Characterization of multiple active forms of the NADPH dehydrogenase component of the oxidase complex from rabbit peritoneal neutrophils by photolabeling with an arylazido derivative of NADP+.
A NADPH cytochrome c oxidoreductase purified from membranes of rabbit peritoneal neutrophil was shown to behave as the NADPH dehydrogenase component of the O2- generating oxidase complex. A photoactivable derivative of NADP+, azido nitrophenyl-gamma-aminobutyryl NADP+ (NAP4-NADP+), was synthesized in its labeled [3H] form and used to photolabel the NADPH cytochrome c reductase at different stages of the purification procedure. Control assays performed in dim light indicated that the reduced form of NADP4-NADP+ generated by reduction with glucose-6-phosphate and glucose-6-phosphate dehydrogenase was oxidized at virtually the same rate as NADPH. Upon photoirradiation of the purified reductase in the presence of [3H]NAP4-NADP+ and subsequent separation of the photolabeled species by sodium dodecyl sulfate polyacrylamide gel electrophoresis, radioactivity was found to be present predominantly in a protein band with a molecular mass of 77-kDa and accessorily in bands of 67-kDa and 57-kDa. Evidence is provided that the 67-kDa and 57-kDa proteins arose from the 77-kDa protein by proteolysis. Despite removal of part of the sequence, the proteolyzed proteins were still active in catalyzing electron transport from NADPH to cytochrome c and in binding the photoactivable derivative of NADP+.


[Prospective monocentric study of the toxicity and the efficacy of concurrent trastuzumab and radiotherapy].
Prospective monocentric study of the toxicities related to concurrent administration of trastuzumab to breast radiotherapy. One hundred and seventy-three patients were treated between June 2003 and March 2009 by concurrent trastuzumab with normofractionated radiotherapy. Trastuzumab was delivered every 3 weeks (8mg/kg in the first infusion then 6mg/kg) during a median time of 12 months (2-62). Left ventricular ejection fraction was assessed by echocardiography or cardiac scintigraphy at baseline, before and after radiotherapy, every 3 months for 1 year and annually. A left ventricular ejection fraction strictly lower than 55% was considered as altered. All toxicities were evaluated using Common Terminology Criteria for Adverse Effects version 3.0. Median follow-up was 52 months (17-88). Median age was 52 years (25-83). One hundred and thirty-four patients (77.5%) received radiotherapy to the internal mammary chain. Acute grade 1, 2 and 3 epithelitis was described in 132 (76.3%), 32 (18.5%) and six patients (3.4%), respectively. At 23 months, grade 1 and 2 fibrosis was observed in 31 and eight patients, respectively (18.8 and 4.6%). Left ventricular ejection fraction remained normal for 159 patients (91.9%) before radiotherapy. Among them, 18 (11.3%) experienced a left ventricular ejection fraction alteration, eight (5.0%) at the completion of radiotherapy. Congestive heart failure occurred in one patient (0.6%). Toxicities related to the association of trastuzumab to breast radiotherapy were mild. Further follow-up is warranted.


Effect of preoperative oral erythromycin, erythromycin-ranitidine, and ranitidine-metoclopramide on gastric fluid pH and volume.
To determine whether combining erythromycin with ranitidine is more efficacious than erythromycin or established ranitidine-metoclopramide combination in reducing the volume and acidity of gastric aspirate. Randomized, double-blind study. Operating room complex. Eighty ASA physical status I and II patients. Patients were divided into 4 groups of 20 patients each. All patients received the study medication (in tablet form) packed in identical gelatin capsules 60 to 90 minutes before surgery in the premedication room. Patients in group PP were given two placebo tablets; group EP received erythromycin 250 mg, and placebo; group ER received erythromycin 250 mg, and ranitidine 150 mg; and group RM was given ranitidine 150 mg, and metoclopramide 10 mg. After tracheal intubation, gastric fluid was aspirated via orogastric tube, and volume and pH of the aspirate were studied. Significantly higher gastric volume occurred in group PP than groups EP, ER, or RM (P < 0.001). There were no differences in volumes among groups EP, ER, and RM. Gastric pH was significantly lower (P < 0.001) in groups PP and EP than in groups ER and RM. Erythromycin and ranitidine combination is more efficacious than erythromycin alone in reducing the acidity and volume of gastric fluid. No difference was found between erythromycin-ranitidine and ranitidine-metoclopramide combination.


Identifying children at high somatic risk: possible effects on the parents' views of the child's health and parents' relationship to the pediatric health services.
Country-wide neonatal screening for alpha 1-antitrypsin deficiency (ATD) was discontinued due to clinical observations of negative psychological effects on the parents. In a subsequent systematic study, hypotheses of long-term negative effects on the parents' views of the child's health and on the parents' relationship to the pediatric services were tested by comparing these characteristics in parents with a child with ATD versus control parents, studied through interviews in the home. The identification of the ATD was found to have had negatively influenced the parents' view of the child's general health, but no evidence was found of increased parental anxiety regarding the child's current health or emotional dependence on medical personnel, of increased (reported) usage of pediatric services, or of more negative attitudes toward the pediatric services.


Infant weight gain and childhood overweight status in a multicenter, cohort study.
To determine whether a rapid rate of weight gain in early infancy is associated with overweight status in childhood. Prospective, cohort study from birth to age 7 years. Twelve sites across the United States. Twenty-seven thousand, eight hundred ninety-nine (27 899) eligible participants born at full term between 1959 and 1965. Overweight status at age 7 years, defined by a body mass index above the 95th percentile of the Centers for Disease Control and Prevention reference data. In the 19 397 participants with complete data (69.6%), the prevalence of overweight status at age 7 years was 5.4%. The rate of weight gain during the first 4 months of life (as 100 g/month) was associated with being overweight at age 7 years, after adjustment for several confounding factors: odds ratio: 1.38; 95% confidence interval: 1.32-1.44. This association was present in each birth weight quintile, and remained significant after adjustment for the weight attained at age 1 year (odds ratio: 1.17; 95% confidence interval: 1.11-1.24). A pattern of rapid weight gain during the first 4 months of life was associated with an increased risk of overweight status at age 7 years, independent of birth weight and weight attained at age 1 year. These findings may lead to new hypotheses regarding the cause of childhood obesity, which may contribute to our understanding of this increasing public health problem in the United States.


Discovery of the inhibitors of tumor necrosis factor alpha with structure-based virtual screening.
Tumor necrosis factor alpha (TNF-α) has been considered as one of the attractive drug targets for allergic diseases including asthma. We have been able to identify five novel TNF-α inhibitors with a drug-design protocol involving the structure-based virtual screening and in vitro cell-based assay for antagonistic activity. Because the newly discovered inhibitors are structurally diverse and have the desirable physicochemical properties as a drug candidate, they deserve a further investigation as anti-asthmatic drugs. The interactions of the identified inhibitors in the binding site of TNF-α dimer are addressed in detail to understand the mechanisms for the stabilization of the inactive dimeric form of TNF-α.


Effects of sex and reproductive state on acoustic responsiveness in hamsters.
Semi-quantitative [14C]2-deoxyglucose (2DG) autoradiography was used to describe the responses of hamsters to 35 kHz mimics of the "ultrasounds" used for communication during mating. The first study examined the processing of ultrasounds and ambient noise by estrous females, some of which were deafened or hemideafened with plastic ear plugs. These data failed to reveal responses specific to the ultrasounds. However, lateralized responses to the ambient noise were apparent, especially in the hemideafened subjects. For the ventral cochlear nucleus (VCN), 2DG uptake was elevated contralateral to the plug and ipsilateral to the effective stimulus. In contrast, uptake by more rostral structures (dorsal n. of the lateral lemniscus = DNLL; ventral n. of the lateral lemniscus = VNLL; central n. of the inferior colliculus = CIC; medial geniculate n.) was elevated contralateral to the stimulus. A second experiment examined the responses of intact or castrated male and female hamsters to unilaterally presented ultrasounds and ambient noise. As before, relative levels of 2DG uptake differed across hemispheres for structures including the VCN, trapezoid body, VNLL, DNLL, and CIC. More surprisingly, intact females showed more 2DG uptake than males in the DNLL, auditory nerve, and lateral lemniscus. Females also tended to show elevated anterior hypothalamic uptake, but just in the hemisphere contralateral to the stimulus. These results suggest that male and female hamsters differ in acoustic responsiveness, and that this difference is mediated by hormonal effects at several brainstem components of the central auditory system.


High-resolution computed tomography scan and airway remodeling in children with severe asthma.
Children with severe asthma have a significantly higher bronchial wall thickness (BWT) on high-resolution computed tomography scan than control children. We sought to determine whether a BWT score correlates with markers of airway remodeling and inflammation. In 37 children with severe asthma, we determined reticular basement membrane thickness; number of intraepithelial neutrophils and eosinophils on bronchial biopsy; IFN-gamma, IL-4, IL-5, and eosinophil cationic protein levels and IFN-gamma/IL-4 ratio on bronchoalveolar lavage specimen; and alveolar nitric oxide (NO) concentration and the maximum airway wall NO flux. The BWT score significantly correlated with reticular basement membrane thickening (r = 0.34; P = .04) and NO production by the airway wall (r = 0.45; P = .02). The correlation with the eosinophil cationic protein level was just significant (r = 0.40; P = .05), whereas there was no correlation with IFN-gamma/IL-4 ratio (r = -0.31; P = .08). The BWT score did not correlate with FEV(1) or forced expiratory flow at 25% to 75% of forced vital capacity. High-resolution computed tomography scan is a noninvasive technique that might be valuable for quantifying airway remodeling in children with severe asthma. The new generations of multislice computed tomography scanners will allow higher definition and lower radiation exposure and probably give a better assessment of airway remodeling and efficacy of treatment in children with asthma.


Historical note: Jules Séglas on language in dementia.
In his book Des troubles du language chez les aliénés (1892) Séglas applied the model of language processing of his teacher, Charcot, to analyze the language disorders of various groups of mentally ill, including patients considered to suffer from dementia. Among the language phenomena he described from dementia are logorrhea, neologisms, embolalia, near-mutism, angophrasia, automatic speech, alexia, and agraphia. Séglas must be credited for his early descriptions of how language behaviors cluster in various psychiatric and dementing diseases.


