Qualitative and Quantitative Evaluation of the Efficiency of the Application of Foams with False Xerostomia.
Xerostomia syndrome is a significant medical and social problem. It is manifested by objective and subjective symptoms of a "dry mouth" and a decrease in sialometry. The aim of the study was to determine the dental status of students of different nationalities, to identify xerostomia induced on a background of stress, and to assess the effectiveness of the use of moisturizing foams in alleviating xerostomia. A prospective cohort study survey (Fox test) of 100 students of the dental faculty was conducted to detect false xerostomia. The study involved 60 people with false xerostomia, divided into four groups of 15 each according to the nationality. The level of oral hygiene was determined using the Simplified Oral Hygiene and Silness-Loe indices and the rate of salivation was assessed with sialometry method by Pozharitskaya. Oral hygiene instructions were given to the participants. They were to apply moisturizing foams with lactoferrin, lactoperoxidase, and aloe vera, two-three times during the day for 3 weeks. A set of statistical programs was used (Microsoft Excel [2007] and the Statistical Package for the Social Sciences [SPSS], version 23) to perform Kolmogorov-Smirnov, Shapiro-Wilk, Kruskal-Wallis, and Wilcoxon tests. A statistically significant improvement in oral hygiene was observed in all study participants. A significant increase was detected in the rate of salivation in students from Russia (P = 0.005), Transcaucasian countries (P = 0.006), and Arab countries (P = 0.005). It has been established that the use of moisturizing foam has a positive effect on the rate of salivation and improves the level of oral hygiene, thereby improving the quality of life for patients.


Non-exponential spontaneous emission dynamics for emitters in a time-dependent optical cavity.
We have theoretically studied the effect of deterministic temporal control of spontaneous emission in a dynamic optical microcavity. We propose a new paradigm in light emission: we envision an ensemble of two-level emitters in an environment where the local density of optical states is modified on a time scale shorter than the decay time. A rate equation model is developed for the excited state population of two-level emitters in a time-dependent environment in the weak coupling regime in quantum electrodynamics. As a realistic experimental system, we consider emitters in a semiconductor microcavity that is switched by free-carrier excitation. We demonstrate that a short temporal increase of the radiative decay rate depletes the excited state and drastically increases the emission intensity during the switch time. The resulting time-dependent spontaneous emission shows a distribution of photon arrival times that strongly deviates from the usual exponential decay: A deterministic burst of photons is spontaneously emitted during the switch event.


Use of mechanistic modeling to assess interindividual variability and interspecies differences in active uptake in human and rat hepatocytes.
Interindividual variability in activity of uptake transporters is evident in vivo, yet limited data exist in vitro, confounding in vitro-in vivo extrapolation. The uptake kinetics of seven organic anion-transporting polypeptide substrates was investigated over a concentration range in plated cryopreserved human hepatocytes. Active uptake clearance (CL(active, u)), bidirectional passive diffusion (P(diff)), intracellular binding, and metabolism were estimated for bosentan, pitavastatin, pravastatin, repaglinide, rosuvastatin, telmisartan, and valsartan in HU4122 donor using a mechanistic two-compartment model in Matlab. Full uptake kinetics of rosuvastatin and repaglinide were also characterized in two additional donors, whereas for the remaining drugs CL(active, u) was estimated at a single concentration. The unbound affinity constant (K(m, u)) and P(diff) values were consistent across donors, whereas V(max) was on average up to 2.8-fold greater in donor HU4122. Consistency in K(m, u) values allowed extrapolation of single concentration uptake activity data and assessment of interindividual variability in CL(active) across donors. The maximal contribution of active transport to total uptake differed among donors, for example, 85 to 96% and 68 to 87% for rosuvastatin and repaglinide, respectively; however, in all cases the active process was the major contributor. In vitro-in vivo extrapolation indicated a general underprediction of hepatic intrinsic clearance, an average empirical scaling factor of 17.1 was estimated on the basis of seven drugs investigated in three hepatocyte donors, and donor-specific differences in empirical factors are discussed. Uptake K(m, u) and CL(active, u) were on average 4.3- and 7.1-fold lower in human hepatocytes compared with our previously published rat data. A strategy for the use of rat uptake data to facilitate the experimental design in human hepatocytes is discussed.


Adverse reactions in myelography.
An attempt was made to assess the usefulness of using animal models to predict the neural tolerability in man of iodinated contrast media (CM) in general, and of the new nonionic dimer iodixanol in particular. For this purpose, the results from 6 animal experiments evaluating excitative and depressive effects of subarachnoidally injected CM in nonanesthetized rabbits were compared with the results from 22 randomized double-blind clinical trials dealing with post-myelographic adverse reactions. Comparisons were made as regards the nonionic monomers metrizamide, iohexol, and iopamidol, and the dimer iotrolan. The results seem to justify the conclusion that the convulsive effects of CM can be reliably predicted from animal experiments. The animal model cannot be used to predict specific types of nonconclusive adverse reactions in man, but reflects well the differences in frequencies of minor reactions following clinical myelography with different nonionic CM. In general, the neural tolerability of iodixanol may be expected to be better than that of the nonionic monomers and approximately equal to that of iotrolan.


The functional -443T/C osteopontin promoter polymorphism influences osteopontin gene expression in melanoma cells via binding of c-Myb transcription factor.
In the present report, the possible role of a recently described functional polymorphism of the osteopontin (OPN) promoter at position -443 (-443T/C) for OPN expression in melanoma cells was addressed. As shown by real-time PCR analysis, melanoma metastases that were homozygous for the -443C allele expressed significantly higher levels of OPN mRNA compared with those that were either heterozygous (-443T/C) or homozygous for the -443T allele. In line with this, immunoblotting showed significantly enhanced baseline and bFGF-induced OPN protein expression in melanoma cell lines which were homozygous for the -443C allele, compared with cell lines with other allelic variants. Similar results were obtained in in vitro luciferase assays. Chromatin immunoprecipitation (ChIP) demonstrated binding of c-Myb to the -443 OPN promoter region, and binding could significantly be enhanced after bFGF stimulation. Moreover, as shown by electrophoretic mobility shift assays (EMSA), recombinant DNA-binding domain of c-Myb bound in a sequence-specific manner to this region. Finally, the role of c-Myb for OPN gene regulation via binding to the -443 promoter region could be further substantiated by ectopic overexpression of c-Myb in melanoma cells, using different reporter gene constructs. Taken together, it is demonstrated that the -443 promoter region exerts influence on OPN gene expression in melanoma cells, and differential binding of c-Myb transcription factor appears to play a major role in this process. These findings might be a feasible explanation for different OPN expression levels in metastatic tumors and may also have prognostic and therapeutic relevance.


Barriers in Hepatitis C Treatment in Somali Patients in the Direct Acting Antiviral Therapy Era.
Hepatitis C virus (HCV) treatment has changed dramatically in the last few years. Our observations suggest that a minority of HCV infected Somalis are treated. In this study, we aimed to evaluate for treatment and health outcome disparities between Somali and non-Somali patients during the direct acting antiviral (DAA) era. Patients with HCV seen in the gastroenterology clinic in 2015 were included in the study. Patients were identified using ICD9 and 10 codes. Electronic medical records were analyzed to evaluate for treatment candidacy, acceptance and reasons for refusal of treatment. Genotype 4 followed by 3 were the most common genotypes in the Somalis while genotype 1 was the most common in the non-Somalis. Majority of patients were offered treatment, active alcohol and substance abuse was a common reason for not offering treatment in non-Somalis while the presence of hepatocellular carcinoma was the most common reason in Somalis. Somalis had higher rates of declining treatment given the asymptomatic nature of their disease and the feeling that treatment is not needed. Sustained virologic response rates were comparable in both groups. Disparities in acceptance of HCV treatment persist in the DAA era. The asymptomatic nature of the infection and potential cultural mistrust makes patients hesitant to undergo treatment. Healthcare providers must find interventions aimed at reducing barriers to treatment and increasing acceptance of HCV treatment.


The effect of Ginkgo extract EGb761 in cisplatin-induced peripheral neuropathy in mice.
Neuroprotective effect of Ginkgo biloba extract EGb761 in cisplatin (cis-diamminedi-chloroplatinum, or CDDP)-induced peripheral neuropathy was investigated. Swiss albino mice were treated with CDDP, 2 mg/kg ip twice a week for nine times. One group of the animals also received EGb761 in the drinking water at an estimated dosage of 100 mg/kg per day. Two other groups received vehicle (control) or EGb761 only. Development of neuropathy was evaluated with changes in sensory nerve conduction velocity (NCV). Following the treatments, dorsal root ganglia (DRGs) were microscopically examined and some were cultured for 3 days. EGb761 proved effective in preventing the reduction in NCV (P < 0.0001) caused by CDDP. CDDP caused a decrease in the number of migrating cells (P < 0.01) and in the length of outgrowing axons (P < 0.01) while EGb761 treatment prevented the latter. CDDP led to smaller nuclear and somatic sizes in neurons (P < 0.01), while with EGb761 co-administration, both were close to control values. Animals having EGb761 only had similar results with controls. In conclusion, EGb761 was found to be effective in preventing some functional and morphological deteriorations in CDDP-induced peripheral neuropathy.


