most inner part of dentine (approximately 300 microns thick) can concentrate up to five times more lead than the total dentine. Comparison of the lead ratio of circumpulpal dentine to that of the total dentine for the different areas demonstrates the greatest tendency for preferential lead accumulation in the circumpulpal dentine. Lead analysis of circumpulpal dentine revealed that in deciduous teeth the lead level was related to the degree of industrialization.


Effect of irradiation on healing of newly made colonic anastomoses in the rat.
Short-term effects of radiotherapy on the healing process of newly made colonic anastomoses are investigated by measuring the anastomotic strength in a rat model. Four groups of Wistar rats were used. In all groups, rats underwent a 1 cm sigmoid resection with end-to-end anastomosis. Group I served as a control group. In group II the anastomosis was irradiated after closure of the abdominal wall with a single dose of 20 Gy of 250 kV x rays. Group III was irradiated with a single dose of 20 Gy while the abdominal wall was not closed, and the surrounding tissues were carefully covered by a lead plate, simulating intra-operative radiotherapy. Group IV was treated as group III, but a larger dose of 25 Gy was applied. Animals were sacrificed 3 or 7 days after the operation. General condition of the rats was determined by observation, weight loss, serum protein and albumin at sacrifice. Anastomotic healing was evaluated by inspection, bursting pressure, hydroxyproline and protein contents of the anastomotic segment. Direct postoperative externally irradiated rats (group II) showed a marked weight loss, hypoproteinaemia and hypo-albuminaemia because of involvement of small bowel in the irradiated volume. With respect to anastomotic healing there were no significant differences between control and irradiated groups. These data suggest that the application of a single dose of irradiation (20 and 25 Gy) on colonic anastomoses given in a direct postoperative or intraoperative model has no measurable side effect on the early healing of newly made colonic anastomoses. Direct postoperative external irradiation results in unwanted side effects in the adjacent bowel.


Some aspects of psychophysiological support of crewmember's performance reliability in space flight.
Crewmembers play an important role in ensuring the efficiency of "crew-spacecraft" system. However, despite of the fact that crewmembers are well trained and highly motivated persons, extreme flight factors may influence negatively on their reliability, and lead to human error occurrence. Therefore, working out methods of human error prevention is very significant to increase crewmember's performance reliability. Human error can occur in the operation of systems for a number of reasons. Within the framework of the present investigation, with use the data collected during "Mir" station missions, the significant (p<0.05) positive correlation of crewmembers errors (CE) frequency with their psychophysiological state (PPS), and work and rest schedule (WRS) intensity has been revealed. Differently, the higher WRS intensity, the crewmember's PPS is worse, and CE frequency is higher. This finding has been based on substantiations of the approach to human reliability management. Its essence will consist of the following: reducing WRS intensity, we thus can improve a crewmember's PPS and, accordingly, reduce CE frequency. This approach is discussed in the paper.


Sustained reduction of intraocular pressure in humans with the calcium channel blocker verapamil.
We investigated the effect of the calcium channel blocker verapamil on intraocular pressure in human volunteers. In the initial trial, 15 subjects with untreated ocular hypertension were tested. After a baseline measurement was obtained with applanation tonometry, a 40-microliter drop of verapamil, 1.25 mg/ml, was instilled in one eye. After 30 minutes, a second reading was taken. In a subsequent trial of 12 untreated ocular hypertensive subjects, the duration of action was determined using the same dose and method of delivery. Results showed that verapamil elicited a mean +/- S.E.M. change in intraocular pressure of -3.8 +/- 0.900 mm Hg in the treated eye, and -1.6 +/- 0.400 mm Hg in the untreated eye. This reduction was statistically different in both eyes (treated eye, P = .0007; untreated eye, P = .005). This decrease in intraocular pressure remained statistically significant when compared to predrug baseline values for up to ten hours.