Potent inhibition of protein-tyrosine phosphatase-1B using the phosphotyrosyl mimetic fluoro-O-malonyl tyrosine (FOMT).
To enhance PTP binding interactions, both inside and outside the pTyr binding pocket, a thioether-cyclized peptide has been designed based on the EGF receptor autophosphorylation sequence (EGFR988-993) "Asp-Ala-Asp-Glu-pTyr-Leu", in which the pTyr resiude has been replaced by the nonphosphorus-containing pTyr mimetic fluoro-O-malonyltyrosine (FOMT, 2). The resulting peptide 4 exhibits a Ki value of 170 nM, making it one of the most potent inhibitors of PTP1B yet reported.


Isolation and structural characterization of sialic acid-containing storage material from mucolipidosis I (sialidosis) fibroblasts.
Sialic acid-containing storage material was isolated from cultured human mucolipidosis I (sialidosis) fibroblasts by gel permeation chromatography on Bio-Gel P-6 followed by medium-pressure anion-exchange chromatography on Mono Q. The structure determination of the isolated sialyloligosaccharides was carried out by 500-MHz 1H-NMR spectroscopy in conjunction with sugar analysis and analytical HPLC. The storage material showed completely sialylated mono-, di- and triantennary N-glycosidic N-acetyllactosamine oligosaccharides having the Man beta 1----4GlcNAc sequence at the reducing end in common. Heterogeneity occurred with respect to the linkages between terminal sialic acid and the penultimate galactose residues (alpha 2----3/alpha 2----6). It turned out that all the identified carbohydrate chains are consistent with the neuraminidase deficiency.


Long-term outcome of nonmyeloablative allogeneic transplantation in patients with high-risk multiple myeloma.
Conventional treatment or autologous transplantation has not been able to achieve long-term remission in patients with multiple myeloma (MM). Nonmyeloablative allogeneic transplantation might offer an option for cure without the high mortality associated with conventional conditioning. Here we present a retrospective analysis of patients with high-risk MM treated with nonmyeloablative allogeneic transplantation. In all, 52 patients with relapsed MM or high-risk features at diagnosis received 2 Gy TBI alone (n=3) or with fludarabine (n=49) as conditioning. Patients were heavily pretreated with a median of eight cycles of conventional chemotherapy and one or more autologous transplants for all but one patient. Regimen-related toxicity was low. Acute graft-versus-host disease II-IV occurred in 37% of patients, and 70% experienced chronic graft-versus-host disease (cGvHD). Median follow-up was 567 days, and transplant-related mortality was 17% in total. Estimated progression-free and overall survival at 18 months was 29.4 and 41.1%, respectively. Patients with cGvHD had a significantly higher progression-free survival, as did patients with up to eight cycles of pretreatment chemotherapy vs those with nine or more. In this highly pretreated patient group, disease control was unsatisfactory and our results suggest that a potential strategy might be to perform allogeneic transplant earlier in the course of the disease.


Intracellular regulation of ion channels in cell membranes.
Cells communicate with their environment through receptor proteins on the cell membrane. Some ion channels are receptors, whereas others are linked to receptors through guanine nucleotide-binding proteins (G proteins). Ion channels control intracellular concentrations of ions such as calcium, and these concentrations control cell functions such as secretion and cell division. This review summarizes the current state of knowledge about the control of ion channels.


Production, binding and cytotoxicity of human/mouse chimeric monoclonal antibody-neocarzinostatin conjugate.
A human/mouse chimeric Fab monoclonal antibody A7 (chFabA7) was covalently coupled to neocarzinostatin (NCS) by the SPDP method at various chFabA7:NCS substitution ratios. The antigen-binding activity of the conjugate, examined by ELISA using fixed antigen-positive colon cancer cells, was identical to that of the parent chFabA7 when one mole of NCS was conjugated, but was reduced with 2 or 3 moles of conjugated NCS. By means of a colony-forming assay, the cytocidal effect of the conjugate on antigen-positive cancer cells was found to be stronger than that of free NCS, whereas in antigen-negative cancer cells it was similar to that of free NCS. This effect was attenuated by adding an excess amount of monoclonal antibody A7. These findings indicate that the conjugate has an antigen-specific cytocidal action, and thus chFabA7-NCS is a promising tool for targeting cancer chemotherapy.


Remarkable effects of cabergoline in a patient with huge prolactinoma resistant to high-dose bromocriptine: case report.
Cabergoline (CAB) has been proposed as the first-line treatment in the management of prolactin (PRL)-secreting tumors (prolactinoma [PRLoma]), including those resistant to standard dopamine agonist (DAA) therapy. The authors report remarkable effects of CAB in a case of huge PRLoma that had been resistant to a long-term, high-dose treatment with bromocriptine (BRC). A 28-year-old man was originally presented with oculomotor paresis when he was 9 years old. After 2 partial resections, he was treated with a maximum 60-mg/d dose of BRC for 18 years. Nonetheless, the tumor grew up to more than 8 cm in diameter, serum PRL increased over 60000 ng/mL, and his visual acuity deteriorated. Cabergoline normalized serum PRL level, shrank the tumor mass remarkably, and caused marked improvement of visual acuity. Prolactin normalization and significant tumor shrinkage could be achieved with CAB even in extremely BRC-resistant PRLomas. Surgical resection should be reserved only for patients who are resistant to cabergoline or who require urgent decompression in such emergency as massive intratumoral hemorrhage.


Periodontal Microbiology.
This article provides a review of current information about periodontal bacteria, their activities within dental plaque biofilm, their interactions with the host immune system, and the infections with which they are associated. Periodontal disease, plaque formation, and the host immune response are also discussed, as are antimicrobial measures used to control the bacteria and the disease.


Schizotypy and altered hemispheric asymmetries: The role of cilia genes.
Schizophrenia patients have a higher probability of altered structural and functional differences between the left and right hemisphere. Schizotypy as its nonclinical manifestation has been related to a higher incidence of non-right-handedness and atypical right-hemispheric language dominance. It has been suggested that genes involved in cilia function might link brain asymmetry and neurodevelopmental disorders. We assessed DNA methylation in the promoter regions of seven candidate genes involved in cilia function and psychiatric disorders from buccal cells and investigated their association with schizotypy and language lateralization in 60 healthy adults. Moreover, we determined microstructural properties of the planum temporale in a subsample of 52 subjects using neurite orientation dispersion and density imaging (NODDI). We found a significant association between schizotypy and DNA methylation in the AHI1 promoter region. Moreover, AHI1 DNA methylation significantly predicted language lateralization and asymmetry in estimated planum temporale neurite density. Finally, stronger leftward asymmetry in estimated neurite density was associated with a more pronounced right ear advantage (left hemisphere dominance) in the forced-right condition of the dichotic listening task, measuring attentional modulation of language lateralization. Our results are in line with a shared molecular basis of schizotypy and functional hemispheric asymmetries that is based on cilia function.


Safety of combining thoracic radiation therapy with concurrent versus sequential immune checkpoint inhibition.
The objective of this study was to evaluate adverse events (AEs) in patients who received both immune checkpoint inhibitors and thoracic radiation therapy (RT). In particular, we compared the rate of toxicities of concurrent versus sequential delivery of thoracic RT and checkpoint inhibitors. Patient and treatment characteristics were collected on all patients at our institution who were treated with programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and/or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors and underwent thoracic RT (n = 79). Receiving both treatments within 1 month was considered concurrent (n = 35; 44%), and any treatment up to 6 months apart was considered sequential (n = 44; 56%). The primary endpoint of this study was the rate of Grade ≥2 AEs from combination therapy (immunotherapy and RT), specifically those that are relevant to thoracic RT: Pneumonitis, other pulmonary events, esophagitis, dermatitis, and fatigue. Further univariate analysis was performed to compare AE rates with clinical and therapy-related variables. A total of 79 patients were identified, with lung cancer (n = 45) and melanoma (n = 15) being the most common primary histology. Sixty-two (78%) patients were treated with anti-PD-1 or anti-PD-L1 antibodies, 12 (15%) with anti-CTLA-4 antibodies, and 5 (6%) received both anti-PD-1/PD-L1 and anti-CTLA-4 antibodies. The median follow-up for survivors was 5.9 months (range, 2.4-55.6 months). Grade ≥2 AEs included pneumonitis (n = 5; 6%), esophagitis (n = 6; 8%), and dermatitis (n = 8; 10%). No statistically significant correlation was found between these AEs when comparing concurrent versus sequential treatment. The only significant variable was a correlation of immunotherapy drug category with Grade ≥2 esophagitis (P = .04). Overall, Grade ≥2 AE rates of thoracic RT and immunotherapy appeared as expected and acceptable. The lack of significant differences in AE rates with concurrent versus sequential treatment suggests that even concurrent immunotherapy and thoracic RT may be safe.


Thrombin cleaves the high molecular weight forms of basic fibroblast growth factor (FGF-2): a novel mechanism for the control of FGF-2 and thrombin activity.
The fgf-2 gene encodes low molecular weight (LMW, 18 kDa) and high molecular weight (HMW, 22-24 kDa) forms that originate from alternative translation of a single mRNA and exhibit diverse biological functions. HMW fibroblast growth factor-2 (FGF-2) inhibits cell migration and induces cell transformation or growth arrest in a cell type- and dose-dependent fashion. Conversely, LMW FGF-2 upregulates both cell proliferation and migration in most cell types. Although transcriptional and translational regulation of HMW and LMW FGF-2 has been extensively investigated, little is known about post-translational control of their relative expression. Here we report that thrombin, a key coagulation factor and inflammatory mediator, cleaves HMW FGF-2 into an LMW FGF-2-like form that stimulates endothelial cell migration and proliferation. The effect of thrombin on these cell functions requires HMW FGF-2 cleavage. This post-translational control mechanism adds a novel level of complexity to the regulation of FGF-2, and links the activities of thrombin and FGF-2 in patho-physiological processes in which both molecules are expressed.


Applying concurrent multidisciplinary care to gender affirmation in transgender women: A case series.
Gender affirmation surgeries, though important for many transgender persons, can be numerous. Combining surgeries, as presented in this case series, affords many benefits to patients without increasing risk or complications.