Next-generation primate genomics: New genome assemblies unlock new questions.
Nonhuman primates provide unique evolutionary and comparative insight into the human phenotype. Genome assemblies are now available for nearly half of the species in the primate order, expanding our understanding of genetic variation within and between species and making important contributions to evolutionary biology, evolutionary anthropology, and human genetics.


A Culturally Adapted Depression Intervention for African American Adults: An Efficacy Trial.
Major depressive disorder (MDD) is one of the most common, costly, and debilitating psychiatric disorders in the United States, and the World Health Organization has identified MDD as a leading cause of disability. Although the rates of MDD among African American and White populations in the US are comparable, African Americans in the US tend to experience higher rates of disability associated with MDD compared to White people. Despite the high burden of MDD among African Americans, their use of mental health services is low, in part due to suboptimal care. This study evaluated the efficacy of a culturally adapted depression intervention (Oh Happy Day Class [OHDC]) compared to an active control, the Coping with Depression (CWD) course. A clustered randomized controlled trial was conducted with a sample of 132 patients with mild to moderate depressive symptoms. They were randomly assigned in a 2-armed randomized controlled trial. They received 1 of 2 (OHDC or CWD) 12-week interventions in weekly in-person group sessions. The primary outcome was a change in depressive symptoms during and post-intervention, measured with the Center for Epidemiologic Studies Depression Scale (CES-D) and the Quick Inventory of Depression Symptoms (QIDS). Analyses included log-rank test and mixed effects linear regression models. Both interventions were efficacious in reducing symptoms of depression. However, a greater dose of the culturally adapted intervention, Oh Happy Day Class, showed a greater reduction in depression symptoms. This study represents the first randomized controlled trial evaluating the culturally adapted treatment depression intervention, Oh Happy Day Class. These findings provide evidence for and the need for culturally adapted treatments. Future research with larger samples of African Americans from different regions across the US could examine effectiveness and generalizability of the Oh Happy Day Class depression treatment.


Exposed CendR Domain in Homing Peptide Yields Skin-Targeted Therapeutic in Epidermolysis Bullosa.
Systemic skin-selective therapeutics would be a major advancement in the treatment of diseases affecting the entire skin, such as recessive dystrophic epidermolysis bullosa (RDEB), which is caused by mutations in the COL7A1 gene and manifests in transforming growth factor-β (TGF-β)-driven fibrosis and malignant transformation. Homing peptides containing a C-terminal R/KXXR/K motif (C-end rule [CendR] sequence) activate an extravasation and tissue penetration pathway for tumor-specific drug delivery. We have previously described a homing peptide CRKDKC (CRK) that contains a cryptic CendR motif and homes to angiogenic blood vessels in wounds and tumors, but it cannot penetrate cells or tissues. In this study, we demonstrate that removal of the cysteine from CRK to expose the CendR sequence confers the peptide novel ability to home to normal skin. Fusion of the truncated CRK (tCRK) peptide to the C terminus of an extracellular matrix protein decorin (DCN), a natural TGF-β inhibitor, resulted in a skin-homing therapeutic molecule (DCN-tCRK). Systemic DCN-tCRK administration in RDEB mice led to inhibition of TGF-β signaling in the skin and significant improvement in the survival of RDEB mice. These results suggest that DCN-tCRK has the potential to be utilized as a novel therapeutic compound for the treatment of dermatological diseases such as RDEB.


Prostate cancer in the elderly patient.
Treatment for prostate cancer (PCa) has evolved significantly over the last decade. PCa is the most prevalent non-skin cancer and the second leading cause of cancer death in men, and it has an increased incidence and prevalence in older men. As a result, physicians and patients are faced with the challenge of identifying optimal treatment strategies for localized, biochemical recurrent, and advanced PCa in the older population. When older patients are appropriately selected, treatment for PCa results in survival benefits and toxicity profiles similar to those experienced in younger patients. However, underlying health status and age-related changes can have an impact on tolerance of hormonal therapy and chemotherapy in men with advanced disease. Therefore, the heterogeneity of the elderly population necessitates a multidimensional assessment to maximize the benefit of medical and/or surgical options. Providing clinicians with the requisite health status data on which to base treatment decisions would help ensure that older patients with PCa receive optimal therapy if it will benefit them and/or active surveillance or best supportive care if it will not. We provide a review of the existing evidence to date on the management of PCa in the older population.


Stockperson attitudes toward pig euthanasia.
Euthanasia is a necessary act for any facility keeping live animals. Nevertheless, the crucial role and responsibility of the stockperson in deciding and conducting on-farm euthanasia has been overlooked. Stockperson characteristics and knowledge that lead to appropriate decision-making and the skills to competently perform the procedure remain to be identified. An important component of the stockperson's characteristics that predict behavior is the stockperson's attitudes. This preliminary study investigated the factors that influence stockperson attitudes toward the practice of on-farm euthanasia in the pork industry. A total of 120 stockpeople from 10 Australian pig farms (ranging in size from 50 to 4,754 sows and from 2 to 32 employees) completed a questionnaire based on focus group input to assess their attitudes toward euthanasia and decision processes. Factors identified included stockperson attitudes and attributes (empathy affect, empathy attribution, feeling bad about euthanizing, and negative attitudes to pigs), beliefs about the working environment (perceived time constraints and relying on others), and factors related to decision-making (comfortable with euthanasia, trouble deciding and avoid if possible, confidence, insufficient knowledge, seeking knowledge, and using sources to get advice). Numerous significant correlations were found between these variables. Furthermore, regression analyses showed confidence as the only significant predictor of being comfortable with euthanasia (12.5% of the variance; < 0.001); insufficient knowledge and empathy attribution both as predictors of trouble deciding and avoid if possible (15.1% of the variance; = 0.001 and = 0.032, respectively); and empathy affect, insufficient knowledge, and perceived time constraints as predictors of feeling bad about euthanizing (23.2% of the variance; < 0.001, = 0.006, and = 0.022, respectively). Stockpeople reported seeking more knowledge if they had not euthanized an animal before working with pigs ( = 0.05), and women reported greater difficulty than men in conducting euthanasia ( < 0.01). The findings indicate that euthanasia, which comprises both a decision-making process and the act itself, can adversely affect stockpeople. This preliminary study offers insights for implementation of successful practical and humane pig euthanasia protocols on farm. This will benefit stockperson well-being and animal well-being alike.


Pain and body awareness: evidence from brain-damaged patients with delusional body ownership.
A crucial aspect for the cognitive neuroscience of pain is the interplay between pain perception and body awareness. Here we report a novel neuropsychological condition in which right brain-damaged patients displayed a selective monothematic delusion of body ownership. Specifically, when both their own and the co-experimenter's left arms were present, these patients claimed that the latter belonged to them. We reasoned that this was an ideal condition to examine whether pain perception can be "referred" to an alien arm subjectively experienced as one's own. Seventeen patients (11 with, 6 without the delusion), and 10 healthy controls were administered a nociceptive stimulation protocol to assess pain perception. In the OWN condition, participants placed their arms on a table in front of them. In the ALIEN condition, the co-experimenter's left (or right) arm was placed alongside the participants' left (or right) arm, respectively. In the OWN condition, left (or right) participants' hand dorsum were stimulated. In the ALIEN condition, left (or right) co-experimenter's hand dorsum was stimulated. Participants had to rate the perceived pain on a 0-5 Likert scale (0 = no pain, 5 = maximal imaginable pain). Results showed that healthy controls and patients without delusion gave scores higher than zero only when their own hands were stimulated. On the contrary, patients with delusion gave scores higher than zero both when their own hands (left or right) were stimulated and when the co-experimenter's left hand was stimulated. Our results show that in pathological conditions, a body part of another person can become so deeply embedded in one's own somatosensory representation to effect the subjective feeling of pain. More in general, our findings are in line with a growing number of evidence emphasizing the role of the special and unique perceptual status of body ownership in giving rise to the phenomenological experience of pain.


Photosynthetic and Growth Responses of Arundo donax L. Plantlets Under Different Oxygen Deficiency Stresses and Reoxygenation.
Promotion of nonfood species production to marginal, degraded lands abandoned by mainstream agriculture is affected by extremes of water availability (droughts and floods), which have increased in frequency and intensity and account for severe yield reduction. Arundo donax L., known as giant cane or giant reed, spontaneously grows in different kinds of environments with limitation to low temperature and is thus widespread in temperate and hot areas around the world. Moreover, this perennial rhizomatous grass has been recognized as a leading candidate crop in the Mediterranean for lignocellulosic feedstock due to its high C3 photosynthetic capacity, positive energy balance and low agroecological management demand. In this study, the photosynthetic performance and growth response of A. donax to waterlogging and submergence stress following a time course as well as their respective re-oxygenation were analyzed under reproducible and controlled environment conditions. Results of growth response showed that biomass production was strongly conditioned by the availability of oxygen. In fact, only waterlogged plants showed similar growth capacity to those under control conditions, while plants under submergence resulted in a dramatic reduction of this trait. The simultaneous measurements of both gas exchanges and chlorophyll fluorescence highlighted an alteration of both stomatal and non-stomatal photosynthetic behaviors during a short/medium period of oxygen deprivation and re-oxygenation. Photosynthetic CO2 uptake was strictly related to a combination of stomatal and mesophyll diffusional constrains, depending on the severity of the treatment and exposure time. Conditions of waterlogging and hypoxia revealed a slight growth plasticity of the species in response to prolonged stress conditions, followed by a fast recovery upon reoxygenation. Moreover, the rapid restoration of physiological functions after O2 deprivation testifies to the environmental plasticity of this species, although prolonged O2 shortage proved detrimental to A. donax by hampering growth and photosynthetic CO2 uptake.


