To what extent are we confident that tapentadol induces less constipation and other side effects than the other opioids in chronic pain patients? a confidence evaluation in network meta-analysis.
A confidence evaluation helps to make informed decisions about the results of meta-analyses. The goal of this work is to perform a confidence evaluation of results of a network meta-analysis (NMA) on the digestive side effects of tapentadol in patients with chronic pain. An updated search in PubMed/Medline and Web of Science search until March 2020 was done to perform pairwise meta-analyses with NMA using random-effect models and confidence in network meta-analysis (CiNeMA) for the confidence analysis. Twenty-five studies were included in the final analyses. Pairwise and indirect comparisons showed a reduced risk of constipation with tapentadol compared to oxycodone. The confidence evaluation did not raise any concerns in terms of confidence for the oxycodone versus tapentadol comparisons. The oxycodone-naloxone versus tapentadol comparisons showed some concerns, particularly in terms of imprecision and incoherence. Regarding the overall risk of any side effects, the confidence evaluation showed a major concern regarding imprecision, but not for the comparison between tapentadol and oxycodone. However, this comparison showed a major heterogeneity. A confidence evaluation in meta-analysis on the effect of tapentadol compared to other opioids in chronic pain showed possible imprecision, heterogeneity and/or incoherence. However, with a high level of confidence, tapentadol was associated with a lower incidence of constipation than oxycodone. Confidence analyses can help to get more information from meta-analyses.


[Clinical studies on surgical treatment of renal hyperparathyroidism].
While patients of chronic renal failure can survive today for a long period thanks to the spread of hemodialysis, establishment of criteria for the treatment of renal hyperparathyroidism is an important problem. In the 15 cases of renal hyperparathyroidism previously operated by the author, preoperative examinations and findings at the time of operation, and technique of operation and postoperative examinations were analyzed together with the effects of operation, and the indications and technique of operation were discussed. Surgical indication Since the histological findings of resected parathyroids presented chief cell hyperplasia in the whole gland and coexistence of fat tissues was hardly recognized, it was estimated that the weight of parathyroid glands directly reflected the secretory function of the parathyroid glands. Accordingly, the relation between the preoperative findings and weight of parathyroid glands was analyzed. As a result, a significant correlation was noted between the preoperative c-PTH and the weight of parathyroid glands. Hence it was proved possible to predict the approximate weight of parathyroid glands from the preoperative level of c-PTH. Further investigations were made on s-Al-P, s-CT, RMC, roentgenographic findings, ca-infusion test, iliac bone biopsy, subjective symptoms, and weight of parathyroid glands, and the following conclusions were obtained with respect to the surgical indication. 1) When the weight of parathyroid glands was estimated to be above 2000 mg, the operation would be an absolute indication. 2) If the weight is estimated between 1000 and 2000 mg, the operation should be preferred because the improvement by conservative treatment may not be expected. 3) In the case of slight swelling of less than 1000 mg, the first choice of treatment should be conservative. However the operation in the early stage would be essential in the case of calcification of the blood vessel wall. Surgical technique In 10 of the 15 cases operated, subtotal parathyroidectomy was performed. For longer period than 6 months after surgery clinical study was performed with respect to the changes in c-PTH, s-Al-P, CT, RMC, bone roentgenographic findings, s-Ca, s-P, iliac bone biopsy, and subjective symptoms. As a result, the postoperative course was good in patients in whom the subtotal parathyroidectomy was performed with 20 to 50 mg of the remaining parathyroid tissue. The value of c-PTH was stabilized in 3 months after the operation, and was thereafter controlled within normal ranges. In view of the possibility of the recurrence, the desirable weight of the remaining parathyroid tissue would be 20 to 30 mg.(ABSTRACT TRUNCATED AT 400 WORDS)


Pattern of Uveitis in Iran: A Systematic Review.
Uveitis is the third leading cause of blindness worldwide. This study aimed to summarize the pattern of uveitis in Iran through a systematic review. This review was conducted according to the guidelines for systematic reviews in the following four steps: literature search, study selection and assessment, inclusion and exclusion criteria, and statistical analysis. One hundred and fifteen articles were identified by an encyclopedic literature search, and three independent investigators examined them according to the defined inclusion and exclusion criteria. Eventually, 109 manuscripts were retrieved and six cross-sectional studies covering 3,567 patients were included and reviewed. According to the results, the mean age of patients was 40 years, and sex was not a statistically significant predisposing factor. The most common anatomical pattern of involvement was anterior uveitis, and the prevalence of the other three types of uveitis, including middle, posterior, and pan-uveitis, were almost equal. Overall, the most common etiologies of uveitis in the Iranian population were idiopathic uveitis, toxoplasmosis, Behcet's syndrome, and Fuchs heterochromic iridocyclitis. This study depicted the pattern of uveitis in the Iranian society; this can help physicians in the diagnostic approach, management, and treatment of patients.


Recent developments in therapeutic protein expression technologies in plants.
Infectious diseases and cancers are some of the commonest causes of deaths throughout the world. The previous two decades have witnessed a combined endeavor across various biological sciences to address this issue in novel ways. The advent of recombinant DNA technologies has provided the tools for producing recombinant proteins that can be used as therapeutic agents. A number of expression systems have been developed for the production of pharmaceutical products. Recently, advances have been made using plants as bioreactors to produce therapeutic proteins directed against infectious diseases and cancers. This review highlights the recent progress in therapeutic protein expression in plants (stable and transient), the factors affecting heterologous protein expression, vector systems and recent developments in existing technologies and steps towards the industrial production of plant-made vaccines, antibodies, and biopharmaceuticals.


DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome.
The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).


A physiome standards-based model publication paradigm.
In this era of widespread broadband Internet penetration and powerful Web browsers on most desktops, a shift in the publication paradigm for physiome-style models is envisaged. No longer will model authors simply submit an essentially textural description of the development and behaviour of their model. Rather, they will submit a complete working implementation of the model encoded and annotated according to the various standards adopted by the physiome project, accompanied by a traditional human-readable summary of the key scientific goals and outcomes of the work. While the final published, peer-reviewed article will look little different to the reader, in this new paradigm, both reviewers and readers will be able to interact with, use and extend the models in ways that are not currently possible. Here, we review recent developments that are laying the foundations for this new model publication paradigm. Initial developments have focused on the publication of mathematical models of cellular electrophysiology, using technology based on a CellML- or Systems Biology Markup Language (SBML)-encoded implementation of the mathematical models. Here, we review the current state of the art and what needs to be done before such a model publication becomes commonplace.


[Management of stable COPD].
The term chronic obstructive pulmonary disease (COPD) is mainly characterised by an irreversible obstructive airway obstruction, that in most cases, is secondary to tobacco exposure. Management of the disease includes an assessment of severity, and measures to decrease FEV decline, to treat bronchial obstruction, to improve exercise tolerance and to correct abnormal gas exchange. Treatment not only requires drug therapy, but also respiratory rehabilitation, surgery of emphysema, and psychosocial support. In this way, a global strategy, adapted to the severity of COPD, can be proposed.


Langerhans cell histiocytosis of the petrous bone with sudden sensorineural hearing loss. Case report.
A 56-year-old woman with Langerhans cell histiocytosis of the petrous bone presented with sudden onset of sensorineural hearing loss and vertigo without other neurological impairment, mimicking idiopathic sudden sensorineural hearing loss. Differential diagnosis was difficult until neuroimaging demonstrated a lesion of the petrous bone. The patient eventually underwent removal of the lesion via the transpetrosal approach, and received postoperative chemotherapy consisting of vinblastine, methotrexate, 6-mercaptopurine, and prednisolone. Although her hearing did not recover, complete remission was achieved, and the patient is currently free from disease. Physicians need to be aware that patients with sudden onset of hearing loss may have an unexpected and hidden disease which requires neuroimaging and histological examinations for definitive diagnosis and appropriate treatment.


Promoter-level expression clustering identifies time development of transcriptional regulatory cascades initiated by ErbB receptors in breast cancer cells.
The analysis of CAGE (Cap Analysis of Gene Expression) time-course has been proposed by the FANTOM5 Consortium to extend the understanding of the sequence of events facilitating cell state transition at the level of promoter regulation. To identify the most prominent transcriptional regulations induced by growth factors in human breast cancer, we apply here the Complexity Invariant Dynamic Time Warping motif EnRichment (CIDER) analysis approach to the CAGE time-course datasets of MCF-7 cells stimulated by epidermal growth factor (EGF) or heregulin (HRG). We identify a multi-level cascade of regulations rooted by the Serum Response Factor (SRF) transcription factor, connecting the MAPK-mediated transduction of the HRG stimulus to the negative regulation of the MAPK pathway by the members of the DUSP family phosphatases. The finding confirms the known primary role of FOS and FOSL1, members of AP-1 family, in shaping gene expression in response to HRG induction. Moreover, we identify a new potential regulation of DUSP5 and RARA (known to antagonize the transcriptional regulation induced by the estrogen receptors) by the activity of the AP-1 complex, specific to HRG response. The results indicate that a divergence in AP-1 regulation determines cellular changes of breast cancer cells stimulated by ErbB receptors.


Immunological and clinical profile of adult patients with selective immunoglobulin subclass deficiency: response to intravenous immunoglobulin therapy.
Selective immunoglobulin (Ig)G3 subclass deficiency in adults, especially its immunological profile, has not been described previously in detail. Therefore, a retrospective chart review was conducted to characterize the immune profile and clinical manifestations in adult patients with selective IgG3 deficiency. We reviewed the charts of 17 adult patients attending our subspeciality immunology clinic with a diagnosis of selective IgG3 deficiency. The following immunological test results were recorded: lymphocyte subsets, proliferative response to mitogens (phytohaemagglutinin, concanavalin A, pokeweed mitogen) and soluble antigens (mumps, Candida albicans, tetanus toxoid), specific antibody response to tetanus toxoid and pneumococcal antigens, neutrophil oxidative burst and natural killer cell cytotoxicity. In addition, we recorded information about the types of infections and other associated diseases, and response to intravenous immunoglobulin therapy (IVIG). In the majority of patients, lymphocyte subsets were normal. Proliferative responses to mitogens and antigens were decreased in 33% and 40% of patients, respectively. Specific antibody responses to tetanus were normal; however, responses to various pneumococcal serotypes were impaired in a subset of patients. Patients suffered from recurrent upper respiratory tract infections, which usually decreased in frequency and severity following treatment with IVIG. The majority of these patients also had concurrent atopic diseases in the form of allergic rhinitis or asthma. Selective IgG3 subclass deficiency should be considered in adults with recurrent upper respiratory tract infections with or without allergic rhinitis or asthma, who may have normal levels of total IgG. IVIG appears to be an effective therapy.