Impact of hepatitis G virus co-infection on the course of hepatitis C virus infection before and after liver transplantation.
Hepatitis G virus (HGV), a new RNA virus that is parenterally transmitted, has frequently been found in patients with chronic hepatitis C (HCV) infection but its role in chronic liver disease is unknown. The purpose of this study was to determine the prevalence of HGV infection in transplantation patients infected with hepatitis C and to assess the impact of HGV co-infection on the course of HCV infection after liver transplantation. Eighty-nine liver transplantation recipients with persistent hepatitis C viremia detected by polymerase chain reaction (PCR) were evaluated. Serum samples were tested before and after liver transplantation for HGV RNA by two different PCR methods: LC assay (Abbott Laboratories) and an RT-PCR procedure which we developed using the silica gel technique for extraction of the HGV RNA. E2 antibodies were detected before orthotopic liver transplantation by an EIA-test. HCV RNA was quantified by branched DNA assay, and HCV genotype was determined. A mean of nine liver biopsy specimens were examined for each patient and the severity of the lesions was compared in HCV-positive patients with or without HGV co-infection. The concordance between the two HGV RNA detection methods was excellent and the reproducibility of our RT-PCR procedure was confirmed. The prevalence of pretransplantation and posttransplantation HGV infection was 11% and 19%, respectively. Pretransplantation HGV infection was positively correlated with posttransplantation HGV infection (p<0.001). Before transplantation the E2 antibodies seroprevalence was 34%. Seven patients became HGV RNA positive after transplantation, but all of them were negative for E2 antibodies. Among the patients who remained RNA negative after liver transplantation, 40% were positive for E2 antibodies (p=0.04). Pretransplantation clinical features (except AST mean value) were not different in patients with HCV and HGV co-infection and those with HCV only. After a mean follow-up of 34 months (range: 6 to 70), 67/89 (75%) patients developed histological features of recurrent hepatitis but the frequency of the occurrence of graft hepatitis was not different between HGV/HCV co-infected patients and those with HCV alone (p=0.89). The mean interval from orthotopic liver transplantation to recurrence was 12.2 months (range: 3-63), which was not different for HVG/HVC-co-infected patients and HCV-infected patients. The histological severity of posttransplantation liver disease, and the graft and patient survival were not different for patients with and without HGV co-infection. Our results suggest the general persistence of HGV infection after liver transplantation, but HGV co-infection did not appear to influence the posttransplantation course of HCV infection. Before transplantation the prevalence of E2 antibodies was 34%, and our data clearly indicate that E2 antibodies were protective against HGV infection.


Identification of the promoter elements involved in the stimulation of ASCT2 expression by glutamine availability in HepG2 cells and the probable involvement of FXR/RXR dimers.
Expression of the glutamine transport protein ASCT2 in the human hepatoma cell line HepG2 is increased when cells are cultured in the presence of glutamine and this has been shown to be due to stimulation of the ASCT2 promoter. Analysis of a number of promoter constructs localised the activation site to be between bases -653 and -543. Gel shift assays identified an IR-1 repeat within a 24bp region of this sequence which bound at least two nuclear proteins. Protein binding to this site was significantly higher in cells grown in glutamine-containing medium than when glutamine was absent. The identity of the higher molecular weight species binding to this promoter element was likely to be FXR/RXR dimers. Simultaneous overexpression of FXR and RXR increased the promoter activity in cells grown without glutamine to the same extent as did glutamine addition; the effects of glutamine and FXR/RXR expression were not additive. Mutagenesis of the FXR/RXR binding site in the promoter construct abolished glutamine and FXR/RXR stimulation. Real-time PCR showed levels of FXR mRNA were significantly increased in response to glutamine. The activity of the FXR promoter was also increased in response to glutamine. These results show that the stimulation of ASCT2 expression in response to glutamine in part involves binding of FXR/RXR to the ASCT2 promoter.


Investigating the Impact of Sample Preparation on Mass Spectrometry-Based Drug-To-Antibody Ratio Determination for Cysteine- and Lysine-Linked Antibody-Drug Conjugates.
Antibody-drug conjugates (ADCs) are heterogeneous biotherapeutics and differ vastly in their physicochemical properties depending on their design. The number of small drug molecules covalently attached to each antibody molecule is commonly referred to as the drug-to-antibody ratio (DAR). Established analytical protocols for mass spectrometry (MS)-investigation of antibodies and ADCs often require sample treatment such as desalting or interchain disulfide bond reduction prior to analysis. Herein, the impact of the desalting and reduction steps-as well as the sample concentration and elapsed time between synthesis and analysis of DAR-values (as acquired by reversed phase liquid chromatography MS (RPLC-MS))-was investigated. It was found that the apparent DAR-values could fluctuate by up to 0.6 DAR units due to changes in the sample preparation workflow. For methods involving disulfide reduction by means of dithiothreitol (DTT), an acidic quench is recommended in order to increase DAR reliability. Furthermore, the addition of a desalting step was shown to benefit the ionization efficiencies in RPLC-MS. Finally, in the case of delayed analyses, samples can be stored at four degrees Celsius for up to one week but are better stored at -20 °C for longer periods of time. In conclusion, the results demonstrate that commonly used sample preparation procedures and storage conditions themselves may impact MS-derived DAR-values, which should be taken into account when evaluating analytical procedures.