A calmodulin-regulated protein kinase linked to neuron survival is a substrate for the calmodulin-regulated death-associated protein kinase.
Death-associated protein kinase (DAPK) is a calmodulin (CaM)-regulated protein kinase and a drug-discovery target for neurodegenerative diseases. However, a protein substrate relevant to neuronal death had not been described. We identified human brain CaM-regulated protein kinase kinase (CaMKK), an enzyme key to neuronal survival, as the first relevant substrate protein by using a focused proteomics- and informatics-based approach that can be generalized to protein kinase open reading frames identified in genome projects without prior knowledge of biochemical context. First, DAPK-interacting proteins were detected in yeast two-hybrid screens and in immunoprecipitates of brain extracts. Second, potential phosphorylation site sequences in yeast two-hybrid hits were identified on the basis of our previous results from positional-scanning synthetic-peptide substrate libraries and molecular modeling. Third, reconstitution assays using purified components demonstrated that DAPK phosphorylates CaMKK with a stoichiometry of nearly 1 mol of phosphate per mole of CaMKK and a K(m) value of 3 microM. Fourth, S511 was identified as the phosphorylation site by peptide mapping using mass spectrometry, site-directed mutagenesis, and Western blot analysis with a site-directed antisera targeting the phosphorylated sequence. Fifth, a potential mechanism of action was identified on the basis of the location of S511 near the CaM recognition domain of CaMKK and demonstrated by attenuation of CaM-stimulated CaMKK autophosphorylation after DAPK phosphorylation. The results raise the possibility of a CaM-regulated protein kinase cascade as a key mechanism in acute neurodegeneration amenable to therapeutic targeting.


Prenatal exposure to virilizing progestins: an adult follow-up study of twelve women.
Psychological data were collected on 12 young women, aged 16 to 27 years, with a history of prenatal progestin exposure. In 11 cases, this exposure had induced virilization of the external genitalia. The 12th woman was an anatomically unaffected sister of one of the other women. The sample was composed of 10 women reported on as children by Ehrhardt and Money (1967), Money and Ehrhardt, (1972) as well as two others who were added to this group because they conformed to the original selection criteria for the Money and Ehrhardt studies. Of the 12 women, 10 had completed high school; of these, 7 were in college, 2 were in graduate school, and was raising a family full-time. None of the 12 had a history of difficulty in establishing friendships or dating relationships. Despite childhood characterizations as "tomboys" and avid interest in high school sports, none of the women pursued sports as a career or major pastime. Because of difficulties in personally contacting all 12 women, data on erotic behavior are available for only 6. Only one of these 6, the youngest, reported no erotic experience, and the remaining 5 reported exclusively heterosexual erotic experience and imagery.


Physical contact between mesenchymal stem cells and endothelial precursors induces distinct signatures with relevance to the very early phase of regeneration.
Multipotent adult stem cells/precursor cells, especially of the mesenchymal and endothelial lineage, may have great potential for bone tissue engineering. Although their potential is highly recognized, not much is known about the underlying molecular mechanisms that initiate the regeneration process, connect osteogenesis, and angiogenesis and, finally, orchestrate renewal of bone tissue. Our study addressed these questions by generating two in vitro cell culture models to examine the changes in the global gene expression patterns of endothelial precursor cells and mesenchymal stem cells after 24 hours of either humoral (conditioned medium) or direct cell-cell interaction (co-culture). Endothelial precursor cells were isolated from human buffy coat and mesenchymal stem cells from the bone marrow of the femoral head. The comparison of the treated and control cells by microarray analyses revealed in total more than 1500 regulated genes, which were analyzed for their affiliation to angiogenesis and osteogenesis. Expression array analyses at the RNA and protein level revealed data with respect to regulated genes, pathways and targets that may represent a valid basis for further dissection of the systems biology of regeneration processes. It may also be helpful for the reconstitution of the natural composition of a regenerative microenvironment when targeting tissue regeneration both in vitro and in situ.


[A 50-year history of new drugs in Japan-the development and progress of anti-diabetic drugs and the epidemiological aspects of diabetes mellitus].
The development and progress of antidiabetic drugs (e.g., insulin preparations and hypoglycemic drugs) are retrospectively investigated in Japan. Their influences on the treatment of diabetes mellitus (DM) and its epidemiological aspects are also discussed. 1) Insulin preparations: Insulin was introduced for DM therapy in 1925, two or three years after its discovery in Canada. The preparations were raw extracts of bovine or porcine pancreas. These did not prevail widely in Japan because of the low incidence of DM before World Wan II. After the war, a shortage of mammalian materials compelled the use of fish pancreatic tissues such as bonito and/or tuna for insulin production. Insulin infection, so-called regular insulin, was first promoted in the 6th "Pharmacopoeia Japonica" (JP6) in 1951 and has been maintained to the present edition (JP14, 2001). Although depot-type insulin preparations were developed in the USA and Europe during the war, the introduction of those preparations to Japan was delayed until 1951, when Protamine zinc insulin appeared. Globin zinc insulin and Isophane insulin were introduced for clinical use in 1952 and 1955, respectively. These were also adopted for JP7 (1961). Biphasic-type insulin, which has a rapid onset and long duration of activity, appeared in 1965. Purified preparations from bovine or porcine sources have been available since 1980, which might be a strong reason for the decrease in insulin allergy. Insulin from animal origin has been supplied for almost 60 years since its discovery. Amino acid sequences of insulins from various species of animals were determined by the pioneering studies of Sanger and his associates. Human insulin, which differs from porcine insulin by only one amino acid, was produced by Novo researchers in 1982 using a semi-synthetic method. Then the Lilly group soon succeeded in obtaining human insulin by recombinant DNA technology in the same year. Both products were introduced to Japan in 1985, and the recombinant products prevailed throughout the 1990s. Human insulin analogues (i.e., Insulin lispro and Insulin aspart) appeared in 2001. These are applied for after-meal glycosmia owing to their ultrarapid onset of activity. Self-injection by DM patients was legalized in 1981. To make the infection technique sure and easy, cartridge (pen-type) and disposable kit-type needles were devised in the 1990s. 2) Oral hypoglycemic drugs: Instead of the exclusive parenteral usage of insulins, there was also demand for oral dosage forms. The first of the sulfonyrlurea (SU) group, BZ-55, was used for DM clinically in 1955 in Germany. But it was soon withdrawn because of its antibacterial action. This led to the development of various SU groups. Tolbutamide (1956), chlorpropamide (1959), acetohexamide (1964) and tolazamide (1961) were introduced to Japan as first-generation SUs. Then glyclopyramide (Kyorin, 1965), glybenclamide (1971), gliclazide (1984) and glimepiride (1999) appeared as the second-generation SUs. These were used orally for Type 2 diabetes. Biguanide (BG) group, phenformin HC1 (1959), metformin HC1 (1961) and buformin HC1 (1961) had also been in use by oral treatment of Type 2 diabetes. SU appears to act by increasing the sensitivity of b-cells, which secrete insulin. BG probably exerts by increasing glucose transport across the membranes of target organs. 3) New types of antidiabetic drugs: a-Glucosidase inhibitors (i.e., acarbose: Bayer, 1993; and voglibose: Takeda, 1994) act on hyperglycemia after meals by decreasing glucose absorption. Thiazolidinedione compounds, such as troglitazone (Sankyo, 1995) and pioglitazone HC1 (Takeda, 1994) act by increasing the insulin sensitivity of the target tissues. These are useful for Type 2 DM patients when SUs are ineffective. Nevertheless, troglitazone was discontinued in 2000 due to severe liver damage. Nateglinide (Ajinomoto Co., 1999), which is a D-phenylalanine derivative acting similar to SUs, is useful orally for after-meal hyperglycemia of Type 2 diabetes. Epalrestat (Ono Yakuhin Co., 1992) is effective for diabetic neuropathy by reducing the formation of sorbitol. These anti-DM drugs were recently studied and developed in Japan. 4) The Japan Diabetes Society proposed a guideline on diagnostic criteria and treatment of diabetes mellitus (DM) in 1999 and revised it in 2002. DM is classified as insulin-dependent DM (Type l) and non-insulin dependent DM (Type 2). Type 1, juvenile onset DM, requires insulin therapy to prevent ketosis and to sustain life. Treatment of type 2, adult onset DM, is recommended as a step-by-step method, starting with dietary-exercise therapy, followed by oral hypoglycemic drugs and then insulin therapy. DM patients with complications should have a therapy devised to match their circumstances. 5) Epidemiological aspects: The mortality rate of DM compared to the time of drug appearance was traced from 1920 to 2000. The curve goes down slowly in the time frame of World War II, but rises from 1950 to 1970. The elevation could not be suppressed by the appearance of SUs, BGs or improved insulin preparations. The curve runs flat from 1980 to 1990, which might be related to the use of purified insulin or human insulin therapy. The mortality rate of DM indicates that death by hyperglycemic coma and other deaths resulting from complications are excluded. The survey of the principal cause of death by DM during the period of 1981-1990 indicates that the death rate due to hyperglycemic coma is only 1.7% of the total deaths caused by DM. The effect of drug therapy on all of the death resulting from DM is not detected. Hospital visitation and admission rates of the DM patients have been recorded since 1952 in Japan. This curve is rising continuously, and none of the antidiabetic drugs has been able to suppress it. These data show that the antidiabetic drugs relieve DM symptoms through their effective hypoglycemic actions, but that they cannot suppress the mortality rate of DM. It is possible that none of the drugs currently available can suppress the increasing tendency of DM patients.


