Solvothermal-assisted in situ rapid growth of octadecylamine functionalized polydopamine-based permanent coating as stationary phase for open-tubular capillary electrochromatography.
In recent years, mussel-inspired polydopamine (PDA) based materials have been widely used as stationary phases for open-tubular capillary electrochromatography (OT-CEC) because of their various excellent properties. Nevertheless, the traditional synthesis routes of functionalized PDA-based capillary columns usually are time-consuming and limited in aqueous solutions. Herein, we report a facile and rapid route to prepare octadecylamine (ODA) functionalized PDA coated OT-CEC columns in organic solvents via a novel one-step in situ solvothermal-assisted coating strategy. Through this developed solvothermal-assisted approach, the growth rate of ODA/PDA coating was significantly speeded up and their hybrid coating process on the capillary inner surface could be rapidly completed in 60 min. The successful preparation of the solvothermal-assisted ODA/PDA hybrid coating were systematically characterized and confirmed by several methods. The influence of the preparation parameters on the formation of hybrid coating and the separation ability of the ODA/PDA modified columns were systematically explored. Consequently, the high-efficiency baseline separation of four kinds of neutral, acidic and basic analytes were achieved based on the ODA/PDA modified columns. The repeatability of the solvothermal-assisted ODA/PDA coated column was also studied, and the relative standard deviations for intra-day, inter-day and column-to-column were all less than 5%. Additionally, the solvothermal-assisted ODA/PDA modified column exhibited good stability and long lifetime.


[Emotions, a managerial resource for collective dynamics].
The hospital environment is changing profoundly and is the terrain of a strong emotional charge that can generate a significant psychosocial risk. Long perceived as irrational and non-productive, emotions today tend to appear as a resource to professional dynamics. On a daily basis, the study of emotions and group phenomena opens the field of conscious and benevolent management in favor of a collective dynamic.


Morphological and morphometrical changes on adult Wistar rat testis caused by chronic sodium arsenite exposure.
Arsenic is a contaminant that occurs naturally in the environment, and it is related to several diseases, such as cancer and severe metabolic diseases. Sodium arsenite effects on testes rats are not fully understood regarding morphology and stereology; thus, it becomes necessary to evaluate possible changes in these parameters under low concentrations and simulating occupational exposure. Therefore, the aim of this study was to analyze the morphometrical and stereological changes on rat testis treated with sodium arsenite. The treatment was accomplished using 5 mg/kg of sodium arsenite by gastric gavage in Wistar rats, which experiment lasted 8 weeks. Organs were weighed and gonadosomatic index (GSI) was calculated. Using the software Image Pro Plus, seminiferous tubule diameter was measured, and the volume densities of testicular parenchymal components were obtained. It was counted 200 hundred spermatozoa and classified as normal or abnormal. The parameters means of control (N = 5) and treated (N = 7) groups were compared by U Mann-Whitney's test, and the results were considered significant for P < 0.05. We observed a decrease in seminiferous tubule diameter, as well as testis weight. These finds may be related with disorders of testosterone metabolism due to activation of immunological responses of macrophage, which inhibit the steroidogenesis. Thus, we conclude that sodium arsenic does not impair the animal's general health, but its exposure induces biochemical and tissue changes.


The protective effect of juglanin on fructose-induced hepatitis by inhibiting inflammation and apoptosis through TLR4 and JAK2/STAT3 signaling pathways in fructose-fed rats.
High fructose-feeding is an essential causative factor leading to the development and progression of hepatitis associated with high levels of endotoxin (LPS). Juglanin, as a natural compound extracted from the crude Polygonum aviculare, displayed inhibitory activity against inflammation response and cancer growth. However, researches about its role on anti-inflammation and apoptosis are far from available. Here, it is the first time that juglanin was administrated to investigate whether it inhibits fructose-feeding-induced hepatitis in rats and to elucidate the possible mechanism by which juglanin might recover it. Fructose-feeding rats were orally administrated with juglanin of 5, 10 and 20mg/kg for 6 weeks, respectively. Juglanin exerted prevention of fructose-feeding-stimulated increased LPS levels, accelerated alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) and up-regulated inflammatory cytokines expression in serum, mainly including tumor necrosis factor-alpha (TNF-a), Interleukin 1beta (IL-1β), Interleukin 6 (IL-6) and Interleukin 18 (IL-18). Meanwhile, toll-like receptor 4 (TLR4)-modulated mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) and apoptosis-related Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway are involved in the progression of hepatic injury and inflammation. And juglanin was found to suppress fructose-feeding-induced activation of these signaling pathways compared with the model group administrated only with fructose. These results indicate that juglanin represses inflammatory response and apoptosis via TLR4-regulated MAPK/NF-κB and JAK2/STAT3 signaling pathway respectively in rats with hepatitis induced by LPS for fructose-feeding. Treatment of juglanin might be an effective therapeutic strategy for preventing hepatitis.


The relationship between the Patient Generated Index (PGI) and measures of HR-QoL following diagnosis with head and neck cancer: are illness and treatment perceptions determinants of judgment-based outcomes?
The primary objectives of this study were to examine the relationship between factors specified in the extended Self-Regulation Model (SRM) (illness and treatment perceptions and coping strategy) and three types of QoL outcome. Secondary objectives were to examine the relationships between outcome measures (general and cancer-specific HR-QoL and the Patient Generated Index (PGI)). Cross-sectional questionnaire study. Eighty-two newly diagnosed patients with head and neck cancer (HNC) completed the Illness Perception Questionnaire--Revised (IPQ-R), the Beliefs about Medicines Questionnaire (BMQ), the Hospital Anxiety and Depression Scale (HADS), the Brief COPE and the Life Orientation Test (LOT-R). Patient outcomes were assessed using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, MOS Short Form Health Survey (SF-12v2) and the Patient Generated Index (PGI). These pre-treatment cross-sectional results have shown that key components of the SRM (beliefs and coping) were explanatory factors of HR-QoL outcomes. The PGI was not associated with any of the components of the SRM. The PGI was partially correlated with HR-QoL measures; in particular, Global QoL/health status (EORTC) and Mental Component Summary scores (SF-12). Our findings suggest that the illness perceptions approach may be a useful method for eliciting and understanding patients' beliefs regarding HNC. In order to maximize outcomes, simple interventions could address particular patient beliefs and coping styles.


Recent advances in the pharmacology of catecholamines.
The availability of dopamine and dobutamine and the possibility of combined use of sympathomimetic amines provides a broad spectrum of haemodynamic effects available for therapy. As shown in Table 2, isoproterenol produces the greatest vasodilation and norepinephrine, the greatest vasoconstriction with dobutamine and dopamine in intermediate positions. Greater flexibility can be obtained by conjoint administration of sympathomimetic amines or by administering alpha-adrenergic blocking agents or nitroprusside with dopamine or norepinephrine.


Tumor necrosis by pretreatment breast MRI: association with neoadjuvant systemic therapy (NAST) response in triple-negative breast cancer (TNBC).
To determine if tumor necrosis by pretreatment breast MRI and its quantitative imaging characteristics are associated with response to NAST in TNBC. This retrospective study included 85 TNBC patients (mean age 51.8 ± 13 years) with MRI before NAST and definitive surgery during 2010-2018. Each MRI included T2-weighted, diffusion-weighted (DWI), and dynamic contrast-enhanced (DCE) imaging. For each index carcinoma, total tumor volume including necrosis (TTV), excluding necrosis (TV), and the necrosis-only volume (NV) were segmented on early-phase DCE subtractions and DWI images. NV and %NV were calculated. Percent enhancement on early and late phases of DCE and apparent diffusion coefficient were extracted from TTV, TV, and NV. Association between necrosis with pathological complete response (pCR) was assessed using odds ratio (OR). Multivariable analysis was used to evaluate the prognostic value of necrosis with T stage and nodal status at staging. Mann-Whitney U tests and area under the curve (AUC) were used to assess performance of imaging metrics for discriminating pCR vs non-pCR. Of 39 patients (46%) with necrosis, 17 had pCR and 22 did not. Necrosis was not associated with pCR (OR, 0.995; 95% confidence interval [CI] 0.4-2.3) and was not an independent prognostic factor when combined with T stage and nodal status at staging (P = 0.46). None of the imaging metrics differed significantly between pCR and non-pCR in patients with necrosis (AUC < 0.6 and P > 0.40). No significant association was found between necrosis by pretreatment MRI or the quantitative imaging characteristics of tumor necrosis and response to NAST in TNBC.


Helping people evaluate health plans: the Minnesota Hospital Association criteria.
The MHA Criteria for Evaluating Plans are a tool to help simplify the process of impacting on a plan. This simplified process facilitates input, which provides for a better planning process, and a better plan.


The ocular graft-versus-host disease: the path from current knowledge to future managements.
Graft-versus-host disease (GVHD) is one of the major complications of allogenic haematopoietic stem cell transplantation (HSCT). The manifestation of ocular GVHD (oGVHD) is variable and may involve cornea, lacrimal gland, conjunctiva, eyelid, and/or nasolacrimal duct. We reviewed and summarized the current managements of oGVHD with specific focus on the emerging therapeutic advances. PubMed, Web of Science, and Google Scholar were searched for relevant literatures published within 20 years. Keywords used included "Graft-Versus-Host Disease", "GVHD", "ocular", "ocular surface", "ocular GVHD", "oGVHD", "dry eye", "keratitis", etc. RESULTS: Current managements of oGVHD can be classified into topical immunosuppressants, local tear-preservatory treatments, local non-pharmacological/surgical interventions, and systemic treatments. Additionally, some innovative therapies with promising treatment effects have been proposed, including topical target therapies, epitheliotrophic and neurotrophic treatments, recombinant DNase eye drops, mesenchymal stromal cell injection, and more. Clinical managements of oGVHD are administered in a symptom-based, stepwise manner. The advances in innovative therapies may help improve clinical outcomes, and it is essential that physicians stay updated with these novel treatment options.


Regulatory aspects of genotoxicity testing: from hazard identification to risk assessment.
This symposium focused on the use of tests for chromosomal damage, and other genotoxicity measures, for detection of potentially harmful chemicals. The speakers discussed the information that has been gained over the last three decades about the use of "short-term tests" for genotoxicity in cultured cells and in animals (mainly rodents), and the ongoing debates about the rational use of data from such experimental systems in trying to extrapolate to an understanding of potential human risk. The overall theme was that the field of regulatory toxicology currently is over-reliant on qualitative outcomes of in vitro hazard-screening tests, generally conducted at the maximum achievable exposures, and needs a more realistic approach that incorporates in vivo exposure levels and dose-response information.


