Combination therapy with eldecalcitol and alendronate has therapeutic advantages over monotherapy by improving bone strength.
Eldecalcitol (ED-71), a 2β-hydroxypropyloxy derivative of 1α,25(OH)(2)D(3), inhibits bone resorption more potently than does alfacalcidol while maintaining osteoblastic function in an estrogen-deficient, high-turnover osteoporosis rat model. Alendronate (ALN) has been reported to increase bone mass by suppressing bone resorption mainly by inducing apoptosis of osteoclasts. The aim of this study was to clarify the combination effect of ED-71 and ALN on bone loss in ovariectomized rats. Wistar-Imamichi rats (32weeks old) were ovariectomized and randomly assigned to 10 groups (n=9-11); 11 rats were sham-operated. Rats were orally administered either vehicle alone, ALN (0.05, 0.2mg/kg), ED-71 (0.015, 0.03μg/kg), or a combination of ALN and ED-71. The treatment started 2weeks after surgery and continued for 12weeks. ED-71 significantly increased calcium and phosphorus in serum and urine; however, the mean values were within the normal range. Bone mineral density (BMD) and maximum load in both the lumbar spine and femur significantly increased with ED-71 monotherapy, and showed a tendency to increase with ALN monotherapy. Compared with ALN monotherapy, the combination of ALN and ED-71 significantly increased BMD and maximum load in both the lumbar spine and femur, suggesting that the combination therapy is more beneficial than ALN monotherapy in this protocol. The combination treatment had an additive suppressive effect on eroded surface and osteoclast number, with the suppressive effect more potent than either ALN or ED-71 monotherapy. Moreover, the combination therapy partially counteracted the suppressive effects of ALN on bone formation and on the histomorphometric indices of osteoblast number and activity. Interestingly, ALN had no effect on the anabolic action of ED-71. In conclusion, the combination therapy of ALN and ED-71 has therapeutic advantages over ALN monotherapy in terms of improving bone mechanical strength without excessive suppression of bone turnover.


Willingness of Older Adults From Culturally Diverse Populations to Participate in COVID-19 Related Treatment Trials and Associated Factors.
This survey study aimed to assess the willingness of culturally diverse older adults to participate in COVID-19 research. The majority of the 276 participants were women (81%, n = 223) and Black/African American (62%, n = 172) or White Hispanic (20%, n = 56). A key finding from the survey was less than 1 of 10 respondents would be likely to participate in COVID-19 related research if given the opportunity. There were no differences observed by gender, race or ethnicity. Implications of these findings are considered. These study findings indicate continued effort and better messaging strategies are required to increase awareness that COVID-19 related research needs to include culturally diverse older adults to ensure vaccines and treatments are efficacious in different populations.


Establishment of an immune microenvironment-based prognostic predictive model for gastric cancer.
The prognoses of patients with gastric cancer(GC) vary in different stages, which is mainly due to the great differences in tumor and tumor microenvironment. This study is aimed to explore the specific differences. Based on RNAseq-based expression data from The Cancer Genome Atlas database and GSE15459 and the latest biological process genelist, stage-related biological processes in gastric cancer were screened out. GSVA, LASSO-COX, univariate and multivariate Cox regression analysis, Kaplan-Meier survival analysis, and pearson correlation analysis were performed for prediction model construction, verification and functional annotation. The immune system process was enriched at advanced stages of gastric cancer. The tumor immune microenvironment-based prognostic risk score could be used to predict the overall survival and disease-free survival of patients with gastric cancer. The prognostic risk score was significantly associated with gastric cancer subtypes, inflammatory factors, and immune processes and a higher risk score indicated stronger tumor immunosuppression. We found immune system processes were significantly elevated in advanced gastric cancer and established an immune-based prognostic predictive risk model for gastric cancer, which could reflect the degree of tumor immunosuppression and might be beneficial for clinical decision-making.


Impact of an ICU EEG monitoring pathway on timeliness of therapeutic intervention and electrographic seizure termination.
We aimed to determine whether implementation of a structured multidisciplinary electroencephalography (EEG) monitoring pathway improved the timeliness of administration of antiseizure medication in response to electrographic seizures in encephalopathic critically ill children. A multidisciplinary team developed a pathway to standardize EEG monitoring and seizure management in encephalopathic critically ill children, aiming to decrease the time from electrographic seizure onset to antiseizure medication administration. Data were collected to inform the team of improvement opportunities, which were then provided by an institutional pathway, staff education, and streamlined communication. Measurements were obtained before and after pathway implementation to assess for improvement. We collected data on 41 patients before and 21 after pathway implementation. There were no differences between the baseline and pathway groups in demographic characteristics, acute encephalopathy etiologies, or antiseizure medications utilized. The median duration [interquartile range, IQR] from seizure onset to antiseizure medication administration was shorter for patients treated with the pathway (64 min [50, 101]) compared to patients treated prior to pathway implementation (139 min [71, 189]; p = 0.0006). The median [IQR] interval from seizure onset to antiseizure medication order was shorter for the pathway group (31 min [20, 49]) than the baseline group (71 min [33, 131]; p = 0.003). The median [IQR] interval from antiseizure medication order to administration was shorter for the pathway group (30 min [19, 40]) than the baseline group (40 min [17, 68]) (p = 0.047). Seizure termination was more likely to occur following initial antiseizure medication administration in the pathway than baseline group (67% vs. 27%, p = 0.002). Implementation of the pathway resulted in a significant reduction in the duration between electrographic seizure onset and antiseizure medication administration, and a significant increase in the rate of electrographic seizure termination following an initial antiseizure medication. Further study is needed to determine whether these changes are associated with improved outcomes.


Carbohydrates in cell recognition.
Telltale surface sugars enable cells to identify and interact with one another. New drugs aimed at those carbohydrates could stop infection and inflammation.


The molecular basis for Mucosal-Associated Invariant T cell recognition of MR1 proteins.
Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved αβ T-cell lineage that express a semi-invariant T-cell receptor (TCR) restricted to the MHC related-1 (MR1) protein. MAIT cells are dependent upon MR1 expression and exposure to microbes for their development and stimulation, yet these cells can exhibit microbial-independent stimulation when responding to MR1 from different species. We have used this microbial-independent, cross-species reactivity of MAIT cells to define the molecular basis of MAIT-TCR/MR1 engagement and present here a 2.85 Å complex structure of a human MAIT-TCR bound to bovine MR1. The MR1 binding groove is similar in backbone structure to classical peptide-presenting MHC class I molecules (MHCp), yet is partially occluded by large aromatic residues that form cavities suitable for small ligand presentation. The docking of the MAIT-TCR on MR1 is perpendicular to the MR1 surface and straddles the MR1 α1 and α2 helices, similar to classical αβ TCR engagement of MHCp. However, the MAIT-TCR contacts are dominated by the α-chain, focused on the MR1 α2 helix. TCR β-chain contacts are mostly through the variable CDR3β loop that is positioned proximal to the CDR3α loop directly over the MR1 open groove. The elucidation of the MAIT TCR/MR1 complex structure explains how the semi-invariant MAIT-TCR engages the nonpolymorphic MR1 protein, and sheds light onto ligand discrimination by this cell type. Importantly, this structure also provides a critical link in our understanding of the evolution of αβ T-cell recognition of MHC and MHC-like ligands.


On the mechanism of conductance control of the arthropod visual cell membrane.
It is assumed that "dark channels" determine a permanent dark conductance of the arthropod visual cell membrane. The light stimulus causes a transient opening of "light channels". The ion selectivity of dark channels and light channels is roughly described. Factors influencing the activation of light channels, as membrane energy metabolism, membrane potential and adjusted calcium ion concentration are specified. The mechanism of the action of calcium ions on the conductance of the visual cell membrane is discussed.


Light to moderate long-term grazing enhances ecosystem carbon across a broad climatic gradient in northern temperate grasslands.
Grasslands are globally abundant and provide many ecosystem services, including carbon (C) storage. While grasslands are widely subject to livestock grazing, the influence of grazing on grassland ecosystem C remains unclear. We studied the effect of long-term livestock grazing on C densities of different ecosystem components in 110 northern temperate grasslands across a broad agroclimatic gradient in Alberta, Canada. These grasslands stored 50 to 180 t ha-1C in live and dead vegetation, as well as soil C to 30 cm depth, with the majority as soil organic C (SOC). The mulch layer comprised a large amount of C (~18 t ha-1C) especially within humid grasslands. Although grazing reduced C densities in litter mass, total ecosystem C was 8.5 % greater under grazing (127.8 t ha-1) compared to those non-grazed (117.8 t ha-1), primarily due to increases in SOC and roots. Increases in SOC were consistently observed in the 0-15 cm layer across all climatic conditions, with changes in SOC of the 15-30 cm layer inversely related to aridity. A structural equation model revealed that increased SOC under grazing was indirectly attributed to increases in eudicot rather than graminoid biomass. In addition, SOC increased with graminoid quality (i.e., a reduced carbon to nitrogen ratio), which together with elevated eudicots, increased litter and mulch C, and ultimately enhanced SOC densities. When applied to spatial maps of habitat type and land use (livestock grazing) activity across the region, an area of ~3.8 M ha of grassland was projected to contain an additional 17.1 M t of C under grazing, primarily in mesic grasslands, worth an estimated $3.1 B (Cdn.) under current C valuation guidelines in Canada. Overall, these results highlight the importance of grasslands for C storage and establishing policies that maintain and promote their sustainable use, including light to moderate grazing.


[The radiobiological characteristics of the P+ variant of Bacillus brevis var. G.--B. in relation to gramicidin S synthesis].
The radiosensitivity of P(+) variant Bacillus brevis var. G.-B. cells cultured under condition of normal and inhibited gramicidin S synthesis, antibiotically high-active strain and high radioresistant cells has been studied. It has been shown that the radioresistance of bacterial cells correlates, in general, with their antibiotic activity: the antibiotic superproduced is more radioresistant than P(+) variant, the inhibition of antibiotic synthesis by beta-phenil-beta-alanin rises a little the sensitivity of P(+) variant cells. But the radioresistant fraction of P(+) variant contains the lower antibiotic amount than the whole population. It has been concluded that the radioprotective action of gramicidin S can not be the only reason of the above-mentioned differences in radiosensitivity.