Does the duration of ambulatory consultations affect the quality of healthcare? A systematic review.
The objective is to examine and synthesise the best available experimental evidence about the effect of ambulatory consultation duration on quality of healthcare. We included experimental studies manipulating the length of outpatient clinical encounters between adult patients and clinicians (ie, therapists, pharmacists, nurses, physicians) to determine their effect on quality of care (ie, effectiveness, efficiency, timeliness, safety, equity, patient-centredness and patient satisfaction). Using controlled vocabulary and keywords, without restriction by language or year of publication, we searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews and Scopus from inception until 15 May 2023. Cochrane Risk of Bias instrument. Narrative synthesis. 11 publications of 10 studies explored the relationship between encounter duration and quality. Most took place in the UK's general practice over two decades ago. Study findings based on very sparse and outdated evidence-which suggested that longer consultations improved indicators of patient-centred care, education about prevention and clinical referrals; and that consultation duration was inconsistently related to patient satisfaction and clinical outcomes-warrant low confidence due to limited protections against bias and indirect applicability to current practice. Experimental evidence for a minimal or optimal duration of an outpatient consultation is sparse and outdated. To develop evidence-based policies and practices about encounter length, randomised trials of different consultation lengths-in person and virtually, and with electronic health records-are needed. OSF Registration DOI:10.17605/OSF.IO/EUDK8.


[The development of the incidence of diabetes mellitus I in children 0 to 14 years of age in Malaga (1982-1993)].
A prospective study was conducted to assess the evolution of the incidence of type 1 diabetes mellitus (insulin-dependent) in Málaga among children less than 14 years of age between 1982 and 1993. The capture-recapture method was chosen for estimating the probability of ascertainment and two sources were used: The hospital registry and Málaga Diabetes Association members. We detected 437 children and the ascertainment achieved was 98.8%. The average annual incidence was 14.3/10(5) and the prevalence at the end of the period was 0.78 patients/10(3). During the last 6 years of the observation period, the incidence rose by 42%. The highest incidence was found among children between 10 and 13 years of age in both sexes. The age of onset and female/male ratio increased during the study period. There was an inverse relationship with monthly temperature. In comparison with other European epidemiological studies, we found a higher incidence and increased rate of growth of the incidence of type 1 diabetes mellitus during the observation period.


The economic implications of animal diseases and disease control at the national level.
The authors examine the economic implications of animal diseases and control programmes at the national level, including the role of government in animal health, the effect of regulations and the use of cost-benefit analysis. Special attention is paid to the role of economic analysis in government decision-making processes. Economics provides a framework for gathering information and for the presentation of that information in a methodical manner, thereby providing a method for the decision maker to examine policy alternatives. In addition, assumptions underlying the analysis must be clearly laid out and explained by the person undertaking the analysis. Economic reasons for government intervention in animal health programmes include externalities, natural monopolies, public goods, coordination failure, information failure and distribution issues. An integrated holistic approach that includes national and international policy objectives is outlined in the paper. In the approach outlined, government coordinates the activities of stakeholders in animal health, including producers, consumers and researchers.


Conference on animal models of aging in the auditory system.
A conference was held to consider conceptual issues, methodological problems and preliminary findings related to auditory research with aging animals. Current concepts from various areas of experimental gerontology were discussed in relation to research on the aging auditory system and to the problem of human presbycusis.


Predictors of serious bacterial infection in children aged 3 to 36 months with fever without source.
Children commonly present with fever without source yet there is no reliable and consistent method of identifying those at risk of serious bacterial infection. In this study, we sought to identify predictors of serious bacterial infection in children aged between three to 36 months with fever without source. Inpatient records of all children aged three to 36 months admitted from the Emergency Department of Singapore's main paediatric hospital between October 2001 to February 2002 with International Classification of Diseases (ninth revision) diagnosis codes 038 (septicaemia), 079 (viral fever), or 780 (pyrexia of unknown origin), were retrieved and reviewed. Patients identified as having fever without source were enrolled. Of 86 enrolled children, 17 (19.8 percent) had serious bacterial infection. Duration of fever and white blood cell count were found to be significant predictors. Children with white blood cell count equal to or greater than 16,000/cubic mm had 6.9 times (95 percent confidence interval [CI] is 1.7 to 28.4) increased risk of serious bacterial infection, while children with fever of duration exceeding three days before presentation had 3.8 times (95 percent CI is 1.1 to 13.1) increased risk of serious bacterial infection. A combination of white blood cell count less than 16,000/cubic mm and duration of fever three days or less had a negative predictive value of 1.0 (95 percent CI is 0.88 to 1.0) and a sensitivity of 1.0 (95 percent CI is 0.82 to 1.0). The two identified predictors offer an estimate of the risk of serious bacterial infection in children aged three to 36 months with fever without source.


Atomically Sharp Dual Grain Boundaries in 2D WS2 Bilayers.
It is shown that tilt grain boundaries (GBs) in bilayer 2D crystals of the transition metal dichalcogenide WS2 can be atomically sharp, where top and bottom layer GBs are located within sub-nanometer distances of each other. This expands the current knowledge of GBs in 2D bilayer crystals, beyond the established large overlapping GB types typically formed in chemical vapor deposition growth, to now include atomically sharp dual bilayer GBs. By using atomic-resolution annular dark-field scanning transmission electron microscopy (ADF-STEM) imaging, different atomic structures in the dual GBs are distinguished considering bilayers with a 3R (AB stacking)/2H (AA' stacking) interface as well as bilayers with 2H/2H boundaries. An in situ heating holder is used in ADF-STEM and the GBs are stable to at least 800 °C, with negligible thermally induced reconstructions observed. Normal dislocation cores are seen in one WS2 layer, but the second WS2 layer has different dislocation structures not seen in freestanding monolayers, which have metal-rich clusters to accommodate the stacking mismatch of the 2H:3R interface. These results reveal the competition between maintaining van der Waals bilayer stacking uniformity and dislocation cores required to stitch tilted bilayer GBs together.


Mechanical forces regulate the reactivity of a thioester bond in a bacterial adhesin.
Bacteria must withstand large mechanical shear forces when adhering to and colonizing hosts. Recent structural studies on a class of Gram-positive bacterial adhesins have revealed an intramolecular Cys-Gln thioester bond that can react with surface-associated ligands to covalently anchor to host surfaces. Two other examples of such internal thioester bonds occur in certain anti-proteases and in the immune complement system, both of which react with the ligand only after the thioester bond is exposed by a proteolytic cleavage. We hypothesized that mechanical forces in bacterial adhesion could regulate thioester reactivity to ligand analogously to such proteolytic gating. Studying the pilus tip adhesin Spy0125 of Streptococcus pyogenes, we developed a single molecule assay to unambiguously resolve the state of the thioester bond. We found that when Spy0125 was in a folded state, its thioester bond could be cleaved with the small-molecule nucleophiles methylamine and histamine, but when Spy0125 was mechanically unfolded and subjected to forces of 50-350 piconewtons, thioester cleavage was no longer observed. For folded Spy0125 without mechanical force exposure, thioester cleavage was in equilibrium with spontaneous thioester reformation, which occurred with a half-life of several minutes. Functionally, this equilibrium reactivity allows thioester-containing adhesins to sample potential substrates without irreversible cleavage and inactivation. We propose that such reversible thioester reactivity would circumvent potential soluble inhibitors, such as histamine released at sites of inflammation, and allow the bacterial adhesin to selectively associate with surface-bound ligands.


