The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy.
Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease, though severe forms are rare. Management of GO is often suboptimal, largely because available treatments do not target pathogenic mechanisms of the disease. Treatment should rely on a thorough assessment of the activity and severity of GO and its impact on the patient's quality of life. Local measures (artificial tears, ointments and dark glasses) and control of risk factors for progression (smoking and thyroid dysfunction) are recommended for all patients. In mild GO, a watchful strategy is usually sufficient, but a 6-month course of selenium supplementation is effective in improving mild manifestations and preventing progression to more severe forms. High-dose glucocorticoids (GCs), preferably via the intravenous route, are the first line of treatment for moderate-to-severe and active GO. The optimal cumulative dose appears to be 4.5-5 g of methylprednisolone, but higher doses (up to 8 g) can be used for more severe forms. Shared decision-making is recommended for selecting second-line treatments, including a second course of intravenous GCs, oral GCs combined with orbital radiotherapy or cyclosporine, rituximab or watchful waiting. Rehabilitative treatment (orbital decompression surgery, squint surgery or eyelid surgery) is needed in the majority of patients when GO has been conservatively managed and inactivated by immunosuppressive treatment.


Immunohistochemical evaluation of seven monoclonal antibodies for differentiation of pleural mesothelioma from lung adenocarcinoma.
A panel of seven monoclonal antibodies including anti-vimentin, anti-keratin markers AE1/AE3 and EAB902, human milk fat globule (HMFG-2), B72.3, anti-carcinoembryonic antigen (CEA), and anti-Leu-M1 were used for an immunoperoxidase staining assay to determine their value in the differentiation of pleural mesothelioma from lung adenocarcinoma. Anti-vimentin positively identified 86% of the mesotheliomas and none of the adenocarcinomas. AE1/AE3, EAB902, and B72.3 reacted with a high percentage of both mesothelioma and adenocarcinoma specimens. With HMFG-2, both membrane and cytoplasmic staining was observed in 92% of the adenocarcinomas and in 14% of the mesotheliomas, whereas 26% of the mesotheliomas only exhibited membrane staining. Eighty percent of the adenocarcinomas and 8% of the mesothelioma tissues stained with anti-Leu-M1. Anti-CEA did not react with any of the 50 mesotheliomas tested but did react with 95% of the lung adenocarcinomas tested. From this study, it was concluded that anti-CEA and anti-Leu-M1 were the most effective of the seven tumor markers evaluated; and that 100% of the pleural mesothelioma tissues could be correctly differentiated from lung adenocarcinomas using a panel consisting of anti-vimentin, HMFG-2, anti-CEA and anti-Leu-M1 monoclonal antibodies.


Machine learning for effectively avoiding overfitting is a crucial strategy for the genetic prediction of polygenic psychiatric phenotypes.
The accuracy of previous genetic studies in predicting polygenic psychiatric phenotypes has been limited mainly due to the limited power in distinguishing truly susceptible variants from null variants and the resulting overfitting. A novel prediction algorithm, Smooth-Threshold Multivariate Genetic Prediction (STMGP), was applied to improve the genome-based prediction of psychiatric phenotypes by decreasing overfitting through selecting variants and building a penalized regression model. Prediction models were trained using a cohort of 3685 subjects in Miyagi prefecture and validated with an independently recruited cohort of 3048 subjects in Iwate prefecture in Japan. Genotyping was performed using HumanOmniExpressExome BeadChip Arrays. We used the target phenotype of depressive symptoms and simulated phenotypes with varying complexity and various effect-size distributions of risk alleles. The prediction accuracy and the degree of overfitting of STMGP were compared with those of state-of-the-art models (polygenic risk scores, genomic best linear-unbiased prediction, summary-data-based best linear-unbiased prediction, BayesR, and ridge regression). In the prediction of depressive symptoms, compared with the other models, STMGP showed the highest prediction accuracy with the lowest degree of overfitting, although there was no significant difference in prediction accuracy. Simulation studies suggested that STMGP has a better prediction accuracy for moderately polygenic phenotypes. Our investigations suggest the potential usefulness of STMGP for predicting polygenic psychiatric conditions while avoiding overfitting.


Baculovirus late and very late gene regulation.
Baculoviruses have adapted novel tactics to transcribe their genes during the late stages of replication. These include a DNA-directed RNA polymerase which is evolutionarily divergent from cellular polymerases. The viral RNA polymerase is a multisubunit and multifunctional RNA polymerase that has the ability to recognize late promoters, transcribe the linked genes, and process the transcripts at both 5' and 3' ends. The viral RNA polymerase binds to late viral gene promoter elements that are compact and differ from early viral gene and cellular promoters. Baculoviruses also encode a number of proteins devoted to the synthesis of late transcripts. Many of these are highly conserved among all the baculovirus genomes sequenced to date, suggesting common transcription mechanisms. Although viral late mRNAs resemble host mRNAs, the transcribing/processing machinery is distinct. Characterization of the late gene transcription apparatus will elucidate new viral mechanisms for transcription.


Poor Outcome of Adult T-Cell Leukemia/Lymphoma with Current Available Therapy: An Experience of Two Centers.
Adult T-cell leukemia lymphoma (ATLL) is an aggressive mature T-cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1) infection. Despite its poor prognosis, there is no standard therapy for ATLL due to its low incidence and the disease affecting only endemic geographical clusters. A retrospective evaluation of patients with the diagnosis of ATLL at Moffitt Cancer Center and Memorial Healthcare System was done to identify patients and disease characteristics along with the progression-free survival (PFS) and overall survival (OS) for the different therapies used. The 61 patients analyzed showed a median age of 58 with 82.5% of them being of African American descent. The acute variant contributed to the majority of cases (43.9%), followed by 36.8% presenting as a lymphoma variant. There was no statistical difference in the PFS (6.4 m, 3.1 m, 2.1 m; p = 0.23) or OS (14 m, 8.9 m, 18.5 m; p = 0.14) between cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), intensive chemotherapy regimens, and other modalities, respectively. However, the patients who had complete or partial remission with first-line therapy had better OS (15.9 m vs. 7.2 m; p = 0.004). The study highlighted the poor outcome of the current regimens and the lack of a unifying protocol for this vicious disease. The acute variants were treated with more intensive regimens, but there was no difference in the OS between the three major options of CHOP, intensified chemotherapy, and others. This underscores the need for more clinical trials to develop better outcomes.


In breast carcinoma tissue, immature dendritic cells reside within the tumor, whereas mature dendritic cells are located in peritumoral areas.
We have analyzed the presence of immature and mature dendritic cells (DCs) within adenocarcinoma of the breast using immunohistochemistry. Immature DCs were defined by expression of CD1a-, Langerin-, and intracellular major histocompatibility complex class II-rich vesicles. Mature DCs were defined by expression of CD83 and DC-Lamp. Breast carcinoma cells were defined by morphology and/or cytokeratin expression. We demonstrate two levels of heterogeneity of DCs infiltrating breast carcinoma tissue: (a) immature CD1a(+) DCs, mostly of the Langerhans cell type (Langerin(+)), were retained within the tumor bed in 32/32 samples and (b) mature DCs, CD83(+)DC-Lamp(+), present in 20/32 samples, are confined to peritumoral areas. The high numbers of immature DCs found in the tumor may be best explained by high levels of macrophage inflammatory protein 3alpha expression by virtually all tumor cells. Confirming the immature/mature DC compartmentalization pattern, in vitro-generated immature DCs adhere to the tumor cells, whereas mature DCs adhere selectively to peritumoral areas. In some cases, T cells are clustering around the mature DCs in peritumoral areas, thus resembling the DC-T cell clusters of secondary lymphoid organs, which are characteristic of ongoing immune reactions.


Maturation of exported proteins in Escherichia coli. Requirement for energy, site and kinetics of processing.
Precursor forms of periplasmic and outer membrane proteins were accumulated in phenethyl-alcohol-treated cells in membrane fractions. After removal of phenethyl alcohol, maturation occurred in the absence but not in the presence of carbonylcyanide m-chlorophenylhydrazone (30 microM). The site and kinetics of processing were investigated for OmpA, LamB and OmpF proteins and for maltose binding protein and TEM beta-lactamase. With regard to sites of processing, no fundamental difference between outer membrane and periplasmic proteins was observed. For maltose binding protein and TEM beta-lactamase, maturation, like that of outer membrane protein precursors, occurred in membrane fractions. Processing of pro-OmpA protein was about as fast as that of pro-LamB protein whereas pro-OmpF protein appeared to mature more slowly. While carbonylcyanide m-chlorophenylhydrazone (30 microM) prevented processing of all precursor forms, arsenate, which alters formation of ATP even when it was used at 1 mM, did not totally prevent maturation occurring. These results are discussed with regard to the biosynthesis and assembly of exported proteins.


InsP3R-RyR Ca2+ channel crosstalk facilitates arrhythmias in the failing human ventricle.
Dysregulated intracellular Ca2+ handling involving altered Ca2+ release from intracellular stores via RyR channels underlies both arrhythmias and reduced function in heart failure (HF). Mechanisms linking RyR dysregulation and disease are not fully established. Studies in animals support a role for InsP3 receptor Ca2+ channels (InsP3R) in pathological alterations in cardiomyocyte Ca2+ handling but whether these findings translate to the divergent physiology of human cardiomyocytes during heart failure is not determined. Using electrophysiological and Ca2+ recordings in human ventricular cardiomyocytes, we uncovered that Ca2+ release via InsP3Rs facilitated Ca2+ release from RyR and induced arrhythmogenic delayed after depolarisations and action potentials. InsP3R-RyR crosstalk was particularly increased in HF at RyR clusters isolated from the T-tubular network. Reduced SERCA activity in HF further facilitated the action of InsP3. Nanoscale imaging revealed co-localisation of InsP3Rs with RyRs in the dyad, which was increased in HF, providing a mechanism for augmented Ca2+ channel crosstalk. Notably, arrhythmogenic activity dependent on InsP3Rs was increased in tissue wedges from failing hearts perfused with AngII to promote InsP3 generation. These data indicate a central role for InsP3R-RyR Ca2+ signalling crosstalk in the pro-arrhythmic action of GPCR agonists elevated in HF and the potential for their therapeutic targeting.


