Chemotherapy alone vs. chemotherapy plus radiotherapy in female adolescent and young adults with Hodgkin's lymphoma: reproductive health outcomes.
To examine the effects of Hodgkin's lymphoma and its treatment on reproductive health in female adolescent and young adults (AYA). We conducted a retrospective, population-based, matched-cohort study of female patients with Hodgkin's lymphoma diagnosed at 15-39 years of age from 1995 to 2014 in Ontario, Canada. Three female individuals with no history of cancer (unexposed) were matched by birth year and census subdivision to each patient with cancer (exposed). In a subset of the cohort (2005 onwards), the Hodgkin's lymphoma patients were further classified into two groups for analysis based on treatment exposure: (1) chemotherapy alone or (2) combined chemotherapy and radiation. Reproductive health outcomes were infertility, childbirth, and premature ovarian insufficiency (POI). Relative risks (RR) were calculated using modified Poisson regression adjusted for income quintile, immigration status, and parity. A total of 1443 exposed and 4329 unexposed individuals formed our cohort. Hodgkin's lymphoma patients were at an increased risk of infertility (aRR 1.86; 95% CI 1.57 to 2.20) and POI (aRR 2.81; 95% CI 2.16 to 3.65). While the risk of infertility persisted in both treatment groups (chemotherapy alone, combined chemotherapy plus radiotherapy), the increased risk of POI was only statistically significant in the chemotherapy plus radiotherapy group. No differences in childbirth rates were observed, overall or by treatment exposure compared with unexposed individuals. Female AYA survivors of Hodgkin's lymphoma face an increased risk of infertility, independent of exposure to chemotherapy alone, or chemotherapy plus radiotherapy. The risk of POI is higher in those requiring radiotherapy vs. chemotherapy alone. These results emphasize the importance of pre-treatment fertility counseling and reproductive health surveillance for AYAs diagnosed with Hodgkin's lymphoma.


Economic decision-making in the continuum between healthy aging and Alzheimer's Disease: A systematic review of 20 years of research.
The effect of pathological aging on economic decision-making is a topic of major relevance as impairments in this domain place older adults at increased risk for financial abuse. This review aims to characterize decision-making across the continuum that goes from healthy aging to Alzheimer's Dementia. We included 42 studies comparing patients with Mild Cognitive Impairment (MCI) and healthy older adults, patients with Alzheimer's Disease (AD) and healthy older adults, and patients with MCI and patients with AD. Substantial evidence emerged suggesting that both MCI as AD affect economic decision-making. However, a non-negligible number of behavioural tasks failed to find significant differences between patients and controls, and no differences were reported between patients with MCI and AD. On the contrary, measures of financial capacity reached more robust findings, showing that healthy older adults had better performance than patients, while MCI patients showed better performance than AD patients. This review presents the main conclusions that may be drawn from significant findings, as well as the hypotheses and recommendations for future research.


Analysis of brain and pituitary RNA metabolism: a review of recent methodologies.
Recent characterization of brain and pituitary RNA metabolism is reviewed. Relative to other tissues, the brain transcribes more of the unique, single-copy DNA. This transcriptional diversity reflects the inherent heterogeneity in organization and development of the brain. The end product of transcriptional regulation in the brain is a population of functional cytoplasmic mRNAs with multiple components, differing in complexity and abundance. Analysis of nuclear and cytoplasmic RNA provides evidence that both brain-specific synthesis and processing may determine the final mRNA population. Both polyadenylated and non-polyadenylated RNA classes contribute significantly to the total brain polysomal mRNA fraction. Characterizations of individual species of mRNA from both brain and pituitary are described. One possible transcriptional modulator in both the pituitary and brain is the presence of steroid hormone at responsive sites. Functional consequences of steroid accumulation within the brain may be (1) interactions with neurotransmitter, especially catecholamine, metabolism and function, (2) developmental interactions with neuronal systems, and (3) differentiation of glial cell function. The pleiotropic nature of steroid hormone effects (both transcriptional and non-transcriptional) within one brain region is considered by examining the biochemical effects of glucocorticoids in the hippocampus.


The outcomes of same-day discharge following holmium laser enucleation of the prostate (HoLEP) surgeries: our experience during the COVID-19 pandemic.
To describe the outcomes of Same-Day Discharge (SDD) following Holmium Laser Enucleation of the Prostate (HoLEP) in patients during the COVID-19 pandemic. A retrospective review of HoLEP surgeries at a single institution between January 2021 and March 2022 was performed. Patient demographic and operative data were collected, and postoperative outcomes were evaluated in terms of safety and efficacy and compared in both groups using a t-test and chi-square test. Logistic regression was also performed to identify factors that correlate with the failure of SDD. A total of 155 patients were identified; 135 patients were successfully discharged on the same day and 20 were admitted (87% SDD rate). Admitted HoLEP patients had a significantly higher median prostate-specific antigen (5.7 vs 3.9 ng/dL, P < 0.001), prostate volume (152.3 vs 100.6 mL, P < 0.001), and enucleated tissue weight (90.3 vs 56.9 g, P = 0.04) compared to the SDD group. The SDD group had a 2.9% (n = 4) readmission rate and a 5.2% (n = 7) Emergency Department (ED) visit rate. There was no significant difference in the rate of postoperative ED visits (P = 0.64), readmissions (P = 0.98), complications, and catheterization time (P = 0.98) between both groups. Preoperative predictors of SDD failure included prostate gland volume > 150 mL (OR = 7.17; CI 2.01-25.67; P < 0.01) and history of antiplatelet/anticoagulation use (OR = 6.59; CI 2.00-21.67; P < 0.01). Same-day discharge following HoLEP is a safe and effective approach that can be performed in most patients using a liberal discharge criteria and relying on postoperative findings only.


Determinants of and disparities in reproductive health service use among adolescent and young adult women in the United States, 2002-2008.
We investigated determinants of and disparities in reproductive health service use among young women in the United States from 2002 to 2008. Using data on 4421 US women aged 15 to 24 years from the National Survey of Family Growth (2002, n = 2157; 2006-2008, n = 2264), we employed descriptive and univariate statistics and multivariate regression models to examine service use across women's sociodemographic and reproductive characteristics and to investigate potential disparate changes in service use over time. More than half the sample (59%) had used services in the past year. In regression models, predictors of service use included age, education, birthplace, insurance, religious participation, mother's education, childhood family situation, age at menarche, sexual intercourse experience, recent number of partners, and previous gynecological diagnosis. Although service use decreased by 8% overall from 2002 to 2006-2008 (P < .001), the magnitude of decline was similar across demographic and socioeconomic groups. Inequalities in reproductive health service use exist among women in the United States, particularly among the youngest and socially disadvantaged women, which may translate to poor and disparate reproductive outcomes. Public health and policy strategies are needed to eliminate inequities in reproductive health service.


The homologue of the Duchenne locus is defective in X-linked muscular dystrophy of dogs.
Duchenne muscular dystrophy (DMD) is the most common and the most severe of the muscular dystrophies in man. It is inherited as an X-linked recessive trait and is characterized by ongoing necrosis of skeletal muscle fibres with regeneration and eventually fibrosis and fatty infiltration. Although the gene and gene product which are defective in DMD have recently been identified, the pathogenesis of the disease is still poorly understood. A myopathy has been described in the dog which has been shown to be inherited as an X-linked trait and which is therefore a potential model of the human disease. We have studied the phenotypic expression of the disease, canine X-linked muscular dystrophy (CXMD), and have examined the molecular relationship between it and DMD. We report here that dogs with CXMD faithfully mimic the phenotype of Duchenne muscular dystrophy and that they lack the Duchenne gene transcript and its protein product, dystrophin.


[Diffusion of smoking among high school students at U.S.L. No. 18 of the Tuscan region].
Between young people: 51% of male have never smoked, and only 38% of the females. If increase the age, increase also the percentage of whom that have had first meeting with cigarette smoke. Begin previously boys and they smoke more strongly. Today young people begin to smoke always more precociously, even if they are more informed.


Down-regulation of PDGFRβ suppresses invasion and migration in osteosarcoma cells by influencing epithelial-mesenchymal transition.
Osteosarcoma (OS) is the most common malignant bone tumor primarily influencing children and adults. Approximately one-fifth of patients have micrometastasis in the lungs when OS is diagnosed. Platelet-derived growth factor receptor (PDGFR) beta (PDGFRβ) is a subtype of PDGFR. PDGFRβ has been noted to be highly expressed in OS cell lines and patient specimens, and is associated with metastasis and poor prognosis of OS. However, mechanistic insights into the exact role of PDGFRβ in OS pathogenesis and development are still lacking. Here we assessed the effects of PDGFRβ on invasive and migratory abilities, such as the epithelial-mesenchymal transition and phosphatidylinositol 3-kinase (PI3K), Akt and mammalian target of rapamycin (mTOR) pathways in HOS cells. Depleting PDGFRβ resulted in reduced migration of HOS cells in the small interfering RNA duplexes specific for the PDGFRβ group compared with the mock and scramble-treated groups in Transwell invasion assays. Using wound-healing assays, we demonstrate the rate of wound healing in the PDGF-BB-stimulated group was higher compared with the mock-treated group. Western blot showed that down-regulation of PDGFRβ decreased the expression of stromal phenotype markers and phosphorylation pathway proteins (PI3K, AKT and mTOR), but the epithelial phenotype marker was increased in HOS cells. Treating HOS cells with PDGF-BB revealed a treatment time-dependent increase of phosphorylated, but not total, PI3K, AKT and mTOR. Taken together, we suggest that PDGFRβ plays an important role in OS invasion, migration and epithelial-mesenchymal transition by influencing the PI3K, Akt and mTOR pathways, hence highlighting PDGFRβ as a potential therapeutic target for OS.


Protective immune responses against systemic candidiasis mediated by phage-displayed specific epitope of Candida albicans heat shock protein 90 in C57BL/6J mice.
Specific epitope (DEPAGE) of Candida albicans heat shock protein 90 (SE-CA-HSP90) was successfully expressed on the surface of filamentous phage fd, fused to the major coat protein pVIII. Protective immune responses mediated by hybrid-phage expressing SE-CA-HSP90 in C57BL/6J mice were evaluated in this paper. The results showed that hybrid-phage particles induced the specific antibody response against SE-CA-HSP90, enhanced delayed-type hypersensitivity (DTH) response, natural killer (NK) cell activity and concanavalin A (ConA)-induced splenocyte proliferation. Furthermore, this study demonstrated that hybrid-phage-immunized mice had fewer colony forming unites (CFU) in the kidneys compared with wild-type phage-immunized mice and TE (1.0mM EDTA, 0.01M Tris-HCl, pH 8.0)-injected mice and showed statistically significant survival advantage over TE-injected group. In conclusion, the results suggest that the hybrid-phage displaying SE-CA-HSP90 may be considered as a potential candidate for producing vaccines against systemic candidiasis.


