Can endoscopic follow-up after acute diverticulitis be rationalised?
Acute diverticulitis (AD) is a common cause of presentation to emergency surgical services. Follow-up with endoluminal investigation to exclude colorectal cancer (CRC) remains controversial. Guidelines are increasingly moving to a more restrictive follow-up based on severity of disease and age. The purpose of this observational study was to assess the prevalence of CRC in AD patients and the impact of follow-up on endoscopy services. Patients admitted with a diagnosis of AD over a 2-year period were reviewed. The proportion of patients undergoing endoscopic follow-up and the CRC detection rate were recorded. The potential impact of a more conservative approach to follow-up was evaluated. There were 484 patients with AD presenting 546 times (M:F = 198:286; median age = 63 years). 80% of admissions were aged 50 or older. There were 43 emergency interventions in 39 patients (10 percutaneous drain; 33 surgery). The remainder were managed conservatively. 28 patients (5.1%) underwent colonic resection with cancer found in one specimen (3.6%). 287 patients underwent endoluminal follow-up with cancer diagnosed in 3 cases (1.0%). There was no significant difference in the prevalence of CRC between patients requiring emergency surgery and those managed conservatively, or between patients with complicated versus uncomplicated diverticulitis. CRC masquerading as acute diverticulitis is rare. The incidence of neoplasia both at endoscopic follow-up and in patients requiring emergency intervention is low. Conservative follow-up strategies appear safe, but their effectiveness in reducing the burden on endoscopy services may be limited by current age-based recommendations. Restricting follow-up to those with complicated AD would reduce the number of patients requiring endoluminal investigation by 70%.


Extracorporeal life support use in limited lung function: a narrative review.
In thoracic surgery, different modalities of extracorporeal life support (ECLS) can be used for cardiorespiratory support in complex scenarios. Decades of learning in clinical practice and physiology associated with technological development led to a great variety of ECLS technologies available. Thoracic surgery procedures with difficult or impossible single lung ventilation may still be performed using different ECLS modalities. The aim of this review is to describe the use of ECLS, with its different modalities, as a solution to perform complex surgeries in a patient with difficult or impossible single lung ventilation. A literature review was conducted using the terms "extracorporeal life support pulmonary resection" and "extracorporeal life support thoracic surgery", and articles were selected according to defined criteria. To support lung function during thoracic surgery, the most efficient and popular variety of ECLS is venovenous extracorporeal membrane oxygenation. Lung resection on a single lung after pneumonectomy, surgery in a patient with severe hypercapnia and/or low respiratory reserve, carinal and airway surgery, and severe thoracic trauma are the main examples of situations where ECLS may be the solution to provide a safe surgical environment in patients who cannot tolerate single lung ventilation. Multidisciplinarity, selection of patients and careful surgical planning are cornerstones in defining the situations that may benefit from ECLS support. Knowledge on techniques of ECLS are essential for every thoracic surgeon. Although rarely used, these techniques of cardiorespiratory support should be considered when planning complex cases with difficulties in ventilation and emergent situations.


Touch and Hearing Mediate Osseoperception.
Osseoperception is the sensation arising from the mechanical stimulation of a bone-anchored prosthesis. Here we show that not only touch, but also hearing is involved in this phenomenon. Using mechanical vibrations ranging from 0.1 to 6 kHz, we performed four psychophysical measures (perception threshold, sensation discrimination, frequency discrimination and reaction time) on 12 upper and lower limb amputees and found that subjects: consistently reported perceiving a sound when the stimulus was delivered at frequencies equal to or above 400 Hz; were able to discriminate frequency differences between stimuli delivered at high stimulation frequencies (~1500 Hz); improved their reaction time for bimodal stimuli (i.e. when both vibration and sound were perceived). Our results demonstrate that osseoperception is a multisensory perception, which can explain the improved environment perception of bone-anchored prosthesis users. This phenomenon might be exploited in novel prosthetic devices to enhance their control, thus ultimately improving the amputees' quality of life.


Polymorphic ochratoxin A hydroxylation in rat strains phenotyped as poor and extensive metabolizers of debrisoquine.
1. Dark agouti (DA) and Lewis rat strains, which show a genetic polymorphism for debrisoquine-4-hydroxylation, were treated either with a single dose of ochratoxin A (OA) or for 8 weeks with 5 doses per week. Levels of OA and its 4-hydroxy metabolite (4-hydroxy-OA) excreted in urine were determined. 2. At all doses, the metabolic ratio of OA:4-hydroxy-OA was two to five times greater in DA than in Lewis rats, as was the metabolic ratio of debrisoquine:4-hydroxy-debrisoquine. These results are consistent with our previous findings in vitro that hepatic and renal OA 4-hydroxylase activity is three to four times lower in DA than in Lewis rats. These data give further support to the possible co-segregation of genes regulating OA and debrisoquine 4-hydroxylation.


Seasonal changes characterise the shark and ray assemblages in a subtropical shallow sandy habitat in the iSimangaliso Wetland Park, South Africa.
Understanding how environmental drivers influence shark and ray spatial and temporal patterns can provide crucial knowledge for their evidence-based protection and long-term monitoring. However, information on which drivers of variation are most important for elasmobranch communities on soft sediments is limited. Using baited remote underwater stereo-video systems (stereo-BRUVs), we investigated how seasonal and environmental variables affected the elasmobranchs of the iSimangaliso Wetland Park marine protected area (MPA) in South Africa (SA). In total, 11 species were identified from 48 sites between 12 m and 33 m water depth in a sandy habitat. While species richness was similar across seasons, the total abundance of elasmobranchs recorded was higher in winter than summer. The species assemblage composition varied significantly between seasons, with the Human's whaler shark Carcharhinus humani prevalent in summer and the Critically Endangered whitespotted wedgefish Rhynchobatus djiddensis more abundant during winter. Most species were sighted throughout the entire depth range, but rays were more common in shallower waters (< 25 m depth), while C. humani and R. djiddensis were more common in the deeper depth zone of this study. This research provides baseline information about this previously unexplored sandy habitat for elasmobranchs in a site of regional and global significance. Records of species of conservation concern in the sampling area highlight the importance of protecting sand environments within an MPA.


Effect of prolactin on lymphocyte activation from systemic lupus erythematosus patients.
The aim was to explore the role of prolactin (PRL) in the lymphocyte activation process in systemic lupus erythematosus (SLE) patients in an in vitro model. Peripheral blood mononuclear cells (PBMCs) were isolated from SLE patients and healthy individuals. The mRNA for PRL and its receptor obtained by standard techniques, with an appropriate primer, were subjected to polymerase chain reaction (PCR) and visualized. The PBMCs were cultured with (a) medium alone as a negative control, (b) unspecific mitogen as a positive control, (c) PRL alone, (d) mitogen plus PRL, (e) mitogen plus antibody anti-PRL, and (f) mitogen plus a nonrelated antibody. Then CD69 and CD154 were determined by flow cytometry analysis. Twelve inactive and 15 active SLE patients were studied. Twenty-five percent of the active patients displayed hyperprolactinemia. Under basal conditions CD69 expression was associated with disease activity. The PBMCs activated in vitro were capable of producing and secreting PRL, measured by mRNA and Nb2 assay. In a similar way, the mRNA for the PRL receptor was visualized. Cells from SLE patients cultivated with PRL alone did not display increased CD69 and CD154 expression. The addition of PRL to the unspecific stimulated culture does not have an additive effect. In contrast, the addition of antibodies against PRL in order to block the autocrine PRL resulted in a striking reduction of CD69 and CD154 expression.


Comparison of the Anesthetic Efficacy of Mepivacaine and Lidocaine in Patients with Irreversible Pulpitis: A Double-blind Randomized Clinical Trial.
The objective of this study was to compare the anesthetic efficacy of 2% mepivacaine combined with 1:100,000 epinephrine with 2% lidocaine combined with 1:100,000 epinephrine during pulpectomy of mandibular posterior teeth in patients with irreversible pulpitis. Forty-two patients with irreversible pulpitis who were admitted to the Emergency Center at the University of São Paulo School of Dentistry volunteered to take part in the study and were randomized to receive conventional inferior alveolar nerve block containing 1.8 or 3.6 mL of either 2% mepivacaine with 1:100,000 epinephrine or 2% lidocaine with 1:100,000 epinephrine. We recorded patients' subjective assessments of lip anesthesia, absence/presence of pulpal anesthesia tested by using electric pulp stimulation, and absence/presence of pain during the subsequent pulpectomy by using a verbal analogue scale. All patients tested reported lip anesthesia after application of either type of inferior alveolar nerve block. Pulpal anesthesia success rates measured by using the pulp tester were satisfactory for both solutions (86% for mepivacaine and 67% for lidocaine). Success rates according to patient report of no pain or mild pain during pulpectomy were higher for mepivacaine solution (55%) than for lidocaine solution (14%). The differences between mepivacaine and lidocaine were statistically significant. Mepivacaine resulted in effective pain control during irreversible pulpitis treatments. The success rates with either solution were not high enough to ensure complete pulpal anesthesia.


Macrophage STING signaling promotes NK cell to suppress colorectal cancer liver metastasis via 4-1BBL/4-1BB co-stimulation.
Macrophage innate immune response plays an important role in tumorigenesis. However, the role and mechanism of macrophage STING signaling in modulating tumor microenvironment to suppress tumor growth at secondary sites remains largely unclear. STING expression was assessed in liver samples from patients with colorectal cancer (CRC) liver metastasis. Global or myeloid stimulator of interferon gene (STING)-deficient mice, myeloid NOD-like receptor protein 3 (NLRP3)-deficient mice, and wild-type (WT) mice were subjected to a mouse model of CRC liver metastasis by intrasplenic injection of murine colon carcinoma cells (MC38). Liver non-parenchymal cells including macrophages and natural killer (NK) cells were isolated for flow cytometry analysis. Bone marrow-derived macrophages pretreated with MC38 were co-cultured with splenic NK cells for in vitro studies. Significant activation of STING signaling were detected in adjacent and tumor tissues and intrahepatic macrophages. Global or myeloid STING-deficient mice had exacerbated CRC liver metastasis and shorten survival, with decreased intrahepatic infiltration and impaired antitumor function of NK cells. Depletion of NK cells in WT animals increased their metastatic burden, while no significant effects were observed in myeloid STING-deficient mice. STING activation contributed to the secretion of interleukin (IL)-18 and IL-1β by macrophages, which optimized antitumor activity of NK cells by promoting the expression of 4-1BBL in macrophages and 4-1BB in NK cells, respectively. Moreover, MC38 treatment activated macrophage NLRP3 signaling, which was inhibited by STING depletion. Myeloid NLRP3 deficiency increased tumor burden and suppressed activation of NK cells. NLRP3 activation by its agonist effectively suppressed CRC liver metastasis in myeloid SITNG-deficient mice. We demonstrated that STING signaling promoted NLRP3-mediated IL-18 and IL-1β production of macrophages to optimize the antitumor function of NK cells via the co-stimulation signaling of 4-1BBL/4-1BB.