Zingiberene attenuates hydrogen peroxide-induced toxicity in neuronal cells.
In this experimental design, we explored the neuroprotective potential of zingiberene (ZGB), a monocyclic sesquiterpene, in hydrogen peroxide (H2O2)-induced toxicity in newborn rat cerebral cortex cell cultures for the first time. The rats were exposed to H2O2 for 6 h to determine the oxidative stress levels. To evaluate cell viability, both 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assays were carried out. Total antioxidant capacity (TAC) and total oxidative stress (TOS) parameters were used to evaluate oxidative changes. Besides determining 8-hydroxy-2-deoxyguanosine (8-OH-dG) levels in vitro, single-cell gel electrophoresis was also performed to measure the resistance of neuronal DNA to H2O2- exposed rats. Our results showed that survival and TAC levels of the cells decreased, while TOS, 8-OH-dG levels and the mean values of the total scores of cells showing DNA damage increased in the H2O2 alone-treated cultures. But pretreatment of ZGB suppressed the cytotoxicity, genotoxicity and oxidative stress that were increased by H2O2. Based on these observations, it is suggested that the sesquiterpene ZGB can be used as a novel and natural potential therapeutic in counteracting oxidative damages in the field of neurodegenerative disorders.


Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants.
Many lifespan-modulating genes are involved in either generation of oxidative substrates and end-products, or their detoxification and removal. Among such metabolites, only lipoperoxides have the ability to produce free-radical chain reactions. For this study, fatty-acid profiles were compared across a panel of C. elegans mutants that span a tenfold range of longevities in a uniform genetic background. Two lipid structural properties correlated extremely well with lifespan in these worms: fatty-acid chain length and susceptibility to oxidation both decreased sharply in the longest-lived mutants (affecting the insulinlike-signaling pathway). This suggested a functional model in which longevity benefits from a reduction in lipid peroxidation substrates, offset by a coordinate decline in fatty-acid chain length to maintain membrane fluidity. This model was tested by disrupting the underlying steps in lipid biosynthesis, using RNAi knockdown to deplete transcripts of genes involved in fatty-acid metabolism. These interventions produced effects on longevity that were fully consistent with the functions and abundances of their products. Most knockdowns also produced concordant effects on survival of hydrogen peroxide stress, which can trigger lipoperoxide chain reactions.


Acoustic neuroma surgery as an interdisciplinary approach: a neurosurgical series of 508 patients.
To evaluate an interdisciplinary concept (neurosurgery/ear, nose, and throat (ENT)) of treating acoustic neuromas with extrameatal extension via the retromastoidal approach. To analyse whether monitoring both facial nerve EMG and BAEP improved the functional outcome in acoustic neuroma surgery. In a series of 508 patients consecutively operated on over a period of 7 years, functional outcome of the facial nerve was evaluated according to the House/Brackmann scale and hearing preservation was classified using the Gardner/Robertson system. Facial monitoring (396 of 508 operations) and continuous BAEP recording (229 of 399 cases with preserved hearing preoperatively) were performed routinely. With intraoperative monitoring, the rate of excellent/good facial nerve function (House/Brackmann I-II) was 88.7%. Good functional hearing (Gardner/Robertson 1-3) was preserved in 39.8%. Acoustic neuroma surgery via a retrosigmoidal approach is a safe and effective treatment for tumours with extrameatal extension. Functional results can be substantially improved by intraoperative monitoring. The interdisciplinary concept of surgery performed by ENT and neurosurgeons was particularly convincing as each pathoanatomical phase of the operation is performed by a surgeon best acquainted with the regional specialties.


[Impact of waste landfills in the Saratov region on the sanitary condition of the soil].
Monitoring of environment in regions of the location of waste landfills includes the implementation of the control over a sanitary condition of soils. The main origins of the spread ofpollutants into soils are the solid particles from aerosol emissions from the functioning of landfills transmitted to surrounding territories. Within zones of the impact of three largest waste landfills in the Saratov region (Aleksandrovsky, Guselsky in the city of Saratov and Balakovsky in the city of Balakovo) there were taken 152 soil samples. According to results of the estimation in soil concentration of gross and motile forms of heavy metals of the first (Zn, Cd, Ni) and the second danger classes (Cu, Cr, Pb) there was performed the analysis of coefficients of danger- K0 and total coefficients ofpollution - Zc. There was executed the assessment of both a sanitary and hygienic condition of soils and degree of danger ofpollution. The most contrast areal features of the distribution of the danger coefficient - Ko in soils are characteristic for motile forms of heavy metals. For all three studied objects persistently there is stood out the dangerous and areal pollution of soils by association of Ni and Cu . The danger ofpollution of soils by gross forms of heavy metals is minimum. The coefficient of total pollution of Zc exceeds admissible level on motile forms of heavy metals only for the soils surrounding the Balakovo landfill. In zones of the impact of waste landfills there are located the processed lands with an adverse sanitary and hygienic condition of soils. In the region of the Guselsky object soils of the processed agricultural grounds are dangerously polluted by motile forms of Ni and Cu. In vicinities of the Balakovo waste landfill considerable areas of private gardening enterprises are dangerously polluted by the motile forms of Ni, Cu and Zn.


Hand-assisted laparoscopic sigmoid colectomy skills acquisition: augmented reality simulator versus human cadaver training models.
The aim of this study was to compare a simulator with the human cadaver model for hand-assisted laparoscopic colorectal skills acquisition training. An observational prospective comparative study was conducted to compare the laparoscopic surgery training models. The study took place during the laparoscopic colectomy training course performed at the annual scientific meeting of the American Society of Colon and Rectal Surgeons. Thirty four practicing surgeons performed hand-assisted laparoscopic sigmoid colectomy on human cadavers (n = 7) and on an augmented reality simulator (n = 27). Prior laparoscopic colorectal experience was assessed. Trainers and trainees completed independently objective structured assessment forms. Training models were compared by trainees' technical skills scores, events scores, and satisfaction. Prior laparoscopic experience was similar in both surgeon groups. Generic and specific skills scores were similar on both training models. Generic events scores were significantly better on the cadaver model. The 2 most frequent generic events occurring on the simulator were poor hand-eye coordination and inefficient use of retraction. Specific events were scored better on the simulator and reached the significance limit (p = 0.051) for trainers. The specific events occurring on the cadaver were intestinal perforation and left ureter identification difficulties. Overall satisfaction was better for the cadaver than for the simulator model (p = 0.009). With regard to skills scores, the augmented reality simulator had adequate qualities for the hand-assisted laparoscopic colectomy training. Nevertheless, events scores highlighted weaknesses of the anatomical replication on the simulator. Although improvements likely will be required to incorporate the simulator more routinely into the colorectal training, it may be useful in its current form for more junior trainees or those early on their learning curve.


Rubroshiraia gen. nov., a second hypocrellin-producing genus in Shiraiaceae (Pleosporales).
Shiraiaceae is an important family in Pleosporales (Dothideomycetes), which includes medical fungi and plant pathogens. Two hypocrellin-producing taxa, Shiraia bambusicola and a novel genus Rubroshiraia gen. nov., typified by Rubroshiraia bambusae are treated in this article. Maximum likelihood analysis, generated via RAxML (GTR+G model), using a combined SSU, LSU, TEF1 and RPB2 sequence dataset, shows that Rubroshiraia is close to Shiraia and belongs to the family Shiraiaceae. Descriptions, illustrations and a taxonomic key are provided for the genera in Shiraiaceae. Rubroshiraia morphologically differs from Shiraia in having small and dark ascostromata and filiform ascospores. Production of the ascostromatal metabolites, hypocrellin A and B, were examined by HPLC and spectrophotometer. The content of hypocrellin A and B of specimen HKAS 102255 (R. bambusae) is twice that produced by HKAS 102253 (S. bambusicola). To clarify the relationship between R. bambusae and Hypocrella bambusae, type material of the latter was examined and provided the illustration.


Expression and regulation of aquaporins 1, 8, and 9 in the testis, efferent ducts, and epididymis of adult rats and during postnatal development.
Aquaporins (AQPs) are membrane protein channels that allow the rapid passage of water through an epithelium containing tight junctions. In the present study, light microscope immunocytochemistry was utilized to localize several members of the AQP family in the testis, efferent ducts, and epididymis of normal adult animals during postnatal development and after various experimental procedures on adult animals. In the testis of normal adult animals, AQP-8 was expressed exclusively in Sertoli cells, while AQP-9 outlined Leydig cells. In the efferent ducts, AQP-1 was expressed on the microvilli, basolateral plasma membranes, and apical endosomes of the nonciliated cells and cilia of ciliated cells, while AQP-9 was present only on the microvilli of nonciliated cells. In the epididymis, AQP-9 was localized to the microvilli of the principal cells of all regions, with the most intense reaction being noted in the initial segment and cauda regions. The clear cells of the cauda region expressed only AQP-9. AQP-1 was not expressed in the testis or the epididymal epithelium, but it was expressed over the endothelial cells of the vascular channels of the efferent ducts and epididymis. After efferent duct ligation or orchidectomy, there was no change in the expression of AQP-1 or -9 over the microvilli or cilia of epithelial cells in the case of the efferent ducts, suggesting that testicular factors do not regulate their expression in this region. In contrast, AQP-9 expression in the principal cells of the initial segment, but not of other regions, and also in the clear cells of the cauda region was dramatically reduced after both treatments. As the expression was not restored to control levels by testosterone replacement, the data suggest that a luminal factor(s) derived from the testis regulates AQP-9 expression in the principal cells of the initial segment and in the clear cells of the cauda region. Postnatal studies revealed that the expression of AQP-1 and -9 in the different cell types of the efferent ducts and epididymis occurred between days 7 and 29, eliminating sperm and high androgen levels as possible regulating factors. Taken together, these data suggest cell specificity with respect to the expression of AQP-8 and -9 in the testis. In the efferent ducts and epididymis, specificity exists in cell, region, and tissue distribution with respect to the expression of AQP-1 and -9, and their expression does not appear to be regulated by androgens.