Autoimmune gastritis: distinct histological and immunohistochemical findings before complete loss of oxyntic glands.
Autoimmune gastritis (AG) can be easily recognized when the histological features are fully developed, but recognizing AG before the complete loss of the oxyntic mucosa is more challenging. One feature of fully developed AG is enterochromaffin cell-like (ECL) hyperplasia, but its presence or absence in earlier stages of AG has not been fully evaluated. A retrospective study of biopsy specimens from 40 patients was performed; all of the patients were originally diagnosed with possible AG based on the presence of lymphocytic infiltration and damage to oxyntic glands and/or the presence of metaplastic epithelium that disproportionately involved the body mucosa. Nineteen cases had follow-up serological studies for anti-parietal cells and/or anti-intrinsic factor antibodies: 13 were positive and 6 negative. The remaining 21 cases were indeterminate because of incomplete testing. The histological findings were similar in the patients who were serologically positive and those who were indeterminate for AG. In all of these cases, the oxyntic mucosa showed lymphoplasmacytic infiltrates within the lamina propria with focal gland infiltration and damage. Sixty-five percent (22/34) of the cases showed intestinal and/or pyloric metaplasia, and 85% (29/34) showed parietal cell pseudohypertrophy. Chromogranin stains were performed in 11 of 13 cases with positive serological markers for AG, and all showed at least linear ECL cell hyperplasia. In contrast, none of the six cases with negative serological studies had linear ECL cell hyperplasia, P <.001. In conclusion, the following constellation of findings supports a diagnosis of AG before the complete loss of oxyntic mucosa: deep or diffuse lymphoplasmacytic infiltrates within the lamina propria with foci of gland infiltration and damage, epithelial metaplasia, parietal cell pseudohypertrophy, and ECL cell hyperplasia at the linear or greater level.


Analytical studies on the charge transfer complexes of loperamide hydrochloride and trimebutine drugs. Spectroscopic and thermal characterization of CT complexes.
Charge transfer complexes of loperamide hydrochloride (LOP.HCl) and trimebutine (TB) drugs as electron donor with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), tetracyanoethylene (TCNE) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) as π-acceptors in acetonitrile were investigated spectrophotometrically to determine the cited drugs in pure and dosage forms. The reaction gives highly coloured complex species which are measured spectrophotometrically at 460, 415 and 842nm in case of LOP.HCl and at 455, 414 and 842nm in case of TB using DDQ, TCNE and TCNQ reagents, respectively. The optimum experimental conditions have been studied carefully and optimized. Beer's law was obeyed over the concentration ranges of 47.70-381.6, 21.50-150.5 and 10.00-100.0μgmL(-1) for LOP.HCl and 37.85-264.9, 38.75-310.0 and 7.75-155.0μgmL(-1) for TB using DDQ, TCNE and TCNQ reagents, respectively. Sandell sensitivity, standard deviation, relative standard deviation, limit of detection and quantification were calculated. The obtained data refer to high accuracy and precision of the proposed method. These results are also confirmed by inter and intra-day precision with percent recovery of 99.18-101.1% and 99.32-101.4% in case of LOP.HCl and 98.00-102.0% and 97.50-101.4% in case of TB using DDQ, TCNE and TCNQ reagents for intra- and inter-day, respectively. These data were compared with those obtained using official methods for the determination of the cited drugs. The stability constants of the CT complexes were determined. The final products of the reaction were isolated and characterized using FT-IR, (1)H NMR, elemental analysis and thermogravimetric analysis (TG). The stoichiometry and apparent formation constant of the complexes formed were determined by applying the conventional spectrophotometric molar ratio method.


Splenosis: ultrasound and CT findings in a case complicated by an intraperitoneal implant traumatic hematoma.
A case of intraperitoneal splenosis, found incidentally at ultrasound examination in a 35-year-old man, is reported. The diagnosis, suspected on the basis of computed tomographic (CT) and radionuclide studies, was established by surgery. Three years later, after direct trauma, ultrasound and CT studies revealed a surgically proven splenosis implant hematoma. The contribution of radiologic examinations in the diagnosis of splenosis is emphasized.


Spatial frequency threshold and contrast sensitivity of an optomotor behavior are impaired in the Ins2Akita mouse model of diabetes.
Diabetic retinopathy can lead to progressive loss of vision and is a leading cause of blindness. The Ins2(Akita) mouse model of diabetes develops significant retinal and systemic pathology, but how these affect visual behavior is unknown. Here, we show that Ins2(Akita) mice have progressive, quantifiable vision deficits in an optomotor behavior. This mouse line is a promising model in which to understand the contribution of retinal neuronal injury during the chronic hyperglycemia and hypoinsulinemia of diabetes to deficits in vision.


Hand-assisted laparoscopic transhiatal esophagectomy using the dexterity pneumo sleeve.
As the use of laparoscopic techniques have expanded to more complicated procedures, limitations of laparoscopy have begun to be realized. To help regain the ability to palpate and bluntly dissect tissues, and handle larger organs, surgeons have begun to utilize devices which allow the surgeon's hand to be inserted into the abdomen during laparoscopic procedures. One such devices is the Dexterity Pneumo Sleeve, which was used here to perform transhiatal esophagectomy in two patients. Two patients with adenocarcinoma of the esophagus underwent hand-assisted laparoscopic transhiatal esophagectomy. The stomach mobilization was carried out using laparoscopic technique facilitated by the use of the surgeon's hand. Blunt dissection of the esophagus through the hiatus was then carried out. Dissection of the proximal esophagus and creation of a cervical esophagogastric anastomosis was then performed in the neck through a cervical incision. The Pneumo Sleeve proved useful for handling the stomach, as well as, blunt dissection of the esophagus while still maintaining the benefits of laparoscopy, including small incisions, and no postoperative ileus. Hand-assisted laparoscopic esophagectomy can be carried out with good, early, postoperative recovery.


Arsenobetaine is not a major metabolite of arsine gas in the rat.
Many organisms can easily dispose of toxic inorganic arsenic species through gradual methylation of the element and further urinary excretion. In order to clarify the urinary excretion of arsenobetaine observed in a human case of intoxication by arsine, the capacity of highly methylated arsenical synthesis has been investigated in rats acutely exposed during 1 h to increasing concentrations of the same gas [4 to 80 mg AsH3/m3]. Urinary metabolites of arsenic were determined with good agreement in two (Belgian and Italian) laboratories using two different analytical procedures. The sum of inorganic, mono- and dimethylated metabolites of arsenic in urine was shown to be related to the intensity of exposure to arsine. A biphasic relationship was observed: 1 h exposure to > 60 mg AsH3/m3 led to metabolite excretion which is roughly 10 times higher than for exposure levels below that limit, suggesting the saturation of a binding site reserve and the availability for metabolism of a greater proportion of the As absorbed above this threshold. Arsenobetaine production, if any, could only be detected when its presence in food was excluded; in addition, amounts appeared negligible and could be disregarded as a common arsenic metabolite in rats.


The Effect of Body Mass Index on Clinical Outcomes in Patients Without Radiographic Evidence of Degenerative Joint Disease After Arthroscopic Partial Meniscectomy.
To examine the effect of obesity on clinical outcomes at 1 year after arthroscopic partial meniscectomy. We conducted a secondary analysis of the ChAMP (Chondral Lesions and Meniscus Procedures) randomized controlled trial (N = 256). The visual analog scale for pain, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee Injury and Osteoarthritis Outcome Score (KOOS), range of motion, and presence of effusion were assessed preoperatively and at 1 year after arthroscopic partial meniscectomy. Body mass index was categorized as normal weight, 24.99 or less; overweight, 25 to 29.99; or obese, 30 or greater. Analysis of variance or the Cochran-Mantel-Haenszel test was used to examine differences in clinical outcomes between body mass index categories, and mean ± standard deviation or number (percentage) is reported. Preoperatively, obese patients had worse WOMAC pain (56.2 ± 17.2 vs 61.3 ± 17.2, P = .02), WOMAC physical function (55.8 ± 17.1 vs 62.8 ± 17.1, P = .004), pain visual analog scale (4.9 ± 2.1 vs 4.2 ± 1.9, P = .01), KOOS pain (49.5 ± 14.9 vs 54.0 ± 15.1, P = .02), and KOOS quality-of-life (27.9 ± 18.3 vs 36.9 ± 17.0, P = .001) scores, as well as decreased flexion (121.8° ± 22.6° vs 132.3° ± 16.5°, P = .003), compared with normal-weight patients. Overweight patients (n = 51 [51.5%], P = .03) and obese patients (n = 56 [52.8%], P = .002) were more likely to have knee effusion before surgery than normal-weight patients (n = 17 [34%]). At 1 year after surgery, overweight (130.2° ± 7.7°, P = .03) and obese (128.1° ± 7.1°, P = .003) patients had decreased flexion compared with normal-weight patients (134.5° ± 8.3°). Obese patients had worse pain, physical functioning, and quality-of-life scores, as well as decreased flexion, compared with normal-weight patients before arthroscopic partial meniscectomy. At 1 year after arthroscopic partial meniscectomy, there were no statistically significant differences in clinical outcomes but obesity was associated with decreased knee flexion. Level II, prospective comparative trial.


Telemedicine in the intensive care unit: A vehicle to improve quality of care?
The high demand for intensive care, which is predicted to further increase in the future, is contrasted by a shortage of trained intensivists and specialized nurses. Telemedicine has been heralded as a promising solution. Yet, there is considerable heterogeneity in tele-critical care when it comes to measurable effects. However, the focus has been on telemedical solutions substituting on-site intensivist functions, and outcome measures have primarily been mortality and length of stay. In a new model of telemedicine for the ICU, telemedicine could be used to increase adherence to best practice guidelines and indicators of process quality. Further, indicators of process quality, functional outcomes and quality of life measures should be incorporated in the evaluation of outcomes, as patients frequently value those higher than mere survival.


A multiparametric flow cytometry method for detection of modifications of antigen expression in polymorphonuclear cells infected by human cytomegalovirus.
Human cytomegalovirus (CMV) has been shown to alter adhesion molecule expression on permissive cells such as endothelial cells. The aim of the present study was to investigate expression of receptors for these molecules on CMV infected polymorphonuclear leukocytes (PMNLs). CMV-induced variations on cellular integrin expression were examined using an in vitro system to obtain infected PMNLs. A triparametric flow cytometry approach was developed, which allows combined detection, in a single experiment, of both viral intranuclear antigen in the selected PMNLs and cellular CD11/CD18 expression. Comparison of infected PMNLs with uninfected cells showed a decrease of up to 50% in the expression of CD11b, CD11c, and CD18. This study thus demonstrates that the presence of CMV in PMNLs, which characterizes active infection, modifies the expression of integrins and may thus affect cell-to-cell interactions and immune functions.


Microtubule retrograde flow retains neuronal polarization in a fluctuating state.
In developing vertebrate neurons, a neurite is formed by more than a hundred microtubules. While individual microtubules are dynamic, the microtubule array has been regarded as stationary. Using live-cell imaging of neurons in culture or in brain slices, combined with photoconversion techniques and pharmacological manipulations, we uncovered that the microtubule array flows retrogradely within neurites to the soma. This flow drives cycles of microtubule density, a hallmark of the fluctuating state before axon formation, thereby inhibiting neurite growth. The motor protein dynein fuels this process. Shortly after axon formation, microtubule retrograde flow slows down in the axon, reducing microtubule density cycles and enabling axon extension. Thus, keeping neurites short is an active process. Microtubule retrograde flow is a previously unknown type of cytoskeletal dynamics, which changes the hitherto axon-centric view of neuronal polarization.