[Fertility changes in women working in greenhouses].
Greenhouse workers (GW) are exposed to environmental contaminants, including pesticides, that may not only cause known immediate effects such as acute poisoning, but also long-term effects related to chronic exposure to low dosages, a problem that has not been extensively studied This study investigated the relationship between fertility changes and exposure to pesticides in a group of women working in greenhouses. The analysis is based on a retrospective cohort of 145 women working in greenhouses located in the province of Latina, Lazio Region, Italy, who were exposed to pesticides at the time of their first pregnancy. Information on health status, lifestyle, work activity, reproductive history and some confounding factors (age, smoking, alcohol abuse, drug consumption) were collected using a questionnaire. Exposure to pesticides was classified in two levels (high or low) according to the work task and the length of exposure. Changes in fertility were measured in terms of time to pregnancy (TTP), that is the number of non-contraceptive cycles that it takes a couple to conceive. A control group was selected among public administration employees in the same province. The difference in average TTP between exposed and non-exposed groups was analysed by using Student t-test. A Cox proportional hazard model was used to compare TTP between the two groups after correction for confounding factors. In the high-level exposure group average TTP was 10.8 months (+/- 2.0), among the non-exposed average TTP was 6.2 months (+/- 1.0). The difference between exposed and non-exposed was thus 4.6 months (p<0.05). Comparison of the distribution of TTP between the high-level exposure group and nonexposed resulted in a hazard ratio of 1.27 (I.C. 95%: 1.03-1.79); the same analysis using the low-level exposure group and non-exposed group yielded a hazard ratio of 1.12 (I.C. 95%: 0.67-1.87). The study showed reduced fertility, in terms of TTP, in the population exposed to pesticides. Among GW, TTP was as much as 50% higher than for the control group. Controlling for confounding factors, the study confirmed an increase in risk for the exposed group. The issue under investigation, however, is complex as health status is not the only factor that needs to be taken into account in studies of reproductive health; emotional status as well as congenital and acquired factors may also have a notable impact on women's fertility. Occupational exposure, therefore, can be said to be a condition requiring careful analysis while bearing in mind that other factors may influence the outcome.


A preliminary study of the health of a populaltion staying in apartments of varying sizes in Singapore.
A study was made of the health of 438 households living in high-rise flats in three public housing estates in Singapore. These households were selected by serial sampling from a total sample of 594 households; 156 (26%) were non-respondents. The study used personal interviews to collect data. Respondents questioned directly indicated a low but positive effect of high-rise living conditions on their physical health. The perceived health status of most of these flat dwellers remained unchanged after moving into their present accomodation. The major findings with regard to mental health were: (a) worry and anxiety were associated with the socio-economic status of the respondents; (b) the recreational activities of the respondents were related to their socio-economic status, although the majority spent most of their spare time at home; (c) living conditions in flats tended to affect the patterns of social contacts of the residents with their extended families and primary groups. Three factors (income, education and ethnic group) affected the social behaviour of the respondents with regard to health: (a) the preference for, and selection of, the first source of medical treatment varied for the different soci-economic and ethnic groups; (b) self-medication was associated with ethnic group; (c) the level of education affected the decision on when to receive antenatal care.


Intrapelvic Protrusion of a Broken Guide Wire Fragment during Fixation of a Femoral Neck Fracture.
During fixation of a femoral neck fracture in a 23-year-old male patient with cannulated screws, a broken guide wire fragment inadvertently advanced through the hip joint and protruded into the pelvis. A second surgical approach was needed to remove the broken fragment from the pelvis. Awareness of such a potentially devastating complication will make surgeons more cautious during implementation of orthopedic instruments and increases patient's safety during surgery.


Cytogenetics in the management of Philadelphia-negative myeloproliferative neoplasms: an update by the Groupe francophone de cytogénétique hématologique (GFCH).
The recent years have witnessed tremendous progress in the molecular characterization of Philadelphia-negative myeloproliferative neoplasms (MPN). Beside a better understanding of pathophysiology, these abnormalities often constitute very useful diagnostic markers in diseases where exclusion of reactive states used to be the strongest argument. However, conventional and molecular cytogenetics keep a major interest in MPN, either as a second line exploration, in cases where no molecular marker is available, for differential diagnosis or as a proof of clonality or in first line for cases with hyperleukocytosis, for differential diagnosis (CML), to evidence druggable targets (ABL1, RET, PDGFR…) or as a prognosis marker. In this article, we will review the interest of cytogenetic techniques in myeloproliferative neoplasms.


Postabortion contraception.
The European Society of Contraception Expert Group on Abortion identified as one of its priorities to disseminate up-to-date evidence-based information on postabortion contraception to healthcare providers. A concise communication was produced which summarises the latest research in an easy-to-read format suitable for busy clinicians. Information about individual methods is presented in boxes for ease of reference.


Quantitative Analysis of the Maturation of the Main and Accessory Olfactory Systems in Monotremes and Metatherians in Comparison to Rodents and Humans.
We have used an unbiased statistical approach to compare the pace of development in the main and accessory olfactory systems in monotremes and metatherians with that in rodents and humans. We hypothesized that if metatherians and monotremes, which are born at small body size, use olfaction to locate the pouch and/or teat/milk field, then olfactory structures should reach structural maturity in metatherians and monotremes at a smaller size than eutherians like humans and rodents. The achievement of key structural milestones in the development of the main and accessory olfactory systems (11 and 7 milestones, respectively) was scored for 354 specimens and compared against a measure of general somatic growth (body length). We used a statistical approach adapted from Kaplan-Meier analysis to determine median body length at which structural milestones were achieved, and to test the differences for statistical significance (Braslow statistic). The laboratory mouse achieved most main olfactory milestones at a smaller body size than all the metatherians and the monotremes, although the dasyurids (which are born at only 5.0 mm) and mouse achieved accessory olfactory milestones at similar body length. All other metatherians and monotremes reached olfactory milestones at body lengths similar to or larger than the laboratory rat. We therefore reject the hypothesis that metatherians and monotremes as a group exhibit advanced development of the olfactory pathways relative to body size. The findings suggest that, if olfaction is used by metatherians and monotremes at birth, it is achieved with only a rudimentary system without structurally mature central components. Anat Rec, 301:1258-1275, 2018. © 2018 Wiley Periodicals, Inc.


[Metal artefact on head and neck cone-beam CT images].
There are only a few factors, where the properties of the CBCT is inferior compared to conventional CT. One of these properties is the low contrast resolution, which has an importance in the discrimination of different soft tissues. Another difference is the image quality degrading effect by metal objects. This latter factor has much higher importance in head and neck region CBCT application. The metal artifact is closely related to other types of artifacts, like beam-hardening and x-ray photon scattering artifacts. In some of the cases, metal artifacts can be avoided by the proper adjustment of the scanning parameters, but sometimes the problem overgrows the possibilities. The current pre- and post-processing algorithms used for the correction of different artifacts can improve the image quality, but these algorithms are not the ultimate solution to the problem. The introduction of iterative reconstruction algorithms into the CBCT market will effectively reduce the most CT artifacts, however, the spread of this algorithms are set back because of the insufficient computational power of today's PCs. Another advantage of the use of iterative algorithms is that the patient dose could be significantly reduced.


Regional disparities in obesity prevalence in the United States: A spatial regime analysis.
Significant clusters of high- and low-obesity counties have been demonstrated across the United States (US). This study examined regional disparities in obesity prevalence and differences in the related structural characteristics across regions of the US. Drawing on model-based estimates from the Centers for Disease Control and Prevention, regional differences in county-level adult obesity prevalence (percent of the adult population [≥ 20 years] that was obese [BMI ≥ 30 kg/m(2) ] within a county, 2009) were assessed with a LISA (Local Indicators of Spatial Association) analysis to identify geographic concentrations of high and low obesity levels. Regional regime analysis was utilized to identify factors that were differentially associated with obesity prevalence between regions of the US. High- and low-obesity county clusters and the effect of a number of county-level characteristics on obesity prevalence differed significantly by region. These included the positive effect of African American populations in the South, the negative effect of Hispanic populations in the Northeast, and the positive effect of unemployed workers in the Midwest and West. Our findings suggest the need for public health policies and interventions that account for different regional characteristics underlying obesity prevalence variation across the US.


LION LBD: a literature-based discovery system for cancer biology.
The overwhelming size and rapid growth of the biomedical literature make it impossible for scientists to read all studies related to their work, potentially leading to missed connections and wasted time and resources. Literature-based discovery (LBD) aims to alleviate these issues by identifying implicit links between disjoint parts of the literature. While LBD has been studied in depth since its introduction three decades ago, there has been limited work making use of recent advances in biomedical text processing methods in LBD. We present LION LBD, a literature-based discovery system that enables researchers to navigate published information and supports hypothesis generation and testing. The system is built with a particular focus on the molecular biology of cancer using state-of-the-art machine learning and natural language processing methods, including named entity recognition and grounding to domain ontologies covering a wide range of entity types and a novel approach to detecting references to the hallmarks of cancer in text. LION LBD implements a broad selection of co-occurrence based metrics for analyzing the strength of entity associations, and its design allows real-time search to discover indirect associations between entities in a database of tens of millions of publications while preserving the ability of users to explore each mention in its original context in the literature. Evaluations of the system demonstrate its ability to identify undiscovered links and rank relevant concepts highly among potential connections. The LION LBD system is available via a web-based user interface and a programmable API, and all components of the system are made available under open licenses from the project home page http://lbd.lionproject.net. Supplementary data are available at Bioinformatics online.


