Near-infrared 940-nm diode laser photobiomodulation of inflamed periodontal ligament stem cells.
Photobiomodulation (PBM) is an acceptable method of stimulating stem cells through its non-invasive absorption by the cell photoreceptors and the induction of cellular response. The current research was aimed at evaluating the effect of near-infrared PBM on proliferation and osteogenic differentiation in inflamed periodontal ligament stem cells (I-PDLSCs). I-PDLSCs were isolated and characterized. Third passage cells were irradiated with 940-nm laser at an output power of 100 mW in a continuous wave. A fluence of 4 J/cm2 in three sessions at 48-h intervals was applied and compared with non-irradiated controls. Cell viability and proliferation were evaluated by MTT assay. Alkaline phosphatase activity, quantitative Alizarin red staining test, and q-RT-PCR were used to evaluate the osteogenic properties of the I-PDLSCs in four groups of (a) osteogenic differentiation medium + laser (ODM + L), (b) osteogenic differentiation medium without laser (ODM), (c) non-osteogenic differentiation medium + laser (L), and (d) non-osteogenic differentiation medium (control). There was a non-significant increase in the viability of cells at 48- and 72-h post last laser irradiation. Alizarin red staining revealed no significant stimulatory effect of PBM at 14 and 21 days. However, alkaline phosphatase activity was significantly higher in the L + ODM group. Expression of osteogenic-related genes had a statistically significant increase at 21-day post irradiation. The irradiation used in the present study showed no significant increase in the proliferation of I-PDLSCs by PBM. However, expression levels of osteogenic-related genes and alkaline phosphatase activity were significantly increased in irradiated groups.


[Effectiveness of parenteral feeding with various hydrolysates in alloxan diabetes in white rats].
The effect of applying various hydrolysates for parenteral feeding (caseine hydrolysate, hydrolysin L-103, aminosol, moriamine S-2) in albino rats with alloxan-induced diabetes was investigated. The assimilation of the hydrolysates introduced was found in these animals to be down by comparison with intact ones. It was only administration of nitrogenous media containing a sufficient amount of aminic nitrogen (moriamine S-2) that helped establish a positive nitrogenous balance and to prevent a loss of weight and the dry weight of the tissues.


Conceptual problems in laypersons' understanding of individualized cancer risk: a qualitative study.
To explore laypersons' understanding of individualized cancer risk estimates, and to identify conceptual problems that may limit this understanding. Risk prediction models are increasingly used to provide people with information about their individual risk of cancer and other diseases. However, laypersons may have difficulty understanding individualized risk information, because of conceptual as well as computational problems. A qualitative study was conducted using focus groups. Semi-structured interviews explored participants' understandings of the concept of risk, and their interpretations of a hypothetical individualized colorectal cancer risk estimate. Eight focus groups were conducted with 48 adults aged 50-74 years residing in two major US metropolitan areas. Participants had high school or greater education, some familiarity with information technology, and no personal or family history of cancer. Several important conceptual problems were identified. Most participants thought of risk not as a neutral statistical concept, but as signifying danger and emotional threat, and viewed cancer risk in terms of concrete risk factors rather than mathematical probabilities. Participants had difficulty acknowledging uncertainty implicit to the concept of risk, and judging the numerical significance of individualized risk estimates. The most challenging conceptual problems related to conflict between subjective and objective understandings of risk, and difficulties translating aggregate-level objective risk estimates to the individual level. Several conceptual problems limit laypersons' understanding of individualized cancer risk information. These problems have implications for future research on health numeracy, and for the application of risk prediction models in clinical and public health settings.


Reactivation of the lipid-depleted pyruvate oxidase system from Escherichia coli with cell envelope neutral lipids.
The pyruvate oxidase system of Escherichia coli is composed of a soluble flavoprotein, pyruvate oxidase (EC 188.8.131.52, pyruvate:ferricytochrome b1 oxidoreductase), and an electron transport system associated with the cell envelope-membrane fraction. The membrane particles contain 15% lipid by weight. Fractionation of the lipids revealed that abut one-third are neutral lipids and two-thirds are phospholipids. The relative ratio of ubiquinone to menaquinone within the neutral lipid fraction is 15:1 on a molar basis. Removal of the lipids from the membrane particles by extraction with aqueous acetone or hydrolysis of the phospholipids by treatment with Bacillus cereus phospholipase C results in a complete loss of electron transport activity. Analysis of the particles extracted with aqueous acetone revealed that practically all the neutral lipids and 65% of the phospholipids are removed by this treatment. Phospholipase treatment results in a loss of 75% of the membrane phospholipid phosphorus; however, the diglycerides and the neutral lipids produced by phospholipase hydrolysis remain associated with the particles. Addition of neutral lipid and a detergent, hepta-DL-alanyl dodecylamide to the acetone-extracted material results in a restoration of 37% of the original particle activity. Addition of neutral lipid and hepta-DL-alanyl dodecylamide to phospholipase-treated particles completely restores the original electron transport activity. Furthermore, addition of ubiquinone from either yeast (UQ6) or E. coli (UQ8) will restore pyruvate oxidase activity when the quinones are supplemented with photoinactivated neutral lipid. No restoration of activity to phospholipase-treated particles is noted upon the addition of either menaquinone 6 or menaquinone 8 to the reconstitution system. In fact, these compounds appear to suppress restoration of activity when they are added to reaction mixtures containing neutral lipid and phospholipase-treated particles.


A single center experience with same-day transradial-PCI patients: a contrast with published guidelines.
Our goal was to compare recently published Consensus Statement from the SCAI/ACC on appropriateness for same-day PCI with patient characteristics from a real-world same-day PCI experience in the United States. Recent practice statement published by the SCAI /ACC in 2009 describes patients suitable for outpatient PCI procedures. Whether this practice statement reflects actual real-world practice in the setting of advances in transradial catheterization needs further exploration. Pre-existing, deidentified, quality assurance data from 100 sequential patients undergoing transradial PCI, and same-day discharge were compared with criteria in SCAI/ACC statement on outpatient PCI. Each had been identified post-PCI as uncomplicated and therefore eligible for same day discharged. Specific attention was placed on whether the patients carried any exclusion to same-day discharge. One hundred six procedures were recorded in 100 patients including 11 women and 89 men, median age 62 (55,71) years all with stable ischemia. Early follow up was done for medication compliance. None were readmitted nor had post-PCI complications. Only 15% met appropriateness criteria for same-day discharge. Older age, distance from the hospital, greater than simple PCI, and the need for specific antiplatelet therapy represented the dominant contraindications to discharge. Using transradial approaches and structured early follow up by advance practice nurses, same-day discharge can be accomplished successfully in a broad range of patients outside of those suggested by the SCAI/ACC 2009 Consensus Document. Confirmation of these results could result in shorter hospitalizations for US patients and align advances in catheterization technology to optimize heath care delivery.


Who smokes? Why?: Psychiatric aspects of continued cigarette usage among lawyers in Washington State.
Eight-hundred two lawyers, a random sample of the Washington State Bar, were surveyed to determine the prevalence of medical and psychological distress. Approximately 15% of this group reported current cigarette use. Greater levels of dysphoric symptoms and greater misuse of alcohol differentiated male smokers from male nonsmokers, whereas no differences were found for females. The implications of these findings for pharmacologic and counseling strategies to further promote smoking cessation are discussed.


Serum CEA levels in a human colonic adenocarcinoma (LOVO) xenograft system.
The relationship between tumor size and circulating CEA titers was examined for a human colonic adenocarcinoma xenografted in Balb/C athymic mice. Xenograft material was derived from line LoVo, which produces moderate amounts of CEA, both in vitro and in vivo. No correlation was found between tumor size and serum CEA levels.


A machine learning approach to distinguish between knees without and with osteoarthritis using MRI-based radiomic features from tibial bone.
Our aim was to assess the ability of semi-automatically extracted magnetic resonance imaging (MRI)-based radiomic features from tibial subchondral bone to distinguish between knees without and with osteoarthritis. The right knees of 665 females from the population-based Rotterdam Study scanned with 1.5T MRI were analyzed. A fast imaging employing steady-state acquisition sequence was used for the quantitative bone analyses. Tibial bone was segmented using a method that combines multi-atlas and appearance models. Radiomic features related to the shape and texture were calculated from six volumes of interests (VOIs) in the proximal tibia. Machine learning-based Elastic Net models with 10-fold cross-validation were used to distinguish between knees without and with MRI Osteoarthritis Knee Score (MOAKS)-based tibiofemoral osteoarthritis. Performance of the covariate (age and body mass index), image features, and combined covariate + image features models were assessed using the area under the receiver operating characteristic curve (ROC AUC). Of 665 analyzed knees, 76 (11.4%) had osteoarthritis. An ROC AUC of 0.68 (95% confidence interval (CI): 0.60-0.75) was obtained using the covariate model. The image features model yielded an ROC AUC of 0.80 (CI: 0.73-0.87). The model that combined image features from all VOIs and covariates yielded an ROC AUC of 0.80 (CI: 0.73-0.87). Our results suggest that radiomic features are useful imaging biomarkers of subchondral bone for the diagnosis of osteoarthritis. An advantage of assessing bone on MRI instead of on radiographs is that other tissues can be assessed simultaneously. • Subchondral bone plays a role in the osteoarthritis disease processes. • MRI radiomics is a potential method for quantifying changes in subchondral bone. • Semi-automatically extracted radiomic features of tibia differ between subjects without and with osteoarthritis.


Disrupted cell cycle arrest and reduced proliferation in corneal fibroblasts from GCD2 patients: a potential role for altered autophagy flux.
This study investigates the role of impaired proliferation, altered cell cycle arrest, and defective autophagy flux of corneal fibroblasts in granular corneal dystrophy type 2 (GCD2) pathogenesis. The proliferation rates of homozygous (HO) GCD2 corneal fibroblasts at 72 h, 96 h, and 120 h were significantly lower (1.102 ± 0.027, 1.397 ± 0.039, and 1.527 ± 0.056, respectively) than those observed for the wild-type (WT) controls (1.441±0.029, 1.758 ± 0.043, and 2.003 ± 0.046, respectively). Flow cytometry indicated a decreased G1 cell cycle progression and the accumulation of cells in the S and G2/M phases in GCD2 cells. These accumulations were associated with decreased levels of Cyclin A1, B1, and E1, and increased expression of p16 and p27. p21 and p53 expression was also significantly lower in GCD2 cells compared to the WT. Interestingly, treatment with the autophagy flux inhibitor, bafilomycin A1, resulted in similarly decreased Cyclin A1, B1, D1, and p53 expression in WT fibroblasts. Furthermore, similar findings, including a decrease in Cyclin A1, B1, and D1 and an increase in p16 and p27 expression were observed in autophagy-related 7 (Atg7; known to be essential for autophagy) gene knockout cells. These data provide new insight concerning the role of autophagy in cell cycle arrest and cellular proliferation, uncovering a number of novel therapeutic possibilities for GCD2 treatment.


