Hepatoprotective effects of gemigliptin and empagliflozin in a murine model of diet-induced non-alcoholic fatty liver disease.
Non-alcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver diseases characterized by steatosis, inflammation, and fibrosis. This study aimed to investigate the potential of dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors in alleviating the progression of NAFLD. The NAFLD model was generated by feeding male C57BL/6J mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 7 weeks. After 2 weeks of CDAHFD feeding, the NAFLD model mice were assigned to four groups, namely (ⅰ) VEHICLE, (ⅱ) gemigliptin (GEMI), (ⅲ) empagliflozin (EMPA), and (ⅳ) GEMI + EMPA. For the next 5 weeks, mice received the vehicle or the drug based upon the group to which they belonged. Thereafter, the triglyceride concentration, extent of fibrosis, and the expression of genes encoding inflammatory cytokines, chemokines, and antioxidant enzymes were analyzed in the livers of mice. The NAFLD activity score and hepatic fibrosis grade were assessed via hematoxylin and eosin and Sirius Red staining of the liver tissue samples. All mice belonging to the GEMI, EMPA, and GEMI + EMPA groups showed improvements in the accumulation of liver triglycerides and the expression of inflammatory cytokines and chemokines. Additionally, the oxidative stress was reduced due to inhibition of the c-Jun N-terminal kinase pathway and upregulation of the antioxidant enzymes. Furthermore, in these three groups, the galectin-3 and interleukin 33-induced activity of tumor necrosis factor-α was inhibited, thereby preventing the progression of liver fibrosis. These findings suggest that the GEMI, EMPA, and GEMI + EMPA treatments ameliorate hepatic steatosis, inflammation, oxidative stress, and fibrosis in CDAHFD-induced NAFLD mouse models.


Genetic lessons learned from X-linked Mendelian susceptibility to mycobacterial diseases.
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare syndrome conferring predisposition to clinical disease caused by weakly virulent mycobacteria, such as Mycobacterium bovis Bacille Calmette Guérin (BCG) vaccines and nontuberculous, environmental mycobacteria (EM). Since 1996, MSMD-causing mutations have been found in six autosomal genes involved in IL-12/23-dependent, IFN-γ-mediated immunity. The aim of this review is to provide the description of the two described forms of X-linked recessive (XR) MSMD. Germline mutations in two genes, NEMO and CYBB, have long been known to cause other human diseases-incontinentia pigmenti (IP) and anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (NEMO/IKKG), and X-linked chronic granulomatous disease (CGD) (CYBB)-but specific mutations in either of these two genes have recently been shown to cause XR-MSMD. NEMO is an essential component of several NF-κB-dependent signaling pathways. The MSMD-causing mutations in NEMO selectively affect the CD40-dependent induction of IL-12 in mononuclear cells. CYBB encodes gp91(phox) , which is an essential component of the NADPH oxidase in phagocytes. The MSMD-causing mutation in CYBB selectively affects the respiratory burst in macrophages. Mutations in NEMO and CYBB may therefore cause MSMD by selectively exerting their deleterious impact on a single signaling pathway (CD40-IL-12, NEMO) or a single cell type (macrophages, CYBB). These experiments of Nature illustrate how specific germline mutations in pleiotropic genes can dissociate signaling pathways or cell lineages, thereby resulting in surprisingly narrow clinical phenotypes.


Multisensory convergence in the thalamus of the pigeon (Columba livia).
Neuronal activity was extracellularly recorded from the nucleus dorsolateralis posterior thalami (DLP) of anesthetized pigeons. The sensitivity of individual cells to stimuli of different sensory modalities: somatosensory, visual and auditory was investigated. A substantial population of the DLP neurons responded to mechanical stimulation of large, often bilateral areas of the animal's body surface. No somatotopic organization could be detected. The functional properties of these neurons resembled those described for mammalian nucleus posterior thalami neurons. The visually responsive cells could be driven from large areas of the visual field. Auditory sensitive neurons were optimally activated by wideband noise. Twenty-nine percent of the DLP recorded neurons showed polysensory properties responding either to somatosensory and visual or to somatosensory and auditory stimuli.


Assessment and validation of the molecular international prognostic scoring system for myelodysplastic syndromes.
The Molecular International Prognostic Scoring System (IPSS-M) is a novel risk stratification model for myelodysplastic syndromes (MDS) that builds on the IPSS and IPSS-R by incorporating mutational data. The model showed improved prognostic accuracy over the IPSS-R across three endpoints: overall survival (OS), leukemia-free survival (LFS) and leukemic transformation. This study aimed to validate the findings of the original in a large cohort of MDS patients, as well as assess its validity in therapy-related and hypoplastic MDS. We retrospectively reviewed clinical, cytogenetic and molecular data for 2355 MDS patients treated at the Moffitt Cancer Center. Correlative analysis between IPSS-R and mean IPSS-M scores and outcome predictions was performed on LFS, OS and leukemic transformation. Using the IPSS-M, patients were classified as Very Low (4%), Low (24%), Moderate-Low (14%), Moderate-High (11%), High (19%) and Very-High risk (28%). Median OS was 11.7, 7.1, 4.4, 3.1, 2.3, and 1.3 years from VL to VH risk subgroups. Median LFS was 12.3, 6.9, 3.6, 2.2, 1.4, and 0.5 years respectively. For patients with t-MDS and h-MDS the model retained its prognostic accuracy. Generalized use of this tool will likely result in more accurate prognostic assessment and optimize therapeutic decision-making in MDS.


Cross-Sectional Patient-Reported Outcome Measuring of Health-Related Quality of Life With Establishment of Cancer- and Treatment-Specific Functional and Symptom Scales in Patients With Penile Cancer.
In the field of uro-oncology, the assessment of quality of life (QoL) is considered an integral part of clinical research. Because of the rarity of penile cancer, there is currently no cancer-specific questionnaire module available to assess the tumor-specific loss of function and symptoms in terms of influencing QoL. The aim of the study was to apply a validated questionnaire (European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30) in a population of patients diagnosed with penile cancer and to compare these results to reference data of the general population. We also developed a new unvalidated questionnaire (Quality of Life Questionnaire-Penile Cancer-Rostock, HRO-PE29) in this population to promote QoL research in the field of uro-oncology. Cross-sectional evaluation of patients with penile cancer after local surgical treatment (n = 76) was performed using EORTC QLQ-C30 and HRO-PE29. The QLQ-C30 provides information on QoL, functional scales, symptom scales, and 6 individual items (inappetence, insomnia, dyspnea, constipation, diarrhea, financial difficulties). Cancer-specific functional and symptom scales (HRO-PE29) were then established for use in different disease states and forms of treatment. These provide information on QoL as well as on cancer-specific function and symptom scores. The global QoL score was 54, which corresponds to an average QoL (score 0-100) and was well below the age-standardized average for German patients. For the general function scores, the following mean values were determined: physical (x¯ = 73), social (x¯ = 61), emotional (x¯ = 60), cognitive functioning (x¯ = 69), and role function (x¯ = 63). With regard to the general symptom scores and the individual items, the following values were found: fatigue (x¯ = 35), nausea (x¯ = 6), pain (x¯ = 27), dyspnea (x¯ = 23), insomnia (x¯ = 41), loss of appetite (x¯ = 25), constipation (x¯ = 19), diarrhea (x¯ = 10), and financial difficulties (x¯ = 25). The following mean values were found for the cancer-specific functional scores: voiding (x¯ = 77), sexuality (x¯ = 69, function and pleasure), body image (x¯ = 64), lymphedema (x¯ = 75), future prospects (x¯ = 72), and adverse effects of systemic treatment (x¯ = 73). Defects of the external genitalia have implications for identity, personality, and interpersonal relationships. The mental stress of these patients results from the diagnosis of cancer as well as the partly mutilating treatment. Reconstructive surgery in penile cancer patients promises to maintain sexual and micturition function and thus improve QoL. Cancer-specific functional losses can be sufficiently named and their influence on QoL determined.


The novel use of heart transplantation for the management of a case with multiple complications after acute myocardial infarction.
Rupture of the interventricular septum after myocardial infarction (MI) is an uncommon but serious complication, usually leading to congestive heart failure and cardiogenic shock. Surgical repair is usually the only definitive treatment for these patients because medical management is associated with a 30-day mortality approaching 100%. However with conventional surgical repair, operative mortality rates range from 33% to 53%. Furthermore, outcomes in patients with posterior ventricular septal defect (VSD) have been reported to have mortality rates up to 86%. Therefore, alternative treatment should be considered to improve management of this mechanical complication. We report the case of a 63-year-old man in whom VSD developed after an inferior MI. The patient presented with shortness of breath and a recent ST-elevation inferior MI. Transthoracic echocardiography revealed a 50% left ventricular ejection fraction with mild-moderate right ventricular dysfunction. A posterior VSD (diameter ≥ 12 mm), moderate ischemic mitral regurgitation (MR), and a posterior pseudoaneurysm were also seen. The operative risk was considered to be too high for VSD repair because the surgery would have to include bypass grafting, mitral valve replacement, and pseudoaneurysm correction. Consequently, an urgent heart transplantation was considered the best option. The patient underwent heart transplantation 9 days after initial symptoms, and the recovery was unremarkable. To achieve a definitive optimal treatment, we propose that patients with posterior VSD with significant MR or pseudoaneurysm, or both, should be considered as heart transplant candidates.


Correction to: Development and validation of a classification algorithm to diagnose and differentiate spontaneous episodic vertigo syndromes: results from the DizzyReg patient registry.
The original version of this article unfortunately contained a mistake. The given names and family names were interchanged.


Stereoselective syntheses of rolliniastatin 1, rollimembrin, and membranacin.
A radical cyclization of beta-alkoxyvinyl sulfoxides-Pummerer rearrangement-allylation protocol was successfully applied to the synthesis of the threo/cis/threo/cis/erythro bis-oxolane moiety in rolliniastatin 1 (1), rollimembrin (2), and membranacin (3).


Nuclear alterations induced by cadmium chloride and L-canavanine in HeLa S3 cells. Accumulation of perichromatin granules.
The effects of L-canavanine and cadmium on the ribonucleoprotein constituents of HeLa S3 cells have been analyzed. Both chemicals induce a similar pattern of alterations in different RNP structures as well as in both RNA and protein synthesis. Pulse and chase autoradiographic experiments reveal that both canavanine and cadmium induce a preferential inhibition of nucleolar RNA synthesis and a slowdown in the transport or processing of nucleolar and extranucleolar RNA. Nucleoli become round and compact. Accumulation of perichromatin granules and fibrils occurs, there is a depletion of interchromatin fibrils, and nuclear formations appear which seem to be involved in the morphogenesis of perichromatin granules accumulated during the treatments. The appearance of clusters of 29- to 35-nm granules might be related with a deficient assembling of constituents of perichromatin granules. The effects of different inhibitors of the transcriptional processes on the accumulation of perichromatin granules suggest that these granules represent a particular subpopulation of hnRNP.


