Mosquito (Diptera: Culicidae) and arbovirus activity on the south coast of New South Wales, Australia, in 1985-1988.
An investigation of the seasonal activity of adult mosquitoes and arboviruses in two native forests revealed a mosquito fauna comprising 33 species for the Mogo State Forest-Batemans Bay locality and 34 species for the Termeil State Forest. The mosquito Aedes vigilax was the most abundant species in salt marshes at Mogo State Forest-Batemans Bay, whereas the freshwater species Anopheles annulipes s.l. and Coquillettidia linealis were most abundant at Termeil State Forest. Major faunal differences between the two environments reflected the extensive saline marsh and mudflat estuarine habitats at Batemans Bay and the predominantly freshwater stream, marsh, and lake habitats of Termeil State Forest. A total of 218 virus isolates was recovered from the mosquitoes, comprising Ross River virus (86 isolates), Gan Gan virus (123 isolates), Termeil virus (2 isolates), and 7 unidentified viruses. The period of greatest arbovirus activity was from midsummer through midautumn and coincided with the overall peak activity of the most common mosquito species. Ae. vigilax yielded most isolates of Ross River and Gan Gan viruses and appeared to be the vector of greatest public health concern.


Characterization of a muscarinic receptor controlling Cl- secretion in hen trachea.
We have attempted to characterize a muscarinic receptor subtype involved in Cl- secretion in isolated epithelium of hen trachea, taking advantage of drugs developed in the last 15 yr. Hen trachea can be stimulated to secrete Cl- equal to approximately 80-90 microA/cm2 by application of acetylcholine (ACh) to the serosal side. The process has an apparent dissociation constant (Kd) for ACh of 740 nM. The Cl- secretion is completely inhibited by 20 microM bumetanide at the serosal side. Of five selective antagonists for muscarinic receptors, pirenzepine, hexahydrosiladifenidol, dicyclomine, 11-([2-[(diethylamino)-methyl]-1-piperidinyl]acetyl)-5,11- dihydro-6H-pyrido(2,3-b)(1,4)benzodiazepine-6-one, and 4 diphenyl acetoxy-N-methylpiperidine methobromide, only the latter had a high affinity for the functional receptor with an apparent Kd of 3 nM. The receptor may be classified as an M4-muscarinic receptor subtype and probably belongs to a group of muscarinic receptors on exocrine glands and mucosal cells involved in ion transport. All the functional responses caused by muscarinic agonists and antagonists tested exhibited exponents (apparent Hill coefficients) in the range from 1.3 to 2.4, indicating a gain in the stimulus secretion coupling mechanism, an aspect of muscarinic receptor function that is not revealed in radioligand binding studies.


Malignant nature of cardiac liposarcoma revealed by fluorine-18 fluorodeoxyglucose positron emission tomographic imaging.
Primary cardiac liposarcoma is very rare and usually asymptomatic. It is often diagnosed at an advanced or incurable stage without being presented in surgical operation. We report a man in his early sixties with primary cardiac liposarcoma originating from the ventricular septum. The malignant nature of the tumor was suspected by positron emission tomography using fluorine-18 fluorodeoxyglucose as the tracer. The final diagnosis was made histopathologically following surgery. Treatment with carbon ion radiotherapy was applied, but failed to induce tumor regression.


Cytosolic protein quality control machinery: Interactions of Hsp70 with a network of co-chaperones and substrates.
The chaperone heat shock protein 70 (Hsp70) and its network of co-chaperones serve as a central hub of cellular protein quality control mechanisms. Domain organization in Hsp70 dictates ATPase activity, ATP dependent allosteric regulation, client/substrate binding and release, and interactions with co-chaperones. The protein quality control activities of Hsp70 are classified as foldase, holdase, and disaggregase activities. Co-chaperones directly assisting protein refolding included J domain proteins and nucleotide exchange factors. However, co-chaperones can also be grouped and explored based on which domain of Hsp70 they interact. Here we discuss how the network of cytosolic co-chaperones for Hsp70 contributes to the functions of Hsp70 while closely looking at their structural features. Comparison of domain organization and the structures of co-chaperones enables greater understanding of the interactions, mechanisms of action, and roles played in protein quality control.


Thyroid Hormone Induces PGC-1α during Dendritic Outgrowth in Mouse Cerebellar Purkinje Cells.
Thyroid hormone 3,3',5-Triiodo-L-thyronine (T3) is essential for proper brain development. Perinatal loss of T3 causes severe growth defects in neurons and glia, including strong inhibition of dendrite formation in Purkinje cells in the cerebellar cortex. Here we show that T3 promotes dendritic outgrowth of Purkinje cells through induction of peroxisome proliferator-activated receptor gamma (PPARγ) co-activator 1α (PGC-1α), a master regulator of mitochondrial biogenesis. PGC-1α expression in Purkinje cells is upregulated during dendritic outgrowth in normal mice, while it is significantly retarded in hypothyroid mice or in cultures depleted of T3. In cultured Purkinje cells, PGC-1α knockdown or molecular perturbation of PGC-1α signaling inhibits enhanced dendritic outgrowth and mitochondrial generation and activation caused by T3 treatment. In contrast, PGC-1α overexpression promotes dendrite extension even in the absence of T3. PGC-1α knockdown also downregulates dendrite formation in Purkinje cells in vivo. Our findings suggest that the growth-promoting activity of T3 is partly mediated by PGC-1α signaling in developing Purkinje cells.


Acidosis-induced zinc-dependent death of cultured cerebellar granule neurons.
Severe acidosis caused death of cultured cerebellar granule neurons (CGNs). Acidosis was accompanied by a progressive increase of the intracellular zinc ions ([Zn(2+)](i)) and decrease of [Ca(2+)](i). Zn(2+) chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), prevented the increase of [Zn(2+)](i) and acidosis-induced neuronal death. However, neuronal death was insensitive to blockade of ASIC1 channels with amiloride, as CGNs display considerably lower expression of ASIC1a than other neurons. The antioxidant trolox and menadione significantly protected neurons from acidotic death. Earlier, we demonstrated that menadione rescues neurons from the deleterious effect of inhibition of mitochondrial complex I (Isaev et al. Neuroreport 15:2227-2231, 2004). We speculate that excessive Zn(2+)-dependent production of reactive oxygen species by mitochondrial complex I may be a general motive for the induction of cell death in CGNs under acidotic conditions.


[Vaginal repair operation for anterior pelvic organ prolapse in elderly women].
To identify the safety and efficacy of individualized vaginal surgery for anterior pelvic organ prolapse (POP) in elderly women so as to provide a clinical basis for studies on improving life quality by treatment in elderly women. The individuation group consisted of 90 patients with a diagnosis of anterior POP. All over 60 years old, they underwent individualized vaginal surgery. The safety and efficacy, POP quantitative examination POP-Q change, cure and recurrence rate and life quality scores on incontinence and pelvic floor distress and impact were assessed. The control group (n = 60) was composed of patients (> 60 yr old) with a diagnosis of anterior POP were performed with Kelly-Kennedy operation. Their safety, efficacy, cure and recurrence rates were compared. Individualized vaginal surgery in elderly women was both safe and effective. The post-therapeutic recovery time was shorter (P < 0.05), the cure rate higher and the recurrence rate lower (P < 0.05) than that of control group. The life quality after individualized surgery improved (P < 0.01). The individualized vaginal surgery is safe and effective for a correction of anterior POP in elderly women. The life quality improves after operation.


Automated analysis of unstructured clinical assessments improves emergency department triage performance: A retrospective deep learning analysis.
Efficient and accurate emergency department (ED) triage is critical to prioritize the sickest patients and manage department flow. We explored the use of electronic health record data and advanced predictive analytics to improve triage performance. Using a data set of over 5 million ED encounters of patients 18 years and older across 21 EDs from 2016 to 2020, we derived triage models using deep learning to predict 2 outcomes: hospitalization (primary outcome) and fast-track eligibility (exploratory outcome), defined as ED discharge with <2 resource types used (eg, laboratory or imaging studies) and no critical events (eg, resuscitative medications use or intensive care unit [ICU] admission). We report area under the receiver operator characteristic curve (AUC) and 95% confidence intervals (CI) for models using (1) triage variables alone (demographics and vital signs), (2) triage nurse clinical assessment alone (unstructured notes), and (3) triage variables plus clinical assessment for each prediction target. We found 12.7% of patients were hospitalized (n = 673,659) and 37.0% were fast-track eligible (n = 1,966,615). The AUC was lowest for models using triage variables alone: AUC 0.77 (95% CI 0.77-0.78) and 0.70 (95% CI 0.70-0.71) for hospitalization and fast-track eligibility, respectively, and highest for models incorporating clinical assessment with triage variables for both hospitalization and fast-track eligibility: AUC 0.87 (95% CI 0.87-0.87) for both prediction targets. Our findings highlight the potential to use advanced predictive analytics to accurately predict key ED triage outcomes. Predictive accuracy was optimized when clinical assessments were added to models using simple structured variables alone.


The subgenus Ortmannicus (Decapoda: Cambaridae) in Texas, with descriptions of new species.
Three crayfishes of the genus Procambarus, subgenus Ortmannicus, are described from Texas, including (1) Procambarus (Ortmannicus) parvus n. sp. from the Victoria-El Campo region of the Coastal Plain; (2) P. (O.) albaughi n. sp. from the Coastal Plain in the vicinity of Houston; and (3) P. (O.) fayettei n. sp. from the eastern versant of the Colorado River drainage south of Giddings. The three new species, P. (O.) acutus, P. (O.) texanus, and P. (O.) zonangulus form a closely allied group. They are distinguished from each other primarily by characters of the first pleopod. The subspecies P. (O.) acutus acutus and P. (O.) a. cuevachicae are elevated to full species. Species accounts are provided for all Texas subgenus members and may include diagnoses, color notes, size data, locality data, life history notes, listings of associates, and information on variation and relationships. A key to the species of Ortmannicus in Texas is also presented.


Bioavailability of griseofulvin from plain tablets in Göttingen minipigs and the correlation with bioavailability in humans.
Intravenous administration of 125 mg of griseofulvin to G ottingen minipigs showed biexponential elimination of the drug from plasma, in which the half lives of the initial and terminal phases were 0.2-0.6 h and 4.3-6.6 h, respectively. The bioavailability of four griseofulvin tablets used in a human bioavailability study was investigated in the pigs and compared with the human results. The differences of Cmax and AUC between the standard product and the others were smaller in the pig than in humans, however, the correlations of Cmax and AUC between humans and minipigs were high for the four products. The differences of Tmax among the products were small, and the Tmax of the standard product was large in the pigs compared with that in humans. In addition, delayed onset of drug absorption was observed in some of the pigs. The findings suggest slow gastric emptying of the drug in the pigs. The statistically small powers for the in vivo parameters observed in the pig, seem to indicate variable absorption of the drug in the animal.