Clinical experiences with a single use Y bagless CAPD system applying a quick disconnect clamp for external occlusion.
The Single Use Y set is a disposable CAPD system that incorporates the use of a Quick Disconnect Clamp (QDC) for external occlusion. The system is designed using two types of twist lock connectology. The twist lock bag connector located at the distal end of the set is designed with a flange that provides a safety shelf for proper hand position during bag connection. The proximal patient connector on the Y set is a twist lock design requiring placement of povidone-iodine in the disinfectant chamber of the connector prior to patient connection. The Single Use Y is discarded after use.


The Swedish studies of the adopted children of alcoholics.
The authors of the widely cited studies analyzing the Swedish adoption records of the children of alcoholics have advanced the notion that there are three distinct paths for the inheritance of alcoholism. One path results in moderate alcoholism in men and a form of somatization but no alcoholism in women. A second path results in severe and mild alcoholism in men and alcoholism in women. The third path results in a particular variety of alcohol abuse in men and a particular variety of somatization in women. This article analyzes the authors' claims. It is argued that the data were improperly analyzed for the conclusions reached and alternative parsimonious explanations for the results are offered. Although the Swedish studies do not offer support for three distinct paths of inheritance of alcoholism, they do support the inheritability of alcoholism and suggest that alcoholism may be linked with somatization in women. Unfortunately, reasonable questions can be raised about the generalizability of the data base.


Pneumatosis intestinalis: An important radiological clue in a case of missed perforated appendicitis.
Pneumatosis intestinalis (PI) is a rare radiological finding, characterized by the presence of gas in the bowel wall. It has a wide spectrum of possible underlying diagnosis ranging from benign to life-threatening conditions. We present a case of a previously healthy male who was initially presented with missed diagnosis of acute appendicitis which had led to perforated appendix. Failure to recognize the significance of PI and its correlation with other clinical information had caused the delay in his surgical intervention. Fortunately, the patient made a steady recovery and was discharged well. It is important to have a high clinical suspicion of life-threatening conditions whenever patients presented with a radiological clue of PI. Failure to incorporate this finding with other clinical clues might lead to devastating consequences and delay the necessary treatment.


In vitro drug-induced spoliation of a keratoprosthetic hydrogel.
To investigate in vitro the effects of selected drugs on the spoliation of poly(2-hydroxyethyl methacrylate) (PHEMA), a synthetic acrylic hydrogel currently used for the manufacture of a keratoprosthesis, AlphaCor. The experiments were carried out both in the presence of simulated aqueous humor (SAH) and in its absence. Disks of PHEMA were incubated and shaken with 9 commonly prescribed drugs at 37 degrees C in sterile conditions for 1 week. Samples were incubated either in SAH only (controls), in each drug preparation, or in each drug for 1 week followed by 1 week in SAH. The drugs selected for this study were steroids (prednisolone, dexamethasone, fluorometholone, medroxyprogesterone), antiglaucoma drugs (timolol maleate and pilocarpine), and antibiotics (chloramphenicol, cephazolin, and ciprofloxacin), as commercially available formulations. Following incubation, the PHEMA specimens were examined visually and then histologically, after staining with alizarin red for the presence of calcium in the spoliating sediments/deposits. Although only 5 of the drug formulations (dexamethasone as Maxidex, fluorometholone as FML, pilocarpine as Isopto Carpine, chloramphenicol as Chlorsig, and medroxyprogesterone as Depo-Ralovera) induced spoliation of the hydrogel in the absence of SAH, all drugs induced spoliation after postincubation in SAH, and calcium was detected in the majority of samples. The deposits on the hydrogel specimens incubated first in cephazolin (as Cefazolin-BC), pilocarpine (as Isopto Carpine), and chloramphenicol (as Chlorsig) and then in SAH did not contain calcium, despite its presence in SAH. The study appears to confirm our earlier clinical observations that topical medication may play a role in the spoliation of the hydrogel ophthalmic devices. Presence of calcium in the deposits seems to be correlated to the nature of drug. Although the incidence of spoliation in real clinical situations is much lower than suggested by this extreme-case in vitro simulation, topical therapy after implantation of AlphaCor should be carefully considered, kept to the minimum required, and additive-free where possible.


Diagnostic Accuracy of APRI, AAR, FIB-4, FI, King, Lok, Forns, and FibroIndex Scores in Predicting the Presence of Esophageal Varices in Liver Cirrhosis: A Systematic Review and Meta-Analysis.
Aspartate aminotransferase-to-platelet ratio (APRI), aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), FIB-4, FI, King, Lok, Forns, and FibroIndex scores may be simple and convenient noninvasive diagnostic tests, because they are based on the regular laboratory tests and demographic data. This study aimed to systematically evaluate their diagnostic accuracy for the prediction of varices in liver cirrhosis.All relevant papers were searched via PubMed, EMBASE, CNKI, and Wanfang databases. The area under the summary receiver operating characteristic curve (AUSROC), sensitivity, specificity, positive and negative likelihood ratio (PLR and NLR), and diagnostic odds ratio (DOR) were calculated.Overall, 12, 4, 5, 0, 0, 4, 3, and 1 paper was identified to explore the diagnostic accuracy of APRI, AAR, FIB-4, FI, King, Lok, Forns, and FibroIndex scores, respectively. The AUSROCs of APRI, AAR, FIB-4, Lok, and Forns scores for the prediction of varices were 0.6774, 0.7275, 0.7755, 0.7885, and 0.7517, respectively; and those for the prediction of large varices were 0.7278, 0.7448, 0.7095, 0.7264, and 0.6530, respectively. The diagnostic threshold effects of FIB-4 and Forns scores for the prediction of varices were statistically significant. The sensitivities/specificities/PLRs/NLRs/DORs of APRI, AAR, and Lok scores for the prediction of varices were 0.60/0.67/1.77/0.58/3.13, 0.64/0.63/1.97/0.54/4.18, and 0.74/0.68/2.34/0.40/5.76, respectively. The sensitivities/specificities/PLRs/NLRs/DORs of APRI, AAR, FIB-4, Lok, and Forns scores for the prediction of large varices were 0.65/0.66/2.15/0.47/4.97, 0.68/0.58/2.07/0.54/3.93, 0.62/0.64/2.02/0.56/3.57, 0.78/0.63/2.09/0.37/5.55, and 0.65/0.61/1.62/0.59/2.75, respectively.APRI, AAR, FIB-4, Lok, and Forns scores had low to moderate diagnostic accuracy in predicting the presence of varices in liver cirrhosis.


Acute abdomen: Added diagnostic value of coronal reformations with 64-slice multidetector row computed tomography.
We sought to assess retrospectively the added value of coronal reformations from isotropic voxels obtained with 64-slice multidetector row computed tomography (CT) of the acute abdomen. This retrospective study was approved by the institutional review board and informed consent was waived. Multidetector helical 64-section CT (section thickness, 0.6 mm; pitch 1.75; table speed 35 mm/sec) was performed in 100 patients (60 women and 40 men; age range, 9-/+85 years; mean age, 45.2 years) with acute nontraumatic abdominal pain who had been referred from the emergency department. Axial images were reconstructed with 5-mm-thick sections at 5-mm intervals. The second data set was reformatted coronally, with 3-mm-thick sections at 3-mm intervals. Four independent, blinded readers with various level of training interpreted first the axial scans alone and then followed immediately by the coronal scans. Confidence in the visualization of anatomy and pathology was scored on a 5-point scale. The final diagnosis was determined by surgical and pathologic reports and by clinical follow-up in those who did not undergo surgery. Based upon the individual patient's clinical history and other comorbid factors, 92 patients received intravenous contrast and 90 patients received oral contrast. In 45 patients, no CT abnormalities were detected for an explanation of the abdominal pain. Mean sensitivity and specificity of axial CT alone were 92.5% and 91%, respectively. No significant differences in sensitivity and specificity were observed for the use of combined axial and coronal images. For the most inexperienced reader, the coronal reformations were helpful in 95% of cases, while for the most experienced reader, the coronal reformations were helpful in 35% of the cases. The coronal images were deemed helpful in an average of 62.3% of the cases for the four readers. However, diagnosing subtle pathology in the abdominal wall was difficult on coronal reformations alone. Overall, coronal reformations improved diagnostic confidence and interobserver agreement over axial images alone for visualization of normal abdominal structures and in the diagnosis of abdominal pathology. Axial and coronal reformations of 64-section multidetector row CT have equal sensitivity and specificity for the diagnosis of acute abdominal pathology. However, coronal reformations improved the diagnostic confidence for all readers but most significantly for the least experienced. Therefore, radiology departments with residents should consider routinely generating coronal images in patients with acute abdominal pain.


[The advance of bioactive peptide RGD in the research of bone regeneration].
Clinically, there has been so far no effective way to repair the bone-missing of large extent due to gash, infection and removal of tumor. The solution of this problem can be assisted by the addition of bioactive substances to substrate materials, because the growth of peripheral tissue and the fiber tissue growing the materials can be induced to the direction of bone-tissue by these biomaterials with bioactive peptides. The peptide Arg-Gly-Asp is the point between the integrin which comes from membrane and the ligand. In certain cases, the artificially synthesized RGD can be competitively combined with the integrin on cell surface, and outer-cell information is transmitted into cells, which will cause a series of physiological changes in cells. Presently, it is reported that the RGD has the ability to induce the growth of osteoblasts, restrain the adhesion between osteoclasts and substrates. This paper reviews and introduces the progress made with the work of RGD-inducing bone regeneration.


Thermal stabilization of bicelles by a bile-salt-derived detergent: a combined ³¹P and ²H nuclear magnetic resonance study.
The properties of bicelles composed of mixtures of long-chain lipids dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG), stabilized by zwitterionic bile salt analogue 3-[(3-cholamidopropyl)dimethyl-d6-ammonio]-2-hydroxy-1-propanesulfonate (CHAPSO-d6), deuterated at both amino methyls, were investigated by a combination of (31)P and (2)H NMR, focusing on the behavior of CHAPSO as a function of temperature. For compositions of molar ratio q = [DMPC + DMPG]/[CHAPSO] = 3, R = [DMPG]/[DMPC + DMPG] = 0, 0.01 and 0.10 and lipid concentration CL = 25 wt % lipid at temperatures of between 30 and 60 °C, magnetic alignment was readily achieved as assessed via both (31)P NMR of the phospholipids and (2)H NMR of CHAPSO-d6. Increasing temperature yielded higher values for the chemical shift anisotropy of the former and the quadrupole splitting of the latter, consistent with the progressive migration of CHAPSO from edge regions into planar regions of the bicellar assemblies. However, relative to dihexadecyl phosphatidylcholine (DHPC), CHAPSO exhibited lower miscibility with DMPC, although the presence of DMPG enhanced this miscibility. At 65 °C, thermal instability became evident in the appearance of a separate isotropic component in both (31)P and (2)H NMR spectra. This isotropic phase was CHAPSO-enriched but less so as a function of increasing DMPG. These findings indicate that the enhanced thermal stability of CHAPSO- versus DHPC-containing bicelles arises from a combination of the larger surface area that edge CHAPSO is able to mask, mole for mole, and its relative preference for edge regions, plus, possibly, specific interactions with DMPG.


