Effects of phorbol ester on vesicle dynamics as revealed by total internal reflection fluorescence microscopy.
Exocytosis of neurotransmitter or hormone-filled vesicles is a highly dynamic process regulated by various proteins and lipids. As mainly revealed indirectly by the electrophysiological methods, exocytosis is believed to involve multiple kinetic steps in which vesicles transit from one state to another. Using total internal reflection fluorescence microscopy which enables direct visualization of individual vesicles, we developed an analytical framework to track and analyze vesicle dynamics. We demonstrated that all subplasmalemmal vesicles generally undergo constant and caged Brownian motion. And they can be classified into three populations that differ in their motion characteristics and fusion competence. Furthermore, we showed that these vesicle pools are differentially modulated by phorbol-12-myristate-13-acetate, a phorbol ester analog to endogenous diacylglycerol, through both protein-kinase-C-dependent and -independent pathways.


Mastoparan M extracted from Vespa magnifica alleviates neuronal death in global cerebral ischemia-reperfusion rat model.
Global cerebral ischemia (GCI), a consequence of cardiac arrest (CA), can significantly damage the neurons located in the vulnerable hippocampus CA1 areas. Clinically, neurological injury after CA contributes to death in most patients. Mastoparan-M extracted from Vespa magnifica (Smith) can be used to treat major neurological disorders. Hence, this study aimed to assess the effects of Mastoparan-M on GCI. To evaluate the neurotoxicity and neuroprotective effect of Mastoparan-M, the CCK8 and Annexin V-FITC/PI apoptosis assays were first performed in hippocampal HT22 neuronal cells in vitro. Then, Pulsinelli's 4-vascular occlusion model was constructed in rats. After treatment with Mastoparan-M (0.05, 0.1, and 0.2 mg/kg, IP) for 3 or 7 days, behavioral tests, H&E staining or Nissl staining, immunohistochemistry, and ELISA were employed to investigate neuroprotective effects of Mastoparan-M on GCI in rats. In vitro, the growth of HT22 neuronal cells was restrained at concentrations of 30-300 µg/ml (at 24 hr, IC50=105.2 µg/ml; at 48 hr, IC50=46.81 µg/ml), and Mastoparan-M treatment (0.1,1 and 5 µg/ml) restrained apoptosis. In vivo, Mastoparan-M improved neurocognitive function and neuronal loss in the hippocampal CA1 area of rats. In addition, these effects were associated with the prevention of neuroinflammation, oxidative stress, and apoptosis. Mastoparan-M acts as a neuroprotective agent to alleviate neuronal death in rats.


The prevalence of cryptococcal antigenemia in newly diagnosed HIV patients in a Southwest London cohort.
To determine the prevalence of cryptococcal antigenemia in a UK HIV cohort and compare baseline characteristics of patients with and without cryptococcal antigenemia. Stored sera were retrospectively tested for cryptococcal antigen (CRAG) among newly diagnosed HIV-infected persons with CD4 < 100 cells/μL, who presented to Croydon University and St George's Hospitals, London, between January 2004 and October 2010. We assessed risk factors for cryptococcal antigenemia and patient outcomes by extracting demographic and clinical information from medical records. 157 patients were identified with a median age of 47 and CD4 count of 26 cells/μL. 102 (65%) were of Black race and 91 (58%) of African origin. Eight patients (5%) had positive serum CRAG. 7/8 had cryptococcal meningitis (CM) as first presentation of HIV, and 1 had sub-clinical infection. 7/8 (88%) CRAG positives were of African origin compared to 84/149 (54%) of CRAG negatives (p = 0.14). Other baseline characteristics did not differ significantly. We found a 5% prevalence of cryptococcal antigenemia in newly diagnosed HIV patients with CD4 < 100 cells/μL in southwest London, the first such data for a UK HIV cohort. Cryptococcal antigenemia occurred almost exclusively in African-born individuals. We recommend a UK CRAG screening strategy targeting newly diagnosed African HIV-infected patients with CD4 < 100 cells/μL.


Two-step asymmetric reaction using the frozen chirality generated by spontaneous crystallization.
N,N-diallyl-4-methyl-1-propyl-2-quinolone-3-carboxamide afforded chiral crystals of a P2(1) crystal system by spontaneous crystallization. The molecular chirality in the crystal was retained after the crystals were dissolved in a solvent at a low temperature, and the frozen molecular chirality was effectively transferred to the products by a two-step reaction involving hydrogenation and intermolecular photocycloaddition reactions.


Stabilization of collagen using plant polyphenol: role of catechin.
Collagen, a unique connective tissue protein finds extensive application as biocompatible biomaterial in wound healing, as drug carriers, cosmetics, etc. A work has been undertaken to study the stabilization of type I collagen using the plant polyphenol catechin. Catechin treated collagen fibres showed a shrinkage temperature around 70 degrees C implying that catechin is able to impart thermal stability to collagen. Catechin treated collagen fibres has been found to be stable even after treatment with high concentration of the secondary structural destabilizer, urea. Circular dichroism studies revealed that there is no major alteration in the structure of collagen on treatment with catechin. The study has demonstrated the involvement of hydrogen bonding and hydrophobic interactions as the major forces involved in the stabilization of collagen by the plant polyphenol, catechin.


Review of COVID-19 testing and diagnostic methods.
More than six billion tests for COVID-19 has been already performed in the world. The testing for SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) virus and corresponding human antibodies is essential not only for diagnostics and treatment of the infection by medical institutions, but also as a pre-requisite for major semi-normal economic and social activities such as international flights, off line work and study in offices, access to malls, sport and social events. Accuracy, sensitivity, specificity, time to results and cost per test are essential parameters of those tests and even minimal improvement in any of them may have noticeable impact on life in the many countries of the world. We described, analyzed and compared methods of COVID-19 detection, while representing their parameters in 22 tables. Also, we compared test performance of some FDA approved test kits with clinical performance of some non-FDA approved methods just described in scientific literature. RT-PCR still remains a golden standard in detection of the virus, but a pressing need for alternative less expensive, more rapid, point of care methods is evident. Those methods that may eventually get developed to satisfy this need are explained, discussed, quantitatively compared. The review has a bioanalytical chemistry prospective, but it may be interesting for a broader circle of readers who are interested in understanding and improvement of COVID-19 testing, helping eventually to leave COVID-19 pandemic in the past.


Electro-optical properties of strained monolayer boron phosphide.
In this paper, we use tight-binding approximation and linear response theory to study the electronic and optical properties of strained monolayer boron-phosphide (h-BP). Compared with the previous DFT study and adding on-site energy variation to the Hamiltonian, we propose a theoretical approach to investigate the strain effects on the electronic and optical properties of the h-BP. Applying tensile strain increases the gap while compressive strain reduces it as the maximum and minimum of the gap are 1.45 eV and 1.14 eV respectively and are related to the biaxial strain. Also, we investigate the optical conductivity and electron energy loss spectrum (EELS) of the pristine and strained h-BP. The absorption peak of the [Formula: see text] appears in energy about 4 eV but applying strain shifts the peak's energy. Optical properties of pristine h-BP are isotopic and biaxial strain preserves this isotropy, but uniaxial strain exerts anisotropic behavior in the system.


Recent new drug approvals, part 2: drugs undergoing active clinical studies in children.
The objective of this 2-part review is to provide information about drugs that have been recently approved by the US Food and Drug Administration. Part 1 reviewed recently approved drugs with pediatric indications. Part 2 reviews drugs recently approved only in adults and have published or ongoing studies in children.


The role of ATP-binding cassette transporters in bacterial pathogenicity.
The ATP-binding cassette transporter superfamily is present in all three domains of life. This ubiquitous class of integral membrane proteins have diverse biological functions, but their fundamental role involves the unidirectional translocation of compounds across cellular membranes in an ATP coupled process. The importance of this class of proteins in eukaryotic systems is well established as typified by their association with genetic diseases and roles in the multi-drug resistance of cancer. In stark contrast, the ABC transporters of prokaryotes have not been exhaustively investigated due to the sheer number of different roles and organisms in which they function. In this review, we examine the breadth of functions associated with microbial ABC transporters in the context of their contribution to bacterial pathogenicity and virulence.


Visceral leishmaniasis in renal transplant recipients: clinical aspects, diagnostic problems, and response to treatment.
Visceral leishmaniasis (VL) is a parasitic infection that uncommonly affects renal transplantation recipients, even in endemic areas. It may be associated with other infections, or masked by these, and may present subclinically and/or atypically for extended periods. The evolution may be particularly severe and diagnosis is often delayed. If not adequately diagnosed and treated, VL can be fatal and so should be suspected in renal transplantation recipients presenting unexplained fever, splenomegaly, and pancytopenia. The authors report 8 cases of VL out of a total of 800 renal transplant recipients from two transplant hospitals centers in Brazil. The clinical, diagnostic, and therapeutic features are reviewed.


Inhibition of CXXC5 function reverses obesity-related metabolic diseases.
Metabolic diseases, including type 2 diabetes, have long been considered incurable, chronic conditions resulting from a variety of pathological conditions in obese patients. Growing evidence suggests the Wnt/β-catenin pathway is a major pathway in adipose tissue remodelling, pancreatic β-cell regeneration and energy expenditure through regulation of key metabolic target genes in various tissues. CXXC5-type zinc finger protein 5 (CXXC5) is identified negative feedback regulator of the Wnt/β-catenin pathway that functions via Dishevelled (Dvl) binding. Expression level of CXXC5 was characterised in clinical samples and diabetes-induced mice model. Diabetes-induced mice model was established by using high-fat diet (HFD). HFD-fed mice treated with KY19334, a small molecule inhibiting CXXC5-Dvl protein-protein interaction (PPI), was used to assess the role of CXXC5 in metabolic diseases. Here, we show that CXXC5 is overexpressed with suppression of Wnt/β-catenin signalling in visceral adipose tissues of patients with obesity-related diabetes. Meanwhile, Cxxc5-/- mice fed an HFD exhibited resistance to metabolic dysregulation. KY19334 restores the lowered Wnt/β-catenin signalling and reverses metabolic abnormalities as observed in HFD-fed Cxxc5-/- mice. Administration of KY19334 on HFD-fed mice had a long-lasting glucose-controlling effect through remodelling of adipocytes and regeneration of pancreatic β-cells. Overall, the inhibition of CXXC5 function by small molecule-mediated interference of Dvl binding is a potential therapeutic strategy for the treatment of obesity-related diabetes.