Urine glyceraldehyde excretion is elevated in the renal Fanconi syndrome.
We analyzed urinary constituents using GC/MS in 16 children with the renal Fanconi syndrome and 13 normal individuals. Urine glyceraldehyde levels were strikingly elevated in the renal Fanconi syndrome group (mean 5.1 +/- 4.8 mg/mg creatinine) compared to levels in the normal group (mean 0.04 +/- 0.04 mg/mg creatinine, P less than 0.001). Urine lactate levels were also elevated in the renal Fanconi syndrome group (mean 2.3 +/- 2.6 mg/mg creatinine) compared to normals (mean 0.01 +/- 0.01 mg/mg creatinine, P less than 0.003). Only small elevations of glyceraldehyde and lactate were found in urine from children with other renal disorders. Serum levels of glyceraldehyde and lactate were no greater in individuals with the Fanconi syndrome than in the normals. The fractional reabsorption of both glyceraldehyde and lactate was virtually complete in the normals, but was markedly impaired in the Fanconi syndrome patients where, in some cases, glyceraldehyde excretion greatly exceeded the excretion of creatinine. We conclude that marked glyceraldehyde excretion is a previously unrecognized feature of the renal Fanconi syndrome which may result from disordered proximal tubular glycolytic metabolism. Further studies will be required to determine the role of glyceraldehyde loss in the pathogenesis of this generalized disturbance of proximal tubular function.


catena-Poly[[[aqua-copper(II)]-μ-(biphenyl-2,2'-di-carboxyl-ato)-μ-[N,N'-bis-(pyridin-4-yl)urea]] 1.25-hydrate].
In the title compound, {[Cu(C14H8O4)(C11H10N4O)(H2O)]·1.25H2O} n , the CuII cations are coordinated in a square-pyramidal fashion by trans carboxyl-ate O-atom donors from two diphenate (dip) ligands, trans pyridyl N-atom donors from two bis-(4-pyrid-yl)urea (bpu) ligands, and a ligated water mol-ecule in the apical position. [Cu(H2O)(dip)(bpu)] n coordination polymer layer motifs are oriented parallel to (02). These layer motifs display a standard (4,4) rectangular grid topology and stack in an AAA pattern along the a-axis direction to form the full three-dimensional crystal structure of the title compound, mediated by N-H⋯O and O-H⋯O hydrogen bonding patterns involving the water mol-ecules of crystallization.


Natriuretic and phosphaturic response to diuretics after parathyroidectomy in dogs.
Intact and acutely parathyroidectomized (TPTX) dogs were studied during hydropenia, volume expansion (VE), volume expansion plus ethacrynic acid (EA), and volume expansion plus acetazolamide (AZ). In intact dogs, VE produced marked increases in both Na+ and phosphate (Pi) excretion; in TPTX dogs, Na+ excretion increased but phosphaturia was minimal. Addition of EA increased Na+ but not Pi excretion in both groups. Discontinuing EA and substituting AZ in intact dogs produced a marked increase in Pi excretion compared to both VE and VE + EA. In TPTX dogs, AZ failed to increase Pi excretion compared to VE alone. The results suggest that increased distal Pi absorption in acutely TPTX dogs is not associated with NaCl reabsorption in the thick ascending loop of Henle or may occur at an alternative nephron site. Furthermore, the increased distal Pi reabsorptive capacity revealed by TPTX can overcome the increased distal Pi delivery produced by the superimposition of AZ on VE.


Heart failure–associated hospitalizations in the United States.
This study sought to characterize temporal trends in hospitalizations with heart failure as a primary or secondary diagnosis. Heart failure patients are frequently admitted for both heart failure and other causes. Using the Nationwide Inpatient Sample (NIS), we evaluated trends in heart failure hospitalizations between 2001 and 2009. Hospitalizations were categorized as either primary or secondary heart failure hospitalizations based on the location of heart failure in the discharge diagnosis. National estimates were calculated using the sampling weights of the NIS. Age- and sex-standardized hospitalization rates were determined by dividing the number of hospitalizations by the U.S. population in a given year and using direct standardization. The number of primary heart failure hospitalizations in the United States decreased from 1,137,944 in 2001 to 1,086,685 in 2009, whereas secondary heart failure hospitalizations increased from 2,753,793 to 3,158,179 over the same period. Age- and sex-adjusted rates of primary heart failure hospitalizations decreased steadily from 2001 to 2009, from 566 to 468 per 100,000 people. Rates of secondary heart failure hospitalizations initially increased from 1,370 to 1,476 per 100,000 people from 2001 to 2006, then decreased to 1,359 per 100,000 people in 2009. Common primary diagnoses for secondary heart failure hospitalizations included pulmonary disease, renal failure, and infections. Although primary heart failure hospitalizations declined, rates of hospitalizations with a secondary diagnosis of heart failure were stable in the past decade. Strategies to reduce the high burden of hospitalizations of heart failure patients should include consideration of both cardiac disease and noncardiac conditions.


Fasting and post-prandial glucagon like peptide 1 and oral contraception in polycystic ovary syndrome.
We aimed to investigate whether fasting and meal regulated glucagon like peptide 1 (GLP-1) secretion are altered in patients with polycystic ovary syndrome (PCOS) compared to healty women and whether oral contraceptive use influence GLP-1 secretion dynamics in the syndrome. Prospective observational study. Fourteen lean normal glucose tolerant patients with PCOS and 11 age- and body mass index (BMI)-matched healthy women. Glucagon like peptide 1, glucose and insulin levels were measured during a standardized meal tolerance test and area under the curves (AUCs) were calculated. Whereas healthy controls were assessed at baseline, all tests were repeated in women with PCOS after treatment with ethinyl estradiol 30 μg/drospirenone 3 mg (EE/DRSP) for 3 months. Both fasting and post-meal levels of GLP-1 were significantly reduced in women with PCOS compared to controls (P = 0·022 and P = 0·028, respectively). AUC for GLP-1 was also lower in PCOS (P = 0·012). Glucose and insulin measurements did not show a significant change between the groups. In the PCOS group, GLP-1, glucose and insulin levels did not show any change after 3 months of EE/DRSP use. GLP-1 levels both at fasting and in response to a meal are blunted in lean women with PCOS compared to healthy women. Short term oral contraception do not alter GLP-1 secretion in PCOS. Disturbance in incretin secretion dynamics might contribute to the risk of impaired glucose tolerance and type 2 diabetes in PCOS.


Abbreviated tables for estimating fetal weight with ultrasound.
Tables containing 23 entries for estimating fetal weight with ultrasound parameters have proven to be equivalent to the longer tables in current use.


Comorbidity and risk of infection among patients with hip fracture: a Danish population-based cohort study.
Impact of comorbidity on infection risk among hip fracture patients is unclear. We found high incidence of infection. Comorbidity was an important risk factor for infection up to 1 year after surgery. Results indicates a need for additional investment in pre- and postoperative programs that assist patients with high comorbidity. Comorbidity level and incidence of infection have increased among older patients with hip fracture. The impact of comorbidity on infection risk is unclear. We conducted a cohort study examining the absolute and relative risks of infection in relation to comorbidity level among hip fracture patients. Utilizing Danish population-based medical registries, we identified 92,600 patients aged ≥ 65 years undergoing hip fracture surgery between 2004 and 2018. Comorbidity was categorized by Charlson comorbidity index scores (CCI): none (CCI = 0), moderate (CCI = 1-2), or severe (CCI ≥ 3). Primary outcome was any hospital-treated infection. Secondary outcomes were hospital-treated pneumonia, urinary tract infection, sepsis, reoperation due to surgical-site infection (SSI), and a composite of any hospital- or community-treated infection. We calculated cumulative incidence and hazard ratios (aHRs) adjusted for age, sex, and surgery year, including 95% confidence intervals (CIs). Prevalence of moderate and severe comorbidity was 40% and 19%, respectively. Incidence of any hospital-treated infection increased with comorbidity level within 0-30 days (none 13% vs. severe 20%) and 0-365 days (none 22% vs. 37% severe). Patients with moderate and severe comorbidity, compared to no comorbidity, had aHRs of 1.3 (CI: 1.3-1.4) and 1.6 (CI: 1.5-1.7) within 0-30 days, and 1.4 (CI: 1.4-1.5) and 1.9 (CI: 1.9-2.0) within 0-365, respectively. Highest incidence was observed for any hospital- or community-treated infection (severe 72%) within 0-365 days. Highest aHR was observed for sepsis within 0-365 days (severe vs. none: 2.7 (CI: 2.4-2.9)). Comorbidity is an important risk factor for infection up to 1 year after hip fracture surgery.


Quinic acid esters from Pluchea indica with collagenase, MMP-2 and MMP-9 inhibitory activities.
Investigation of collagenase inhibitory natural components afforded two quinic acid esters (1 and 2) and quercetin (3) from the leaves of Pluchea indica (Compositae). Of these, compounds 1 and 2 exhibited collagenase inhibitory activity (IC(50)) at a concentration of less than 10 microm, and 1 showed matrix metalloproteinase (MMP)-2 and -9 inhibitory activity (IC(50)) at 2.5 and 6.4 microm, respectively.


"They just say how stupid I was for being conned". Cyberscams and acquired brain injury: A qualitative exploration of the lived experience of survivors and close others.
Individuals with acquired brain injury (ABI) may be vulnerable to cyberscams due to their cognitive and psychosocial impairments. However, the lived experiences of cyberscam survivors with ABI and their close others is not understood, and no effective intervention has been identified. This qualitative study aimed to explore the perspectives of cyberscam survivors with ABI (n = 7) and their close others (n = 6). Semi-structured interviews explored the scam experience, impacts, vulnerabilities and interventions. Reflexive thematic analysis of interview transcripts identified seven themes: "who is at the helm?: vulnerabilities," "the lure: scammer tactics," "scammers aboard: scam experience," "the discovery," "sinking in: impacts," "responding to the mayday: responses from others," and "lifesavers: suggestions for intervention." The journey towards scam victimisation was complex, and complicated by the ABI. Cyberscams contributed to substantial financial disadvantage, loss of trust and shame. ABI related impairments and social isolation reportedly increased scam vulnerability and interfered with intervention attempts by family and professionals. Confusion, denial and disbelief created further barriers to discovery. The practical and emotional impacts on both cyberscam survivors with ABI and their family members, and a lack of effective intervention, highlight the need for increased education and awareness in order to improve online safety for those with ABI.