[Products toxic to reproduction used in the occupational environment: Definition, risk assessment, classification].
European regulations (transcribed into French law) aimed at protecting employees from chemicals toxic to reproduction enable classification and labelling of such substances, if they are liable to cause an alteration of male or female reproductive functions or capacity, or to induce non-hereditary harmful effects on their offspring. Three categories can be used to classify these substances in two areas, namely their impairment of fertility and their effects on development. This classification is rarely based on epidemiological study results, but most often on those of experimental toxicological studies conducted by substance manufacturers. These reproduction toxicological studies are only compulsory above a certain tonnage placed on the market. The high level of this tonnage means that these tests are effectively only conducted on rare occasions. It is reckoned that there is no reproduction experimental data for over 95% of substances newly placed on the market. These products therefore appear to be reproduction non-toxic only because they have not been tested. This is a major fault in the current labelling system, which does not allow non-toxic products to be differentiated from non-tested products. The future EU regulatory framework for Registration, Evaluation and Authorisation of CHemicals (REACH) will only slightly enhance information in this area. It can be estimated that over 80% of chemical products will not be exhaustively tested for reproduction and nearly 75% will not be tested to any degree.


The C system of cattle blood groups. 1. Additional factors in the system.
Four additional cattle blood group antigenic factors, provisionally termed F1, F6, F10 and F15, were shown to belong to the C system. Factor F1 appears to be a linear subtype of C" (initially designated F2, or P1B1). It is suggested that future international nomenclature should adopt C"1 and C"2 in place of F1 and C". No phenogroup was found to include C" together with C2 or C1, but a few phenogroups lack the three factors. Thus C1, C2 and C" do not form a closed system within the C system as concluded by Duniec et al. (1973). The effectiveness of the additional factors to uncover the genetic variability of the C system, and to translate phenotypes into genotypes is exemplified in the Charolais breed.


Acute disseminated encephalomyelitis following seasonal influenza vaccination in an elderly patient.
Although such occurrences are rare, it should be recognized that certain vaccines might trigger serious neurological immune phenomena such as Guillain-Barre syndrome, seizures, cranial neuropathy, and acute disseminated encephalomyelitis (ADEM). Here we report on an elderly woman with ADEM following seasonal influenza vaccination who recovered after plasma exchange.


The Role of Exosomes in Breast Cancer.
Although it has been long realized that eukaryotic cells release complex vesicular structures into their environment, only in recent years has it been established that these entities are not merely junk or debris, but that they are tailor-made specialized minimaps of their cell of origin and of both physiological and pathological relevance. These exosomes and microvesicles (ectosomes), collectively termed extracellular vesicles (EVs), are often defined and subgrouped first and foremost according to size and proposed origin (exosomes approximately 30-120 nm, endosomal origin; microvesicles 120-1000 nm, from the cell membrane). There is growing interest in elucidating the relevance and roles of EVs in cancer. Much of the pioneering work on EVs in cancer has focused on breast cancer, possibly because breast cancer is a leading cause of cancer-related deaths worldwide. This review provides an in-depth summary of such studies, supporting key roles for exosomes and other EVs in breast cancer cell invasion and metastasis, stem cell stimulation, apoptosis, immune system modulation, and anti-cancer drug resistance. Exosomes as diagnostic, prognostic, and/or predictive biomarkers and their potential use in the development of therapeutics are discussed. Although not fully elucidated, the involvement of exosomes in breast cancer development, progression, and resistance is becoming increasingly apparent from preclinical and clinical studies, with mounting interest in the potential exploitation of these vesicles for breast cancer biomarkers, as drug delivery systems, and in the development of future novel breast cancer therapies.


The Effect of Seat Back Inclination on Spinal Alignment in Automotive Seating Postures.
Experimental studies have demonstrated a relationship between spinal injury severity and vertebral kinematics, influenced by the initial spinal alignment of automotive occupants. Spinal alignment has been considered one of the possible causes of gender differences in the risk of sustaining spinal injuries. To predict vertebral kinematics and investigate spinal injury mechanisms, including gender-related mechanisms, under different seat back inclinations, it is needed to investigate the effect of the seat back inclination on initial spinal alignment in automotive seating postures for both men and women. The purpose of this study was to investigate the effect of the seat back inclination on spinal alignments, comparing spinal alignments of automotive seating postures in the 20° and 25° seat back angle and standing and supine postures. The spinal columns of 11 female and 12 male volunteers in automotive seating, standing, and supine postures were scanned in an upright open magnetic resonance imaging system. Patterns of their spinal alignments were analyzed using Multidimensional Scaling presented in a distribution map. Spinal segmental angles (cervical curvature, T1 slope, total thoracic kyphosis, upper thoracic kyphosis, lower thoracic kyphosis, lumbar lordosis, and sacral slope) were also measured using the imaging data. In the maximum individual variances in spinal alignment, a relationship between the cervical and thoracic spinal alignment was found in multidimensional scaling analyses. Subjects with a more lordotic cervical spine had a pronounced kyphotic thoracic spine, whereas subjects with a straighter to kyphotic cervical spine had a less kyphotic thoracic spine. When categorizing spinal alignments into two groups based on the spinal segmental angle of cervical curvature, spinal alignments with a lordotic cervical spine showed significantly greater absolute average values of T1 slope, total thoracic kyphosis, and lower thoracic kyphosis for both the 20° and 25° seat back angles. For automotive seating postures, the gender difference in spinal alignment was almost straight cervical and less-kyphotic thoracic spine for the female subjects and lordotic cervical and more pronounced kyphotic thoracic spine for the male subjects. The most prominent influence of seatback inclination appeared in Total thoracic kyphosis, with increased angles for 25° seat back, 8.0° greater in spinal alignments with a lordotic cervical spine, 3.2° greater in spinal alignments with a kyphotic cervical spine. The difference in total thoracic kyphosis between the two seatback angles and between the seating posture with the 20° seat back angle and the standing posture was greater for spinal alignments with a lordotic cervical spine than for spinal alignments with a kyphotic cervical spine. The female subjects in this study had a tendency toward the kyphotic cervical spine. Some of the differences between average gender-specific spinal alignments may be explained by the findings observed in the differences between spinal alignments with a lordotic and kyphotic cervical spine.


PRL-3/PTP4A3 phosphatase regulates integrin β1 in adhesion structures during migration of human ocular melanoma cells.
In a previous transcriptomic analysis of 63 ocular melanomas of the uvea, we found that expression of the PRL-3/PTP4A3 gene, encoding a phosphatase that is anchored to the plasma membrane, was associated with the risk of metastasis, and a poor prognosis. We also showed that PRL-3 overexpression in OCM-1 ocular melanoma cells significantly increased cell migration in vitro and invasiveness in vivo, suggesting a direct role for PRL-3 in the metastatic spreading of uveal melanoma. Here, we aimed to identify PRL-3 substrates at the plasma membrane involved in adhesion to the extracellular matrix. We focused on integrin β1, which is the most highly expressed integrin in our cohort of uveal melanomas. We show that preventing PRL-3 anchorage to the plasma membrane i) abolishes PRL-3-induced migration in OCM-1 cells, ii) specifically enhances the spreading of OCM-1 cells overexpressing PRL-3, and iii) favors the maturation of large focal adhesions (FAs) containing integrin β1 on collagen I. Knockdown experiments confirmed integrin β1 involvement in PRL3-induced migration. We identified interactions between PRL-3 and integrin β1, as well as with FAK P-Y397, an auto-activated form of Focal Adhesion Kinase found in FAs. We also show that integrin β1 may be dephosphorylated by PRL-3 in its intracytoplasmic S/T region, an important motif for integrin-mediated cell adhesion. Finally, we observed that PRL-3 regulated the clustering of integrin β1 in FAs on collagen I but not on fibronectin. This work identifies PRL-3 as a new regulator of cell adhesion structures to the extracellular matrix, and further supports PRL-3 as a key actor of metastasis in uveal melanoma, of which molecular mechanisms are still poorly understood.


A rapid and selective synthesis of α,α-fluorohalo esters via fluorohalogenative or difluorinative hydration of ynol ethers.
A Selectfluor-mediated fluorohalogenative or difluorinative hydration of ynol ethers is described, giving various α,α-fluorohalo esters including α,α-bromofluoro, α,α-chlorofluoro, α,α-fluoroiodo, and α,α-difluoro derivatives in a highly selective manner under very mild reaction conditions. The resultant products can be applied to the facile synthesis of α-monofluoro-α-amino acids. This reaction represents a new advance in the trifunctionalization of alkynes.


Cytokine networks in Pemphigus vulgaris: An integrated viewpoint.
Pemphigus vulgaris (PV) is an autoimmune bullous skin disease where tolerance to the desmosomal protein desmoglein 3 (Dsg3), and perhaps additional epidermal targets, is lost, leading to the production of autoantibodies directed against cellular adhesion molecules. As auto-reactive T cells are involved in the induction and maintenance of antibody production, it has been hypothesized that cytokines play a crucial role in disease pathogenesis. Qualitative and quantitative alterations in cytokine profiles have been previously reported; however, despite recent advancements, the characterization of the disease supporting cytokine network in PV has yet to be fully elucidated. It is overwhelmingly suggested that PV is a TH2-mediated disease, confirmed by the majority of studies demonstrating an increase in TH2-type cytokines. Recently, a focus has been placed on the contribution of the newly discovered TH17 subset to autoimmune states, and current evidence suggests that this inflammatory pathway may play a role in PV as well. Anti-cytokine medications are on the forefront as potential therapeutic options, and the growing number of reports of clinical benefit serves to confirm the major contribution of various inflammatory mediators in the development of disease phenotype. This work aimed to comprehend the complexity of cytokine and T cell involvement in pemphigus, taking account of known information and emphasizing the areas where additional research would be of great benefit, particularly in pharmacological development and expansion of the pemphigus therapeutic armamentarium.