Antimicrobial resistance and molecular epidemiology of carbapenem-resistant Escherichia coli from urinary tract infections in Shandong, China.
Urinary tract infection (UTI) is one of the most common extraintestinal infections, and uropathogenic Escherichia coli (UPEC) is the main cause of UTIs. However, the ability to treat UTI has been compromised by the increase in antimicrobial resistance, especially carbapenem resistance. Here, we aimed to characterize the antimicrobial resistance and molecular epidemiology of carbapenem-resistant UPEC isolated in Shandong, China. In total, 17 carbapenem-resistant UPEC (CR-UPEC) isolates were collected from July 2017 to May 2020 in the Shandong Provincial Hospital. Whole-genome sequencing and bioinformatics analyses were performed to understand the molecular epidemiology of CR-UPEC. Phylogenetic groups, drug resistance genes, biofilm formation, and virulence-related gene profiles of the isolates were analyzed. Plasmid profiling and conjugation assay were performed to evaluate the ability to transfer carbapenem resistance-related genes to other E. coli isolates. Biofilm formation was also evaluated, as it is important for the persistence of infectious diseases. We observed that 15 out of 17 CR-UPEC strains were blaNDM producers, among which 4 isolates could transfer blaNDM to recipient cells. The predominant sequence type was ST167 (6/17), followed by ST410 (3/17). The most prevalent phylogenetic group was phylogenetic group A (10/17), followed by phylogenetic group C (3/17). One isolate was resistant to polymyxin, which was caused by the carriage of a transferable plasmid harboring mcr-1. Statistical analysis did not reveal any significant difference in the carriage rate of fimbriae-coding genes between strong and weak biofilm producers. Our observations may assist in developing new therapeutic methods for drug-resistant organisms.


Severe Fever with Thrombocytopenia Syndrome Virus in Ticks and SFTS Incidence in Humans, South Korea.
During 2016-2018, we collected 3,193 ticks from rural areas in South Korea to investigate the prevalence of severe fever with thrombocytopenia syndrome virus (SFTSV). We detected SFTSV in ticks at an infection rate (IR) of 11.1%. We noted increases in the human IR associated with the monthly SFTSV IR in ticks.


Reduce Mortality and Morbidity in Acute Myeloid Leukemia With Hyperleukocytosis With Early Admission in Intensive Care Unit: A Retrospective Analysis.
Patients presenting with acute myeloid leukemia (AML) at diagnosis are at high risk of severe complications and death, particularly with high white blood cell (WBC) count. In this retrospective study, we evaluate interest of early and systematic support in the intensive care unit (ICU) for AML with hyperleukocytosis (AML-HL) at diagnosis. Patients with AML-HL, defined by WBC > 50 × 109/L, primary referred in ICU ("Early ICU") without organ failure and before initiating chemotherapy induction were compared to patients first admitted in the Hematology Department who required a secondary transfer in ICU ("Late ICU") or not ("No ICU"). Primary end point was mortality during the first month, and secondary end points were the use of life-sustaining therapies in ICU and risk factors for ICU transfer and mortality. One hundred fifty-four patients were included: 77 (50%) to the group "No ICU", 18 (12%) to "Late ICU" and 59 (38%) to "Early ICU". Mortality at day 30 was higher in "Late ICU" than in "Early ICU" and "No ICU", with 27.8%; 16.9% and 2.6% respectively (P < 0.001). "Late ICU" patients had an increased use of life-sustaining therapy comparing to "Early ICU" patients (56% vs. 29%, P = 0.04). Early referral to ICU reduces morbidity and seems an effective strategy to reduce short-term mortality in AML-HL at diagnosis.


Nb5+-Doped SrCoO3-δ Perovskites as Potential Cathodes for Solid-Oxide Fuel Cells.
SrCoO3-δ outperforms as cathode material in solid-oxide fuel cells (SOFC) when the three-dimensional (3C-type) perovskite structure is stabilized by the inclusion of highly-charged transition-metal ions at the octahedral positions. In a previous work we studied the Nb incorporation at the Co positions in the SrCo1-xNbxO3-δ system, in which the stabilization of a tetragonal P4/mmm perovskite superstructure was described for the x = 0.05 composition. In the present study we extend this investigation to the x = 0.10-0.15 range, also observing the formation of the tetragonal P4/mmm structure instead of the unwanted hexagonal phase corresponding to the 2H polytype. We also investigated the effect of Nb5+ doping on the thermal, electrical, and electrochemical properties of SrCo1-xNbxO3-δ (x = 0.1 and 0.15) perovskite oxides performing as cathodes in SOFC. In comparison with the undoped hexagonal SrCoO3-δ phase, the resulting compounds present high thermal stability and an increase of the electrical conductivity. The single-cell tests for these compositions (x = 0.10 and 0.15) with La0.8Sr0.2Ga0.83Mg0.17O3-δ (LSGM) as electrolyte and SrMo0.8Fe0.2CoO3-δ as anode gave maximum power densities of 693 and 550 mW∙cm-2 at 850 °C respectively, using pure H₂ as fuel and air as oxidant.


Apparent sympatry of Stiphrornis pyrrholaemus Schmidt & Angehr, 2008 and S. xanthogaster Sharpe, 1903 (Passeriformes: Muscicapidae) in Gabon, and taxonomic implications.
We report the occurrence of the recently-described Stiphrornis pyrrholaemus in the Makokou area, northeastern Gabon, more than 600 kilometers NE from its type locality, in areas covered by dense primary to secondary forest. The previous records of Stiphrornis from the same area were referred to S. xanthogaster. We confirm this attribution on the basis of museum specimens. Although several recent sources treat all Stiphrornis as a single species, our findings strongly suggest the sympatric coexistence of two Stiphrornis species and thus that they should be treated as separate species under the Biological Species Concept.


The process of cognitive behaviour therapy for chronic fatigue syndrome: which changes in perpetuating cognitions and behaviour are related to a reduction in fatigue?
Cognitive behaviour therapy (CBT) can significantly reduce fatigue in chronic fatigue syndrome (CFS), but little is known about the process of change taking place during CBT. Based on a recent treatment model (Wiborg et al. J Psych Res 2012), we examined how (changes in) cognitions and behaviour are related to the decrease in fatigue. We included 183 patients meeting the US Centers for Disease Control criteria for CFS, aged 18 to 65 years, starting CBT. We measured fatigue and possible process variables before treatment; after 6, 12 and 18 weeks; and after treatment. Possible process variables were sense of control over fatigue, focusing on symptoms, self-reported physical functioning, perceived physical activity and objective (actigraphic) physical activity. We built multiple regression models, explaining levels of fatigue during therapy by (changes in) proposed process variables. We observed large individual variation in the patterns of change in fatigue and process variables during CBT for CFS. Increases in the sense of control over fatigue, perceived activity and self-reported physical functioning, and decreases in focusing on symptoms explained 20 to 46% of the variance in fatigue. An increase in objective activity was not a process variable. A change in cognitive factors seems to be related to the decrease in fatigue during CBT for CFS. The pattern of change varies considerably between patients, but changes in process variables and fatigue occur mostly in the same period.


FLJ10849, a septin family gene, fuses MLL in a novel leukemia cell line CNLBC1 derived from chronic neutrophilic leukemia in transformation with t(4;11)(q21;q23).
A t(4;11)(q21;q23) has been described in 50-70% of cases of infant acute lymphoblastic leukemia and, less frequently, in cases of pediatric and adult acute lymphoblastic leukemia and acute myeloid leukemia (AML). In t(4;11)(q21;q23) leukemias, the AF4 gene has been cloned as a fusion partner of the MLL gene. A human myeloid leukemia cell line, chronic neutrophilic leukemia (CNL)BC1, was established from a peripheral blood specimen of a patient with CNL in leukemic transformation. As with the original leukemia cells, the established line had a t(4;11)(q21;q23). We showed that the MLL gene on 11q23 was fused to the FLJ10849 gene on 4q21. The protein encoded by FLJ10849 belongs to the septin family, sharing highest homology with human SEPT6, which is one of the fusion partners of MLL in t(X;11)(q13;q23) AML. Our results suggest that FLJ10849 might define a new septin family particularly involved in the pathogenesis of 11q23-associated leukemia. The established cell line, CNLBC1, could provide a useful model for analyzing the pathogenesis of MLL-septin leukemias and chronic neutrophilic leukemia.


Skin tumors and skin infections in kidney transplant recipients vs. patients with pemphigus vulgaris.
Pemphigus vulgaris is an autoimmune disease of the skin and mucous membrane. Renal transplantation is a common procedure in Iraq, and these patients required prolonged use of immunosuppressive drugs. To study the frequency of skin tumors and infections in patients with pemphigus vulgaris compared with renal transplant recipients and normal controls. One hundred kidney transplant recipients, their ages ranged from 14 to 70 (46.65 ± 4.74) years, and 50 patients with pemphigus vulgaris, their ages ranged from 22 to 70 (43.32 ± 3.46) years, were studied in Baghdad Hospital from June 2009 to August 2010. Patients were treated with immunosuppressive drugs for 0.5-25 years. Patients were examined for tumors and infections and compared with the general population as controls (100 individuals). In renal transplant recipients, the following infections were observed: herpetic, 25 patients (25%); bacterial, 11 (11%); and fungal, 22 (22%). These infections appeared early in the course of immunosuppression. Benign tumors increased, most importantly viral warts in 40 (40%) and actinic keratosis, 14 (14%). The malignant tumors were basal cell carcinomas in 4 (4%), squamous cell carcinomas 2 (2%), and Kaposi's sarcoma 3 (3%). These malignancies usually appeared late in the course of immunosuppression. Patients with pemphigus vulgaris showed no important skin infections or tumors. Healthy controls showed no infections apart from herpetic infections in 7 (7%) and viral warts in 9 (9%). No tumors were seen. Pemphigus vulgaris in prolonged immunosuppression is immunoprotective against skin infections and skin tumors while kidney transplant recipients are not protective.


Total synthesis and bioactivity of some naturally occurring pterulones.
The naturally occurring pterulones 1, 3, and 13 were synthesized in high overall yield from readily available methyl 3-(2-propenyl)-4-(2-propenyloxy)benzoate (6) by employing ring-closing metathesis (RCM) as a key step. The biological activities of the synthesized pterulones were tested using cells of Rhodotorulaglutinis and Saccharomyces cerevisiae.


Signal transduction in development: holding the key.
The unrelated GSK-3 and CK1 families stand out among the protein kinases because of their phosphorylated substrate recognition sites. Two papers in the March 22nd issue of Cell highlight the importance of this priming phosphorylation for signal transduction during development.


