What Limits the Distribution of Liriomyza huidobrensis and Its Congener Liriomyza sativae in Their Native Niche: When Temperature and Competition Affect Species' Distribution Range in Guatemala.
Factors limiting distribution range for most species are generally unknown regardless of whether they are native or invasive. We studied factors that could enable or restrict the distribution of two cosmopolitan invasive leafminer fly species, Liriomyza huidobrensis (Blanchard) and Liriomyza sativae (Blanchard) in their native niche. In order to test which ecological and environmental factors affect leafminer distribution we conducted thermal tolerance assays, sampled along elevation gradients and modeled species distribution. Findings from the field and rearing chambers showed a physiological restriction due to high temperatures for L. huidobrensis at 28-29 °C, above which adult emergence is compromised. We also found that maximum temperatures below 22 °C, typical of tropical highlands, favored L. huidobrensis. L. sativae was found across a wider temperature range (i.e., from 21 to 36 °C) in Guatemala. Our finding of a physiological threshold in temperature for L. huidobrensis may enable us to predict its invasive risk when combined with the environmental conditions at horticultural ports of entry and the global agricultural landscape. Further, it strengthens our predictions on shifts in distribution of the leafminer fly under future climate. We also found a temperature mediated competitive exclusion interaction between the two herbivore species, where L. sativae occurred at temperatures < 22 °C only in the absence of L. huidobrensis. We show that parasitoids had a negative effect on the leafminer flies, which varied with host plant. Finally, we show the importance of taking a multiaspect approach when investigating what limits distribution and invasiveness of a species.


Bisphenol A triggers axonal injury and myelin degeneration with concomitant neurobehavioral toxicity in C57BL/6J male mice.
Bisphenol A (BPA) is a ubiquitously distributed endocrine disrupting chemical (EDC). BPA exposure in humans has been a matter of concern due to its increased application in the products of day to day use. BPA has been reported to cause toxicity in almost all the vital organ systems even at a very low dose levels. It crosses the blood brain barrier and causes neurotoxicity. We studied the effect of BPA on the cerebral cortex of C57BL/6J mice and examined whether BPA exposure alters the expression of axonal and myelin structural proteins. Male mice were dosed orally to 40 μg and 400 μg BPA/kg body weight for 60 days. BPA exposure resulted in memory loss, muscle coordination deficits and allodynia. BPA exposure also caused degeneration of immature and mature oligodendrocytes as evaluated by decreased mRNA levels of 2',3'-cyclic nucleotide 3' phosphodiesterase (CNPase), nestin, myelin basic protein (MBP) and myelin-associated glycoprotein-1 (MAG-1) genes revealing myelin related pathology. It was observed that subchronic BPA exposure caused neuroinflammation through deregulation of inflammatory cytokines mRNA and protein expression which further resulted into neurotoxicity through axonal as well as myelin degeneration in the brain. BPA also caused increased oxidative stress in the brain. Our study indicates long-term subchronic low dose exposure to BPA has the potential to cause axonal degeneration and demyelination in the oligodendrocytes and neurons which may have implications in neurological and neuropsychological disorders including multiple sclerosis (MS), neuromyelitis optica and others.


Mutations in the canilicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin-Johnson syndrome.
Members of the ATP-binding cassette (ABC) transporter superfamily are mutated to cause diseases that include cystic fibrosis, hyperinsulinemia, adrenoleukodystrophy, Stargardt disease and multidrug resistance. We recently isolated a novel human member of ABC transporter superfamily as the candidate transporter for the glucuronide and glutathione-conjugated antitumor agents, and found it highly homologous to the rat cmoat gene. consistent with recent findings of defects in the homologous cmoat gene in two rat models of hyperbilirubinemia (TR- and Eisai), we report two deletions and a missense mutation in the active transport family signature region in the gene in patients with hyperbilirubinemia II/Dubin-Johnson syndrome (DJS; MIM 237500), respectively. These results strongly implicate the cMOAT gene as responsible for the defects in DJS patients.


A Review of Recent Research on the Role of MicroRNAs in Renal Cancer.
Renal cell carcinoma (RCC) is a most common type of urologic neoplasms; it accounts for 3% of malignant tumors, with high rates of relapse and mortality. The most common types of renal cancer are clear cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal carcinoma (chRCC), which account for 90%, 6-15%, and 2-5%, respectively, of all renal malignancies. Although surgical resection, chemotherapy, and radiotherapy are the most common treatment method for those diseases, their effects remain dissatisfactory. Furthermore, recent research shows that the treatment efficacy of checkpoint inhibitors in advanced RCC patients is widely variable. Hence, patients urgently need a new molecular biomarker for early diagnosis and evaluating the prognosis of RCC. MicroRNAs (miRNAs) belong to a family of short, non-coding RNAs that are highly conserved, have long half-life evolution, and post-transcriptionally regulate gene expression; they have been predicted to play crucial roles in tumor metastasis, invasion, angiogenesis, proliferation, apoptosis, epithelial-mesenchymal transition, differentiation, metabolism, cancer occurrence, and treatment resistance. Although some previous papers demonstrated that miRNAs play vital roles in renal cancer, such as pathogenesis, diagnosis, and prognosis, the roles of miRNAs in kidney cancer are still unclear. Therefore, we reviewed studies indexed in PubMed from 2017 to 2020, and found several studies suggesting that there are more than 82 miRNAs involved in renal cancers. The present review describes the current status of miRNAs in RCC and their roles in progression, diagnosis, therapy targeting, and prognosis of RCC.


Tumor protein D52 (TPD52): a novel B-cell/plasma-cell molecule with unique expression pattern and Ca(2+)-dependent association with annexin VI.
We generated a murine monoclonal antibody (B28p) detecting an antigenic determinant shared by the immunoglobulin superfamily receptor translocation-associated 1 (IRTA1) receptor (the immunogen used to raise B28p) and an unrelated 28-kDa protein that was subsequently subjected to extensive characterization. The expression of the 28-kDa protein in normal lymphohematopoietic tissues was restricted to B cells and plasma cells and clearly differed from that expected for IRTA1 (selectively expressed by mucosa-associated lymphoid tissue [MALT] marginal zone B cells). Two-dimensional polyacrylamide gel electrophoresis (2D-PAGE)/mass-spectrometry analysis identified the 28-kDa protein as human tumor protein D52 (TPD52), whose expression had been previously described only in normal and neoplastic epithelia. Specific B28p reactivity with TPD52 was confirmed by immunostaining/immunoblotting of TPD52-transfected cells. TPD52 expression pattern in normal and neoplastic B cells was unique. In fact, unlike other B-cell molecules (paired box 5 [PAX5], CD19, CD79a, CD20, CD22), which are down-regulated during differentiation from B cells to plasma cells, TPD52 expression reached its maximum levels at the plasma cell stage. In the Thiel myeloma cell line, TPD52 bound to annexin VI in a Ca(2+)-dependent manner, suggesting that these molecules may act in concert to regulate secretory processes in plasma cells, similarly to what was observed in pancreatic acinar cells. Finally, the anti-TPD52 monoclonal antibody served as a valuable tool for the diagnosis of B-cell malignancies.


Preparing for and Executing the Ideal Posterior Labral Repair.
Posterior labral tears are a source of pain and instability of the shoulder. Despite being relatively uncommon (reported in approximately 10% of instability cases), the incidence of posterior labral tear is increasingly recognized as underestimated in highly active populations. Posterior labral tears can result from a traumatic posterior dislocation or repetitive microtrauma, leading to posterior chondral/labral attrition. Patients often present with vague, deep-seated shoulder discomfort rather than the sensation of instability. Unfavorable results with nonsurgical management will indicate which patients will most benefit from surgery. Arthroscopic stabilization has proven to be an effective and reliable treatment, and many techniques for posterior labral repair have been described. It is important to highlight the evaluation, preparation, and execution of arthroscopic stabilization of an isolated posterior labral repair using high-strength knotless all-suture anchors to allow for a stable, efficient, reproducible, and reliable repair while maintaining a low-profile construct that minimizes damage to the surrounding tissue.


Failure of Digital Device Performance in Monitoring Physical Exercise in a Pilot Study in Sedentary Persons with HIV.
Digital devices have gained popularity in the last 10 years as a tool for exercise prescription, the monitoring of daily physical activity, and nutrition for the management of a health-related parameter. Therefore, the aim of this study was to assess the effectiveness of the use of digital devices to monitor exercise data in sedentary persons with HIV who exercise following an individualized activity pacing (AP) protocol on cardiorespiratory fitness body composition, blood lipid profile, and psychological parameters. Twenty-four PLWH were enrolled in an 18-week randomized, open-label, pilot AP exercise protocol. All participants were monitored by a Health Band connected to a mobile app that transmitted the data to a server. At week 3, they were randomized either in an experimental group (EG), in which an open device configuration enabled them to receive training data feedback (n = 12), or continued with no data feedback (control group, n = 12). The primary endpoint was improvement from the baseline of 15% of steady-state oxygen consumption (V˙O2) during a 6-min walking test. Technical issues occurred when pairing the health band with the app, which prevented EG participants from regularly receiving data feedback, and with data transmission to the server, which enabled only 40% monitoring of the total training days. Consequently, the study outcomes could not be compared between the two groups, and participants also lost confidence in the study. However, 19 out of 24 participants completed the AP program. Overall, only 6 (32%) improved steady-state V˙O2, with no significant changes at W18 from the baseline. Significant reductions were observed of BMI (p = 0.040), hip circumference (p = 0.027), and total-(p = 0.049) and HDL-cholesterol (p = 0.045). The failure of digital device performance substantially affected study procedures, monitoring, and participants' engagement, and likely limited the potential benefits of the AP exercise program.


[First and second derivatives of central pulse curves in bloodless methods of study of the force and rate of myocardial contractions].
An original technique was developed for the analysis of volume sphygmograms of the central pulse and of their derivatives that permit an indirect judgement of the maximum speed of aortic pressure growth and maximum acceleration. The technique of the examination, the methods of calculations, their substantiation and normal limits are presented. Examples are given of the employment of the technique in cases of functional and pharmacological tests. The method may be widely used under clinical conditions for the study of the functional state of the myocardium and of the individual effect of drugs (cardiac glycosides, alpha-and beta-adrenergic receptors blockers, etc.).


