Cultured peritoneal mesothelial cells exhibit apical primary cilia.
This study examined primary cilia on cultured human and rabbit peritoneal mesothelial cells (PMC) and investigated factors that influence ciliary expression. Primary cilia were examined with indirect immunocytochemistry, laser scanning confocal microscopy and scanning electron microscopy. Ciliary expression was evaluated in cultures with or without l-cysteine (0.25 mM) or exposure to Ca(2+)-free Krebs-Ringer solution supplemented with EGTA, 0.5 mM. This treatment disrupted cell monolayer integrity. Cilia were counted and normalized to total cell counts using NIH image. Primary cilia were identified on both human and rabbit PMC. Cells treated with l-cysteine expressed significantly more cilia compared with monolayers deprived of l-cysteine. Exposure to Ca(2+)-free Krebs-Ringer solution significantly reduced cilia (5.9+/-1.0%, n=7). Although ciliary expression could be augmented with l-cysteine, approximately 60% of human PMC and 84% of rabbit PMC did not exhibit cilia. Together, these data show that monolayers of PMC express apical cilia that can be augmented with l-cysteine, independently of increased cell density.


Feedback between bottom-up and top-down control of stream biofilm mediated through eutrophication effects on grazer growth.
Algal biofilms in streams are simultaneously controlled by light and nutrient availability (bottom-up control) and by grazing activity (top-down control). In addition to promoting algal growth, light and nutrients also determine the nutritional quality of algae for grazers. While short-term experiments have shown that grazers increase consumption rates of nutrient-poor algae due to compensatory feeding, nutrient limitation in the long run can constrain grazer growth and hence limit the strength of grazing activity. In this study, we tested the effects of light and phosphorus availability on grazer growth and thus on the long-term control of algal biomass. At the end of the experiment, algal biomass was significantly affected by light, phosphorus and grazing, but the interactive effects of the three factors significantly changed over time. At both high light and phosphorus supply, grazing did not initially reduce algal biomass, but the effect of grazing became stronger in the final three weeks of the experiment. Snail growth was enhanced by light, rather than phosphorus, suggesting that algal quantity rather than quality was the main limiting factor for grazer growth. Our results highlight the role of feedback effects and the importance of long-term experiments in the study of foodweb interactions.


Risk of severe primary graft dysfunction in patients bridged to heart transplantation with continuous-flow left ventricular assist devices.
Primary graft dysfunction (PGD) remains a significant cause of post-transplant morbidity and mortality. The exact mechanism and risk factors for this phenomenon remain unknown in the contemporary era. In this study we reviewed adult patients undergoing heart transplantation (HT) at our institution between 2009 and 2017. Severe PGD was defined as the need for mechanical circulatory support (MCS) within the first 24 hours after HT. Multivariate logistic regression analysis was used to identify risk factors for severe PGD, focusing on those bridged to transplant (BTT) with a continuous-flow left ventricular assist device (CF-LVAD). Fifty-six of 480 (11.7%) HT patients experienced severe PGD. Eighty percent of the severe PGD patients were BTT with a CF-LVAD (odds ratio [OR] 3.86, 95% confidence interval [CI] 1.94 to 7.68, p < 0.001). Among the BTT patients, significant associations between >1 year of CF-LVAD support (OR 2.48, 95% CI 1.14 to 5.40, p = 0.022), pre-HT creatinine (OR 3.35, 95% CI 1.42 to 7.92, p = 0.006), elevated central venous pressure/pulmonary capillary wedge pressure (CVP/PCWP) ratio (OR 3.32, 95% CI 1.04 to 10.60, p = 0.043), use of amiodarone before HT (OR 2.69, 95% CI 1.20 to 6.20, p = 0.022), and severe PGD were identified. RADIAL score did not accurately predict severe PGD in this contemporary cohort. Those patients who developed severe PGD had decreased 1-year post-transplant survival (78.3% vs 91.8%, p = 0.007). Use of CF-LVAD as BTT is associated with an increased risk of severe PGD. Increased time on device support, renal dysfunction, right ventricular dysfunction as assessed by CVP/PCWP ratio, and pre-transplant amiodarone may identify those patients at high risk. Further research is warranted focusing on optimal timing of device implantation and transplantation, as well as the underlying mechanisms of PGD.


Characterization of the novel HLA-DQB1*05:272 allele in a South African patient by next-generation sequencing.
HLA-DQB1*05:272 has a single transversion compared to the most similar variant, HLA-DQB1*05:01:01 in IPD-IMGT/HLA database.


Mutagenicity and clastogenicity of proflavin in L5178Y/TK +/- -3.7.2.C cells.
We evaluated the ability of proflavin to induce specific-locus mutations at the heterozygous thymidine kinase (tk) locus of L5178Y/TK +/- -3.7.2C mouse lymphoma cells, which appears to permit the recovery of mutants due to single-gene and chromosomal mutations. Proflavin was highly mutagenic at the tk locus, producing 724-965 TK mutants/10(6) survivors (background = 56-85/10(6); survival = 29-32%). Most of the mutants were small colonies, which suggested that proflavin may induce chromosomal mutations. The potent clastogenicity of proflavin was confirmed by cytogenetic analysis for chromosomal aberrations. At the highest dose analyzed (1.5 micrograms/ml), proflavin produced 82 aberrations/100 metaphaes (background = 2/100). The large-colony TK mutant frequency produced by proflavin (48-109/10(6) survivors; background = 23/10(6); survival = 57-61%) was similar to published HPRT mutant frequencies produces by proflavin in L5178Y and CHO cells (50-100/10(6) survivors; background = 2-50/10(6); survival = 50-62%). These results lead to the conclusion that proflavin is a potent clastogen and induces a high frequency of small-colony TK mutants; however, it induces a low frequency of HPRT mutants and a low frequency of large-colony TK mutants.


Epigenetics and early life origins of chronic noncommunicable diseases.
In light of the increasing threats of chronic noncommunicable diseases in developing countries, the growing recognition of the early life origins of chronic disease, and innovative breakthroughs in biomedical research and technology, it is imperative that we harness cutting-edge data to improve health promotion and maintenance. It is well recognized that chronic diseases are complex traits affected by a wide range of environmental and genetic factors; however, the role of epigenetic factors, particularly with regard to early life origins, remains largely unexplored. Given the unique properties of the epigenome-functionality during critical time windows, such as the intrauterine period, heritability, and reversibility-enhancing our understanding of epigenetic mechanisms may offer new opportunities for the development of novel early prediction and prevention paradigms. This may present an unparalleled opportunity to offer maternal and child health professionals important tools with the translational value to predict, detect, and prevent disease at an early age, long before its clinical occurrence, and as such, break lifelong and transgenerational cycles of disease. In doing so, modern technology can be leveraged to make great contributions to population health, quality of life, and reducing the burdensome economic costs of noncommunicable diseases in developing countries.


National and State-Specific Td and Tdap Vaccination of Adult Populations.
The Advisory Committee on Immunization Practices recommends a single dose of tetanus, diphtheria, and acellular pertussis vaccine (Tdap) for adults followed by tetanus and diphtheria toxoids (Td) booster doses every 10 years thereafter. This study assessed recent Td and Tdap vaccination among adult populations. The 2013 Behavioral Risk Factor Surveillance System data were analyzed in 2015 to assess Td and Tdap vaccination coverage among adults at national and state levels. Multivariable logistic regression and predictive marginal models were performed to identify factors independently associated with vaccination. Overall, national vaccination coverage among adults aged ≥18 years for Td was 57.5% and for Tdap was 28.9%. Among states, Td vaccination coverage ranged from 47.8% in Nevada to 73.1% in Minnesota, and Tdap coverage ranged from 17.7% in Mississippi to 47.6% in Minnesota. Characteristics independently associated with an increased likelihood of Tdap vaccination among adults aged ≥18 years were younger age; being female; American Indian/Alaska Native race; being never married; higher education; not being in the workforce; reporting a household income ≥$75,000; living in the West or Midwest U.S.; reporting excellent, very good, good, or fair health; having health insurance; having a healthcare provider; having a routine checkup in the previous year; receipt of influenza vaccination in the previous year; and having ever received pneumococcal vaccination. By 2013, Td and Tdap vaccination coverage were 57.5% and 28.9%, respectively. Coverage varied by state. Implementation of evidence-based programs is needed to improve Td and Tdap vaccination levels among adult populations.


Artificial liver support systems for hepatitis B virus-associated acute-on-chronic liver failure: A meta-analysis of the clinical literature.
To evaluate the short-term and long-term survival efficacy of an artificial liver support system (ALSS) in patients with acute-on-chronic liver failure (ACLF). A systematic search was performed for relevant published data in PubMed, Web of Science and Cochrane Library databases. Studies that evaluated the efficacy of ALSS in patients with ACLF and provided the short-term or long-term survival rate were included. A total of 10 studies involving 3685 patients were included in this analysis. The pooled 28-day survival rate and 90-day survival rate were 68.7% (95% CI: 64.5%-72.9%) and 53.4% (95% CI: 45.5%-61.4%), respectively. The pooled estimates of the OR for the 28-day and 90-day survival rates between the ALSS group and the control group were 1.91 (95% CI: 1.21-3.04) and 1.41 (95% CI: 1.17-1.70), respectively. Subgroup analysis showed that patients treated with lower levels of TBIL and MELD scores had a higher 28-day survival rate (χ2 = 15.75, p < 0.01; χ2 = 13.80, p < 0.01). The present meta-analysis suggests that ALSS treatment could remarkably improve short-term survival rates in HBV-ACLF patients, which implies that treatment with ALSS may help to reduce high mortality. Further prospective randomized trials are needed to validate these findings.


Distress related to subclinical negative symptoms in a non-clinical sample: Role of dysfunctional attitudes.
Negative symptoms are a prominent feature of schizophrenia that are intimately linked to poor outcomes characterizing the illness. One mechanistic model suggests that these symptoms are produced and maintained, at least in part, through maladaptive attitudes. Beyond mechanisms, it remains phenomenologically unclear if these symptoms are particularly distressing. In the present study we examined whether subclinical negative symptoms evaluated in a non-clinical sample of young adults (N=370) were distressful or bothersome to participants and, further, whether these symptoms were associated with dysfunctional attitudes. We found that greater severity of subclinical negative symptoms such as amotivation and anhedonia were associated with higher ratings of distress specifically attributable to these symptoms. This relationship held even after controlling for severity of depressive symptoms. Moreover, greater negative symptom burden was associated with greater endorsement of defeatist performance beliefs. Negative symptoms expressed in the general population were found to be particularly distressing. Maladaptive cognitive schemas are implicated in the expression of these symptoms, as well as the amount of distress these symptoms instil. A greater understanding of the mechanisms underlying negative symptoms, including both neurobiological and cognitive, is needed in order to effectively develop treatment strategies for these disabling symptoms.