"How can we make it work for you?" Enabling sporting assemblages for disabled young people.
Disabled young people have lower levels of participation in community life than nondisabled peers across a number of domains, including sporting activities, with profound implications for health, wellbeing and life course opportunities. Playing sport is a defining feature of identity for many young people in Aotearoa/New Zealand. Participation in sporting activities provides opportunities to develop competencies, to have fun and to compete, while also providing a sense of inclusion and peer group belonging. However, despite policies promoting inclusion of disabled young people in school and club sport, ableist attitudes and practices still function to exclude individuals who do not fit able-bodied norms. Drawing on recent 'assemblage thinking' in health and cultural geography, this paper explores the material, social and affective dimensions of 'enabling' and 'disabling' sporting assemblages, drawing on interviews with 35 disabled young people (12-25 years), parents and key informants. Many reported instances of demoralising exclusion in mainstream sporting activities. Some turned to adaptive sporting codes, designed for inclusion. In our exploration of participants' embodied experiences of enabling and disabling assemblages we employ assemblage theory to examine how social, affective and material forces and processes converge to either enable or constrain participation in local sporting activities. We close with a brief assessment of the implications of our analysis for ongoing efforts to promote inclusion for disabled youth in physical activity.


DSM-III diagnosis and code types of the Diagnostic Inventory of Personality and Symptoms in public hospital settings.
The relationships of high-point code types of the Diagnostic Inventory of Personality and Symptoms (DIPS) to the Diagnostic and statistical manual III of the American Psychiatric Association (DSM-III) were explored for public hospital patients (N = 448). Nineteen DIPS code types that relate code types to Axis I diagnoses are prepared. The three DIPS personality disorder cluster scales and the eight combinations thereof are presented as well. Eight of the personality disorder cluster scale code types that relate to DSM-III Axis II categories are identified. Finally, a narrative summation of each of the code types is given.


The organization of the pretectal nuclei in the trout: a revision based on experimental holodogical studies.
The neuronal tracer DiI was applied to different brain centers of the rainbow trout in order to study the connections of pretectal nuclei. Our results showed that some pretectal nuclei receive a direct projection from the contralateral retina: the parvocellular superficial pretectal nucleus, the central pretectal nucleus, the intermediate pretectal nucleus and the ventral accessory optic nucleus. In turn, the central pretectal, the intermediate pretectal and the ventral accessory optic nuclei, together with the paracommissural nucleus, project to the cerebellum and the torus longitudinalis. The magnocellular superficial pretectal nucleus does not receive retinal projections, but receives ipsilateral projections from the optic tectum and the mesencephalic tegmentum. In turn, it projects to the ipsilateral oculomotor nucleus and lateral nucleus of the valvula. The posterior pretectal nucleus and the parvocellular superficial pretectal nucleus receive afferents from the ipsilateral nucleus isthmi. The posterior pretectal nucleus projects to the inferior hypothalamic lobe. Our results reveal a conspicuous projection from the ipsilateral parvocellular superficial pretectal nucleus to the contralateral one and also to the contralateral posterior prectectal nucleus, not reported in previous experimental studies of teleosts. Pretectal centers appear to integrate visual/optic-related centers mainly with the hypothalamus and the cerebellum. The organization of the trout pretectum was compared with the pretectal organization patterns proposed in various teleosts.


Nonhealing boils.
It seemed clear that the growth was linked to a recent trip to a tropical location. But the true cause wasn't the one that was originally suspected.


Is visual illusion decrement based on selective adaptation?
Illusion decrement is the reduction in the magnitude of visual geometric illusions with continued exposure, and it has been explained in two ways. The first explanation is the selective adaptation, or fatigue, of neural channels carrying orientation and/or spatial frequency information; the second explanation involves perceptual learning, in which the observer changes viewing strategy after continued exposure to a stimulus. Either mechanism could cause changes in the perception of a stimulus over time. One hundred twenty observers were tested in an illusion-decrement paradigm under exposure conditions that altered the amount of selective adaptation of specific neural channels. Observers were also measured on the magnitude of the transfer-of-decrement effect. Both decrement and transfer of decrement occurred, but there was no significant difference across exposure conditions. In addition, the pattern of transfer differed from that observed in selective adaptation paradigms. These results argue against a neural adaptation interpretation of illusion decrement.


Can Surgical Resection of Metastatic Lesions Be Beneficial to Pancreatic Ductal Adenocarcinoma Patients with Isolated Lung Metastasis?
In the era of effective chemotherapy on pancreatic ductal adenocarcinoma (PDAC) with distant metastasis, data on the effects of metastatectomy are lacking. So, we investigated the effect of metastatectomy on survival after metastasis in PDAC patients with isolated lung metastasis. This retrospective study analyzed 1342 patients who were histologically diagnosed with PDAC with distant metastasis from January 2007 to December 2018, of which 83 patients had isolated pulmonary metastasis. Additionally, 4263 patients were extracted from the National Cancer Database (NCDB) and analyzed. Log-rank test and Kaplan−Meier survival analysis were used to analyze survival after metastasis. The five-year survival rate was significantly higher in patients who underwent pulmonary metastatectomy than in those who received only chemotherapy or supportive treatment (60.6% vs. 6.2% vs. 0.0%, p < 0.001). A similar trend was observed in the NCDB (two-year survival rate, 27.4% vs. 15.8% vs. 4.7%, p < 0.001). In the multivariate analysis, lung lesion multiplicity (hazard ratio (HR) = 2.004, p = 0.017), metastatectomy (HR = 0.278, p = 0.036), chemotherapy (HR = 0.434, p = 0.024), and chemotherapy cycles (HR = 0.300, p < 0.001) had significant effects on survival. Metastatectomy with primary pancreatic lesions is recommended with effective chemotherapy in PDAC patients with isolated lung metastasis.


High Efficiency Organic/Silicon-Nanowire Hybrid Solar Cells: Significance of Strong Inversion Layer.
Organic/silicon nanowires (SiNWs) hybrid solar cells have recently been recognized as one of potentially low-cost candidates for photovoltaic application. Here, we have controllably prepared a series of uniform silicon nanowires (SiNWs) with various diameters on silicon substrate by metal-assisted chemical etching followed by thermal oxidization, and then fabricated the organic/SiNWs hybrid solar cells with poly(3,4-ethylenedioxythiophene): poly(styrenesulfonate) ( PSS). It is found that the reflective index of SiNWs layer for sunlight depends on the filling ratio of SiNWs. Compared to the SiNWs with the lowest reflectivity (LR-SiNWs), the solar cell based on the SiNWs with low filling ratio (LF-SiNWs) has a higher open-circuit voltage and fill factor. The capacitance-voltage measurements have clarified that the built-in potential barrier at the LF-SiNWs/ PSS interface is much larger than that at the LR-SiNWs/PEDOT one, which yields a strong inversion layer generating near the silicon surface. The formation of inversion layer can effectively suppress the carrier recombination, reducing the leakage current of solar cell, and meanwhile transfer the LF-SiNWs/ PSS device into a p-n junction. As a result, a highest efficiency of 13.11% is achieved for the LF-SiNWs/ PSS solar cell. These results pave a way to the fabrication of high efficiency organic/SiNWs hybrid solar cells.


Biofilm development with an emphasis on Bacillus subtilis.
Our understanding of the molecular mechanisms involved in biofilm formation has increased tremendously in recent years. From research on diverse bacteria, a general model of bacterial biofilm development has emerged. This model can be adjusted to fit either of two common modes of unicellular existence: nonmotile and motile. Here we provide a detailed review of what is currently known about biofilm formation by the motile bacterium Bacillus subtilis. While the ability of bacteria to form a biofilm appears to be almost universal and overarching themes apply, the combination of molecular events necessary varies widely, and this is reflected in the other chapters of this book.


Periodically spilled-oil input as a trigger to stimulate the development of hydrocarbon-degrading consortia in a beach ecosystem.
In this study, time-series samples were taken from a gravel beach to ascertain whether a periodic oil input induced by tidal action at the early stage of an oil spill can be a trigger to stimulate the development of hydrocarbon-degrading bacteria under natural in situ attenuation. High-throughput sequencing shows that the microbial community in beach sediments is characterized by the enrichment of hydrocarbon-degrading bacteria, including Alcanivorax, Dietzia, and Marinobacter. Accompanying the periodic floating-oil input, dynamic successions of microbial communities and corresponding fluctuations in functional genes (alkB and RDH) are clearly indicated in a time sequence, which keeps pace with the ongoing biodegradation of the spilled oil. The microbial succession that accompanies tidal action could benefit from the enhanced exchange of oxygen and nutrients; however, regular inputs of floating oil can be a trigger to stimulate an in situ "seed bank" of hydrocarbon-degrading bacteria. This leads to the continued blooming of hydrocarbon-degrading consortia in beach ecosystems. The results provide new insights into the beach microbial community structure and function in response to oil spills.


Substance Use and Abuse and Its Effects on Mental Disorders in Trinidad and Tobago - The Available Prevention and Management Strategies.
This paper deals with the relationship between substance abuse and mental illness in Trinidad and Tobago, its implications and management strategies. Dealing with mental health issues is an uphill battle and an attempt will be made in this paper to address the major issues at hand.


Minimally invasive versus open surgery for acute Achilles tendon rupture: a systematic review of overlapping meta-analyses.
A number of meta-analyses have been carried out to evaluate the effects of minimally invasive surgery (MIS) versus open surgery (OS) for acute Achilles tendon rupture. However, discordant findings were seen in these meta-analyses. The present study, performing a systematic review of overlapping meta-analyses regarding MIS versus OS of acute Achilles tendon rupture, aimed to assist decision-makers interpret and choose among conflicting meta-analyses, as well as to offer treatment recommendations based on current best evidence. The literature search was performed to identify systematic reviews comparing MIS with OS for Achilles tendon rupture. Meta-analyses only comprising randomized controlled trials (RCTs) were included. Two authors individually evaluated the quality of meta-analysis and extracted data. The Jadad decision algorithm was conducted to ascertain which meta-analysis offered the best evidence. A total of four meta-analyses was included. All these meta-analyses comprised RCTs or quasi-RCTs and were determined as Level-II evidence. The scores of the Assessment of Multiple Systematic Reviews (AMSTAR) ranged from 7 to 10 (median 9.5). The Jadad algorithm indicated that the best meta-analysis should be chosen according to the search strategies and application of selection. A high-quality meta-analysis with more RCTs was chosen, which suggested that there was no statistically significant difference between MIS and OS regarding rerupture rate, tissue adhesion, sural nerve injury, deep infection, and deep vein thrombosis. However, MIS could decrease superficial infection rate, and had a better patient satisfaction for good to excellent outcomes in comparison to OS. Based on the best available evidence, MIS may be superior to OS for treating acute Achilles tendon rupture. However, due to some limitations, this should be cautiously interpreted, and further high-quality studies are needed.