Behavioral immune system activity predicts downregulation of chronic basal inflammation.
Here, we present a mechanistically grounded theory detailing a novel function of the behavioral immune system (BIS), the psychological system that prompts pathogen avoidance behaviors. We propose that BIS activity allows the body to downregulate basal inflammation, preventing resultant oxidative damage to DNA and promoting longevity. Study 1 investigated the relationship between a trait measure of pathogen avoidance motivation and in vitro and in vivo proinflammatory cytokine production. Study 2 examined the relationship between this same predictor and DNA damage often associated with prolonged inflammation. Results revealed that greater trait pathogen avoidance motivation predicts a) lower levels of spontaneous (but not stimulated) proinflammatory cytokine release by peripheral blood mononuclear cells (PBMCs), b) lower plasma levels of the proinflammatory cytokine interleukin-6 (IL-6), and c) lower levels of oxidative DNA damage. Thus, the BIS may promote health by protecting the body from the deleterious effects of inflammation and oxidative stress.


Adhesion and spreading of Limulus blood cells on artificial surfaces.
The horseshoe crab Limulus has a single cell type in the blood, the granular amoebocyte. These cells, which are non-adhesive and non-motile in the blood, transform to an adhesive and motile state following extravasation. In the present study, the events of transformation were studied by time-lapse microcinematography of cells plated on to glass. Following attachment of cells to the glass, the cells protrude filopods and engage in active motility. Motile cells show 2 convertible forms; a contracted form and a reversibly flattened form. Eventually the motile cells undergo irreversible flattening which is accompanied by spontaneous degranulation. The shapes of irreversibly spread cells are influenced by the arrangement of cell-substrate contacts established prior to degranulation, and by the pattern of contact of domains of granule-derived membrane introduced into the cell surface during granule exocytosis and their subsequent endoctyosis by the cell. The clottable protein released by spontaneous degranulation of the amoebocytes undergoes gelation in the absence of bacterial endotoxin. The ability to undergo spontaneous gelation stands in marked contrast to the absolute requirement for endotoxin for gelation of the clottable protein present in 'Limulus amoebocyte lysate', a commercially valuable preparation obtained from amoebocytes used to detect endotoxin.


Alloaffinity filtration: a general approach to the purification of dynein and dynein-like molecules.
Alloaffinity filtration simply and specifically separates certain axonemal dyneins and dynein arm components from crude mixtures on the basis of their ability to bind and decorate Tetrahymena axonemal microtubules on a filter in the absence of ATP and to detach and pass into the eluate when 0.5 mM ATP is added. The procedure, which may be performed repetitively, is successful in purifying a Tetrahymena dynein that has characteristics of 30 S dynein prepared by conventional methods, while other dyneins originally present in the mixture, e.g., 14 S Tetrahymena dynein, are not found in the ATP eluate. A relatively homogeneous population of dynein oligomers is obtained. Alloaffinity-purified 30 S Tetrahymena dynein consists of heavy-, intermediate-, and light-chain polypeptides that cosediment in a sucrose gradient in fixed molar ratios and that have structural features of in situ Tetrahymena arms. Dyneins from other species will bind to Tetrahymena microtubules and can be purified by this method. Alloaffinity-purified Chlamydomonas dynein is a set of polypeptides including the four heavy chains that characterize the outer arm.


[Successful therapy of hepatorenal syndrome with norepinephrine].
A 39-year-old female with alcoholic cirrhosis was admitted with signs of an alcoholic hepatitis. Within one week a hepatorenal syndrome (HRS) (Creatinin 5.83 mg/100 ml, Harnstoff 235 mg/100 ml) evolved in the absence of additional causes. She had a diminished water (urine volume 31 ml/h) and sodium excretion (10 mmol/l). Urine flow was increased to 131 ml/h by plasma expansion with i.v. infusion of volume and albumin and with infusion of dopamine (3 micrograms/kg/min) and, as there was no diuretic pretreatment and thus, no HRS secondary to diuretic treatment, furosemide (500 mg/24 h). However, impairment of renal function remained unchanged with this therapy. Therefore, norepinephrine (NE) therapy was initiated. A dosage of 0.1-0.12 microgram/kg/min was necessary to achieve the desired increase in the mean arterial pressure of 10-20 mm Hg. During the NE infusion the urine volume increased further to 231 ml/h, the sodium excretion raised to 44 mmol/l, and serum levels of creatinine and urea decreased to 1.91 mg/100 ml and 141 mg/100 ml, respectively. With recovering liver function the NE infusions could be discontinued after 5 days without recurrence of a HRS until discharge after 3 weeks. Beside the vasopressin analogon ornipressin, the combination of norepinephrine and dopamine seems to be useful for the therapy of HRS. Norepinephrine has the advantage of an easy accessibility in ICUs and seems to exert less side effects.


Etiology, Clinical Course, and Outcomes of Pneumonia in the Elderly: A Retrospective and Prospective Cohort Study in Thailand.
Pneumonia is a leading cause of hospitalization and death among elderly adults. We performed a retrospective and prospective observational study to describe the etiology, clinical course, and outcomes of pneumonia for patients 60 years and older in Thailand. We enrolled 490 patients; 440 patients were included in the retrospective study and 50 patients were included in the prospective study. The CURB-65 score and a modified SMART-COP score (SMART-CO score) were used to assess disease severity. The median patient age was 80 years (interquartile range, 70-87 years); 51.2% were men. Klebsiella pneumoniae (20.4%) and Pseudomonas aeruginosa (15.5%) were the most common causative agents of pneumonia. A significant minority (23%) of patients were admitted to the intensive care unit (ICU), and mortality among this subset of patients was 45%. Most patients (80.8%) survived and were discharged from the hospital. The median duration of hospitalization was 8 days (interquartile range, 4-16 days). In contrast, 17.6% of patients died while undergoing care and 30-day mortality was 14%. Factors significantly associated with mortality were advanced age (P = 0.004), male sex (P = 0.005), multiple bacterial infections (P = 0.007; relative risk [RR], 1.88; 95% confidence interval [CI], 1.19-2.79), infection with multi-drug-resistant/extended-spectrum B-lactamase-producing organisms (P < 0.001; RR, 2.82; 95% CI, 1.83-4.85), ICU admission (P < 0.001; RR, 1.8; 95% CI, 1.4-2.3), and complications of pneumonia (P < 0.001; RR, 2.5; 95% CI, 1.8-3.4). Patients with higher SMART-CO and CURB-65 scores had higher rates of ICU admission and higher 30-day mortality rates (P < 0.001). These results emphasize the importance of Gram-negative bacteria, particularly K. pneumoniae and P. aeruginosa, as major causes of pneumonia among the elderly in contrast to other reports, Streptococcus pneumoniae is a common cause of pneumonia among elderly individuals worldwide. The SMART-COP and CURB-65 scores were developed to assess pneumonia severity and predict mortality of young adults with pneumonia. Few studies have examined the appropriateness of these scores for elderly patients with multiple comorbidities. A limited number of studies have used modified versions of these scores among elderly individuals. We found that Gram-negative bacteria has a major role in the etiology of pneumonia among elderly individuals in Southeast Asia. A significant proportion of elderly individuals with low CURB-65 scores were admitted to the hospital, indicating that hospital admission may reflect fragility among elderly individuals with low CURB-65 scores. The modified SMART-COP score (SMART-CO score) sufficiently predicted intensive care unit admission and the need for intensive vasopressor or respiratory support. A SMART-CO score ≥ 7 accurately predicted 30-day mortality.


Salivary Metabolomics for Prognosis of Oral Squamous Cell Carcinoma.
This study aimed to identify salivary metabolomic biomarkers for predicting the prognosis of oral squamous cell carcinoma (OSCC) based on comprehensive metabolomic analyses. Quantified metabolomics data of unstimulated saliva samples collected from patients with OSCC (n = 72) were randomly divided into the training (n = 35) and validation groups (n = 37). The training data were used to develop a Cox proportional hazards regression model for identifying significant metabolites as prognostic factors for overall survival (OS) and disease-free survival. Moreover, the validation group was used to develop another Cox proportional hazards regression model using the previously identified metabolites. There were no significant between-group differences in the participants' characteristics, including age, sex, and the median follow-up periods (55 months [range: 3-100] vs. 43 months [range: 0-97]). The concentrations of 5-hydroxylysine (p = 0.009) and 3-methylhistidine (p = 0.012) were identified as significant prognostic factors for OS in the training group. Among them, the concentration of 3-methylhistidine was a significant prognostic factor for OS in the validation group (p = 0.048). Our findings revealed that salivary 3-methylhistidine is a prognostic factor for OS in patients with OSCC.


The telomeric protein Pot1 from Schizosaccharomyces pombe binds ssDNA in two modes with differing 3' end availability.
Telomere protection and length regulation are important processes for aging, cancer and several other diseases. At the heart of these processes lies the single-stranded DNA (ssDNA)-binding protein Pot1, a component of the telomere maintenance complex shelterin, which is present in species ranging from fission yeast to humans. Pot1 contains a dual OB-fold DNA-binding domain (DBD) that fully confers its high affinity for telomeric ssDNA. Studies of S. pombe Pot1-DBD and its individual OB-fold domains revealed a complex non-additive behavior of the two OB-folds in the context of the complete Pot1 protein. This behavior includes the use of multiple distinct binding modes and an ability to form higher order complexes. Here we use NMR and biochemical techniques to investigate the structural features of the complete Pot1-DBD. These experiments reveal one binding mode characterized by only subtle alternations to the individual OB-fold subdomain structures, resulting in an inaccessible 3' end of the ssDNA. The second binding mode, which has equivalent affinity, interacts differently with the 3' end, rendering it available for interaction with other proteins. These findings suggest a structural switch that contributes to telomere end-protection and length regulation.


Follow-up of chronic coughers improves tuberculosis case finding: results from a community-based cohort study in southern Ethiopia.
Untreated smear-positive tuberculosis (TB) patients are the primary source of infection; however, a large number of TB cases have not been identified and are untreated in many sub-Saharan African countries, including Ethiopia. This study determined whether or not a community-based follow-up of chronic coughers improves detection of TB cases and the risk factors for death among such cases. We conducted a census in six rural communities in Sidama, southern Ethiopia. Based on interview and sputum investigation, we identified 724 TB smear-negative chronic coughers, and did a cohort study of these chronic coughers and 1448 neighbourhood controls. For both chronic coughers and neighbourhood controls, we conducted a TB screening interview and performed sputum microscopy, as required, at 4, 7 and 10 months. Between September 2011 and June 2012, we followed chronic coughers and neighbourhood controls for 588 and 1,204 person-years of observation, respectively. Of the chronic coughers, 23 developed smear-positive TB (incidence rate = 3912/105 person-years) compared to three neighbourhood controls who developed smear-positive TB (incidence rate = 249/105 person-years). The male-to-female ratio of smear-positive TB was 1:1. We demonstrated that chronic coughers (adjusted hazards ratio [aHR], 13.5; 95% CI, 4.0-45.7) and the poor (aHR, 2.6; 95% CI, 1.1-5.8) were at high-risk for smear-positive TB. Among the study cohort, 15 chronic coughers and two neighbourhood controls died (aHR, 14.0; 95% CI, 3.2-62.4). A community-based follow-up of chronic coughers is helpful in improving smear-positive TB case detection, it benefits socioeconomically disadvantaged people in particular; in rural settings, chronic coughers had a higher risk of death.


