Taurine increases glucose sensitivity of UCP2-overexpressing beta-cells by ameliorating mitochondrial metabolism.
A low-taurine diet during fetal or early postnatal life causes abnormal pancreatic beta-cell development. Tissue and plasma taurine concentrations can also be low in diabetic patients. We examined the effect of taurine on impaired glucose responses in diabetic rat beta-cells adenovirally overexpressing uncoupling protein (UCP)2, which is upregulated in obesity-related type 2 diabetes. We found that taurine pretreatment restored the ATP-to-ADP (ATP/ADP) ratio and glucose-stimulated insulin secretion in UCP2-infected islets. ATP-sensitive K(+) channel sensitivity to dihydroxyacetone, another insulin secretagogue, was similar in both UCP2-infected and control beta-cells. In freshly isolated mitochondria from UCP2-overexpressing insulin-secreting (INS)-1 beta-cells, methyl pyruvate-mediated mitochondrial Ca(2+) increase was significantly ameliorated by taurine. A mitochondrial Ca(2+) uniporter blocker, ruthenium red, inhibited the action of taurine. This study suggests that taurine enhances the glucose sensitivity of UCP2-overexpressing beta-cells, probably by increasing mitochondrial Ca(2+) influx through the Ca(2+) uniporter, thereby enhancing mitochondrial metabolic function and increasing the ATP/ADP ratio.


Plantar Molluscum Contagiosum in an Adult Patient.
Molluscum contagiosum is a viral infection of the skin. It may occur anywhere on the skin surface but is most common in skinfolds, on the face, and in the genital region. Atypical presentations are usually seen in conditions with altered immunity, but they may occur in immunocompetent patients as well. We present a case of an unusual presentation of molluscum contagiosum lesions (multiple normal and one giant) on the plantar area of the foot in an adult.


Fall of the iron curtain: male life expectancy in Slovakia, in the Czech Republic and in Europe.
Year 1989, the fall of communism, represents a dramatic watershed. Changes and reforms reflected also upon the quality of health care and the health of populations living on eastern side of the divide. Until then, Eastern Europe had free socialized medicine, albeit troubled by lack of up-to-date medications and absence of modern diagnostic equipment. Noting the admirable progress in health in some regions of the former Soviet empire during its transformation provides invaluable sociological lesson. Furthermore, focusing on health trends in two Central European countries, the Czech republic (CZ) and Slovakia (SK), brings about another quality to such evaluation. Dramatic improvement in the life expectancy (LE) is represented mainly in the decrease of cardiovascular mortality, more in the Czech Republic than in Slovakia. Favorable trend of male LE in the Czech Republic exceeded several established West European countries, while in Russia, Belarus and Ukraine the life expectancy actually deteriorated. When life expectancy in Slovakia is compared with the Czech Republic, its poorer outcome results from a higher cardiovascular mortality, as well as from liver, digestive and respiratory disorders. Root causes of this difference are possibly in a marked difference in funding of health care between SK and CZ, higher consumption of alcohol and cigarettes, as well as in a sizeable disadvantaged Roma minority in Slovakia.


Acidity of Carboxylic Acid Ligands Influences the Formation of VO2(A) and VO2(B) Nanocrystals under Solvothermal Conditions.
Vanadium dioxide (VO2) can adopt many different crystal structures at ambient temperature and pressure, each with different, and often desirable, electronic, optical, and chemical properties. Understanding how to control which crystal phase forms under various reaction conditions is therefore crucial to developing VO2 for various applications. This paper describes the impact of ligand acidity on the formation of VO2 nanocrystals from the solvothermal reaction of vanadyl acetylacetonate (VO(acac)2) with stoichiometric amounts of water. Carboxylic acids examined herein favor the formation of the monoclinic VO2(B) phase over the tetragonal VO2(A) phase as the concentration of water in the reaction increases. However, the threshold concentration of water required to obtain phase-pure VO2(B) nanocrystals increases as the pKa of the carboxylic acid decreases. We also observe that increasing the concentration of VO(acac)2 or the concentration of acid while keeping the concentration of water constant favors the formation of VO2(A). Single-crystal electron diffraction measurements enable the identification of vanadyl carboxylate species formed in reactions that do not contain enough water to promote the formation of VO2. Increasing the length of the carbon chain on aliphatic carboxylic acids did not impact the phase of VO2 nanocrystals obtained but did result in a change from nanorod to nanoplatelet morphology. These results suggest that inhibiting the rate of hydrolysis of the VO(acac)2 precursor either by decreasing the ratio of water to VO(acac)2 or by increasing the fraction of water molecules that are protonated favors the formation of VO2(A) over VO2(B).


Identification of Multisialylated LacdiNAc Structures as Highly Prostate Cancer Specific Glycan Signatures on PSA.
Serum prostate-specific antigen (PSA) test is the current gold standard for screening and diagnosis of prostate cancer (PCa), while overdiagnosis and overtreatment are social problems. In order to improve the specificity and exclude a false positive diagnosis in PSA test, PCa-specific glycosylation subtypes of PSA were explored using in-depth quantitative profiling of PSA glycoforms based on mass spectrometric oxonium ion monitoring technology. As a result of analysis using sera from 15 PCa or 15 benign prostate hyperplasia (BPH) patients whose PSA levels were in the "gray zone" (4.0-10.0 ng/mL), 52 glycan structures on PSA were quantitatively observed. We found that abundance of multisialylated LacdiNAc (GalNAcβ1-4GlcNAc) structures were significantly upregulated in the PCa group compared to the BPH group. A couple of those glycoforms were then extracted and subjected to establish a novel PCa-specific diagnosis model (PSA G-index). When the diagnostic power was assessed using an independent validation sample set (15 PCa and 15 BPH patients in the PSA gray zone), an AUC of PSA G-index was 1.00, while that of total PSA or PSA f/T ratio was 0.50 or 0.60, respectively. Moreover, both PSA glycoforms showed significant correlation with Gleason scores. Lectin histochemical staining analysis also showed that PCa cells overexpressed glycoproteins containing LacdiNAc and sialic acids moieties. Thus, PSA G-index could serve as not only an effective secondary screening method to exclude false positive diagnosis in PSA screening, but also a potential grading biomarker for PCa.


Predictive value of the Eustachian Tube Dysfunction Questionnaire-7 for identifying obstructive Eustachian tube dysfunction: A systematic review.
To perform a systematic review to determine if a total score of ≥14.5 (mean score ≥ 2.1) on the ETDQ-7 accurately identifies patients with obstructive Eustachian tube dysfunction (OETD) on impedance tympanometry (peak compliance <0.2 mL or middle ear pressure of -100 daPa) or other objective measures of OETD. A systematic review without a meta-analysis was performed of studies in four electronic databases (Pubmed, Embase, Web of Science, and Scopus) that used the ETDQ-7 and at least one objective measure of OETD. Six-hundred and fifty-two studies were identified in the initial literature search. Abstracts from 337 studies were screened, followed by full-text review of 61 studies, and qualitative synthesis of 12 studies. Tympanometry was used as an objective measure in ten studies. Eight of the 12 included studies had patient cohort selection bias. Eight studies administered the ETDQ-7 in cohorts of patients with or without OETD, already confirmed on tympanometry, and found a sensitivity of 91%-100% and specificity of 67%-100%. Four studies administered the ETDQ-7 to patients who had not previously undergone objective testing and found a sensitivity of 49%-80% and specificity of 24%-78%. The ETDQ-7 is an important patient-reported outcome measure. However, based upon existing literature, the ETDQ-7 appears limited as a diagnostic tool for OETD or as an objective measure of Eustachian tube function.


Closure of Oroantral Communication Using Platelet-rich Fibrin: A Report of Two Cases.
Oroantral communication (OAC) is an abnormal connection between the maxillary sinus and oral cavity. It is mostly formed after the extraction of the first and second upper molars. Platelet-rich fibrin (PRF) created by Choukroun's protocol concentrates most platelets and leukocytes from a blood harvest to a single autologous fibrin biomaterial. It has been used widely in oral and maxillofacial surgery. However, no data are available concerning the use of PRF alone as a clot and a membrane for the closure of OACs. Two clinical cases presented with OAC, created after extraction of tooth #16 in two patients, were closed with PRF as a clot and a membrane and monitored until the epithelization of the sockets was ended successfully. Two months postclosure, the sockets were evaluated clinically and on waters' view radiography. The results of these case reports showed that PRF can be successfully applied for the closure of OACs.


Self-control and unhealthy body weight: The role of impulsivity and restraint.
We examine the relationship between trait self-control and body weight. Data from a population representative household survey reveal that limited self-control is strongly associated with both unhealthy body weight and poorer subjective weight-related well-being. Those with limited self-control are characterized by reduced exercising, repeated dieting, unhealthier eating habits, and poorer nutrition. We propose an empirical method to isolate two facets of self-control limitations-high impulsivity and low restraint. Each has differential predictive power. Physical activity, dieting, and overall body weight are more strongly associated with restraint; impulsivity is relatively more predictive of when, where, and what people eat.


A distributed model of solid waste anaerobic digestion: sensitivity analysis.
A distributed model of anaerobic digestion of solid waste was developed to describe the balance between the rates of polymer hydrolysis and methanogenesis during the anaerobic conversion of rich and lean wastes in batch and continuous-flow reactors. Waste, volatile fatty acids (VFAs), methanogenic biomass and sodium concentrations are the model variables. Diffusion and advection of VFAs inhibiting both polymer hydrolysis and methanogenesis were considered. A sensitivity analysis by changing the key model parameter values was carried out. The model simulations showed that the effective distance between the areas of hydrolysis/acidogenesis and methanogenesis is very important. An initial spatial separation of rich waste and inoculum enhances the methane production and waste degradation at high waste loading if relatively low VFA diffusion into the methanogenic area is taking place. When both hydrolysis and methanogenesis are strongly inhibited by high levels of VFA, fluctuations in biomass concentration are thought to be responsible for initiating the expansion of methanogenic area over the reactor space.