Multiple-dose up-titration study to evaluate the pharmacokinetics, safety and antitumor activity of apatinib in advanced gastric adenocarcinoma.
The objective of this study was to investigate the pharmacokinetics, safety, and antitumor activity of apatinib, a vascular endothelial growth factor receptor 2 inhibitor, in advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma and evaluate the effect of dose titration on dosage optimization for individual patients. Patient with advanced gastric adenocarcinoma progressed after at least one line of chemotherapy were enrolled. Apatinib was given orally once daily starting at 500 mg for 14 days, then up-titrated to 750 mg for 14 days, and then proceeded to a maximum dose of 850 mg. Dose up-titration determination was based on toxicity. The 28-day treatment cycles continued until disease progression, intolerable toxicities, withdrawal of consent, or investigator' decision. A total of 60 patients were enrolled, with 17, 18, and 25 patients receiving a maximum dose of 500 mg, 750 mg, and 850 mg, respectively. The pharmacokinetic parameters varied considerably, with the interpatient coefficient of variation for steady state areas under the plasma concentration time curve (AUCss) and the mean maximum concentration of both > 50%. During 500 mg and 750 mg dosing stage, drug exposures in patients with a maximum dosage of 850 mg were lower than in those not titrated to 850 mg. Patients with total gastrectomy exhibited significantly lower AUCss than patients with partial or no gastrectomy (p = 0.004 and 0.032, respectively). Toxicities were tolerable, and disease control rate was 39.5% (95% CI 25.0%-55.6%). Apatinib dose titration based on toxicity could be used in clinical practice to provide optimal dosage for individual patients. https://clinicaltrials.gov/ct2/show/NCT02764268?term=NCT02764268&draw=2&rank=1, NCT02764268.


Numerical changes in the mitochondrial DNA displacement loop in lung lesions induced by N-nitrosobis(2-hydroxypropyl)amine in rats.
Mutations in the mitochondrial DNA (mtDNA) displacement loop (D-loop) region were investigated to clarify the possible molecular mechanisms underlying the development of lung tumors induced by N-nitrosobis(2-hydroxypropyl)amine (BHP) in rats. Male Wistar rats, 6 weeks of age, were given 2000 ppm BHP in their drinking water for 12 weeks and then maintained without further treatment until sacrifice at 25 weeks. Genomic DNA was extracted from paraffin-embedded tissues and polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) analysis, followed by nucleotide sequencing, was performed. Eleven out of 24 hyperplasias (45.6%), 8 out of 16 adenomas (50.0%), and 14 out of 21 adenocarcinomas (66.7%) showed numerical changes, in a polymeric C-tract at positions 16,086-16,092 of the mtDNA D-loop, with a one base insertion of cytosine increasing the length of the C-tract, from the seven nucleotides observed in normal lung tissues from non-BHP treated rats, to eight. These changes were all homoplasmic and no changes were found in lung lesions when the length of the C-tract in the normal lung tissues adjacent to the lesions was seven. These results suggest that alterations in the mtDNA D-loop may occur in an early phase of lung carcinogenesis induced in rats by BHP.


Effect of maternal body mass index on pregnancy outcome and newborn weight.
Maternal obesity has been associated with adverse pregnancy outcomes, such as pre-eclampsia, eclampsia, pre- and post-term delivery, induction of labor, macrosomia, increased rate of caesarean section, and post-partum hemorrhage. The objective of this study was to determine the effect of maternal Body Mass Index (BMI) on pregnancy outcomes. 1000 pregnant women were enrolled in the study. In order to explore the relationship between maternal first trimester Body Mass Index and pregnancy outcomes, participants were categorized into five groups based on their first trimester Body Mass Index. The data were analyzed using Pearson Chi-square tests in SPSS 18. Differences were considered significant if p < 0.05. Women with an above-normal Body Mass Index had a higher incidence of pre-eclampsia, induction of labor, caesarean section, pre-term labor, and macrosomia than women with a normal Body Mass Index (controls). There was no significant difference in the incidence of post-term delivery between the control group and other groups. Increased BMI increases the incidence of induction of labor, caesarean section, pre-term labor and macrosomia. The BMI of women in the first trimester of pregnancy is associated with the risk of adverse pregnancy outcome.


Failure of preenucleation radiation to decrease uveal melanoma mortality.
We analyzed uveal melanoma metastases in a group of 41 patients who received 20 Gy of preenucleation radiation in a Northern California Oncology Group preliminary phase I/II study, and compared their survival rates with a retrospective control group of 31 patients with characteristics matching the entrance criteria but treated with enucleation alone. Using the Cox proportional hazards model, we found that increased tumor diameter, mixed or epithelioid cell type, and radiation adversely affected survival. In vivo studies of cell cycling indicated that 20 Gy of preenucleation radiation appeared to diminish the reproductive integrity of the tumor cells. It is most likely that the failure of preenucleation irradiation to prolong patient survival was because of micrometastases that occurred before treatment.


Serum human chorionic gonadotropin decline following aspiration abortion in early pregnancy less than 42 days gestation.
To define serum human chorionic gonadotropin (hCG) decline following complete aspiration abortion. We performed a secondary analysis of 86 patients who underwent uncomplicated aspiration abortion for ultrasound-confirmed pregnancy ≤42 days gestation and had serum hCG at the time of aspiration and within 3 days postprocedure. Median hCG declines were 72.9% by day 1 (n = 14), 87.6% by day 2 (n = 50), and 92.8% by day 3 (n = 22). Ninetieth percentile declines were 67.8%, 81.5%, and 90.8%. Minimum hCG declines were 56.2%, 77.3%, and 83.2%. Trends did not vary by gestational age or by initial hCG <3000 mIU/mL. Postprocedure hCG trend varies over the first few days in early gestation. At ≤42 days gestation, serial hCG decline at 1 day after completed aspiration abortion is greater than 50%, consistent with the decline observed in medication abortion. This study confirms previously estimated human chorionic gonadotropin decline after aspiration abortion of at least 50% at 24 hours for completed procedure in very early gestations. Minimum declines on days 2 and 3 are approximately 70% and 80%.


Factors to consider when selecting a culture of Lactobacillus acidophilus as a dietary adjunct to produce a hypocholesterolemic effect in humans.
Significant variations in bile tolerance and ability to assimilate cholesterol were observed among 12 cultures of Lactobacillus acidophilus of human origin. The degree of bile tolerance as measured by rapidity of growth in MRS broth supplemented with .3% oxgall could not be predicted by the rapidity of growth in the broth without oxgall. There was no apparent direct relationship between bile tolerance and cholesterol assimilation. However, among the cultures that most actively assimilated cholesterol, there were significant differences in bile tolerance. The most active cholesterol-assimilating cultures also varied in the ability to produce bacteriocins. A culture of L. acidophilus of human origin, which assimilates cholesterol, grows well in presence of bile, and produces bacteriocins can be selected for use as a dietary adjunct for humans. A culture of L. acidophilus possessing all these characteristics should have an advantage over one that does not in establishing and functioning in the intestinal tract to assimilate cholesterol.


Conformational promiscuity in triazolamers derived from quaternary amino acids mimics peptide behaviour.
1,4-Substituted triazole oligomers made from quaternary amino acid derivatives present a conformational behaviour with similarities to that of natural peptides. Twisted strand and zig-zag type conformations have both been obtained in the crystal state. In a solution signs of weakly ordered structures have been detected depending on the substituents and the solvents used.


Regulatory interrelations between GABA and polyamines. I. Brain GABA levels and polyamine metabolism.
Elevation of brain GABA levels by GABA-T inhibition is accompanied by a decrease of S-adenosylmethionine decarboxylase activity. This is followed by an increase of ornithine decarboxylase activity and a severalfold increase of brain putrescine levels. Spermidine and spermine levels are not significantly affected under these conditions. These unexpected findings support a regulatory interaction between GABA and polyamine metabolism.


Comparison of cardiovascular disease risk in women with and without breast cancer: secondary data analysis with the 2014-2018 korean national health and nutrition examination survey.
Aging breast cancer survivors may be at an elevated risk of cardiovascular disease (CVD), but little is known about CVD risk assessment and breast cancer in Korean women. We hypothesized that Korean breast cancer survivors would have higher risks of future CVD within the next 10 years (i.e., Framingham Risk Score [FRS]) than women without cancer. (1) To compare FRS-based CVD risks in women with and without breast cancer based on propensity score matching; and (2) To explore adiposity-related measures in relation to FRS in Korean women with breast cancer. Using the cross-sectional data from the 2014-2018 Korean National Health and National Survey (KNHANES), we identified 136 women with breast cancer aged 30-74 years who had no other cancer and no CVD. The comparison group of 544 women with no cancer were selected by 1:4 nearest-neighbor propensity score matching based on breast cancer diagnosis. CVD risk was assessed by FRS based on multiple traditional risk factors (e.g., cholesterol, blood pressure, diabetes, and smoking). Adiposity was measured by physical examination, including body mass index (BMI) and waist-to-height ratio (WHtR). Physical activity and health behaviors were assessed by self-reports. Women with breast cancer (mean age of 57 years) had similar FRS levels at a low-risk category (< 10%) to women with no cancer (4.9% vs. 5.5%). Breast cancer survivors (mean 8.5 survival years) presented at significantly lower levels of total cholesterol, BMI, and WHtR (all p values < 0.05) than their counterpart. Within the breast cancer group, WHtR ≥ 0.5 was associated with higher FRS, compared to WHtR < 0.5. FRS was not different by survival < 5 years or ≥ 5 years after breast cancer diagnosis. FRS-based CVD risks were not different in Korean, mostly postmenopausal, women by breast cancer status. Whereas breast cancer survivors had even lower levels of lipid and adiposity measures than women without cancer, those values indicating borderline cardiometabolic risk suggest continued screening and management efforts for these aging women. Future studies are needed to examine longitudinal trajectories of CVD risk factors and CVD outcomes among Korean breast cancer survivors.