Inflammatory biomarkers in children with cerebral palsy: A systematic review.
An exacerbated systemic inflammatory response has been associated with the occurrence of central nervous system injuries that may determine, in long term, motor, sensorial and cognitive disabilities. Persistence of this exacerbated inflammatory response seems to be involved in the pathophysiology of cerebral palsy (CP). A systematic search was conducted in Bireme, Embase, PubMed and Scopus including studies that were published until August 2019. The key words used were "cerebral palsy", "brain injury", "inflammation", "oxidative stress", "cytokines", "chemokines", "neuropsychomotor development", "neurodevelopment outcomes" and "child". The quality of the eligible studies was determined according to the criteria suggested by the Newcastle-Ottawa Scale (NOS). Fourteen eligible studies aimed to investigate the association between peripheral inflammatory molecules and neurodevelopment in infants. The studies differed regarding CP-related risk factors and its classification. Inflammatory proteins were measured in blood, plasma, serum, cerebrospinal fluid or urine. In ten studies, higher circulating levels of cytokines, including IL-1β, IL-6, TNF and CXCL8/IL-8, were associated with abnormal neurological findings. The investigation of the potential association between inflammatory molecules and neurological development in children with CP requires further original studies in order to clarify the influence of prenatal and perinatal inflammation on neurological outcomes.


No increased mortality from donor or recipient hepatitis B- and/or hepatitis C-positive serostatus after related-donor allogeneic hematopoietic cell transplantation.
Limited data exist on allogeneic transplant outcomes in recipients receiving hematopoietic cells from donors with prior or current hepatitis B (HBV) or C virus (HCV) infection (seropositive donors), or for recipients with prior or current HBV or HCV infection (seropositive recipients). Transplant outcomes are reported for 416 recipients from 121 centers, who received a human leukocyte antigen-identical related-donor allogeneic transplant for hematologic malignancies between 1995 and 2003. Of these, 33 seronegative recipients received grafts from seropositive donors and 128 recipients were seropositive. The remaining 256 patients served as controls. With comparable median follow-up (cases, 5.9 years; controls, 6.7 years), the incidence of treatment-related mortality, survival, graft-versus-host disease, and hepatic toxicity, appears similar in all cohorts. The frequencies of hepatic toxicities as well as causes of death between cases and controls were similar. Prior exposure to HBV or HCV in either the donor or the recipient should not be considered an absolute contraindication to transplant.


Kainic acid-induced seizure activity alters the mRNA expression and G-protein activation of the opioid/nociceptin receptors in the rat brain cortex.
The opioid/nociceptin receptors are involved in many neurological disorders such as Alzheimer's disease, Parkinson's disease and epilepsy. Kainic acid (KA) is an analog of the excitatory amino acid transmitter glutamate and the systemic administration of KA induces status epilepticus (SE) in rodents. In this study, we examined the alterations in the G-protein activity and the gene expression levels of mu, kappa, delta opioid and nociceptin receptors (MOPr, KOPr, DOPr and NOPr) as well as PNOC, the precursor polypeptide of nociceptin-OFQ (N/OFQ) in KA-induced seizures in the rat brain cortex. KA was used to create seizures with the dose of 10 mg/kg body weight i.p. Following the KA administration, the rats were observed for 3 h to assess seizure activity. Seizures occurred approximately 45 min after the KA injection. Only rats exhibiting full limbic seizures, forelimb clonus with rearing, were used in this study. All animals were decapitated 4 h after the administration of KA. Our [(35)S]GTPγS binding results showed that there was a significant difference in both the affinity and efficacy particularly one of NOPr stimulation following KA treatment. Slight, but significant increase was observed for MOPr. Moreover PNOC, NOPr and MOPr mRNA levels were increased by KA treatment but there were no significant changes in the levels of DOPr and KOPr mRNAs. These results show that the activities of opioid/nociceptin receptors can be modified by KA-treatment, and MOPr, PNOC and NOPr are the most responsive to KA-induced seizures in the rat brain cortex.


Clinical factors and outcomes in patients with acute mesenteric ischemia in the emergency department.
The purpose of this study was to determine the initial clinical characteristics of acute mesenteric ischemia and identify variables associated with adverse outcomes in the emergency department (ED). The charts of 124 consecutive patients with surgically and pathologically identified acute mesenteric ischemia from September 1990 to September 2000 were reviewed retrospectively to obtain data about demographics, initial clinical presentations, predisposing diseases, previous medications, laboratory tests, and common findings on computed tomography scans with contrast. Only patients admitted through the ED and treated on medical or surgical wards were enrolled. Mean patient age was 71.1 years (range, 25-100 years). The overall mortality rate was 50%. There were no significant differences in gender, underlying disease, previous medication, initial signs and symptoms, and causes of mesenteric infarction, between survivors and non-survivors. Univariate analysis demonstrated that older age, bandemia, hepatic and renal impairment, hyperamylasemia, metabolic acidosis, hypoxia, intramural pneumatosis, and septic syndrome, were more frequent in patients who died than in those who survived (p < 0.05). Logistic regression identified the following variables as independent predictors of death: old age (odds ratio, OR, 1.077; 95% confidence interval, Cl, 1.013, 1.146; p = 0.02); bandemia (OR, 3.894; 95% Cl, 1.160, 13.074; p = 0.03); elevated serum aspartate aminotransferase (AST; OR, 4.532; 95% Cl, 1.274, 16.122; p = 0.02); increased blood urea nitrogen (BUN; OR, 7.219; 95% Cl, 1.166, 44.696; p = 0.03); and metabolic acidosis (OR, 6.604; 95% Cl, 1.804, 24.171; p < 0.01). A high index of suspicion and aggressive diagnostic imaging can facilitate early diagnosis and improve outcomes for patients with acute mesenteric ischemia. Risk stratification showed that elderly patients with metabolic acidosis, bandemia, or elevated AST and BUN had a poor prognosis. Greater therapeutic intervention is advocated to reduce mortality in high-risk patients with acute mesenteric ischemia.


[Geriatric multimorbidity in claims data - part 1. Analysis of hospital data and long-term care insurance data].
In Germany, typical geriatric multimorbidity is--next to age itself--of special significance for the identification of target groups for specific geriatric care offers. The present article primarily focuses on typical geriatric multimorbidity in the claims data of statutory health insurance and long-term care insurance in Germany. Using the definition of "the geriatric patient" that is agreed on by providers of services as well as by cost bearers, geriatric multimorbidity is defined as the coexistence of at least 2 of 15 typical geriatric conditions. A suggestion made by the German Geriatric Association was to assign ICD-10-GM codes to each of these 15 conditions. Thus, it becomes possible to identify the corresponding geriatric conditions in claims data. The article investigates the frequency of geriatric conditions and, thus, of geriatric multimorbidity of patients aged ≥ 60 years admitted to a hospital with a geriatric ward. Patients treated in a geriatric ward were compared with those who did not receive geriatric care. In anticipation of a high correlation between typical geriatric conditions and specific features that are preconditions for receiving long-term care insurance benefits (such as care levels and status of a nursing home resident), claims data of the long-term care insurance were included for external validation. The analyses showed a distinctly higher proportion of insured people with typical geriatric multimorbidity or rather a certain care level among the geriatrically treated cases than among those patients not receiving geriatric treatment (68.5%/67.9% versus 24.2%/33.4%). The different proportions of typical geriatric multimorbidity coded among the patients with features of a certain care level in the two given groups give rise to the suspicion that typical geriatric multimorbidity is not always statistically recorded--especially in cases of treatment without provision of geriatric care. The frequency of cases of typical geriatric multimorbidity and a certain care level shows that--even when a specific geriatric offer exists--a considerable proportion of cases with typical geriatric conditions are treated in other medical departments.


Robust state estimation for a class of uncertain nonlinear systems: Comparison of two approaches.
In this paper, two approaches for robust state estimation of a class of Lipschitz nonlinear systems are proposed. First, a novel Unknown Input Observer (UIO) is designed without observer matching condition satisfaction. Then, an H∞ observer for approximate disturbance decoupling is proposed. Sufficient conditions for the existence of both proposed observers are derived based on a Lyapunov function. The achieved conditions are formulated in terms of a set of linear matrix inequalities (LMIs) and optimal gain matrices are obtained. The minimum values of the disturbance attenuation levels for both methods are obtained through solving optimization problems. Finally, the proposed approaches are compared by simulation studies of an automated highway system.


Neurogenesis along the septo-temporal axis of the hippocampus: are depression and the action of antidepressants region-specific?
In recent years, both major depression and antidepressant therapy have been linked to adult hippocampal neurogenesis. The hippocampus is not a homogeneous brain area, and a converging body of evidence indicates a functional dissociation along its septo-temporal axis, the dorsal part being involved more in learning/memory and spatial navigation, while the ventral sub-region is linked more to emotional behavior and regulation of the neuroendocrine stress axis. Research has therefore been conducted in an attempt to relate effects of models of depression and of antidepressant therapies to adult neurogenesis along the septo-temporal axis of the hippocampus. The present paper reviews the current literature addressing this question and discusses the possible mechanisms involved and the functional significance of such regional effects. This review shows that animal models of depression elicit an effect restricted to the ventral hippocampus more frequently than a dorsal-specific effect. However, this is also stage specific, and concerns neurogenesis, rather than cell proliferation or survival. Surprisingly, the same does not apply regarding the effects of selective serotonin re-uptake inhibitors that act in a more uniform way on dorsal and ventral adult neurogenesis in most studies. Some recently introduced clinical compounds (e.g., agomelatine) or putative antidepressants have a specific action on the ventral sub-region, indicating that an action restricted to this part of the brain may be sufficient to achieve remission. Finally, non-pharmacological manipulations that are also endowed with antidepressant effects, such as environmental enrichment or physical exercise, also act on both subdivisions, although some studies pointed to specificity of dorsal neurogenesis. The different treatments, acting either on the dorsal or on the ventral sub-regions, could promote recovery by improving either ventral- or dorsal-related functions, both contributing in a different way to treatment efficacy.


