Interprofessional global health competencies of South Korean health professional students: educational needs and strategies.
There is growing recognition of the importance of educating health professional students to enhance their competence in collaborating with individuals from other health professions in the area of global health. This study aimed to identify the performance levels in interprofessional global health competencies (IGHC) of health professional students, their educational needs, and the strategies for successfully developing IGHC. This study used a mixed methods design involving an online survey followed by focus group interviews. A sample of 325 fourth-year undergraduate students from 14 health-related majors completed a self-report online survey (38.8% response rate). The performance of IGHC was measured on a five-point Likert scale using the IGHC items developed by the Consortium of Universities for Global Health. Additionally, 12 senior students and five professors in global health-related majors participated in focus group interviews. The students' educational needs and priorities were analysed using the Borich needs assessment and the Locus for Focus model. The participants' IGHC mean score was 3.11 (SD = 0.55) and differed by previous global health activity experiences (t = - 2.10, p = .037). Nine competencies in six domains using the Locus for Focus model were identified as a priority for global health education. Suggested strategies to enhance IGHC included establishing IGHC education in formal curricula, developing value-based content and outcomes, and engaging students in learning activities. It is necessary to design an interprofessional pre-departure course to achieve the priority IGHC and to organise learning activities where there is cooperation in problem solving while applying the expertise of each major within resource-limited settings. This study supports future health professional education that should foster enhanced roles and scopes of practice as changing agents to assure the achievement of sustainable development goals.


Transfundal transfer of embryos using ultrasound.
Ultrasonically guided transfer of embryos was performed transabdominally in 10 patients. The uterus was punctured by a 16-gauge needle with a stylet through a full urinary bladder. When the needle tip was in the uterine cavity the stylette was removed and a transfer catheter loaded with the embryos was inserted. No complications or technical difficulties were experienced. None of the patients became pregnant.


Adaptive function of duodichogamy: Why do chestnut trees have two pollen emission phases?
Intersexual mating facilitation in flowering plants has been largely underexplored. Duodichogamy is a rare flowering system in which individual plants flower in the sequence male-female-male. We studied the adaptive advantages of this flowering system using chestnuts (Castanea spp., Fagaceae) as models. These insect-pollinated trees produce many unisexual male catkins responsible for a first staminate phase and a few bisexual catkins responsible for a second staminate phase. We hypothesized that duodichogamy increases female mating success by facilitating pollen deposition on stigmas of the rewardless female flowers through their proximity with attractive male flowers responsible for the minor staminate phase. We monitored insect visits to 11 chestnut trees during the entire flowering period and explored reproductive traits of all known duodichogamous species using published evidence. In chestnuts, insects visited trees more frequently during the first staminate phase but visited female flowers more frequently during the second staminate phase. All 21 animal-pollinated duodichogamous species identified are mass-flowering woody plants at high risk of self-pollination. In 20 of 21 cases, gynoecia (female flower parts) are located close to androecia (male flower parts), typically those responsible for the second minor staminate phase, whereas androecia are often distant from gynoecia. Our results suggest that duodichogamy increases female mating success by facilitating pollen deposition on stigmas by means of the attractiveness of the associated male flowers while effectively limiting self-pollination.


Multimorbidity in Older Patients with Cardiovascular Disease.
Multimorbidity affects more than two thirds of older individuals and the vast majority of patients with chronic cardiovascular disease. Patients with multimorbidity have high resource utilization, poor mobility, and poor health status and are at an increased risk for death. The presence of multimorbidity imposes numerous management challenges in caring for patients with chronic cardiovascular disease. It complicates decision-making, promotes fragmented care, and imposes an immense burden on the patient and their social support system. Novel models of care, such as the cardiovascular patient-centered medical home, are needed to provide high-quality, efficient, effective care to this growing population.


The photosynthetic characteristics of papyrus in a tropical swamp.
Photosynthesis and transpiration was measured in the large emergent C4 sedge Cyperus papyrus (papyrus) which occupies wide areas of wetland on the African continent. The maximum observed value of net assimilation was 35 μmol CO2 m-2 s-1 at full sunlight but light saturation of photosynthesis did not occur. The quantum yield of photosynthesis obtained from the initial slope of the light response curves (0.06 mol mol-1 incident light) was relatively high and close to previously recorded values for some C4 grasses. Measurements made over two days showed that stomatal conductance was sensitive to the ambient air vapour pressure deficit (VPD) and was consistently lower on the day when VPD's were higher. There was, however, no marked midday closure of the stomata. Photosynthesis was also reduced on the day when VPD's were higher. The relationship between net photosynthesis and stomatal conductance was close to linear over the range of measurement conditions, with the result that intercellular CO2 concentrations (C i ) did not vary markedly. There was some evidence that C i decreased at high VPD's. The regulation of stomatal movement in papyrus appears to minimise excessive water loss while not severely limiting photosynthesis. The significance of this strategy for a wetland species with plentiful supplies of water is discussed.


Coronary sinus atresia with persistent left superior vena cava: unusual clinical presentation and endovascular management.
Atresia of the coronary sinus (ACS) is a rare congenital anomaly. When associated with persistent left superior vena cava (PLSVC), this defect could have no significant hemodynamic effect, and the patient might remain asymptomatic. However, vascular interventions might induce changes or complications that could show the anomaly. Appropriate management requires a good understanding of this condition. We present the first reported case of ACS and PLSVC occurring after thrombosis of the innominate vein (IV) after central venous catheter placement. The patient presented with atypical subacute chest pain and recurrent extrasystoles. Diagnosis and characterization of vascular anomalies was made by computed tomography phlebography, and the patient was successfully managed by endovascular recanalization of the IV.


Immune profile of an atypical EAE model in marmoset monkeys immunized with recombinant human myelin oligodendrocyte glycoprotein in incomplete Freund's adjuvant.
Experimental autoimmune encephalomyelitis (EAE) in the common marmoset monkey (Callithrix jacchus) is a relevant preclinical model for translational research into immunopathogenic mechanisms operating in multiple sclerosis (MS). Prior studies showed a core pathogenic role of T and B cells specific for myelin oligodendrocyte glycoprotein (MOG). However, in those studies, the quality of the response against MOG epitopes was strongly biased by bacterial antigens in the complete Freund's adjuvant (CFA), in which the immunizing recombinant human (rh) MOG protein had been formulated. In response to the need of a more refined EAE model, we have tested whether disease could also be induced with rhMOG in incomplete Freund's adjuvant (IFA). Marmosets were immunized with rhMOG emulsified in IFA in the dorsal skin. Monkeys that did not develop neurological deficit were given booster immunizations at 28-day interval with the same antigen preparation. In a second experiment, three marmoset twin pairs were sensitized against MOG peptides in IFA to study a possibility for suppressive activity towards pathogenic T cells directed against the encephalitogenic epitope MOG40-48. Despite the absence of strong danger signals in the rhMOG/IFA inoculum, all monkeys developed clinically evident EAE symptoms. Moreover, in all monkeys, demyelinated lesions were present in the white matter and in two cases also in the cortical grey matter. Immune profiling at height of the disease showed a dominant T cell response against the overlapping peptides 14-36 and 24-46, but reactivity against the pathogenically most relevant peptide 34-56 was conspicuously absent. In the second experiment, there was an indication for a possible suppressive mechanism. Immunization of marmoset monkeys with rhMOG in IFA elicits clinical EAE in all animals. Moreover, rhMOG contains pathogenic and regulatory epitopes, but the pathogenic hierarchy of rhMOG epitopes is strongly influenced by the adjuvant in which the protein is formulated.


The selective endothelin ETA receptor antagonist BQ123 antagonizes endothelin-1-mediated mitogenesis.
The mitogenic effects of endothelin isopeptides and the selective ETA receptor antagonist BQ123 were evaluated in rat aortic vascular smooth muscle cells. Endothelin-1 (ET-1) and endothelin-3 (ET-3) produced concentration-dependent increases in [3H]thymidine incorporation (EC50 = 0.1 and 25 nM, respectively). The ETB-selective agonist sarafotoxin 6c did not produce significant effects on [3H]thymidine incorporation. BQ123 produced selective and concentration-dependent inhibition of ET-1-mediated [3H]thymidine incorporation. These data demonstrate that ET-1-mediated mitogenesis in vascular smooth muscle is mediated by ETA receptors.


Constraints on priming in spatial memory: naturally learned versus experimentally learned environments.
In four experiments, we explored constraints on priming in spatial memory. In Experiments 1 and 2, subjects who were familiar with the locations of buildings on the Vanderbilt campus participated in a recognition test. The subjects' task was to decide whether or not named buildings were on the campus. Foils in this recognition test were realistic but fictional names of buildings. In principle, the subjects could have performed this task without using spatial knowledge; in fact, they must not have used spatial knowledge, because there was no evidence of priming in recognition as a function of the spatial relations between buildings on the campus. This result differs from those obtained in earlier experiments that have examined memory of spatial layouts learned in laboratory settings. In Experiment 3, the fictional foils were replaced by names of buildings in an area of the campus separated geographically from the main campus. Evidently, this change induced subjects to retrieve spatial knowledge, because the spatial priming effect materialized. A fourth experiment replicated the above findings in a single experiment and demonstrated that spatial priming could be obtained when the configuration of buildings was learned experimentally. These results are explained by appealing to the "decontextualization" that takes place in memory over time.


Radioprotection of nonhuman biota.
Radioprotection has historically focused on humans with the assumption that human protection confers protection of nonhuman biota. However, there is a need to scientifically and independently demonstrate protection of nonhuman biota. Approaches to address impacts of radiation on nonhuman biota include applying an ecological risk assessment paradigm, setting dose limits, defining reference organisms, and assessing a geographic region. Recommendations include harmonization of a radioprotection framework for both humans and nonhuman biota, a consistent methodology to evaluate radionuclide and nonradionuclide contaminants, a graded assessment approach, development of dosimetric models for reference organisms, compilation of a radiological effects database, and periodic expert review of methodology.


Confirmation of FWT1 as a Wilms' tumour susceptibility gene and phenotypic characteristics of Wilms' tumour attributable to FWT1.
A susceptibility gene for Wilms' tumour (WT), designated FWT1, was previously mapped to chromosome 17q12-q21 by linkage analysis of a single family. We now confirm the existence of this gene by analysis of additional cases in the original family (3-point LOD score=5.69), and by detecting strong evidence of linkage to this region in an unrelated pedigree with seven cases of WT (3-point LOD score=2.56). Analysis of 11 smaller WT families confirms that there is genetic heterogeneity in familial WT, as three families exhibit strong evidence against linkage to FWT1. One of these was subsequently found to have a predisposing WT1 mutation. However, the other two families show evidence against both FWT1 and WT1, suggesting that at least one further familial WT gene exists. Analysis of the phenotype of 16 WT cases from the families linked to FWT1 demonstrates that they present at a significantly older age and a significantly later stage than both sporadic WT and the six cases from two families unlinked to either FWT1 or WT1. The results confirm the role of FWT1 in susceptibility to WT, provide strong evidence for genetic heterogeneity in familial WT and suggest there are phenotypic differences between familial WT due to FWT1, familial WT due to other genes and non-familial WT.