Trajectories of pro re nata (PRN) medication prescribing and administration in long-term care facilities.
Little is known about changes in pro re nata (PRN) medication prescribing and administration in residential aged care facilities (RACFs) over time. To determine the prevalence and factors associated with PRN medication administration in RACFs and examine changes over 12-months. Secondary analyses utilizing data from the SIMPLER randomized controlled trial (n = 242 residents, 8 RACFs) was undertaken. PRN medication data were extracted from RACF medication charts. Factors associated with PRN medication administration in the preceding week were explored using multivariable logistic regression. At baseline, 211 residents (87.2%) were prescribed ≥1 PRN medication, with 77 (36.5%) administered PRN medication in the preceding week. PRN administration was more likely in non-metropolitan areas, and less likely among residents with more severe dementia symptoms and greater dependence with activities of daily living. No significant differences in overall PRN prescribing or administration in 162 residents alive at 12-month follow-up were observed. Despite being frequently prescribed, the contribution of PRNs to overall medication use in RACFs is small. PRN prescribing and administration was relatively static over 12-months despite likely changes in resident health status over this period, suggesting further exploration of PRN prescribing in relation to resident care needs may be warranted.


A shared vision to prevent heart disease and stroke through united action.
Cardiovascular diseases are the second and fourth leading causes of death in North Carolina, and when combined become the leading killers of North Carolinians. A key strategy for reducing this disease burden and saving lives is to focus on prevention through a combined approach of policy change and program implementation.


Gene expression resulting from PrPC ablation and PrPC overexpression in murine and cellular models.
The cellular prion protein (PrP(C)) plays a key role in prion diseases when it converts to the pathogenic form scrapie prion protein. Increasing knowledge of its participation in prion infection contrasts with the elusive and controversial data regarding its physiological role probably related to its pleiotropy, cell-specific functions, and cellular-specific milieu. Multiple approaches have been made to the increasing understanding of the molecular mechanisms and cellular functions modulated by PrP(C) at the transcriptomic and proteomic levels. Gene expression analyses have been made in several mouse and cellular models with regulated expression of PrP(C) resulting in PrP(C) ablation or PrP(C) overexpression. These analyses support previous functional data and have yielded clues about new potential functions. However, experiments on animal models have shown moderate and varied results which are difficult to interpret. Moreover, studies in cell cultures correlate little with in vivo counterparts. Yet, both animal and cell models have provided some insights on how to proceed in the future by using more refined methods and selected functional experiments.


A free vascularised iliac bone flap based on superficial circumflex iliac perforators for head and neck reconstruction.
We describe a novel free vascularised iliac bone flap based on superficial circumflex iliac perforators (SCIPs). Compared with a conventional iliac bone flap, which is based on deep circumflex iliac vessels, this flap is less invasive, less bulky and can include a reliable skin island. In addition, an SCIP-deep inferior epigastric perforator (DIEP) bipedicle soft--tissue flap has been developed, which can contribute to safer transfer of larger DIEP flaps. We successfully applied these new flaps to a case of maxillary reconstruction.


A high-flux antibacterial poly(amidoxime)-polyacrylonitrile blend membrane for highly efficient uranium extraction from seawater.
Uranium is an important fuel for nuclear power, with 4.5 billion tons of it stored in the oceans, 1,000 times more than on land. Polymer membrane materials are widely used in the marine resources fields, due to their convenient collection, good separation and can work continuously. Herein, a poly(amidoxime)-polyacrylonitrile blend membrane (PCP) with high flux, excellent antibacterial properties and uranium adsorption performance has been prepared by using the phase inversion method, and the prepared membrane was used for highly efficient uranium extraction from seawater. In static adsorption experiments, the PCP membrane reached adsorption equilibrium after 48 h, and the adsorption capacity was 303.89 mg/g (C0 =50 mg/L). In dynamic adsorption experiments, it was found that the lower flow rate and higher number of membrane layers were favorable for dynamic adsorption. In addition, the water flux of the PCP membrane was 7.4 times higher than that of the PAN membrane. The adsorption mechanism can be attributed to the chelation between amino and hydroxyl groups in CS, amidoxime group in poly(amidoxime) and uranyl ions. The simple preparation process coupled with the excellent adsorption performance indicated that the PCP membrane would be a promising material for the uranium extraction from seawater.


Costs of Definitive Chemoradiation, Surgery, and Adjuvant Radiation Versus De-Escalated Adjuvant Radiation per MC1273 in HPV+ Cancer of the Oropharynx.
De-escalated treatment for human papillomavirus (HPV)+ oropharynx squamous cell carcinoma (OPSCC) has shown promising initial results. Health-care policy is increasingly focusing on high-value care. This analysis compares the cost of care for HPV+ OPSCC treated with definitive chemoradiation (CRT), surgery and adjuvant radiation (RT), and surgery and de-escalated CRT on MC1273. MC1273 is a prospective, phase 2 study evaluating adjuvant CRT to 30 to 36 Gy plus docetaxel for HPV+ OPSCC after surgery for high-risk patients. Matched standard-of-care control groups were retrospectively identified for patients treated with definitive CRT or adjuvant RT. Standardized costs were evaluated before radiation, during treatment (during RT), and at short-term (6 month) and long-term (7-24 month) follow-up periods. A total of 56 definitive CRT, 101 adjuvant RT, and 66 MC1273 patients were included. The CRT arm had more T3-4 disease (63% vs 17-21%) and higher N2c-N3 disease (52% vs 20-24%) vs both other groups. The total treatment costs in the CRT, adjuvant RT, and MC1273 groups were $47,763 (standard deviation [SD], $19,060], $57,845 (SD, $17,480), and $46,007 (SD, $9019), respectively, and the chemotherapy and/or RT costs were $39,936 (SD, $18,480), $26,603 (SD, $12,542), and $17,864 (SD, $3288), respectively. The per-patient, per-month, average short-term follow-up costs were $3860 (SD, $10,525), $1072 (SD, $996), and $972 (SD, $833), respectively, and the long-term costs were $978 (SD, $2294), $485 (SD, $1156), and $653 (SD, $1107), respectively. After adjustment for age, T-stage, and N-stage, treatment costs remained lower for CRT and MC1273 versus adjuvant RT ($45,450 and $47,114 vs $58,590, respectively; P < .001), whereas the total per-patient, per-month follow-up costs were lower in the MC1273 study group and adjuvant RT versus CRT ($853 and $866 vs $2030, respectively; P = .03). MC1273 resulted in 10% and 20% reductions in global costs compared with standard-of-care adjuvant RT and definitive CRT treatments. Substantial cost savings may be an added benefit to the already noted low toxicity and maintained quality of life of treatment per MC1273.


[The attitude of patients in geriatric rehabilitation towards nursing homes].
For the group of individuals reaching higher age, living arrangements providing care increase in importance. Increasing dependence can lead to a relocation to a nursing home. The attitude towards nursing homes is important in preparing for this event and the psychological response to it but has hardly been studied so far. The aim of this study was to determine what older people think about and how they evaluate nursing homes depending on their subjective feeling of control, their experiences and on how informed they are. A total of 150 geriatric rehabilitation patients were interviewed on their attitudes toward nursing homes with a first version of a questionnaire (n = 64) or a revised version (n = 86). A polarity profile showed a more positive attitude toward nursing homes; however, the participants gave mainly negative statements in a free response format. The majority of the participants had an anxious attitude towards a relocation to a residential home. A stronger feeling of control, a higher level of information, and positive experiences with nursing homes are related to a positive attitude towards the relocation to a nursing home. Given the named fears, a common low level of information, and a great defensiveness of some participants, it is important to proactively inform older people and to involve them more closely in the decision process for suitable living arrangements. Recent developments towards more reliable quality assessment of nursing homes can be helpful.


A suspected lysosomal storage disease in Abyssinian cats. Part I: genetic, clinical and clinical pathological aspects.
The genetic, clinical and clinical pathological findings of a neurological syndrome in Abyssinian kittens are described. The findings are compared with similar cases in the literature and a tentative diagnosis of a lysosomal storage disease is proposed.


The Maternal Infant Health Outreach Worker program in low-income families.
Vanderbilt University Medical Center's Maternal Infant Health Outreach Worker program (MIHOW) is a community-based intervention dedicated to enhancing birth outcomes and healthy child development. Trained neighborhood women provide home and group services to underserved families in rural and inner city communities. This report describes MIHOW's history and work in Tennessee, Kentucky, West Virginia, Mississippi, and Louisiana.


Usefulness of the assessment of the appropriateness of left ventricular mass to detect left ventricular systolic and diastolic abnormalities in absence of echocardiographic left ventricular hypertrophy: the LIFE study.
Conventional definitions of left ventricular (LV) hypertrophy do not account for interindividual differences in loading conditions. We may define LV mass as inappropriately high when exceeding 128% of theoretical values predicted by gender, height(2.7), and stroke work, which explain up to 82% of the variability of LV mass in normal reference subjects. In 652 participants in the Losartan Intervention For Endpoint reduction in hypertension study without clinically overt cardiovascular disease or diabetes, we investigated whether inappropriately high LV mass is associated with relevant LV abnormalities independent of traditional definition of LV hypertrophy (ie, LV mass index >116 g/m(2) in men and >104 g/m(2) in women). The study sample was divided into three groups: patients with inappropriately high LV mass but without LV hypertrophy were compared to patients with LV hypertrophy and to patients with appropriate LV mass and without LV hypertrophy. Patients with inappropriately high but nonhypertrophic LV mass had higher body mass index and relative wall thickness, and lower LV myocardial systolic function, than patients with appropriate LV mass or patients with LV hypertrophy. In multivariate analyses, inappropriately high LV mass was independently associated with lower myocardial systolic function independent of LV hypertrophy and other covariates. Inappropriately high LV mass was also associated with prolonged isovolumic relaxation time and lower mitral E/A ratio independent of covariates. In conclusion, inappropriately high LV mass was associated with relevant, often preclinical, manifestations of cardiac disease in the absence of traditionally defined echocardiographic LV hypertrophy and concentric geometry.