Different median levels of serum triple markers in the second trimester of pregnancy in a Thai Ethnic Group.
The aim of the present study was to establish Thai-specific reference ranges of triple markers for fetal Down syndrome as a function of gestational age as well as weight correction models and to compare the false positive rates when using Thai-specific model relative to Caucasian-specific model. A total of 993 normal Thai pregnant women were determined for mid-trimester serum levels of alpha-fetoprotein (AFP), free-beta human chorionic gonadotropin (hCG), and unconjugated estriol (uE3), using DefiaXpress system (Perkin Elmer, Waltham, MA, USA). The models of Thai-specific medians for AFP, b-hCG, and uE3, as well as the models for weight correction were derived and the normal reference ranges were constructed. The best fitted equation for AFP, b-hCG and uE3 are as follows: predicted median = 2.675 × 10((0.153 × GA in week)), r = 0.979; 10((-0.717 + 57.487/GA in week)) , r = 0.991; and 10((5.678-69.346/GA) (in) (week)), r = 0.99, respectively. The models were properly applied to another group of 302 Thai women, signifying that they were reliable models. The weight-adjusted gestation-specific medians derived from Caucasian models were significantly higher than those based on Thai models and the false positive rate could be reduced from 10 to 7.1% when Thai models were applied. Thai reference ranges of triple screen markers as a function of gestational age as well as weight correction models have been established. The Caucasian reference range, even after weight correction, gives a positive rate that is much higher than that it should be, strongly suggesting the need for ethnicity-specific medians.


Influence of skull biometrics on cosmetic reconstruction after incisivectomy and nasal planectomy reconstruction in dogs.
To identify biometric skull measurements that are associated with tension and excess narrowing of the resultant nasal aperture during cosmetic nasal planectomy reconstruction. Ex vivo study. Twenty cadavers of mesocephalic dogs. Cosmetic reconstruction was performed after incisivectomy and nasal planectomy. Preoperative and intraoperative skull measurements included width of the nasal planum, rostral and caudal maxilla, labial flap, and maxilla at ostectomy site; the length of the nose, labial flap, and philtrum incision; lip thickness; and philtrum placement. Ratios of select width to length measurements were calculated. Correlation was tested between skull biometrics and tension during reconstruction as well as resulting opening of the nasal aperture. Breeds included golden retriever, pit bull, Labrador retriever, beagle, shepherd, basset hound, boxer mix, cocker spaniel, and Great Dane. No biometric ratios were predictive of procedural success. The most important objective measurements that were significantly correlated with inferior outcome included width of the nasal planum (>3 cm), width of the caudal maxilla (>6.2 cm), lip thickness (>0.5 cm), width of the labial flap (>2.9 cm), length of the incision created to make the cosmetic "philtrum" (longer incisions >2.8 cm), and philtrum placement (more dorsal placement). Tension during reconstruction and decreased resultant nasal aperture were associated with wider facial features and thicker lips as well as directly impacted by cosmetic philtrum design and placement. Standardized preoperative measurements may help guide clinical decision making in choosing and executing a nasal planectomy reconstructive technique.


Perceived facilitators and barriers by esophageal cancer survivors participating in a post-treatment exercise program.
Participation in a post-treatment exercise program improves cardiorespiratory fitness and aspects of quality of life for esophageal cancer survivors. For optimal effects, high adherence to the exercise intervention is important. We assessed which facilitators and barriers to exercise adherence are perceived by esophageal cancer survivors, who participate in a post-treatment exercise program. The current qualitative study was performed within the randomized controlled PERFECT trial, in which we investigated effects of a 12-week supervised exercise program with moderate-to-high intensity and daily physical activity advice. Semi-structured interviews were conducted with patients randomized to the exercise group. A thematic content approach was used to derive perceived facilitators and barriers. Thematic saturation was reached after inclusion of sixteen patients. Median session attendance was 97.9% (IQR 91.7-100%), and relative dose intensity (compliance) to all exercises was ≥90.0%. Adherence to the activity advice was 50.0% (16.7-60.4%). Facilitators and barriers were captured in seven themes. The most important facilitators were patients' own intention to engage in exercise and supervision by a physiotherapist. Barriers were mainly experienced in completion of the activity advice, and included logistic factors and physical complaints. Esophageal cancer survivors are well capable to attend a moderate-to-high intensity post-treatment exercise program, and to fulfill the exercises according to protocol. This is facilitated by patients' own intention to engage in exercise and supervision of the physiotherapist, and only minimally affected by barriers as logistic factors and physical complaints. When implementing postoperative exercise programs in clinical care, it can be useful to be aware of perceived facilitators and barriers of cancer survivors in order to achieve optimal exercise adherence and maximize beneficial exercise effects. Dutch Trial Register NTR 5045.


IOP-lowering and drug-sparing effects of trabectome surgery with or without cyclodialysis ab interno.
To compare the postoperative intraocular pressure (IOP) after ab interno trabeculectomy (AIT; trabectome surgery) alone or combined with cyclodialysis ab interno (AITC). Forty-three eyes with insufficiently controlled open-angle glaucoma were included in this consecutive case series. All eyes received AIT, combined with phacoemulsification and IOL-implantation in phakic instances, with or without additional cyclodialysis ab interno. Postoperative visual acuity, IOP, number of IOP-lowering medications and complications were registered over 12 months. A total of 19 eyes (14 patients) received AIT and 24 (19 patients) received AITC. Both groups were comparable for baseline IOP (AIT: 19.7 ± 8.2 mmHg; AITC: 19.4 ± 6.8 mmHg; p = 0.96), there was a comparable IOP reduction after 6 months (AIT: - 3.8 ± 12.3, median (interquartile range (IQR)): - 3.8 (- 7.8-4.8) mmHg; AITC: - 4.9 ± 8.3, median (IQR): - 2.0 (- 10.8-2.0) mmHg; p = 0.95) and 12 months (AIT: - 4.3 ± 6.6, median (IQR): - 4.0 (- 8.0 to - 1.0) mmHg; AITC: - 3.7 ± 6.7, median (IQR): - 1.5 (- 5.5 to - 0.5) mmHg; p = 0.49). While final visual acuity was similar between the groups, they differed regarding topical IOP-lowering medications (baseline: AIT 2.9 ± 1.2 and AITC 2.9 ± 1.2; 1 year after surgery: AIT 2.6 ± 1.5 (p = 0.16) and AITC 1.3 ± 1.3; p < 0.001)). Depending on the definition, a complete or qualified success of 33.4-45.8% was achieved in AITC compared to 15.8-21.1% in AIT. The additional suprachoroidal outflow when AIT is combined with cyclodialysis ab interno (AITC) seems to result in an additional drug sparing effect for at least 1 year without critical safety signals. Thus, AITC might be further investigated prospectively prior to advocating its use in routine minimally invasive glaucoma surgery.


Checkpoint kinase 1 is essential for meiotic cell cycle regulation in mouse oocytes.
Checkpoint kinase 1 (Chk1) plays key roles in all currently defined cell cycle checkpoints, but its functions in mouse oocyte meiosis remain unclear. In this study, we report the expression, localization and functions of Chk1 in mouse oocyte meiosis. Chk1 was expressed from germinal vesicle (GV) to metaphase II (MII) stages and localized to the spindle from pro-metaphase I (pro-MI) to MII stages in mouse oocytes. Chk1 depletion facilitated the G 2/M transition while Chk1 overexpression inhibited the G 2/M transition as indicated by germinal vesicle breakdown (GVBD), through regulation of Cdh1 and Cyclin B1. Chk1 depletion did not affect meiotic cell cycle progression after GVBD, but its overexpression after GVBD activated the spindle assembly checkpoint and prevented homologous chromosome segregation, thus arresting oocytes at pro-MI or metaphase I (MI) stages. These results suggest that Chk1 is indispensable for prophase I arrest and functions in G 2/M checkpoint regulation in meiotic oocytes. Moreover, Chk1 overexpression affects meiotic spindle assembly checkpoint regulation and thus chromosome segregation.


Inhibition of adenylyl cyclase by neuronal P2Y receptors.
P2Y receptors inhibiting adenylyl cyclase have been found in blood platelets, glioma cells, and endothelial cells. In platelets and glioma cells, these receptors were identified as P2Y(12). Here, we have used PC12 cells to search for adenylyl cyclase inhibiting P2Y receptors in a neuronal cellular environment. ADP and ATP (0.1 - 100 microM) left basal cyclic AMP accumulation unaltered, but reduced cyclic AMP synthesis stimulated by activation of endogenous A(2A) or recombinant beta(2) receptors. Forskolin-dependent cyclic AMP production was reduced by <or=1 microM and enhanced by 10 - 100 microM ADP; this latter effect was turned into an inhibition when A(2A) receptors were blocked. The nucleotide inhibition of cyclic AMP synthesis was not altered when P2X receptors were blocked, but abolished by pertussis toxin. The rank order of agonist potencies for the reduction of cyclic AMP was (IC(50) values): 2-methylthio-ADP (0.12 nM)=2-methylthio-ATP (0.13 nM)>ADPbetaS (71 nM)>ATP (164 nM)=ADP (244 nM). The inhibition by ADP was not antagonized by suramin, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid, or adenosine-3'-phosphate-5'-phosphate, but attenuated by reactive blue 2, ATP(alpha)S, and 2-methylthio-AMP. RT - PCR demonstrated the expression of P2Y(2), P2Y(4), P2Y(6), and P2Y(12), but not P2Y(1), receptors in PC12 cells. In Northern blots, only P2Y(2) and P2Y(12) were detectable. Differentiation with NGF did not alter these hybridization signals and left the nucleotide inhibition of adenylyl cyclase unchanged. We conclude that P2Y(12) receptors are expressed in neuronal cells and inhibit adenylyl cyclase activity.


Large-scale chromosome flip-flop reversible inversion mediates phenotypic switching of expression of antibiotic resistance in lactococci.
Bacteria can gain resistance to antimicrobials by acquiring and expressing genetic elements that encode resistance determinants such as efflux pumps and drug-modifying enzymes, thus hampering treatment of infection. Previously we showed that acquisition of spectinomycin resistance in a lactococcal strain was correlated with a reversible genomic inversion, but the precise location and the genes affected were unknown. Here we use long-read whole-genome sequencing to precisely define the genomic inversion and we use quantitative PCR to identify associated changes in gene expression levels. The boundaries of the inversion fall within two identical copies of a prophage-like sequence, located on the left and right replichores; this suggests possible mechanisms for inversion through homologous recombination or prophage activity. The inversion is asymmetrical in respect of the axis between the origin and terminus of the replication and modulates the expression of a SAM-dependent methyltransferase, whose heterologous expression confers resistance to spectinomycin in lactococci and that is up-regulated on exposure to spectinomycin. This study provides one of the first examples of phase variation via large-scale chromosomal inversions that confers a switch in antimicrobial resistance in bacteria and the first outside of Staphylococcus aureus.


Congenital, spontaneously regressing histiocytosis: case report and review of the literature.
A patient had numerous skin lesions at birth and they regressed over the next few weeks. Results of the peripheral blood smear and bone marrow examinations were normal. The diagnosis of self-healing histiocytosis was substantiated by the clinical course and characteristic histology. This was subsequently confirmed by the electron microscopic finding of Langerhans' granules within the histiocytic cells, which were positive for S100 by immunoperoxidase.