The revised digital transcutaneous PCO2/SpO2 ear sensor is a reliable noninvasive monitoring tool in patients after cardiac surgery.
The aim of this study was to validate the revised SenTec V-Sign 2 sensor (SenTec AG, Therwil, Switzerland) for combined noninvasive continuous assessment of pulse rate, pulse oximetry (SpO(2)), and transcutaneous carbon dioxide tension (PtcCO(2)) in adults after cardiac surgery. A prospective clinical study. A single-center university hospital. Twenty adult patients aged 36 to 84 years after cardiac surgery. SpO(2) and PtcCO(2) values of three V-Sign 2 sensors (SenTec AG) attached at the earlobe, forehead, and cheek and SpO(2) values of the Nellcor Durasensor (Model DS-100A; Nellcor Puritan Bennett Inc, Pleasanton, CA) were compared with simultaneous measurements of blood gases and end-expiratory carbon dioxide. Measurements were performed during periods of hyper-, normo-, and hypocapnia and then at 30-minute intervals up to 5 hours. Bland-Altman analysis and simple regression analysis were used. The detection failures for PtcCO(2) were 0.3% to 1.3%, for SpO(2) 10% to 25%, and for pulse rate 5% to 10%. The V-Sign 2 earlobe sensor provided the best results. The mean bias and limits of agreement for PtcCO(2ear) and PaCO(2) were 1.1 and -3.4/+5.5 mmHg. The drift of PtcCO(2) was negligible at all locations. The mean bias and limits of agreement of V-Sign SpO(2ear) and SaO(2), as well as V-Sign pulse rate and the electrocardiogram, were -1.7% and -6.8/+3.9% and 1.2 beats/min and -3.3/+5.8 beats/min. End-expiratory carbon dioxide showed a weak correlation with PaCO(2) (r(2) = 0.47). Transcutaneous capnometry using the revised V-Sign 2 sensor at the earlobe is a reliable monitoring tool during the recovery period of patients after cardiac surgery. This approach has the potential to reduce the number of arterial blood gas samples.


Viability of microencapsulated bifidobacteria in simulated gastric juice and bile solution.
Microencapsulated cells of Bifidobacterium longum B6 and Bifidobacterium infantis CCRC 14633 were prepared by spray drying the cell suspension containing the test organism and 10% (w/w) of the carrier material of either gelatin, soluble starch, skim milk or gum arabic. Survival of these microencapsulated and free cells of bifidobacteria in simulated gastric juice (pH 2.0 and 3.0) and bile solution (0.5% and 2.0%) was then examined. B. infantis CCRC 14633 was more susceptible than B. longum B6 to the simulated gastric environment and bile solution tested. Microencapsulated bifidobacteria exhibited a lower population reduction than free cells during exposure to simulated gastric environment and bile solution. This phenomenon was most pronounced when the test organism was exposed to gastric juice at pH 2.0 or 2.0% bile solution. Moreover, it was also observed that the protective effect exerted by encapsulation with spray drying varied with the carriers used and the strains of bifidobacteria.


BDNF and the central control of feeding: accidental bystander or essential player?
A considerable body of evidence links diminished brain-derived neurotrophic factor (BDNF) signaling to energy balance dysregulation and severe obesity in humans and rodents. Because BDNF exhibits broad neurotrophic properties, the underpinnings of these effects and its true role in the central regulation of food intake remain topics of debate in the field. Here, I discuss recent evidence supporting a critical role for this neurotrophin in physiological mechanisms regulating nutrient intake and body weight in the mature brain. They include reports of functional interactions of BDNF with central anorexigenic and orexigenic signaling pathways and evidence of recognized appetite hormones exerting neurotrophic effects similar to those of BDNF.


Frauke Zipp.
Frauke Zipp is a clinician scientist and expert in multiple sclerosis and other neurological disorders. In an interview with Neuron, she talks about her early work in neuroimmunology and how her lab's research has advanced our understanding of the interplay between the immune and nervous systems in health and disease.


Atypical form of Mayer-Rokitansky-Küster-Hauser syndrome: A case report.
Mayer-Rokitansky-Küster-Hauser syndrome (MRKH) is a congenital disorder syndrome characterized by failure of the uterine and vaginal organs to develop normally. The prevalence of MRKH is estimated to occur in about 1 in 5000 of female live births. A 25-year-old female patient comes to a general obstetric and gynecological polyclinic with complaints of not being able to menstruate at all since birth. There is a history of vaginal discharge but it is neither viscous nor had an odor. On ultrasound examination, the structure of the uterus and ovaries was not found in a normal place. On follow up MRI examination showed agenesis of the uterus and proximal two-third of the vagina accompanied by abnormal positioning of both ovaries, thus supporting to atypical form of MRKHS. The patient is not given drug therapy, but she was planned to transplant the uterine organs. This case report suggests MRKH syndrome can be characterized by ectopic ovaries and a uterus that is not fully developed and can also be accompanied by agenesis of the vaginal organs. Pelvic ultrasound is the main modality chosen to be performed in patients with symptoms of primary amenorrhea. When pelvic organs cannot be visualized properly, it will be performed MRI examination. MRI examination is known to have sensitivity and specificity up to 100% in diagnosing MRKH syndrome. This case report describes a 25-year-old woman with primary amenorrhea with MRKH syndrome. MRI is a sensitive and specific examination to confirm the diagnosis.


Pharmacokinetics and bioavailability of etintidine in beagle dogs: effects of routes of administration, doses, dosage forms, and chronic dosing.
Etintidine HCl is an H2 receptor antagonist which has been under clinical trial for the treatment of duodenal ulcer diseases. Our studies are to determine the effects of routes of administration, doses, dosage forms, and chronic dosing on the bioavailability and pharmacokinetics of etintidine (E) in the beagle dog. Salient findings are: 1. Plasma levels of etintidine after i.v. administration of 200 mg of E followed a 3-exponential decay with a terminal t1/2 of 1.7h. 2. Following oral administration of 200 mg of E in capsules, tablets, or a solution dosage form to dogs, etintidine was rapidly and nearly completely absorbed with no significant first-pass elimination. 3. A proportional increase in the amount of etintidine absorbed in the dogs occurred as the administered doses increased from 30 to 180 mg kg-1 and this relationship did not change with repeated dosing. 4. Some accumulation of etintidine took place during the 52 weeks of chronic dosing.


Factor V Leiden and the risk for venous thromboembolism in the adult Danish population.
Odds ratios for venous thromboembolism (deep venous thrombosis and pulmonary embolism) derived from case-control studies range from 3 to 16 for heterozygotes compared with noncarriers and up to 79 for homozygotes compared with noncarriers. To estimate risks for venous thromboembolism in the adult Danish population according to factor V Leiden genotype. Cohort study with 23 years of follow-up. Adult Danish population. 9253 randomly selected individuals. Hospitalization and death from venous thromboembolism, factor V Leiden genotype, and additional thromboembolic risk factors. Adjusted hazard ratios in heterozygotes and homozygotes compared with noncarriers were 2.7 (95% CI, 1.8 to 3.8) and 18 (CI, 4.1 to 41) for venous thromboembolism overall, 2.4 (CI, 1.3 to 3.8) and 22 (CI, 0 to 60) for deep venous thrombosis, and 3.0 (CI, 1.7 to 4.9) and 11 (CI, 0 to 33) for pulmonary embolism. The lowest absolute 10-year risks for venous thromboembolism in factor V Leiden heterozygotes and homozygotes--0.7% (CI, 0.5% to 1.0%) and 3% (CI, 1% to 8%)--were found in nonsmokers younger than 40 years of age with a body mass index below 25 kg/m2; the corresponding highest risks--10% (CI, 7% to 14%) and 51% (CI, 13% to 100%)--were found in smokers older than 60 years of age with a body mass index above 30 kg/m2. Hazard ratios for venous thromboembolism in factor V Leiden heterozygotes and homozygotes compared with noncarriers in the adult Danish population were approximately 3 and 18, respectively. The simultaneous presence of smoking, obesity, and old age resulted in absolute 10-year thromboembolic risks of 10% in heterozygotes and 51% in homozygotes.


Fractional hepatic localization of 14CHCl3 in mice and rats treated with chlordecone or mirex.
In rodents chlordecone, but not mirex, a nonketonic structural analog, significantly augments CHCl3-induced liver damage, at least in part, by increasing CHCl3 bioactivation. To determine whether the fractional distribution of CHCl3 was altered in chlordecone-pretreated animals, the irreversible binding of 14CHCl3 to various liver constituents (a measure of CHCl3 bioactivation) was examined in vivo in mice and rats. Chlordecone, but not mirex, increased both total and irreversibly bound 14CHCl3; furthermore, changes in the 14C localization between lipid, protein and acid-soluble fractions were noted. Thus, the results suggest that differences exist between chlordecone and mirex with respect to their capacity to increase the quantity of CHCl3-derived reactive metabolite and the eventual distribution of reactive metabolite.


Polymorphisms of the HTR3B gene are associated with post-surgery emesis in a Chinese Han population.
The serotoninergic receptor 5-hydroxytryptamine (serotonin) receptor 3 (HTR3) is instrumental in the regulation of nausea and emesis (vomiting).This study investigated whether common genomic variations of the A and B subunits of HTR3 (HTR3A, HTR3B) are associated with the incidence of post-operative vomiting in a Chinese Han population. Two hundred and thirty-one female Chinese Han patients undergoing gynaecological surgery with standardized general anaesthesia were recruited for the study. Clinical symptoms after surgery were recorded and direct DNA sequencing was performed to detect polymorphisms of HTR3A and HTR3B. Five single nucleotide polymorphisms (SNPs) in HTR3A and HTR3B were found, with R(2) > 0·8 and minor allele frequency > 10%. One of these (rs3758987 in HTR3B) was statistically associated with vomiting, after adjusting for body weight, body mass index and duration of general anaesthesia in dominant and additive models (P = 0·047 and P = 0·034). The HTR3B rs3758987 SNP might serve as a predictor of post-operative vomiting in Chinese Han patients undergoing gynaecological laparoscopic surgery.