"Vagina" Is Not a Bad Word: Historical and Contemporary Censorship of the Word "Vagina".
To characterize instances of censorship of the word "vagina" to better understand perceptions and behaviors surrounding the word. Internet and relevant database (PubMed, Academic OneFile, Proquest, Health Business Elite, etc) searches were conducted for the words "vagina," "censor," and related wildcard terms. Search results were filtered by three independent reviewers for relevance. Related articles were summarized and reviewed for common themes. In addition, interviews were conducted with three people who have personal experience with censorship of the word "vagina." Interviews were transcribed and also reviewed for common themes. Examples of censorship of the word "vagina" were compiled, and several themes were identified: (1) Policies surrounding censorship are unclear; (2) Policies appear highly variable; (3) There are differing standards between references to male and female genitalia; and (4) Objections often call the use of "vagina" overtly sexual, profane, or unprofessional. The word "vagina" is censored across multiple platforms and policies regarding censorship are inconsistent and unclear. Pervasive censorship of the word "vagina" perpetuates a culture of ignorance and shame about women's bodies. Until we normalize the word "vagina," we cannot make progress on women's pelvic health.


Hypofractionated whole-breast radiation therapy: does breast size matter?
To evaluate the effects of breast size on dose-volume histogram parameters and clinical toxicity in whole-breast hypofractionated radiation therapy using intensity modulated radiation therapy (IMRT). In this retrospective study, all patients undergoing breast-conserving therapy between 2005 and 2009 were screened, and qualifying consecutive patients were included in 1 of 2 cohorts: large-breasted patients (chest wall separation>25 cm or planning target volume [PTV]>1500 cm3) (n=97) and small-breasted patients (chest wall separation<25 cm and PTV<1500 cm3) (n=32). All patients were treated prone or supine with hypofractionated IMRT to the whole breast (42.4 Gy in 16 fractions) followed by a boost dose (9.6 Gy in 4 fractions). Dosimetric and clinical toxicity data were collected and analyzed using the R statistical package (version 2.12). The mean PTV V95 (percentage of volume receiving>=95% of prescribed dose) was 90.18% and the mean V105 percentage of volume receiving>=105% of prescribed dose was 3.55% with no dose greater than 107%. PTV dose was independent of breast size, whereas heart dose and maximum point dose to skin correlated with increasing breast size. Lung dose was markedly decreased in prone compared with supine treatments. Radiation Therapy Oncology Group grade 0, 1, and 2 skin toxicities were noted acutely in 6%, 69%, and 25% of patients, respectively, and at later follow-up (>3 months) in 43%, 57%, and 0% of patients, respectively. Large breast size contributed to increased acute grade 2 toxicity (28% vs 12%, P=.008). Adequate PTV coverage with acceptable hot spots and excellent sparing of organs at risk was achieved by use of IMRT regardless of treatment position and breast size. Although increasing breast size leads to increased heart dose and maximum skin dose, heart dose remained within our institutional constraints and the incidence of overall skin toxicity was comparable to that reported in the literature. Taken together, these data suggest that hypofractionated radiation therapy using IMRT is a viable and appropriate therapeutic modality in large-breasted patients.


Chemical aspects of glycogen contrast-staining by potassium osmate.
To obtain contrast-staining of glycogen in electron microscopy, various contrast-enhancing additives can be used in combination with potassium osmate. Examples are potassium ferrocyanide and certain nitrogen heterocyclic compounds, such as triazoles. In the reaction sequence leading to contrast-stained glycogen, a primary reaction is the formation of glycogen osmate. This reaction was studied with isolated glycogen. On the basis of the stoichiometric findings, a molecular structure of the reaction product is proposed; apparently, osmate is bound by glycogen because of the presence of suitably located hydroxyl groups. The resulting compound is not itself sufficiently electron dense, but it binds 1,2,4-triazole as an additional ligand. Secondary reactions can result in additional osmium binding, and finally to osmium (IV) deposits, leading to contrast.


Global mental health research and practice: a decolonial approach.
The global health movement is having a paradigm crisis-a period characterised by a questioning of one's values, goals, and sense of identity. Despite important advances in population health worldwide, global health and global mental health often produce and reproduce power imbalances and patterns of oppression and exploitation that perpetuate the current modern world system (ie, Eurocentric, capitalist, and patriarchal) and its entangled global hierarchies (eg, gender, economic, epistemic, and linguistic). A consensus is emerging to decolonise global mental health, but it is not clear how to move from rhetoric to action. In this Personal View, we aim to share our experiences and the practices developed in the context of the COVID-19 health care workers (HEROES) Study. To do so, we present our HEROES decolonial team approach, which comprises three underlying principles: epistemic justice, pragmatic solidarity, and sovereign acts. We have developed decolonial team practices such as co-creating communication spaces to foster horizontal and equitable dialogue, locating and managing the study database in Chile, and ensuring local teams' rights and access to the data without barriers.


Spinal Cord Stimulation Efficacy and Erroneous Conclusions of the Cochrane Library Review of Spinal Cord Stimulation for Low Back Pain by Traeger et al.
Neuromodulation, through the use of spinal cord stimulation, is an evolving therapeutic alternative for the management of chronic and refractory pain [...].


Virtual screening for Raf-1 kinase inhibitors based on pharmacophore model of substituted ureas.
A three-dimensional (3D) quantitative pharmacophore model was developed from a training set of structurally diverse substituted ureas against Raf-1 kinase, which was well validated to be highly predictive by two methods, namely, test set prediction and Cat-Scramble method. Then a virtual database searching was performed with the pharmacophore model as a 3D query, and the bioactivities of the retrieved hits were predicted by the pharmacophore. Subsequently, molecular docking was carried out on the selected hits whose estimated IC(50) was less than 1 microM. Finally, 29 hits were identified as potential leads against Raf-1 kinase, which exhibited good estimated activities, high docking scores, similar binding mode to experimentally proven compounds and favorable drug-like properties. The study may facilitate the discovery and rational design of novel leads with potent inhibitory activity targeting Raf-1 kinase.


Effects of oxygen concentration on the intermediary metabolism of Leishmania major promastigotes.
Leishmania major promastigotes grown in late log phase were incubated with glucose as sole exogenous carbon source in the presence of 5% CO2 and the amounts of glucose consumed and of the major products formed--succinate, pyruvate, alanine, acetate, glycerol, and D-lactate--were measured as a function of pO2. Glucose consumption increased as pO2 was lowered to 6% (a positive Pasteur effect) and then declined to the same level at 95% N2 as at 95% O2. The production of D-lactate and of glycerol increased as pO2 dropped from 95%, reaching a maximum at about 2% O2. Succinate production, however, increased dramatically when pO2 was reduced to 6% and remained at that level with further reduction of pO2. The amount of succinate produced relative to the amount of glucose carbon consumed suggests utilization of an endogenous carbon source. Acetate production did not change between 95% O2 and 6% O2 and then declined with decreasing pO2. These observations suggest the presence of two sensors, one with a high and one with a low affinity for oxygen. When glycerol or alanine were the only exogenous sources of carbon, the primary products released were acetate and succinate. Acetate production from alanine declined slightly as pO2 was reduced to 2%, and then dropped markedly when pO2 was reduced to 0%. Acetate production from glycerol increased over 4-fold when the pO2 was reduced from 95% to 4%, and then declined with further reduction in pO2. No succinate was formed from either substrate until complete anaerobiosis. This pattern of response, while differing from that when glucose was sole exogenous carbon source, is also consistent with the regulation of metabolism by a high and a low affinity O2 sensor. Cells from cultures in early stationary phase, before the appearance of metacyclic forms, consumed glucose at about the same rate as log phase promastigotes, but did not show a Pasteur effect. Stationary cells also consumed glycerol at the same rate as did log phase promastigotes, but consumed alanine at a much lower rate. Reduction of pO2 affected product formation from each of these substrates differently than for log phase promastigotes, demonstrating the sensitivity of several pathways of intermediary metabolism to regulation by pO2 during the transition from log to stationary phase.


Rev-erbα regulates hepatic ischemia-reperfusion injury in mice.
Hepatic ischemia-reperfusion (I/R) injury is a complex pathophysiological process that often times occurs in liver transplantation, hepatectomy, and ischemic shock. Aberrant activation of inflammatory responses has been implicated in hepatic I/R injury. In this study, we aimed to investigate the role of circadian clock gene Rev-erbα (a well-known regulator of inflammation) in hepatic I/R injury. We first showed that Rev-erbα ablation sensitized mice to hepatic I/R injury as evidenced by higher levels of plasma alanine aminotransferase and aspartate aminotransferase, an increased histological score, as well as enhanced hepatic myeloperoxidase activity in Rev-erbα-/- mice. More severe hepatic I/R injury in Rev-erbα-/- mice was accompanied by higher expression of pro-inflammatory cytokines, exacerbated activation of Nlrp3 inflammasome, and more extensive infiltration of inflammatory cells. Moreover, pharmacological activation of Rev-erbα by SR9009 significantly alleviated the hepatic damage and inflammatory responses. In addition, I/R operation started at ZT18 (corresponding to low Rev-erbα expression) caused more severe liver damage and inflammatory responses in wild-type mice as compared to operation started at ZT6 (corresponding to high Rev-erbα expression), supporting a protective effect of Rev-erbα on hepatic I/R injury. Collectively, Rev-erbα protects hepatic I/R injury probably via repression of inflammatory responses, and targeting Rev-erbα may be a promising approach for management of hepatic I/R injury.


The up-regulation of long non-coding RNA AFAP1-AS1 is associated with the poor prognosis of NSCLC patients.
Long non-coding RNA (lncRNA) is actively transcribed from human genome and has been considered to participate in many processes of various cancers. The purpose of this study was to investigate the expression of LncRNA AFAP1-AS1 and its prognostic value in NSCLC. LncRNA AFAP1-AS1 expression was detected by qRT-PCR which demonstrated that the expression was significantly increased in tumor tissues compared with the adjacent non-cancerous tissues and healthy tissues. The clinical stage, smoking history, infiltration degree, lymph node metastasis and distant metastasis were all proved to impact the expression of LncRNA AFAP1-AS1 (P<0.05). Kaplan-Meier analysis was performed to evaluate the overall survival of NSCLC patients with different expression level of LncRNA AFAP1-AS1, and results showed that patients with high LncRNA AFAP1-AS1 expression lived shorter than those with low LncRNA AFAP1-AS1 expression (Log rank test, P<0.001). Besides, the prognostic value of LncRNA AFAP1-AS1 as well as the clinical features was assessed by Cox regression analysis. The outcome revealed that LncRNA AFAP1-AS1 was closely related to the prognosis of NSCLC. Taken together, LncRNA AFAP1-AS1 was up-regulated in NSCLC tissues and it could be an independent prognostic indicator for NSCLC patients.