Locally recurrent prostate cancer after initial radiation therapy: a comparison of salvage radical prostatectomy versus cryotherapy.
We compared the treatment outcomes of salvage radical prostatectomy and salvage cryotherapy for patients with locally recurrent prostate cancer after initial radiation therapy. We retrospectively reviewed the medical records of patients who underwent salvage radical prostatectomy at the Mayo Clinic between 1990 and 1999, and those who underwent salvage cryotherapy at M. D. Anderson Cancer Center between 1992 and 1995. Eligibility criteria were prostate specific antigen less than 10 ng/ml, post-radiation therapy biopsy showing Gleason score 8 or less and prior radiation therapy alone without pre-salvage or post-salvage hormonal therapy. We assessed the rates of biochemical disease-free survival, disease specific survival and overall survival in each group. Biochemical failure was assessed using the 2 definitions of 1) prostate specific antigen greater than 0.4 ng/ml and 2) 2 increases above the nadir prostate specific antigen. Mean followup was 7.8 years for the salvage radical prostatectomy group and 5.5 years for the salvage cryotherapy group. Compared to salvage cryotherapy, salvage radical prostatectomy resulted in superior biochemical disease-free survival by both definitions of biochemical failure (prostate specific antigen greater than 0.4 ng/ml, salvage cryotherapy 21% vs salvage radical prostatectomy 61% at 5 years, p <0.001; 2 increases above nadir with salvage cryotherapy 42% vs salvage radical prostatectomy 66% at 5 years, p = 0.002) and in superior overall survival (at 5 years salvage cryotherapy 85% vs salvage radical prostatectomy 95%, p = 0.001). There was no significant difference in disease specific survival (at 5 years salvage cryotherapy 96% vs salvage radical prostatectomy 98%, p = 0.283). After adjusting for post-radiation therapy biopsy Gleason sum and pre-salvage treatment serum prostate specific antigen on multivariate analysis salvage radical prostatectomy remained superior to salvage cryotherapy for the end points of any increase in prostate specific antigen greater than 0.4 ng/ml (HR 0.24, p <0.0001), 2 increases in prostate specific antigen (HR 0.47, p = 0.02) and overall survival (HR 0.21, p = 0.01). Young, healthy patients with recurrent prostate cancer after radiation therapy should consider salvage radical prostatectomy as it offers superior biochemical disease-free survival and may potentially offer the best chance of cure.


Donor natural killer cells trigger production of β-2-microglobulin to enhance post-bone marrow transplant immunity.
Allogeneic hematopoietic transplantation is a powerful treatment for hematologic malignancies. Posttransplant immune incompetence exposes patients to disease relapse and infections. We previously demonstrated that donor alloreactive natural killer (NK) cells ablate recipient hematopoietic targets, including leukemia. Here, in murine models, we show that infusion of donor alloreactive NK cells triggers recipient dendritic cells (DCs) to synthesize β-2-microglobulin (B2M) that elicits the release of c-KIT ligand and interleukin-7 that greatly accelerate posttransplant immune reconstitution. An identical chain of events was reproduced by infusing supernatants of alloreactive NK/DC cocultures. Similarly, human alloreactive NK cells triggered human DCs to synthesize B2M that induced interleukin-7 production by thymic epithelial cells and thereby supported thymocyte cellularity in vitro. Chromatography fractionation of murine and human alloreactive NK/DC coculture supernatants identified a protein with molecular weight and isoelectric point of B2M, and mass spectrometry identified amino acid sequences specific of B2M. Anti-B2M antibody depletion of NK/DC coculture supernatants abrogated their immune-rebuilding effect. B2M knock-out mice were unable to undergo accelerated immune reconstitution, but infusion of (wild-type) NK/DC coculture supernatants restored their ability to undergo accelerated immune reconstitution. Similarly, silencing the B2M gene in human DCs, before coculture with alloreactive NK cells, prevented the increase in thymocyte cellularity in vitro. Finally, human recombinant B2M increased thymocyte cellularity in a thymic epithelial cells/thymocyte culture system. Our studies uncover a novel therapeutic principle for treating posttransplant immune incompetence and suggest that, upon its translation to the clinic, patients may benefit from adoptive transfer of large numbers of cytokine-activated, ex vivo-expanded donor alloreactive NK cells.


An Activating STAT3 Mutation Causes Neonatal Diabetes through Premature Induction of Pancreatic Differentiation.
Activating germline mutations in STAT3 were recently identified as a cause of neonatal diabetes mellitus associated with beta-cell autoimmunity. We have investigated the effect of an activating mutation, STAT3K392R, on pancreatic development using induced pluripotent stem cells (iPSCs) derived from a patient with neonatal diabetes and pancreatic hypoplasia. Early pancreatic endoderm differentiated similarly from STAT3K392R and healthy-control cells, but in later stages, NEUROG3 expression was upregulated prematurely in STAT3K392R cells together with insulin (INS) and glucagon (GCG). RNA sequencing (RNA-seq) showed robust NEUROG3 downstream targets upregulation. STAT3 mutation correction with CRISPR/Cas9 reversed completely the disease phenotype. STAT3K392R-activating properties were not explained fully by altered DNA-binding affinity or increased phosphorylation. Instead, reporter assays demonstrated NEUROG3 promoter activation by STAT3 in pancreatic cells. Furthermore, proteomic and immunocytochemical analyses revealed increased nuclear translocation of STAT3K392R. Collectively, our results demonstrate that the STAT3K392R mutation causes premature endocrine differentiation through direct induction of NEUROG3 expression.


Can Malawi's poor afford free tuberculosis services? Patient and household costs associated with a tuberculosis diagnosis in Lilongwe.
To assess the relative costs of accessing a TB diagnosis for the poor and for women in urban Lilongwe, Malawi, a setting where public health services are accessible within 6 kilometers and provided free of charge. Patient and household direct and opportunity costs were assessed from a survey of 179 TB patients, systematically sampled from all public and mission health facilities in Lilongwe. Poverty status was determined from the 1998 Malawi Integrated Household Survey (MIHS). On average, patients spent US$ 13 (MK 996 or 18 days' income) and lost 22 days from work while accessing a TB diagnosis. For non-poor patients, the total costs amounted to 129% of total monthly income, or 184% after food expenditures. For the poor, this cost rose to 248% of monthly income or 574% after food. When a woman or when the poor are sick, the opportunity costs faced by their households are greater. Patient and household costs of TB diagnosis are prohibitively high even where services are provided free of charge. In scaling up TB services to reach the Millennium Development Goals, there is an urgent need to identify strategies for diagnosing TB that are cost-effective for the poor and their households.


Clinical impact of tumor-infiltrating lymphocytes for survival in curatively resected stage IV colon cancer with isolated liver or lung metastasis.
The most reliable prognostic factor to date is tumor, node, metastasis stage. However, prognostic significance of tumor-infiltrating lymphocytes (TILs) in curatively resected stage IV colon cancer with isolated liver or lung lesion has not been clarified. The aim of this study was to assess and compare the prognostic role of TILs in curatively resected stage IV colon cancers. Immunohistochemistry was used to assess the densities of CD8(+), CD45RO(+), and FOXP3(+) according to tumor sites (primary tumor, liver, and lung) from 79 stage IV colon cancers. These were evaluated for association with histopathologic features and patients' overall survival (OS). Higher density of CD45RO(+) at primary and metastatic sites was associated with better patient outcomes (P = 0.009 and 0.027, respectively). The estimated 3-year OS rates for high-density CD45RO(+) at metastatic and primary sites was 82.6 and 62.4 %, respectively, compared to 60.8 and 27.1 % in low-density CD45RO(+). In multivariate analysis, CD45RO(+) at the colon primary site (P = 0.007; relative risk 0.108; 95 % confidence interval 0.021-0.546) was the strongest prognostic factor. High density of CD45RO(+) TILs showed independent prognostic significance for OS. This result may help to improve the prognostication of curatively resected stage IV colon cancer.


Acute chest pain syndrome during bleomycin infusions.
The authors describe 12 episodes of severe chest pain suggesting acute cardiac or pulmonary events which occurred during infusions of bleomycin. The incidence of the syndrome was low, occurring in 2.8% of those receiving the drug. Typically, the chest pain was sudden in onset and described either as substernal pressure or pleuritic in character. Few associated symptoms were noted. Evaluations for the etiology of the pain were unrevealing except for electrocardiographic changes suggestive of pericarditis in two cases and radiographic evidence of a small pleural effusion in one. The syndrome was self-limited or relieved with analgesics. There were no long-term cardiac or pulmonary sequelae. Discontinuation of bleomycin was not necessary although improvement was seen when the infusions were stopped. Further courses of bleomycin did not lead to recurrent episodes in most patients and are not contraindicated. Chest pain during continuous bleomycin infusion should suggest the possibility of a drug effect.


Source apportionment of population representative samples of PM(2.5) in three European cities using structural equation modelling.
Apportionment of urban particulate matter (PM) to sources is central for air quality management and efficient reduction of the substantial public health risks associated with fine particles (PM(2.5)). Traffic is an important source combustion particles, but also a significant source of resuspended particles that chemically resemble Earth's crust and that are not affected by development of cleaner motor technologies. A substantial fraction of urban ambient PM originates from long-range transport outside the immediate urban environment including secondary particles formed from gaseous emissions of mainly sulphur, nitrogen oxides and ammonia. Most source apportionment studies are based on small number of fixed monitoring sites and capture well population exposures to regional and long-range transported particles. However, concentrations from local sources are very unevenly distributed and the results from such studies are therefore poorly representative of the actual exposures. The current study uses PM(2.5) data observed at population based random sampled residential locations in Athens, Basle and Helsinki with 17 elemental constituents, selected VOCs (xylenes, trimethylbenzenes, nonane and benzene) and light absorbance (black smoke). The major sources identified across the three cities included crustal, salt, long-range transported inorganic and traffic sources. Traffic was associated separately with source categories with crustal (especially Athens and Helsinki) and long-range transported chemical composition (all cities). Remarkably high fractions of the variability of elemental (R(2)>0.6 except for Ca in Basle 0.38) and chemical concentrations (R(2)>0.5 except benzene in Basle 0.22 and nonane in Athens 0.39) are explained by the source factors of an SEM model. The RAINS model that is currently used as the main tool in developing European air quality management policies seems to capture the local urban fraction (the city delta term) quite well, but underestimates crustal particle levels in the three cities of the current study. Utilizing structural equation modelling parallel with traditional principal component analysis (PCA) provides an objective method to determine the number of factors to be retained in a model and allows for formal hypotheses testing.