Ribosome biogenesis is a downstream effector of the oncogenic U2AF1-S34F mutation.
U2 Small Nuclear RNA Auxiliary Factor 1 (U2AF1) forms a heterodimeric complex with U2AF2 that is primarily responsible for 3' splice site selection. U2AF1 mutations have been identified in most cancers but are prevalent in Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML), and the most common mutation is a missense substitution of serine-34 to phenylalanine (S34F). The U2AF heterodimer also has a noncanonical function as a translational regulator. Here, we report that the U2AF1-S34F mutation results in specific misregulation of the translation initiation and ribosome biogenesis machinery. The net result is an increase in mRNA translation at the single-cell level. Among the translationally up-regulated targets of U2AF1-S34F is Nucleophosmin 1 (NPM1), which is a major driver of myeloid malignancy. Depletion of NPM1 impairs the viability of the U2AF1-S34F mutant cells and causes ribosomal RNA (rRNA) processing defects, thus indicating an unanticipated synthetic interaction between U2AF1, NPM1, and ribosome biogenesis. Our results establish a unique molecular phenotype for the U2AF1 mutation that recapitulates translational misregulation in myeloid disease.


Upregulated heme biosynthesis increases obstructive sleep apnea severity: a pathway-based Mendelian randomization study.
Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Iron and heme metabolism, implicated in ventilatory control and OSA comorbidities, was associated with OSA phenotypes in recent admixture mapping and gene enrichment analyses. However, its causal contribution was unclear. In this study, we performed pathway-level transcriptional Mendelian randomization (MR) analysis to investigate the causal relationships between iron and heme related pathways and OSA. In primary analysis, we examined the expression level of four iron/heme Reactome pathways as exposures and four OSA traits as outcomes using cross-tissue cis-eQTLs from the Genotype-Tissue Expression portal and published genome-wide summary statistics of OSA. We identify a significant putative causal association between up-regulated heme biosynthesis pathway with higher sleep time percentage of hypoxemia (p = 6.14 × 10-3). This association is supported by consistency of point estimates in one-sample MR in the Multi-Ethnic Study of Atherosclerosis using high coverage DNA and RNA sequencing data generated by the Trans-Omics for Precision Medicine project. Secondary analysis for 37 additional iron/heme Gene Ontology pathways did not reveal any significant causal associations. This study suggests a causal association between increased heme biosynthesis and OSA severity.


[Expression of aquaporin 2, a water channel, in human endometrium during the menstrual cycle].
To examine the expression of aquaporin 2 (AQP2) in human endometrium. Specimens of human endometrium were collected from 87 women at different menstrual cycles, aged 30 +/- 3, 23 cases in the proliferative phase, 30 cases in the early secretory phase and 34 cases in the mid-secretory phase respectively. Immunohistochemistry and Western blotting were utilized to detect the localization and expression of AQP2 in the endometrium. Reverse transcription-polymerase chain reaction (RT-PCR) was employed to detect its messenger RNA. The PCR product was cloned and sequenced. Positive immunoreactivity of AQP2 was found in the epithelia cells and glandular epithelial cells of all specimens of human endometrium at different phases of the menstrual cycle, and all stromal cells were not stained. The reactive substance was primarily distributed in the membrane and cytoplasm, but not in the nuclei of all positive cells. In Western blotting showed dominant bands with relative molecular weight between 35,000 Da and 50,000 Da, which was corresponded to the glycosylated form of AQP2 by the positive control from rat kidney. Semi-quantitative analysis showed that the relative expression of AQP2 in the mid-secretory phase was 1.63 +/- 0.15, significantly higher than those in the early secretory phase (1.33 +/- 0.14, P < 0.05) and that in the proliferative phase (1.03 +/- 0.10, P < 0.01). Message RNA was found out in all cases by RT-PCR and the PCR product was confirmed in nearly exact (99%) consistency with the GenBank by sequencing. AQP2 mRNA was expressed in all normal endometrium at different phases, and was weakly expressed in the endometrium at the proliferative phase. Sequencing showed that the AQP2 sequence was 99% homologous with that in the GenBank. AQP2 expression in the human endometrium suggests that AQP2 may be involved in the regulation of uterine fluid homeostasis influenced by ovarian steroid hormones in the menstrual cycle.


Familial hypophosphataemic rickets: experience with 24 children from Kuwait.
Between 1982 and 1988, familial hypophosphataemic rickets (FHR) was diagnosed in 24 children, in nine during screening of the families of index patients. The average annual incidence was 0.2/1000 live births. There were 16 boys and 8 girls in 10 families, of which nine had more than one affected child. Their ages at the onset of the disease ranged between 10 months and 14 years (mean 6.9 yrs). Growth retardation and bowing of the legs were the most prominent features, observed in all index patients and in four of the patients diagnosed by screening. Treatment with 1 alpha-hydroxyvitamin D3 and phosphates was associated with acceleration of growth in all children, healing of rickets in 21, and normalization of the serum phosphate in 22. Two children with late diagnosis are now older than 16 years with a final height below the 3rd centile. Three more pubertal children are also shorter than the 3rd centile. In areas where nutritional rickets is common, FHR is likely to be missed and the treatment delayed with grave consequences; in particular, growth retardation and bone deformity.


[Persistent infiltrative pulmonary disease].
Two patients, a woman aged 63 and a man aged 64 years, were admitted with pulmonary complaints and persistent infiltrative lung abnormalities as revealed in chest X-rays. Routine diagnostic analysis did not lead to a diagnosis. However, a pathological examination of biopsies acquired by means of video-assisted thoracoscopic surgery (VATS), revealed bronchiolitis obliterans organising pneumonia (BOOP). In the first patient the BOOP manifested itself as a rapidly progressive disease with fever, pulmonary complaints and X-ray abnormalities. There was no response to standard antibiotic treatment. The other patient had suffered from rheumatoid arthritis for a considerable time and gradually developed BOOP. Both patients recovered following adequate therapy with high doses of oral corticosteroids. BOOP is a pathological-anatomical entity. It is a nonspecific excessive repair response to a variety of stimuli, such as infection, drugs, collagen vascular diseases, inflammatory disorders, transplantation, intoxication and irradiation. BOOP can also occur idiopathically. A high-resolution CT-scan is useful in distinguishing BOOP from interstitial pulmonary fibrosis and other interstitial lung diseases. An open lung biopsy is necessary for the diagnosis BOOP and is best performed by means of VATS. The treatment of BOOP consists of administering high doses of corticosteroids (prednisone 1 mg/kg/day) and if treated adequately, the prognosis is fairly good. Due to the extensive variety in aetiology, the specific diagnostic procedures and the good response to necessary treatment, BOOP should be considered in the differential diagnosis of patients with persistent infiltrative lung disease.


Endothelial-Myocardial Angiocrine Signaling in Heart Development.
Vascular endothelial cells are a multifunctional cell type with organotypic specificity in their function and structure. In this review, we discuss various subpopulations of endothelial cells in the mammalian heart, which spatiotemporally regulate critical cellular and molecular processes of heart development via unique sets of angiocrine signaling pathways. In particular, elucidation of intercellular communication among the functional cell types in the developing heart has recently been accelerated by the use of single-cell sequencing. Specifically, we overview the heterogeneic nature of cardiac endothelial cells and their contribution to heart tube and chamber formation, myocardial trabeculation and compaction, and endocardial cushion and valve formation via angiocrine pathways.


Regulation of aging and cancer by enhanced environmental activation of a hypothalamic-sympathoneural-adipocyte axis.
Social and environmental factors impact cancer and energy balance profoundly. Years ago, our lab established the existence of a novel brain-fat interaction we termed the "hypothalamic-sympathoneural-adipocyte (HSA) axis", through which complex environmental stimuli provided by an enriched environment regulate body composition, energy balance, and development of cancer. We have spent a significant portion of the past decade to further characterize the broad health benefits of an enriched environment (for example, leanness, enhanced immune function, and cancer resistance), and to identify mediators in the brain and periphery along the HSA axis. This review summarizes our recent work regarding the interface between endocrinology, immunology, cancer biology, aging, and neuroscience. We will discuss the interplay between these systemic phenomena and how the HSA axis can be targeted for regulation of cancer and aging.


Proton affinity and gas phase basicity of diamandoid molecules: diamantane to C131H116.
Calculated proton affinities (PAs) and gas phase basicities (GPBs) are reported for diamantane (C14H20), triamantane (C18H24), 'globular and planar' isomers of tetramantane (C22H28) and pentamantane (C26H32), and for one 'globular' isomer of each of the larger diamondoid molecules: C51H58, C78H72, C102H90, and C131H116. Assuming CxHy as the parent diamondoid molecule, we calculated PA and GPB values for a variety of CxHy+1+ isomers, as well as for the reaction CxHy + H+ yielding CxHy-1+ + H2(g); the latter is slightly favored based on GPB values for diamantane through pentamantane, but less favored compared to certain CxHy+1+ isomers of C51H58, C102H90, and C131H116. Indeed, the GPB values of C51H58, C102H90, and C131H116 classifiy them as 'superbases'. Calculations that had the initial location of the proton in an interstitial site inside the diamondoid molecule always showed the H having moved to the outside of the diamondoid molecule; for this reason, we focused on testing a variety of initial configurations with the proton placed in an initial position on the surface. Additional protons were added to determine the limiting number that could be, per these calculations, taken up by the diamondoid molecules and the maximum number of protons are shown in parentheses: C14H20(2), C18H24(3), C22H28(3), C26H32(3), C51H58(4). Bader charge distributions obtained for CxHy+1+ isomers (for diamantane through pentamantane) suggest that the positive charge is essentially completely delocalized over all the H atoms. NMR spectra were calculated for different isomers of C14H19+, and compared to the published NMR spectrum for when diamantane was mixed with magic acid and H2(g) was produced.