The influence of virus-induced changes in plants on aphid vectors: insights from luteovirus pathosystems.
Plant virus infection can alter the suitability of host plants for their aphid vectors. Most reports indicate that virus-infected plants are superior hosts for vectors compared to virus-free plants with respect to vector growth rates, fecundity and longevity. Some aphid vectors respond preferentially to virus-infected plants compared to virus-free ones, while others avoid infected plants that are inferior hosts. Thus, it appears vectors can exploit changes in host plant quality associated with viral infection. Enhanced vector performance and preference for virus-infected plants might also be advantageous for viruses by promoting their spread and possibly enhancing their fitness. Our research has focused on two of the most important luteoviruses that infect wheat (Barley yellow dwarf virus), or potato (Potato leafroll virus), and their respective aphid vectors, the bird-cherry oat aphid, Rhopalosiphum padi, and the green peach aphid, Myzus persicae. The work has demonstrated that virus infection of host plants enhances the life history of vectors. Additionally, it has shown that virus infection alters the concentration and relative composition of volatile organic compounds in host plants, that apterae of each vector species settle preferentially on virus-infected plants, and that such responses are mediated by volatile organic compounds. The findings also indicate that plants respond heterogeneously to viral infection and as a result different plant parts change in attractiveness to vectors during infection and vector responses to virus-infected plants are dynamic. Such dynamic responses could enhance or reduce the probability of virus acquisition by individual aphids searching among plants. Finally, our work indicates that compared to non-viruliferous aphids, viruliferous ones are less or not responsive to virus-induced host plant volatiles. Changes in vector responsiveness to plants after vectors acquire virus could impact virus epidemiology by influencing virus spread. The potential implications of these findings for virus ecology and epidemiology are discussed.


Association of phase angle with hospital-acquired functional decline in older patients undergoing cardiovascular surgery.
The aim of this study was to examine whether preoperative phase angle (PhA) measured by bioelectrical impedance analysis was associated with a hospital-acquired functional decline in older patients undergoing cardiovascular surgery. This was an observational study of prospectively collected data of 114 patients (>65 y of age) with cardiovascular disease who underwent elective cardiovascular surgery between September 2019 and August 2020. Patients were classified into tertiles based on PhA levels. Factors associated with the occurrence of hospital-acquired functional decline (postoperative recovery to preoperative physical function was not possible) were analyzed using univariate and multivariate analyses. Patients in the low PhA group were significantly older than those in the middle and high PhA groups; were predominantly women; had higher New York Heart Association cardiovascular and EuroSCORE severity scores; and had significantly lower levels of body mass index, Geriatric Nutritional Risk Index, hemoglobin, and albumin. There was a significant correlation between PhA and nutrition and physical function. The incidence of hospital-acquired functional decline occurred in 26.3% of all patients, with a significantly higher incidence in patients in the low PhA group. Multivariate analysis showed that PhA was extracted as a factor for the hospital-acquired functional decline in all the models. PhA was associated with hospital-acquired functional decline in older patients undergoing cardiovascular surgery. PhA is likely to be a comprehensive indicator of physical health that indicates nutritional status, physical function, and geriatric syndrome (frailty/sarcopenia), and is an important predictor of hospital-acquired functional decline in this group of older patients.


Regulation by prostaglandin E2 of interleukin release by T lymphocytes in mucosa.
Regulation of immune cell activation in lymphocyte-bearing human tissues is a pivotal host function, and metabolites of arachidonic acid (prostaglandin E2 in particular) have been reported to serve this function at non-mucosal sites. However, it is unknown whether prostaglandin E2 is immunoregulatory for the large lymphocyte population in the lamina propria of intestine; whether low (nM) concentrations of prostaglandin E2 modulate immune responses occurring there; and whether adjacent inflammation per se abrogates prostaglandin E2's regulatory effects. To address these issues, intestine-derived lymphocytes and T hybridoma cells were assessed, T cell activation was monitored by release of independently quantitated lymphokines, and dose-response studies were performed over an 8-log prostaglandin E2 concentration range. IL-3 release by normal intestinal lamina propria mononuclear cells was reduced (up to 78%) in a dose-dependent manner by prostaglandin E2, when present in as low a concentration as 10(-10) M. PGE2 also inhibited (by > or = 60%) mucosal T lymphocytes' ability to destabilize the barrier function of human epithelial monolayers. Further, with an intestine-derived T lymphocyte hybridoma cell line, a prostaglandin E2 dose-dependent reduction in IL-3 and IL-2 (90 and 95%, respectively) was found; this was true for both mitogen- and antigen-driven T cell lymphokine release. Concomitant [3H] thymidine uptake studies suggested this was not due to a prostaglandin E2-induced reduction in T cell proliferation or viability. In contrast, cells from chronically inflamed intestinal mucosa were substantially less sensitive to prostaglandin E2, e.g., high concentrations (10(-6) M) of prostaglandin E2 inhibited IL-3 release by only 41%. We conclude that prostaglandin E2 in nM concentrations is an important modulator of cytokine release from T lymphocytes derived from the gastrointestinal tract, and it may play a central role in regulation of lamina propria immunocyte populations residing there.


Mucosal boosting enhances vaccine protection against SARS-CoV-2 in macaques.
A limitation of current SARS-CoV-2 vaccines is that they provide minimal protection against infection with current Omicron subvariants1,2, although they still provide protection against severe disease. It has been hypothesized that enhanced mucosal immunity will be required to block infection and onward transmission. Intranasal administration of current vaccines has proven inconsistent3-7, suggesting that alternative immunization strategies may be required. Here we show that intratracheal boosting with a bivalent Ad26 based SARS-CoV-2 vaccine results in substantial induction of mucosal humoral and cellular immunity and near complete protection against SARS-CoV-2 BQ.1.1 challenge. 40 previously immunized rhesus macaques were boosted with a bivalent Ad26 vaccine by the intramuscular, intranasal, and intratracheal routes or with a bivalent mRNA vaccine by the intranasal route. Ad26 boosting by the intratracheal route led to substantial expansion of mucosal neutralizing antibodies, IgG and IgA binding antibodies, and CD8+ and CD4+ T cell responses, which exceeded those induced by Ad26 boosting by the intramuscular and intranasal routes. Intratracheal Ad26 boosting also led to robust upregulation of cytokine, NK, T and B cell pathways in the lung. Following high-dose SARS-CoV-2 BQ.1.1 challenge, intratracheal Ad26 boosting provided near complete protection, whereas the other boosting strategies proved less effective. Protective efficacy correlated best with mucosal humoral and cellular immune responses. These data demonstrate that novel immunization strategies induce robust mucosal immunity, suggesting the feasibility of developing vaccines that block respiratory viral infections.


Right arm involvement and pain extension can help to differentiate coronary diseases from chest pain of other origin: a prospective emergency ward study of 278 consecutive patients admitted for chest pain.
In a prospective study of 278 consecutive patients admitted to an emergency ward for chest pain, the 115 clinical and paraclinical parameters available at the time of admission were evaluated by computer comparison with the final diagnoses. The most valuable items for making the diagnosis were classified according to their sensitivity, specificity and predictive value. Among the 278 patients, 100 individuals had myocardial infarctions (MI), 47 had unstable angina, 25 had stable angina and 106 patients had a non-coronary disease. The twelve most sensitive items for distinguishing MI from other conditions were the following: sudden onset of pain (70%); duration of more than 60 min (88%); constriction and squeezing (79%); oppression (75%); prior anginal attacks (61%); sex male (72%); age over 60 years (74%); abnormal heart auscultation (62%); abnormal electrocardiogram (ECG) (98%); segment (ST) disturbances (86%); increased glucose level (77%); CKMB fraction greater than 6% of total creatine kinase (CK) level (63%). Among the twelve most specific items, also with the best positive predictive value, irradiation in the right arm is of most importance; among the 51 patients with right arm involvement, 48 suffered from a coronary disease and 41 from a myocardial infarction. The largest extension of pain was reported in the latter group. It is concluded that chest pain with a wide irradiation involving the right arm strongly suggests that a myocardial infarction is ongoing.


Inflammation in IgA nephropathy.
Immunoglobulin A nephropathy (IgAN) is the most frequently occurring primary glomerulonephritis in Caucasian and Asian populations. Nonetheless, therapeutic recommendations are based on weak evidence, large controlled trials are scarce and, in particular, the additional value of immunosuppression beyond comprehensive supportive measures is not well-established. The use of immunosuppressants is supported by experimental insights into IgAN pathogenesis that suggest an autoimmune component in disease development. The so-called "multi-hit" theory comprises multiple steps, starting with defective glycosylation of IgA subclass IgA1 that results in overproduction of galactose-deficient IgA1 (Gd-IgA1), occurrence of anti-Gd-IgA1 autoantibodies, and mesangial deposition of nephritogenic immune complexes. This eventually results in an increased mesangial cell proliferation, inflammatory responses, and complement activation. Recent genome-wide association studies have identified several susceptibility genes, many of which support the "multi-hit" concept. In light of these discoveries, it is astonishing that the vast majority of adult IgAN patients obviously do not need and/or benefit from immunosuppressive therapies in the first place. In fact, a number of supportive measures are highly effective in reducing the risk for disease progression in many patients. These measures need to be optimized before immunosuppression should be considered at all. In this review we focus on the underlying pathogenetic cornerstones and the central question of whether systemic inflammation in adult IgAN patients should be treated. Treatment options in children with IgAN are also discussed.