Age and glucose tolerance in healthy subjects.
An important and still controversial issue is the role played by the aging process itself in the metabolic alterations observed in aged people. We previously reported that a group of normal elderly people exhibited glucose disposal comparable to that of young controls. In the present study we investigated the effect of age on beta-cell secretion, by analyzing C-peptide measurements. Ten elderly men (E, 70 +/- 2 years) with normal oral glucose test and ten young subjects (Y, 27 +/- 1 years) with matching ideal body weight formed the study group. They were studied under highly dynamic conditions by means of a 0.3 g/kg i.v. glucose tolerance test. Fasting glucose and insulin were not different in the two groups (Y: 87 +/- 2 mg/di, E: 88 +/- 3, p greater than 0.1; Y: 50 +/- 7 pM, E: 36 +/- 7, p greater than 0.05). Glucose-insulin data set was analyzed by means of the minimal model of glucose disappearance which provided two parameters for every individual, yielding a quantitative description of glucose utilization: i.e., SI, the index of insulin sensitivity, and SG, the fractional glucose disappearance at basal insulin (glucose effectiveness). Both parameters were unaltered by age (SI = Y: 6.30 +/- 0.41 10(-4)min-1/(microU/ml), E: 7.11 +/- 0.72, p greater than 0.1; SG = Y: 0.020 +/- 0.003 min-1, E: 0.019 +/- 0.002, p greater than 0.1). C-peptide time course in elderly people was systematically lower than in the control group (basal levels: Y: 252 +/- 36 pM, E: 129 +/- 17, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)


In-situ constructing amidoxime groups on metal-free g-C3N4 to enhance chemisorption, light absorption, and carrier separation for efficient photo-assisted uranium(VI) extraction.
The development of inexpensive and efficient semiconductor catalysts for photo-assisted uranium extraction from seawater remains a huge challenge. Herein, we have successfully synthesized amidoxime-rich g-C3N4 (AO-C3N4) by simply amidoximing a cyano-rich precursor for photo-assisted uranium extraction from seawater. The amidoxime groups not only served as the U(VI) binding sites for efficient uranium adsorption, but also significantly improved the visible light absorption capacity and carrier separation efficiency via introducing defect energy level, resulting in the excellent photocatalytic activity for AO-C3N4 towards photo-assisted uranium extraction. In the process of photo-assisted uranium extraction, U(VI) was first adsorbed by the amidoxime groups on the AO-C3N4 and then reduced to U(IV), while (UO2)O2·2H2O and (UO2)O2·4H2O were further formed by the oxidation of U(IV) by superoxide radicals (·O2-). Moreover, the generated reactive oxygen species (ROS) under light endowed AO-C3N4 with outstanding antibacterial properties, preventing the limitation of uranium extraction capacity from marine biofouling.


Determination of limonin in rat plasma by liquid chromatography-electrospray mass spectrometry.
A simple, sensitive and selective liquid chromatography coupled with electrospray ionization mass spectrometry (LC/ESI/MS) method for determination of limonin (LM) in rat plasma has been developed and validated. The method had advantages of a single liquid-liquid extraction with ether and high sensitivity. Analyses were conducted at a flow rate of 0.2 ml/min by a gradient elution. The detection utilized selected ion monitoring in the negative ion mode at m/z 460.00 and 423.15 for the deprotonated molecular ions of LM and the internal standard, respectively. The quantitation limit for LM in rat plasma was 1.0 ng/ml. The linearity was also excellent over the concentration range of 1.9-500 ng/ml of LM. The intra- and inter-day precision (relative standard deviation (R.S.D.%)) was lower than 10% and accuracy ranged from 90 to 110%, showing a good reproducibility. This developed method was successfully applied to analysis of LM in biological fluids.


Non-random sampling in human genetics: estimation of familial correlations, model testing, and interpretation.
By choice or necessity, human geneticists and genetic epidemiologists often design studies that involve non-random sampling of clusters of individuals, and yet address hypotheses appropriate to the population as a whole. Failure to adjust for the non-randomness of data often leads to biased parameter estimates and misspecification of predictive models that cause familial resemblance of traits. We develop an approach to adjust for common forms of non-randomness in the context of estimating familial correlation with minimal distributional assumptions and discuss its implications in connection with adjustments for concomitant variables.


A comparison of the suitability of cathode ray tube (CRT) and liquid crystal display (LCD) monitors as visual stimulators in mfERG diagnostics.
The aim of this study was to determine up to which extent the specific characteristics of cathode ray tube (CRT) and liquid crystal display (LCD) monitors influence the retinal biosignal when used as stimulators in ocular electrophysiology. In a conventional CRT monitor, each pixel lights up only for a duration of a few milliseconds during each frame. In contrast, liquid crystal displays are quasi-static, i.e. each pixel has a constant luminance during the whole length of the frame, but lights up only with a certain delay after the trigger. These different display characteristics may affect the mfERG signal. The temporal and spatial luminance distributions of a CRT and an LCD monitor were measured in white flashes. The total amount of emitted light was calculated by integration of the intensity versus time curves. By means of an mfERG recording system (RETIsystem, Roland Consult, Brandenburg, Germany) first-order kernel (FOK) mfERG signals were computed and then analysed using customized MATLAB (TheMathWorks, Natick, MA, USA) software. With the two stimulator monitors, differences in the mfERG signal were observed. The latencies of mfERG responses recorded with the LCD monitor were significantly increased by 7.1 ms for N1 and 9.5 ms for P1 compared to the CRT. Due to a higher luminance, the N1 amplitude was significantly higher by approx. 2 dB in measurements with the LCD monitor while no significant difference could be detected with regard to the more contrast sensitive P1 amplitude. When using LCD monitors as stimulators the increase in latencies and differences in the luminance versus time profile must be taken into account. Prior to clinical application, the establishment of guidelines for the use of LCD monitors is recommended.


Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial.
Optimal dosing and duration of adjuvant treatment with PD-1 and CTLA-4 immune checkpoint inhibitors have not been established. Prior to their regulatory approval we investigated a low-dose regimen of nivolumab with or without ipilimumab in a sequential dual-cohort phase II clinical trial. Following the complete resection of melanoma metastases, patients were treated with a single fixed dose of ipilimumab (50 mg) plus 4 bi-weekly fixed doses of nivolumab (10 mg) (cohort-1), or nivolumab for 1 year (10 mg fixed dose, Q2w x9, followed by Q8w x4) (cohort-2). Twelve-months relapse-free survival (RFS) served as the primary endpoint. After a median follow-up of 235 weeks for cohort-1 (34 patients), and 190 weeks for cohort-2 (21 patients), the 12-months RFS-rate was, respectively, 55.9% (95% CI, 39-72), and 85.7% (95% CI, 70-100). Treatment-related adverse events occurred in 27 (79%), and 18 (86%) patients, with 3 (9%), and 1 (5%) grade 3 adverse events in cohort-1 and -2, respectively. Immunohistochemical quantification of intra- and peritumoral CD3+ T cells and CD20+ B cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. One year of adjuvant low-dose nivolumab could be an effective and economically advantageous alternative for standard dosing, at the condition of further confirmation in a larger patient cohort. A shorter low-dose nivolumab plus ipilimumab regimen seems inferior and less tolerable.


Chrysophanol attenuates hepatitis B virus X protein-induced hepatic stellate cell fibrosis by regulating endoplasmic reticulum stress and ferroptosis.
Hepatitis B virus X protein (HBx) and hepatic stellate cells (HSCs) are critical for liver fibrosis development. Anti-fibrosis occurs via reversion to quiescent-type HSCs or clearance of HSCs via apoptosis or ferroptosis. We aimed to elucidate the role of chrysophanol in rat HSC-T6 cells expressing HBx and investigate whether chrysophanol (isolated from Rheum palmatum rhizomes) influences cell death via ferroptosis in vitro. Analysis of lipid reactive oxygen species (ROS), Bip, CHOP, p-IRE1α, GPX4, SLC7A11, α-SMA, and CTGF showed that chrysophanol attenuated HBx-repressed cell death. Chrysophanol can impair HBx-induced activation of HSCs via endoplasmic reticulum stress (ER stress) and ferroptosis-dependent and GPX4-independent pathways.


Application of a nanostructured platform and imprinted sol-gel film for determination of chlorogenic acid in food samples.
Chlorogenic acid (CGA) is a polyphenol derivative that widely exists in higher plants like fruits, vegetables, black teas, and some traditional Chinese medicines. In this work, we have proposed a sensitive and selective electrochemical sensor for detection of CGA. The sensor was based on a glassy carbon electrode (GCE) modified with a functional platform by grafting vinyltrimethoxysilane (VTMS) in multi-walled carbon nanotubes (MWCNTs) and covered by a molecularly imprinted siloxane (MIS) film prepared using the sol-gel process. The VTMS was grafted onto the surface of the MWCNTs via in situ free radical polymerization. The MIS was obtained from the acid-catalyzed hydrolysis/condensation of a solution consisting of tetraethoxysilane (TEOS), phenyltriethoxysilane (PTEOS), (3-aminopropyl)trimethoxysilane (APTMS), and CGA as a template molecule. The modification procedure was evaluated by differential pulse voltammetry (DPV) and scanning electron microscopy (SEM). Under optimized operational conditions, a linear response was obtained covering a concentration ranging from 0.08μmolL(-1) to 500μmolL(-1) with a detection limit (LOD) of 0.032μmolL(-1). The proposed sensor was applied to CGA determination in coffee, tomato, and apple samples with recoveries ranging from 99.3% to 108.6%, showing a promising potential application in food samples. Additionally, the imprinted sensor showed a significantly higher affinity for target CGA than the non-imprinted siloxane (NIS) sensor.


A meta-analysis of treatment effects of imiquimod for basal cell carcinoma.
We conducted this meta-analysis to assess the efficacy and safety of imiquimod in comparison with other treatments in patients with BCC. A comprehensive literature search was performed in the database of PubMed, Embase, and Web of Science. Outcomes of interest included histological/composite clearance rate, success rate, complete response rate, tumor free survival, and adverse events. Pooled risk ratio (RR) with 95% confidence intervals (CIs) using a fixed-effects or random-effects model were determined for each outcome. A total of 13 studies involving 4256 patients were identified. Imiquimod was associated with significantly higher histological clearance rate (RR = 9.28, 95%CI: 5.56, 15.49; P < .001) and composite clearance rate (RR = 34.24, 95%CI: 21.29, 55.06; P = .001). Moreover, imiquimod also significantly increased complete response rate (RR = 3.15, 95%CI: 1.55, 6.38; P = .001) but had no effect in the success rate (RR = 0.98, 95%CI: 0.89, 1.08; P = .727) and probability of tumor-free survival (RR = 1.15, 95%CI: 0.98, 1.35; P = .088), as compared with other treatments. There were more patients in imiquimod group who developed adverse events than in other treatment group (RR = 2.00, 95%CI: 1.39, 2.88; P < .001). This study indicated the effects of imiquimod in improving the histological/composite clearance rates as compared with other treatments. However, its treatment-related adverse events also should be noticed. Our findings supported that, imiquimod could be used as the first-choice treatment for BCC.