Increased excitability in tat-transgenic mice: role of tat in HIV-related neurological disorders.
HIV-1 associated neurocognitive disorders (HAND) are a major complication of HIV-1 infection. The mechanism(s) underlying HAND are not completely understood but, based on in vitro studies, the HIV-1 Tat protein may play an important role. In this study, the effect of prolonged exposure to endogenously produced Tat in the brain was investigated using a tat-transgenic (TT) mouse model constitutively expressing the HIV-1 tat gene. We found that stimulus-evoked glutamate exocytosis in the hippocampus and cortex was significantly increased in TT as compared with wild-type control (CC) mice, while GABA exocytosis was unchanged in the hippocampus and decreased in the cortex. This suggests that Tat generates a latent hyper-excitability state, which favors the detrimental effects of neurotoxic and/or excitotoxic agents. To challenge this idea, TT mice were tested for susceptibility to kainate-induced seizures and neurodegeneration, and found to exhibit significantly greater responses to the convulsant agent than CC mice. These results support the concept that constitutive expression of tat in the brain generates a latent excitatory state, which may increase the negative effects of damaging insults. These events may play a key role in the development of HAND.


Intensive imaging assessment for successful minimally invasive cardiac surgery.
To clarify special imaging assessment that is useful for minimally invasive cardiac surgery (MICS), we examined 141 cases of MICS operations with ministernotomy or minithoracotomy. In the 141 patients, 62 valve, 42 coronary, 37 congenital heart, and 2 other procedures were successfully completed without conversion to full sternotomy. Preoperative chest x-ray, computed tomography, and/or magnetic resonance imaging were necessary for determining the level of ministernotomy, especially in aortic valve operations. Transthoracic echocardiography was useful for selecting procedures of mitral valve or intracardiac repair through the MICS approach. Intraoperative transesophageal echocardiography was essential for continuous monitoring of cardiac function, intracardiac flow, air bubbles, and so forth. The above results suggest that intensive imaging assessment might be very important for successful MICS operations with ministernotomy or minithoracotomy and that extensive indications for this technique exist for various cardiovascular diseases.


Is acupuncture a risk factor for hepatitis? Systematic review of epidemiological studies.
Acupuncture has been repeatedly associated with infectious hepatitis. The aim of the present systematic review was therefore to critically evaluate such data from epidemiological investigations. Four independent literature searches were carried out to identify all epidemiological evidence linking acupuncture with hepatitis. All studies were validated by the authors and data extracted according to predefined criteria. Fifteen investigations fulfilled our inclusion criteria. Most studies originated from Asia. One study included markers to hepatitis A virus, three to hepatitis B virus, and 13 to hepatitis C virus. Five investigations reported associations between acupuncture and seropositivity to hepatitis C virus. In those studies, acupuncture increased the risk only modestly. A modest association between hepatitis C and acupuncture has been reported in some countries. This emphasizes the importance of exclusively using disposable acupuncture needles.


Autism spectrum disorder in Say-Barber-Biesecker-Young-Simpson syndrome.
Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS), also known as Ohdo syndrome SBBYS type, is a rare genetic disorder characterised by dysmorphic facial features and severe intellectual disability, as well as cardiac, dental and hearing abnormalities. There has been little psychiatric or psychological description of children with SBBYSS, although previous reports noted repetitive self-injurious behaviours, sensitivity to light and noise and severe deficits in communication. In this report, a 4-year-old male with SBBYSS is described with a focus on psychiatric and psychological assessment, including formal testing for autism spectrum disorder (ASD). Results of multiple behavioural assessment scales are reported. Testing revealed characteristic ASD features, and the patient met criteria for ASD diagnosis in the context of SBBYSS. His behaviours improved with Applied Behavioural Analysis therapy and communication skills training. This is the first documented case of ASD reported alongside SBBYSS. These results suggest ASD may be a clinical feature of SBBYSS.


Designer Drug, 25D-NBOMe, Has Reinforcing and Rewarding Effects through Change of a Dopaminergic Neurochemical System.
2-(2,5-Dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)_ethanamine (25D-NBOMe), an analogue of the 2C family, is a newly synthesized psychoactive substance. It acts as an agonist at the 5-HT2A receptor and has a similar mechanism to that of NBOMe compounds. However, the pharmacological mechanism for its rewarding and reinforcing effects has not been revealed. In the present study, intravenous self-administration (IVSA) test and conditioned place preference (CPP) test were performed to investigate whether 25D-NBOMe has abuse potential. We also evaluated the effects of 25D-NBOMe on neurochemical changes using western blot analysis and microdialysis. The IVSA test revealed increased self-administration in 25D-NBOMe (0.03 mg/kg)-treated rats. In addition, the CPP test revealed rewarding effects in 25D-NBOMe (1 mg/kg)-treated mice. In the neurochemical studies, 25D-NBOMe treatment affected the expression of dopamine (DA) receptor D1 (DRD1), DA receptor D2 (DRD2), tyrosine hydroxylase, DA transporter (DAT), and phospho-DAT (p-DAT) in the nucleus accumbens (NAc). In addition, microdialysis revealed that treatment with progressively increasing doses (1, 3, and 10 mg/kg) of 25D-NBOMe increased the extracellular levels of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the rat NAc. Taken together, our results show the abuse potential and neurochemical changes related to addictive behavior after administration of 25D-NBOMe.


Lack of awareness of need to clean CFC-free metered-dose inhalers.
Chlorofluorocarbon (CFC)-free metered-dose inhalers (MDIs) were introduced into Australia in 1999. Device care instructions were modified (e.g., CFC-free salbutamol inhalers to be washed weekly), but this information was not communicated directly to health care professionals. This pilot study aimed to assess the level of awareness of device care protocols for CFC-free MDIs by patients and their pharmacists. Purchasers of CFC-free MDIs were recruited from four community pharmacies. They were interviewed regarding information sources, knowledge of propellant change, and awareness of and adherence to device care protocols. The dispensing pharmacists were interviewed for knowledge of CFC-free device care. The primary outcome variable was awareness of the relevant device care protocol. Thirty-nine patients were interviewed. Most patients (77%) were aware of the change to CFC-free propellant. Only nine patients (23%) were aware of the need to wash the device holder, and four patients (10% of total) complied with the specified protocol. One of the ten dispensing pharmacists could describe correct device care protocols for the CFC-free MDIs. Although most patients are aware that MDIs are now CFC-free, there is a low level of awareness of the device care required for these inhalers, and a very low rate of compliance with recommended practice. Although the clinical impact of failing to wash the device holder is unclear, this added instruction may have substantial implications for patient satisfaction and medication delivery. Pharmaceutical manufacturers need to highlight to health care professionals any clinically important changes in device care instructions, so that appropriate information may be passed on to patients.


Cell migration in schizophrenia: Patient-derived cells do not regulate motility in response to extracellular matrix.
Schizophrenia is a highly heritable psychiatric disorder linked to a large number of risk genes. The function of these genes in disease etiology is not fully understood but pathway analyses of genomic data suggest developmental dysregulation of cellular processes such as neuronal migration and axon guidance. Previous studies of patient-derived olfactory cells show them to be more motile than control-derived cells when grown on a fibronectin substrate, motility that is dependent on focal adhesion kinase signaling. The aim of this study was to investigate whether schizophrenia patient-derived cells are responsive to other extracellular matrix (ECM) proteins that bind integrin receptors. Olfactory neurosphere-derived cells from nine patients and nine matched controls were grown on ECM protein substrates at increasing concentrations and their movement was tracked for 24h using automated high-throughput imaging. Control-derived cells increased their motility as the ECM substrate concentration increased, whereas patient-derived cell motility was little affected by ECM proteins. Patient and control cells had appropriate integrin receptors for these ECM substrates and detected them as shown by increases in focal adhesion number and size in response to ECM proteins, which also induced changes in cell morphology and cytoskeleton. These observations indicate that patient cells failed to translate the detection of ECM proteins into appropriate changes in cell motility. In a sense, patient cells act like a moving car whose accelerator is jammed, moving at the same speed without regard to the external environment. This focuses attention on cell motility regulation rather than speed as key to impairment of neuronal migration in the developing brain in schizophrenia.


Rare-earth metal methylidene complexes with Ln3(μ3-CH2)(μ3-Me)(μ2-Me)3 core structure.
Trinuclear rare-earth metal methylidene complexes with a Ln3(μ3-CH2)(μ3-Me)(μ2-Me)3 structural motif were synthesized by applying three protocols. Polymeric [LuMe3]n (1-Lu) reacts with the sterically demanding amine H[NSiMe3(Ar)] (Ar = C6H3iPr2-2,6) in tetrahydrofuran via methane elimination to afford isolable monomeric [NSiMe3(Ar)]LuMe2(thf)2 (4-Lu). The formation of trinuclear rare-earth metal tetramethyl methylidene complexes [NSiMe3(Ar)]3Ln3(μ3-CH2)(μ3-Me)(μ2-Me)3(thf)3 (7-Ln; Ln = Y, Ho, Lu) via reaction of [LnMe3]n (1-Ln; Ln = Y, Ho, Lu) with H[NSiMe3(Ar)] is proposed to occur via an "intermediate" species of the type [NSiMe3(Ar)]LnMe2(thf)x and subsequent C-H bond activation. Applying Lappert's concept of Lewis base-induced methylaluminate cleavage, compounds [NSiMe3(Ar)]Ln(AlMe4)2 (5-Ln; Ln = Y, La, Nd, Ho) were converted into methylidene complexes 7-Ln (Ln = Y, Nd, Ho) in the presence of tetrahydrofuran. Similarly, tetramethylgallate complex [NSiMe3(Ar)]Y(GaMe4)2 (6-Y) could be employed as a synthesis precursor for 7-Y. The molecular composition of complexes 4-Ln, 5-Ln, 6-Y and 7-Ln was confirmed by elemental analyses, FTIR spectroscopy, (1)H and (13)C NMR spectroscopy (except for holmium derivatives) and single-crystal X-ray diffraction. The Tebbe-like reactivity of methylidene complex 7-Nd with 9-fluorenone was assessed affording oxo complex [NSiMe3(Ar)]3Nd3(μ3-O)(μ2-Me)4(thf)3 (8-Nd). The synthesis of 5-Ln yielded [NSiMe3(Ar)]2Ln(AlMe4) (9-Ln; Ln = La, Nd) as minor side-products, which could be obtained in moderate yields when homoleptic Ln(AlMe4)3 were treated with two equivalents of K[NSiMe3(Ar)].