Association of preoperative retinal microcirculation and perioperative outcomes in patients undergoing congenital cardiac surgery.
Microcirculatory dysfunction is associated with increased morbidity and mortality in cardiac surgery patients. This study aimed to investigate the association between preoperative retinal microcirculation evaluated using optical coherence tomography angiography (OCTA) and perioperative outcomes in patients with congenital heart disease (CHD). This prospective, observational study was performed from May 2017 to January 2021. OCTA was used to automatically quantify the vessel density (VD) of the superficial capillary plexus, deep capillary plexus (DCP), and radial peripapillary capillary (RPC) preoperatively. The primary outcome was excessive postoperative bleeding, defined as bleeding volume > 75th percentile for 24-hour postoperative chest tube output. The secondary outcome was composite adverse outcomes, including one or more operative mortalities, early postoperative complications, and prolonged length of stay. The association between retinal VD and outcomes was assessed using Poisson regression. In total, 173 CHD patients who underwent cardiac surgery were included (mean age, 26 years). Among them, 43 (24.9%) and 46 (26.6%) developed excessive postoperative bleeding and composite adverse outcomes, respectively. A lower VD of DCP (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.08-1.43; P = 0.003) was independently associated with excessive postoperative bleeding, and a lower VD of RPC (OR, 1.97; 95% CI, 1.08-3.57; P = 0.027), and DCP (OR, 2.17; 95% CI, 1.08-4.37; P = 0.029) were independently associated with the postoperative composite adverse outcomes. Preoperative retinal hypoperfusion was independently associated with an increased risk of perioperative adverse outcomes in patients with CHD, suggesting that retinal microcirculation evaluation could provide valuable information about the outcomes of cardiac surgery, thereby aiding physicians in tailoring individualized treatment.


Clinical experience with a TriPollar radiofrequency system for facial and body aesthetic treatments.
Non-invasive aesthetic treatments aiming at circumference reduction and facial wrinkle improvement are becoming increasingly popular. TriPollar treatments for the purpose of body contouring and skin tightening procedures have recently gained interest. Our aim was to evaluate the safety and efficacy of the Apollo device for non invasive treatment of localized excess fat and facial tightening. 37 female patients were treated for wrinkles, laxity and circumference reduction on different facial and body areas. Facial results were objectively analyzed with the Primos 3D imaging system. Body results were evaluated using photographs and circumferential measurements. Five volunteer patients underwent blood tests to assess changes in liver function and lipid profile following treatment. Significant reductions in body circumferences were measured. The average circumference reduction in main body areas (abdomen, buttocks, thighs), was 3.6 +/- 2.4 cm with a maximum reduction of up to 10.5 cm in the abdomen. An improvement of perioral and periorbital wrinkles was achieved and analyzed. No significant changes were found in any of the liver function and lipid profile indicators. Findings confirm safety and efficacy of the new treatment modality for localized fat reduction and for body and face contouring.


Total body irradiation, thiotepa, and cyclophosphamide as a conditioning regimen for children with acute lymphoblastic leukemia in first or second remission undergoing bone marrow transplantation with HLA-identical siblings.
Allogeneic hematopoietic stem-cell transplantation (HSCT) from HLA-identical siblings can be used to treat children with acute lymphoblastic leukemia (ALL). However, a significant proportion of patients with ALL who undergo HSCT relapse. For this reason, we prospectively evaluated a preparative regimen that included total body irradiation (TBI), thiotepa (TT), and cyclophosphamide (CY) in patients with high-risk ALL in first complete remission (CR) and in children with ALL in second CR. Forty children (median age, 9 years; range, 1 to 18 years) with ALL in first or second CR who underwent allogeneic HSCT from HLA-identical siblings were conditioned with a combination of fractionated TBI, TT (10 mg/kg), and CY (120 mg/kg over 2 days). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine administered intravenously at a dose of 1 to 3 mg/kg/d for the first 21 days and subsequently orally at a dose of 6 mg/kg/d. All assessable patients were engrafted, with a median time of 11 and 24 days for neutrophil and platelet recovery, respectively. The preparative regimen was well tolerated. Only one patient died as a result of regimen-related causes. Eight patients relapsed at a median time of 8 months after transplantation (range, 3 to 9 months), and this determined a cumulative probability of relapse of 23%. Twenty-six of 40 patients (65%) are alive and in complete hematologic remission, with a median observation time of 36 months (range, 14 to 57 months), which results in a disease-free survival (DFS) at 3 years of 65%. The 13 patients who underwent transplantation in first CR had a DFS of 85%, whereas the 27 patients who underwent HSCT in second CR had a DFS of 56%. These data suggest that TT is an effective cytotoxic drug that can be safely added to the classical TBI-CY regimen. Because of its cell cycle-independent action, good CNS diffusion, and limited extramedullary toxicity, TT may contribute to increasing the percentage of children with ALL who are successfully cured with allogeneic BMT.


Actin Cytoskeleton and Golgi Involvement in Barley stripe mosaic virus Movement and Cell Wall Localization of Triple Gene Block Proteins.
Barley stripe mosaic virus (BSMV) induces massive actin filament thickening at the infection front of infected Nicotiana benthamiana leaves. To determine the mechanisms leading to actin remodeling, fluorescent protein fusions of the BSMV triple gene block (TGB) proteins were coexpressed in cells with the actin marker DsRed: Talin. TGB ectopic expression experiments revealed that TGB3 is a major elicitor of filament thickening, that TGB2 resulted in formation of intermediate DsRed:Talin filaments, and that TGB1 alone had no obvious effects on actin filament structure. Latrunculin B (LatB) treatments retarded BSMV cell-to-cell movement, disrupted actin filament organization, and dramatically decreased the proportion of paired TGB3 foci appearing at the cell wall (CW). BSMV infection of transgenic plants tagged with GFP-KDEL exhibited membrane proliferation and vesicle formation that were especially evident around the nucleus. Similar membrane proliferation occurred in plants expressing TGB2 and/or TGB3, and DsRed: Talin fluorescence in these plants colocalized with the ER vesicles. TGB3 also associated with the Golgi apparatus and overlapped with cortical vesicles appearing at the cell periphery. Brefeldin A treatments disrupted Golgi and also altered vesicles at the CW, but failed to interfere with TGB CW localization. Our results indicate that actin cytoskeleton interactions are important in BSMV cell-to-cell movement and for CW localization of TGB3.


A phase I study of OGX-011, a 2'-methoxyethyl phosphorothioate antisense to clusterin, in combination with docetaxel in patients with advanced cancer.
Clusterin is a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum treatment resistance. OGX-011 is a 2'-methoxyethyl-modified phosphorothioate antisense oligonucleotide that is complementary to clusterin mRNA, has a prolonged tissue half life, enhances drug efficacy in xenograft models, and reduces clusterin expression in humans with a biologically effective dose of 640 mg. The objective of this study was to determine a recommended phase II dose of OGX-011 in combination with docetaxel. Patients with cancers known from the literature to express clusterin were eligible. OGX-011 was given by 2-h i.v. infusion starting at 40 mg weekly after loading doses on days 1, 3, and 5. Docetaxel was given i.v. 30 mg/m(2) weekly for 5 of 6 weeks (schedule A) or 75 mg/m(2) every 3 weeks (schedule B). All patients had serial samples of peripheral blood mononuclear cells and serum assessed for clusterin expression. Forty patients were enrolled to eight cohorts. OGX-011 could be given at the full biologically effective single-agent dose of 640 mg with both docetaxel schedules. Toxic effects were primarily myelosuppression, fatigue, hair loss, gastrointestinal effects (expected docetaxel effects), as well as dose-related chills and fever (expected OGX-011 effects). OGX-011 AUC and C(max) increased proportionally with no apparent effect on docetaxel pharmacokinetics. At the end of cycle 1, serum clusterin showed mean decreases of 34% and 38% (range, 15-99%) at the 640-mg dose levels. OGX-011 can be given at a biologically effective dose with standard doses of docetaxel. Phase II trials of combined OGX-011 and chemotherapy are ongoing in patients with prostate, breast, and lung cancers.


Adherence to a Dash-style diet in relation to depression and aggression in adolescent girls.
The aim of this study was to assess adherence to the Dietary Approach to Stop Hypertension (DASH) dietary pattern in relation to depression and aggression in adolescent girls. The study was carried out among 580 girls aged between 12 and 18 years of age. DASH scores were determined according to the method of Fung et al. A Persian version of the Beck Depression Inventory and Buss-Perry questionnaire were used for the assessment of depression and aggression. We analysed our data using crude and adjusted models. Adjustments were made for age, energy intake, mother's job status, passive smoking, start of menstruation, parental death, parental divorce, physical activity level and body mass index, using three different models. A high adherence to a Dash-style diet (for individuals in the upper quartile) was associated with a lower odds of depression compared with subjects with lower adherence (those in the lowest quartile) (OR 0.47; 95% CI 0.26-0.84, P-value = 0.009); these associations remained significant after adjustments. However, we did not obtain any significant relationship between a DASH-style diet and aggression. We observed a significant inverse relationship between greater adherence to a DASH diet and lower odds of depression. Further prospective studies are needed to confirm these findings.


Maternal uniparental heterodisomy of chromosome 14: chromosomal mechanism and clinical follow up.
To our knowledge, 22 cases of chromosome 14 maternal uniparental disomy (UPD(14)mat) have been reported so far. The majority of cases were ascertained because of an abnormal phenotype associated with a Robertsonian translocation involving chromosome 14. We report here on a child with UPD(14)mat detected prenatally and resulting from trisomy rescue in a maternal meiosis I non-disjunction trisomic zygote. After four years of clinical follow up, in addition to intrauterine growth retardation (IUGR), only short stature and small hands and feet were observed. These clinical data as well as the ascertainment and mechanism of origin of UPD(14)mat were compared with those observed in previously reported cases. It appears that the clinical spectrum of UPD(14)mat is milder in our patient than in patients with UPD(14)mat resulting from other chromosomal mechanisms. In addition, a hypothesis based on abnormal imprinting is proposed to explain the variability of the UPD(14)mat.