Aggregation and deposition kinetics of carboxymethyl cellulose-modified zero-valent iron nanoparticles in porous media.
Transport and deposition of carboxymethyl cellulose (CMC)-modified nanoparticles of zero-valent iron (NZVI) were investigated in laboratory-scale sand packed columns. Aggregation resulted in a change in the particle size distribution (PSD) with time, and the changes in average particle size were determined by nanoparticle tracking analysis (NTA). The change in PSD over time was influenced by the CMC-NZVI concentration in suspension. A particle-particle attachment efficiency was evaluated by fitting an aggregation model with NTA data and subsequently used to predict changes in PSD over time. Changes in particle sizes over time led to corresponding changes in single-collector contact efficiencies, resulting in altered particle deposition rates over time. A coupled aggregation-colloid transport model was used to demonstrate how changes in PSD can reduce the transport of CMC-NZVI in column experiments. The effects of particle concentrations in the range of 0.07 g L(-1) to 0.725 g L(-1) on the transport in porous media were evaluated by comparing the elution profiles of CMC-NZVI from packed sand columns. Changes in PSD over time could reasonably account for a gradual increase in effluent concentration between 1 and 5 pore volumes (PVs). Processes such as detachment of deposited particles also likely contributed to the gradual increase in effluent concentrations. The particle-collector attachment efficiency increased with CMC-NZVI particle concentration due to a rise in dissolved Na(+) concentration with increased addition of Na-CMC. This inadvertent change in ionic strength led to decreased effluent concentrations at higher CMC-NZVI concentrations.


Incidence and risk factors of infusion reactions in patients with breast cancer administered trastuzumab plus pertuzumab-based regimen.
Pertuzumab (Per) is a humanized monoclonal antibody used in combination with trastuzumab (Tra) in the treatment of human epidermal growth factor receptor-2 (HER2)-positive breast cancer. The administration of biologics, such as Tra and Per, frequently causes infusion reactions (IRs) with fever and chills. This study aimed to clarify the characteristics of and risk factors for IRs in Tra + Per combination therapy. Between March 2013 and December 2019, 64 patients with breast cancer who started Tra + Per combination therapy were included in the study. The severity of IRs was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The incidence of IRs in the Tra + Per combination therapy was 48.4% (31/64). The severity of IRs in the Tra + Per combination therapy was Grade 1 (9 patients) and Grade 2 (22 patients). Lymphocyte counts were significantly different between the IR and non-IR groups in patients receiving Tra + Per combination therapy (univariate analysis, p = 0.006; multivariate analysis, p = 0.050). ROC curve analysis found the cutoff value of lymphocyte counts were 1.60 (× 103/µL). The incidence of IRs in the lymphocyte counts ≥ 1.60 group was significantly higher than that in the lymphocyte counts < 1.60 group (p < 0.001). Our study indicates that the severity of IRs in most patients is moderate or less and the risk of IRs is higher in patients with higher lymphocyte counts (≥ 1.60 × 103/µL).


A stereoselective blockade by naloxone of opioid and non-opioid-induced granulocyte activation.
Naloxone was found to prevent both opioid and non-opioid-induced migration of human granulocytes in a stereoselective way. Indeed, besides being able to inhibit morphine-induced migration, (-) but not (+), naloxone isomer proved to abolish either casein, serum of fMLP-induced chemotaxis. It is concluded that opioid-induced modulation of granulocyte migration is likely to be mediated through specific receptors, possibly of the mu type. Moreover, the antichemotactic effect of naloxone suggests an involvement of opioid receptors and/or endogenously released opioids in the mechanism of granulocyte activation by different chemoattractants.


Deposition and clearance of inhaled diesel exhaust particles in the respiratory tract of Fischer rats.
The fate of inhaled diesel particles was determined in male Fischer 344 rats using radioactive tracers of 131Ba and 14C. Test animals were exposed in a 'nose-only' inhalation chamber for 40-45 min to diluted diesel exhaust generated from diesel engines burning type 2D diesel fuel containing either 131Ba labelled barium dodecylbenzene sulfonate or 14C labelled n-hexadecane. Immediately after exposure, the deposition efficiency of inhaled diesel particles in the respiratory tract was determined to be 15 +/- 6% by external gamma counting of 131Ba and 17 +/- 2% by liquid scintillation counting of 14C in the lung tissue samples. Elimination of the particles was observed by measuring the 131Ba activity in which 40% of the initial deposition was excreted in the feces via the GI tract in 4 days. The long-term retention was determined with the 14C tag in the insoluble 'core' of the diesel particles. Two distinct phases of clearance were evident in the experimental data collected up to 105 days. Clearance half-times of 1 day and 62 days were found for mucociliary and alveolar clearance, respectively. A small fraction of the particles, about 6% of the initial deposition, was found in the mediastinal lymph nodes after 28 days. This demonstrated that the lymphatic system was also involved in the removal of diesel particles from the pulmonary airways.


Alignment of supramolecular J-aggregates based on uracil-functionalized BODIPY dye for polarized photoluminescence.
A BODIPY dye functionalized with uracil-ethynyl groups at the 2,6-positions supramolecularly polymerized into J-aggregates directed by intermolecular H-bonds and featured intense absorption and resonant fluorescence. The alignment of J-aggregated chromophores in a thin film was achieved by a rubbing method and polarized photoluminescence with a dichroic ratio up to 14.3 was obtained.


Low Susceptibility of Pigs against Experimental Infection with HPAI Virus H5N1 Clade 126.96.36.199b.
We found that nasal and alimentary experimental exposure of pigs to highly pathogenic avian influenza virus H5N1 clade 188.8.131.52b was associated with marginal viral replication, without inducing any clinical manifestation or pathological changes. Only 1 of 8 pigs seroconverted, pointing to high resistance of pigs to clade 22.214.171.124b infection.


Using dinoprostone vaginal insert for induction of labor: A single institute experience.
To evaluate the factors associated with the successful induction of labor (IOL) in women treated with dinoprostone slow-released vaginal insert. A retrospective study was conducted between June 2017 and December 2017, enrolling 65 patients who underwent dinoprostone slow-released vaginal insert-induced labor. The correlation between the characteristics of the pregnant women and its success, as well as perinatal complications and adverse outcomes were analyzed. Fifty-three of 65 (81.5%) achieved a successful vaginal delivery. Only multi-parous pregnant women were an independent predictor factor for successful induction after dinoprostone slow-released vaginal insert, since all of them succeeded after this strategy treatment (100%, n = 18), compared to 74.5% (35/47) of successful rate in the nulliparous pregnant women with a statistically significant difference (p = 0.018). There were no adverse events occurred in both mothers and their offspring. Dinoprostone slow-released vaginal insert is a good choice for multiparous pregnant women who need IOL, regardless of which reasons are indicated. For nulliparous women, more studies might be needed to evaluate the effectiveness of PGE2 for IOL.


PARASITIC HELMINTH COMMUNITY OF THE PUDDINGWIFE WRASSE HALICHOERES RADIATUS (LINNAEUS) IN REEFS FROM VERACRUZ, MEXICO.
A total of 1,218 helminths ascribed to 11 taxa (6 at species, 3 at generic, 1 at family, and 1 at order level) in 101 specimens of Halichoeres radiatus (Pisces: Labridae) were caught in the Veracruz Coral Reef System National Park, southern Gulf of Mexico. These helminths include 4 trematode species (3 adults and 1 metacercaria), a cestode species (larvae), 5 nematode species (2 adults and 3 larvae), and an acanthocephalan species (juvenile). Nine correspond to new host records, 2 of them are new geographic records, and 6 species were recorded with 1 helminth per infected host. The larvae of Scaphanocephalus expansus (Creplin, 1842) Jägerskiöld, 1903, and larvae of the order Tetraphyllidea were the parasites with the highest prevalence and mean intensity. Species richness (S = 11) and the Shannon-Wiener diversity index (H' = 1.1) were lower than those recorded for host-parasite communities in the locality. The fact that 10 of the total of 11 parasitic species were found in fish intestines suggests that infection is a result of host feeding habits.


National Infection Control Program in Turkey: The healthcare associated infection rate experiences over 10 years.
The prevalence of healthcare associated infection (HAI) is generally higher in countries with limited resources than developed countries. To address the high prevalence of HAI, Turkish Ministry of Health introduced a national infection control program in 2005. Device associated (DA)-HAIs routinely surveyed included ventilator associated events, urinary catheter associated urinary tract infection and central line associated blood stream infection. Rates in DA-HAI were examined from 2008 to 2017 by type of hospitals, bed capacity, and geographic location of hospitals. All DA-HAIs declined significantly from 2008 to 2017 nationally for ventilator associated events from 16.69 to 4.86 per 1,000 device days (IRR = 0.29, P < .0001), catheter associated urinary tract infection from 4.98 to 1.59 per 1,000 catheter days (IRR = 0.31, P < .0001) and central line associated blood stream infection from 5.65 to 2.82 per 1,000 catheter days (IRR = 0.47, P < .0001). The rates for DA-HAIs declined significantly in hospitals with ≥200 beds and <200 bed capacity and in all 4 type of hospitals. By 2017 all DA-HAI had significantly improved across all regions. The introduction of a new national surveillance system supported by a national infection control program has significantly reduced 3 major DA-HAIs that are associated with risk of treatment failure and death. The next critical step in sustaining this crucial improvement will require timely feedback to hospitals using technology and continued buy-in from clinicians for their commitment to safety associated with DA-HAIs using aspirational DA-HAI rates.


Phylogeny of yeasts and related filamentous fungi within Pucciniomycotina determined from multigene sequence analyses.
In addition to rusts, the subphylum Pucciniomycotina (Basidiomycota) includes a large number of unicellular or dimorphic fungi which are usually studied as yeasts. Ribosomal DNA sequence analyses have shown that the current taxonomic system of the pucciniomycetous yeasts which is based on phenotypic criteria is not concordant with the molecular phylogeny and many genera are polyphyletic. Here we inferred the molecular phylogeny of 184 pucciniomycetous yeast species and related filamentous fungi using maximum likelihood, maximum parsimony and Bayesian inference analyses based on the sequences of seven genes, including the small subunit ribosomal DNA (rDNA), the large subunit rDNA D1/D2 domains, the internal transcribed spacer regions (ITS 1 and 2) of rDNA including the 5.8S rDNA gene; the nuclear protein-coding genes of the two subunits of DNA polymerase II (RPB1 and RPB2) and the translation elongation factor 1-α (TEF1); and the mitochondrial gene cytochrome b (CYTB). A total of 33 monophyletic clades and 18 single species lineages were recognised among the pucciniomycetous yeasts employed, which belonged to four major lineages corresponding to Agaricostilbomycetes, Cystobasidiomycetes, Microbotryomycetes and Mixiomycetes. These lineages remained independent from the classes Atractiellomycetes, Classiculomycetes, Pucciniomycetes and Tritirachiomycetes formed by filamentous taxa in Pucciniomycotina. An updated taxonomic system of pucciniomycetous yeasts implementing the 'One fungus = One name' principle will be proposed based on the phylogenetic framework presented here.