Home-Based Psychoeducational Intervention for Breast Cancer Survivors.
It is important to manage psychological distress and improve the quality of life (QOL) in patients after breast cancer treatment. The aim of this study was to evaluate the effects of a home-based, psychoeducational program on distress, anxiety, depression, and QOL in breast cancer survivors. The study was a single-group pretest and posttest quasi-experimental design. The data were collected using the Distress Thermometer, the Hospital Anxiety and Depression Scale, and the Turkish version of the World Health Organization Quality of Life Instrument, short form. The home-based, individual, face-to-face psychoeducational program was structured according to breast cancer survivors' needs and the Neuman Systems Model. A total of 32 Turkish breast cancer survivors participated in this study. There were statistically significant differences in the mean scores for distress, anxiety, and depression in the breast cancer survivors over 4 measurements. The mean scores for all subscales of the QOL at 6 months postintervention were significantly higher than the mean scores at baseline. The results indicated that the psychoeducational program may be effective in reducing distress, anxiety, and depression and in improving the QOL in breast cancer survivors. Psychoeducational programs may be effective and should be considered as part of the survivorship care for breast cancer survivors.


Epidemiologic, clinical, diagnostic and therapeutic aspects of visceral leishmaniasis in renal transplant recipients: experience from thirty cases.
Visceral leishmaniasis is a disease caused by the protozoan Leishmania sp. and is transmitted by Lutzomyia longipalpis (sand fly). In renal transplant recipients, visceral leishmaniasis causes severe damage to the liver, spleen, and hematopoietic system, as well as poor outcomes for patients with transplanted kidneys. This study describes the largest series of cases of visceral leishmaniasis in renal transplant recipients, providing important information about the diagnostic routines and therapeutic strategies in this patient population. A retrospective, descriptive study was performed to analyze the distribution and evaluate the extent of the epidemiologic, clinical, diagnostic and therapeutic aspects of 30 renal transplant recipients from endemic regions who presented with visceral leishmaniasis in the post-transplantation period. In this study, visceral leishmaniasis was more frequent in men (80%). The mean age of presentation was 40 ± 10.5 years. The majority of patients worked in urban areas (66.7%), cohabitated with domestic animals (90%), and were from low-income households. In 73.3% of cases, diagnosis was made by direct isolation of Leishmania forms. Patients were treated with liposomal amphotericin, resulting in a high degree of disease remission (80%). This study describes the largest series of visceral leishmaniasis in renal transplant recipients and expands clinical-epidemiological knowledge for transplantation teams to perform adequate disease management for this specific patient population.


Pembrolizumab with or without enzalutamide in selected populations of men with previously untreated metastatic castration-resistant prostate cancer harbouring programmed cell death ligand-1 staining: a retrospective study.
The purpose of this retrospective study was to evaluate the survival outcomes of pembrolizumab (PEM) plus enzalutamide (ENZ) versus PEM alone in selected populations of men with previously untreated metastatic castration-resistant prostate cancer (mCRPC) harbouring programmed cell death ligand-1 (PD-L1) staining. Consecutive men with previously untreated mCRPC harbouring PD-L1 staining who underwent treatment with PEM plus ENZ (PE) or PEM alone (PA) at our medical centre from January 1, 2017, to January 31, 2021, were retrospectively identified. Follow-up was conducted monthly during the first year and then every 1 month thereafter. The primary outcomes of the study were overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the frequency of key adverse events (AEs). In total, 302 men were retrospectively reviewed, 96 of whom were deemed to be ineligible per the exclusion criteria, leaving 206 men (PE: n = 100, median age 64 years [range, 43-85] and PA: n = 106, 65 years [range, 45-82]) who were eligible for the study. The median follow-up for both groups was 34 months (range, 2-42). At the final follow-up, the median OS was 25.1 months (95% confidence interval [CI], 22.3-27.6) in the PE group versus 18.3 months (95% CI, 16.5-20.9) in the PA group (hazard ratio [HR] 0.56; 95% CI, 0.39-0.80; p = 0.001). A marked distinction was also observed in the median PFS (6.1 months [95% CI, 4.7-7.8] for PE vs. 4.9 months for PA (95% CI, 3.2-6.4) for PA; HR 0.55, 95% CI, 0.41-0.75; p = 0.001). There were noteworthy differences in the rate of the key AEs between the two groups (72.0% for PE vs. 45.3% for PA, p < 0.001). Noteworthy differences were also detected for fatigue events (7.0% in the PE group vs. 0.9% in the PA group, p = 0.025) and musculoskeletal events (9.0% for PE vs. 0.9% for PA, p = 0.007), but these events tended to be manageable. Among selected populations of men with previously untreated mCRPC harbouring PD-L1 staining, PEM added to ENZ treatment may significantly increase the survival benefits compared with PEM treatment alone regardless of tumor mutation status. The safety profile for PE plus ENZ tends to be manageable.


Mouse response to influenza immunosomes.
Immunosome preparations consisting of surface glycoproteins, extracted from five influenza virus strains and anchored onto performed liposomes, were tested in mice. Serum antibody responses were essentially similar to those elicited by whole virus vaccines and higher than responses induced by subunit preparations. Antibody titres were assessed by haemagglutination-inhibition technique. Survival of mice immunized with 6 micrograms haemagglutinin of attenuated, inactivated, subunit or immunosome A/Aichi/2/68 vaccines and later challenged with variants of the same subtype was also assessed. All vaccine preparations induced similar percentage survival when mice were challenged with variants prevalent from 1968 to 1977. However, the attenuated vaccine induced a significant higher protection level against the 1979 variant.


Fluorescence microscopy methods for examining telomeres during cell aging.
Telomeres are protective structures, composed of nucleic acids and a complex protein mixture, located at the end of the chromosomes. They play an important role in preventing genomic instability and ensuring cell health. Defects in telomere integrity result in cell dysfunction and the development of diseases, including neurodegenerative disorders, cancer and premature aging syndromes, among others. Loss of telomere integrity during normal cell aging also initiates DNA damage signals that culminate in the senescence phenotype. Fluorescence microscopy has allowed researchers to study the dynamics, shape, localization, and co-distribution of telomeres with proteins of interest. The microscopy tools to investigate these structures have evolved, making it possible to understand in greater detail the molecular mechanisms affecting telomeres that contribute to cell aging and the development of age-related diseases. Using human fibroblasts as an example, we will highlight several characteristics of telomeres that can be investigated using three different microscopy systems, including wide-field microscopy, and the two super-resolution techniques called 3D Structured Illumination Microscopy (3D-SIM) and direct Stochastic Optical Reconstruction Microscopy (dSTORM). In this review, we will also discuss their limitations and highlight their importance in answering telomere-related scientific questions.


Experimental insights into anodic oxidation of hexafluoropropylene oxide dimer acid (GenX) on boron-doped diamond anodes.
GenX is the trade name of the ammonium salt of hexafluoropropylene oxide dimer acid (HFPO-DA) and is used as a replacement for the banned perfluorooctanoic acid (PFOA). However, recent studies have found GenX to be more toxic than PFOA. This work deals with the electrochemical degradation of HFPO-DA using boron-doped diamond anodes. For the first time, an experimental study was conducted to investigate the influence of sulfate concentration and other operating parameters on HFPO-DA degradation. Results demonstrated that sulfate radicals were ineffective in HFPO-DA degradation due to steric hindrance by -CF3 branch. Direct electron transfer was found as the rate-determining step. By comparing degradation of HFPO-DA with that of PFOA, it was observed that the steric hindrance by -CF3 branch in HFPO-DA decreased the rate of electron transfer from the carboxyl head group even though its defluorination rate was faster. Conclusively, a degradation pathway is proposed in which HFPO-DA mineralizes to CO2 and F- via formation of three intermediates.


Research on measurement and improvement path of industrial green development in China: a perspective of environmental welfare efficiency.
The increasing concern about the environmental issue and its serious adverse effects on human health has made China's industrial green transformation being a matter of public concern. In this study, a network slack-based measure (NSBM) was applied to explore China's industrial green development level from the perspective of environmental welfare efficiency (EWE), considering not only the impact of industrial development on environment and economy, but also the impact on human well-being. Based on the data of 30 provincial administrative regions in China from 2004 to 2017, the comprehensive efficiency (CE) of China's industrial sector was measured and decomposed. The results show that the industrial production efficiency (IPE) is much higher than the EWE, and the improvement of the EWE will be the key to realize the green transformation of China's industry. On this basis, considering the effects of spatial interaction, the spatial Durbin model was established to analyze the driving factors of EWE. Finally, this research puts forward promotion path of industrial green development.


Isokinetic muscle assessment after treatment of pectoralis major muscle rupture using surgical or non-surgical procedures.
Rupture of the pectoralis major muscle appears to be increasing in athletes. However, the optimal treatment strategy has not yet been established. To compare the isokinetic shoulder performance after surgical treatment to that after non-surgical treatment for pectoralis major muscle rupture. We assessed 33 pectoralis major muscle ruptures (18 treated non-surgically and 15 treated surgically). Horizontal abduction and adduction as well as external and internal rotation at 60 and 120 degrees/s were tested in both upper limbs. Peak torque, total work, contralateral deficiency, and the peak torque agonist-to-antagonist ratio were measured. Contralateral muscular deficiency did not differ between the surgical and non-surgical treatment modalities. However, the surgical group presented twice the number of athletes with clinically acceptable contralateral deficiency (<20%) for internal rotators compared to the non-surgical group. The peak torque ratio between the external and internal rotator muscles revealed a similar deficit of the external rotation in both groups and on both sides (surgical, 61.60% and 57.80% and non-surgical, 62.06% and 54.06%, for the dominant and non-dominant sides, respectively). The peak torque ratio revealed that the horizontal adduction muscles on the injured side showed similar weakness in both groups (surgical, 86.27%; non-surgical, 98.61%). This study included the largest single series of athletes reported to date for this type of injury. A comparative analysis of muscular strength and balance showed no differences between the treatment modalities for pectoralis major muscle rupture. However, the number of significant clinical deficiencies was lower in the surgical group than in the non-surgical group, and both treatment modalities require greater attention to the rehabilitation process, especially for the recovery of muscle strength and balance.


Favourable pregnancy outcome in a woman with secondary pulmonary hypertension complicating mitral stenosis.
Pulmonary hypertension (PH) is a rare condition with a high incidence of maternal and perinatal mortality (30-56% and 10-13%, respectively). Pulmonary hypertension is a contraindication to pregnancy because of high risk of maternal death, therefore the World Health Organisation (WHO) advises to discuss a termination in the event of pregnancy with women suffering from PH.