Control of body size by oxygen supply reveals size-dependent and size-independent mechanisms of molting and metamorphosis.
Body size profoundly affects many aspects of animal biology, including metamorphosis, allometry, size-dependent alternative pathways of gene expression, and the social and ecological roles of individuals. However, regulation of body size is one of the fundamental unsolved problems in developmental biology. The control of body size requires a mechanism that assesses size and stops growth within a characteristic range of sizes. Under normal growth conditions in Manduca sexta, the endocrine cascade that causes the brain to initiate metamorphosis starts when the larva reaches a critical weight. Metamorphosis is initiated by a size-sensing mechanism, but the nature of this mechanism has remained elusive. Here we show that this size-sensing mechanism depends on the limited ability of a fixed tracheal system to sustain the oxygen supply to a growing individual. As body mass increases, the demand for oxygen also increases, but the fixed tracheal system does not allow a corresponding increase in oxygen supply. We show that interinstar molting has the same size-related oxygen-dependent mechanism of regulation as metamorphosis. We show that low oxygen tension induces molting at smaller body size, consistent with the hypothesis that under normal growth conditions, body size is regulated by a mechanism that senses oxygen limitation. We also found that under poor growth conditions, larvae may never attain the critical weight but eventually molt regardless. We show that under these conditions, larvae do not use the critical weight mechanism, but instead use a size-independent mechanism that is independent of the brain.


Acceptability and clinical outcomes of first- and second-trimester surgical abortion by suction aspiration in Colombia.
Since partial decriminalization of abortion in Colombia, Oriéntame has provided legal abortion services through 15 weeks gestation in an outpatient primary care setting. We sought to document the safety and acceptability of the second trimester compared to the first-trimester surgical abortion in this setting. This was a prospective cohort study using a consecutive sample of 100 women undergoing surgical first-trimester abortion (11 weeks 6 days gestational age or less) and 200 women undergoing second-trimester abortion (12 weeks 0 days-15 weeks 0 days) over a 5-month period in 2012. After obtaining informed consent, a trained interviewer collected demographic and clinical information from direct observation and the patient's clinical chart. The interviewer asked questions after the procedure regarding satisfaction with the procedure, physical pain and emotional discomfort. Fifteen days later, the interviewer assessed satisfaction with the procedure and any delayed complications. There were no major complications and seven minor complications. Average measured blood loss was 37.87 mL in the first trimester and 109 mL in the second trimester (p<.001). Following the procedure, more second-trimester patients reported being very satisfied (81% vs. 94%, p=.006). Satisfaction was similar between groups at follow-up. There were no differences in reported emotional discomfort after the procedure or at follow-up, with the majority reporting no emotional discomfort. The majority of women (99%) stated that they would recommend the clinic to a friend or family member. Second-trimester surgical abortion in an outpatient primary care setting in Colombia can be provided safely, and satisfaction with these services is high. This is one of the first studies from Latin America, a region with a high proportion of maternal mortality due to unsafe abortion, which documents the safety and acceptability of surgical abortion in an outpatient primary care setting. Findings could support increased access to safe abortion services, particularly in the second trimester.


Results of stereotactic aspiration in 175 cases of putaminal hemorrhage.
Believing that improved therapeutic results in cases of intracerebral hematoma might be obtained by minimal invasion of the brain, we used computed tomographic-guided stereotactic aspiration in 175 of 241 patients with putaminal hemorrhage. These patients, who were treated 6 or more hours after onset, had hematomas larger than 8 ml and were unable to raise an arm and/or leg on the affected side. Craniotomy was performed in 15 other patients, most of whom were brought to the hospital with large hematomas within 6 hours of onset. The remaining patients either had mild deficits of consciousness (33 patients) or severe deficits and/or were elderly (18 patients) and were treated conservatively. Thirteen patients (7.4%) showed rebleeding after stereotactic aspiration (6 instances of major and 7 instances of minor rebleeding). Craniotomy and removal of the hematoma were required in three of these patients. Aspiration should be avoided in patients who have a tendency for bleeding, even if mild, because rebleeding occurred in 6 of 23 such patients (26%) in these study. The consciousness level improved in 66 patients (38%), was unchanged in 103 patients (59%), and was worse in 6 patients (3%) 1 week postoperatively. Motor function of the arm improved in 55 patients (31%) and was worse in 23 patients (14%). Six months after surgery, the results for the 175 patients who underwent stereotactic aspiration were: 19% excellent, 32% good, 35% fair, 7% poor, 6% dead, and 1% unknown. For the entire series of 241 patients, the results were: 24% excellent, 26% good, 31% fair, 7% poor, 11% dead, and 1% unknown.(ABSTRACT TRUNCATED AT 250 WORDS)


Small-size effect on wrinkle and fracture of monolayer graphene subjected to in-plane shear.
Controlling surface patterns are useful in a wide range of applications including flexible electronics, biological templates, microelectromechanical systems and device fabrication. The present paper investigates the wrinkling and fracture of graphene subjected to in-plane shear. It is found that the size of a graphene sheet has significant effect on the wrinkle and fracture based on both molecular dynamics simulation and nonlocal plate theory. The analytical expressions for wrinkle amplitude and wavelength are deduced. The nonlocal parameter of nonlocal plate theory is evaluated. Furthermore, the higher aspect ratio has enhanced the wrinkle resistance and shear strength of graphene. Temperature and chirality have insignificant impact on the wrinkling, but significantly influence the fracture of the graphene sheet. This work is expected to provide a better understanding of the mechanism of nanometer scale wrinkles.


Antihyperlipidemic and antiapoptotic potential of zingerone on alcohol induced hepatotoxicity in experimental rats.
The ultimate aim of this present study was to investigate the antihyperlipidemic and antiapoptotic potential of zingerone (ZO) on alcohol induced hepatotoxicity in experimental rats. Male albino wistar rats were divided in four groups. Groups 1 and 2 rats received isocaloric glucose and dimethyl sulphoxide (2% DMSO), liver toxicity was induced in groups 3 and 4 by supplementing 30% ethanol post orally for 60 days. In addition to, groups 2 and 4 received zingerone (20 mg/kg body weight in 2% DMSO) daily during the final 30 days of the experimental period. Ethanol alone administered rats showed increased levels/activities of plasma total cholesterol (TC), triglycerides (TG), free fatty acids (FFA), phospholipids (PL), low density lipoproteins (LDL), very low density lipoproteins (VLDL), tissue TC, TG, FFA, PL, HMG-CoA reductase, phase I xenobiotic enzymes, collagen and fat accumulation, DNA damage and increased Bax, caspase-3 and caspase-9 expressions and decrease in the levels/activities of plasma high density lipoproteins (HDL), lipoprotein lipase (LPL), lecithin cholesterol acyl transferase (LCAT), phase II xenobiotic enzymes and a decreased Bcl-2 expression. Zingerone supplementation was able to counter and reverse the ethanol induced changes in all the above parameters in experimental rats. Together results portray zingerone exhibits antihyperlipidemic and antiapoptotic potential on alcohol induced hepatotoxicity.


Depressive Symptoms and Onset of Functional Disability Over 2 Years: A Prospective Cohort Study.
This prospective cohort study examined the relationship between depressive symptoms and onset of functional disability over 2 years among US Chinese older adults, a rapidly growing minority older adult population. This study used survey data from 2713 Chinese older adults who completed both baseline (2011-2013) and follow-up (2013-2015) interviews of the Population Study of Chinese Elderly in Chicago. Depressive symptoms were assessed at baseline by the nine-item Patient Health Questionnaire. Functional disability was measured by three validated scales, Katz Index of Independence in Activities of Daily Living (ADLs), the Lawton Instrumental Activities of Daily Living (IADLs) scale, and the Rosow and Breslau mobility scale. Multivariate logistic regression was conducted to examine the relationship between baseline depressive symptoms and the development of functional disability (ADLs, IADLs, mobility) at 2-year follow-up while adjusting for covariates. Of the 2713 participants, 5.2% experienced ADL disability onset, 35.6% experienced IADL disability onset, and 23.3% experienced mobility disability onset over 2 years. After adjusting for covariates, the odds of ADL disability onset (odds ratio [OR] = 1.06; 95% confidence interval [CI] = 1.02-1.11), IADL disability onset (OR = 1.05; 95% CI = 1.01-1.09), and mobility disability onset (OR = 1.05; 95% CI = 1.01-1.09) were consistently higher in US Chinese older adults with higher levels of depressive symptoms than their less-depressed counterparts. Other significant risk factors included older age and more chronic physical conditions. Study findings underscore a significant relationship between depressive symptoms and onset of functional disability. Screening and, subsequently, treating depressive symptoms have the potential to reduce disability among US Chinese older adults. Culturally relevant depressive symptom screening may help identify Chinese older adults who are at greater risks for the development of functional disability. J Am Geriatr Soc 67:S538-S544, 2019.


Biological activities and antibacterial biomarker of Sesbania grandiflora bark extract.
In the present study, the fractionated extracts of Sesbania grandiflora bark were prepared and evaluated for their biological activities. The ethyl acetate fractionate (EAF) showed high antioxidant activity along with free radical scavenging and reducing mechanisms. The free radical scavenging antioxidant activity of EAF was 69.3 ± 3.6% where its Trolox equivalent antioxidant capacity was 13.6 ± 0.7 mM/mg. EAF exhibited the reducing power equivalent to ferrous sulfate at 152 ± 2 mM/mg and equivalent to gallic acid at 1.05 ± 0.01 mM/mg. In addition, EAF presented high potential on inhibition of bacterial growth with the minimum bactericidal concentration less than 1 mg/mL. Further isolation of EAF using normal-phase open column of silica gel 60, showed that the fractions eluted with the mixture of chloroform and methanol at the ratios of 4:1, 3:2, and 2:3 possessed antibacterial activity. The recovery activity of total different active fractions was 5% EAF, 20 times less than that of EAF. The chromatogram of EAF from a high-performance liquid chromatography was compared with caffeic acid, catechin, coumaric acid, ellagic acid, gallic acid, quercetin, syringin, naringic acid, trans-cinnamic acid, and vanilic acid. The result demonstrated that one major compound of EAF was gallic acid. These results suggest that the fractionated extracts of S. grandiflora bark contained antioxidant and antibacterial activities.