A sensitivity analysis of process design parameters, commodity prices and robustness on the economics of odour abatement technologies.
The sensitivity of the economics of the five most commonly applied odour abatement technologies (biofiltration, biotrickling filtration, activated carbon adsorption, chemical scrubbing and a hybrid technology consisting of a biotrickling filter coupled with carbon adsorption) towards design parameters and commodity prices was evaluated. Besides, the influence of the geographical location on the Net Present Value calculated for a 20 years lifespan (NPV20) of each technology and its robustness towards typical process fluctuations and operational upsets were also assessed. This comparative analysis showed that biological techniques present lower operating costs (up to 6 times) and lower sensitivity than their physical/chemical counterparts, with the packing material being the key parameter affecting their operating costs (40-50% of the total operating costs). The use of recycled or partially treated water (e.g. secondary effluent in wastewater treatment plants) offers an opportunity to significantly reduce costs in biological techniques. Physical/chemical technologies present a high sensitivity towards H2S concentration, which is an important drawback due to the fluctuating nature of malodorous emissions. The geographical analysis evidenced high NPV20 variations around the world for all the technologies evaluated, but despite the differences in wage and price levels, biofiltration and biotrickling filtration are always the most cost-efficient alternatives (NPV20). When, in an economical evaluation, the robustness is as relevant as the overall costs (NPV20), the hybrid technology would move up next to BTF as the most preferred technologies.


The impact of COVID-19 on campus-based support programs serving students with foster care experience: Focus groups with administrators and students.
The onset of the Coronavirus disease (COVID-19) pandemic forced higher education institutions to abruptly transition to remote services and online learning. Students with a foster care background are a subgroup of students who have been particularly hard hit by the pandemic, as were the campus-based programs (CSPs) designed to support them. The purpose of this study was to learn about the impact of the pandemic on CSPs and CSP participants. Focus groups were conducted with CSP administrators and separately with CSP students from two- and four-year colleges in California. The first theme that emerged from the data focused on challenges exacerbated by the pandemic, with six subthemes zeroing in on breaks in social connections, academic disruptions, technology woes, gaps in basic needs, employment challenges, and the toll on mental health. The second theme described participants' responses, including their creative and collaborative actions. Administrators quickly adapted service delivery, formed partnerships with new units and organizations to ensure students' needs were met, and found creative ways to stay connected with students during a time of pervasive isolation. Students talked about their own efforts to access resources, connect with peers, and use of strategies to manage challenges such as burnout and depression. A second subtheme highlighted the ways participants displayed resilience, such as creating boundaries to manage their own self-care and leaning on each other for support. The findings from this study increase our understanding of the experiences students faced during the pandemic and shed light on implications moving forward to support students with foster care histories in higher education.


Antipsychotic-induced weight gain.
Novel 'atypical' antipsychotic drugs represent a substantial improvement on older 'typical' drugs. However, clinical experience has shown that some, but not all, of these drugs can induce substantial weight gain. This interferes with compliance with drug taking and has expected effects on morbidity and mortality. In this review, we summarize current thinking on: (i) the extent to which different 'atypical' drugs induce weight gain; (ii) the possible roles of various neurotransmitters and neuropeptides in this adverse drug reaction; and (iii) the state of development of animal models in this area. We also outline major areas for future research.


Highly sensitive and selective organophosphate screening in twelve commodities of fruits, vegetables and herbal medicines by dispersive liquid-liquid microextraction.
The article describes a simple sample pretreatment procedure for the analysis of ten organophosphorus pesticides using dispersive liquid-liquid microextraction (DLLME) followed by gas chromatography-mass spectrometry (GC-MS) in three distinctively different types of matrices: fresh fruits, fresh vegetables and dried herbs. The method was carefully developed, focusing on the chemistry of various dispersive solvents, to achieve simultaneous, comprehensive extraction and preconcentration in a great span of selected matrices. According to matrix-matched validation study, the set of optimized DLLME conditions has been proven robust to determine target OPPs within a wide linear range from 0.1 to 1000 μg L(-1). With limited usage of organic extractants, remarkable enrichment factors up to 100-fold were obtained, enabling ultra-trace pesticide quantification down to sub-ppt levels at 0.12-4.92 ng kg(-1). Practical application of the method was illustrated by quantitative recovery (70-119%) and good precision (2.6-10% R.S.D.) in a representative range of three fruits and four vegetable commodities featured by the CODEX Alimentarius classification as well as their unique matrix compositions. A careful selection of dried herbs was further classified based on their morphological structures to validate analytical ruggedness of the method. Compared with existing methods for food analysis vis-à-vis OPPs, the present method is superior in terms of high sample throughput, minimal solvent consumption, and small sample size requirement. An additional, significant aspect of this universal DLLME method is that it models sample pretreatment methods with wide coverage of analytical matrices that are more effective, more comprehensive, and more flexible than those currently being used.


Sonocatalytic decolorization of textile wastewater using synthesized γ-FeOOH nanoparticles.
γ-FeOOH nanoparticles were synthesized and applied for decolorization of a textile wastewater containing reactive orange 29 (RO29) by ultrasonic/γ-FeOOH/H2O2 process. X-ray diffraction, transmittance electron microscope, scanning electron microscope, and nitrogen adsorption/desorption analysis approved synthesis of γ-FeOOH nanoparticles with the average width of 60-70 nm. The catalyst dosage, H2O2 concentration, pH, and ultrasonic power had significant effect on catalytic performance of γ-FeOOH nanoparticles. γ-FeOOH nanoparticles can be effectively used as catalyst in successive US/γ-FeOOH/H2O2 processes without significant activity loss. Gas chromatography-mass spectrometry analysis was used to verify the main intermediates produced through the RO29 degradation. Mineralization of the textile wastewater during treatment process was determined by chemical oxygen demand analysis.


Differential sensitivity to Wnt signaling gradients in human gastric organoids derived from corpus and antrum.
Wnt signaling regulates gastric stem cell proliferation and differentiation. Although similar Wnt gradients exist within the corpus and antrum of the human stomach, there are striking differences in gland architecture and disease manifestation that suggest Wnt may differentially regulate progenitor cell function in each compartment. In this study, we tested sensitivities to Wnt activation in human gastric corpus and antral organoids to determine whether progenitor cells have region-specific differences in Wnt responsiveness. Human patient-matched corpus and antral organoids were grown in the presence of varying concentrations of the Wnt pathway activator CHIR99021 to assess regional sensitivity to Wnt signaling on growth and proliferation. Corpus organoids were further studied to understand how high Wnt affected cellular differentiation and progenitor cell function. A lower concentration of CHIR99021 stimulated peak growth in corpus organoids compared with patient-matched antral organoids. Supramaximal Wnt signaling levels in corpus organoids suppressed proliferation, altered morphology, reduced surface cell differentiation, and increased differentiation of deep glandular neck and chief cells. Surprisingly, corpus organoids grown in high CHIR99021 had enhanced organoid forming potential, indicating that progenitor cell function was maintained in these nonproliferative, deep glandular cell-enriched organoids. Passaging high-Wnt quiescent organoids into low Wnt rescued normal growth, morphology, and surface cell differentiation. Our findings suggest that human corpus progenitor cells have a lower threshold for optimal Wnt signaling than antral progenitor cells. We demonstrate that Wnt signaling in the corpus regulates a bimodal axis of differentiation, with high Wnt promoting deep glandular cell differentiation and suppressing proliferation while simultaneously promoting progenitor cell function.NEW & NOTEWORTHY This study demonstrates that human gastric corpus organoids have a lower Wnt signaling threshold to drive optimal growth relative to patient-matched antral organoids. Paradoxically, supramaximal Wnt levels suppress corpus organoid proliferation, yet promote differentiation toward deep glandular cell types while simultaneously enhancing progenitor cell function. These findings provide novel insights into how Wnt signaling differentially regulates homeostasis in the human gastric corpus and antrum and contextualizes patterns of Wnt activation diseases.


An Illustrative Review of Substance Use-Specific Insights From the National Longitudinal Study of Adolescent to Adult Health.
The purpose of this illustrative, thematic review was to demonstrate the utility of data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) for substance use research and to describe substance use-specific insights gained from Add Health research over the past 2 decades. We searched multiple electronic databases (PubMed, PsycInfo, and Web of Science) and selected an illustrative sample of 40 articles that used Add Health data and longitudinally examined a measure of alcohol, marijuana, or illicit drug use or prescription drug misuse as the exposure or outcome in association with diverse domains of additional factors assessed (social, emotional, behavioral, contextual, biological, and genetic). Included articles identified several key associations between substance use behaviors and additional factors from a wide range of domains. For example, results from several studies indicated that experiences of sexual violence, adolescent dating violence, and intimate partner violence are associated with an increased likelihood of later prescription opioid misuse, heavy drinking, and marijuana use, with some differences by biological gender and race/ethnicity. Results from other studies showed that bidirectional associations between substance use and mental health differ by specific type of substance and mental health condition. Existing research using Add Health data has provided valuable insights regarding substance use by leveraging the study's longitudinal design, the prospective nature of data collection, the breadth and depth of substance use questions assessed from adolescence to adulthood, the size and diversity of the cohort, and the wide range of additional factors measured over time.