Assessment of ventilation-perfusion mismatching in mechanically ventilated patients.
The multiple inert gas elimination technique (MIGET) is a robust tool to assess both ventilation-perfusion (V'A/Q') distributions and the role of extrapulmonary factors determining arterial oxygenation during spontaneous breathing and in mechanically ventilated patients. Mixed expired gas sampling used in the MIGET is most often obtained from a 10-L mixing box (10L-MB) placed in the expiratory side of the ventilator circuit. Consequently, a considerable increase in the compression volume (Vc) would be expected which, in turn, can give rise to potential errors in the estimation of the effective tidal volume delivered to the patient. The effects of the 10L-MB on the Vc were compared with those produced by a newly designed 1-L, mixing box (IL-MB). At a given peak pressure (Ppeak) within the ventilator circuit, the Vc generated by the 10L-MB was about six-times higher than that produced by the 1L-MB. At a Ppeak =50 cmH2O, the Vc were 377 mL (10L-MB) and 67 mL (1L-MB) (p<0.001). In six patients, the mixed expired partial pressures of the six inert gases simultaneously collected from the two mixing boxes fell on the identity line. V'A/Q' distributions recovered using each of the two mixing boxes were equivalent. With the IL-MB, the effects of different positive end-expiratory pressure levels (0, 6 and 12 cmH2O) on Vc and arterial carbon dioxide tension were negligible. In conclusion, the new 1-L mixing box provides efficient gas mixing and substantially decreases the compression volume. It is, therefore, recommended when studies requiring mixed expired gas are performed in ventilated patients.


Residential relocation to assess impact of changes in the living environment on cardio-respiratory health: A narrative literature review with considerations for exposome research.
Residential relocation studies have become increasingly valuable tools for evaluating the effects of changing living environments on human health, but little is known about their application to multiple aspects of the living environment and the most appropriate methodology. This narrative review explores the utility of residential relocation as a natural experiment for studying the impact of changing urban exposures on cardio-metabolic health in high-income settings. It provides a comprehensive overview of the use of residential relocation studies, evaluates their methodological approaches, and synthesizes findings related to health behaviors and cardio-metabolic outcomes. Our search identified 43 relevant studies published between January 1995 and February 2023, from eight countries, predominantly the USA, Canada, and Australia. The majority of eligible studies were published between 2012 and 2021 and examined changes in various domains of the living environment, such as walkability, the built and social environments, but rarely combinations of exposures. Included studies displayed heterogeneity in design and outcomes, 25 involving only movers and 18 considering both movers and non-movers. To mitigate the issue of residential self-selection bias, most studies employed a "change-in-change" design and adjusted for baseline covariates but only a fraction of them accounted for time-varying confounding. Relocation causes simultaneous changes in various features of the living environment, which presents an opportunity for exposome research to establish causal relationships, using large datasets with increased statistical power and a wide range of health outcomes, behaviors and biomarkers. Residential relocation is not a random process. Thus, studies focusing on living environment characteristics need to carefully select time-varying covariates and reference group. Overall, this review informs future research by guiding choices in study design, data requirements, and statistical methodologies. Ultimately, it contributes to the advancement of the urban exposome field and enhances our understanding of the complex relationship between urban environments and human health.


DNDI-6174 is a preclinical candidate for visceral leishmaniasis that targets the cytochrome bc1.
New drugs for visceral leishmaniasis that are safe, low cost, and adapted to the field are urgently required. Despite concerted efforts over the last several years, the number of new chemical entities that are suitable for clinical development for the treatment of Leishmania remains low. Here, we describe the discovery and preclinical development of DNDI-6174, an inhibitor of Leishmania cytochrome bc1 complex activity that originated from a phenotypically identified pyrrolopyrimidine series. This compound fulfills all target candidate profile criteria required for progression into preclinical development. In addition to good metabolic stability and pharmacokinetic properties, DNDI-6174 demonstrates potent in vitro activity against a variety of Leishmania species and can reduce parasite burden in animal models of infection, with the potential to approach sterile cure. No major flags were identified in preliminary safety studies, including an exploratory 14-day toxicology study in the rat. DNDI-6174 is a cytochrome bc1 complex inhibitor with acceptable development properties to enter preclinical development for visceral leishmaniasis.


Use of Traumatic Brain Injury Prediction Rules With Clinical Decision Support.
We determined whether implementing the Pediatric Emergency Care Applied Research Network (PECARN) traumatic brain injury (TBI) prediction rules and providing risks of clinically important TBIs (ciTBIs) with computerized clinical decision support (CDS) reduces computed tomography (CT) use for children with minor head trauma. Nonrandomized trial with concurrent controls at 5 pediatric emergency departments (PEDs) and 8 general EDs (GEDs) between November 2011 and June 2014. Patients were <18 years old with minor blunt head trauma. Intervention sites received CDS with CT recommendations and risks of ciTBI, both for patients at very low risk of ciTBI (no Pediatric Emergency Care Applied Research Network rule factors) and those not at very low risk. The primary outcome was the rate of CT, analyzed by site, controlling for time trend. We analyzed 16 635 intervention and 2394 control patients. Adjusted for time trends, CT rates decreased significantly (P < .05) but modestly (2.3%-3.7%) at 2 of 4 intervention PEDs for children at very low risk. The other 2 PEDs had small (0.8%-1.5%) nonsignificant decreases. CT rates did not decrease consistently at the intervention GEDs, with low baseline CT rates (2.1%-4.0%) in those at very low risk. The control PED had little change in CT use in similar children (from 1.6% to 2.9%); the control GED showed a decrease in the CT rate (from 7.1% to 2.6%). For all children with minor head trauma, intervention sites had small decreases in CT rates (1.7%-6.2%). The implementation of TBI prediction rules and provision of risks of ciTBIs by using CDS was associated with modest, safe, but variable decreases in CT use. However, some secular trends were also noted.


[Environmental health: concepts and activities].
The objective of this study is to provide information and a conceptual framework that will facilitate the work of persons in charge of systematizing institutions devoted to environmental health. The notion of "environment" is examined and a definition is proposed, while a look is also taken at the place held by environmental health within the context of environmental problems and their "green" and "blue" components. A number of definitions are put forth before presenting the official definition of environmental health issued by WHO in Sofia (1993). Subsequently a list is presented of the basic areas that have been assigned to the field of environmental health by different organizations or at various meetings, with PAHO, WHO, and Program 21 among them. From this a rather exhaustive list of areas and subareas is constructed, with the finding that all lists are, in reality, an asystematic grouping of three different components: determining factors (from the physical world), processes (types of interventions), and roles (series of administrative tasks) which can be conceived as a matrix and which allow for the description of individual activities by the environmental health services. Certain rules of operation are proposed which make it possible, through a form of algebra, to construct expressions for describing such activities and their aggregates with some precision. Thus, it becomes possible to employ a common symbolic language which can facilitate intercommunication, teaching, and research in the area of environmental health.


Transcriptome Reveals the Rice Response to Elevated Free Air CO2 Concentration and TiO2 Nanoparticles.
Increasing CO2 levels are speculated to change the effects of engineered nanomaterials in soil and on plant growth. How plants will respond to a combination of elevated CO2 and nanomaterials stress has rarely been investigated, and the underlying mechanism remains largely unknown. Here, we conducted a field experiment to investigate the rice (Oryza sativa L. cv. IIyou) response to TiO2 nanoparticles (nano-TiO2, 0 and 200 mg kg-1) using a free-air CO2 enrichment system with different CO2 levels (ambient ∼370 μmol mol-1 and elevated ∼570 μmol mol-1). The results showed that elevated CO2 or nano-TiO2 alone did not significantly affect rice chlorophyll content and antioxidant enzyme activities. However, in the presence of nano-TiO2, elevated CO2 significantly enhanced the rice height, shoot biomass, and panicle biomass (by 9.4%, 12.8%, and 15.8%, respectively). Furthermore, the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that genes involved in photosynthesis were up-regulated while most genes associated with secondary metabolite biosynthesis were down-regulated in combination-treated rice. This indicated that elevated CO2 and nano-TiO2 might stimulate rice growth by adjusting resource allocation between photosynthesis and metabolism. This study provides novel insights into rice responses to increasing contamination under climate change.


Occulsion amblyopia.
There have been a number of reports on the effects of early occlusion on the visual system of cats, monkeys, and humans. In the present paper, a patient with amblyopia resulting from prolonged early occlusion in the treatment of strabismus is described, and implications for management of early strabismus are discussed.


Selectively Disrupting m6A-Dependent Protein-RNA Interactions with Fragments.
We report a crystallographic analysis of small-molecule ligands of the human YTHDC1 domain that recognizes N6-methylated adenine (m6A) in RNA. The 30 binders are fragments (molecular weight < 300 g mol-1) that represent 10 different chemotypes identified by virtual screening. Despite the structural disorder of the binding site loop (residues 429-439), most of the 30 fragments emulate the two main interactions of the -NHCH3 group of m6A. These interactions are the hydrogen bond to the backbone carbonyl of Ser378 and the van der Waals contacts with the tryptophan cage. Different chemical groups are involved in the conserved binding motifs. Some of the fragments show favorable ligand efficiency for YTHDC1 and selectivity against other m6A reader domains. The structural information is useful for the design of modulators of m6A recognition by YTHDC1.