Drug users' involvement in the drug economy: implications for harm reduction and HIV prevention programs.
The purpose of this article is to explore individual and social characteristics associated with drug users' involvement in the drug economy among a sample of low-income heroin and cocaine users (n = 1,288) in Baltimore, Maryland. The study sample had participated in a network-oriented intervention study of human immunodeficiency virus (HIV) risk behaviors among drug users. Of the sample, 44% (n = 569) held at least one role in the drug economy, performing an average of 1.17 roles. A significantly higher percentage of those involved in the drug economy reported being daily drug users (60.6% vs. 40.2%), injecting heroin daily (36.0% vs. 21.8%), injecting speed daily (23.6% vs. 14.7%), and snorting heroin daily (18.3% vs. 13.4%). In terms of social networks, those involved in the drug economy reported a significantly larger social network (9.98 vs. 8.97), greater percentage of active drug users in their social network (47% vs. 44%), greater percentage of daily drug users in their social network (40% vs. 33%), and larger drug support networks (6.7 vs. 5.6). The study indicates the far-reaching influence of drug use on many aspects of their lives, including their involvement with the drug economy. Reducing drug users' frequency of use could have the consequence of decreasing this involvement. Being a part of the drug economy exposes drug users to many risks, but also places them in a position to influence others. Examining drug users' social networks could provide insight into the composition of their immediate social environment and could inform HIV prevention programs.


Gender differences in schizophrenia.
Lewine (Psychol. Bull., 90: 432-444, 1981) has proposed sex differences, specific to schizophrenics, in age at first psychiatric hospitalization, age at first reported symptoms, and premorbid social competence. To evaluate Lewine's hypothesis we collected data on 64 schizophrenic and 30 nonschizophrenic psychiatric outpatients. As no interaction between sex and diagnostic groups was found, our data failed to demonstrate sex differences specific and unique to schizophrenia. It is possible that Lewine's evidence is due to a cultural artifact.


Haplotype diversity in "source-sink" dynamics of Escherichia coli urovirulence.
FimH, the mannose-specific, type 1 fimbrial adhesin of Escherichia coli, acquires amino acid replacements adaptive in extraintestinal niches (the genitourinary tract) but detrimental in the main habitat (the large intestine). This microevolutionary dynamics is reminiscent of an ecological "source-sink" model of continuous species spread from a stable primary habitat (source) into transient secondary niches (sink), with eventual extinction of the sink-evolved populations. Here, we have adapted two ecological analytical tools-diversity indexes DS and alpha--to compare size and frequency distributions of fimH haplotypes between evolutionarily conserved FimH variants ("source" haplotypes) and FimH variants with adaptive mutations (putative "sink" haplotypes). Both indexes show two- to threefold increased diversity of the sink fimH haplotypes relative to the source haplotypes, a pattern that ran opposite to those seen with nonstructural fimbrial genes (fimC and fimI) and housekeeping loci (adk and fumC) but similar to that seen with another fimbrial adhesin of E. coli, papG-II, also implicated in extraintestinal infections. The increased diversity of the sink pool of adhesin genes is due to the increased richness of the haplotypes (the number of unique haplotypes), rather than their evenness (the extent of similarity in relative abundances). Taken together, this pattern supports a continuous emergence and extinction of the gene alleles adaptive to virulence sink habitats of E. coli, rather than a one-time change in the habitat conditions. Thus, ecological methods of species diversity analysis can be successfully adapted to characterize the emergence of microbial virulence in bacterial pathogens subject to source-sink dynamics.


The Effect of Optive and Optive Advanced Artificial Tears on the Healthy Tear Film.
To evaluate the impact of Optive (Allergan, Irvine, CA) and Optive Advanced (Allergan, Irvine, CA) on tear film stability and quality during a one-hour observation period when compared to saline (Pfizer, Perth, WA). This was a double-masked, cross-over study. Twenty participants attended three visits, randomly receiving either Optive, Optive Advanced or saline. Oculus Keratograph 5M (Oculus, Arlington, WA, USA), non-invasive keratograph break-up time (NIKBUT), Lipiview (TearScience Inc, Morrisville, NC, USA), lipid layer thickness (LLT) and comfort were measured prior to and 5, 15 and 60 min after drop instillation. Optive Advanced demonstrated a significant increase in LLT between baseline (57.5 ± 12.3 nm) and both 5 min (67.5 ± 18.8 nm, p = 0.04) and 15 min (68.9 ± 17.3 nm, p = 0.04) but not 60 min (61.6 ± 14.3 nm, p = 0.47). Optive and saline were not different between timepoints for LLT (p > 0.05). There was no difference between timepoints for any of the drops for NIKBUT (p = 0.75). Comfort was significantly better at 5 min compared to baseline for Optive (8.3 ± 1.2 and 7.3 ± 1.4, respectively, p = 0.03) but not different for Optive Advance or saline (p > 0.05). Optive Advanced increased LLT for 15 min following instillation, returning to baseline within one hour. This did not however, translate into an improvement in tear film stability over this time period. Only Optive demonstrated an improvement in comfort.


Valbenazine: First Global Approval.
Valbenazine (Ingrezza™) is an orally bioavailable, selective, vesicular monoamine transporter 2 (VMAT2) inhibitor being developed by Neurocrine Biosciences for the treatment of various central nervous system disorders. Valbenazine has been approved in the USA for the treatment of adults with tardive dyskinesia (TD), is at various stages of development in other countries for TD and is in phase 2 development in the USA for Tourette syndrome. This article summarizes the milestones in the development of valbenazine leading to its first global approval in the USA for the treatment of adults with TD.


Assessing the Spontaneous Spread of Climate-Adapted Woody Plants in an Extensively Maintained Collection Garden.
Climate change may strongly modify the habitat conditions for many woody plant species. Some species could disappear from their natural habitats and become endangered, while others could adapt well to the changed environmental conditions and continue to survive successfully or even proliferate more easily. A similar process can occur within the artificial urban environment as the hitherto popularly planted urban trees may suffer from the extremities of the urban climate. However, among the planted taxa, there are species that spread spontaneously and appear as weeds in extensively managed gardens. In our study, we evaluated the native and non-native species involved in spontaneous spreading in the institutional garden of Buda Arboretum (Budapest) during the COVID-19 period in 2020-2021 when entry was prohibited, and maintenance went on in a restricted, minimal level. We investigated the correlation between spontaneously settling and planted individuals, and then performed multivariate analyses for native and non-native spreading plants for spatial and quantitative data. During our studies, we observed the spontaneous spreading of 114 woody species, of which 38 are native and 76 are non-native. Taking the total number of individuals into account, we found that, in addition to the 2653 woody species planted, a further 7087 spontaneously emerged weeds developed, which creates an additional task in the maintenance.


Agrobacterium transformation of Arabidopsis thaliana roots: a quantitative assay.
Arabidopsis thaliana has become a major model system for investigating plant molecular, genetic, and biochemical processes. Arabidopsis is highly susceptible to Agrobacterium-mediated transformation using "flower dip" and "vacuum infiltration" protocols. However, Arabidopsis has also become a major system to investigate the mechanism of Agrobacterium-mediated transformation of somatic tissue. Such investigations require a reproducible, quantitative assay system to determine transformation frequency. We describe here an Arabidopsis root transformation protocol that can be used to determine transformation frequencies for wild-type and mutant Agrobacterium strains and for various Arabidopsis wild-type and mutant lines.


Equilibrative nucleoside transporter 2 regulates associative learning and synaptic function in Drosophila.
Nucleoside transporters are evolutionarily conserved proteins that are essential for normal cellular function. In the present study, we examined the role of equilibrative nucleoside transporter 2 (ent2) in Drosophila. Null mutants of ent2 are lethal during late larval/early pupal stages, indicating that ent2 is essential for normal development. Hypomorphic mutant alleles of ent2, however, are viable and exhibit reduced associative learning. We additionally used RNA interference to knock down ent2 expression in specific regions of the CNS and show that ent2 is required in the alpha/beta lobes of the mushroom bodies and the antennal lobes. To determine whether the observed behavioral defects are attributable to defects in synaptic transmission, we examined transmitter release at the larval neuromuscular junction (NMJ). Excitatory junction potentials were significantly elevated in ent2 mutants, whereas paired-pulse plasticity was reduced. We also observed an increase in stimulus dependent calcium influx in the presynaptic terminal. The defects observed in calcium influx and transmitter release probability at the NMJ were rescued by introducing an adenosine receptor mutant allele (AdoR(1)) into the ent2 mutant background. The results of the present study provide the first evidence of a role for ent2 function in Drosophila and suggest that the observed defects in associative learning and synaptic function may be attributable to changes in adenosine receptor activation.


Lessons in Program Evaluation: The ACTV Batterer Program Study and Its Claims.
The "Evaluation of the Acceptance and Commitment Therapy (ACT) curriculum for domestic violence offenders" illustrates the methodological issues associated with interpreting program evaluations and applying them to policy. Despite the "preliminary" evidence, the authors promote ACTV as more effective in terms of recidivism compared with DU/CBT (cognitive-behavioral therapy) programming. A more critical consideration of the research, however, exposes further limitations that counter the initial speculations and interpretations of the study outcome. Consequently, the effectiveness of ACTV over the DU/CBT option remains in question and raises the need for a broader discourse on program effectiveness.


Adsorption of iodine in metal-organic framework materials.
Nuclear power will continue to provide energy for the foreseeable future, but it can pose significant challenges in terms of the disposal of waste and potential release of untreated radioactive substances. Iodine is a volatile product from uranium fission and is particularly problematic due to its solubility. Different isotopes of iodine present different issues for people and the environment. 129I has an extremely long half-life of 1.57 × 107 years and poses a long-term environmental risk due to bioaccumulation. In contrast, 131I has a shorter half-life of 8.02 days and poses a significant risk to human health. There is, therefore, an urgent need to develop secure, efficient and economic stores to capture and sequester ionic and neutral iodine residues. Metal-organic framework (MOF) materials are a new generation of solid sorbents that have wide potential applicability for gas adsorption and substrate binding, and recently there is emerging research on their use for the selective adsorptive removal of iodine. Herein, we review the state-of-the-art performance of MOFs for iodine adsorption and their host-guest chemistry. Various aspects are discussed, including establishing structure-property relationships between the functionality of the MOF host and iodine binding. The techniques and methodologies used for the characterisation of iodine adsorption and of iodine-loaded MOFs are also discussed together with strategies for designing new MOFs that show improved performance for iodine adsorption.


Canonical and non-canonical Notch signaling in CD4⁺ T cells.
For T cells to become fully activated, they must integrate a myriad of signals, both extrinsic and intrinsic. External stimuli accrued through various cell surface receptors are transduced and amplified through a coordinated circuitry of signaling cascades that ultimately result in the transcription of new genes. Along the way, extracellular and intracellular signaling components function to impart a fully activated state. Evidence is accumulating to show that the Notch family of cell surface receptors, long known to function as transcriptional regulators through their interactions with the canonical nuclear binding protein CSL/RBP-J, may also be playing an as-yet-unappreciated role in T cell activation by virtue of its signaling via non-canonical as well as nonnuclear mechanisms. In this review we will discuss these and other better-known means by which Notch signaling influences T cell responses.