Health workers' perspectives of hepatitis B-related stigma among Aboriginal and Torres Strait Islander people in New South Wales, Australia.
Experiences of stigma and discrimination can act as a significant barrier to testing, monitoring, and treatment for hepatitis B virus (HBV). Aboriginal and Torres Strait Islander Australians are a population disproportionately impacted by HBV and yet limited research has explored HBV-related stigma in these communities. To begin preliminary explorations of HBV-related stigma among Aboriginal and Torres Strait Islander people, we interviewed health workers about their perceptions regarding HBV infection and HBV-related stigma. Participants were recruited from staff involved in the Deadly Liver Mob (DLM) program which is a health promotion program that offers incentives for Aboriginal and Torres Strait Islander clients to be educated on viral hepatitis, recruit and educate peers, and receive screening and treatment for blood-borne viruses (BBVs) and sexually transmissible infections (STIs), and vaccination. Semi-structured interviews were conducted with 11 Aboriginal and Torres Strait Islander and non-Aboriginal or Torres Strait Islander health workers who have been involved in the development, implementation, and/or management of the DLM program within participating services in New South Wales, Australia. Findings suggest that stigma is a barrier to accessing mainstream health care among Aboriginal and Torres Strait Islander clients, with stigma being complex and multi-layered. Aboriginal and Torres Strait Islander people contend with multiple and intersecting layers of stigma and discrimination in their lives, and thus HBV is just one dimension of those experiences. Health workers perceived that stigma is fuelled by multiple factors, including poor HBV health literacy within the health workforce broadly and among Aboriginal and Torres Strait Islander clients, shame about social practices associated with viral hepatitis, and fear of unknown transmission risks and health outcomes. The DLM program was viewed as helping to resist and reject stigma, improve health literacy among both health workers and clients, and build trust and confidence in mainstream health services. Health promotion programs have the potential to reduce stigma by acting as a 'one stop shop' for BBVs and STIs through one-on-one support, yarning, and promotion of the HBV vaccine, monitoring for chronic HBV, and treatment (where required).


Carbon import among vegetative tillers within two bunchgrasses: assessment with carbon-11 labelling.
Carbon allocation among bunchgrass tillers was examined with carbon-11 (11CO2) steady state labelling. Labelled carbon was continuously transported from parent tillers to anatomically attached daughter tillers at a time when morphological characteristics indicated that tiller maturation had occurred. Steady state levels of import into monitored daughter tillers increased within 30 min of either defoliation or shading. Import levels decreased within 30 min of the removal of shading, but remained accelerated throughout an 84 h observation period following defoliation. A second defoliation further increased carbon import into a monitored tiller above the previously accelerated level resulting from the initial defoliation. Carbon import by vegetative tillers in the two bunchgrass species examined may be most appropriately viewed as a series of potentially accelerated import levels above a low level of continuous import.


Anthropometric, Cardiopulmonary and Metabolic Benefits of the High-Intensity Interval Training Versus Moderate, Low-Intensity or Control for Type 2 Diabetes: Systematic Review and Meta-Analysis.
Abstract: This study aims to evaluate the effectiveness of high-intensity interval training compared with no intervention and other types of training interventions for people with Type 2 Diabetes. A systematic review and meta-analysis of randomized controlled trials that used high-interval intensity training to improve anthropometric, cardiopulmonary and metabolic conditions were conducted. The search was performed during October-December 2017 using the databases PubMed, Web of Science and Physiotherapy Evidence Database (PEDro). The methodological quality of the studies was evaluated using the PEDro scale. A total of 10 articles were included in this meta-analysis. After statistical analysis, favorable results were obtained for high-Intensity Interval Training compared with control (non-intervention): [Weight: Standardized mean difference (SMD) = -2.09; confidence interval (CI) 95%: (-3.41; -0.78); body-mass index: SMD = -3.73; CI 95%: (-5.53; -1.93); systolic blood pressure: SMD = -4.55; CI 95%: (-8.44; -0.65); VO2max: SMD = 12.20; CI 95%: (0.26; 24.14); HbA1c: SMD = -3.72; CI 95%: (-7.34; -0.10)], moderate intensity continuous training: [body-mass index: SMD = -0.41; CI 95%: (-0.80; -0.03); VO2max: SMD = 1.91; CI 95%: (0.18; 3.64)], and low intensity training: [Weight: SMD = -2.06; CI 95%: (-2.80; -1.31); body-mass index: SMD = -3.04; CI 95%: (-5.16; -0.92); systolic blood pressure: SMD = -2.17; CI 95%: (-3.93; -0.41); HbA1c: SMD = -1.58; CI 95%: (-1.84; -1.33)]. The results show that high-intensity interval training can be a useful strategy in order to improve anthropometric, cardiopulmonary and metabolic parameters in people with Type 2 diabetes. Despite this, it could be essential to clarify and unify criteria in the intervention protocols, being necessary new lines of research.


Effect of Al2Cu constituent layer thickness discrepancy on the tensile mechanical behavior of Cu/Al2Cu/Al layered composites: a molecular dynamics simulation.
Nano-polycrystalline Cu/Al2Cu/Al layered composites with different layer thicknessesdof single-crystal Al2Cu constituent are constructed. The effects ofdon the strength and fracture modes of nano-polycrystalline Cu/Al2Cu/Al layered composites are systematically investigated by molecular dynamics simulations. The uniaxial tensile results show that the ultimate strength and fracture mode of the nano-polycrystalline Cu/Al2Cu/Al layered composites do not change monotonically with the change of single crystal Al2Cu constituent layer thicknessd, the ultimate strength peaking atd= 2.44 nm, and the toughness reaching the optimum atd= 4.88 nm. The improvement of deformation incompatibility between Cu, Al and Al2Cu components increases the ultimate strength of polycrystalline Cu/Al2Cu/Al laminated composites. Due to the high activity of Cu dislocation and the uniformity of strain distribution of single crystal Al2Cu, the fracture of nano-crystalline Cu/Al2Cu/Al layered composites changes from brittleness to toughness. This study is crucial to establish the organic connection between microstructure and macroscopic properties of Cu/Al layered composites. To provide theoretical basis and technical support for the application of Cu/Al layered composites in high-end fields, such as automotive and marine, aerospace and defense industries.


Hip fractures risks in edoxaban versus warfarin users: A propensity score-matched population-based cohort study with competing risk analyses.
The three direct oral anticoagulants (DOAC), rivaroxaban, apixaban and dabigatran have been associated with lower risks of fractures compared to warfarin. However, no large scale studies have explored the associations with the newest DOAC, edoxaban, with fracture risk. The present study aims to elucidate the effects of edoxaban on the risk of hip fracture amongst elderly patients by comparing the incidence of new onset hip fracture between edoxaban and warfarin users in a Chinese population. This was a retrospective population-based cohort study of patients with edoxaban or warfarin use between January 1st, 2016 and December 31st, 2019 in Hong Kong, China. Patients with less than one-month exposure, medication switching between warfarin and edoxaban, those who died within 30 days after drug exposure, prior human immunodeficiency virus infection, age <50 years old, and those with prior hip fractures were excluded. Propensity score matching (1:2) between edoxaban and warfarin users using the nearest neighbour method was performed based on demographics, prior comorbidities, and use of different medications. The study outcomes were new onset hip fractures, medically attended falls and all-cause mortality. A total of 5014 patients including 579 edoxaban users and 4435 warfarin users (median age: 70 years old [interquartile range (IQR): 62-79], 56.66% males) with a median follow-up of 637.5 (IQR: 320-1073) days were included. In the matched cohort, edoxaban users had significantly lower rates of new onset hip fractures, medically attended falls and all-cause mortality. The protective value of edoxaban use against new onset hip fracture (hazard ratio [HR]: 0.13, 95% confidence interval [CI]: [0.03-0.54], p = 0.0051), medically attended falls (HR: 0.47, [0.29-0.75], p = 0.0018) and all-cause mortality (HR: 0.61, [0.42-0.87], p = 0.0059) in comparison to warfarin use persisted after matching. The significant relationship between edoxaban use and lower fracture risk was preserved in all sensitivity analyses using different approaches using the propensity score. Edoxaban use is associated with lower risks of new onset hip fractures, medically attended falls and mortality risks compared to warfarin after propensity score matching.


Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury.
Previous studies have shown beneficial effects of mesenchymal stem cell (MSC) transplantation in central nervous system (CNS) injuries, including traumatic brain injury (TBI). Potential repair mechanisms involve transdifferentiation to replace damaged neural cells and production of growth factors by MSCs. However, few studies have simultaneously focused on the effects of MSCs on immune cells and inflammation-associated cytokines in CNS injury, especially in an experimental TBI model. In this study, we investigated the anti-inflammatory and immunomodulatory properties of MSCs in TBI-induced neuroinflammation by systemic transplantation of MSCs into a rat TBI model. MSCs were transplanted intravenously into rats 2 h after TBI. Modified neurologic severity score (mNSS) tests were performed to measure behavioral outcomes. The effect of MSC treatment on neuroinflammation was analyzed by immunohistochemical analysis of astrocytes, microglia/macrophages, neutrophils and T lymphocytes and by measuring cytokine levels [interleukin (IL)-1α, IL-1β, IL-4, IL-6, IL-10, IL-17, tumor necrosis factor-α, interferon-γ, RANTES, macrophage chemotactic protein-1, macrophage inflammatory protein 2 and transforming growth factor-β1] in brain homogenates. The immunosuppression-related factors TNF-α stimulated gene/protein 6 (TSG-6) and nuclear factor-κB (NF-κB) were examined by reverse transcription-polymerase chain reaction and Western blotting. Intravenous MSC transplantation after TBI was associated with a lower density of microglia/macrophages and peripheral infiltrating leukocytes at the injury site, reduced levels of proinflammatory cytokines and increased anti-inflammatory cytokines, possibly mediated by enhanced expression of TSG-6, which may suppress activation of the NF-κB signaling pathway. The results of this study suggest that MSCs have the ability to modulate inflammation-associated immune cells and cytokines in TBI-induced cerebral inflammatory responses. This study thus offers a new insight into the mechanisms responsible for the immunomodulatory effect of MSC transplantation, with implications for functional neurological recovery after TBI.


Anterior mitral valve aneurysm: a subaortic complication of aortic valve endocarditis: a case report and review of literature.
Mitral valve aneurysm is a rare cause of mitral regurgitation, and is usually associated with aortic valve endocarditis. Prompt diagnosis and early surgical treatment can prevent complications such as embolization and rupture of the aneurysm. The authors report a case of aortic valve endocarditis and mitral valve aneurysm in a patient who initially presented with urinary tract infection.