Constitutive modelling and pipeline flow of thixotropic viscoplastic wastewater sludge.
Due to the inherent rheological complexity of wastewater sludges, conventional sludge pipeline design based on simplified rheological models can result in inefficient sludge transportation systems. These inefficiencies are further exacerbated by a global need for the processing of more concentrated wastewater sludges that have a more pronounced non-Newtonian character, and hence require greater energy for transportation. However, the complex rheology of these materials (typically visco-elastic and thixotropic) requires sophisticated methods for constitutive modelling that are impractical to implement for complex materials such as sewerage sludges. We address this challenge by developing a novel viscoplastic thixotropic constitutive model that exploits the separation of timescales between the thixotropic and viscoelastic processes, leading to simpler and more robust experimental methods, parameter estimation and process simulation methods. This constitutive model combines a kinetic model for thixotropic degradation and agglomeration via a classical structural parameter (λ) approach coupled nonlinearly with a Herschel-Bulkley model to yield a thixotropic viscoplastic model of sludge rheology. Experimental data for thickened digested sludge between 3 and 4.9% solids were collected to validate the assumption for the separation of viscoelastic and thixotropic responses. The fitting procedure was found to be robust and efficient, and several rheological parameters were found to be invariant with solids concentration. Simplified energy calculations for a typical sludge pipeline showed that the pumping energy could be significantly under- or overestimated without considering thixotropy. These simple and robust constitutive models and fitting methods can accurately predict (and hence design and optimise) sludge behaviour over a wide range of wastewater processes.


Knockdown of UCA1 attenuated the progression of alcoholic fatty disease by sponging miR-214.
Alcoholic fatty liver (AFL) is the initial manifestation of Alcoholic liver disease which can develop into alcoholic cirrhosis even extensive necrosis of liver cells, which induces liver failure finally. This study aims to focus on the role of long noncoding RNA UCA1 in AFL and further explored possible mechanism of this disease. We first downloaded GSE28619 to identify the expression of UCA1 in patients with AFL and use lncRNAs microarray to confirm UCA1 expression in serum of patients with AFL. Then we established ethanol-induced L02 cell model to mimic hepatocyte injury condition. By conducting qRT-PCR, we measured the expression of LncRNA UCA1 and miR-214 in serum of patients and ethanol-induced L02 cell. MTT assay, transwell migration, ELISA, qRT-PCR, and western blotting analysis were applied to evaluating the effect of UCA1 on ethanol-induced L02 cell. The bioinformatics analysis and the rescue experiment were devoted to the underlying mechanism. In this study, we first detected the expression of UCA1 was up-regulated in serum of patients with AFL and ethanol-induced L02 cells. And knockdown of UCA1 reversed the inhibiting effect of ethanol on the biological behavior of L02 cells including cell proliferation, migration, and apoptosis. Besides, lncRNA UCA1 regulated the expression of KLF5 by sponging miR-214. LncRNA UCA1 regulated the biological behavior of ethanol-induced L02 cells by sponging miR-214, which may provide novel therapeutic strategies for alcoholic fatty liver.


Coiled coils direct assembly of a cold-activated TRP channel.
Transient receptor potential (TRP) channels mediate numerous sensory transduction processes and are thought to function as tetramers. TRP channel physiology is well studied; however, comparatively little is understood regarding TRP channel assembly. Here, we identify an autonomously folded assembly domain from the cold- and menthol-gated channel TRPM8. We show that the TRPM8 cytoplasmic C-terminal domain contains a coiled coil that is necessary for channel assembly and sufficient for tetramer formation. Cell biological experiments indicate that coiled-coil formation is required for proper channel maturation and trafficking and that the coiled-coil domain alone can act as a dominant-negative inhibitor of functional channel expression. Our data define an authentic TRP modular assembly domain, establish a clear role for coiled coils in ion channel assembly, demonstrate that coiled-coil assembly domains are a general feature of TRPM channels, and delineate a new tool that should be of general use in dissecting TRPM channel function.


Acceptability of the health-related quality of life instrument EQ-5D-Y-5L among patients in child and adolescent psychiatric inpatient care.
The generic EuroQol 5 Dimensions Youth 5 Level (EQ-5D-Y-5L) measures health-related quality of life among children from 8 years. Respondents report their health on five dimensions with five severity levels and rate their overall health on a visual analogue scale (EQ VAS). The aim of the study was to explore acceptability of the EQ-5D-Y-5L instrument among patients in child and adolescent psychiatric inpatient care. A convenience sample of patients within a psychiatric inpatient care clinic in Region Stockholm, Sweden, was used. Follow-up questions were answered directly after filling in the EQ-5D-Y-5L. Conventional qualitative content analysis was chosen to analyse the open-ended questions on how they perceived answering the instrument. In total, 52 patients (83% girls), mean age 15.4 years (range 13-17), were included. Three themes emerged: generic content of the EQ-5D-Y-5L descriptive system; design and wording of the EQ-5D-Y-5L descriptive system and the EQ VAS; self-reporting health with the EQ-5D-Y-5L descriptive system and the EQ VAS. The inclusion of physical health dimensions was perceived as positive, but some patients considered the descriptive system too generic. The results indicate that these patients in general could self-report their health in a meaningful way with the EQ-5D-Y-5L instrument.


18p-Mosaicism: case report and review.
The case of a 5-month-old male infant with 18p- mosaic, who has intractable seizures and severe ophthalmological abnormalities in addition to many clinical manifestations usually described in the 18p- syndrome, is reported. The proportions of abnormal cells are 7-8% in blood and 55% in skin. About 35% of the short arm of chromosome 18 is deleted. to our knowledge the present report is the fifth one of 18p-mosaic. The main interest of this case resides in the fact that it shows a serious clinical picture despite the low proportion of abnormal cells in blood and the small degree of deletion of the short arm of chromosome 18.


Teratologic evaluation of styrene given to rats and rabbits by inhalation or by gavage.
Pregnant Sprague-Dawley rats and New Zealand white rabbits inhaled 0, 300 or 600 ppm of styrene 7 h/day from days 6 through 15 (rats) and 6 through 18 (rabbits) of gestation. Additional groups of rats were given styrene by gavage at dose levels of 0, 90 or 150 mg/kg twice daily (0, 180 or 300 mg/kg, respectively) from days 6 through 15 of gestation. Embryotoxicity and fetotoxicity were not evident in rats or rabbits inhaling styrene or in rats given the compound orally. Maternal effects (decreased body weight gain and decreased food consumption) were noted in all groups of rats given styrene but none were observed in rabbits. No teratogenic effect was detected in either species inhaling styrene or in rats given styrene by gavage.


Cloning and sequence analysis of the fermentative alcohol-dehydrogenase-encoding gene of Escherichia coli.
A 6-kb fragment of DNA, which complemented defects in the alcohol dehydrogenase (ADH)-encoding gene (adhE) of Escherichia coli, was cloned into a multicopy vector. Both ADH and coenzyme-A-linked acetaldehyde dehydrogenase (ACDH) activities were encoded by the plasmid, pHIL8. The adhE gene was identified as an open reading frame of 891 codons encoding an Mr 96,008 protein (minus the initiating methionine). Codon usage analysis indicates that adhE should be highly expressed. This gene shows no significant homology to any previously sequenced ADH-encoding gene.


The caspase-8/RIPK3 signaling axis in antigen presenting cells controls the inflammatory arthritic response.
Caspase-8 is a well-established initiator of apoptosis and suppressor of necroptosis, but maintains functions beyond cell death that involve suppression of receptor-interacting serine-threonine kinases (RIPKs). A genome-wide association study meta-analysis revealed an SNP associated with risk of rheumatoid arthritis (RA) development within the locus containing the gene encoding for caspase-8. Innate immune cells, like macrophages and dendritic cells, are gaining momentum as facilitators of autoimmune disease pathogenesis, and, in particular, RA. Therefore, we examined the involvement of caspase-8 within these antigen-presenting cell populations in the pathogenesis of an arthritis model that resembles the RA effector phase. Cre LysM Casp8 flox/flox and Cre CD11c Casp8 flox/flox mice were bred via a cross between Casp8 flox/flox and Cre LysM or Cre CD11c mice. RIPK3 -/- Cre LysM Casp8 flox/flox and RIPK3 -/- Cre CD11c Casp8 flox/flox mice were generated to assess RIPK3 contribution. Mice were subjected to K/BxN serum-transfer-induced arthritis. Luminex-based assays were used to measure cytokines/chemokines. Histological analyses were utilized to examine joint damage. Mixed bone marrow chimeras were generated to assess synovial cell survival. Flow cytometric analysis was employed to characterize cellular distribution. For arthritis, differences between the groups were assessed using two-way analysis of variance (ANOVA) for repeated measurements. All other data were compared by the Mann-Whitney test. We show that intact caspase-8 signaling maintains opposing roles in lysozyme-M- and CD11c-expressing cells in the joint; namely, caspase-8 is crucial in CD11c-expressing cells to delay arthritis induction, while caspase-8 in lysozyme M-expressing cells hinders arthritis resolution. Caspase-8 is also implicated in the maintenance of synovial tissue-resident macrophages that can limit arthritis. Global loss of RIPK3 in both caspase-8 deletion constructs causes the response to arthritis to revert back to control levels via a mechanism potentially independent of cell death. Mixed bone marrow chimeric mice demonstrate that caspase-8 deficiency does not confer preferential expansion of synovial macrophage and dendritic cell populations, nor do caspase-8-deficient synovial populations succumb to RIPK3-mediated necroptotic death. These data demonstrate that caspase-8 functions in synovial antigen-presenting cells to regulate the response to inflammatory stimuli by controlling RIPK3 action, and this delicate balance maintains homeostasis within the joint.


Elevated CO2 alters deployment of roots in "small" growth containers.
Previously we examined how limited rooting space and nutrient supply influenced plant growth under elevated atmospheric CO2 concentrations (McConnaughay et al. 1993). We demonstrated that plant growth enhancement under elevated CO2 was influenced more by the concentration of nutrients added to growth containers than to either the total nutrient content per pot or amount or the dimensions of available rooting space. To gain insight into how elevated CO2 atmospheres affect how plants utilize available belowground space when rooting space and nutrient supply are limited we measured the deployment of roots within pots through time. Contrary to aboveground responses, patterns of belowground deployment were most strongly influenced by elevated CO2 in pots of different volume and shape. Further, elevated CO2 conditions interacted differently with limited belowground space for the two species we studied,Abutilon theophrasti, a C3 dicot with a deep taproot, andSetaria faberii, a C4 monocot with a shallow fibrous root system. ForSetaria, elevated CO2 increased the size of the largest region of low root density at the pot surface in larger rooting volumes independent of nutrient content, thereby decreasing their efficiency of deployment. ForAbutilon, plants responded to elevated CO2 concentrations by equalizing the pattern of deployment in all the pots. Nutrient concentration, and not pot size or shape, greatly influenced the density of root growth. Root densities forAbutilon andSetaria were similar to those observed in field conditions, for annual dicots and monocots respectively, suggesting that studies using pots may successfully mimic natural conditions.