GRISEA, a copper-modulated transcription factor from Podospora anserina involved in senescence and morphogenesis, is an ortholog of MAC1 in Saccharomyces cerevisiae.
The initial characterization of Grisea suggested that this gene codes for a transcription factor involved in the genetic control of cellular copper homeostasis in Podospora anserina. Here we demonstrate that GRISEA activates in vivo gene expression in Saccharomyces cerevisiae and is characterized by a modular organization. The DNA-binding domain was mapped to the first 168 N-terminal amino acids and the transactivation domain to the C-terminal half of the protein. Increased levels of copper in the growth medium lead to repression of the transactivation function possibly via intramolecular interactions between parts of the DNA-binding domain and the transactivation domain. The wild-type copy of Grisea was found to complement the phenotype of the mac1-1 mutant of S. cerevisiae. GRISEA is able to bind to the promoter of CTR1, a MAC1 target gene that encodes a high-affinity copper transporter. Taken together, the data reported here and in earlier investigations indicate that GRISEA is an ortholog of the yeast transcription factor MAC1 and suggest at least a partial conservation of the molecular machinery involved in the control of cellular copper homeostasis in eukaryotes. Remarkably, in P. anserina, the spectrum of phenotypes affected by this regulatory protein is much broader than that known in yeast and includes morphogenetic traits as well as lifespan and senescence.


Stimulation by polyamines of carbamylphosphate:glucose phosphotransferase and glucose-6-phosphate phosphohydrolase activities of multifunctional glucose-6-phosphatase.
The effects of added polyamines on carbamylphosphate (carbamyl-P):glucose phosphotransferase and glucose-6-phosphate (Glc-6-P) phosphohydrolase activities of rat hepatic D-Glc-6-P phosphohydrolase (EC 184.108.40.206) of intact and detergent-treated microsomes have been investigated. With the former preparation, in the presence of 1.4 mM phosphate substrate and 90 mM D-glucose (phosphotransferase), 1 mM spermine, spermidine, and putrescine activated Glc-6-P phosphohydrolase 67%, 57%, and 35%, respectively. Carbamyl-P:glucose phosphotransferase, under comparable conditions, was activated 57%, 34%, and 18%. NH+4 (0.25--5.0 mM) produced at best but a minor activation (0--14%), while poly(L-lysine) (Mr = 3400; degree of polymerization 16) equimolar relative to other polyamines with respect to ionized free amino groups activated the hydrolase 358% and the transferase 222%. Treatment of microsomes with the detergent deoxycholate reduced, but did not abolish, polyamine-induced activation. The stimulatory effects of polyamines persisted in the presence of excess catalase, indicating their independence from H2O2 formation; and were eliminated in the presence of Ca2+. Kinetic analysis revealed that all tested polyamines decreased the apparent Michaelis constant values for carbamyl-P and Glc-6-P, but had no effect on the Km for glucose. Poly(L-lysine) increased the V value for both Glc-6-P phosphohydrolase and apparent V values for phosphotransferase extrapolated to infinite concentrations of either carbamyl-P or glucose. The other tested polyamines elevated only this last velocity parameter. It is proposed that a major mechanism by which polyamines activate glucose-6-phosphatase-phosphotransferase is through their electrostatic interactions with phospholipids of the membrane of the endoplasmic reticulum of which this enzyme is a part. Conformational alterations thus induced may in turn affect catalytic behavior. It is suggested that polyamines, or similar positively charged peptides, might participate in the cellular regulation of synthetic and hydrolytic activities of glucose-6-phosphatase.


Rat strain specific attenuation of estrogen action in the anterior pituitary gland by dietary energy restriction.
The purpose of this study was to compare the effects of a 40% restriction of dietary energy consumption, relative to that consumed by rats allowed to feed ad libitum, on the ability of 17beta-estradiol (E2) to induce pituitary tumorigenesis in two inbred rat strains, ACI and Copenhagen (COP), which are very closely related genetically. Ovary-intact ACI and COP rats were fed either a control or an energy-restricted diet beginning at 8 wk of age. Continuous treatment with E2, released from subcutaneous Silastic tubing implants, was initiated at 9 wk of age and the animals were killed 12 wk later. Estrogen-induced pituitary tumorigenesis is associated with rapid induction of lactotroph hyperplasia, increased pituitary mass, and hyperprolactinemia. E2 significantly increased pituitary mass and circulating prolactin (PRL) in both ACI and COP rats, and this response was significantly greater in ACI rats relative to COP. Dietary energy restriction did not inhibit E2-induced pituitary growth in the ACI rat. By contrast, E2-induced pituitary growth in COP rats was attenuated by dietary energy restriction, as evidenced by quantification of pituitary mass, pituitary weight to body weight ratio, circulating PRL, and pituitary cell proliferation. This study indicates that sensitivity to the inhibitory actions of dietary energy restriction on E2-induced pituitary tumorigenesis is genetically determined.


Freeze-all, oocyte vitrification, or fresh embryo transfer? Lessons from an egg-sharing donation program.
To compare the outcomes of ETs using cryopreserved embryos, cryopreserved oocytes, or fresh embryos. Observational, cohort study. Private university-affiliated fertility center. This study included 8,210 mature oocytes obtained from 425 oocyte donors. Of those, 5,440 were used for the donors' own cycles (Fresh Oocyte Cycles Group), and 2,770 were cryobanked for 425 recipients (Banked Donor Egg Group). All of the oocytes were sperm injected, resulting in 4,585 embryos from the donors' own cycles and 2,128 embryos from the recipients' cycles. For the donor cycles, embryos were either cryopreserved and transferred during a subsequent cycle (Thaw Cycles Group, 3,209 embryos), or they were transferred during a fresh cycle (Fresh Cycles Group, 1,307 embryos). For the recipient cycles, embryos derived from vitrified oocytes were transferred (Vitrified Oocytes Group, n = 425 cycles, 2,128 embryos). Oocyte/embryo vitrification and intracytoplasmic sperm injection. Embryo quality, pregnancy, and implantation rates. Decreased embryo quality and lower rates of blastocyst formation were observed among embryos derived from vitrified oocytes. The highest pregnancy and implantation rates were noted for the Thaw Cycles Group, followed by the Banked Donor Egg Group; the Fresh Cycles Group had the lowest rates. Oocyte vitrification followed by intracytoplasmic sperm injection leads to lower embryo developmental competence compared with when fresh insemination methods are used. However, pregnancy and implantation rates are higher when embryos are transferred into a "more receptive" endometrium, free of the adverse effects of gonadotropin. Moreover, the freeze-all method leads to exceptional clinical outcomes.


Continuous epidural anesthesia with double catheters for cesarean section in a patient with severe pulmonary hypertension: A case report.
Pregnancy in a woman with pulmonary hypertension (PH) carries prohibitively high risks of cardiopulmonary complications and high maternal and fetal morbidity and mortality. Anaesthetic management during delivery or cesarean section is very important for the prognosis of pregnant women with PH. The choice between general anesthesia or intraspinal anesthesia is controversial. There have been few case reports of anesthetic management under continuous epidural anesthesia with double catheters in such patients. A 35-year-old pregnant woman presented to the emergency department with fatigue and shortness of breath for 10 days at 16 weeks of gestation. According to transthoracic echocardiogram, her pulmonary artery pressure (PAP) was 75 mm Hg, and she had a dilated left ventricle (67 mm) and a ventricular septal defect (1.7 mm) with a bidirectional shunt. Elective cesarean section under continuous epidural anesthesia with double catheters to terminate a pregnancy in order to avoid development of cardiac failure. The pregnant woman underwent cesarean section safely and steadily under continuous epidural anesthesia with double catheters. She was discharged on the seventh postoperative day. The advantages of continuous epidural anesthesia with double catheters are stable hemodynamics and complete analgesia. The continuous epidural anesthesia with double catheters can be applied to patients with cardiopulmonary disease like severe PH. Compared with general anesthesia, spinal anesthesia, and single-catheter epidural anesthesia continuous epidural anesthesia is a better option for patients with both PH and heart failure.


Molecular basis of dimerization of initiator caspase was revealed by crystal structure of caspase-8 pro-domain.
The assembly of death-inducing signaling complex (DISC) for activation of initiator caspase is a key step for the receptor-mediated apoptosis signaling. Many death effector domain (DED)-containing proteins are involved in DISC assembly and controlling. One of the main DISC component, caspase-8, contains DED and DED-mediated dimerization and oligomerization in the DISC is critical for the activation of this initiator caspase. There have been intensive studies to understand DED-mediated dimerization and oligomerization for the DISC assembly but no clear answer has been provided and there are many controversial arguments. Here, we suggested novel dimerization process of tandem DED of caspase-8 with crystallographic study.


Characteristics of patients with incidental eosinophilia admitted to a tertiary hospital in southern China.
The characteristics of patients with eosinophilia are heterogeneous and the outcomes can vary from asymptomatic to severe. To describe the feature of patients with eosinophilia in a single center. Based on the electronic medical records from Yangjiang People's Hospital in China, the inpatients admitted between June 2018 and February 2021 with measured blood eosinophil counts were evaluated. Eosinophilia was defined as a peripheral blood eosinophil count of ≥0.5 × 109/L. Differences were compared by eosinophilia severity. The medical records of patients with moderate to severe eosinophilia were reviewed and summarized in terms of examination, diagnoses and management. And these patients were matched with patients without incidental eosinophilia by propensity score and the differences were compared. A total of 7,835 patients with eosinophilia were identified out of 131,566 total inpatients. All types of eosinophilia were most common in males (8.2%; 5,351/65,615), and in patients aged 0-6 years (11.6%; 1,760/15,204), and in the pediatric (10.8%; 1,764/16,336) department, followed by dermatology (10.6%; 123/1,162), Oncology (7.5%; 394/5,239) and Intensive care unit (ICU) (7.4%; 119/1,608). Patients with moderate to severe eosinophilia were more likely to admit to ICU (moderate: 1.3%; severe: 0.50%). In patients with moderate to severe eosinophilia, only 205/621 (33%) had eosinophilia mentioned in their records, and only 63/621 (10.1%) underwent investigations for eosinophilia. The majority of patients with moderate to severe eosinophilia (372/621, 59.9%) had an infectious disease, and little examination (7.4%; 46/621) was taken to identify the cause of eosinophilia, and only 39/621 (6.3%) of patients had a discrete cause of eosinophilia identified. Patients with moderate to severe eosinophilia (24.3%; 151/621) exhibited certain chance to have organ dysfunction. Incidental eosinophilia in inpatients was frequently neglected and less investigated. Multidisciplinary consultation may improve outcomes of inpatients with moderate to severe eosinophilia.