Feedback regulation of immune responses by immune complexes; possible involvement of a suppressive lymphokine by FcR gamma-bearing B cell.
Inoculations of antigen-antibody complexes (immune complexes) with the intact Fc portion generates suppressor cells in vivo by binding to FcR gamma on B cells via Fc portions. The cell type responsible for the suppression appears to be B cells bearing FcR gamma. Neither T cells nor macrophages participate in both the inductive and effective phases of this type of regulation. The suppression caused by splenic B cells, previously stimulated with immune complexes in vivo, is mediated by humoral factor(s) released from them. The suppressive factor(s) have H-2 gene product(s) coded by the right-hand side of the H-2 gene complex, but not for FcR gamma themselves or immunoglobulins. It has shared component(s) with suppressive B cell factor (SBF) released from FcR gamma + B cells stimulated with immune complexes in vitro, and it resembles SBF in its mode of action. These findings indicate that immune complexes, the final products of antibody responses, control the immune responses by stimulating surface FcR gamma on B cells. It is of interest that this type of regulation functions in vivo.


The advent of biosimilar therapies in rheumatology--"O brave new world".
Patents for many key biological agents will soon expire. Third-party companies are, therefore, in the process of developing their own versions, termed biosimilar agents, of these innovator products. However, manufacture of biosimilar agents is complicated by the requirement for their production in biological systems, small variations in which can influence the structure, activity and metabolism of the biosimilar product. The development of biosimilar therapies for the treatment of patients with rheumatic diseases could potentially result in substantial cost savings for patients and health care providers, and consequently, increased availability of effective therapies. However, legislation that regulates the manufacture, registration and approval of biosimilar therapies varies considerably between different countries. In addition, major safety and efficacy concerns must be addressed before a rheumatologist can routinely substitute an innovator pharmaceutical with a biosimilar product.


A Methodology for the Analysis of Spontaneous Reactions in Automated Hearing Assessment.
Audiology is the science of hearing and auditory processes study. The evaluation of hearing capacity is commonly performed by an audiologist using an audiometer, where the patient is asked to show some kind of sign when he or she recognizes the stimulus. This evaluation becomes much more complicated when the patient suffers some type of cognitive decline that hinders the emission of visible signs of recognition. With this group of patients, a typical question-answer interaction is not applicable, so the audiologist must focus his attention on the patient's spontaneous gestural reactions. This manual evaluation entails a number of problems: it is highly subjective, difficult to determine in real time (since the expert must pay attention simultaneously to the audiological process and the patient's reactions), etc. Considering this, in this paper, we present an automatic methodology for processing video sequences recorded during the performance of the hearing test in order to assist the audiologist in the detection of these spontaneous reactions. This screening method analyzes the movements that occur within the eye area, which has been pointed out by the audiologists as the most representative for these patients. By the analysis of these movements, the system helps the audiologist to determine when a positive gestural reaction has taken place increasing the objectivity and reproducibility.


Regulation of UMSBP activities through redox-sensitive protein domains.
UMSBP is a CCHC-type zinc finger protein, which functions during replication initiation of kinetoplast DNA minicircles and the segregation of kinetoplast DNA networks. Interactions of UMSBP with origin sequences, as well as the protein oligomerization, are affected by its redox state. Reduction yields UMSBP monomers and activates its binding to DNA, while oxidation drives UMSBP oligomerization and impairs its DNA-binding activity. Kinetics analyses of UMSBP-DNA interactions revealed that redox affects the association of free UMSBP with the DNA, but has little effect on its dissociation from the nucleoprotein complex. A previously proposed model, suggesting that binding of DNA is regulated via the reversible interconversions of active UMSBP monomers and inactive oligomers, was challenged here, revealing that the two redox-driven processes are not interrelated. No correlation could be observed between DNA-binding inhibition and UMSBP oligomerization, upon oxidation of UMSBP. Moreover, while the presence of zinc ions was found to be essential for the interaction of UMSBP with DNA, UMSBP oligomerization occurred through zinc-depleted, unfolded zinc finger domains. Site directed mutagenesis analysis of UMSBP suggested that its unique methionine residue, which can be oxidized into methionine sulfoxide, is not involved in the redox-mediated regulation of UMSBP-DNA interactions.


The miR-30 family: Versatile players in breast cancer.
The microRNA family, miR-30, plays diverse roles in regulating key aspects of neoplastic transformation, metastasis, and clinical outcomes in different types of tumors. Accumulating evidence proves that miR-30 family is pivotal in the breast cancer development by controlling critical signaling pathways and relevant oncogenes. Here, we review the roles of miR-30 family members in the tumorigenesis, metastasis, and drug resistance of breast cancer, and their application to predict the prognosis of breast cancer patients. We think miR-30 family members would be promising biomarkers for breast cancer and may bring a novel insight in molecular targeted therapy of breast cancer.


Mechanical loading and autophagy: A study on the BoNT-A injection-induced condylar cartilage degeneration.
Botulinum toxin A (BoNT-A) has emerged as a treatment option for temporomandibular disorder (TMD). By injecting BoNT-A into the masseter muscle, it is possible to reduce mechanical loading on the temporomandibular joint (TMJ). However, numerous prior studies have indicated excessive reduction in mechanical loading can have detrimental effects on TMJ cartilage. This study proposes that autophagy, a process influenced by mechanical loading, could play a role in BoNT-A-induced mandibular condyle cartilage degeneration. To explore this hypothesis, we employed both BoNT-A injection and an excessive biting model to induce variations in mechanical loading on the condyle cartilage of C57BL/6 mice, thereby simulating an increase and decrease in mechanical loading, respectively. Results showed a significant reduction in cartilage thickness and downregulation of Runt-related transcription factor 2 (Runx2) expression in chondrocytes following BoNT-A injection. In vitro experiments demonstrated that the reduction of Runx2 expression in chondrocytes is associated with autophagy, possibly dependent on decreased YAP expression induced by low mechanical loading. This study reveals the potential involvement of the YAP/LC3/Runx2 signaling pathway in BoNT-A mediated mandibular condylar cartilage degeneration.


Erythropoietin and interleukin-2 activate distinct JAK kinase family members.
The erythropoietin (EPO) receptor and the interleukin-2 (IL-2) receptor beta-chain subunit are members of the cytokine receptor superfamily. They have conserved primary amino acid sequences in their cytoplasmic domains and activate phosphorylation of common substrates, suggesting common biochemical signaling mechanisms. We have generated a cell line, CTLL-EPO-R, that contains functional cell surface receptors for both EPO and IL-2. CTLL-EPO-R cells demonstrated similar growth kinetics in EPO and IL-2. Stimulation with EPO resulted in the rapid, dose-dependent tyrosine phosphorylation of JAK2. In contrast, stimulation with IL-2 or the related cytokine IL-4 resulted in the rapid, dose-dependent tyrosine phosphorylation of JAK1 and an additional 116-kDa protein. This 116-kDa protein was itself immunoreactive with a polyclonal antiserum raised against JAK2 and appears to be a novel member of the JAK kinase family. Immune complex kinase assays confirmed that IL-2 and IL-4 activated JAK1 and EPO activated JAK2. These results demonstrate that multiple biochemical pathways are capable of conferring a mitogenic signal in CTLL-EPO-R cells and that the EPO and IL-2 receptors interact with distinct JAK kinase family members within the same cellular background.


Bimodal displays improve speech comprehension in environments with multiple speakers.
Attending to a single voice when multiple voices are present is a challenging but common occurrence. An experiment was conducted to determine (a) whether presenting a video display of the target speaker aided speech comprehension in an environment with competing voices, and (b) whether the "ventriloquism effect" could be used to enhance comprehension, as found by Driver (1996), using ecologically valid stimuli. Participants listened for target words from videos of an actress reading while simultaneously ignoring the voices of 2 to 4 different actresses. Target-word detection declined as participants had to ignore more distracting voices; however, this decline was reduced when a video display of the target speaker was provided. Neither a signal-detection analysis of performance data nor a gaze-contingent analysis revealed a ventriloquism effect. Providing a video display of a speaker when competing voices are present improves comprehension, but obtaining the ventriloquism effect appears elusive in naturalistic circumstances. Actual or potential applications of this research include those circumstances in which a listener must filter a relevant stream of speech from among multiple, competing voices, such as air traffic control and military environments.


Association of Systemic Anaplastic Large Cell Lymphoma and Active Toxoplasmosis in a Child.
Anaplastic large cell lymphoma is a subset of non-Hodgkin lymphoma and an unusual disease in children. Herein we have reported a 7- year- old girl with a large necrotic skin ulcer on the chest caused by systemic form of anaplastic large-cell lymphoma and simultaneous active toxoplasmosis diagnosed by PCR on lymph node specimen. There were few reports showing a role for toxoplasma infection to cause some malignancies such as lymphoma in adults. Based to our knowledge, this has been the first report of simultaneous systemic anaplastic large cell lymphoma and active toxoplasmosis, documented by positive PCR on tissue biopsy in a child. This case report has suggested more attention to the accompanying Toxoplasma gondii infection as a probable cause of some types of lymphomas.


Effect of intrinsic curvature on semiflexible polymers.
Recently many important biopolymers have been found to possess intrinsic curvature. Tubulin protofilaments in animal cells, FtsZ filaments in bacteria and double stranded DNA are examples. We examine how intrinsic curvature influences the conformational statistics of such polymers. We give exact results for the tangent-tangent spatial correlation function C(r)=<t(s).t(s+r)>, both in two and three dimensions. Contrary to expectation, C(r) does not show any oscillatory behavior, rather decays exponentially and the effective persistence length has strong length dependence for short polymers. We also compute the distribution function P(R) of the end to end distance R and show how curved chains can be distinguished from wormlike chains using loop formation probability.