Detection of secreted and intracellular annexin II by a radioimmunoassay.
A simple radioimmunoassay for detection of secreted and intracellular annexin II in human cells is presented. Annexin II is a multifunctional protein in human cells and may have a role in several types of cancers. No enzymatic activity has been associated with the protein, thus making its detection difficult. Using purified annexin II from human placenta, we have developed a sensitive radioimmunoassay protocol. A linear response was observed up to a concentration of 0.5 microgram purified protein in the assay. Using this radioimmunoassay protocol, annexin II can be detected in undiluted clinical human samples such as bronchoalveolar lavages and various tissue extracts. We demonstrate the applicability of this technique to measure intracellular annexin II in extracts of a human adenocarcinoma cell line (HeLa) and secreted annexin II from bronchoalveolar lavage fluid from a human patient. Using HeLa cell extracts and BAL, we observed a linear response with up to 10 micrograms total protein in the assay. We further demonstrate the applicability of this technique to measure differences in intracellular and secreted annexin II in the human pancreatic adenocarcinoma cell lines CD-11, CD-18 and Capan-2. While CD-11 and CD-18 do not secrete annexin II, the cell line Capan-2 secretes high levels of the protein.


Immobilization of glucose oxidase on graphene and cobalt phthalocyanine composite and its application for the determination of glucose.
We described a simple and facile chemical reduction strategy for the preparation of graphene (GR)-cobalt phthalocyanine (CoPc) composite and explored it for the enzymatic determination of glucose. CoPc is an active mediator and electrocatalysts for the immobilization of GOx and determination of glucose. However, it is not stable on the electrode surface and also suffers from lack of conductivity. Here, we have employed GR as the suitable support to stabilize CoPc through simple chemical reduction method and the resulting composite has been used for the glucose biosensor application. Scanning electron microscopy, X-ray diffraction and Energy-dispersive X-ray spectroscopy studies confirmed the successful formation of composite. Direct electron transfer of glucose oxidase (GOx) was observed with well defined redox peaks at the formal potential of -0.44 V. The amount of electroactive GOx (Г) and electron transfer rate constant (ks) were calculated to be 3.77×10(-10) mol cm(-2) and 3.57 s(-1), respectively. The fabricated amperometric biosensor detects glucose in wide linear concentration range from 10 μM to 14.8 mM with high sensitivity of 5.0 9μA mM(-1) cm(-2). The sensor offered very low detection limit (LOD) of 1.6 μM. In addition, practical feasibility of the sensor has been explored in screen printing carbon electrode with accurate determination of glucose present in human blood serum and urine samples. Furthermore, the sensor exhibited appreciable stability, repeatability and reproducibility results.


Rapid Anxiolytic Effects of RS67333, a Serotonin Type 4 Receptor Agonist, and Diazepam, a Benzodiazepine, Are Mediated by Projections From the Prefrontal Cortex to the Dorsal Raphe Nucleus.
Activation of serotonin (5-HT) type 4 receptors (5-HT4Rs) has been shown to have anxiolytic effects in a variety of animal models. Characterizing the circuits responsible for these effects should offer insights into new approaches to treat anxiety. We evaluated whether acute 5-HT4R activation in glutamatergic axon terminals arising from the medial prefrontal cortex (mPFC) to the dorsal raphe nucleus (DRN) induced fast anxiolytic effects. Anxiolytic effects of an acute systemic administration (1.5 mg/kg, intraperitoneally) or intra-mPFC infusion with the 5-HT4R agonist, RS67333 (0.5 μg/side), were examined in mice. To provide evidence that anxiolytic effects of RS67333 recruited an mPFC-DRN neural circuit, in vivo recordings of firing rate of DRN 5-HT neurons, cerebral 5-HT depletion, and optogenetic activation and silencing were performed. Acute systemic administration and intra-mPFC infusion of RS67333 produced fast anxiolytic effects and increased DRN 5-HT cell firing. Serotonin depletion prevented anxiolytic effects induced by mPFC infusion of RS67333. Surprisingly the anxiolytic effects of mPFC infusion diazepam (1.5 μg/side) were also blocked by 5-HT depletion. Optogenetically activating mPFC terminals targeting the DRN reduced anxiety, whereas silencing this circuit blocked RS67333 and diazepam mPFC infusion-induced anxiolytic effects. Finally, anxiolytic effects induced by an acute systemic RS67333 or diazepam administration were partially blocked after optogenetically inhibiting cortical glutamatergic terminals in the DRN. Our findings suggest that activating 5-HT4R acutely in the mPFC or targeting mPFC pyramidal cell terminals in the DRN might constitute a strategy to produce a fast anxiolytic response.


Immunogenicity and safety of AZD1222 (ChAdOx1 nCoV-19) against SARS-CoV-2 in Japan: a double-blind, randomized controlled phase 1/2 trial.
Immunogenicity and safety of the AZD1222 (ChAdOx1 nCoV-19) vaccine was evaluated in Japanese adults in an ongoing phase 1/2, randomized, double-blind, parallel-group, placebo-controlled, multi-centre trial (NCT04568031). Adults (n=256, age ≥18 years) seronegative for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were stratified by age into 18-55- (n=128), 56-69- (n=86) and ≥70-year-old cohorts (n=42), and randomized 3:1 to receive AZD1222 or placebo (two intramuscular injections 4 weeks apart). Immunogenicity and safety were coprimary endpoints. Data collected up to Day 57 are reported. Positive seroresponses to SARS-CoV-2 spike and receptor-binding domain antigens were seen in all 174 participants who received two doses of AZD1222. Neutralizing antibody seroresponses were seen in 67.5%, 60.3% and 50.0% of participants receiving AZD1222 aged 18-55, 56-69 and ≥70 years, respectively. Solicited adverse events (AEs) were typically mild/moderate in severity and included pain and tenderness at the injection site, malaise, fatigue, muscle pain and headache. Common unsolicited AEs included pain and tenderness at the injection site, fatigue and elevated body temperature. No vaccine-related serious AEs or deaths were reported. AZD1222 elicited a strong humoral immune response against SARS-CoV-2, and was well tolerated in Japanese participants, including elderly participants.


Relative frequencies and significance of faecal coliforms as indicators related to water temperature.
The faecal coliforms at different sites of a hypereutrophic lake near Valencia (Albufera) were identified and their relative amounts established along an annual cycle. Using lauryl tryptose broth at 35 degrees C, followed by incubation at 44.4 degrees C in 2% brilliant green bile, Escherichia coli and Klebsiella pneumoniae are practically the only coliforms present. A positive correlation was found between the water temperature and the relative amount of these two coliforms: K. pneumoniae predominates at high water temperatures, whereas E. coli shows preponderance during the cold period. The role of K. pneumoniae as the only faecal indicator under the circumstances described in the work is emphasized and discussed.


Tipless transseptal cannula concept combines improved hemodynamic properties and risk-reduced placement: An in silico proof-of-concept.
As a leading cause of death worldwide, heart failure is a serious medical condition in which many critically ill patients require temporary mechanical circulatory support (MCS) as a bridge-to-recovery or bridge-to-decision. In many cases, the TandemHeart system is used to unload the left heart by draining blood from the left atrium (LA) to the femoral artery via a transseptal multistage cannula. However, even though the correct positioning of the cannula is crucial for a safe treatment, the long cannula tip currently used in transseptal cannulas complicates positioning, making the cannula vulnerable to displacement during MCS. To overcome these limitations, we propose the development of a new tipless transseptal cannula with improved hemodynamic properties. We discuss the tipless cannula concept by comparing it to the common multistage cannula concept using computational fluid dynamics simulations and assess the flow field in the LA, the wall shear stresses (WSS), and the pressure loss. Across the two distinct time points of end-systole and end-diastole and two drainage flow rates of 3.5 and 5.0 L/min, we find a more homogeneous inlet flow pattern for the tipless cannula concept, accompanied by a remarkably reduced area of platelet-activating WSS (up to 10-times smaller area compared to the multistage cannula). Moreover, pressure loss is up to 14.5% lower in the tipless cannula concept, confirming overall improved hemodynamic properties of the tipless cannula concept. Finally, a diameter-dependent study reveals that lower WSS and pressure losses can be further reduced by large-lumen designs for any simulation setting. Overall, our results suggest that a tipless cannula concept remedies the crucial disadvantages of a long-tip multistage cannula by reducing the risk of misplacement, and it furthermore promotes optimized hemodynamics. With this successful proof-of-concept, we underscore the potential for and encourage the realization of further experimental investigations regarding the development of a tipless transseptal cannula for MCS.


Impaction bone grafting and a cemented cup after acetabular fracture.
Patients suffering from post traumatic osteoarthritis of the acetabulum often require a total hip arthroplasty at a relatively young age. Long-term data outcome studies for this population are lacking. We report on the long-term outcome of 20 acetabular fractures in 20 patients treated with impaction bone grafting and a cemented cup after a mean follow-up of 18 years (range, 12-26 years). The group consisted of 14 males (70%) and six females (30%) with an average age of 53.3 years (range, 35-75 years) at time of surgery. No patients were lost to follow-up. Four patients died and three patients underwent a revision; at review 13 patients were still living with their implant in situ. Survivorship analysis was performed at 20 years follow-up for three endpoints. Survival rate with endpoint revision for any reason at 20 years postoperative was 74.7% (95% confidence interval (CI), 40-91%), 80.0% (95% CI, 41-95%) for endpoint aseptic loosening, and 63.9% (95% CI 32-84%) for endpoint radiographic failure. Three acetabular components were revised at 14.5, 15.3, and 16.7 years postoperative. Two cups failed for aseptic loosening and one cup failed due to septic loosening. The average postoperative Harris hip score was 82 (range, 56-100). Acetabular reconstruction with impaction bone grafting and the use of a cemented cup after acetabular fracture is an attractive technique with acceptable long-term results and a low complication and re-operation rate.


GRB2 promotes thymocyte positive selection by facilitating THEMIS-mediated inactivation of SHP1.
The T-lineage restricted protein THEMIS has been shown to play a critical role in T cell development. THEMIS, via its distinctive CABIT domains, inhibits the catalytic activity of the tyrosine phosphatase SHP1 (PTPN6). SHP1 and THEMIS bind to the ubiquitous cytosolic adapter GRB2, and the purported formation of a tri-molecular THEMIS-GRB2-SHP1 complex facilitates inactivation of SHP1 by THEMIS. The importance of this function of GRB2 among its numerous documented activities is unclear as GRB2 binds to multiple proteins and participates in several signaling responses in thymocytes. Here, we show that similar to Themis-/- thymocytes, the primary molecular defect in GRB2-deficient thymocytes is increased catalytically active SHP1 and the developmental block in GRB2-deficient thymocytes is alleviated by deletion or inhibition of SHP1 and is exacerbated by SHP1 overexpression. Thus, the principal role of GRB2 during T cell development is to promote THEMIS-mediated inactivation of SHP1 thereby enhancing the sensitivity of TCR signaling in CD4+CD8+ thymocytes to low affinity positively selecting self-ligands.