Apolipoprotein C-III itself stimulates the Syk/cPLA2-induced inflammasome activation of macrophage to boost anti-tumor activity of CD8+ T cell.
Increased prevalence of cancer in obese individuals is involved with dyslipidemia- induced chronic inflammation and immune suppression. Although apolipoprotein C-III (ApoC3)-transgenic mice (ApoC3TG mice) or poloxamer 407 (P407)-treated mice had hyperlipidemia, CD8+ T cells with upregulated antitumor activities were observed in ApoC3TG mice, and decreased CD8+ T cell activities were observed in P407-treated mice. Increased ApoC3 expression in hepatocellular carcinoma was associated with increased infiltration of CD8+ T cells and predicted survival. Recombinant ApoC3 had no direct effects on CD8+ T cells. The upregulation of CD8+ T cells in ApoC3TG mice was due to cross-talk with context cells, as indicated by metabolic changes and RNA sequencing results. In contrast to dendritic cells, the macrophages of ApoC3TG mice (macrophagesTG) displayed an activated phenotype and increased IL-1β, TNF-α, and IL-6 production. Coculture with macrophagesTG increased CD8+ T cell function, and the adoptive transfer of macrophagesTG suppressed tumor progression in vivo. Furthermore, spleen tyrosine kinase (Syk) activation induced by TLR2/TLR4 cross-linking after ApoC3 ligation promoted cellular phospholipase A2 (cPLA2) activation, which in turn activated NADPH oxidase 2 (NOX2) to promote an alternative mode of inflammasome activation. Meanwhile, mitochondrial ROS produced by increased oxidative phosphorylation of free fatty acids facilitated the classical inflammasome activation, which exerted an auxiliary effect on inflammasome activation of macrophagesTG. Collectively, the increased antitumor activity of CD8+ T cells was mediated by the ApoC3-stimulated inflammasome activation of macrophages, and the mimetic ApoC3 peptides that can bind TLR2/4 could be a future strategy to target liver cancer.


Is naturalistic driving research possible with highly instrumented cars? Lessons learnt in three research centres.
This paper provides an overview of the experiences using Highly Instrumented Cars (HICs) in three research Centres across Europe; Spain, the UK and Greece. The data collection capability of each car is described and an overview presented relating to the relationship between the level of instrumentation and the research possible. A discussion then follows which considers the advantages and disadvantages of using HICs for ND research. This includes the obtrusive nature of the data collection equipment, the cost of equipping the vehicles with sophisticated Data Acquisition Systems (DAS) and the challenges for data storage and analysis particularly with respect to video data. It is concluded that the use of HICs substantially increases the depth of knowledge relating to the driver's behaviour and their interaction with the vehicle and surroundings. With careful study design and integration into larger studies with Low(ly) instrumented Cars (LICs), HICs can contribute significantly and in a relatively naturalistic manner to the driver behaviour research.


Childhood trauma, sexually transmitted diseases and the perceived risk of contracting HIV in a drug using population.
This cross-sectional study explored the association among childhood trauma, sexually transmitted diseases histories, and perceived risk of contracting AIDS in 358 women and 338 male drug users in San Antonio, Texas. Women addicts were less educated, more likely to be in a common-law relationship, living with someone of the opposite sex or separated, and had lower incomes in comparison to men addicts. Significant findings were that women with increasing severity of abuse (emotional, physical, and sexual) histories as measured by the Childhood Trauma Questionnaire had increasing numbers of sexually transmitted diseases and perceptions of contracting HIV. These findings have implications for future directions in HIV and sexually transmitted disease intervention programs.


MR staging in carcinoma of the endometrium and carcinoma of the cervix.
This study aimed to evaluate MR as an imaging modality for the assessment of myometrial and cervical invasion in endometrial carcinoma and for the assessment of parametrial and lymph node involvement in cervical carcinoma. Twenty-eight patients with a preoperative histological diagnosis of endometrial carcinoma/cervical carcinoma were included in the study. The findings were compared with the surgical staging and the histopathological report of the hysterectomy specimen. Accuracy in detecting myometrial and cervical involvement in patients with endometrial carcinoma was 78% for both. Accuracy in detecting parametrial and lymph node involvement in patients with cervical carcinoma was 71% and 86% respectively. MR is a reliable method for preoperative assessment of endometrial and cervical carcinoma. It helps decide operability, the type of operation and aids in the selection of patients who need to be considered for specialist referral to a gynaecologist oncologist.


Antibacterial prescriptions for acute gastrointestinal infections: uncovering the iceberg.
A prospective survey was conducted in patients admitted to 11 randomly selected general practices and eight hospitals located in six provinces of Poland. For each patient meeting the international acute gastrointestinal infection (AGI) case definition criteria, information was collected on healthcare resources used. Antibacterial drug consumption was assessed using defined daily doses (DDD) and extrapolated to the national level using results from a parallel study of AGI incidence in the community. Additionally, a logistic multivariable model was fitted assessing determinants of antibacterial drug administration. Valid questionnaires were collected from 385 general practitioner (GP) consultations and 504 hospital admissions. Antibacterials for systemic use were prescribed during 60 (16%) GP consultations and 179 (36%) hospital admissions. The estimated societal AGI-related consumption of antibacterials amounted to 5·48 million DDD (95% uncertainty interval 1·56-14·12 million DDD). Antibacterial prescription was associated with work in large practices [adjusted odds ratio (aOR) 3·16] and hospital wards (aOR 2·87), compared to small general practices, referral for microbiological testing (aOR 2·88), presence of fever (aOR 2·50), presence of mucus or blood in stool (aOR 1·94), age >65 years vs. <5 years (aOR 1·88), and rural vs. urban residence (aOR 1·53). Despite the fact that antibacterials were prescribed to a minority of consulted AGI patients, their consumption in society was not negligible due to the high prevalence of AGI symptoms. Prescription of antibacterial drugs should be restricted to cases with specific indications, preferably following microbiological investigation of AGI aetiology. To achieve this, clear national recommendations should be widely disseminated to physicians, and included in medical training curricula.


Does Fracture Severity of Intertrochanteric Fracture in Elderly Caused by Low-Energy Trauma Affected by Gluteus Muscle Volume?
The aim of this study was to determine whether there is a correlation between the type and stability of intertrochanteric fractures caused by low-energy trauma and gluteus muscle volume. A total of 205 elderly (>65 years) patients with intertrochanteric fractures caused by low-energy trauma treated from January 2018 to December 2020 were included in this study. The mean age of patients was 81.24 years (range, 65-100 years). Fractures were classified according to the Jensen modification of the Evans classification. The cross-sectional area of the contralateral gluteus muscle (minimus, medius, and maximus) was measured in preoperative axial computed tomography slices. An analysis and comparison of age, body mass index (BMI), weight, height, and the gluteus muscle area in each fracture type group was performed. In the uni-variable analysis, statistically significant taller height was observed in patients in the stable intertrochanteric fracture (modified Evans 1 and 2) group compared with those in the unstable intertrochanteric fracture (modified Evans 3, 4, and 5) group (P<0.05). In addition, significantly higher BMI-adjusted gluteus muscle area (gluteus muscle area/BMI) was observed for the stable intertrochanteric fracture group compared with the unstable intertrochanteric fracture group except for the BMI-adjusted gluteus minimus area (P=0.112). In multivariable analysis, only the BMI-adjusted gluteus maximus (P=0.042) and total gluteus areas (P=0.035) were significantly higher in the stable group. Gluteal muscularity around the hip, especially the gluteus maximus, had a significant effect on the stability of intertrochanteric fractures.


[Advancement of patch-clamp technique and its application in drug high-throughput screening].
The patch-clamp technique, a dominant technique in cellular electrophysiology, is always being regarded as the gold standard for ion channel research. Application of the patch-clamp technique can demonstrate the existences of ion channels and provide valuable information for ion channels, including their electrophysiological properties, molecular structures and the mechanism of drug action. Genomics and proteomics research has showed that the development of drugs for ion channel target would be very promising in future. In recent years, numerous improvements have been achieved, which will facilitate the application of patch clamp technique in drug high-throughput screening. These techniques will break through the bottleneck in the development of drugs aiming at ion channels. New advancements in patch-clamp technique and application in drug high-throughput screening are reviewed in the paper.


Quasi-variational coupled-cluster theory: Performance of perturbative treatments of connected triple excitations.
Quasi-variational coupled-cluster methods are applied to a selection of diatomic molecules. The potential energy curves, spectroscopic constants, and size consistency errors are calculated and compared to those obtained from both single- and multi-reference methods. The effects of connected triple excitations are introduced with either the standard perturbative (T) formulation, or in the renormalised form, and its symmetrised approximation. It is found that the renormalised ansatz is significantly superior to the standard formulation when describing bond breaking and that in most circumstances, the computationally simpler symmetrisation gives nearly identical results.


Late onset adrenoleukodystrophy: A review related clinical case report.
Our objective is to review the initial presentation, evolution, progression, final stage, and images in the follow up of an adult patient who presented an uncommon peroxisomal disease (1/20,000 males) that occurred by ABCD1 gene mutation in the Xq28 chromosome; to bring forward the imaging features (which nowadays is the most useful and accessible diagnostic tool) and clinical presentation of adrenoleukodystrophy in adulthood; to propose a differential diagnosis in aid of a prompt recognition of the disease hereafter from a neurologist approach. In relation of a clinical case we reviewed the literature to correlate the principal findings and evolution of the disease. This thrilling but at the same time unfortunate disease is not only a diagnostic problem is also a therapeutic quest besides all the related familial, labor, and social related problems. The very-long chain fatty acids (VLCFA) accumulation leads to a not completely understood mechanisms that precipitate the specific malfunction of the nervous system and adrenal gland. The initial corticospinal bilateral involvement provokes a spastic paraparesis but with the affection of others pathways multiple manifestations appears, with dementia and finally loss of the most of cortical functions secondary to the white matter affection. Since the hematopoietic stem cell transplantation can be treated with variable results, other treatments, as the Lorenzo's oil, have not been consistent with a substantial improvement of the affected individual. The genetic advice and support to the patient and the family are essentials as well as the screening in individuals at risk before the onset of the disease.