Intrafraction 4D-cone beam CT acquired during volumetric arc radiotherapy delivery: kV parameter optimization and 4D motion accuracy for lung stereotactic body radiotherapy (SBRT) patients.
Elekta XVI 5.0 allows for four-dimensional cone beam computed tomography (4D CBCT) image acquisition during treatment delivery to monitor intrafraction motion. These images can have poorer image quality due to undersampling of kV projections and treatment beam MV scatter effects. We determine if a universal intrafraction preset can be used for stereotactic body radiotherapy (SBRT) lung patients and validate the accuracy of target motion characterized by XVI intrafraction 4D CBCT. The most critical parameter within the intrafraction preset is the nominal AcquisitionInterval, which controls kV imaging acquisition frequency. An optimal value was determined by maximizing the kV frame number acquired up to 1000 frames, typical of pretreatment 4D CBCT. CIRS motion phantom intrafraction phase images for 16 SBRT beams were obtained. Mean target position, time-weighted standard deviation, and amplitude for these images as well as target motion for three SBRT lung patients were compared to respective pretreatment 4D CBCTs. Evaluation of intrafraction 4D CBCT reconstruction revealed inclusion of MV only images acquired to remove MV scatter effects. A workaround to remove these images was developed. AcquisitionInterval of 0.1°/frame was optimal. The number of kV frames acquired was 567-1116 and showed strong linear correlation with beam monitor unit (MUs). Phantom target motion accuracy was excellent with average differences in target position, standard deviation and amplitude range of ≤0.5 mm. Target tracking for SBRT patients also showed good agreement. Evaluation of phase sorting wave forms showed that inclusion of MV only images significantly impacts intrafraction image reconstruction for patients and use of workaround is necessary. A universal intrafraction imaging preset can be used safely for SBRT lung patients. The number of kV projections with MV delivery parameters varies; however images with fewer kV projections still provided accurate target position information. Impact of the reconstruction workaround was significant and is mandated for all 4D CBCT intrafraction imaging performed at our institution.


Bioactivity-guided isolation of anti-inflammatory components from Phyllanthus emblica.
Phyllanthus emblica (P. emblica) is a traditionally edible fruit that is good for treatment of biliary diseases, bronchitis, etc. It has obvious anti-inflammatory activity, but few studies focus on its anti-inflammatory active substance basis. The purpose of this study was to explore the material basis of anti-inflammatory activity of P. emblica, purify, and identify anti-inflammatory active monomers. Fisetin and gallic acid, which were identified after separation from ethanol extract components of P. emblica, exhibited the best anti-inflammatory effects, markedly inhibiting nitric oxide and proinflammatory cytokine levels in LPS-stimulated macrophages. In particular, fisetin with significant anti-inflammatory activity was firstly identified from P. emblica. For the first time, our research systematically revealed the material basis of the anti-inflammatory effects of P. emblica from the perspective of the composition of the bioactive substances and provided scientific research methods and ideas for researching bioactive monomers in other plant extracts.


Muscarinic receptor protein expression in the ocular tissues of the chick during normal and myopic eye development.
Muscarinic receptor signalling has been implicated in both the embryonic and postnatal development of ocular structures as well as in myopic eye growth. A radioligand binding assay was used to determine whether changes in muscarinic receptor density and/or affinity occurred in the chick retina, choroid and sclera during early post-hatching development or with the induction of myopia. Specific receptor binding sites were saturable with increasing concentrations of the muscarinic receptor ligand [3H]N-methyl-scopolamine in the retina and choroid but not in the sclera. In normal eyes, binding density in the retina was not altered from age P5 to P10 (447+/-14 vs. 411+/-13 fmol/mg of protein, P=0.07). However, in the choroid, the number of receptor binding sites significantly increased between P5 and P10 (637+/-39 vs. 1125+/-121 fmol/mg of protein, P<0.01). Binding affinity (K(D)) was not altered with age in either the retina or choroid. Myopia was induced in chicks by deprivation of form vision, using translucent diffusers, from age P3. Despite the induction of significant degrees of ocular elongation and myopia at P5 (-8.7+/-0.3 D, P<0.01) and P10 (-22.5+/-1.3 D, P<0.01), neither muscarinic receptor density nor affinity were altered in the retina or choroid of myopic eyes. These findings indicate that regulation of muscarinic receptor numbers in the chick choroid is occurring in normal post-hatching development of this tissue. However, myopic eye enlargement was not associated with changes in muscarinic receptor protein expression in the chick retina and choroid.


Correlation of Peripheral Immunity With Rapid Amyotrophic Lateral Sclerosis Progression.
Amyotrophic lateral sclerosis (ALS) has an immune component, but previous human studies have not examined immune changes over time. To assess peripheral inflammatory markers in participants with ALS and healthy control individuals and to track immune changes in ALS and determine whether these changes correlate with disease progression. In this longitudinal cohort study, leukocytes were isolated from peripheral blood samples from 35 controls and 119 participants with ALS at the ALS Clinic of the University of Michigan, Ann Arbor, from June 18, 2014, through May 26, 2016. Follow-up visits occurred every 6 to 12 months. Fifty-one participants with ALS provided samples at multiple points. Immune cell populations were measured and compared between control and ALS groups. Surface marker expression of CD11b+ myeloid cells was also assessed. Changes over time were correlated with disease progression using multivariate regression. The number of immune cells per milliliter of blood and the fold expression of cell surface markers. Multivariate regression models were used to correlate changes in immune metrics with changes on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Thirty-five controls (17 women [48.6%] and 18 men [51.4%]; mean [SD] age, 63.5 [9.9] years) and 119 participants with ALS (50 women [42.0%] and 69 men [68.0%]; mean [SD] age, 61.4 [11.5] years) were enrolled. Compared with controls, participants with ALS had increased mean (SEM) counts ( × 106/mL) of total leukocytes (4.57 [0.29; 95% CI, 3.94-5.11] vs 5.53 [0.16; 95% CI, 5.21-5.84]), neutrophils (2.87 [0.23; 95% CI, 2.40-3.35] vs 3.80 [0.12; 95% CI, 3.56-4.04]), CD16+ monocytes (0.03 [0.003; 95% CI, 0.02-0.04] vs 0.04 [0.002; 95% CI, 0.03-0.04]), CD16- monocytes (0.25 [0.02; 95% CI, 0.21-0.30] vs 0.29 [0.01; 95% CI, 0.27-0.31]), and natural killer cells (0.13 [0.02; 95% CI, 0.10-0.17] vs 0.18 [0.01; 95% CI, 0.16-0.21]). We also observed an acute, transient increase in a population of CD11b+ myeloid cells expressing HLA-DR, CD11c, and CX3CR1. Finally, early changes in immune cell numbers had a significant correlation with disease progression measured by change in ALSFRS-R score, particularly neutrophils (-4.37 [95% CI, -6.60 to -2.14] per 11.47 × 104/mL [SD, 58.04 × 104/mL] per year) and CD4 T cells (-30.47 [95% CI, -46.02 to -14.94] per -3.72 × 104/mL [SD, 26.21 × 104/mL] per year). Changes in the immune system occur during ALS and may contribute to the pathologic features of ALS.


Lipid oxidation in plasma and tissues from estrogenized chicken hens.
Four groups of 5-month-old chicken hens were given estradiol treatments and/or 5% dietary oil supplement for 14 days, after which blood plasma, liver, heart, and skeletal muscle were analyzed for lipid oxidation by TBA assay for malonaldehyde. Plasma from estradiol-treated birds had 8-fold higher levels of malonaldehyde compared to untreated birds. The bulk of this effect was due to a 5-fold increase in plasma lipid, but this lipid also contained a 70% higher concentration of malonaldehyde. Estradiol treatments produced significantly increased TBA numbers in liver, heart, and skeletal muscle. Corn oil supplementation significantly increased the malonaldehyde concentration in fat extracted from liver and heart, but not from plasma or skeletal muscle. It was concluded that estradiol treatment, in addition to generally increasing the deposition of fat in plasma and organs, also enhanced the concentration of malonaldehyde equivalents in plasma and organ fat.


Serotonin increases glial cell line-derived neurotrophic factor release in rat C6 glioblastoma cells.
Antidepressants, which increase monoamine levels, induce glial cell line-derived neurotrophic factor (GDNF) release in C6 cells. Thus, we examined whether monoamines affect on GDNF release in C6 cells. We found that serotonin (5-HT) specifically increased GDNF mRNA expression and GDNF release in a dose- and time-dependent manner. The 5-HT-induced GDNF release was mediated through the MEK/mitogen-activated protein kinase (MAPK) pathway and, at least, 5-HT(2A) receptors. The action of 5-HT on GDNF release may provide important insights into the mechanism of antidepressants.


Zschokkella epinepheli n. sp. (Myxosporea: Myxidiidae) infecting the gallbladder of the white grouper Epinephelus aeneus (Serranidae) from Tunisian waters.
A new coelozoic myxosporean species, Zschokkella epinepheli n. sp., collected from the gallbladder of the white grouper Epinephelus aeneus (Perciformes: Serranidae) from the bay of Bizerte, Tunisia, is described based on morphological and molecular characteristics. Myxospores and plasmodia were observed floating free in the bile. Mature plasmodia were polysporic and subspherical in shape, measuring 85.0-94.0 μm long and 70.0-82.0 μm wide. Mature myxospores were ovoid in valvular view, measuring 10.0 ± 1.7 (8.0-11.0) μm in length and 7.0 ± 0.3 (6.6-7.5) μm in width. Polar capsules were pyriform and equal in size, measuring 3.0 ± 0.2 (2.8-3.6) μm in length and 2.3 ± 0.3 (1.8-2.7) μm in width. Myxospore valves had 12-14 longitudinal striations. Based on the small subunit rDNA, the new species Z. epinepheli n. sp. differs from all other Zschokkella species for which there is a DNA sequence deposited in GenBank. Phylogenetic analysis revealed that Z. epinepheli n. sp. clustered in the marine subclade of Zschokkella species within the biliary tract IV clade. This is the first report of a Zschokkella species from the gallbladder of an epinephelin fishes.


Preparation of homogeneous grafting cellulose and partial substitution for polyethersulfone membrane material.
The homogeneous grafting was carried out by using N,N-dimethylacetamide/lithium chloride as the solvent of cellulose. The results showed that the efficient reaction conditions were as follows: reaction time, 2 h; mass ratio of monomer/cellulose, 1/1(g/g); mass ratio of initiator/cellulose, 6/50 (g/g); and reaction temperature, 80 °C. Under these conditions, the grafting percentage could reach 76%. The grafted polymer was characterized by Fourier transform infrared spectroscopy, scanning electron microscope and thermogravimetric analysis. An exploration about the partial substitution of grafted cellulose for polyethersulfone membrane material was carried out by preparing blend membranes. The blend membranes were characterized by tensile testing, pure water flux, scanning electron microscope and differential scanning calorimetry. The results showed that the blend membrane was a compatible system and the blend ratio should be controlled in about 1:16. The introduction of the grafted cellulose may result in the increase of pores size and pure water flux.