Mapping and characterization of a sequential epitope on the rabies virus glycoprotein which is recognized by a neutralizing monoclonal antibody, RG719.
We have established a murine hybridoma cell line RG719 which produces a rabies virus-neutralizing IgM-type monoclonal antibody (referred to as MAb RG719). Immunoblot analysis indicated that the antibody recognized a sequential epitope of G protein. Among four rabies virus strains tested, the antigenicity to MAb RG719 was absent from the Nishigahara strain, while the other three strains (HEP, ERA and CVS) reacted to the MAb. Studies with deletion mutants of the G protein indicated that the epitope was located in a middle region of the primary structure of G protein, ranging from position 242 to 300. By comparing the estimated amino acid sequence of the four strains, we found in this region two amino acids (at positions 263 and 291) which are common to three of those strains but are not shared by the Nishigahara strain. The site-directed point mutagenesis revealed that replacement of phenylalanine-263 by leucine destroyed the epitope of the HEP G protein, while the epitope was generated on the Nishigahara G protein whose leucine-263 was replaced by phenylalanine. These observations suggest that phenylalanine-263 is essential for constructing the epitope for MAb RG719. The synthetic 20-mer peptide produced by mimicking the amino acid sequence (ranging from amino acid positions 249 to 268) of the presumed epitope region was shown to bind specifically to MAb RG719 and also to raise the virus-neutralizing antibodies in rabbits. Vaccination with the HEP vaccine produced in Japan induced in humans and rabbits production of significant amounts of the antibodies which reacted with the 20-mer peptide.


N-substituted tetrahydro-2,4-dioxoquinazolin-1-yl acetic acids as aldose reductase inhibitors.
Novel N-substituted tetrahydro-2,4-dioxoquinazolin-1-yl acetic acids characterized by formal replacement of the substituted benzyl moiety by cyclohexylmethyl and n-heptyl residues, respectively, were synthesized and evaluated as aldose reductase inhibitors.


Distributions of polycyclic aromatic hydrocarbons in the Daliao River Estuary of Liaodong Bay, Bohai Sea (China).
The distributions of 16 polycyclic aromatic hydrocarbons (PAHs) were determined in the aqueous phase, suspended particulate matter (SPM), sediment, and pore water of the Daliao River Estuary in Liaodong Bay, Bohai Sea (China). Total PAH concentrations ranged from 139.16 to 1717.87ngL(-1) in surface water, from 226.57 to 1404.85ngL(-1) dry weight in SPM, from 276.26 to 1606.89ngg(-1) dry weight in sediments, and from 10.20 to 47.27microgL(-1) in pore water. PAH concentrations were at relatively moderate levels in water, SPM, sediment and pore water in comparison with those reported for other estuary and marine systems around the world. Sedimentary PAH concentrations decreased offshore owing to active deposition of laterally-transported river-borne particles. PCA analysis of the possible PAH source suggested petrogenic and pyrolytic PAH inputs in the studied region.


The PRP19 Ubiquitin Ligase, Standing at the Cross-Roads of mRNA Processing and Genome Stability.
mRNA processing factors are increasingly being recognized as important regulators of genome stability. By preventing and resolving RNA:DNA hybrids that form co-transcriptionally, these proteins help avoid replication-transcription conflicts and thus contribute to genome stability through their normal function in RNA maturation. Some of these factors also have direct roles in the activation of the DNA damage response and in DNA repair. One of the most intriguing cases is that of PRP19, an evolutionarily conserved essential E3 ubiquitin ligase that promotes mRNA splicing, but also participates directly in ATR activation, double-strand break resection and mitosis. Here, we review historical and recent work on PRP19 and its associated proteins, highlighting their multifarious cellular functions as central regulators of spliceosome activity, R-loop homeostasis, DNA damage signaling and repair and cell division. Finally, we discuss open questions that are bound to shed further light on the functions of PRP19-containing complexes in both normal and cancer cells.


[Effects of balanced fertilization and soil amendment on growth and yield of sanqi in continuous cropping].
To explore the solution of continuous cropping obstacle of Panax notoginseng. The effects of balanced fertilization and soil amendment on the emergence rate, survival rate, growth and yield of P. notoginseng were studied with a pot culture experiment in 3-year-interval continuous cropping soil. The result showed that the content of total N, total P, available N, available P and other available components in continuous cropping soil were higher than those in fresh soil while available K and the rate of K/N were declined, and available Cu and some other micro elements were lack. The way of balanced fertilization "low N + fused calcium-magnesium-phosphate fertilizer + high K + lime + micro elements" would significantly enhance the rate of survival, biomass and yield. It also promoted the growth of P. notoginseng in continuous cropping. The bagasse could relieve the continuous cropping obstacle obviously, the survival rate was improved for 31.6% and the yield of medicinal materials was 19.5%. The fly ash had also some effect in relieving the continuous cropping obstacle. The overall results suggested that the adequate fertilization plan is the applying lime, reducing N, applying calcium-magnesium-phosphate fertilizer, improving K and supplying mircoelement as well as applying bagasse to resolve the problem of continuous cropping obstacle of P. notoginseng.


Diagnosis of Indigenous Non-Malarial Vector-Borne Infections from Malaria Negative Samples from Community and Rural Hospital Surveillance in Dhalai District, Tripura, North-East India.
The aetiology of non-malaria vector-borne diseases in malaria-endemic, forested, rural, and tribal-dominated areas of Dhalai, Tripura, in north-east India, was studied for the first time in the samples collected from malaria Rapid Diagnostic Kit negative febrile patients by door-to-door visits in the villages and primary health centres. Two hundred and sixty serum samples were tested for the Dengue NS1 antigen and the IgM antibodies of Dengue, Chikungunya, Scrub Typhus (ST), and Japanese Encephalitis (JE) during April 2019-March 2020. Fifteen Dengue, six JE, twelve Chikungunya, nine ST and three Leptospirosis, and mixed infections of three JE + Chikungunya, four Dengue + Chikungunya, three Dengue + JE + Chikungunya, one Dengue + Chikungunya + ST, and one Dengue + ST were found positive by IgM ELISA tests, and four for the Dengue NS1 antigen, all without any travel history. True prevalence values estimated for infections detected by Dengue IgM were 0.134 (95% CI: 0.08-0.2), Chikungunya were 0.084 (95% CI: 0.05-0.13), Scrub were 0.043 (95% CI: 0.01-0.09), and Japanese Encephalitis were 0.045 (95% CI: 0.02-0.09). Dengue and Chikungunya were associated significantly more with a younger age. There was a lack of a defined set of symptoms for any of the Dengue, Chikungunya, JE or ST infections, as indicated by the k-modes cluster analysis. Interestingly, most of these symptoms have an overlapping set with malaria; thereby, it becomes imperative that malaria and these non-malaria vector-borne disease diagnoses are made in a coordinated manner. Findings from this study call for advances in routine diagnostic procedures and the development of a protocol that can accommodate, currently, in practicing the rapid diagnosis of malaria and other vector-borne diseases, which is doable even in the resource-poor settings of rural hospitals and during community fever surveillance.


Thyroid gland metastasis mimicking thyroid carcinoma in a lung cancer patient and dramatic response to crizotinib: A case report.
Metastasis of lung adenocarcinoma to the thyroid is extremely rare. Since treatment for primary thyroid cancer and non thyroid malignancy is totally different, precise diagnosis is clinically important.


Fentanyl Inhibits Lung Cancer Viability and Invasion via Upregulation of miR-331-3p and Repression of HDAC5.
Non-small cell lung cancer (NSCLC) accounts for more than 80% of lung cancer cases and remains the primary cause of cancer-related deaths worldwide. Fentanyl is a commonly utilized anesthetic during the process of tumor resection, and exhibits inhibitory effects on the progression of numerous cancer types, including pancreatic cancer, colorectal cancer and gastric cancer. However, the effects of fentanyl on the cell viability and invasion of NSCLC has not been investigated. Current study aimed to investigate the effects and the mechanisms underlying the effects of fentanyl on NSCLC. The expression of μ-opioid receptor (MOR) was proved by flow cytometry. The expression of microRNA-331-3p (miR-331-3p) and histone deacetylase 5 (HDAC5) in NSCLC tissues and cell lines are evaluated by reverse transcription-quantitative PCR (RT-qPCR) and Western blot, respectively. Cell viability and invasion are measured by cell counting kit-8 (CCK-8) assay and transwell assay, respectively. The interaction between miR-331-3p and 3'-untranslated region (UTR) of HDAC5 is predicted by TargetScan 7.1 (http://www.targetscan.org/vert_71/), validated by dual luciferase assay, RT-qPCR and Western blot. There was lower miR-331-3p expression and higher HDAC5 expression in NSCLC cell lines A549 and CALU-1 compared with BEAS-2B, which was reversed by fentanyl administration. miR-331-3p targeted 3'-UTR of HDAC5 in NSCLC cell lines A549 and CALU-1. miR-331-3p inhibitor partially abrogated the inhibitory effects of fentanyl on NSCLC cell viability and invasion by targeting HDAC5. In addition, there was higher HDAC5 expression and lower miR-331-3p expression in tumor tissues which were isolated from patients with NSCLC compared to the adjacent normal tissues, and miR-331-3p was negatively correlated with HDAC5 in NSCLC tumor tissues. Fentanyl inhibits the viability and invasion of NSCLC cells by induction of miR-331-3p and reduction of HDAC5.


Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer.
Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa). To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active surveillance (AS). Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively. Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis. Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR)=1.96 (95% confidence interval [CI]=1.004-3.84, p=0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR=2.74 (95% CI=1.26-5.96, p=0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p=0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3+3 at diagnosis to GS ≥4+3 (4.1% vs 0.7%, p=0.01) versus GS 3+4 (2.1% vs 0.6%; p=0.03). Results are limited by the small number of mutation carriers and an intermediate end point. Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS. Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer.


Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology.
Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one of its least studied members. We discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. By combining genomics with functional in vivo and in vitro assays, we show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS mutation affects CHD6 protein folding and impairs its ability to recruit co-remodelers in response to DNA damage or autophagy stimulation. This leads to accumulation of DNA damage burden and senescence-like phenotypes. We therefore uncovered a molecular mechanism explaining HSS onset via chromatin control of autophagic flux and genotoxic stress surveillance.


Joint estimation of CD4+ cell progression and survival in untreated individuals with HIV-1 infection.
We compiled the largest dataset of seroconverter cohorts to date from 25 countries across Africa, North America, Europe, and Southeast/East (SE/E) Asia to simultaneously estimate transition rates between CD4 cell stages and death, in antiretroviral therapy (ART)-naive HIV-1-infected individuals. A hidden Markov model incorporating a misclassification matrix was used to represent natural short-term fluctuations and measurement errors in CD4 cell counts. Covariates were included to estimate the transition rates and survival probabilities for each subgroup. The median follow-up time for 16 373 eligible individuals was 4.1 years (interquartile range 1.7-7.1), and the mean age at seroconversion was 31.1 years (SD 8.8). A total of 14 525 individuals had recorded CD4 cell counts pre-ART, 1885 died, and 6947 initiated ART. Median (interquartile range) survival for men aged 20 years at seroconversion was 13.0 (12.4-13.4), 11.6 (10.9-12.3), and 8.3 years (7.9-8.9) in Europe/North America, Africa, and SE/E Asia, respectively. Mortality rates increase with age (hazard ratio 2.22, 95% confidence interval 1.84-2.67 for >45 years compared with <25 years) and vary by region (hazard ratio 2.68, 1.75-4.12 for Africa and 1.88, 1.50-2.35 for Asia compared with Europe/North America). CD4 cell decline was significantly faster in Asian cohorts compared with Europe/North America (hazard ratio 1.45, 1.36-1.54). Mortality and CD4 cell progression rates exhibited regional and age-specific differences, with decreased survival in African and SE/E Asian cohorts compared with Europe/North America and in older age groups. This extensive dataset reveals heterogeneities between regions and ages, which should be incorporated into future HIV models.


Do the young and the old perceive emotional intervals differently when shown on a younger or older face?
Many authors have analysed the effects of emotion recognition on time perception, showing that the more arousing the stimuli are the greater is the effect on duration perception. Visual stimuli, in particular faces, are the most recurrent stimuli employed in the literature. However, pictures in which emotional faces of older individuals have rarely been used, and when used, only young participants were tested. Hence, the present study is designed not only to analyse differences as regards duration perception in younger and older participants, but also to investigate the effects of neutral, happy, and angry facial expressions on younger and older participants when younger or older faces express those emotions. Results showed overestimation when emotional stimuli were presented. Interestingly, we observed temporal underestimation when the temporal intervals were marked by the image of younger participants and this was true in particular for older adults participants. Results are discussed in accordance with the internal clock model and in accordance with an inferential/reconstructive process occurring in memory and acting on temporal judgments.


Use of nicotine replacement therapy in adolescent smokers and nonsmokers.
Assessing whether and how adolescents use nicotine replacement therapy (NRT) will be important given recent recommendations to make NRT more accessible by lowering its price, increasing its distribution, and advising health care professionals to suggest its use for smoking cessation. To report the prevalence, ease of access, and reasons for NRT use and describe inappropriate use in adolescent smokers and nonsmokers. Cross-sectional survey of 4078 high school students during the school term of 1998. City schools in Memphis, Tenn. Community-based self-reported prevalence of NRT use and characteristics of those using NRT. Approximately 5% of adolescents reported trying or using nicotine gum or patches. Females were less likely than males and African Americans were less likely than others to use NRT. For African American smokers, NRT use was highest at lower smoking levels, while other smokers showed the opposite pattern. Almost 40% of former smokers reported using NRT to try to quit smoking; however, 75% of current smokers endorsed using NRT for reasons other than trying to quit smoking. Other inappropriate use of NRT was reported; 18% of NRT users reported themselves as never smokers. More than 50% of students reported that it would be easy for them to get NRT. Nicotine replacement therapy is used by adolescent smokers and nonsmokers, is easily accessible, and is used for reasons other than trying to quit smoking. Efforts are needed to discourage NRT use in nonsmoking youth and to encourage appropriate use of NRT in young smokers to maximize its potential for successful cessation.


H2O2 scavenging inhibits G1/S transition by increasing nuclear levels of p27KIP1.
The aim of the present study was to evaluate cell cycle regulation by scavenging H(2)O(2) in tumor cells. A significant arrest in the G1 phase of the cell cycle was demonstrated in CH72-T4 carcinoma cells exposed to catalase, associated with a decrease in cyclin D1 and an increase in the CDK inhibitory protein p27(KIP1). Moreover, we found a differential intracellular distribution of p27(KIP1), which remained in the nucleus after catalase treatment. In vivo experiments showed an increase in nuclear levels of p27(KIP1) associated with the inhibition of tumor growth by H(2)O(2) scavenging, confirming in vitro results. To conclude, H(2)O(2) scavenging may induce cell cycle arrest through the modulation of cyclin D1 and p27(KIP1) levels and nuclear localization of p27(KIP1). To our knowledge, this is the first report that demonstrates that the modulation of ROS alters the intracellular localization of a key regulatory protein of G1/S transition.


Roles of Phosphatidylinositol 4-Phosphorylation in Non-vesicular Cholesterol Trafficking.
Cholesterol (Chol) is an essential component of all eukaryotic cell membranes that affects the function of numerous peripheral as well as integral membrane proteins. Chol is synthesized in the ER, but it is selectively enriched within the plasma membrane (PM) and other endomembranes, which requires Chol to cross the aqueous phase of the cytoplasm. In addition to the classical vesicular trafficking pathways that are known to facilitate the bulk transport of membrane intermediates, Chol is also transported via non-vesicular lipid transfer proteins that work primarily within specialized membrane contact sites. Some of these transport pathways work against established concentration gradients and hence require energy. Recent studies highlight the unique role of phosphoinositides (PPIns), and phosphatidylinositol 4-phosphate (PI4P) in particular, for the control of non-vesicular Chol transport. In this chapter, we will review the emerging connection between Chol, PPIns, and lipid transfer proteins that include the important family of oxysterol-binding protein related proteins, or ORPs.


Moving from efficacy to effectiveness trials in prevention research.
Efficacy trials test whether interventions work under optimal, highly controlled conditions whereas effectiveness trials test whether interventions work with typical clients and providers in real-world settings. Researchers, providers, and funding bodies have called for more effectiveness trials to understand whether interventions produce effects under ecologically valid conditions, which factors predict program effectiveness, and what strategies are needed to successfully implement programs in practice settings. The transition from efficacy to effectiveness with preventive interventions involves unique considerations, some of which are not shared by treatment research. The purpose of this article is to discuss conceptual and methodological issues that arise when making the transition from efficacy to effectiveness research in primary, secondary, and tertiary prevention, drawing on the experiences of two complimentary research groups as well as the existing literature. We address (a) program of research, (b) intervention design and conceptualization, (c) participant selection and characteristics, (d) providers, (e) context, (f) measurement and methodology, (g) outcomes, (h) cost, and (i) sustainability. We present examples of research in eating disorder prevention that demonstrate the progression from efficacy to effectiveness trials.


Ethanologenesis and respiration in a pyruvate decarboxylase-deficient Zymomonas mobilis.
Zymomonas mobilis is an alpha-proteobacterium with a rapid ethanologenic pathway, involving Entner-Doudoroff (E-D) glycolysis, pyruvate decarboxylase (Pdc) and two alcohol dehydrogenase (ADH) isoenzymes. Pyruvate is the end-product of the E-D pathway and the substrate for Pdc. Construction and study of Pdc-deficient strains is of key importance for Z. mobilis metabolic engineering, because the pyruvate node represents the central branching point, most novel pathways divert from ethanol synthesis. In the present work, we examined the aerobic metabolism of a strain with partly inactivated Pdc. Relative to its parent strain the mutant produced more pyruvate. Yet, it also yielded more acetaldehyde, the product of the Pdc reaction and the substrate for ADH, although the bulk ADH activity was similar in both strains, while the Pdc activity in the mutant was reduced by half. Simulations with the kinetic model of Z. mobilis E-D pathway indicated that, for the observed acetaldehyde to ethanol production ratio in the mutant, the ratio between its respiratory NADH oxidase and ADH activities should be significantly higher, than the measured values. Implications of this finding for the directionality of the ADH isoenzyme operation in vivo and interactions between ADH and Pdc are discussed.


Clopidogrel in non-ST segment elevation acute coronary syndromes: an overview of the submission by the British Cardiac Society and the Royal College of Physicians of London to the National Institute for Clinical Excellence, and beyond.
A comprehensive appraisal was undertaken on behalf of the British Cardiac Society and the Royal College of Physicians of London to assess the use of clopidogrel in acute coronary syndromes. The appraisal was submitted to the National Institute for Clinical Excellence (NICE) in August 2003 and contributed to the development of the recently published guidelines for the use of clopidogrel in acute coronary syndromes. The submission to NICE and more recent publications evaluating the use of clopidogrel are reviewed.


Absence of receptor outer segments in the retina of rds mutant mice.
In mice homozygous for the newly reported rds (retinal degeneration slow) gene, a progressive loss of visual cells occurs throughout life. Histogenesis of the retina proceeds normally with the exception of the receptor layer which remains rudimentary. Electron microscopic observations of the retina at different stages of development have revealed that the outer segments of the visual cells in this mutant fail to develop and that the receptor layer consists of inner segments only. In the absorption spectra of the retinal extract from the mutant the characteristic rhodopsin peak is lacking.


Additive or Multiplicative? Predicting Academic Outcomes from Self-Regulation and Context.
Many studies have documented the role of self-regulation in predicting academic outcomes. However, fewer have comprehensively measured self-regulation or considered it simultaneously with contextual variables to test formally the often-advanced "risk-buffering" hypothesis, wherein self-regulatory skill protects against contextual risk factors. In a large, regionally representative sample of U.S. adolescents, we linked self-reported demographics, self-regulation, and academic outcomes to Census data assessing neighborhood context and administrative data measuring economic disadvantage and achievement levels on state end-of-grade tests. We find inconsistent evidence for a risk-buffering role of self-regulation in the prediction of academic outcomes. Rather, we demonstrate that self-regulation is independently associated with academic outcomes, even when controlling for demographics and context.