Toxicities and Response Rates of Secondary CNS Lymphoma After Adoptive Immunotherapy With CD19-Directed Chimeric Antigen Receptor T Cells.
Secondary CNS involvement in systemic B-cell lymphoma (SCNSL) is difficult to treat and displays dismal clinical outcomes. Chimeric antigen receptor (CAR) T cells emerged as a powerful treatment for systemic lymphoma. We aimed to evaluate whether CAR T cells also represent a safe and effective therapy for SCNSL. We retrospectively searched our institutional database for patients with SCNSL treated with CD19-directed CAR T cells. We identified 10 cases, including 7 patients with intraparenchymal lesions and 3 patients with leptomeningeal disease. CNS staging at 1 month after CAR T-cell transfusion showed disease response (stable disease, partial response, and complete response) in 7 patients (70%), including 2 cases of long-lasting complete response (20%). One patient developed pseudoprogression, which resolved under steroids. Response of CNS disease was associated with systemic 1-month response. With a median follow-up of 6 months, median overall and systemic progression-free survival was 7 and 3 months, respectively. Neurotoxic symptoms occurred in 6 patients, with 3 patients developing severe neurotoxicity (American Society for Transplantation and Cellular Therapy grade ≥3). CAR T cells induce considerable antitumor effects in SCNSL, and CNS response reflects systemic response. Neurotoxicity appears similar to previous reports on patients with lymphoma without CNS involvement. CAR T cells may therefore represent an effective and safe therapy for SCNSL.


Immunohistochemical localization of the delta antigen associated with hepatitis B virus in liver biopsy sections embedded in Araldite.
Immunohistochemical localization of the delta antigen in the nuclei of the liver tissue embedded in Araldite was successfully carried out by an indirect immunoperoxidase technique. Deplasticization, using sodium ethoxide solution, was required prior to application of immunochemical reagents. The specificity of the staining was confirmed by the abolition of positive staining after absorption of the antibody with the delta antigen.


Analysis of the Best Timing for Applying Tirofiban in PCI Operation for the Patients with ST Segment Elevation Myocardial Infarction.
This study is a comparative analysis of the best timing for applying tirofiban in the PCI emergency treatment for STEMI patients. We selected 109 patients with ST-segment elevation myocardial infarction from October 2013 to October 2014 and divided them into two groups, the early treatment group (53 cases) received tirofiban during the operation and the later treatment group (56 cases) received tirofiban after operation. The analysis was then conducted. The proportion of IRA forward flow in TIMI2-3 for the 1st group during the radiography was higher than 2nd group, 50 cases with TIMI3 blood flow and 52 cases with TIMI3 blood flow in later treatment group. Comparing the TIMI3 flow of both groups, the difference was not statistically significant; for the CK-MB 4h and 8h after operation as well as the LVEF after operation, the differences are were not statistically significant. The occurrence rate of hemorrhage complication was low for both groups. The early use of tirofiban can make the thrombus fully dissolve and coronary blood flow remains in a good state, which is not only beneficial for myocardial perfusion but also helpful for deciding the length and side branch situation of coronary artery pathological changes.


Elective right hemicolectomy: a twenty-year retrospective analysis of a single general surgeon's practice.
Changes in working practices implemented over the last decade particularly with respect to subspecialisation have changed the working practices of the traditional general surgeon. The majority of non-colorectal specialists who wish to continue abdominal surgery have been limited to pursue right sided colorectal pathology only. The aim of this study was to assess the outcomes of colorectal procedures performed by one non-colorectal specialist general surgeon who commenced consultant practice in 1991 and compare these outcomes against the outcomes recorded in the literature for low and high volume caseload surgeons. The patient records of 131 patients who underwent right hemicolectomy by a single surgeon between March 1991 and December 2010 were retrieved and retrospectively analysed. All patients underwent midline laparotomy with two-layer handsewn end-end or end-side ileocolonic anastomoses. Complications of interest were postoperative deaths and clinically relevant anastomotic leaks as well as clinically diagnosed medical complications. The mean age of patients was 61.5 years (range 17-83). A total of 92 patients were operated upon for colorectal malignancy and 39 patients for crohn's disease. No anastomotic leaks occurred. There was only a single inpatient death secondary to acute myocardial infarction. Our small study of a single surgeon's career long practice for elective right hemicolectomies demonstrates that high standards in terms of anastomotic leak rates and operative mortality can be achieved in clinical practice by the non-specialist General Surgeon. However, prospective data collection would be required to apply this to the broader non-colorectal specialist community.


Sensory irritation of acetic acid, hydrogen peroxide, peroxyacetic acid and their mixture in mice.
The expiratory bradypnoea indicative of upper airway irritation in mice was evaluated during a period of 60 min of oronasal exposure to acetic acid, hydrogen peroxide and peroxyacetic acid vapours. The airborne concentration resulting in a 50% decrease in the respiratory rate of mice (RD50) was calculated for each chemical. The concentration-response curves of acetic acid, hydrogen peroxide and peroxyacetic acid had similar slopes. The results did however show that the three chemicals had different irritant potencies. The RD50 values of acetic acid, hydrogen peroxide and peroxyacetic acid were 227, 113 and 5.4 p.p.m. respectively. Moreover, a mixture containing 53% acetic acid, 11% hydrogen peroxide and 36% peroxyacetic acid had an RD50 of 10.6 ppm, 3.8 ppm being peroxyacetic acid, which is 1.4 times lower than the theoretical value estimated from the fractional concentrations and the respective RD50s of the individual components. On the basis of a TLV-STEL (threshold limit value for short-term exposure limit) equal to 0.1 RD50, the TLV-STELs for acetic acid, hydrogen peroxide and peroxyacetic acid should not exceed 20, 10 and 0.5 p.p.m. respectively. On the basis of a TLV-TWA (time-weighted average) equal to 0.03 RD50, the TLV-TWAs for these same chemicals should not exceed 5, 3 and 0.2 p.p.m. respectively. Finally, these values and existing TLVs in Europe and the USA are compared.


Evaluation of postoperative dental implant primary stability using 3D finite element analysis.
The goal of this work was to use finite element analysis (FEA) to evaluate the primary stability of the dental implant without further in vivo measurements. Through proper simulations the information about stability could be obtained faster and easier than in vitro or in vivo studies. Four dental implants were chosen to evaluate their implant stability in various grades of bone. The 3D CAD models of these implants were reengineered via stereo microscopic measurements and the reengineered models were placed in artificial bone samples. Our approach was to simulate the micro mobility with FEA in various types of dental implants to see the differences between them and to convert the simulated micro mobility to Implant Stability Quotient (ISQ). The ISQ was chosen as the representation of implant stability because it is a general index-number of implant stability and it could also be measured with a standard commercially available device in clinics. After performing the simulations, the effect of the predrilling procedures on one exact implant type was investigated. Due to the numerous simulations it can be concluded that the implant stability (ISQ) can be effectively simulated via FEA, moreover the behavior of different implants in different type of surrounding bone tissues can also be evaluated. With this method it is possible to predict and to monitor the stability of known and also of novel dental implants before implantation.


Reentrant behavior of grafted poly(sodium styrenesulfonate) chains investigated with a quartz crystal microbalance.
Poly(sodium styrenesulfonate) (PSSNa) chains have been grafted onto a SiO(2)-coated resonator surface. The conformational changes of grafted chains have been investigated using a quartz crystal microbalance with dissipation (QCM-D) in the presence of monovalent or multivalent salts as a function of ionic strength. In the case of monovalent counterions, the changes in frequency (Δf) and dissipation (ΔD) indicate that the highly extended PSSNa chains first shrink into a loose and inhomogeneous layer as the ionic strength increases. As the ionic strength increases further, the chains will collapse and form a denser and more homogeneous layer. In the case of divalent or trivalent counterions, the grafted PSSNa chains also collapse into a dense layer as the ionic strength increases. However, when the ionic strength is above a critical value, the chains would re-expand so that the layer becomes partially extended due to the charge inversion. Additionally, the effect of ion-specificity on the conformational changes of the chains has also been examined.


Adjusting finite sample bias in traffic safety modeling.
Poisson and negative binomial regression models are fundamental statistical analysis tools for traffic safety evaluation. The regression parameter estimation could suffer from the finite sample bias when event frequency is low, which is commonly observed in safety research as crashes are rare events. In this study, we apply a bias-correction procedure to the parameter estimation of Poisson and NB regression models. We provide a general bias-correction formulation and illustrate the finite sample bias through a special scenario with a single binary explanatory variable. Several factors affecting the magnitude of bias are identified, including the number of crashes and the balance of the crash counts within strata of a categorical explanatory variable. Simulations are conducted to examine the properties of the bias-corrected coefficient estimators. The results show that the bias-corrected estimators generally provide less bias and smaller variance. The effect is especially pronounced when the crash count in one stratum is between 5 and 50. We apply the proposed method to a case study of infrastructure safety evaluation. Three scenarios were evaluated, all crashes collected in three years, and two hypothetical situations, where crash information was collected for "half-year" and "quarter-year" periods. The case-study results confirm that the magnitude of bias correction is larger for smaller crash counts. This paper demonstrates the finite sample bias associated with the small number of crashes and suggests bias adjustment can provide more accurate estimation when evaluating the impacts of crash risk factors.


Linear IgA bullous dermatosis: an unusual cause of upper eyelid cicatricial entropion.
Chronic cicatrizing conjunctivitis is a relatively uncommon condition resulting in significant ophthalmic morbidity, including keratoconjunctivitis sicca, cicatricial entropion, trichiasis, corneal scarring, significant discomfort, and visual loss. The potential causes of cicatrizing conjunctivitis are varied and include commonly encountered entities such as ocular cicatricial pemphigoid, Stevens-Johnson syndrome, and trachoma and many more rare causes which are particularly difficult to diagnose and treat and may not be familiar to the ophthalmologist. The authors herein present a case of chronic cicatrizing conjunctivitis, cicatricial entropion, and trichiasis caused by a rare entity called linear IgA bullous dermatosis. The case presentation conforms to the tenets of the Declaration of Helsinki and is Health Insurance Portability and Accountability Act compliant. This chronic dermatosis has a varied presentation, and the ophthalmic manifestations in particular have been infrequently described. This case demonstrates the benefits of immunohistochemistry in diagnosis and the difficulties in medical and surgical management of linear IgA bullous dermatosis while underscoring the lifelong difficulties in managing chronic inflammatory conditions causing ocular cicatrization.


Highly efficient copper-catalyzed cascade synthesis of quinazoline and quinazolinone derivatives.
We have developed a general and highly efficient copper-catalyzed method for synthesis of quinazoline and quinazolinone derivatives, the target products were obtained in good to excellent yields via cascade reactions of amidine hydrochlorides with substituted 2-halobenzaldehydes, 2-halophenylketones, or methyl 2-halobenzoates, and the method is of simple, economical and practical advantages.


