Acid phosphatase localization in endocytosed horizontal cell gap junctions.
Gap junction (GJ) endocytosis appears to be part of a cycle of GJ renewal in horizontal cells of the teleost fish retina. At least three stages of GJ endocytosis in these neurons have been identified using conventional electron microscopy (EM): invagination of GJ membranes (GJ blebs); free GJ vesicles; and GJ vesicle fusion with mature lysosomes (Vaughan & Lasater, 1990a). In the present study, EM-level acid phosphatase (AP) histochemistry of white bass retina was used to determine at what stage enzymatic degradation of endocytosed GJs begins. Electron-dense AP reaction product was observed within the trans face of the Golgi apparatus, mature lysosomes, and occasional, internal GJ vesicles. In contrast, GJ blebs, peripheral GJ vesicles, and most internal GJ vesicles lacked AP reaction product. These results support the idea that at least some of the GJ vesicles observed within these retinal neurons arise from endocytosis, are on a degradative pathway, and can be termed GJ "endosomes." Furthermore, GJ vesicles appear to be initially free of AP, but some later acquire it (presumably from transport vesicles bearing degradative enzymes). It is still unclear whether our previous report of GJ vesicle fusion with mature lysosomes is a subsequent step in GJ degradation or part of a different degradative pathway altogether.


Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case-control study.
Although methotrexate (MTX) is used in the effective treatment of inflammatory disorders, its use is hampered by the risk of liver fibrosis. Non-invasive methods for the diagnosis of liver fibrosis, such as transient elastography (FibroScan) and FibroTest could be useful for monitoring MTX-liver toxicity. The aim of this case-control study was to determine factors associated with liver fibrosis in a large cohort of patients requiring MTX. Consecutive adults with various benign inflammatory diseases were prospectively assessed using FibroScan and FibroTest when they were treated with MTX (cases) or before beginning treatment (controls). Among 518 included patients, 44 patients (8.5%) had FibroScan and/or FibroTest results suggesting severe liver fibrosis. In a multivariate analysis, factors associated with abnormal markers of liver fibrosis were the body mass index >28 kg/m(2) and high alcohol consumption. Neither long MTX duration nor cumulative doses were associated with elevated FibroScan or FibroTest results. Severe liver fibrosis is a rare event in patients treated with MTX and is probably unrelated to the total dose. Patients with other risk factors for liver disease should be closely monitored with non-invasive methods before and during MTX treatment.


The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis.
This prospective, randomized, controlled trial compared the progression of vascular and cardiac valve calcification in 360 prevalent adult hemodialysis patients with secondary hyperparathyroidism treated with either cinacalcet plus low-dose vitamin D sterols or flexible doses of vitamin D sterols alone. Eligible subjects were on hemodialysis for ≥ 3 months with parathyroid hormone (PTH) > 300 pg/mL or PTH 150-300 pg/mL with calcium-phosphorus product > 50 mg(2)/dL(2) while receiving vitamin D. All subjects received calcium-based phosphate binders. Coronary artery calcification (CAC) and aorta and cardiac valve calcium scores were determined both by Agatston and volume scoring using multi-detector computed tomography. Subjects with Agatston CAC scores ≥ 30 were randomized to cinacalcet (30- 180 mg/day) plus low-dose calcitriol or vitamin D analog (≤ 2 μg paricalcitol equivalent/dialysis), or flexible vitamin D therapy. The primary end point was percentage change in Agatston CAC score from baseline to Week 52. Median (P10, P90) Agatston CAC scores increased 24% (-22%, 119%) in the cinacalcet group and 31% (-9%, 179%) in the flexible vitamin D group (P = 0.073). Corresponding changes in volume CAC scores were 22% (-12%, 105%) and 30% (-6%, 133%; P = 0.009). Increases in calcification scores were consistently less in the aorta, aortic valve and mitral valve among subjects treated with cinacalcet plus low-dose vitamin D sterols, and the differences between groups were significant at the aortic valve. In hemodialysis patients with moderate to severe secondary hyperparathyroidism, cinacalcet plus low-dose vitamin D sterols may attenuate vascular and cardiac valve calcification.


Does initial length of stay impact 30-day readmission risk in pediatric asthma patients?
Accountable care puts pressure on hospitals to manage care episodes. Initial length of stay (ILOS) and readmission risk are important elements of a care episode and measures of care quality. Understanding the association between these two measures can guide hospital efforts in managing care episodes. This study was designed to explore the association between ILOS and readmission risk in a cohort of pediatric asthma patients. The sample cohort (n = 4965) consisted of all asthma patients discharged from Children's Hospitals and Clinics of Minnesota (CHC MN) from January 2008 through August 2012. Asthma discharges included cases with a principal diagnosis of asthma or certain respiratory cases with asthma listed as a secondary diagnosis. Multiple logistic regression was used to test associations, adjusting for covariates. Adjusting for covariates, we found no significant association between ILOS and readmission (OR: 1.04 [95% CI: 0.98-1.10]). Analyzing ILOS categorically by length of stay, one-day stays did not have a significantly higher readmission risk (OR:1.27 [95% CI: 0.87-1.85]) than two-day stays, which had the lowest observed readmission risk. Risk increased as ILOS exceeded two days but was not significantly different by day. We found no association when comparing the difference in actual versus expected ILOS and readmission risk (shorter than expected OR: 1.13 [95% CI: 0.74-1.71]; longer than expected OR: 0.97 [95% CI: 0.69-1.38]). Attempts to prolong ILOS would dramatically increase costs with little impact on readmissions. For example, increasing one-day visits to two-day visits would increase hospital patient days 38% (1870 d) in this cohort while decreasing total readmissions by 3.8% [95% CI: 3.6-4.0%]. Understanding the mechanisms that impact readmissions is essential in evaluating cost-effective approaches to improving patient outcomes and lowering the cost of care.


The Complex Associations Between Early Childhood Adversity, Heart Rate Variability, Cluster B Personality Disorders, and Aggression.
Early childhood adversity can cause an imbalance in the autonomic function, which may in turn lead to the development of trauma-spectrum disorders and aggressive behavior later in life. In the present study, we investigated the complex associations between early adversity, heart rate variability (HRV), cluster B personality disorders, and self-reported aggressive behavior in a group of 50 male forensic inpatients (M age = 41.16; SD = 10.72). Structural Equation Modeling analysis revealed that patients with cluster B personality disorders were more likely to have adverse early childhood experiences and reduced sympathetic dominance in response to a threat than patients without cluster B personality disorders. In addition, HRV and cluster B personality disorders did not significantly mediate the association between early childhood adversity and self-reported aggressive behavior. These findings are important for clinical practice to facilitate specific treatment programs for those affected.


SHAPE analysis of the FIV Leader RNA reveals a structural switch potentially controlling viral packaging and genome dimerization.
Feline immunodeficiency virus (FIV) infects many species of cat, and is related to HIV, causing a similar pathology. High-throughput selective 2' hydroxyl acylation analysed by primer extension (SHAPE), a technique that allows structural interrogation at each nucleotide, was used to map the secondary structure of the FIV packaging signal RNA. Previous studies of this RNA showed four conserved stem-loops, extensive long-range interactions (LRIs) and a small, palindromic stem-loop (SL5) within the gag open reading frame (ORF) that may act as a dimerization initiation site (DIS), enabling the virus to package two copies of its genome. Our analyses of wild-type (wt) and mutant RNAs suggest that although the four conserved stem-loops are static structures, the 5' and 3' regions previously shown to form LRI also adopt an alternative, yet similarly conserved conformation, in which the putative DIS is occluded, and which may thus favour translational and splicing functions over encapsidation. SHAPE and in vitro dimerization assays were used to examine SL5 mutants. Dimerization contacts appear to be made between palindromic loop sequences in SL5. As this stem-loop is located within the gag ORF, recognition of a dimeric RNA provides a possible mechanism for the specific packaging of genomic over spliced viral RNAs.


Substituted pyrazinecarboxamides as abiotic elicitors of flavolignan production in Silybum marianum (L.) gaertn cultures in vitro.
Substituted pyrazinecarboxamides markedly influenced production of flavonolignans in Silybum marianum callus and suspension cultures. In this study the effect of two compounds, N-(3-iodo-4-methylphenyl)pyrazine-2-carboxamide (1) and N-(3-iodo-4-methylphenyl)-5-tert-butyl-pyrazine-2-carboxamide (2), as abiotic elicitors on flavono-lignan production in callus culture of S. marianum was investigated. Silymarin complex compounds have hepatoprotective, anticancer and also hypocholesterolemic activity. In vitro flavonolignan concentration in cells is very low and the elicitation is one of the methods to increase production. Elicitors were tested at three concentrations and at different culture times. In the case of elicitation with 1, the greatest increase of flavonolignan and taxifoline production was observed at concentration c(1a) after 6-hours of elicitation and after 24 and 72-hours at concentration c(1b). However, increased production of silychristin, one of the compounds in the silymarin complex, was achieved after only 6-hours elicitation with c(1a) (2.95 x 10(-4) mol/L). The content of silychristin was 2-times higher compared to the control sample. An increased production of silychristin was reached with compound 2 at the concentration c(2) (2.53 x 10(-3) mol/L) after 72 h of elicitation. The production of silychristin in this case was increased 12-times compared to control.


Sexual behaviors, risks, and sexual health outcomes for adolescent females following bariatric surgery.
Adolescents females with severe obesity are less likely to be sexually active, but those who are sexually active engage in risky sexual behaviors. To examine patterns and predictors of sexual risk behaviors, contraception practices, and sexual health outcomes in female adolescents with severe obesity who did or did not undergo bariatric surgery across 4 years. Five academic medical centers. Using a prospective observational controlled design, female adolescents undergoing bariatric surgery (n = 111; Mage = 16.95 ± 1.44 yr; body mass index: MBMI = 50.99 ± 8.42; 63.1% white) and nonsurgical comparators (n = 68; Mage = 16.18 ± 1.36 yr; MBMI = 46.47 ± 5.83; 55.9% white) completed the Sexual Activities and Attitudes Questionnaire at presurgery/baseline and 24- and 48-month follow-up, with 83 surgical females (MBMI = 39.27 ± 10.08) and 49 nonsurgical females (MBMI = 48.56 ± 9.84) participating at 48 months. Most experienced sexual debut during the 4-year study period, with a greater increase in behaviors conferring risk for sexually transmitted infections (STIs) for surgical females (P = .03). Half (50% surgical, 44.2% nonsurgical, P = .48) reported partner condom use at last sexual intercourse. The proportion of participants who had ever contracted an STI was similar (18.7% surgical, 14.3% nonsurgical). Surgical patients were more likely to report a pregnancy (25.3% surgical, 8.2% nonsurgical, P = .02) and live birth (16 births in 15 surgical, 1 nonsurgical), with 50% of offspring in the surgical cohort born to teen mothers (age ≤19 yr). Bariatric care guidelines and practices for adolescent females must emphasize the risks and consequences of teen or unintended pregnancies, sexual decision-making, dual protection, and STI prevention strategies to optimize health and well-being for the long term.