Complex modulation of peptidolytic activity of cathepsin D by sphingolipids.
Cathepsin D is an aspartic peptidase involved in cellular processes including proliferation and apoptosis and implicated in human pathologies such as cancer and neurodegeneration. Our knowledge about the relationship between proteolysis and bioactive sphingolipids is still very limited. Here, we describe a complex pattern of modulation of the peptidolytic activity of cathepsin D by sphingolipids. A panel of sphingolipid derivatives was screened in a FRET-based assay; these molecules demonstrated negative or positive modulation of cathepsin D peptidolytic activity, depending on the sphingolipid structure. Certain sphingosines and ceramides inhibited cathepsin D in the submicromolar range, and structural requirements for this inhibitory effect were evaluated. The interaction of cathepsin D with sphingolipids was also demonstrated by fluorescence polarization measurements and determined to follow a competitive inhibition mode. In contrast, monoester phosphosphingolipids, especially ceramide-1-phosphate, were identified as activators of cathepsin D peptidolytic activity at submicromolar concentrations. Thus, sphingolipids and phosphosphingolipids, known to be antagonistic in their cell-signaling functions, displayed opposite modulation of cathepsin D. Sphingolipid-based modulators of cathepsin D are potentially involved in the control of cathepsin D-dependent processes and might serve as a scaffold for the development of novel regulators of this therapeutic target.


Diagnosis and classification of mastocytosis in non-specialized versus reference centres: a Spanish Network on Mastocytosis (REMA) study on 122 patients.
The diagnosis of 'rare diseases', such as mastocytosis, remains a challenge. Despite this, the precise benefits of referral of mastocytosis patients to highly specialized reference centres are poorly defined and whether patients should be managed at non-specialized versus reference centres remains a matter of debate. To evaluate the quality and efficiency of diagnostic procedures performed at the reference centres for mastocytosis in Spain (REMA) versus other non-reference centres, we retrospectively analysed a series of 122 patients, for the overall degree of agreement obtained for the World Health Organization (WHO) diagnostic and classification criteria betwen the referring and REMA centres. Our results showed that not all WHO diagnostic criteria were frequently investigated at the referring centres. Among the five WHO diagnostic criteria, the highest degree of agreement was obtained for serum tryptase levels [median 90% (95% confidence interval 84-96%)]; in turn, the overall agreement was significantly lower for the major histopathological criterion [80% (72-89%)], and the other three minor criteria: cytomorphology [68% (56-80%)] immunophenotyping of BM mast cells [75% (62-87%)] and detection of the KIT mutation [34% (8-60%)]. Referral of patients with diagnostic suspicion of mastocytosis to a multidisciplinary reference centre improves diagnostic efficiency and quality.


WITHDRAWN: Versatility of different melting temperature (Tm) calculator software for robust PCR and Real-time PCR oligonucleotide design: A practical guide.
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.


Team structure, team climate and the quality of care in primary care: an observational study.
To determine whether practice structure (for example, list size, number of staff) predicts team processes and whether practice structure and team process in turn predict team outcomes Observational study using postal questionnaires and medical note audit. Team process was assessed through a measure of "climate" which examines shared perceptions of organisational policies, practices, and procedures. Primary care. Members of the primary health care team from 42 practices. Objective measures of quality of chronic disease management, patients' evaluations of practices, teams' self-reported ratings of effectiveness, and innovation. Team climate was better in singlehanded practices than in partnerships. Practices with longer booking intervals provided superior chronic disease management. Higher team climate scores were associated with superior clinical care in diabetes, more positive patient evaluations of practice and self-reported innovation and effectiveness. Although the conclusions are preliminary because of the limited sample size, the study suggests that there are important relationships between team structure, process, and outcome that may be of relevance to quality improvement initiatives in primary care. Possible causal mechanisms that might underlie these associations remain to be determined.


Loss of methylation at chromosome 11p15.5 is common in human adult tumors.
Chromosome 11p15 deletion is frequent in human tumors, suggesting the presence of at least one tumor suppressor gene within this region. While mutation analyses of local genes revealed only rare mutations, we have previously described a mechanism, gain of imprinting, that leads to loss of expression of genes located on the maternal 11p15 chromosome in human hepatocarcinomas. Loss of expression was often associated with loss of maternal-specific methylation at the KvDMR1 locus. Here, we show that loss of the maternal KvDMR1 methylation is common, ranging from 30 to 50%, to a variety of adult neoplasms, including liver, breast, cervical and gastric carcinomas. We found that other 11p15.5 loci were concomitantly hypomethylated, indicating that loss of KvDMR1 methylation occurred in the context of a common mechanism affecting the methylation of a large 11p15 subchromosomal domain. These epigenetic abnormalities were not detected in any normal somatic tissue. Therefore, it seems possible that, contrary to the repression of promoter activity caused by hypermethylation, loss of gene expression at 11p15.5 may result from the activation, by hypomethylation, of one or more negative regulatory elements.


Molecular investigations on outbreaks of ovine theileriosis among sheep and goats in Haryana, India.
During February 2020 to October 2020, four outbreaks of theileriosis in small ruminants were recorded with overall morbidity, mortality and case fatality rates of 27.95%, 17.46% and 62.5%, respectively. The disease was characterized by high fever (up to 106°F), superficial lymphadenopathy, anaemia, anorexia, lethargy, respiratory distress and death. The presence of pleomorphic intra-erythrocytic piroplasms of Theileria species in Giemsa's stained blood smears was a common finding in all the episodes. Significant haematological alterations including high total leucocyte count and low haemoglobin and packed cell volume were characteristic. Necropsy findings of the icteric liver, enlarged spleen, pulmonary oedema and abomasal ulcerations were observed in three flocks. Smear-positive blood samples from all the episodes were screened by PCR using 18S rRNA gene-specific primer sets for T. lestoquardi, T. luwenshuni, T. uilenbergi and T. ovis. T. lestoquardi which was detected in all four flocks, while there was co-infection of T. ovis in two flocks. Phylogenetic analysis revealed that T. ovis and T. lestoquardi identified in this study had 100% and ~ 99.86% homology, respectively, with the published sequences used for comparison. This is the first confirmed report of outbreaks of malignant ovine theileriosis in the Haryana state of India which caused high morbidity, mortality and case fatality among sheep and goats. Further studies on theilerioses in small ruminants are required to understand epidemiology better.


Chiral amine-thioureas bearing multiple hydrogen bonding donors: highly efficient organocatalysts for asymmetric Michael addition of acetylacetone to nitroolefins.
New bifunctional organocatalysts amine-thioureas bearing multiple hydrogen bonding donors were synthesized and applied in catalytic asymmetric Michael addition of acetylacetone to aryl and alkyl nitroolefins. Multiple hydrogen bonding donors play a significant role in accelerating reactions, improving yields and enantioselectivities.


[Injury hazards in deliveries using the Shute forceps (analysis of 1016 forceps deliveries)].
Report about 1016 deliveries by means of the parallel forceps (W. B. Shute). This group contains pathologic-anatomical results of 30 stillbirthes or died newborns. Accordingly to the classification in subarachnoidal, subependymal or subdural hämorrhage there are only in two cases signs of obstetrical brain damage. The hypoxia is the most important reason of intracraniale haemorrhage. In order to an objektive indication, without progredient signs of fetal hypoxia the extraction by means of parallel forceps is not dangerous. We have used the instrument for extraction as well term as preterm infants with good results.


The management of penile fracture based on clinical and magnetic resonance imaging findings.
To present our experience with repairing penile fracture, based on clinical and magnetic resonance imaging (MRI) findings. Between December 2002 and October 2004, 14 men (19-64 years old) presented to our centre with a penile fracture. Two patients had urethral bleeding. MRI was used before surgery in all patients, and the repair comprised a localized longitudinal penile incision in 13 men. This incision was designed according to the tunical tear site and size already depicted by MRI. One case was managed conservatively, as MRI confirmed an intercavernosal haematoma with no tunical tear. The follow-up was 4-21 months. The tear involved one corpus cavernosum in 11 patients; two were associated with urethral injury. The course after repair was uneventful in all men; the follow-up showed no erectile dysfunction in any. The patients reported neither pain nor penile curvature during erection. MRI is a simple and informative investigation for evaluating and documenting a penile fracture, and it improves the management plan.


Temperature distribution in human skin and subdermal tissues.
Temperature profiles have been computed in the skin and subdermal part of a human body for (i) various values of environmental temperature, rate of sweat evaporation and wind velocity, (ii) rate of blood mass flow, (iii) rate of metabolic heat generation and (iv) three different sets of thicknesses of skin layers. The mathematical equations have been considered for a one-dimensional steady-state case. The two important physical parameters, namely rate of blood mass flow and rate of metabolic heat generation, have been assigned position-dependent values. The latter is also taken as linearly dependent on the tissue temperature. Analytic solutions have been obtained for the three layers of the region. These forms of solution facilitate the study of parameter dependence.


Human lymphocyte antigen in actinic prurigo.
Thirty-one patients with actinic prurigo were human lymphocyte antigen (HLA)-typed. The results showed an association of this disease with the alleles B40 and Cw3, both usually found in linkage disequilibrium in most populations. Because these two antigens are more frequent in Amerindians than in whites, it is suggested that they may partly account for the restricted ethnic distribution of this disease.


Atypical cardiopulmonary manifestations in pediatric Behçet's disease.
Behçet's disease (BD) is a multisystem autoinflammatory disease of unknown etiology. Cardiopulmonary involvement is rare, especially in young patients, and carries high morbidity and mortality rates. Of 26 patients with pediatric BD enlisted in our center, we encountered three patients with severe atypical cardiorespiratory presentations. Our aim was to describe the manifestations and the course that led to the diagnosis of BD. Three adolescents presented with intracardiac thrombi and left anterior descending obstruction causing myocardial infarction, pulmonary artery aneurysm with pulmonary embolism in situ, and suspected epiglottitis. Two patients had a delayed diagnosis of BD, and all had a good response to anti-inflammatory agents. This study demonstrated that pediatric BD is associated with atypical cardiopulmonary manifestations which maybe life threatening. Since diagnosis maybe challenging, a high index of suspicion is needed especially in young patients, to promptly diagnose and treat these complications. Cardiopulmonary signs and symptoms, though uncommon, maybe the first manifestation and a clue to the diagnosis of this rare disease.


Alterations of insulin and glucose metabolism during cardiopulmonary bypass under normothermia.
Anesthesia, surgical trauma, heparinization, priming volume composition, and temperature control of the heart-lung machine individually affect carbohydrate, protein, or lipid metabolism during cardiac operations. The impact of some of these factors on glucose and insulin regulation was assessed before, during, and after normothermic cardiopulmonary bypass in nondiabetic patients with use of a servo-controlled insulin delivery system. With a glucose-free prime, cardiopulmonary bypass induced a slight hyperglycemia but no endogenous insulin response, suggesting a partial inhibition of insulin secretion. Nonetheless, insulin release could be stimulated by exogenous glucagon. A glucose load in the priming fluid led to marked and persistent hyperglycemia without commensurate insulin release. Elevated stress hormone levels, a concomitant reduction of insulin release and insulin action, and a depression of peripheral glucose utilization, as demonstrated by glucose clamp experiments, contributed to these perturbations of glucose and insulin metabolism. Although the metabolic alterations observed are not critical in routine cardiac operations, they may become clinically significant in postoperative states with unusual persistence of stress conditions.