Using Oscillating Sounds to Manipulate Sleep Spindles.
EEG oscillations known as sleep spindles have been linked with various aspects of cognition, but the specific functions they signal remain controversial. Two types of EEG sleep spindles have been distinguished: slow spindles at 11-13.5 Hz and fast spindles at 13.5-16 Hz. Slow spindles exhibit a frontal scalp topography, whereas fast spindles exhibit a posterior scalp topography and have been preferentially linked with memory consolidation during sleep. To advance understanding beyond that provided from correlative studies of spindles, we aimed to develop a new method to systematically manipulate spindles. We presented repeating bursts of oscillating white noise to people during a 90-min afternoon nap. During stage 2 and slow-wave sleep, oscillations were embedded within contiguous 10-s stimulation intervals, each comprising 2 s of white noise amplitude modulated at 12 Hz (targeting slow spindles), 15 Hz (targeting fast spindles), or 50 Hz followed by 8 s of constant white noise. During oscillating stimulation compared to constant stimulation, parietal EEG recordings showed more slow spindles in the 12-Hz condition, more fast spindles in the 15-Hz condition, and no change in the 50-Hz control condition. These effects were topographically selective, and were absent in frontopolar EEG recordings, where slow spindle density was highest. Spindles during stimulation were similar to spontaneous spindles in standard physiological features, including duration and scalp distribution. These results define a new method to selectively and noninvasively manipulate spindles through acoustic resonance, while also providing new evidence for functional distinctions between the 2 types of EEG spindles.


Mothers in a cooperatively breeding bird increase investment per offspring at the pre-natal stage when they will have more help with post-natal care.
In many cooperative societies, including our own, helpers assist with the post-natal care of breeders' young and may thereby benefit the post-natal development of offspring. Here, we present evidence of a novel mechanism by which such post-natal helping could also have beneficial effects on pre-natal development: By lightening post-natal maternal workloads, helpers may allow mothers to increase their pre-natal investment per offspring. We present the findings of a decade-long study of cooperatively breeding white-browed sparrow-weaver, Plocepasser mahali, societies. Within each social group, reproduction is monopolized by a dominant breeding pair, and non-breeding helpers assist with nestling feeding. Using a within-mother reaction norm approach to formally identify maternal plasticity, we demonstrate that when mothers have more female helpers, they decrease their own post-natal investment per offspring (feed their nestlings at lower rates) but increase their pre-natal investment per offspring (lay larger eggs, which yield heavier hatchlings). That these plastic maternal responses are predicted by female helper number, and not male helper number, implicates the availability of post-natal helping per se as the likely driver (rather than correlated effects of group size), because female helpers feed nestlings at substantially higher rates than males. We term this novel maternal strategy "maternal front-loading" and hypothesize that the expected availability of post-natal help either allows or incentivizes helped mothers to focus maternal investment on the pre-natal phase, to which helpers cannot contribute directly. The potential for post-natal helping to promote pre-natal development further complicates attempts to identify and quantify the fitness consequences of helping.


Policy influences on community trail development.
This study explores processes and policies that facilitate the development of community trails. With funding from Active Living Research and the research framework of the Physical Activity Policy Research Network (PAPRN), we conducted a multiple-site case study. A total of six trails in Hawaii, Massachusetts, Missouri, North Carolina, South Carolina, and Washington were chosen for study. The goals of this case study were to identify the policy influences on trail development, explore the roles of key players in trail development, and compare and contrast findings from the different trails. Trail development can be a long process. Some of the trails took over a decade to complete because of funding, opposition, and roadblocks in the form of design standard policies. Work in trail development requires a team of many players, and it is necessary to balance their varied motives to accomplish a shared overall goal. Foresight through the master planning process is also a vital component of successful trail development. Finally, community involvement is key. Communities contemplating trail development should explore the effects of policy on the trail projects reported here to proactively identify potential influence.


Competition avoidance drives individual differences in response to a changing food resource in sticklebacks.
Within the same population, individuals often differ in how they respond to changes in their environment. A recent series of models predicts that competition in a heterogeneous environment might promote between-individual variation in behavioural plasticity. We tested groups of sticklebacks in patchy foraging environments that differed in the level of competition. We also tested the same individuals across two different social groups and while alone to determine the social environment's influence on behavioural plasticity. In support of model predictions, individuals consistently differed in behavioural plasticity when the presence of conspecifics influenced the potential payoffs of a foraging opportunity. Whether individuals maintained their level of behavioural plasticity when placed in a new social group depended on the environmental heterogeneity. By explicitly testing predictions of recent theoretical models, we provide evidence for the types of ecological conditions under which we would expect, and not expect, variation in behavioural plasticity to be favoured.


[Transduction of streptomycin resistance in group A streptococci by virulent streptococcal phage CA1].
The author studied the Smr transduction in hemolytic streptococci, group A, by the virulent CA1 phage. This phage differed from the A12 and A25 by the spectrum of lytic activity and was affiliated to them serologically. In comparable experiments CA1 phage exceeded A25 phage by the transducing activity. Phage CA1 transduced the cultures of various serological types. The efficiency of transduction depended on the multiplicity of the infection (the optimum--0.1--0.03), the age of the recipient culture (the optimum--1--2-day) and the time of phenotypical expression (the optimum--2--3 hours). It was possible to increase the frequency of transduction by one order with the aid of UV irradiation. Still a theoretically possible output of the transducers determined by calculation was not reached because of some abortiveness of the process.


Sequence of the circle junction of human immunodeficiency virus type 1: implications for reverse transcription and integration.
The sequence of the LTR-LTR circle junction of human immunodeficiency virus type 1 (HIV-1) was determined. The circle junction sequences were amplified by the polymerase chain reaction and cloned into M13 sequencing vectors. The circle junction contains 4 base pairs that are not present in the integrated provirus. We show that reverse transcription in HIV-1 initiates with the addition of a dC to the tRNA primer, suggesting that the tRNA used to initiate reverse transcription ends with the consensus CCA triplet. This indicates that the source of one of the four bases in the circle junction is probably the terminal A of the tRNA primer used to initiate reverse transcription. We propose that, in HIV-1, removal of the tRNA primer by RNase H cleavage shows an unusual specificity such that cleavage occurs between the terminal rA and the adjacent rC of the tRNA primer. These data also imply that the HIV-1 integration protein removes two bases from each end of the linear viral DNA during integration as has been described for other well-studied retroviruses.


Knee osteotomy and meniscal transplantation: indications, technical considerations, and results.
Meniscal transplantation for the symptomatic postmeniscectomized knee has become an accepted procedure. Successful outcomes depend on patient selection and having a stable, nonarthritic, well-aligned knee, in addition to the technical aspects. In achieving limb preventing overload of the transplanted meniscal tissue, osteotomy around the knee has become an essential component of the surgical procedure. This paper reviews the indications, evaluation, planning, technique, and results for meniscal transplantation combined with osteotomy.


Whole grain germinated brown rice intake modulates the gut microbiota and alleviates hypertriglyceridemia and hypercholesterolemia in high fat diet-fed mice.
Hyperlipidemia is a common clinical disorder of lipid metabolism in modern society and is considered to be one of the major risk factors leading to cardiovascular-related diseases. Germinated brown rice (GBR) is a typical whole grain food. The lipid-lowering effect of GBR has received increasing attention, but its mechanism of action is not fully understood. The gut microbiota has been proposed as a novel target for the treatment of hyperlipidemia. The aim of this study was to investigate the effects of GBR on the gut microbiota and lipid metabolism in high-fat diet (HFD)-fed C57BL/6J mice. The effect of GBR on hyperlipidemia was evaluated by measuring blood lipid levels and by pathological examination. The gut microbiota was detected by 16S rRNA sequencing, and the protein and mRNA expression levels involved in cholesterol metabolism were detected by western blotting and RT-qPCR to find potential correlations. The results showed that GBR supplementation could effectively reduce the levels of TC, TG, LDL-C and HDL-C in the serum and alleviate the excessive accumulation of fat droplets caused by HFD. Moreover, GBR intervention improved HFD-fed gut microbiota disorder via increasing the diversity of the gut microbiota, reducing the Firmicutes/Bacteroidetes ratio, and improving gut barrier damage. In addition, GBR could inhibit endogenous cholesterol synthesis and promote cholesterol transport and excretion. These findings suggest that GBR may be a competitive candidate for the development of functional foods to prevent abnormal lipid metabolism.