Long-term follow-up of endoscopic stapled diverticulotomy.
We report a consecutive series of 31 patients who underwent endoscopic stapled diverticulotomy. The patients' notes were reviewed retrospectively to gather data on their original admission and a postal survey was conducted to establish patient satisfaction, their ability to swallow and re-operation data. Three patients were lost to follow-up. Nine of the remaining 28 died at a median of 18 months. The remaining 21 were followed up for a median of 59 months. The data showed that, at 5 years, 94.4% of patients had an improvement in their swallowing, and 50% had an entirely normal swallow. In order to achieve this result, 19% of patients required a second procedure, and one patient (3.2%) required a third (open) procedure. Endoscopic stapled diverticulotomy has well-established, short-term advantages. This series shows that it has a good long-term outcome that is similar to established open techniques and probably better than other techniques of endoscopic diverticulotomy, i.e. diathermy or laser.


Safety of Cubital Tunnel Release Under General versus Regional Anesthesia.
The aim of this study was to evaluate the occurrence of early (<6 weeks) post-operative complications following ulnar nerve decompressions at the cubital tunnel performed under regional anesthesia compared to those performed under general anesthesia. In situ ulnar nerve decompressions at the cubital tunnel performed at a single institution from 2012 through 2019 were retrospectively reviewed. Post-operative complications were compared between subjects who underwent the procedure with regional versus general anesthesia. Ninety-one ulnar nerve in situ decompressions were included in the study, which were performed under regional anesthesia in 55 and general anesthesia in 36 cases. The occurrence of post-operative complications was not significantly different between patients who received regional (n = 7) anesthesia and general (n = 8) anesthesia. None of the complications were directly attributed to the type of anesthesia administered. The change in pre- and post-operative McGowan scores were not significantly different between anesthesia groups (p = 0.81). In situ ulnar nerve decompression at the cubital tunnel under regional anesthesia does not result in increased post-operative complications compared to those surgeries performed under general anesthesia. In situ ulnar nerve decompression performed under regional anesthesia is a safe and reliable option for patients who wish to avoid general anesthesia. III.


Optimization of Culture Conditions for Enrichment of Saccharomyces cerevisiae with Dl-α-Tocopherol by Response Surface Methodology.
Designing enriched probiotic supplements may have some advantages including protection of probiotic microorganism from oxidative destruction, improving enzyme activity of the gastrointestinal tract, and probably increasing half-life of micronutrient. In this study Saccharomyces cerevisiae enriched with dl-α-tocopherol was produced as an accumulator and transporter of a lipid soluble vitamin for the first time. By using one variable at the time screening studies, three independent variables were selected. Optimization of the level of dl-α-tocopherol entrapment in S. cerevisiae cells was performed by using Box-Behnken design via design expert software. A modified quadratic polynomial model appropriately fit the data. The convex shape of three-dimensional plots reveal that we could calculate the optimal point of the response in the range of parameters. The optimum points of independent parameters to maximize the response were dl-α-tocopherol initial concentration of 7625.82 µg/mL, sucrose concentration of 6.86 % w/v, and shaking speed of 137.70 rpm. Under these conditions, the maximum level of dl-α-tocopherol in dry cell weight of S. cerevisiae was 5.74 µg/g. The resemblance between the R-squared and adjusted R-squared and acceptable value of C.V% revealed acceptability and accuracy of the model.


Modulation of angiotensin II-mediated signalling by heparan sulphate glycosaminoglycans.
Heparin and angiotensin-converting enzyme inhibitors can be used as a therapeutic option in diabetic nephropathy (DN). Although the mode of action is poorly understood, both agents may retard the progression of DN. Previously, we demonstrated that angiotensin II (Ang II) has an inhibitory effect on the production of heparan sulphate proteoglycan (HSPG) in mesangial cells (MCs). We have now studied the influence of heparin on the Ang II-induced intracellular Ca(2+) release and activation of nuclear factor kappa B (NF-kappaB). Human MCs were isolated from renal cortex and cultivated to measure Ca(2+) influx and NF-kappaB activation. Stimulation of MCs with 100 nM Ang II resulted in a rapid increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)), followed by a decline to baseline level. The addition of heparin resulted in an oscillatory pattern of Ca(2+) influxes upon Ang II stimulation. Whereas the rapid increase in [Ca(2+)](i) was most likely due to release from intracellular stores, oscillations in [Ca(2+)](i) were dependent on the presence of extracellular Ca(2+). Heparin alone did not induce Ca(2+) influx. Both the initial increase and the subsequent oscillations in [Ca(2+)](i) could be blocked by losartan. In MCs with chemically or enzymatically altered membrane-associated heparan sulphate glycosaminoglycan (HS-GAG), Ang II stimulation resulted in [Ca(2+)](i) oscillations. Interestingly, in these cells, the addition of heparin or GAG completely prevented [Ca(2+)](i) oscillations. Heparin inhibited NF-kappaB activation in Ang II-stimulated MCs that expressed either normal or chemically altered GAG. These findings suggest that alterations in HS-GAG chemistry or metabolism under pathological conditions, such as DN, may have direct functional consequences for the local effect of Ang II.


Optimization of real time RT-PCR methods for the analysis of gene expression in mouse eggs and preimplantation embryos.
This study was carried out to optimize conditions for using real time RT-PCR as an efficient and precise quantitative method for estimating the transcript levels of genes expressed in samples containing miniscule amounts of RNA, such as single mammalian oocytes and embryos. First, using mouse eggs and blastocysts, we tested three kinds of RNA isolation or collection methods: TRIZOL reagent, oligo-dT conjugated beads, or three freeze/thaw cycles with the reverse transcription buffer. There were no significant differences among three groups in mRNA quantity as assayed by real time RT-PCR analysis. Second, we compared the efficacy of real time analysis between TaqMan fluorescent probes and the SYBR-green dye system. The two systems presented similar real time RT-PCR profiles for the 16s ribosomal protein gene from oocytes to blastocysts. Third, RNA from mouse embryos at defined stages of preimplantation development were isolated and the levels of transcripts encoded by several housekeeping genes (GAPDH, beta-actin, ribosomal protein L7, 16s ribosomal protein, histone H2A.Z) were quantitatively analyzed by real time RT-PCR. The histone H2A.Z and 16s ribosomal protein slightly increased from the egg to blastocyst stages by approximately 10- and 30-fold, respectively. However, other transcripts increased more than 300-fold as a function of developmental stage from eggs to blastocysts. Our results suggest that the simple freezing/thawing method for RNA collection, the economic SYBR-green dye system, and histone H2A.Z gene as an internal control should be useful for the real time RT-PCR analysis of single mouse eggs and preimplantation embryos.


[Alcohol delirium--pathogenesis and therapy].
Alcohol-induced delirium tremens (DT) is a well-known disease with an unpredictable, either favorable or fatal, spontaneous course. The cardinal symptoms are disorientation, hallucinations and autonomic lability. The pathogenesis of DT is still unknown, and the numerous hypothesis have spawned as many therapeutic approaches. Drugs with a cross-tolerance to alcohol have so far proved best. Benzodiazepines and clomethiazole have been considered the drugs of first choice for the past 20 years and more. Improvements in intensive care has helped lower the mortality rate to 3 to 8%. Major tranquilizers with a strong antipsychotic effect and anti-epileptic agents can effectively expand the sedative management of DT. Cerebral convulsions at the beginning of DT appear to dispose the patient to a prolonged course, and preexisting or concomitant disease affecting other organs (complicated DT) clearly prolongs the duration of delirium. The risks and contraindications of clomethiazole are emphasized. The course and outcome of DT is unpredictable--in our patients we found a mortality rate of 3.7% and 12.3% end up in a defective state.


Re-exposure to nicotine-associated context from adolescence enhances alcohol intake in adulthood.
Alcohol and nicotine are the two most commonly-abused substances and are often used together. Nicotine enhances alcohol-drinking behaviors in humans and in animals, and was suggested to enhance the reinforcing properties of other reinforcers. Here, we show that nicotine-associated environment, rather than nicotine itself, enhances alcohol intake in rats. Adolescent rats received repeated intermittent injections of nicotine (0.4 mg/kg, i.p., 5 injections, every 3rd day) or saline. The injection was paired with their home cage, or with the subsequent alcohol self-administration context. Rats were then trained to self-administer 20% alcohol. Nicotine given in the home cage did not alter subsequent alcohol intake. However, pairing nicotine with the operant chamber during adolescence led to a long-lasting increased alcohol self-administration in adulthood, compared to nicotine pre-treatment in other contexts. This effect persisted 3 months after nicotine cessation, in a relapse test after abstinence. Furthermore, re-exposure to the nicotine-associated context in adult rats led to a decrease in glial cell line-derived neurotrophic factor (Gdnf) mRNA expression in the ventral tegmental area, an effect that leads to increased alcohol consumption, as we have previously reported. Our findings suggest that retrieval of nicotine-associated contextual memories from adolescence may gate alcohol intake in adulthood, with a possible involvement of GDNF.


Cost effectiveness of a latrine revision programme in Kabul, Afghanistan.
We assessed a household latrine revision intervention implemented in Kabul, Afghanistan for evidence of a reduction in diarrhoeal disease. A case-control design involving 1238 cases and 625 controls was used. Logistic regression modelling was performed both for children < 5 years and < or = 11 years, and the parameter estimates were later used with results from a stratified cluster sample survey. This survey used a verbal autopsy methodology to enable an estimation of the number of deaths averted over a 1-year period. A cost-effectiveness analysis using direct and indirect costs for the intervention was then conducted and the results compared with primary health care interventions identified from a Medline search. Conditional logistic regression showed that patients were less likely than controls to live in households with revised latrines (odds ratio (OR) 0.57, 95% confidence interval (CI) = 0.42-0.77 for children < 5 years, and OR 0.53, 95% = CI 0.41-0.67 for children < or = 11 years). The results from the survey of cause-specific mortality by verbal autopsy enabled estimation of the number of deaths averted over a 1-year period due to the intervention; these estimations were 235 (95% CI = 109-360) for children < 5 years and 285 (95% CI = 180-397) for children < or = 11 years. Estimates of cost effectiveness ranged from approximately US dollars 1800 to US dollars 4100 per death averted depending on age and payer perspective. These estimates are conservative because only 1 year of effectiveness is considered, yet they compare favourably with a review of other paediatric interventions. These results are important because funding for sanitation interventions is often limited by the belief that the interventions are not cost-effective.