Augmenting Community Diagnosis of Safe Ear Disease Through Tele-Myringoscopy with Borescope Using AIML Tecniques.
This study utilized AIML (artificial intelligence & machine learning) techniques to analyze 115 images of central perforation of tympanic membrane obtained from Telemyringoscopy through Borescope in order to establish a facilitation-model for the community ear diagnosis. The Modified VGG19 with batch normalization revealed the highest training accuracy of 85 as compared to other CNN techniques. The training accuracy started to saturate around mid-70% and the Test accuracy was around 50%. Although AIML did not reveal a high predictive value, its potential based on our observations cannot be underestimated considering many limitations (sample size, image-quality, associated pathologies, illumination-factor) in this study. Such limitations if resolved may revolutionize community ear care through a better cost effective tele-myringoscopy with innovations in AIML/ telemedicine.


An unusual case of cocoon abdomen in a patient on hemodialysis.
"Cocoon abdomen" or sclerosing encapsulating peritonitis is a rare cause of intestinal obstruction. It has been described in patients on continuous ambulatory peritoneal dialysis. The exact etiology is unknown, but pathogenesis rests on chronic peritoneal inflammation. No case has been reported so far in patients on hemodialysis. We hereby report a case of cocoon abdomen presenting as refractory ascites with intestinal obstruction in a patient on maintenance hemodialysis.


Impact of a work-focused intervention on the productivity and symptoms of employees with depression.
To test a new program's effectiveness in reducing depression's work burden. A brief telephonic program to improve work functioning was tested in an early-stage randomized controlled trial involving 79 Maine State Government employees who were screened in for depression and at-work limitations (treatment group = 59; usual care group = 27). Group differences in baseline to follow-up change scores on the Work Limitations Questionnaire (WLQ), WLQ Absence Module, and Patient Health Questionnaire (PHQ)-9 depression severity scale were tested with analysis of covariance. Although there were no baseline group differences (P ≥ 0.05), by follow-up, the treatment group had significantly better scores on every outcome and differences in the longitudinal changes were all statistically significant (P = 0.0.27 to 0.0001). The new program was superior to usual care. The estimated productivity cost savings is $6041.70 per participant annually.


Exchange and efflux of tryptophan from superfused cerebral cortex slices.
The efflux and exchange of L-tryptophan (Trp) from rat cerebral cortex slices were studied in a superfusion system. The substrate specificity of Trp exchange was assessed by measuring the stimulation of [3H]Trp exit provoked by other extracellular amino acids. Large neutral amino acids were the most potent, but also glutamic acid, lysine and glycine had some effect. The stimulation caused by extracellular Trp and phenylalanine persisted also at 0 degrees C though severalfold attenuated. Only intracellular histidine provoked slight inhibition of [3H]Trp efflux and intracellular Trp, phenylalanine and lysine had a small stimulatory effect. The results suggest an involvement of carrier-mediated processes in the exchange and efflux of Trp. The substrate specificities of the exchange and efflux are not apparently identical.


Acute cardiac and hemodynamic effects of sildenafil on resistant hypertension.
Failure to control blood pressure (BP) despite the use of three or more drugs characterizes resistant hypertension (RHTN). Impaired endothelial function is associated with this condition and phosphodiesterase-5 inhibitors (PDE5i)-inhibiting cGMP breakdown-reduce BP in RHTN patients. We hypothesized that acute administration of PDE5i could ameliorate hemodynamic, endothelial parameters and left ventricular diastolic function (LVDF) in RHTN patients. Also, an exploratory analysis was performed to assess the influence of the T-786C endothelial NO synthase polymorphism on those responses. Subjects (n = 26) underwent a 6-month clinical screening for RHTN diagnosis. Increasing doses of oral sildenafil were given at 30 min intervals (37.5, 50 and 100 mg) while continuous non-invasive hemodynamic measures were assessed. LVDF, flow mediated dilation (FMD), nitrite and cGMP levels were also determined. Mean arterial pressure and total peripheral resistance decreased in all patients (84.17 ± 21.04 to 75 ± 17.21 mmHg; 1149 ± 459.7 to 1037 ± 340 dyn.s/cm(-5), respectively). Likewise, sildenafil improved diastolic dysfunction parameters (Left atrial volume: 25 ± 5.8 to 20 ± 4.4; IVRT: 104 ± 19.33 to 88 ± 15.22; E/e' septal: 9.7 ± 3.8 to 7.9 ± 2.9; E/e' lateral: 7.7 ± 3.4 to 6.4 ± 3.2). No statistical changes were found in FMD, nitrite and cGMP with PDE5i. Our data suggest PDE5i acutely improves diastolic function and hemodynamic profile in RHTN subjects, despite unchanging endothelial dysfunction.


Characterization of sedation and anesthesia complications in patients with alternating hemiplegia of childhood.
Alternating hemiplegia of childhood (AHC) pathophysiology suggests predisposition to sedation and anesthesia complications. Hypotheses: 1) AHC patients experience high rates of sedation-anesthesia complications. 2) ATP1A3 mutation genotype positivity, age, and AHC severity correlate with more severe complications. 3) Prior short QTc correlates with cardiac rhythm complications. Analysis of 34 consecutive AHC patients who underwent sedation or anesthesia. Classification of complications: mild (not requiring intervention), moderate (intervention), severe (intervention, risk for permanent injury or potential life-threatening emergency). Fisher Exact test, Spearman correlations. These patients underwent 129 procedures (3.79 ± 2.75 procedures/patient). Twelve (35%) experienced complications during at least one procedure. Fourteen/129 procedures (11%) manifested one or more complications (2.3% mild, 7% moderate, 1.6% severe). Of the total 20 observed complications, six (33.3%) were severe: apneas (2), seizures (2), bradycardia (1), ventricular fibrillation that responded to resuscitation (1). Moderate complications: non-life-threatening bradycardias, apneas, AHC spells or seizures. Complications occurred during sedation or anesthesia and during procedures or recovery periods. Patients with disease-associated ATP1A3 variants were more likely to have moderate or severe complications. There was no correlation between complications and age or AHC severity. Presence of prior short QTc correlated with cardiac rhythm complications. After this series was analyzed, another patient had severe recurrent laryngeal dystonia requiring tracheostomy following anesthesia with intubation. During sedation or anesthesia, AHC patients, particularly those with ATP1A3 variants and prior short QTc, are at risk for complications consistent with AHC pathophysiology. Increased awareness is warranted during planning, performance, and recovery from such procedures.


Identification of enzymes and quantification of metabolic fluxes in the wild type and in a recombinant aspergillus oryzae strain
Two alpha-amylase-producing strains of Aspergillus oryzae, a wild-type strain and a recombinant containing additional copies of the alpha-amylase gene, were characterized with respect to enzyme activities, localization of enzymes to the mitochondria or cytosol, macromolecular composition, and metabolic fluxes through the central metabolism during glucose-limited chemostat cultivations. Citrate synthase and isocitrate dehydrogenase (NAD) activities were found only in the mitochondria, glucose-6-phosphate dehydrogenase and glutamate dehydrogenase (NADP) activities were found only in the cytosol, and isocitrate dehydrogenase (NADP), glutamate oxaloacetate transaminase, malate dehydrogenase, and glutamate dehydrogenase (NAD) activities were found in both the mitochondria and the cytosol. The measured biomass components and ash could account for 95% (wt/wt) of the biomass. The protein and RNA contents increased linearly with increasing specific growth rate, but the carbohydrate and chitin contents decreased. A metabolic model consisting of 69 fluxes and 59 intracellular metabolites was used to calculate the metabolic fluxes through the central metabolism at several specific growth rates, with ammonia or nitrate as the nitrogen source. The flux through the pentose phosphate pathway increased with increasing specific growth rate. The fluxes through the pentose phosphate pathway were 15 to 26% higher for the recombinant strain than for the wild-type strain.


Composition of cyclic and non-cyclic vole populations: On the causes of variation in individual quality among Clethrionomys glareolus in Sweden.
A cyclic Clethrionomys glareolus population from north Sweden was compared with a non-cyclic population from south Sweden regarding age structure, body weight, reproductive development and suppression, and sex ratios.The non-cyclic population, after years with winter breeding, was characterized by especially early and intense breeding in spring and many post-reproductive animals in autumn. Non-cyclic populations with no winter reproduction were similar to increase years in cyclic populations. In peak and especially in decline phases of cyclic populations reproduction decreased clearly below the level in non-cyclic populations. Animal weights varied insignificantly between years in the non-cyclic population but changed greatly in the cyclic population.A unifying hypothesis for explaining variations in animal quality between different populations is proposed: Maternal conditions related to food supply are assumed to affect body growth and sexual maturation of the young. Predictions from this hypotheses are outlined and compared with those from competing ideas.


Circadian rhythms of RNA, DNA and protein in the rat thyroid, adrenal and testis, in chronic pesticide exposure. IV. Effects of the herbicide 2,4-dichlorophenoxyacetic acid.
Ninety days of the rats exposure to the herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D)(100 ppm/day) leads to circadian rhythm alterations in the thyroid and the adrenal and to a much lesser degree in the testis. 2,4-D thus affects the time structure of the adrenal and of the thyroid with apparently free-running circadian rhythms in thyroid DNA and adrenal RNA, phase delay in thyroid RNA and phase advance in adrenal DNA. In the testis, the circadian DNA and RNA rhythms ae unchanged, with the exception of a slightly lowered DNA amplitude, and the circadian protein rhythm shows a small but statistically significant phase advance. Sampling without regard for time might lead to erroneous conclusions.


ODAM inhibits RhoA-dependent invasion in breast cancer.
Odontogenic ameloblast-associated protein (ODAM) contributes to cell adhesion. In human cancer, ODAM is down-regulated, and the overexpression of ODAM results in a favourable prognosis; however, the molecular mechanisms underlying ODAM-mediated inhibition of cancer invasion and metastasis remain unclear. Here, we identify a critical role for ODAM in inducing cancer cell adhesion. ODAM induced RhoA activity and the expression of downstream factors, including Rho-associated kinase (ROCK). ODAM-mediated RhoA signalling resulted in actin filament rearrangement by activating PTEN and inhibiting the phosphorylation of AKT. When ODAM is overexpressed in MCF7 breast cancer cells and AGS gastric cancer cells that activate RhoA at high levels, it decreases motility, increases adhesion and inhibits the metastasis of MCF7 cells. Conversely, depletion of ODAM in cancer cells inhibits Rho GTPase activation, resulting in increased cancer migration and invasion. These results suggest that ODAM expression in cells maintains their adhesion, resulting in the prevention of their metastasis via the regulation of RhoA signalling in breast cancer cells. SIGNIFICANCE Breast cancer represents the first most frequent cancer, and the ratio of mortality is high in women. Of utmost importance for reducing risk by breast cancer are their anti-invasion mechanisms, particularly in the non-invasive cancer cells because metastasis is the principal cause of death among cancer patients. ODAM induced RhoA activity. ODAM-mediated RhoA signalling resulted in actin filament rearrangement, increased cell adhesion and inhibited the migration/invasion of MCF7 cells. These results suggest that ODAM expression maintains their adhesion, resulting in the prevention of their metastasis via the regulation of RhoA signalling in breast cancer cells.