Growth of submillimeter SrTaO2N single crystals by an NH3-assisted SrCl2 flux method.
Perovskite-type oxynitrides have recently been highlighted due to their dielectric and photocatalytic properties. Numerous studies have addressed the synthesis and characterization of their nanocrystals and ceramics. However, few research works have considered single-crystal formation in such systems due to difficulties in melt growth. In this study, we explore the crystal growth of perovskite-type oxynitride SrTaO2N by an NH3-assisted SrCl2 flux method. Submillimeter-sized single crystals with lengths of approximately 300 μm were grown at a temperature of 1200 °C for 10 h with a solute concentration of 1.5 mol%. Subsequently, the crystal growth mechanism of SrTaO2N in an SrCl2 flux was studied systematically through experiments with variable holding temperature, holding time, cooling rate, and solute concentration. Our results suggest that SrTaO2N crystal growth is induced by the evaporation of SrCl2 flux.


Insulin resistance and metformin in polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is a heterogeneous disorder with widespread systemic manifestations affecting 5-10% of women of reproductive age. The accompanying insulin resistance and hypeinsulinemia mark this syndrome as a prediabetic state, with high incidence of impaired glucose tolerance, gestational diabetes, and overt diabetes. Other metabolic and biochemical changes, such as hypertension and dyslipidemia, increase the risk of cardiovascular disease. Fertility may also be impaired due to anovulation, impaired implantation, and higher rates of spontaneous abortions. All of these effects may also be related to hyperinsulinemia. Metformin, as insulin-sensitizing drug, is being evaluated for its potential long-term disease-modifying effect, such as prevention of diabetes. Its use may also help restore spontaneous ovulation and improve menstrual cyclicity, improve the success rate of induction of ovulation with clomiphene citrate and FSH, and decrease the high rate of ovarian hyperstimulation and early pregnancy loss. Nevertheless, these new exiting potential benefits of metformin should be evaluated in large randomized controlled studies, and clinicians must counsel women appropriately before the initiation of metformin therapy.


Correlation of serum apelin level with carotid intima-media thickness and insulin resistance in a sample of Egyptian patients with type 2 diabetes mellitus.
Type 2 diabetes mellitus (T2DM) is a growing health problem in Egypt, with a significant impact on morbidity and mortality. Measurement of the carotid Intima-media thickness (CIMT) allows early detection of atherosclerotic blood vessel diseases. Apelin is an adipose tissue-derived hormone that may be associated with insulin resistance (IR). This study aimed to assess the level of serum apelin in patients with T2DM and its relation to IR and CIMT. A case-control study was conducted on 60 patients with T2DM and 30 healthy controls. T2DM was diagnosed based on American Diabetes Association criteria. The study was carried out at Al-Zahraa University Hospital, Cairo, Egypt, through the period from June to December 2019. The laboratory investigations included serum apelin and blood glucose hemostasis markers. CIMT was assessed using B-mode ultrasonography. Patients' group had a statistically significant higher apelin level than healthy controls (407.96 ± 291.07 versus 83.32 ± 10.55 ng/dL, P < 0.001). The correlation analysis showed that the serum apelin level correlated positively with glycemic indices, body weight, and waist circumference (P < 0.05). At cutoff value of >96 ng/dL, the serum apelin exhibited a sensitivity of 98.3% and specificity of 96.7%, positive predictive value of 98.1%, and negative predictive value of 96.5%, with a diagnostic accuracy of 95.1%. Serum apelin correlated positively with CIMT (r = 0.296, P = 0.022). Logistic regression analysis showed that systolic and diastolic blood pressures, Homeostasis Model Assessment of IR, and CIMT were independent predictors of serum apelin. Serum apelin may be correlated with the degree of carotid atherosclerosis and hence can be used as a prognostic biomarker.


Actions of pituitary hormones beyond traditional targets.
Studies over the past decade have challenged the long-held belief that pituitary hormones have singular functions in regulating specific target tissues, including master hormone secretion. Our discovery of the action of thyroid-stimulating hormone (TSH) on bone provided the first glimpse into the non-traditional functions of pituitary hormones. Here we discuss evolving experimental and clinical evidence that growth hormone (GH), follicle-stimulating hormone (FSH), adrenocorticotrophic hormone (ACTH), prolactin, oxytocin and arginine vasopressin (AVP) regulate bone and other target tissues, such as fat. Notably, genetic and pharmacologic FSH suppression increases bone mass and reduces body fat, laying the framework for targeting the FSH axis for treating obesity and osteoporosis simultaneously with a single agent. Certain 'pituitary' hormones, such as TSH and oxytocin, are also expressed in bone cells, providing local paracrine and autocrine networks for the regulation of bone mass. Overall, the continuing identification of new roles for pituitary hormones in biology provides an entirely new layer of physiologic circuitry, while unmasking new therapeutic targets.


[Application of sensitive sulphur electrode assay to measure and analyze cystathionine-gamma-lyase/hydrogen sulfide pathway of cardiovascular tissues, cells and plasma in rats].
To construct a method of measurement microamount hydrogen sulfide (H(2)S) using sensitive sulphur electrode. According to the physical and chemical characters of H(2)S, H(2)S, which in the fluids by mean of physical dissolve and chemical shape, is turned to sulphur ion (S(2-)) by chemical responses. After the microamount of S(2-) was measured by sensitive sulphur electrode, and the concentration of H(2)S was converted, a method was constructed to measure the H(2)S. It was used to analyze the concentrations of H(2)S of plasma in rats and humans, the endogenous concentration of H(2)S of cardiovascular tissue in rats, and CSE activity of cardiovascular tissues and cells. The exponential regression of S(2-) in the extent including 1 to 80 micromol/L was found using sensitive sulphur electrode. The H(2)S levels of plasma in male and female rats were 40+/-4 and 41+/-5 micromol/L, respectively, and significant difference was not found; those in venous blood plasma of men and women were 33+/-4 micromol/L and 35+/-5 micromol/L respectively, without significant difference. There were not significant differences in the aortic endogenous levels of H(2)S (24+/-6 and 25+/-5 nmol/mg pro) and myocardial levels (19+/-4 and 19+/-6 nmol/mg protein) between female and male rats. There were no different results of CSE activity in aortal tissue using sensitive sulphur electrode or traditional methods, however, the CSE activity of vascular smooth muscle cells could be accurately measured using sensitive sulphur electrode, which was difficult in using traditional method. The sensitive sulphur electrode assay was fit for the analysis of CSE/H(2)S pathway in cardiovascular research.


Single-tube, highly parallel mutation enrichment in cancer gene panels by use of temperature-tolerant COLD-PCR.
Multiplexed detection of low-level mutations presents a technical challenge for many technologies, including cancer gene panels used for targeted-resequencing. Analysis of mutations below approximately 2%-5% abundance in tumors with heterogeneity, samples with stromal contamination, or biofluids is problematic owing to increased noise from sequencing errors. Technologies that reduce noise via deep sequencing unavoidably reduce throughput and increase cost. Here we provide proof of principle that coamplification at lower denaturation temperature (COLD)-PCR technology enables multiplex low-level mutation detection in cancer gene panels while retaining throughput. We have developed a multiplex temperature-tolerant COLD-PCR (fast-TT-COLD-PCR) approach that uses cancer gene panels developed for massively parallel sequencing. After multiplex preamplification from genomic DNA, we attach tails to all amplicons and perform fast-TT-COLD-PCR. This approach gradually increases denaturation temperatures in a step-wise fashion, such that all possible denaturation temperatures are encompassed. By introducing modified nucleotides, fast-COLD-PCR is adapted to enrich for melting temperature (Tm)-increasing mutations over all amplicons, in a single tube. Therefore, in separate reactions, both Tm-decreasing and Tm-increasing mutations are enriched. Using custom-made and commercial gene panels containing 8, 50, 190, or 16 000 amplicons, we demonstrate that fast-TT-COLD-PCR enriches mutations on all examined targets simultaneously. Incorporation of deoxyinosine triphosphate (dITP)/2,6-diaminopurine triphosphate (dDTP) in place of deoxyguanosine triphosphate (dGTP)/deoxyadenosine triphosphate (dATP) enables enrichment of Tm-increasing mutations. Serial dilution experiments demonstrate a limit of detection of approximately 0.01%-0.1% mutation abundance by use of Ion-Torrent and 0.1%-0.3% by use of Sanger sequencing. Fast-TT-COLD-PCR improves the limit of detection of cancer gene panels by enabling mutation enrichment in multiplex, single-tube reactions. This novel adaptation of COLD-PCR converts subclonal mutations to clonal, thereby facilitating detection and subsequent mutation sequencing.


Crohn's Disease Patient Experiences and Preferences With Disease Monitoring: An International Qualitative Study.
Strategies incorporating objective disease monitoring in Crohn's disease (CD), beyond clinical symptoms are important to improve patient outcomes. Little evidence exists to explore patient understanding of CD treatment goals, nor preferences and experiences with monitoring options. This qualitative study aimed to explore patient experiences and preferences of CD monitoring to inform monitoring strategies, improve patient engagement, and optimize a patient-centered approach to care. This study used a patient-oriented, qualitative descriptive design. Convenience and snowball sampling were used to recruit adult participants diagnosed with CD who had experience with at least 2 types of disease monitoring. Online focus groups were conducted and data were analyzed using thematic analysis. This international study included 37 participants from Australia, Canada, United Kingdom, and the United States. Overall, participants preferred more noninvasive types of monitoring [eg, intestinal ultrasound (IUS)] but were willing to undergo more invasive monitoring (eg, colonoscopy) if required. To improve disease monitoring, participants wanted increased access to IUS, establishment of a patient-centered interdisciplinary team and access to information and self-testing. Participants identified challenges with communication between patients and providers and stressed the importance of participating in shared decision making and being equal team members in their care. It is imperative to incorporate patient-driven preferences into how we can best structure monitoring strategies, to ensure equitable access to those preferred modalities and embrace a shared decision-making approach to disease management in CD.