Perfusing the Jehovah's Witness patient with heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) is an uncommon, yet dangerous side-effect of heparin therapy. The problems associated with the HIT patient while undergoing cardiopulmonary bypass increase dramatically when the patient is also of Jehovah's Witness faith. This case report depicts the techniques utilized and the decisions made over the course of a simple surgical procedure for an extremely high-risk patient.


Valine needs of male broilers from 42 to 56 days of age.
An experiment was conducted using Ross x Ross 308 males to estimate the proportion of dietary valine needed to optimize performance in broilers from 42 to 56 d of age. All birds received common feeds from 0 to 42 d, and then experimental diets were given to 56 d of age. A diet consisting of corn, soybean meal, and corn gluten meal (17% CP, 3.25 kcal of ME/g) having 0.60% valine served as basal feed. All other essential amino acids were above recommended levels. Successive additions of 0.07% of L-valine were isonitrogenously substituted for L-glutamic acid up to a total of 0.81%. Regression analysis (95% of response) indicated that valine at 0.72% of the diet maximized body weight gain, whereas 0.73% optimized feed conversion. Depot fat removed from the abdominal cavity after processing was unaltered, and weights of resultant chilled carcasses maximized at 0.73% valine in parallel with final live weight. The amount of fillets recovered from chilled carcasses optimized at 0.73% valine; however, the incidence of distinctive blood streaks in the meat (splash) progressively increased with valine as did the level of redness apart from streaking, based on light reflectance. Given lysine at 0.85%, a ratio of 0.86 with valine appears to be adequate. The presently determined requirement of 0.73% total valine (0.67% digestible) for broiler males from 42 to 56 d of age is slightly higher than the 0.70% recommended by the NRC.


Comparison of World Health Organization 2000/2004 and World Health Organization 2010 classifications for gastrointestinal and pancreatic neuroendocrine tumors.
Gastroenteropancreatic neuroendocrine tumors (GEPNETs) were divided into 4 groups based on tumor diameter and stage in World Health Organization (WHO) 2000/2004 classification as well-differentiated endocrine tumor benign (WDETB), well-differentiated endocrine tumor with uncertain behavior (WDETUB), well-differentiated endocrine carcinoma (WDEC), and poorly differentiated endocrine carcinoma (PDEC). World Health Organization 2000/2004 was not widely accepted because of stage-related classification and the category of "uncertain behavior." The European NET Society proposed a grading classification and site-specific staging system in 2010. Gastroenteropancreatic NETs were divided into 3 groups as NET grade 1 (G1), NET grade 2 (G2), and neuroendocrine carcinoma (NEC) grade 3 (G3) based on mitoses and the Ki-67 index. We evaluated 63 GEPNET cases according to both classifications. We compared two classifications and the tumor groups in terms of prognostic parameters (diameter, mitosis, Ki-67 index, angioinvasion, perineural invasion, necrosis, and metastasis) and pathologic stage. All 14 cases diagnosed as PDEC were included in the NEC G3 according to WHO 2010. Seventeen cases were diagnosed as WDETB, 9 as WDETUB, and 23 as WDEC. There was statistically significant difference between these groups in terms of all prognostic parameters except for necrosis, mitosis, Ki-67 index, and grade. All WDETB cases, 89% of WDETUBs, and 87% of WDECs were included in the NET G1. There were 45 cases evaluated as NET G1 and 4 cases as NET G2 according to WHO 2010. Metastasis and perineural invasion were more common in NET G2, no significant differences in other parameters. In conclusion, WHO 2010 is easier to use, whereas WHO 2000/2004 shows higher correlation with prognosis. However, it includes benign and uncertain behavior categories, although small tumors with low proliferative activity can also cause metastases. All GEPNETs should be considered potentially malignant.


A human beta-endorphin pituitary adenoma.
A beta-endorphin (beta END)-containing pituitary adenoma was demonstrated by immunocytochemical, biochemical, and ultrastructural methods in a 43-yr-old man who had impotence, slight testicular atrophy, and an enlarged sella turcica (grade II0), but no manifestations of Cushing's disease. Preoperative hormone data revealed hyperprolactinemia (97 ng/ml), low plasma cortisol levels without circadian rhythm, undetectable plasma ACTH, and normal plasma FSH and LH levels, with an impaired response to LRH. After hypophysectomy, these hormone levels normalized and responded normally to dynamic tests. Immunocytochemically, 30% of the tumor cells reacted only with beta END antiserum. beta END immunoreactivity was the only component revealed by RIA and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A characteristic ultrastructural aspect is also described. These findings demonstrate dissociation in the secretion of the proopiomelanocortin-derived peptides and suggest a relationship between hyperprolactinemia and tumor secretion of beta END.


Association between free thyroid hormones values and the lipid profile in middle-aged women with chronic symptoms.
To determine the association between the thyroid hormones(FT3, FT4 and TSH) and the lipid profile markers(HDL-c, LDL-c and triglycerides) values in middle-aged women with no metabolic disorders and recurrent chronic symptomatology. We carried out an analytical cross-sectional study in euthyroid women with recurrent chronic symptoms of at least six months with no apparent diagnosis who attended the endocrinological gynaecology outpatient service of a private clinic in Lima-Peru during 2012-2014. Participants who met the eligibility criteria were evaluated according to their thyroid hormones(FT3, FT4 and TSH) and lipid profile markers(HDL-c, LDL-c and triglycerides) values. We elaborated univariate/multivariate linear regression models to evaluate the association between the thyroid markers and the lipid profile levels. The reported association measure was the beta coefficient(β) with its respective p-value. We analyzed 211 participants, the average age was 44.9 ± 14.0(SD) years, the FT3 and FT4 mean levels were 3.2 ± 0.4 pg/mL and 1.2 ± 0.2 ng/dL respectively, while the TSH median was 2.8(IQR:1.9-4.0) μU/mL. The mean or median levels of LDL-c, HDL-c and triglycerides were of 137.5 ± 37.9 mg/dL, 54.0 ± 15.0 mg/dL and 118.5(IQR:79.5-169.5) mg/dL respectively. In the multivariate linear regression model between the FT3 and LDL-c levels, we found that for each increase in a FT3 unit, the LDL-c values decreased on average 30.85 mg/dL(p < 0.01). We found no statistically significant associations in the other multivariate models of linear regression, among the other thyroid hormones and lipid markers. We found an inverse association between the FT3 and LDL-c values in women with chronic gynaecological symptoms.


Expression of histone acetyltransferase GCN5 and histone deacetylase 1 in the cultured mouse preimplantation embryos.
To investigate the possible mechanisms of the abnormal expression patterns of many genes in the embryos in vitro, the expression of histone acetyltransferase GCN5 and histone deacetylase 1 (HDAC1) were detected in mouse preimplantation embryos. For the in vitro group, the pronucleus embryos were obtained from superovulated mice, and cultured in vitro to get the two-cell, four-cell, eightcell, morula and blastocyst stages embryos. For the in vivo group, embryos at different stages were obtained from pregnant mice directly. Reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry were used to detect the mRNA and protein expression levels of GCN5 and HDAC1. Compared with the embryos in vivo, the expression levels of Gcn5 in the embryos in vitro significantly increased except those in four-cell embryos. The expression of Gcn5 in eight-cell embryos in vivo and in four-cell and eight-cell embryos in vitro was higher than those at other stages within the same group. Compared with the expressions of Hdac1 in embryo in vivo, only those at two-cell embryo in vitro showed decreased level. The expression of Hdac1 enhanced after two-cell embryo stage in vitro, but no difference showed in vivo. The protein expression of GCN5and HDAC1 in the embryo in vitro at every stage showed a lower level with the control of those in the embryos in vivo. Our studies indicated that in vitro culture could induce the expressed alteration of GCN5 and HDAC1, which might be related to the expression patterns of many other epigenetically regulated genes.


Brain acetylcholinesterase, acid phosphatase, and 2',3'-cyclic nucleotide-3'-phosphohydrolase and plasma butyrylcholinesterase activities in hens treated with a single dermal neurotoxic dose of S,S,S-tri-n-butyl phosphorotrithioate.
The changes in brain acetylcholinesterase (AChE), acid phosphatase (APase), and 2',3'-cyclic nucleotide-3'-phosphohydrolase (CNP), and plasma butyrylcholinesterase (BuChE) activities were investigated in hens treated with a single, dermal dose (100-1000 mg/kg) of S,S,S-tri-n-butyl phosphorotrithioate (DEF). Three control groups consisted of hens left untreated, given a single, dermal dose of 500 mg/kg tri-o-cresyl phosphate (TOCP, positive control for organophophorous compound-induced delayed neurotoxicity), or 10 mg/kg O,O-diethyl O-4-nitrophenyl phosphorothioate (parathion, negative control). Brain AChE activity, determined 28 days after application, was significantly inhibited in hens given 500-1,000 mg/kg DEF and in TOCP- and parathion-treated hens. In contrast, brain APase and CNP activities were significantly higher in all treatments as compared with those of the untreated hens. Parathion, however, caused the least increase in these enzymatic activities as compared to DEF or TOCP. A single, dermal dose of DEF or TOCP also caused an initial decrease in plasma BuChE activity with maximum depression of enzymatic activity observed 1 to 7 days after administration. This decrease was dose dependent and the enzymatic activity showed partial recovery with time. Hens treated with single, dermal doses of DEF, ranging from 250 to 1000 mg/kg, developed ataxia which progressed to paralysis in some hens. Histopathologic examination revealed axon and myelin degeneration of the spinal cord and peripheral nerves of some hens. The severity and frequency of the neuropathologic lesions were dose dependent. Neurologic dysfunctions and neuropathologic lesions seen in DEF-treated hens were similar to those exhibited in TOCP-treated hens. While parathion produced acute cholinergic effects, it did not cause delayed neurotoxicity. The changes in brain and plasma enzymes are discussed in relation to their role in the pathogenesis of DEF-induced delayed neurotoxicity.