Pulmonary vascular response to high-frequency oscillatory ventilation in dogs: lack of effect of indomethacin.
The role of prostaglandins (PG) in the pulmonary hypertension associated with high-frequency oscillatory ventilation (HFOV) was investigated in 7 pentobarbital-anesthetized dogs. The magnitude and time course of the mean pulmonary artery pressure (PAP) changes induced by HFOV (20 Hz) was quantified before and after PG-production blockade with 15 mg/kg indomethacin (INDO) i.v. It was found that HFOV before INDO induced a 27.2 +/- 5.6% increase in PAP above baseline and a 30.0 +/- 7.2% one hour after INDO administration. This difference was not statistically significant. The time course of the PAP changes induced by HFOV before and after blocking PG-production by INDO were also similar. Mean airway pressure, PaO2 and PaCO2 during HFOV, before and after INDO were not statistically different. It is concluded that the acute increase in PAP induced by HFOV is not due to PG release.


Human thymic stromal lymphopoietin promotes dendritic cell-mediated CD4+ T cell homeostatic expansion.
T cell homeostasis is a self-regulating process for maintaining the size of the peripheral T cell pool. Although dendritic cells (DCs) seem to be important in T cell homeostasis, the molecular regulation of DC-mediated T cell homeostasis is unknown. We show that human DCs activated by thymic stromal lymphopoietin (TSLP) induced a robust expansion of autologous CD4(+) T cell populations, which depended on self peptide-major histocompatibility complex. The proliferating T cells adopted and maintained a central memory polyclonal phenotype and could differentiate into T helper type 1 or type 2 effector cells. These results, together with findings of TSLP expression in epithelial cells of mucosal lymphoid tissues and thymus, indicate that TSLP is involved in DC-mediated CD4(+) T cell homeostasis.


Origins of chemoreceptor curvature sorting in Escherichia coli.
Bacterial chemoreceptors organize into large clusters at the cell poles. Despite a wealth of structural and biochemical information on the system's components, it is not clear how chemoreceptor clusters are reliably targeted to the cell pole. Here, we quantify the curvature-dependent localization of chemoreceptors in live cells by artificially deforming growing cells of Escherichia coli in curved agar microchambers, and find that chemoreceptor cluster localization is highly sensitive to membrane curvature. Through analysis of multiple mutants, we conclude that curvature sensitivity is intrinsic to chemoreceptor trimers-of-dimers, and results from conformational entropy within the trimer-of-dimers geometry. We use the principles of the conformational entropy model to engineer curvature sensitivity into a series of multi-component synthetic protein complexes. When expressed in E. coli, the synthetic complexes form large polar clusters, and a complex with inverted geometry avoids the cell poles. This demonstrates the successful rational design of both polar and anti-polar clustering, and provides a synthetic platform on which to build new systems.


Measuring employment during COVID-19: challenges and opportunities.
Measuring the economy during COVID-19 has created a set of hurdles and prospects for the U.S. statistical agencies, the private sector, and academia. This included how to deal with unprecedented movements in economic variables while ensuring data quality. At the same time, new entrants released data that are sometimes at odds with gold standard releases. Given the multitude of data, this article focuses on both existing and new ways to track the employment statistics. The results leave more questions than answers.


Surface electromyography activity of upper limb muscle during wheelchair propulsion: Influence of wheelchair configuration.
Biomechanical studies have linked handrim wheelchair propulsion with a prevalence of upper limb musculoskeletal disorders. The purpose of this study was to record upper limb muscle recruitment patterns using surface electromyography during wheelchair propulsion. Recordings were made for various wheelchair configurations to understand the effect of wheelchair configuration on muscle recruitment. Ten paraplegic and ten able-bodied subjects propelled a test wheelchair on a roller ergometer system at a comfortable speed. Twelve wheelchair configurations were tested. Upper limb surface electromyography and kinematics were recorded for each configuration. Based on the hand position relative to the handrim, the propulsion cycle was divided into three phases to explain the activation patterns. Compared to the able-bodied subjects, the paraplegic subjects presented higher activation. This is the case for all muscles in the early push phase, for the triceps brachii, pectoralis major and latissimus dorsi in the late push phase and for the trapezius, triceps brachii and latissimus dorsi during recovery. During early push, activation of nearly all muscles was affected by the axle position, where as seat height only affected biceps brachii and pectoralis major activation. During late push, the deltoid anterior was affected by axle position and the biceps brachii by seat height. During recovery, the trapezius was affected by axle position, the deltoid posterior by seat height and the biceps brachii by both. Upper limb muscle recruitment differences highlight that future studies on wheelchair propulsion should only be done with wheelchair experienced paraplegic subjects. Furthermore, this study provides indications on how muscle recruitment is affected by wheelchair configuration.


The GC-TOF/MS-based Metabolomic analysis reveals altered metabolic profiles in nitrogen-deficient leaves and roots of tea plants (Camellia sinensis).
Nitrogen (N) fertilizer is commonly considered as one of the most important limiting factors in the agricultural production. As a result, a large amount of N fertilizer is used to improve the yield in modern tea production. Unfortunately, the large amount of N fertilizer input has led to increased plant nitrogen-tolerance and decreased amplitude of yield improvement, which results in significant N loss, energy waste and environment pollution. However, the effects of N-deficiency on the metabolic profiles of tea leaves and roots are not well understood. In this study, seedlings of Camellia sinensis (L.) O. Kuntze Chunlv 2 were treated with 3 mM NH4NO3 (Control) or without NH4NO3 (N-deficiency) for 4 months by sandy culture. The results suggested that N-deficiency induced tea leaf chlorosis, impaired biomass accumulation, decreased the leaf chlorophyll content and N absorption when they were compared to the Control samples. The untargeted metabolomics based on GC-TOF/MS approach revealed a discrimination of the metabolic profiles between N-deficient tea leaves and roots. The identification and classification of the altered metabolites indicated that N deficiency upregulated the relative abundances of most phenylpropanoids and organic acids, while downregulated the relative abundances of most amino acids in tea leaves. Differentially, N-deficiency induced the accumulation of most carbohydrates, organic acids and amino acids in tea roots. The potential biomarkers screened in N-deficient leaves compared to Control implied that N deficiency might reduce the tea quality. Unlike the N-deficient leaves, the potential biomarkers in N-deficient roots indicated an improved stress response might occur in tea roots. The results demonstrated N deficiency had different effects on the primary and secondary metabolism in tea leaves and roots. The findings of this study will facilitate a comprehensive understanding of the N-deficient tea plants and provide a valuable reference for the optimized N nutrient management and the sustainable development in the tea plantations.


Pharmacokinetics of recombinant factor VIII in adults with severe hemophilia A: fixed-sequence single-dose study of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa.
Efanesoctocog alfa is a new class of factor (F) VIII replacement therapy designed to provide high sustained factor levels for longer by overcoming the von Willebrand factor half-life ceiling. To assess the pharmacokinetics and safety of standard half-life (octocog alfa) and extended half-life (rurioctocog alfa pegol) FVIIIs and efanesoctocog alfa. This phase 1 study (NCT05042440; EudraCT 2021-000228-37) enrolled previously treated adult men with severe hemophilia A. Patients received sequential single 50-IU/kg doses of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa after appropriate washout periods between each dose. Thirteen participants were enrolled. Geometric mean elimination half-life of octocog alfa, rurioctocog alfa pegol, and efanesoctocog alfa was 11.0, 15.4, and 43.3 hours, respectively, and area under the FVIII activity-time curve was 1670, 2820, and 10,100 IU × h/dL, respectively. Efanesoctocog alfa maintained mean FVIII activity levels of >40 IU/dL for up to 4 days and at ∼10 IU/dL on day 7. Corresponding times for >40 IU/dL and >10 IU/dL were <1 and <2 days, respectively, for octocog alfa and 1 day and <3 days, respectively, for rurioctocog alfa pegol. No serious treatment-emergent adverse events were reported for efanesoctocog alfa, and no inhibitor development to FVIII was detected. Efanesoctocog alfa had 3- to 4-fold longer elimination half-life and 3- to 6-fold greater exposure (area under the FVIII activity-time curve, 6.03 and 3.57 folds) than octocog alfa and rurioctocog alfa pegol. Efanesoctocog alfa provided high sustained FVIII activity in the normal-to-near-normal range (>40 IU/dL) for up to 4 days after the dose and at ∼10 IU/dL on day 7.


Total rhinotomy for midline lesions of the ethmoids and the nose.
Total rhinotomy is a technique previously used to gain access to the sella in hypophyseal surgery. In our experience, total rhinotomy is an excellent approach not only for benign midline naso-ethmoidal lesions but also for bilateral malignant tumours of the ethmoid complex and the nose, provided that there is no dural or orbital involvement. Total rhinotomy is contraindicated for malignant lesions extending into the nasopharynx.


Chronic opioid use during pregnancy: maternal and fetal implications.
Current trends in the United States suggest that chronic narcotic use has increased in reproductive aged women over the past 10 years. Regular exposure to such substances during pregnancy has maternal and fetal implications. Appropriate prenatal care is critical to optimizing outcomes. Management options for narcotic dependence should be patient-specific and may include discontinuation of narcotics with careful observation, limitation of prescription dispensing, or substitution therapy with methadone or buprenorphine. A multidisciplinary, collaborative approach is highly recommended. This review discusses usage of narcotic medications, associated maternal and fetal risks, and management strategies for the antepartum, intrapartum, and postpartum periods.


Defending in 4-4-2 or 5-3-2 formation? small differences in footballers' collective tactical behaviours.
This study explored footballers' tactical behaviours, based on their position data, as an effect of two defending formations, 4-4-2 and 5-3-2, using an experimental approach. Sixty-nine youth footballers participated in this 11-versus-11 study, performing 72 trials of attack-versus-defence. Players' position data were tracked using a local positioning system, and processed to calculate measures of collective movement. This was supplemented by the analysis of passing networks. The results showed small differences between the two conditions. Compared to a 4-4-2 formation, defending in 5-3-2 reduced dispersion (-0.69 m,p=0.012), midfield-forward distance (-0.81 m, p=0.047), and defence-forward distance (-1.29 m, p=0.038); the consequent effects on attacking teams included reduced team widths (-1.78 m, p=0.034), reduced necessity for back-passes to the goalkeeper, and less connectivity in the passing network. The effects of the two defending formations seem to have the greatest impact on fullbacks of the attacking teams, since they were main contributors of the reduced team widths, received more passes, and had higher betweenness centrality in the right-back position during 5-3-2 defending. In summary, the present study potentially demonstrates how the underlying mechanisms in players' collective movements and passing behaviours show that the 5-3-2 is more conservatively defensive than the 4-4-2.