LAG3 and PD1 Regulate CD8+ T Cell in Diffuse Large B-cell Lymphoma Patients.
Diffuse large B-cell lymphoma (DLBCL) is a clinically and genetically heterogeneous lymphoid malignancy. The unsatisfactory outcome for refractory patients has prompted efforts to explore new therapeutic approaches for DLBCL. However, the mechanisms involved in treatment associated with immune checkpoints remain unclear. This study is aimed at investigating the potential roles of programmed cell death protein 1 (PD1) and lymphocyte activation gene 3 (LAG3) in CD8+ T cells for treatment in DLBCL. Utilizing flow cytometry, we examined the content of T cells, the levels of cytokines, and the expression of PD1 and LAG3 in patients with DLBCL as well as in healthy controls. Levels of cytokines in CD8+ T cells from DLBCL patients before and after treatment were compared by blocking of PD1 and LAG3 in magnetic bead-sorted CD8+ T cells. We found that the proportion of CD4+ T cells and CD8+ T cells was increased in DLBCL patients after treatment. The levels of cytokines trended toward those of healthy controls in treatment. PD1 (+), LAG3 (+), or PD1 (+) LAG3 (+) were all expressed in lower amounts in CD4+ T cells and CD8+ T cells after treatment than in untreated DLBCL patients. In addition, blockade of PD1 and LAG3 in sorted CD8+ T cells markedly inhibited cytokine production in response to treatment. PD1 and LAG3 in CD8+ T cells may be important targets of therapy and play therapeutic role in patients with DLBCL.


Oil separation from oil in water emulsion by coalescence filtration using kapok fibre.
In this study, the stable emulsion of engine oil in water of concentration 10% was prepared using a non-ionic surfactant. Kapok fibres were used as filter beds to separate oil from the oil-water emulsion. The surface morphology of fibres was investigated using Scanning Electron Microscope (SEM) analysis and chemical bond analysis of fibres done using Fourier transform infrared (FTIR). Kapok filter beds were prepared with three different bed heights 10, 20 and 30 mm each with four different porosities 0.90, 0.92, 0.95 and 0.98 for preparing the coalescence filter. The oil-water emulsion (influent) was pumped into the filtration column and the coalesced oil droplets, water, as well as un-coalesced oil droplets, especially the finer oil droplets, were collected as effluent. Oil separation efficiency was evaluated in terms of change in droplet size (D50) and oil concentration from influent to effluent. With increasing porosity and bed height, apart from porosity of 0.92, the separation efficiency increases. Increasing the bed heights at lower porosities does not improve the efficiency of the process. A combination of 0.98 porosity and a bed height of 30 mm provided the highest filtration performance in terms of oil separation efficiency and D50 droplet ratio. At 0.98 porosity, increasing the bed height from 10 mm to 30 mm resulted in a D50 droplet ratio of 0.25-0.14, representing a significant decrease in droplet size in the effluent and therefore an increase in oil separation efficiency from 91.3% to 99.63%.


P-glycoprotein, multidrug resistance and tumor progression.
P-glycoprotein (Pgp) is a plasma membrane protein that was first characterised in multidrug resistant cell lines. The occurrence of Pgp in clinical tumors has been widely studied. Recent investigations have begun to focus on the relationship between Pgp detection in tumors and treatment outcome. In several types of tumors, detection of Pgp correlates with poor response to chemotherapy and shorter survival. P-glycoprotein over-expression often occurs upon relapse from chemotherapy but may also occur at the time of diagnosis. Studies of experimental rat liver carcinogenesis have shown that Pgp expression increases in late stages of carcinogenesis, suggesting that Pgp may be involved in tumor progression. While some of the Pgp isoforms are known to transport hydrophobic chemotherapeutic drugs out of tumor cells, the biologic effects of Pgp overexpression in tumor cells are not fully understood, because the spectrum of substrates for Pgp-mediated transport has not been determined. In the rat liver carcinoma model, strong expression of Pgp is associated with a highly vascular stroma, suggesting that Pgp in tumor cells may affect the connective tissue stroma. The regulation of Pgp appears to be complex, and little is known about how it is up-regulated during carcinogenesis. Further studies of the role of Pgp in malignancy may contribute to our understanding of molecular mechanisms which underlie tumor progression.


Synthesis and characterization of cationic tungsten(V) methylidynes.
Cationic tungsten(V) methylidynes [L4W(X)[triple bond]CH]+[B(C6F5)4]- [L = PMe3, 0.5dmpe (dmpe = Me2PCH2CH2PMe2), X = Cl, OSO2CF3] have been prepared in high yield by a one-electron oxidation of the neutral tungsten(IV) methylidynes L4W(X)[triple bond]CH with [Ph3C]+[B(C6F5)4]-. The ease and reversibility of the one-electron oxidation of L4W(X)[triple bond]CH were demonstrated by cyclic voltammetry in tetrahydrofuran (E1/2 is approximately -0.68 to -0.91 V vs Fc). The paramagnetic d1 (S = 1/2) complexes were characterized in solution by electron spin resonance (g = 2.023-2.048, quintets due to coupling to 31P) and NMR spectroscopy and Evans magnetic susceptibility measurements (mu = 2.0-2.1 muB). Single-crystal X-ray diffraction showed that the cationic methylidynes are structurally similar to the neutral precursor methylidynes. In addition, the neutral (PMe3)4W(Cl)[triple bond]CH was deprotonated with a strong base at the trimethylphosphine ligand to afford (PMe3)3(Me2PCH2)W[triple bond]CH, a tungsten(IV) methylidyne complex that features a (dimethylphosphino)methyl ligand.


Pre-eclampsia and Cardiovascular Disease: From Pregnancy to Postpartum.
Hypertensive disorders of pregnancy (HDP) complicate approximately 10% of pregnancies. In addition to multiorgan manifestations related to endothelial dysfunction, HDP confers an increased risk of cardiovascular disease during delivery hospitalisation, such as heart failure, pulmonary oedema, acute MI and cerebrovascular events. However, the cardiovascular legacy of HDP extends beyond birth since these women are significantly more likely to develop cardiovascular risk factors in the immediate postnatal period and major cardiovascular disease in the long term. The main mediator of cardiovascular disease in women with a history of HDP is chronic hypertension, followed by obesity, hypercholesterolaemia and diabetes. Therefore, optimising blood pressure levels from the immediate postpartum period until the first months postnatally could have beneficial effects on the development of hypertension and improve long-term cardiovascular health. Peripartum screening based on maternal demographic, and clinical and echocardiographic data could help clinicians identify women with HDP at highest risk of developing postpartum hypertension who would benefit from targeted primary cardiovascular prevention.


Nuclear factor Y is required for basal activation and chromatin accessibility of fibroblast growth factor receptor 2 promoter in osteoblast-like cells.
Fibroblast growth factor receptor 2 (FGFR2) plays an important regulatory role in bone development. However, the regulatory mechanisms controlling FGFR2 expression remain poorly understood. Here we have identified a role for the nuclear factor Y (NF-Y) in constitutive activation of FGFR2. A unique DNase I hypersensitive site was detected in the region encompassing nucleotides -270 to +230 after scanning a large range covering 33.3 kilobases around the transcription start site of FGFR2. Using a PCR-based chromatin accessibility assay, an open chromatin conformation was detected around the proximal 5' fragment of FGFR2 gene. Deletion constructs of the 5'-flanking region of FGFR2 were fused to a luciferase reporter gene. After transient transfection in C3H10T1/2, ME3T3-E1, and C2C12 as well as primary osteoblasts, a minimal region -86/+139 that is highly homologous to the human sequence and bears a CCAAT box was identified as the core promoter. Electrophoretic mobility shift assay supershift and chromatin immunoprecipitation demonstrated that the CCAAT box was the binding site for NF-Y. Deletion of NF-Y consensus sequence resulted in the total loss of NF-Y promoter activity. Overexpression of NF-Y protein and transfection of NF-Y small interfering RNAs in the cells substantially changed the promoter activity. Moreover, NF-Y small interfering RNAs greatly inhibited the endogenous FGFR2 transcription level and the chromatin accessibility and H3 acetylation across the promoter. Taken together, our results demonstrate that interaction of NF-Y at the CCAAT box is pivotal to FGFR2 gene transcription partly through the construction of a local open chromatin configuration across the promoter.


Evidence-Based Planning Target Volume Margin Reduction for Modern Lung Stereotactic Ablative Radiation Therapy Using Deformable Registration.
Standard planning target volume (PTV) margins for lung stereotactic ablative radiation therapy (SABR) are 5 mm. High-dose-rate volumetric modulated arc therapy delivered using flattening filter-free (FFF) beams with modern immobilization systems may allow for PTV margin reduction. This study assesses whether PTV margins can be reduced from 5 to 3 mm. Target intrafractional motions derived from pretreatment and posttreatment cone beam computed tomography (CBCT) scans for 33 patients receiving lung SABR treated with 10XFFF energy and 5-mm PTV margins from 2016 to 2019 were used to calculate the required PTV margin. Deformable registration of the planning CT scan and internal gross tumor volume (IGTV) contour to posttreatment CBCT scans for 36 consecutive patients with 4 fraction schedules was completed to capture volume changes and intrafractional movement. Plans were replanned with 3-mm margins and recalculated on each deformed CT scan to assess deformed IGTV (d-IGTV) coverage and organ-at-risk doses. Margin analysis showed PTV margins may be reduced to 3 mm. The mean d-IGTV coverage (percentage of the d-IGTV receiving ≥100% of the prescription dose [V100%] and the minimum dose covering 99.9% of the d-IGTV volume [D99.9%]) over 4 fractions for each patient was >95% with both margins. With 5-mm PTV margins, all 144 fractions had a d-IGTV V100% of >95% and a D99.9% >95%. With 3-mm PTV margins, the d-IGTV V100% was >95% in 99.3% of fractions (143 of 144) and the D99.9% was >95% in 98.6% of fractions (142 of 144). With 3-mm PTV margins, significant reductions in body V50%, body V80%, the volume of the lung receiving ≥20 Gy, and the mean lung dose and chest wall dose to 0.035 cm3 and 30 cm3 were observed (all P < .001). Using theoretical models, the normal tissue complication probability for radiation pneumonitis decreased by a mean of 0.8% (range, 0.1%-2.7%), and the mean 2-year tumor control probability was 96.1% and 95.2% with 5-mm and 3-mm PTV margins, respectively. With modern treatment and immobilization techniques in lung SABR, 3-mm PTV margins maintain acceptable IGTV coverage, modestly reduce toxicity to organs at risk, and maintain a calculated 2-year local control rate of >95%.


[Localization of antigenic sites for monoclonal antibodies against alpha-subunit of Go-protein from the bovine brain].
The properties of monoclonal antibodies (MA) specifically raised against the alpha-subunit of the GTP-binding protein from bovine brain, G0, were studied. The hybridoma clones were found to secrete MA capable to interact with different antigenic sites of G0 alpha. Clone 1D2 MA interacted with the N-terminal domain of G0 alpha. The antigenic sites for clones 3DE. 1H6 and 2E3 MA were localized in the C-terminal domain of the protein molecule. Using clone 1H6 MA, the site of G0 alpha involved in the interaction with the beta gamma complex located in the C-terminal domain of the alpha-subunit, was revealed. It was found that the interaction of the alpha-subunit with the beta gamma complex changed the conformation of the C-terminal fragment of G0 alpha (Mr5000) together with an increase in the alpha-subunit affinity for clone 2E3 MA. It was concluded that the observed conformational changes may be the reason for the increased affinity of the alpha-subunit for the receptor.