Pediatric radiation exposure and effective dose reduction during voiding cystourethrography.
To compare radiation exposure and effective dose in children who underwent voiding cystourethrography (VCUG) performed with grid-controlled variable-rate pulsed fluoroscopy (GCPFL) with radiation exposure and effective dose in children who underwent VCUG performed with continuous fluoroscopy (CFL) and to compare these effective doses with those estimated with radionuclide cystography (RNC). Institutional review board approval was obtained, and the informed consent requirement was waived for this HIPAA-compliant retrospective study. Radiation exposure and fluoroscopy time during VCUG were reviewed in 145 children (75 girls, 70 boys; age range, 3 days to 8 years) who underwent GCPFL or CFL between 2001 and 2002. Children were grouped on the basis of the fluoroscopy unit used and their supine anteroposterior abdominal diameter (group 1, 8.0-8.5-cm diameter; group 2, 10-11-cm diameter; group 3, 12-13-cm diameter). Analysis of variance was used to compare radiation exposure and fluoroscopy time between fluoroscopy units and patient diameter groups. Effective doses were calculated and compared for both fluoroscopes and for estimated RNC dose values. GCPFL resulted in a significant reduction in total radiation exposure, which was at least eight times lower than that with CFL in all three groups (P < .001 for all). There was no significant difference in fluoroscopy time (P > .50). Effective radiation doses from GCPFL were approximately one order of magnitude lower than those from CFL but one order of magnitude higher than those from RNC. In children, VCUG can be performed with a GCPFL unit that delivers radiation exposures that are at least eight times lower than those delivered by a conventional CFL unit. http://radiology.rsnajnls.org/cgi/content/full/2492062066/DC1.


[Medico-legal assessment in the sequelae of burns (1st part)].
The assessment of physical injury in after-effects of burns is very specific. Indeed, the evolution of burn scars is particular compared to the scarring process in general. The expert needs to know these specific aspects in order to objectively assess the after-effects due to burns, in order to compensate for the loss of autonomy in major burn victims. The assessment has to analyze all the effects, functional and aesthetic, of the after-effects due to burns and has to particularly specify: the mending, which can never be set before one year, the pressure test allowing to check the complete maturation of the scars; the functional disability which results from skin retractions (due to after-effects) on the limbs mobility but which also must consider the burnt skin surface; the aesthetic damage, often important, with a discrimination between hypertrophic and keloid scars; the suffering, always significant in view of specialized and prolonged therapeutics; the sexual damage, often unrecognized in this type of injured people.


Is Polymorphism in the Apoptosis and Inflammatory Pathway Genes Associated With a Primary Response to Anti-TNF Therapy in Crohn's Disease Patients?
Anti-tumor necrosis factor (TNF) therapy is used for the induction and maintenance of remission in Crohn's disease (CD) patients. However, primary nonresponders to initial treatment constitute 20%-40% of cases. The causes of this phenomenon are still unknown. In this study, we aimed to determine the genetic predictors of the variable reactions of CD patients to anti-TNF therapy. Using long-range PCR libraries and the next-generation sequencing (NGS) method, we performed broad pharmacogenetic studies including a panel of 23 genes (TNFRSF1A, TNFRSF1B, CASP9, FCGR3A, LTA, TNF, FAS, ADAM17, IL17A, IL6, MMP1, MMP3, S100A8, S100A9, S100A12, TLR2, TLR4, TLR9, CD14, IL23R, IL23, IL1R, and IL1B) in a group of 107 diagnosed and clinically characterized CD patients following anti-TNF therapy. In the studied group, we indicated, in total, 598 single nucleotide variants for all analyzed genomic targets. Twelve patients (11.2%) did not respond to the induction therapy, which was associated with alleles in 11 loci located in FCGR3A (rs7539036, rs6672453, rs373184583, and rs12128686), IL1R (rs2041747), TNFRSF1B (rs5746053), IL1B (rs1071676, rs1143639, rs1143637, and rs1143634), and FAS (rs7896789) genes. After multiple comparison corrections, the results were not statistically significant, however for nonresponders the alleles distribution for those loci presented large differences and specified scheme compared to responders and populations. These findings require further investigation in an independent larger cohort before introducing them for a clinical setting, however, we identified an interesting direction. Polymorphism of the FCGR3A, IL1R, TNFRSF1B, IL1B, and FAS genes could be a predictor of the primary response to anti-TNF therapy in CD patients.


Deletion of pksA attenuates the melanogenesis, growth and sporulation ability and causes increased sensitivity to stress response and antifungal drugs in the human pathogenic fungus Fonsecaea monophora.
Fonsecaea monophora, which is very similar to Fonsecaea pedrosoi in morphological features, has been commonly misdiagnosed as F. pedrosoi. Like F. pedrosoi, F. monophora has been also identified as a predominant pathogen of Chromoblastomycosis (CBM). Melanin has been recognized as a virulence factor in several fungi, however, it is still largely unknown about the biological role of melanin and how melanin is synthesized in F. monophora. In this study, we identified two putative polyketide synthase genes (pks), AYO21_03016 (pksA) and AYO21_10638, by searching against the genome of F. monophora. AYO21_03016 and AYO21_10638 were further targeted disrupted by Agrobacterium tumefaciens-mediated transformation (ATMT). We discovered that pksA gene was the major polyketide synthase required for melanin synthesis in F. monophora, rather than AYO21_10638. Phenotypic analysis showed that, knocking out of the pksA gene attenuated melanogenesis, growth rate, sporulation ability and virulence of F. monophora, as compared with wild-type and complementation strain (pksA-C). Furthermore, the ΔpksA mutant was confirmed to be more sensitive to the oxidative stress, extreme pH environment, and antifungal drugs including itraconazole (ITC), terbinafine (TER), and amphotericin B (AMB). Taken together, these findings enabled us to comprehend the role of pksA in regulating DHN-melanin pathway and its effect on the biological function of F. monophora.


Soft tissue contour and radiographic evaluation of ridge preservation in early implant placement: A randomized controlled clinical trial.
To compare two ridge preservation techniques and spontaneous healing in terms of hard and soft tissue changes 2 months after tooth extraction. The study was designed as a randomized controlled trial and included 75 patients. After single tooth extraction in the maxillary incisor/premolar area, patients were randomly allocated to one of the following groups: (a) ridge preservation with a xenogeneic bone substitute covered with a collagen matrix (CM-group), (b) ridge preservation with a xenogeneic bone substitute covered with a free palatal graft (PG-group) or (c) spontaneous healing (control). Eight weeks after tooth extraction, implants were placed and clinical, profilometric and radiographic evaluations were performed. In addition, the need for further guided bone regeneration (GBR) at implant placement was assessed. The differences between the treatment groups were compared with the One-way ANOVA or Kruskal-Wallis test with the corresponding post hoc analysis. The proportions of the categorical parameters were compared with the Fisher´s exact test. Seventy-five patients underwent early implant placement 8 weeks after tooth extraction and were evaluated. CM-group (-0.9 SD 0.6 mm) and PG-group (-1.0 SD 0.8 mm) showed less horizontal bone resorption compared to the control group (-3.2 SD 2.1 mm) (p < .001). Moreover, the necessity of GBR at implant placement was significantly less in CM-group (32%) and PG-group (24%) when compared to control group (72%) (p = .001). Patients in CM-group experienced less pain than PG-group, one week after tooth extraction (p = .042). No significant differences were found regarding graft evaluation, post-operative complications, and soft tissue contour. Ridge preservation using a xenogeneic bone substitute covered with a collagen matrix or a palatal graft, results in less bone resorption and fewer GBR procedures at early implant placement compared to spontaneous healing.


The influence of striking object characteristics on the impact energy.
A common form of violence investigated in legal medicine is blunt trauma caused by striking with different objects. The injuries and medical consequences have been widely examined, whereas the forces and especially the energies acting on impact have rarely been analyzed. This study focuses on how the impact energy of different striking objects depends on their characteristics. A total of 1170 measurements of horizontal strikes against a static and relatively heavy pendulum have been acquired with 13 volunteers. The main focus was laid on how the weight, the length, and the center of mass of the different striking objects influenced the striking energy. The results show average impact energies in the range of 67.3 up to 311.5 J for men with an optimum weight of about 1.3 kg with its center of mass in the far end quarter for a 1-m-long striking object. The average values for women range from 30 to 202.6 J, with an optimum weight between 1.65 and 2.2 kg and similar settings for the center of mass as the men. Also, the impact energies are getting higher with shorter object lengths and reach a maximum at a length of about 0.3 to 0.4 m. The male volunteers' impact energy was on average by 84.2% higher than the values of the female volunteers, where the impact masses were very similar and the impact velocities played the key role.


Comparison of the effect of continuous intravenous infusion of sodium valproate and midazolam on management of status epilepticus in children.
Status epilepticus as a pediatric emergency requires rapid seizure control in order to prevent subsequent disabilities. Therefore, the present study was conducted to compare the efficacy and side effects of continuous intravenous infusion of sodium valproate versus midazolam as a third-line treatment of status epilepticus in children. This randomized clinical trial study included all children with convulsive and non-convulsive status epilepticus admitted to the pediatric intensive care unit (PICU) of the Bu-Ali Sina Hospital in Sari City (Mazandaran Province, Iran) who had not responded to first-line treatment with diazepam and second-line treatment with phenytoin or phenobarbital. They were consequently treated with continuous intravenous infusion of sodium valproate or midazolam to control persistent seizures. The study comprised 70 patients who were randomly assigned to two equal groups of sodium valproate or midazolam treatment. The mean age of patients in group A (sodium valproate) and group B (midazolam) was 3.97 ± 3.33 and 3.84 ± 2.93 years, respectively. In the present study, the most common etiology of status epilepticus was remote symptomatic, accounting for 35% of cases in the two groups. Sodium valproate was effective in controlling status epilepticus in 91.4% of patients, while midazolam was found to be effective in 85.7% of patients (p > 0.05). Patients who received sodium valproate had shorter seizure duration after administration of the drug compared to those who received midazolam (p = 0.01). Eight patients in the midazolam group and two patients in the sodium valproate group were intubated (p = 0.023). The mean duration of stay in the PICU was 3.2 ± 1.4 and 5.6 ± 2.8 days in groups A and B, respectively, showing a significant difference (p = 0.001). According to our findings, intravenous infusion of sodium valproate can be used as an effective and relatively safe treatment in children with all types of status epilepticus, especially in challenging situations such as lack of intensive care units or respiratory problems.


A childhood-onset nemaline myopathy caused by novel heterozygote variants in the nebulin gene with literature review.
Nemaline myopathy, a rare congenital myopathy, is characterized by generalized muscle weakness, hypotonia, respiratory insufficiency, and the presence of rod structures on muscle biopsy, which is caused by mutations in at least 13 known genes. A patient showing gradually deteriorated proximal muscle weakness and rod-shaped structures found in muscle fibers was suspected of having nemaline myopathy, following by the next-generation sequencing. We report two novel compound heterozygous variants in nebulin gene in a family residing in China. One is an intron event caused by an underlying variant at the + 3 position of the donor site. Another is a novel nonsense variant, which may lead to the end of protein translation and have a significant impact on protein function. The pathogenicity of this novel compound heterozygous variant remains to be verified. Variants reported here could help to diagnose NM for clinicians.