Alcohol consumption is associated with a lower incidence of acute myocardial infarction: results from a large prospective population-based study in Norway.
Compelling evidence suggests that light-to-moderate alcohol consumption is associated with a reduced risk of acute myocardial infarction (AMI), but several issues from previous studies remain to be addressed. The aim of this study was to investigate some of these key issues related to the association between alcohol consumption and AMI risk, including the strength and shape of the association in a low-drinking setting, the roles of quantity, frequency and beverage type, the importance of confounding by medical and psychiatric conditions, and the lack of prospective data on previous drinking. A population-based prospective cohort study of 58 827 community-dwelling individuals followed for 11.6 years was conducted. We assessed the quantity and frequency of consumption of beer, wine and spirits at baseline in 1995-1997 and the frequency of alcohol intake approximately 10 years earlier. A total of 2966 study participants had an AMI during the follow-up period. Light-to-moderate alcohol consumption was inversely and linearly associated with AMI risk. After adjusting for major cardiovascular disease risk factors, the hazard ratio for a one-drink increment in daily consumption was 0.72 (95% confidence interval 0.62-0.86). Accounting for former drinking or comorbidities had almost no effect on the association. Frequency of alcohol consumption was more strongly associated with lower AMI risk than overall quantity consumed. Light-to-moderate alcohol consumption was linearly associated with a decreased risk of AMI in a population in which abstaining from alcohol is not socially stigmatized. Our results suggest that frequent alcohol consumption is most cardioprotective and that this association is not driven by misclassification of former drinkers.


Experimental study and modelling of lead solubility as a function of pH in mixtures of ground waters and cement waters.
The purpose of this study was the simulation of lead solubility equilibria in mixtures of concrete lixiviation waters and ground waters in order to obtain the data necessary for the modelling of lead behaviour. The lixiviation water was impossible to obtain in sufficient quantity by compression of concrete specimens and was replaced by cement water prepared by mixing a CLC or CPA cement suspension in distilled water under argon. Three lead salts, PbCl2, PbSO4 and PbCO3, were studied; they correspond to the anions found most frequently in the ground waters. The experimental curves of lead solubility were determined, at 20 degrees C, from pH 5 to 13, for various systems: cement water/lead salt/ground water. The modelling of 10 systems was carried out by the PHREEQC code from the solution compositions (ground water and cement water mixtures) and the thermodynamic constants obtained from the MINTEQ data base. The chemical models included the nature of the species in solution and the solid phases in equilibrium together with the corresponding values for the logarithms of the formation constants or solubility products. These models were validated by comparing the experimental pH and solubilised lead concentration values with the values calculated using the PHREEQC code.


Resectable adenocarcinoma of the rectosigmoid and rectum. II. The influence of blood vessel invasion.
Several series have examined the influence of blood vessel invasion (BVI) by tumor on survival of patients with colorectal cancer; however, little data are available regarding its influence on patterns of failure. In an effort to determine the influence of BVI on the patterns of failure and survival in rectosigmoid and rectal cancer, a retrospective review of 168 patients who underwent potentially curative surgery at the New England Deaconess Hospital was performed. In patients who had tumors with extramural BVI, there was a significant decrease in five-year actuarial survival compared with patients who had tumors with intramural BVI or were BVI-negative (BVI-). When the intramural and extramural types of BVI were combined, no significant impact was noted on the patterns of failure or survival in patients with BVI+ versus those with BVI- tumors. In contrast, the presence of lymphatic vessel invasion was found to significantly decrease survival. By using a proportional hazards analysis, it was found that BVI was not an independent prognostic variable. Therefore, the use of BVI alone is not recommended for selecting patients with rectosigmoid and rectal cancer who may benefit from adjuvant therapy.


Factors affecting the stability of nutritional emulsion mixtures.
The stability of oil droplets in complex nutritional admixtures is known to be affected by the presence of amino acids, dextrose and electrolytes. Hospital Pharmacists unable to meet demands for TPN admixtures sometimes turn to specialised commercial units but the supply of lipid admixtures by any facility remote from the user raises further challenges to admixture stability from various sources through exposure to temperature variations, transit effects etc. A number of interesting variances have been found in lipid admixtures arising from factors not previously recognised as significant. The batch of emulsion, container type and conditions of storage prior to use have been demonstrated to affect a moderately stable admixture. Whilst requiring further investigation, such factors must be considered for all new regimens and particularly to ensure the robustness of mixtures provided through a Compounding Service for Hospital or Home patients.


[Current status of diagnosis and treatment of chronic lymphocytic leukemia in China: A national multicenter survey research].
Objective: To understand the current status of diagnosis and treatment of chronic lymphocytic leukemia (CLL) /small lymphocytic lymphoma (SLL) among hematologists, oncologists, and lymphoma physicians from hospitals of different levels in China. Methods: This multicenter questionnaire survey was conducted from March 2021 to July 2021 and included 1,000 eligible physicians. A combination of face-to-face interviews and online questionnaire surveys was used. A standardized questionnaire regarding the composition of patients treated for CLL/SLL, disease diagnosis and prognosis evaluation, concomitant diseases, organ function evaluation, treatment selection, and Bruton tyrosine kinase (BTK) inhibitor was used. Results: ①The interviewed physicians stated that the proportion of male patients treated for CLL/SLL is higher than that of females, and the age is mainly concentrated in 61-70 years old. ②Most of the interviewed physicians conducted tests, such as bone marrow biopsies and immunohistochemistry, for patient diagnosis, in addition to the blood test. ③Only 13.7% of the interviewed physicians fully grasped the initial treatment indications recommended by the existing guidelines. ④In terms of cognition of high-risk prognostic factors, physicians' knowledge of unmutated immunoglobulin heavy-chain variable and 11q- is far inferior to that of TP53 mutation and complex karyotype, which are two high-risk prognostic factors, and only 17.1% of the interviewed physicians fully mastered CLL International Prognostic Index scoring system. ⑤Among the first-line treatment strategy, BTK inhibitors are used for different types of patients, and physicians have formed a certain understanding that BTK inhibitors should be preferentially used in patients with high-risk factors and elderly patients, but the actual use of BTK inhibitors in different types of patients is not high (31.6%-46.0%). ⑥BTK inhibitors at a reduced dose in actual clinical treatment were used by 69.0% of the physicians, and 66.8% of the physicians had interrupted the BTK inhibitor for >12 days in actual clinical treatment. The use of BTK inhibitors is reduced or interrupted mainly because of adverse reactions, such as atrial fibrillation, severe bone marrow suppression, hemorrhage, and pulmonary infection, as well as patients' payment capacity and effective disease progression control. ⑦Some differences were found in the perceptions and behaviors of hematologists and oncologists regarding the prognostic assessment of CLL/SLL, the choice of treatment options, the clinical use of BTK inhibitors, etc. Conclusion: At present, a gap remains between the diagnosis and treatment of CLL/SLL among Chinese physicians compared with the recommendations in the guidelines regarding the diagnostic criteria, treatment indications, prognosis assessment, accompanying disease assessment, treatment strategy selection, and rational BTK inhibitor use, especially the proportion of dose reduction or BTK inhibitor discontinuation due to high adverse events.


Multilayered polycaprolactone/gelatin fiber-hydrogel composite for tendon tissue engineering.
Regeneration of injured tendon and ligament (T&L) remains a clinical challenge due to their poor intrinsic healing capacity. Tissue engineering provides a promising alternative treatment approach to facilitate T&L healing and regeneration. Successful tendon tissue engineering requires the use of three-dimensional (3D) biomimetic scaffolds that possess the physical and biochemical features of native tendon tissue. We report here the development and characterization of a novel composite scaffold fabricated by co-electrospinning of poly-ε-caprolactone (PCL) and methacrylated gelatin (mGLT). We found that photocrosslinking retained mGLT, resulted in a uniform distribution of mGLT throughout the depth of scaffold and also preserved scaffold mechanical strength. Moreover, photocrosslinking was able to integrate stacked scaffold sheets to form multilayered constructs that mimic the structure of native tendon tissues. Importantly, cells impregnated into the constructs remained responsive to topographical cues and exogenous tenogenic factors, such as TGF-β3. The excellent biocompatibility and highly integrated structure of the scaffold developed in this study will allow the creation of a more advanced tendon graft that possesses the architecture and cell phenotype of native tendon tissues. The clinical challenges in tendon repair have spurred the development of tendon tissue engineering approaches to create functional tissue replacements. In this study, we have developed a novel composite scaffold as a tendon graft consisting of aligned poly-ε-caprolactone (PCL) microfibers and methacrylated gelatin (mGLT). Cell seeding and photocrosslinking between scaffold layers can be performed simultaneously to create cell impregnated multilayered constructs. This cell-scaffold construct combines the advantages of PCL nanofibrous scaffolds and photocrosslinked gelatin hydrogels to mimic the structure, mechanical anisotropy, and cell phenotype of native tendon tissue. The scaffold engineered here as a building block for multilayer constructs should have applications beyond tendon tissue engineering in the fabrication of tissue grafts that consist of both fibrous and hydrogel components.


Influence of the fat/carbohydrate component of snack food on energy intake pattern and reinforcing properties in rodents.
Hedonic intake of strongly rewarding foods is independent from biological needs and, thus, a common cause of obesity. The effect of potato chips on energy intake in a snacking model could be explained by their fat/carbohydrate content (FCHc). The present study investigated if the FCHc shapes energy intake patterns and reward processing of satiated rodents. Modulation of energy intake patterns was studied in an established snacking model offering FCHc rich food for 3 × 10 min/day to satiated rats. Reward processing was analyzed by a previously established conditioned place preference tests in satiated mice. The limited access to FCHc rich food led to higher daily energy intake compared to days without access (110 ± 10 vs. 96 ± 5 kcal/day) indicating that fat/carbohydrate intake was not fully compensated by reducing standard chow intake during the rest of the day. Furthermore, fat/carbohydrate snacking led to binge eating episodes with up to 55% of the daily energy intake consumed during limited access. Forced withdrawal from fat/carbohydrate snacking opportunities for six weeks increased the total daily energy intake and the relative amount of energy consumed by FCHc after reintroducing fat/carbohydrate snacking. Snack food and fat/carbohydrate food were powerful food reinforcers in satiated mice in contrast to standard chow. Altogether, these data suggest that the FCHc of snack food has strong reinforcing properties, which are probably responsible for the significant modulation of the amount and pattern of food intake in ad libitum fed animals.