Luteolin as a potential host-directed immunotherapy adjunct to isoniazid treatment of tuberculosis.
Tuberculosis (TB) remains a major health problem throughout the world with one third of the population latently infected and ~1.74 million deaths annually. Current therapy consists of multiple antibiotics and a lengthy treatment regimen, which is associated with risk for the generation of drug-resistant Mycobacterium tuberculosis variants. Therefore, alternate host directed strategies that can shorten treatment length and enhance anti-TB immunity during the treatment phase are urgently needed. Here, we show that Luteolin, a plant-derived hepatoprotective immunomodulator, when administered along with isoniazid as potential host directed therapy promotes anti-TB immunity, reduces the length of TB treatment and prevents disease relapse. Luteolin also enhances long-term anti-TB immunity by promoting central memory T cell responses. Furthermore, we found that Luteolin enhances the activities of natural killer and natural killer T cells, both of which exhibit antitubercular attributes. Therefore, the addition of Luteolin to conventional antibiotic therapy may provide a means to avoid the development of drug-resistance and to improve disease outcome.


Acute effects of different warm-up protocols with and without a weighted vest on jumping performance in athletic women.
The purpose of this study was to examine the acute effects of 3 different warm-up protocols with and without a weighted vest on vertical jump (VJ) and long jump (LJ) performance in athletic women. Sixteen subjects (19.7 +/- 1.4 years, 67.0 +/- 10.7 kg, 165.7 +/- 11.4 cm) participated in 3 testing sessions in random order on 3 nonconsecutive days. Prior to the testing of the VJ and LJ, the subjects performed 1 of the following 10-minute warm-up protocols: (a) low- to moderate-intensity stationary cycling followed by 4 lower-body static stretches (SS) (3 x 20 seconds); (b) 12 moderate- to high-intensity dynamic exercises (DY); and (c) the same 12 dynamic exercises with a weighted vest (10% of body mass) worn for the last 4 exercises (DYV). Analysis of the data revealed that VJ performance was significantly greater (p < 0.05) following DYV (43.9 +/- 6.7 cm) and DY (43.6 +/- 6.5 cm) as compared to SS (41.7 +/- 6.0 cm). Long jump performance was significantly greater (p < 0.05) following DYV (186.8 +/- 19.5 cm) as compared to DY (182.2 +/- 19.1 cm), which in turn was significantly greater (p < 0.05) than performance following SS (177.2 +/- 18.8 cm). Warm-up protocols that include dynamic exercise may be a viable method of enhancing jumping performance in athletic women as compared to stationary cycling and static stretching. In addition, these data suggest that it may be desirable for athletic women to perform dynamic exercises with a weighted vest on some movements prior to the performance of the long jump.


Pathological analysis of transmyocardial laser revascularization for acute myocardial ischemia.
Transmyocardial laser revascularization (TMLR) is an alternative surgical procedure for the patients with intractable coronary artery disease. Efficacy of the treatment has been established, however, the mechanism of TMLR is still controversial. In this study, we investigated the effect of TMLR on acute myocardial ischemia with pathological analysis. Under general anesthesia, the hearts of mongrel dogs were exposed. Then, the anterior descending branch of the left coronary artery was ligated to make the ischemic area on the left ventricle. Laser punctures were made 30 minutes after coronary ligation in the TMLR group (n = 5), and no further procedure was performed after coronary ligation in the AMI group (n = 5). One month after these operations, the hearts were extirpated for pathological studies. The avascular area and the viable area in the infarcted area were macroscopically separated by Evans blue dye and triphenyltetrazolium chloride (TTC) staining. Thickness of the left ventricular wall in the infarcted area was also measured and compared. Furthermore, all of the infarcted area and the lased area were microscopically examined with Masson's trichrome stain. The size of the infarcted area in the TMLR group was smaller than that in the AMI group. It was significantly different (p < 0.05) in the basal and apical regions. As a result, the ratio of the viable area by the avascular area was larger in the TMLR group than in the AMI group. It was significantly different (p < 0.05) in the apical region. In the basal region, the thickness of the left ventricle in the AMI group was thinner than that of untreated dogs (normal group: n = 5), and there was no difference between the normal group and the TMLR group. Whereas in the apical region, significant difference of the thickness was found among AMI, TMLR, and normal groups (p < 0.05). In conclusion, our study supported; 1) TMLR reduced overall infarcted size, and increased the viable area in the infarcted area, 2) TMLR prevented the thinning of the left ventricular wall.


Plasmids of enterotoxigenic Escherichia coli H10407: evidence for two heat-stable enterotoxin genes and a conjugal transfer system.
Three species of plasmids, associated with virulence and conjugal transfer, were identified in a clinically isolated enterotoxigenic Escherichia coli strain, H10407 (serotype O78:H11). pCS1, a non-self-transmissible plasmid species with a molecular weight of 62 X 10(6) and a 47 mol% guanine-plus-cytosine content, specified colonization factor antigen I and heat-stable enterotoxin (ST) production, as reported by others previously. A second non-self-transmissible plasmid species, designated pJY11, with a molecular weight of 42 X 10(6) and a 51 mol% guanine-plus-cytosine content, specified ST and heat-labile enterotoxin production and manifested T5/T6 phage restriction. The third plasmid species, pTRA1, also had a molecular weight of 42 X 10(6) and had a guanine-plus-cytosine content of 51 mol%; this species was self-transmissible and promoted transfer of both pCS1 and pJY11 to other bacterial cells. pCS1 may have originated from species of bacteria with a lower guanine-plus-cytosine content than E. coli. Finally, although demonstrating some heterogeneity with each other, both STs encoded by pCS1 and pJY11 belonged to the STa group.


Controllable Cleavage of C-N Bond-Based Fluorescent and Photoacoustic Dual-Modal Probes for the Detection of H2S in Living Mice.
Hydrogen sulfide (H2S) has been recognized to influence a wide range of physiological and pathological processes. Its underlying molecular events, however, are still poorly understood. An activatable H2S probe for photoacoustic (PA) imaging is desirable to further explore the role of H2S in vivo. Nevertheless, only a few activatable PA probes for H2S detection have been reported. In particular, examples of dual-modal H2S probes with the combined advantages of fluorescence (high sensitivity and resolution) and PA imaging (deep penetration) are very rare. Herein the controllable cleavage of the C-N bond in nitrobenzoxadiazole (NBD) amine derivatives by H2S is presented for the first time. The cleavage reactivity was found to be accelerated by the introduction of an electron-withdrawing group. Through this strategy, a series of fluorescent and PA dual-modal probes (1-3) were developed for H2S detection. Among them, probe 3 shows a high fluorescence on-off response rate (k2 = 4.04 M-1 s-1) and excellent selectivity for H2S over other biothiols. Moreover, probe 3 can also work as an activatable PA H2S probe because of the significant shift of its absorption peak from 468 to 532 nm in the H2S reaction. Importantly, probe 3 demonstrates its capability for fluorescence and PA imaging of H2S in living cells and mice. These results indicate that the controllable cleavage of the C-N bond can serve as an efficient strategy for designing fluorescent and PA dual-modal H2S probes.


Calcineurin is required for hyphal elongation during mating and haploid fruiting in Cryptococcus neoformans.
Cryptococcus neoformans is a fungal pathogen that causes meningitis in immunocompromised patients. Its growth is sensitive to the immunosuppressants FK506 and cyclosporin, which inhibit the Ca2+- calmodulin-activated protein phosphatase calcineurin. Calcineurin is required for growth at 37 degrees C and virulence of C.neoformans. We found that calcineurin is also required for mating. FK506 blocks mating of C.neoformans via FKBP12-dependent inhibition of calcineurin, and mutants lacking calcineurin are bilaterally sterile. Calcineurin is not essential for the initial fusion event, but is required for hyphal elongation and survival of the heterokaryon produced by cell fusion. It is also required for hyphal elongation in diploid strains and during asexual haploid fruiting of MATalpha cells in response to nitrogen limitation. Because mating and haploid fruiting produce infectious basidiospores, our studies suggest a second link between calcineurin and virulence of C.neoformans. Calcine urin regulates filamentation and 37 degrees C growth via distinct pathways. Together with studies revealing that calcineurin mediates neurite extension and neutrophil migration in mammals, our findings indicate that calcineurin plays a conserved role in the control of cell morphology.


Maternal and neonatal risk factors for childhood type 1 diabetes: a matched case-control study.
An interaction between genetic susceptibility and environmental factors is thought to be involved in the aetiology of type 1 diabetes. The aim of this study was to investigate maternal and neonatal risk factors for type 1 diabetes in children under 15 years old in Grampian, Scotland. A matched case-control study was conducted by record linkage. Cases (n = 361) were children born in Aberdeen Maternity Hospital from 1972 to 2002, inclusive, who developed type 1 diabetes, identified from the Scottish Study Group for the Care of Diabetes in the Young Register. Controls (n = 1083) were randomly selected from the Aberdeen Maternity Neonatal Databank, matched by year of birth. Exposure data were obtained from the Aberdeen Maternity Neonatal Databank. Conditional logistic regression was used to evaluate the association between various maternal and neonatal factors and the risk of type 1 diabetes. There was no evidence of statistically significant associations between type 1 diabetes and maternal age, maternal body mass index, previous abortions, pre-eclampsia, amniocentesis, maternal deprivation, use of syntocinon, mode of delivery, antepartum haemorrhage, baby's sex, gestational age at birth, birth order, birth weight, jaundice, phototherapy, breast feeding, admission to neonatal unit and Apgar score (P > 0.05). A significantly decreased risk of type 1 diabetes was observed in children whose mothers smoked at the booking appointment compared to those whose mothers did not, with an adjusted OR of 0.67, 95% CI (0.46, 0.99). This case-control study found limited evidence of a reduced risk of the development of type 1 diabetes in children whose mothers smoked, compared to children whose mothers did not. No evidence was found of a significant association between other maternal and neonatal factors and childhood type 1 diabetes.


Evidence for a revertant at the La locus in regenerating hypocotyl segments in tomato.
Leafy and leafless phenotypes were regenerated in vitro from hypocotyl segments of leafless forms (reduced and modified) of the homozygous lanceolate (La) mutant in tomato. Segregation of progeny of leafy regenerates into homozygous. mutant (La La), heterozygote (La La (+)) and normal (La (+) La (+)) indicates that cells forming the shoot apical meristems undergo a genetic reversion, and that the nutrient medium might be selecting for the heterozygote. Among the progeny of the regenerates is a true breeding, unlobed variant. Leaves of the variant are pinnately compound and the margins are entire. Opposite cotyledons followed in development by two simple leaves before the appearance of a pinnately compound leaf with an occasional lanceolate-shaped leaflet suggests that the unlobed variant is morphologically intermediate between La La (+) and La (+) La (+).