Review article: the current status of CT-guided needle biopsy of the spine.
CT-guided percutaneous needle biopsy of the spine is a well-described technique for determining the nature of indeterminate vertebral lesions or establishing a diagnosis of spinal infection, the high diagnostic accuracy and the safety of the procedure having been extensively documented. The purpose of the current article is to review the literature to date on CT-guided spinal biopsy. Specifically, indications for spinal biopsy, techniques for optimising yield, detail of the approaches for various spinal levels which is dependent upon both the region within the spinal column and lesion location within the vertebra (body vs. neural arch), determinants of biopsy outcome and complications are covered. It is hoped that the review will be of particular benefit to junior radiologists who are required to perform this procedure.


Sports injuries of the shoulder.
Much strain is placed on the shoulder joint in all sports. Sports injuries may be caused by a single, violent incident. Fractures of the clavicle, acromioclavicular and sternoclavicular traumas, isolated fractures of the greater tuberosity and shoulder dislocations are frequent clinical pictures which today can be managed by well established procedures. Other sports injuries, however, involve over-use of the shoulder which, through repetitive harmful movements, can bring about microtraumatic lesions of the rotator cuff, glenoid labrum, acromioclavicular joint and certain peripheral nerves around the suprascapularis. In all cases, a programmed, comparative, clinical examination and complementary, sequential examinations will indicate suitable curative and preventive treatment.


Exogenous melatonin improves tea quality under moderate high temperatures by increasing epigallocatechin-3-gallate and theanine biosynthesis in Camellia sinensis L.
Global warming has multifarious effects on crop growth and productivity. Nonetheless, the effects of moderate-high temperatures and melatonin on tea yield and quality remain unclear. In this study, we found that melatonin, a universal growth stimulatory molecule, not only promotes photosynthesis and biomass accumulation in tea plants (Camellia sinensis L.) but also improves tea quality under sub high temperature (SHT). SHT increased the dry biomass and photosynthesis by 40.8% and 28.1%, respectively, and exogenous melatonin caused a further improvement. Moreover, SHT increased the total polyphenol concentrations and decreased the free amino acid concentrations, leading to a significant increase (68.2%) in polyphenol to free amino acid ratio. However, melatonin decreased the polyphenol to free amino acid ratio by delicately improving the concentrations of polyphenols and amino acids. Consistent with the total polyphenol, melatonin increased the concentrations of (-)-catechin, (-)-gallocatechin (GC), and (-)-epigallocatechin-3-gallate (EGCG) in tea leaves. The qRT-PCR analysis revealed that melatonin increased the transcript levels of catechins biosynthesis genes, such as CsCHS, CsCH1, CsF3H, CsDFR, CsANS, CsLAR, and CsANR under SHT. Meanwhile, the theanine concentration was decreased by SHT, which was attributed to the attenuated expression of CsGS, CsGOGAT, CsGDH, and CsTS1. Nonetheless, melatonin significantly increased those transcripts and the content of theanine under SHT. Melatonin also increased the caffeine content by inducing the expression of CsTIDH, CssAMS, and CsTCS1. These results suggest that melatonin could positively alter tea growth and quality by modulating the photosynthesis and biosynthesis of polyphenols, amino acids, and caffeine in tea leaves under SHT.


Predictive equation for estimating the basal metabolic rate of Malaysian Armed Forces naval trainees.
The basal metabolic rate (BMR) is essential in deriving estimates of energy requirements for a population. The aim of this study was to measure the BMR in order to derive a predictive equation for the Malaysian Armed Forces (MAF) naval trainees. A total of 79 naval trainees aged 18 to 25 years from a training centre (Group A) and on board a ship (Group B) participated in the study. Anthropometric measurements included height and weight. Body fat and free fat mass were measured using the bioelectrical impedance analysis method. BMR was measured by indirect calorimetry with a canopy system. The mean height, weight and body fat for Group A was 1.67 +/- 0.04 m, 61.0 +/- 3.9 kg and 12.7 percent +/- 2.5 percent, respectively, and 1.67 +/- 0.05 m, 62.3 +/- 6.2 kg and 14.0 percent +/- 3.5 percent, respectively, for Group B. The mean BMR for Group A (6.28 +/- 0.40 MJ/ day) did not differ significantly (p is more than 0.05) from that of Group B (6.16 +/- 0.67 MJ / day). The Food and Agriculture Organization/World Health Organization/United Nations University and the Henry and Rees equations overestimated the measured BMR by 9 percent (p is less than 0.001) and 0.5 percent (p is more than 0.05), respectively, while the Ismail et al equation underestimated the measured BMR by 5.6 percent (p is less than 0.001). A predictive equation, BMR = 3.316 + 0.047 (weight in kg) expressed in MJ /day with weight as the only independent variable, was derived using regression analysis. We recommend that this predictive equation be used to estimate the energy requirements of MAF naval trainees.


Percutaneous insertion of the spinal end of a cysto-peritoneal shunt as definitive treatment to relieve cord compression from a spinal arachnoid cyst.
A case of myelopathy with both intradural and extradural spinal arachnoid cysts is reported treated by cysto-peritoneal shunt, the spinal end of which was inserted percutaneously under fluoroscopic control. The site of drainage was determined by findings at computed myelography. The case illustrates the value of the latter in demonstrating the pathological bio-mechanics producing myelopathy in this condition.


Microglial P2X4 receptors promote ApoE degradation and contribute to memory deficits in Alzheimer's disease.
Numerous evidences support that microglia contributes to the progression of Alzheimer's disease. P2X4 receptors are ATP-gated channels with high calcium permeability, which are de novo expressed in a subset of reactive microglia associated with various pathological contexts, contributing to microglial functions. P2X4 receptors are mainly localized in lysosomes and trafficking to the plasma membrane is tightly regulated. Here, we investigated the role of P2X4 in the context of Alzheimer's disease (AD). Using proteomics, we identified Apolipoprotein E (ApoE) as a specific P2X4 interacting protein. We found that P2X4 regulates lysosomal cathepsin B (CatB) activity promoting ApoE degradation; P2rX4 deletion results in higher amounts of intracellular and secreted ApoE in both bone-marrow-derived macrophage (BMDM) and microglia from APPswe/PSEN1dE9 brain. In both human AD brain and APP/PS1 mice, P2X4 and ApoE are almost exclusively expressed in plaque-associated microglia. In 12-month-old APP/PS1 mice, genetic deletion of P2rX4 reverses topographical and spatial memory impairment and reduces amount of soluble small aggregates of Aß1-42 peptide, while no obvious alteration of plaque-associated microglia characteristics is observed. Our results support that microglial P2X4 promotes lysosomal ApoE degradation, indirectly altering Aß peptide clearance, which in turn might promotes synaptic dysfunctions and cognitive deficits. Our findings uncover a specific interplay between purinergic signaling, microglial ApoE, soluble Aß (sAß) species and cognitive deficits associated with AD.


Clozapine in the treatment of psychosis in Parkinson's disease.
Clozapine is an antipsychotic medication that is virtually free of extrapyramidal side effects. We report our successful treatment of 6 patients with idiopathic Parkinson's disease and various psychoses using clozapine on a chronic basis along with carbidopa/L-dopa.


Effect of FK506 on expression of hepatocyte growth factor in murine spinal cord following peripheral nerve injury.
This study is to investigate the effect of FK506 on expression of hepatocyte growth factor (HGF) in rats' spinal cord following peripheral nerve injury and to elucidate the mechanisms for neuroprotective property of FK506. Fifty male rats were randomly divided into normal group, injury group and treatment group. Models of peripheral nerve injury were established by bilateral transection of sciatic nerve 0.5 cm distal to piriform muscle. Then the treatment group received subcutaneous injection of FK506 (1 mg/kg) at the back of neck, while the injury group was given 0.9% saline. The L(4-6) spinal cords were harvested at various time points after the surgery. Western blotting and immunofluorescent staining were used to detect the level and position of HGF in spinal cord. Immunofluorescent staining showed that HGF-positive neurons were located in anterior horn, intermediate zone and posterior horn of gray matter in normal spinal cord. Western blotting revealed that there was no significant difference in the expressions of HGF between the injury group and the normal group, while the expression of HGF was significantly higher in the treatment group than in the injury group 7 and 14 days after surgery. It is suggested that peripheral nerve injury does not result in up-regulation of the expression of HGF in spinal cord, while FK506 may induce high expression of endogenous HGF after injury thereby protecting neurons and promoting axonal outgrowth.


Fixel-Based Analysis Reveals Whole-Brain White Matter Abnormalities in Cervical Dystonia.
Cervical dystonia (CD) is a form of isolated focal dystonia typically associated to abnormal head, neck, and shoulder movements and postures. The complexity of the clinical presentation limits the investigation of its pathophysiological mechanisms, and the neural networks associated to specific motor manifestations are still the object of debate. We investigated the morphometric properties of white matter fibers in CD and explored the networks associated with motor symptoms, while regressing out nonmotor scores. Nineteen patients affected by CD and 21 healthy controls underwent diffusion-weighted magnetic resonance imaging. We performed fixel-based analysis, a novel method evaluating fiber orientation within specific fiber bundles, and compared fiber morphometric properties between groups. Moreover, we correlated fiber morphometry with the severity of motor symptoms in patients. Compared to controls, patients exhibited decreased white matter fibers in the right striatum. Motor symptom severity negatively correlated with white matter fibers passing through inferior parietal areas and the head representation area of the motor cortex. Abnormal white matter integrity at the basal ganglia level may affect several functional networks involved, for instance, in motor preparation and execution, visuomotor coordination, and multimodal integration. This may result in progressive maladaptive plasticity, culminating in overt symptoms of dystonia. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


The role of microtubules in human natural killer cell-mediated cytotoxicity.
The effect of four different microtubule (MT) inhibitors on the various stages of human natural killer (NK) cell-mediated cytotoxicity was studied. The MT-disrupting effect of the drugs was monitored by indirect immunofluorescence microscopy and transmission electron microscopy. All the drugs tested, vinblastine sulfate, demecolcine, nocodazole, and taxol, had only a slight inhibitory effect on NK activity. Cells with nonfunctional MT were capable of normal conjugate formation and polarization of actin-containing microfilaments. Natural killer cell cytotoxic factor (NKCF) activity produced by cells with nonfunctional MT was slightly diminished. MT disruption caused enlargement of Golgi cisternae, but did not, however, dissociate the overall structural organization of the Golgi complex. The results indicate that fresh human NK cells are capable of lytic activity without functional MT although MT play a small supportive role in production or secretion of NKCF and mediation of the lytic activity. Previous experiments by us and others have strongly suggested that NK cells mediate their cytolytic activity by directed secretion of toxic material. As NK cells with unfunctional microtubules are capable of close to normal secretion the results presented in this report are not inconsistent with the earlier suggested stimulus-secretion model.