The superficial elevated and depressed lesion type is an independent factor associated with non-curative endoscopic submucosal dissection for early gastric cancer.
The expanded criteria for endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) have led to an increase in the number of EGC patients who receive curative treatment involving endoscopic techniques. Identifying the factors that are associated with treatment outcomes would be helpful in the application of ESD for EGC. Potential factors associated with incomplete ESD and with non-curative ESD were investigated using a multiple logistic regression model in EGC patients who consecutively underwent ESD according to the expanded criteria. A total of 363 patients with 398 EGC lesions were enrolled. The rates of complete ESD and curative ESD were 96.2 % (383/398) and 85.7 % (341/398), respectively. No significant factors associated with incomplete ESD were identified. In contrast, a tumor size >20 mm [odds ratio (OR) 3.31; 95 % confidence interval (CI) 1.74-6.29], the superficial elevated and depressed type (0-IIa + IIc or IIc + IIa) (OR 4.37; 95 % CI 1.88-9.88), and the undifferentiated type (OR 5.93; 95 % CI 1.65-19.41) were identified as independent factors associated with non-curative ESD. The superficial elevated and depressed type in particular was found to be highly related to submucosal and lymphovascular invasion. The rate of non-curative ESD in cases of this macroscopic type occurring together with a tumor size >20 mm was 58.3 %, and the adjusted OR was 16.48 (95 % CI 4.69-62.09). The results suggest that the superficial elevated and depressed type is an independent factor associated with non-curative ESD and that the risk of non-curative ESD is increased when this macroscopic type is present along with a large tumor size.


The forespore line of gene expression in Bacillus subtilis.
Endospore formation by Bacillus subtilis involves three differentiating cell types, the predivisional cell, the mother cell, and the forespore. Here we report the program of gene expression in the forespore, which is governed by the RNA polymerase sigma factors sigma(F) and sigma(G) and the DNA-binding proteins RsfA and SpoVT. The sigma(F) factor turns on about 48 genes, including the gene for RsfA, which represses a gene in the sigma(F) regulon, and the gene for sigma(G). The sigma(G) factor newly activates 81 genes, including the gene for SpoVT, which turns on (in nine cases) or stimulates (in 11 cases) the expression of 20 genes that had been turned on by sigma(G) and represses the expression of 27 others. The forespore line of gene expression consists of many genes that contribute to morphogenesis and to the resistance and germination properties of the spore but few that have metabolic functions. Comparative genomics reveals a core of genes in the sigma(F) and sigma(G) regulons that are widely conserved among endospore-forming species but are absent from closely related, but non-spore-forming Listeria spp. Two such partially conserved genes (ykoU and ykoV), which are members of the sigma(G) regulon, are shown to confer dry-heat resistance to dormant spores. The ykoV gene product, a homolog of the non-homologous end-joining protein Ku, is shown to associate with the nucleoid during germination. Extending earlier work on gene expression in the predivisional cell and the mother cell, we present an integrated overview of the entire program of sporulation gene expression.


Structural insights into DarT toxin neutralization by cognate DarG antitoxin: ssDNA mimicry by DarG C-terminal domain keeps the DarT toxin inhibited.
In the DarTG toxin-antitoxin system, the DarT toxin ADP-ribosylates single-stranded DNA (ssDNA), which stalls DNA replication and plays a crucial role in controlling bacterial growth and bacteriophage infection. This toxic activity is reversed by the N-terminal macrodomain of the cognate antitoxin DarG. DarG also binds DarT, but the role of these interactions in DarT neutralization is unknown. Here, we report that the C-terminal domain of DarG (DarG toxin-binding domain [DarGTBD]) interacts with DarT to form a 1:1 stoichiometric heterodimeric complex. We determined the 2.2 Å resolution crystal structure of the Mycobacterium tuberculosis DarT-DarGTBD complex. The comparative structural analysis reveals that DarGTBD interacts with DarT at the DarT/ssDNA interaction interface, thus sterically occluding substrate ssDNA binding and consequently inactivating toxin by direct protein-protein interactions. Our data support a unique two-layered DarT toxin neutralization mechanism of DarG, which is important in keeping the toxin molecules in check under normal growth conditions.


Promoting outdoor recreation among older adults in Sweden - a theoretical and empirical foundation for the development of an intervention.
Disengagement from outdoor recreation may diminish the positive benefits on health and well-being in old age. The purpose of this study is to present a contextual, theoretical, and empirical rationale for an intervention, aiming to promote continued engagement in outdoor recreation for older adults in a Swedish context. The paper includes a contextualization of outdoor recreation in Sweden, a presentation of evidence on health benefits related to engagement in outdoor recreation, together with theoretical frameworks that may guide future intervention designs. To add empirical knowledge, a mixed methods approach was applied, including an empirical data collection based on a quantitative survey (n = 266) and individual semi-structured interviews with older adults (n = 12). Survey data were presented with descriptive statistics. Associations between disengagement from previously performed activities and age and gender was analyzed with Chi2 tests. Transcripts and handwritten notes from the interviews were analyzed qualitatively to identify key themes, as well as patterns and disparities among respondents. Outdoor recreation was rated as important/very important by 90% of respondents of the survey. The interviews highlighted that engagement in outdoor recreation aided respondents to keep fit but had also relevance in terms of identity, experiences, and daily routines. Outdoor recreation close to the place of residence was most common and walking was the most frequently reported activity. While 80% considered their health to be good/very good, disability and long-term diseases were common and during the previous year, more than half of all respondents had disengaged from activities previously performed. Reasons for disengagement were mainly related to health decline or that activities were too demanding but also due to social loss. The interviews indicated that continued engagement was important but challenging, and that disengagement could be considered as a loss or accepted due to changing circumstances. In the design of an intervention aiming to promote engagement in outdoor recreation for older adults, the following features are proposed to be considered: person-centeredness, promoting functioning, addressing self-ageism, providing environmental support, promoting subjective mobility needs and adaptation to find new ways to engage in outdoor recreation.


miR-421 up-regulation by the oleanolic acid derivative K73-03 regulates epigenetically SPINK1 transcription in pancreatic cancer cells leading to metabolic changes and enhanced apoptosis.
SPINK1 overexpression promotes cancer cell aggressiveness and confers chemo-resistance to multiple drugs in pancreatic cancer. Oleanolic acid (OA) derivatives possess active effects against different cancers. Here we report the effect of K73-03, a new novel OA derivative, against pancreatic cancer through mitochondrial dysfunction via miR-421/SPINK1 regulation. We examined the binding ability of miR-421 with SPINK1-3'UTR Luciferase reporter assays. Moreover, miR-421/SPINK1 expressions in pancreatic cancer, with or without K73-03 treatment, were evaluated. Cells viability, migration, autophagy, mitochondrial function and apoptosis were examined with or without K73-03 treatment. We established that the K73-03 effect on the miR-421 that plays a crucial role in the regulation of SPINK1 in pancreatic cancer. Our findings indicated that K73-03 inhibited the mitochondrial function that led to inducing autophagy and apoptosis through epigenetic SPINK1 down-regulation via miR-421 up-regulation in pancreatic cancer. Furthermore, the inhibition of miR-421 expression in pancreatic cancer cells abolished the efficacy of K73-03 against SPINK1 oncogenic properties. We found an interesting finding that the interaction between miR-421 and SPINK1 is related to mitochondrial function through the effect of K73-03. Further, SPINK1 appear to be the molecular targets of K73-03 especially more than gemcitabine.


Stage Ia1 cervical squamous cell carcinoma: conservative management after laser conization with positive margins.
Cone margin status has been reported to be the most important predictor of recurrent disease in patients with cervical intraepithelial neoplasia (CIN) undergoing cervical conization. Our purpose was to evaluate the conservative management of selected patients with microinvasive (FIGO stage Ia1) squamous cell carcinoma who have been treated by cervical conization with positive margins. Twenty-seven patients underwent KTP laser conization and vaporization for stage Ia1 squamous cell carcinoma followed by careful observation. Involved margins were diagnosed if CIN III or more was present at the ectocervical or endocervical margin and 7 patients formed the basis of the present study. Follow-up consisted of cytology, histology, and pelvic examination. Disease recurrence was defined as a histology diagnosis of CIN III or more on colposcopically directed biopsy or endocervical curettage. The endocervical margins were involved by carcinoma in situ in seven (26%) patients. No ectocervical margin involvement was detected. No lymph-vascular space involvement (LVSI) and confluent invasion were seen. All seven patients were free of recurrent disease during median follow-up of 4.0 (range 2.3-7.6) years. These results suggest that laser conization and vaporization may be a reasonable treatment option in patients with microinvasive (FIGO Stage Ia1) squamous cell carcinoma despite positive cone margins without invasive disease when LVSI is not demonstrated.


Determination of cationic surfactants in pharmaceuticals based on competitive aggregation in ternary amphiphile mixtures.
The surfactant to dye binding degree (SDBD) method was extended for the first time to the determination of cationic amphiphiles. For this purpose, Cresyl Violet (CV) and sodium dodecylsulphate (SDS) were selected as dye and reactant surfactant, respectively. This chemical system was used for the determination of cationic surfactants in pharmaceuticals. The approach was based on the competition established between the dye and cationic analytes to form mixed aggregates with the anionic surfactant (SDS-CV and SDS-analyte), which resulted in an increase of the amount of SDS required to reach a given SDS-CV binding degree. The feasibility of the proposed method to determine quaternary ammonium surfactants belonging to different structural groups (alkyldimethylbenzylammonium chlorides, alkyltrimethylammonium bromides and alkylpyridinium chlorides) in a wide variety of pharmaceutical formulations (solutions, creams and powders) was proved. The analytical features of the SDBD method (versatility, high precision and selectivity, ruggedness, rapidity, simplicity and low cost) made it an advantageous alternative to the conventional methods used in cationic surfactant quality control.


Consistent estimation of Y STR haplotype probabilities.
Many methods have been proposed to estimate Y-STR haplotype probabilities in a population, but no consensus has been achieved. In this paper a consistency principle for statistical models to provide such probabilities is proposed, in which it is required that the probability of a given haplotype profile on n loci cannot exceed that of any sub-haplotype matching on any n - 1 or fewer loci. If this consistency principle is violated by a Y haplotype probability model, then it could render the presentation of such probabilities highly problematic in a courtroom setting. We show, using publicly available datasets and two recently proposed graphical models for estimating probabilities of Y-STR haplotypes for illustration, that such violations can occur, and that the violations can in some instances be quite large. Some implications of this are discussed.