The inhibitory effect of ovomucoid from egg white on biofilm formation by Streptococcus mutans.
Streptococcus mutans, the main pathogen associated with tooth decay, forms cariogenic biofilms on tooth surfaces. Therefore, controlling oral biofilm helps prevent dental caries. Hen's egg is a nutrient-dense food, and egg white is a good source of protein. Ovomucoid is one of the major proteins in egg white, with a 28 kDa molecular weight. The present study aimed to investigate the inhibitory effects of ovomucoid on the biofilm formation of S. mutans by suppressing virulence factors, including bacterial adherence, cellular aggregation and exopolysaccharide (EPS) production. Crystal violet staining showed that biofilm formation by S. mutans was inhibited by ovomucoid at 0.25-1 mg mL-1 levels. Field emission scanning electron microscopy also confirmed this inhibition. In addition, ovomucoid reduced mature biofilm, water-insoluble EPS synthesis and the metabolic activity of bacterial cells in the biofilm. The bacterial adhesion and aggregation abilities of S. mutans were also decreased in the presence of ovomucoid. Ovomucoid downregulated the expression of comDE and vicR genes involved in the two-component signal transduction system and gtfA and ftf genes involved in EPS production. Ovomucoid has the potential for use as an anti-biofilm agent for dental caries treatment because of its inhibitory effects on the virulence factors of S. mutans. © 2023 Society of Chemical Industry.


A first-degree family history in lone atrial fibrillation patients.
Atrial fibrillation (AF) may be due to an inherited trait, particularly in lone AF patients. A family history of AF in lone AF patients has not previously been compared with a family history of patients with AF and established risk factors (non-lone AF). The purpose of this study was to compare the frequency of having a first-degree relative with AF in lone and non-lone AF patients. We performed a case-control study of consecutive subjects presenting to a single electrophysiology laboratory. A convenience sample of subjects with no known arrhythmias was also enrolled. Four hundred twenty-nine subjects were enrolled: 136 had AF (54 with lone AF), 84 had atrial flutter, 158 had other supraventricular arrhythmias, and 51 had no known arrhythmias. Significantly more subjects with AF reported a first-degree family history of AF compared with the remainder of the cohort (25% vs. 5%; P <.001). In multivariable analysis adjusting for potential confounders, AF patients had a 6-fold greater odds of having a family member with AF (95% confidence interval [CI] 2.93-12.7; P <.001). Lone AF patients had a first-degree family member with AF substantially more often than those with non-lone AF (41% vs. 14%; P <.001). After adjusting for potential confounders, lone AF patients remained significantly more likely than other AF patients to have a first-degree relative with AF (OR 7.2; 95% CI 2.1-24.7; P = .002). Lone AF patients have a first-degree family member with AF substantially more often than other AF patients. This suggests that an inherited trait may be particularly important in this subgroup of patients.


Lumenal labeling of rat hepatocyte endocytic compartments. Distribution of several acid hydrolases and membrane receptors.
We used a combination of subcellular fractionation and lactoperoxidase-mediated iodination to examine the polypeptide compositions of three hepatocyte endocytic compartments: early endosomes, late endosomes, and lysosomes. A chemical conjugate of asialoorosomucoid and lactoperoxidase which binds specifically to asialoglycoprotein receptors was perfused through isolated rat livers at 37 degrees C. Subcellular fractions enriched in various endocytic compartments were then isolated by differential and isopycnic centrifugation, and the lactoperoxidase moiety of the internalized conjugate was used to catalyze the iodination of lumenal-facing proteins. The 125I profiles of early and late endosomes were strikingly similar after gel electrophoresis. Using immunoprecipitation, we directly identified and compared the relative amounts of the Na+,K(+)-ATPase and several different acid hydrolases and membrane receptors in all three fractions. The asialoglycoprotein receptor and the low density lipoprotein related protein were approximately nine times more abundant in early endosomes than late endosomes, suggesting that they recycle from early endosomes. In addition, cathepsin D, but not cathepsin L, beta-glucuronidase, and lgp 120, was detected in early endosomes; however, all of these molecules were detected in lysosomes. Our findings provide strong evidence that early endosomes mature into late endosomes and that there is either selective delivery or selective retention of hydrolases at discrete points in the endocytic pathway.


Efficacy of the microscopic parachute end-to-side technique for creating large-to-small venous anastomoses in free flaps in the extremities.
The availability of reliable and suitably sized veins is limited for creating free flaps to treat severe trauma and infection, and it is important to manage vessel size discrepancy between the recipient and flap veins. We evaluated the clinical outcomes of free flaps with large-to-small venous end-to-side (ETS) anastomoses using the microscopic parachute end-to-side (MPETS) anastomosis in soft tissue defects in the extremities. This procedure comprises mainly a wide-slit venotomy and parachute procedure at the heel. We examined 24 free flaps in 23 patients given a large-to-small venous anastomosis using the MPETS technique. Patient demographics, details of vessel anastomoses, and flap outcomes and complications were obtained from medical records. Two veins were anastomosed in six flaps. Thirty anastomosed veins were assessed, and 24 deep veins, all of which accompanied main arteries, were chosen as recipient veins. The mean diameters were 1.5 mm in the recipient veins and 2.7 mm in the flap veins, and the mean vessel size discrepancy was 1.8-fold (range 1.3-3.3 fold). Because of the presence of venous valves at the anastomotic site, trimming of venous cusps was performed in six veins. All flaps survived, though one venous thrombosis occurred because of pedicle kinking in a case with a short pedicle. The MPETS technique is simple, reliable, and useful for performing various types of venous anastomoses regardless of a vessel size discrepancy and the presence of a venous valve. This may be a good option for large-to-small venous anastomosis in free flaps.


Cation channels of the transient receptor potential superfamily: their role in physiological and pathophysiological processes of smooth muscle cells.
Smooth muscle cells (SMC) are essential components of many tissues of the body. Ion channels regulate their membrane potential, the intracellular Ca(2+) concentration ([Ca(2+)](i)) and their contractility. Among the ion channels expressed in SMC cation channels of the transient receptor potential (TRP) superfamily allow the entry of Na(+), Ca(2+) and Mg(2+). Members of the TRP superfamily are essential constituents of tonically active channels (TAC), receptor-operated channels (ROC), store-operated channels (SOC) and stretch-activated channels (SAC). This review focusses on TRP channels (TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, TRPC7, TRPV2, TRPV4, TRPM4, TRPM7, TRPP2) whose physiological functions in SMC were dissected by downregulating channel activity in isolated tissues or by the analysis of gene-deficient mouse models. Their possible functional role and physiological regulation as homomeric or heteromeric channels in SMC are discussed. Moreover, TRP channels may also be responsible for pathophysiological processes involving SMC-like airway hyperresponsiveness and pulmonary hypertension. Therefore, they present important drug targets for future pharmacological interventions.


11C-acetate and 18F-fluorodeoxyglucose positron emission tomography/computed tomography dual imaging for the prediction of response and prognosis after transarterial chemoembolization.
The aim of the present study was to evaluate the clinical significance of dual radiotracer studies, C-acetate and F-fluoro-D-glucose positron emission tomography/computed tomography (F-FDG PET/CT), for the prediction of response and recurrence after transarterial chemoembolization (TACE).This study retrospectively included a total 42 hepatoceullar carcinoma (HCC) patients (median age, 59; range, 34-85 years old) who underwent C-acetate and F-FDG PET/CT concurrently. Tumor uptake normalized by liver uptake (TNR; maximum tumor SUV to mean normal liver SUV ratio) was obtained first. Then, FAratio, which is the ratio of F-FDG TNR (TNR_FDG) to C-acetate TNR, was obtained and correlated with response after TACE and recurrence-free survival (RFS), using a Cox multivariate proportional-hazard model.Among clinical factors, including the Hepatoma Arterial Embolization Prognostic score and positron emission tomography (PET) parameters, multiple regression analysis revealed FAratio and tumor size to be the only significant factors. As a PET parameter, FAratio exhibited the largest area under the curve in the prediction of response after TACE. In the Cox multivariate proportional-hazard model, TNR_FDG was the only significant predictive factor for RFS. In subgroup analysis, TNR_FDG was the only significant predictive factor for recurrence in intermediate stage patients. However, FAratio was the only significant predictive factor for recurrence in advanced stage patients.Dual radiotracer use of C-acetate and F-FDG PET/CT contributed to the prediction of response and recurrence after TACE. Used in addition to F-FDG, C-acetate PET/CT could give additional information in advanced stage patients. Based on the characteristics of tumor metabolism assessed by dual radiotracer PET/CT, treatment plans could be more personalized and optimized.


Use of a 660-nm Laser to Aid in the Healing of Necrotic Alveolar Mucosa Caused by Extruded Sodium Hypochlorite: A Case Report.
The extrusion of sodium hypochlorite through the apical foramen is an accident that can occur during the flushing procedure in endodontic treatment. The symptomatology is immediate and intense, and there is a long period before the tissues return to normal. Low-level laser therapy might be useful as an adjunctive treatment for damaged soft tissues because of its anti-inflammatory and analgesic effects, which may reduce edema and prevent infection. In this clinical case, the accidental leakage of 1% sodium hypochlorite during the preparation of the root canal of a maxillary right central incisor is reported. This leakage caused immediate and intense pain and edema formation and resulted in an extensive necrotic area in the alveolar mucosa adjacent to the root of the treated tooth. The conventional treatment protocol was combined with low-level laser therapy. Clinical and radiographic examinations after 7 months revealed complete repair of the necrotic area with no paresthesia and further indicated the integrity of the apical region of the tooth where the extrusion of sodium hypochlorite occurred. The combination of low-level laser therapy with a conventional treatment protocol in this case of the extrusion of 1% sodium hypochlorite resulted in the healing of the wounds.


Subcellular localization and kinetic properties of arginase from the liver of Genypterus maculatus.
1. From the liver of the teleost fish Genypterus maculatus, a partially purified preparation of arginase was obtained and characterized. 2. The Km value for arginine was found to be 9.1 mM at pH 7.5 and 11.5 mM at the optimum pH of 9.5. At both pH values, competitive inhibition was caused by ornithine and lysine, whereas proline, leucine, valine and isoleucine caused a non-competitive inhibitory effect. Branched chain amino acids were more inhibitory than proline. 3. The enzyme was found localized in the mitochondrial matrix of the liver of Genypterus maculatus. It is suggested that this localization would be of importance in the use of arginine as an energy source.