Disease surveillance in England and Wales, September 2017.
Current and emerging issues: Schmallenberg virusHighlights from the scanning surveillance networkon international disease threats Salmonella investigations in ruminants These are among matters discussed in the Animal and Plant Health Agency's (APHA's) disease surveillance report for September 2017.


The physiological origin of the slow afterwave in muscle action potentials.
Both intramuscularly-recorded motor unit action potentials (MUAPs) and surface recorded MUAPs and compound muscle action potentials (CMAPs) have slow afterwaves which can contribute as much as half their measured duration. This study tested the hypothesis that the slow afterwave has its physiological origin in the negative afterpotential of the muscle fiber intracellular action potential (IAP). We investigated the slow afterwave in MUAPs and CMAPs from brachial biceps, tibialis anterior, first dorsal interosseous, thenar and hypothenar muscles in 15 normal subjects, and using computer simulations. The slow afterwaves did not match the time constant of the amplifier's high-pass filter, and so were not filtering artifacts. They lasted long after propagation had terminated at the muscle/tendon junction, and so were not due to the temporal or spatial dispersion of propagating single-fiber potentials. Their amplitude and polarity varied with the recording site as predicted by computer simulations that modeled the IAP as having a negative afterpotential. They also changed with double-pulse stimulation and decreasing temperature in ways consistent with the results of intracellular studies of the IAP negative afterpotential. The presented results support our hypothesis that the slow afterwave is a manifestation of the IAP negative afterpotential.


Radioisotope diagnosis of splenic trauma.
Multiple injury or delay in seeking medical attention may prevent confident clinical diagnosis of splenic trauma. The spleen scan is a rapid, simple, noninvasive test useful in such circumstances. When peritoneal lavage is contraindicated, unrevealing, or inapproapriate, radioisotope imaging of the spleen can help confirm a suspicion of splenic injury.


Salivary gland tumors in a Brazilian population: a retrospective study of 496 cases.
Salivary gland tumors are uncommon and the microscopical features can be complex. Epidemiological data of these tumors in the various parts of the world can be helpful for a better understanding of its biology and clinical characteristics. In this study, 496 epithelial and mesenchymal tumors of major and minor salivary glands diagnosed at Londrina Cancer Institute during the period from 1972 to 2001 were reviewed. Out of all cases, 335 (67.5%) were classified as benign and 161 (32.5%) as malignant. The majority of the cases occurred in the parotid gland (67.7%), followed by the minor salivary glands (22.8%) and submandibular gland (9.5%). Among the minor salivary gland tumors, the palate was the most frequent location (67%). The tumors affected more commonly adult patients with peak incidence between 40 and 50 years of age and with a slightly predominance in females. Pleomorphic adenoma was the most frequent tumor representing 54.2% of all cases, followed by mucoepidermoid carcinoma (13.5%), Warthin's tumor (8.5%) and adenoid cystic carcinoma (7.9%).


Monitoring Lactate Dynamics in Individual Macrophages with a Genetically Encoded Probe.
Lactate, the product of aerobic glycolysis, plays a dual role as fuel and intercellular signal in inflammation, immune evasion, and tumor progression. The production of lactate by macrophages has been associated with their polarization and function. Here we describe imaging protocols to characterize the metabolism of cultured human macrophages using a genetically encoded fluorescent sensor-specific for lactate. By superfusing cultures with increasing lactate concentrations and pharmacological inhibitors, it is possible to estimate the kinetic parameters of monocarboxylate transporter 4 (MCT4) and lactate production. Practical advice is given regarding sensor expression, imaging, and data analysis. The spatiotemporal resolution of this technique is amenable to the study of fast events at the single-cell level in different immune and other cell types.


Impact of dental and orofacial trauma on oral health-related quality of life in adults: A systematic review.
Dental and orofacial trauma among the adult population constitutes a major public health problem. The impact is not just physical but also psychological. To analyse the impacts of dental and orofacial trauma on oral health-related quality of life (OHRQoL) in adults and determine whether the 2 variables are closely interlinked. This is a systematic review. The terms "dental trauma", "orofacial trauma", "oral health", "oral health related impact life", "OHRQoL", "positive and negative affect scale", "quality of life", "facial injuries", "adults", and "young adults" were researched in the databases of PubMed, ScienceDirect, Scopus and Google Scholar for associated studies up to December 30, 2022. A comprehensive search was designed and the articles were independently screened for eligibility by 2 reviewers. The included studies' author, year of publication, the country where the study was conducted, population demographics (number and age), an instrument used for assessing OHRQoL and the relevant result were recorded and compared. The quality of the evidence was assessed using Joanna Briggs Institute checklist for observational studies. Out of 482 unique records, 3 articles were included for data extraction. Observational studies were included. Two studies did not mention confounding factors. Different scales were used for dental and orofacial trauma and OHRQoL. OHRQoL has a directly proportional relationship with orofacial trauma. Adolescents with orofacial trauma have a significant impact on this value with a prevalence of 88.4%. The highest impact on OHRQoL was seen immediately after the diagnosis of an orofacial trauma. The impact increases with the severity of the trauma. Therefore, to promote overall dental and general health, health education initiatives should include information on the causes, prevention, and requirement for prompt responses by the populace in seeking dental intervention.


Phase Ib trial of lenalidomide as post-remission therapy for older adults with acute myeloid leukemia: Safety and longitudinal assessment of geriatric functional domains.
Novel, non-cytotoxic agents are driving a paradigm shift for treatment of older adults with acute myeloid leukemia (AML). Older patients who initially receive intensive cytotoxic induction may choose to not proceed with cytotoxic consolidation therapy. Lenalidomide is an orally-administered immunomodulatory small molecule with activity in AML and a favorable safety profile in older adults with active leukemia. We conducted a phase Ib study of lenalidomide as post-remission therapy in older adults and assessed its impact on geriatric functional domains. Participants were patients with AML over age 60 years who had undergone induction therapy and were poor candidates for cytotoxic consolidation. Lenalidomide was administered for 28 days in three dose cohorts. A Bayesian dose-escalation method determined cohort assignment and maximum tolerated dose (MTD). Geriatric assessment (GA) was performed before and after the cycle of lenalidomide. Nineteen patients with median age 68 were treated with at least one 28-day course of lenalidomide. Dose-limiting toxicities were observed in three participants at 25 mg, zero participants at 35 mg, and one participant at 50 mg. MTD was 35 mg. Median relapse-free survival was 4.3 months. GA was completed before and after treatment in fifteen patients, demonstrating improved cognitive function and no changes in physical, psychological, or social function after lenalidomide. Lenalidomide can be safely administered to older adults with AML with preservation of functional domains important to older patients. Serial GA can be performed in a novel drug study as a tool to characterize treatment tolerability.


A policy in the management of urethral fistula.
Our experience with repair of urethral fistula in 33 patients over a 5-year period is reviewed. The ages ranged from 2 to 12 years with an average of 8 years. Meatal advancement and glanuloplasty (MAGPI) were performed in five patients; there was no recurrence. A layered repair was used in 26 patients; of these, 12 recurred. Twelve patients needed a second operation and, of these, one had urethral dilatation with spontaneous cure of the fistula and the remaining 11 had a layered repair with a recurrence in five. Five patients had a third repair with further recurrence in three. Suprapubic urinary division was used in 13 cases with a failure rate of 77% (10 cases), while transurethral drainage was used in 31 cases with a failure rate of 35% (11 cases). Three of the cases with a MAGPI procedure had no urinary division. It is concluded that the MAGPI principle should be used in the repair of coronal and some subcoronal urethral fistulae as it carries a good healing rate with a short hospital stay. Transurethral bladder drainage should be used more frequently.


Microdensitometric analysis of bone structures in X-ray images.
The careful evaluation of bony structure is important in the study of normal bone and bone disorders. This study describes bony structure as seen in the X-ray pattern of the phalanges of the hand using quantitative microdensitometry. Normalised scans of bony density show the regular and irregular distribution of the trabeculae. Two properties were determined from these densitometric findings: the mean transverse coarseness (C) indicating fluctuations of horizontal density and the overall standard deviation indicating axial homogeneity (H). This investigation demonstrates the applicability of the method: it shows a significant correlation with radiological diagnosis and that microdensitometry is a reliable method for quantifying the coarseness and homogeneity of bone structure.


Trimethoprim: kinetic and mechanistic considerations in photochemical environmental fate and AOP treatment.
Trimethoprim (TMP), a bacteriostatic antibiotic, has recently been detected in wastewater and surface waters. In this study the sunlight mediated photochemical fate, and treatment using advanced oxidation and reduction (free radical) processes, have been investigated with respect to their effect on TMP. Photochemical fate, in the presence of humic acid, and advanced oxidation treatment both involve the hydroxyl radical (OH) as one of the reactive species of interest. Another reactive oxygen species, singlet oxygen (1O2), may also be important in the photochemical fate of TMP. The bimolecular reaction rate constants of TMP with 1O2 and OH were evaluated to be (3.2±0.2)×10(6) M(-1) s(-1) and 8.66×10(9) M(-1) s(-1), respectively. The reaction kinetics for the sub-structural moieties of TMP, 1,2,3-trimethoxybenzene (TMBz) and 2,4-diaminoprimidine (DAP), was evaluated to facilitate an understanding of the loss mechanisms. For TMBz and DAP the reaction rate constants with 1O2 were <1.0×10(4) and (3.0±0.1)×10(6) M(-1) s(-1), while with OH they were 8.12×10(9) and 1.64×10(9) M(-1) s(-1), respectively. The data suggests that the 1O2 attacks the DAP and the OH radical attacks the TMBz moiety. However, for TMP, 1O2 and OH reactions accounted for only ∼19% and ∼6%, of its total photodegradation, respectively. Therefore, the reaction of TMP with excited state natural organic matter is postulated as a significant degradation pathway for the loss of TMP in sunlit waters containing natural organic matter. There was no effect of pH on the direct or indirect photolysis of TMP. To complete the study for reductive treatment processes, the solvated electron reaction rates for the destruction of TMP, TMBz and DAP were also evaluated. The absolute bimolecular reaction rates obtained were, (13.6±0.01)×10(9), (6.36±0.11)×10(7) and (10.1±0.01)×10(9) M(-1) s(-1), respectively.