Smooth muscle cells of human intracranial aneurysms assume phenotypic features similar to those of the atherosclerotic plaque.
Characterize the phenotypic features of smooth muscle cells (SMCs) in the wall of human saccular intracranial aneurysms (sIAs). We investigated by means of immunohistochemistry the expression of the cytoskeletal differentiation markers α-smooth muscle actin (α-SMA), smooth muscle myosin heavy chains (SMMHCs), and smoothelin in 26 sIAs and 15 nonaneurysmal cerebral arteries. In addition, S100A4, a recently identified marker of dedifferentiated SMCs in atherosclerotic plaques, was also investigated. Six sIAs and 5 nonaneurysmal arteries were used for morphometric analysis. sIAs displayed a significant medial atrophy compared with nonaneurysmal cerebral arteries; moreover, sIA SMCs showed marked decrease of α-SMA and SMMHCs expression and disappearance of smoothelin. Unexpectedly, S100A4 was strongly up-regulated in media SMCs of sIAs. In sIAs, media SMCs acquire a dedifferentiated phenotype and show de novo expression of S100A4, characteristic features of atherosclerotic plaque SMCs.


Integrated manganese (III)-doped nanosystem for optimizing photothermal ablation: Amplifying hyperthermia-induced STING pathway and enhancing antitumor immunity.
Despite the great promise initially demonstrated by photothermal ablation (PTA) therapy, its inability to completely ablate large tumors is problematic, because this has been found to result in residual tumors at ablation margins and bring a relative high rate of subsequent recurrences and metastases. To address this issue, we herein report a smart photothermal nanosystem (PBM) based on FDA-approved Prussian blue (PB) nanoparticles, doped with Mn (III) to suppress the tumor debris left by incomplete ablation. Notably, our study demonstrated that PTA-induced hyperthermia plays a crucial role in initiating the cGAS-STING pathway by generating damaged cytosolic DNA. This PBM nanosystem, which consumes glutathione and continuously releases Mn(II), further amplifies the PTA-induced cGAS-STING pathway in CT26 colon and 4T1 breast tumor models. Moreover, treatment with PBM following PTA boosted the robust immune response in situ and extended to the whole body with a remarkable suppression effect on both local residual and distant tumors. This work, which improves the antitumor efficacy of nonablated areas utilizing hyperthermia-enhanced immune therapy, may therefore provide a promising adjuvant antitumor strategy for the issue of incomplete ablation. STATEMENT OF SIGNIFICANCE: This work discovered, for the first time, that photothermal ablation-induced hyperthermia plays a crucial role in initiating the cGAS-STING pathway. Taking advantage of this finding, we developed a smart photothermal material (PBM) tailored for incomplete tumor ablation. This integrated Mn(III)-doped nanosystem (PBM) demonstrated superior therapeutic benefits due to the thermal ablation process and immune enhancement. As the photothermal ablation-induced cGAS-STING pathway was triggered, the released Mn(III) consumes GSH while continuously transferred to Mn(II), which further amplified STING activation and facilitated a more robust antitumor immunity, thereby remarkably inhibiting both local residual and distant tumors in virtue of the biological changes under thermal ablation.


Which severe COVID-19 patients could benefit from high dose dexamethasone? A Bayesian post-hoc reanalysis of the COVIDICUS randomized clinical trial.
The respective benefits of high and low doses of dexamethasone (DXM) in patients with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and acute respiratory failure (ARF) are controversial, with two large triple-blind RCTs reaching very important difference in the effect-size. In the COVIDICUS trial, no evidence of additional benefit of high-dose dexamethasone (DXM20) was found. We aimed to explore whether some specific patient phenotypes could benefit from DXM20 compared to the standard of care 6 mg dose of DXM (DXMSoC). We performed a post hoc exploratory Bayesian analysis of 473 patients who received either DXMSoc or DXM20 in the COVIDICUS trial. The outcome was the 60 day mortality rate of DXM20 over DXMSoC, with treatment effect measured on the hazard ratio (HR) estimated from Cox model. Bayesian analyses allowed to compute the posterior probability of a more than trivial benefit (HR < 0.95), and that of a potential harm (HR > 1.05). Bayesian measures of interaction then quantified the probability of interaction (Pr Interact) that the HR of death differed across the subsets by 20%. Primary analyses used noninformative priors, centred on HR = 1.00. Sensitivity analyses used sceptical and enthusiastic priors, based on null (HR = 1.00) or benefit (HR = 0.95) effects. Overall, the posterior probability of a more than trivial benefit and potential harm was 29.0 and 51.1%, respectively. There was some evidence of treatment by subset interaction (i) according to age (Pr Interact, 84%), with a 86.5% probability of benefit in patients aged below 70 compared to 22% in those aged above 70; (ii) according to the time since symptoms onset (Pr Interact, 99%), with a 99.9% probability of a more than trivial benefit when lower than 7 days compared to a < 0.1% probability when delayed by 7 days or more; and (iii) according to use of remdesivir (Pr Interact, 91%), with a 90.1% probability of benefit in patients receiving remdesivir compared to 19.1% in those who did not. In this exploratory post hoc Bayesian analysis, compared with standard-of-care DXM, high-dose DXM may benefit patients aged less than 70 years with severe ARF that occurred less than 7 days after symptoms onset. The use of remdesivir may also favour the benefit of DXM20. Further analysis is needed to confirm these findings. NCT04344730, date of registration April 14, 2020 ( https://clinicaltrials.gov/ct2/show/NCT04344730?term=NCT04344730&draw=2&rank=1 ); EudraCT: 2020-001457-43 ( https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-001457-43 ).


Akinetic mutism: a report of three cases.
To report 3 new cases of akinetic mutism, a clinical syndrome defined by silent immobility with preserved visual alertness not accountable by lesion of the areas and/or effector pathways of speech and voluntary movements. Anatomopathological studies were performed in Cases 1 and 2; clinical follow-up, EEG, angiography and CT scans in Case 3. Case 1: Bipallidal necrosis; Case 2: Left pallidal necrosis with right frontoparietal cortico-subcortical infarction; Case 3: Striato-capsular infarction on the left side, involving the caudate nucleus and the anterior arm of the internal capsule, together with obstructive hydrocephalus. The roles of both globus pallidus and prefrontostriatal circuits in the onset of voluntary movements are discussed.


Modifier effect of the Toll-like receptor 4 D299G polymorphism in children with cystic fibrosis.
Clinical phenotype varies amongst cystic fibrosis (CF) patients with identical CF transmembrane regulator (CFTR) genotype, suggesting genetic modifiers exist. One potential modifier is the Toll-like receptor 4 (TLR4) gene. TLR4 binds lipopolysaccharide (LPS), a constituent of Pseudomonas aeruginosa (PA), activating innate immunity and promoting inflammation. TLR4 polymorphisms are associated with LPS-hyporesponsiveness and may be protective in CF due to decreased inflammation. DNA was extracted from blood of recruited CF subjects, and PCR performed to establish TLR4 D299G genotype. Case-notes were reviewed to obtain clinical data. Subjects possessing the TLR4 299G allele were compared with age, sex, and CFTR genotype-matched wild-type (299DD) subjects and also with all controls. 100 subjects (mean age 8.9 years) were studied, with 11 299DG heterozygotes identified. On case-matched analyses, no statistically significant differences between groups were found for mean +/- SEM rates of change of %predicted FEV(1)/year (0.9 +/- 2.3 (DD) vs. - 3.9 +/- 2.8 (DG), p = 0.22), %predicted FEV(1) (76 +/- 8 vs. 74 +/- 11), p = 0.91), or z scores for height ( - 0.47 +/- 0.26 vs. - 0.24 +/- 0.19, p = 0.48) and weight ( - 0.01 +/- 0.22 vs. - 0.29 +/- 0.27, p = 0.44). Median +/- SE survival age at first PA isolation was also not significantly different (3.5 +/- 2.1 vs. 6.5 +/- 2.4 years, p = 0.29). No statistically significant differences were noted when 299DG heterozygotes were compared with all controls. Potential reasons for absence of modifier effect include the basolateral location of TLR4 receptors on respiratory epithelium, or because inflammatory response to PA in the CF airway is so overwhelming that even a blunted response (as suggested for the 299G allele) results in increased inflammation and lung damage.


Management of inflammatory neurologic and psychiatric manifestations of systemic lupus erythematosus: A systematic review.
The neurological and psychiatric manifestations of systemic lupus erythematosus (NPSLE) are a heterogeneous group of conditions with variable clinical presentation and significant morbidity and mortality. Our aim was to comprehensively assess and present the evidence for treatments used in the management of inflammatory NPSLE. Medline, Embase, CINHAL and Cochrane CENTRAL were searched from 1990 to end of March 2019 using key words that related to NPSLE and treatment. Included studies comprised clinical trials, observational studies or case series with ≥5 patients and sufficient data related to treatment and outcome in NPSLE patients. There were 7222 studies identified in the search, of which 90 were included in the review. There was a notable paucity of clinical trials, with only two randomised controlled trials and one pilot study. Treatment categories included corticosteroids (14 studies), cyclophosphamide (18 studies), synthetic DMARDs (7 studies), biologic therapies (14 studies), therapeutic plasma exchange (6 studies), intravenous immunoglobulin (2 studies), autologous stem cell transplant (3 studies), other therapies (8 studies), combination therapies (6 studies), studies with grouped outcome data (5 studies) and observational studies with therapy-specific associations (7 studies). Corticosteroids are accepted as first line treatment in NPSLE and there is low-moderate evidence supporting their benefit. Moderate evidence, based on consistent data in numerous studies and some trial data, supports the use of cyclophosphamide in the treatment of NPSLE. Limited data support some synthetic DMARDs such as mycophenolate, azathioprine and intrathecal methotrexate. In refractory disease, low-moderate evidence supports rituximab therapy and limited evidence supports benefit following autologous stem cell transplant. Regarding adjuvant treatments, limited evidence favours addition of plasma exchange, intravenous immunoglobulin and hydroxychloroquine. There exists very limited data for other therapies. There are multiple therapeutic options for the management of inflammatory NPSLE including systemic, biologic and interventional therapies; however, currently there is a paucity of high-quality trial data to guide firm recommendations. In order to better understand the optimal treatment of NPSLE and its different subtypes, further well-designed clinical trials are needed.