A multi-cycle signal amplification-mediated single quantum dot nanosensor for PIWI-interacting RNA detection.
We construct a single quantum dot-based nanosensor for piRNA detection based on ligation-mediated multi-cycle signal amplification. This nanosensor is homogenous, selective, and sensitive with a detection limit of 0.104 fM. Moreover, it can detect the endogenous piRNA level in different cell lines, and discriminate cancer tissues from normal tissues.


Dynamic switching of hole character and single photon polarization using the quantum confined Stark effect in quantum dot-in-dot structures.
The engineering of the three-dimensional (3D) heterostructure potential in GaAs/AlGaAs pyramidal quantum dot-in-dots (DiDs) provides control over the valence band symmetry and hence on the polarization of the emitted photons. We propose a technique for dynamic switching of hole character and photon polarization in DiDs by means of an applied electric field. The structural parameters required for producing this effect are discussed. Asymmetric DiDs are found to be particularly suitable for obtaining switching with fields smaller than 1 kV cm( - 1). The proposed device enables generation of single photons with dynamic control on the photon polarization, with potential applications in quantum information technology.


Attachment organization as a moderator of the link between friendship quality and adolescent delinquency.
This study examined attachment organization as a moderator of the link between the quality of the adolescents' current friendships and delinquent behavior. Data were gathered from a moderately at-risk sample of 71 ethnically and socioeconomically diverse adolescents. Results revealed a moderating effect of attachment organization (as assessed by the AAI) such that strong and supportive friendships were linked to lower levels of delinquency, but only when adolescents' attachment organization reflected an orientation toward heightened attention to attachment relationships (via preoccupation or via clear lack of dismissal of attachment). These results suggest that attachment organization plays an important role in delineating the conditions under which the qualities of social relationships are likely to be linked to important psychosocial outcomes.


2-Methoxyestradiol, an endogenous 17β-estradiol metabolite, inhibits microglial proliferation and activation via an estrogen receptor-independent mechanism.
17β-Estradiol (estradiol) inhibits microglia proliferation. 2-Methoxyestradiol (2-ME) is an endogenous metabolite of estradiol with little affinity for estrogen receptors (ERs). We hypothesize that 2-ME inhibits microglial proliferation and activation and contributes to estradiol's inhibitory effects on microglia. We compared the effects of estradiol, 2-hydroxyestradiol [2-OE; estradiol metabolite produced by cytochrome P450 (CYP450)], and 2-ME [formed by catechol-O-methyltransferase (COMT) acting upon 2-OE] on microglial (BV2 cells) DNA synthesis, cell proliferation, activation, and phagocytosis. 2-ME and 2-OE were approximately three- and 10-fold, respectively, more potent than estradiol in inhibiting microglia DNA synthesis. The antimitogenic effects of estradiol were reduced by pharmacological inhibitors of CYP450 and COMT. Inhibition of COMT blocked the conversion of 2-OE to 2-ME and the antimitogenic effects of 2-OE but not 2-ME. Microglia expressed ERβ and GPR30 but not ERα. 2,3-Bis(4-hydroxyphenyl)-propionitrile (ERβ agonist), but not 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (ERα agonist) or G1 (GPR30 agonist), inhibited microglial proliferation. The antiproliferative effects of estradiol, but not 2-OE or 2-ME, were partially reversed by ICI-182,780 (ERα/β antagonist) but not by 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole (ERα antagonist) or G15 (GPR30 antagonist). Lipopolysaccharide increased microglia iNOS and COX-2 expression and phagocytosing activity of microglia; these effects were inhibited by 2-ME. We conclude that in microglia, 2-ME inhibits proliferation, proinflammatory responses, and phagocytosis. 2-ME partially mediates the effects of estradiol via ER-independent mechanisms involving sequential metabolism of estradiol to 2-OE and 2-ME. 2-ME could be of potential therapeutic use in postischemic stroke injuries. Interindividual differences in estradiol metabolism might affect the individual's ability to recover from stroke.


Control of the magnetism and magnetic anisotropy of a single-molecule magnet with an electric field.
Through systematic density functional calculations, the mechanism of the substrate induced spin reorientation transition in FePc/O-Cu(110) is explained in terms of charge transfer and rearrangement of Fe-3d orbitals. Moreover, we find giant magnetoelectric effects in this system, manifested by the sensitive dependence of its magnetic moment and magnetic anisotropy energy on an external electric field. In particular, the direction of magnetization of FePc/O-Cu(110) is switchable between in-plane and perpendicular axes, simply by applying an external electric field of 0.5 eV/Å along the surface normal.


Antimetastatic and immunomodulating effect of water extracts from various mushrooms.
This experiment was conducted to evaluate inhibitory effects against lung metastasis and promotion of splenocytes by water extracts from various mushrooms including Armillaria mellea, Grifola frondosa, Garnoderma frondosa, Codyceps militaris, Hericium erinaceus, Coriolus versicolor, Agaricus Blazei with Lycium Chinense Miller (known as M8). Analysis of carbohydrate using HPTLC showed that beta-glucan and pachyman were some of the major components of M8. Oral administration of M8 resulted in a dose-dependent tendency to inhibit lung metastasis after intravenous injection of colon26-L5 cells. Treatment with M8 resulted in a significant increase of T cell and B cell mitogenic stimuli. The population of CD3, CD19, CD4, and CD8 positive cells increased in a dose dependent manner of M8 administration. However, no significant results were obtained from the population of Mac-1 and NK1.1 positive cells. Oral administration of M8 resulted in the increased production of IFN-gamma and IL-4 by splenocytes stimulated with Con A compared with untreated controls. These results show that M8 has antitumor activities which may be useful as an antimetastatic agent.


Antimicrobial resistance profiles of Campylobacter jejuni isolates from wild birds in Sweden.
In order to determine the occurrence and frequency of resistant strains of the bacterium Campylobacter jejuni and to establish baseline MICs in isolates from an environmental reservoir, the resistance profiles of 10 antimicrobial substances were determined for 137 C. jejuni isolates from wild birds in Sweden. Observed MICs were generally low, with only low to moderate incidence of resistance to the tested compounds. One isolate, however, was resistant to nalidixic acid and ciprofloxacin, indicating that quinolone-resistant genotypes of C. jejuni have the potential to spread to wild bird hosts.


Blunt duodenal injuries in children.
Duodenal injury secondary to blunt trauma continues to pose a diagnostic challenge. The purpose of this study is to evaluate the cause, radiologic findings, and management of duodenal injuries from a Level I pediatric trauma center. A retrospective review of our trauma registry from 1990 to 2000 identified 24 children with blunt duodenal injuries. Clinical and radiographic findings and management strategies were assessed and compared in children with duodenal hematomas and perforations. The majority of injuries were secondary to motor vehicle collisions. Pancreatic (42%) injuries were most commonly associated with duodenal trauma. With the exception of hematocrit level, initial clinical and laboratory findings were similar between groups. Of the 19 (79%) with duodenal hematomas, computed tomographic (CT) scan alone identified 15 and the remaining 4 were confirmed by duodenography. Incision and drainage of a hematoma was performed in two children. Duodenal perforation was identified in five (21%) children. Extraluminal air by CT scan was present in three of five children with perforation; however, none had extravasation of contrast. Four (80%) children with perforations underwent primary repair and one (20%) required segmental resection. CT scanning remains a valuable tool in the diagnosis of blunt duodenal injuries in children. Although extravasation of oral contrast was not beneficial, the presence of extraluminal air was highly suggestive of perforation. The vast majority of hematomas were successfully managed nonoperatively, and duodenorrhaphy was safe and effective therapy for perforations.


Next generation sequencing for clinical diagnostics-principles and application to targeted resequencing for hypertrophic cardiomyopathy: a paper from the 2009 William Beaumont Hospital Symposium on Molecular Pathology.
During the past five years, new high-throughput DNA sequencing technologies have emerged; these technologies are collectively referred to as next generation sequencing (NGS). By virtue of sequencing clonally amplified DNA templates or single DNA molecules in a massively parallel fashion in a flow cell, NGS provides both qualitative and quantitative sequence data. This combination of information has made NGS the technology of choice for complex genetic analyses that were previously either technically infeasible or cost prohibitive. As a result, NGS has had a fundamental and broad impact on many facets of biomedical research. In contrast, the dissemination of NGS into the clinical diagnostic realm is in its early stages. Though NGS is powerful and can be envisioned to have multiple applications in clinical diagnostics, the technology is currently complex. Successful adoption of NGS into the clinical laboratory will require expertise in both molecular biology techniques and bioinformatics. The current report presents principles that underlie NGS including sequencing library preparation, sequencing chemistries, and an introduction to NGS data analysis. These concepts are subsequently further illustrated by showing representative results from a case study using NGS for targeted resequencing of genes implicated in hypertrophic cardiomyopathy.


[Femoral head epiphyseolysis].
Slipped capital femoral epiphysis could be regarded as exceeding of a physiological process in puberty in which overweight of the patients seems to be the essential factor. Early clinical and radiological diagnosis are important to perform simple surgical procedures stopping further lysis and avoiding later osteoarthritis. Fixation of the femoral epiphysis with K.-wires are emphasized worldwide because of the lower complication rate. In case of severe slip osteotomies for realignment are more problematic. Long term follow-up studies have shown poor results mostly because of chondrolysis and femoral head necrosis in a high percentage. The demand on renunciation of realignment procedures in s.c.f.e. however, can't be supported. In our own patients, recently followed up, realignment osteotomies were without greater problems with no complications like chondrolysis or head necrosis. Stabile fixation of osteotomies allowed early mobilisation just after operation and may be one reason that chondrolysis didn't exist in our patient group. Considering our knowledge today therapeutic procedure of slipped capital femoral epiphysis is described.