Flavonoids‑targeted metabolomic analysis following rice yellowing.
Flavonoids are the main metabolites responsible for yellowing of rice. However, the accumulation pattern of flavonoids and the metabolic basis of flavonoid biosynthesis during rice yellowing remain unclear. Thus, flavonoid-targeted metabolomics was used to investigate the composition and concentration of flavonoids in rice during yellowing. The results indicated the differential flavonoids at Month 3 and Month 5 of storage were more in composition and concentration with higher antioxidant capacity. Accumulated flavonoids were mainly flavones, flavonols, isoflavones, and anthocyanidins, of which rutin, farrerol, naringenin, cyanidin 3-rutinoside, and diosmetin were the indicators of rice yellowing. Metabolic association among flavonoids demonstrated the formation of yellow pigments was jointly induced by flavones, flavonols, isoflavones, and anthocyanidins metabolism. Examination of flavonoid metabolism presented in this study enhanced current understanding of the relationship between flavonoid metabolites and development of rice yellowing. It also offers a theoretical basis for targeted prediction of rice yellowing in the future.


Genetic Dissection of Variation in Hippocampal Intra- and Infrapyramidal Mossy Fibers in the Mouse.
This chapter describes the genetic analysis of a morphometric neuroanatomic trait. We used the extended BXD family of recombinant inbred mouse strains with the intent to analyze the genetic bases of heritable differences in hippocampal neurocircuitry and to identify Quantitative Trait Loci that underlie these variations. A detailed description of a GeneNetwork analysis is provided using data for the intra- and infrapyramidal mossy fiber (IIPMF) terminal fields which are strongly correlated with spatial navigation/radial maze learning.


Key role of chemistry versus bias in electrocatalytic oxygen evolution.
The oxygen evolution reaction has an important role in many alternative-energy schemes because it supplies the protons and electrons required for converting renewable electricity into chemical fuels1-3. Electrocatalysts accelerate the reaction by facilitating the required electron transfer4, as well as the formation and rupture of chemical bonds5. This involvement in fundamentally different processes results in complex electrochemical kinetics that can be challenging to understand and control, and that typically depends exponentially on overpotential1,2,6,7. Such behaviour emerges when the applied bias drives the reaction in line with the phenomenological Butler-Volmer theory, which focuses on electron transfer8, enabling the use of Tafel analysis to gain mechanistic insight under quasi-equilibrium9-11 or steady-state assumptions12. However, the charging of catalyst surfaces under bias also affects bond formation and rupture13-15, the effect of which on the electrocatalytic rate is not accounted for by the phenomenological Tafel analysis8 and is often unknown. Here we report pulse voltammetry and operando X-ray absorption spectroscopy measurements on iridium oxide to show that the applied bias does not act directly on the reaction coordinate, but affects the electrocatalytically generated current through charge accumulation in the catalyst. We find that the activation free energy decreases linearly with the amount of oxidative charge stored, and show that this relationship underlies electrocatalytic performance and can be evaluated using measurement and computation. We anticipate that these findings and our methodology will help to better understand other electrocatalytic materials and design systems with improved performance.


Surgical considerations in treatment of intraductal carcinoma of the prostate.
Intraductal carcinomas of the prostate comprise about 3 per cent of all prostatic carcinomas and constitute a heterogeneous group of tumors that include 1) transitional or squamous cell carcinoma, 2) intraductal adenocarcinoma, 3) endometrioid carcinoma and 4) mixed ductal carcinoma. Generally, these tumors are poorly responsive to endocrine and radiation therapy, and complete surgical excision offers the best chance for long-term survival. A case of intraductal adenocarcinoma is presented that illustrates many of the features of these tumors.


Möbius carbon nanobelts interacting with heavy metal nanoclusters.
The interaction between carbon nanostructures and heavy metal clusters is of great interest due to their potential applications as sensors and filters to remove the former from environment. In this work, we investigated the interaction between two types of carbon nanobelts (Möbius-type nanobelt and simple nanobelt) and nickel, cadmium, and lead nanoclusters. Our aim was to determine how both systems interact which would shed light on the potential applications of the carbon nanostructures as pollutant removal and detecting devices. To investigate the interaction between carbon nanostructures and heavy metal nanoclusters, we utilized the semiempirical tight binding framework provided by xTB software with the GFN2-xTB Hamiltonian. We performed calculations to determine the best interaction site, lowest energy geometries, complexes stability (using molecular dynamics at 298K), binding energy, and electronic properties. We also carried out a topological study to investigate the nature and intensity of the bonds formed between the metal nanoclusters and the nanobelts. Our results demonstrate that heavy metal nanoclusters have a favorable binding affinity towards both nanobelts, with the Möbius-type nanobelt having a stronger interaction. Additionally, our calculations reveal that the nickel nanocluster has the lowest binding energy, displaying the greatest charge transfer with the nanobelts, which was nearly twice that of the cadmium and lead nanoclusters. Our combined results lead to the conclusion that the nickel nanoclusters are chemisorbed, whereas cadmium and lead nanoclusters are physisorbed in both nanobelts. These findings have significant implications for the development of sensor and filtering devices based on carbon and heavy metal nanoclusters.


Systematical characterization of gypenosides in Gynostemma pentaphyllum and the chemical composition variation of different origins.
Gynostemma pentaphyllum (Thunb.) Makino is an herbaceous plant of Cucurbitaceae family, which has been widely used as an herbal tea and traditional Chinese medicine. Since its saponins are similar to ginsenosides and have a wide range of activities, it has attracted wide interest. However, there are still a large number of unknown saponins that have not been isolated, especially some trace gypenosides. In the present study, a HILIC × RP offline two-dimensional liquid separation combined with a multimode data acquisition was developed for the systematical characterization of gypenosides. On top of the negative mode information, considering that saponins are prone to in-source fragmentations in positive ion mode, a precursor ion list data acquisition method was used for the targeted acquisition of multistage positive data. Reference herbal drug was taken as a golden sample to probe the chemical composition of G. pentaphyllum. The mixed sample of commercially available samples were also analyzed in parallel. Furthermore, the chemical compositions of commercially available samples from different sources were compared. In total, 1108 saponins were characterized, among which 588 were accurately characterized, with 574 identified in the reference herbal drug and 700 in the mixed commercially available samples. The commercially available samples showed great composition variation. These findings clarified the material basis and provided clues for quality control of G. pentaphyllum.


Females and attention to eye gaze: effects of the menstrual cycle.
It is well known that an observer will attend to the location cued by another's eye gaze and that in some circumstances, this effect is enhanced when the emotion expressed is threat-related. This study explored whether attention to the gaze of threat-related faces is potentiated in the luteal phase of the menstrual cycle when detection of threat is suggested to be enhanced, compared to the follicular phase. Female participants were tested on a gaze cueing task in their luteal (N = 13) or follicular phase (N = 15). Participants were presented with various emotional expressions with an averted eye gaze that was either spatially congruent or incongruent with a forthcoming target. Females in the luteal phase responded faster overall to targets on trials with a 200-ms stimulus onset asynchrony interval. The results suggest that during the luteal phase, females show a general and automatic hypersensitivity to respond to stimuli associated with socially and emotionally relevant cues. This may be a part of an adaptive biological mechanism to protect foetal development.


Adolescent sexuality.
Adolescent sexuality is surveyed from three angles: the emergence of adult sexual functions, the participation in sexual behaviors, and the relationship of sexuality to the developmental tasks of adolescence. Common medical problems arising from adolescent sexual activity are also discussed.


Emerging and potential therapies for Alzheimer's disease.
The amyloid beta (Abeta) peptide is critical to the development of Alzheimer's disease (AD), the major neurodegenerative disease of the elderly for which there is currently no cure. To review the literature on emerging treatments and potential therapeutic strategies for AD. Available published literature and information from pharmaceutical companies was utilised. Several of the current treatments to combat AD are aimed at inhibiting the production, blocking the oligomerisation/aggregation or enhancing the degradation of Abeta. In our opinion, albeit based on limited available data, a future potential therapeutic strategy is to mimic the mechanism by which the normal cellular form of the prion protein inhibits the beta-secretase beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and hence the production of Abeta.


Testing for density dependence : A cautionary note.
The robustness and sensitivity of a test for density dependence in an animal population against departures from the assumed null and alternative model is assessed via simulation. The test is shown to be nonrobust and insensitive to departures from the assumed models.


[Comparison of the clinicopathological characteristics of colorectal cancer between elderly and young patients].
To compare the clinicopathological characteristics between elderly and young patients with colorectal cancer (CRC). A total of 727 patients with CRC treated between Jan 2003 and Dec 2005 were divided into elderly group (≥ 60 years old), middle-aged group (36-59 years old), and young group (≤ 35 years old). The clinicopathological characteristics of the 3 groups were analyzed retrospectively. The tumor occurred mainly in the rectum, sigmoid colon and ascending colon of the patients. The major initial symptoms included hemafecia and changes in bowel habits in the elderly and middle-aged cases, as compared to abdominal pain and hemafecia in the young group. The elderly patients had greater ratio of well differentiated neoplasm than the middle-aged and young patients. The ratio of radical operation was markedly higher in the elderly and middle-aged group than in the young group. The elderly patients were more likely to have stage II and III tumors than the middle-aged and young patients, having also significantly higher incidences of such complications as heart and lung diseases upon diagnosis. Compared with the middle-aged and young patients, elderly patients with CRC are more likely to have well differentiated tumor, multiple complications upon diagnosis, and higher radical operation rate.


Association between trigger points in hamstring, posterior leg, foot muscles and plantar fasciopathy: A cross- sectional study.
Plantar Fasciopathy (PF) is soreness or irritability experienced underneath infero-medial aspect of the heel. It is a multifactorial disorder where myofascial involvement also seems to be associated with it, in which, muscles of posterior thigh, leg and foot muscles are affected. Trigger points in these muscles may interfere with biomechanics and normal functioning of the lower limb. To find an association between trigger points of the posterior thigh, leg and foot muscles and plantar fasciopathy. A cross sectional study. 100 patients with plantar fasciopathy who fulfilled inclusion criteria were included in this study. They were examined for trigger points by manual palpation in posterior thigh, leg and foot muscles. Totally 15 muscles were examined on both affected and unaffected side. Results showed that myofascial trigger points were more prevalent in medial gastrocnemius (98%, Chi-square: 110.07, p < 0.05, Phi-0.74), quadratus plantae (83%, Chi-square:126.96, p < 0.05, Phi- 0.79), soleus (69%, Chi-square: 28.88, p < 0.05, Phi-0.38), tibialis posterior (46%, Chi-square 41.98 p<0.05%, Phi-0.50), abductor hallucis (42%, Chi-square: 43.61 p<0.05% Phi-0.46), flexor halluces longus (41%, Chisquare: 39.25, p < 0.05, Phi-0.44) than other muscles on the affected side. Whereas, on the unaffected side, trigger points were more prevalent among peroneus longus (50%, Chi-square: 26.14, p < 0.05, Phi-0.36) followed by medial gastrocnemius (26%, Chisquare: 110.07, p < 0.05, Phi-0.74). Plantar fasciopathy is strongly associated with trigger points of medial gastrocnemius, quadratus plantae followed by soleus, tibialis posterior, abductor hallucis and flexor hallucis longus.