NOD1/NOD2 and RIP2 Regulate Endoplasmic Reticulum Stress-Induced Inflammation during Chlamydia Infection.
The inflammatory response to Chlamydia infection is likely to be multifactorial and involve a variety of ligand-dependent and -independent recognition pathways. We previously reported the presence of NOD1/NOD2-dependent endoplasmic reticulum (ER) stress-induced inflammation during Chlamydia muridarum infection in vitro, but the relevance of this finding to an in vivo context is unclear. Here, we examined the ER stress response to in vivo Chlamydia infection. The induction of interleukin 6 (IL-6) production after systemic Chlamydia infection correlated with expression of ER stress response genes. Furthermore, when tauroursodeoxycholate (TUDCA) was used to inhibit the ER stress response, an increased bacterial burden was detected, suggesting that ER stress-driven inflammation can contribute to systemic bacterial clearance. Mice lacking both NOD1 and NOD2 or RIP2 exhibited slightly higher systemic bacterial burdens after infection with Chlamydia Overall, these data suggest a model where RIP2 and NOD1/NOD2 proteins link ER stress responses with the induction of Chlamydia-specific inflammatory responses.IMPORTANCE Understanding the initiation of the inflammatory response during Chlamydia infection is of public health importance given the impact of this disease on young women in the United States. Many young women are chronically infected with Chlamydia but are asymptomatic and therefore do not seek treatment, leaving them at risk of long-term reproductive harm due to inflammation in response to infection. Our manuscript explores the role of the endoplasmic reticulum stress response pathway initiated by an innate receptor in the development of this inflammation.


p38alpha-selective MAP kinase inhibitor reduces tumor growth in mouse xenograft models of multiple myeloma.
Multiple myeloma (MM) is a clonal plasma cell malignancy, which is currently incurable. Therefore, new mono- or combined therapy treatment regimens in the early and advanced phases of MM are urgently needed to combat this disease. Recently, p38 mitogen-activated protein kinase (MAPK) has been implicated as playing an important role in MM. Therefore, the effect of a p38alpha-selective MAPK inhibitor, SCIO-469 (indole-5-carboxamide, ATP-competitive inhibitor), or its structural analog, SD-282 (indole-5-carboxamide, ATP-competitive inhibitor) was examined in mouse xenograft models of MM using human RPMI-8226 or H-929 plasmacytoma inocula. Oral treatment with SCIO-469 (10, 30, 90 mg/kg) twice daily was initiated in mice with palpable tumors of RPMI-8226 origin, a condition that mimics early human myeloma disease. In mice with palpable tumors, 14 days of SCIO-469 treatment significantly reduced RPMI-8226 tumor growth in a dose-dependent manner. A significant dose-dependent reduction in RPMI-8226 tumor growth was also observed when SCIO-469 oral treatment at doses of 10, 30 and 90 mg/kg twice daily was initiated in mice with tumors of pronounced size, a condition that mimics advanced human myeloma disease. In a similar set of studies employing the SCIO-469 analogue SD-282 at 90 mg/kg/bid orally, histological assessment at the end of the study demonstrated a significant reduction in RPMI-8226 tumor growth and angiogenesis. SD-282 treatment was additionally shown to significantly reduced expression of heat-shock protein-27 (HSP-27) and phospho-p38 in the tumor cells. Furthermore, co-administration of SCIO-469 with dexamethasone elicited antitumor properties in dexamethasone-sensitive H-929 tumors at much lower than the typically effective doses of dexamethasone, suggesting its potential for combined therapy. In conclusion, p38 inhibitors reduced human myeloma cell growth in vivo both at early and advanced phases of the disease. The current study also provides evidence of potential for co-therapy with dexamethasone.


Varenicline versus nicotine replacement therapy for long-term smoking cessation: an observational study using the Clinical Practice Research Datalink.
Smoking is the leading avoidable cause of illness and premature mortality. The first-line treatments for smoking cessation are nicotine replacement therapy and varenicline. Meta-analyses of experimental studies have shown that participants allocated to the varenicline group were 1.57 times (95% confidence interval 1.29 to 1.91 times) as likely to be abstinent 6 months after treatment as those allocated to the nicotine replacement therapy group. However, there is limited evidence about the effectiveness of varenicline when prescribed in primary care. We investigated the effectiveness and rate of adverse events of these medicines in the general population. To estimate the effect of prescribing varenicline on smoking cessation rates and health outcomes. Clinical Practice Research Datalink. We conducted an observational cohort study using electronic medical records from the Clinical Practice Research Datalink. We extracted data on all patients who were prescribed varenicline or nicotine replacement therapy after 1 September 2006 who were aged ≥ 18 years. We investigated the effects of varenicline on smoking cessation, all-cause mortality and cause-specific mortality and hospitalisation for: (1) chronic lung disease, (2) lung cancer, (3) coronary heart disease, (4) pneumonia, (5) cerebrovascular disease, (6) diabetes, and (7) external causes; primary care diagnosis of myocardial infarction, chronic obstructive pulmonary disease, depression, or prescription for anxiety; weight in kg; general practitioner and hospital attendance. Our primary outcome was smoking cessation 2 years after the first prescription. We investigated the baseline differences between patients prescribed varenicline and patients prescribed nicotine replacement therapy. We report results using multivariable-adjusted, propensity score and instrumental variable regression. Finally, we developed methods to assess the relative bias of the different statistical methods we used. People prescribed varenicline were healthier at baseline than those prescribed nicotine replacement therapy in almost all characteristics, which highlighted the potential for residual confounding. Our instrumental variable analysis results found little evidence that patients prescribed varenicline had lower mortality 2 years after their first prescription (risk difference 0.67, 95% confidence interval -0.11 to 1.46) than those prescribed nicotine replacement therapy. They had similar rates of all-cause hospitalisation, incident primary care diagnoses of myocardial infarction and chronic obstructive pulmonary disease. People prescribed varenicline subsequently attended primary care less frequently. Patients prescribed varenicline were more likely (odds ratio 1.46, 95% confidence interval 1.42 to 1.50) to be abstinent 6 months after treatment than those prescribed nicotine replacement therapy when estimated using multivariable-adjusted for baseline covariates. Patients from more deprived areas were less likely to be prescribed varenicline. However, varenicline had similar effectiveness for these groups. Patients prescribed varenicline in primary care were more likely to quit smoking than those prescribed nicotine replacement therapy, but there was little evidence that they had lower rates of mortality or morbidity in the 4 years following the first prescription. There was little evidence of heterogeneity in effectiveness across the population. Future research should investigate the decline in prescribing of smoking cessation products; develop an optimal treatment algorithm for smoking cessation; use methods for using instruments with survival outcomes; and develop methods for comparing multivariable-adjusted and instrumental variable estimates. Not all of our code lists were validated, body mass index and Index of Multiple Deprivation had missing values, our results may suffer from residual confounding, and we had no information on treatment adherence. This trial is registered as NCT02681848. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 9. See the NIHR Journals Library website for further project information.


[Pancreatico-pleural fistula in chronic pancreatitis with necrosis of the pancreatic tail].
A 68-year-old male was admitted to the hospital with progressive dyspnea and thoracic pain radiating to the shoulder, back and upper abdomen. The patients medical history included hypertension, diabetes and chronic pancreatitis with splenic vein thrombosis. Laboratory findings showed no signs of myocardial infarction, but pronounced inflammation. The ECG was normal. Chest X-ray revealed a massive left-side pleural effusion with partial lung atelectasis. An abdominal CT-scan showed no signs of acute pancreatitis. Puncture of the pleural effusion revealed elevated amylase and lipase. ERCP showed pancreatic duct stenosis, partial necrosis of the pancreatic body and peripancreatic necrosis with a pancreatico-pleural fistula. After ballon-dilatation of the constricted pancreatic duct, a plastic stent and a nasopancreatic drain were inserted into the necrosis and into the fistula. Drainage and antibiotic therapy led to regression of the necrosis within 3 weeks. With external pleural drainage and octreotide therapy almost complete regression of the pleural effusion and closure of the pancreatico-pleural fistula could be achieved within 3 weeks. Complications of chronic pancreatitis such as necrosis and fistulas are rare, but important differential diagnoses in patients with chronic pancreatitis and chest pain. A combination of transpapillary or transgastral endoscopic drainage procedures and pleural drainage, sometimes with additional octreotide therapy is the treatment of choice.


A lysine-cysteine redox switch with an NOS bridge regulates enzyme function.
Disulfide bonds between cysteine residues are important post-translational modifications in proteins that have critical roles for protein structure and stability, as redox-active catalytic groups in enzymes or allosteric redox switches that govern protein function1-4. In addition to forming disulfide bridges, cysteine residues are susceptible to oxidation by reactive oxygen species, and are thus central not only to the scavenging of these but also to cellular signalling and communication in biological as well as pathological contexts5,6. Oxidized cysteine species are highly reactive and may form covalent conjugates with, for example, tyrosines in the active sites of some redox enzymes7,8. However, to our knowledge, regulatory switches with covalent crosslinks other than disulfides have not previously been demonstrated. Here we report the discovery of a covalent crosslink between a cysteine and a lysine residue with a NOS bridge that serves as an allosteric redox switch in the transaldolase enzyme of Neisseria gonorrhoeae, the pathogen that causes gonorrhoea. X-ray structure analysis of the protein in the oxidized and reduced state reveals a loaded-spring mechanism that involves a structural relaxation upon redox activation, which is propagated from the allosteric redox switch at the protein surface to the active site in the protein interior. This relaxation leads to a reconfiguration of key catalytic residues and elicits an increase in enzymatic activity of several orders of magnitude. The redox switch is highly conserved in related transaldolases from other members of the Neisseriaceae; for example, it is present in the transaldolase of Neisseria meningitides (a pathogen that is the primary cause of meningitis and septicaemia in children). We surveyed the Protein Data Bank and found that the NOS bridge exists in diverse protein families across all domains of life (including Homo sapiens) and that it is often located at catalytic or regulatory hotspots. Our findings will inform strategies for the design of proteins and peptides, as well as the development of new classes of drugs and antibodies that target the lysine-cysteine redox switch9,10.