Counter-current chromatographic separation of nucleic acid constituents with a hydrophilic solvent system.
Nucleic acid constituents such as nucleobases, nucleosides and nucleotides were separated by counter-current chromatography using type J coil planet centrifuge. The separation was performed with a hydrophilic solvent system composed of 1-propanol/800 mM potassium phosphate buffer (pH 7.4) (1:1, v/v) by eluting the lower aqueous phase at a flow-rate of 0.5 ml/min. Eight selected nucleic acid constituents (4.0 mg, 0.5 mg of each), uridine monophosphate (UMP), adenosine monophosphate (AMP), deoxyadenosine monophosphate (dAMP), uridine, urasile, deoxy uridine, adenosine and adenine were well resolved within 160 min.


Antimicrobial resistant Salmonella spp. isolated from double-crested cormorants (Phalacrocorax auritus) and common loons (Gavia immer) in Florida.
Antimicrobial resistant Salmonella spp. were found in double-crested cormorants and common loons in Florida. Single or multiple resistance occurred in all Salmonella agona isolates from cormorants, primarily to ampicillin, sulfonamids, streptomycin, neomycin, and kanamycin. Similar patterns of resistance were found in S. agona isolates from common loons. In addition, isolates of S. Saint paul from loons were found resistant to tetracycline and streptomycin, while 2 of 7 isolates of S. infantis were resistant to tetracycline only.


Effect of heat on foot-and-mouth disease virus (FMDV) in the components of milk from FMDV-infected cows.
Foot-and-mouth disease virus (FMDV) survived in skim milk, cream and the pelleted cellular debris components of milk obtained from FMDV-infected cows after pasteurization at 72 degrees C for 0-25 min. Virus was recovered from whole milk of infected cows after that milk was heated at 72 degrees C. for 5 min. and from the skim milk component after it was heated at the same temperature for 2 min. Evaporation of the whole milk samples after they were heated at 72 degrees C. for 3 min. did not inactivate the virus, but evaporation of infected skim milk samples after they were heated at 72 degrees C. for 0-5 min. did inactivate the virus. FMDV survived in the cream component after it was heated at 93 degrees C. for 0-25 min.


Characterization of macrolide efflux pump mef subclasses detected in clinical isolates of Streptococcus pyogenes isolated between 1999 and 2005.
The macrolide efflux mechanism of resistance, mef, was characterized in community-acquired respiratory tract infections with Streptococcus pyogenes. Fifty-four (4.6%) M phenotype isolates were screen tested as negative for mef(A). Of these 54 isolates, 5 (0.4%), 27 (2.3%), and 1 (0.1%) were considered to be mef(I) positive, a novel mosaic variant of mef, or a novel subclass of mef, respectively. This study shows (i) the definitive presence of mef(E) in S. pyogenes and its global distribution, (ii) the presence of a mosaic variant of mef composed of mef(A) and mef(E), (iii) the previously undescribed presence of mef(I) in S. pyogenes, and (iv) the presence of a novel subclass of mef in S. pyogenes.


Synthesis, characterization and biological studies of sulfonamide Schiff's bases and some of their metal derivatives.
A new series of Schiff base ligands derived from sulfonamide and their metal(II) complexes [cobalt(II), copper(II), nickel(II) and zinc(II)] have been synthesized and characterized. The nature of bonding and structure of all the synthesized compounds has been explored by physical, analytical and spectral data of the ligands and their metal(II) complexes. The authors suggest that all the prepared complexes possess an octahedral geometry. The ligands and metal(II) complexes have been screened for their in vitro antibacterial activity against bacterial strains, Escherichia coli, Shigella flexneri, Pseudomonas aeruginosa, Salmonella typhi and for antifungal activity against fungal strains, Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glabrata. These assays enabled the identification of the metal complexes as an effective antimicrobial agent with low cytotoxicity.


The impact of COVID-19 restrictions on needle and syringe programme provision and coverage in England.
The restrictions introduced in response to COVID-19 present many challenges, particularly for vulnerable and marginalised populations. These include maintaining access to Needle and Syringe Programmes (NSPs) to reduce the harms associated with injecting drugs. NSPs effectiveness is coverage dependent, but lockdowns and social distancing limit NSP access and availability. The impact on NSP provision in England is explored using enhanced monitoring data. Data collected through an established comprehensive regional monitoring system from five four-week periods, centred on the implementation of restrictions in the UK in mid-March 2020, are examined. Weekly averages are compared to allow for public holidays and weekly variation in activity. The restrictions resulted in the number of NSP clients decreasing by 36%, visits by 36%, and needles distributed by 29%. NSP coverage for those injecting psychoactive drugs halved, declining from 14 needles per-week during the 4-weeks to 15th March 2020 to 7 needles per-week by mid-April, and coverage has remained at this level since then. Though it is currently unclear if there has been a decline in injecting, the decline in NSP coverage is so marked that it almost certainly reflects decreased utilisation among those in need, indicating increased equipment reuse and risk.


Variability in susceptibility of the nervous system to toxic insult.
There is a marked variability in the susceptibility of different cell types in the nervous system to toxic insult. Some of this variation is associated with factors related to the specific functions of the cells, but some also reflects genetic differences in metabolism. It is important that the role of genetic polymorphisms are considered, along with the broader aspects of susceptibility to neurotoxins, in the development of certain neurological disorders.


Growth dependent induction of high affinity gamma-amino-butyric acid transport in cultures of a normal human brain cell line.
Dense, growth inhibited cultures of the human putative glial cell line U-787CG were found to take up gamma-aminobutyric acid (GABA) via a high-affinity transport mechanism (Km = 1.2 microM) not detectable in sparse, rapidly growing cultures. The uptake of GABA was essentially the same in young and old dense cultures indicating that the induction of the high-affinity GABA transport was dependent on cell density and/or growth rate rather than time in culture after trypsinization.


Formation and repair of unavoidable, endogenous interstrand cross-links in cellular DNA.
Genome integrity is essential for life and, as a result, DNA repair systems evolved to remove unavoidable DNA lesions from cellular DNA. Many forms of life possess the capacity to remove interstrand DNA cross-links (ICLs) from their genome but the identity of the naturally-occurring, endogenous substrates that drove the evolution and retention of these DNA repair systems across a wide range of life forms remains uncertain. In this review, we describe more than a dozen chemical processes by which endogenous ICLs plausibly can be introduced into cellular DNA. The majority involve DNA degradation processes that introduce aldehyde residues into the double helix or reactions of DNA with endogenous low molecular weight aldehyde metabolites. A smaller number of the cross-linking processes involve reactions of DNA radicals generated by oxidation.


Low free testosterone is associated with increased mortality in frail surgical patients.
Preoperative frailty has been associated with adverse postoperative outcomes. Additionally, low testosterone has been associated with physical frailty and cognitive decline. However, the impact of simultaneous frailty and low testosterone on surgical outcomes is understudied. Preoperative frailty status and testosterone levels were obtained in patients undergoing a diverse range of surgical procedures. Preoperative frailty was evaluated independently and in combination with testosterone through the creation of composite risk groups. Relationships between preoperative frailty and composite risk groups with overall survival were determined using Kaplan-Meier and logistic regression analyses. Bivariate analysis was used to determine the associations between frailty and testosterone status on postoperative complications, length of hospital stay, and readmission rates. Median age of the cohort was 63 years, and the median follow-up time was 105 weeks. Thirty-one patients (23%) were frail, and 36 (27%) had low free testosterone. Bivariate analysis demonstrated a statistically significant relationship between preoperative frailty and overall survival (P = .044). In multivariate analysis, coexisting frailty and low free testosterone were significantly associated with decreased overall survival (hazard ratio 4.93, 95% confidence interval, 1.68-14.46, P = .004). We observed preoperative frailty, both independently and in combination with low free testosterone levels, to be significantly associated with decreased overall survival across various surgical procedures. Personalizing the surgical risk assessment through the incorporation of preoperative frailty and testosterone status may serve to improve the prognostication of patients undergoing major surgery.


Effect of Exogenous Application of Nicotinic Acid on Morpho-Physiological Characteristics of Hordeum vulgare L. under Water Stress.
Abiotic stresses, such as high temperature and drought conditions, greatly influence the development of plants and the quality and quantity of products. Barley (Hordeum vulgare L.) crop production is largely impacted by drought, affecting growth, yield, and ultimately the productivity of the crop in hot arid/semi-arid conditions. The current pot experiment was directed to observe the outcome of nicotinic acid (NA) treatments on barley's physiological, biochemical, and production attributes at two capacity levels, i.e., 100% normal range and withholding water stress. Randomized complete block design (RCBD) was used during the experimentation with the two-factor factorial arrangement. NA was applied exogenously by two different methods, i.e., foliar and soil application (fertigation). NA solution contained various application levels, such as T1 = control, foliar applications (T2 = 0.7368 gL-1, T3 = 1.477 gL-1, T4 = 2.2159 gL-1), and soil applications (T5 = 0.4924 gL-1, T6 = 0.9848 gL-1, and T7 = 1.4773 gL-1). Results depicted that, overall, foliar treatments showed better effects than control and soil treatments. Plant growth was preeminent under T4 treatment, such as plant height (71.07 cm), relative water content (84.0%), leaf water potential (39.73-MPa), leaf area index (36.53 cm2), biological yield (15.10 kgha-1), grain yield (14.40 kgha-1), harvest index (57.70%), catalase (1.54 mmolg-1FW-1), peroxidase (1.90 g-1FWmin-1), and superoxide dismutase (52.60 µgFW-1) were superior under T4 treatment. Soil plant analysis development (54.13 µgcm-2) value was also higher under T4 treatment and lowest under T7 treatment. In conclusion, NA-treated plants were more successful in maintaining growth attributes than non-treated plants; therefore, the NA foliar treatment at the rate of 2.2159 gL-1 is suggested to find economical crop yield under drought conditions. The present study would contribute significantly to improving the drought tolerance potential of barley through exogenous NA supply in water deficit areas.