Pharmacokinetic study of copper (II) acetylsalicylate.
This study was aimed at determination of pharmacokinetic parameters of copper (II) acetylsalicylate (CAS). Ten volunteers received a 60-mg dose of CAS. Blood samples were collected just before and after 0.25, 0.5, 0.75, 1.0, 1.5, 2.5, 3.0, 3.5, 4.0, 4.5, 5.5, 7.0, 10, and 12.0 h of administration of the drug. The plasma samples were analyzed for CAS and its metabolites by a validated high-performance liquid chromatography method having a suitable lower limit of quantification. The dose of 60 mg was well tolerated without any adverse effect. The maximum plasma concentration of CAS was found to be 0.38 mg L(-1) with t (max) of 0.72 h. The plasma half-life, clearance, and volume of distribution of CAS were 8.67 h, 66.30 L h(-1) and 829 L kg(-1), respectively. The elimination of CAS, acetylsalicylic acid, copper salicylate, and salicylic acid follows the first order kinetics with r (2) 0.979, 0.880, 0.991, and 0.998, respectively. The study provided for the first time the pharmacokinetic data for CAS after oral administration of CAS. The data were found to be useful in understanding the claimed enhanced anti-inflammatory activity of the drug as compared with that of acetylsalicylic acid.


Chaperone activity in the lens.
alpha-crystallin, the major protein of the eye lens, is a molecular chaperone that is able to prevent the precipitation of denatured proteins. This activity is thought to be important for the maintenance of lens transparency. Loss of the activity has been postulated to contribute to the development of cataract. The purpose of this study was to determine how chaperone activity was affected by growth and ageing of the lens. alpha-crystallins were purified from nine concentric tissue layers removed from an adult bovine lens. The ability to inhibit the precipitation of beta(L)-crystallin, following thermal denaturation, was used to assess the chaperone activity of these proteins. The molar ratio of alpha-crystallin/beta(L)-crystallin required to inhibit the precipitation of beta(L)-crystallin by 50 per cent was used as a measure of the affinity of the chaperone for denatured protein. As evidenced by a gradual increase in the ratio, from 0.52 to 1.24, the protective ability of alpha-crystallin decreased from the outside of the lens into the centre. alpha-crystallin from the cortex of the lens provided greater protection against precipitation of proteins than older alpha-crystallin from the nucleus. The reasons for this were investigated. Gel electrophoresis of the proteins from each concentric layer revealed an increase in degraded polypeptides from approximately one per cent in the cortex to more than nine per cent in the centre of the lens. This increase appears to be correlated with the decrease in chaperone ability. Renaturing alpha-crystallin obtained from the nucleus did not increase its chaperone activity, indicating conformational changes were not responsible for the decreased activity. Phosphorylation did not appear to have any significant effect on the chaperone activity. The loss of chaperone activity, accompanying fibre cell compression into the centre of the lens, can be attributed to degradation of the alpha-crystallin polypeptides.


Are perceptions of penalties stable across time? The problem of causal ordering in deterrence applied to road safety.
This study addressed the causal ordering problem in deterrence research by examining the perceptual stability of deterrence variables over time and comparing the results via cross-sectional and longitudinal surveys. This research extends upon scant previous research by including three key classical deterrence variables (i.e., the perceived certainty of apprehension and the perceived severity and swiftness of punishment), as well as Homel's (1988) extra-legal deterrence-related variables of the fear of physical loss, material loss and social sanctions. A longitudinal survey design was utilised over a three month-time period (N = 200, Mage = 20.38 years, 71 males) that examined the stability of the deterrence-related variables for three road rule violations, consisting of 1) exceeding the speed limit by more than 10 km/hr, 2) reading a message on a phone while driving and 3) using the social media platform of Snapchat while driving. Overall, fluctuations were found in all the deterrence-related variables (both legal and extra-legal sanctions), with the largest difference being for the perceptions of the certainty of apprehension. Consequently, it can be suggested that: (a) longitudinal surveys are more reliable when measuring the impact of deterrence perceptions on engagement in offending behaviour and (b) the problem of causal ordering regarding utilising cross-sectional surveys is further illuminated. The results suggest that deterrence is a dynamic process, constantly changing based upon individual experiences, which reinforces the need for continued enforcement efforts (both legal and non-legal), within the road safety arena to maximise rule compliance.


Survey Analysis of the Use, Effectiveness, and Patient-Reported Tolerability of Inhaled Oxygen Compared With Injectable Sumatriptan for the Acute Treatment of Cluster Headache.
In this secondary analysis of the Clusterbusters® Medication Use survey, the use, effectiveness, and tolerability of inhaled oxygen were investigated and compared with injectable sumatriptan. We also sought to understand the predictors of medication response. Inhaled oxygen is a mainstay abortive intervention in cluster headache but is not approved by the Food and Drug Administration (FDA). Unlike injectable sumatriptan, the only FDA-approved pharmacologic intervention for cluster headache, oxygen can be used multiple times a day, which is highly relevant for a condition with numerous daily attacks. In addition to obstacles in obtaining oxygen therapy, optimal oxygen delivery (ie, mask, flow rate) is not uniformly employed in cluster headache. These factors lead to underuse and imprecise therapeutic response rates. A secondary analysis was conducted using deidentified data from the Clusterbusters® Medication Use survey, which was modeled after previously published surveys and available online. Subjects were recruited from headache clinics and cluster headache websites. Most responses were chosen from a list; others were free-texted. The final analysis included responses from 493 adult participants with a validated diagnosis of cluster headache. This analysis of deidentified data from the Clusterbusters® Medication Use survey received institutional approval. The most commonly used delivery system used by subjects was a non-rebreather-type mask. The use of oxygen flow rates >10 L/min was a positive predictor of medication response (OR = 2.36, P = .016). Among those who used flow rates >10 L/min, both inhaled oxygen (81.5%) and injectable sumatriptan (80.5%) were efficacious and did not differ significantly from each other in any specific group examined. At flow rates >10 L/min, positive predictors of oxygen response were male gender (OR = 2.07, P = .031) and cigarette smoking (current or historical; OR = 2.25, P = .017). Among the groups examined, there were no predictors of sumatriptan response. Most comments about side effects and concerns were directed at triptans. Therapeutic response to inhaled oxygen at sufficiently high flow rates (>10 L/min) had comparable efficacy to that of injectable sumatriptan for the acute treatment of cluster headache. Other factors in oxygen delivery (ie, flow rate changes) should be explored for optimization of therapy. The reasons for improved oxygen response in males and those with a cigarette smoking history require further exploration. While both oxygen and sumatriptan can be effective in the management of cluster headache, patient-reported side effects and concerns were more commonly directed at triptan medications. Current restrictions on access to inhaled oxygen, which exist at many levels, limit the therapeutic options available for patients with cluster headache, thereby doing a disservice to this patient population and the providers who deliver their care.


PSL, a nuclear cell-cycle associated antigen is increased during retinoic acid-induced differentiation of HL-60 cells.
PSL(p55) is a nuclear 55kD antigen present in various mammalian cell systems, which has been first identified by use of human autoimmune antibodies (Barque et al. 1983, EMBO J. 2, 743). It has been shown to be associated with interphase chromatine and to be synthesized in during the S phase of the cell cycle. In this work, we have analysed the status of PSL in promyelocytic HL-60 human cells in exponential or stationary growth, or undergoing granulocytic differentiation in presence of Retinoic acid. By use of 2-dimensional electrophoresis, PSL was found to be composed of two acidic proteins designated p55A and p55B. Unexpectedly, estimated 10-20 fold higher amounts of each species were found in cells treated for 5 days with 10(-6)M Retinoic acid, than in asynchronously growing cells or resting cells. Moreover, the p55A protein was phosphorylated during the process. On the basis of these results, PSL appears to be involved in some steps of the granulocytic differentiation process.


Results of the laparoscopic Heller-Dor procedure for pediatric esophageal achalasia.
Esophageal achalasia is not a frequent disorder in children and different treatments have been proposed during past decades. This study reviews the results of the laparoscopic Heller-Dor procedure performed in pediatric patients in two different surgical units. We included the patients aged <14 years with a minimum follow-up of 6 months operated on in the period 1994-2001. A single longitudinal anterior esophageal myotomy (Heller) and a 180 degrees anterior gastropexy (Dor) were laparoscopically performed. The patients were checked to detect intra- or postoperative complications and recurrence. Twenty children were operated on. Mean follow-up was 45 months (range 6-102). Postoperative clinical score was Visick 1 in 15 cases and Visick 2 in five. As complication and recurrence rates are very low we consider modified Heller myotomy and Dor gastropexy through a laparoscopic approach our first choice to treat esophageal achalasia in the pediatric population.