NLRP1 and NLRC4 inflammasomes are not responsible for the induction of inflammation in pulp tissues from carious teeth.
Inflammation is a risk factor for dental complications. Inflammasomes are a set of intracellular sensors which participate in the induction of inflammation. As the main factors involved in the induction of pulp inflammation in the carious teeth are yet to be clarified, this study was aimed to evaluate NLRP1 and NLRC4 expression levels in the inflamed and healthy pulps. Fifty inflamed and fifty healthy pulps were evaluated regarding the multiRNA levels of NLRP1 and NLRC4 using real-time polymerase chain reaction technique. Results demonstrated that expression of NLRP1 (P = 0.985) and NLRC4 (P = 0.581) did not significantly differ in inflamed in comparison to healthy pulps. NLRP1 (P = 0.989) and NLRC4 (P = 0.170) did not change in males when compared with females in inflamed pulps. Furthermore, NLRP1 (P = 0.133) and NLRC4 (P = 0.642) were not altered in males in comparison to females in healthy pulps. Although NLRP1 and NLRC4 are the main inflammasomes, it appears that they are not the responsible molecules involved in the human pulp inflammation in the carious teeth.


Development and evaluation of an undergraduate curriculum on non-communicable disease research in Guam: The Pacific Islands Cohort of College Students (PICCS).
The non-communicable disease (NCD) epidemic among Pacific Islanders prompted the declaration of a regional state of NCD emergency throughout the United States-Affiliated Pacific Islands (USAPIs) in 2010. Subsequently, the University of Guam Health Science Program launched a pilot study on NCD research in its undergraduate curriculum modeled after the Pacific Data for Decision Making (DDM) framework - a field epidemiology training program employed in the USAPIs. The primary objective of the research is to conduct annual assessments of student health indicators with plans for longitudinal follow-up. Here, development and evaluation of the undergraduate research curriculum are described. The Pacific DDM framework covering knowledge and skills in resourcing, types of data and indicators, data sources, data management, information products, and data dissemination and use were incorporated in undergraduate core courses of the Health Science Program. During the data collection pilot years, 2013 and 2014, a survey containing questions predominantly on NCD risk factors was launched at the university. The survey was administered by upperclassmen in the Health Science Program and evolved into the Pacific Islands Cohort of College Students (PICCS) research study. The initial years were spent developing the infrastructure. Program outputs were tracked annually to measure program success. Students in the Health Science Program obtained research knowledge and skills through various courses while enrolled in the program. The PICCS data collection continued annually as a cross-sectional survey from 2015 to current. Numerous successes have resulted including student abstracts and publications, acceptances to summer programs and fellowships, a sustained annual health fair for college students, a grant award, and other program-related impacts. The PICCS framework provided the organizational structure and documented tools, protocols, roles, and responsibilities to enhance consistency and reproducibility. Undergraduate students applied their knowledge and skills to an ongoing study focused on NCD risk factor surveillance of college students. Additionally, multiple research successes have been achieved through the PICCS curriculum. Plans are underway to begin the longitudinal design of the PICCS research study and sustain it through the curriculum, with room for adaptation as courses are updated over time.


Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial.
Weight-loss drugs produce an additional mean weight loss of only 3-5 kg above that of diet and placebo over 6 months, and more effective pharmacotherapy of obesity is needed. We assessed the efficacy and safety of tesofensine-an inhibitor of the presynaptic uptake of noradrenaline, dopamine, and serotonin-in patients with obesity. We undertook a phase II, randomised, double-blind, placebo-controlled trial in five Danish obesity management centres. After a 2 week run-in phase, 203 obese patients (body-mass index 30-</=40 kg/m(2)) were prescribed an energy restricted diet and randomly assigned with a list of randomisation numbers to treatment with tesofensine 0.25 mg (n=52), 0.5 mg (n=50), or 1.0 mg (n=49), or placebo (n=52) once daily for 24 weeks. The primary outcome was percentage change in bodyweight. Analysis was by modified intention to treat (all randomised patients with measurement after at least one dose of study drug or placebo). The study is registered with ClinicalTrials.gov, number NCT00394667. 161 (79%) participants completed the study. After 24 weeks, the mean weight loss produced by diet and placebo was 2.0% (SE 0.60). Tesofensine 0.25 mg, 0.5 mg, and 1.0 mg and diet induced a mean weight loss of 4.5% (0.87), 9.2% (0.91), and 10.6% (0.84), respectively, greater than diet and placebo (p<0.0001). The most common adverse events caused by tesofensine were dry mouth, nausea, constipation, hard stools, diarrhoea, and insomnia. After 24 weeks, tesofensine 0.25 mg and 0.5 mg showed no significant increases in systolic or diastolic blood pressure compared with placebo, whereas heart rate was increased by 7.4 beats per min in the tesofensine 0.5 mg group (p=0.0001). Our results suggest that tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved drugs. However, these findings of efficacy and safety need confirmation in phase III trials.


Direct Observation of the Biaxial Stress Effect on Efficiency Droop in GaN-based Light-emitting Diode under Electrical Injection.
Light-emitting diode (LED) efficiency has attracted considerable interest because of the extended use of solid-state lighting. Owing to lack of direct measurement, identification of the reasons for efficiency droop has been restricted. A direct measurement technique is developed in this work for characterization of biaxial stress in GaN-based blue LEDs under electrical injection. The Raman shift of the GaN E2 mode evidently decreases by 4.4 cm(-1) as the driving current on GaN-based LEDs increases to 700 mA. Biaxial compressive stress is released initially and biaxial tensile stress builds up as the current increases with respect to the value of stress-free GaN. First-principles calculations reveal that electron accumulation is responsible for the stress variation in InxGa1-xN/GaN quantum wells, and then reduces the transition probability among quantum levels. This behavior is consistent with the measured current-dependent external quantum efficiency. The rule of biaxial stress-dependent efficiency is further validated by controlling the biaxial stress of GaN-based LEDs with different sapphire substrate thicknesses. This work provides a method for direct observation of the biaxial stress effect on efficiency droop in LEDs under electrical injection.


Bayesian machine learning improves single-wavelength anomalous diffraction phasing.
Single-wavelength X-ray anomalous diffraction (SAD) is a frequently employed technique to solve the phase problem in X-ray crystallography. The precision and accuracy of recovered anomalous differences are crucial for determining the correct phases. Continuous rotation (CR) and inverse-beam geometry (IBG) anomalous data collection methods have been performed on tetragonal lysozyme and monoclinic survivin crystals and analysis carried out of how correlated the pairs of Friedel's reflections are after scaling. A multivariate Bayesian model for estimating anomalous differences was tested, which takes into account the correlation between pairs of intensity observations and incorporates the a priori knowledge about the positivity of intensity. The CR and IBG data collection methods resulted in positive correlation between I(+) and I(-) observations, indicating that the anomalous difference dominates between these observations, rather than different levels of radiation damage. An alternative pairing method based on near simultaneously observed Bijvoet's pairs displayed lower correlation and it was unsuccessful for recovering useful anomalous differences when using the multivariate Bayesian model. In contrast, multivariate Bayesian treatment of Friedel's pairs improved the initial phasing of the two tested crystal systems and the two data collection methods.


Lung complications of Sjogren syndrome.
Primary Sjogren syndrome (pSS) is a systemic autoimmune disease characterised by lymphocytic infiltration of exocrine glands and by a number of systemic manifestations, including those regarding the lung. Pulmonary involvement in pSS includes interstitial lung disease (ILD) and airway disease, together with lymphoproliferative disorders.Patients with pSS-ILD report impaired health-related quality of life and a higher risk of death, suggesting the importance of early diagnosis and treatment of this type of pulmonary involvement. In contrast, airway disease usually has little effect on respiratory function and is rarely the cause of death in these patients.More rare disorders can be also identified, such as pleural effusion, cysts or bullae.Up to date, available data do not allow us to establish an evidence-based treatment strategy in pSS-ILD. No data are available regarding which patients should be treated, the timing to start therapy and better therapeutic options. The lack of knowledge about the natural history and prognosis of pSS-ILD is the main limitation to the development of clinical trials or shared recommendations on this topic. However, a recent trial showed the efficacy of the antifibrotic drug nintedanib in slowing progression of various ILDs, including those in pSS patients.


LncRNA TUG1 contributes to ESCC progression via regulating miR-148a-3p/MCL-1/Wnt/β-catenin axis in vitro.
Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies. Latest studies report that long noncoding RNAs (LncRNAs) play an essential role in diversified pathological processes of ESCC, although the mechanism by which they do so remains unknown. This study aimed to explore the parts of lncRNA taurine upregulated gene 1 (TUG1) in ESCC tissues and cells, its biofunctional effect and its underlying regulatory mechanism in ESCC. The levels of TUG1 and miR-148a-3p were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in ESCC cells and tissues. The biofunctional effects were examined by MTT, flow cytometry, and transwell assay. The protein expression levels of epithelial-mesenchymal transition (EMT)-related proteins and MCL-1 were determined by western blot analysis. The binding sites between miR-148a-3p and TUG1 or MCL-1 were predicted by online software starBase and confirmed by dual luciferase reporter assay. The mRNA expression of TUG1 was significantly upregulated in ESCC tissues or cells, and was negatively correlated to miR-148a-3p expression in tissues. Knockdown of TUG1 inhibited the proliferation, migration, and invasion, promoted apoptosis, and relieved the EMT progression in EC9706 and OE19 cells. Besides, knockdown of miR-148a-3p inverted positive effects from TUG1 deletion on ESCC cells. Besides, MCL-1 reversed the inhibitive effects from TUG1 deletion on expression of EMT-associated proteins (Wnt1, C-myc, CyclinD1, and β-catenin) above subsequently. TUG1 regulated the biofunction and EMT progression of ESCC by mediating miR-148a-3p/MCL-1/Wnt/β-catenin axis in vitro.


The "Fas counterattack" is not an active mode of tumor immune evasion in colorectal cancer with high-level microsatellite instability.
Microsatellite instability (MSI) is an alternative pathway of colorectal carcinogenesis. It is found in 10% to 15% of sporadic colorectal neoplasms and is characterized by failure of the DNA mismatch-repair system. High-level MSI (MSI-H) is associated with tumor-infiltrating lymphocytes (TILs) and a favorable prognosis. Expression of Fas ligand (FasL/CD95L) by cancer cells may mediate tumor immune privilege by inducing apoptosis of antitumor immune cells. The aim of this study was to investigate the relationship between FasL expression and MSI status in primary colon tumors. Using immunohistochemistry, we detected FasL expression in 91 colorectal carcinoma specimens, previously classified according to the level of MSI as MSI-H (n = 26), MSI-low (MSI-L) (n = 29), and microsatellite stable (n = 36). Tumor-infiltrating lymphocyte density was quantified by immunohistochemical staining for CD3. MSI-H tumors were significantly associated with reduced frequency (P = .04) and intensity (P = .066) of FasL expression relative to non-MSI-H (ie, microsatellite stable and MSI-L) tumors. Higher FasL staining intensity correlated with reduced TIL density (P = .059). Together, these findings suggest that the abundance of TILs found in MSI-H tumors may be due to the failure of these tumor cells to up-regulate FasL and may explain, in part, the improved prognosis associated with these tumors.