Value of diffusion-weighted imaging for the discrimination of pancreatic lesions: a meta-analysis.
We aimed to explore the role of diffusion-weighted imaging (DWI) in the discrimination of pancreatic lesions through meta-analysis. The MEDLINE, EMBASE, Cancerlit, and Cochrane Library databases, from January 2001 to August 2011, were searched for studies evaluating the diagnostic performance of DWI in the discrimination of pancreatic lesions. We determined sensitivities and specificities across studies, calculated positive and negative likelihood ratios (LR+ and LR-), and constructed summary receiver operating characteristic curves. A total of 11 studies with 586 patients, who fulfilled all of the inclusion criteria, were considered for the analysis. No publication bias was found. The pooled sensitivity of DWI was 0.86 [95% (confidence interval (CI), 0.78, 0.91] and the pooled specificity was 0.91 (95% CI, 0.81, 0.96). Overall, LR+ was 9.8 (95% CI, 4.1, 23.3) and LR- was 0.15 (95% CI, 0.09, 0.26). The area under the curve of the summary receiver operating characteristic was 0.94 (95% CI, 0.91-0.96). In subgroup analysis, prospectively designed studies had the highest pooled sensitivity (0.87, 95% CI 0.75, 0.94) and specificity (0.96, 95% CI 0.91, 0.99) (P<0.05). Study sensitivity was not correlated with the prevalence of pancreatic lesions (R=0.1076, P=0.3247). A limited number of small studies suggest that DWI is a potentially technically feasible measure to differentiate malignant from benign pancreatic lesions. However, it is still controversial and is limited in that it can only distinguish certain lesions. High-quality prospective studies on DWI for the discrimination of pancreatic lesions still need to be conducted.


Synaptosomal plasma membrane glycoproteins. II. Isolation of fucosyl-glycoproteins by affinity chromatography on the Ulex europeus lectin specific for L-fucose.
After solubilization in sodium dodecyl sulphate, almost 90% of synaptosomal plasma membrane glycoproteins were separated from the bulk of synaptosomal plasma membrane proteins by sequential affinity chromatography on two immobilized lectins: concanavalin A and the Ulex europeus lectin specific for L-fucose. Four fractions were obtained and their sugar composition and electrophoretic patterns were determined. Fucosyl-glycoproteins contain more than 26% of protein and 85% of the protein-bound sugar of synaptosomal plasma membrane; hence they constitute a major class of glycoproteins in these membranes. The presence of some glucose in glycoproteins fractions obtained after affinity chromatography on the two lectins suggests that this sugar could be a structural component of some brain glycoproteins. Polyacrylamide gel electrophoresis revealed at least 28 major bands in fucosylglycoprotein fractions, and 11 in other fractions. Several of these major bands appear to contain more than one glycoprotein each. This heterogeneity appears to be mostly the result of the heterogeneity of the neuronal population in the central nervous system. Microheterogeneity of glycoprotein sugar chains and possible contamination of synaptosomal plasma membranes play, in our opinion, only a minor role.


Predicting Falls in Nursing Homes: A Prospective Multicenter Cohort Study Comparing Fall History, Staff Clinical Judgment, the Care Home Falls Screen, and the Fall Risk Classification Algorithm.
To evaluate and compare the predictive accuracy of fall history, staff clinical judgment, the Care Home Falls Screen (CaHFRiS), and the Fall Risk Classification Algorithm (FRiCA). Prospective multicenter cohort study with 6 months' follow-up. A total of 420 residents from 15 nursing homes participated. Fall history, clinical judgment of staff (ie, physiotherapists, nurses and nurses' aides), and the CaHFRiS and FRiCA were assessed at baseline, and falls were documented in the follow-up period. Predictive accuracy was calculated at 1, 3, and 6 months by means of sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio, Youden Index, and overall accuracy. In total, 658 falls occurred and 50.2% of the residents had at least 1 fall with an average fall rate of 1.57 (SD 2.78, range 0-20) per resident. The overall accuracy for all screening methods at all measuring points ranged from 54.8% to 66.5%. Fall history, FRiCA, and a CaHFRiS score of ≥4 had better sensitivity, ranging from 64.4% to 80.8%, compared with the clinical judgment of all disciplines (sensitivity ranging from 47.4% to 71.2%). The negative predictive value (ranging from 92.9% at 1 month to 59.6% at 6 months) had higher scores for fall history, FRiCA, and a CaHFRiS score of ≥4. Specificity ranged from 50.3% at 1 month to 77.5% at 6 months, with better specificity for clinical judgment of physiotherapists and worse specificity for FRiCA. Positive predictive value ranged from 22.2% (clinical judgment of nurses' aides) at 1 month to 67.8% at 6 months (clinical judgment of physiotherapists). No strong recommendations can be made for the use of any screening method. More research on identifying residents with the highest fall risk is crucial, as these residents benefit the most from multifactorial assessments and subsequent tailored interventions.


Dissemination of responsible service of alcohol initiatives to rugby league clubs.
To determine the acceptability of intervention strategies that increase the responsible service of alcohol by non-metropolitan rugby league clubs. Rugby league clubs were provided an information kit and advice by local public health workers, police and a lead agency regarding their responsible service of alcohol practices. Rugby League clubs and public health workers completed an acceptability survey at the conclusion of the study. Data were collected from 160 contactable clubs (100% consent) and 12 of 14 participating public health workers. Almost all clubs reported of contact with the lead agency, public health workers and police to be acceptable. Fifty-nine percent of clubs reported contact with public health workers to be useful. One-third of the public health workers considered that they were not the most suitable professional group to be involved in delivering the intervention. In spite of a suggested culture of harmful alcohol consumption among rugby league participants and spectators, non-metropolitan rugby league clubs appear receptive to public health strategies that increase their responsible service of alcohol. The ability of the public health sector to meet this opportunity appears limited, and may require additional strategies to increase the capacity of public health workers to develop/deliver inter-sectorial interventions in this setting.


Biology of halophilic bacteria, Part II. Membrane lipids of extreme halophiles: biosynthesis, function and evolutionary significance.
Archaebacteria (archaea) are comprised of three groups of prokaryotes: extreme halophiles, methanogens and thermoacidophiles (extreme thermophiles). Their membrane phospholipids and glycolipids are derived entirely from a saturated, isopranoid glycerol diether, sn-2,3-diphytanylglycerol ('archaeol') and/or its dimer, dibiphytanyldiglyceroltetraether ('caldarchaeol'). In extreme halophiles, the major phospholipid is the archaeol analogue of phosphatidylglycerolmethylphosphate (PGP-Me); the glycolipids are sulfated and/or unsulfated glycosyl archaeols with diverse carbohydrate structure characteristic of taxons on the generic level. Biosynthesis of these archaeol-derived polar lipids occurs in a multienzyme, membrane-bound system that is absolutely dependent on high salt concentration (4 M). The highly complex biosynthetic pathways involve intermediates containing glycerol ether-linked C20-isoprenyl groups which are reduced to phytanyl groups to give the final saturated polar lipids. In methanogens, polar lipids are derived both from archaeol and caldarchaeol, and thermoacidophiles contain essentially only caldarchaeol-derived polar lipids. The function of these membrane polar lipids in maintaining the stability, fluidity and ionic properties of the cell membrane of extreme halophiles, as well as the evolutionary implications of the archaeol and caldarchaeol-derived structures will be discussed.


Role of endogenous opioids in syncope induced by head-up tilt test and its relationship with isoproterenol-dependent and isoproterenol-independent neurally-mediated syncope.
This study was designed to evaluate the role of endogenous opioids in neurally-mediated syncope. Head-up tilt test was performed on 35 patients with syncope of unknown origin. Plasma beta-endorphin was measured (1) at baseline, (2) at the end of tilt test or at time of syncope, (3) 15 min before isoproterenol-test, (4) at the end of the isoproterenol-test or at time of syncope. Subjects with a positive tilt testing showed a larger rise in plasma beta-endorphin concentrations at time of syncope (baseline 13.7+/-8.0 vs. syncope 41.4+/-26.4 pmol l(-1); P<0.01). On the contrary, patients with a positive isoproterenol-test showed no rise in plasma beta-endorphin levels (baseline 7.9+/-3.6 vs. syncope 7.4+/-2.7 pmol l(-1); P=ns). Patients with a passive negative tilt test (baseline 6.7+/-2.8 vs. end of test 7.0+/-3.3 pmol l(-1); P=ns) and negative isoproterenol tilt test (baseline 7.4+/-3.8 vs. end of test 8.1+/-3.4 pmol l(-1); P=ns) showed no changes in beta-endorphin concentrations. To further examine the efficacy of i.v. naloxone to prevent syncope, 10 patients were randomized to naloxone (0.02 mg/kg) or placebo. Second head-up tilt testing was negative in 1/5 patients with naloxone and in 2/5 patients with placebo. We conclude that, (1) endogenous opioids seem to be involved in vasovagal syncope induced by baseline head-up tilt test, (2) changes in plasma beta-endorphin concentrations show significant differences between patients who have isoproterenol-dependent and isoproterenol-independent syncope, this finding might occur in the setting of different pathophysiologic mechanisms, and (3) intravenous naloxone at a dose of 0.02 mg/kg was not superior to placebo in order to prevent positive responses to baseline tilt test.


Teaching binocular indirect ophthalmoscopy to novice residents using an augmented reality simulator.
To compare the traditional teaching approach of binocular indirect ophthalmoscopy (BIO) to the EyeSI augmented reality (AR) BIO simulator. Prospective randomized control trial. 28 post-graduate year one (PGY1) ophthalmology residents. Residents were recruited at the 2012 Toronto Ophthalmology Residents Introductory Course (TORIC). 15 were randomized to conventional teaching (Group 1), and 13 to augmented reality simulator training (Group 2). 3 vitreoretinal fellows were enrolled to serve as experts. Evaluations were completed on the simulator, with 3 tasks, and outcome measures were total raw score, total time elapsed, and performance. Following conventional training, Group 1 residents were outperformed by vitreoretinal fellows with respect to all 3 outcome measures. Following AR training, Group 2 residents demonstrated superior total scores and performance compared to Group 1 residents. Once the Group 1 residents also completed the AR BIO training, there was a significant improvement compared to their baseline scores, and were now on par with Group 2 residents. This study provides construct validity for the EyeSI AR BIO simulator and demonstrates that it may be superior to conventional BIO teaching for novice ophthalmology residents.


Comparison of stillbirth rates by cause among Haitians and non-Haitians in Canada.
To compare rates of stillbirth among Haitians and non-Haitians in Canada. A retrospective cohort study was performed using data on all stillborn and live-born singletons weighing at least 500 g in the province of Quebec, Canada, from 1981 to 2010. Stillbirth rates were computed, and hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for Haitians relative to non-Haitians. The main outcome measure was stillbirth by cause of death. Data for 9657 stillbirths (124 Haitian) and 2 414 751 live births (17 165 Haitian) were included. Stillbirth rates were higher for Haitians than non-Haitians (7.17 [95% CI 5.91-8.43] vs 3.96 [95% CI 3.88-4.04] per 1000 births), particularly for cord prolapse (adjusted HR 1.87, 95% CI 1.10-3.18) and placental abruption (adjusted HR 2.84, 95% CI 1.95-4.15). Haitians had higher risks of stillbirth due to cord prolapse and abruption at every week of pregnancy. Risks were not elevated for stillbirth due to congenital anomaly, a cause less responsive to urgent intervention. Stillbirth rates among Haitians are disproportionately high in Canada, particularly fetal death due to cord prolapse and placental abruption. The potential to reduce stillbirth rates through optimal emergency care in vulnerable minorities requires further investigation.