Detailed investigation of the diagnostic value in tumour histopathology of ICR.2, a new monoclonal antibody to epithelial membrane antigen.
The production and detailed immunostaining properties of a new rat monoclonal antibody (ICR.2) to epithelial membrane antigen are reported. The antibody was selected for its ability to compete with the polyclonal antiserum (M7), used in the original immunohistological studies, in order that it might serve as a direct replacement in diagnosing epithelial tumours. Most of the staining reactions on normal tissues were identical to those previously reported with M7 but there were some important differences. They included: positivity of renal and adrenal capsular fibroblasts, perineurium, some myoepithelial and smooth muscle cells, occasional osteoblasts and squamous and thyroid follicular epithelium in the normal state. The intercellular canaliculi of sweat glands and secretory canaliculi of gastric oxyntic cells were clearly demonstrated. These staining reactions could be obtained with M7 when a sensitive detection system was used although the results were usually weak and inconsistent. Nearly all adenosquamous and transitional carcinomas were positive. The remaining tumours fell into three major groups: (1) those which were consistently or nearly consistently negative--melanoma, seminoma, rhabdomyosarcoma, alveolar soft part sarcoma, adrenal cortical carcinoma, granulocytic sarcoma, paraganglioma, non-Hodgkin's lymphoma. Hodgkin's disease and embryonal carcinoma: (2) those which were either negative or positive with distinctive patterns of staining--basal cell carcinoma, embryonal tumours: and (3) non-epithelial tumours that were consistently positive--epithelioid sarcoma, synovial sarcoma, osteosarcoma, chordoma and myeloma--or positive in a significant minority of cases--leiomyosarcoma, malignant fibrous histiocytoma, clear cell sarcoma of tendon sheath, various neuroectodermal tumours.(ABSTRACT TRUNCATED AT 250 WORDS)


Bilateral internal mammary artery for coronary revascularization. Early experience of 100 cases.
One hundred cases are presented in which both right and left internal mammary artery (IMA) were used as coronary bypass grafts. Special indications were thrombosis of previous venous graft (14 cases), poor venous resources (10) and small-vessel (probe less than 1.5 mm) disease (34), but bilateral IMA was used also for routine revascularization (42 cases). The total 212 distal IMA anastomoses included 12 jump grafts, three free grafts and seven thrombendarterectomies. There were 3.8 distal anastomoses per patient, 2.1 with IMA and 1.7 with vein graft. The right IMA was preferably inserted into LAD and the left into diagonal or obtuse marginal coronary artery. Excessive postoperative bleeding was the only major complication attributable to bilateral IMA grafting in the 97 survivors of surgery. In routine revascularization the procedure involved minimal morbidity and no mortality. The superiority of the IMA as regards long-term patency is widely recognized. Since many thrombosed vein grafts will require replacement, we believe that bilateral IMA grafting will become common, and it is also an option when no suitable vein is available.


Interleukin-2 enhances biopterins and catecholamines production during adoptive immunotherapy for various cancers.
Biopterins production during three different protocols for adoptive immunotherapy for human cancer was investigated. Adoptive immunotherapy treatment with interleukin-2 (IL-2) was carried out for 13 patients with malignant melanoma; eight with metastatic renal cell carcinoma; and three with metastatic colon cancer. The authors estimated total biopterins in plasma and lymphokine (IL-2)-activated killer cells (LAK) from these patients before and during various treatment phases to determine if increased biopterins production reflects leukocyte activation by IL-2 or antitumor activity. They noted an increased synthesis of total "biopterins," i.e., biopterin; 7,8-dehydrobiopterin; and L-neopterin in LAK cells and plasma which correlated with IL-2 exposure. Mean plasma biopterins were normal (1.2 +/- 0.5 ng/ml) before therapy; in contrast, biopterins increased significantly to 3.4 +/- 1.9 ng/ml and 3.9 +/- 1.9 ng/ml during IL-2 and IL-2 + LAK treatment each, respectively. Similar biopterin elevations were noted irrespective of the different adoptive immunotherapy protocols used. Elevated biopterins decreased to normal levels (1.2 +/- 0.7 ng/ml) when IL-2 treatment was omitted. Tumor regression with adoptive immunotherapy did not correlate with increased plasma biopterins. Increased biopterins production was also associated with increase in plasma catecholamine after IL-2 treatment during adoptive immunotherapy. Conceivably increased biopterins, induced by IL-2 activation of a leukocyte population, is a cell-mediated consequence not necessarily serving as a signal for the antitumor effect associated with adoptive immunotherapy.


Prognostic role of extracapsular spread in planned neck dissection after chemoradiotherapy.
The purpose of this study is to evaluate the prognostic significance of nodes with extracapsular spread (ECS) in patients treated with a planned neck dissection after chemoradiotherapy. We carried out a retrospective study of 109 cN+ patients who achieved a complete response in the primary location after chemoradiotherapy and treated with a planned neck dissection. The 5-year disease-specific survival for patients without residual metastatic nodes in the neck dissection (pN0, n = 69) was 75.7% (95% CI: 64.4%-87.0%). For patients with metastatic nodes without ECS (pN+/ECS-negative, n = 17), the corresponding figure was 74.0% (95% CI: 48.2%-99.8%), and for patients with metastatic neck nodes with ECS (pN+/ECS-positive, n = 23) it was 8.7% (95% CI: 0.0%-24.3%) (P = .0001). The presence of ECS in the pathologic study of the planned neck dissections carried out after chemoradiotherapy in patients with human papillomavirus-negative (HPV-negative) head and neck squamous cell carcinoma (SCC) allows identification of a group of patients with a high risk of failure.


Effects of intra-fourth ventricle injection of crocin on capsaicin-induced orofacial pain in rats.
Crocin, a constituent of saffron and yellow gardenia, possesses anti-nociceptive effects. In the present study, we investigated the effects of intra-fourth ventricle injection of crocin in a rat model of orofacial pain. The contribution of opioid system was assessed using intra-fourth ventricle injection of naloxone, an opioid receptor antagonist. A guide cannula was implanted into the fourth ventricle of brain in anesthetized rats. Orofacial pain was induced by subcutaneous (s.c.) injection of capsaicin (1.5 µg/20 µl) into the right vibrissa pad. The time spent face rubbing/grooming was recorded for a period of 20 min. Locomotor activity was measured using an open-field test. Intra-fourth ventricle injection of crocin (10 and 40 µg/rat) and morphine (10 and 40 µg/rat) and their co-administration (2.5 and 10 µg/rat of each) suppressed capsaicin-induced orofacial pain. The analgesic effect induced by 10 µg/rat of morphine, but not crocin (10 µg/rat), was prevented by 20 µg/rat of naloxone pretreatment. The above-mentioned chemical compounds did not affect locomotor activity. The results of this study showed that the injection of crocin into the cerebral fourth ventricle attenuates capsaicin-induced orofacial pain in rats. The anti-nociceptive effect of crocin was not attributed to the central opioid receptors.


Lack of Content Uniformity in MMR Vaccine.
The measles, mumps, and rubella (MMR) vaccine is a vaccine used to prevent measles, mumps, and rubella (German measles). The vaccine is mandated for children to attend public school in nearly all US states. However, measles cases have been increasing in the past decade, and quality problems have recently been noted by the US Food and Drug Administration (FDA) with the vaccine manufacturer. Intra-lot and inter-lot variability in the spectra of MMR (measles, mumps, and rubella) vaccine was detected in the Drug Quality Study (DQS) using Fourier transform near-infrared spectrometry (FTNIR). Six vials of 12 (50%) sampled from Merck lot U006488 appeared 14.5 SDs from the other vials on a subcluster detection test, suggesting that they represent different material. Spectra of 198 vials from 12 lots in the spectral library contained 140 vials in one tight ellipsoidal group, and 58 vials (30%) were outside that group (39.7 SDs using a subcluster detection test), suggesting that the library vials also contain differing materials.


Characterization of Ionotropic Receptor Gene EonuIR25a in the Tea Green Leafhopper, Empoasca onukii Matsuda.
Ionotropic receptors (IRs) play a central role in detecting chemosensory information from the environment and guiding insect behaviors and are potential target genes for pest control. Empoasca onukii Matsuda is a major pest of the tea plant Camellia sinensis (L.) O. Ktze, and seriously influences tea yields and quality. In this study, the ionotropic receptor gene EonuIR25a in E. onukii was cloned, and the expression pattern of EonuIR25a was detected in various tissues. Behavioral responses of E. onukii to volatile compounds emitted by tea plants were determined using olfactometer bioassay and field trials. To further explore the function of EonuIR25a in olfactory recognition of compounds, RNA interference (RNAi) of EonuIR25a was carried out by ingestion of in vitro synthesized dsRNAs. The coding sequence (CDS) length of EonuIR25a was 1266 bp and it encoded a 48.87 kD protein. EonuIR25a was enriched in the antennae of E. onukii. E. onukii was more significantly attracted by 1-phenylethanol at a concentration of 100 µL/mL. Feeding with dsEonuIR25a significantly downregulated the expression level of EonuIR25a, after 3 h of treatment, which disturbed the behavioral responses of E. onukii to 1-phenylethanol at a concentration of 100 µL/mL. The response rate of E. onukii to 1-phenylethanol was significantly decreased after dsEonuIR25a treatment for 12 h. In summary, the ionotropic receptor gene EonuIR25a was highly expressed in the antennae of E. onukii and was involved in olfactory recognition of the tea plant volatile 1-phenylethanol. The present study may help us to use the ionotropic receptor gene as a target for the behavioral manipulation of E. onukii in the future.


Thermally stable and color-tunable bi-activated (Dy3+/Eu3+) alkaline earth metasilicate phosphor for luminescent devices.
A solid-state reaction methodology has been adopted to synthesize Dy3+ (dysprosium)/Eu3+ (europium) co-activated Na4Ca4Si6O18 (NCMS) phosphors. The structural, morphological, and luminescence characteristics of the prepared materials have been investigated. The phase purity of the material was confirmed by X-ray diffraction (XRD) by comparing the diffraction peaks with the JCPDS standard pattern (JCPDS card no. 75-1687). The photoluminescence (PL) spectra of NCMS phosphors activated with Dy3+ and co-activated with Dy3+ (sensitizer)/Eu3+ (activator) ions were investigated. The as-prepared NCMS phosphors co-activated with Dy3+/Eu3+ ions were excited with near-ultraviolet light (λex = 348 nm) and showed the utmost energy transfer of up to 97.80% from sensitizer to activator. Dexter and Reisfeld's approximation specifically confirms that the energy transfer from sensitizer to activator was through electric dipole-dipole interactions. The Dy3+-activated NCMS phosphor showed an illumination shift from yellow to red by varying the Eu3+ ion concentration and colour tunability is also observed by altering the excitation energy. The emission intensity was sustained up to 92.21% at 423 K (∼150 °C), indicating an excellent thermal stability of the bi-activated NCMS phosphor. The Dy3+/Eu3+ co-doped NCMS phosphors display excellent thermal stability with flexible color tunability to emerge as promising contenders in the field of lighting and display technologies.