Development and evaluation of a sandwich ELISA method for the detection of human CD306.
CD306, also known as soluble leukocyte-associated immunoglobulin-like receptor-2 (LAIR-2), is a member of an immunoglobulin superfamily with the shared characteristic of an immunoglobulin-like C2-type domain. CD306 is speculated to be secretory and has 84% similarity with the extracellular domain of CD305, which binds to the same ligands as CD306. However, data on its distribution are absent due to the lack of an efficient method to detect it. In this study, we successfully cloned the cDNA of CD306 from the peripheral blood mononuclear cells (PBMCs) of patients with hemorrhagic fever with renal syndrome. The fusion proteins were expressed and purified, and three strains of monoclonal antibodies (mAbs) against CD306 were prepared and characterized. The sandwich ELISA for detecting CD306 was established and optimized with sensitivity up to 15 pg/ml, and the assay showed high specificity for the detection of CD306. With this method, a right skewed frequency distribution of CD306 in the sera of healthy subjects was determined. The concentrations of CD306 in sera and urine were detected in patients with different diseases. Aberrantly high levels of CD306 were found in the sera of pregnant women and patients with inflammation and rheumatic heart disease and in the urine of pregnant women. Meanwhile, there was a positive correlation between CD306 and soluble CD305 expression and secretion levels in sera and urine samples from patients, and both proteins inhibited CD305-mediated immunosuppressive functions. Our results demonstrate that CD306 represents a potentially useful predictor for disease diagnosis and that the method developed has potential for clinical application.


Effects of experimental embolization of superior mesenteric artery branch on the intestine.
A primary mesenteric branch of the superior mesenteric artery was embolized with Amicar-mixed clots in seven dogs and with gelatin sponges in five dogs. All of the dogs embolized with Amicar-mixed clots survived the experimental period and no mesenteric damage was found with postmortem studies. Three of the five dogs embolized with gelatin sponges showed a local stricture within the embolized segment of intestine. Collateral blood supply to the strictured segment of bowel in these three dogs developed via arterial arcades, mural branches of the vasa recta and omental arteries.


Solid phase ELISA for determination of the virus dose dependent sensitivity of human cytomegalovirus to antiviral drugs in vitro.
The main problems in determining the true in vivo susceptibility of human cytomegalovirus (CMV) to antiviral compounds are the influence of the size of the viral inoculum, the variation in the replication capacity of different CMV strains and the subjective evaluation of the inhibition of viral growth in the plaque assay. In this study, a specific assay was developed which reproducibly determines the sensitivity of primary isolates of CMV. The assay includes simultaneous virus titration and determination of the antiviral sensitivity. When individual virus doses were evaluated, the IC50 was generally dependent on the virus dose, except for resistant isolates, where the IC50 did not change irrespective of the dose of virus. The novel method of IC50 calculation takes into account all values derived from the linear part of the inhibition curve. This may better reflect the in vivo conditions, where the antiviral drug encounters different amounts of virus in different organs. Two human fibroblast-derived cell lines showed similar results.


Extended haplotype association study in Crohn's disease identifies a novel, Ashkenazi Jewish-specific missense mutation in the NF-κB pathway gene, HEATR3.
The Ashkenazi Jewish population has a several-fold higher prevalence of Crohn's disease (CD) compared with non-Jewish European ancestry populations and has a unique genetic history. Haplotype association is critical to CD etiology in this population, most notably at NOD2, in which three causal, uncommon and conditionally independent NOD2 variants reside on a shared background haplotype. We present an analysis of extended haplotypes that showed significantly greater association to CD in the Ashkenazi Jewish population compared with a non-Jewish population (145 haplotypes and no haplotypes with P-value <10(-3), respectively). Two haplotype regions, one each on chromosomes 16 and 21, conferred increased disease risk within established CD loci. We performed exome sequencing of 55 Ashkenazi Jewish individuals and follow-up genotyping focused on variants in these two regions. We observed Ashkenazi Jewish-specific nominal association at R755C in TRPM2 on chromosome 21. Within the chromosome 16 region, R642S of HEATR3 and rs9922362 of BRD7 showed genome-wide significance. Expression studies of HEATR3 demonstrated a positive role in NOD2-mediated NF-κB signaling. The BRD7 signal showed conditional dependence with only the downstream rare CD-causal variants in NOD2, but not with the background haplotype; this elaborates NOD2 as a key illustration of synthetic association.


The role of Candida albicans FAR1 in regulation of pheromone-mediated mating, gene expression and cell cycle arrest.
Candida albicans cells homozygous for the MTLa locus respond to alpha-mating pheromone by activating gene expression and triggering morphological changes, and the cells undergo a pheromone-mediated cell cycle arrest that can be influenced by nutritional conditions. Disruption of C. albicans ORF19.7105, which is the predicted homologue of the yeast FAR1 gene, blocks pheromone-mediated morphological changes, prevents pheromone-mediated cell cycle arrest, greatly compromises mating and also blocks pheromone-triggered gene induction. C. albicans ORF19.7105 is not pheromone inducible, but overexpression of this gene from the actin promoter greatly enhances pheromone-mediated cell cycle arrest, leading to clear halos in growth inhibition assays on a variety of solid media. Transcriptional profiling of the ORF19.7105-overexpressing strain has established an enhanced responsiveness of pheromone-induced genes. Thus the C. albicans FAR1 gene is a dosage-dependent regulator of the pheromone response, and is critically required for all aspects of mating process of this pathogenic fungus.


Plasmodium early transcribed membrane proteins appear tailored to the host range of malaria parasites.
Early transcribed membrane proteins form a unique protein family in malaria parasites. These molecules are expressed during Plasmodium intracellular phases and inserted at the parasite parasitophorus vacuole membrane, which constitutes the host-parasite interface. Upregulated in infectious sporozoites 4 (UIS4) is an essential early transcribed membrane protein of liver stages of the murine malaria model parasite Plasmodium berghei. Despite its relevance for liver stage maturation, the molecular functions of UIS4 remain elusive, and UIS4 orthologs in human malaria parasites have not yet been identified. In order to characterise functional domains of UIS4, we generated P. berghei parasites carrying a carboxy-terminally truncated version of UIS4. We observed that uis4Δc parasites are severely impaired in liver stage development, similar to uis4(-) parasites, indicating an important role of the C-terminal domain for UIS4 function. To test whether members of the P. falciparum early transcribed membrane protein family are potential UIS4 orthologs, we selected candidates based on structural homology and parasitophorous vacuole membrane localization. We generated transgenic P. berghei parasites where UIS4 was replaced by Plasmodium falciparum ETRAMP8 or ETRAMP10.3. Both early transcribed membrane proteins were expressed in transgenic parasite lines, but liver stage maturation was impaired, indicating that the selected early transcribed membrane proteins failed to substitute the function of UIS4. As a control, we included the UIS4 ortholog from the murine parasite Plasmodium chaubaudi. We observed that PcUIS4 successfully restores UIS4 function in P. berghei. Together, these results suggest that Plasmodium parasites express tailor-made parasitophorous vacuole membrane proteins that might at least partially explain the narrow host range of malaria parasites.


Leaching of diethylhexyl phthalate from polyvinyl chloride bags into intravenous etoposide solution.
To compare the release of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags from four different manufacturers into intravenous etoposide solutions. Etoposide solutions, 0.4 mg/mL, containing the vehicle polysorbate 80 were prepared in 5% dextrose or 0.9% sodium chloride injection PVC bags and stored at room temperature for 24 h. DEHP content was analysed by high-performance liquid chromatography. Substantial amounts of DEHP (up to 20 microg/mL at room temperature) leached into the etoposide solutions. However, no significant differences were found in the amounts of DEHP leached into the etoposide infusion solutions prepared using either 5% dextrose or 0.9% sodium chloride injection and stored in the four different containers. To minimize patient exposure o DEHP, etoposide solutions should ideally be stored in a glass or polyolefin container.


Applications of SBA-15 supported Pd metal catalysts as nanoreactors in C-C coupling reactions.
Nanoreactors are material structures with engineered internal cavities which create exclusive confined nanoscale surroundings for chemical reactions. The cavities of mesoporous silica SBA-15 can be used as nanoreactors for incorporating catalytic species such as metal nanoparticles, complexes etc. Since SBA-15 silica has a neutral framework, organic functional groups and heteroatoms have been embedded by direct or post-synthesis approaches in order to modify their functionality. Palladium is the most used transition metal for C-C bond formations. Because of the great importance of C-C coupling reactions, this review article aims at providing a deep insight into the state of art in the field of the synthesis and the application of mesoporous SBA-15 silica-supported Pd catalysts in C-C coupling transformations. In most cases, synthesis and modification of the catalyst, time and yield of reactions, recyclability and leaching of the Pd species from the SBA-15 support are discussed to reveal the role of SBA-15 in C-C coupling reactions.


The role of transitionals in mouth rehabilitation.
Mouth rehabilitation calls for the greatest skills we possess as dentists. We have a moral and professional responsibility to our patients to do what is best for them. This can only be achieved by careful checking and cross-checking of our procedures during fabrication. Transitional prostheses, therefore, may serve as a valuable adjunct toward the achievement of success in mouth rehabilitation.


Pseudomonas exotoxin antisense RNA selectively kills hepatitis B virus infected cells.
To present an approach for selectively killing retrovirus-infected cells that combines the toxicity of Pseudomonas exotoxin (PE) and the presence of reverse transcriptase (RT) in infected cells. PE antisense toxin RNA has palindromic stem loops at its 5' and 3' ends enabling self-primed generation of cDNA in the presence of RT. The RT activity expressed in retrovirus-infected cells converts "antisense-toxin-RNA" into a lethal toxin gene exclusively in these cells. Using cotransfection studies with PE-expressing RNAs and beta-gal expressing reporter plasmids, we show that, in HepG2 and HepG2.2.15 hepatoma cells as well as in duck hepatitis B virus (DHBV) infected cells, HBV or DHBV-polymerase reverse transcribe a lethal cDNA copy of an antisense toxin RNA, which is composed of sequences complementary to a PE gene and eukaryotic transcription and translation signals. This finding may have important implications as a novel therapeutic strategy aimed at the elimination of HBV infection.


In vitro expression of soluble and cell surface-associated CD44 on endometrial cells from women with and without endometriosis.
Endometriosis is one of the most common benign gynaecological diseases, and attachment of retrogradely shed viable endometrial cells is considered to be important in its development. CD44 is a multifunctional adhesion molecule that undergoes alternative splicing, giving rise to different isoforms. The expression of cell surface-associated CD44 std, v4, v5, v6 and v10 variants before and after cytokine treatment was investigated in endometrial cultures derived from 10 endometriosis patients and 22 women without the disease using immunocytochemistry. The immunoreactivity of soluble CD44 std, v5 and v6 variants was measured in culture medium using an enzyme immunoassay kit. We report on the presence of soluble CD44 in endometrial culture supernatants. In particular, circulating CD44 standard form levels were significantly higher than levels of splice variants. We also found that both epithelial and stromal cells express surface-associated CD44 molecules in a distinct pattern and that this expression is not modulated by tumour necrosis factor (TNF)-alpha or/and interleukin 1 (IL-1) alpha/beta. Finally, cell surface-associated as well as soluble CD44 expression was similar in the two groups. Our results indicate that endometrial cells can serve as a source of circulating CD44, but a direct role in the pathogenesis of endometriosis is rather improbable.