ERANET JTC 2011: Submission and Activation of an International Academic Translational Project in Advanced Breast Cancer. Experience From the ET-FES Study.
Background: Academic research is important to face unmet medical needs. The Oncological community encounters many hurdles in setting up multicenter investigator-driven trials mainly due to administrative complexity. The purpose of a network organization at a multinational level is to facilitate clinical trials through standardization, coordination, and education for drug development and regulatory approval. Methods: The application of an European grant foresees the creation of a consortium which aims at facilitating multi-center academic clinical trials. Results: The ERA-NET TRANSCAN Call 2011 on "Validation of biomarkers for personalized cancer medicine" was released on December 2011. This project included Italian, Spanish, French and German centers. The approval process included Consortium constitution, project submission, Clinical Trial Submission, and activation on a national level. The different timescales for submitting study documents in each Country and the misalignment of objections by each Competent Authority CA, generated several requests for changes to the study documents which meant amendments had to be made; as requested by the 2001/20/EC Directive, the alignment of core documents is mandatory. This procedure impacted significantly on study activation timelines. Time to first patient in was 14, 10, 28, and 31 months from the date of submission in Italy, France, Spain, and Germany, respectively. Accrual was stopped on 22nd January 2021 due to an 18F FES shortage as the primary reason but also for having exceeded the project deadlines with consequent exhaustion of the funds allocated for the project. Conclusions: Pharmaceutical companies might be reluctant to fund research projects aimed at treatment individualization if the approval for a wider indication has already been achieved. Academic trials therefore become fundamental for promoting trials which are not attractive to big pharma. It was very difficult and time consuming to activate an academic clinical trial, for this reason, a study may become "old" as new drugs entered into the market. National institutions should promote the development of clinical research infrastructures and network with competence in regulatory, ethical, and legal skills to speed up academic research.


A Brief Review of Scanning Electron Microscopy With Energy-Dispersive X-ray Use in Forensic Medicine.
Scanning electron microscopy with energy-dispersive x-ray (SEM/EDX) analysis is an investigation whose potential has become increasingly important in the field of forensic research and diagnosis. We present the procedure to perform a well-carried-out SEM/EDX analysis on corpses affected by different types of injuries, such as blunt force trauma, ligature strangulation, electrocution, sharp force trauma, gunshot wounds, and intoxication. After the areas of forensic interest have been macroscopically identified, the sampling can be performed in 2 different ways: apposition of the double-sided graphite tape on the damaged area or performing the excision of a biological sample. In both cases, a proper negative control sample is required. In all cases, SEM/EDX analysis can detect exogenous microtraces consistent with the types of injuries involved. In blunt force trauma, microparticles of different nature deriving from the contact of the blunt instrument with the victim may be observed; in sharp force trauma, metal microtraces (Fe, Cr, Al, Ti) can be identified. In ligature strangulation, exogenous microtraces may be found in the cutaneous furrow. In electrocution, it allows to identify the pathognomonic metal pattern (Cu, Zn, Fe) of the "electric mark." In gunshot wounds, the main applications regards the detection of metal particles (Pb, Ba, Sb) of gunshot residues. Finally, in the analysis of intoxicants, it may identify traces of toxic substances. Thus, the authors conclude that SEM/EDX analysis can provide essential information to assist in the medicolegal investigation of death.


Animal feeds as likely vehicles of clostridial infections in livestock.
A total of sixteen samples were collected from various food items on seven farms in three States of Nigeria. These samples yielded thirty one clostridial isolates which were identified as eleven species. The species most frequently isolated was Clostridium perfringens representing 35.5% of the isolates. The next highest was C. bifermentans with a frequency of 22.6%. The other nine species identified were each isolated at frequencies less than 10%. No farm yielded all the species isolated. The farms with the highest distribution of the species of Clostridium were Government Farm, Buruku (Kaduna State), Kano Farm Centre and Government Farm, Butura (Plateau State) with frequency distributions of 36.4% each of the species isolated. Except at the Dairy Cattle Multiplication Centre, Shika (Kaduna State), where the frequency distribution was 27.3%, at none of the other three farms was the distribution more than 20%.


Impact of long-term irrigation with municipal reclaimed wastewater on the uptake and degradation of organic contaminants in lettuce and leek.
A two years drip irrigation of lettuce and leek crops with treated municipal wastewater without and with spiking with fourteen wastewater relevant contaminants at 10 μg/L concentration level was conducted under greenhouse cultivation conditions to investigate their potential accumulation in soil and leaves and to assess human health related risks. Lettuce and leek crops were selected as a worse-case scenario since leafy green vegetable has a high potential for organic contaminants uptake. The results revealed limited accumulation of contaminants in soil and plant leaves, their concentration levels being in the range of 1-30 ng/g and 1-660 ng/g range in soil and leaves, respectively. This was likely related to abiotic and biotic transformation or simply binding processes in soil, which limited contaminants plant uptake. This assumption was underpinned by studies of the enantiomeric fractionation of chiral compounds (e.g. climbazole and metoprolol) in soil as pieces of evidence of biodegradation and by the identification of transformation products or metabolites in leaves by means of liquid chromatography - high resolution - mass spectrometry using a suspect screening workflow. The high bioconcentration factors were not limited to compounds with intermediate Dow (100 to 1000) such as carbamazepine but also observed for hydrophilic compounds such as clarithromycin, hydrochlorothiazide and the food additives acesulfame and sucralose. This result assumed that accumulation was not only driven by passive processes (e.g. lipoidal diffusion through lipid bilayer cell membranes or Casparian strip) but might be supported by carrier-mediated transporters. As a whole, this study confirmed earlier reports on the a de minimis human health risk related to the consumption of raw leafy green vegetable irrigated with domestic TWW containing organic contaminants residues.


Cardiac adverse effects associated with mitoxantrone (Novantrone) therapy in patients with MS.
Mitoxantrone (MITO) is associated with dose-related cardiotoxicity when administered concomitantly with other cytotoxic agents with or without radiotherapy for leukemia and solid tumors. To review observed cardiotoxicity of single-agent MITO therapy for MS. Records of 1,378 patients from three clinical trials of MITO treatment for MS were reviewed for signs and symptoms of cardiac dysfunction and left ventricular ejection fraction (LVEF) results. Duration of follow-up was a median of 29 months (4,084 patient-years). No patients experienced congestive heart failure (CHF) before treatment. Cumulative MITO doses ranged from 2 to 183 mg/m(2) (mean 60.5 mg/m(2), median 62.5 mg/m(2)), and 141 patients received >100 mg/m(2). Two of 1,378 patients experienced CHF after initiating MITO therapy. Of 1,378 patients, 779 completed baseline and scheduled follow-up LVEF testing. Baseline LVEF was >50% in all 779 patients. Seventeen of 779 patients had asymptomatic LVEF of <50% (incidence proportion = 2.18%, 95% CI = 1.28 to 3.47%). Although the incidence of asymptomatic LVEF of <50% was not significantly related to monthly versus 3-monthly therapy, duration of therapy, age, or gender, asymptomatic LVEF of <50% trended higher with a cumulative dose of >/=100 mg/m(2) (5.0%) than with <100 mg/m(2) (1.8%) (p = 0.06). The observed incidence of CHF in patients with MS who received a mean cumulative dose of 60.5 mg/m(2) MITO was <0.20%. Continued monitoring of patients with MS who are receiving MITO is needed to determine whether the incidence of CHF increases with higher cumulative MITO doses and prolonged follow-up.


Single institution experience with the transobturator sling suspension system AdVance® in the treatment of male urinary incontinence: mid-term results.
To evaluate the clinical outcome after placement of AdVance® sling in men with stress urinary incontinence after prostate surgery. Incontinence was assessed on basis of number of pad usage. Patients' satisfaction was evaluated using a non-validated patient questionnaire at 12 months post-operatively. Incontinence cure rate (no pad usage) was 61.5% (16/26) and improvement (1-2 pads per day) was seen in 26.9% (7/26). No improvement was observed in 11.5% (3/26) of patients. A total of 87.5% (21/24) of patients were very satisfied with the operation 22 months after surgery. Success rate in patients with prior radiation therapy (20% cure; 40% improvement) was significantly worse. Placement of the AdVance® sling represents an effective and safe treatment option for patients with post prostate surgery incontinence. Patients that underwent radiotherapy after prostate surgery had lower success rate.


Beyond flat weals: validation of a three-dimensional imaging technology that will improve skin allergy research.
Skin-prick tests (SPTs) are a standard way to test for sensitizations to allergens, but to date, techniques that allow for high-quality measurements of the resulting weals for research purposes are lacking. In this study, we assessed a new three-dimensional (3D) imaging technology for its accuracy and consistency. We found that this new technology showed very little intraoperator and interoperator variation for repeated measurements of a model of known area by each of two operators. We also found that repeated measurements of the same object over 4 months showed virtually no variation. Finally, 3D imaging was superior to traditional ruler measurements for assessing SPT reactions to histamine and allergen. For high-quality measurements of SPT reactions, 3D imaging is accurate, consistent and reliable.


Factors influencing the use of outcome measures in physical therapy practice.
Use of outcome measures in physical therapy practice is central to evaluating the effectiveness of treatment interventions, providing accountability and addressing quality of physical therapy programs. There is limited discussion on barriers and facilitators to using outcome measures in physical therapy practice. The purpose of this study was to identify factors that influence a physical therapist when deciding to use outcome measures in clinical practice. Participants were 21 physical therapists, seven each from skilled nursing facilities, outpatient clinics, and inpatient rehabilitation facilities. A grounded theory approach was used for interview and data collection. Common themes were determined from the data and a theory developed to explain the rationale behind physical therapists' decisions to use or not use outcome measures in clinical practice. Three overlapping themes related to (1) concepts of time, (2) knowledge, and (3) facility culture were indentified as factors influencing the use of outcome measures. A fourth encompassing theme, professionalism, identified the value placed on the use of outcome measures in practice. Data revealed that therapists require more information on the outcome measures available, and this information needs to be easily accessible within the workplace. Therapists value information generated by using outcome measures in the clinical setting, but need information on what measures are available and psychometric properties. Information must be easily accessible and measures easy to use. Newer graduates and recent learners have a foundation in the use of outcome measures, but more needs to be done in the clinic and through continuing education to promote increased use and understanding.