Interference between drug-resistant and drug-sensitive stocks of Trypanosoma congolense in goats.
A study was undertaken in goats to investigate the ability of two unrelated stocks of Trypanosoma congolense, one of which is highly sensitive to isometamidium chloride and one which is drug-resistant, to become established in the presence of an existing infection with the other stock. The goats, which were initially infected with the sensitive strain and were then challenged with the resistant strain, were cured by treatment at 0.1 mg kg-1 isometamidium, indicating that the resistant stock did not establish an infection. Goats initially infected with the resistant stock, which were then challenged with the sensitive stock, experienced temporary remission of infection followed by relapse after treatment at 0.1 mg kg-1 isometamidium. In contrast, the goat infected only with the resistant stock remained parasitaemic following treatment at 0.1 mg kg-1. This suggests that superinfection with the sensitive stock resulted in the establishment of infection, which suppressed the resistant stock to below the limit of detection of the method used. These observations suggest that isometamidium-resistant stocks may be less viable than sensitive strains, and could explain the relative scarcity of isometamidium resistant in the field.


Immunomodulation for unexplained recurrent implantation failure: where are we now?
Immune dysfunction may contribute to or cause recurrent implantation failure. This article summarizes normal and pathologic immune responses at implantation and critically appraises currently used immunomodulatory therapies. Recurrent implantation failure (RIF) may be defined as the absence of pregnancy despite the transfer of ≥3 good-quality blastocysts and is unexplained in up to 50% of cases. There are currently no effective treatments for patients with unexplained RIF. Since the maternal immune system is intricately involved in mediating endometrial receptivity and embryo implantation, both insufficient and excessive endometrial inflammatory responses during the window of implantation are proposed to lead to implantation failure. Recent strategies to improve conception rates in RIF patients have focused on modulating maternal immune responses at implantation, through either promoting or suppressing inflammation. Unfortunately, there are no validated, readily available diagnostic tests to confirm immune-mediated RIF. As such, immune therapies are often started empirically without robust evidence as to their efficacy. Like other chronic diseases, patient selection for immunomodulatory therapy is crucial, and personalized medicine for RIF patients is emerging. As the literature on the subject is heterogenous and rapidly evolving, we aim to summarize the potential efficacy, mechanisms of actions and side effects of select therapies for the practicing clinician.


Transcription modulates chromatin dynamics and locus configuration sampling.
In living cells, the 3D structure of gene loci is dynamic, but this is not revealed by 3C and FISH experiments in fixed samples, leaving a notable gap in our understanding. To overcome these limitations, we applied the highly predictive heteromorphic polymer (HiP-HoP) model to determine chromatin fiber mobility at the Pax6 locus in three mouse cell lines with different transcription states. While transcriptional activity minimally affects movement of 40-kbp regions, we observed that motion of smaller 1-kbp regions depends strongly on local disruption to chromatin fiber structure marked by H3K27 acetylation. This also substantially influenced locus configuration dynamics by modulating protein-mediated promoter-enhancer loops. Importantly, these simulations indicate that chromatin dynamics are sufficiently fast to sample all possible locus conformations within minutes, generating wide dynamic variability within single cells. This combination of simulation and experimental validation provides insight into how transcriptional activity influences chromatin structure and gene dynamics.


Exciton Hall effect in monolayer MoS2.
The spontaneous Hall effect driven by the quantum Berry phase (which serves as an internal magnetic flux in momentum space) manifests the topological nature of quasiparticles and can be used to control the information flow, such as spin and valley. We report a Hall effect of excitons (fundamental composite particles of electrons and holes that dominate optical responses in semiconductors). By polarization-resolved photoluminescence mapping, we directly observed the Hall effect of excitons in monolayer MoS2 and valley-selective spatial transport of excitons on a micrometre scale. The Hall angle of excitons is found to be much larger than that of single electrons in monolayer MoS2 (ref. ), implying that the quantum transport of the composite particles is significantly affected by their internal structures. The present result not only poses a fundamental problem of the Hall effect in composite particles, but also offers a route to explore exciton-based valleytronics in two-dimensional materials.


Integrating biobehavioral information to predict mood disorder suicide risk.
The will to live and the ability to maintain one's well-being are crucial for survival. Yet, almost a million people die by suicide globally each year (Aleman and Denys, 2014), making premature deaths due to suicide a significant public health problem (Saxena et al., 2013). The expression of suicidal behaviors is a complex phenotype with documented biological, psychological, clinical, and sociocultural risk factors (Turecki et al., 2019). From a brain disease perspective, suicide is associated with neuroanatomical, neurophysiological, and neurochemical dysregulations of brain networks involved in integrating and contextualizing cognitive and emotional regulatory behaviors. From a symptom perspective, diagnostic measures of dysregulated mood states like major depressive symptoms are associated with over sixty percent of suicide deaths worldwide (Saxena et al., 2013). This paper reviews the neurobiological and clinical phenotypic correlates for mood dysregulations and suicidal phenotypes. We further propose machine learning approaches to integrate neurobiological measures with dysregulated mood symptoms to elucidate the role of inflammatory processes as neurobiological risk factors for suicide.


Relationship between daunorubicin concentration and apoptosis induction in leukemic cells.
Aiming to determine if a concentration window exists in which apoptosis induction by daunorubicin (DNR) is optimal, we studied the relationship between DNR concentration and apoptosis induction in HL60 and K562 cells and in peripheral leukemic cells isolated from three patients with acute myelogenous leukemia (AML). Cells were incubated for 2hr with increasing DNR concentrations and thereafter for 22hr in drug-free medium. Apoptosis was measured by detection of caspase-3-like activity and DNA fragmentation assayed by propidium iodide and flow cytometry. High DNR concentrations initiated faster apoptosis in HL60 cells and in AML cells, as shown by caspase-3 and DNA fragmentation data. DNA fragmentation into small fragments was preceded by the formation of a narrow peak on the left side of the G1 peak, most likely large DNA fragments, but further studies are required for unequivocal confirmation. This peak could easily be misinterpreted as a G1 peak without careful time monitoring. In K562 cells, no left peak was detected, apoptosis was slow and not related to concentration. In AML cells, large interindividual variations were observed in the time course of DNA fragmentation at 0.25microg DNR/mL. In conclusion, our findings support the concept of dose intensification for optimal apoptosis induction as higher doses correlate with earlier and more rapid caspase-3 induction and DNA fragmentation in leukemic cells. The DNA fragmentation assay may be a valuable tool to determine leukemic cells' chemosensitivity to apoptosis.


Visual hallucinations in dementia with Lewy bodies originate from necrosis of characteristic neurons and connections in three-module perception model.
Mathematical and computational approaches were used to investigate dementia with Lewy bodies (DLB), in which recurrent complex visual hallucinations (RCVH) is a very characteristic symptom. Beginning with interpretative analyses of pathological symptoms of patients with RCVH-DLB in comparison with the veridical perceptions of normal subjects, we constructed a three-module scenario concerning function giving rise to perception. The three modules were the visual input module, the memory module, and the perceiving module. Each module interacts with the others, and veridical perceptions were regarded as a certain convergence to one of the perceiving attractors sustained by self-consistent collective fields among the modules. Once a rather large but inhomogeneously distributed area of necrotic neurons and dysfunctional synaptic connections developed due to network disease, causing irreversible damage, then bottom-up information from the input module to both the memory and perceiving modules were severely impaired. These changes made the collective fields unstable and caused transient emergence of mismatched perceiving attractors. This may account for the reason why DLB patients see things that are not there. With the use of our computational model and experiments, the scenario was recreated with complex bifurcation phenomena associated with the destabilization of collective field dynamics in very high-dimensional state space.


Synthesis and in vitro evaluation of hydrazinyl phthalazines against malaria parasite, Plasmodium falciparum.
In this report, we describe the synthesis of 1-(Phthalazin-4-yl)-hydrazine using bronsted acidic ionic liquids and demonstrate their ability to inhibit asexual stage development of human malaria parasite, Plasmodium falciparum. Through computational studies, we short-listed chemical scaffolds with potential binding affinity to an essential parasite protein, dihydroorotate dehydrogenase (DHODH). Further, these compounds were synthesized in the lab and tested against P. falciparum. Several compounds from our library showed inhibitory activity at low micro-molar concentrations with minimal cytotoxic effects. These results indicate the potential of hydralazine derivatives as reference scaffolds to develop novel antimalarials.


Enabling Anionic Redox Stability of P2-Na5/6 Li1/4 Mn3/4 O2 by Mg Substitution.
Oxygen-based anionic redox reactions have recently emerged as a lever to increase the capacity of Mn-rich layered oxide cathodes in addition to the charge compensation based on cationic redox reactions for sodium-ion batteries. Unfortunately, the irreversibility of anionic redox often aggravates irreversible structure change and poor cycling performance. Here, a stable anionic redox is achieved through substituting Na ions by Mg ions in P2-type Na0.83 Li0.25 Mn0.75 O2 . Density functional theory (DFT) calculations reveal that Mg substitution effectively decreases the oxygen chemical potential, causing an improvement in lattice oxygen stability. Moreover, at a highly desodiated state, Mg ions that remain in the lattice and interact with O 2p orbitals can decrease the undercoordinated oxygen and the nonbonded, electron-deficient O 2p states, facilitating the reversibility of oxygen redox. When cycled in the voltage range of 2.6-4.5 V where only anionic redox occurs for charge compensation, Na0.773 Mg0.03 Li0.25 Mn0.75 O2 presents a much better reversibility, giving a 4 times better cycle stability than that of Na0.83 Li0.25 Mn0.75 O2 . Experimentally, Na0.773 Mg0.03 Li0.25 Mn0.75 O2 exhibits a ≈1.1% volume expansion during sodium insertion/extraction, suggestive of a "zero-strain" cathode. Overall, the work opens a new avenue for enhancing anionic reversibility of oxygen-related Mn-rich cathodes.