Anaplasma phagocytophilum in European bison (Bison bonasus) and their ticks from Lithuania and Poland.
The increasing population of European bison (Bison bonasus) can contribute to the prevalence of zoonotic pathogens. The aim of the present study was to assess the presence of A. phagocytophilum infection in European bison tissues as well as ticks removed from European bison in Lithuania and Poland. A further objective of this work was to compare the detected A. phagocytophilum strains. A total of 85 tissue samples (spleen) of European bison and 560 ticks belonging to two species, Ixodes ricinus (n = 408) and Dermacentor reticulatus (n = 152) were tested. DNA of A. phagocytophilum was detected based on RT-PCR in 40% of the European bison samples, 8.8% of the I. ricinus and 5.9% of the D. reticulatus ticks. Analysis of the obtained partial 16S rRNA gene sequences of A. phagocytophilum revealed the presence of three variants with two polymorphic sites. Furthermore, phylogenetic analysis with partial msp4 gene sequences grouped A. phagocytophilum variants into three clusters. This study revealed that the groEL gene sequences of A. phagocytophilum from European bison and their ticks grouped into ecotype I and only one sequence from Lithuanian European bison belonged to ecotype II. The results of the present study indicated that European bison may play a role as a natural reservoir of A. phagocytophilum.


Altered Intrinsic Brain Activity Related to Neurologic and Motor Dysfunction in Diabetic Peripheral Neuropathy Patients.
Brain functional alterations in type 2 diabetes with diabetic peripheral neuropathy (DPN) related to motor dysfunction remain largely unknown. We aimed to explore intrinsic resting brain activity in DPN. A total of 28 patients with DPN, 43 patients with diabetes and without DPN (NDPN), and 32 healthy controls (HCs) were recruited and underwent resting-state functional magnetic resonance imaging. We calculated the amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), and regional homogeneity (ReHo). One-way analysis of covariance was applied to evaluate the above indicators among the 3 groups, and the mean ALFF/fALFF/ReHo values of altered brain regions were then correlated with clinical features of patients. Compared with the NDPN group, the DPN group showed significantly decreased ALFF values in the right orbital superior frontal gyrus (ORBsup) and medial superior frontal gyrus (SFGmed), and increased ALFF values in the left inferior temporal gyrus (ITG) and decreased fALFF values in the right SFGmed. Compared with HCs, the NDPN group showed increased ALFF values in the right ORBsup, middle frontal gyrus, and left orbital middle frontal gyrus, and decreased fALFF values in the right middle temporal gyrus. Notably, the mean ALFF values of the right ORBsup were significantly negatively correlated with Toronto Clinical Scoring System scores and gait speed in diabetics. The mean ALFF/fALFF values of right SFGmed and the mean ALFF values of left ITG and right ORBsup were significantly differentiated between DPN and patients witht NDPN in receiver operating characteristic curve analysis. Patients with DPN have abnormal brain activity in sensorimotor and cognitive brain areas, which may implicate the underlying neurophysiological mechanisms in intrinsic brain activity.


Potassium citrate and metabolic acidosis in children with epilepsy on the ketogenic diet: a prospective controlled study.
To investigate if potassium citrate, a mild alkaline compound, can prevent metabolic acidosis in children with epilepsy treated with the ketogenic diet without reducing antiepileptic efficacy. In this prospective controlled study, we investigated the frequency of initial uncompensated metabolic acidosis in 51 participants. There were 22 participants with and 29 without potassium citrate supplementation. The ketogenic diet was used as add-on treatment to children with drug resistant epilepsy. We also estimated the proportion of participants with a greater than 50% seizure reduction after 7 months. None of the 22 participants (15 males, seven females; median age 1y 7mo, interquartile range [IQR] 3y 3mo) with, and 10 of 29 (12 males, 17 females; median age 6y 1mo, IQR 4y 8mo) without potassium citrate developed metabolic acidosis (odds ratio=0.04, 95% CI 0.00-0.75 [p<0.01]); median pH 7.32 vs 7.24; [p<0.001]), and median bicarbonate 19.7mmol/L vs 14.0mmol/L (p<0.001). The number of seizures was reduced by more than 50% in 9 of 22 with potassium citrate and 8 of 29 participants without potassium citrate, 7 months after introducing a ketogenic diet (p=0.4). In the ketogenic diet, potassium citrate supplementation can prevent metabolic acidosis, without reducing antiepileptic efficacy. Citrate supplementation prevents metabolic acidosis in children treated with a ketogenic diet. Efficacy of the ketogenic diet is not affected by supplementation with citrate. Citrate supplementation does not affect beta-hydroxybuturate concentration. Potassium citrate reduces the time needed to reach an optimal ketogenic ratio. This article is commented on by Schoeler on page 8 of this issue.


Antifeedant activity of citrus waste wax and its fractions against the dry wood termite, Cryptotermes brevis.
The wood protective action of citrus wax, a waste from the citrus industry that is a mixture of citrus fruit epicuticular waxes and essential oils, was evaluated against the termite Cryptotermes brevis Walker (Isoptera: Kalotermitidae). The antifeedant index (AI) of the total wax and fractions was calculated. The total citrus wax exhibited an AI₅₀ value of 24.69 mg/cm³, the wax after hydrodistillation showed the strongest antifeedant property (AI₅₀ 11.68 mg/cm³). Fractionation of the wax and gas chromatography-mass spectrometric analysis allowed the identification of coumarins and furancoumarins as the active compounds. These results suggest the potential use of these industrial residues as a natural approach to termite control.


Psychosocial rehabilitation: the role of the psychiatric nurse.
The roles and functions of Nurses working in Rehabilitation Psychiatry are varied and complex, new challenges are arising out of historical and emerging contexts. This paper explores problems faced by the Psychiatric Nurse and explains some of the functions and roles that contribute to the rehabilitation process.


Low temperature steam and formaldehyde sterilization.
A standard low temperature steam/formaldehyde autoclave was tested according to the manufacturer's instructions, using a range of test pieces containing Bacillus stearothermophilus spores as the challenge organism. There were failures in killing the challenge organism and the reasons for these are discussed. A description of modifications made to the autoclave is given together with details of an improved operating cycle. The performance of the modified autoclave was greatly improved and conditions were established for reliable and consistent sterilization of all the test pieces. A commercially produced prototype autoclave similarly modified also showed effective sterilization.


iCrotoK-PseAAC: Identify lysine crotonylation sites by blending position relative statistical features according to the Chou's 5-step rule.
Among different post-translational modifications (PTMs), one of the most important one is the lysine crotonylation in proteins. Its importance cannot be undermined related to different diseases and essential biological practice. The key step for finding the hidden mechanisms of crotonylation along with their occurrence sites is to completely apprehend the mechanism behind this biological process. In previously reported studies, researchers have used different techniques, like position weighted matrix (PWM), support vector machine (SVM), k nearest neighbors (KNN), and many others. However, the maximum prediction accuracy achieved was not such high. To address this, herein, we propose an improved predictor for lysine crotonylation sites named iCrotoK-PseAAC, in which we have incorporated various position and composition relative features along with statistical moments into PseAAC. The results of self-consistency testing were 100% accurate, while the 10-fold cross validation gave 99.0% accuracy. Based on the validation and comparison of model, it is concluded that the iCrotoK-PseAAC is more accurate than the previously proposed models.


Identification of non-invasive miRNAs biomarkers for prostate cancer by deep sequencing analysis of urinary exosomes.
The aim of this study was to identify microRNAs in urinary exosomes that are differently expressed in prostate cancer patients and healthy donors. For this purpose, RNA was extracted from urinary exosomes from 20 prostate cancer patients and 9 healthy males and the microRNAs were analyzed by next generation sequencing. Interestingly, 5 microRNAs - miR-196a-5p, miR-34a-5p, miR-143-3p, miR-501-3p and miR-92a-1-5p - were significantly downregulated in exosomes from prostate cancer patients. Furthermore, RT-qPCR analysis of an independent cohort of 28 prostate cancer patients and 19 healthy males confirmed that miR-196a-5p and miR-501-3p were downregulated in prostate cancer samples. These results suggest that specific microRNAs in urinary exosomes might serve as non-invasive biomarkers for prostate cancer. In particular, miR-196a-5p and miR-501-3p are promising biomarkers that need to be further studied in large patient cohorts.


Short wait times for patients seeking cosmetic botulinum toxin appointments with dermatologists.
Wait times for both routine and urgent dermatology appointments typically exceed 3 to 4 weeks. Many factors affecting physician workforce adequacy and patient access have been explored, but little is known about the impact of increasing numbers of doctors offering cosmetic services. We sought to evaluate access to dermatologists for patients requesting cosmetic services. Scripted patient telephone calls were made to 898 dermatologists in 12 metropolitan areas to assess wait times for an appointment to receive cosmetic botulinum toxin injections. The areas chosen were surveyed completely, and respondents represented about one tenth of practicing dermatologists in the United States. The methodology was identical to that used in a previous study of wait times for evaluation of a changing mole (a possible indicator of malignancy). Half of dermatologist respondents (455, 50.7%) offered appointments for botulinum toxin injections, and the median wait time was 8 days. Acceptance rates and wait times varied greatly by geographic area (range of median wait times 6.0-32.5 days), with dermatologists in Miami, Fla, and Orange County, California, most likely to provide a botulinum toxin appointment with a short wait time. Many dermatologists (241, 27%) employed physician extenders, and 39% of these extenders also offered appointments for botulinum toxin injections (median wait time 6 days). In comparison with a previous study showing median wait times of 26 days for evaluation of a changing mole in these communities, wait times for cosmetic injections were significantly shorter (P < .001). The metropolitan areas surveyed contain no highly rural areas and do not represent a random sample of all US dermatology practice sites. The cosmetic and medical studies were not conducted concurrently, but were carried out in the same metropolitan areas. Patients seeking a cosmetic botulinum toxin injection have more rapid access to dermatologists than has been previously reported for patients seeking urgent consultation for a changing mole. This study cannot differentiate between many possible explanations for the observed differences in wait times. Because physicians in many other specialties with physician shortages are also offering cosmetic services, further studies are needed to assess the broader policy implications of these findings.