Informal caregivers of people with dementia: problems, needs and support in the initial stage and in subsequent stages of dementia: a questionnaire survey.
The ageing of the population is expected to lead to an increase in the prevalence of dementia. Providing support to informal caregivers is essential to promote their wellbeing and prevent serious caregiver burden. The aim of the study is to investigate whether differences occur between the initial and later stages of dementia in terms of (1) problems experienced by informal caregivers in the provision of care, (2) use of professional support by persons with dementia, (3) informal caregivers' needs for additional professional support. The data were collected within the framework of the Dutch National Dementia Program, which was instigated in 2005 by the Dutch Ministry of Health, Welfare and Sport to improve integrated care for people with dementia and their informal caregivers. This paper is based on data of a questionnaire survey among 1494 informal caregivers, collected between September 2007 and December 2008. Most informal caregivers (98-99%) experienced problems in caring for a person with dementia, irrespective of the stage of the illness process. In later stages, informal caregivers more often experienced problems in their social networks. Most dementia patients (87-94%) received ambulatory professional support. Since informal caregivers indicate a need for additional professional support in all stages of dementia, professional support should be provided during the entire illness process. Informal caregivers need advice on how to cope with symptoms of dementia, how to deal with behavior problems and receive more information about (early and advanced stages of) dementia and the supply of support.


Rationale for combination therapy as initial treatment for hypertension.
Recent hypertension guidelines recommend initiating antihypertensive therapy with a combination of two or more agents in patients whose blood pressure exceeds their appropriate blood pressure goal by 20/10 mm Hg. This recommendation is based on the knowledge that the majority of patients with blood pressures of this magnitude will not achieve sufficient blood pressure reduction with monotherapy. Further, compared with high-dose monotherapy, combination therapy is often associated with fewer adverse effects and, for this reason, may improve patient adherence. Bringing patients to blood pressure goal quickly is likely to improve clinical outcomes. This article discusses the rationale for using combination antihypertensive therapy as initial therapy for high blood pressure in selected patients and reviews data from a study of 364 high-risk patients with Stage 2 hypertension in which a fixed-dose combination product (amlodipine besylate/benazepril HCl) proved more successful as initial therapy than high-dose monotherapy (amlodipine besylate) in reducing blood pressure.


An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia.
Hippocampal atrophy has been described in postmortem and magnetic resonance imaging studies of schizophrenia. The specificity of this finding to schizophrenia remains to be determined. The neuropathology of bipolar disorder is understudied, and temporal lobe structures have only recently been evaluated. Twenty-four bipolar, 20 schizophrenic, and 18 normal comparison subjects were evaluated using magnetic resonance brain imaging. Image data were acquired using a three-dimensional spoiled GRASS sequence, and brain images were reformatted in three planes. Temporal lobe structures including the amygdala, hippocampus, parahippocampus, and total temporal lobe were measured to obtain volumes for each structure in the three subject groups. Severity of symptoms in both patient groups was assessed at the time the magnetic resonance images were obtained. Hippocampal volumes were significantly smaller in the schizophrenic group than in both bipolar and normal comparison subjects. Further, amygdala volumes were significantly larger in the bipolar group than in both schizophrenic and normal comparison subjects. The results suggest differences in affected limbic structures in patients with schizophrenia and bipolar disorder. These specific neuroanatomic abnormalities may shed light on the underlying pathophysiology and presentation of the two disorders.


Testosterone treatment in the aging male: myth or reality?
The definition of late onset hypogonadism in the aging male is controversially debated, and according to the latest literature consists of at least three especially sexual symptoms such as loss of morning erection, low sexual desire and erectile dysfunction as well as a total testosterone <8-11 nmol/l. Testosterone replacement therapy in the aging male has been shown to have a beneficial effect on muscle and fat mass as well as on bone mineral density, with more conflicting effects observed on muscle strength, sexual function, mood and quality of life. The prescriptions for testosterone products for the aging male increased by over 170% in the previous five years. Furthermore, there is a lot of epidemiological data showing an inverse relationship between testosterone levels and obesity, insulin resistance, the metabolic syndrome and type 2 diabetes mellitus. However, only few small randomised placebo-controlled studies have investigated the effect of testosterone replacement therapy on insulin resistance and HbA1c levels, with controversial results. Importantly, so far the long-term safety and efficacy of testosterone replacement therapy has not been established. Although until now no clear evidence has been found that testosterone replacement therapy has a causative role in prostate cancer or indeed in changes of the biology of the prostate, in a recent meta-analysis a 4-fold increased risk of prostate-associated event rates in testosterone treated elderly men sounds a note of caution. Also the risk for cardiovascular events is still not clear and caution is warranted especially in elderly men with cardiovascular disease and limited mobility. In summary, the actual available evidence of long-term risks and outcome of testosterone replacement therapy is still very limited and carefully designed placebo-controlled trials of testosterone administration to assess the risks and benefits of such a therapy are required. Until then, testosterone treatment in elderly men should be restricted to elderly men with clearly low testosterone levels in the presence of clinical symptoms, and the advantages and disadvantages need to be accurately weighted. A careful monitoring of potential side effects is necessary.


α-Aminoazoles/azines: key reaction partners for multicomponent reactions.
Aromatic α-aminoazaheterocycles are the focus of significant investigations and exploration by researchers owing to their key role in diverse biological and physiological processes. The existence of their derivatives in numerous drugs and alkaloids is due to their heterocyclic nitrogenous nature. Therefore, the synthesis of a structurally diverse range of their derivatives through simple and convenient methods represents a vital field of synthetic organic chemistry. Multicomponent reactions (MCRs) provide a platform to introduce desirable structure diversity and complexity into a molecule in a single operation with a significant reduction in the use of harmful organic waste, and hence have attracted particular attention as an excellent tool to access these derivatives. This review covers the advances made from 2010 to the beginning of 2020 in terms of the utilization of α-aminoazaheterocycles as synthetic precursors in MCRs.


Intravenous immunoglobulin for Guillain-Barré syndrome.
Guillain-Barré syndrome (GBS) is an acute, paralysing, inflammatory peripheral nerve disease. Intravenous immunoglobulin (IVIg) is beneficial in other autoimmune diseases. This is an update of a review first published in 2001 and previously updated in 2003, 2005, 2007 and 2010. Other Cochrane systematic reviews have shown that plasma exchange (PE) significantly hastens recovery in GBS compared with supportive treatment alone, and that corticosteroids alone are ineffective. To determine the efficacy of IVIg for GBS. We searched the Cochrane Neuromuscular Disease Group Specialized Register (15 August 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (January 1966 to August 2011) and EMBASE (January 1980 to August 2011). We checked the bibliographies in reports of the randomised trials and contacted the authors and other experts in the field to identify additional published or unpublished data. Randomised and quasi-randomised trials of IVIg compared with no treatment, placebo treatment, PE, or other immunomodulatory treatments in children and adults with GBS of all degrees of severity. We also included trials in which IVIg was added to another treatment. Two authors independently selected papers, extracted data and assessed quality. We collected data about adverse events from the included trials. In this review, seven trials with a variable risk of bias compared IVIg with PE in 623 severely affected participants. In five trials with 536 participants for whom the outcome was available, the mean difference (MD) of change in a seven-grade disability scale after four weeks was not significantly different between the two treatments: MD of 0.02 of a grade more improvement in the intravenous immunoglobulin than the plasma exchange group; 95% confidence interval (CI) 0.25 to -0.20. There were also no statistically significant differences in the other measures considered. Three studies including a total of 75 children suggested that IVIg significantly hastens recovery compared with supportive care.In one trial involving 249 participants comparing PE followed by IVIg with PE alone, the mean grade improvement was 0.2 (95% CI -0.14 to 0.54) more in the combined treatment group than in the PE alone group; not clinically significantly different, but not excluding the possibility of significant extra benefit. Another trial with 37 participants comparing immunoabsorption followed by IVIg with immunoabsorption alone did not reveal significant extra benefit from the combined treatment.Adverse events were not significantly more frequent with either treatment, but IVIg is significantly much more likely to be completed than PE.Small trials in children showed a trend towards more improvement with high-dose compared with low-dose IVIg, and no significant difference when the standard dose was given over two days rather than five days. A previous Cochrane review has shown that PE hastens recovery compared with supportive treatment alone. There are no adequate comparisons of IVIg with placebo in adults, but this review provides moderate quality evidence that, in severe disease, IVIg started within two weeks from onset hastens recovery as much as PE. Adverse events were not significantly more frequent with either treatment but IVIg is significantly much more likely to be completed than PE. Also, according to moderate quality evidence, giving IVIg after PE did not confer significant extra benefit. In children, according to low quality evidence, IVIg probably hastens recovery compared with supportive care alone. More research is needed in mild disease and in patients whose treatment starts more than two weeks after onset. Dose-ranging studies are also needed.


A review of the health effects of ingested asbestos.
Occupational studies indicate that a human health hazard may exist for ingested asbestos since the death rates due to digestive system cancers are elevated in asbestos workers. This finding may be related to the swallowing of asbestos that was inhaled and cleared from the respiratory system via the respiratory clearance mechanism. Published animal ingestion experiments have serious shortcomings in their design and execution which make their interpretation very difficult. Animal ingestion and human autopsy studies suggest that asbestos fibers may penetrate the digestive tract and migrate to other locations in the body.


Effectiveness of Lusutrombopag in Patients with Mild to Moderate Thrombocytopenia.
Thrombocytopenia is a common complication among patients with chronic liver disease (CLD). To increase platelet counts, lusutrombopag, a small-molecule, second-generation thrombopoietin receptor agonist, was developed in September 2015. Lusutrombopag is mainly used in patients with platelet counts <50,000/µL. However, its usefulness in patients with platelet counts ≥50,000/µL remains unknown. We studied the effectiveness of lusutrombopag administration in patients with platelet counts of ≥50,000/µL. We evaluated 36 patients who received lusutrombopag for CLD. Changes in platelet counts were evaluated. A treatment response was defined as an increasing platelet count ≥20,000/µL from baseline after drug administration. The differences related to these changes between platelet counts ≥50,000 and <50,000/µL were evaluated. Of the patients, 25 had platelet counts ≥50,000/µL. The increase in platelet count and the date in which it reached a maximum did not significantly differ between the groups. The effectiveness of lusutrombopag did not significantly differ between the groups. In both groups, no adverse reaction was observed during lusutrombopag administration. In this study, we showed the effectiveness of lusutrombopag, which had no complications. This study is the first to report that the effectiveness of lusutrombopag was the same for patients with platelet counts ≥50,000/µL and <50,000/µL.


Pioneer saturn infrared radiometer: preliminary results.
The effective temperature of Saturn, 94.4 + 3 K, implies a total emission greater than two times the absorbed sunlight. The infrared data alone give an atmospheric abundance of H(2) relative to H(2) + He of 0.85 +/- 0.15. Comparison of infrared and radio occultation data will give a more precise estimate. Temperature at the 1-bar level is 137 to 140 K, and 2.5 K differences exist between belts and zones up to the 0.06-bar level. Ring temperatures range from 60 to 70 K on the south (illuminated) side and from < 60 to 67 K in the planet's shadow. The average temperature of the north (unilluminated) side is approximately 55 K. Titan's 45-micrometer brightness temperature is 80 +/- 10 K.