Semitransparent polymer-based solar cells with aluminum-doped zinc oxide electrodes.
With the use of two transparent electrodes, organic polymer-fullerene solar cells are semitransparent and may be combined to parallel-connected multijunction devices or used for innovative applications like power-generating windows. A challenging issue is the optimization of the electrodes, to combine high transparency with adequate electric properties. In the present work, we study the potential of sputter-deposited aluminum-doped zinc oxide as an alternative to the widely used but relatively expensive indium tin oxide (ITO) as cathode material in semitransparent polymer-fullerene solar cells. Concerning the anode, we utilized an insulator-metal-insulator structure based on ultrathin Au films embedded between two evaporated MoO3 layers, with the outer MoO3 film (capping layer) serving as a light coupling layer. The performance of the ITO-free semitransparent polymer-fullerene solar cells was systematically studied as dependent on the thickness of the capping layer and the active layer as well as the illumination direction. These variations were found to have strong impact on the obtained photocurrent densities. We performed optical simulations of the electric field distribution within the devices using the transfer-matrix method, to analyze the origin of the current density variations in detail and provide deep insight into the device physics. With the conventional absorber materials studied here, optimized ITO-free and semitransparent devices reached 2.0% power conversion efficiency and a maximum optical transmission of 60%, with the device concept being potentially transferable to other absorber materials.


[Expression of P-glycoprotein as a multidrug resistance gene product in human reactive astrocytes and astrocytoma].
The immunohistochemical detection of multidrug resistance (MDR1) gene products and their mRNA within brain tumor cells has already been described by Fojo et al. 1987. 63 specimens of astrocytomas and glioblastomas were analysed in the present study (Grading type 1 to 4) by means of the monoclonal antibody JSB1. The endothelial cells were positive only in astrocytic tumors with a grading of 1. Increasing tumor grading resulted in more positive immunological reactions in tumor cells. The most impressive reaction could be found in anaplastic astrocytoma and glioblastoma (G3 and G4). Overexpression of this P-glycoprotein, a plasma membrane component of a relative molecular mass of 170 kDa was not only found in tumor cells of anaplastic astrocytomas, but also in endothelial cells and some non-neoplastic brain diseases. Positive immunological reactions in protoplasmatic astrocytes could be demonstrated in cases of phenylketonuria (1/1), tuberculous leptomeningitis (2/2), SSPE (3/4), X-ray necrosis (1/1) and necrotizing viral encephalitis (1/4). According to this, it seems that astrocytes are able to express P-glycoprotein under the influence of some special metabolic conditions. This underlines the detoxicating function of reactive astrocytes within the total number of cells in the CNS.


Electronic transport in smectic liquid crystals.
Time-of-flight measurements of transient photoconductivity have revealed bipolar electronic transport in phenylnaphthalene and biphenyl liquid crystals (LC), which exhibit several smectic mesophases. In the phenylnaphthalene LC, the hole mobility is significantly higher than the electron mobility and exhibits different temperature and phase behavior. Electron mobility in the range approximately 10(-5) cm(2)/V s is temperature activated and remains continuous at the phase transitions. However, hole mobility is nearly temperature independent within the smectic phases, but is very sensitive to smectic order, 10(-3) cm(2)/V s in the smectic-B (Sm-B) and 10(-4) cm(2)/V s in the smectic-A (Sm-A) mesophases. The different behavior for holes and electron transport is due to differing transport mechanisms. The electron mobility is apparently controlled by rate-limiting multiple shallow trapping by impurities, but hole mobility is not. To explain the lack of temperature dependence for hole mobility within the smectic phases we consider two possible polaron transport mechanisms. The first mechanism is based on the hopping of Holstein small polarons in the nonadiabatic limit. The polaron binding energy and transfer integral values, obtained from the model fit, turned out to be sensitive to the molecular order in smectic mesophases. A second possible scenario for temperature-independent hole mobility involves the competion between two different polaron mechanisms involving so-called nearly small molecular polarons and small lattice polarons. Although the extracted transfer integrals and binding energies are reasonable and consistent with the model assumptions, the limited temperature range of the various phases makes it difficult to distinguish between any of the models. In the biphenyl LCs both electron and hole mobilities exhibit temperature activated behavior in the range of 10(-5) cm(2)/V s without sensitivity to the molecular order. The dominating transport mechanism is considered as multiple trapping in the impurity sites. Temperature-activated mobility was treated within the disorder formalism, and activation energy and width of density of states have been calculated.


The risk for immediate postoperative complications after pancreaticoduodenectomy is increased by high frequency of acinar cells and decreased by prevalent fibrosis of the cut edge of pancreas.
Soft pancreas is considered as a factor for pancreatitis after pancreaticoduodenectomy, which in turn constitutes a high risk for local complications. The aim was to analyze the proportion of different cell types in the cut edge of pancreas (CEP) in relation to postoperative pancreatitis and other complications after pancreaticoduodenectomy. Data from postoperative follow-up was collected on 40 patients who had undergone pancreaticoduodenectomy. Positive urine trypsinogen-2, an early detector of pancreatitis, was checked on days 1 to 6 after operation. Drain amylase was measured on postoperative day 3. Anastomotic leakages, delayed gastric emptying, and other complications were registered. The areas of different cell types were calculated from the entire hematoxylin-eosin-stained section of CEP. High frequency of acinar cells in the CEP significantly increased positive urine trypsinogen-2 days, drain amylase values, and delayed gastric emptying. In a subgroup of patients with more than 40% acini in the CEP, there were significantly more postoperative complications. Increased fibrosis correlated with a small number of positive urine trypsinogen-2 days and postoperative complications. A large number of acinar cells in the CEP increases, whereas extensive fibrosis in the CEP decreases, the risk for postoperative complications after pancreaticoduodenectomy. These results emphasize the importance of acini in the development of postoperative complications.


Genotype-Based Score Test for Association Testing in Families.
The multiplex-case and control design in which multiple cases are sampled from the same family is considered. In such studies phenotype information of the un-genotyped relatives might be available. We intend to use additional family information when performing genetic association tests. A score test is revisited to provide a flexible framework to accommodate various genetic models and to improve power of the association test by adding available family information. The proposed test accounts for correlations induced by multiple cases from the same pedigree, directly deals with X-linked SNPs in mixed-sex-related samples, and incorporates additional phenotypic information such as the number of (un-genotyped) siblings and parents with similar symptoms by assigning the weights to (genotyped) multiplex cases. In addition, the score test directly incorporates posterior probabilities of imputed genotypes, which leads to an efficiency measure that reflects imputation uncertainty on the test conducted. The proposed test is applied to real applications for illustration. Its efficiency is demonstrated via simulations.


Activity and motor unit size in partially denervated rat medial gastrocnemius.
The aim of the study was to determine whether increased motoneuron activity induced by treadmill walking would alter the extent of motoneuron sprouting in the partially denervated rat medial gastrocnemius muscle. An extensive partial denervation was effected by unilateral section of the L5 ventral root, and it is very likely that all units remaining in the medial gastrocnemius were used in treadmill walking. Rats were trained for 1.5 h/day and after 14 days were walking at least 1 km/day. Motor unit characteristics were determined 24 days after the partial denervation and were compared with units from partially denervated control (PDC) animals and with units from normal (control) animals. In PDC rats, force developed by slow, fast fatigue-resistant, and fast intermediate-fatigable motor units increased substantially compared with control animals; that of fast-fatigable units did not increase. In partially denervated exercised animals, force developed by slow and fast-fatigue-resistant units showed no further increase, but fast-intermediate- and fast-fatigable units showed significant increases compared with those in PDC animals. The changes in force were closely paralleled by changes in innervation ratios. We concluded that neuronal activity is an important factor in determining the rate of motoneuron sprouting.


The MISLI-Drive, a modular sterilizable robotic driver for steerable laparoscopic instruments.
Introduction: Based on the success of the former "Shaft-Actuated, Tip-Articulated" SATA-Drive, a prototype robotic instrument driver for modular, steerable, laparoscopic instruments, a new driver is designed and tested to improve previously lacking features concerning cleanability, instrument adaptation, practical application and control. The design of the driver engages these issues with a modular design aimed at re-use of both the instrument and the driver, for which a set of design requirements are established. Methods: A new modular design has been developed to improve cleanability through separation of the electro-motors and the instrument mechanism which clutches the instrument. Contamination of the driver's robotic side is prevented though a combination of a drape and a Sterile barrier interface, while the instrument side is made sterilizable. A novel instrument clutching mechanism enables quick-release features, while a motor-axis latching mechanism enables plug-and-play assembly. Embedded sensors allow precise and fast control. A user-experiment was conducted on instrument exchange and assembly time, while mechanical and electrical tests were conducted on the driver's responsiveness. Results: The driver has proven its ability to control the instrument, after which it can be disassembled for cleaning and inspection. The driver is designed for re-use through disassembled sterilization where all possibly contaminated surfaces are exposable for cleaning and inspection. The new standardized instrument clutches allow easy instrument (dis-)assembly. Instrument exchange is possible in two methods, the fastest of which is a median of 11 (6.3-14.6) seconds. The driver's instrument mechanism is separated in a median of 3.7 (1.8-8.1) seconds. After assembly, the driver is operational in less than 2 s. Discussion: Instrument exchange times are similar to the semi-reusable Da Vinci systems, yet the MISLI-Drive is designed for sterilization, inspection and continual re-use. The modular build of the driver also allows easier parts replacement during maintenance, and requires minimal adaptation to different future scenarios, which is expected to reduce the overall cost of use.


Modulation of glucose-induced insulin secretion from a rat clonal beta-cell line.
The present studies demonstrate that the beta-cell line RINr1046-38 (RIN-38) retains the capability to secrete insulin in response to glucose. The maximal effect of glucose was a 5- to 9-fold stimulation of insulin secretion from RIN-38 cells. This glucose-induced insulin secretion was maximal at 0.6 mM and was modulated by other secretagogues. Potassium concentrations of 10 mM, adenylate cyclase activators (glucagon-like peptide-1 and forskolin), and a phosphodiesterase inhibitor (isobutylmethylxanthine) potentiated glucose-induced insulin secretion, but had little or no effect on insulin secretion in the absence of glucose. Potassium concentrations of 20 mM or more, glibenclamide, and carbachol (Cch) stimulated insulin secretion 8- to 12-fold in the absence of glucose, while only Cch potentiated the effect of glucose on insulin secretion. Amino acids (alanine, arginine, leucine, and ketoisocaproate) also stimulated insulin secretion. The alpha 2-adrenergic agonist clonidine (1 microM), low extracellular calcium (less than or equal to 0.5 mM), and extended culture of RIN-38 cells at low glucose concentrations (0.33 mM) inhibited the stimulatory effect of glucose on insulin secretion. Insulin secretion was retained in RIN-38 cells for up to 98 passages. However, extended passage was associated with a decline in cellular insulin content (83% decline over 89 passages). In addition, high passage cells lost the ability to secrete insulin in response to glucose, but continued to respond to other secretagogues (K+, alanine, and carbachol). In fact, in the absence of glucose the effect of Cch on insulin secretion was well maintained in high passage cells (8- and 9.9-fold increase in insulin secretion, passages 9 and 70, respectively). Thus, low passage RIN-38 cells secrete insulin in response to glucose and other insulin secretagogues. High passage cells do not respond to glucose, but continue to respond to other secretagogues. Based on these results we propose that high and low passage RIN-38 cells provide a model for examining molecular mechanisms of glucose-induced insulin secretion. In addition, these findings emphasize that passage information is essential for interpretation of secretion studies with RIN cell lines.