Topical application of lindane cream (Kwell) and antipyrine metabolism.
The transcutaneous absorption of a 1% lindane cream (Kwell) was determined after application according to the official label. By 3 days after application the plasma lindane level increased from nondetectable to 10.3 +/- 2.2 ng/ml. Sufficient lindane was absorbed to increase the plasma clearance of antipyrine from 0.027 +/- 0.009 to 0.037 +/- 0.011 1/kg/hr (p less than 0.05). these findings indicate significant transcutaneous absorption of lindane occurs following a single application and are compatible with the neurological toxicity reported following the topical application of lindane cream.


Isolation of a Low Number of Sperm Cells from Female DNA in a Glass-PDMS-Glass Microchip via Bead-Assisted Acoustic Differential Extraction.
We report an improved separation method for the isolation of sperm cells from dilute, "large volume" samples containing female DNA using bead-assisted acoustic trapping. In an enclosed glass-PDMS-glass (GPG) resonator, we exploit a three-layer microfluidic architecture to generate "trapping nodes" in ultrasonic standing waves. We investigate the dependence of trapping efficiency on particle concentration for both sperm cells and polymeric beads. After determination of the critical concentration of polymeric beads required to seed the trapping event, sperm cells in dilute solution are trapped as a result of the enhanced secondary radiation force (SRF). Sperm-cell-containing samples with volumes up to 300 μL and cell concentrations as low as ∼10 cells/μL are amenable to effective trapping in the presence of an abundance of female DNA in solution. Complete processing of samples is accomplished with separation of the female and male fractions within 15 min. We demonstrate that the collected fractions are amenable to subsequent DNA extraction, short tandem repeat PCR, and the generation of STR profiles for the isolated sperm cells.


[Experimental research on non-invasive near-infrared detection of early hepatocirrhosis].
This experiment was carried out to make an exaluation on the non-invasive near-infrared detection of early hepatocirrhosis. The model of early hepatocirrhosis was established by injecting carbon tetrachloride in mice. Blood and oxygen content in liver tissue were detected with Runman System. The undulated forms of blood and oxygen variation were extracted and analyzed under the software MATLAB. Non-invasive near-infrared detection was found to react sensitively to the variation of the blood and oxygen content in the early hepatocirrhosis. The rhythm of the undulated forms of blood and oxygen in the early hepatocirrhosis was irregular. The main frequency peak of auto-power spectrum was found to move back to the rang 1.0-1.5 Hz and multi-peak was seen. These show that the non-invasive near-infrared detection is of some value in detecting early hepatocirrhosis.


Nanoscale stiffness topography reveals structure and mechanics of the transport barrier in intact nuclear pore complexes.
The nuclear pore complex (NPC) is the gate for transport between the cell nucleus and the cytoplasm. Small molecules cross the NPC by passive diffusion, but molecules larger than ∼5 nm must bind to nuclear transport receptors to overcome a selective barrier within the NPC. Although the structure and shape of the cytoplasmic ring of the NPC are relatively well characterized, the selective barrier is situated deep within the central channel of the NPC and depends critically on unstructured nuclear pore proteins, and is therefore not well understood. Here, we show that stiffness topography with sharp atomic force microscopy tips can generate nanoscale cross-sections of the NPC. The cross-sections reveal two distinct structures, a cytoplasmic ring and a central plug structure, which are consistent with the three-dimensional NPC structure derived from electron microscopy. The central plug persists after reactivation of the transport cycle and resultant cargo release, indicating that the plug is an intrinsic part of the NPC barrier. Added nuclear transport receptors accumulate on the intact transport barrier and lead to a homogenization of the barrier stiffness. The observed nanomechanical properties in the NPC indicate the presence of a cohesive barrier to transport and are quantitatively consistent with the presence of a central condensate of nuclear pore proteins in the NPC channel.


[Acute leukemia and pregnancy].
It is reported on an undifferentiated cell leukosis of the type PAS in the 2nd trimenon of a pregnancy. The paralymphoblastosis could well be influenced by a prednisolone monotherapy so that a healthy baby was born. After birth very quickly developed a severe recidivation of leucosis which no more could be influenced therapeutically so that the patient dies on the 10th day after birth. The problems of the therapy of undifferentiated cell leucosis during pregnancy are discussed and possible hormonal protective mechanisms are taken into consideration.


Simultaneous in situ reflectance and probe beam deflection measurements at solid electrode-aqueous electrolyte interfaces.
A method is herein described for performing simultaneous in situ normal incidence reflectance spectroscopy (DeltaR/R, lambda = 633 nm) and probe beam deflection (PBD) measurements at solid electrodes in aqueous electrolytes, while scanning the potential linearly between two prescribed limits. Results obtained for Au in 0.1 M HClO4 and for Pt in both 0.1 M HClO4 and 0.1 M NaOH were found to be in excellent agreement with those reported in the literature for each individual spectroelectrochemical technique under otherwise similar conditions. Data collected for Pt electrodes in CO-saturated 0.1 M HClO4 revealed rather sudden changes in both DeltaR/R and PBD signals in the voltammetric region where the characteristic sharp peak associated with the oxidation of adsorbed CO occurs. This behavior was ascribed, respectively, to oxide formation (DeltaR/R) and to changes in the electrolyte composition in region neighboring the electrode, involving predominantly the acid concentration (PBD). In contrast, CO oxidation on Pt in 0.1 M NaOH yielded a PBD response consistent with formation of solution-phase carbonate via the reaction of the product, CO2, with hydroxyl ion. The exquisite sensitivity of DeltaR/R and PBD to interfacial phenomena was further illustrated using a monolayer of hemin irreversibly adsorbed on glassy carbon surfaces in 0.1 M Na2B4O7 (pH approximately 9.2). For this system, DeltaR/R was found to be proportional to the relative fractions of hemin and its reduced counterpart, while the PBD signal could be correlated with corresponding variations in the electrolyte concentration induced by the surface-bound redox process.


Highly pathogenic avian influenza A(H5N1) mutants transmissible by air are susceptible to human and animal neutralizing antibodies.
A laboratory-generated reassortant H5 hemagglutinin (HA)/influenza A(H1N1) strain containing 4 mutations in influenza A(H5N1) HA has become transmissible by air among mammals. Here, we constructed 15 influenza A(H5N1) pseudoviruses containing a single mutation or a combination of mutations and showed that the pseudoviruses were susceptible to neutralizing antibodies from patients with influenza A(H5N1) infection and from mice immunized with a vaccine containing the conserved HA1 sequence of influenza A(H5N1). These results indicate that antibodies in patients currently infected by influenza A(H5N1) and antibodies induced by vaccines containing conserved sequences in HA1 of wild-type influenza A(H5N1) are highly effective in cross-neutralizing future influenza A(H5N1) mutants with airborne transmissibility, suggesting that human influenza pandemics caused by these influenza A(H5N1) variants can be prevented.


Methods for the identification of Lexian, Poisson and Markovian variations in the secondary sex ratio.
One of the problems arising in the identification of the type of process generating the secondary sex ratio in human and other populations is that of 'spurious contagion'. A model is presented which allows the simultaneous estimation of the effects of (i) variation in the biological predisposition of couples to have children of a particular sex, (ii) variation in this predisposition with birth order, (iii) a Markov association between the sexes of adjacent sibs as the result of in utero interaction, and (iv) the socio-psychological predisposition of couples to limit families once they have obtain a desirable composition. Restricted forms of the model allow one to test for the presence of each of these effects whilst controlling for the others. The model is applied to data from the United States and Finland.


Does anti-p53 antibody status predict for clinical outcomes in metastatic colorectal cancer patients treated with fluoropyrimidine, oxaliplatin, plus bevacizumab as first-line chemotherapy?
TP53 gene mutation is widely known as one of the determinants of impaired chemosensitivity. p53 is a tumor-suppressor protein in humans encoded by the TP53 gene. Some studies have shown that TP53 gene mutation and accumulation of the p53 protein are closely related with serum anti-p53 antibody positivity. This study aimed to evaluate the predictive significance of the serum p53 antibody status in metastatic colorectal cancer (mCRC) patients treated with fluoropyrimidine, oxaliplatin, plus bevacizumab as first-line chemotherapy. Ninety patients treated with fluoropyrimidine, oxaliplatin plus bevacizumab as first-line chemotherapy were enrolled, including 70 whose KRAS genotype was revealed at the beginning of treatment. Before chemotherapy initiation, the serum p53 antibody level was quantified by enzyme-linked immunosorbent assay using MESACUP® anti-p53 test kits. The cutoff value for positivity was 1.3 U/mL, as calculated previously. The KRAS genotype of the tumor samples was analyzed using the Luminex® assay. Overall response rates of Response Evaluation Criteria in Solid Tumors criteria were 77.7 % (42/54) in anti-p53-negative patients and 69.4 % (25/36) in anti-p53-positive patients. The odds ratio was 1.07. Median overall survival was 36.1 months in the anti-p53-positive patients, and not available in the anti-p53-negative patients (hazard ratio, 0.81; 95 % confidence interval, 0.37-1.77; P = 0.61). The corresponding values for median progression-free survival were 13.3 months and 14.6 months (hazard ratio, 0.69; 95 % confidence interval, 0.41-1.17; P = 0.17), respectively. Serum anti-p53 antibody positivity did not predict chemoresistance in mCRC treated with fluoropyrimidine, oxaliplatin, plus bevacizumab as first-line chemotherapy.


Multifunctional role of exosomes in viral diseases: From transmission to diagnosis and therapy.
Efforts to discover antiviral drugs and diagnostic platforms have intensified to an unprecedented level since the outbreak of COVID-19. Nano-sized endosomal vesicles called exosomes have gained considerable attention from researchers due to their role in intracellular communication to regulate the biological activity of target cells through cargo proteins, nucleic acids, and lipids. According to recent studies, exosomes play a vital role in viral diseases including covid-19, with their interaction with the host immune system opening the door to effective antiviral treatments. Utilizing the intrinsic nature of exosomes, it is imperative to elucidate how exosomes exert their effect on the immune system or boost viral infectivity. Exosome biogenesis machinery is hijacked by viruses to initiate replication, spread infection, and evade the immune response. Exosomes, however, also participate in protective mechanisms by triggering the innate immune system. Besides that, exosomes released from the cells can carry a robust amount of information about the diseased state, serving as a potential biomarker for detecting viral diseases. This review describes how exosomes increase virus infectivity, act as immunomodulators, and function as a potential drug delivery carrier and diagnostic biomarker for diseases caused by HIV, Hepatitis, Ebola, and Epstein-Barr viruses. Furthermore, the review analyzes various applications of exosomes within the context of COVID-19, including its management.