[Non ST elevation acute coronary syndromes and normal coronary angiography: is it truly good news?].
Among 10% of all patients presenting with non ST elevation acute coronary syndromes (ACS), coronary angiography do not show non lesions at all (50%) or mild atheromatous stenosis (50%). ACS without angiographic stenosis are more prevalent in female sex and young patients but can be seen in older ones and in men. Pathogenic mechanisms include acute evolution of vulnerable non-significant plaques and endothelial dysfunction. In hospital and mean term prognosis is not as benign as expected. Six months deaths and myocardial infarction incidence is around 6%. Numerous rehospitalizations due to ischemic recurrences are also very often seen. Therefore, such surprising coronary angiograms do not preclude a fair follow-up. These patients need a careful therapeutic strategy.


Pharmacokinetics of coadministered guanfacine extended release and lisdexamfetamine dimesylate.
In clinical practice, α₂-adrenoceptor agonists have been adjunctively administered with psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD). Two studies have examined the adjunctive use of guanfacine extended release (GXR, Intuniv®; Shire Development LLC, Wayne, PA, USA) with psychostimulants in children and adolescents with a suboptimal response to psychostimulant treatment. However, the potential for pharmacokinetic drug-drug interactions (DDIs) between GXR and lisdexamfetamine dimesylate (LDX, Vyvanse®; Shire US LLC, Wayne, PA, USA) has not been thoroughly evaluated. The primary objective of this study was to examine the pharmacokinetics of GXR 4 mg and LDX 50 mg given as single doses alone and in combination. This was an open-label, randomized, three-period crossover, DDI study. The study was conducted in a single clinical research center. Forty-two healthy adults were randomized in this study. Subjects were administered single oral doses of GXR 4 mg, LDX 50 mg, or GXR and LDX in combination. Blood samples collected predose and up to 72 h postdose assessed guanfacine, LDX, and d-amphetamine levels. Bioequivalence was defined as the 90% confidence intervals (CIs) of the geometric mean ratios of the area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) and maximum plasma concentration (Cmax) falling within the bioequivalence reference interval (0.80-1.25). Safety measures included adverse events, vital signs, and electrocardiograms (ECGs). Forty subjects completed the study. Following administration of LDX alone or in combination with GXR, the statistical comparisons of the AUC0-∞ and Cmax of d-amphetamine fell entirely within the reference interval. For guanfacine, the 90% CI of the geometric mean ratio of AUC∞ for the two treatments was within the bioequivalence criteria, but for Cmax the upper bound of the 90% CI exceeded the standard range for bioequivalence by 7%. This relatively small change is unlikely to be clinically meaningful. Treatment-emergent adverse events (TEAEs) were reported by 42.9% of subjects; the most commonly reported TEAEs included dizziness (5.0, 7.3, and 7.3%) and headache (7.5, 4.9, and 7.3%) following administration of GXR, LDX, and GXR and LDX in combination, respectively. Clinically significant ECG abnormalities occurred in one subject following administration of LDX and in one subject following coadministration of GXR and LDX. In healthy adults, coadministration of GXR and LDX did not result in a clinically meaningful pharmacokinetic DDI compared with either treatment alone. No unique TEAEs were observed with coadministration of GXR and LDX compared with either treatment alone.


Sheep, wolf, or werewolf: cancer stem cells and the epithelial-to-mesenchymal transition.
Multiple cancers contain subpopulations that exhibit characteristics of cancer stem cells (CSCs), the ability to self-renew and seed heterogeneous tumors. Recent evidence suggests two potentially overlapping models for these phenotypes: one where stem cells arise from multipotent progenitor cells, and another where they are created via an epithelial to mesenchymal transition. Unraveling this issue is critical, as it underlies phenomena such as metastasis and therapeutic resistance. Therefore, there is intense interest in understanding these two types of CSSs, how they differ from differentiated cancer cells, the mechanisms that drive their phenotypes, and how that knowledge can be incorporated into therapeutics.


Long-term neurologic outcome of infants born by cesarean section.
Prevention of neurologic injury to the fetus through skilled and attentive care during the peripartum period is designed to identify signs of fetal distress so that appropriate obstetric interventions can occur. The impact of mode of delivery on neurologic outcome varies depending on the clinical indication for cesarean delivery and the associated maternal and fetal conditions. This review summarizes current knowledge of the impact of mode of delivery on long-term neurologic outcome.


Gender differences among long-stay inpatients with schizophrenia in China: A cross-sectional study.
We sought to examine the independent correlates of long-term hospitalization in a sample of Chinese inpatients with schizophrenia (SCZ) from a gender-based perspective. This was a cross-sectional study that was carried out in a tertiary psychiatric hospital. All adult inpatients in this hospital were screened from January to March 2020, 251 of whom were identified as long-stay inpatients with SCZ (LSIS) and 224 as short-stay inpatients with SCZ (SSIS). Demographic and clinical information of the two groups was collected through medical records, scale assessments and interviews. Gender differences were analyzed, and independent correlates of long-stay between genders were explored by logistic regression analyses. Compared to SSIS, greater proportions of LSIS patients were male (64.1%), single (82.1%), unemployed (81.7%) and had no family caregivers (54.2%). For LSIS per se, proportionally more males were single (88.8%), had no family caregiver (65.8%), had concomitant physical disease (65.2%) and had a history of hazardous behavior (27.3%) than their female counterparts. For females, the top independent risk factors for a long stay included poor functioning (OR = 5.9, 95% CI: 2.9-12.0), older age (OR = 4.3, 95% CI: 2.1-9.1) and being single (OR = 3.9, 95% CI: 1.8-8.4). Similar to women, both older age (OR = 5.3, 95% CI: 2.5-11.2) and poor functioning (OR = 4.0, 95% CI: 2.1-7.9) were also independent factors for long-term hospitalization of male patients; however, having no family caregiver (OR = 10.2, 95% CI: 4.6-22.6) was the primary risk factor for men. Both clinical and nonclinical factors play important roles in long-term hospitalization in Chinese patients with schizophrenia. There are overlaps and distinctions across genders with respect to the independent factors of long stays. These findings provide clues for developing better service strategies for this population, and highlight the importance of paying attention to gender differences in further research in this field.


Violence-related mortality and morbidity of humanitarian workers.
(1) To determine the rate of violence-related deaths, medical evacuations, and hospitalizations occurring to national and expatriate staff of participating humanitarian organizations; (2) to describe the distribution of all-cause and cause-specific mortality and morbidity of humanitarian workers with regard to possible risk factors. Surveillance study of field-based humanitarian workers; data were regularly collected from headquarters of participating organizations via e-mail and telephone between September 2002 and December 2005. Eighteen humanitarian organizations reported on any death, medical evacuation, or hospitalization of any national or expatriate staff for any cause, in any field location during the study period. None. Risk of violence-related events was calculated as the number of deaths, medical evacuations, and hospitalizations during the study period divided by the total number of field staff for organizations that had staff in those countries where events occurred to the staff of any participating organization. Distribution descriptions are presented as simple proportions. Risk of violence-related deaths, medical evacuations, and hospitalizations was six per 10,000 aid worker person-years. Fifty percent of intentional violence cases were lethal. Intentional violence accounted for 55 percent of all deaths reported, followed by coincidental illness (27 percent) and accidents (15 percent). Aid worker deaths in this group were more frequently caused by intentional violence than either accidents or coincidental illness. The rate of six intentional violence events per 10,000 person-years can be used as a baseline by which to track changes in risk over time.


Ultrasonic evaluation of extremity soft-tissue lesions with arthrographic correlation.
Diagnostic ultrasound is a fast and accurate method to detect extremity soft-tissue lesions, including popliteal (Baker) cysts, abscess, rupture of the suprapatellar bursa, peripheral artery aneurysms, and soft-tissue tumors.


Late calcific mitral stenosis after MitraClip procedure in a dialysis-dependent patient.
The EVEREST II trial investigated the MitraClip (Abbott Vascular, Menlo Park, CA) in patients with severe mitral regurgitation (MR) undergoing surgical procedures. Although mitral stenosis was not reported in this cohort, this trial excluded patients receiving dialysis. We report a case of a 43-year-old HIV-positive, dialysis-dependent patient with nonischemic cardiomyopathy and severe MR, who was considered at high operative risk because of frailty. She was treated with a MitraClip as part of the REALISM high-risk registry. Her symptomatic MR improved but severe symptomatic mitral stenosis developed 28 months after the MitraClip procedure. At that point, she was felt to be a better operative candidate but required open mitral valve replacement. Pathologic examination demonstrated significant calcification of the leaflets around the MitraClip devices.


The Severity of Gliosis in Hippocampal Sclerosis Correlates with Pre-Operative Seizure Burden and Outcome After Temporal Lobectomy.
Astrogliosis and microgliosis in hippocampal sclerosis (HS) are widespread and are postulated to contribute to the pro-excitatory neuropathological environment. This study aimed to establish if seizure burden at the time of surgery or post-surgical outcome were correlated with the extent of gliosis in HS. As a secondary aim, we wanted to determine if the degree of gliosis could be predicted by pre-operative neuroimaging.Children and adults who underwent epilepsy surgery for HS between 2002 and 2011 were recruited (n = 43), and age-matched autopsy controls obtained (n = 15). Temporal lobe specimens were examined by DAB immunohistochemistry for astrocytes (glial fibrillary acidic protein (GFAP)) and microglia (CD68). Cell counting for GFAP and CD68 was performed and quantitative densitometry undertaken for GFAP. Seizure variables and outcome (Engel) were determined through medical record and patient review. Seizure frequency in the 6 months prior to surgery was measured to reflect the acute seizure burden. Duration of seizures, age at onset and age at operation were regarded to reflect chronic seizure burden. Focal, lobar and generalized atrophy on pre-operative MRI were independently correlated with the degree of cortical gliosis in the surgical specimen.In HS, both acute and chronic seizure burden were positively correlated with the degree of gliosis. An increase in reactive astrocyte number in CA3 was the strongest predictor of poor post-operative seizure outcome at 1 and 3 years post-operatively in this cohort. Changes in lower cortical astrocyte and upper cortical microglial number also correlated with post-operative outcome at 1 year. Post-surgical seizure outcome (1, 3 and 5 years) did not otherwise correlate with GFAP immunoreactivity (GFAP-IR) or CD68 immunoreactivity (CD68-IR). Increased microglial activation was detected in patients with pre-operative bilateral convulsive seizures, compared to those without convulsive seizures. Furthermore, focal, lobar and generalized atrophy on pre-operative neuroimaging were independently correlated with the degree of cortical gliosis in the surgical specimen.