Retrospective illumination correction of retinal images.
A method for correction of nonhomogenous illumination based on optimization of parameters of B-spline shading model with respect to Shannon's entropy is presented. The evaluation of Shannon's entropy is based on Parzen windowing method (Mangin, 2000) with the spline-based shading model. This allows us to express the derivatives of the entropy criterion analytically, which enables efficient use of gradient-based optimization algorithms. Seven different gradient- and nongradient-based optimization algorithms were initially tested on a set of 40 simulated retinal images, generated by a model of the respective image acquisition system. Among the tested optimizers, the gradient-based optimizer with varying step has shown to have the fastest convergence while providing the best precision. The final algorithm proved to be able of suppressing approximately 70% of the artificially introduced non-homogenous illumination. To assess the practical utility of the method, it was qualitatively tested on a set of 336 real retinal images; it proved the ability of eliminating the illumination inhomogeneity substantially in most of cases. The application field of this method is especially in preprocessing of retinal images, as preparation for reliable segmentation or registration.


Antihypertensive and vasoprotective effects of Clausena lansium fruits extract in L-NAME induced hypertensive rats.
Oxidative stress is considered to play an important role in the pathophysiology of hypertension. The aim of this research was to find out whether Clausena lansium (Lour.) Skeels of Wampee (WP) fruits extract attenuate the progression of high blood pressure, endothelial dysfunction and preservation of antioxidant status with using a nitric oxide synthase (NOS) inhibitor, N(G) (-nitro-L-arginine methyl ester (L-NAME) induced hypertension and oxidative stress in rats. Healthy adult male rats were received L-NAME at dose of 50mg/kg/day in drinking water for 4 weeks and were orally administered 250 or 500mg/kg of an aqueous extract of WP fruits extract daily for 2 consecutive weeks. Quercetin (QC; 25 mg/kg) was served as a positive control. The results showed that arterial blood pressure, vascular superoxide production, and plasma malondialdehyde level were markedly induced in L-NAME treated rats. In addition, serum nitric oxide, and glutathione levels were also reduced after L-NAME administration. However, daily administration with the high dose of WP fruits extract significantly alleviated these deleterious effects by attenuated high blood pressure, reversed the L-NAME-induced suppression in serum levels of nitric oxide, mitigated endothelial dysfunction, reduced oxidative stress and restored antioxidant glutathione. This suggests that WP fruits extract is a potential candidate for the development as a novel antihypertensive agents in the future.


Risk communication and radiological/nuclear terrorism: a strategic view.
It is now widely recognized that effective communication is a crucial element in radiological/nuclear terrorism preparedness. Whereas in the past, communication and information issues were sometimes viewed as secondary in comparison with technical concerns, today the need to improve risk communication, public information, and emergency messaging is seen as a high priority. The process of improving radiological/nuclear terrorism risk communication can be conceptualized as occurring in four overlapping phases. The first phase involves the recognition that communication and information issues will be pivotal in shaping how a radiological/nuclear terrorism incident unfolds and in determining its outcome. This recognition has helped shape the second phase, in which various research initiatives have been undertaken to provide an empirical basis for improved communication. In the third and most recent phase, government agencies, professional organizations and others have worked to translate research findings into better messages and informational materials. Like the first and second phases, the third phase is still unfolding. The fourth phase in risk communication for radiological/nuclear terrorism-a mature phase-is only now just beginning. Central to this phase is a developing understanding that for radiological/nuclear terrorism risk communication to be fully effective, it must go beyond crafting better messages and materials (as essential as that may be). This emerging fourth phase seeks to anchor radiological/nuclear communication in a broader approach: one that actively engages and partners with the public. In this article, each of the four stages is discussed, and future directions for improving radiological/nuclear terrorism risk communication are explored.


Comparison of serum copper, magnesium, zinc and calcium levels between G6PD deficient and normal Chinese adults.
Minerals are important for normal hematopoiesis and may play a role in acute hemolytic anemia induced by G6PD deficiency. To compare serum magnesium, copper, zinc and calcium levels between G6PD deficiency and normal control adults, we investigated 69 G6PD deficient (28 male, 41 female) and 61 age- matched G6PD normal adults (26 male, 35 female). Serum magnesium, copper, zinc and calcium levels were determined by atomic absorbance spectrometry. Our results revealed that male adults with G6PD deficiency had significantly higher serum copper and magnesium levels than those of the control group (P < 0.01, < 0.05, respectively). In G6PD normal adults, serum copper levels were significantly lower in males than in females (P < 0.01). In the group of G6PD deficiency adults, serum copper levels in males (103.0 +/- 10.4 ug/dL) were significantly lower than those in females (139.0 +/- 34.3 ug/dL) (P < 0.01). Serum magnesium values and zinc values in males (2.42 +/- 0.38 mEq/L and 102.2 +/- 26.5 ug/dL) were significantly higher than those in females (2.07 +/- 0.20 mEq/L and 87.0 +/- 14.9 ug/dL) (P all < 0.01). Female adults with G6PD deficiency had significantly higher serum calcium levels and lower magnesium levels than those of the control group (P all < 0.01). The significantly higher levels of serum copper and magnesium in G6PD deficient male adults may play some role concerning red blood cells in resistance to plasmodium falciparum.


Phenotype of Antigen Unexperienced TH Cells in the Inflamed Central Nervous System in Experimental Autoimmune Encephalomyelitis.
Multiple sclerosis is a chronic, disseminated inflammation of the central nervous system which is thought to be driven by autoimmune T cells. Genetic association studies in multiple sclerosis and a large number of studies in the animal model of the disease support a role for effector/memory T helper cells. However, the mechanisms underlying relapses, remission and chronic progression in multiple sclerosis or the animal model experimental autoimmune encephalomyelitis, are not clear. In particular, there is only scarce information on the role of central nervous system-invading naive T helper cells in these processes. By applying two-photon laser scanning microscopy we could show in vivo that antigen unexperienced T helper cells migrated into the deep parenchyma of the inflamed central nervous system in experimental autoimmune encephalomyelitis, independent of their antigen specificity. Using flow cytometric analyses of central nervous system-derived lymphocytes we found that only antigen-specific, formerly naive T helper cells became activated during inflammation of the central nervous system encountering their corresponding antigen.


Repolarizing responses of BKCa-Cav complexes are distinctly shaped by their Cav subunits.
Large-conductance Ca(2+)- and voltage-activated potassium (BK(Ca)) channels shape the firing pattern in many types of excitable cell through their repolarizing K(+) conductance. The onset and duration of the BK(Ca)-mediated currents typically initiated by action potentials (APs) appear to be cell-type specific and were shown to vary between 1 ms and up to a few tens of milliseconds. In recent work, we showed that reliable activation of BK(Ca) channels under cellular conditions is enabled by their integration into complexes with voltage-activated Ca(2+) (Cav) channels that provide Ca(2+) ions at concentrations sufficiently high (> or =10 microM) for activation of BK(Ca) in the physiological voltage range. Formation of BK(Ca)-Cav complexes is restricted to a subset of Cav channels, Cav1.2 (L-type) and Cav2.1/2.2 (P/Q- and N-type), which differ greatly in their expression pattern and gating properties. Here, we reconstituted distinct BK(Ca)-Cav complexes in Xenopus oocytes and culture cells and used patch-clamp recordings to compare the functional properties of BK(Ca)-Cav1.2 and BK(Ca)-Cav2.1 complexes. Under steady-state conditions, K(+) currents mediated by BK(Ca)-Cav2.1 complexes exhibit a considerably faster rise time and reach maximum at potentials markedly more negative than complexes formed by BK(Ca) and Cav1.2, in line with the distinct steady-state activation and gating kinetics of the two Cav subtypes. When AP waveforms were used as a voltage command, K(+) currents mediated by BK(Ca)-Cav2.1 occurred at shorter APs and lasted longer than that of BK(Ca)-Cav1.2. These results demonstrate that the repolarizing K(+) currents through BK(Ca)-Cav complexes are shaped by the respective Cav subunit and that the distinct Cav channels may adapt BK(Ca) currents to the particular requirements of distinct types of cell.


[A case of Kennedy-Alter-Sung syndrome with type IIa hyperlipidemia--study on sex hormone receptor and lipid metabolism].
A 57-year-old man of Kennedy-Alter-Sung syndrome (K-A-S) with type IIa hyperlipidemia was reported with studies of several sex hormone receptors. He noticed tremulous movements of hands on gripping at age 40 and gynecomastia at age 46. He had been pointed out to waddle since 52 years old, and also noticed difficulty in going up stairs and standing up at age 54. He was admitted to our Neurology Service on June 5, 1989. On general physical examinations, gynecomastia, eyelids xanthomas and hypertrophy of Achilles tendons were found. Neurologic examination revealed clear consciousness and slight dysarthric speech with nasal voice. Cranial nerves showed mild bilateral facial weakness, poor uvula and soft palatal movements, atrophy and weakness of bilateral sternocleidomastoid muscles, and atrophy of tongue with fasciculation. The four extremities were hypotonic, and proximal muscular atrophy and weakness of four extremities were seen. Deep tendon reflexes were absent in four extremities and fasciculation on both thighs was noted on contraction. Sensory and cerebellar functions were intact. Waddling gait and Gowers' sign were present. In K-A-S syndrome, abnormal lipid metabolism such as a family of type IIa hyperlipidemia, or familial and sporadic cases of type IV hyperlipidemia has been documented. In the family of our cases, his elder sister was found to have type IIa hyperlipidemia, while his son had type IV hyperlipidemia. The coexistence of these two types of hyperlipidemia in the same family of K-A-S syndrome has not been reported so far to our knowledge.(ABSTRACT TRUNCATED AT 250 WORDS)


Recent advances in clinical application of optical coherence tomography of human skin.
Optical coherence tomography (OCT) is an emerging noninvasive imaging method that uses infrared light and interferometric techniques. The method has become increasingly popular in skin research as well as daily dermatology practice. In the present brief review, we focused on recent (2009-2014) OCT studies on the human skin, which included a reasonable sample size and statistics. Twenty-five papers were selected and briefly described OCT of epidermal thickness, skin appendages, wound healing, extracellular matrix and skin fibrosis, vascular malformations, and skin tumors such as basal cell carcinoma, actinic keratoses, and malignant melanoma.