ReNaApp: increasing the long-term effects of oncological rehabilitation through an application after medical rehabilitation (ReNaApp): a quasi-randomized longitudinal study of prospective design.
Breast cancer is the most common malignant disease in women. Compared with other cancer types, breast cancer has a higher survival rate. The majority of breast cancer patients are overstrained to implement cancer-specific recommendations relating to changes in health behaviour. Numerous epidemiological studies have shown a positive correlation between physical activity and quality of life as well as the course of disease during and after breast cancer treatment. However, many patients have difficulties integrating physical activity into their everyday lives due to cancer symptoms. To develop physical activity into a daily routine, an aftercare programme for breast cancer patients will be developed. In particular, the programme is structured in terms of the validated concept "Neues Credo". The basic concept is converted into a mobile application. The study sample includes n = 740 rehabilitants (370 for the intervention group and for the control group) from five different rehab clinics in Northern Germany. The evaluation is as follows: a) Quasi-randomized, prospective longitudinal study (sequential study design). The intervention group receives a mobile application after rehabilitation, and the control group receives treatment as usual. The study evaluation is carried out through a questionnaire at three stages (at the beginning of the rehabilitation, at the end of the rehabilitation, and after 12 months). b) Qualitative analysis of interviews and focus groups in terms of feasibility and acceptance. c) Formative evaluation of the app. Above all, the aftercare programme ReNaApp increases the long-term effects of oncological rehabilitation. By documenting physical activity in ReNaApp, rehabilitants become more motivated to engage in physical activity in their everyday lives. Currently, there is no scientifically evaluated app for breast cancer patients in the German language. Thus, ReNaApp ensures an aftercare treatment for breast cancer patients with high-quality performance regardless of their place of residence. By adopting a participatory approach and a user-centred design, ReNaApp corresponds to the demands of the rehabilitants. German Register of Clinical Trials, www.drks.de. Identifier: DRKS00019017; Registered: November 7th, 2019. Date and version identifier: April 17th 2020; vesion 2.


Theory of fast nondeterministic physical random-bit generation with chaotic lasers.
We theoretically show that completely stochastic fast physical random bit generation at a rate of more than one gigabit per second can be realized by using lasers with optical delayed feedback which creates high-dimensional chaos of laser light outputs. The theory is based on the mixing property of chaos, which transduces microscopic quantum noise of spontaneous emission in lasers into random transitions between discrete macroscopic states.


An assessment of the utility of suicide prediction.
Efforts to predict a future event assume varying levels of confidence depending on its base rate and the error rate of the prediction instrument. Most researchers working with suicide prediction instruments seem tacitly to assume they will be able to predict a future suicide most of the time. Applying basic decision theory on a neuropsychiatric hospital population indicates that researchers using a prediction schedule will be unlikely to predict a future suicide beyond a 20% level of efficiency. Contrary to the general clinical view, eliminating false negatives was shown to be more practical than eliminating false positives in increasing the efficiency of a predictive schedule.


Affective and Enjoyment Responses to Sprint Interval Training in Healthy Individuals: A Systematic Review and Meta-Analysis.
Sprint interval training (SIT) is characterized by intensity of "all-out" effort and superior time-efficiency compared to traditional moderate-intensity continuous training (MICT) and has been proposed as one viable solution to address the commonly reported barrier of lack of time for physical activity. While substantial physiological benefits of participation in SIT have been well-documented, the psychological responses to SIT are less clear. No systematic review has been conducted thus far to respond to the assumption that its supramaximal intensity will induce adverse feelings. Therefore, the aim of the present study was to synthesize studies analyzing affective and enjoyment responses to SIT and to compare the responses to SIT with MICT and other high intensity interval training (HIIT) protocols with lower intensities. After searching relevant databases up until 22nd March 2021, twenty-five studies meeting the inclusion criteria were included in the present review. Random effect meta-analysis using the pooled data demonstrated that SIT induced similar post-exercise affective valences during the training compared to MICT and HIIT, but lower affective valences immediately post-exercise compared to MICT. Moreover, affective responses during SIT decreased to negative valences according to the results from most included studies, while low-volume SIT protocols with shorter sprint duration and repetitions induced more positive affective responses. Level of enjoyment after SIT were positive and were comparable to MICT or HIIT. Overall, the results from the existing literature indicate that SIT might cause unpleasant feelings during the training and be perceived less pleasurable than MICT immediately post training but could be a comparably enjoyable modality for healthy individuals in relation to MICT or HIIT, despite its supramaximal intensity. Low-volume SIT may be a realistic option for individuals seeking a time-efficient workout with comparable affective responses to MICT or HIIT. [https://www.crd.york.ac.uk/PROSPERO], Identifier [CRD42021284898].


Utilization of acyl-homoserine lactone quorum signals for growth by a soil pseudomonad and Pseudomonas aeruginosa PAO1.
Acyl-homoserine lactones (AHLs) are employed by several Proteobacteria as quorum-sensing signals. Past studies have established that these compounds are subject to biochemical decay and can be used as growth nutrients. Here we describe the isolation of a soil bacterium, Pseudomonas strain PAI-A, that degrades 3-oxododecanoyl-homoserine lactone (3OC12HSL) and other long-acyl, but not short-acyl, AHLs as sole energy sources for growth. The small-subunit rRNA gene from strain PAI-A was 98.4% identical to that of Pseudomonas aeruginosa, but the soil isolate did not produce obvious pigments or AHLs or grow under denitrifying conditions or at 42 degrees C. The quorum-sensing bacterium P. aeruginosa, which produces both 3OC12HSL and C4HSL, was examined for the ability to utilize AHLs for growth. It did so with a specificity similar to that of strain PAI-A, i.e., degrading long-acyl but not short-acyl AHLs. In contrast to the growth observed with strain PAI-A, P. aeruginosa strain PAO1 growth on AHLs commenced only after extremely long lag phases. Liquid-chromatography-atmospheric pressure chemical ionization-mass spectrometry analyses indicate that strain PAO1 degrades long-acyl AHLs via an AHL acylase and a homoserine-generating HSL lactonase. A P. aeruginosa gene, pvdQ (PA2385), has previously been identified as being a homologue of the AHL acylase described as occurring in a Ralstonia species. Escherichia coli expressing pvdQ catalyzed the rapid inactivation of long-acyl AHLs and the release of HSL. P. aeruginosa engineered to constitutively express pvdQ did not accumulate its 3OC12HSL quorum signal when grown in rich media. However, pvdQ knockout mutants of P. aeruginosa were still able to grow by utilizing 3OC12HSL. To our knowledge, this is the first report of the degradation of AHLs by pseudomonads or other gamma-Proteobacteria, of AHL acylase activity in a quorum-sensing bacterium, of HSL lactonase activity in any bacterium, and of AHL degradation with specificity only towards AHLs with long side chains.


Wedge pulmonary angiography to determine the accuracy of pulmonary wedge pressure.
Wedge pulmonary angiography was done in 11 patients with acute respiratory failure, to assess the accuracy of pulmonary arterial wedge pressure (WP) as an estimation of left ventricular end-diastolic pressure (LVEDP). The pulmonary artery (PA) catheter tip was placed into a dependent position in the lungs. Although the pulmonary vein was not visualized in 7 of 11 patients, in no case was there a significant difference between WP and LVEDP. When WP is no greater than 15 mm Hg, wedge pulmonary angiography does not reflect the accuracy of WP; however, left ventricular filling pressure can be accurately estimated by WP in most of these patients.


Dissociation of the GroEL-GroES asymmetric complex is accelerated by increased cooperativity in ATP binding to the GroEL ring distal to GroES.
A kinetic analysis of the ATP-dependent dissociation of wild-type GroEL and mutants from immobilized GroES was carried out using surface plasmon resonance. Excellent fits of the data were obtained using a double-exponential equation with a linear drift. Both the fast and slow observed dissociation rate constants are found to have a sigmoidal dependence on the concentration of ATP. The values of the Hill coefficients corresponding to the fast and slow observed rate constants of dissociation of wild-type GroEL and the Arg197-->Ala mutant are in good agreement with the respective values of the Hill coefficients previously determined for these proteins from plots of initial rates of ATP hydrolysis as a function of ATP concentration, in the presence of GroES. Our results are consistent with a kinetic mechanism for dissociation of the GroEL-GroES complex according to which GroES release takes place after an ATP-induced conformational change in the trans ring that is preceded by ATP hydrolysis and a subsequent conformational change in the cis ring. It is shown that the rate of complex dissociation increases with increasing positive cooperativity in ATP binding by the GroEL ring distal to GroES in the GroEL-GroES complex.


[Noncompacted cardiomyopathy in infants and children. Clinical findings and diagnostic techniques].
Noncompaction of the ventricular myocardium (NcCM) represents an arrest in the normal process of myocardial compaction, and has only recently been recognized as a distinct form of cardiomyopathy. It was previously termed as "spongy myocardium" and it is an extremely rare form of CM especially in infants and children. The last 20 years 23 cases aged 3 days-17 years mean: 60,3 months were diagnosed with NcCM (previously "spongy CM") based on echo-morphological criteria in our Institute. Our purpose was to assess the diagnostic value of Echo/ and MRI using conventional Echo and TDI parameters. 0.5-17 years, mean 6.3 years. We introduced in our country the MRI, also in the pediatric population with NcCM. Echo/MRI diagnosis was in good agreement in the diagnosis of pediatric NcCM. TEI index correlated well with MRI EF (r: 0.96, p<0.01). The prognosis of NcCM in infants was very poor, with a 43% half year mortality, with one successful heart transplantation. All children were stable hemodynamic condition for a longer period. We think our result will contribute to the early diagnosis, adequate treatment of NcCM with improvement of the prognosis, and to the better knowledge of prevalence and family screening of this very severe disease.


The Impact of Patient Infection Rate on Emergency Department Patient Flow: Hybrid Simulation Study in a Norwegian Case.
The COVID-19 pandemic put emergency departments all over the world under severe and unprecedented distress. Previous methods of evaluating patient flow impact, such as in-situ simulation, tabletop studies, etc., in a rapidly evolving pandemic are prohibitively impractical, time-consuming, costly, and inflexible. For instance, it is challenging to study the patient flow in the emergency department under different infection rates and get insights using in-situ simulation and tabletop studies. Despite circumventing many of these challenges, the simulation modeling approach and hybrid agent-based modeling stand underutilized. This study investigates the impact of increased patient infection rate on the emergency department patient flow by using a developed hybrid agent-based simulation model. This study reports findings on the patient infection rate in different emergency department patient flow configurations. This study's results quantify and demonstrate that an increase in patient infection rate will lead to an incremental deterioration of the patient flow metrics average length of stay and crowding within the emergency department, especially if the waiting functions are introduced. Along with other findings, it is concluded that waiting functions, including the waiting zone, make the single average length of stay an ineffective measure as it creates a multinomial distribution of several tendencies.