Use of an autosampler for dynamic headspace extraction of volatile compounds from grains and effect of added water on the extraction.
An autosampler attached to a purge and trap instrument was used to aid routine analyses of grain samples for volatile compounds associated with off-odors. Trapped volatiles were transferred to a gas chromatograph/mass spectrometer instrument for separation and detection. Dynamic extraction of volatiles from approximately 18 g of whole grain at 80 degrees C was accomplished by purging helium through a sample vial with a Teflon-lined septum on each end. The autosampler automatically added internal standard to the sample before purging began, which required the addition of 1 mL of water for complete transfer of the standard to the sample. The added water enhanced extraction of 1-octen-3-ol, 1-octen-3-one, and some other compounds from soybeans but not from starchy grains such as corn and wheat. Addition of a free radical scavenger, such as citric acid, greatly diminished the recovery of 1-octen-3-ol and 1-octen-3-one from soybeans.


Cerebrovascular instability in a subset of patients with stroke and transient ischemic attack.
In six patients, we observed remarkably unsteady blood flow and indications of vasospasms on the arteriolar level in connection with episodes of focal cerebral ischemia. The patients originated from a prospective consecutive study of 53 patients with stroke and transient ischemic attack who had been examined by cerebral angiography and rapidly repeated regional cerebral blood flow measurements using the intracarotid xenon 133 method. In 47 patients, regional cerebral blood flow values, flow patterns, and clinical condition were stable during the repeated regional cerebral blood flow measurements. In six patients, pronounced regional hypoperfusion and hyperperfusion developed during the course of examination. In the hypoperfused regions, flow was transiently reduced to values consistent with ischemia, and in four of these patients this was accompanied by transient neurological deficits. The arteriogram and isotope angiograms ruled out spasms of large arteries or thromboembolism. A condition of cerebrovascular instability on the arteriolar level probably was induced by the examination procedure. These patients were hypersensitive to the provoking stimuli either habitually or as a consequence of previous ischemic accidents. It is suggested that in some patients with focal cerebral ischemia, the primary cause might be spasms of the smallest resistance vessels rather than thromboembolism.


Pretreatment data is highly predictive of liver chemistry signals in clinical trials.
The goal of this retrospective analysis was to assess how well predictive models could determine which patients would develop liver chemistry signals during clinical trials based on their pretreatment (baseline) information. Based on data from 24 late-stage clinical trials, classification models were developed to predict liver chemistry outcomes using baseline information, which included demographics, medical history, concomitant medications, and baseline laboratory results. Predictive models using baseline data predicted which patients would develop liver signals during the trials with average validation accuracy around 80%. Baseline levels of individual liver chemistry tests were most important for predicting their own elevations during the trials. High bilirubin levels at baseline were not uncommon and were associated with a high risk of developing biochemical Hy's law cases. Baseline γ-glutamyltransferase (GGT) level appeared to have some predictive value, but did not increase predictability beyond using established liver chemistry tests. It is possible to predict which patients are at a higher risk of developing liver chemistry signals using pretreatment (baseline) data. Derived knowledge from such predictions may allow proactive and targeted risk management, and the type of analysis described here could help determine whether new biomarkers offer improved performance over established ones.


Clonal origin of inherited medullary thyroid carcinoma and pheochromocytoma.
A black female with inherited medullary thyroid carcinoma and pheochromocytoma was a mosaic for glucose-6-phosphate dehydrogenase types A and B in normal tissues (blood, thyroid, and adrenal gland); both the medullary carcinoma and pheochromocytoma tissue showed a B pattern only. This finding suggests a single clone origin for each of the tumors. Other inherited tumors similarly studied in man have appeared to be multiclonal in origin.


Clinical Efficacy of Photobiomodulation on Dental Implant Osseointegration: A Systematic Review.
Photobiomodulation (PBM) has been shown to have a positive effect on dental implant osseointegration and stability in in vitro and animal studies; however, its usefulness in dental implant clinical practice is yet unclear. The objective was to assess the clinical effectiveness of PBM on dental implants' osseointegration. Two reviewers independently conducted a comprehensive electronic search of articles published from inception up to January 10, 2020, in PubMed, Cochrane Library and Embase databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Randomized clinical trials (RCTs) and nonrandomized clinical studies that compared the effect of PBM on dental implant stability with control groups were included. Animals and in vitro studies studies as well as studies with confounders such as application of orthodontic were excluded. Risk of bias (using Cochrane Risk of Bias tool for RCTs and Risk of Bias in Non-Randomized Studies of Interventions tool for nonrandomized studies) was assessed by both authors. Owing to substantial heterogeneity, only a narrative synthesis of the included studies is presented. Seven relevant clinical studies were included, and they used a variety of PBM parameters and devices. The posterior region of the jaw was found to be more frequently evaluated. For assessing the effect of PBM on implant stability, five studies used resonance frequency analysis and two used periotest; three studies additionally used biomarkers for assessment. Four studies found that PBM has a potential positive effect on the outcome of dental implant stability, whereas three studies reported that PBM has no effect on implant stability. The findings of this systematic review suggest that postoperative application of PBM may potentially have some positive effect on dental implant's osseointegration and stability. However, additional studies are required with uniformity in methods to provide a more robust assessment of this effect.


Thermal Injury-induced Hepatic Parenchymal Hypoperfusion: Risk of Hepatocellular Carcinoma Recurrence after Radiofrequency Ablation.
Purpose To retrospectively evaluate whether thermal injury-induced hepatic parenchymal hypoperfusion can be a significant risk factor for tumor recurrence after radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). Materials and Methods The institutional review board approved this retrospective study, and the requirement to obtain informed consent was waived. The study population comprised 130 patients (87 men, 43 women; mean age, 61.4 years ± 8.95; age range, 39-84 years) with single nodular HCCs smaller than 5 cm who underwent RFA between January 2011 and December 2012. The development of RFA-induced hepatic parenchymal hypoperfusion was assessed with follow-up computed tomography (CT). After a mean follow-up of 36.7 months ± 10.8, the authors analyzed the overall and recurrence-free survival and the cumulative incidence of each type of recurrence (ie, local tumor progression [LTP], intrahepatic distant recurrence [IDR], and extrahepatic metastasis) by evaluating prognostic factors with use of the Kaplan-Meier method and Cox proportional hazard regression model. Results RFA-induced hepatic parenchymal hypoperfusion developed in 41 of the 130 patients (31.5%) but did not have a significant effect on overall survival (P = .634). However, the estimated 3-year recurrence-free survival rate was 43.3% in the 41 patients with RFA-induced hepatic parenchymal hypoxia and 61.9% in the 89 patients without hypoxia, a statistically significant difference (P = .019). The 3-year cumulative incidence of IDR was significantly higher in patients with RFA-induced hepatic parenchymal hypoperfusion than in those without hypoxia (33.3% vs 54.1%, P = .006). Conversely, the 3-year cumulative incidence of LTP and extrahepatic metastases showed no significant differences (P > .05 for both). Conclusion The development of RFA-induced hepatic parenchymal hypoperfusion is a significant predictive factor of recurrence (of IDR in particular) after RFA of a single nodular HCC. © RSNA, 2016 Online supplemental material is available for this article.


Helicobacter pylori and the liver: any relationship?
Helicobacter pylori infection is being correlated to a number of human diseases, among which also those of the liver. From a clinical point of view, 4 "areas of interest" for the suggested correlation can be identified: 1. Helicobacter pylori and portal hypertension-related congestive gastropathy in cirrhotics. There are, in the literature, at least 7 studies confirming that the microorganism has no role in causing or worsening the disease. 2. Helicobacter pylori and duodenal ulcer in cirrhotic patients. Apparently, in the cirrhotic patient, the microorganism has no role in causing duodenal ulcer. 3. Helicobacter pylori, ammonia production and hepatic encephalopathy. In this case, there are at least three studies showing that Helicobacter pylori infection increases the risk of developing encephalopathy in the cirrhotic patient, this being a somewhat expected finding. 4. Helicobacter pylori infection in chronic liver disease and its diagnosis. Evidence in the literature suggests: a) that hypertensive gastropathy might not represent a favourable environment for Helicobacter pylori thus making the diagnostic sensitivity of the biopsy lower than expected, and b) that even serological diagnosis might provide data of difficult interpretation, as shown in non alcoholic cirrhosis and, by our own group, in primary biliary cirrhosis. More intriguing are the data generated with respect to the potential capacity of Helicobacter pylori and Helicobacter pylori-like bacteria such as, in particular, Helicobacter hepaticus to damage the liver by producing toxins with a granulating effect on liver cell lines which, in vivo, through the portal tract, might reach the liver, thus causing hepatocellular damage. The point has been addressed by a number of investigators and autoimmune mechanisms have also been suggested. In summary, from the clinical point of view, some evidence suggests that Helicobacter pylori infection might be relevant in the pathogenesis of hepatic encephalopathy in cirrhosis. The data being generated with respect to a direct hepatotoxicity are, at present, stimulating but only speculative.


[Development of the paravascular bed of the vessels of the human heart during the prenatal period of ontogenesis].
The paravascular bed of the cardiac vessels has been studied in 128 human fetuses at the age of 3-9 lunar months. Anatomical and histological techniques have been used, morphometrical analysis has been carried out. The paravascular bed of the cardiac wall vessels begins to form from the vascular epicardial network and from the paraneural vessels in 5-month-old fetuses. The paravasal longitudinal tracts are the first to form (the venous ones preceed the arterial). During the seventh month the nutritive vessels and the intramural networks of the main cardiac arteries and veins develop. The formation of the paraarterial bed is connected with the vascular diameter and with thickness of the arterial walls. Certain regularities in development of the venous paravascular bed are defined. By the beginning of the 8th month there are all main components of the paravascular bed of the cardiac vessels.


[Giant cell arteritis].
Giant cell arteritis (GCA) or temporal arteritis is the most frequent systemic vasculitis in our area, and its incidence may be on the increase in the last years. GCA involves large and medium-sized vessels, with preference to the extracranial arteries, and it affects persons older than 50 years. The aetiopathogenesis is unknown, although several infectious agents may be implicated. A normal temporal artery biopsy do not exclude a GCA since the lesions may be skip. The most feared complications of GCA are permanent visual loss, ischemic strokes and thoracic and abdominal aortic aneurysms. The treatment consists of high-dose corticoids, and nowadays there is no effective therapeutic alternative without important adverse effects. The mortality of treated patients with GCA does not seem to be increased, probably due to a correct diagnosis and management of this entity.