Impact of Media in Transport Study on Cell Monolayer Integrity and Permeability.
Literature review shows that various media have been used for in vitro transport study, but their impact on the monolayer integrity and permeability has been somehow neglected, and there is no systemic study on this subject. This study aims to investigate the impact of 6 commonly used media on Madin-Darby Canine Kidney cell viability and adherence, and the permeation of mannitol and propranolol. Dulbecco's modified Eagle medium (DMEM), cMedium (DMEM with serum), Hanks' balanced salt solution (HBSS), HBSS- (without Ca2+/Mg2+), Dulbecco's phosphate-buffered saline (DPBS), and DPBS- (without Ca2+/Mg2+) exhibited no cytotoxicity. Cell detachment was observed in 4 media in the order of DPBS- ≈ HBSS- > DPBS > HBSS. HBSS-/DPBS- caused 70% TEER reduction and 4-fold higher apparent permeability (Papp) of mannitol than the other media. The addition of D-glucose in DPBS- decreased the Papp of mannitol. Cations and glucose negligibly influenced the Papp of propranolol. The addition of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) in HBSS increased the Papp of both mannitol and propranolol for 2-3 folds without TEER reduction. In conclusion, the media compositions (Ca2+/Mg2+, glucose, vitamins, amino acids, and HEPES) can affect the monolayer integrity and permeability. DMEM and cMedium without HEPES are hence suggested as the media in transport study to avoid the potential impact on the monolayer integrity and permeability by the media.


Assessing Variability of Control Within a Single Day in Intermittent Exotropia.
To assess intra-individual hour-to-hour variability of control in intermittent exotropia using a simple office scale: Look And Cover, then Ten seconds of Observation Scale for Exotropia (LACTOSE). In this prospective cross-sectional study, the degree of control for distance and near was measured using the LACTOSE, a 5-point scale ranging from 0 to 4. A single investigator performed multiple measurements of the control of each patient with at least an hour interval between measurements. Of the 95 patients with intermittent exotropia enrolled, 66 (69.5%) were assessed two times and 29 (30.5%) were assessed three times for their control. Most patients had consistent control scores across multiple assessments for distance (n = 63, 66.3%) and near (n = 70, 73.7%). Forty-five (47.4%) patients demonstrated variable control for either distance or near, mostly (n = 27, 60.0%) showing a one-step difference. None presented with more than a two-step difference in the control score on repeated measurements. An initial LACTOSE score of 4 (very poor control) or 1 (very good control) remained unchanged in subsequent assessments for both distance (P = .049) and near (P < .001). One-third of patients with intermittent exotropia showed variable control scores even during a single day across multiple measurements using the LACTOSE scale. Those who showed consistent control had very good or very poor control, whereas those with variable control had not had very good or very poor control on their initial LACTOSE measurements. [J Pediatr Ophthalmol Strabismus. 2020;57(6):378-383.].


Yinchen decoction protects against cholic acid diet-induced cholestatic liver injury in mice through liver and ileal FXR signaling.
Cholestasis is a pathophysiological syndrome characterized by the accumulation of bile acids (BAs) that leads to severe liver disease. Artemisia capillaris is documented in Chinese Pharmacopoeia as the authentic resources for Yinchen. Although Yinchen (Artemisia capillaris Thunb.) decoction (YCD) has been used in China for thousands of years to treat jaundice, the underlying mechanisms to ameliorate cholestatic liver injury have not been elucidated. To investigate the molecular mechanism of how YCD protects against 1% cholic acid (CA) diet-induced intrahepatic cholestasis through FXR signaling. Wild-type and Fxr-deficient mice were fed a diet containing 1% CA to establish the intrahepatic cholestasis model. The mice received low-, medium-, or high-dose YCD for 10 days. Plasma biochemical markers were analyzed, liver injury was identified by histopathology, and hepatic and plasma BA content was analyzed. Western blot was used to determine the expression levels of transporters and enzymes involved in BA homeostasis in the liver and intestine. In wild-type mice, YCD significantly improved plasma transaminase levels, multifocal hepatocellular necrosis, and hepatic and plasma BA contents, upregulated the expression of hepatic FXR and downstream target enzymes and transporters. Meanwhile, YCD significantly induced the expressions of intestinal FXR and FGF15 and hepatic FGFR4. In contrast, the hepatic protective effect of YCD on cholestasis was abolished in Fxr-deficient mice. YCD protects against cholestatic liver injury induced by a CA diet by restoring the homeostasis of BAs via activation of the liver FXR/SHP and ileal FXR/FGF15 signaling pathways. Furthermore, chlorogenic acid and caffeic acid may be the pharmacological agents in YCD responsible for protecting against cholestatic liver injury.


The role of chemical (CO2) drive in the apnea induced by high frequency ventilation in the cat.
The purpose of the present study was to compare the relative roles of PaCO2 and pulmonary mechanoreceptors in the generation of apnea during high frequency ventilation (HFV) and conventional mechanical ventilation (CMV) in the anesthetized cat. Our hypothesis was that PaCO2 primarily determines the appearance of apnea, while mechanoreceptor input plays an important but secondary role. We calculated the tidal volume which would have a 50% chance of inducing apnea (VT50) for each combination of ventilator settings, and used it as a standard for comparison of mechanical dynamic inputs. When either 2% or 5% CO2 was added to the bias flow during HFV, the VT50 was significantly increased over that seen with a room air bias flow. Apnea was observed during either mode of ventilation only when PaCO2 was reduced below normocapnic levels. The mean tidal volume associated with each apnea group was larger than that for the corresponding nonapnea group. There was no difference in the PaCO2 for apnea between HFV and CMV, but the EMG of the diaphragm did differ. With HFV-apnea tonic activity was observed, while CMV-apnea showed abolition of all activity. We conclude that both HFV- and CMV-induced apnea depend primarily on lowering the chemical drive (PaCO2), and secondarily on inhibitory mechanical input (VT). The excitation of rapidly adapting receptors during HFV could explain the tonic EMG activity.


Progress in reducing cancer mortality in the United States by congressional district, 1996-2003 to 2012-2020.
United States cancer death rates have been steadily declining since the early 1990s, but information on disparities in progress against cancer mortality across congressional districts is lacking. This study examined trends in cancer death rates, overall and for lung, colorectal, female breast, and prostate cancer by congressional district. County level cancer death counts and population data from the National Center for Health Statistics were used to estimate relative change in age-standardized cancer death rates from 1996-2003 to 2012-2020 by sex and congressional district. From 1996-2003 to 2012-2020, overall cancer death rates declined in every congressional district, with most congressional districts showing a 20%-45% decline among males and a 10%-40% decline among females. In general, the smallest percent of relative declines were found in the Midwest and Appalachia, whereas the largest declines were found in the South along the East Coast and the southern border. As a result, the highest cancer death rates generally shifted from congressional districts across the South in 1996-2003 to districts in the Midwest and central divisions of the South (including Appalachia) in 2012-2020. Death rates for lung, colorectal, female breast, and prostate cancers also declined in almost all congressional districts, although with some variation in relative changes and geographical patterns. Progress in reducing cancer death rates during the past 25 years considerably vary by congressional district, underscoring the need for strengthening existing and implementing new public health policies for broad and equitable application of proven interventions such as raising tax on tobacco and Medicaid expansion.


Does site of specimen extraction affect incisional hernia rate after robot assisted laparoscopic radical prostatectomy?
Robot assisted laparoscopic radical prostatectomy (RALP) spread in the last decade as a minimally invasive alternative to open radical prostatectomy for men with localized prostate cancer. It is associated with excellent surgical, functional and oncological results with less postoperative pain and shorter convalescence. Anyway, the development of an incisional hernia (IH), may negate known benefits as it can lead not only to bothersome symptoms but also to severe complications, such as bowel obstruction, strangulation and perforation. Port-site or extraction site hernias, whose incidence rate is underdiagnosed, have become more commonly after minimally invasive surgery; but IH rate after robot-assisted radical prostatectomy has not been well characterized. This study aimed to evaluate the impact of extraction-site location (vertical supra-umbilical incision versus an off-midline incision) on incisional hernia rates in robotic prostatectomy. We included in the study 800 patients undergone RALP, 400 with a supra-umbilical incision for specimen extraction and 400 with off-midline incision. All were followed up for at least 3 years. The main study end point was IH occurrence at the extraction site (midline versus off-midline). IH rate for the entire series was 4.75%, in particular 5% for the midline group and 4.5% for the off-midline group. The hernias were diagnosed at a mean of 20.2 and 18.2 months after surgery, respectively in the two groups. There was no statistically significant differences in baseline characteristics; anyway larger prostate weight, wound infection and history of prior cholecystectomy were associated with higher proportion of IH. Extraction site hernias are a rare but a potentially serious complication following RALP. In our series, the midline extraction doesn't result in a significantly higher IH rate in comparison with the off-midline extraction site.


The potter's wheel: the host's role in sculpting its microbiota.
Animals, ranging from basal metazoans to primates, are host to complex microbial ecosystems; engaged in a symbiotic relationship that is essential for host physiology and homeostasis. Epithelial surfaces vary in the composition of colonizing microbiota as one compares anatomic sites, developmental stages and species origin. Alterations of microbial composition likely contribute to susceptibility to several distinct diseases. The forces that shape the colonizing microbial composition are the focus of much current investigation, and it is evident that there are pressures exerted both by the host and the external environment to mold these ecosystems. The focus of this review is to discuss recent studies that demonstrate the critical importance of host factors in selecting for its microbiome. Greater insight into host-microbiome interactions will be essential for understanding homeostasis at mucosal surfaces, and developing useful interventions when homeostasis is disrupted.