High-definition transcranial direct current stimulation (HD-tDCS) of the left middle temporal gyrus (LMTG) improves mathematical reasoning.
The role of the visuospatial network in mathematical processing has been established, but the role of the semantic neural network in mathematical processing is still poorly understood. The current study used high-definition transcranial direct current stimulation (HD-tDCS) to examine whether the semantic network supports mathematical processing. Using a single-blind, randomized, sham-controlled experimental design, 48 participants were randomly assigned to receive either anodal or sham HD-tDCS on the left middle temporal gyrus (LMTG), a core region of the semantic network. A number series completion task was used to measure mathematical reasoning and an arithmetical computation task was used as a control condition. Both tasks were administered before and after the 20 min HD-tDCS. The results showed that anodal HD-tDCS on the LMTG enhanced performance on the number series completion task, but not on the arithmetical computation task. Trial-level analysis further showed greater improvement at the more difficult problems of the number series completion task. These results demonstrate that the semantic network plays an important role in mathematical processing.


Complications of endoscopic third ventriculostomy.
Although endoscopic third ventriculostomy (ETV) is considered as the first choice in the management of noncommunicating hydrocephalus, it is not without risk or complication. The patients who had undergone ETV only between 1998 and 2005 were retrospectively reviewed. There were 85 males and 70 females, and 173 ETVs were performed in 155 patients. The patients' age ranged from 2 months to 77 years. Complications were categorized as (1) intraoperative, (2) early postoperative (<1 month), and (3) late postoperative (>1 month). Follow-up of the patients ranged from 1 to 86 months. Overall complication rate per patient was 15.4%, and complication per procedure was 18%. Complication rate significantly varied with the etiology of hydrocephalus (P = 0.013). The patients with Chiari type I malformation and tumor had no or very low complication rates. The complication risk was significantly higher in repeat endoscopic procedure (55.5%) than in the first procedure (10%; P = 0.0001). ETV should be the first choice in the management of noncommunicating hydrocephalus. Training, experience, and meticulous technique will decrease the complication rate. Patients undergoing ETV should be followed in a similar manner to patients with cerebrospinal fluid shunts.


Outcomes of operative vaginal delivery managed by residents under supervision and attending obstetricians: a prospective cross-sectional study.
To assess both severe maternal and neonatal mortality and morbidity after attempted operative vaginal deliveries by residents under supervision and by attending obstetricians. Secondary analysis of a 5-year prospective study with cross-sectional analysis including 2192 women with live singleton term fetuses in vertex presentation who underwent an attempted operative vaginal delivery in a tertiary care university hospital. Obstetricians who attempted or performed an operative vaginal delivery were classified into 2 groups according to their level of experience: attending obstetricians (who had 5 years or more of experience) and obstetric residents (who had less than 5 years of experience) under the supervision of an attending obstetrician. We used multivariate logistic regression and propensity score methods to compare outcomes associated with attending obstetricians and obstetric residents. Severe maternal morbidity was defined as third- or fourth-degree perineal laceration, perineal hematoma, cervical laceration, extended uterine incision for cesareans, postpartum hemorrhage >1500 mL, surgical hemostatic procedures, uterine artery embolization, blood transfusion, infection, thromboembolic events, admission to the intensive care unit, or maternal death; severe neonatal morbidity was defined as a 5-minute Apgar score <7, umbilical artery pH <7.00, need for resuscitation or intubation, neonatal trauma, intraventricular hemorrhage greater than grade 2, neonatal intensive care unit admission for more than 24 hours, convulsions, sepsis, or neonatal death. High prepregnancy body mass index, high dose of oxytocin, manual rotation, persistent occiput posterior or transverse positions, operating room delivery, midpelvic delivery, forceps, and spatulas were significantly more frequent in deliveries managed by attending obstetricians than residents whereas a second-stage pushing phase longer than 30 minutes was significantly more frequent in deliveries managed by residents. The rate of severe maternal morbidity was 7.8% (115/1475) for residents vs 9.9% (48/484) for attending obstetricians; for severe neonatal morbidity, the rates were 8.3% (123/1475) vs 15.1% (73/484), respectively. In the univariate, multivariable, and sensitivity analyses, attempted operative vaginal delivery managed by a resident was significantly and inversely associated with severe neonatal but not maternal morbidity. After propensity score matching, delivery managed by a resident was not significantly associated with severe maternal morbidity (adjusted odds ratio, 0.74; 95% confidence interval, 0.39-1.38) and was no longer associated with neonatal morbidity (adjusted odds ratio, 0.51; 95% confidence interval, 0.25-1.04). Management of attempted operative vaginal deliveries by residents under the supervision of attending obstetricians, compared with by the attending obstetricians themselves, does not appear to be associated with either maternal or neonatal morbidity. These reassuring results support the continued use of residency programs for training in operative vaginal deliveries under the supervision of attending obstetricians.


The excretion of hydrogen ion by the isolated amphibian skin: effects of antidiuretic hormone and amiloride.
H+ extrusion by the isolated skins of two amphibia, Rana ridibunda and Bufo bufo, was studied in order to test for the presence of exchange mechanisms of the type Na+/H+ and Cl-/HCO3-, which have been described in several epithelial structures. The preparations were mounted in chambers of the Ussing type, so that the short-circuit current could be used as a function of Na+ transport and the pH-stat techinique was utilize to determine the rates of H+ extrusion under different experimental conditions. The conditions were either the withdrawal of the ions intervening the mentioned exchanges (Cl- or Na+), or the addition of drugs with well-known effects on Na+ up-take and transport (antidiuretic hormone and amiloride). In the frog skin, H+ excretion was detected in solutions containing either Cl- or SO4-2-, with identical rates. Again, Na+ substitution by Mg-2+ had no effect on H+ excretion rates, neither did the suppression of Na+ influx by amiloride or its stimulation by antidiuretic hormone. These experiments were repeated with similar results in gland-free preparations of the epidermis of frog skin separated from the corion by the action of collagenase. Experiments in toad skin that H+ excretion could not be detected whan Cl- was present in the outer medium, but became apparent if an impermant anion, SO4-2-, was used. This observation is compatible with the existence of an exchange mechanism of the type Cl-/HCO3-. Secondly, in these preparations H+ extrusion increased after stimulation with antidiuretic hormone and decreased when amiloride was used or when Na+ was substituted by Mg+, suggesting that a least a fraction of the total H+ efflux is linked to Na+ influx. In the isolated frog skin this mechanism does not seem to be operative.


Release of DNA from Dermanyssus gallinae during the Biting Process.
Dermanyssus gallinae is a hematophagous ectoparasitic mite that usually infests poultry, but is also known for occasionally attacking other animals and humans. It represents a major problem for poultry systems all over the world, with detrimental effects for both production and animal welfare. Despite the significance of D. gallinae, very little is known about the biting process to date. Therefore, this study has aimed to verify if mite DNA is injected into the host skin during the blood meal. Mite DNA has been detected by seminested PCR from infested chicken skin and quantified by real-time PCR. Furthermore, its localization within the host tissue has been checked by fluorescent in situ hybridization. Results showed that a very little amount of D. gallinae DNA can be released by mites, suggesting that the latter do not introduce whole or partially destroyed cells into the host, but rather it injects traces of nucleic acids, possibly together with merocrine secretions.


The WHO programme for prevention and control of viral, chlamydial, and rickettsial diseases. Brief review.
Through the advancement of biological and medical sciences and the application of modern technology, the disease burden imposed by viral, chlamydial and rickettsial disease has steadily decreased. Smallpox has been eradicated, poliomyelitis is under control in many countries, and measles, mumps and rubella viruses may eventually be eliminated in many developed countries. New and improved vaccines have also recently become available for rabies and hepatitis. These are major advancements. Not to be overshadowed however, are the developments which may lead to the prevention or control of other infectious diseases. For many agents, recently acquired knowledge relating to virology, replication, structural and genetic characteristics, and host responses to infection pave the way for disease intervention in numerous ways. For other agents, recent advances in molecular biology make possible new classes of effective vaccines. It is crucial that these advances be incorporated as soon as possible into effective public health programmes for developing as well as developed nations. Much work yet remains, particularly in the prevention and control of respiratory diseases, diarrhoeal diseases, vector-borne diseases and hepatitis. The WHO Viral Diseases Programme has a major role in supporting laboratory and field research on new technologies and intervention strategies, in disseminating technological advances through teaching and training, and in translating the newer knowledge into action programmes for the prevention and control of viral, chlamydial and rickettsial diseases.


Induction of mutations in males of the fish Oryzias latipes at a specific locus after gamma-irradiation.
We have studied frequencies of mutations induced at the b locus of the fish, Medaka Oryzias latipes, after gamma-irradiation. Homozygotes for the b locus have colorless melanophores whose phenotypic expression can be distinguished from that of the wild type. An advantage of the use of oviparous fish for detection of skin color mutations is that the mutant phenotype can be confirmed as early as 1.5 days after fertilization because of the transparent egg membrane of the embryo. Wild-type (B/B) male fish were exposed to 4.75 or 9.5 Gy of 137Cs gamma-rays at a dose rate of 0.95 Gy/min and then mated with the female testers (b/b). A total of 77,761 F1 offspring were examined for mutation and other abnormalities. In the control, we had 1 mutant among 22,068 offspring, resulting in a mutation rate of 4.53 X 10(-5)/locus/gamete. However, this mutant embryo died before hatching. Therefore, in an attempt to present specific-locus mutation frequencies in the fish, the frequencies of color mutants that survived more than 4 days after hatching were used as frequencies of viable mutants; (number of viable color mutants)/(number of hatched fry that survived more than 4 days after hatching). In the 4.75 Gy-irradiated group the viable mutant frequencies were 45.0 X 10(-5), 69.7 X 10(-5) and 0/locus/gamete, while exposure to 9.5 Gy resulted in mutation rates of 217 X 10(-5), 130 X 10(-5) and 8.06 X 10(-5), respectively, for sperm, spermatids and spermatogonia. In comparison with viable color mutant frequencies those of the total color mutants, which include such mutants as ones that died before hatching (defined as number of total color mutants/number of fertilized eggs minus number of early deaths), were considerably higher. For sperm, spermatids, and spermatogonia after exposure to 4.75 Gy, the frequencies were 1180 X 10(-5), 629 X 10(-5) and 9.90 X 10(-5)/locus/gamete, respectively, and in 9.5-Gy-irradiated fish, the frequencies were 1940 X 10(-5), 953 X 10(-5) and 55.5 X 10(-5). Although our data are incomplete, the present results were compared with mutation induction in mice. We concluded that the frequencies of viable color mutants in the fish can be compared with those in mice.