Current Paradigms and Emerging Opportunities in Nephrology Training.
Nephrology is facing a period of remarkable and unprecedented change. The pipeline of device and therapeutic drug development, the growing success of clinical trials, and the emergence of novel clinical practice and training pathways each hold the promise of transforming patient care. Nephrology is also at the forefront of health policy in the United States, given the recent Advancing American Kidney Health initiative. Despite these developments, significant barriers exist to ensure a robust pipeline of well-qualified nephrologists, including but not limited to trainees' declining trainee interest in the specialty, lower board pass rates, and a perceived erosion in stature of the subspecialty. There is a lack of consensus among training program directors regarding procedural training requirements, the number of fellowship positions needed, and the value of the match. There is widespread agreement, however, that any initiative to reassert the value of nephrology must include significant focus on reinvigorating the trainee experience before and during fellowship. We discuss the current state of education in nephrology (from medical school to beyond fellowship) and highlight ways to increase interest in nephrology to reinvigorate the specialty.


Expression pattern of zebrafish rxfp2 homologue genes during embryonic development.
RXFP2 is one of the 4 receptors for relaxin insulin-like peptides, in particular it binds with high affinity the INSL3 peptide. INSL3/RXFP2 pair is essential for testicular descent during placental mammalian development. The evolutionary history of this ligand/receptor pair has received much attention, since its function in vertebrate species lacking testicular descent, such as the fishes, remains elusive. Herein, we analyzed the expression pattern of three rxfp2 homologue genes in zebrafish embryonic development. For all the three rxfp2 genes (rxfp2a, rxfp2b, and rxfp2-like) we showed the presence of maternally derived transcripts. Later in the development, rxfp2a is only expressed at larval stage, whereas rxfp2b is expressed in all the analyzed stage with highest level in the larvae. The rxfp2-like gene is expressed in all the analyzed stage with a transcript level that increased starting at early pharyngula stage. The spatial localization analysis of rxfp2-like gene showed that it is expressed in many cell clusters in the developing brain. In addition, other rxfp2-like-expressing cells were identified in the retina and oral epithelium. This analysis provides new insights to elucidate the evolution of rxfp2 genes in vertebrate lineage and lays the foundations to study their role in vertebrate embryonic development.


The influence of HLA-DR4 (0401) on the immune response to type II collagen and the development of collagen induced arthritis in mice.
Rheumatoid arthritis (RA) is an autoimmune disease that is genetically associated with the MHC class II molecule HLA-DRbeta1*0401 (DR4). In order to determine if this MHC can influence the immune response to the candidate autoantigen type II collagen (CII), we have studied collagen induced arthritis (CIA) resistant C57BL/6 mice, made transgenic (Tg) for human DR4. These DR4 Tg mice exhibited a strong T cell proliferative response to CII and its DR4 restricted peptide p261-273 after immunization with these antigens that was not seen in the C57BL/6 wild type mice. DR4 Tg mice also exhibited an increase in IFN-gamma production in response to CII, indicating the activation of Th1 cells. While these Tg mice produced IgM anti-CII antibodies, they failed to produce a detectable level of IgG2a (Th1 type) anti-bCII antibody and did not develop CIA. This study shows that a Th1 type T cell response to CII can be established in CIA non-susceptible mice by introducing the human transgene, DR4. This T cell response, however, is not sufficient to induce an antibody isotype switch to IgG2a, nor is it sufficient for the induction of CIA. These results may help to explain why many individuals expressing HLA-DRbeta1*0401 do not develop RA.


Prothrombotic states in migraine.
The increased risk of cardiovascular and cerebrovascular events in patients with migraine remains unexplained. Prothrombotic states are thought to contribute to this increased risk. The present study aimed to compare the prevalence of prothrombotic states in patients with migraine and headache-free controls. We conducted a case-control study to screen for prothrombotic states protein C, protein S (PS), antithrombin III, factor V Leiden, lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein 1 antibodies in 101 consecutive patients with migraine and 148 controls. An underlying prothrombotic state was encountered in 11.8% of the patients with migraine, PS deficiency being the most common (4.0%). There was no significant difference in the prevalence of prothrombotic states in patients with migraine compared to controls. Traditional prothrombotic states do not seem to have a higher prevalence in patients with migraine compared to controls.


An easy technique for the removal of a hemodialysis catheter stuck in central veins.
Central venous catheters are currently used for long-term hemodialysis (HD) in a large number of patients. When the catheter needs to be removed, the removal is usually achieved without difficulty after dissection of the cuff from the tunnel. However, when the catheter is stuck in the central vein, the removal becomes complex or unsuccessful. Herein, a simple and easy technique is described for the removal of an HD catheter stuck in the central vein. Attempts were made to remove an HD catheter from a 65-year-old male by making an incision in the skin over the exit site of the catheter to dissect the cuff from the tunnel and by pulling the catheter, but without success because the catheter was stuck in the central vein. Through a second skin incision in the neck, the subcutaneous portion of the catheter was retrieved from the tunnel and then an introducer sheath was inserted over the catheter into the internal jugular vein while the catheter was held in place. The sheath was advanced around the catheter into the central vein. The catheter was then easily pulled out from the central vein. The reported cases of stuck catheters in the literature were reviewed to acknowledge the difficulties encountered in the removal attempts. The technique described herein can be used for the removal of a variety of catheters and wires stuck in the central vein.


Strengthening prevention performance using technology: a formative evaluation of interactive Getting To Outcomes.
Communities face challenges implementing evidence-based prevention programs. To help, policymakers are exploring how to build community-level capacity for prevention for thousands of organizations or communities across the United States. This article reports on a formative evaluation within 2 states' prevention systems of an Internet system designed to build capacity on a large scale, interactive Getting To Outcomes(R) (iGTO). In Tennessee, 30 coalitions were randomly assigned to receive either the iGTO system or nothing. In Missouri, 18 coalitions receiving iGTO were compared with 8 like coalitions who did not receive iGTO. The primary outcome was iGTO's impact on the performance of the coalitions' programs, assessed through interviews at baseline and after a year of iGTO implementation. Analyses suggest that iGTO-programs improved their performance of prevention practices over non-iGTO programs. Semi-structured interviews of iGTO users and state-level stakeholders showed that iGTO was adopted by most iGTO-assigned coalitions, albeit in mostly an elementary fashion. Perceptions of the iGTO system were mixed. The findings suggest that more comprehensive integration requires that state leadership also use iGTO and provide more support for its use at the local level.


Similar Ro/SS-A autoantibody epitope and titer responses in annular erythema of Sjögren's syndrome and subacute cutaneous lupus erythematosus.
Studies were conducted to determine whether certain types of Ro autoantibodies are unique to subacute cutaneous lupus erythematosus and annular erythema of Sjögren's syndrome. Ten American subacute cutaneous lupus erythematosus sera, 11 Japanese annular erythema of Sjögren's syndrome sera, and 39 control sera were tested by enzyme-linked immunosorbent assay with recombinant 52- and 60-kd Ro fusion proteins, native 60-kd Ro protein, and native La/SS-B protein. Japanese annular erythema of Sjögren's syndrome sera and American subacute cutaneous lupus erythematosus sera share several types of anti-52-kd and anti-60-kd Ro autoantibodies. However, these antibodies were found significantly more often and in significantly higher titers in sera from patients with Sjögren's syndrome who did not manifest these skin diseases. Patients with high Ro autoantibody titers were likely to have overt exocrine gland dysfunction. The failure to identify disease-specific Ro autoantibodies in subacute cutaneous lupus erythematosus and annular erythema of Sjögren's syndrome sera suggests that additional factors influence the development of these skin diseases. However, similarities in the Ro autoantibody responses and in the clinical features of subacute cutaneous lupus erythematosus and annular erythema of Sjögren's syndrome suggest that these two skin diseases might arise from a similar pathogenic process.


Clinical parameters affecting prediction accuracy of postoperative lung function in non-small cell lung cancer.
Despite significant development in chemotherapy and radiotherapy, surgery is still the cornerstone for curative lung cancer treatment. Accurate prediction of postoperative lung function is mandatory. The goal of this study was to identify important clinical factors affecting prediction accuracy of postoperative lung function for more careful patient selection. The medical records of non-small cell lung cancer patients undergoing pulmonary resection were reviewed. An accuracy index, apo/ppoFEV(1) was defined as the ratio of actual postoperative FEV(1) [apoFEV(1)] to predicted postoperative FEV(1) [ppoFEV(1)]. We used multivariate analysis to inspect the relationship between the accuracy index and seven tentative clinical factors: age, gender, preoperative FEV(1), time interval between operation and the first postoperative FEV(1), bronchodilator response (%), resected lung portion, and the number of resected lung segments. A total of 82 patients were analyzed. Accuracy index of quantitative perfusion lung scan-based prediction was better than that of simple calculation. Multivariate analysis identified the number of resected lung segments and preoperative FEV(1) as the significant clinical factors affecting the accuracy index (P=0.026 and 0.002, respectively). Preoperative FEV(1) and the number of resected lung segments are significant clinical factors affecting prediction accuracy of postoperative lung function.


Effect of liposomal muramyl tripeptide phosphatidylethanolamine and indomethacin on hematopoietic recovery in irradiated mice.
The effects of liposomal muramyl tripeptide phosphatidylethanolamine (MTP-PE/MLV, radioprotective immunomodulator; 10 mg/kg) and indomethacin (INDO, inhibitor of prostaglandin production; 2 mg/kg) on post-irradiation recovery of hematopoietic functions in mice were investigated. Two agents with distinct radioprotective mechanisms were administered alone or in combination 24 h and 3 h before exposure to 7 Gy (60)Co radiation. In the post-irradiation period (3-14 days) combined pre-treatment of mice accelerated recovery of bone marrow cellularity, weight of spleen and myelopoietic and erythropoietic activity in both hematopoietic organs, compared to treatment with MTP-PE/MLV or indomethacin alone. In the peripheral blood, improved radioprotective effects of combined drug administration were found in the recovery of reticulocytes and platelet count. No further significant differences in the recovery of leukocyte count were observed in the examined groups until post-irradiation day 14. Within the first 3-6 post-irradiation days, the bone marrow and peripheral blood smears of mice pre-treated with indomethacin alone or its combination with MTP-PE/MLV more frequently featured blast cells and large cells with abundant cytoplasm which could be considered the hematopoietic stem cells.