7-Ketocholesterol-induced lysosomal dysfunction exacerbates vascular smooth muscle cell calcification via oxidative stress.
Vascular calcification is known to reduce the elasticity of aorta. Several studies have suggested that autophagy-lysosomal pathway (ALP) in vascular smooth muscle cells (VSMCs) is associated with vascular calcification. A major component of oxidized low-density lipoproteins, 7-ketocholesterol (7-KC), has been reported to promote inorganic phosphorus (Pi)-induced vascular calcification and induce ALP. The aim of this study was to unravel the relationship between ALP and the progression of calcification by 7-KC. Calcification of human VSMCs was induced by Pi stimulation in the presence or absence of 7-KC. FACS analysis showed that 7-KC-induced apoptosis at a high concentration (30 μM), but not at a low concentration (15 μM). Interestingly, 7-KC promoted calcification in VSMCs regardless of apoptosis. Immunoblotting and immunostaining showed that 7-KC inhibits not only the fusion of autophagosomes and lysosomes but also causes a swell of lysosomes with the reduction of cathepsin B and D. Moreover, lysosomal protease inhibitors exacerbated the apoptosis-independent calcification by 7-KC although inhibition of autophagosome formation by Atg5 siRNA did not. Finally, the 7-KC-induced progression of calcification was alleviated by the treatment with antioxidant. Taken together, our data showed that 7-KC promotes VSMC calcification through lysosomal-dysfunction-dependent oxidative stress.


Draft Genome Sequence of Bradyrhizobium japonicum Is-34, Which Is Incompatible with Rj4 Genotype Soybeans.
We report here the draft genome sequence of Bradyrhizobium japonicum Is-34, which is incompatible with Rj4 genotype soybeans. A candidate gene involved in this incompatibility was found to be present in this genome.


Low genetic diversity of the Human T-cell Lymphotropic Virus (HTLV-1) in an endemic area of the Brazilian Amazon basin.
The Human T-cell Lymphotropic Virus (HTLV-1) is a Deltaretrovírus that was first isolated in the 1970s, and associated with Adult T-cell Leucemia-Lymphoma (ATLL), and subsequently to Tropical Spastic Paraparesis-Myelopathy (TSP/HAM). The genetic diversity of the virus varies among geographic regions, although its mutation rate is very low (approximately 1% per thousand years) in comparison with other viruses. The present study determined the genetic diversity of HTLV-1 in the metropolitan region of Belém, in northern Brazil. Blood samples were obtained from patients at the UFPA Tropical Medicine Nucleus between January 2010 and December 2013. The DNA was extracted and the PX region of the HTLV was amplified using nested PCR. The positive samples were then digested using the Taq1 enzyme for the identification and differentiation of the HTLV-1 and HTLV-2. The 5'LTR region of the positive HTLV-1 samples were amplified by nested PCR, and then sequenced genetically. The phylogenetic analysis of the samples was based on the maximum likelihood method and the evolutionary profile was analyzed by the Bayesian approach. Overall, 78 samples tested positive for HTLV-1, and 44 were analyzed here. The aA (cosmopolitan-transcontinental) subtype was recorded in all the samples. The following evolutionary rates were recorded for the different subtypes-a: 2.10-3, b: 2.69. 10-2, c: 6.23. 10-2, d: 3.08. 10-2, e: 6. 10-2, f: 1.78. 10-3, g: 2.2. 10-2 mutations per site per year. The positive HTLV-1 samples tested in the present study were characterized by their low genetic diversity and high degree of stability.


In Silico Approaches In Carcinogenicity Hazard Assessment: Current Status and Future Needs.
Historically, identifying carcinogens has relied primarily on tumor studies in rodents, which require enormous resources in both money and time. In silico models have been developed for predicting rodent carcinogens but have not yet found general regulatory acceptance, in part due to the lack of a generally accepted protocol for performing such an assessment as well as limitations in predictive performance and scope. There remains a need for additional, improved in silico carcinogenicity models, especially ones that are more human-relevant, for use in research and regulatory decision-making. As part of an international effort to develop in silico toxicological protocols, a consortium of toxicologists, computational scientists, and regulatory scientists across several industries and governmental agencies evaluated the extent to which in silico models exist for each of the recently defined 10 key characteristics (KCs) of carcinogens. This position paper summarizes the current status of in silico tools for the assessment of each KC and identifies the data gaps that need to be addressed before a comprehensive in silico carcinogenicity protocol can be developed for regulatory use.


Understanding community member and health care professional perspectives on gender-affirming care-A qualitative study.
Transgender and gender diverse (TGD) people experience significant barriers to accessing affirming health services. There is a paucity of literature examining how both community members and health care professionals (HCPs) understand potential causes and solutions for these barriers, particularly in non-urban settings. We present the first systematic examination of perspectives from community members and HCPs regarding barriers to and solutions for promoting access to gender-affirming health care. Study activities were conducted through the Plan and Act for Transgender Health (PATH) Project, a health needs assessment of TGD people. Community members in the catchment area were recruited to participate in focus group discussions about access to gender-affirming health care and optimal health service delivery models in March-October 2019. HCPs were recruited to participate in focus group discussions or in-depth interviews about experiences working with TGD clients. Data were analyzed using an inductive grounded theory approach. 25 rural counties in Massachusetts, New York, Connecticut, Vermont, and New Hampshire. Study participants included 61 adult TGD community members and 23 HCPs working in the catchment area. Both community members and HCPs spoke of the need for connectedness and linkages among disparate health system components for gender-affirming health care. Participants expressed this priority through calls for systems-level improvements within existing services (e.g., expanded data collection, expanded mental health services, inclusive and affirming health care environments, and TGD staff). They also expressed the need for expanded TGD community outreach and engagement (e.g., incorporation of a patient feedback process, TGD health navigators, and resource mapping). Findings specifically reflect the perspectives of community members and HCPs in the rural New England area. Furthermore, the study sample was predominantly White non-Hispanic. Interventions to achieve accessible gender-affirming health care must address the diverse perspectives and needs of both community members and HCPs.


Modeling prognosis for patients with malignant astrocytic gliomas: quantifying the expression of multiple genetic markers and clinical variables.
The disparate lengths of survival among patients with malignant astrocytic gliomas (anaplastic astrocytomas [AAs] and glioblastoma multiforme [GBM]) cannot be adequately accounted for by clinical variables (patient age, histology, and recurrent status). Using real-time quantitative reverse transcription-polymerase chain reaction, we quantified the expression of four genes that were putative prognostic markers (CDK4, IGFBP2, MMP2, and RPS9) in a set of 43 AAs, 41 GBMs, and seven adjacent normal brain tissues. We previously explicated the expression and prognostic value of PAX6, PTEN, VEGF, and EGFR in these glioma tissues and established a comprehensive prognostic model (Zhou et al., 2003). This study attempts to improve that model by including four additional genetic markers, which exhibited a differential expression (P < 0.001) among tumor grades and between tumor and normal tissues. By including eight log-scaled gene expression variables, three clinical variables, and interaction terms among the eight genes, we established a prognostic model that accounted for two thirds of the variation (R2) in survival for this set of patients. To improve the R2 of the model without compromising its clinical utility, our data demonstrated that incorporating genes from different pathways markedly strengthens the model. Spearman rank correlation analysis of gene expression demonstrated a statistically significant positive correlation (P < 0.01) between the expression of IGFBP2-MMP2 and IGFBP2-VEGF in GBMs, but not in AAs. This finding suggests that the expression of IGFBP2 is associated with pathways activated specifically in GBMs that result in enhancing invasiveness and angiogenesis.


Tissue reservoirs of HIV.
Tissue reservoirs of HIV may promote the persistent immunopathology responsible for non-AIDS morbidity and data support multifocal reactivation from tissues as the source of viral rebound during antiretroviral therapy (ART) interruption. The heterogeneity of tissue reservoirs and incomplete knowledge about their composition are obstacles to an HIV cure. In addition to the higher concentration of infected CD4 T cells found in both central lymphoid tissues and gut, specific subsets of CD4 T cells appear to play a disproportionate role in HIV persistence. Recently, a subset of central memory T cells enriched in lymph node germinal centers called T-follicular helper cells has been identified that expresses more viral RNA and occupies an anatomic niche inaccessible to cytotoxic T lymphocyte killing. Additional observations suggest that antiretroviral drug (ARV) concentrations may be lower in some tissues, raising the possibility for localized, low-level viral replication. Finally, some recent data implicate the persistence of infected, non-CD4 T-cell types in tissues during ART. The retention of infected cells in a wide variety of tissues, often with distinct viral and cellular characteristics, underscores the importance of studying tissue reservoirs in the development and assessment of cure strategies. Both inhibitory ARVs and latency-reversing drugs must reach these sites, and novel strategies may be needed to attack virus in cells as variable as T-follicular helper cells and macrophages.


An unnecessary response is detected faster than an insufficient response.
Error-related negativity is an event-related potential component that is observed when participants make errors and reflects action monitoring that involves error detection. In this study, an over-response error (responding with both hands when participants were asked to respond with only one hand) and an under-response error (responding with one hand when asked to respond with both hands) were assessed by the characteristics of the error-related negativity during a modified Eriksen flankers task. The results indicated that a bimanual response error also elicited the error-related negativity, and that the onset latency of the error-related negativity was shorter for an over-response error than for an under-response error. Thus, these results suggest that the error-detection process is more sensitive to an unnecessary response than to an insufficient response.


Limitations of autograft and allograft: new synthetic solutions.
Autogenous cancellous bone is widely regarded as an ideal construct for graft procedures, supplying osteoinductive growth factors, osteogenic cells, and a structural scaffold. However, procurement morbidity and constraints on obtainable quantities limit its use. Allograft is the next best alternative at present; however, minor immunogenic rejection and risk of disease transmission are unresolved issues. Although synthetic grafting materials eliminate these risks, these materials do not transfer osteoinductive or osteogenic elements to the host site. To offer the advantages of autograft and allograft, a composite graft may be considered. Such a graft can combine a synthetic scaffold with biologic elements to stimulate cell infiltration and new bone formation.