Doppler ultrasound measurements in the central circulation of anesthetized fetal sheep during obstruction of umbilical-placental blood flow.
To establish by Doppler ultrasound the effects of acute blockage of umbilical cord vessels on the fetal central circulation. Experimental study in anesthetized pregnant sheep. In 11 anesthetized pregnant sheep (0.66 of gestation), Doppler velocity profiles and/or venous flow rates were recorded in the ductus venosus, the fetal aorta, the umbilical arteries and the umbilical vein. This involved three phases. In Phase 1, the abdominal wall was closed (n = 9); Phase 2 was during fetoscopy after laparotomy (n = 8); Phase 3 was after coagulation of one of the umbilical arteries (n = 10). As an additional intervention in six fetuses, the umbilical cord was clamped for 5-15 s while blood flow velocity changes in the ductus venosus were observed. There were no significant differences between Doppler recordings in Phases 1 and 2. During Phase 3, the pulsatility index of the aorta and of the coagulated umbilical artery increased significantly. The umbilical vein blood flow rate was significantly reduced from a median of 408 (range, 243-575) mL/min/kg in Phase 1 to a median of 173 (range, 107-426) mL/min/kg in Phase 3, but the blood flow rate in the ductus venosus (median, 94; range, 56-148 mL/min/kg vs. median, 92; range, 33-237 mL/min/kg) remained unchanged. The ductus venosus/umbilical vein ratio increased from a median of 0.22 (range, 0.13-0.41) to 0.56 (range, 0.17-0.97) (P < 0.05). Compression of the cord (5-15 s) immediately reduced the time averaged maximum velocity in the ductus venosus from a mean of 51 (standard deviation, 11) cm/s to 20 (standard deviation, 6) cm/s (P < 0.001) without significant changes of the velocity profile. However, the pulsatility index increased from a mean of 0.55 (standard deviation, 0.19) to 1.89 (standard deviation, 0.73) (P < 0.001). Central venous flows in anesthetized fetal sheep are unaffected by laparotomy and hysterotomy. Obliteration of one umbilical artery increases the ductus venosus/umbilical vein volume flow (mL/min/kg) ratio. Compression of the umbilical cord shifts down blood flow velocity profiles in the ductus venosus, and the pulsatility index thus increases.


Diagnosis of calcium pyrophosphate dihydrate deposition disease by fine needle aspiration biopsy: a case report.
Calcium pyrophosphate dihydrate deposition disease is a relatively rare disease with variable clinical presentations. A 73-year-old man presented with worsening lower back pain and fever. Fine needle aspiration biopsy of the lumbar vertebral bodies (L3-L4) revealed abundant neutrophils admixed with small, birefringent, rhomboid crystals in Diff-Quik-stained smears. These crystals were confirmed as calcium pyrophosphate dihydrate on cell block sections. A diagnosis of osteomyelitis and calcium pyrophosphate dihydrate deposition disease was rendered. The patient was treated with antibiotics and responded well. Calcium pyrophosphate dihydrate deposition disease can be diagnosed by fine needle aspiration biopsy, and an accurate diagnosis can be greatly facilitated by cell block sections. However, such a diagnosis may be neglected if the specimen is not carefully inspected.


Analysis of factors influencing pancreatic beta-cell function in Japanese patients with type 2 diabetes: association with body mass index and duration of diabetic exposure.
To elucidate the clinical factors affecting beta-cell function, serum C-peptide immunoreactivity (CPR) levels of patients with type 2 diabetes were analyzed. Seven hundred Japanese patients with type 2 diabetes were enrolled. beta-Cell function was evaluated by fasting CPR (FCPR), 6 min after intravenous injection of 1mg glucagon (CPR-6 min), and the increment of CPR (DeltaCPR). Simple regression analysis between FCPR, CPR-6 min, and DeltaCPR and measures of variables and stepwise multiple regression analysis were carried out. Years from diagnosis and BMI were the major independent variables predicting beta-cell function. Years from diagnosis was negatively correlated with CPR-6 min (P<0.0001, r=-0.271), and decrease in CPR-6 min was 0.050 ng/(ml year). BMI was positively correlated with CPR-6 min (P<0.0001, r=0.369). When subjects were divided according to BMI, the decrease in CPR-6 min per year in the high-BMI group (0.068 ng/(ml year)) was greater than that in the low-BMI group (0.035 ng/(ml year)). A linear decline in endogenous insulin secretion over more than several decades of diabetes was confirmed by this cross-sectional study. The duration of diabetes exposure and BMI are thus major factors in beta-cell function in Japanese patients with type 2 diabetes.


Commment on the review entitled "A critical appraisal of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer" by Chiva LM and Gonzalez-Martin A.
•We raised some methodological concerns and made some comments on the systematic review by Chiva and colleague.•To state that Cytoreduction & HIPEC is not beneficial in front line and platinum sensitive recurrence is highly disputable.•Anyway, the combined treatment should be offered in the context of clinical trial; randomized data are urgently needed.


Unraveling the multivalent binding of a marine family 6 carbohydrate-binding module with its native laminarin ligand.
Laminarin is an abundant brown algal storage polysaccharide. Marine microorganisms, such as Zobellia galactanivorans, produce laminarinases for its degradation, which are important for the processing of this organic matter in the ocean carbon cycle. These laminarinases are often modular, as is the case with ZgLamC which has an N-terminal GH16 module, a central family 6 carbohydrate-binding module (CBM) and a C-terminal PorSS module. To date, no studies have characterized a true marine laminarin-binding CBM6 with its natural carbohydrate ligand. The crystal structure of ZgLamCCBM6 indicates that this CBM has two clefts for binding sugar (variable loop site, VLS; and concave face site, CFS). The ZgLamCCBM6 VLS binds in an exo-manner and the CFS interacts in an endo-manner with laminarin. Isothermal titration calorimetry (ITC) experiments on native and mutant ZgLamCCBM6 confirm that these binding sites have different modes of recognition for laminarin, in agreement with the 'regional model' postulated for CBM6-binding modules. Based on ITC data and structural data, we propose a model of ZgLamCCBM6 interacting with different chains of laminarin in a multivalent manner, forming a complex cross-linked protein-polysaccharide network. PDB code 5FUI.


Variation in the BMP2 gene: bone mineral density and ultrasound in young adult and elderly women.
Bone morphogenetic protein-2 (BMP2) plays a key role in bone formation and maintenance. Studies of polymorphisms within the gene in relation to bone mineral density (BMD) and fracture have been inconsistent. Our aim was to investigate associations between polymorphisms in the BMP2 gene and bone mass, fracture, and quantitative ultrasound (QUS) measures at different stages of skeletal development. Study subjects were participants of two population-based cohorts of Swedish women: the PEAK-25 cohort of young adult women aged 25 years (n = 993) and the OPRA cohort of elderly women aged 75 years (n = 1,001). We analyzed four single-nucleotide polymorphisms (SNPs) across the BMP2 gene including the Ser37Ala SNP previously identified in relation to BMD, QUS of the calcaneus, and, in the elderly women, fracture. BMP2 gene variations were associated with QUS of bone, independent of BMD, but only in the young women. Even after adjusting for confounding factors, SNP rs235754 in the 3' region of the gene was significantly associated with the ultrasound parameters speed of sound (P = 0.003) and stiffness (P = 0.002). The 5' SNP rs235710 showed trends for QUS parameters (P = 0.02-0.07). No association with BMP2 SNPs was observed in either cohort for either BMD or fracture. While further, more extensive genotyping across the gene is recommended, as we may not have captured all information, our preliminary data suggest that variation in BMP2 may play a previously unidentified role in aspects of bone quality, which may be age- and site-dependent.


The clinical course of a Mexican female with cystic fibrosis and the novel genotype S531P/S531P.
The case of a 16 year-old Mexican female with cystic fibrosis and the novel genotype S531P/S531P is presented. Her clinical course has consisted of recurrent pancreatitis and rapidly progressive lung disease complicated by Mycobacterium kansasii and Penicillium infection. This report illustrates the need for better characterization of CFTR mutations in a Hispanic population to aid in clinical care.


Differential effects of butyrate and dibutyryl cAMP on mRNA levels of muscarinic acetylcholine receptor subtypes expressed in neurohybrid cell lines.
NCB-20 cells expressed m1- and m4-muscarinic acetylcholine receptor (mAChR) mRNAs, while NG108-15 cells expressed only m4-mAChR mRNA. Butyrate induced a time-dependent increase in the level of m1-mAChR mRNA with no change in the m4-mAChR mRNA level in NCB-20 cells. Similarly, butyrate did not affect the m4-mAChR mRNA level in NG108-15 cells. In contrast, dibutyryl cAMP caused a significant time-dependent decrease in the level of m4-mAChR mRNA in NCB-20 and NG108-15 cells as well as m1-mAChR mRNA in NCB-20 cells. Our results suggest that these two differentiating agents are important physiological regulators of the transcription and/or stability of the mRNA of certain mAChR subtypes expressed in these two neurohybrid cell lines.


In-line skating injuries. Epidemiology and recommendations for prevention.
In 1993 there was an estimated 12.6 million in-line skaters in the US. In-line skating is popular because of its affordability and its exercise and recreational value. The main risk factors for injury include speed, obstacles and hard surfaces. Using the National Electronic Injury Surveillance System in US hospitals, 31,000 skaters were reported injured over a 12 month period. Fractures, dislocations, sprains, strains and avulsion made up 67% of all injuries. It is recommended that skaters wear protection equipment including, helmet, wrist guards, knee-pads and elbow-pads. Although head injuries from skating appear low in numbers, helmet protection is also recommended. Further studies are required that assess risk factors for injury and environmental and behavioural aspects.


A new insect cell line from the longicorn beetle Plagionotus christophi (Coleoptera: Cerambycidae).
We have established a continuous cell line from the fat body tissue of the longicorn beetle Plagionotus christophi. The cells have been serially subcultured in MGM450 medium, and the line has been designated as PC-1. The cells were grown in suspension and comprise largely flattened spindle- or oval-shaped cells morphologically related to blood cells of longicorn beetles. The chromosome number ranged from 19 to 36, with a mode of 20 (diploid). The growth curve was determined at the 100th passage, and the population doubling time was calculated to be 3.79 d. Isozyme analysis of malic enzyme, phosphoglucose isomerase, and phosphoglucomutase revealed that PC-1 cells were enzymatically distinct from coleopteran XP-1, AnCu-35, dipteran AeAl-2, and lepidopteran GaMe-LF1 cell lines.


Partitioning of upper airway resistance in Friesian and double-muscled calves.
Respiratory resistance in calves was partitioned in two components: upper airway resistance and pulmonary resistance. The former one was divided into naso-pharyngeal and laryngeal resistance. A comparison between seven healthy unsedated double-muscled calves of the Belgian White and Blue breed (BWB) and five healthy unsedated Friesian (F) calves was performed. Respiratory resistance was significantly greater in the BWB calves, due to the significantly higher values of the naso-pharyngeal and the laryngeal resistances. This finding might be related to the higher prevalence of laryngitis in this breed.