Fabry Nephropathy: An Evidence-Based Narrative Review.
Fabry disease (FD) is a rare, X-linked disorder caused by mutations in the GLA gene encoding the enzyme α-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, endothelial cells, epithelial cells, and tubular cells contribute to the renal symptoms of FD, which manifest as proteinuria and reduced glomerular filtration rate leading to renal insufficiency. A correct diagnosis of FD, although challenging, has considerable implications regarding treatment, management, and counseling. The diagnosis may be confirmed by demonstrating the enzyme deficiency in males and by identifying the specific GLA gene mutation in male and female patients. Treatment with enzyme replacement therapy, as part of the therapeutic strategy to prevent complications of the disease, may be beneficial in stabilizing renal function or slowing its decline, particularly in the early stages of the disease. Emergent treatments for FD include the recently approved chaperone molecule migalastat for patients with amenable mutations. The objective of this report is to provide an updated overview on Fabry nephropathy, with a focus on the most relevant aspects of its epidemiology, diagnosis, pathophysiology, and treatment options.


Surveillance of HPV-Positive Head and Neck Squamous Cell Carcinoma with Circulating and Salivary DNA Biomarkers.
Head and neck squamous cell carcinoma (HNSCC) manifests in the mucosal epithelial lining of the oral cavity, oropharynx, hypopharynx, nasopharynx or larynx and has a tremendous disease burden worldwide. Smoking and alcohol consumption were once major risk factors, but HPV-associated infection has emerged as the major contributor to HNSCC occurrence in developed countries. Circulating biomarker evaluations in biofluids, also known as liquid biopsy, are an attractive alternative for cancer screening as they are minimally invasive, potentially low cost, and easily repeatable on a serial basis. This review summarizes the current knowledge and potential of assessing circulating blood and salivary HPV DNA and HPV antibodies for the surveillance of HPV-positive HNSCC. Additionally, the biological underpinnings of the presence and relevance of circulating HPV DNA is discussed.


Mechanisms of endothelin-1-induced contraction in pulmonary arteries from chronically hypoxic rats.
Endothelin-1 (ET-1), a potent vasoconstrictor, is believed to contribute to the pathogenesis of hypoxic pulmonary hypertension. Previously we demonstrated that contraction induced by ET-1 in intrapulmonary arteries (IPA) from chronically hypoxic (CH) rats occurred independently of changes in intracellular Ca2+ concentration ([Ca2+]i), suggesting that ET-1 increased Ca2+ sensitivity. The mechanisms underlying this effect are unclear but could involve the activation of myosin light chain kinase, Rho kinase, PKC, or tyrosine kinases (TKs), including those from the Src family. In this study, we examined the effect of pharmacological inhibitors of these kinases on maximum tension generated by IPA from CH rats (10% O2 for 21 days) in response to ET-1. Experiments were conducted in the presence of nifedipine, an L-type Ca2+ channel blocker, to isolate the component of contraction that occurred without a change in [Ca2+]i. The mean change in tension caused by ET-1 (10(-8) M) expressed as a percent of the maximum response to KCl was 184.0+/-39.0%. This response was markedly inhibited by the Rho kinase inhibitors Y-27632 and HA-1077 and the TK inhibitors genistein, tyrphostin A23, and PP2. In contrast, staurosporine and GF-109203X, inhibitors of PKC, had no significant inhibitory effect on the tension generated in response to ET-1. We conclude that the component of ET-1-induced contraction that occurs without a change in [Ca2+]i in IPA from CH rats requires activation of Rho kinase and TKs, but not PKC.


Evaluation of cage micro-environment of mice housed on various types of bedding materials.
A variety of environmental factors can affect the outcomes of studies using laboratory rodents. One such factor is bedding. Several new bedding materials and processing methods have been introduced to the market in recent years, but there are few reports of their performance. In the studies reported here, we have assessed the cage micro-environment (in-cage ammonia levels, temperature, and humidity) of mice housed on various kinds of bedding and their combinations. We also compared results for bedding supplied as Nestpaks versus loose bedding. We studied C57BL/6J mice (commonly used) and NOD/LtJ mice (heavy soilers) that were maintained, except in one study, in static duplex cages. In general, we observed little effect of bedding type on in-cage temperature or humidity; however, there was considerable variation in ammonia concentrations. The lowest ammonia concentrations occurred in cages housing mice on hardwood bedding or a mixture of corncob and alpha cellulose. In one experiment comparing the micro-environments of NOD/LtJ male mice housed on woodpulp fiber bedding in static versus ventilated caging, we showed a statistically significant decrease in ammonia concentrations in ventilated cages. Therefore, our data show that bedding type affects the micro-environment in static cages and that effects may differ for ventilated cages, which are being used in vivaria with increasing frequency.


Novel insights in the HPA-axis during critical illness.
Critical illness represents a major challenge for the human body, implicating that an adequate stress response is indispensable for survival. Therefore, for a long time, activation of the hypothalamic pituitary adrenal axis was assumed to be increased to respond to this stressful situation. Recent novel insights, however, provided evidence that the HPA-axis is regulated differently during critical illness. Cortisol metabolism was shown to be reduced which contributed to hypercortisolism in an energy efficient way without increasing cortisol production dramatically. Yet, the concomitant low ACTH levels, explained by negative feedback inhibition, could lead to an understimulation of the adrenal gland and affect adrenal structure and function, given the crucial role of ACTH for adrenal gland maintenance. This side-effect could negatively affect outcome predominantly in the prolonged phase of critical illness and could explain the increased incidence of adrenal failure in these patients. Altogether, novel findings represent a paradigm shift in our current understanding of HPA-axis regulation during critical illness and redirect future research perspectives with an urgent need to well-designed clinical trials to further explore HPA-axis functioning during critical illness.


Exploitation of Aspergillus terreus for the Production of Natural Statins.
The fungus Aspergillus (A.) terreus has dominated the biological production of the "blockbuster" drugs known as statins. The statins are a class of drugs that inhibit HMG-CoA reductase and lead to lower cholesterol production. The statins were initially discovered in fungi and for many years fungi were the sole source for the statins. At present, novel chemically synthesised statins are produced as inspired by the naturally occurring statin molecules. The isolation of the natural statins, compactin, mevastatin and lovastatin from A. terreus represents one of the great achievements of industrial microbiology. Here we review the discovery of statins, along with strategies that have been applied to scale up their production by A. terreus strains. The strategies encompass many of the techniques available in industrial microbiology and include the optimization of media and fermentation conditions, the improvement of strains through classical mutagenesis, induced genetic manipulation and the use of statistical design.


Glucose Oxidase Driven Hydrogen Sulfide-Releasing Nanocascade for Diabetic Infection Treatment.
Diabetic ulcers have received much attention in recent years due to their high incidence and mortality, motivating the scientific community to develop various strategies for such chronic disease treatments. However, the therapeutic outcome of these approaches is highly compromised by invasive bacteria and a severe inflammatory microenvironment. To overcome these dilemmas, microenvironment-responsive self-delivery glucose oxidase@manganese sulfide (GOx@MnS) nanoparticles (NPs) are developed by one-step biomineralization. When they encounter the high glucose level in the ulcer site, GOx particles catalyze glucose to decrease the local pH and trigger the steady release of both manganese ions (Mn2+) and hydrogen sulfide (H2S). Mn2+ reacts with hydrogen peroxide to generate hydroxyl radicals for the elimination of bacterial infection; meanwhile, H2S is able to suppress the inflammatory response and accelerate diabetic wound healing through macrophage polarization. The excellent biocompatibility, strong bactericidal activity, and considerable immunomodulatory effect promise GOx@MnS NPs have great therapeutic potential for diabetic wound treatment.


Pioneers in trauma care at Harborview Medical Center.
Harborview Medical Center in Seattle has been home to the pioneering work of University of Washington (UW) Medicine physicians and staff who have led innovations to improve trauma care for more than 40 years. As the only level I adult and pediatric trauma center and regional burn center for Washington, Alaska, Montana, and Idaho, Harborview provides cares for more than 6500 critically injured trauma and burn patients per year. Our physicians, researchers and staff are recognized as national experts and as collaborative partners with nursing in the delivery of outstanding clinical care, research, and education. Beginning with the establishment of Seattle Medic One in the late 1960s, a groundbreaking program to train firefighters as paramedics, Harborview and the work of UW Medicine has been recognized locally and globally as a leader in every component of the ideal trauma system, as defined by the American College of Surgeons: prevention, access, acute hospital care, rehabilitation, education, and research activities.


[Principles of oncologic drug therapy following surgery for bowel cancer].
Adjuvant chemotherapy for 6 months following curative resection of colorectal cancer (CRC) reduces recurrence risk and improves survival in lymph node positive, stage III disease. In stage II CRC the benefit of adjuvant chemotherapy is smaller and only recommended if high risk prognostic factors are present. Microsatellite instability in stage II CRC is associated with a favourable prognosis and when present adjuvant chemotherapy is not needed. Adjuvant chemotherapy improves disease outcome also in elderly patients (≥ 70 years) with stage III CRC, but is not recommended in stage II disease. Adjuvant chemotherapy should be started within 8 weeks following surgery.


Low-dose Pressurized Intrathoracic Aerosol Chemotherapy (PITAC) as an Alternative Therapy for Pleuropulmonary Involvement in Pseudomyxoma Peritonei.
Pseudomyxoma peritonei (PMP) is a rare disease characterized by mucinous ascites and widespread peritoneal implants. It usually originates from the rupture of an adenoma/adenocarcinoma of the appendix. Although this tumor is only superficially invasive and does not metastasize, it could be a fatal disease. Extra-abdominal spread of PMP is an unusual occurrence with few reports in medical literature. A 50-year-old man was diagnosed with PMP according to the findings of thorax and abdomen CT scan and cytologic and histological examinations. The radiological exam showed irregular thickening on the surface of left diaphragmatic and parietal pleura. First, cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy (HIPEC) for the abdominal disease was performed. Histopathological examination confirmed the diagnosis of low grade PMP. The radiological evaluation performed 5 months later showed a dimensional increase in pleural nodules. The treatment consisted of an extensive intrathoracic cytoreductive surgery in combination with pressurized intra-thoracic aerosol chemotherapy (PITAC). Postoperative course was uneventful. PMP with pleural extension is a rare phenomenon and carries an unfavourable prognosis. Due to the rarity of this presentation, its correct treatment is still unclear. We present a therapeutic approach to be applied in selected patients.