A Pretargeted Imaging Strategy for EGFR-Positive Colorectal Carcinoma via Modulation of Tz-Radioligand Pharmacokinetics.
Previously, we successfully developed a pretargeted imaging strategy (atezolizumab-TCO/[99mTc]HYNIC-PEG11-Tz) for evaluating programmed cell death ligand-1 (PD-L1) expression in xenograft mice. However, the surplus unclicked [99mTc]HYNIC-PEG11-Tz is cleared somewhat sluggishly through the intestines, which is not ideal for colorectal cancer (CRC) imaging. To shift the excretion of the Tz-radioligand to the renal system, we developed a novel Tz-radioligand by adding a polypeptide linker between HYNIC and PEG11. Pretargeted molecular probes [99mTc]HYNIC-polypeptide-PEG11-Tz and cetuximab-TCO were synthesized. [99mTc]HYNIC-polypeptide-PEG11-Tz was evaluated for in vitro stability and in vivo blood pharmacokinetics. In vitro ligation reactivity of [99mTc]HYNIC-polypeptide-PEG11-Tz towards cetuximab-TCO was also tested. Biodistribution assay and imaging of [99mTc]HYNIC-polypeptide-PEG11-Tz were performed to observe its excretion pathway. Pretargeted biodistribution was measured at three different accumulation intervals to determine the optimal pretargeted interval time. Pretargeted (cetuximab-TCO 48 h/[99mTc]HYNIC-PEG11-Tz 6 h) and (cetuximab-TCO 48 h/[99mTc]HYNIC-Polypeptide-PEG11-Tz 6 h) imagings were compared to examine the effect of the excretion pathway on tumor imaging. [99mTc]HYNIC-polypeptide-PEG11-Tz showed favorable in vitro stability and rapid blood clearance in mice. SEC-HPLC revealed almost complete reaction between cetuximab-TCO and [99mTc]HYNIC-polypeptide-PEG11-Tz in vitro, with the 8:1 Tz-to-mAb reaction providing a conversion yield of 87.83 ± 3.27 %. Biodistribution and imaging analyses showed that the Tz-radioligand was cleared through the kidneys. After 24, 48, and 72 h of accumulation in HCT116 tumor, the tumor-to-blood ratio of cetuximab-TCO was 0.83 ± 0.13, 1.40 ± 0.31, and 1.15 ± 0.21, respectively. Both pretargeted (cetuximab-TCO 48 h/[99mTc]HYNIC-PEG11-Tz 6 h) and (cetuximab-TCO 48 h/[99mTc]HYNIC-polypeptide-PEG11-Tz 6 h) clearly delineated HCT116 tumor. Pretargeted imaging strategy using cetuximab-TCO/[99mTc]HYNIC-polypeptide-PEG11-Tz could be used for diagnosing CRC, as the surplus unclicked [99mTc]HYNIC-polypeptide-PEG11-Tz was cleared through the urinary system, leading to low abdominal uptake background. Our novel pretargeted imaging strategy (cetuximab-TCO/[99mTc]HYNIC-polypeptide-PEG11-Tz) was useful for imaging CRC, broadening the application scope of pretargeted imaging strategy. The pretargeted imaging strategy clearly delineated HCT116 tumor, showing that its use could be extended to selection of internalizing antibodies.


A history of diabetes is associated with an adverse outcome among patients admitted to hospital alive after an out-of-hospital cardiac arrest.
Factors of importance for the outcome among patients who are admitted to hospital alive after an out-of-hospital cardiac arrest are not well described in the literature. The importance of a history of diabetes for the outcome among these patients has not been reported in detail previously. This survey aims to describe the outcome among patients who were admitted to hospital after an out-of-hospital cardiac arrest in relation to whether they had a history of diabetes. All patients who were admitted to hospital alive after an out-of-hospital cardiac arrest in the two city hospitals in the Municipality of Göteborg between 1980 and 2002 were included in the survey. In all, 1377 patients fulfilled the inclusion criteria and 187 (14%) of them had a history of diabetes. Patients with diabetes differed from those without diabetes by having a previous history of myocardial infarction, angina pectoris, hypertension and heart failure more frequently. Furthermore, they were older, with a mean age of 70 years versus 66 years for patients without diabetes. Among patients with diabetes, 25% were discharged alive, as compared with 37% of patients without diabetes (p=0.002). When adjusting for differences at baseline, the adjusted odds ratio for diabetic patients being discharged alive (versus no diabetes) was 0.57 (95% confidence interval, 0.39-0.80). Among patients admitted to hospital after an out-of-hospital cardiac arrest, 14% had a history of diabetes. These patients had a lower survival rate compared with those without diabetes, even after correcting for dissimilarities at baseline. It remains to be determined whether an early metabolic intervention in these patients will improve survival.


The role of cultural models in local perceptions of SFM--differences and similarities of interest groups from three boreal regions.
Differences in the way local and regional interest groups perceive Sustainable Forest Management in regions with different forest use histories were studied using Southeastern Finland, the Mauricie in Quebec and Central Labrador in Canada as examples of regions with high, medium and low importance of commercial forestry. We present a conceptual model illustrating the cyclic interaction between the forest, cultural models about forests and forest management. We hypothesized that peoples' perceptions would be influenced by their cultural models about forests and would thus vary amongst regions with different forest use histories and among different interest groups. The weightings of the environmental, economic and social components of sustainability as well as themes important for each of the interest groups were elicited using individual listing of SFM indicators and group work aimed at developing a consensus opinion on a common indicator list. In Southeastern Finland the views of the different groups were polarized along the environment-economy axis, whereas in Central Labrador all groups were environmentally oriented. The social dimension was low overall except among the Metis and the Innu in Labrador. Only environmental groups were similar in all three research regions, the largest differences between regions were found among the forestry professionals in their weightings concerning economy and nature. As the importance of commercial forestry increased, a greater importance of economic issues was expressed whereas the opposite trend was observed for issues regarding nature. Also inter-group differences grew as the importance of commercial forestry increased in the region. Forest management and forest use can be seen as factors strongly influencing peoples' cultural models on forests.


Generation of ligand specificity and modes of oligomerization in β-prism I fold lectins.
β-Prism I fold lectins constitute one of the five widely occurring structural classes of plant lectins. Each single domain subunit is made up of three Greek key motifs arranged in a threefold symmetric fashion. The threefold symmetry is not reflected in the sequence except in the case of the lectin from banana, a monocot, which carries two sugar-binding sites instead of the one in other lectins of known three-dimensional structure, all from dicots. This is believed to be a consequence of the different evolutionary paths followed by the lectin in monocots and dicots. The galactose-specific lectins among them have two chains produced by posttranslational proteolysis and contain three aromatic residues at the binding site. The extended binding sites of galactose- and mannose-specific lectins have been thoroughly characterized. Ligand binding at the sites involves both conformational selection and induced fit. Molecular plasticity of some of the lectins in the family has been characterized. The plasticity appears to be such as to promote variability in quaternary association which could be dimeric, tetrameric, or octameric. Structural and evolutionary reasons for the variability have been explored, and the relation of oligomerization to ligand binding and conformational selection investigated.


Effect of treatment with Copolymer 1 (Cop-1) on the in vivo and in vitro manifestations of experimental allergic encephalomyelitis (EAE).
Injections of Copolymer 1 (Cop-1), a synthetic cathodic polymer, have been reported to prevent and treat successfully acute and recurrent EAE and has been employed in patients with multiple sclerosis (MS). It has been suggested that the therapeutic effect is due to cell-mediated immune (CMI) cross-reactivity between Cop-1 and myelin basic protein (MBP), the antigen that induces EAE. We found that Cop-1 treatment of guinea pigs (GP) sensitized with MBP in adjuvant (20 micrograms/animal): (a) lowers the incidence of clinical disease (8/20 vs 14/15); (b) decreases severity of disease in affected GP; (c) has little effect on pathologic lesions (mean pathology index +/- SEM: 1.2 +/- 0.2 vs 1.6 +/- 0.3; P greater than 0.1). Lymphocytes of MBP-sensitized GP treated with Cop-1 exhibited in vitro proliferative responses to MBP equivalent to lymphocytes of untreated EAE-GP (14,134 +/- 6,532 vs 11,821 +/- 3,874; mean cpm +/- SEM). GP sensitized to MBP or Cop-1 (100 micrograms/animal) showed reactivity to the sensitizing antigen but little in vitro reactivity to the other antigen. There was no correlation between the in vitro lymphocytes response to MBP and Cop-1 in individual GP. Treatment of MBP sensitized GP with calf-thymus histone (CTH) also resulted in a lower incidence of clinical EAE with less severe disease in affected GP. There was little effect on the pathologic index and no evidence of either inhibition of MBP-induced lymphocyte proliferative responses or cross-reactivity between MBP and CTH. Thus, treatment with Cop-1 or CTH inhibits clinical manifestations of acute EAE without suppressing inflammatory cell infiltrates or sensitization to MBP.


Estradiol-mimetic probes. Preparation of 17 alpha-(6-aminohexynyl)estradiol biotin, fluorescein and acridinium conjugates.
3-O-tert-Butyldimethylsilyl-17 alpha-(6-mesyloxyhexynyl)estradiol was converted to the azide in 60-70% yield with NaN3/DMPU, then reduced to the corresponding amine (> 95% yield). Acylation with the N-hydroxysuccinimide esters of biotin, 5-carboxyfluorescein and 10-(3-sulfopropyl)-N-tosyl-N-(3- carboxypropyl)acridinium-9-carboxamide gave the title conjugates. The KDs of the tracers with an estradiol antibody ranged from 97-197 nM.


Compensatory and long-range changes in picosecond-nanosecond main-chain dynamics upon complex formation: 15N relaxation analysis of the free and bound states of the ubiquitin-like domain of human plexin-B1 and the small GTPase Rac1.
The formation of a complex between Rac1 and the cytoplasmic domain of plexin-B1 is one of the first documented cases of a direct interaction between a small guanosine 5'-triphosphatase (GTPase) and a transmembrane receptor. Structural studies have begun to elucidate the role of this interaction for the signal transduction mechanism of plexins. Mapping of the Rac1 GTPase surface that contacts the Rho GTPase binding domain of plexin-B1 by solution NMR spectroscopy confirms the plexin domain as a GTPase effector protein. Regions neighboring the GTPase switch I and II regions are also involved in the interaction and there is considerable interest to examine the changes in protein dynamics that take place upon complex formation. Here we present main-chain nitrogen-15 relaxation measurements for the unbound proteins as well as for the Rho GTPase binding domain and Rac1 proteins in their complexed state. Derived order parameters, S2, show that considerable motions are maintained in the bound state of plexin. In fact, some of the changes in S2 on binding appear compensatory, exhibiting decreased as well as increased dynamics. Fluctuations in Rac1, already a largely rigid protein on the picosecond-nanosecond timescale, are overall diminished, but isomerization dynamics in the switch I and II regions of the GTPase are retained in the complex and appear to be propagated to the bound plexin domain. Remarkably, fluctuations in the GTPase are attenuated at sites, including helices alpha6 (the Rho-specific insert helix), alpha7 and alpha8, that are spatially distant from the interaction region with plexin. This effect of binding on long-range dynamics appears to be communicated by hinge sites and by subtle conformational changes in the protein. Similar to recent studies on other systems, we suggest that dynamical protein features are affected by allosteric mechanisms. Altered protein fluctuations are likely to prime the Rho GTPase-plexin complex for interactions with additional binding partners.


Synchrotron infrared measurements of dense hydrogen to 360 GPa.
Diamond-anvil-cell techniques have been developed to confine and measure hydrogen samples under static conditions to pressures above 300 GPa from 12 to 300 K using synchrotron infrared and optical absorption techniques. A decreasing absorption threshold in the visible spectrum is observed, but the material remains transparent at photon energies down to 0.1 eV at pressures to 360 GPa over a broad temperature range. The persistence of the strong infrared absorption of the vibron characteristic of phase III indicates the stability of the paired state of hydrogen. There is no evidence for the predicted metallic state over these conditions, in contrast to recent reports, but electronic properties consistent with semimetallic behavior are observed.