Does more education always lead to better health? Evidence from rural malaysia.
Background. Education is usually associated with improvement in health; there is evidence that this may not be the case if education is not fully utilised at work. This study examines the relationship between education level, occupation, and health outcomes of individuals in rural Malaysia. Results. The study finds that the incidence of chronic diseases and high blood pressure are higher for tertiary educated individuals in agriculture and construction occupations. This brings these individuals into more frequent contact with the health system. These occupations are marked with generally lower levels of education and contain fewer individuals with higher levels of education. Conclusions. Education is not always associated with better health outcomes. In certain occupations, greater education seems related to increased chronic disease and contact with the health system, which is the case for workers in agriculture in rural Malaysia. Agriculture is the largest sector of employment in rural Malaysia but with relatively few educated individuals. For the maintenance and sustainability of productivity in this key rural industry, health monitoring and job enrichment policies should be encouraged by government agencies to be part of the agenda for employers in these sectors.


Coagulation changes associated with the hemolytic uremic syndrome.
The hemolytic uremic syndrome (HUS) is characterized by hemolytic anemia, acute renal failure, and thrombocytopenia. The pathological correlate is thrombotic microangiopathy of glomerular capillaries and arterioles in the kidneys and almost every other organ. The presence of platelet thrombi without extensive soluble coagulation system activation is a constant feature of HUS and thrombotic thrombocytopenic purpura (TTP). Damage to the endothelial cell seems to be a central event in the pathogenesis of HUS and TTP, resulting in loss of fibrinolytic properties and subsequent thrombotic occlusion of the microvasculature. According to earlier and recent studies, a variety of hemostatic alterations have been described. Among the many findings, low platelet counts, increased von Willebrand's factor (vWF), and normal fibrinogen are almost invariably observed. The dubious long-term outcome, even of postdiarrheal HUS, which is believed to have a more favorable prognosis than HUS of other etiopathogenic origin, necessitates further investigation of the pathophysiology of thrombotic microangiopathy and meticulous reevaluation of treatment strategies aimed at interfering with the process of thrombosis early in the disease course. The intention of this article is to highlight findings possibly relevant for disease management and to give an overview of the putative pathomechanisms involved.


[Problems during the recovery of patients following coronary artery bypass surgery: the follow up by nurses in the first month after hospital discharge].
Patients may present problems after coronary artery bypass surgery and nurses play an important role in the detection of such problems. With the purpose to determine the problems of 25 patients during the first month after hospital discharge, they were followed up via telephone as well as when they returned to hospital. Content analyses of detailed nurses' recording revealed eight categories of problems. The most frequently related problems were related to the surgical incision site (76%), pharmacological therapy (28%), other pathologies (24%), mood alterations (20%) and sleep pattern disturbances (16%). The strategy chosen showed to be efficient to analyze the recovery of these patients during the first month after hospital discharge.


Evaluation of the desired sensation level [input/output] algorithm for adults with hearing loss: the acceptable range for amplified conversational speech.
This study had two related purposes: first, to define the range of optimal ear canal levels of aided speech in both high frequency and low frequency regions for adults, using both subjective and objective definitions of optimal; and second, to determine whether a prescribed frequency response, such as that given by Desired Sensation Level [Input/Output], falls within the adult listener's optimal range. Twenty-three adult listeners with mild to moderately severe sensorineural hearing loss were selected from a pool of research volunteers. They were fitted in the laboratory with the Siemens Signia hearing instrument and tested with 20 nominally different frequency responses. All advanced processing options of the hearing instrument were disabled. Subjective ratings of loudness and quality and objective measures of consonant identification were obtained for every frequency response. These adult listeners had, on average, a 10 dB range of measured responses in both the low and the high frequencies that resulted in optimal performance on all the measurements. The range did not vary with degree or configuration of hearing loss, or previous hearing aid experience. Desired-Sensation-Level Input/Output targets were within the optimal range for the low frequencies, and 3 dB above the optimal range for the high frequencies. A range of aided ear canal frequency responses was determined within which adults with mild to moderately severe hearing loss performed optimally on both objective and subjective outcomes. Clinical implications of this finding include the following: prescriptive methods providing different targets may all result in optimal fittings; and a range of targets may be more appropriate than a single target when setting the frequency-gain characteristics of the hearing instrument.


Evaluation of N-Acetylmannosamine Administration to Restore Sialylation in GNE-Deficient Human Embryonal Kidney Cells.
A key mechanism in the neuromuscular disease GNE myopathy (GNEM) is believed to be that point mutations in the GNE gene impair sialic acid synthesis - maybe due to UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) activity restrictions - and resulting in muscle tissue loss. N-acetylmannosamine (ManNAc) is the first product of the bifunctional GNE enzyme and can therefore be regarded as a precursor of sialic acids. This study investigates whether this is also a suitable substance for restoring the sialic acid content in GNE-deficient cells. A HEK-293 GNE-knockout cell line was generated using CRISPR-Cas9 and analyzed for its ability to synthesize sialic acids. The cells were then supplemented with ManNAc to compensate for possible GNE inactivity and thereby restore sialic acid synthesis. Sialic acid levels were monitored by immunoblot and high performance liquid chromatography (HPLC). The HEK-293 GNE-knockout cells showed almost no polysialylation signal (immunoblot) and a reduced overall (-71%) N-acetylneuraminic acid (Neu5Ac) level (HPLC) relative to total protein and normalized to wild type level. Supplementation of GNE-deficient HEK-293 cells with 2 mM ManNAc can restore polysialylation and free intracellular sialic acid levels to wild type levels. The addition of 1 mM ManNAc is sufficient to restore the membrane-bound sialic acid level. Although the mechanism behind this needs further investigation and although it remains unclear why adding ManNAc to GNE-deficient cells is sufficient to elevate polysialylation back to wild type levels - since this substance is also converted by the GNE, all of this might yet prove helpful in the development of an appropriate therapy for GNEM.


Alternatives to vitamin B1 uptake revealed with discovery of riboswitches in multiple marine eukaryotic lineages.
Vitamin B1 (thiamine pyrophosphate, TPP) is essential to all life but scarce in ocean surface waters. In many bacteria and a few eukaryotic groups thiamine biosynthesis genes are controlled by metabolite-sensing mRNA-based gene regulators known as riboswitches. Using available genome sequences and transcriptomes generated from ecologically important marine phytoplankton, we identified 31 new eukaryotic riboswitches. These were found in alveolate, cryptophyte, haptophyte and rhizarian phytoplankton as well as taxa from two lineages previously known to have riboswitches (green algae and stramenopiles). The predicted secondary structures bear hallmarks of TPP-sensing riboswitches. Surprisingly, most of the identified riboswitches are affiliated with genes of unknown function, rather than characterized thiamine biosynthesis genes. Using qPCR and growth experiments involving two prasinophyte algae, we show that expression of these genes increases significantly under vitamin B1-deplete conditions relative to controls. Pathway analyses show that several algae harboring the uncharacterized genes lack one or more enzymes in the known TPP biosynthesis pathway. We demonstrate that one such alga, the major primary producer Emiliania huxleyi, grows on 4-amino-5-hydroxymethyl-2-methylpyrimidine (a thiamine precursor moiety) alone, although long thought dependent on exogenous sources of thiamine. Thus, overall, we have identified riboswitches in major eukaryotic lineages not known to undergo this form of gene regulation. In these phytoplankton groups, riboswitches are often affiliated with widespread thiamine-responsive genes with as yet uncertain roles in TPP pathways. Further, taxa with 'incomplete' TPP biosynthesis pathways do not necessarily require exogenous vitamin B1, making vitamin control of phytoplankton blooms more complex than the current paradigm suggests.


[Diagnosis of sleeping sickness stage: towards a new approach].
Diagnosis of the neurological disease stage in Trypanosoma brucei (T.b.) gambiense infection is essential to select an optimal chemotherapy. The actual parameters for stage determination, the cerebrospinal fluid (CSF) cell count, total protein concentration and trypanosome detection, are insufficiently specific and sensitive. In order to identify new parameters for stage determination, we studied the neuro-inflammatory immune response in the central nervous system, notably the intrathecal humoral immune response in sleeping sickness patients. The presence of intrathecal IgM synthesis was identified as an excellent marker of central nervous system involvement. However, intrathecal IgM detection cannot be performed under field conditions. As a consequence of the strong intrathecal IgM synthesis, extremely high concentrations of IgM are found in the CSF of sleeping sickness. We therefore developed a latex agglutination field test (LATEX/IgM) indicative for intrathecal IgM synthesis and CNS involvement in sleeping sickness. Based on our observations on the intrathecal immune response and with LATEX/IgM, we propose a new approach for stage determination in sleeping sickness.


Clinical influences.
Mark Ylvisaker influenced a paradigm shift on approaches to assessment and intervention of individuals with a traumatic brain injury (TBI). This article describes the influence of Mark Ylvisaker on my speech-language therapy practice in TBI rehabilitation, from shaping assessment research through supporting a practical, problem-solving approach to intervention. In this article, only a small selection of his therapeutic concepts and recommendations are described. The concepts selected-context and meaningfulness, collaboration, and measuring performance-are those that are pertinent to functional communication assessment. The three interventions chosen illustrate the applicability of Mark Ylvisaker's work in different contexts and across different levels of disability following TBI. They are also selected as they promote personally satisfying communication for the client and illustrate the contribution that speech-language therapy may make to TBI rehabilitation overall.


A clinical study of adult human parvovirus B19 infection.
We investigated the clinical aspects of adult human parvovirus (HPV) B19 infection. We retrospectively reviewed the charts of 21 consecutive patients [4 males, aged 32 to 43 years (average 38.0 years), and 17 females, aged 15 to 43 (average 34.2)] with adult HPV B19 infection who visited our outpatient department between July 1997 and June 1998. All diagnoses of adult HPV B19 infection were based on positive anti-HPV B19 IgM antibody in serum and/or positive HPV B19 DNA in peripheral blood. The predominant signs and symptoms of the patients were: fever (81.0%), arthralgia/myalgia (61.9%), skin rash (47.6%), general fatigue (42.9%), lymph node swelling (38.1%) and edema (38.1%). Six patients had the following underlying diseases or complications: pregnancy, myoma uteri, cervical cancer of the uterus, lupus diathesis/ endometriosis, hereditary spherocytosis, and multiple sclerosis. The following abnormal laboratory findings (more or less than normal limits) were observed: anemia (81.0%), leukopenia (33.3%), elevated transaminases (28.6%), and elevated lactate dehydrogenase (LDH) (57.1%). Six patients were considered to have persistent infection. HPV B19 can infect healthy adults and causes more predominant signs and symptoms (arthralgia, myalgia and fever) than in children, and adult HPV B19 infection can be suspected from the familial history and clinical findings. Accordingly, more attention must be paid to adult HPV B19 infection, particularly when erythema infectiosum is prevalent in children.