Building Culturally Centered System Dynamics Logic Models for the Brown Buttabean Motivation Organization: Protocol for a Systems Science Approach.
Brown Buttabean Motivation (BBM) is an organization providing support for Pacific people and Indigenous Māori to manage their weight, mainly through community-based exercise sessions and social support. It was started by DL, a man of Samoan and Māori descent, following his personal weight loss journey from a peak weight of 210 kg to less than half that amount. DL is a charismatic leader with a high media profile who is successful in soliciting donations from corporations in money and kindness. Over time, BBM's activities have evolved to include healthy eating, food parcel provision, and other components of healthy living. A co-design team of university researchers and BBM staff are evaluating various components of the program and organization. The purpose of this study is to build culturally centered system dynamics logic models to serve as the agreed theories of change for BBM and provide a basis for its ongoing effectiveness, sustainability, and continuous quality improvements. A systems science approach will clarify the purpose of BBM and identify the systemic processes needed to effectively and sustainably achieve the study's purpose. Cognitive mapping interviews with key stakeholders will produce maps of their conceptions of BBM's goals and related cause-and-effect processes. The themes arising from the analysis of these maps will provide the initial indicators of change to inform the questions for 2 series of group model building workshops. In these workshops, 2 groups (BBM staff and BBM members) will build qualitative systems models (casual loop diagrams), identifying feedback loops in the structures and processes of the BBM system that will enhance the program's effectiveness, sustainability, and quality improvement. The Pacific and Māori team members will ensure that workshop content, processes, and outputs are grounded in cultural approaches appropriate for the BBM community, with several Pacific and Māori frameworks informing the methods. These include the Samoan fa'afaletui research framework, which requires different perspectives to be woven together to create new knowledge, and kaupapa Māori-aligned research approaches, which create a culturally safe space to conduct research by, with, and for Māori. The Pacific fonofale and Māori te whare tapa whā holistic frameworks for interpreting people's dimensions of health and well-being will also inform this study. Systems logic models will inform BBM's future developments as a sustainable organization and support its growth and development beyond its high dependence on DL's charismatic leadership. This study will adopt a novel and innovative approach to co-designing culturally centered system dynamics logic models for BBM by using systems science methods embedded within Pacific and Māori worldviews and weaving together a number of frameworks and methodologies. These will form the theories of change to enhance BBM's effectiveness, sustainability, and continuous improvement. Australian New Zealand Clinical Trial Registry ACTRN 12621-00093-1875; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382320. PRR1-10.2196/44229.


Lessons from the Analysis of a Retrospective Cohort of Patients Who Underwent Large Open Abdominal Surgery Under Total Intravenous Opioid-Free Anesthesia.
Opioid-free anesthesia (OFA) is a new method of anesthesia based on a paradigm shift. Under general anesthesia, the physiology and/or the pathophysiological variations clinically observed are more a reflection of a systemic reaction to the stress (surgical and anesthesia stresses) than a true reflection of pain. To report the results of a large monocenter, retrospective, non-interventional observational study of all consecutive patients who received a total intravenous (IV)-OFA protocol for the surgical management of major open abdominal and urological surgery. We retrospectively extracted the anesthesia files of 311 consecutive patients (regional anesthesia excluded). No opioids were administered to any of these patients during the surgery. IV morphine administered in the recovery room was the primary endpoint of the study. The secondary endpoints included the amount of opioid required during the first two postoperative days, as well as the maximum pain intensity. Only very small doses of IV morphine were administered. The mean total morphine titration was 2 mg (1.9 ± 2.9 mg), corresponding to control of the maximal level of pain to 2.1 ± 2.6 as evaluated with a numerical scale in the postoperative care unit. Similarly, we observed a very low level of morphine consumption during the first two postoperative days. These results highlight the safety and the feasibility of our total IV-OFA protocol, thus confirming this new paradigm. Under general anesthesia, the cardiovascular and inflammatory response to the stress could be reliably managed through a multimodal approach without a need for opioids. In the postoperative period, very low doses of opioids were required.


Inflammatory Breast Cancer in Pregnancy and Lactation.
Inflammatory breast cancer (IBC) represents only 1% to 5% of all breast malignancies and is an extremely aggressive subtype. At time of diagnosis, up to 85% of patients will present with regional nodal metastases and up to 30 % will have metastasis to distant organs. There is limited medical literature describing treatment guidelines for IBC during gestation. The best diagnostic tools are core needle and full-thickness skin punch biopsies to assess presence of dermal lymphatic invasion. Breast Ultrasound is preferred to mammogram, but mammography could still be done with proper fetal shielding. Ultrasound and Magnetic resonance imaging are used for staging. Pregnant patients should be managed with special attention to the health of the fetus by a multidisciplinary team. Treatment based on current guidelines consist of a sequence of systemic chemotherapy followed by mastectomy with axillary dissection (modified radical mastectomy), and even if good clinical nodal response to neoadjuvant therapy is obtained, sentinel node biopsy is not recommended. Radiation therapy is to be given once the baby has been delivered. Chemotherapy is not recommended in the first trimester, and anti-estrogen hormonal therapy, as well as targeted Her2-neu therapies are contraindicated during the length of the pregnancy. There is no evidence that early termination improves the outcome. However, given the poor prognosis of IBC, patients should be fully counseled on the risks and benefits of continuing or terminating an early pregnancy.


[Analysis on the gastrointestinal motility disorder of gastroesophageal reflux disease and the mechanism of acupuncture-moxibustion from the perspective of autonomic nervous system].
From the perspective of autonomic nervous system, this paper analyzes the mechanism, current western medicine treatment methods and acupuncture-moxibustion treatment mechanism of gastroesophageal reflux disease (GERD). It is believed that the main cause of GERD is that the gastric acid goes to the wrong place due to gastrointestinal motility disorder, which belongs to "acid dislocation". At present, western medical treatment cannot effectively target the pathogenesis of the disease, and its effect is limited. Acupuncture-moxibustion could regulate the neuroendocrine immune network to regulate the function of autonomic nerve, restore the power of digestive tract to treat GERD, which is worthy of further research.


A prospective study of the effects of sexual or physical abuse on back pain.
A prospective investigation of the effects of abuse on future pain and disability was conducted in order to understand better the possible causal role of abuse. Participants were 422 females from a previous population study (Pain 73 (1997) 47-53) who either reported no spinal pain (n=194) or some spinal pain (n=228) at the baseline. A standardized questionnaire was used to assess self-reported physical and sexual abuse during childhood and as an adult. One year later, a follow-up questionnaire was used to evaluate pain and physical function outcomes. Results for the No Pain Group showed that only self-reported physical abuse at baseline was associated with an increased occurrence of new episodes of back pain (odds RATIO=2.65). Both sexual and physical abuse were linked to as much as four-fold increase in the occurrence of a new episode of functional problems at follow-up. However, for the Pain Group, no significant differences were found between those reporting and not reporting abuse at baseline and either pain or disability at follow-up. This unique prospective study with individuals from the general population underscores the probable importance of abuse in the etiology of a pain or disability problem. Nevertheless, since no clear relationship between abuse and pain was shown for those already reporting pain at baseline, the role of abuse in the development of persistent pain is still not comprehensible. There is a need for investigations with prospective designs employing patients as well as nonpatients as subject.


Risk of fatal cerebrovascular accidents after external beam radiation therapy for early-stage glottic laryngeal cancer.
This study compared the risk of fatal cerebrovascular accidents (CVAs) in patients with early-stage glottic laryngeal cancer receiving surgery or external beam radiation therapy (EBRT). Using a competing risks survival analysis, we compared the risk of death because of CVA among patients with early-stage glottic laryngeal cancer receiving surgery or EBRT in the Surveillance, Epidemiology, and End Results (SEER) database. The cumulative incidence of fatal CVA at 15 years was higher in patients receiving EBRT (2.8%; 95% confidence interval [CI], 2.3% to 3.4%) compared to surgery (1.5%; 95% CI, 0.8% to 2.3%; p = .024). In multivariable competing risks regression models, EBRT remained associated with an increased risk of fatal CVA compared to surgery (adjusted hazard ratio [HR], 1.75; 95% CI, 1.04-2.96; p = .037). Treatment for early-stage glottic laryngeal cancer with EBRT was associated with a small increase in the risk of late fatal CVA events relative to surgery.


Silencing of retroviral vector transduced LacZ reporter gene by frameshift mutation.
Moloney murine leukemia virus-based vector expressing Escherichia coli beta-galactosidase (lacZ) as reporter gene and the transposon Tn5 neomycin resistance (neo) gene was transduced at low-multiplicity of infections into NIH 3T3 cells. Geneticin (G418)-resistant cells were recloned and cell lines containing beta-galactosidase positive or beta-galactosidase negative cells were obtained. Both positive and negative cell lines contained a single proviral copy at distinct integration sites. RNA complementary to lacZ was detected in beta-galactosidase positive as well as in one of three investigated beta-galactosidase negative cell lines. DNA sequence analysis of proviral LacZ gene in beta-galactosidase negative cell line C6 showed a single nucleotide insertion at position 1567 resulting in reading frame shift and translational stop codon at position 1629. This mutation explains the enzyme inactivation. The absence of beta-galactosidase after retroviral transduction of LacZ reproter gene may be a consequence of definite mutation but not a consequence of ineffective transduction or transcriptional inactivation of transgene.


Orbital apocrine hidrocystoma with ptosis.
To describe a patient with orbital apocrine hidrocystoma presenting with ptosis and subsequent management. A 43-year-old woman presented to the oculoplastic surgery clinic with a left-sided ptosis and enlarging but painless mass in the sulcus of the left upper eyelid. Magnetic resonance imaging demonstrated a large, circumscribed T2 bright cystic lesion in the extraconal space. Surgical excision and histopathology confirmed a diagnosis of apocrine hidrocystoma. Although uncommon, ptosis may be a presenting symptom of an orbital apocrine hidrocystoma, which should be considered in the differential diagnosis for an extraconal cystic lesion. Apocrine hidrocystomas are benign tumors and are cured with surgical excision with rare recurrence.


Genetic Parameters for Age at First Calving and First Calving Interval of Beef Cattle.
The objective of this study was to estimate genetic parameters for age at first calving (AFC) and first calving interval (FCI) for the entire beef cattle population and separately for the Charolais (CH) and Aberdeen Angus (AA) breeds in the Czech Republic. The database of performance testing between the years 1991 and 2019 was used. The total number of cows was 83,788 from 11 breeds. After editing, the data set contained 33,533 cows, including 9321 and 4419 CH and AA cows, respectively. The relationship matrix included 85,842 animals for the entire beef population and 24,248 and 11,406 animals for the CH and AA breeds, respectively. A multibreed multitrait animal model was applied. The estimated heritability was low to moderate. Genetic correlations between AFC and FCI varied depending on the breeds from positive to negative. Differences between variance components suggest that differences between breeds should be considered before selection and breeding strategy should be developed within a breed.