Risk Factors for Rotator Cuff Repair Failure and Reliability of the Rotator Cuff Healing Index (RoHI) in Thai Patients: Comparison of the RoHI With a Modified Scoring System.
The success rate of surgical treatment for rotator cuff (RC) tear ranges from 16% to 94%. The Rotator Cuff Healing Index (RoHI) is a system for predicting failure after RC repair and is based on a combined score of factors, including age, anteroposterior (AP) tear size, tendon retraction, fatty infiltration of the infraspinatus muscle, bone mineral density (BMD), and level of work activity. To determine the factors leading to RC repair failure in a Thai population, to test the reliability of the RoHI in this population, and to compare the RoHI with a modified RoHI (m-RoHI) based on the factors for repair failure as determined. Case-control study; Level of evidence, 3. This study included 133 Thai patients who underwent arthroscopic RC repair between February 2012 and February 2021. Postoperative magnetic resonance imaging was performed at 6 to 24 months to evaluate RC healing. Variables that might affect failure rates were evaluated, including demographic characteristics, AP tear size and retraction, radiographic measurements, and magnetic resonance imaging findings. The m-RoHI was created using factors that significantly predicted repair failure on multivariate analysis. The area under the receiver operating characteristic curve was calculated to determine the reliability of the RoHI and to compare the reliability of the RoHI and m-RoHI to predict failure rates. Multivariate logistic regression analysis revealed that body mass index ≥23 (adjusted odds ratio [OR], 9.02; P = .034), high work activity (adjusted OR, 19.53; P = .008), AP tear size ≥2.5 cm (adjusted OR, 19.04; P = .001), and a retraction size of 2 to <3 cm (adjusted OR, 20.36; P = .013) were the independent factors that predicted repair failure in our population. BMD was not independently predictive of repair failure. We used these 4 significant independent factors to generate the m-RoHI. The area under the curve of the final adjusted m-RoHI was slightly improved as compared with the original RoHI, but this difference was not significant (0.827 [95% CI, 0.741-0.913] vs 0.780 [95% CI, 0.686-0.875], respectively; P = .447). The m-RoHI had a similar predictive value for repair failure to the original RoHI in our study population, but it did not require obtaining BMD. The m-RoHI may be useful in populations where BMD is not routinely obtained.


Adherence to oral bisphosphonates: 30 more minutes in dosing instructions matter.
Low adherence to treatment with bisphosphonates significantly impedes its effectiveness. The objectives were: (1) to compare adherence to oral weekly and monthly bisphosphonates with emphasis on dosing instructions; and (2) to study associations between adherence and beliefs about the bisphosphonate treatment among women ≥ 55 years. A multicenter survey was performed in secondary-care patients with osteoporosis. Osteoporosis Specific Morisky Medication Adherence Scale (OS-MMAS), questions on compliance with five dosing instructions and Beliefs about Medicines Questionnaire (BMQ) Specific were used. As many as 363 questionnaires (response rate 95%) were analyzed. Respondents (mean age 69 years) were treated with weekly bisphosphonates (37%) or monthly ibandronate (63%). Based on OS-MMAS, 67% of respondents showed high adherence with no differences between the subgroups. Only 44% of respondents were compliant with all dosing instructions. Compliance with dosing instructions concerning time interval (fasting and staying upright) was 71% in weekly and 52% in monthly subgroups, respectively (p < 0.001). Compliance with dosing instructions correlated positively with education (p = 0.009). The mean BMQ necessity score of 18.4 was greater than the mean BMQ concerns score of 13.3. OS-MMAS score correlated with necessity (p = 0.010). Persistence derived from OS-MMAS correlated with both necessity (p = 0.014) and concerns (p = 0.041). Despite relatively high adherence to the treatment, most patients do not follow dosing instructions. Reduced bioavailability, particularly of monthly ibandronate, can be expected in clinical practice. Adherence-related outcomes are associated with beliefs about the oral treatment with bisphosphonates.


Hepatitis C virus infections in oral lichen planus: a systematic review and meta-analysis.
A role for hepatitis C virus in oral lichen planus has been postulated. This systematic review and meta-analysis of the existing epidemiological studies was conducted to determine if there is a correlation between oral lichen planus and hepatitis C virus infection. We examined the association between hepatitis C virus and oral lichen planus by conducting a systematic review and meta-analysis of case-control studies that examined the prevalence of anti-HCV antibodies in the serum of cases and controls. We searched PubMed, Embase and The Cochrane Library databases from 2005 to January 2015. Associations were measured using random-effect odds ratios (ORs) combined with 95% confidence intervals. Nineteen eligible studies, encompassing 1807 cases of OLP and 2519 controls, were retrieved and included in this review. The summary estimate OR for all studies was 6.07 (95% CI: 2.73-13.48), showing a statistically significant difference in the proportion of HCV seropositivity among oral lichen planus patients, compared with controls and substantial heterogeneity between studies (I(2) = 65%) as a result of a variety of geographical distributions. The association of hepatitis C virus infection with oral lichen planus emphasizes the importance of hepatitis C virus screening in oral lichen planus patients.


Effects of direct intravitreal dopamine injection on sclera and retina in form-deprived myopic rabbits.
The aim of this study was to investigate morphologic changes of retina and sclera in form-deprived myopic rabbits following intravitreal dopamine injection. Neonatal rabbits were monocularly deprived of form vision by suturing the right eyelids after natural eye opening. In the form deprivation (FD) group, the right eye received FD alone. In the dopamine-form deprivation (DA-FD) group, the deprived eye received an intravitreal injection of 20 microg of dopamine every 5 days for a total of 4 injections. In the saline-FD group, the deprived eye received saline injections to the same schedule as the DA-FD group. The untreated contralateral eyes were used as controls. After an 8-week treatment period, the effects of DA on sclera and retina anterior and posterior to the equator were evaluated by light and electron microscopy. Treated eyes in the FD and saline-FD groups developed form deprivation myopia. These eyes had markedly reduced scleral thickness and smaller diameter scleral collagen fibrils posterior to the equator. In addition, the normal gradient of fibril size from the outer to the inner layers of the posterior sclera was absent in the treated eyes of both the FD and saline-FD groups. In contrast, posterior scleral thickness was greater in DA-FD eyes than in contralateral controls. A distinct swelling of retinal pigment epithelium mitochondria was observed in the treated eye of the DA-FD group, but no obvious retinal abnormalities were found in the treated eyes of the other two groups. The sclera, especially posterior sclera, plays an important role in both the induction and inhibition of myopia. An additional finding was that changes in the sclera of rabbits with low myopia were similar to those of the sclera of other mammals with high myopia. The results of this study will contribute to the understanding of the mechanisms of myopia development and inhibition by intravitreal dopamine injection.


Schools, parents, and youth violence: a multilevel, ecological analysis.
Using data from the National Longitudinal Study of Adolescent Health (Add Health), this study utilized an ecological approach to investigate the joint contribution of parents and schools on changes in violent behavior over time among a sample of 6,397 students (54% female) from 125 schools. This study examined the main and interactive effects of parent and school connectedness as buffers of violent behavior within a hierarchical linear model, focusing on both students and schools as the unit of analysis. Results show that students who feel more connected to their schools demonstrate reductions in violent behavior over time. On the school level, our findings suggest that school climate serves as a protective factor for student violent behavior. Finally, parent and school connectedness appear to work together to buffer adolescents from the effects of violence exposure on subsequent violent behavior.


Outcomes in hepatitis C virus-infected recipients of living donor vs. deceased donor liver transplantation.
In this retrospective study of hepatitis C virus (HCV)-infected transplant recipients in the 9-center Adult to Adult Living Donor Liver Transplantation Cohort Study, graft and patient survival and the development of advanced fibrosis were compared among 181 living donor liver transplant (LDLT) recipients and 94 deceased donor liver transplant (DDLT) recipients. Overall 3-year graft and patient survival were 68% and 74% in LDLT, and 80% and 82% in DDLT, respectively. Graft survival, but not patient survival, was significantly lower for LDLT compared to DDLT (P = 0.04 and P = 0.20, respectively). Further analyses demonstrated lower graft and patient survival among the first 20 LDLT cases at each center (LDLT <or=20) compared to later cases (LDLT > 20; P = 0.002 and P = 0.002, respectively) and DDLT recipients (P < 0.001 and P = 0.008, respectively). Graft and patient survival in LDLT >20 and DDLT were not significantly different (P = 0.66 and P = 0.74, respectively). Overall, 3-year graft survival for DDLT, LDLT >20, and LDLT <or=20 were 80%, 79% and 55%, with similar results conditional on survival to 90 days (84%, 87% and 68%, respectively). Predictors of graft loss beyond 90 days included LDLT <or=20 vs. DDLT (hazard ratio [HR] = 2.1, P = 0.04), pretransplant hepatocellular carcinoma (HCC) (HR = 2.21, P = 0.03) and model for end-stage liver disease (MELD) at transplantation (HR = 1.24, P = 0.04). In conclusion, 3-year graft and patient survival in HCV-infected recipients of DDLT and LDLT >20 were not significantly different. Important predictors of graft loss in HCV-infected patients were limited LDLT experience, pretransplant HCC, and higher MELD at transplantation.


Inhibitory effect of novel Eugenol Tosylate Congeners on pathogenicity of Candida albicans.
The global prevalence of fungal diseases is increasing rapidly, which affects more than a billion people every year with significant mortality rate. On the other hand, the development of new drugs to treat these fungal infections is slow, while the current antifungal therapy is insufficient and associated with adverse side effects and emerging multidrug resistance. Therefore, development of novel antifungal drugs with least or no toxicity and multi-target mechanisms of action is an immediate priority. Natural products have long been known to possess antimicrobial activities and are source of new drugs. Currently, modifying natural products to synthesize derivatives/analogues are of great scientific focus for discovering novel drugs with improved potency and safety. Modifications in eugenol to synthesize eugenol derivatives with enhanced antifungal activity have already been reported. In this study, three most active novel eugenol tosylate congeners (ETC-5, ETC-6 and ETC-7) were selected from our previous study to investigate their effect on major virulence factors of Candida albicans which include adherence, morphogenesis, hydrolytic enzymes secretion, biofilm formation and on expression of genes related to these virulence factors. Adherence and biofilm formation were studied by alamarBlue dye and XTT reduction assays respectively, hydrolytic enzyme secretion was evaluated by plate assays. Further, morphological transition was monitored microscopically and RT-qPCR was used to assess the gene expression levels. ETCs significantly inhibited adherence in C. albicans with an inhibition range of 16-66%, and completely inhibited the morphogenesis at MIC values. Inhibition of proteinase and phospholipase activity was in the range of 2-48% and 8-34% respectively. Test compounds also significantly inhibit biofilm formation in C. albicans in the range of 7-77%. Furthermore, RT-qPCR results indicated a significant down regulation in expression levels of genes (ALS1, ALS2, ALS3, ALS9, CPH1, HWP1, SAP1, SAP2, SAP3 and PLB1) in C. albicans cells after treated with ETCs. The results indicated that these novel ETCs target major virulence factors of C. albicans and avert this commensal microbe to turn into pathogenic. However, further in-depth studies may facilitate the mechanisms involved by ETCs in targeting these virulence factors.