Determination of climatologically suitable places in Türkiye for feedlot cattle production using the Comprehensive Climate Index model.
The purpose of this study was to determine climatologically suitable places to raise feedlot cattle in Türkiye. The Comprehensive Climate Index (CCI), a model that enables one to quantify beef cattle performance based on environmental conditions (temperature, relative humidity, wind speed, solar radiation) at any time in the year, was used to predict dry matter intake (DMI), average daily gain (ADG), and feed efficiency (FE) of feedlot cattle. Thirty years of daily average temperature, relative humidity, and wind speed values were obtained for 15 cities, namely, Antalya, Balikesir, Çorum, Diyarbakir, Edirne, Elazig, Erzincan, Erzurum, Eskisehir, Isparta, Izmir, Kayseri, Konya, Sivas, and Van. Measured daily solar radiation values were not available and values were calculated based on a formula that takes hemisphere, latitude, and day of the year into account. Since mostly dairy breed calves are placed into a feedlot in Türkiye, the Holstein option in the CCI model was chosen to calculate the maintenance energy requirement. Based on previous feedlot feeding studies conducted in Türkiye, it was assumed that calves would be placed on feed at 250 kg and be marketed at 520 kg, that the diet would have 2600 kcal/kg metabolic energy, and that DMI would be 2.31% of the body weight. Results indicate that cattle raised in Antalya (the hottest place) and Erzurum (the coldest place) had the lowest and highest DMI, respectively (P<0.05). Summer months depressed the DMI of cattle in hotter cities and winter months increased the DMI of cattle in colder cities (P<0.05). Feedlot cattle raised in hotter and colder regions of Türkiye had lower ADG than other places having a more temperate climate (P<0.05). In general, cattle raised in a hotter climate had better FE than those raised in a cold climate (P<0.05).


Use of topological defects as templates to direct assembly of colloidal particles at nematic interfaces.
In this work, we experimentally investigate the ability of topological defects to guide interfacial assembly of spherical particles with homeotropic anchoring confined to nematic interfaces. We propose two different systems: In the first one, particles are trapped at an air/nematic interface where they spontaneously form various 2D patterns. We demonstrate that the phase transition between these patterns can be controlled by defects formed in the nematic bulk. In the second system, we explore the behavior of particles at the surface of bipolar nematic drops. We found that particles assemble into linear chains and interact with surface defects at the North and South poles of the drop, giving rise to the formation of star structures in a self-assembly process. We detail the mechanism that guides the behavior of particles and discuss the role of defects in the formation of the observed patterns.


Has decentralisation affected child immunisation status in Indonesia?
The past two decades have seen many countries, including a number in Southeast Asia, decentralising their health system with the expectation that this reform will improve their citizens' health. However, the consequences of this reform remain largely unknown. This study analyses the effects of fiscal decentralisation on child immunisation status in Indonesia. We used multilevel logistic regression analysis to estimate these effects, and multilevel multiple imputation to manage missing data. The 2011 publication of Indonesia's national socio-economic survey (Susenas) is the source of household data, while the Podes village census survey from the same year provides village-level data. We supplement these with local government fiscal data from the Ministry of Finance. The findings show that decentralising the fiscal allocation of responsibilities to local governments has a lack of association with child immunisation status and the results are robust. The results also suggest that increasing the number of village health centres (posyandu) per 1,000 population improves probability of children to receive full immunisation significantly, while increasing that of hospitals and health centres (puskesmas) has no significant effect. These findings suggest that merely decentralising the health system does not guarantee improvement in a country's immunisation coverage. Any successful decentralisation demands good capacity and capability of local governments.


Predicting vulnerability to acoustic injury with a noninvasive assay of olivocochlear reflex strength.
Permanent noise-induced damage to the inner ear is a major cause of hearing impairment, arising from exposures occurring during both work- and pleasure-related activities. Vulnerability to noise-induced hearing loss is highly variable: some have tough, whereas others have tender ears. This report documents, in an animal model, the efficacy of a simple nontraumatic assay of normal ear function in predicting vulnerability to acoustic injury. The assay measures the strength of a sound-evoked neuronal feedback pathway to the inner ear, the olivocochlear efferents, by examining otoacoustic emissions created by the normal ear, which can be measured with a microphone in the external ear. Reflex strength was inversely correlated with the degree of hearing loss after subsequent noise exposure. These data suggest that one function of the olivocochlear efferent system is to protect the ear from acoustic injury. This assay, or a simple modification of it, could be applied to human populations to screen for individuals most at risk in noisy environments.


The principle of procreative beneficence: old arguments and a new challenge.
In the last ten years, there have been a number of attempts to refute Julian Savulescu's Principle of Procreative Beneficence; a principle which claims that parents have a moral obligation to have the best child that they can possibly have. So far, no arguments against this principle have succeeded at refuting it. This paper tries to explain the shortcomings of some of the more notable arguments against this principle. I attempt to break down the argument for the principle and in doing so, I explain what is needed to properly refute it. This helps me show how and why the arguments of Rebecca Bennett, Sarah Stoller and others fail to refute the principle. Afterwards, I offer a new challenge to the principle. I attack what I understand to be a fundamental premise of the argument, a premise which has been overlooked in the literature written about this principle. I argue that there is no reason to suppose, as Savulescu does, that morality requires us to do what we have most reason to do. If we reject this premise, as I believe we have reason to do, the argument for Procreative Beneficence fails.


Intraocular pressure, specular microscopy, and prostaglandin E2 concentration in dogs with mature and hypermature cataract.
This study aimed to evaluate and correlate intraocular pressure (IOP), endothelial cell density (CD), and hexagonality (HEX), and the aqueous humor prostaglandin E2 (PGE2 ) concentration in dogs with mature (MG, n = 8) and hypermature (HG, n = 8) cataracts. Eight laboratory beagles with no ocular abnormalities were included as a control group (CG). The IOP was measured using a digital applanation tonometer. Noncontact specular microscopy was used to evaluate CD and HEX. Samples of aqueous humor were used to determine prostaglandin E2 concentration using enzyme-linked immunoassay. Data were compared by anova and Bonferroni's multiple comparison test, and possible correlations among the PGE2 aqueous concentration and corneal endothelium cell parameters were assessed by Person's test (P < 0.05). Average values of IOP (P = 0.45) and CD (P = 0.39) were not significantly different between MG, HM, and CG. Average values of HEX were lower, and PGE2 concentration was increased in the MG and HG in comparison with CG (P < 0.05); however, such parameters did not change significantly between MG and HG (P > 0.05). PGE2 values did not correlate with IOP, CD, and HEX in any group (P > 0.05). Although there were a small number of dogs studied, our results demonstrated that cataract progression from mature to hypermature did not have a significant change in PGE2 aqueous concentration, IOP, corneal endothelial cell count, or morphology. In addition, PGE2 concentration was not correlated with parameters of the corneal endothelium or IOP in dogs with mature or hypermature cataracts.


The volatility of stock market prices.
If the volatility of stock market prices is to be understood in terms of the efficient markets hypothesis, then there should be evidence that true investment value changes through time sufficiently to justify the price changes. Three indicators of change in true investment value of the aggregate stock market in the United States from 1871 to 1986 are considered: changes in dividends, in real interest rates, and in a direct measure of intertemporal marginal rates of substitution. Although there are some ambiguities in interpreting the evidence, dividend changes appear to contribute very little toward justifying the observed historical volatility of stock prices. The other indicators contribute some, but still most of the volatility of stock market prices appears unexplained.


Innervation of the cornea of monkeys and the effects of denervation.
Preliminary results of an attempt to determine the sources of nerve fibers of the monkey cornea and the consequences of its denervation are reported. Keratitis neuroparalytica was observed on the second day after combined ophthalmic and maxillary neurectomies. It reached a peak on the third day and by the fifth day recovery was nearly complete without recurrence up to 106 days. Tarsorraphy delayed the development of keratitis neuroparalytica with poor recovery up to 28 days after sensory denervation. Coincidence of reduction and recovery of lacrimal secretion and corneal changes suggest that the former might be a factor in the production of keratitis neuroparalytica. Epithelial changes accompanying keratitis neuroparalytica were observed and described. Numerous stromal nerve fibers remained uanaffected four days after ophthalmic and maxillary neurectomies. There is a possibility that these fibers are from sources other than the trigeminal.


Stress-evoked tyrosine phosphorylation of signal regulatory protein α regulates behavioral immobility in the forced swim test.
Severe stress induces changes in neuronal function that are implicated in stress-related disorders such as depression. The molecular mechanisms underlying the response of the brain to stress remain primarily unknown, however. Signal regulatory protein alpha (SIRPalpha) is an Ig-superfamily protein that undergoes tyrosine phosphorylation and binds the protein tyrosine phosphatase Shp2. Here we show that mice expressing a form of SIRPalpha that lacks most of the cytoplasmic region manifest prolonged immobility (depression-like behavior) in the forced swim (FS) test. FS stress induced marked tyrosine phosphorylation of SIRPalpha in the brain of wild-type mice through activation of Src family kinases. The SIRPalpha ligand CD47 was important for such SIRPalpha phosphorylation, and CD47-deficient mice also manifested prolonged immobility in the FS test. Moreover, FS stress-induced tyrosine phosphorylation of both the NR2B subunit of the NMDA subtype of glutamate receptor and the K+-channel subunit Kvbeta2 was regulated by SIRPalpha. Thus, tyrosine phosphorylation of SIRPalpha is important for regulation of depression-like behavior in the response of the brain to stress.