[The myth of "tabula rasa"].
The history of the philosophy has witnessed a controversy between those who maintain that the human being is born with inherited knowledge and those who assert that the mind of man is like a "tabula rasa", a tablet on which nothing has been written. Recent experiments have shown that the last group was wrong. The human being is born endowed with certain types of knowledge which were already present in those animals which preceded us in the evolution. The fear of snakes, the number sense and the recognition of familiar faces are three typical examples among others.


Blood conservation techniques in spinal deformity surgery: a retrospective review of patients refusing blood transfusion.
A retrospective review. To review the effectiveness of blood conservation techniques in the spinal fusion of patients that refuse blood transfusion; specifically the Jehovah's witnesses population. Spinal surgery can be challenging in patients refusing blood transfusion. There is paucity in the literature examining blood conservation techniques in spinal surgery. The radiographic and medical records of 19 Jehovah's witnesses patients who underwent spinal deformity surgery at a single institution between 2000 and 2003 were reviewed. Patients were assessed for excessive blood loss (EBL), deformity correction, operative time, perioperative complications, and hospital stay. At latest follow-up (mean, 40 months; range, 8-76) the patients were examined for radiographic fusion, progression and complications. Spinal fusion was attempted in 19 patients, with a mean age of 17 years (range, 10-36 years). All 19 patients were identified through the "Bloodless Surgery Program." Hypotensive anesthesia, hemodilution, and cell saver was employed for all 19 cases. Erythropoietin with supplemental iron was used in 15 patients. Aprotinin was used in 3 patients. EBL and blood returned by cell saver averaged 855 and 341 mL, respectively. Operative times average 315 minutes. The average drop in hemoglobin from after surgery was 3.1 g/dL. There were 2 intraoperative complications: (i) transient loss of somatosensory evoked potential/motor evoked potential signals; and (ii) one surgery abandoned due to EBL. The average spinal deformity correction was 58%. There were 3 postoperative complications, none related to their refusal of a transfusion. 17 patients were available for radiographic and clinic follow-up of at least 24 months. All displayed radiographic fusion without progression. These blood conservation techniques allow satisfactory completion of deformity surgery on those patients not willing to be transfused and without major anesthetic or medical complications.


Systematic Review and Meta-Analysis of Racial and Ethnic Differences in Dementia Caregivers' Well-Being.
Studies comparing racial/ethnic differences on measures of psychological and physical well-being for dementia caregivers have reported differences between minority and white caregivers. Recruitment methods often differ for minority and white participants due to enrollment targets and may lead to biased comparisons, especially in convenience samples. We aimed to examine racial/ethnic differences in dementia caregiver outcomes and to determine whether differences vary between studies with population-based or convenience samples. We systematically reviewed articles with primary data from PubMed, Google Scholar, and PsycINFO. We included studies comparing African American or Hispanic/Latino to white dementia caregivers on measures of psychological well-being or physical well-being. Reviewers screened titles and abstracts, reviewed full texts and conducted risk-of-bias assessments. Meta-analyses were conducted to assess effects by race/ethnicity and study bias. A total of 159 effects were extracted from 38 studies, 2 of which were population based. Random-effects models revealed small but statistically significant effects with better psychological well-being in African American caregivers compared with white caregivers in both population-based (d = -0.22) and convenience sample studies (d = -0.21). Hispanics/Latino caregivers reported lower levels of physical well-being than white caregivers (d = 0.12), though these effects varied by level of rated study bias. Consistency across study methods raises confidence in the validity of previous reports of better psychological well-being in African American caregivers. Future studies should use population-based samples with subgroups of Hispanic/Latino, Asian American, and American Indian caregivers that are culturally distinct on factors such as country of origin and tribe.


Simulation environment of X-ray rotational angiography using 3D+t coronary tree model.
The newly introduced cardiac rotational angiography (RA) can provide a large amount of projections from different angles which greatly improve the 3D coronary tree reconstruction. However, the reconstruction methods are difficult to be objectively evaluated due to the complicated topology of coronary tree and non-linear cardiac motion. In this paper, we present a simulation environment of rotational angiography acquisition system to facilitate the improvements and the evaluations of reconstruction algorithms. A 3D+t coronary tree model reconstructed from MSCT sequence is employed to enhance the reality of simulation. A simulation environment of X-ray coronary angiography is developed based on distance-driven projection algorithm. The static angiography is firstly simulated to verify the dynamic model by comparing the displacements of landmarks with the real static angiography of the same patient. Rotational simulation results are then obtained with real system parameters to provide a complete and true-to-life RA sequence representing the morphology of moving coronary tree.


Technique for specimen collection of postsurgical exudate of wounds.
Postsurgical sepsis due to anaerobic microoganisms is often difficult to diagnose. The difficulty arises primarily because of inadequate specimen collection techniques and because of delays in the transport of the specimen to the microbiologic laboratory. Three acceptable techniques for anaerobic specimen collection and transportation have been offered. All of these techniques have in common the minimization of contact between the collected specimen and the atmosphere, a step which helps to preserve the viability of many of the fastidious anaerobic bacteria frequently implicated in surgical sepsis.


Eye Movement Disorders in Movement Disorders.
Oculomotor assessment is an essential element of the neurological clinical examination and is particularly important when evaluating patients with movements disorders. Most of the brain is involved in oculomotor control, and thus many neurological conditions present with oculomotor abnormalities. Each of the different classes of eye movements and their features can provide important information that can facilitate differential diagnosis. This educational review presents a clinical approach to eye movement abnormalities that are commonly seen in parkinsonism, ataxia, dystonia, myoclonus, tremor, and chorea. In parkinsonism, subtle signs such as prominent square wave jerks, impaired vertical optokinetic nystagmus, and/or the "round the houses" sign suggest early progressive supranuclear gaze palsy before vertical gaze is restricted. In ataxia, nystagmus is common, but other findings such as oculomotor apraxia, supranuclear gaze palsy, impaired fixation, or saccadic pursuit can contribute to diagnoses such as ataxia with oculomotor apraxia, Niemann-Pick type C, or ataxia telangiectasia. Opsoclonus myoclonus and oculopalatal myoclonus present with characteristic phenomenology and are usually easy to identify. The oculomotor exam is usually unremarkable in isolated dystonia, but oculogyric crisis is a medical emergency and should be recognized and treated in a timely manner. Gaze impersistence in a patient with chorea suggests Huntington's disease, but in a patient with dystonia or tremor, Wilson's disease is more likely. Finally, functional eye movements can reinforce the clinical impression of a functional movement disorder.


Detection of genetically isolated entities within the Mediterranean species of Bemisia tabaci: new insights into the systematics of this worldwide pest.
The taxonomy of the species complex Bemisia tabaci, a serious agricultural pest worldwide, is not well resolved yet, even though species delimitation is critical for designing effective control strategies. Based on a threshold of 3.5% mitochondrial (mtCOI) sequence divergence, recent studies have identified 28 putative species. Among them, mitochondrial variability associated with particular symbiotic compositions (=cytotypes) can be observed, as in MED, which raises the question of whether it is a single or a complex of biological species. Using microsatellites, an investigation was made of the genetic relatedness of Q1 and ASL cytotypes that belong to MED. Samples of the two cytotypes were collected in West Africa where they live in sympatry on the same hosts. Genotyping revealed a high level of differentiation, without evidence of gene flow. Moreover, they differed highly in frequencies of resistance alleles to insecticides, which were much higher in Q1 than in ASL. Q1 and ASL are sufficiently reproductively isolated for the introgression of neutral alleles to be prevented, suggesting that they are actually different species. This indicates that nuclear genetic differentiation must be investigated within groups with less than 3.5% mtCOI divergence in order to elucidate the taxonomy of B. tabaci at a finer level. Overall, these data provide important information for pest management.


Application of ion exchange resin in floating drug delivery system.
The purpose of this study was to explore the application of low-density ion exchange resin (IER) Tulsion(R) 344, for floating drug delivery system (FDDS), and study the effect of its particle size on rate of complexation, water uptake, drug release, and in situ complex formation. Batch method was used for the preparation of complexes, which were characterized by physical methods. Tablet containing resin with high degree of crosslinking showed buoyancy lag time (BLT) of 5-8 min. Decreasing the particle size of resin showed decrease in water uptake and drug release, with no significant effect on the rate of complexation and in situ complex formation for both preformed complexes (PCs) and physical mixtures (PMs). Thus, low-density and high degree of crosslinking of resin and water uptake may be the governing factor for controlling the initial release of tablet containing PMs but not in situ complex formation. However, further sustained release may be due to in situ complex formation.


[Occurrence of bronchial asthma and age at initial asthma diagnosis-first results of the German National Cohort].
Asthma is one of the most common chronic diseases in both children and adults. Asthma first occurring in adulthood (adult-onset asthma, AOA) is associated with poorer prognosis compared to childhood-onset asthma (COA), which urgently calls for more research in this area. The aim of this work was to analyze the data on asthma collected in the German National Cohort and compare it with the German Health Interview and Examination Survey for Adults (DEGS), in particular regarding AOA. Our analysis was based on the dataset of the main questionnaire at mid-term of the German National Cohort baseline examination, comprising 101,723 participants. Variables considered in the analyses were self-reported diagnosis of asthma, age at first diagnosis, asthma treatment in the past 12 months, age, and sex. In the midterm dataset, 8.7% of women and 7.0% of men in the German National Cohort reported that they had ever been diagnosed with asthma. Approximately one third of participants with asthma received their initial diagnosis before their 18th birthday. COA affected 2.2% of women and 2.8% of men, whereas AOA affected 6.5% of women and 4.2% of men. During the previous 12 months, 33% of COA cases and 60% of AOA cases were medically treated. The proportion of persons affected by asthma in the German National Cohort, as well as observed patterns regarding age and gender, corresponds to other data sources such as DEGS. However, in our analysis, the proportion of individuals with AOA was higher than described in the literature. The increase in cumulative asthma diagnoses with age is markedly steeper in younger participants, indicating a rising trend over time.