Finger Tapping Task Activation vs. TMS Hotspot: Different Locations and Networks.
Both functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) have been used to non-invasively localize the human motor functional area. These locations can be clinically used as stimulation target of TMS treatment. However, it has been reported that the finger tapping fMRI activation and TMS hotspot were not well-overlapped. The aim of the current study was to measure the distance between the finger tapping fMRI activation and the TMS hotspot, and more importantly, to compare the network difference by using resting-state fMRI. Thirty healthy participants underwent resting-state fMRI, task fMRI, and then TMS hotspot localization. We found significant difference of locations between finger tapping fMRI activation and TMS hotspot. Specifically, the finger tapping fMRI activation was more lateral than the TMS hotspot in the premotor area. The fMRI activation peak and TMS hotspot were taken as seeds for resting-state functional connectivity analyses. Compared with TMS hotspot, finger tapping fMRI activation peak showed more intensive functional connectivity with, e.g., the bilateral premotor, insula, putamen, and right globus pallidus. The findings more intensive networks of finger tapping activation than TMS hotspot suggest that TMS treatment targeting on the fMRI activation area might result in more remote effects and would be more helpful for TMS treatment on movement disorders.


Induction of arthritis by single monoclonal IgG anti-collagen type II antibodies and enhancement of arthritis in mice lacking inhibitory FcgammaRIIB.
IgG anti-collagen type II (CII) antibodies (Ab) can induce arthritis in healthy mice. Here we have investigated if single monoclonal IgG anti-CII Ab can induce arthritis in CIA-susceptible DBA/1 mice and if there is an IgG subclass dependency. The involvement of Fc receptors for IgG (FcgammaR) in anti-CII Ab-mediated arthritis was also investigated by comparing the clinical outcome in DBA/1 mice to those in FcgammaR-deficient mice. We demonstrate for the first time that single mAb to naive DBA/1 mice can induce persistent arthritis. Histology of the inflamed joints revealed massive cellular infiltrate and cartilage and bone destruction. All IgG subclasses tested (IgG1, IgG2a and IgG2b) were arthritogenic, with the IgG1 and IgG2b isotypes as the dominating arthritogenic Ab. Pathogenicity was dependent on engagement of activating FcgammaR, as FcRgamma-deficient mice were completely resistant to Ab-mediated arthritis. The arthritis induced with the IgG1 and IgG2b Ab was also inhibited by FcgammaRIII disruption, whereas arthritis mediated by the IgG2a Ab was not substantially affected. The arthritic response of the IgG1 and IgG2b isotypes, but not of the IgG2a Ab, was further enhanced in mice lacking the inhibitory FcgammaRIIB. These results demonstrate that single IgG anti-CII mAb can induce erosive arthritis and that IgG anti-CII Ab mediate arthritis by engagement of FcgammaR.


Pharmacological analysis of protein kinases responsible for chemotaxis of rat peritoneal neutrophils.
Several types of kinase inhibitors were used to investigate the possible signaling pathways leading to the chemotaxis of rat peritoneal neutrophils toward macrophage inflammatory protein-2, cytokine-induced neutrophil chemoattractant-1, and platelet-activating factor. The chemotaxis and shape changes induced by each of these chemoattractants were strongly inhibited by a tyrosine kinase inhibitor (herbimycin A) and protein kinase C inhibitors (H-7 (1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride) and calphostin C). The formation of phosphatidyl 3,4,5-triphosphate in chemoattractant-stimulated neutrophils was completely inhibited by 100 nM of wortmannin, an inhibitor of phosphatidylinositol 3-kinase, whereas the chemotaxis toward each of these chemoattractants was partially inhibited (50% inhibition). The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK-1) inhibitor PD 98059 did not inhibit the neutrophil chemotaxis. These findings suggest that the activation of tyrosine kinase and protein kinase C strongly participates in neutrophil chemotaxis and that the activation of phosphatidylinositol 3-kinase is partially involved, but that the activation of mitogen-activated protein kinase is not involved in neutrophil chemotaxis. The cross-linking of the signaling pathways for chemotaxis toward each chemoattractant was also examined.


Pretreatment Immune Parameters Predict for Overall Survival and Toxicity in Early-Stage Non-Small-Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy.
We determined whether pretreatment immunologic parameters could predict the outcomes and toxicity in early-stage non-small-cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). The pretreatment leukocyte, lymphocyte, and neutrophil counts, serum albumin levels, neutrophil-to-lymphocyte ratio (NLR,) and platelet-to-lymphocyte ratio (PLR) were evaluated to determine the association with locoregional control, distant metastasis-free survival (DMFS), disease-specific survival (DSS), overall survival (OS), and treatment-related toxicity. The survival rates were estimated with Kaplan-Meier analysis and multivariate analysis using the Cox proportional hazards model. The data from 118 patients with a median follow-up period of 28.9 months were assessed. The 3-year local control, regional control, and DMFS rates were 97%, 87%, and 92%, respectively. The 3-year OS and DSS rates were 77% and 85%, respectively. On univariate analysis, none of the pretreatment immune parameters predicted for disease control. A higher NLR (P = .008), PLR (P = .002), neutrophil count (P = .059), and the presence of lymphocytopenia (P = .032) independently prognosticated for poor OS. Receiver operating characteristic curve analysis found NLRs > 2.18 and PLRs > 187.27 optimally predicted for poor 3-year OS (P = .0262 and P = .0089, respectively). A higher NLR predicted against the development of any symptomatic toxicity and against the development of symptomatic (grade ≥ 2) radiation pneumonitis on univariate analysis, and a higher serum albumin level independently predicted for the development of symptomatic radiation pneumonitis (P = .0491). In the setting of SBRT, an elevated pretreatment NLR, PLR, and neutrophil count and the presence of lymphocytopenia independently predicted for poor OS. Patients who presented with higher NLRs and lower serum albumin levels experienced less treatment-related symptomatic toxicity.


Attitudes and knowledge about obstructive sleep apnea among Latin American primary care physicians.
We aimed to evaluate Latin American primary care physicians' knowledge and attitudes about obstructive sleep apnea (OSA) using a Spanish-language version of the OSA Knowledge and Attitudes (OSAKA) questionnaire and to evaluate its psychometric properties. We used a cross-sectional survey of general practice physicians in Ecuador, Peru, and Venezuela who completed the Spanish-language version OSAKA questionnaire. Of 684 primary care physicians surveyed, 367 (65%) responded (mean age, 45 years; range, 21-75 years). Mean total knowledge (proportion of 18 items correctly answered) was 60% (range, 0-100%). Less than half of physicians correctly answered the questions about the association between OSA and hypertension. We found no significant differences in overall knowledge in gender or time since graduation (< or =5 years vs. >5 years). Although 73.5% of the physicians felt confident in identifying patients at risk for OSA, only 35.4% felt confident in managing those patients and 22.1% felt confident in managing patients with continuous positive airway pressure (CPAP) therapy. The Spanish-language version of the OSAKA questionnaire had comparable psychometric properties to the English-language version. This Spanish-language version of the OSAKA yielded considerable variance in Spanish-speaking physicians' knowledge about OSA and confidence in identifying and managing patients with OSA. Focused OSA education for Latin American general physicians is needed.


Synthesis and inhibition studies towards the discovery of benzodiazepines as potential antimalarial compounds.
The target-based discovery of therapeutics against apicoplast, an all-important organelle is an overriding perspective. MEP pathway, an accredited drug target provides an insight into the importance of apicoplast in the survival of the parasite. In this study, we present the rational design strategy employing sustainable catalysis for the synthesis of benzodiazepine (BDZ) conformers followed by their biological evaluation as prospective inhibitors against the potential target of the IPP pathway, 1-deoxy-D-xylulose-5-phosphatereductoisomerase (DXR). The study reported the inhibitory profile of 8c and 6d against the quintessential step of the only drug target in the erythrocytic stages of parasite development. The potential compounds were identified to represent a novel class of inhibitors that serve as the lead molecules to impede the pathway and further affect the survival of the parasite.


Vascular natriuretic peptide receptor-linked particulate guanylate cyclases are modulated by nitric oxide-cyclic GMP signalling.
(1) The sensitivity of the particulate guanylate cyclase-cyclic guanosine-3',5'-monophosphate (cGMP) system to atrial (ANP) and C-type (CNP) natriuretic peptides was investigated in aortae and mesenteric small arteries from wild-type (WT) and endothelial nitric oxide synthase (eNOS) knockout (KO) mice. (2) ANP and CNP produced concentration-dependent relaxations of mouse aorta that were significantly attenuated by the natriuretic peptide receptor (NPR)-A/B antagonist HS-142-1 (10(-5) M). Both ANP and CNP were more potent in aortae from eNOS KO mice compared to WT. (3) The potency of ANP and CNP in aortae from WT animals was increased in the presence of the NOS inhibitor, N(G)-nitro-L-arginine (3 x 10(-4) M) and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolol[4,3,a]quinoxalin-1-one (5 x 10(-6) M). (4) In contrast, the potency of ANP and CNP in aortae from eNOS KO animals was reduced following pretreatment of tissues with supramaximal concentrations of the NO-donor, glyceryl trinitrate (3 x 10(-5) M, 30 min) or ANP (10(-7) M, 30 min). (5) Responses to acetylcholine in aortae from WT mice (dependent on the release of endothelium-derived NO) were significantly reduced following pretreatment of tissues with GTN (3 x 10(-5) M, 30 min) and ANP (10(-7) M, 30 min). (6) CNP and the NO-donor, spermine-NONOate caused concentration-dependent relaxations of mesenteric small arteries from WT animals that were significantly increased in eNOS KO mice compared to WT. ANP was unable to significantly relax mesenteric arteries from WT or eNOS KO animals. (7) In conclusion, both NPR-A- and NPR-B-linked pGC pathways are modulated by NO-cGMP in murine aorta and mesenteric small arteries and crossdesensitisation occurs between NPR subtypes. The biological activity of endothelium-derived NO is also influenced by the ambient concentration of NO and natriuretic peptides. Such an autoregulatory pathway may represent an important physiological homeostatic mechanism and link the paracrine activity of NO and CNP with the endocrine functions of ANP and BNP in the regulation of vascular tone and blood pressure.