Likelihood of Bacterial Infection in Patients Treated With Broad-Spectrum IV Antibiotics in the Emergency Department.
Best practice guidelines and quality metrics recommend immediate antibiotic treatment for all patients with suspected sepsis. However, little is known about how many patients given IV antibiotics in the emergency department are ultimately confirmed to have bacterial infection. We performed a retrospective study of adult patients who presented to four Massachusetts emergency departments between June 2015 and June 2018 with suspected serious bacterial infection, defined as blood cultures drawn and broad-spectrum IV antibiotics administered. Structured medical record reviews were performed on a random sample of 300 cases to determine the post hoc likelihood of bacterial infection, categorized as definite, likely, unlikely, or definitely none. None. Among the 300 patients with suspected serious bacterial infections, mean age was 68 years (sd 18), median hospital length of stay was 5 days (interquartile range, 3-8 d), 45 (15%) were admitted directly to ICU, and 14 (5%) died in hospital. Overall, 196 (65%) had definite (n = 115; 38%) or likely (n = 81; 27%) bacterial infection, whereas 104 (35%) were unlikely (n = 55; 18%) or definitely not infected (n = 49; 16%). Antibiotic treatment durations differed by likelihood of infection (median 15 days for definite, 9 for likely, 7 for unlikely, and 3 for definitely not infected). The most frequent post hoc diagnoses in patients with unlikely or definitely no bacterial infection included viral infections (28%), volume overload or cardiac disease (9%), drug effects (9%), and hypovolemia (7%). The likelihoods of infection were similar in the subset of 96 cases in whom emergency department providers explicitly documented possible or suspected sepsis and in the 45 patients admitted from the emergency department to the ICU. One third of patients empirically treated with broad-spectrum antibiotics in the emergency department are ultimately diagnosed with noninfectious or viral conditions. These findings underscore the difficulty diagnosing serious infections in the emergency department and have important implications for guidelines and quality measures that compel immediate empiric antibiotics for all patients with possible sepsis.


Knowledge and beliefs about the use/abuse of oral contraceptive pills among males: A mixed-method explanatory sequential study in community pharmacy settings.
Oral contraceptive pills (OCPs) are considered one of the most important birth control methods globally. However, these pills were designed for female administration rather than males. This study was designed to investigate patterns of OCPs use and abuse among Jordanian males, according to the community pharmacists' observations. A mixed-method explanatory sequential study was conducted using an online self-administered survey, followed by semi-structured in-depth interviews for registered pharmacists, assistant pharmacists and pharmacy interns. The interviews were utilized using a conceptual framework. Inductive thematic analysis and descriptive/regression analyses were completed using Nvivo and SPSS, respectively. A total of 158 questionnaire responses and 22 interviews were included in our analysis. Around half (48.4%) of the questionnaire responses confirmed that males could use OCPs for hair growth enhancement, muscle gain and acne treatment 12.7%, 31.7% and 4.4%, respectively. Through the interviews, the participating pharmacists highlighted that males use OCPs mostly for bodybuilding purposes, according to recommendations by their coaches at the gym. The most abused OCPs containing estrogen (Ethinyl estradiol) and progestins (Drospirenone or Levonorgestrel). This study provided insight into unexpected uses of OCPs by males in Jordan. Community pharmacists have a crucial role in the management of OCPs use and abuse. However, restricted regulations and monitoring must be released and implemented on the community to limit such practices.


Glyphosate residues in rural groundwater, Nottawasaga River Watershed, Ontario, Canada.
The objective of this study was to investigate the occurrence of glyphosate residues (glyphosate and its metabolite AMPA) in shallow groundwater in a catchment dominated by agriculture, and to examine the potential for this groundwater to store and transmit these compounds to surface waters. Glyphosate residues were found in some of the groundwater samples collected in riparian (surface seeps), upland (mostly <20 m below ground) and wetland settings (<3 m below ground). Overall, glyphosate and AMPA were detected in 10.5 and 5.0%, respectively, of the groundwater samples analyzed as part of this study. All concentrations of glyphosate were well below Canadian guidelines for drinking water quality and for protection of aquatic life. Seasonal differences in concentrations in riparian seeps were possibly related to cycles of weather, herbicide application and degradation of glyphosate. Highest concentrations were at upland sites (663 ng L(-1) of glyphosate, 698 ng L(-1) of AMPA), apparently related to localized applications. Most glyphosate detections in wetlands were >0.5 km distant from possible areas of application, and, combined with other factors, suggest an atmospheric transport and deposition delivery mechanism. In both upland and wetland settings, highest glyphosate concentrations were sometimes not at the shallowest depths, indicating influence of hydrological factors. The glyphosate/AMPA detections in riparian seeps demonstrated that these compounds are persistent enough to allow groundwater to store and transmit glyphosate residues to surface waters. Detections in the wetlands support earlier evidence that atmospheric transport and deposition may lead to glyphosate contamination of environments not intended as targets of applications. This interpretation is further supported by detections of both glyphosate and AMPA in precipitation samples collected in the same watershed. © 2016 Her Majesty the Queen in Right of Canada Pest Management Science © 2016 Society of Chemical Industry.


Uptake of methylamine and methanol by Pseudomonas sp. strain AM1.
The uptake of methylamine and of methanol by the facultative methylotroph Pseudomonas sp. strain AM1 was investigated. It was found that this organism possesses two uptake systems for methylamine. One of these operates when methylamine is the sole source of carbon, nitrogen, and energy. It has a Km of 1.33 X 10(-4) M and a Vmax of 67 nmol/min per mg of cells (dry weight). The other system, found when methylamine is the sole nitrogen source only, has a Km of 1.2 X 10(-5) M and a Vmax of 8.9 nmol/min per mg of cells (dry weight). Both uptake systems were severely inhibited by azide, cyanide, carbonyl cyanide-m-chlorophenyl hydrazone, and N-ethylmaleimide, but only the high-affinity system was inhibited by ammonium ions with a Ki of 7.7 mM. Both systems were susceptible to osmotic shock treatment, competitively inhibited by ethylamine, and unaffected by most amino acids. Methanol uptake showed a Km of 4.8 microM and a Vmax of 60.6 nmol/min per mg of cells (dry weight) and was not inhibited by osmotic shock treatment. Azide, cyanide, and N-ethylmaleimide curtailed uptake, but carbonyl cyanide-m-chlorophenyl hydrazone merely reduced the rate of uptake. A methanol dehydrogenase mutant, M15A, was unable to take up methanol. It is proposed that methanol diffuses into the cell where it is rapidly oxidized by methanol dehydrogenase.


An in vitro shear bond strength study of enamel/dentin bonding systems on enamel.
The purpose of this study was to compare the enamel shear bond strengths achieved with four acid conditioners employed by current enamel/dentin bonding systems (maleic acid, citric acid, nitric acid, oxalic acid) with a 37% phosphoric acid etching technique. The study also compared enamel shear bond strengths between the manufacturers' enamel/dentin conditioner used with an unfilled enamel bonding resin. The facial surfaces of 135 bovine incisors were ground flat and divided into nine test groups of n=15. Conditioning and bonding procedures were carried out following manufacturers' instructions. The phosphoric acid groups were etched for 15 seconds, rinsed for 30 seconds, and dried for 20 seconds with compressed air. All bonding was accomplished at a constant temperature of 21 degrees C and a relative humidity of 60%. A single composite restorative resin (Z-100) was used with all specimens to eliminate variables between composite materials. All specimens were thermocycled 2500 times (5 to 45 degrees C) and had a total storage time of 21 days prior to shear testing on an Instron at a crosshead speed of 1.0 mm/minute. Shear strengths were calculated by dividing load at failure by specimen area. A light microscope was used to determine failure mode. The data were subjected to Bartlett's test for homogeneity of variance and were found not to be homogeneous. The Welch Test was applied and indicated that the treatments used had influence on bond strength at P<0.05. There was no significant difference in bond strength values between traditional phosphoric acid/enamel bonding resin and Mirage Bond Dentin and Enamel Adhesive, Clearfil Liner Bond System, and Scotchbond Multi-Purpose Dental Adhesive System.


Contributed Review: Camera-limits for wide-field magnetic resonance imaging with a nitrogen-vacancy spin sensor.
Sensitive, real-time optical magnetometry with nitrogen-vacancy centers in diamond relies on accurate imaging of small (≪10-2), fractional fluorescence changes across the diamond sample. We discuss the limitations on magnetic field sensitivity resulting from the limited number of photoelectrons that a camera can record in a given time. Several types of camera sensors are analyzed, and the smallest measurable magnetic field change is estimated for each type. We show that most common sensors are of a limited use in such applications, while certain highly specific cameras allow achieving nanotesla-level sensitivity in 1 s of a combined exposure. Finally, we demonstrate the results obtained with a lock-in camera that paves the way for real-time, wide-field magnetometry at the nanotesla level and with a micrometer resolution.


Complementary landmarks facilitate ant navigation.
Visual landmarks are important navigational aids to many animals, and when more than one is available their juxtaposition can convey valuable new information to a navigator about progress toward a goal, depending on the landmarks' comparative distinctiveness. We investigated the effect of presenting rock ant colonies (Temnothorax albipennis) with identical horizontal landmarks either side of their route, versus one horizontal landmark paired with a sloping landmark, as they navigated to a new nest site. Our findings suggest that ants can obtain more navigational information from a combination of dissimilar landmarks: the average tortuosity of the route taken between old and new nests was significantly lower when a horizontal landmark was paired with a monotonically downward sloping landmark (the paths were more direct). The impact on available navigational information from the similarity or dissimilarity of nearby landmarks is likely made through more distinctive visual panoramas, and could be an influential factor in individual and collective animal decision-making about which routes are followed. Furthermore, the effect of landmark complementarity may be relevant to a wide range of species, including other insects or birds, and highlights the possibility that there is an intrinsic difference in the informational content of natural vs. artificial environments.


Mutational analysis of FOLR1 and FOLR2 genes in children with Myelomeningocele.
Myelomeningocele (MMC) is a congenital disease. For a long time, molecular mechanism of MMC, the role of folate receptor and transporter proteins remain unclear. Folate from maternal lumen to developing embryo is carried out with the help of folate transporters (SLC46A1, SLC19A1, FOLH1 and SLC25A32) and folate receptor (FOLR1, FOLR2 and FOLR3). Due to the loss of function of these important genes, complications can facilitate the risk of MMC. This study focused on the mutational analysis of FOLR1 and FOLR2 genes in children suffering from MMC. Myelomeningocele is a rare disorder so twenty blood samples from the children were collected. Primers of selected exons for FOLR1 and FOLR2 genes were designed with the help of PrimerFox software. Extracted DNA was amplified, and PCR based mutational analysis was done to check any type of mutation/SNPs in these genes. Sanger sequencing method was performed to confirm mutation in FOLR1 and FOLR2 genes. The results showed that certain environmental factors (smoking, low socio-economic status of mother bearing MMC fetus) were found to be significantly (P<0.05) associated with MMC but no mutation in the selected exons of FOLR1 and FOLR2 genes was detected. Thus, genetic variations in the folate transporter gene may have no role in the progression of MMC in the studied population.