HIV and human herpesvirus 8 co-infection across the globe: Systematic review and meta-analysis.
HIV-infection is an important risk factor for developing Kaposi sarcoma (KS), but it is unclear whether HIV-positive persons are also at increased risk of co-infection with human herpesvirus 8 (HHV-8), the infectious cause of KS. We systematically searched literature up to December 2012 and included studies reporting HHV-8 seroprevalence for HIV-positive and HIV-negative persons. We used random-effects meta-analysis to combine odds ratios (ORs) of the association between HIV and HHV-8 seropositivity and conducted random-effects meta-regression to identify sources of heterogeneity. We included 93 studies with 58,357 participants from 32 countries in sub-Saharan Africa, North and South America, Europe, Asia, and Australia. Overall, HIV-positive persons were more likely to be HHV-8 seropositive than HIV-negative persons (OR 1.99, 95% confidence interval [CI] 1.70-2.34) with considerable heterogeneity among studies (I(2) 84%). The association was strongest in men who have sex with men (MSM, OR 3.95, 95% CI 2.92-5.35), patients with hemophilia (OR 3.11, 95% CI 1.19-8.11), and children (OR 2.45, 95% CI 1.58-3.81), but weaker in heterosexuals who engage in low-risk (OR 1.42, 95% CI 1.16-1.74) or high-risk sexual behavior (OR 1.66, 95% CI 1.27-2.17), persons who inject drugs (OR 1.66, 95% CI 1.28-2.14), and pregnant women (OR 1.68, 95% CI 1.15-2.47), p value for interaction <0.001. In conclusion, HIV-infection was associated with an increased HHV-8 seroprevalence in all population groups examined. A better understanding of HHV-8 transmission in different age and behavioral groups is needed to develop strategies to prevent HHV-8 transmission.


Genetic polymorphism of ABO and Rh system in relation to bronchial asthma: preliminary report.
115 asthmatic children and 1001 healthy voluntary blood donors were studied in order to determine the distribution of blood groups among them. Gene frequencies were also calculated in asthmatic patients and controls. No difference was noted between Rh system in both groups; but the ABO system showed an excess of blood group A among asthmatic patients. Gene frequency of A (p) and gene frequency of O (r) was quite different too for asthmatics and controls. No difference was noted in blood groups B and AB; nor in the gene frequency of B(q). The difference in the distribution of blood group A and O between control and asthmatic groups was found to be highly significant (P less than 0.02) with the chi-square test.


Molecular dynamics simulations of cold welding of nanoporous amorphous alloys: effects of welding conditions and microstructures.
Nanoscale cold welding is a promising method in the bottom-up fabrication of nanodevices. Herein, cold welding mechanisms of Cu50Zr50 nanoporous amorphous alloys (NPAAs) are investigated by molecular dynamics simulations, along with the mechanical properties of the welded products. Effects of welding conditions and microstructural parameters are considered. Our results demonstrate that the welded joint has superior mechanical properties. The ultimate strength of the welded NPAAs can be as high as 94-99% that of the original NPAAs but 62-75% for the yield strength and elastic modulus. Voronoi analysis declares that the changes in atomic clusters of NPAAs caused by cold welding are mild. The welding conditions do not have remarkable influences on the mechanical responses of the welded structure. The NPAAs with smaller ligament sizes are more suitable for cold welding, benefiting from the size effect of amorphous alloys. We also successfully use cold welding to fabricate gradient NPAAs and repair fractured NPAAs. It is found that the ultimate tensile strength of the NPAAs changes very little with each successful cold welding. After ten fracture-welding cycles, the ultimate strength of the as-welded specimen is slightly lower than that of the raw materials.


Biomechanical stress-induced signaling in smooth muscle cells: an update.
The vascular wall is an integrated functional component of the circulatory system that is continually remodelling or is developing atherosclerosis in response to hemodynamic or biomechanical stress. In this process mechanical force is an important modulator of Vascular Smooth Muscle Cell (VSMC) morphology and function, including apoptosis, hypertrophy and proliferation that contribute to the development of atherosclerosis, hypertension, and restenosis. How VSMCs sense and transduce the extracellular mechanical signals into the cell nucleus resulting in quantitative and qualitative changes in gene expression is an interesting and important research field. It has been demonstrated that mechanical stress rapidly induces phosphorylation of the platelet-derived growth factor (PDGF) receptor, activation of integrin receptor, stretch-activated cation channels, and G proteins, which might serve as mechanosensors. Once the mechanical force is sensed, protein kinase C and Mitogen Activated Protein Kinases (MAPKs) were activated, leading to increased transcription factor activation. Thus, mechanical stresses can directly stretch the cell membrane and alter receptor or G protein conformation, thereby initiating signaling pathways, usually used by growth factors. Based on the progress in this field, this article attempts to formulate a biomechanical stress hypothesis, i.e. that physical force initiates signal pathways leading to vascular cell death and inflammatory response followed by VSMC proliferation. These findings have provided promising information for designing new drugs or genes for therapeutic interventions for vascular diseases.


Fabrication of membrane absorbers based on amphiphilic carbonaceous derivatives for selective endotoxin clearance.
In this study, several novel blend membranes based on ligand-immobilized amphiphilic carbonaceous particles (ACPs) and matrix polymer polyvinylidene fluoride (PVDF) were prepared by an immersion phase inversion method. The effects of the ACP content on filtration performance of the membrane were investigated. Endotoxin removal with blend membranes at different pH values and ionic strengths was analyzed and discussed. The results indicated that the use of ACPs not only achieved uniform and stable incorporation of water-soluble ligands into the hydrophobic polymer membrane but also improved its filtration properties, including permeability, strength, hydrophilicity and antifouling ability. The blend membranes with the optimum particle content showed good performances in filtration and were highly effective in removing endotoxins from both buffer and protein solutions under properly chosen conditions. More than 99.8% of endotoxin removal and more than 90% of BSA recovery were achieved when 1 mg L-1 of BSA solution with 116 EU mL-1 of the endotoxin content was treated at pH 4.7. All the above suggested that the carrier-dispersed method described herein was one of the effective methods in constructing functionalized blend membrane absorbers.


PreservCyt transport medium used for the ThinPrep Pap test is a suitable medium for detection of Chlamydia trachomatis by the COBAS Amplicor CT/NG test: results of a preliminary study and future implications.
The commercial COBAS Amplicor CT/NG test (Roche Diagnostic Systems, Meylan, France) is a sensitive and specific method for detection of Chlamydia trachomatis infections. This test currently consists of using a nucleic acid amplification method to detect C. trachomatis in first-void urine specimens and in endocervical swabs collected in 2-sucrose-phosphate (2SP) transport medium. We conducted a prospective study to determine whether the automated COBAS Amplicor CT/NG test can detect C. trachomatis in cervical specimens collected in PreservCyt transport medium (ThinPrep Pap Test; Cytyc Corporation, Boxborough, Mass.). PreservCyt medium is used to preserve cervical samples before the preparation of ThinPrep slides. We collected 1,000 cervical specimens from young women (age range, 15 to 25 years) during routine Pap smear tests. Only specimens with normal cytology and in which the gynecologist found no clinical evidence of urogenital infections were selected. The samples were stored in PreservCyt transport medium at 15 to 20 degrees C. C. trachomatis was detected in 22 of the 1,000 cervical specimens that had been stored in PreservCyt. To confirm the positive samples, the test was repeated on new endocervical swab specimens collected in 2SP transport medium. Only 9 of the 22 positive patients agreed to undergo this control, but all 9 retested positive. To evaluate the influence of storage conditions on the sensitivity of the C. trachomatis PCR test, all of the positive samples were stored at 15 to 20 degrees C in PreservCyt transport medium and were retested every 2 weeks for 6 weeks. C. trachomatis was successfully amplified from all 22 specimens for the whole 6-week period. The prevalence of C. trachomatis infection was 2.2% in our study population. These results demonstrate that PreservCyt transport medium is a suitable transport medium for detection of C. trachomatis by the COBAS Amplicor CT/NG test. The ThinPrep Pap Test may enable gynecologists to monitor for both cervical lesions and C. trachomatis infections with a single endocervical specimen.


Applicability of the FDA-approved Immunohistochemical Panel for Identification of MMRd Phenotype in Uterine Endometrioid Carcinoma.
Recently, the US Food and Drug Administration (FDA) approved the Ventana MMR RxDx Panel as the first immunohistochemical companion diagnostic test for identification of tumors with mismatch repair (MMR) status. The aim of this study was to investigate the accuracy of this test in comparison with polymerase chain reaction (PCR)-based microsatellite instability (MSI) analysis. We assessed the MMR/MSI concordance rate in 140 cases of endometrioid carcinoma. MMR status was evaluated by immunohistochemistry (MMR-IHC), and MSI status was evaluated by PCR-based analysis (MSI-PCR). Potential molecular mechanisms responsible for MSH6 staining variations were also analyzed. Immunohistochemistry showed that 34 tumors (24.3%) were MMRd; these included 26 with combined MLH1/PMS2 loss, 2 with combined MSH2/MSH6 loss, and 6 with isolated MSH6 loss. Heterogeneous MSH6 loss was found in 10 tumors and was recognized only in tumors with combined MLH1/PMS2 loss. Eight of 10 tumors with heterogeneous MSH6 loss harbored MSH6 C8 tract instability, suggesting a secondary somatic event after MLH1/PMS2 loss. MSI-PCR revealed that 102 tumors were MSS, 4 were MSI-low, and 34 were MSI-high. Consequently, MMR-IHC and MSI-PCR showed perfect concordance (kappa=0.080, P <0.0001). However, 10 of the 34 MSI-high tumors, including the 6 tumors with isolated MSH6 loss, showed only minimal microsatellite shift by MSI-PCR, which may have been erroneously interpreted as MSS or MSI-low. On the basis of these findings, we consider that the FDA-approved immunohistochemical panel can detect MMR variations consistently and is more accurate than MSI-PCR for determining the applicability of immune checkpoint inhibitors for treatment of endometrioid carcinomas.


[Characteristics of distribution of nitric oxide synthase containing neurons in the medullary cardiovascular centers of dogs and rats].
The aim of the study was to characterize species-related differences in the distribution of nitric oxide synthase (NOS)-containing neurons in the medullary structures of dogs and rats involved in the regulation of the sympathetic or parasympathetic drives. Two main results have been obtained, namely: (i) the average number of NOS-containing neurons in the dorsomedial and ventrolateral medulla per section in dog was larger than that in rat, while the density of the positive cells in the both regions in dog was less than that in rat. (ii) Within the dorsal motor nucleus of vagus a lot of NOS-containing cells (preganglionic vagal neurons) were observed only in dog. Differences in the distribution of NO-generating neurons in the medullary cardiovascular centers, and heterogeneity in the basal level of NO release may contribute to the peculiarities of the hemodynamic responses induced by NOS inhibitors in these species.