Review: Markers and proxies to monitor ruminal function and feed efficiency in young ruminants.
Developing the rumen's capacity to utilise recalcitrant and low-value feed resources is important for ruminant production systems. Early-life nutrition and management practices have been shown to influence development of the rumen in young animals with long-term consequences on their performance. Therefore, there has been increasing interest to understand ruminal development and function in young ruminants to improve feed efficiency, health, welfare, and performance of both young and adult ruminants. However, due to the small size, rapid morphological changes and low initial microbial populations of the rumen, it is difficult to study ruminal function in young ruminants without major invasive approaches or slaughter studies. In this review, we discuss the usefulness of a range of proxies and markers to monitor ruminal function and nitrogen use efficiency (a major part of feed efficiency) in young ruminants. Breath sulphide and methane emissions showed the greatest potential as simple markers of a developing microbiota in young ruminants. However, there is only limited evidence for robust indicators of feed efficiency at this stage. The use of nitrogen isotopic discrimination based on plasma samples appeared to be the most promising proxy for feed efficiency in young ruminants. More research is needed to explore and refine potential proxies and markers to indicate ruminal function and feed efficiency in young ruminants, particularly for neonatal ruminants.


Platelet activation and secretion in patients with major depression, thoracic aortic atherosclerosis, or renal dialysis treatment.
Relatively little is known concerning the magnitude of alterations of platelet activation and secretion markers of patients with major depression when compared to patients at increased risk for, or with current, clinically significant atherosclerosis. Markers of in vivo platelet stimulation and secretion were measured under basal conditions in normal comparison subjects (n = 12) and three patient groups: patients diagnosed with DSM-IV major depression (n = 15), dialysis-dependent patients (n = 12), and patients with severe thoracic aortic atherosclerosis (n = 10). In comparison to normal comparison subjects, depressed patients and patients with thoracic aortic atherosclerosis exhibited the greatest platelet stimulation as detected by increased anti-LIBS platelet binding. Dialysis-dependent patients exhibited the highest plasma concentrations of the renally-excreted platelet-specific secretion protein, beta-thromboglobulin. This study extends previous observations of increased platelet activation in patients with major depression and documents similar alterations in patients with transesophageal echocardiography (TEE)-documented thoracic aortic atherosclerosis. Future studies will determine whether the magnitude of platelet stimulation and secretion in patients with comorbid depression and atherosclerotic aortic disease is greater than that observed in nondepressed patients with atherosclerotic aortic disease or major depression alone. These findings provide further evidence for either increased platelet activation and/or intrinsic heightened platelet reactivity as one of the biological substrates underlying the increased risk of depressed patients for cardiovascular disease.


Preparation of Phase Change Microcapsules with the Enhanced Photothermal Performance.
The performance of solar-thermal conversion systems can be improved by incorporation of encapsulated phase change materials. In this study, for the first time, CrodathermTM 60 as a phase change material (PCM) was successfully encapsulated within polyurea as the shell supporting material. While preparing the slurry samples, graphite nanoplatelet (GNP) sheets were also incorporated to enhance the thermal and photothermal properties of the prepared materials. The morphology and chemical properties of these capsules were characterized by scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectrum, respectively. The results show the spherical-like and core-shell structure of capsules with an average diameter size of 3.34 μm. No chemical interaction was observed between the core and the supporting materials. The thermal characteristics of the microencapsulated PCMs (MEPCMs), analyzed by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA), indicate that the prepared samples with 0.1 weight percentage of GNP possess the latent heat of 95.5 J/g at the phase transition temperature of about 64 °C. Analyzing the rheological properties of the prepared slurry with 16 wt % of MEPCMs proves that the prepared material meet the requirements given by the heat transfer applications. The thermal storage capacity, good thermal stability, and improved photothermal performance of the prepared material make it a potential candidate for using in direct absorption solar thermal applications.


Differential expression of N- and B-cadherin during lens development.
To analyze the dynamics of N- and B-cadherin cell adhesion molecule expression and cytoskeletal interaction during embryonic chick lens development. Localization of N- and B-cadherin, F-actin, and connexin 56 were determined by immunohistochemistry of developing lenses or immunocytochemistry of differentiating primary lens cultures. Biochemical analysis of cytoskeletal linkage of N- or B-cadherin was assessed by differential detergent extraction, electrophoresis, and immunoblotting. The results indicate that although both cadherins are expressed throughout lens development, N-cadherin expression detected was similar in both lens epithelial and fiber cells, whereas B-cadherin was preferentially localized to the lens fiber cells. During differentiation, both cadherins become increasingly associated with the lens cytoskeleton, as indicated biochemically by a transition from largely Triton X-100-soluble to Triton X-100-insoluble pools and immunocytologically by cadherin localization to cell-cell borders and colocalization with the actin cytoskeleton. Although a significant fraction of N-cadherin remains Triton X-100-soluble as the lens cells differentiate, B-cadherin becomes resistant to extraction by both Triton X-100 as well as RIPA buffers. As detected immunocytochemically in lens cell cultures, the temporal localization of N-cadherin to cell-cell interfaces precedes that of B-cadherin. Furthermore, temporal localization of B-cadherin, as opposed to N-cadherin, to cell-cell borders more closely parallels that of connexin 56 in vitro as well as in vivo. CONCLUSIONS; These results suggest that while both N- and B-cadherin are expressed during lens cell differentiation, both their patterns of expression as well as their cytoskeletal association differ between epithelial and fiber cells.


Identification of sex-specific thresholds for accumulation of visceral adipose tissue in adults.
The purpose of this study was to measure the linearity of visceral adipose tissue (VAT) accumulation with measures of total body adiposity to determine whether a threshold exists and to explore the association with cardiometabolic risk factors in adults. Using a cross-sectional design, data were obtained from 723 adults (324 females) age 19-47 years. Body mass index ranged from 15 to 52 kg/m(2) . Segmented linear regression was used to identify sex-specific percent body fat thresholds at which VAT slope changes. Linear regression measured the association of VAT mass, total fat mass, and subcutaneous fat with cardiometabolic risk factors above and below each threshold. Adiposity thresholds were identified at 23.4% body fat in males and 38.3% body fat in females beyond which the slope of VAT per unit of percent body fat increased to strongly positive. Males and females above these adiposity thresholds had significant dyslipidemia (P<0.001), increased insulin resistance (P<0.001), and higher fat mass across all depots. From these cross-sectional data, the following were inferred: the accumulation of VAT mass is not linear with increasing adiposity; increases in visceral accumulation above threshold are associated with decreased insulin sensitivity and cardiovascular risk in males and females independent of total body fat.


Comparative analysis of dermatoglyphic traits in Albanian and Turkish population living in Kosovo.
The aim of the study was to compare quantitative dermatoglyphic traits of two ethnic groups with different origin and customs, living on the same territory. The dermatoglyphic prints were collected from 800 inhabitants of the Dukagjin valley in southwest Kosovo, of Albanian (400) and Turkish (400) ethnic origin. The quantitative analysis comprised the number of ridges and triradii on the fingers, and the number of ridges in the interdigital areas on the palm (a-b, b-c, and c-d) as well as the size of the atd angle. The statistical analysis showed significant differences between the Albanian and the Turkish males for two fingers and pattern intensity index left, and on palms for a-b rc and c-d rc on both hands and b-c re on the left hand, and between females for six fingers and almost all palmar traits. Significant inter-population variations were observed for most palmar areas in both sexes but more pronouncedly in females. The differences found between the examined population groups show that admixture between Albanian and Turkish population in Kosovo has been small, and the Turks have retained their ethnic identity for several centuries.


The Genetic Determinants of Axial Length: From Microphthalmia to High Myopia in Childhood.
The axial length of the eye is critical for normal visual function by enabling light to precisely focus on the retina. The mean axial length of the adult human eye is 23.5 mm, but the molecular mechanisms regulating ocular axial length remain poorly understood. Underdevelopment can lead to microphthalmia (defined as a small eye with an axial length of less than 19 mm at 1 year of age or less than 21 mm in adulthood) within the first trimester of pregnancy. However, continued overgrowth can lead to axial high myopia (an enlarged eye with an axial length of 26.5 mm or more) at any age. Both conditions show high genetic and phenotypic heterogeneity associated with significant visual morbidity worldwide. More than 90 genes can contribute to microphthalmia, and several hundred genes are associated with myopia, yet diagnostic yields are low. Crucially, the genetic pathways underpinning the specification of eye size are only now being discovered, with evidence suggesting that shared molecular pathways regulate under- or overgrowth of the eye. Improving our mechanistic understanding of axial length determination will help better inform us of genotype-phenotype correlations in both microphthalmia and myopia, dissect gene-environment interactions in myopia, and develop postnatal therapies that may influence overall eye growth.


Integrated extraction and purification of total bioactive flavonoids from Toona sinensis leaves.
An integrated procedure was developed to extract and purify total flavonoids from Toona sinensis leaves for the first time, in which pressurized liquid extraction was performed in tandem with HPD100 macroporous resin column. Consequently, the total flavonoids can be extracted using 10% EtOH, and the recovery and purity of total flavonoids was 71.05% and 66.60%. Moreover, products of high quality were obtained in an environmentally friendly process with lower consumption of time and solvent. The results demonstrated that the integrated extraction-adsorption procedure was an efficient process for the preparation of total bioactive flavonoids from Toona sinensis leaves.


Genetic loci inherited from hens lacking maternal behaviour both inhibit and paradoxically promote this behaviour.
A major step towards the success of chickens as a domesticated species was the separation between maternal care and reproduction. Artificial incubation replaced the natural maternal behaviour of incubation and, thus, in certain breeds, it became possible to breed chickens with persistent egg production and no incubation behaviour; a typical example is the White Leghorn strain. Conversely, some strains, such as the Silkie breed, are prized for their maternal behaviour and their willingness to incubate eggs. This is often colloquially known as broodiness. Using an F2 linkage mapping approach and a cross between White Leghorn and Silkie chicken breeds, we have mapped, for the first time, genetic loci that affect maternal behaviour on chromosomes 1, 5, 8, 13, 18 and 19 and linkage group E22C19W28. Paradoxically, heterozygous and White Leghorn homozygous genotypes were associated with an increased incidence of incubation behaviour, which exceeded that of the Silkie homozygotes for most loci. In such cases, it is likely that the loci involved are associated with increased egg production. Increased egg production increases the probability of incubation behaviour occurring because egg laying must precede incubation. For the loci on chromosomes 8 and 1, alleles from the Silkie breed promote incubation behaviour and influence maternal behaviour (these explain 12 and 26% of the phenotypic difference between the two founder breeds, respectively). The over-dominant locus on chromosome 5 coincides with the strongest selective sweep reported in chickens and together with the loci on chromosomes 1 and 8, they include genes of the thyrotrophic axis. This suggests that thyroid hormones may play a critical role in the loss of incubation behaviour and the improved egg laying behaviour of the White Leghorn breed. Our findings support the view that loss of maternal incubation behaviour in the White Leghorn breed is the result of selection for fertility and egg laying persistency and against maternal incubation behaviour.