An amino acid mixture enhances insulin-stimulated glucose uptake in isolated rat epitrochlearis muscle.
Protein and certain amino acids (AA) have been found to lower blood glucose. Although these glucose-lowering AA are important modulators of skeletal muscle metabolism, their impact on muscle glucose uptake remains unclear. We therefore examined how an AA mixture consisting of 2 mM isoleucine, 0.012 mM cysteine, 0.006 mM methionine, 0.0016 mM valine, and 0.014 mM leucine impacts skeletal muscle glucose uptake in the absence or presence of a submaximal (sINS) or maximal insulin (mINS) concentration. The AA mixture, sINS, and mINS significantly increased 2-[(3)H]deoxyglucose (2-DG) uptake by 63, 79, and 298% above basal, respectively. When the AA mixture was combined with sINS and mINS, 2-DG uptake was further increased significantly by 26% (P = 0.028) and 14% (P = 0.032), respectively. Western blotting analysis revealed that the AA mixture increased basal and sINS Akt substrate of 160 kDa (AS160) phosphorylation, while AA mixture did not change phosphorylation of Akt or mammalian target of rapamycin (mTOR) under these conditions. Interestingly, addition of the AA mixture to mINS increased phosphorylation of mTOR, Akt as well as AS160, compared with mINS alone. These data suggest that certain AA increase glucose uptake in the absence of insulin and augment insulin-stimulated glucose uptake in an additive manner. Furthermore, these effects appear to be mediated via a pathway that is independent from the canonical insulin cascade and therefore may prove effective as an alternative therapeutic treatment for insulin resistance.


Four-year maintenance treatment with adalimumab in patients with moderately to severely active ulcerative colitis: Data from ULTRA 1, 2, and 3.
The safety and efficacy of adalimumab for patients with moderately to severely active ulcerative colitis (UC) has been reported up to week 52 from the placebo-controlled trials ULTRA (Ulcerative Colitis Long-Term Remission and Maintenance with Adalimumab) 1 and 2. Up to 4 years of data for adalimumab-treated patients from ULTRA 1, 2, and the open-label extension ULTRA 3 are presented. Remission per partial Mayo score, remission per Inflammatory Bowel Disease Questionnaire (IBDQ) score, and mucosal healing rates were assessed in adalimumab-randomized patients from ULTRA 1 and 2 up to week 208. Corticosteroid-free remission was assessed in adalimumab-randomized patients who used corticosteroids at lead-in study baseline. Maintenance of remission per partial Mayo score and mucosal healing was assessed in patients who entered ULTRA 3 in remission per full Mayo score and with mucosal healing, respectively. As observed, last observation carried forward (LOCF) and nonresponder imputation (NRI) were used to report efficacy. Adverse events were reported for any adalimumab-treated patient. A total of 600/1,094 patients enrolled in ULTRA 1 or 2 were randomized to receive adalimumab and included in the intent-to-treat analyses of the studies. Of these, 199 patients remained on adalimumab after 4 years of follow-up. Rates of remission per partial Mayo score, remission per IBDQ score, mucosal healing, and corticosteroid discontinuation at week 208 were 24.7%, 26.3%, 27.7% (NRI), and 59.2% (observed), respectively. Of the patients who were followed up in ULTRA 3 (588/1,094), a total of 360 patients remained on adalimumab 3 years later. Remission per partial Mayo score and mucosal healing after ULTRA 1 or 2 to year 3 of ULTRA 3 were maintained by 63.6% and 59.9% of patients, respectively (NRI). Adverse event rates were stable over time. Remission, mucosal healing, and improved quality of life were maintained in patients with moderately to severely active UC with long-term adalimumab therapy, for up to 4 years. No new safety signals were reported.


Virtual-pinhole PET.
We proposed and tested a novel geometry for PET system design analogous to pinhole SPECT called the virtual-pinhole PET (VP-PET) geometry to determine whether it could provide high-resolution images. We analyzed the effects of photon acolinearity and detector sizes on system resolution and extended the empiric formula for reconstructed image resolution of conventional PET proposed earlier to predict the resolutions of VP-PET. To measure the system resolution of VP-PET, we recorded coincidence events as a (22)Na point source was stepped across the coincidence line of response between 2 detectors made from identical arrays of 12 x 12 lutetium oxyorthosilicate crystals (each measuring 1.51 x 1.51 x 10 mm(3)) separated by 565 mm. To measure reconstructed image resolution, we built 4 VP-PET systems using 4 types of detectors (width, 1.51-6.4 mm) and imaged 4 point sources of (64)Cu (half-life = 12.7 h to allow a long acquisition time). Tangential and radial resolutions were measured and averaged for each source and each system. We then imaged a polystyrene plastic phantom representing a 2.5-cm-thick cross-section of isolated breast volume. The phantom was filled with an aqueous solution of (64)Cu (713 kBq/mL) in which the following were imbedded: 4 spheric tumors ranging from 1.8 to 12.6 mm in inner diameter (ID), 6 micropipettes (0.7- or 1.1-mm ID filled with (64)Cu at 5x, 20x, or 50x background), and a 10.0-mm outer-diameter cold lesion. The shape and measured full width at half maximum of the line spread functions agree well with the predicted values. Measured reconstructed image resolution (2.40-3.24 mm) was +/-6% of the predicted value for 3 of the 4 systems. In one case, the difference was 12.6%, possibly due to underestimation of the block effect from the low-resolution detector. In phantom experiments, all spheric tumors were detected. Small line sources were detected if the activity concentration is at least 20x background. We have developed and characterized a novel geometry for PET. A PET system following the VP-PET geometry provides high-resolution images for objects near the system's high-resolution detectors. This geometry may lead to the development of special-purpose PET systems or resolution-enhancing insert devices for conventional PET scanners.


Comparative effectiveness of antiarrhythmics for out-of-hospital cardiac arrest: A systematic review and network meta-analysis.
Despite their wide use in the prehospital setting, randomized control trials (RCTs) have failed to demonstrate that any antiarrhythmic agent improves survival to hospital discharge following out-of-hospital cardiac arrest. To assess the use of antiarrhythmic drugs for patients experiencing out-of-hospital cardiac arrest (OHCA). Electronic searches of Medline, EMBASE and Cochrane Central Register of Controlled Trials were conducted and reference lists were hand-searched. Randomized controlled trials (RCTs) investigating the use of antiarrhythmic agents administered during resuscitation for adult (≥18years) patients suffering non-traumatic OHCA were included. Direct and indirect evidence were combined in a network meta-analysis (NMA) using a frequentist approach with fixed-effects models and reported as relative risks (RR) with 95% confidence intervals (CIs). For each pairwise comparison, the certainty of direct, indirect, and network evidence was assessed using the GRADE approach. 8 RCTs involving 4464 patients were combined to compare the effectiveness of 5 antiarrhythmic agents and placebo administered during resuscitation following OHCA. Lidocaine was associated with a statistically significant increase in ROSC compared to placebo (1.15; 95% CI: 1.03-1.28) and was also superior to bretylium (1.61; 95% CI: 1.00-2.60) for ROSC. When compared to placebo, both amiodarone (1.18; 95% CI: 1.08-1.30) and lidocaine (1.18; 95% CI: 1.07-1.30) were associated with a statistically significant increase in survival to hospital admission. However, no antiarrhythmic was statistically more effective than placebo for survival to hospital discharge or neurologically intact survival, and no antiarrhythmic was convincingly superior to any other for any outcome. Amiodarone and lidocaine were the only agents associated with improved survival to hospital admission in the NMA. For the outcomes most important to patients, survival to hospital discharge and neurologically intact survival, no antiarrhythmic was convincingly superior to any other or to placebo.


Comparison of healing time of the 2 degree burn wounds with two dressing methods of fundermol herbal ointment and 1% silver sulfadiazine cream.
Burn wounds are one of the health problems in modern societies that are associated with irreparable harms and many side problems for patients and their families. Infection due to burn wounds is the main cause of death in such patients. One of the methods to prevent infection of burn wounds is topical antibiotic ointments. This study aimed to investigate and identify effective ointments to treat burn wounds. For this purpose, the effects of two types of ointment, fundermol and 1% silver sulfadiazine cream on second degree burn wounds were compared. This was a clinical trial study conducted in 2008. Using convenient and continuous sampling method, 50 patients referred to Imam Mousa Kazem Burn Injury Clinic in Isfahan, Iran with 2(nd) degree burn wounds in 1% to 10% surface area were enrolled. The patients were randomly divided into two groups of treatment with fundermol and sulfadiazine and the dressing was changed once a day. The healing time for burn wounds in each patient was recorded in a checklist and data were analyzed by independent t-test via SPSS software. The healing time of burn wounds in the group treated with fundermol was shorter than that in the group treated with sulfadiazine (p < 0.001). The present study showed that fundermol ointment accelerates burn wound healing. Therefore, fundermol can be introduced as a good replacement for current treatments of burn wounds.


The biomechanics of foraging determines face length among kangaroos and their relatives.
Increasing body size is accompanied by facial elongation across a number of mammalian taxa. This trend forms the basis of a proposed evolutionary rule, cranial evolutionary allometry (CREA). However, facial length has also been widely associated with the varying mechanical resistance of foods. Here, we combine geometric morphometrics and computational biomechanical analyses to determine whether evolutionary allometry or feeding ecology have been dominant influences on facial elongation across 16 species of kangaroos and relatives (Macropodiformes). We found no support for an allometric trend. Nor was craniofacial morphology strictly defined by dietary categories, but rather associated with a combination of the mechanical properties of vegetation types and cropping behaviours used to access them. Among species examined here, shorter muzzles coincided with known diets of tough, resistant plant tissues, accessed via active slicing by the anterior dentition. This morphology consistently resulted in increased mechanical efficiency and decreased bone deformation during incisor biting. Longer muzzles, by contrast, aligned with softer foods or feeding behaviours invoking cervical musculature that circumvent the need for hard biting. These findings point to a potential for craniofacial morphology to predict feeding ecology in macropodiforms, which may be useful for species management planning and for inferring palaeoecology.