Reduced All-cause Child Mortality After General Measles Vaccination Campaign in Rural Guinea-Bissau.
Randomized trials have shown that measles vaccine (MV) prevents nonmeasles deaths. MV campaigns are conducted to eliminate measles infection. The overall mortality effect of MV campaigns has not been studied. Bandim Health Project (BHP) surveys children aged 0-4 years in rural Guinea-Bissau through a health and demographic surveillance system. A national MV campaign in 2006 targeted children aged 6 months to 15 years. In a Cox proportional hazards model with age as the underlying timescale, we compared mortality of children aged 6-59 months after the campaign with mortality in the same age group during the 2 previous years. Eight thousand one hundred fifty eight children aged 6-59 months were under BHP surveillance during the 2006 campaign and 7999 and 8108 during similar periods in 2004 and 2005. At least 90% of the eligible children received MV in the campaign. There were 161 nonaccident deaths in 12 months after the campaign compared with 203 and 206 deaths in the 2 previous years, the adjusted mortality rate ratio (aMRR) comparing all children in 2006 with all children in 2004 to 2005 being 0.80 (95% confidence interval: 0.66-0.96). Censoring deaths caused by measles infection, the aMRR was 0.83 (0.69-1.00). The mortality reduction was separately significant for girls [aMRR = 0.74 (0.56-0.97)] and for children who also had received routine MV [MRR = 0.59 (0.36-0.99)]. Mortality levels were stable during 2004 and 2005, but a significant drop occurred after the 2006 MV campaign and was not explained by the prevention of measles deaths. If MV campaigns reduce nonmeasles-related mortality, the policies for measles vaccination should take this into account.


ALA10, a Phospholipid Flippase, Controls FAD2/FAD3 Desaturation of Phosphatidylcholine in the ER and Affects Chloroplast Lipid Composition in Arabidopsis thaliana.
The biogenesis of photosynthetic membranes relies on galactoglycerolipids, which are synthesized via pathways that are dispatched over several cell compartments. This membrane biogenesis requires both trafficking of lipid intermediates and a tight homeostatic regulation. In this work, we address the role of ALA10 (for aminophospholipid ATPase), a P4-type ATPase, in a process counteracting the monogalactosyldiacylglycerol (MGDG) shortage in Arabidopsis (Arabidopsis thaliana) leaves. ALA10 can interact with protein partners, ALIS1 (for ALA-interacting subunit1) or ALIS5, leading to differential endomembrane localizations of the interacting proteins, close to the plasma membrane with ALIS1 or to chloroplasts with ALIS5. ALA10 interacts also with FATTY ACID DESATURASE2 (FAD2), and modification of ALA10 expression affects phosphatidylcholine (PC) fatty acyl desaturation by disturbing the balance between FAD2 and FAD3 activities. Modulation of ALA10 expression downstream impacts the fatty acyl composition of chloroplast PC. ALA10 expression also enhances leaf growth and improves the MGDG-PC ratio, possibly through MGDG SYNTHASE1 (MGD1) activation by phosphatidic acid. The positive effect of ALA10 on leaf development is significant in conditions such as upon treatment of plants with Galvestine-1, an inhibitor of MGDG synthases, or when plants are grown at chilling temperature.


Pharmacokinetics, Antitumor Activity, and Safety of ODM-201 in Patients with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: An Open-label Phase 1 Study.
ODM-201 is a novel second-generation androgen receptor inhibitor for the treatment of metastatic castration-resistant prostate cancer (mCRPC). To evaluate the pharmacokinetics of ODM-201 tablet products and preliminary long-term safety, tolerability, and antitumor activity of ODM-201 in chemotherapy-naive men with mCRPC. Thirty patients were enrolled in this open-label phase 1 trial. Patients received a single 600-mg dose of ODM-201 in capsules with food and one 600-mg dose of ODM-201 tablet product (TabA or TabB) with food and in the fasted state in a random order. In the extension, patients received 600mg twice daily ODM-201 taken with food in capsules. We analyzed the pharmacokinetics of ODM-201 tablet formulations. Safety and tolerability were assessed until disease progression or an intolerable adverse event (AE). Antitumor activity was assessed by prostate-specific antigen (PSA) levels and imaging. The capsule:TabA ratio of area under the concentration-time curve from time zero to the last sample at 48h was 1.06 (90% confidence interval [CI], 0.91-1.24); the capsule:TabB ratio was 0.97 (90% CI, 0.82-1.14). At week 12, 25 of 30 patients (83%) had a PSA response (≥50% reduction from baseline). Median time to radiographic progression was 66 wk (95% CI, 41-79). Most common AEs were fatigue (n=4 [13%]) and nausea (n=4 [13%]). The study showed that the tablet formulation of ODM-201 had similar pharmacokinetics compared with the capsule. Treatment with a 600-mg twice daily dose of ODM-201 provided anticancer activity and was well tolerated in men with chemotherapy-naive mCRPC. The findings of this study showed that ODM-201 is well tolerated and provided antitumor activity in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC) and that the 300-mg tablet formulation can be used in further clinical studies. A phase 3 trial with ODM-201 600mg twice daily in patients with non-mCRPC is ongoing.