Synergistic role of β-catenin1 and 2 in ovarian differentiation and maintenance of female pathway in Nile tilapia.
Two β-catenin (β-cat) genes exist in teleosts but little is known about their expression and function in ovarian development. We identified β-cat1 and β-cat2 from the Nile tilapia. β-cat1 and β-cat2 displayed a similar expression pattern in the ovary during development, and were mainly expressed in the oogonia and oocytes. In luciferase assays, β-cat1 activated the TOPFlash reporter dose-dependently, whereas β-cat2 failed to do so. Cotransfection of β-cat1 and β-cat2 synergistically enhanced the expression of the reporter. A specific interaction between β-cat1 and β-cat2 was also observed in a mammalian two-hybrid assay. Furthermore, tilapia recombinant Dkk1, an inhibitor of the β-cat pathway, decreased β-cat1 and β-cat2, while increased sox9, dmrt1, cyp11b2 and foxl2 expression in the in vitro cultured tilapia ovary, which could be abolished by simultaneous treatment with Bio, an agonist of β-cat. Consistently, β-cat1 or β-cat2 knockdown in XX fish by TALENs caused the retardation of ovarian differentiation and masculinization, as reflected by the upregulation of dmrt1, cyp11b2, sox9, and serum 11-KT level. On the contrary, serum E2 level was unchanged even though foxl2 transcription was upregulated. These data suggestes that both β-cat1 and β-cat2 are important members and play synergistic roles in the canonical Wnt signal pathway in fish. Independent of Foxl2-leading estrogen pathway, they might be involved in ovarian differentiation and repression of the male pathway gene expression in tilapia.


Snail and Slug, key regulators of TGF-β-induced EMT, are sufficient for the induction of single-cell invasion.
TGF-β plays a dual role in cancer; in early stages it inhibits tumor growth, whereas later it promotes invasion and metastasis. TGF-β is thought to be pro-invasive by inducing epithelial-to-mesenchymal transition (EMT) via induction of transcriptional repressors, including Slug and Snail. In this study, we investigated the role of Snail and Slug in TGF-β-induced invasion in an in vitro invasion assay and in an embryonic zebrafish xenograft model. Ectopic expression of Slug or Snail promoted invasion of single, rounded amoeboid cells in vitro. In an embryonic zebrafish xenograft model, forced expression of Slug and Snail promoted single cell invasion and metastasis. Slug and Snail are sufficient for the induction of single-cell invasion in an in vitro invasion assay and in an embryonic zebrafish xenograft model.


Evaluation of a novel silicone oil free primary packaging system with PTFE-based barrier stopper for biologics.
In order to overcome silicone oil related problems for biopharmaceuticals, novel container systems are of interest with a focus on the reduction, fixation or complete avoidance of silicone oil in the primary container. Ultimately, silicone oil free (SOF) container systems made from cyclic olefin (co-)polymer or glass combined with the respective silicone-oil free plungers were developed. In the following study we evaluated the potential of a SOF container system based on a glass barrel in combination with a fluoropolymer coated syringe plunger. In a long-term stability study, the system was compared to other alternative container systems in terms of functionality and particle formation when filled with placebo buffers. The system proved to be a valuable alternative to marketed siliconized container systems with acceptable and consistent break-loose gliding forces and it was clearly superior in terms of particle formation over storage time. Additionally, we evaluated the importance of the glass barrel surface for functionality. The interaction of the fill medium with the glass surface significantly impacted friction forces. Consequently, storage conditions and production processes like washing and sterilization, which can easily alter the surface properties, should be carefully evaluated, and controlled. The novel combination of non-lubricated glass barrel and fluoropolymer coated plunger provides a highly valuable SOF packaging alternative for biopharmaceuticals.


Evaluation of the diffusion of corticosteroids between the distal interphalangeal joint and navicular bursa in horses.
To determine whether clinically effective concentrations of methylprednisolone or triamcinolone can be achieved in the navicular bursa after injection of methylprednisolone acetate (MPA) or triamcinolone acetonide (TA) into the distal interphalangeal joint (DIPJ) and whether clinically effective concentrations of these drugs can be achieved in the DIPJ after injecting the navicular bursa with the same doses of MPA or TA. 32 healthy horses. Horses in groups 1 through 4 received 40 mg of MPA in the DIPJ, 10 mg of TA in the DIPJ, 40 mg of MPA in the navicular bursa, and 10 mg of TA in the navicular bursa, respectively. Concentrations of corticosteroids that diffused into the adjacent synovial structure were determined. For group 1, injection of MPA into the DIPJ yielded a mean +/- SD concentration of 0.24 +/- 0.072 microg of methylprednisolone/mL in the navicular bursa. For group 2, injection of TA into the DIPJ yielded 0.124 +/- 0.075 microg of triamcinolone/mL in the navicular bursa. For group 3, injection of MPA into the navicular bursa yielded 0.05 +/- 0.012 microg of methylprednisolone/mL in the DIPJ. For group 4, injection of TA into the navicular bursa yielded 0.091 +/- 0.026 microg of triamcinolone/mL in the DIPJ. A clinically effective concentration of methylprednisolone or triamcinolone diffused between the DIPJ and navicular bursa after intra-articular or intrabursal injection, which would justify injection of the DIPJ with MPA or TA to ameliorate inflammation of the navicular bursa.


[Determination of metal dusts in aerosols using x-ray fluorescence. Comparison with other analytical methods].
Determination of metals in aerosol collected as thin layer on membran filters has made employing X-ray fluorescence. Standards are prepared in suitable chambers: dust collected on membran filter is weighted. The problems of methodology are discussed. Calibration curves have been prepared for Pb - Fe - Cd - Si; comparisons have been made with other methods employing atomic absorption spectroscopy.


Ultra-high-performance liquid chromatography-tandem high-resolution elevated mass spectrometry profiling of anti-methicillin-resistant Staphylococcus aureus metabolites from the endophytic bacteria collected from the weeds of a previous dumpsite.
The culturable endophytic bacteria from the weeds Cleome rutidosperma of the family Cleomaceae and Digitaria sanguinalis of the family Poaceae obtained from a previous dumpsite in Pampanga, Philippines have been assessed for their anti-methicillin-resistant Staphylococcus aureus (MRSA) activity, and the analytes with such activity should be identified. However, due to the limited amounts collected from the isolation process, 1.8 mg yield of compound 1 from the endophyte of C. rutidosperma and 1.2 mg of a mixture from the endophyte of D. sanguinalis were selected for LC-MSE analysis. The production of compounds from the culturable endophytic bacteria Pseudomonas aeruginosa- determined by gene-sequencing, an untargeted and data-independent analysis (DIA) by ultra-high performance liquid chromatography-high resolution-elevated energy mass spectrometry (UHPLC-HR-MSE) technique was employed to profile the metabolites present in the two high-performance liquid chromatography (HPLC) fractions. The analytes present from P. aeruginosa detected by UHPLC-HR-MSE isolated from C. rutidosperma was phenazine-1-carboxylic acid (1), and for D. sanguinalis were chamigrenal (2), dialkyl resorcinol (3), and a pyoverdine elicitor (4). This study proves that UHPLC-HR-MSE could identify the anti-MRSA constituents in P. aeruginosa from commensal weeds C. rutidosperma and D. sanguinalis. The UHPLC-HR-MSE could help strengthen metabolomics antibacterial research and its related applications from a future perspective. Application of metabolomics research using UHPLC-HR-MSE could enhance the rehabilitation of dumpsites by the microbial community present.


Plant-inspired multifunctional fluorescent cellulose nanocrystals intelligent nanocomposite hydrogel.
Intelligent hydrogel has great application potentials in flexible sensing and artificial intelligence devices due to its intrinsic characteristics. However, developing an intelligent hydrogel with favorable properties including high strength, superior toughness, excellent conductivity and ionic sensing via a facile route is still a challenge. Herein, inspired by biologically chelating interactions of phytic acid (PA) in plants, a plant-inspired versatile intelligent nanocomposite hydrogel was readily fabricated by incorporating PA into the interface of fluorescent cellulose nanocrystals (F-CNC). Under PA "molecular bridge", the hydrogel simultaneously realized superflexibility (1000 %), high strength, superb self-healing ability, remarkable fluorescence and chloride ion sensibility as well as good ionic conductivity (2.4 S/m). The hydrogel could be assembled as a flexible sensor for real-time monitoring of human motion with excellent sensitivity and stability since high sensitivity toward both strain and pressure. F-CNC acted as a functional trigger could confer the hydrogel good fluorescence and high sensitivity toward chloride ion. This design confirms the synergy of F-CNC in boosting strength, ionic sensing, and ionic conductivity, addressing a long-standing dilemma among strength, stretchability, and sensitivity for intelligent hydrogel. The one-step incorporating tactic under mild ambient conditions may open an innovative avenue for the construction of intelligent hydrogel with novel properties.


A derivative of staurosporine (CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity.
Analogues of staurosporine were synthesized and their ability to inhibit protein kinases was examined. Staurosporine is a potent but non-selective inhibitor of in vitro protein kinase C(PKC) activity (IC50 6.0 nM). The derivative CGP 41 251 had reduced PKC activity with an IC50 of 50 nM but showed a high degree of selectivity when assayed for inhibition of cyclic AMP-dependent protein kinase (IC50 2.4 microM), S6 kinase (IC50 5.0 microM) and tyrosine-kinase-specific activity of epidermal growth factor receptor (IC50 3.0 microM). Staurosporine and CGP 41 251 exerted growth inhibition in the human bladder carcinoma line T-24, human promyelocytic leukemia line HL-60 and bovine corneal endothelial cells at concentrations which correlated well with in vitro PKC inhibition. In addition, both compounds inhibited the release of H2O2 from human monocytes pre-treated with 12-O-tetradecanoyl-phorbol-13-acetate at non-toxic concentrations. In vivo anti-tumor activity was examined in T-24 human bladder carcinoma xenografts in athymic nude mice. Tumor growth inhibition tests revealed significant anti-tumor activity (2p less than 0.001) at 1/10 of the maximum tolerated doses for both compounds. By contrast, a closely related derivative of staurosporine (CGP 42 700) was inactive at concentrations of over 100 microM in all in vitro enzyme and anti-proliferative assays as well as in animal tumor models. Our data suggest an association between PKC inhibition and anti-proliferative and anti-tumor activity.