Role of anoctamin-1 and bestrophin-1 in spinal nerve ligation-induced neuropathic pain in rats.
Calcium-activated chloride channels (CaCCs) activation induces membrane depolarization by increasing chloride efflux in primary sensory neurons that can facilitate action potential generation. Previous studies suggest that CaCCs family members bestrophin-1 and anoctamin-1 are involved in inflammatory pain. However, their role in neuropathic pain is unclear. In this investigation we assessed the involvement of these CaCCs family members in rats subjected to the L5/L6 spinal nerve ligation. In addition, anoctamin-1 and bestrophin-1 mRNA and protein expression in dorsal root ganglion (DRG) and spinal cord was also determined in the presence and absence of selective inhibitors. L5/L6 spinal nerve ligation induced mechanical tactile allodynia. Intrathecal administration of non-selective CaCCs inhibitors (NPPB, 9-AC and NFA) dose-dependently reduced tactile allodynia. Intrathecal administration of selective CaCCs inhibitors (T16Ainh-A01 and CaCCinh-A01) also dose-dependently diminished tactile allodynia and thermal hyperalgesia. Anoctamin-1 and bestrophin-1 mRNA and protein were expressed in the dorsal spinal cord and DRG of naïve, sham and neuropathic rats. L5/L6 spinal nerve ligation rose mRNA and protein expression of anoctamin-1, but not bestrophin-1, in the dorsal spinal cord and DRG from day 1 to day 14 after nerve ligation. In addition, repeated administration of CaCCs inhibitors (T16Ainh-A01, CaCCinh-A01 or NFA) or anti-anoctamin-1 antibody prevented spinal nerve ligation-induced rises in anoctamin-1 mRNA and protein expression. Following spinal nerve ligation, the compound action potential generation of putative C fibers increased while selective CaCCs inhibitors (T16Ainh-A01 and CaCCinh-A01) attenuated such increase. There is functional anoctamin-1 and bestrophin-1 expression in rats at sites related to nociceptive processing. Blockade of these CaCCs suppresses compound action potential generation in putative C fibers and lessens established tactile allodynia. As CaCCs activity contributes to neuropathic pain maintenance, selective inhibition of their activity may function as a tool to generate analgesia in nerve injury pain states.


Effect of the gel elasticity of model skin matrices on the distance/depth-dependent transmission of vibration energy supplied from a cosmetic vibrator.
The purpose of this study was to determine how the energies supplied from a cosmetic vibrator are deeply or far transferred into organs and tissues, and how these depths or distances are influenced by tissue elasticity. External vibration energy was applied to model skin surfaces through a facial cleansing vibrator, and we measured a distance- and depth-dependent energy that was transferred to model skin matrices. As model skin matrices, we synthesized hard and soft poly(dimethylsiloxane) (PDMS) gels, as well as hydrogels with a modulus of 2.63 MPa, 0.33 MPa and 21 kPa, respectively, mostly representing those of skin and other organs. The transfer of vibration energy was measured either by increasing the separation distances or by increasing the depth from the vibrator. The energies were transmitted deeper into the hard PDMS than into the soft PDMS and hydrogel matrices. This finding implies that the vibration forces influence a larger area of the gel matrices when the gels are more elastic (or rigid). There were no appreciable differences between the soft PDMS and hydrogel matrices. However, the absorbed energies were more concentrated in the area closest to the vibrator with decreasing elasticity of the matrix. Softer materials absorbed most of the supplied energy around the point of the vibrator. In contrast, harder materials scattered the external energy over a broad area. The current results are the first report in estimating how the external energy is deeply or distantly transferred into a model skins depending on the elastic moduli of the models skins. In doing so, the results would be potentially useful in predicting the health of cells, tissues and organs exposed to various stimuli.


Oral health and oral treatment needs in patients fulfilling the DSM-IV criteria for dental phobia: Possible influence on the outcome of cognitive behavioral therapy.
To describe oral health and oral treatment needs in a group of dental phobic patients (DSM-IV) and to explore possible relationships between these factors and changes in self-reported dental anxiety before and after phobia treatment. Forty patients (25 women) fulfilling the DSM-IV criteria for specific phobia were included in the study. Mean age of the group was 34.9 years (range 19-60) and mean dental avoidance was 11.2 years (range 3-30 years). They were treated with cognitive behavioral therapy (CBT) during either one session (3 h) or five sessions (1 h each). Oral health was evaluated by orthopantomogram and clinical examination. The outcome of the CBT was measured by the change in dental anxiety scores (DAS, DFS) and in positive and negative thoughts during a standardized dental behavior test from pretreatment to 1-year follow-up. Mean (SD) DMFT was 16.5 (5.8), range 3-26; DT was 6.6 (4.2). Mean number of teeth with dental treatment need (restorative, periodontal, extractions, etc.) was 9.6 (6.9), range 1-28. There were statistically significant correlations between number of decayed teeth and decrease in negative thoughts (r=-0.39, p=0.048) and maximum anxiety (r=-0.65, p=0.001). The total number of teeth with treatment need correlated with an increase in positive thoughts (r=0.60, p=0.001) and decrease in maximum anxiety (r=0.50, p=0.015). There are large variations in oral health and treatment needs among patients fulfilling the DSM-IV criteria for dental phobia. Patients with the best dental health and lowest treatment needs experience the largest increase in positive cognitions during exposure to dental treatment at 1-year follow-up.


A longitudinal study of patients with multidirectional instability of the shoulder with seven- to ten-year follow-up.
The purpose of our study was to evaluate the long-term outcomes of patients with multidirectional instability of the shoulder initially treated with rehabilitation exercises. Sixty-four patients were treated for atraumatic multidirectional instability of the shoulder between 1987 and 1990. Preliminary evaluation was performed 2 years after initiation of treatment, and final evaluation of the patients was performed at a mean of 8 years after initiation of treatment. At the preliminary evaluation, 5 patients were lost to follow-up. Of the remaining 59 patients, 20 had undergone surgical treatment for stabilization of their shoulder. Of the 39 nonsurgically treated patients, 19 continued to have significant pain, and 18 continued to have significant instability of their shoulder. Of the 59 patients, 28 subjectively rated their shoulder condition as better or much better after conservative treatment. At the final evaluation, 2 more patients were lost to follow-up, and 1 additional patient had had surgical treatment. Thus, of the 57 patients available for final follow-up, 36 had received nonsurgical care, and 21 had undergone surgical treatment. Of the 36 nonsurgically treated patients, 23 rated their shoulders as good or excellent with regard to pain, and 17 were good or excellent with regard to instability. By the modified Rowe grading scale, 5 of 36 patients had excellent results, and 12 had good results. The remaining 19 patients were rated as having poor results. Only 8 patients reported that their shoulders were free of all pain and instability. Overall, of the entire group of 57 patients evaluated between 7 and 10 years after initiation of care, 17 had a satisfactory outcome from nonsurgical management based on stability and Rowe scores, 23 had good or excellent results with regard to pain, and 20 subjectively rated their shoulders as good or excellent. This review revealed a relatively poor response to nonsurgical treatment of multidirectional instability in this population of young, athletic patients.


Clinical and genetic spectrum in Chinese families with Fabry disease: a single-centre case series.
Fabry disease (FD) is an X-linked genetic disease caused by mutations in the GLA gene that leads to deficient activity of lysosomal enzymes, accumulation of globotriaosylceramide in multi-organ systems, and variant clinical manifestations. We aimed to detail the clinical and genetic spectrum of FD in Chinese families. Five male probands with unexplained left ventricular hypertrophy and their family members were investigated. Genetic screening was available in 11 subjects of the 5 families, 10 of whom proved to be carriers of either GLA gene mutation, including 3 previous reported missense mutations (c.128G > A, c.811G > A, c.950T > C), 1 novel missense mutation (c.37G > C), and 1 novel deletion mutation (c.1241delT). A total of 17 patients were definitely or possibly diagnosed of FD, given their clinical manifestations and hereditary nature of FD. Echocardiography demonstrated normal cardiac structure and function in six female patients. Electrocardiographic pre-excitation occurred in 80% (4/5) of men and 16.7% (1/6) of women. Six patients (6/14, 42.9%) had chronic kidney disease with decreased renal function and all were male (6/7, 85.7%). Six patients presented with acroparesthesia, hypohidrosis, or both. Three female patients and two male patients experienced sudden death, and one male patient with the mutation (c.128G > A) died of progressive heart failure, between 41 and 66 years of age. We reported five unrelated families of FD with different GLA mutations. Clinical manifestations were highly heterogeneous between male and female patients even within the same family. Female patients showed relatively low risks of structural heart disease and renal insufficiency. However, the long-term outcomes might be adverse in both sexes. Our study underlines the importance of molecular screening of the GLA gene for early identification and clinical decision making in patients with FD.


Exosomes in virus-associated cancer.
Exosomes are phospholipid bilayer membrane-enclosed vesicles in a size from 30 to 150 nm, carrying a variety of active components, such as proteins, mRNA and miRNAs, and are involved in intercellular communication. Exosomes are released by almost all living cells and detected in various biological fluids. Viruses especially oncogenic viruses have been reported to influence the formation of virus-associated cancer through reshaping the tumor microenvironment via exosomes. In this review, a role of exosomes released by oncogenic virus-infected cells in promoting or inhibiting cancer formation is outlined. Moreover, the prospects and challenges of exosome applications in cancer therapies are critically discussed.


Physiological response, microbial diversity characterization, and endophytic bacteria isolation of duckweed under cadmium stress.
Duckweed is a cadmium (Cd) hyperaccumulator. However, its enrichment characteristics and physiological responses to Cd have not been systematically studied. The physiological responses, enrichment characteristics, diversity of endophytic bacterial communities, and isolation of Cd-resistant endophytes in duckweed (Lemna minor 0014) were studied for different durations and Cd concentrations. The results indicated that peroxidase (POD) and catalase (CAT) activities decreased while superoxide dismutase activity first increased and then decreased with increasing Cd stress duration. POD activities, CAT activities, and O2- increased as Cd concentrations increased. Malondialdehyde content and Cd accumulation in duckweed increased with increasing concentrations and time. This endophytic diversity study identified 488 operational taxonomic units, with the dominant groups being Proteobacteria, Firmicutes, and Actinobacteria. Paenibacillus sp. Y11, a strain tolerant to high concentrations of Cd and capable of significantly promoting duckweed growth, was isolated from the plant. Our study revealed the effects of heavy metals on aquatic plants, providing a theoretical basis for the application of duckweed in water pollution.


Nonlinear effects and effect modification at the participant-level in IPD meta-analysis part 2: methodological guidance is available.
To review methodological guidance for nonlinear covariate-outcome associations (NL), and linear effect modification and nonlinear effect modification (LEM and NLEM) at the participant level in individual participant data meta-analyses (IPDMAs) and their power requirements. We searched Medline, Embase, Web of Science, Scopus, PsycINFO and the Cochrane Library to identify methodology publications on IPDMA of LEM, NL or NLEM (PROSPERO CRD42019126768). Through screening 6,466 records we identified 54 potential articles of which 23 full texts were relevant. Nine further relevant publications were published before or after the literature search and were added. Of these 32 references, 21 articles considered LEM, 6 articles NL or NLEM and 6 articles described sample size calculations. A book described all four. Sample size may be calculated through simulation or closed form. Assessments of LEM or NLEM at the participant level need to be based on within-trial information alone. Nonlinearity (NL or NLEM) can be modeled using polynomials or splines to avoid categorization. Detailed methodological guidance on IPDMA of effect modification at participant-level is available. However, methodology papers for sample size and nonlinearity are rarer and may not cover all scenarios. On these aspects, further guidance is needed.