Addressing variations: is there hope for the future?
The papers by Robert Berenson and by Steven Lieberman and colleagues show that variations remain a true challenge for those trying to improve the delivery of health care. Recent clarifications in the understanding of unwarranted variations allow us to address variations in a more logical and manageable fashion. In this Perspective we describe key challenges in addressing variations in the context of these recent clarifications. The Centers for Medicare and Medicaid Services (CMS) needs to move forward on information-sharing interventions and use demonstrations to pursue innovative strategies to improve the delivery of care through its purchasing power.


Glimpses of a Cassel Hospital outpatient group.
The following is a selective account of the experience of conducting a weekly out-patient analytic group at the Cassel Hospital, London. Certain features of this experience are highlighted: in particular, the significance and value of a male and female co-therapy pair as conductors. Attention is drawn to the fundamentally reparative potential for damaged individuals in group psychotherapy. Such an experience may be valuable, especially in terms of it facilitating a greater degree of personality integration. Certain suggestions are made as to the prerequisites for such a psychotherapeutic approach. The observations may be useful in the provision of psychotherapy services in the Australian health care system.


Isolation of Murine Spermatogenic Cells using a Violet-Excited Cell-Permeable DNA Binding Dye.
Isolation of meiotic spermatocytes is essential to investigate molecular mechanisms underlying meiosis and spermatogenesis. Although there are established cell isolation protocols using Hoechst 33342 staining in combination with fluorescence-activated cell sorting, it requires cell sorters equipped with an ultraviolet laser. Here we describe a cell isolation protocol using the DyeCycle Violet (DCV) stain, a low cytotoxicity DNA binding dye structurally similar to Hoechst 33342. DCV can be excited by both ultraviolet and violet lasers, which improves the flexibility of equipment choice, including a cell sorter not equipped with an ultraviolet laser. Using this protocol, one can isolate three live-cell subpopulations in meiotic prophase I, including leptotene/zygotene, pachytene, and diplotene spermatocytes, as well as post-meiotic round spermatids. We also describe a protocol to prepare single-cell suspension from mouse testes. Overall, the procedure requires a short time to complete (4-5 hours depending on the number of needed cells), which facilitates many downstream applications.


Phase 1b study of motesanib, an oral angiogenesis inhibitor, in combination with carboplatin/paclitaxel and/or panitumumab for the treatment of advanced non-small cell lung cancer.
Motesanib is a small-molecule antagonist of vascular endothelial growth factor receptor 1, 2, and 3, platelet-derived growth factor receptor, and Kit. This phase 1b study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics, and explored the objective response of motesanib plus carboplatin/paclitaxel and/or the fully human anti-epidermal growth factor receptor monoclonal antibody panitumumab in advanced non-small cell lung cancer (NSCLC). Patients with unresectable NSCLC received sequentially escalating doses of motesanib [50, 125 mg once daily; 75 mg twice daily] orally continuously plus carboplatin/paclitaxel (arm A; first line) or panitumumab (arm B; first and second line) once every 21-day cycle or 125 mg once daily plus carboplatin/paclitaxel and panitumumab (arm C; first line). Forty-five patients received motesanib. Three dose-limiting toxicities occurred: grade 4 pulmonary embolism (n = 1; arm A, 50 mg once daily) and grade 3 deep vein thrombosis (n = 2; arm A, 125 mg once daily; arm C). The MTD was 125 mg once daily. Common motesanib-related adverse events were fatigue (60% of patients), diarrhea (53%), hypertension, (38%), anorexia (27%), and nausea (22%). Three cases of cholecystitis occurred but only in the 75-mg twice-daily schedule, which was subsequently discontinued. At 125 mg once daily, motesanib pharmacokinetics were not markedly changed with carboplatin/paclitaxel coadministration; however, exposure to paclitaxel was moderately increased. The objective response rates were 17%, 0%, and 17% in arms A, B, and C, respectively. Treatment with motesanib was tolerable when combined with carboplatin/paclitaxel and/or panitumumab, with little effect on motesanib pharmacokinetics at the 125-mg once daily dose level. This dose is being investigated in an ongoing phase 3 study in NSCLC.


Germline mutations in retinoma patients: relevance to low-penetrance and low-expressivity molecular basis.
To study phenotype-genotype correlation in patients who have retinoma, which is a benign tumor resembling the post irradiation regression pattern of retinoblastoma (RB). We selected patients who had retinoma and positive family history for RB and patients who had retinoma in one eye and either retinoma or RB in the other eye. The study included 22 patients with available DNA: 18 from 11 families and four sporadic cases. DNA was extracted from peripheral blood leukocytes. The RB1 gene was screened by DHPLC and direct sequencing of the promoter and all the exons. We identified 17 occurrences of 11 distinct germline mutations in two sporadic and in 15 familial cases (nine families). The 11 identified mutations were located in exons 1, 10,11,13,14, and 19 to 23. Four of the identified mutations were not previously reported, including g.64407delT, g.153236A>T, g.156743delTCTG, and g.162078delA. Eight out the 11 mutations were truncating and three were nontruncating (missense). There was no correlation between the type of mutation and the number of tumor foci per eye (RB or retinomas). Highly heterogeneous intrafamilial expressivity was observed. To our knowledge, this study is the largest series of mutations of consecutive retinoma patients. The present data suggest that the type of inherited mutations underlying retinoma is undistinguishable from RB related ones, i.e., largely dominated by truncating mutants. This finding is in contrast with the RB1 genotypic spectrum of mutations associated with low-penetrance RB, i.e., nontruncating mutants. The molecular mechanism underlying low-penetrance and attenuated expressivity (retinomas) appeared to be distinct.


Cp1/cathepsin L is required for autolysosomal clearance in Drosophila.
Macroautophagy/autophagy is a highly conserved lysosomal degradative pathway important for maintaining cellular homeostasis. Much of our current knowledge of autophagy is focused on the initiation steps in this process. Recently, an understanding of later steps, particularly lysosomal fusion leading to autolysosome formation and the subsequent role of lysosomal enzymes in degradation and recycling, is becoming evident. Autophagy can function in both cell survival and cell death, however, the mechanisms that distinguish adaptive/survival autophagy from autophagy-dependent cell death remain to be established. Here, using proteomic analysis of Drosophila larval midguts during degradation, we identify a group of proteins with peptidase activity, suggesting a role in autophagy-dependent cell death. We show that Cp1/cathepsin L-deficient larval midgut cells accumulate aberrant autophagic vesicles due to a block in autophagic flux, yet later stages of midgut degradation are not compromised. The accumulation of large aberrant autolysosomes in the absence of Cp1 appears to be the consequence of decreased degradative capacity as they contain undigested cytoplasmic material, rather than a defect in autophagosome-lysosome fusion. Finally, we find that other cathepsins may also contribute to proper autolysosomal degradation in Drosophila larval midgut cells. Our findings provide evidence that cathepsins play an essential role in the autolysosome to maintain basal autophagy flux by balancing autophagosome production and turnover.Abbreviations: 26-29-p: 26-29kD-proteinase; ADCD: autophagy-dependent cell death; Atg8a: Autophagy-related protein 8a; Cp1/cathepsin L: Cysteine proteinase-1; CtsB: Cathepsin B; cathD: cathepsin D; CtsF: Cathepsin F; GFP: green fluorescent protein; LAMP1: lysosomal-associated membrane protein 1; Mitf: microphthalmia associated transcription factor; PCA: principal component analysis; RNAi: RNA interference; RPF: relative to puparium formation.


Promoting alkali and alkaline-earth metals on MgO for enhancing CO2 capture by first-principles calculations.
Developing next-generation solid sorbents to improve the economy of pre- and post-combustion carbon capture processes has been challenging for many researchers. Magnesium oxide (MgO) is a promising sorbent because of its moderate sorption-desorption temperature and low heat of sorption. However, its low sorption capacity and thermal instability need to be improved. Various metal-promoted MgO sorbents have been experimentally developed to enhance the CO2 sorption capacities. Nevertheless, rigorous computational studies to screen an optimal metal promoter have been limited to date. We conducted first-principles calculations to select metal promoters of MgO sorbents. Five alkali (Li-, Na-, K-, Rb-, and Cs-) and 4 alkaline earth metals (Be-, Ca-, Sr-, and Ba-) were chosen as a set of promoters. Compared with the CO2 adsorption energy on pure MgO, the adsorption energy on the metal-promoted MgO sorbents is higher, except for the Na-promoter, which indicates that metal promotion on MgO is an efficient approach to enhance the sorption capacities. Based on the stabilized binding of promoters on the MgO surface and the regenerability of sorbents, Li, Ca, and Sr were identified as adequate promoters among the 9 metals on the basis of PW91/GGA augmented with DFT+D2. The adsorption energies of CO2 on metal-promoted MgO sorbents for Li, Ca, and Sr atoms are -1.13, -1.68, and -1.48 eV, respectively.


Prospects for useful fission from singlet states higher than S1 in aggregated organic chromophores.
The few known reports and the likely prospects of finding new efficient routes to exciton fission from higher excited singlet states, Sn (n > 1), are reviewed. Aggregates of molecules that have large S2-S1 electronic energy spacings and/or emit measurable "contra-Kasha" emission may offer further opportunities. Among these, electronically excited molecular systems that exhibit known efficient (T1 + T1) triplet-triplet annihilation producing S2 could exhibit efficient singlet fission in aggregates when appropriately substituted to meet the necessary energy requirements. The potential problem of loss of triplet excitons via 2T1 → Tn>1 + S0 triplet-triplet annihilation following (S2 + S0) singlet fission is addressed. Aggregates of substituted azulenes and aliphatic thiones and dithiones are particularly attractive and are discussed in detail.