Nanobacteria and calcinosis cutis.
The nanobacteria are a recently characterized group of extremely small bacteria capable of precipitating calcium salts implicated in the pathogenesis of urinary calculi and calcific atherosclerosis. The pathogenesis of calcinosis cutis and its significance in conjunction with a variety of unrelated scarring and pre-existing cutaneous entities are incompletely understood. A series of cases, including basal cell carcinoma with dystrophic calcification, subepidermal calcified nodule, pilomatricoma, and tumoral calcinosis, were ultrastructurally examined for the presence of Nanobacteria sp. All cases, including three basal cell carcinomas, two subepidermal calcified nodules, three cases of pilomatricoma, and two cases of tumoral calcinosis, were negative for Nanobacteria. The dystrophic calcification that occurs in conjunction with the above entities does not likely involve a bacterial-induced etiology. The cause of these entities remains unknown.


Immunohistochemical identification of quinolinic acid phosphoribosyltransferase in glial cultures from rat brain.
Glial cell cultures were shown to contain 3 identifiable classes of cells which could be specifically stained with antibodies directed against quinolinic acid phosphoribosyltransferase (QPRT), the catabolic enzyme of the endogenous excitotoxin quinolinic acid. Some, but not all, QPRT-positive cells also contained glial fibrillary acidic protein. These cultures may constitute an in vitro system in which cerebral quinolinic acid metabolism and function can be examined.


Rapid induction of chromatin-associated DNA mismatch repair proteins after MNNG treatment.
Treatment with low concentrations of monofunctional alkylating agents induces a G2 arrest only after the second round of DNA synthesis in mammalian cells and requires a proficient mismatch repair (MMR) pathway. Here, we have investigated rapid alkylation-induced recruitment of DNA repair proteins to chromosomal DNA within synchronized populations of MMR proficient cells (HeLa MR) after N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) treatment. Within the first hour, the concentrations of MutS alpha and PCNA increase well beyond their constitutive chromosomally bound levels and MutL alpha is newly recruited to the chromatin-bound MutS alpha. Remarkably, immunoprecipitation experiments demonstrate rapid association of these proteins on the alkylation-damaged chromatin, even when DNA replication is completely blocked. The extent of association of PCNA and MMR proteins on the chromatin is dependent upon the concentration of MNNG and on the specific type of replication block. A subpopulation of the MutS alpha-associated PCNA also becomes monoubiquitinated, a known requirement for PCNA to interact with translesion synthesis (TLS) polymerases. In addition, chromatin-bound SMC1 and NBS1 proteins, associated with DNA double-strand-breaks (DSBs), become phosphorylated within 1-2h of exposure to MNNG. However, these activated proteins are not co-localized on the chromatin with MutS alpha in response to MNNG exposure. PCNA, MutS alpha/MutL alpha and activated SMC1/NBS1 remain chromatin-bound for at least 6-8h after alkylation damage. Thus, cells that are exposed to low levels of alkylation treatment undergo rapid recruitment to and/or activation of key proteins already on the chromatin without the requirement for DNA replication, apparently via different DNA-damage signaling pathways.


Synthesis, crystal structure and anti-inflammatory properties of curcumin analogues.
Curcuminoids have been reported to possess multifunctional bioactivities, especially the ability to inhibit proinflammatory induction. Since it has been suggested that the seven-carbon beta-diketone linker in curcumin is responsible for its instability, nine mono-carbonyl five-carbon linker containing analogues were designed and synthesized. Their bioactivity against lipopolysaccharide-induced TNF-alpha amd IL-6 secretion was evaluated by using mouse J774.1 macrophages. The results showed that the 3'-methoxyl plays an important role in bioactivity and cyclohexanone containing analogues exhibited stronger inflammatory inhibition than acetone and cyclopentanone analogues. Subsequently the most active analogue 3c was determined using single-crystal X-ray diffraction. X-ray analysis and comparison with curcumin reveals that the presence of cyclohexanone in 3c, which remotely resembles the 6-membered ring in the enol tautomer in curcumin, may play an important role in the bioactivity. It is suggested that five-carbon linker analogues containing a cyclohexane ring which are synthetically assessable may be pharmacologically important.


[Enterogenous cyst of the spinal cord associated with mucomyelia (author's transl)].
A woman of 22 years developed heavy pain in the neck and arms with weakness and paresthesia. She died two days after a myelography which was normal. At autopsy an enterogenous extra- and intra-medullary cyst of the cervical cord (C3, C4) was found. In addition the cervical cord apart from the cyst and the uppermost thoracic cord presented central clefts which were filled with mucilage. These findings are named mucomyelia and have not been reported previously.


Comparative transcriptome and WGCNA reveal key genes involved in lignocellulose degradation in Sarcomyxa edulis.
The developmental transcriptomes of Sarcomyxa edulis were assessed to explore the molecular mechanisms underlying lignocellulose degradation. Six stages were analyzed, spanning the entire developmental process: growth of mycelium until occupying half the bag (B1), mycelium under low-temperature stimulation after occupying the entire bag (B2), appearance of mycelium in primordia (B3), primordia (B4), mycelium at the harvest stage (B5), and mature fruiting body (B6). Samples from all six developmental stages were used for transcriptome sequencing, with three biological replicates for all experiments. A co-expression network of weighted genes associated with extracellular enzyme physiological traits was constructed using weighted gene co-expression network analysis (WGCNA). We obtained 19 gene co-expression modules significantly associated with lignocellulose degradation. In addition, 12 key genes and 8 kinds of TF families involved in lignocellulose degradation pathways were discovered from the four modules that exhibited the highest correlation with the target traits. These results provide new insights that advance our understanding of the molecular genetic mechanisms of lignocellulose degradation in S. edulis to facilitate its utilization by the edible mushroom industry.


Sucrose and glycerol effects on photosystem II.
Photosystem II catalyzes the oxidation of water and the reduction of plastoquinone. The active site cycles among five oxidation states, which are called the S(n) states. PSII purification procedures include the use of the cosolvents, sucrose and/or glycerol, to stabilize water splitting activity and for cryoprotection. In this study, the effects of sucrose and glycerol on PSII were investigated. Sucrose addition was observed to stimulate the steady-state rate of oxygen evolution in the range from 0 to 1.35 M. Glycerol addition was observed to stimulate oxygen evolution in the range from 0 to 30%. Both cosolvents were observed to be inhibitory at higher concentrations. Sucrose addition was shown to have no effect on the rate of Q(A)(-) oxidation or on the K(M) for exogenous acceptor. PSII was then treated to remove extrinsic proteins. In these samples, sucrose addition stimulated activity, but glycerol addition was inhibitory at concentrations higher than approximately 0.5 M. This inhibitory effect of glycerol at relatively low concentrations is attributed to glycerol binding to the active site, when extrinsic subunits are not present. Reaction induced FTIR spectra, associated with the S(1) to S(2) transition of the water-oxidizing complex, exhibited significant differences throughout the 1,800-1,200 cm(-1) region, when glycerol- and sucrose-containing samples were compared. These measurements suggest a cosolvent-induced shift in the pK(A) of an aspartic or glutamic acid side chain, as well as structural changes at the active site. These structural alterations are attributed to a change in preferential hydration of the oxygen-evolving complex.


Evaluation of antibody synthesis in broadly sensitized patients.
This study was conducted to evaluate the rate of lymphocyte antibody synthesis in broadly sensitized patients. Antibody synthesis was estimated utilizing two approaches. In one, the time required by the antibodies to reach half their original values was determined by quantitating their levels by flow cytometry over periods of several months. In the other approach we measured the rate at which antibodies rose after inducing an artificial reduction by means of plasma exchanges. Patients not previously transplanted and not transfused during the study period showed low antibody synthesis and decreasing panel reactivity. In most previously transplanted patients panel reactivity did not change during the observation period. However, some patients displayed low antibody synthesis activity whereas others produced antibodies at a high rate. Extensive studies in one patient demonstrated active antibody synthesis even though he had not been transfused for more than two years. The results suggest that while frequent plasma exchanges can reduce antibody concentrations, concomitant use of immunosuppression may be needed only in patients shown to be actively producing antibodies.


Determining the depth of insertion of dynamically invisible membrane peptides by gel-phase ¹H spin diffusion heteronuclear correlation NMR.
Solid-state NMR determination of the depth of insertion of membrane peptides and proteins has so far utilized (1)H spin diffusion and paramagnetic relaxation enhancement experiments, which are typically conducted in the liquid-crystalline phase of the lipid bilayer. For membrane proteins or peptide assemblies that undergo intermediate-timescale motion in the liquid-crystalline membrane, these approaches are no longer applicable because the protein signals are broadened beyond detection. Here we show that the rigid-solid HETCOR experiment, with an additional spin diffusion period, can be used to determine the depth of proteins in gel-phase lipid membranes, where the proteins are immobilized to give high-intensity solid-state NMR spectra. Demonstration on two membrane peptides with known insertion depths shows that well-inserted peptides give rise to high lipid cross peak intensities and low water cross peaks within a modest spin diffusion mixing time, while surface-bound peptides have higher water than lipid cross peaks. Furthermore, well-inserted membrane peptides have nearly identical (1)H cross sections as the lipid chains, indicating equilibration of the peptide and lipid magnetization. Using this approach, we measured the membrane topology of the α-helical fusion peptide of the paramyxovirus, PIV5, in the anionic POPC/POPG membrane, in which the peptide undergoes intermediate-timescale motion at physiological temperature. The gel-phase HETCOR spectra indicate that the α-helical fusion peptide is well inserted into the POPC/POPG bilayer, spanning both leaflets. This insertion motif gives insight into the functional role of the α-helical PIV5 fusion peptide in virus-cell membrane fusion.


The insulator protein CTCF represses transcription on binding to the (gt)(22)(ga)(15) microsatellite in intron 2 of the HLA-DRB1(*)0401 gene.
The insulator and transcription factor CTCF is a highly conserved 11 zinc finger protein possessing multiple specifities in DNA sequence recognition. CTCF regulates transcription of several genes, like the human oncogene c-myc or the chicken lysozyme gene by binding extremely divergent DNA sequences with different sets of its 11 zinc fingers. Recently, an insulator function was demonstrated for several CTCF binding elements. Here we show that CTCF binds to the (gt)(22)(ga)(15) microsatellite repeat A9 in intron 2 of the HLA-DRB1(*)0401 gene. Reporter gene activity is repressed by the A9 element. This repression is dependent on coexpressed CTCF and is even stronger compared with the CTCF binding site F1 of the chicken lysozyme gene, for which a silencer activity has been shown. This is the first report suggesting a function for microsatellite sequences in regulating specific gene expression.


wMel replacement of dengue-competent mosquitoes is robust to near-term change.
Rising temperatures are impacting the range and prevalence of mosquito-borne diseases. A promising biocontrol technology replaces wild mosquitoes with those carrying the virus-blocking Wolbachia bacterium. Because the most widely used strain, wMel, is adversely affected by heat stress, we examined how global warming may influence wMel-based replacement. We simulated interventions in two locations with successful field trials using Coupled Model Intercomparison Project Phase 5 climate projections and historical temperature records, integrating empirical data on wMel's thermal sensitivity into a model of Aedes aegypti population dynamics to evaluate introgression and persistence over one year. We show that in Cairns, Australia, climatic futures necessitate operational adaptations for heatwaves exceeding two weeks. In Nha Trang, Vietnam, projected heatwaves of three weeks and longer eliminate wMel under the most stringent assumptions of that symbiont's thermal limits. We conclude that this technology is generally robust to near-term (2030s) climate change. Accelerated warming may challenge this in the 2050s and beyond.