Sleeve Gastrectomy Outcomes in Patients with BMI Between 30 and 35-3 Years of Follow-Up.
Laparoscopic sleeve gastrectomy (LSG) in patients with a BMI between 30 and 35 kg/m2 plus comorbidities has shown to be safe and effective. The purpose of this study is to describe our outcomes in this group of patients after 3 years of follow-up. Retrospective descriptive analysis of patients with initial BMI between 30 and 35 kg/m2 plus comorbidities were submitted to LSG between 2006 and 2013. We analyzed gender, age, comorbidities, BMI, total weight loss (%TWL), excess weight loss (%EWL), comorbidity resolution, morbidity, and mortality. Postoperative success was defined as %TWL over 20% and EWL% over 50% maintained for at least 1 year and comorbidity remission with no need of medication. Of the patients, 477 underwent a LSG in the above period and 252 met inclusion criteria; 188 (75%) were female and 64 (25%) were male. Median age was 39 years (15-70). Three-year follow-up was 43.9% (111 patients). Median preoperative BMI was 32.3 kg/m2 (30-34.3). Median postoperative %TWL was 12.9, 23.2, 28.2, 24.3, and 22.1% at 1, 6, 12, 24, and 36 months, respectively. %EWL was 42.88, 77.44, 98.42, 83.2, and 75.8%. Median surgical time was 86.9 min (40-120). There was comorbidity remission at 36 months. Insulin resistance was remitted in 89.4%, dyslipidemia 52%, non-alcoholic fatty liver disease 84.6%, hypertension 75%, and GERD 65%. T2DM had 60% of complete remission and 40% improvement. There were morbidity in six patients (2.4%), two reoperations, no leaks, and no mortality. Performing LSG in patients with grade I obesity is safe and effective. BMI should not be the only indicator to consider bariatric and metabolic surgery. We still require further studies and longer follow-up.


Pretreatment C-reactive protein was an independent prognostic factor for patients with diffuse large B-cell lymphoma treated with RCHOP.
We assessed the prognostic significance of pretreatment C-reactive protein (CRP) concentration in diffuse large B-cell lymphoma (DLBCL) patients. We retrospectively reviewed 156 patients with newly diagnosed DLBCL. Receiver operating characteristic (ROC) curve analysis was used to generate a cutoff value for CRP. Both log-rank test and multivariable analysis by Cox regression model were used to assess the impact of pretreatment CRP concentrations on the overall survival (OS) and progression-free survival (PFS). Among those 156 patients enrolled, increased CRP concentration was seen in 51 patients before treatment (≥20mg/l), while the other 105 patients were considered with low CRP concentration. There was no obvious difference in the baseline characteristics between two groups. Increased CRP concentration was significantly associated with poorer OS and PFS than those patients with low CRP concentration (P=0.001 and P=0.000, respectively). Multivariable analysis further showed that CRP concentration was an independent predictor of OS (hazard ratio [HR]=0.47; 95% confidence interval [CI]=0.24-0.92, P=0.028) and PFS (HR=0.37; 95% CI=0.30-0.87, P=0.013). CRP concentration before treatment was an independent prognostic factor in patients with DLBCL.


Prematurity stereotyping and mothers' interactions with their premature and full-term infants during the first year.
To longitudinally assess stability and correlates of prematurity stereotyping and perceptions of infant vulnerability in mothers of premature (N = 56) and full-term (N = 59) infants. At 5, 9, and 12 months, mothers rated videotapes of unfamiliar infants with a full-term label (FTL) or a preterm label (PL), interacted with their own infant, and completed other questionnaires. A subgroup of infants were administered a developmental assessment at 32 months. Mothers rated PL infants more negatively than FTL infants at each age. Individual differences in stereotyping were not stable. Mothers who negatively rated infants labeled with the same birth status of their own infants exhibited more negative interactive behaviors with their infants. Mothers who viewed their own infant as more vulnerable and who showed more prematurity stereotyping at 5 months had infants with lower 32-month mental scores. The results suggest an association between early maternal cognitions and both contemporaneous maternal behavior and later child developmental outcomes.


Evaluation of a real-time PCR kit for detecting Escherichia coli O157 in bovine fecal samples.
A commercially available real-time, rapid PCR test was evaluated for its ability to detect Escherichia coli O157. Both the sensitivity and specificity of the assay were 99% for isolates in pure culture. The assay detected 1 CFU of E. coli O157:H7 g(-1) in artificially inoculated bovine feces following enrichment.


Synthesis of Tetrapeptides Containing Dehydroalanine, Dehydrophenylalanine and Oxazole as Building Blocks for Construction of Foldamers and Bioinspired Catalysts.
The incorporation of dehydroamino acid or fragments of oxazole into peptide chain is accompanied by a distorted three-dimensional structure and additionally enables the introduction of non-typical side-chain substituents. Thus, such compounds could be building blocks for obtaining novel foldamers and/or artificial enzymes (artzymes). In this paper, effective synthetic procedures leading to such building blocks-tetrapeptides containing glycyldehydroalanine, glycyldehydrophenylalanine, and glycyloxazole subunits-are described. Peptides containing serine were used as substrates for their conversion into peptides containing dehydroalanine and aminomethyloxazole-4-carboxylic acid while considering possible requirements for the introduction of these fragments into long-chain peptides at the last steps of synthesis.


Fascinated Nanofiber Yarns: From Experiment to Industrialization.
Bubble electrospinning patent has been commercially used for the massproduction of various nanofibers, but its application to the fabrication of nanofiber yarns is less studied. We assume that there is great potential in this direction. This paper focuses on bubble electrospinning with an emphasis on new technologies for the fabrication of fascinated nanofiber yarns by the bubble electrospinning. The paper begins with the mechanism of the bubble electrospinning to introduce how it produces fascinated nanofiber yarns experimentally, then the industrialization of fascinated nanofiber yarns is illustrated. The bubble electrospinning is extremely suitable for the fabrication of fascinated nanofiber yarns with a hierarchical structure, and the hierarchy can be designed biomimetically according to some natural fibers. This paper sheds light on both experimental study and industrial applications of fascinated nanofiber yarns.


Serum levels of interleukin-1, interleukin-6 and tumour necrosis factor-alpha in patients with gastric carcinoma.
The possible role of inflammation-associated cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) was investigated by measuring the levels of these cytokines in serum samples from 21 patients with advanced gastric carcinoma. These values were compared with those detected in 17 age-matched controls. The levels of IL-1 beta and IL-6 were significantly increased (approximately sixfold) in gastric cancer patients. While there was a modest increase (approximately twofold) in the level of IL-1 alpha, the circulating level of TNF-alpha was greatly reduced (approximately threefold) in the patient group.


Combined chemo-photothermal treatment of three-dimensional head and neck squamous cell carcinomas by gold nano-architectures.
Synergistic combined treatments are currently practiced in clinics for the management of several neoplasms. While surgery, radiotherapy, and chemotherapy remain as the standards of care for monomodal and co-treatments, emerging modalities like hyperthermia (HT) demonstrate promising features as (neo)adjuvant, particularly for recurrent cancers. However, the clinical relevance of HT is still debated due to a number of challenges, such as tumor specific temperature increase, uneven heating of the target, and the lack of agents that concurrently execute HT in combination with radio- and/or chemotherapy. Here, the application of non-persistent ultrasmall-in-nano gold architectures for synergistic chemo-photothermal treatment of head and neck squamous cell carcinomas (HNSCCs) is presented. The nano-architectures are composed of excretable narrow near-infrared (NIR)-absorbing gold ultrasmall nanoparticles and an endogenously double controlled cisplatin prodrug. The efficiency of the nano-architectures is evaluated on three-dimensional (3D) models of HNSCCs with positive or negative human papillomavirus (HPV) status. The combined treatment causes a more pronounced antitumor action on HPV-positive HNSCCs. Overall, the findings demonstrate the potential clinical relevance of translatable noble metal-based synergistic treatments in tumors management.


Genetic modification of haematopoietic cells for combined resistance to podophyllotoxins, other agents covered by MDR1-mediated efflux activity and nitrosoureas.
Genetic transfer and expression of drug-resistance functions into haematopoietic stem and progenitor cells is a promising means to overcome both the acute and longterm side-effects of cytotoxic drugs in bone marrow. Here, we describe a functional analysis of a retroviral vector that co-expresses human cDNAs for multidrug resistance 1/P-glycoprotein (MDR1) and a double mutant of O(6)-alkylguanine-alkyltransferase (hATPA/GA) to high levels. The hATPA/GA protein contains two amino acid substitutions that render it resistant to compounds such as O(6)-benzylguanine that inhibit the wild-type protein which is often overexpressed in resistant tumour cells. Evidence for simultaneous drug resistance of genetically modified primary murine progenitor cells to colchicine or the podophyllotoxin etoposide, both covered by MDR1-mediated efflux activity, and the nitrosourea BCNU, which is counteracted by hATPA/GA, is presented using in vitro colony assays.


The Importance of Sociocultural Context When Choosing to Eat Healthier.
To explore how working women in metropolitan Malaysia make food decisions. A grounded theory approach and semistructured interviews. A large university in metropolitan Malaysia. Twenty-four female employees purposively recruited to vary in ethnicity, body mass index, age, and marital status via convenience sampling. Perceptions of sociocultural influences on healthy eating behavior among working women. Researchers audio-recorded interviews and analyzed verbatim transcripts. Working women shared a desire to eat a healthier, more balanced diet by reducing processed food consumption through home-cooked meals. Participants described aspects of their living situations and cultural values about food that made it seem impossible to change their diets. Living with other people limited their ability to cook the food they wanted to eat. In addition, unspoken rules about communal eating in Malaysia, such as not refusing food and not wasting food, prevented working women from practicing healthy eating. In this population of working women in metropolitan Malaysia, experiences of time scarcity and limited sociocultural support for behavior change were major barriers to healthy eating. Interventions could prioritize leveraging these realities about food to facilitate environments in which women feel like they have control of their own food intake.