[Effects of esmolol- and sodium nitroprusside-induced controlled hypotension on hepatocellular integrity in patients undergoing endonasal sinus surgery].
Controlled hypotension (CH) is an established method to reduce intraoperative bleeding. The aim of the study was to investigate the influence of CH induced by sodium nitroprusside (SN) or esmolol on hepatocellular integrity. Prospective, randomized, controlled study. 45 patients scheduled for elective endonasal sinus surgery were allocated to one of the following three groups: 1. SN-group (n = 15): CH induced by SN. 2. Esmolol-group: CH induced by esmolol. In both groups mean arterial pressure was kept between 50-55 mmHg. 3. Control group (n = 15): no hypotension was performed (MAP > 70 mmHg). The cytosolic liver enzyme alpha-glutathione S-transferase (alpha-GST) and standard liver enzymes (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase) were measured at the following timepoints: preoperative (T0), at the end of surgery (T1), 2 h (T2), 24 h (T3) and 48 h (T4) postoperatively. alpha-GST concentrations were significantly higher in patients receiving CH (SN: 5.9 +/- 3.4; Esmolol: 6.5 +/- 2.8 microg/L) in comparison with controls (2.5 +/- 1.4 microg/L) at T1. Already at T2 there were no significant differences between the three groups. Standard liver enzymes showed a similar course in all groups. The small but significant increase of alpha-GST in both hypotension groups suggests that hypotension induces a mild damage of hepatocellular integrity.


Tin-doped NiFe2O4 nanoblocks grown on an iron foil for efficient and stable water splitting at large current densities.
Developing low-cost and self-supported bifunctional catalysts for highly efficient water splitting devices is of great significance. Herein, different from previously reported NiFe2O4-based electrocatalysts, we have grown nano-NiFe2O4 directly onto the iron foil (IF) surface and in situ introduced Sn4+ into NiFe2O4. The resulting experimental phenomena confirmed that the as-synthesized Sn-NiFe2O4/IF can deliver large-current densities (>1000 mA cm-2) during oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) processes at a low overpotential. The needed overpotentials at the current density of 10 and 1000 mA cm-2 are 231 and 368 mV for OER and 57 and 439 mV for HER, respectively. Additionally, when applied for the two-electrode water splitting, the corresponding needed voltage for Sn-NiFe2O4/IF at the current density of 10 mA cm-2 was only 1.56 V, which was comparable to the commercial Pt/C-RuO2/IF electrode. Thus, the introduced Sn4+ greatly enhanced the electrocatalytic property of Sn-NiFe2O4/IF, resulting in a superior bifunctional catalyst that can be applied for large-scale hydrogen production.


Curcumin reverses impaired cognition and neuronal plasticity induced by chronic stress.
Chronic stress occurs in everyday life and induces impaired spatial cognition, neuroendocrine and plasticity abnormalities. A potential therapeutic for these stress related disturbances is curcumin, derived from the curry spice turmeric. Previously we demonstrated that curcumin reversed the chronic stress-induced behavioral deficits in escape from an aversive stimulus, however the mechanism behind its beneficial effects on stress-induced learning defects and associated pathologies are unknown. This study investigated the effects of curcumin on restraint stress-induced spatial learning and memory dysfunction in a water maze task and on measures related neuroendocrine and plasticity changes. The results showed that memory deficits were reversed with curcumin in a dose dependent manner, as were stress-induced increases in serum corticosterone levels. These effects were similar to positive antidepressant imipramine. Additionally, curcumin prevented adverse changes in the dendritic morphology of CA3 pyramidal neurons in the hippocampus, as assessed by the changes in branch points and dendritic length. In primary hippocampal neurons it was shown that curcumin or imipramine protected hippocampal neurons against corticosterone-induced toxicity. Furthermore, the portion of calcium/calmodulin kinase II (CaMKII) that is activated (phosphorylated CaMKII, pCaMKII), and the glutamate receptor sub-type (NMDA(2B)) expressions were increased in the presence of corticosterone. These effects were also blocked by curcumin or imipramine treatment. Thus, curcumin may be an effective therapeutic for learning and memory disturbances as was seen within these stress models, and its neuroprotective effect was mediated in part by normalizing the corticosterone response, resulting in down-regulating of the pCaMKII and glutamate receptor levels.


Brain: supratentorial cortical anatomy.
Knowledge of the cerebral cortical lobes and gyri is critical for the localization of lesions and for the correlation of radiologic findings with neurologic symptoms and signs. This article deals with the six cerebral lobes-frontal, parietal, occipital, temporal, limbic, and insula-and the fissures and imaginary lines that divide them. The major gyri and sulci of each lobe are individually considered. Anatomy and function are correlated for a few selected areas of particular clinical importance.


The Prevalence of Hepatitis C Virus Core Amino Acid 70 Substitution and Genotypes of Polymorphisms Near the IFNL3 Gene in Iranian Patients With Chronic Hepatitis C.
Molecular studies have demonstrated that the hepatitis C virus (HCV) genotype and host genetics play predictive roles in the management of patients infected with HCV. This study aimed to investigate the HCV genotype, core amino acid (aa) 70 substitution, and polymorphisms near the IFNL3 gene (including rs12979860 and rs8099917) among Iranian patients with chronic hepatitis C (CHC). In this cross-sectional study, the molecular profiles of the HCV genotype, core aa 70 substitution, and rs12979860 and rs8099917 polymorphisms and plasma HCV RNA levels were determined in 429 CHC patients including 141 hemophilic, 84 thalassemic, and 204 non-hemophilic, non-thalassemic patients. The hepatitis C virus subtype 1a was the most common subtype in the study population. Core aa substitution Arg70Gln was strongly associated with cirrhosis (OR = 2.49; 95% CI = 1.13 - 5.50; P = 0.020). Core aa 70 substitutions were more frequently observed in patients with the HCV subtype 1b than in patients with any other HCV subtypes (P < 0.001). Core aa 70 substitutions were also more common in patients with the rs12979860 TT genotype than in patients with non-TT genotypes (17.3% vs. 8.5%, P = 0.022) and also in rs8099917 non-TT genotypes than in the TT genotype (14.0% vs. 7.0%, P = 0.026). The HCV genotypes and rs8099917 polymorphisms were correlated in which HCV subtype 1b was in favor of rs8099917 GG and HCV subtype 3a favored rs8099917 TT (P = 0.021). Furthermore, the rs12979860 TT and rs8099917 GG genotypes showed significantly lower HCV RNA levels than the other genotypes (P < 0.001). There is an as yet unexplained association between HCV and host parameters with unknown mechanisms in patients with chronic HCV infection. The assessments of core aa 70 substitution and polymorphisms near the IFNL3 gene could offer promising steps to improve the management of patients with HCV.


Harassment issues should be dealt with before they become problems.
Sexual and other forms of harassment are common in the medical work environment. Physicians who are employers and medical educators as well as clinicians should be aware they may be held responsible for the harassing conduct of colleagues, employees and others unless measures are in place in the workplace that show reasonable efforts have been made to prevent the behaviour and deal with it appropriately when it occurs. This article uses a US case to illustrate the evolution of a sexual-harassment complaint over several years.


Evolutionary history of the symbiosis between fungus-growing ants and their fungi.
The evolutionary history of the symbiosis between fungus-growing ants (Attini) and their fungi was elucidated by comparing phylogenies of both symbionts. The fungal phylogeny based on cladistic analyses of nuclear 28S ribosomal DNA indicates that, in contrast with the monophyly of the ants, the attine fungi are polyphyletic. Most cultivated fungi belong to the basidiomycete family Lepiotaceae; however, one ant genus, Apterostigma, has acquired a distantly related basidiomycete lineage. Phylogenetic patterns suggest that some primitive attines may have repeatedly acquired lepiotaceous symbionts. In contrast, the most derived attines have clonally propagated the same fungal lineage for at least 23 million years.


[Sociomedical aspects of detection and treatment of patients with tuberculosis under present conditions].
By analyzing the present-day tuberculosis epidemiological situation in the country and sociomedical characteristics of new cases, the authors present methods for detecting and treating patients, which are of paramount importance for today. Of the most significance is the need to promptly identify patients with strains on their referral to the general somatic hospitals for complaints by using 3-multiple sputum bacterioscopy for Mycobacterium tuberculosis by the Ziehl-Neelsen method. The vital problem is also to change chemotherapeutical regimens as more severe progressive types of the disease require more active treatment in the first months after detection especially in the cohort of socially disadapted persons.


Super-atmospheric pressure chemical ionization mass spectrometry.
Super-atmospheric pressure chemical ionization (APCI) mass spectrometry was performed using a commercial mass spectrometer by pressurizing the ion source with compressed air up to 7 atm. Similar to typical APCI source, reactant ions in the experiment were generated with corona discharge using a needle electrode. Although a higher needle potential was necessary to initiate the corona discharge, discharge current and detected ion signal were stable at all tested pressures. A Roots booster pump with variable pumping speed was installed between the evacuation port of the mass spectrometer and the original rough pumps to maintain a same pressure in the first pumping stage of the mass spectrometer regardless of ion source pressure. Measurement of gaseous methamphetamine and research department explosive showed an increase in ion intensity with the ion source pressure until an optimum pressure at around 4-5 atm. Beyond 5 atm, the ion intensity decreased with further increase of pressure, likely due to greater ion losses inside the ion transport capillary. For benzene, it was found that besides molecular ion and protonated species, ion due to [M + 2H](+) which was not so common in APCI, was also observed with high ion abundance under super-atmospheric pressure condition.


Characterization of microtubule-associated protein MAP1B: phosphorylation state, light chains, and binding to microtubules.
We have recently described a procedure for the purification of microtubule associated protein 1B (MAP1B) from calf brain [Pedrotti, B., & Islam K. (1995) Cell Motil. Cytoskeleton 30, 301-309], and this study further characterizes the purified protein and its interaction with microtubules. We show that purified MAP1B (1) is thermostable; (2) is mainly phosphorylated at the casein kinase II (CKII) sites but only partially phosphorylated at the proline-directed protein kinase (PDPK) sites; (3) both the CKII and PDPK sites can be dephosphorylated by alkaline phosphatase; and (4) dephosphorylation results in an increased mobility on SDS-PAGE gels. The ability of MAP1B to interact with microtubules was also examined and shows that (1) phosphorylated (1B-P), alkaline phosphatase-treated (1B-AP), and heat-treated (1B-P), alkaline phosphatase-treated (1B-AP), and heat-treated (1B-HT) MAP1B bind to taxol-stabilized microtubules; (2) 1 mol of 1B-P, 1B-AP, or 1B-HT each binds about 13-14 tubulin dimers; (3) light chain interaction with MAP1B heavy chain is not affected by AP- or heat-treatment; (4) MAP1B can be displaced from taxol-stabilized microtubules by titration with salt; (5) higher salt concentrations are required to displace 1B-AP compared with 1B-P from taxol-stabilized microtubules; and (6) MAP2 is able to displace both 1B-P and 1B-AP from taxol-stabilized microtubules. The role of phosphorylation in regulating MAP1B interaction with microtubules and light chains is discussed.