A pediatric trial of radiation/cetuximab followed by irinotecan/cetuximab in newly diagnosed diffuse pontine gliomas and high-grade astrocytomas: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study.
Diffuse intrinsic pontine gliomas (DIPGs) and high-grade astrocytomas (HGA) continue to have dismal prognoses. The combination of cetuximab and irinotecan was demonstrated to be safe and tolerable in a previous pediatric phase 1 combination study. We developed this phase 2 trial to investigate the safety and efficacy of cetuximab given with radiation therapy followed by adjuvant cetuximab and irinotecan. Eligible patients of age 3-21 years had newly diagnosed DIPG or HGA. Patients received radiation therapy (5,940 cGy) with concurrent cetuximab. Following radiation, patients received cetuximab weekly and irinotecan daily for 5 days per week for 2 weeks every 21 days for 30 weeks. Correlative studies were performed. The regimen was considered to be promising if the number of patients with 1-year progression-free survival (PFS) for DIPG and HGA was at least six of 25 and 14 of 26, respectively. Forty-five evaluable patients were enrolled (25 DIPG and 20 HGA). Six patients with DIPG and five with HGA were progression free at 1 year from the start of therapy with 1-year PFS of 29.6% and 18%, respectively. Fatigue, gastrointestinal complaints, electrolyte abnormalities, and rash were the most common adverse events and generally of grade 1 and 2. Increased epidermal growth factor receptor copy number but no K-ras mutations were identified in available samples. The trial did not meet the predetermined endpoint to deem this regimen successful for HGA. While the trial met the predetermined endpoint for DIPG, overall survival was not markedly improved from historical controls, therefore does not merit further study in this population.


Mixed diabetic retinopathy screening coverage results in Indigenous Australian primary care settings: A nurse-led model of integrated diabetes care.
To determine eye screening coverage and adherence to national eye screening recommendations of a nurse-led retinal image-based model of diabetes education and eye screening in Indigenous primary care clinics. A pre-post study. During January 2018-March 2020 Indigenous Australians with diabetes at three regional Australian clinics were offered eye screening by a nurse-diabetes educator/retinal imager. At the main site the nurse recruited/scheduled participants, and at satellite sites local clinic staff did so. Visual acuity was tested and digital retinal images acquired and graded. Participants were offered rescreening at or before 12-months based on baseline results. In total 203 adults with diabetes attending Indigenous primary care clinics were screened, with divergent results based on the recruitment methods. At the main clinic 135 of 172 eligible adults (79%) were screened. At the satellite sites, 15 of 85 (18%) and 21 of 77 (27%) diabetes patients were screened. Combined coverage 51%. A credentialed nurse-educator implemented a model of retinal image-based diabetes education, measured eye screening coverage and adherence to national eye screening guidelines, met the 'acceptable 75% eye screening coverage' benchmark and improved patient eye screening guideline adherence at the one site where the nurse-educator had access to patient recruitment and scheduling. This novel nurse-led primary care iDEES model of retinal image-based diabetes education can improve the currently low Indigenous diabetes eye screening coverage in Australia. Importantly, the nurse-managed iDEES model of integrated diabetes care is readily adaptable to other settings and populations where access to and/or uptake of eye care is suboptimal. ANZCTRN1261800120435.


The Rubber Hand Illusion in Healthy Younger and Older Adults.
Percepts about our body's position in space and about body ownership are informed by multisensory feedback from visual, proprioceptive, and tactile inputs. The Rubber Hand Illusion (RHI) is a multisensory illusion that is induced when an observer sees a rubber hand being stroked while they feel their own, spatially displaced, and obstructed hand being stroked. When temporally synchronous, the visual-tactile interactions can create the illusion that the rubber hand belongs to the observer and that the observer's real hand is shifted in position towards the rubber hand. Importantly, little is understood about whether these multisensory perceptions of the body change with older age. Thus, in this study we implemented a classic RHI protocol (synchronous versus asynchronous stroking) with healthy younger (18-35) and older (65+) adults and measured the magnitude of proprioceptive drift and the subjective experience of body ownership. As an adjunctive objective measure, skin temperature was recorded to evaluate whether decreases in skin temperature were associated with illusory percepts, as has been shown previously. The RHI was observed for both age groups with respect to increased drift and higher ratings of ownership following synchronous compared to asynchronous stroking. Importantly, no effects of age and no interactions between age and condition were observed for either of these outcome measures. No effects were observed for skin temperature. Overall, these results contribute to an emerging field of research investigating the conditions under which age-related differences in multisensory integration are observed by providing insights into the role of visual, proprioceptive, and tactile inputs on bodily percepts.


Treatment of Die-Punch Fractures with 3D Printing Technology.
We evaluated the feasibility, accuracy and effectiveness of applying three-dimensional (3D) printing technology for preoperative planning for die-punch fractures. A total of 107 patients who underwent die-punch fracture surgery were enrolled in the study. They were randomly divided into two groups: 52 cases in the 3D model group and 55 cases in the routine group. A 3D digital model of each die-punch fracture was reconstructed in the 3D group. The 3D digital model was imported to a 3D printer to build the full solid model. The operation time, blood loss volume, and the number of intraoperative fluoroscopy were recorded. Follow-up was performed to evaluate the patients' surgical outcomes. Treatment of die-punch fractures using the 3D printing approach reduced the number of intraoperative fluoroscopy, blood loss volume, and operation time, but did not improve wrist function compared to those in the routine group. The patients wanted the doctor to use the 3D model to introduce the condition and operative plan because it was easier for them to understand. The orthopedic surgeons thought that the 3D model was useful for communicating with their patients, but their satisfaction with the preoperative plan was much lower than the benefit of using the 3D model to communicate with their patients. 3D printing technology produced more accurate morphometric information for orthopedists to provide personalized surgical planning and communicate better with their patients. However, it is difficult to use widely in the department of orthopedics.


Application of light sensitive chemicals to probe protein structure and function.
These results suggest that important information regarding the conformation of complementary binding sites and the behavior of various charged states of inhibitors can be obtained from studies of the pH dependence of photoaffinity labeling experiments. This information may assist in identifying the pKas of key residues controlling the binding interaction. This technique should prove very useful in probing binding site structure on nonfunctioning targets, such as enzyme zymogens, as well as complicated receptor interactions.


A Novel Method for Extrinsic Calibration of Multiple RGB-D Cameras Using Descriptor-Based Patterns.
This paper presents a novel method to estimate the relative poses between RGB-D cameras with minimal overlapping fields of view. This calibration problem is relevant to applications such as indoor 3D mapping and robot navigation that can benefit from a wider field of view using multiple RGB-D cameras. The proposed approach relies on descriptor-based patterns to provide well-matched 2D keypoints in the case of a minimal overlapping field of view between cameras. Integrating the matched 2D keypoints with corresponding depth values, a set of 3D matched keypoints are constructed to calibrate multiple RGB-D cameras. Experiments validated the accuracy and efficiency of the proposed calibration approach.


Delayed presentation of traumatic diaphragmatic rupture.
We present a case of traumatic diaphragmatic rupture that presented two years after the initial thoracic injury. The patient presented with intestinal obstruction and colonic perforations. Through laparotomy, the diaphragmatic defect was repaired and the colonic perforations were closed. The patient had an uneventful post-operative recovery.


Use of Extracorporeal Membrane Oxygenation in Refractory Cardiogenic Shock.
Cardiogenic shock is a condition marked by low cardiac output and end-organ hypoperfusion frequently requiring hemodynamic support, and it carries a high mortality. Extracorporeal membrane oxygenation (ECMO) is an effective tool in providing mechanical circulatory support in patients with cardiogenic shock refractory to conventional medical therapies. ECMO can be an essential bridge to recovery, ventricular assist device implantation or transplant. A multidisciplinary team approach is needed in managing such patients and intensive monitoring is required to avoid complications from ECMO. Nevertheless, randomized clinic trials are warranted to prove a survival benefit.


Pre-steady-state and steady-state kinetic analysis of the low molecular weight phosphotyrosyl protein phosphatase from bovine heart.
The complete time course of the hydrolysis of p-nitrophenyl phosphate catalyzed by the low molecular weight (acid) phosphotyrosyl protein phosphatase from bovine heart was elucidated and analyzed in detail. Burst titration kinetics were demonstrated for the first time with this class of enzyme. At pH 7.0, 4.5 degrees C, a transient pre-steady-state "burst" of p-nitrophenol was formed with a rate constant of 48 s-1. The burst was effectively stoichiometric and corresponded to a single enzyme active site/molecule. The burst was followed by a slow steady-state turnover of the phosphoenzyme intermediate with a rate constant of 1.2 s-1. Product inhibition studies indicated an ordered uni-bi kinetic scheme for the hydrolysis. Partition experiments conducted for several substrates revealed a constant product ratio. Vmax was constant for these substrates, and the overall rate of hydrolysis was increased greatly in the presence of alcohol acceptors. An enzyme-catalyzed 18O exchange between inorganic phosphate and water was detected and occurred with kcat = 4.47 x 10(-3) s-1 at pH 5.0, 37 degrees C. These results were all consistent with the existence of a phosphoenzyme intermediate in the catalytic pathway and with the breakdown of the intermediate being the rate-limiting step. The true Michaelis binding constant Ks = 6.0 mM, the apparent Km = 0.38 mM, and the rate constants for phosphorylation (k2 = 540 s-1) and dephosphorylation (k3 = 36.5 s-1) were determined under steady-state conditions with p-nitrophenyl phosphate at pH 5.0 and 37 degrees C in the presence of phosphate acceptors. The energies of activation for the enzyme-catalyzed hydrolysis at pH 5.0 and 7.0 were 13.6 and 14.1 kcal/mol, respectively. The activation energy for the enzyme-catalyzed medium 18O exchange between phosphate and water was 20.2 kcal/mol. Using the available equilibrium and rate constants, an energetic diagram was constructed for the enzyme-catalyzed reaction.