Disruption of Ankyrin B and Caveolin-1 Interaction Sites Alters Na+,K+-ATPase Membrane Diffusion.
The Na+,K+-ATPase is a plasma membrane ion transporter of high physiological importance for ion homeostasis and cellular excitability in electrically active tissues. Mutations in the genes coding for Na+,K+-ATPase α-subunit isoforms lead to severe human pathologies including Familial Hemiplegic Migraine type 2, Alternating Hemiplegia of Childhood, Rapid-onset Dystonia Parkinsonism, or epilepsy. Many of the reported mutations lead to change- or loss-of-function effects, whereas others do not alter the functional properties, but lead to, e.g., reduced protein stability, reduced protein expression, or defective plasma membrane targeting. Na+,K+-ATPase frequently assembles with other membrane transporters or cellular matrix proteins in specialized plasma membrane microdomains, but the effects of these interactions on targeting or protein mobility are elusive so far. Mutation of established interaction motifs of the Na+,K+-ATPase with ankyrin B and caveolin-1 are expected to result in changes in plasma membrane targeting, changes of the localization pattern, and of the diffusion behavior of the enzyme. We studied the consequences of mutations in these binding sites by monitoring diffusion of eGFP-labeled Na+,K+-ATPase constructs in the plasma membrane of HEK293T cells by fluorescence correlation spectroscopy as well as fluorescence recovery after photobleaching or photoswitching, and observed significant differences compared to the wild-type enzyme, with synergistic effects for combinations of interaction site mutations. These measurements expand the possibilities to study the consequences of Na+,K+-ATPase mutations and provide information about the interaction of Na+,K+-ATPase α-isoforms with cellular matrix proteins, the cytoskeleton, or other membrane protein complexes.


Incorporation of dehydrodieugenol, a neolignan isolated from Nectandra leucantha (Lauraceae), in lipid Langmuir monolayers as biomembrane models.
Dehydrodieugenol, a neolignan isolated from the Brazilian plant Nectandra leucantha (Lauraceae) with reported antiprotozoal and anticancer activity, was incorporated in Langmuir monolayers of selected lipids as cell membrane models, aiming to comprehend its action mechanism at the molecular level. The interaction of this compound with the lipids dipalmitoylphosphatidylcholine (DPPC), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylserine (DPPS), and dipalmitoylphosphatidylglycerol (DPPG) was inferred through tensiometry, infrared spectroscopy, and Brewster angle microscopy. The interactions had different effects depending on the chemical nature of the lipid polar head, with expansion for DPPC monolayers, condensation for DPPE, and expansion (at low surface pressures) followed by the overlap of the isotherms (at high surface pressure values) for DPPS and DPPG. Effects caused by dehydrodieugenol in the negatively charged lipids were distinctive, which was also reflected in the hysteresis assays, surface potential-area isotherms, and rheological measurements. Infrared spectroscopy indicated that the drug interaction with the monolayer affects not only the polar groups, but also the acyl lipid chains for all lipids. These results pointed to the fact that the interaction of the drug with lipid monolayers at the air-water interface is modulated by the lipid composition, mainly considering the polar head of the lipids, as well as the hydrophobicity of the lipids and the drug. As negatively charged lipids pointed to distinctive interaction, we believe this can be related to the antiprotozoal and anticancer properties of the compound.


Application of molecular dynamics simulation to predict the compatability between water-insoluble drugs and self-associating poly(ethylene oxide)-b-poly(epsilon-caprolactone) block copolymers.
In the present work, molecular dynamics (MD) simulation was applied to study the solubility of two water-insoluble drugs, fenofibrate and nimodipine, in a series of micelle-forming PEO-b-PCL block copolymers with combinations of blocks having different molecular weights. The solubility predictions based on the MD results were then compared with those obtained from solubility experiments and by the commonly used group contribution method (GCM). The results showed that Flory-Huggins interaction parameters computed by the MD simulations are consistent with the solubility data of the drug/PEO-b-PCL systems, whereas those calculated by the GCM significantly deviate from the experimental observation. We have also accounted for the possibility of drug solubilization in the PEO block of PEO-b-PCL.


The Role of Internal Medicine-Pediatric Programs and Transition Champions in Graduate Medical Trainee Health Care Transition Development.
Transition to adult health care for adolescents and young adults (AYAs), especially those with chronic conditions, is a critical time. Medical trainees lack competency in providing transition care, but little is known about the factors contributing to the development of health care transition (HCT) knowledge, attitudes, and practice. This study examines how Internal Medicine-Pediatrics (Med-Peds) programs and institutional HCT champions influence trainee HCT knowledge, attitudes, and practices. A 78-item electronic survey regarding the knowledge, attitudes, and practices of caring for AYA patients was sent to trainees from 11 graduate medical institutions. A total of 149 responses were analyzed, including 83 from institutions with Med-Peds programs and 63 from institutions without Med-Peds programs. Trainees with an institutional Med-Peds Program were more likely to identify an institutional HCT champion (odds ratio, 10.67; 95% confidence interval, 2.40-47.44; p = .002). The mean HCT knowledge scores and use of a routine, standardized HCT tools were higher in trainees with an institutional HCT champion. Trainees without an institutional Med-Peds program experienced more barriers to HCT education. Trainees with institutional HCT champions or Med-Peds programs reported greater comfort in providing transition education and using validated, standardized transition tools. The presence of a Med-Peds residency program was associated with a greater likelihood of a visible institutional HCT champion. Both factors were associated with increased HCT knowledge, positive attitudes, and HCT practices. Both clinical champions and adoption of Med-Peds program curricula will enhance HCT training within graduate medical education.


Hereditary angioedema: A rare but serious and commonly misdiagnosed disease.
Hereditary angioedema is a rare and commonly misdiagnosed disease characterized by recurrent, painful, nonurticarial, and nonpruritic deep tissue swelling attacks, including potentially life-threatening asphyxiation. Nurses can assist in identifying disease hallmarks and provide emergency care, patient support, and education about injectable or infused medications.


Subungual melanoma: a 25-year review of cases.
The purpose of this study was to evaluate subungual melanoma as a site-specific entity, to determine the influence of regional nodal involvement, and to ascertain where possible the role of histologic grading of the primary site. Thirty-three patients with subungual melanoma whose median age was 56 yr underwent treatment between 1950 and 1975. There were 11 male and 22 female patients. Forty-eight per cent of lesions were 11 male and 22 female patients. Forty-eight per cent of lesions occurred on the hand. Of 23 clinical stage I patients, seven patients underwent amputation only, while 16 patients underwent amputation and regional nodal dissection. Histologic examination of the primary tumor suggested a trend towards thicker/ulcerated lesions to be associated with metastatic melanoma in regional lymph nodes and/or death due to disease. Early survival patterns favored female patients but there was no significant difference in 10-year survival when analysed by patient sex. Clinical/pathologic stages were the most significant factors affecting long-term survival with 5- and 10-year survivals of 66% and 55% in stage I patients and 22% and 0% in stage II patients.


Postpartum care of women with gestational diabetes: survey of healthcare professionals.
To assess the knowledge and practices of healthcare professionals on the postpartum care of women with gestational diabetes. We surveyed 106 healthcare professionals including obstetricians, diabetologists, general practitioners and midwives in East London and West Midlands in England (September 2014). The questionnaire assessed postpartum screening practices, care provision, future risk and strategies to prevent diabetes in women with gestational diabetes. The response rate was 87% (92/106). Nearly all respondents offered advice on diet (99%; CI 95%, 100%) and exercise (92%; CI 85%, 97%) postnatally in women with diagnosis of gestational diabetes. The preferred screening time for diabetes was 6 weeks to 3 months postpartum (76%; CI 66%, 85%). Overall, oral glucose tolerance test was the preferred test (57%; CI 46%, 67%), although general practitioners preferred fasting glucose (50%; CI 33%, 67%) and glycated hemoglobin (47%; CI 30%, 64%). Most midwives (81%, 17/21) and obstetricians (52%, 11/21) either underestimated or were unsure of the future risk of diabetes. There was lack of consensus on responsibility for immediate postpartum screening. The survey highlights the need for improved awareness of future risk of diabetes in women with gestational diabetes, consensus on optimal postpartum screening and identification of the main healthcare provider responsible for further management. This is particularly important for areas of social deprivation.


Evaluation of the airway of the SimMan full-scale patient simulator.
SimMan is a full-scale patient simulator, capable of simulating normal and pathological airways. The performance of SimMan has never been critically evaluated. Sixty subjects (anesthesiologists, nurse anesthetists, and anesthesia residents) performed mask ventilation, laryngeal mask insertion and endotracheal intubation on SimMan. The simulator's airway was evaluated using visual analog scales (VAS) and by measuring the subject's performances. The SimMan full-scale patient simulator's airway is generally acceptably realistic but it significantly differs from the human airway in important aspects. Mask seal was more difficult than in humans whereas Laryngeal mask (LMA) insertion and function was acceptable. The distance from the teeth to the vallecula was too short. Cervical spine mobility was significantly reduced in the 'reduced neck movement' mode but the intubation was only slightly more difficult than in the 'normal' mode. The SimMan full-scale patient simulator's airway is generally acceptably realistic but it significantly differs from the human airway in important aspects. The user must be aware of these aspects in order to obtain maximum benefit from training and evaluation scenarios and when using the simulator for testing new equipment and techniques.


Degradation of benzoic acid and its derivatives in subcritical water.
In this research, the stability of benzoic acid and three of its derivatives (anthranilic acid, salicylic acid, and syringic acid) under subcritical water conditions was investigated. The stability studies were carried out at temperatures ranging from 50 to 350°C with heating times of 10-630 min. The degradation of the benzoic acid derivatives increased with rising temperature and the acids became less stable with longer heating time. The three benzoic acid derivatives showed very mild degradation at 150°C. Severe degradation of benzoic acid derivatives was observed at 200°C while their complete degradation occurred at 250°C. However, benzoic acid remained stable at temperatures up to 300°C. The degradation products of benzoic acid and the three derivatives were identified and quantified by HPLC and confirmed by GC/MS. Anthranilic acid, salicylic acid, syringic acid, and benzoic acid in high-temperature water underwent decarboxylation to form aniline, phenol, syringol, and benzene, respectively.


Enhanced naloxone potency and the development of narcotic tolerance.
When various biogenic amine modifying drugs were administered to mice which were pretreated with morphine, none of the drugs except atropine and haloperidol altered the usual doubling of the naloxone efficacy which is observed in morphine-pretreated mice. Atropine appeared to decrease the potency of naloxone. Haloperidol, which did not alter naloxone potency in normal mice, further increased the naloxone potency in morphine-pretreated mice. When the biogenic amine modifiers were injected chronically to mice during the development of morphine tolerance, again none of the drugs, except haloperidol and atropine altered the development of tolerance. Haloperidol appeared to enhance and atropine to inhibit the degree of tolerance. These results indicate that it is the alteration in the narcotic-induced enhancement of naloxone potency and not the mere alteration of noloxone potency by various drugs, which can be used as an indicator of the alterations in the development of tolerance.