[Repigmentation of gray hair after thyroid hormone treatment].
Darkening of gray and white hairs occurred in 2 patients with increased exogenous triiodothyronine (T3) due to treatment of myxedema coma in one case and iatrogenic hyperthyroidism in the other. We hypothesized that thyroid hormone may affect the homeostasis of hair follicles. To test our hypothesis and investigate the influence of thyroid hormone on the hair cycle, we used an in vivo murine model and an in vitro model based on culture of follicular units. We used the standard C57BL/6 murine model of the hair cycle. T3 (0.5 microg) dissolved in ethanol was applied topically once daily for 10 days to a depilated area in the telogen phase on the backs of the mice. Follicular units, obtained from hair transplant interventions, were cultured in vitro with different concentrations of T3. On day 5, all T3-treated mice entered the anagen phase, whereas the anagen phase started spontaneously in control mice on day 9, and not until day 15 had all controls entered this phase. In the in vitro experiment, follicular units treated with 100 nmol/L T3 grew significantly larger compared to the control group. These data suggest that follicles in the telogen phase can be induced to enter the anagen phase by the topical application of T3. This thyroid hormone may reverse graying of the terminal hair. In the in vitro experiments, T3 stimulated hair shaft growth. Follicular melanocytes may be the target cell for these actions.


Effects of maggot antimicrobial peptides on growth performance, immune function, and cecal flora of yellow-feathered broilers.
This study investigated the effects of maggot antimicrobial peptides on growth performance, blood parameters, immune organ index, and cecum microbial diversity in yellow broilers. The addition of 100-300 mg/kg maggots antimicrobial peptides to the corn-soybean meal basal diet was evaluated. Two hundred and forty one-day-old yellow-feathered broilers were randomly divided into four groups (60 chickens in each group): basal diet group (BC group), basal diet group + 100, 200, 300 mg/kg maggots antimicrobial peptides (MDAL group, MDAM group, and MDAH group). The result showed that the average daily feed intake (ADFI) of the BC group, MDAM group, and MDAH group was higher than that of the MDAL group (P > 0.05), the average daily gain of MDAM group and MDAH group was significantly higher than that of BC group and MDAL group (P < 0.05), but the feed-weight ratio (F/G) was significantly lower than that of BC group (P < 0.05). The total protein (TP) content in the MDAM group and MDAH group was significantly higher than that in the BC group (P < 0.05), and the albumin (ALB) content in the MDAH group was higher than that in the BC group (P > 0.05). The contents of IgA and IgG in the MDAH group were significantly higher than those in the BC group (P < 0.05). In contrast, the content of alanine aminotransferase (ALT) in the MDAH group was significantly lower than that in the BC group (P < 0.05). The thymus and spleen indexes of the MDAH group were significantly higher than those of the BC group (P < 0.05). 16S rDNA sequencing results showed that Bacteroidota and Bacteroides were the dominant phylum and genus of cecal microorganisms at the phylum and genus levels, respectively. Cecum microorganisms are mainly involved in biological processes such as energy production and conversion, amino acid transport and metabolism, and carbohydrate transport and metabolism. It was concluded that adding different doses of maggot antimicrobial peptide to the basal diet could improve yellow-feathered broilers' growth and immune performance and change the cecum flora. The appropriate dose of antimicrobial peptide addition was 300 mg/kg.


Congenitally corrected transposition of great vessels with infundibular pulmonary stenosis with ventricular septal defect, presenting with atypical atrioventricular nodal reentrant tachycardia: a rare association.
Congenitally corrected transposition of great vessels (CCTGV) is a rare congenital heart disease (CHD) accounting for <1% of CHDs. CCTGV with infundibular pulmonary stenosis (PS) with ventricular septal defect (VSD) is part of Fallot's physiology. It is known to be associated with bradyarrhythmias like atrioventricular (AV) blocks, and acquired complete AV block occurs at a rate of 2% per year. Patients can have left-sided accessory pathways, which may cause atrioventricular reentrant tachycardia (AVRT). Tachyarrhythmias like atrioventricular nodal reentrant tachycardia (AVNRT) are very rare in such patients. A 30-year-old woman, a known case of CCTGV with PS with VSD, not corrected surgically and not on any drugs, presented with the syndrome of paroxysmal supraventricular tachycardia without hemodynamic compromise. Electrocardiogram showed atypical AVNRT. She was pharmacologically cardioverted to normal sinus rhythm with adenosine. CTGV with PS with VSD known to be associated with AV blocks, and preexcitation can sometimes present with atypical AVNRT.


Contrast-enhanced ultrasound imaging for monitoring the efficacy of near-infrared photoimmunotherapy.
Near-infrared photoimmunotherapy (NIR-PIT) is a promising cancer therapy combining NIR-light irradiation with an antibody and IR700DX, a light-sensitive substance, to destroy tumours. However, homogeneous irradiation is difficult because the light varies depending on the distance and tissue environment. Therefore, markers that indicate sufficient irradiation are necessary. Nanoparticles sized 10∼200 nm show enhanced permeation and retention within tumours, which is further enhanced via NIR-PIT (super enhanced permeability and retention, SUPR). We aimed to monitor the effectiveness of NIR-PIT by measuring SUPR. A xenograft mouse tumour model was established by inoculating human cancer cells in both buttocks of Balb/C-nu/nu mice, and NIR-PIT was performed on only one side. To evaluate SUPR, fluorescent signal examination was performed using QD800-fluorescent nanoparticles and NIR-fluorescent poly (d,l-lactide-co-glycolic acid) (NIR-PLGA) microparticles. Harmonic signals were evaluated using micro-bubbles of the contrast agent Sonazoid and contrast-enhanced ultrasound (CEUS) imaging. The correlation between SUPR immediately after treatment and NIR-PIT effectiveness on the day after treatment was evaluated. QD800 fluorescent signals persisted only in the treated tumours, and the intensity of remaining signals showed high positive correlation with the therapeutic effect. NIR-PLGA fluorescent signals and Sonazoid-derived harmonic signals remained for a longer time in the treated tumours than in the controls, and the kE value of the two-compartment model correlated with NIR-PIT effectiveness. SUPR measurement using Sonazoid and CEUS imaging could be easily adapted for clinical use as a therapeutic image-based biomarker for monitoring and confirming of NIR-PIT efficacy. This research was supported by ARIM JAPAN of MEXT, the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, 21K07217) (JSPS), CREST (JPMJCR19H2, JST), and FOREST-Souhatsu (JST). Mochida Memorial Foundation for Medical and Pharmaceutical Research; Takeda Science Foundation; The Japan Health Foundation; and Princess Takamatsu Cancer Research Fund. Funders only provided financial support and had no role in the study design, data collection, data analysis, interpretation, and writing of the report.


The effect of pH on the stabilization and digestive characteristics of soybean lipophilic protein oil-in-water emulsions with hypromellose.
The development of functional foods requires a detailed understanding of the behavior of lipophilic protein (LP) in the presence of emulsion stabilizers at different pH conditions. In this study, we examined the interaction between hydroxypropyl methylcellulose (hypromellose, HPMC) and soybean lipophilic protein. To that end, we examined the stabilities of LP-HPMC emulsions at pH 3, 5, and 7, as well as the oil-release behavior of LP-HPMC emulsions during digestion. Fluorescence data showed that HPMC binds to LP with quenching at a single binding site that did not change with pH. Atomic-force microscopy, emulsification, and oxidation-stability analyses showed that HPMC improves the pH stability of the LP-HPMC emulsions, while simulated in-vitro digestion experiments showed that added HPMC delayed the release of lipids to varying degrees. The results of this study will aid in the development of emulsion-based functional foods, pharmaceutical carriers with controlled-release or sustained-release functional ingredients.


Effects of phorbol esters on contraction and protein kinase C activation in rabbit aorta.
This study investigates the relationship between the contractile efficacy of phorbol esters and their ability to activate protein kinase C in intact rabbit aorta. Phorbol dibutyrate (PDB) induced a maximal contraction approximately 3.5-fold greater than that to phorbol myristate acetate (PMA). The magnitude of maximal PDB- and PMA-induced contraction correlated with the magnitude of protein kinase C activation, as assessed by the decrease in cytosolic protein kinase C activity. KCl (60 mM) did not potentiate the PMA-induced decrease in cytosolic protein kinase C activity. These results suggest that the lack of efficacy of PMA is due to its inability to activate protein kinase C in the intact rabbit aorta. It is speculated that the different contractile efficacies of phorbol esters result from selective activation of protein kinase C isoforms, and that the amounts of these isoforms varies amongst vascular tissues.


MRI findings of the normal and diseased trigeminal nerve ganglion and branches: a pictorial review.
The trigeminal nerve is the largest cranial nerve with both a sensory and motor function. MRI is an excellent technique to evaluate the trigeminal nerve. We report the MRI findings and illustrate the normal and diseased trigeminal nerve at Meckel's cave, the cavernous sinus, the skull base foramina, the pterygopalatine fossa and the peripheral branches.


Synthesis and in vitro cytotoxic evaluation of novel N-(3,4,5-trimethoxyphenyl)pyridin-2(1H)-one derivatives.
A series of novel [Formula: see text]-(3,4,5-trimethoxyphenyl)pyridin-2([Formula: see text])-one derivatives were designed, synthesized, and evaluated for their in vitro cytotoxicity against human colon cancer cells HCT-116. The key steps involved consecutive Chan-Lam- and Buchwald-Hartwig couplings. Most of these C-6 substituted pyridone derivatives showed moderate antiproliferative activity. The preliminary SAR indicated that the conformationally restricted pyridones exhibited more potent cytotoxicity than the flexible counterparts. In addition, cell cycle analysis of the selected compounds 4b and e showed a G2/M arrest, suggesting a possible antitubulin mechanism for these novel pyridone derivatives.


Coordinated regulation of vegetative phase change by brassinosteroids and the age pathway in Arabidopsis.
Vegetative phase change in plants is regulated by a gradual decline in the level of miR156 and a corresponding increase in the expression of its targets, SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) genes. Gibberellin (GA), jasmonic acid (JA), and cytokinin (CK) regulate vegetative phase change by affecting genes in the miR156-SPL pathway. However, whether other phytohormones play a role in vegetative phase change remains unknown. Here, we show that a loss-of-function mutation in the brassinosteroid (BR) biosynthetic gene, DWARF5 (DWF5), delays vegetative phase change, and the defective phenotype is primarily attributable to reduced levels of SPL9 and miR172, and a corresponding increase in TARGET OF EAT1 (TOE1). We further show that GLYCOGEN SYNTHASE KINASE3 (GSK3)-like kinase BRASSINOSTEROID INSENSITIVE2 (BIN2) directly interacts with and phosphorylates SPL9 and TOE1 to cause subsequent proteolytic degradation. Therefore, BRs function to stabilize SPL9 and TOE1 simultaneously to regulate vegetative phase change in plants.