Association between dietary calcium intake and the risk of cardiovascular disease among Korean adults.
Although dietary calcium intake is associated with a risk of cardiovascular disease (CVD), it has not been studied extensively in Asian populations. We therefore investigated the association between dietary calcium intake and CVD among Korean adults and the effect of obesity on this association. In total, 9186 participants were included in the analysis after excluding 844 with prevalent CVD/cancer or implausible energy intake. Nutrient intake, including dietary calcium, was estimated using a validated semi-quantitative food frequency questionnaire. CVD included myocardial infarction, coronary artery disease, and stroke per the World Health Organization criteria. Cox proportional hazards models were used to calculate multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). In the fully adjusted model, HRs of CVD across increasing quintiles of dietary calcium intake were 1.0 (reference), 0.85 (95% CI: 0.66-1.10), 0.77 (95% CI: 0.58-1.02), 0.59 (95% CI: 0.42-0.83), and 0.72 (95% CI: 0.48-1.08); a significant linear trend was detected (p for trend = 0.04). However, this association varied according to the obesity status. High dietary calcium intake was associated with a reduced CVD risk among nonobese participants (body mass index [BMI] < 25 kg/m2; p for trend = 0.02), whereas this was not significant among obese participants (BMI ≥ 25 kg/m2; p for trend = 0.88). The association between dietary calcium intake and incident CVD may be influenced by obesity status. We provide evidence for developing dietary calcium intake guidelines for Koreans, allowing for the effects of obesity.


Serum concentration of depot neuroleptics in tardive dyskinesia.
Using radioimmunoassay techniques, serum levels of depot neuroleptics, fluphenazine and flupenthixol, were estimated in two groups of chronic schizophrenic patients with, and without, tardive dyskinesia. There were high significant difference in dose-related serum levels of either drug between the groups. The hypothesis that patients with tardive dyskinesia develop the syndrome because they do not metabolise neuroleptics as efficiently as those without the syndrome was not supported by the data.


Global impact of vaccine nationalism during COVID-19 pandemic.
Vaccines are the best chance to control the pandemic-unless leaders succumb to vaccine nationalism. Vaccine nationalism is a frequent recurrence, especially during a brand-new market distribution. The development of safe and effective COVID-19 vaccines in such a short space of time is a testament to modern scientific abilities. It will also test the world's political will and moral commitment to end this pandemic. As desperate as the COVID-19 pandemic, vaccine nationalism is already setting a foundation for itself and is considered socially and economically counterproductive. Vaccine equity is not just a theoretical slogan, and it protects people worldwide from new vaccine-resistant variants. Understanding and anticipating the consequences is vital, and creating a global solution approach to avoid them. This article evaluates the common issues previously faced and the plausible ones during this pandemic. A few recommendations are made to warn and accentuate the reality of this dire matter.


The investigation of MCM-48-type and MCM-41-type mesoporous silica as oral solid dispersion carriers for water insoluble cilostazol.
To explore the suitable application of MCM-41 (Mobil Composition of Matter number forty-one)-type and MCM-48-type mesoporous silica in the oral water insoluble drug delivery system. Cilostazol (CLT) as a model drug was loaded into synthesized MCM-48 (Mobil Composition of Matter number forty-eight) and commercial MCM-41 by three common methods. The obtained MCM-41, MCM-48 and CLT-loaded samples were characterized by means of nitrogen adsorption, thermogravimetric analysis, ultraviolet-visible spectrophotometry, scanning electron microscopy, transmission electron microscopy, differential scanning calorimetry and powder X-ray diffractometer. It was found that solvent evaporation method was preferred according to the drug loading efficiency and the maximum percent cumulative drug dissolution. MCM-48 with 3D cubic pore structure and MCM-41 with 2D long tubular structure are nearly spherical particles in 300-500 nm. Nevertheless, the silica carriers with similar large specific surface areas and concentrating pore size distributions (978.66 m(2)/g, 3.8 nm for MCM-41 and 1108.04 m(2)/g, 3.6 nm for MCM-48) exhibited different adsorption behaviors for CLT. The maximum percent cumulative drug release of the two CLT/silica solid dispersion (CLT-MCM-48 and CLT-MCM-41) was 63.41% and 85.78% within 60 min, respectively; while in the subsequent 12 h release experiment, almost 100% cumulative drug release were both obtained. In the pharmacokinetics aspect, the maximum plasma concentrations of CLT-MCM-48 reached 3.63 mg/L by 0.92 h. The AUC0-∞ values of the CLT-MCM-41 and CLT-MCM-48 were 1.14-fold and 1.73-fold, respectively, compared with the commercial preparation. Our findings suggest that MCM-41-type and MCM-48-type mesoporous silica have great promise as solid dispersion carriers for sustained and immediate release separately.


Intermittent doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) maintains a high level of viral suppression in virologically suppressed people living with HIV.
We aimed to determine whether doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) given 5 or 4 days a week was able to maintain viral suppression in people living with HIV (PLHIV). In this observational, retrospective study, we included all PLHIVs who had received intermittent DOR/3TC/TDF between 10/01/2019 and 01/31/2021, in two French hospitals. Forty-three PLHIVs were included, median (IQR) age: 52 years (48-58), ART duration: 15 years (8-23), duration of virological suppression: 6 years (2-10). Median follow-up was 78 weeks (IQR 62-97). One virological failure (VF) occurred at W38 (HIV-RNA = 61 and 76 copies/mL), in a patient with no viral resistance at baseline or at time of VF, and during the study period five individuals discontinued DOR/3TC/TDF due to adverse events. There were no significant changes during follow-up in the CD4 count, CD4/CD8 ratio, body weight or residual viremia rate. These findings suggest the potential for intermittent DOR/3TC/TDF to maintain virological control.


Fluorescence Correlation Spectroscopy: A Tool to Study Protein Oligomerization and Aggregation In Vitro and In Vivo.
Fluorescence correlation spectroscopy (FCS) is a highly sensitive analytical technique used to measure dynamic molecular parameters, such as diffusion time (from which particle size can be calculated), conformation, and concentration of fluorescent molecules. It has been particularly powerful in characterizing size distributions in molecular associations (e.g., dimer/multimer formation) both in well-behaved thermodynamically equilibrated systems in vitro as well as in more complex environments in vivo. Protein aggregation reactions like amyloid formation, in contrast, are complex, often involving a series of uniquely structured aggregation intermediates appearing at different time scales. Nonetheless, FCS can be used in appropriate cases to characterize the early stages of some aggregation reactions. Here are described step-by-step protocols and experimental procedures for the study of molecular complex formation in aggregation systems as observed in simple buffer systems, cell extracts, and living cells. The methods described are illustrated with examples from studies of the self-assembly of huntingtin fragments, but in principle can be adapted for any aggregating system.


Enhance production of diterpenoids in yeast by overexpression of the fused enzyme of ERG20 and its mutant mERG20.
Yeast has been widely used for large-scale production of terpenoids. In yeast, modifications of terpenoid biosynthetic pathways have been intensively studied. tHMG1 (encoding the catalytic domain of 3-hydroxy-3-methylglutaryl coenzyme A reductase of yeast) and UPC2-1 (the G888D mutant of UPC2 encoding a transcription factor) were integrated into yeast chromosome, and ERG9 (the squalene synthase gene of yeast) was knocked down to yield the chassis strain DH02. A F96C mutation in ERG20 (farnesyl diphosphate synthase of yeast) was conducted to obtain mERG20 which can function as a geranylgeranyl diphosphate synthase (GGPS). Then, three fused genes, including BTS1 (the yeast innate GGPS)-ERG20, ERG20-mERG20 and mERG20-ERG20, were constructed, and expressed either by the pESC-based plasmids in DH02, or by being integrated into DH02 chromosome. The highest geranylgeraniol (GGOH) content was observed in the extracts of DH12 integrated with ERG20-mERG20, corresponding to 3.2 and 2.3 folds of those of the strains integrated with BTS1 and mERG20, respectively. Finally, three genes encoding nor-copalyl diphosphate synthase (nor-CPS), ent-CPS and syn-CPS were integrated into the chromosome of DH12, respectively, to construct yeasts for producing corresponding copalyl diphosphates (CPPs). Thus, a yeast-based platform was built for characterizing all types of diterpene synthases using GGPP or various CPPs as their substrates.


Leu-enkephalin, substance P, and somatostatin immunohistochemistry combined with the retrograde transport of horseradish peroxidase in sympathetic preganglionic neurons.
Preganglionic neurons in the lower lumbar spinal cord were labeled with horseradish peroxidase applied to the cut ends of the intermesenteric trunk in golden hamsters. A black granular reaction product was obtained in HRP-labeled cells by soaking spinal cord tissue in a cobalt chloride solution prior to treatment with diaminobenzidine (DAB) and hydrogen peroxide. Spinal cord sections containing labeled preganglionic neurons were processed with the immunoperoxidase (PAP) technique. Immunoreactive processes appeared as rust-brown beads. Concentrations of beaded processes exhibiting enkephalin-like, substance P-like (SPI) and somatostatin-like (SOMI) immunoreactivity were present around HRP-labeled preganglionic neurons in the intermediolateral cell column and in the dorsal commissural nucleus. Immunoreactivity was also present in the superficial dorsal horn, the dorsolateral funiculus and around the central canal. A prominent fiber system exhibiting SPI and SOMI extended from the ventral white matter to the ventral horn.


The safety and efficacy of electroconvulsive therapy in patients over age 75.
To examine the safety and efficacy of electroconvulsive therapy (ECT) in patients over the age of 75 years. Retrospective study of all patients over 75 years treated with ECT in three hospitals between 1995 and 1997. Ninety-three ECT courses were administered during the study period. Ten patients (10.8%) suffered complications following ECT. The most common adverse events were prolonged confusion and hypomania, all of which resolved within 2 weeks of the cessation of treatment. Eighty-five per cent of patients made a marked or moderate response to treatment. ECT is a relatively safe and effective procedure in patients over age 75.


Impacts of anthropogenic disturbances at deep-sea hydrothermal vent ecosystems: a review.
Deep-sea hydrothermal-vent ecosystems have stimulated decades of scientific research and hold promise of mineral and genetic resources that also serve societal needs. Some endemic taxa thrive only in vent environments, and vent-associated organisms are adapted to a variety of natural disturbances, from tidal variations to earthquakes and volcanic eruptions. In this paper, physicochemical and biological impacts of a range of human activities at vents are considered. Mining is currently the only anthropogenic activity projected to have a major impact on vent ecosystems, albeit at a local scale, based on our current understanding of ecological responses to disturbance. Natural recovery from a single mining event depends on immigration and larval recruitment and colonization; understanding processes and dynamics influencing life-history stages may be a key to effective minimization and mitigation of mining impacts. Cumulative impacts on benthic communities of several mining projects in a single region, without proper management, include possible species extinctions and shifts in community structure and function.