Genome architecture and stability in the Saccharomyces cerevisiae knockout collection.
Despite major progress in defining the functional roles of genes, a complete understanding of their influences is far from being realized, even in relatively simple organisms. A major milestone in this direction arose via the completion of the yeast Saccharomyces cerevisiae gene-knockout collection (YKOC), which has enabled high-throughput reverse genetics, phenotypic screenings and analyses of synthetic-genetic interactions1-3. Ensuing experimental work has also highlighted some inconsistencies and mistakes in the YKOC, or genome instability events that rebalance the effects of specific knockouts4-6, but a complete overview of these is lacking. The identification and analysis of genes that are required for maintaining genomic stability have traditionally relied on reporter assays and on the study of deletions of individual genes, but whole-genome-sequencing technologies now enable-in principle-the direct observation of genome instability globally and at scale. To exploit this opportunity, we sequenced the whole genomes of nearly all of the 4,732 strains comprising the homozygous diploid YKOC. Here, by extracting information on copy-number variation of tandem and interspersed repetitive DNA elements, we describe-for almost every single non-essential gene-the genomic alterations that are induced by its loss. Analysis of this dataset reveals genes that affect the maintenance of various genomic elements, highlights cross-talks between nuclear and mitochondrial genome stability, and shows how strains have genetically adapted to life in the absence of individual non-essential genes.


Micelle stacking in micellar electrokinetic chromatography.
In order to understand the role of stacked micelles in sample preconcentration, it is necessary to understand the factors that contribute to the micelle stacking phenomenon. Various MEKC background electrolyte (BGE) solutions were prepared in the presence of Sudan III in order to monitor the micelle stacking phenomenon in the anionic sodium dodecyl sulfate and sodium cholate micelle systems. The data show that micelle stacking is a dynamic process that is strongly dependent upon the relative conductivities of the sample matrix and BGE, the relative column length of the sample plug, and the mobilities of the ions involved in the stacking process regardless of electric field conditions (i.e., field-amplified stacking, sweeping, or high-salt stacking). Conditions under which micelle stacking can be expected to occur are presented, and the extent of micelle stacking is quantified. The micelle stacking phenomenon is correlated to the separation performance of a series of neutral alkaloids. It is shown that neutral analytes migrate rapidly through the evolving stacked micelle region in the initial moments of the separation. As a consequence of this transient interaction, analytes with small retention factors spend less time in the stacked micelle region and experience lower stacked micelle concentrations than analytes with large retention factors that spend more time in the growing stacked micelle region. It is also demonstrated that the extent of analyte enrichment generally increases with injection length, by facilitating greater interaction time with stacked micelles; however, enrichment will eventually plateau with increasing injection length as a function of an analyte's affinity for the micelle. Finally, it is shown that, in contrast to conventional wisdom, a range of long injection plugs exist where separation efficiency can be dramatically improved due to analyte interaction with an actively growing stacked micelle region.


Detection of Low Copy Number Integrated Viral DNA Formed by In Vitro Hepatitis B Infection.
Hepatitis B Virus (HBV) is a common blood-borne pathogen causing liver cancer and liver cirrhosis resulting from chronic infection. The virus generally replicates through an episomal DNA intermediate; however, integration of HBV DNA fragments into the host genome has been observed, even though this form is not necessary for viral replication. The exact purpose, timing, and mechanism(s) by which HBV DNA integration occurs is not yet clear, but recent data show that it occurs very early after infection. Here, the in vitro generation and detection of HBV DNA integrations are described in detail. Our protocol specifically amplifies single copies of virus-cell DNA integrations and allows both absolute quantification and single-base pair resolution of the junction sequence. This technique has been applied to various HBV-susceptible cell types (including primary human hepatocytes), to various HBV mutants, and in conjunction with various drug exposures. We foresee this technique becoming a key assay to determine the underlying molecular mechanisms of this clinically relevant phenomenon.


The European Medicines Agency Review of Gilteritinib (Xospata) for the Treatment of Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia with an FLT3 Mutation.
On October 24, 2019, a marketing authorization valid through the European Union (EU) was issued for gilteritinib monotherapy for adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an Fms-like tyrosine kinase 3 (FLT3) mutation. Gilteritinib inhibits FLT3 receptor signaling and proliferation in cells exogenously expressing FLT3 including FLT3 internal tandem duplication (ITD), FLT3 D835Y, and FLT3 ITD D835Y, and it induced apoptosis in leukemic cells expressing FLT3 ITD. The recommended starting dose of gilteritinib is 120 mg (three 40 mg tablets) once daily. Gilteritinib was evaluated in one, phase III, open-label, multicenter, randomized study of gilteritinib (n = 247, gilteritinib arm) versus salvage chemotherapy (n = 124, salvage chemotherapy arm) in patients with relapsed or refractory AML with FLT3 mutation. Overall survival (OS) was statistically significantly different between the two groups with a median OS of 9.3 months in the gilteritinib arm compared with 5.6 months for salvage chemotherapy (hazard ratio, 0.637; 95% confidence interval, 0.490-0.830; p = .0004 one-sided log-rank test). The most common adverse reactions with gilteritinib treatment were blood creatine phosphokinase increase, alanine aminotransferase increase, aspartate aminotransferase increase, blood alkaline phosphatase increase, diarrhea, fatigue, nausea, constipation, cough, peripheral edema, dyspnea, dizziness, hypotension, pain in extremity, asthenia, arthralgia, and myalgia. The objective of this article is to summarize the scientific review of the application leading to regulatory approval in the EU. IMPLICATIONS FOR PRACTICE: Xospata was approved in the European Union as monotherapy for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an Fms-like tyrosine kinase 3 (FLT3) mutation. Gilteritinib resulted in a clinically meaningful and statistically significant improvement of overall survival compared with salvage chemotherapy. At the time of the marketing authorization of gilteritinib, there were no approved standard therapies specifically for adult patients diagnosed with relapsed or refractory AML with FLT3 mutation. In terms of safety, the overall accepted safety profile was considered manageable.


The Occurrence of Diseases and Related Factors in a Center for Asylum Seekers in Italy.
Italy is the main recipient of asylum seekers in the European region, and Sicily is their first point of arrival. This geographical position creates a large job for Health Authorities to identify and deal with the health of immigrants. This study evaluates the prevalence of disease among asylum seekers, assessing which are associated factors. A cross-sectional study was conducted to analyse demographic and clinical data in an Acceptance Centres for Asylum Seekers from February 2012 to May 2013. All variables that were found to be significant on unvariable analysis for the most frequent pathologies were included in a multivariable logistic regression model. Post-traumatic stress disorders with 17.4% and major depression with 7.3% were the most frequent diseases. The factors associated with post-traumatic stress disorders among asylum seekers were: major depression diagnosis (OR=2.91, p=0.004), Pakistan as a country of origin (OR=3.88, p<0.001), the largest number of medical visits (OR=1.02, p=0.033) and refugee status (OR=1.97, p=0.036). The variables linked with the diagnosis of major depression from the multivariable analysis were: suffering from post-traumatic stress disorders (OR=3.83, p<0.001), Pakistan as a country of origin (OR=3.45, p=0.004) and the highest number of visits to psychologist (OR=1.15, p<0.001). The mental wellbeing of asylum seekers needs special attention, and interventions should be done to prevent the consolidation of psychiatric morbidity. A short psychological screening after the arrival might prove helpful here. Moreover, carefully designed longitudinal studies should be carried out when political recommendations try to change the organization of psychological and healthcare services.


Are Waterpipe Café, Vape Shop, and Traditional Tobacco Retailer Locations Associated with Community Composition and Young Adult Tobacco Use in North Carolina and Virginia?
We examined whether waterpipe café, vape shop, and traditional tobacco retailer (e.g. stores selling cigarettes, cigars, smokeless tobacco) locations were associated with census tract composition and tobacco use among young adults in North Carolina and Virginia. Methods: We identified waterpipe cafés, vape shops, and traditional tobacco retailers in North Carolina and Virginia and conducted multivariable analyses between community characteristics (gender, race, ethnicity, education, college enrollment, and poverty) and density per 1000 population. Using fall 2017 data from 1099 young adults residing in North Carolina and Virginia, we conducted logistic regression analyses to determine whether tobacco retailer density and proximity were associated with tobacco use. Results: Waterpipe café, vape shop, and traditional retailer density were higher in communities with more people who were Hispanic, college-educated, and college-enrolled (each p < .05). Waterpipe café and traditional retailer density were higher in communities with more people living below the poverty level (each p < .05). Waterpipe café density was higher in communities with more people who were male (p < .05), while traditional retailer density was lower (p < .05). Waterpipe café and vape shop proximity were associated with increased likelihood of waterpipe tobacco use in the past 6 months (each p < .05; unadjusted). Traditional retailer proximity and waterpipe café, vape shop, and traditional retailer density were not associated with tobacco use. Conclusions: Waterpipe cafés and vape shops are located in both impoverished and college-educated communities in North Carolina and Virginia, similar to where traditional tobacco retailers are located. Further research is needed to examine associations with tobacco use.