Systematic review and meta-analysis on the therapeutic reference range for escitalopram: Blood concentrations, clinical effects and serotonin transporter occupancy.
A titration within a certain therapeutic reference range presupposes a relationship between the blood concentration and the therapeutic effect of a drug. However, this has not been systematically investigated for escitalopram. Furthermore, the recommended reference range disagrees with mean steady state concentrations (11-21 ng/ml) that are expected under the approved dose range (10-20 mg/day). This work systematically investigated the relationships between escitalopram dose, blood levels, clinical effects, and serotonin transporter occupancy. Following our previously published methodology, relevant articles were systematically searched and reviewed for escitalopram. Of 1,032 articles screened, a total of 30 studies met the eligibility criteria. The included studies investigated escitalopram blood levels in relationship to clinical effects (9 studies) or moderating factors on escitalopram metabolism (12 studies) or serotonin transporter occupancy (9 studies). Overall, the evidence for an escitalopram concentration/effect relationship is low (level C). Based on our findings, we propose a target range of 20-40 ng/ml for antidepressant efficacy of escitalopram. In maintenance treatment, therapeutic response is expected, when titrating patients above the lower limit. The lower concentration threshold is strongly supported by findings from neuroimaging studies. The upper limit for escitalopram's reference range rather reflects a therapeutic maximum than a tolerability threshold, since the incidence of side effects in general is low. Concentrations above 40 ng/ml should not necessarily result in dose reductions in case of good clinical efficacy and tolerability. Dose-related escitalopram concentrations in different trials were more than twice the expected concentrations from guideline reports. [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=215873], identifier [CRD42020215873].


Unilateral Optic Neuritis in Children: Experience of a Tertiary Centre.
Optic neuritis (ON) is an inflammation of the optic nerve that can be associated with a multitude of different systemic conditions and primary CNS disorders. In children, only around 25% of unilateral ON cases are considered idiopathic. Despite being considered a clinical diagnosis per se, neuroimaging plays a crucial role in the diagnostic pathway for these patients. Demographic, clinical, and imaging data of all patients presenting with unilateral ON at a tertiary paediatric centre over 40 months (January 1, 2016, to April 30, 2019) were retrospectively analyzed. A total of 10 patients filled the inclusion criteria. The average age of presentation was 14.1 years. Patients in this series had ON associated with multiple sclerosis (n = 2), anti-MOG demyelinating disorders (n = 2), and neuromyelitis optica with anti-AQP4 antibodies (n = 1). ON was determined to be secondary to Toxocara canis infection in 1 case and a side effect of anti-TNFα therapy (adalimumab) in another. MR imaging showed T2 hyperintensity and/or gadolinium enhancement of one of the optic nerves in all but 3 patients, and coincidently these were the cases with monophasic idiopathic ON (average follow-up period of 2 years). Additional brain MR findings directly contributed to the final diagnosis in half of the cases. These cases are demonstrative of the wide range of possible causes of unilateral ON in the paediatric population. The absence of typical ON features in MR imaging was strongly suggestive of idiopathic ON in this cohort (p < 0.01).


Effect of premedication to provide analgesia as a supplement to inferior alveolar nerve block in patients with irreversible pulpitis.
The authors' objective was to determine whether scientific evidence supports the use of oral premedication to increase the efficacy of inferior alveolar nerve block (IANB) and to decrease endodontic treatment pain in patients with diagnosed irreversible pulpitis. The authors included randomized controlled trials that involved enteral premedication and 2% lidocaine IANB for adults with irreversible pulpitis compared with placebo. In particular, the authors reviewed studies comparing nonsteroidal anti-inflammatory drugs (NSAIDs), benzodiazepines, acetaminophen, and corticosteroids with placebo. The authors searched the following electronic databases: the Cochrane Library, MEDLINE, and Web of Science. The authors analyzed 9 randomized controlled clinical trials. Patients who took the NSAIDs under study, including ibuprofen, ketorolac, diclofenac, indomethacin, and lornoxicam, 1 hour before endodontic treatment showed statistically significant improvement in the outcome of having "little or no pain" during endodontic treatment compared with patients who took a placebo 1 hour before endodontic treatment (risk ratio [RR], 1.989; 95% confidence interval [CI], 1.495-2.646; P < .001). Benzodiazepines were not as well represented in the literature, but the 2 included studies did not show a significant improvement in patients' having "little or no pain" during endodontic treatment over placebo (RR, 0.989; 95% CI, 0.677-1.444; P = .954). There is moderate evidence to support the use of oral NSAIDs-in particular, ibuprofen (600 milligrams)-1 hour before the administration of IANB local anesthetic (1.8-3.6 milliliters of 2% lidocaine) to provide additional analgesia to the patient.


The technique of episiotomy.
Episiotomy is frequently performed, with an incidence of 70-80 per cent in someunits, but is still often poorly executed and repaired with little thought as to the importance of a supple pain-free scar.


Micronucleus frequency is correlated with antioxidant enzyme levels in workers occupationally exposed to pesticides.
Oxidative stress can cause DNA damage leading to nuclear anomalies such as micronuclei (MN). Antioxidant enzymes involved in protection against intracellular oxidative stress include glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), and catalase (CAT). Pesticide exposure induces oxidative stress and alters antioxidant defense mechanisms, including detoxification and scavenger enzymes. The aim of this study was to evaluate MN frequency in workers occupationally exposed to pesticides and their relationship with antioxidant enzyme activities. A cross-sectional study was conducted in 201 individuals, some of whom were dedicated to the spraying of pesticides. The cytokinesis-block micronucleus (CBMN) assay was conducted, and the activities of GPx, GR, SOD, and CAT were determined. The geometric mean (GM) of MN was 5.4 (1-26 MN). The GM for the antioxidant enzymes was 198.68 U/mL for GPx, 38.96 U/g Hb for GR, 94.78 U/mL for SOD, and 69.77 U/g Hb for CAT. There was a lower MN frequency in males than that in females, and a higher nuclear index. In addition, age affected MN frequency. There was a negative correlation between MN frequency and GPx activity, but a positive one between MN frequency and GR activity. These findings suggest the involvement of GPx in MN frequency.


Isolated choroid plexus separation on second-trimester sonography: natural history and postnatal importance.
This study was undertaken to investigate the natural history and clinical importance of choroid plexus separation (a > or = 3 mm distance between the choroid plexus and medial wall of the lateral ventricle) as an isolated finding in the second trimester. This was a 5-year retrospective review of an ultrasound database, looking for singleton fetuses with a menstrual age of 16 to 26 weeks and a finding of isolated choroid plexus separation. There were 78 cases available for study. The finding of choroid plexus separation was usually transient. Resolution was noted in 37% of the cases that were rescanned within 2 weeks and 71% of the cases that were rescanned more than 2 weeks after the initial diagnosis. Two abnormal karyotypes (trisomy 21 and 47,XXY) and 3 cases with abnormal development not associated with an abnormal karyotype were noted on neonatal follow-up. Cases with abnormal development were quite varied in their presentation. The finding of isolated choroid plexus separation is usually temporary, resolving in most cases within 4 weeks of the initial diagnosis. Most infants with this finding have no abnormalities. The clinical implication of the lone case of trisomy 21 was limited by a major preexisting risk in this patient. The 3 cases of abnormal development had varying presentations; the causal nature of this association is not yet clear. No trends were noted between the changing choroid plexus appearance with time and abnormal neonatal outcome, but the number of abnormal cases was quite limited.


Effects of gaseous anaesthetics and inert gases on the phase transition in smectic mesophases of dipalmitoyl phosphatidylcholine.
The phase transition in smectic mesophase of dipalmitoyl phosphatidyl-choline was studied under high pressures of helium (340 atm), nitrogen (340 atm), nitrous oxide (43 atm), cyclopropane (4.4 atm) and n-propane (8.2 atm), using a turbidimetric technique. Helium and nitrogen increased the transition temperature by 0.021 and 0.006 degree C/atm, respectively, compared with 0.024 degrees C/atm for hydrostatic pressure. Nitrous oxide reduced the transition by 0.58 degree C/atm. The hydrocarbon gases spread the transition width and lowered the transition temperature with increasing effect at higher doses. Comparisons with other membrane probes are made and the concentration of gases in the bilayer which lower the transition temperature by 1 degree C are estimated, in mol%: He, 10.2; N2, 13.2: N2O, 9.04; n-C3H8, 6.3 and cyclopropane, 12.8.


Adaptation to oxidative stress induced by polyunsaturated fatty acids in yeast.
To create a conditional system for molecular analysis of effects of polyunsaturated fatty acids (PUFA) on cellular physiology, we have constructed a strain of yeast (Saccharomyces cerevisiae) that functionally expresses, under defined conditions, the Delta12 desaturase gene from the tropical rubber tree, Hevea brasiliensis. This strain produces up to 15% PUFA, exclusively under inducing conditions resulting in production of 4-hydroxy-2-nonenal, one of the major end products of n-6 polyunsaturated fatty acid peroxidation. The PUFA-producing yeast was initially more sensitive to oxidative stress than the wild-type strain. However, over extended time of cultivation it became more resistant to hydrogen peroxide indicating adaptation to endogenous oxidative stress caused by the presence of PUFA. Indeed, PUFA-producing strain showed an increased concentration of endogenous ROS, while initially increased hydrogen peroxide sensitivity was followed by an increase in catalase activity and adaptation to oxidative stress. The deletion mutants constructed to be defective in the catalase activity lost the ability to adapt to oxidative stress. These data demonstrate that the cellular synthesis of PUFA induces endogenous oxidative stress which is overcome by cellular adaptation based on the catalase activity.