Polyphosphoinositide hydrolysis in endothelial cells and carotid artery segments. Bradykinin-2 receptor stimulation is calcium-independent.
Bovine aortic and cerebral microvascular endothelial cells and cultured segments of canine common carotid artery possess functional receptors for the nonapeptide bradykinin which mediate a rapid increase in the formation of [3H]inositol 1-phosphate, [3H]inositol 1,4-bisphosphate, and [3H]inositol 1,4,5-trisphosphate from cell membranes containing isotopically labeled myo-inositol. Bradykinin stimulated the formation of [3H]inositol phosphates from cells in culture or tissues at threshold concentrations of 0.1 nM and 1 nM, and with a half-maximal effective concentration of 0.6-1.0 nM and 30 nM, respectively. In cultured cells, the formation of [3H]inositol trisphosphate and [3H]inositol bisphosphate preceded the formation of [3H]inositol monophosphate. Similarly, [3H]inositol phosphate formation was not inhibited by addition of calcium channel blockers, a calcium chelator, or an intracellular calcium antagonist. Calcium ionophore A23187 did not promote [3H]inositol phosphate accumulation. The receptor selectivity of the bradykinin response in cultured cells was most compatible with a type-2 mediated response. Kallidin stimulated with the same potency as bradykinin but was more potent than methionyl-lysyl-bradykinin or des-Arg9-bradykinin. The B1 receptor antagonists des-Arg9-[Leu8]-bradykinin and des-Arg10-[Leu9]-kallidin were without effect. The rapidity of the inositol phosphate response as well as the close correspondence between the bradykinin type-2 receptor mediated hydrolysis of polyphosphoinositides and changes in prostacyclin synthesis, vessel dilation, and permeability suggests that breakdown products of inositol lipids serve as second messengers mediating the effects of bradykinin on the vascular endothelium.


Cytotoxicity, radiosensitization, and chemosensitization of tumor cells by 2-deoxy-D-glucose in vitro.
The glucose analog 2-deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolytic ATP production, is the most widely investigated metabolic inhibitor for targeting glucose metabolism. Besides depleting energy in cells, 2-DG has also been found to alter N-linked glycosylation leading to unfolded protein responses and induce changes in gene expression and phosphorylation status of proteins involved in signaling, cell cycle control, DNA repair, calcium influx, and apoptosis. Inhibition of cell proliferation and induction of apoptosis have been observed as cytotoxic effects in a wide variety of tumor cells in vitro, while sensitization of tumor cells to ionizing radiation and certain chemotherapeutic drugs is associated with enhanced mitotic as well as apoptotic cell death induced by the primary therapeutic agent. Therefore, there has been a considerable amount of interest in developing 2-DG as a therapeutic agent or adjuvant in the radiotherapy and chemotherapy of tumors.


Function of Hsf1 in SV40 T‑antigen‑transformed HEK293T cells.
Heat shock factor 1 (HSF1), a main regulator of the heat shock response in eukaryotes, increases cell survival in numerous pathophysiological conditions. The aim of the present study was to o bserve the function of defective HSF1 expression in HEK293T cells. shRNA of human HSF1 was constructed into the retroviral vector pLTHR generating pLTHR‑shRNA‑HSF1. The shRNA was transiently transfected into HEK293T cells to silence the expression of the HSF1 gene. Cell colony formation, MTT and cell cycle assays were used to analyze the SV40 T‑antigen (Ag)‑transformed cell proliferation rate. Immunoblotting was used to study the protein expression of HSF1, SV40 T‑Ag, p53, p21, heat shock protein 90 (Hsp90), Hsp70 and Hsp25. The results revealed that a deficiency in HSF1 expression inhibited cellular growth. Defective HSF1 upregulated the protein expression of p53, retinoblastoma protein (Rb) and SV40 T‑Ag, and reduced the association between SV40 T‑Ag and p53/Rb, which resulted in growth inhibition of SV40 T‑Ag‑transformed cells. In conclusion, HSF1 is involved in the regulation of SV40 T‑Ag‑induced cell growth and modulates the expression of p53 and Rb proteins.


CRISPR/Cas9-mediated efficient and heritable targeted mutagenesis in tomato plants in the first and later generations.
The CRISPR/Cas9 system has successfully been used in various organisms for precise targeted gene editing. Although it has been demonstrated that CRISPR/Cas9 system can induce mutation in tomato plants, the stability of heredity in later generations and mutant specificity induced by the CRISPR/Cas9 system in tomato plants have not yet been elucidated in detail. In this study, two genes, SlPDS and SlPIF4, were used for testing targeted mutagenesis in tomato plants through an Agrobacterium tumefaciens-mediated transformation method. A high mutation frequency was observed in all tested targets in the T0 transgenic tomato plants, with an average frequency of 83.56%. Clear albino phenotypes were observed for the psd mutants. High frequencies of homozygous and biallelic mutants were detected even in T0 plants. The majority of the detected mutations were 1- to 3-nucleotide deletions, followed by 1-bp insertions. The target mutations in the T0 lines were stably transmitted to the T1 and T2 generations, without new modifications or revision. Off-target activities associated with SlPDS and SlPIF4 were also evaluated by sequencing the putative off-target sites, and no clear off-target events were detected. Our results demonstrate that the CRISPR/Cas9 system is an efficient tool for generating stable and heritable modifications in tomato plants.


Radiological tests in investigations of atypical chest pain.
Atypical chest pain (ACP) is a diagnostic challenge that often requires multiple laboratory and radiological investigations. While radiological procedures may not be the first line of investigation in most cases, they are invaluable when appropriately applied. Physicians need to have a good understanding of the capabilities and limitations of these constantly evolving imaging modalities. This article provides an overview of radiological modalities as they relate to the investigation of ACP. The focus is on radiological procedures that general practitioners may come across when investigating their patients. A brief outline is provided of specialist radiological investigations. The nature of the procedures, their diagnostic yield and appropriateness are addressed. Nonradiological procedures such as coronary angiography, stress tests, ventilation/perfusion scan, resting myocardial perfusion scan, echocardiography and gastroscopies are not discussed. While a thorough history and careful physical examination is paramount, diagnostic imaging is indispensable in patients presenting with ACP. Chest X-ray is almost universally obtained. Other modalities are of value only when appropriately applied.


Accuracy of ultrasonography and magnetic resonance imaging in detecting failure of breast implants filled with silicone gel.
We prospectively studied the accuracy of magnetic resonance imaging (MRI) and ultrasonography (US) for preoperative detection of rupture in 35 single-lumen implants filled with silicone gel in 18 patients. The positive predictive value of US for rupture of an implant was 70% and the negative predictive value 64%. Sensitivity and specificity were 44% and 87%, respectively. Accuracy, defined as the total true positive and true negative values divided by the total number of implants studied was 66%. The positive predictive value of MRI was 100% and the negative predictive value 90%. The corresponding sensitivity and specificity were 88% and 100% and the accuracy 94%. MRI offers significantly better diagnostic sensitivity (p = 0.02) and accuracy (p = 0.004), and should be regarded as the "gold standard" in the evaluation of rupture of breast implants filled with silicone gel. When MRI is not readily available, US is an acceptable alternative.


Effect of radiation therapy on thoracic and lumbar bone marrow: evaluation with MR imaging.
Bone marrow suppression is often the limiting factor in the use of radiation therapy. In order to determine if MR imaging can be used to quantify bone marrow changes, we performed a serial prospective study of patients with lung cancer (six cases) and lymphoma (six cases). Quantitative and qualitative assessments of T1-weighted sagittal images, 750/33 (TR/TE), obtained at 0.6 T before, during, and after radiotherapy showed increased signal intensity in the radiated portions of the spine. These changes appeared as early as 2 weeks after the beginning of radiation, continued to increase until a maximum value was attained, and then persisted during the follow-up period of 2 years. A significantly higher (p less than .04) ratio of pretreatment to maximum posttreatment signal intensity was seen in patients with lymphoma than in those with lung cancer, and pretreatment values in patients with lymphoma were significantly lower (p less than .01). The lower pretreatment values found in the patients with lymphoma may have been due to the smaller amount of yellow marrow in these patients, who were significantly younger (33 vs 62 years). The higher ratio of pre- and posttreatment signal intensity may have been related to the larger amount of hematopoietic marrow available to undergo fatty replacement. The persistence of elevated signal intensity for as long as 2 years after radiation suggests an endpoint in the process of marrow conversion, but not reversal in the form of regeneration of hematopoietic bone marrow. Quantitative MR evaluation of bone marrow may be of considerable value as a noninvasive means of monitoring the effects of radiotherapy.


Development of intrahepatic cholangiocarcinoma at the remnant intrahepatic cyst portion 10 years after resection of type IV choledochal cyst.
Complete resection of Todani type IV choledochal cyst (CC) is not possible, because the intrahepatic portion is not resectable. We present a case of intrahepatic cholangiocarcinoma that arose from the remnant CC portion that was located within the liver 10 years after resection. A 59-year-old female patient had undergone resection of type IV CC 10 years ago, leaving large remnant portions of CC at the liver and pancreas. Two and four years after resection of the extrahepatic CC, cholangitis with intrahepatic stones developed hence these episodes were treated with percutaneous transhepatic cholangioscopy. Ten years after the first operation, intrahepatic stones and a new mass were identified in follow-up imaging studies. Because the mass was identified as adenocarcinoma on biopsy, we performed left hepatectomy with redo hepaticojejunostomy. Pathologic examination showed a 4.5-cm-sized moderately differentiated adenocarcinoma arising from the remnant CC with lymph node metastasis. The patient recovered uneventfully and is currently undergoing adjuvant chemotherapy. Our case indicates that the remnant intrahepatic CC can undergo malignant transformation long after resection of CC. Since the intrahepatic CC portion in type IV CC is usually unresectable, wide hepaticojejunostomy and life-long observation with regular imaging study follow-up are highly recommended for prevention and early detection of malignant transformation.


Scanning laser microscope for biological investigations.
The theory and design of a special purpose scanning laser microscope are described. This microscope, particularly suited for biological investigations, is intended for the observation of objects embedded within transparent or translucent bodies, such as nerve cells in an intact brain. Some photographs made with a prototype are shown.


New Kid on the Block Turns Ten! The Brief, Remarkable History of the National Physicians Alliance.
Founded in 2005 by General Surgeon Lydia J Vaias, MD, MPH, the National Physicians Alliance is a 501c3 public charity with a mission to create research and education programs that promote health and foster active engagement of physicians with their communities to achieve high-quality, affordable health care for all. The National Physicians Alliance offers a professional home to physicians across medical specialties who share a commitment to professional integrity and health justice. As the organization celebrates its tenth birthday, the history and scope of this mission-aligned group is described.