Social Media and Psychological Well-Being Among Youth: The Multidimensional Model of Social Media Use.
Social media use is almost ubiquitous among adolescents and emerging adults. Although much has been studied about the psychological implications of social media use, there is currently no integrative model in which multiple dimensions of social media are considered. The goal of this theoretical article is to introduce the Multidimensional Model of Social Media Use (MMSMU), which aims to provide a useful framework for researchers and practitioners to study and understand young people's social media use in relation to their psychological well-being. The model attends to three major dimensions: activities performed on social media, motives for social media use, and communication partners connected through social media. We present empirical evidence showing whether each dimension is associated with better or poorer well-being and identify or propose mechanisms explaining the associations. Before concluding the article, we discuss clinical implications and possible ways to further expand the proposed model.


Evaluating the Quality of Rural Intensive Case Management Services using Administrative Data: an Exploratory Study.
Assertive Community Treatment (ACT) for people with severe mental illness is an effective approach that is increasingly implemented in rural areas. Low-cost methods of evaluating fidelity to program models are needed to assure services are delivered as intended. In 2007, the Veterans Health Administration implemented an ACT-like Mental Health Intensive Case Management (ACT/ICM) program for SMI veterans in rural areas. This study demonstrates the use of administrative data, reflecting patient characteristics and intensity of service delivery, to characterize services delivered by these programs, to compare them to general mental health programs at the same VA medical centers, and to each other. A total of 298,509 veterans received mental health services at VA medical centers that also operated a rural ACT/ICM program in FY 2012. Altogether 854 (0.29%) received ACT/ICM services for 1 year or more (long term participants) and 259 (.09%) received them for less than 1 year (new entrants). Logistic regression showed ACT/ICM patients were distinguished by diagnoses of schizophrenia, bipolar disorder, and major depression; larger numbers of psychiatric or substance abuse visits; and use of 3 or more classes of psychotropic medication. The model had a high c statistic of 0.91. Propensity scores allowed clear identification of programs most and least conforming to the profile of a "typical" rural ACT/ICM program. Low cost administrative data can be used to identify programs successfully conforming to an empirically derived rural model of ACT/ICM. Further validation of this approach is needed.


Presence, formation and putative biological activities of N-acyl serotonins, a novel class of fatty-acid derived mediators, in the intestinal tract.
Following the discovery of the endocannabinoid arachidonoyl ethanolamide (anandamide) and other N-acyl-ethanolamines, several other compounds have been found in which amino acids or neurotransmitters rather than ethanolamide are linked to fatty acids. Studies have shown that the local availability of fatty acid precursors, which in turn is modulated by dietary intake of lipids, determines the pattern of conjugates formed. Less information is available whether the same might be true for the amines or neurotransmitters involved. We hypothesized that N-arachidonoyl-serotonin (AA-5-HT) and its analogs could be endogenously present in those tissues that have high contents of serotonin. We investigated the endogenous presence of N-acyl serotonins in different parts of the gastro-intestinal tract of pigs and mice. We discovered that AA-5-HT, oleoyl-serotonin, palmitoyl-serotonin, and stearoyl-serotonin were endogenously present, particularly in the jejunum and ileum. Their formation in vitro was stimulated by the addition of serotonin to intestinal tissue incubations. Furthermore, in a mouse study we showed that the pattern of formation is dependent on the relative amount of fatty acids in the diet. The formation of docosahexaenoyl-serotonin and eicosapentaenoyl-serotonin was elevated in mice fed with a diet containing fish oil. Preliminary data showed that several of the serotonin conjugates are able to inhibit glucagon-like peptide-1 secretion and FAAH activity in vitro. Taken together, our data suggest that N-acyl serotonins are a novel class of lipid mediators present in the gut with highly promising biological properties.


Does obesity affect acetabular cup position, spinopelvic function and sagittal spinal alignment? A prospective investigation with standing and sitting assessment of primary hip arthroplasty patients.
Total hip arthroplasty (THA) instability is influenced by acetabular component positioning, spinopelvic function and sagittal spinal alignment. Obesity is considered as a risk factor of THA instability, but the causal relationship remains unknown. This study aimed to investigate the influence of BMI on (1) spinopelvic function (lumbar flexibility, pelvic mobility and hip motion), (2) sagittal spinal alignment pre- and postoperatively and (3) acetabular cup position postoperatively in primary THA patients in a prospective setting. One hundred ninety patients receiving primary total hip arthroplasty were enrolled in a prospective cohort study and retrospectively analysed. All patients received stereoradiography (EOS) in standing and relaxed sitting position pre-and postoperatively. C7-sagittal vertical axis (C7-SVA), lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), anterior plane pelvic tilt (APPT), and pelvic femoral angle (PFA) were assessed. Key parameters of the spinopelvic function were defined as lumbar flexibility (∆ LL = LLstanding - LLsitting), pelvic mobility (∆ PT = PTstanding - PTsitting) and hip motion (∆ PFA = PFAstanding - PFAsitting). Pelvic mobility was further defined based on ∆ PT as stiff, normal and hypermobile (∆ PT < 10°; 10°-30°; > 30°). The patients were stratified to BMI according to WHO definition: normal BMI ≥ 18.5-24.9 kg/m2 (n = 68), overweight ≥ 25.0-29.9 kg/m2 (n = 81) and obese ≥ 30-39.9 kg/m2 (n = 41). Post-hoc analysis according to Hochberg's GT2 was applied to determine differences between BMI groups. Standing cup inclination was significant higher in the obese group compared to the normal BMI group (45.3° vs. 40.1°; p = 0.015) whereas standing cup anteversion was significantly decreased (22.0° vs. 25.3°; p = 0.011). There were no significant differences for spinopelvic function key parameter lumbar flexibility (∆ LL), pelvic mobility (∆ PT) and hip motion (∆ PFA) in relation to BMI stratified groups. The obese group demonstrated significant enhanced pelvic retroversion compared to the normal BMI group (APPT - 1.8° vs. 2.4°; p = 0.028). The preoperative proportion of stiff pelvic mobility was decreased in the obese group (12.2%) compared to normal (25.0%) and overweight (27.2%) groups. Spinal sagittal alignment in C7-SVA and PI-LL mismatch demonstrated significantly greater imbalance in the obese group compared to the normal BMI group (68.6 mm vs. 42.6 mm, p = 0.002 and 7.7° vs. 1.2°, p = 0.032, respectively) The proportion of patients with imbalanced C7-SVA was higher in the obese (58.5%) than in the normal BMI group (44.1%). The significantly increased spinal sagittal imbalance with altered pelvic mechanics is a potential cause for the reported increased risk of THA dislocations in obese patients. Consequently, the increased spinal sagittal imbalance in combination with normal pelvic mobility need to be taken into account when performing THA in obese patients.


Data-driven resuscitation training using pose estimation.
Cardiopulmonary resuscitation (CPR) training improves CPR skills while heavily relying on feedback. The quality of feedback can vary between experts, indicating a need for data-driven feedback to support experts. The goal of this study was to investigate pose estimation, a motion detection technology, to assess individual and team CPR quality with the arm angle and chest-to-chest distance metrics. After mandatory basic life support training, 91 healthcare providers performed a simulated CPR scenario in teams. Their behaviour was simultaneously rated based on pose estimation and by experts. It was assessed if the arm was straight at the elbow, by calculating the mean arm angle, and how close the distance between the team members was during chest compressions, by calculating the chest-to-chest distance. Both pose estimation metrics were compared with the expert ratings. The data-driven and expert-based ratings for the arm angle differed by 77.3%, and based on pose estimation, 13.2% of participants kept the arm straight. The chest-to-chest distance ratings by expert and by pose estimation differed by 20.7% and based on pose estimation 63.2% of participants were closer than 1 m to the team member performing compressions. Pose estimation-based metrics assessed learners' arm angles in more detail and their chest-to-chest distance comparably to expert ratings. Pose estimation metrics can complement educators with additional objective detail and allow them to focus on other aspects of the simulated CPR training, increasing the training's success and the participants' CPR quality. Not applicable.


[Differential diagnosis of nasal obstruction].
Nasal obstruction can have a variety of different causes. The following text describes important diseases of the nose and paranasal sinuses, which are associated with the symptom of nasal obstruction and discusses specifics of diagnosis and therapy.


Are screening scales for bipolar disorder good enough to be used in clinical practice?
Bipolar disorder is often underdiagnosed. Recommendations for improving the detection of bipolar disorder include the use of screening questionnaires. The most widely studied screening scale is the Mood Disorders Questionnaire (MDQ). Studies of the performance of the MDQ in heterogeneous samples of psychiatric outpatients presenting for treatment have raised concerns about the adequacy of the MDQ as a screening measure because of its relatively low sensitivity. The sensitivity of a scale is not an inherent property of the instrument but depends on the threshold used to identify positive cases. Prior studies used the scoring recommendations of the developers of the MDQ to examine its performance; none examined the performance of the scale across the range of cutoff scores to determine whether a lower threshold would be more appropriate for the purposes of screening. The goal of the present study was to examine the operating characteristics of the MDQ at all cutoff scores to determine the cutoff point that would be appropriate for the purpose of screening. Seven hundred fifty-two psychiatric outpatients were interviewed with the Structured Clinical Interview for DSM-IV, and completed the MDQ. When MDQ caseness was based only on symptom score without regard to level of impairment, the cutoff score associated with at least 90% sensitivity was 5. At this cutoff the specificity of the MDQ was 60.7%, and its positive predictive value was 22.1%. These findings indicate that when the cutoff to identify cases on the MDQ was set to achieve a desired level of sensitivity as a screening instrument most cases screening positive on the scale did not have bipolar disorder. Low positive predictive value does not support the use of the MDQ or any bipolar disorder screening scale in psychiatric clinical practice.


Lack of gradual regulation of tetracycline-controlled gene expression by the tetracyclin-repressor/VP16 transactivator (tTA) in cultured cells.
Von Willebrand factor (vWF) is an essential multimeric protein for adhesion of platelets to an injured vessel wall. Endothelial cells secrete vWF by either a constitutive or a regulated pathway. It is unknown whether the secretory partitioning of vWF is dependent on the level of vWF synthesis. We employed the widely applied tetracycline-controlled transactivator system (tTA) to study the regulation of vWF mRNA synthesis in stably transfected Madin Darby kidney (MDCK-II) cells in a quantitative manner. Immunofluorescence staining with anti-vWF antibodies revealed that increasing the concentration of tetracycline resulted in a decreased number of MDCK-II cells that synthesize vWF. Apparently, tTA-regulated gene expression in an individual cell functions as an 'on/off' system rather than regulating the level of gene expression in a dose-response manner, as reported previously.