Nested and teleconnected vulnerabilities to environmental change.
The vulnerability of distant peoples and places to global change in environment and society is nested and teleconnected. Here, we argue that such vulnerabilities are linked through environmental change process feedbacks, economic market linkages, and flows of resources, people, and information. We illustrate these linkages through the examples of the global transmission of severe acute respiratory syndrome (SARS) and the interdependent vulnerabilities and adaptations of coffee farmers in Vietnam and Mexico. These cases demonstrate that the vulnerability of specific individuals and communities is not geographically bounded but, rather, is connected at different scales, so that the drivers of their exposure and sensitivity are inseparable from large-scale processes of sociocultural change and market integration. Aggregate outcomes of government policies, trends in global commodity markets, and even decisions by individuals to improve livelihood security can have negative repercussions, not only locally, through transformations of ecological systems and social relations, but also at larger scales.


Quantitative differences in phase I and II metabolism between rat precision-cut liver slices and isolated hepatocytes.
Testosterone (250 microM), 7-ethoxycoumarin (25 microM), and 1-chloro-2,4-dinitrobenzene (CDNB, 50 microM) were used as substrates to compare phase I and II metabolism in rat precision-cut liver slices and rat hepatocytes. Overall clearance to metabolites was significantly greater in hepatocytes for testosterone (1.9- to 16.9-fold), 7-ethoxycoumarin (O-deethylation, 14.8-fold; glucuronidation, 3.1-fold), and CDNB (8.7-fold). The same metabolites for each of the substrates were detected in slices and hepatocytes. However, the ratio of sulfate to glucuronide conjugation was higher in slices, in line with the markedly slower rate of formation of 7-hydroxycoumarin. The slower rate of CDNB conjugation could not be explained by differences in the intracellular concentration of glutathione. These data suggest that metabolism in precision-cut slices is limited by diffusion of the substrate. This was illustrated by the use of 2-(5'-chloro-2'-phosphoryloxyphenyl)-6-chloro-4-(3H)-quinazolinone as a fluorescent probe to investigate diffusion in slices and hepatocytes.


Submerged vs non-submerged reconstructive approach for surgical treatment of peri-implantitis: Re-analysis of two prospective clinical studies.
This report stems from a homogeneous patient cohort from two similarly designed prospective controlled studies in the same center on surgical reconstructive treatment of peri-implantitis. The aim of this re-analysis study was exploring prognostic factors associated with surgical outcomes. Individual patient data of both studies were gathered. The initial study employed a submerged healing approach via primary wound closure with implant supra-structure removal and complete coverage of grafted sites. The second study employed a non-submerged healing protocol in which healing abutments were kept in place and the implant was not fully submerged. Both studies measured all outcomes at similar timepoints throughout 1 year, to include clinical and radiographic defect fill (DF and RDF), reduction of pocket depth (PDR) and bleeding on probing (BOP). Multi-level regression was used for statistical assessment of outcomes, relative to the impact of site-/local-, surgical- and patient-related variables. Overall, 59 implants (30 in submerged and 29 in the non-submerged group) were treated. A statistically significant higher DF (on average 0.9 mm higher), RDF (1.7 mm) and PDR (1.3 mm) were observed when a submerged reconstructive approach was performed, whereas BOP reduction was similar. After controlling for treatment (submerged/non-submerged), there were no other significant associations with patient- (age, gender, smoking, prior periodontitis etc.), or implant-related (previous prosthesis type, arch, KTW, etc.) factors. Within its limitations, we conclude that a submerged reconstructive approach for surgical management of peri-implantitis leads to significantly enhanced clinical and radiographic outcomes when compared to a non-submerged approach.


Viral Infection of the Heart: Pathogenesis and Diagnosis.
Viral infections of the heart cause serious clinical problems, either as infectious myocarditis, which usually is a consequence of acute infection or as idiopathic dilated cardiomyopathy, resulting rather from a chronic infection. This minireview presents an up-to-date view on pathomechanisms of viral infection of the heart tissues, the role of immune system in controlling infectious process at its various stages and current possibilities of recognizing viral infection of the heart with use of both cardiological and virological methods. Our goal was to present the variety of known viral agents causing heart infection, level of complexity in mutual virus-cell interactions, and consequent clinical scenarios.


Listeria monocytogenes in Food-Processing Facilities, Food Contamination, and Human Listeriosis: The Brazilian Scenario.
Listeria monocytogenes is a foodborne pathogen that contaminates food-processing environments and persists within biofilms on equipment, utensils, floors, and drains, ultimately reaching final products by cross-contamination. This pathogen grows even under high salt conditions or refrigeration temperatures, remaining viable in various food products until the end of their shelf life. While the estimated incidence of listeriosis is lower than other enteric illnesses, infections caused by L. monocytogenes are more likely to lead to hospitalizations and fatalities. Despite the description of L. monocytogenes occurrence in Brazilian food-processing facilities and foods, there is a lack of consistent data regarding listeriosis cases and outbreaks directly associated with food consumption. Listeriosis requires rapid treatment with antibiotics and most drugs suitable for Gram-positive bacteria are effective against L. monocytogenes. Only a minority of clinical antibiotic-resistant L. monocytogenes strains have been described so far; whereas many strains recovered from food-processing facilities and foods exhibited resistance to antimicrobials not suitable against listeriosis. L. monocytogenes control in food industries is a challenge, demanding proper cleaning and application of sanitization procedures to eliminate this foodborne pathogen from the food-processing environment and ensure food safety. This review focuses on presenting the L. monocytogenes distribution in food-processing environment, food contamination, and control in the food industry, as well as the consequences of listeriosis to human health, providing a comparison of the current Brazilian situation with the international scenario.


Estimating Heterogeneous Treatment Effects with Observational Data.
Individuals differ not only in their background characteristics, but also in how they respond to a particular treatment, intervention, or stimulation. In particular, treatment effects may vary systematically by the propensity for treatment. In this paper, we discuss a practical approach to studying heterogeneous treatment effects as a function of the treatment propensity, under the same assumption commonly underlying regression analysis: ignorability. We describe one parametric method and two non-parametric methods for estimating interactions between treatment and the propensity for treatment. For the first method, we begin by estimating propensity scores for the probability of treatment given a set of observed covariates for each unit and construct balanced propensity score strata; we then estimate propensity score stratum-specific average treatment effects and evaluate a trend across them. For the second method, we match control units to treated units based on the propensity score and transform the data into treatment-control comparisons at the most elementary level at which such comparisons can be constructed; we then estimate treatment effects as a function of the propensity score by fitting a non-parametric model as a smoothing device. For the third method, we first estimate non-parametric regressions of the outcome variable as a function of the propensity score separately for treated units and for control units and then take the difference between the two non-parametric regressions. We illustrate the application of these methods with an empirical example of the effects of college attendance on womens fertility.


Th1 and Th2 cells help CD8 T-cell responses.
Help from CD4 T cells is often important for the establishment of primary and memory CD8 T-cell responses. However, it has yet to be determined whether T helper polarization affects the delivery of help and/or whether responding CD8 T cells helped by Th1 or Th2 cells express distinct effector properties. To address these issues, we compared CD8 T-cell responses in the context of Th1 or Th2 help by injecting dendritic cells copulsed with the major histocompatibility complex class I-restricted OVA peptide plus, respectively, bacterial or helminth antigens. We found that Th2 cells, like Th1 cells, can help primary and long-lived memory CD8 T-cell responses. Experiments in interleukin-12 (IL-12)-/- and IL-4-/- mice, in which polarized Th1 or Th2 responses, respectively, fail to develop, indicate that the underlying basis of CD4 help is independent of attributes acquired as a response to polarization.


Multiple levels of regulation specify the polarity of an asymmetric cell division in C. elegans.
Wnt signaling systems play important roles in the generation of cell and tissue polarity during development. We describe a Wnt signaling system that acts in a new way to orient the polarity of an epidermal cell division in C. elegans. In this system, the EGL-20/Wnt signal acts in a permissive fashion to polarize the asymmetric division of a cell called V5. EGL-20 regulates this polarization by counteracting lateral signals from neighboring cells that would otherwise reverse the polarity of the V5 cell division. Our findings indicate that this lateral signaling pathway also involves Wnt pathway components. Overexpression of EGL-20 disrupts both the asymmetry and polarity of lateral epidermal cell divisions all along the anteroposterior (A/P) body axis. Together our findings suggest that multiple, inter-related Wnt signaling systems may act together to polarize asymmetric cell divisions in this tissue.


Design and synthesis of tailored human caseinolytic protease P inhibitors.
Human caseinolytic protease P (hClpP) is important for degradation of misfolded proteins in the mitochondrial unfolded protein response. We here introduce tailored hClpP inhibitors that utilize a steric discrimination in their core naphthofuran scaffold to selectively address the human enzyme. This novel inhibitor generation exhibited superior activity compared to previously introduced beta-lactones, optimized for bacterial ClpP. Further insights into the bioactivity and binding to cellular targets were obtained via chemical proteomics as well as proliferation- and migration studies in cancer cells.


Dengue vaccines for travelers.
Dengue is an arthropod-borne infection caused by a flavivirus and spread by the Aedes mosquitoes. Many of the countries where dengue is endemic are popular tourist destinations and the disease is an increasingly important problem encountered by international travelers. Personal protection against the day-feeding dengue vectors is problematic, indicating the urgent need for a dengue vaccine. This review discusses the challenges of vaccine development, current vaccine strategies and the prospects for the availability of a vaccine for travelers in the future. Cost-effectiveness studies will need to take into account many factors, including the attack rate of dengue in travelers, the proportion of travelers who will need hospitalization, the cost of altered travel itineraries, the cost of the vaccine, duration of travel, destination and season. To be licensed as a travelers' vaccine, vaccine trials must address safety, immunogenicity, duration of protection, schedules and boosters in adults (in particular in immunologically naive adults), trials that may differ from those conducted in endemic countries. Vaccine schedules with long intervals would be a major obstacle to the uptake of the vaccine by travelers. Enhanced reactogenicity or interference with immunization must be effectively excluded for travelers with prior or concurrent vaccination against other flaviviruses, such as yellow fever or Japanese encephalitis. Licensing dengue as a travelers' vaccine poses unique challenges beyond the development of a vaccine for the endemic population.