Measurements on images retrieved from holograms.
This paper deals with measurements on images retrieved from holograms when no reference points are on the object and the distance from the holographic recording plane to the object is unknown. For this case, object coordinates formulation was developed and experimentally tested for the cases of stereoscopic and direct measurements in the image plane. Comparing these methods, the direct one was found to be simpler and faster without reducing the accuracy of the results.


Education and disability pension: a stronger association than previously found.
Although the Norwegian Welfare Law includes rigorous medical criteria for granting disability pensions, several non-medical factors have been shown to be associated with and possible causal factors of pensioning. We analysed the relationship between disability pension and detailed information on educational attainment in different diagnostic groups. All ethnic Norwegians aged 18-66 years and alive on 31 December 2003 (n = 2,522,430) were included. Age, sex, the receipt of a disability pension on 31 December 2003, and the diagnosis on the medical certificate were taken from a national social security file. The file also included six levels of education: primary school, low-level secondary school, secondary school, low-level university, university, and research level. We found a dramatic increase in the prevalence of persons granted disability pension with decreasing years of education across all levels of education. The disparities were much stronger than those seen for other health-related parameters and were especially strong for those with musculoskeletal diagnoses. The disability pension is more a consequence of health problems than a proxy for health status. The demonstrated relationship between education and disability pension may be partly explained by exclusion from the work force because of health-related work problems. To facilitate a more inclusive working life, attention should be focused on the work place's capacity to include people with different levels of competence and functioning rather than on the health problems of the employees.


Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing.
HFE and transferrin receptor 2 (TFR2) are membrane proteins integral to mammalian iron homeostasis and associated with human hereditary hemochromatosis. Here we demonstrate that HFE and TFR2 interact in cells, that this interaction is not abrogated by disease-associated mutations of HFE and TFR2, and that TFR2 competes with TFR1 for binding to HFE. We propose a new model for the mechanism of iron status sensing that results in the regulation of iron homeostasis.


Tympanosclerosis and mini grommets: the relevance of grommet design.
Fifty children with otitis media with effusion undergoing grommet insertion had into one ear a Mini-titanium grommet inserted and into the other ear a Mini-teflon grommet. Post-operative follow-up until after extrusion of the grommets demonstrated only a small difference between the extrusion times of the two grommets (a significant difference of 41 days) and no difference in the degree of tympanosclerosis seen with each grommet. We propose that the mass of a grommet appears to play less of a role than has previously been suggested in the pathogenesis of tympanosclerosis following grommet insertion and that duration of intubation may be the most significant factor.


Association of the gonadotrophin-regulated testicular RNA helicase gene polymorphism with human male infertility.
Gonadotrophin-regulated testicular RNA helicase (GRTH) plays an important role in RNA functions including nuclear transcription, pre-mRNA splicing and it regulates the translation of specific genes required for the progression of spermatogenesis. In this study, we analysed the association of GRTH gene IVS6+55G/T and c.852C/T polymorphisms with human male infertility. The study showed c.852 T allele was associated with an increased risk of male infertility (OR: 3.16, P = 0.008), whereas IVS6+55G/T allele conferred no risk. In Indian population, this is the first report on association of GRTH gene SNP polymorphism and male infertility and it underscores the significance of GRTH genotypes in modulating the risk of male infertility.


Generation and functional analysis of monoclonal antibodies against the second extracellular loop of human M3 muscarinic acetylcholine receptor.
The M3 muscarinic acetylcholine receptor (M3R) plays a crucial role in the activation of salivary and lachrymal glands. The M3R contains four extracellular domains (the N-terminal, and the first, second, and third extracellular loops), and we recently detected antibodies against each of these four domains in a subgroup of patients with Sjögren's syndrome (SS). Functional analysis indicated that the influence of such anti-M3R antibodies on salivary secretion might differ based on the epitopes to which they bind. To clarify the relationship between B-cell epitopes on the M3R and its function, we generated two hybridomas producing anti-M3R monoclonal antibodies against the second extracellular loop of M3R (anti-M3R(2nd) mAbs) and analyzed their function by Ca(2+)-influx assays, using a human salivary gland (HSG) cell line. These two anti-M3R(2nd) mAbs suppressed Ca(2+)-influx in the HSG cells induced by cevimeline stimulation, suggesting that autoantibodies against the second extracellular loop of M3R could be involved in salivary dysfunction in patients with SS.


The Organizer and Its Signaling in Embryonic Development.
Germ layer specification and axis formation are crucial events in embryonic development. The Spemann organizer regulates the early developmental processes by multiple regulatory mechanisms. This review focuses on the responsive signaling in organizer formation and how the organizer orchestrates the germ layer specification in vertebrates. Accumulated evidence indicates that the organizer influences embryonic development by dual signaling. Two parallel processes, the migration of the organizer's cells, followed by the transcriptional activation/deactivation of target genes, and the diffusion of secreting molecules, collectively direct the early development. Finally, we take an in-depth look at active signaling that originates from the organizer and involves germ layer specification and patterning.


A High Prevalence of Anti-EBNA1 Heteroantibodies in Systemic Lupus Erythematosus (SLE) Supports Anti-EBNA1 as an Origin for SLE Autoantibodies.
That Epstein-Barr virus (EBV) infection is associated with systemic lupus erythematosus (SLE) is established. The challenge is to explain mechanistic roles EBV has in SLE pathogenesis. Previous studies identify four examples of autoantibody cross-reactions between SLE autoantigens and Epstein-Barr nuclear antigen 1 (EBNA1). For two of these examples, the earliest detected autoantibody specifically cross-reacts with EBNA1; thereby, defined EBNA1 epitopes induce a robust autoantibody response in animals. These results suggest that the autoantibodies initiating the process leading to SLE may emerge from the anti-EBNA1 heteroimmune response. If this hypothesis is true, then anti-EBNA1 responses would be more frequent in EBV-infected SLE patients than in EBV-infected controls. We tested this prediction. We evaluated published East Asian data by selecting those with a positive anti-viral capsid antigen (VCA) antibody immunoglobulin G (IgG) test and determining whether anti-EBNA1 was more common among the EBV-infected SLE cases than among matched EBV-infected controls with conditional logistic regression analysis. All the qualifying SLE patients (100%) in this dataset were EBV-infected compared to age- and sex-matched controls (92.2%) [odds ratio (OR) = 28.6, 95% CI 6.4-∞, p = 8.83 × 10-8], confirming the known close association of EBV infection with SLE. Furthermore, virtually all the SLE cases have both anti-VCA IgG and anti-EBNA1 IgG antibodies [124 of 125 (99.2%)], which are more frequently present than in age- and sex-matched EBV-infected controls [232 of 250 (93.2%)] (OR = 9.7, 95% CI 1.5-414, p = 0.0078) for an 89.7% SLE attributable risk from anti-EBNA1, which is in addition to the 100% SLE risk attributable to EBV infection in these data. The association of EBV infection with SLE is reconfirmed. The prediction that anti-EBNA1 is more frequent in these SLE cases than in EBV-infected controls is true, consistent with the hypothesis that anti-EBNA1 contributes to SLE. This second EBV-dependent risk factor is consistent with a molecular mimicry model for the generation of SLE, starting with EBV infection, progressing to anti-EBNA1 response; then molecular mimicry leads to anti-EBNA1 antibodies cross-reacting with an SLE autoantigen, causing autoantibody epitope spreading, and culminating in clinical SLE. These results support the anti-EBNA1 heteroimmune response being a foundation from which pathogenic SLE autoimmunity emerges.


X-Ray absorption spectroscopy of H3O.
We report the X-ray absorption of isolated H3O+ cations at the O 1s edge. The molecular ions were prepared in a flowing afterglow ion source which was designed for the production of small water clusters, protonated water clusters, and hydrated ions. Isolated H2O+ cations have been analyzed for comparison. The spectra show significant differences in resonance energies and widths compared to neutral H2O with resonances shifting to higher energies by as much as 10 eV and resonance widths increasing by as much as a factor of 5. The experimental results are supported by time-dependent density functional theory calculations performed for both molecular cations, showing a good agreement with the experimental data. The spectra reported here could enable the identification of the individual molecules in charged small water clusters or liquid water using X-ray absorption spectroscopy.


Spatial and temporal variations of halogenated flame retardants and organophosphate esters in landfill air: Potential linkages with gull exposure.
Landfills represent important sources of local emissions of organic contaminants, including halogenated (HFR) and organophosphate ester (OPE) flame retardants used in a large variety of consumer products. Gulls foraging in landfills may be exposed to elevated atmospheric concentrations of HFRs and OPEs that may vary spatially and temporally within a landfill site, thus modulating their exposure. The objective of the present study was to investigate the spatial and temporal variability of HFR and OPE concentrations in air samples collected from a major landfill in the Montreal area (QC, Canada) that is frequently visited by gulls for foraging. Miniature stationary passive air samplers (PASs) and high-volume active air samplers (AASs) were deployed in six different areas within this landfill site for 34 days to collect HFRs and OPEs in air. During the same period, wild-caught ring-billed gulls (Larus delawarensis) were equipped on their back with a similar miniature PAS that was deployed in the landfill along with a GPS datalogger to monitor their movements for ten days. Elevated concentrations of certain OPEs (e.g., tris(2-chloroethyl) phosphate and tris(2-chloroisopropyl) phosphate) and brominated diphenyl ether (BDE)-209 were measured in stationary PASs and AASs, although they were homogenously distributed within this landfill site. Temporal variability was observed for concentrations of BDE-209, -99 and -47 measured in AASs as well as tributyl phosphate during the 34-day deployment period. Moreover, air concentrations of BDE-209, -207 and -206 and selected OPEs (tris(1,3-dichloro-2-propyl) phosphate and tris(methylphenyl) phosphate) determined using AASs were positively correlated with ambient air temperatures. Gulls that visited a landfill at least once exhibited significantly greater concentrations of BDE-47 measured in PASs they carried on their back, suggesting that landfill air may represent a source of exposure to PBDEs for these birds, and potentially other urban-adapted wildlife using these sites for foraging.