Enterocyte synthesizes and secrets uric acid as antioxidant to protect against oxidative stress via the involvement of Nrf pathway.
The gut is an important site to excreting uric acid (UA) in addition to the kidney. The gastrointestinal tract is constantly exposed to various potentially harmful substances, triggering intestinal oxidative damage. In the present study, the hypothesis that UA is can be synthesized to function as an antioxidant in the gut is evaluated. The synthesis and secretion of UA by enterocytes were analyzed in the presence of inosine, a precursor of UA, febuxostat (Fx), an inhibitor of xanthine oxidase (XOR), and H2O2. The regulation of Nrf2 pathway on UA secretion and transport were evaluated in the present of agonist (TBHQ) and inhibitor (ML385) of Nrf2. The in vivo result showed that UA and its oxidation product allantoin were presented in gut contents along the gastrointestinal tract and the highest level of UA and allantoin were detected in duodenum and jejunum respectively. The genes in the de novo purine nucleotide synthesis and salvage-catabolism pathways, and UA transporters were expressed in the intestinal tract. In the in vitro cultured enterocytes and everted gut sacs, inosine stimulated UA synthesis and secretion. H2O2 stimulated UA synthesis and secretion and meanwhile induced oxidative damage. UA attenuated H2O2-induced oxidative damage by Nrf2 pathway. UA secretion and transport were reduced by blocking Nrf2 with ML385, while increased by activating Nrf2 with TBHQ. This study provides new insights into the antioxidant effects if UA on intestinal lumen. The result suggests that activation of Nrf2 pathway is involved in the transportation and secretion of UA.


Platelet-derived growth factor receptor alpha (PDGFRα) is overexpressed in NK/T-cell lymphoma and mediates cell survival.
Nasal-type natural killer/T-cell lymphoma (NKTCL) is a subtype of non-Hodgkin lymphoma (NHL) that is clinically aggressive and has a poor prognosis. Platelet-derived growth factor receptors (PDGFRs) and their ligands (PDGFs) play important roles in angiogenesis, cancer cell proliferation, survival, migration and poor prognosis in various tumours. However, the significance of PDGFRs in NKTCL remains unknown. Herein, the present study aimed to investigate the important role of PDGFRα in pathogenesis, progression and prognisis of NKTCL. Firstly, we performed immunohistochemical staining, qRT-PCR and western blotting to determine PDGFRα expression in formalin-fixed, paraffin-embedded tissue sections from 78 NKTCL cases and in cell lines. Secondly, correlations between PDGFRα expression and NKTCL clinical parameters and prognosis were analysed. Moreover, a biological assessment of PDGFRα blockade in two NKTCL cell lines was conducted through proliferation assay, cell-cycle evaluation and apoptosis detection by flow cytometry analyses. Furthermore, we detected in vivo activity of imatinib in mouse model of NKTCL. We found that the expression of PDGFRα was significantly higher in NKTCL tissues compared to the reactive lymphoid hyperplasia of the nasopharynx (P = 0.028). High PDGFRα expression was strongly associated with a high LDH level (P = 0.028) and III-IV stage (P = 0.013). NKTCL patients with high PDGFRα expression displayed a reduced median overall survival time and progression-free survival time when compared with those with low PDGFRα expression (P = 0.011, P = 0.005, respectively). Cox multivariate analysis showed that III-IV stage (P = 0.024) and high PDGFRα expression (P = 0.003) were independent prognostic factors in NKTCL patients. Biological assessment assays in two NKTCL cell lines revealed that a specific PDGFR antagonist, imatinib, inhibited cell viability, blocked cell cycle progression at G0/G1 stage and induced apoptosis. Similarly, the in vivo assay showed that imatinib delayed mouse model tumour growth. In conclusion, NKTCL tumour cells have prominent PDGFRα expression, which can serve as a candidate prognostic marker. PDGFR antagonists have significant biological effect on NKTCL and may be useful therapeutic agents for treatment of NKTCL.


Exosome-mediated transfer of SNHG7 enhances docetaxel resistance in lung adenocarcinoma.
Long noncoding RNA (lncRNA) small nucleolar RNA host gene 7 (SNHG7) has been widely reported in various cancers, including lung adenocarcinoma (LUAD). However, it is largely unknown whether SNHG7 is involved in docetaxel resistance of LUAD. In the current study, we identified the high expression of SNHG7 in docetaxel-resistant cells. Through functional assays, we determined that silencing of SNHG7 decreased IC50 value of LUAD cells to docetaxel and suppressed proliferation and autophagy in LUAD cells, and reversed M2 polarization in macrophages. Mechanistically, we uncovered that SNHG7 promoted autophagy via recruiting human antigen R (HuR) to stabilize autophagy-related genes autophagy related 5 (ATG5) and autophagy related 12 (ATG12). Moreover, exosomal SNHG7 was transmitted from docetaxel-resistant LUAD cells to parental LUAD cells and thus facilitated docetaxel resistance. Additionally, exosomal SNHG7 activated the phosphatidylinositol 3-kinase (PI3K)/AKT pathway to promote M2 polarization in macrophages via recruiting cullin 4A (CUL4A) to induce ubiquitination and degradation of phosphatase and tensin homolog (PTEN). Taken together, we concluded that exosomal SNHG7 enhances docetaxel resistance of LUAD cells through inducing autophagy and macrophage M2 polarization. All findings in the study suggested that SNHG7 may be a promising target for relieving docetaxel resistance in LUAD.


Internet Filtering Technology and Aversive Online Experiences in Adolescents.
To evaluate the effectiveness of Internet filtering tools designed to shield adolescents from aversive experiences online. A total of 1030 in-home interviews were conducted with early adolescents aged from 12 to 15 years (M = 13.50, SD = 1.18) and their caregivers. Caregivers were asked about their use of Internet filtering and adolescent participants were interviewed about their recent online experiences. Contrary to our hypotheses, policy, and industry advice regarding the assumed benefits of filtering we found convincing evidence that Internet filters were not effective at shielding early adolescents from aversive online experiences. Preregistered prospective and randomised controlled trials are needed to determine the extent to which Internet filtering technology supports vs thwarts young people online and if their widespread use justifies their financial and informational costs.


Insights into the mechanism of carbocatalysis for peracetic acid activation: Kinetic discernment and active site identification.
Peracetic-acid-based advanced oxidation processes (PAA-AOPs) on metal-free catalysts have emerged as charming strategies for water contaminant removal. However, the involved reactive species and their corresponding active sites are ambiguous. Herein, using carbon nanotube (CNT) as a model carbocatalyst, we demonstrated that, under neutral conditions, the CNT-PAA* complex was the dominant reactive species to oxidize phenolic compounds via electron-transfer process (ETP), whereas the surface-bound hydroxyl radicals (·OHsurface) played a minor role on the basis of quenching and electrochemical tests as well as Raman spectroscopy. More importantly, the experimental and density functional theory (DFT) calculation results collaboratively proved that the active site for ETP was the sp2-hybridized carbon on the CNT bulk, while that for radical generation was the edge-located hydroxyl group (C-OH), which lowered the energy barrier for cleaving the O-O bond in CNT-PAA* complex. We further discerned the oxidation kinetic constants (koxid) of different pollutants from the apparent kinetic constants in CNT/PAA system. The significant negative linear correlation between lnkoxid and half-wave potential of phenolic compounds suggests that the pollutants with a lower one-electron oxidation potential (i.e., stronger electron-donating ability) are more easily oxidized. Overall, this study scrutinizes the hybrid radical and non-radical mechanism and the corresponding active sites of the CNT/PAA system, providing insights into the application of PAA-AOPs and the development of ETP in the remediation of emerging organic pollutants.


Changes in cerebral blood flow during anaesthesia and surgery in the sitting position.
Serial measurements of global cerebral blood flow (CBF) were made in 15 patients undergoing elective neurosurgical procedures in the sitting position, using a modified intravenous 133Xenon technique. The mean supine CBF rose from 43 (+/-3) ml/100g/min to 62 (+/-6) ml/100g/min in the sitting position and remained elevated at the end of surgery at 62 (+/-5) ml/100g/min. Both increases in CBF were statistically significant with respect to baseline supine values.


Health visitors' perceived priority needs in relation to their genetics education.
There is a growing recognition, nationally and internationally of the need to increase the genetics education of health professionals. Nurses in primary care are expected to be an important link between people undergoing genetic investigation and regional clinical genetic centres. Core competencies in relation to genetics for all nurses, midwives and health visitors have recently been identified within the United Kingdom. This paper reports a study that sought to investigate health visitors' views on the components of these core competencies in genetics and their self reported educational needs in the area of genetics. A questionnaire based survey of 345 health visitors was undertaken in Northern Ireland, as one region of the United Kingdom during late 2003. Completed questionnaires were returned by 194 health visitors (56.2% response). Respondents largely supported the components of the core competencies now endorsed by the Nursing and Midwifery Council and reported their need for further education in relation to genetics. However, they had a limited view on their role in supporting parents of children undergoing genetic investigation. Further action needs to be taken to provide health visitors with the necessary genetic knowledge and skills in order that they are in stronger position to provide 'collateral' support for people undergoing genetic investigation.


Developmental expression of a Theileria annulata merozoite surface antigen.
Culture of a lymphoblastoid cell line infected with the macroschizont stage of the protozoan parasite Theileria annulata at 41 degrees C induces differentiation to the next stage, the merozoite. We have demonstrated that this development results in the loss of monoclonal antibody epitopes associated with the macroschizont stage, and the appearance of epitopes associated with the piroplasm (the intra-erythrocytic stages). One of the monoclonals (5E1) was shown by immunoelectron microscopy to bind to the surface of heat-induced culture forms which had size and structural characteristics of the merozoite. The monoclonal was found to detect two polypeptides of 30 kDa and 25 kDa in extracts of piroplasms. The 30-kDa polypeptide was also detected in a merozoite extract, but was not detected in an extract derived from macroschizont-infected lymphoblastoid cells. We conclude that the heat-induced differentiation of T. annulata in vitro results in the expression of a 30-kDa molecule which is located at the surface of the merozoite, and discuss the potential of this molecule as a component in a subunit vaccine.