Lipogranulomatosis of the mesentery.
This paper describes a 21-year-old man with lipogranulomatosis of the mesentery. This condition is characterized by a non-specific inflammatory process of the adipose tissue in the radix mesenterii. So far as could be established, this is the first patient in whom vascular anomalies and displacement of lymphatic vessels and lymph nodes have been described. However, these changes are hardly specific so that definite conformation of the diagnosis must be obtained by a biopsy. The aetiology is unknown. There is no established therapy for this benign, self-limiting disease.


Filling the gap with a bulky diaryl boron group: fluorinated and non-fluorinated copper pyrazolates fitted with a dimesityl boron moiety on the backbone.
Successful synthesis has been reported of 4-Mes2B-3,5-(CF3)2PzH and 4-Mes2B-3,5-(CF3)2PzH bearing sterically demanding diarylboron moieties at the pyrazole ring 4-position, and their corresponding copper(I) pyrazolate complexes. They show visible blue photoluminescence in solution. The X-ray crystal structures revealed that the fluorinated {[4-BMes2-3,5-(CF3)2Pz]Cu}3 crystallizes as discrete trinuclear molecules whereas as the non-fluorinated {[4-BMes2-3,5-(CH3)2Pz]Cu}3 forms dimers of trimers with two close inter-trimer Cu⋯Cu separations. The solid {[4-BMes2-3,5-(CF3)2Pz]Cu}3 featuring a sterically confined Cu3N6 core displays bright blue phosphorescence while {[4-BMes2-3,5-(CH3)2Pz]Cu}3, which is a dimer of a trimer, is a red phosphor at room temperature. This work illustrates the modulation of photo-physical properties of metal pyrazolates by adjusting the supporting ligand steric features and introducing secondary diarylboron luminophores. Computational analysis of the structures and photophysical properties of copper complexes are also presented.


Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive.
Calcineurin inhibitors, such as cyclosporine A and FK506, are used as immunosuppressant drugs, but their adverse effects on male reproductive function remain unclear. The testis expresses somatic calcineurin and a sperm-specific isoform that contains a catalytic subunit (PPP3CC) and a regulatory subunit (PPP3R2). We demonstrate herein that male mice lacking Ppp3cc or Ppp3r2 genes (knockout mice) are infertile, with reduced sperm motility owing to an inflexible midpiece. Treatment of mice with cyclosporine A or FK506 creates phenocopies of the sperm motility and morphological defects. These defects appear within 4 to 5 days of treatment, which indicates that sperm-specific calcineurin confers midpiece flexibility during epididymal transit. Male mouse fertility recovered a week after we discontinued treatment. Because human spermatozoa contain PPP3CC and PPP3R2 as a form of calcineurin, inhibition of this sperm-specific calcineurin may lead to the development of a reversible male contraceptive that would target spermatozoa in the epididymis.


A review of psychosocial factors and personality in the treatment of obstructive sleep apnoea.
Effective treatment of obstructive sleep apnoea (OSA) is primarily determined by adherence to the selected intervention. The most common treatment pathways are mechanical devices such as continuous positive airway pressure (CPAP) or a mandibular advancement device, often combined with weight loss therapy. Weight reduction is usually an adjunct therapy but may be used as a secondary treatment in mild-to-moderate OSA when mechanical treatments cannot be tolerated. To enhance the uptake and adherence to treatment, clinicians may assess patient's personality profiles and psychological readiness. There is a paucity of evidence related to these aspects of patient care and this article outlines the current research in relation to patient presentation, treatment uptake and barriers, and methods to enhance treatment adherence.This article disseminates personality traits observed in patients with OSA and identifies vulnerable groups who may require additional support to increase treatment adherence. It summarises the current evidence for treatment barriers in patients with OSA. Low self-efficacy in relation to CPAP and weight loss adherence will be explored as well as the potential to predict treatment responders and enhance therapeutic uptake and adherence. Extending personality traits into research and clinical practice could potentially result in more successful CPAP therapy and weight loss treatment outcomes.


Aging exacerbates cognitive and anxiety alterations induced by an intracerebroventricular injection of amyloid-β1-42 peptide in mice.
An increasing body of evidence indicates that the activation of indoleamine-2,3-dyoxigenase (IDO), a first and rate-limiting enzyme in the kynurenine (KYN) pathway, is involved in Aβ1-42-neurotoxicity and AD pathogenesis. We have reported for the first time that brain IDO activation is related to Aβ1-42 exposure in young mice. Because aging is characterized by a brain dyshomeostasis and because it remains the most dominant risk factor for AD, the purpose of this study was to determine whether aging is associated with a higher sensitivity to behavioural and neurochemical alterations elicited by an intracerebroventricular (i.c.v.) injection of Aβ1-42 (400 pmol/mice), and whether KYN pathway is involved in these effects. We confirmed that aged mice displayed higher cognitive deficit in the object recognition test and higher anxiety-like behaviour in the elevated plus-maze and open field tests after the Aβ1-42 administration. Aged mice also responded to Aβ1-42 with a higher deficiency of brain-derived neurotrophic factor, glutathione levels and total radical-trapping antioxidant capacity, a higher IDO activity, and a higher KYN and KYN/tryptophan ratio in the prefrontal cortex and hippocampus. These effects of Aβ1-42 were associated with a higher proinflammatory status, as measured by higher levels of interleukin-6, lower levels of interleukin-10 and higher expression of glial fibrillary acidic protein (GFAP) and allograft inflammatory factor 1 (Iba1) in the brain of aged mice. These results represent primary evidence suggesting that age-associated inflammatory signature and down-regulation of neuroprotectants in the brain render aged mice more vulnerable to Aβ1-42-induced memory loss, anxiety symptoms and KYN pathway dysregulation.


Lingual cysticercosis--a case report.
Cysticercosis is unlikely to be the first diagnosis for a swelling over the tongue. In this report we document an unusual case of lingual cysticercosis presenting as an isolated lesion.


Convenient TLC-based Identification Test for the Crude Drug "Pogostemoni Herba".
TLC and HPLC were used to identify possible chemical markers for evaluating the quality of the crude drug "Pogostemoni herba" (aerial part of Pogostemon cablin), which is a component of Kampo medicines. In addition to the reported patchouli alcohol and 2-hydroxy-6-methyl-3-(4-methylpentanoyl)-4-pyrone, three phenylethanoids were isolated from this plant material for the first time: acteoside, isoacteoside, and crenatoside. The usefulness of these compounds as indicators of the crude commercial drug under various TLC conditions was examined, and patchouli alcohol was found to give a definite spot with a reproducible Rf value. Therefore, we propose TLC of the methanol (MeOH) extract using patchouli alcohol as a marker as a convenient method for identifying the crude drug Pogostemoni herba.


Effect of lithium on incorporation of bromodeoxyuridine and tritiated thymidine into human parathyroid cells.
To measure lithium chloride-stimulated incorporation of tritiated thymidine (3H-TdR) and bromodeoxyuridine (BrdU) by human parathyroid cells as an indicator of lithium's growth-promoting properties. Cell suspensions derived from abnormal human parathyroid tissue were incubated for 5 days with graded concentrations of lithium and pulsed with either 0.074 MBq of 3H-TdR or 0.6 microgram of BrdU. The 3H-TdR incorporation was measured by counting cell filtrates in a beta counter, and nuclear BrdU incorporation was determined by counting nuclei positively stained by an antibody to BrdU. Counts of BrdU-positive cells by two observers unaware of incubation conditions were correlated with 3H-TdR counts. Cell suspensions derived from adenomatous and hyperplastic parathyroid glands demonstrated a dose-related increase in 3H-TdR incorporation. There was close correlation between the two observers' counts of BrdU-positive cells (r = 0.70, P = .01) and between each observer's counts and 3H-TdR counts (r = 0.70, P = .02, and r = 0.90, P = .01, respectively). Lithium stimulates in vitro incorporation of 3H-TdR and BrdU by abnormal human parathyroid cells, consistent with a growth-promoting effect.


Effect of Gonadotropin Types and Indications on Homologous Intrauterine Insemination Success: A Study from 1251 Cycles and a Review of the Literature.
To evaluate the IUI success factors relative to controlled ovarian stimulation (COS) and infertility type, this retrospective cohort study included 1251 couples undergoing homologous IUI. We achieved 13% clinical pregnancies and 11% live births. COS and infertility type do not have significant effect on IUI clinical outcomes with unstable intervention of various couples' parameters, including the female age, the IUI attempt rank, and the sperm quality. Further, the COS used seemed a weak predictor for IUI success; therefore, the indications need more discussion, especially in unexplained infertility cases involving various factors. Indeed, the fourth IUI attempt, the female age over 40 years, and the total motile sperm count <5 × 106 were critical in decreasing the positive clinical outcomes of IUI. Those parameter cut-offs necessitate a larger analysis to give infertile couples more chances through IUI before carrying out other ART techniques.


Classical immunomodulatory therapy in multiple sclerosis: how it acts, how it works.
Interferon beta (IFNβ) and glatiramer acetate (GA) were the first immunomodulators approved to the treatment of relapsing-remitting multiple sclerosis (MS) and clinically isolated syndromes. Despite the enlargement of the therapeutic armamentarium, IFNβ and GA remain the most widely drugs and the therapeutic mainstay of MS. To review the mechanisms of action of IFNβ and GA and main clinical results in MS. IFNβ modulates T and B-cell activity and has effects on the blood-brain barrier. The well proved mechanism of GA is an immune deviation by inducing expression of anti-inflammatory cytokines. Some authors favor the neuroprotective role of both molecules. Clinical trials showed a 30% reduction on the annualized relapse rate and of T2 lesions on magnetic resonance. Although the precise mechanisms how IFNβ and GA achieve their therapeutics effects remain unclear, these drugs have recognized beneficial effects and possess good safety and tolerability profiles. The large clinical experience in treating MS patients with these drugs along almost two decades deserves to be emphasized, at a time where the appearance of drugs with more selective mechanisms of action, but potentially less safer, pave the way to a better selection of the most appropriate individualized treatment.