Frequency of molar incisor hypomineralization and associated factors among children with special health care needs.
Molar incisor hypomineralization (MIH) is a frequently encountered oral condition that varies from mild opacities to posteruptive enamel breakdown. No previous published studies have investigated the frequency of MIH and associated risk factors among children with special health care needs (CSHCN) to our awareness. Assess the frequency of MIH and associated risk factors among CSHCN. Cross-sectional. Schools in provincial city of Saudi Arabia. The study was conducted among 400 (180 boys and 220 girls) special needs children. Diagnosis of MIH was according to the European Academy of Paediatric Dentistry criteria. Result of logistic regression analysis that assessed the association between MIH prevalence and associated prenatal, perinatal, and postnatal factors. 400 (180 boys and 220 girls) special needs children. Among 400 CSHCN, 98 (24.5%) presented with MIH. Children with multiple disabilities had a 3.89 times greater risk of MIH (95% CI: 1.91-6.19, P=.002). Children with positive prenatal factors had an adjusted odds ratio (aOR) of 2.31 times for MIH (95% CI: 1.22-4.73, P=.012). Children with a childhood infection history had an aOR of 2.43 times for MIH (95% CI: 1.31-5.85, P=.014). Children with a breastfeeding history >18 months had an aOR of 3.73 for MIH (95% CI: 1.62-8.60, P=.002). Permanent maxillary first molars were the most frequently affected teeth, and demarcated opacity was the most frequent MIH type. MIH should be recognized as one of the prevalent oral health problems among CSHCN to prevent tooth mortality. A cross-sectional study cannot establish a causal relationship. None.


Hyperhomocysteinaemia and the risk of recurrent venous thrombosis: results from the MEGA follow-up study.
The measurement of homocysteine is still part of routine thrombosis or thrombophilia work-up in many thrombosis centres in the world. Previous observational studies have shown that hyperhomocysteinaemia is associated with an increased risk of first and recurrent venous thrombosis (VT). Randomised trials, however, showed no benefit of homocysteine-lowering therapy on the risk of first or recurrent VT. This discrepancy could be explained by incomplete adjustment for confounders in the observational studies. We investigated in a large population-based follow-up study whether if the levels of homocysteine and its metabolites, methionine and cysteine, were associated with recurrent VT. Approximately three months after discontinuation of anticoagulant treatment, homocysteine, methionine and cysteine concentrations were measured in 2210 patients with VT. During a median follow-up of 6·9 years, 340 patients developed a recurrence (incidence rate, 2·8/100 patient-years). We found that elevated homocysteine concentrations were not associated with an increased risk of recurrent VT, neither as a continuous variable per 5 μmol/l increase (hazard ratio [HR] 0·98 (95% confidence interval [CI], 0·90-1·04)) nor when levels were >95th (>23·0 μmol/l) percentile (HR 1·03 (95% CI, 0·65-1·64)). Similar results were obtained for cysteine and methionine values. We conclude that hyperhomocysteinaemia is not associated with an increased risk of recurrent VT.


Regulation of initiation of DNA synthesis in Chinese hamster cells. I. Production of stable, reversible G1-arrested populations in suspension culture.
Suspension cultures of Chinese hamster cells (line CHO) were grown to stationary phase (approximately 8-9 x 10(5) cells/ml) in F-10 medium. Cells remained viable (95%) for at least 80 hr in stationary phase, and essentially all of the cells were in G(1) Upon resuspension or dilution with fresh medium, the cells were induced to resume traverse of the life cycle in in synchrony, and the patterns of DNA synthesis and division were similar to those observed in cultures prepared by mitotic selection. Immediately after dilution, the rates of synthesis of RNA and protein increased threefold. This system provides a simple technique for production of large quantities of highly synchronized cells and may ultimately provide information on the biochemical mechanisms regulating cell-cycle traverse.


An Anti-Adhesion Technique in Microfluidic Channel Using Dielectrophoresis for Particle Processing Microfluidic Chip Applications.
Particle adhesion to the walls of microfluidic channels is a prominent cause of deteriorating performance and reliability in miniaturized analytical devices; it can also cause unexpected changes in their structures and operating conditions. Therefore, the demand of anti-adhesion for wall loss reduction on particle processing chips is high. This paper demonstrates an anti-adhesion technique using dielectrophoresis. The proposed technique is applied to a distribution microchannel for a feasibility test and is then applied to a blood plasma filter, which is a human blood cell and plasma separation device. In the distribution microchannel, the application of electric potentials of 0-20 V(pp) at 3 MHz caused the wall loss of polystyrene latex (PSL) particles to decrease with decreasing particle diameter. When an electric potential of 20 V(pp) was applied in a distribution microchannel experiment using PSL particles, the wall loss decreased by 52.7 ± 3% for 10-μm-diameter particles. On the other hand, when a 20 V(pp) electric potential was applied in a distribution microchannel experiment using human blood cells, the wall loss decreased by 66.4 ± 6%. In the blood plasma filter, the wall loss decreased by 54.89 ± 5% at 20 V(pp) and 1 MHz. The purity efficiency of the blood plasma filter was 69.56% without the wall loss reduction technique and 95.14% when the applied electric potential was 20 V(pp).


Coexistence of malignant struma ovarii and Graves' disease.
To report an unusual case of hyperthyroidism from Graves' disease that was coexistent with malignant struma ovarii. We summarize the clinical history, physical findings, laboratory data, imaging studies, pathologic features, and treatment in a patient with recurrent hyperthyroidism and discuss the incidence of ovarian tumors of various histologic origins, including thyroid tissue (that is, struma ovarii). Five years after diagnosis of Graves' disease and resolution of symptoms with 1 year of antithyroid drug therapy, a 53-year-old woman had recurrence of palpitations, tremors, and weight loss. Results of thyroid function tests showed high total and free thyroxine levels and a low thyrotropin level. Thyroid radioiodine uptake was high (69% at 24 hours). Abdominal ultrasound studies disclosed a cystic mass in the right adnexal area. Total abdominal hysterectomy and bilateral oophorectomy revealed a 7.5-cm cystic right ovary that contained a 1.0-cm struma ovarii with a 0.4-cm nodule of follicular variant papillary thyroid carcinoma within it. The patient was treated with methimazole and radioiodine ablation of the thyroid. Three months later, a massive myocardial infarction resulted in her death. The concomitant presence of Graves' disease complicates the management of struma ovarii and raises interesting questions about treatment and prognosis.


Conjunctive encoding of movement and reward by ventral tegmental area neurons in the freely navigating rodent.
As one of the two main sources of brain dopamine, the ventral tegmental area (VTA) is important for several complex functions, including motivation, reward prediction, and contextual learning. Although many studies have identified the potential neural substrate of VTA dopaminergic activity in reward prediction functions during Pavlovian and operant conditioning tasks, less is understood about the role of VTA neuronal activity in motivated behaviors and more naturalistic forms of context-dependent learning. Therefore, VTA neural activity was recorded as rats performed a spatial memory task under varying contextual conditions. In addition to reward- and reward predicting cue-related firing commonly observed during conditioning tasks, the activity of a large proportion of VTA neurons was also related to the velocity and/or acceleration of the animal's movement. It is important to note that movement-related activity was strongest when rats displayed more motivation to obtain reward. Furthermore, many cells displayed a dual code of movement- and reward-related activity. These two modes of firing, however, were differentially regulated by context information, suggesting that movement- and reward-related firing are two independently regulated modes of VTA neuronal activity and may serve separate functions.


Microanatomical and histological assessment of the content of superior genial spinal foramen and its bony canal.
To assess histologically the true content of the superior genial spinal foramen and to match these findings to the microanatomical canal content observed using high-resolution magnetic resonance images of the same region. Ten human mandibular specimens were imaged using a 9.4 Tesla MRI unit. Afterwards, eight specimens were decalcified, embedded in paraffin and serially sectioned (7 microm) for histological examination; the remaining two were embedded in methylmethacrylate and sectioned (50-60 microm). All sections were examined using routine light microscopy to inspect the superior genial spinal foramen region and its content. Histological observations of the superior genial spinal foramen confirmed the presence of a well-defined neurovascular bundle, with branches of the lingual nerve and lingual artery. The canal had an average diameter exceeding 1 mm and could thus be considered significant. The present study confirms the existence of a true superior genial spinal foramen's bony canal with neural and blood vessel content. These findings imply that surgical procedures should consider a proper preoperative assessment of the neurovascular trajectory of the superior genial spinal foramen.


[Effect of Kv1.3 and KCa3.1 potassium ion channels on the proliferation and migration of monocytes/macrophages].
This study was aimed to investigate the effects of blockade of Ca(2+) activated channel KCa3.1 and voltage-gated potassium channel Kv1.3 of the monocytes/macrophages on inflammatory monocyte chemotaxis. Chemotaxis assay was used to test the inflammatory Ly-6C(hi) monocyte chemotaxis caused by the monocytes/macrophages. The proliferation of monocytes/macrophages was detected by cell counting kit-8 (CCK8). Enzyme-linked immunosorbent assay (ELISA) was applied to detect the C-C motif ligand 7 (CCL7) in cultured media. The results showed that the recruitment of Ly-6C(hi) monocyte induced by monocytes/macrophages was suppressed by the potent Kv1.3 blocker Stichodactyla helianthus neurotoxin (ShK) or the specific KCa3.1 inhibitor TRAM-34. Meanwhile, the proliferation of monocytes/macrophages was significantly inhibited by ShK. The response of Ly-6C(hi) monocyte pretreated with ShK or TRAM-34 to CCL2 was declined. These results suggest that KCa3.1 and Kv1.3 may play an important role in monocytes/macrophages' proliferation and migration.


99mTc-HDP pinhole SPECT findings of foot reflex sympathetic dystrophy: radiographic and MRI correlation and a speculation about subperiosteal bone resorption.
Reflex sympathetic dystrophy (RSD) is a common rheumatic disorder manifesting painful swelling, discoloration, stiffening and atrophy of the skin. Radiographic alterations include small, spotty subperiosteal bone resorption (SBR) and diffuse porosis, and MR imaging shows bone and soft-tissue edema. The purposes of current investigation were to assess 99mTc HDP pinhole SPECT (pSPECT) findings of RSD, to correlate them with those of radiography and MRI and to speculate about causative mechanism of SBR which characterizes RSD. pSPECT was performed in five patients with RSD of the foot. pSPECT showed small, discrete, spotty hot areas in the subperiosteal zones of ankle bones in all five patients. Diffusely increased tracer uptake was seen in the retrocalcaneal surface where the calcaneal tendon inserts in two patients with atrophic RSD. pSPECT and radiographic correlation showed spotty hot areas, that reflect focally activated bone turnover, to closely match with SBR. Further correlation with MRI showed both spotty hot areas and SBR to coincide in location with the insertions of ligaments and tendons, onto which pulling strain is constantly exerted. In contrast, the disuse osteoporosis in unstrained bones did not show any more significantly increased tracer uptake than normal cancellous bones.