Anxiety-like behavior and anxiolytic treatment in the Rett syndrome natural history study.
Rett syndrome (RTT) is a neurodevelopmental disorder most often related to a pathogenic variant in the X-linked MECP2 gene. Internalizing behaviors appear to be common, but standard methods of diagnosing anxiety are not readily applied in this population which typically has cognitive impairment and limited expressive language. This study aims to describe the frequency of anxiety-like behavior and anxiolytic treatments along with associated clinical features in individuals with RTT. Parental reports and medication logs provided data from 1380 females with RTT participating in two iterations of the multicenter U.S. RTT Natural History Study (RNHS) from 2006 to 2019. Most participants with RTT (77.5%) had at least occasional anxious or nervous behavior. Anxiety was reported to be the most troublesome concern for 2.6%, and within the top 3 concerns for 10.0%, of participants in the second iteration. Parents directly reported treatment for anxious or nervous behavior in 16.6% of participants in the second iteration with most reporting good control of the behavior (71.6%). In the medication logs of both RNHS iterations, the indication of anxiety was listed for a similar number of participants (15% and 14.5%, respectively). Increased use of anxiolytics and selective serotonin reuptake inhibitors (SSRIs) was related to more frequent anxiety-like behaviors (P < 0.001), older age (P < 0.001), and mild MECP2 variants (P = 0.002). Anxiety-like behavior is frequent at all ages and is a significant parental concern in RTT. Older individuals and those with mild MECP2 variants are more likely to be treated with medications. Better diagnosis and treatment of anxiety in RTT should be a goal of both future studies and clinical care. NCT00299312 and NCT02738281.


Cancer cachexia: Comparing diagnostic criteria in patients with incurable cancer.
Cancer cachexia (CC) is a multifactorial syndrome that is associated with worse outcomes. Several criteria for its diagnosis have been suggested, but notable disparities exist. This study compared different diagnostic criteria for CC in patients with incurable cancer who are in palliative care. A prospective cohort study was conducted at the National Cancer Institute in Brazil. Patients were classified by three CC diagnostic criteria, and comparisons between clinical, nutritional, and functional variables were verified according to the CC stage identified. Kaplan-Meier survival curves and Cox regression were used for the survival analysis. Concordance statistics were used to test the prognostic predictive accuracy of the criteria. The prevalence of cachexia in the 1384 patients included in the study varied from 13.8% to 53.9% according to the classification criteria used. All criteria distinguished noncachectic patients from other categories according to the majority of the domains studied. However, the results were inconsistent in distinguishing patients with intermediate cachexia (mainly precachexia) from noncachectic and cachectic patients. Patients with cachexia or refractory cachexia faced a higher risk of 90-d mortality. The criteria described by Vigano et al. were found to be better at distinguishing the stages of CC regarding overall survival (hazard ratio increases according to CC severity: 1.87 to 2.87; concordance statistic: 0.74). Our results demonstrate the disparities in existing CC diagnostic criteria and their inability to discriminate intermediate stages. Vigano et al.'s criteria is/was the most effective in predicting the prognosis. The development of new diagnostic criteria to improve CC classification requires future exploration.


A patient showing features of both SBBYSS and GPS supports the concept of a KAT6B-related disease spectrum, with mutations in mid-exon 18 possibly leading to combined phenotypes.
Genitopatellar syndrome (GPS) and Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) are two distinct clinically overlapping syndromes caused by de novo heterozygous truncating mutations in the KAT6B gene encoding lysine acetyltransferase 6B, a part of the histone H3 acetyltransferase complex. We describe an 8-year-old girl with a KAT6B mutation and a combined GPS/SBBYSS phenotype. The comparison of this patient with 61 previously published cases with KAT6B mutations and GPS, SBBYSS or combined GPS/SBBYSS phenotypes allowed us to separate the KAT6B mutations into four groups according to their position in the gene (reflecting nonsense mediated RNA decay and protein domains) and their clinical outcome. We suggest that mutations in mid-exon 18 corresponding to the C-terminal end of the acidic (Asp/Glu-rich) domain of KAT6B may have more variable expressivity leading to GPS, SBBYSS or combined phenotypes, in contrast to defects in other regions of the gene which contribute more specifically to either GPS or SBBYSS. Notwithstanding the clinical overlap, our cluster analysis of phenotypes of all known patients with KAT6B mutations supports the existence of two clinical entities, GPS and SBBYSS, as poles within the KAT6B-related disease spectrum. The awareness of these phenomena is important for qualified genetic counselling of patients with KAT6B mutations.


Brain-wide mapping reveals that engrams for a single memory are distributed across multiple brain regions.
Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos+ brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage.


Effects of the slow calcium-channel blocker verapamil on phosphatic metabolism of crystalline lens.
The effects of calcium-channel blockade on phosphate metabolism in the rabbit lens ex vivo was studied using phosphorus-31 nuclear magnetic resonance (NMR) spectroscopy. Rates-of-change of the intralenticular pH and the following phosphatic metabolites in the lens were determined: ATP, ADP, inorganic orthophosphate, sugar phosphates, nucleoside diphosphosugars, phosphodiesters, dinucleotides, and an uncharacterized resonance peak at 6 delta in the 31P spectrum. Incubation in 20, 200 or 2000 micrograms/ml verapamil led to the same qualitative changes in the lens's metabolic profile at each different concentration; only the rates of metabolite change were altered significantly by verapamil concentration. Compared with the control, the entire orthophosphate resonance band increased relative to the signals of ATP, and the alpha-glycerophosphate and nucleoside monophosphate resonances increased in relation to inorganic orthophosphate, and these two resonance groups shifted relative to each other so that they coalesced, indicating that the two groups of signals arose from compounds in relatively different pH compartments. In addition to altering metabolic rates, verapamil reduced the intralenticular pH of the sugar phosphate and inorganic orthophosphate pools with respect to those containing the nucleoside monophosphates; the pH-change difference was about one order of magnitude smaller for the mononucleotide pool. Despite the metabolic alterations and changes in pH during verapamil incubation, lens clarity was unchanged.


Mental health literacy among primary healthcare workers in South Africa and Zambia.
In developing countries, mental health literacy (MHL) still needs to be improved due to the high prevalence of mental disorders. It is widely recognized that MHL can improve health outcomes for both individuals and populations. Healthcare professionals' development in MHL is crucial to the prevention of mental disorders. The aim of this study was to assess MHL of primary healthcare (PHC) workers in South Africa (SA) and Zambia and determinants thereof. Limited evidence is available on the levels of MHL among PHC workers in the sub-Saharan Africa region, which faces a large burden of mental disorders. The study population for this cross-sectional survey comprised PHC workers (n = 250) in five provinces of SA and Zambia. MHL was measured with the Mental Health Literacy Scale (MHLS). We conducted a multivariate analysis to explore determinants of MHL. Results showed moderate MHL among PHC professionals, but with a wide range from low to high MHL. Knowledge-related items had a greater dispersion than other attributes of MHL. PHC workers with more education showed a greater ability to recognize mental health-related disorders. Those who had experience in the use of mental health-related assessment scales or screening tools reported a higher total MHL. The results confirmed strong internal consistency for the MHLS. The results highlighted varying mental health perceptions and knowledge in PHC. Implementation of specifically developed formal training programs and interventions to improve MHL in PHC workers to strengthen their competence may help bridge the treatment gap.


The hydroxylation of tryptophan.
Products of the chemical hydroxylation of tryptophan by Fenton and Udenfriend reactions are similar to those obtained by ionizing radiation. When tryptophan is exposed to either of these systems, a mixture of four hydroxytryptophans, oxindole-3-alanine, and N-formylkynurenine is formed. This observation indicates that the hydroxyl radical attacks the aromatic nucleus as well as the 2 and 3 positions of the pyrrole ring. During gamma-radiolysis of nitrous oxide-saturated tryptophan solution and in the absence of oxygen or ferric edta, the hydroxyl radical adduct (or hydroxycyclohexadienyl radical) of tryptophan undergoes dimerization and polymerization, which results in a yellow product with maximal absorbance at 425 nm. In the presence of ferric edta, or in a Fenton system, the hydroxyl radical adduct disproportionates, and hydroxylated derivatives are formed. The yields of the hydroxytryptophans are proportional to the concentration of ferric edta to a limiting yield of 54% of the theoretical yield, which is taken to be one hydroxylated product per two hydroxyl radicals. Under these conditions, 4-, 5-, 6-, and 7-hydroxy-derivatives of tryptophan are found in the proportion 4:2:2:3, respectively. The presence of dioxygen during gamma-radiolysis increases the yield of N-formylkynurenine, but does not affect the total yield of hydroxytryptophans. Similarly, tryptophan subjected to the Udenfriend reaction yields 4-, 5-, 6-, and 7-hydroxytryptophan and N-formylkynurenine in approximately equal amounts.


Current status and future challenge of population-based organized colorectal cancer screening: Lesson from the first decade of Taiwanese program.
Colorectal cancer (CRC) is the most common cancer in Taiwan, and is the third leading cause of cancer-related death. Screening has been proven the most effective way to reduce CRC mortality, and stool-based screening is currently the most popular method of screening worldwide. In 2004, Taiwanese government launched a nationwide screening program and fecal immunochemical test (FIT) is offered biennially to individuals aged 50 to 75. The results from the program have demonstrated that FIT screening could effectively reduce the mortality from CRC. Nevertheless, there were some problems needed to deal with. First, the occurrence of interval cancers, which are associated with the performance of screening tests or quality of colonoscopy, has affected the program sensitivity. Second, increasing participation in the program has increased the demand for colonoscopy and the burden on public health workers. Third, some individuals are non-compliant with FIT screening, and with the recommendation for colonoscopy after a positive FIT, which may be the result of insufficient awareness toward CRC and screening of the public. Fourth, long-lasting financial support for this program is necessary for its success. All of these problems need to be solved via collaboration between the screening organizer, screening distributor, and professional societies.


Application of solid-phase microextraction to the analysis of volatile compounds in virgin olive oils.
Solid-phase microextraction was used as a technique for headspace sampling of extra virgin olive oil and virgin olive oil samples with different off-flavours. A 100 microm coated polydimethylsiloxane fiber was used to extract volatile aldehydes, the sampling temperature was 45 degrees C and the fiber has been exposed to the headspace for 15 min. Nonanal and 2-decenal were present in all the olive oils with extraction off-flavours but were not in extra virgin olive oil sample.