A broad assessment of covid-19 vaccine safety using tree-based data-mining in the vaccine safety datalink.
Except for spontaneous reporting systems, vaccine safety monitoring generally involves pre-specifying health outcomes and post-vaccination risk windows of concern. Instead, we used tree-based data-mining to look more broadly for possible adverse events after Pfizer-BioNTech, Moderna, and Janssen COVID-19 vaccination. Vaccine Safety Datalink enrollees receiving ≥1 dose of COVID-19 vaccine in 2020-2021 were followed for 70 days after Pfizer-BioNTech or Moderna and 56 days after Janssen vaccination. Incident diagnoses in inpatient or emergency department settings were analyzed for clustering within both the hierarchical ICD-10-CM code structure and the post-vaccination follow-up period. We used the self-controlled tree-temporal scan statistic and TreeScan software. Monte Carlo simulation was used to estimate p-values; p = 0.01 was the pre-specified cut-off for statistical significance of a cluster. There were 4.1, 2.6, and 0.4 million Pfizer-BioNTech, Moderna, and Janssen vaccinees, respectively. Clusters after Pfizer-BioNTech vaccination included: (1) unspecified adverse effects, (2) common vaccine reactions, such as fever, myalgia, and headache, (3) myocarditis/pericarditis, and (4) less specific cardiac or respiratory symptoms, all with the strongest clusters generally after Dose 2; and (5) COVID-19/viral pneumonia/sepsis/respiratory failure in the first 3 weeks after Dose 1. Moderna results were similar but without a significant myocarditis/pericarditis cluster. Further investigation suggested the fifth signal group was a manifestation of mRNA vaccine effectiveness after the first 3 weeks. Janssen vaccinees had clusters of unspecified or common vaccine reactions, gait/mobility abnormalities, and muscle weakness. The latter two were deemed to have arisen from confounding related to practices at one site. We detected post-vaccination clusters of unspecified adverse effects, common vaccine reactions, and, for the mRNA vaccines, chest pain and palpitations, as well as myocarditis/pericarditis after Pfizer-BioNTech Dose 2. Unique advantages of this data mining are its untargeted nature and its inherent adjustment for the multiplicity of diagnoses and risk intervals scanned.


Valgus slipped capital femoral epiphysis: presentation, treatment, and clinical outcomes using patient-reported measurements.
Valgus slipped capital femoral epiphysis (SCFE), is rare. This study describes the diagnosis, treatment and outcome of valgus SCFE in Uruguay. The medical records and radiographs were reviewed in eight consecutive children [mean age 11.9 years (range 9-13; six female)] with valgus SCFE between 1997-2017. In 2018-2019, all patients were reexamined clinically, new radiographs obtained, and patient-reported outcomes completed using the international tool of hip results (iHOT-12). The prevalence of clinical femoroacetabular impingement (FAI), avascular necrosis, and surgical complications were also studied. There were 11 valgus SCFEs in eight patients; two had primary bilateral SCFEs, and one child later developed a valgus SCFE in the contralateral hip. Seven out of eight patients were overweight. All were stable idiopathic SCFEs. The mean femoral head shaft angle on the anteroposterior radiographs for the 11 SCFEs was 145° (range 140-168) and 141° (range 139-145) for the six healthy contralateral hips. Slip severity measured on the Lauenstein projection was mild (<30°) in eight hips and moderate (30°-60°) in three hips. At a mean follow-up of 87 months (range 24-252), there were no cases of avascular necrosis. The mean iHOT12 was 74 (range 13-97). Significant remodeling was detected in both head shaft angle (8°) and alpha angle (10°) in the affected hips. Nine hips (81%) demonstrated clinical signs of FAI. Our study is the first to describe long-term results using both clinical and patient outcome measures (iHOT-12). A majority of patients have residual symptoms, likely associated with FAI.


General properties of autoimmune thyroid diseases and associated morbidities.
Background Autoimmune thyroid diseases (ATDs) can be classified into two basic diseases: Graves' disease (GD) and Hashimoto's thyroiditis (HT). Here, we review the effectiveness of laboratory and imaging methods used for the early diagnosis of ATD and draw attention to methods that may improve screening. Methods Retrospective data of 142 patients diagnosed with ATD between January 2010 and December 2015 at our paediatric endocrinology clinic were used. Sociodemographic characteristics, clinical findings, treatments and follow-up data of patients were statistically evaluated. Results Of the ATD cases, 81% (n = 115) were female. The median age was 12.5 ± 3.5 (range 1-17) years and 91% (n = 129) of patients were in puberty. There was a significant positive correlation between the height (standard deviation score) and follow-up time for patients with HT (r = 0.156, p < 0.01). Thyroglobulin antibody (TgAb) positivity was found in 75% (45/60) of females with a positive maternal ATD history (p = 0.045). Thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4) values were significantly altered during the treatment follow-up period in female patients with GD and HT, while only fT4 values were found to be significantly altered in boys with HT. Conclusion Although GD and HT have similar mechanisms, they differ in terms of treatment duration and remission and relapse frequencies. Ultrasonography (USG) screening is a non-invasive procedure that is suitable for all patients with ATD. Based on our results, TgAb could be useful in the screening of girls with a history of maternal ATD.


Impact of Renal Function Trajectory on Renal Replacement Therapy and Mortality Risk after Renal Artery Revascularization.
To determine the impact of renal function trajectory, defined as the change in renal function over time before and after renal artery stent placement, on long-term risk for renal replacement therapy (RRT) and mortality. Estimated glomerular filtration rates (eGFRs) 6-12 months before renal artery stent placement, at the time of intervention, and 6-12 months after intervention were determined in 398 patients. The effect of eGFR change before and after renal artery stent placement was calculated. Cox proportional-hazards ratio was used to determine the risks for RRT and all-cause mortality. The risk for RRT was significantly influenced by eGFR change from the time of intervention to follow-up at 6-12 month after treatment (P = .02). In addition, among patients with a postintervention eGFR ≤ 40 mL/min/1.73 m2, for every 1 unit of eGFR increase, there was a significant decrease in RRT and all-cause mortality (P < .001 and P < .001, respectively). Secondary parameters that increased RRT risk included diabetes at the time of intervention (P = .03), increased baseline proteinuria (P < .001), and stage 4 or 5 chronic kidney disease (CKD; P = .01 and P = .003, respectively). Multivariate analysis demonstrated higher all-cause mortality rates among patients with diabetes at the time of intervention (P = .009). Postintervention eGFR trajectory improvement approaching 40 mL/min/1.73 m2 was associated with decreased RRT and mortality risk. These findings suggest that patients with advanced CKD and renal artery stenosis may benefit from revascularization regardless of their preinterventional renal function measurement.


Naringenin inhibits alcoholic injury by improving lipid metabolism and reducing apoptosis in zebrafish larvae.
Alcoholic liver disease (ALD) includes a spectrum of hepatic abnormalities that range from isolated alcoholic steatosis to steatohepatitis and cirrhosis. Naringenin, a predominant flavanone in grapefruit, increases resistance to oxidative stress and inflammation and protects against multiple organ injury in various animal models. However, the specific mechanisms responsible for protection against alcoholic injury are poorly understood. In the present study, we aimed to investigate the effect of naringenin on alcoholic events and the molecular regulatory mechanisms of naringenin in the liver and whole body of zebrafish larvae following exposure to 350 mmol/l ethanol for 32 h. Zebrafish larvae {4 days post‑fertilization (dpf); wild-type (WT) and a transgenic line with liver-specific eGFP expression [Tg(lfabp10α-eGFP)]} were used to establish an alcoholic fatty liver model in order to evaluate the effects of naringenin treatment on anti-alcoholic injury. Naringenin significantly reduced alcoholic liver morphological phenotypes and the expression of alcohol and lipid metabolism-related genes, including cyp2y3, cyp3a65, hmgcra, hmgcrb, fasn, fabp10α, fads2 and echs1, in zebrafish larvae. Naringenin also attenuated hepatic apoptosis in larvae as detected by TUNEL staining, consistent with the expression of critical biomarkers of endoplasmic reticulum stress and of DNA damage genes (chop, gadd45αa and edem1). The present study showed that naringenin inhibited alcohol-induced liver steatosis and injury in zebrafish larvae by reducing apoptosis and DNA damage and by harmonizing alcohol and lipid metabolism.


Application of Scanning Electron Microscopy With Energy-Dispersive X-Ray Spectroscopy for Analyzing Ocular Surface Particles on Schirmer Strips.
To demonstrate the application of scanning electron microscopy with energy-dispersive x-ray spectroscopy (SEM/EDS) for analyzing Schirmer strips for particle concentration, size, morphology, and type distribution. A cross-sectional design was used. Patients were prospectively recruited from the Miami Veterans Affairs (VA) Healthcare System eye clinic, and they underwent a complete ocular surface examination. The size, type, and chemical composition of particulate matter on Schirmer strips (from the left eye) were analyzed using SEM/EDS. Schirmer strips from all 6 patients showed particle loading, ranging from 1 to 33 particles, whereas the blank Schirmer strip that served as a control showed no particle loading. Most particles were coarse, with an average size of 19.7 μm (95% confidence interval 15-24.4 μm). All samples contained organic particles (eg, pollen and mold), and 5 of the 6 samples contained nonorganic particles. The nonorganic particles were composed of silicon, minerals, and metals, including gold and titanium. The size of aluminum and iron particles was ≥62 μm, whereas the size of 2 other metals, zinc and gold, was smaller, that is, <20 μm. Most metal particles were elongated compared with the organic particles, which were round. Although SEM/EDS has been extensively used in biomedical research, its novel application to assess the size, morphology, and chemical composition of the ocular surface particles offers an unprecedented opportunity to tease out the role of particulate matter exposure in ocular surface disease and disorders.


Health-Related Quality of Life and Cancer-Related Symptoms During Interdisciplinary Outpatient Rehabilitation for Malignant Brain Tumor.
The aim of the study was to determine the relationships between functional outcomes, clinical symptoms, and health-related quality of life among patients with malignant brain tumors receiving interdisciplinary outpatient rehabilitation. A prospective study of 49 adults with malignant brain tumors participating in outpatient therapies was performed. Outcome measures included the Functional Assessment of Cancer Therapy-Brain (FACT-Br) for health-related quality of life and the Patient-Reported Outcome Measures Instrument Survey (PROMIS) Depression and Pain Behavior scales measured at admission, discharge, 1 and 3 mos after discharge. Day Rehabilitation Outcome Scale (DayROS), a functional measure, was measured at admission and discharge. The FACT-Br scores, PROMIS pain, and PROMIS depression scores did not significantly change. There were many negative associations seen between FACT-Br and PROMIS depression (all P < .0001) and less associations with PROMIS pain. There was a positive correlation between Day Rehabilitation Outcome Scale and FACT-Br (P = .0058) and a negative association with PROMIS pain (P = .028), but not with PROMIS depression. There were no correlations between Day Rehabilitation Outcome Scale gains and change in PROMIS depression, FACT-Br total, or PROMIS pain. Health-related quality of life, pain, and depression did not worsen. Patients who reported less depression and pain had better reported health-related quality of life. Level of function was also associated with HRQOL and pain, but not depression.