Growth modulation of human prostatic cancer cells by interleukin-1 and interleukin-1 receptor antagonist.
The effects of interleukin-1 (IL-1 alpha or IL 1 beta) on androgen-dependent LNCaP and androgen-independent JCA-1 human prostatic cancer cell proliferation were investigated. IL-1 alpha or IL-1 beta induced a dose dependent growth reduction by 50-80% as determined by cell cycle phase distribution, cell number and clonal growth in short and long term cultures. IL-1 negated the androgen growth effect on equal molar basis but the androgen receptors were not blocked by IL-1. The presence of intracellular IL-1 receptors was detected by flow cytometry and the IL-1 mediated growth reduction could be blocked with a 500 fold excess of the IL-1 receptor antagonist (hIL-1ra), revealing a growth control involving IL-1, HIL-1ra, androgen and their receptors.


Role of atopy in chronic rhinosinusitis with nasal polyps: does an atopic condition affect the severity and recurrence of disease?
The role of atopy in chronic rhinosinusitis is unclear: it is particularly controversial in chronic rhinosinusitis with nasal polyps. A prospective study of 210 patients with chronic rhinosinusitis with nasal polyps was performed. Patient demographics, visual analogue scale scores, Lund-Kennedy endoscopy scores, Lund-Mackay computed tomography scores, serum total immunoglobulin E levels, serum eosinophil cationic protein (ECP) levels and Phadiatop test findings were analysed. There were no significant differences in age, sex, visual analogue scale score, Lund-Mackay computed tomography score, total serum immunoglobulin E level, serum ECP level or Phadiatop test results between patients with primary and recurrent chronic rhinosinusitis with nasal polyps. A total of 99 patients (47 per cent) had positive atopy tests. No significant differences in sex, visual analogue scale score, Lund-Kennedy endoscopy score, Lund-Mackay computed tomography score or recurrence rates were found between atopic and non-atopic patients; however, atopic patients were significantly younger than non-atopic patients. Atopy status did not correlate with disease severity. There was no association between atopy status and either disease severity or recurrence in patients with chronic rhinosinusitis with nasal polyps, although atopic patients were younger than non-atopic patients.


Drug-related headache.
A survey was made of 10,506 reports to the WHO Collaboration Centre for International Drug Monitoring from five countries concerning headache, migraine, aggravated migraine and intracranial hypertension associated with drugs. The ten drugs most frequently reported to be associated with headache were indomethacin, nifedipine, cimetidine, atenolol, trimethoprim-sulphamethoxazole, zimeldine, glyceryl trinitrate, isosorbide dinitrate, zomepirac and ranitidine. Regarding migraine, oral contraceptives were also among the most implicated drugs. Most reports of intracranial hypertension concerned tetracyclines, isotretinoin and trimethoprim-sulphamethoxazole. Vasodilatation and salt and water retention with subsequent redistribution of intracranial fluid seem to be common mechanisms underlying drug-related headache. For certain frequently reported drugs, however, the mechanisms of the headache are unknown.


[Artificial intelligence in ex vivo confocal laser scanning microscopy].
Visual data, such as clinical photographs or pictures from imaging examination methods, such as ex vivo confocal laser scanning microscopy (CLSM), are particularly suitable for machine learning techniques. The aim was to find out whether data have already been published on this innovative application in ex vivo CLSM and what potential challenges and limitations could arise. Review of the literature and summary of current knowledge and personal experience on the use of artificial intelligence (AI) in ex vivo CLSM. Successful integration of digital hematoxylin-eosin-like staining has made ex vivo CLSM significantly more accessible for digital assessments. Several machine learning techniques have been developed to date in such a way that they have been able to identify malignant skin lesions on clinical photographs and pathological microscopic images with similar accuracy compared to experts, or even find visual patterns that have been overlooked by experts and that correlate with certain dermatological diseases. One study on the use of AI in ex vivo CLSM for automated tumor detection has been published to date. Several challenges and limitations can arise when using AI in ex vivo CLSM. The already digitized ex vivo CLSM, which was established for rapid section examination purposes, is a predestined method for the development and use of new applications with machine learning in the healthcare sector. The results of further studies on this topic are anticipated with great hope.


Ocular proteomic and transcriptomic changes with aging in a rabbit model of lensectomy with intraocular lens insertion.
Children that undergo intraocular surgery have an exaggerated postoperative response compared to adults that can result in significant postoperative challenges and reduced post-operative visual acuity. Rabbits were used as an animal model for investigating aging differences, treatment options, and surgical techniques for anterior chamber surgical interventions due to similarities in anterior chamber size and decreasing postoperative response with age. In our study, juvenile and adult rabbits underwent lensectomy with intraocular lens (IOL) insertion to determine how ocular RNA transcripts and proteins change with age. Rabbits underwent lensectomy with IOL insertion, and aqueous humor (AH) was collected immediately prior to surgery and at the peak of the postoperative response on post-operative day 3. Proteins related to coagulation and inflammation were assessed using targeted mass spectrometry. In addition, the cornea and iris/ciliary body tissues were dissected, and transcripts analyzed using RNA sequencing. While clinically, juvenile rabbits have greater fibrin formation following intraocular surgery compared to older rabbits, this change does not appear to be related to relative abundance levels of coagulation and inflammatory proteins in the AH. Gene transcript levels from a variety of immune response and inflammatory pathways reflected significant increases when comparing operated to unoperated ocular tissues, indicating the significant impact that surgery has on each ocular structure. This work further advances our understanding of how the rabbit eye proteomic and transcriptomic changes in response to surgery with aging, as we seek to ultimately identify the mechanisms for the exaggerated postoperative responses after pediatric intraocular surgery.


Combination drug therapy for gastroesophageal reflux disease.
To evaluate the role of combination therapy with proton-pump inhibitors (PPIs) and histamine(2) receptor antagonists in gastroesophageal reflux disease (GERD). Clinical literature identified through MEDLINE (January 1966-August 2001). Key search terms included gastroesophageal reflux, benzimidazoles; omeprazole; lansoprazole; pantoprazole; rabeprazole; receptor antagonists, histamine(2); therapy, combination drug; therapy, combined modality; and combinations, drug. Approximately 80-90% of patients show healing of reflux esophagitis after 8 weeks of once-daily PPI therapy. Patients taking PPI therapy twice daily still have nocturnal acid breakthrough (periods of gastric pH <4 lasting for > or =60 min during the night) as much as 70% of the time. The clinical application of this finding has not been shown. One trial has shown that omeprazole in the morning plus ranitidine at bedtime is not as effective as omeprazole twice daily given before the morning and evening meals at controlling nocturnal acid breakthrough. Further, 1 small trial in healthy subjects without GERD showed that the addition of a 1-time dose of ranitidine at bedtime to a twice-daily regimen of omeprazole may decrease the occurrence of nocturnal acid breakthrough. However, the clinical significance of this finding is not clear. No studies in patients with GERD demonstrate that the addition of histamine(2) receptor antagonists to twice-daily PPI therapy provides any further benefit above that derived from PPIs alone. The parameter used to measure the efficacy of combination regimens for GERD thus far--nocturnal acid breakthrough--has not been proven to correlate with improvement of GERD symptoms in any controlled or prospective clinical trials. Further investigation is needed to determine optimal therapy in patients refractory to standard doses of PPIs.


Movement-related cortical potentials in patients with Machado-Joseph disease.
Movement-related cortical potentials (MRCP; nomenclature of MRCP components according to Shibasaki and Hallett (Shibasaki H, Hallett M. What is the Bereitschaftspotential? Clin Neurophysiol 2006;117:2341-56) were studied in patients with Machado-Joseph disease (MJD) to elucidate the pathophysiology of voluntary movement. We studied nine genetically proven MJD patients and eight age-matched healthy subjects. Multi-channel electroencephalogram (EEG) recordings were obtained during self-paced fast extensions of the wrist. EEG epochs were time-locked to electromyography (EMG) onset or offset of the voluntary EMG burst and averaged. In the MJD patients, the early Bereitschaftspotential (early BP, -1500 to -500ms) was not affected but the late BP was reduced over the central midline area and contralaterally to the movement side. The amplitude of the fpMP, a post-movement MRCP component, was also reduced. In addition, the offset cortical potential in the first 500ms after EMG offset (Moff+500) was attenuated bilaterally over a wide cortical area. Findings suggest that cortical activations associated with the initiation and termination of a voluntary movement are impaired in MJD patients. Abnormalities of pre- and post-movement MRCP components provide researchers with pathophysiological insight into voluntary motor dysfunction in MJD.


Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2.
Synaptic transmission from excitatory nerve cells in the mammalian brain is largely mediated by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors located at the surface of dendritic spines. The abundance of postsynaptic AMPA receptors correlates with the size of the synapse and the dimensions of the dendritic spine head. Moreover, long-term potentiation is associated with the formation of dendritic spines as well as synaptic delivery of AMPA receptors. The molecular mechanisms that coordinate AMPA receptor delivery and spine morphogenesis are unknown. Here we show that overexpression of the glutamate receptor 2 (GluR2) subunit of AMPA receptors increases spine size and density in hippocampal neurons, and more remarkably, induces spine formation in GABA-releasing interneurons that normally lack spines. The extracellular N-terminal domain (NTD) of GluR2 is responsible for this effect, and heterologous fusion proteins of the NTD of GluR2 inhibit spine morphogenesis. We propose that the NTD of GluR2 functions at the cell surface as part of a receptor-ligand interaction that is important for spine growth and/or stability.


Cortisol response to dexamethasone and noradrenergic function in depression.
Positive correlations between measures of hypothalamic-pituitary-adrenal (HPA)-axis activity and noradrenergic turnover have been reported in depression. To investigate this relationship the authors measured peak postdexamethasone cortisol levels (8 a.m., 4 p.m. and 11 p.m.) and the 24-hour urinary 3-methoxy-4-hydroxy-phenylglycol (MHPG) flow in 84 depressed patients. The results show that there is no positive association between those measures of HPA-axis and noradrenergic activity. On the contrary, patients with severe non-suppression (greater than or equal to 10 micrograms/dl or 277 nmol/l) tended to have a lower MHPG-excretion.