Frequency and distribution in East Asia of 12 mutations identified in the SLC25A13 gene of Japanese patients with citrin deficiency.
Deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier (AGC), encoded by the SLC25A13 gene on chromosome 7q21.3, causes autosomal recessive disorders: adult-onset type II citrullinemia (CTLN2) and neonatal hepatitis associated with intrahepatic cholestasis (NICCD). So far, we have described 12 SLC25A13 mutations: 11 were from Japan and one from Israel. Three mutations found in Chinese and Vietnamese patients were the same as those in Japanese patients. In the present study, we identified a novel mutation IVS6+1G>C in a Japanese CTLN2 patient and widely screened 12 SLC25A13 mutations found in Japanese patients in control individuals from East Asia to confirm our preliminary results that the carrier frequency was high in Asian populations. Mutations 851-854del and 1638-1660dup were found in all Asian countries tested, and 851-854del associated with 290-haplotype in microsatellite marker D7S1812 was especially frequent. Other mutations frequently detected were IVS11+1G>A in Japanese and Korean, S225X in Japanese, and IVS6+5G>A in Chinese populations. We found a remarkable difference in carrier rates in China (including Taiwan) between north (1/940) and south (1/48) of the Yangtze River. We detected many carriers in Chinese (64/4169 = 1/65), Japanese (20/1372 = 1/69) and Korean (22/2455 = 1/112) populations, suggesting that over 80,000 East Asians are homozygotes with two mutated SLC25A13 alleles.


Influence of 2-substituent on the activity of imidazo[1,2-a] pyridine derivatives against human cytomegalovirus.
The synthesis of various 2-substituted imidazo[1,2-a]pyridine bearing a thioether side chain in position 3 was reported. The new compounds were characterized by 1H and 13C NMR spectra. A conformational study was obtained by X-ray crystallographic analysis for 2-biphen-4-ylimidazopyridine 7. The antiviral activity against human cytomegalovirus (HCMV) was investigated. It was strongly influenced by the nature of C-2 substituent.


National Population-Based Study Comparing Treatment-Related Toxicity in Men Who Received Intensity Modulated Versus 3-Dimensional Conformal Radical Radiation Therapy for Prostate Cancer.
To compare, in a national population-based study, severe genitourinary (GU) and gastrointestinal (GI) toxicity in patients with prostate cancer who were treated with radical intensity modulated radiation therapy (IMRT) or 3-dimensional conformal radiation therapy (3D-CRT). Patients treated with IMRT (n=6933) or 3D-CRT (n=16,289) between January 1, 2010 and December 31, 2013 in the English National Health Service were identified using cancer registry data, the National Radiotherapy Dataset, and Hospital Episodes Statistics, the administrative database of care episodes in National Health Service hospitals. We developed a coding system that identifies severe toxicity (at least grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events scoring system) according to the presence of a procedure and a corresponding diagnostic code in patients' Hospital Episodes Statistics records after radiation therapy. A competing risks regression analysis was used to estimate hazard ratios (HRs), comparing the incidence of severe GI and GU complications after IMRT and 3D-CRT, adjusting for patient, disease, and treatment characteristics. The use of IMRT, as opposed to 3D-CRT, increased from 3.1% in 2010 to 64.7% in 2013. Patients who received IMRT were less likely than those receiving 3D-CRT to experience severe GI toxicity (4.9 vs 6.5 per 100 person-years; adjusted HR 0.66; 95% confidence interval 0.61-0.72) but had similar levels of GU toxicity (2.3 vs 2.4 per 100 person-years; adjusted HR 0.94; 95% confidence interval 0.84-1.06). Prostate cancer patients who received radical radiation therapy using IMRT were less likely to experience severe GI toxicity, and they had similar GU toxicity compared with those who received 3D-CRT. These findings in an unselected "real-world" population support the use of IMRT, but further cost-effectiveness studies are urgently required.


A systematic and critical review of the evolving methods and applications of value of information in academia and practice.
This article provides a systematic and critical review of the evolving methods and applications of value of information (VOI) in academia and practice and discusses where future research needs to be directed. Published VOI studies were identified by conducting a computerized search on Scopus and ISI Web of Science from 1980 until December 2011 using pre-specified search terms. Only full-text papers that outlined and discussed VOI methods for medical decision making, and studies that applied VOI and explicitly discussed the results with a view to informing healthcare decision makers, were included. The included papers were divided into methodological and applied papers, based on the aim of the study. A total of 118 papers were included of which 50 % (n = 59) are methodological. A rapidly accumulating literature base on VOI from 1999 onwards for methodological papers and from 2005 onwards for applied papers is observed. Expected value of sample information (EVSI) is the preferred method of VOI to inform decision making regarding specific future studies, but real-life applications of EVSI remain scarce. Methodological challenges to VOI are numerous and include the high computational demands, dealing with non-linear models and interdependency between parameters, estimations of effective time horizons and patient populations, and structural uncertainties. VOI analysis receives increasing attention in both the methodological and the applied literature bases, but challenges to applying VOI in real-life decision making remain. For many technical and methodological challenges to VOI analytic solutions have been proposed in the literature, including leaner methods for VOI. Further research should also focus on the needs of decision makers regarding VOI.


Reactions of women underscreened for cervical cancer who received unsolicited human papillomavirus self-sampling kits.
To evaluate experiences and reactions after receiving a mailed, unsolicited human papillomavirus self-sampling kit and identify psychosocial correlates of using kits. Survey participants were underscreened women aged 30-64 who were mailed human papillomavirus kits as part of a pragmatic trial at Kaiser Permanente Washington, a United States integrated health care system. Six months after the mailing, we invited kit returners and non-returners to complete a web survey that measured psychosocial factors (e.g. cervical cancer/human papillomavirus knowledge, attitudes toward screening), experiences, and reactions to kits. We compared responses between kit returners and non-returners. Comparing 116 kit returners (272 invited) and 119 non-returners (1083 invited), we found no clinically significant differences in psychosocial factors. Overall, survey respondents showed knowledge gaps in human papillomavirus natural history (82% did not know human papillomavirus infection can clear on its own) and interpreting human papillomavirus test results (37% did not know a human papillomavirus-negative result indicates low cancer risk). Kit returners found kits convenient and easy to use (>90%). The most common reason for non-return was low confidence in ability to correctly use a kit, although many non-returners (49%) indicated that they would consider future use. Women reported low trust in human papillomavirus testing to identify women at high risk for cervical cancer (52% in returners, 42% in non-returners). Screening programs could improve uptake and acceptability of human papillomavirus self-sampling through outreach materials that emphasize the high efficacy of human papillomavirus testing for cervical cancer screening and educate patients about how to interpret results.


A novel PAX9 mutation causing oligodontia.
An extended family presenting with several members affected by developmentally missing teeth was investigated by analysis of the MSX1 and PAX9 genes. Saliva samples were collected and DNA extracted. Primers were designed to span the exons and intron-exon junctions of the MSX1 and PAX9 genes. These primers were optimised using gradient Polymerase Chain Reaction. The amplified fragments were sent for Sanger sequencing RESULTS: a novel heterozygote missense mutation in exon 3 of PAX9 (c.296G > C, p.A99P), was found in two severely affected members of the family as well as a potentially pathogenic heterozygote variant (c.119C > G, p.A40G) in exon 1 of the MSX1 gene. The PAX9 A99P mutation is in the DNA binding domain and is predicted to be pathogenic.


Clinical evaluation of acetylsalicylic acid to improve glycemia in type II diabetic patients.
The glycoregulation of 17 type II diabetics was observed to improve by administering 1 g of acetylsalicylic acid three times per day, during a one-year study. The subjects did not lose weight during the experimental period, but the insulin daily requirement of 7 patients did decrease by 60%.


Development of a novel ELISA for serodiagnosis of Leptospirosis and additional detection of pathogenic Leptospira by polymerase chain reaction for veterinary routine diagnostics.
A multi-serovar ELISA based on the outer membrane Lipoprotein L41 (LipL41) of pathogenic Leptospira was developed to increase sensitivity by using a single test antigen. A sensitivity of 99 % and a specifity of 92 % could be achieved. The established diagnostic polymerase chain reaction is also able to detect fast and reliably pathogenic Leptospira in different clinical samples.


Serum albumin and gamma globulin in Trypanosoma cruzi infections.
This paper examines the association between serum protein levels and infection with Trypanosoma cruzi in a region of Central Brazil. 148 people 6 to 78 years of age, were included in this study. There were no statistically significant difference in albumin levels between those with positive T. cruzi serology (2.94 +/- 0.74 g/100 ml) and those with negative serology (3.04 +/- 0.61 g/100 ml). Thus the null hypothesis of no association between infection with T. cruzi and serum albumin is accepted. Gamma-globulin levels were elevated in both groups and were significantly greater (p less than 0.05) in the group with positive T. cruzi serology (1.91 +/- 0.41 g/100 ml) than in the group with negative serology (1.75 +/- 0.41 g/100 ml). The serum albumin levels suggest that malnutrition (either associated with low protein intake or increased loss due to hookworm) is a major problem and unlikely to change if T. cruzi transmission was controlled.


Calcium-promoted resonance energy transfer between fluorescently labeled proteins during aggregation of chromaffin granule membranes.
Proteins of the chromaffin granule membrane were covalently labeled in situ with sulfhydryl-specific fluorophores. Using MIANS (maleimide iodoaminonaphthyl sulfonate) as the donor and fluorescein mercury acetate or fluorescein-5-maleimide as the acceptor. Förster fluorescence resonance energy transfer (FRET) could be employed to measure the degree of inter-membrane and intra-membrane protein-protein contact upon Ca2+-induced aggregation of the membranes. The four major findings were: (1) Raising the Ca2+ concentration to approx. 500 microM causes the proteins to aggregate in the plane of the membrane. This is demonstrated by Ca2+-induced increases in the fluorescence resonance energy transfer in double labeled membranes. This effect is not protein-concentration dependent and occurs at calcium concentrations too low for granule aggregation, implying intra-membrane protein clustering or patching. To our knowledge this is the first direct demonstration of the fluid mosaic nature of subcellular organelles. (2) If two sets of granules are labeled separately, Ca2+-induced aggregation brings at least 74% of the labeled proteins into close transmembrane proximity. This effect is also observed at 10-100-fold slower rates in the absence of calcium and can be greatly reduced by depleting the granule membrane of labeled peripheral proteins. It is enhanced if the granules are aggregated by Ca2+ or K+. We conclude that (some) peripheral proteins can transfer from one membrane surface to another. (3) Aggregation of separately labeled sets of membranes by Ca2+ also produces transmembrane energy transfer since: (a) the Km for Ca2+-induced quantum transfer is in the same range as the Km for aggregation; (b) the reaction is protein-concentration dependent; (c) reversal of aggregation also (partially) reverses donor quenching. (4) A kinetic analysis of the transmembrane effect shows it to be 5-10-fold slower than aggregation itself, supporting earlier suggestions (Haynes, D.H., Kolber, M. and Morris, S.J., (1979) J. Theor. Biol. 81, 713-743) that lipid and protein rearrangements are secondary to granule membrane aggregation.