Classical homocystinuria: vascular risk and its prevention.
Homocystinuria due to cystathionine beta-synthase deficiency is the second most treatable aminoacidopathy. The reported incidence varies from 1 in 344,000 worldwide to 1 in 65,000 in Ireland. Untreated patients with homocystinuria have severe hyperhomocysteinaemia. Amongst its pathological sequelae, which include mental retardation, ectopia lentis and osteoporosis, vascular events remain the major cause of morbidity and mortality in untreated patients. Recognized modalities of treatment include pyridoxine, in combination with folic acid and vitamin B12; methionine-restricted, cystine-supplemented diet; and betaine. The natural history of vascular events is such that half will have an event before age 30 years and there is a predicted one event per 25 years at the time of maximal risk. In 158 patients with 2822 patient-years of treatment, there would be a predicted 112 events if left untreated, but instead only 17 vascular events were recorded during treatment (relative risk 0.09, 95% CI 0.036 to 0.228; p < 0.0001). Appropriate chronic treatment to lower hyperhomocysteinaemia is effective in reducing the potentially life-threatening vascular risk in patients with homocystinuria. These findings may also have relevance to the significance of mild hyperhomocysteinaemia that is commonly found in patients with premature vascular disease.


Role of autophagy in high linear energy transfer radiation-induced cytotoxicity to tumor cells.
Heavy-ion radiotherapy has a potential advantage over conventional radiotherapy due to improved dose distribution and a higher biological effectiveness in cancer therapy. However, there is a little information currently available on the cellular and molecular basis for heavy-ion irradiation-induced cell death. Autophagy, as a novel important target to improve anticancer therapy, has recently attracted considerable attention. In this study, the effect of autophagy induced by high linear energy transfer (LET) carbon ions was examined in various tumor cell lines. To our knowledge, our study is the first to reveal that high-LET carbon ions could induce autophagy in various tumor cells effectively, and the autophagic level in the irradiated cells increased in a dose- and LET-dependent manner. The ability of carbon ions to inhibit the activation of the PI3K/Akt pathway rose with increasing their LET. Moreover, modulation of autophagy in tumor cells could modify their sensitivity to high-LET radiation, and inhibiting autophagy accelerated apoptotic cell death, resulting in an increase in radiosensitivity. Our data imply that targeting autophagy might enhance the effectiveness of heavy-ion radiotherapy.


Real-World Outcomes of Nivolumab, Pembrolizumab, and Atezolizumab Treatment Efficacy in Korean Veterans with Stage IV Non-Small-Cell Lung Cancer.
To provide a comprehensive analysis of ICI usage and treatment outcomes in elderly Korean veterans with stage IV NSCLC. Patients diagnosed with stage IV NSCLC between 2016 and 2021 were included, and three cohorts were derived according to the type of ICI received. Thereafter, the clinical characteristics and survival outcomes were compared. Of the 180 patients with NSCLC (median age, 76 years) included in this study, 49 (27.7%), 61 (33.9%), and 70 (38.9%) received pembrolizumab, nivolumab, and atezolizumab, respectively, and 19.4%, 36.1%, and 34.4% had PD-L1 expressions < 1%, 1-49%, and ≥50%, respectively. The pembrolizumab, nivolumab, and atezolizumab groups, the objective response rates (ORR), and the disease control rates (DCR) were 22.4%, 8.2%, and 4.3% (p = 0.004), and 59.2, 55.7%, and 30.0% (p = 0.001), respectively. However, no difference in the overall survival (OS) rate was noted among the groups (12.6 months vs. 8.4 months vs. 7.7 months, p = 0.334). Similarly, there was no treatment specific OS benefit with respect to the tumor PD-L1 expression status. Interestingly, multivariate analysis identified bone metastasis as a significant poor prognostic factor for OS (HR = 2.75 [95% CI, 1.31-5.76], p = 0.007). Pembrolizumab and nivolumab showed stronger associations with increases in ORR and DCR than atezolizumab, but no statistically significant differences were observed with respect to OS.