AFM imaging of ALYGNSA polymer-protein surfaces: evidence of antibody orientation.
Previous investigations found the combination of recombinant bacterial protein G (rProG) and poly(methyl methacrylate) (PMMA) to produce a greater proportion of oriented antibodies. PMMA-rProG yielded a sixfold greater availability of antibody Fab regions compared with other bacterial affinity linker protein and polymer pairings, including commercially available polystyrene (PS) high-binding 96-well microplates. Given the name ALYGNSA, the PMMA-rProG combination was developed into a fluorescence assay and evaluated in conjunction with commercially available cancer biomarker enzyme-linked immunosorbent assays (ELISAs). In each study, a lower limit of detection was seen with the ALYGNSA assay. The purpose of this investigation was to examine the ALYGNSA substrate in contrast with a commonly used ELISA substrate and analyze the affinity-immobilized antibodies for additional evidence of orientation. Non-contact atomic force microscopy is a logical method as it operates in ambient conditions, can be used directly on biological samples without modification, and offers the resolution necessary to identify the position of the antibody on the surface. Dynamic contact angle studies were employed to examine untreated PMMA and PS samples and revealed important differences in their surface characters. Comparative height threshold grain analysis of the prepared ALYGNSA surface, a similarly treated mica surface, and a gold colloid sizing standard evaluated and confirmed the antibody orientation of the ALYGNSA system.


Statins for atherosclerotic cardiovascular disease prevention in people living with HIV in Thailand: a cost-effectiveness analysis.
People living with HIV (PLHIV) have an elevated risk of atherosclerotic cardiovascular disease (CVD) compared to their HIV-negative peers. Expanding statin use may help alleviate this burden. However, the choice of statin in the context of antiretroviral therapy is challenging. Pravastatin and pitavastatin improve cholesterol levels in PLHIV without interacting substantially with antiretroviral therapy. They are also more expensive than most statins. We evaluated the cost-effectiveness of pravastatin and pitavastatin for the primary prevention of CVD among PLHIV in Thailand who are not currently using lipid-lowering therapy. We developed a discrete-state microsimulation model that randomly selected (with replacement) individuals from the TREAT Asia HIV Observational Database cohort who were aged 40 to 75 years, receiving antiretroviral therapy in Thailand, and not using lipid-lowering therapy. The model simulated each individual's probability of experiencing CVD. We evaluated: (1) treating no one with statins; (2) treating everyone with pravastatin 20mg/day (drug cost 7568 Thai Baht ($US243)/year) and (3) treating everyone with pitavastatin 2 mg/day (drug cost 8182 Baht ($US263)/year). Direct medical costs and quality-adjusted life-years (QALYs) were assigned in annual cycles over a 20-year time horizon and discounted at 3% per year. We assumed the Thai healthcare sector perspective. Pravastatin was estimated to be less effective and less cost-effective than pitavastatin and was therefore dominated (extended) by pitavastatin. Patients receiving pitavastatin accumulated 0.042 additional QALYs compared with those not using a statin, at an extra cost of 96,442 Baht ($US3095), giving an incremental cost-effectiveness ratio of 2,300,000 Baht ($US73,812)/QALY gained. These findings were sensitive to statin costs and statin efficacy, pill burden, and targeting of PLHIV based on CVD risk. At a willingness-to-pay threshold of 160,000 Baht ($US5135)/QALY gained, we estimated that pravastatin would become cost-effective at an annual cost of 415 Baht ($US13.30)/year and pitavastatin would become cost-effective at an annual cost of 600 Baht ($US19.30)/year. Neither pravastatin nor pitavastatin were projected to be cost-effective for the primary prevention of CVD among PLHIV in Thailand who are not currently using lipid-lowering therapy. We do not recommend expanding current use of these drugs among PLHIV in Thailand without substantial price reduction.


Effect of transforming growth factor-β3 on the expression of Smad3 and Smad7 in tenocytes.
Tendon adhesion is a common problem in the healing of injured tendons. The molecular mechanisms of the TGF-β/Smad signaling pathway have been determined, and the role of TGF-β has been well characterized in wound healing. However, the intracellular mechanism or downstream signals by which TGF-β3 modulates its effects on tendon healing have not been well elucidated. The aim of this study was to determine the effect of TGF‑β3 on the TGF-β/Smad signaling pathway in tenocytes. Quantitative polymerase chain reaction and western blot analysis were used to analyze the effect of TGF‑β3 on the regulation of the expression of Smad proteins in tenocytes. The results demonstrated that TGF‑β3 has no significant effect on the proliferation of tendon cells. The addition of TGF‑β3 to tenocytes can significantly downregulate the expression of Smad3 and upregulate the expression of Smad7 at the gene and protein levels. The results demonstrate that TGF‑β3 may regulate Smad3 and Smad7 proteins through the TGF-β/Smad signaling pathway to minimize extrinsic scarring. Thus, it may provide a novel approach to decrease tendon adhesion and promote tendon healing.


MouseTox: An online toxicity assessment tool for small molecules through Enalos Cloud platform.
Advances in the drug discovery research substantially depend on in silico methods and techniques that capitalize on experimental data to enable the accurate property/activity assessment by employing a variety of computational techniques. These in silico tools can significantly reduce expensive and time consuming experimental procedures required and are strongly recommended to avoid animal testing, especially as far as toxicity evaluation and risk assessment is concerned. In this context, in the present work we aim to develop a predictive model for the cytotoxic effects of a wide range of compounds based solely on calculated molecular descriptors that account for their topological, geometric and structural characteristics. The developed model was fully validated and was released online via Enalos Cloud platform accessible through http://enalos.insilicotox.com/MouseTox/. This ready-to-use web service offers, through a user-friendly interface, free access to the model results and therefore can act as a toxicity prediction tool for the risk assessment of novel compounds, without any special requirements or prior programming skills.


Assessment of Heavy Metal Pollution in Sediments of Inflow Rivers to Lake Taihu, China.
Lake Taihu, the third-largest freshwater body in China, has many functions, including drinking water supply, flood control, cultivation, navigation, and tourism. In this study, sediment samples were collected at 31 sites from 11 inflow rivers in 2012, to investigate the distribution and concentration of heavy metals copper (Cu), zinc (Zn), lead (Pb), nickel (Ni), and chromium (Cr), and to assess their potential ecological risk. The highest mean concentration was found for Zn, followed by Cu, Cr, Pb, and Ni. Generally, heavy metal pollution was more serious in Wu Jingang River and Caoqiao River, probably because they receive large amounts of wastewater from various local industrial enterprises. The potential ecological risk values of the heavy metals were larger than 120 in more than 25.8% of the sediment samples, indicating a very high risk. The largest ecological risk was due to copper. Furthermore, the results of a principal component analysis and subsequent analysis of variance showed that heavy metal concentrations in the sediment of inflow rivers were higher than those of the lake, which created a large hazard for the aquatic ecosystems of Lake Taihu.


Cytotoxic effects of 109 reference compounds on rat H4IIE and human HepG2 hepatocytes. III: Mechanistic assays on oxygen consumption with MitoXpress and NAD(P)H production with Alamar Blue™.
In vitro toxicity screening can reduce the attrition rate of drug candidates in the pharmaceutical industry in the early development process. The focus in this study is to compare the sensitivity for cytotoxicity of a time-resolved fluoro metric oxygen probe with that of a fluoro metric Alamar Blue™ (AB) assay. Both assays measure mitochondrial activity by either oxygen consumption (LUX-A65N-1 (MitoXpress, Luxcel) probe) or NADH/FADH conversion (AB). Both assays were carried out with increasing concentrations of 109 reference compounds using rat H4IIE and human HepG2 hepatocytes at incubation periods of 24, 48 and 72 h. Prior to this study, the influence on medium with either glucose or galactose was studied to analyze the rate of glycolysis and oxygen consumption, which latter process may be impaired in hepatoma cells. Inhibitors of oxygen consumption in combination with a glucose up-take inhibitor showed the largest consumption rate differences in the presence of 5mM of glucose. The choice for the 109 reference compounds was based on the so-called Multicentre Evaluation for In vitro Cytotoxicity (MEIC) and on diverse drug categories. For 59 toxic reference compounds, an evaluation for both assays was carried up to 10(-3)M. Toxicity was demonstrated with MitoXpress for 23 (39%) and 36 (61%) compounds in H4IIE and HepG2 cells, respectively, and with AB for 44 (75%) and 40 (68%) compounds. For 50 more pharmaceutical drugs more physiological concentrations were used up to 3.16×10(-5)M, and only 19 (38%) of these compounds appeared to be toxic in both assays. In conclusion, overall 63 (58%) and 60 (55%) compounds showed toxic effects with the MitoXpress and AB assays on rat H4IIE and human HepG2 hepatocytes, respectively. AB assays were more sensitive with respect to H4IIE cells and MitoXpress assays with respect to HepG2 cells. At all tested time intervals, MitoXpress showed its sensitivity, while AB is more sensitive at 48 and 72 h. With AB more toxic compounds were identified, whereas MitoXpress was more sensitive for a few compounds. A species specific difference was clearly found with digoxin, a human specific potassium channel inhibitor. Thus both assays are valuable identifiers of early toxicity with discrimination in time, compounds and species.


Developmental acquisition of type X collagen in the embryonic chick tibiotarsus.
The temporal and spatial distribution of short chain skeletal (Type X) collagen was immunohistochemically examined in the chick tibiotarsus from 6 days of embryonic development to 1 day posthatching. The monoclonal antibody employed (AC9) was recently produced and characterized as being specific for an epitope located within the helical domain of the type X collagen molecule (T. M. Schmid and T. F. Linsenmayer, J. Cell Biol., in press). The earliest detectable appearance of type X collagen was at 7.5 days, at which time it was restricted to a middiaphyseal location (i.e., in the primary center of ossification). This was in marked contrast to type II collagen, which appears earlier and is distributed throughout the cartilaginous anlagen. With increasing embryonic age, the reactivity with the type X antibody progressively extended toward the epiphyses, lagging somewhat behind the progression of chondrocyte hypertrophy. The anti-type X collagen antibody also reacted with the bony matrix itself, but the immunofluorescent signal produced by this source was considerably less than that produced by cartilage. At 19 days of development, a new small site of type X deposition was initiated in an epiphyseal location, which subsequently enlarged in circumference. These results are consistent with our previous biochemical studies suggesting that, in cartilage, type X collagen is specifically a product of that population of chondrocytes which have undergone hypertrophy.


[Infective endocarditis of the tricuspid valve: echocardiographic diagnosis and a therapeutic approach].
The authors report a case of Infective Endocarditis (IE) to emphasize the most characteristic echocardiographic features that permit to detect the tricuspid valve involvement in IE, the management of the medica and/or surgical therapy of this disease and the limitations of this noninvasive technique.


Assessing recovery rates of distinct exogenous controls for gDNA extraction efficiency using phenol-chloroform or silica-column based extractions.
Assessment of genomic DNA (gDNA) extraction efficiency is required for accurate bacterial quantification by qPCR. Exogenous DNA molecules are often added after bacterial cultures are lysed, but before DNA purification steps, to determine extraction efficiency. Herein we found that different exogenous DNA controls have different recovery rates, suggesting distinct DNA extraction efficiencies. Recovery rates are also affected by the gDNA extraction method being more affected in silica-based columns than in phenol-chloroform extraction. Overall, we determined that the use of long DNA fragments, such as gDNA, as exogenous controls have a higher recovery rate than use of smaller size DNA molecules.