First metatarsophalangeal arthroscopy in patients with post-traumatic hallux valgus.
Post-traumatic hallux valgus is relatively rare and has been reported after rupture of the medial collateral ligament of the first metatarsophalangeal (MTP-1) joint; Lisfranc joint injury; turf toe injury; medial plantar nerve entrapment secondary to tibial fracture or first metatarsal fracture. Post-traumatic hallux valgus after medial collateral ligament injury has a high incidence of MTP-1 pathology. Detailed history and clinical examination can facilitate differentiation of the source(s) of the patient's symptoms and assist accurate formulation of the surgical plan. First, MTP arthroscopy is a feasible diagnostic and therapeutic tool to manage the MTP-1 joint pain in hallux valgus following injury to the MTP-1 joint.


The membrane biofilm reactor (MBfR) for water and wastewater treatment: principles, applications, and recent developments.
The membrane biofilm reactor (MBfR), an emerging technology for water and wastewater treatment, is based on pressurized membranes that supply a gaseous substrate to a biofilm formed on the membrane's exterior. MBfR biofilms behave differently from conventional biofilms due to the counter-diffusion of substrates. MBfRs are uniquely suited for numerous treatment applications, including the removal of carbon and nitrogen when oxygen is supplied, and reduction of oxidized contaminants when hydrogen is supplied. Major benefits include high gas utilization efficiency, low energy consumption, and small reactor footprints. The first commercial MBfR was recently released, and its success may lead to the scale-up of other applications. MBfR development still faces challenges, including biofilm management, the design of scalable reactor configurations, and the identification of cost-effective membranes. If future research and development continue to address these issues, the MBfR may play a key role in the next generation of sustainable treatment systems.


The source of the dispersity of gramicidin A single-channel conductances. The L X Leu5-gramicidin A analog.
The L X Leu5-gramicidin A analog has been designed, synthesized, and verified for the purpose of testing the perspective that different side-chain distributions are responsible for the dispersity of single-channel conductances. The structural analysis shows that the L . Leu5 analog would limit the possible number of side-chain distributions and that the dispersity of channel conductances would decrease. The finding is the expected decrease in less probable conductance states and the associated increase in the probability of the most probable conductance state.


Assessment of diclofenac permeation with different formulations: anti-inflammatory study of a selected formula.
The aim of this study was to improve the transdermal permeation of sodium diclofenac. Permeation studies were carried out in vitro using human skin (0.4 mm thick) from plastic surgery as a membrane. Four liquid formulations of 1% (w/w) sodium diclofenac were assayed: three ternary solvent systems (M4, M5, M6) and one microemulsion (M3). A 1% (w/w) solution of sodium diclofenac and a commercially available semisolid preparation were tested as reference formulations. The following permeation parameters for diclofenac were assessed: permeability coefficient, flux and drug permeated and retained in the skin at 24 h. The highest values of these parameters were obtained with formula M4, which contains transcutol 59.2%, oleic acid 14.9% and d-limonene 5% (w/w) as permeation enhancers. The anti-inflammatory activity of this formula was compared with that of the semisolid preparation on carrageenan-induced paw edema in rats. As expected from in vitro results, the M4 diclofenac delivery system showed higher activity than the semisolid preparation, both when applied locally (to the inflammation area) and when applied systemically (to the back). Neither treatment irritated the skin when tested on rabbits in a 72-h trial. These results suggest that topical delivery of sodium diclofenac with an absorption enhancer such as a mixture of oleic acid and d-limonene (M4) may be an effective medication for both dermal and subdermal injuries.


Design and synthesis of novel 6-aryl substituted 4-anilinequinazoline derivatives as potential PI3Kδ inhibitors.
In this study, a series of new 6-aryl substituted 4-anilinequinazolines was designed and synthesized as PI3Kδ inhibitors based on our reported chemical structures. The preliminary structure-activity relationship (SAR) was established, and compounds 13h and 13k displayed most potent PI3Kδ inhibitory activities with the IC50 values of 9.3nM and 9.7nM, respectively. Compound 13h demonstrated similar anti-proliferative profiles to idelalisib against three human B cell lines. Three key hydrogen bonding interactions were found in the docking of 13h with PI3Kδ enzyme. These results suggest that compound 13h possessed nanomolar PI3Kδ inhibitory activity and distinctive chemical structure, deserving further structural optimization.


Prosthetic mitral inflow mimicking severe aortic regurgitation (revisited). An echocardiographic challenge.
Assessing aortic regurgitation (AR) severity in patients with mitral valve prosthesis may pose an echocardiographic challenge. We present a case of mild AR in whom difficulty occurred in judging its severity due to eccentric mitral prosthetic inflow signals filling practically completely the proximal left ventricular outflow tract in diastole mimicking severe AR. Frame-by-frame analysis of two-dimensional transthoracic echocardiographic images using a small sector depth and width was helpful in clarifying the true severity of AR.


Mechanistic link between PKR dimerization, autophosphorylation, and eIF2alpha substrate recognition.
The antiviral protein kinase PKR inhibits protein synthesis by phosphorylating the translation initiation factor eIF2alpha on Ser51. Binding of double-stranded RNA to the regulatory domains of PKR promotes dimerization, autophosphorylation, and the functional activation of the kinase. Herein, we identify mutations that activate PKR in the absence of its regulatory domains and map the mutations to a recently identified dimerization surface on the kinase catalytic domain. Mutations of other residues on this surface block PKR autophosphorylation and eIF2alpha phosphorylation, while mutating Thr446, an autophosphorylation site within the catalytic-domain activation segment, impairs eIF2alpha phosphorylation and viral pseudosubstrate binding. Mutational analysis of catalytic-domain residues preferentially conserved in the eIF2alpha kinase family identifies helix alphaG as critical for the specific recognition of eIF2alpha. We propose an ordered mechanism of PKR activation in which catalytic-domain dimerization triggers Thr446 autophosphorylation and specific eIF2alpha substrate recognition.


Fused primary teeth: a documented familial report of case.
A case report of fused teeth in two of five siblings is described. Both siblings had fusion of contralateral lower primary canines and lateral incisors. One had aplasia of one of the succedaneous lateral incisors.


High-throughput Evaluation of Protein Migration and Localization after Laser Micro-Irradiation.
DNA- and histone-related research frequently comprises the quantitative analysis of protein modifications, such as histone phosphorylation. Analysis of accumulation and disappearance of protein foci are used to monitor DNA damage and repair kinetics. If the protein of interest doesn't accumulate in foci, laser micro-irradiation of single nuclei provides an alternative method to monitor DNA repair proteins and histone dynamics at the DNA damage site. We have developed an automated evaluation tool for standardized, high-throughput analysis of micro-irradiated cells featuring single cell background subtraction and detection across multiple fluorescence channels, allowing for robust statistics.


High-performance affinity chromatography of oligonucleotides on nucleic acid analogue immobilized silica gel columns.
The nucleic acid analogues poly(9-vinyladenine) (PVAd), poly(9-adenylethyl methacrylate) and poly(thymylethyl methacrylate) (PTM) were chemically bonded to porous silica gel, which had been pretreated with 3-trimethoxysilylpropyl methacrylate, by free radical copolymerization to produce novel packing materials for affinity chromatographic columns. The columns separated nucleosides and nucleotide dimers on the basis of hydrophobic interaction using an aqueous buffer and complementary hydrogen bonding interaction in methanol as an eluent. The PVAd- and PTM-silica gel columns gave a nucleobase-selective separation of oligonucleotides differing in length from mixtures of oligoadenylic and oligouridylic acids. On the PVAd-silica gel column terminal phosphate isomers of oligouridylic acid up to seven mer were resolved and the elution order of the isomers was different from that on an ODS column.


Optimizing antimicrobial therapy in children.
Management of common infections and optimal use of antimicrobial agents are presented, highlighting new evidence from the medical literature that enlightens practice. Primary therapy of staphylococcal skin abscesses is drainage. Patients who have a large abscess (>5 cm), cellulitis or mixed abscess-cellulitis likely would benefit from additional antibiotic therapy. When choosing an antibiotic for outpatient management, the patient, pathogen and in vitro drug susceptibility as well as tolerability, bioavailability and safety characteristics of antibiotics should be considered. Management of recurrent staphylococcal skin and soft tissue infections is vexing. Focus is best placed on reducing density of the organism on the patient's skin and in the environment, and optimizing a healthy skin barrier. With attention to adherence and optimal dosing, acute uncomplicated osteomyelitis can be managed with early transition from parenteral to oral therapy and with a 3-4 week total course of therapy. Doxycycline should be prescribed when indicated for a child of any age. Its use is not associated with dental staining. Azithromycin should be prescribed for infants when indicated, whilst being alert to an associated ≥2-fold excess risk of pyloric stenosis with use under 6 weeks of age. Beyond the neonatal period, acyclovir is more safely dosed by body surface area (not to exceed 500 mg/m(2)/dose) than by weight. In addition to the concern of antimicrobial resistance, unnecessary use of antibiotics should be avoided because of potential later metabolic effects, thought to be due to perturbation of the host's microbiome.


Haplotype tagging efficiency in worldwide populations in CTLA4 gene.
The cytotoxic T lymphocyte antigen 4 (CTLA4) acts as a potent negative regulator of T-cell response, and has been suggested as a pivotal candidate gene for autoimmune disorders such as Graves' disease, type 1 diabetes and autoimmune hypothyroidism, among others. Several single-nucleotide polymorphisms (SNPs) have been proposed as the susceptibility variants, or to be in strong linkage disequilibrium (LD) with the variant. Nevertheless, contradictory results have been found, which may be due to lack of knowledge of the genetic structure of CTLA4 and its geographic variation. We have typed 17 SNPs throughout the CTLA4 gene region in order to analyze the haplotype diversity and LD structure in a worldwide population set (1262 individuals from 44 populations) to understand the variation pattern of the region. Allele and haplotype frequency differentiation between populations is consistent with genomewide averages and points to a lack of strong population-specific selection pressures. LD is high and its pattern is not significantly different within or between continents. However, haplotype composition is significantly different between geographical groups. A continent-specific set of haplotype tagging SNPs has been designed to be used for future association studies. These are portable among populations, although their efficiency might vary depending on the population haplotype spectrum.