Interference resolution in the elderly: evidence suggestive of differences in strategy on measures of prepotent inhibition and dual task processing.
The ability to effectively resolve interference was investigated in young and elderly participants using a test of inhibition and a dual task measure. The tasks stressed the ability to suppress prepotent responding, and balance primary and secondary task demands, respectively. Successful performance on both measures hinged on the ability to minimize the distraction generated between competing aspects of each task. Increasing demands resulted in performance decrements despite titration for individual differences in span size and generalized slowing. These were more pronounced on the hardest condition of each task, especially in older participants. Furthermore, the nature of the decrements suggested the use of different strategies between groups. It is argued that a fundamental source of the age-associated variability in cognition is due to compromised ability to effectively resolve interference, and cannot be sufficiently explained by memory span differences or generalized slowing.


Illusions in reasoning about consistency.
Reasoners succumb to predictable illusions in evaluating whether sets of assertions are consistent. We report two studies of this computationally intractable task of "satisfiability." The results show that as the number of possibilities compatible with the assertions increases, the difficulty of the task increases, and that reasoners represent what is true according to assertions, not what is false. This procedure avoids overloading memory, but it yields illusions of consistency and of inconsistency. These illusions modify our picture of human rationality.


Hemopoietic function after use of IL-1 with chemotherapy or irradiation.
IL-1 has putative chemo- and radioprotective properties, but its effects on primitive hemopoietic stem cell (PHSC) and early multilineage precursor function when given with these modalities is unknown. C57BL6/J (B6) mice, given IL-1 20 h before cyclophosphamide (200 mg/kg for four biweekly doses) or before irradiation (500 cGy), were sacrificed after 4 wk. Their marrow was used as donor cells, and that from B6-Hbb(dGpi1a) (B6-GPI) mice was used as competitor cells in competitive repopulation. Percentages of B6 cells were measured at 30 and 150 days. Stem cell numbers were estimated using binomial statistics. IL-1 alone did not affect stem cell function. As expected, significant declines in early multilineage precursor and PHSC function occurred with chemotherapy and radiation alone. IL-1 with chemotherapy led to exacerbation of these losses in function and numbers (p < 0.05). A similar reduction in function occurred using IL-1 before irradiation. In summary, IL-1 with chemotherapy or radiation worsened chemotherapy- and radiation-induced functional damage to PHSC and other hemopoietic precursors, suggesting that improvements in survival do not necessarily translate into preservation of hemopoietic function.


Lowering the cost of healthcare through an effective safety program.
Today there are many concerns about the seemingly "unrestrained runaway battle" with health care costs. The author discusses three trends that result in increased patient costs, as well as how to use engineering controls, education, and employee "openness" to reduce overhead costs in order to benefit the patient and the hospital.


Relationship between hyperuricemia and other cardiovascular disease risk factors among adult males in Taiwan.
Hyperuricemia is associated with cardiovascular disease risk factors such as obesity, impaired glucose tolerance, hypertension, and hyperlipidemia. However, this relationship between serum uric acid (SUA) concentrations and cardiovascular disease (CVD) is a controversial one, especially among males. The purpose of this study is to evaluate the association between SUA concentrations and other CVD risk factors among adult males in Taiwan. After multi-stage sampling procedures, we randomly selected 1743 Taiwanese males with a mean age of 35 years (from 22 to 54) in this study. Anthropometric, blood pressure and biochemical variables, including serum uric acid, glucose, total cholesterol and triglyceride concentrations, were measured. Among the study population, the mean SUA concentration was 6.5 +/-1.5 mg/dl. There were 290 (16.6%) subjects with SUA concentrations > or = 8.0 mg/dl (defined as hyperuricemia). Compared to normouricemic subjects, hyperuricemic subjects had significantly greater age-adjusted body weight (75.3 vs. 69.2 kg, p < 0.001), body mass index (BMI, 25.5 vs. 23.6 kg/m2, p < 0.001), higher blood pressure (BP, 120.2 vs. 115.2 mmHg for systolic BP and 78.5 vs. 75.3 mmHg for diastolic BP, both p < 0.001) and blood lipid concentrations (193.8 vs. 182.1 mg/dl for total cholesterol and 123.7 vs. 94.4 mg/dl for triglycerides, both p < 0.001). SUA concentration was positively correlated with body weight, BMI, BP and serum lipid concentrations (all p < 0.001). In multivariate regression analyses, after adjusting for potential confounders, SUA concentration was significantly positively associated with diastolic BP, serum total cholesterol and triglyceride concentrations. An increase of 1 mg/dl of SUA was associated with a 2.1 mg/dl elevation in serum total cholesterol (p < 0.001) and a 5.4 mg/dl increase in triglyceride (p < 0.001). From this study, we found that hyperuricemia in subjects is associated with being overweight, and having high blood pressure and hyperlipidemia. There is a significantly positive association between SUA concentration and other CVD risk factors among adult males in Taiwan.


Mutagenicity of smoke condensates from Canadian cigarettes with different design features.
There is currently limited knowledge regarding the impact of different cigarette designs on the toxicological properties of cigarette smoke condensate (CSC). This study used the Salmonella Mutagenicity Assay to examine the mutagenic activity of mainstream CSCs from 11 commercial Canadian cigarette brands with different design features or tobacco blend. The brands were selected to include design features that are common for cigarettes sold in the Canadian market, as well as cigarettes with alternate filters (charcoal or MicroBlue™), the super slim design, and cigarettes containing mixed blends of different tobacco types. CSCs were obtained using the International Organization for Standardization (ISO) and Health Canada Intense (HCI) smoking regimes, and mutagenic activity was assessed using Salmonella strains TA98, YG1041 and YG5185. Comparisons of the commercial brands to the Kentucky 3R4F, the Canadian Monitor 8 reference and a Canadian best seller revealed no significant reduction in CSC mutagenicity for cigarettes with alternate filters. However, the super slim design did afford some reduction in mutagenic potency. Nevertheless, since the study did not attempt to evaluate the impact of the cigarette designs on human health at the individual or population level, the super slim cigarettes cannot be considered 'reduced-harm' cigarettes.


Licensed Vocational Nurse Residency Program in Primary Care.
This article will explain one organization's experience in developing a licensed vocational nurse residency program in an ambulatory setting, the barriers and challenges, and program outcomes. It outlines results of the program in building competence and confidence for vocational nurses to perform as effective team members in the primary care office setting. Learnings from this experience may be applied to enhance new and transitioning employee orientation and education programs in ambulatory and inpatient settings.


The spectrum of lower motor neuron syndromes.
This review discusses the most important lower motor neuron syndromes. This relatively rare group of syndromes has not been well described clinically. Two subgroups can be distinguished: patients in whom motor neurons (lower motor neuron disease (LMND)) are primarily affected or motor axons and their surrounding myelin (multifocal motor neuropathy (MMN)), both leading to muscle atrophy and weakness. Both hereditary and sporadic forms of LMND have been described. The discussion of recent advances in the genetic knowledge of several hereditary forms of LMND may lead to a better understanding of the pathophysiology and the development of therapeutic strategies. By contrast, the pathogenesis of sporadic LMND is largely unknown. It is, therefore, difficult to consider the various sporadic forms of LMND, discussed in this review, as separate diseases. Because the diagnostic and therapeutic options may differ, it would seem rational to consider sporadic LMND as a spectrum of syndromes which can be distinguished from each other on the basis of clinical presentation.MMN is a lower motor neuron syndrome with presumed immunemediated pathogenesis. Evidence of motor conduction block on nerve conduction studies and a positive response to treatment with intravenous immunoglobulins (IVIg) are considered the most relevant criteria for the diagnosis of MMN. As it is treatable, it is important to distinguish MMN from LMND. Careful electrophysiological analysis in the search for conduction block is, therefore, required in all adult patients with pure lower motor neuron syndromes. For the individual patient, distinction between the various lower motor neuron syndromes is important as it enables the physician to provide adequate information over the disease course in LMND and to facilitate early treatment in MMN.


[Theoretically probable assessment of the effectiveness of individualized combined antibiotic therapy of patients with suppurative inflammatory processes].
Efficiency of individual combined antibiotic therapy of patients was estimated in comparison to the use of single antibiotics of their fixed combinations without any special control group. Since the essence of the study was practically in successive appliance of the 2 methods of therapy to the same group of the patients, it was possible to carry out theoretically probable estimation of the final result as a summation effect of both methods and to define the probable result of the 2 nd method. The study of the results of the treatment of the patients with purulent-inflammatory processes showed significant advantages of the individual combined antibiotic therapy.


Decreased morbidity and mortality after pancreatoduodenectomy.
In two 5 year periods (1975 to 1979 and 1980 to 1984), 96 patients underwent pancreatoduodenal resection, which included 74 partial pancreatic resections and 22 total pancreatectomies. Thirty-seven of these patients had resections with preservation of the pylorus. Substantial reductions in perioperative mortality (2 percent versus 10 percent) and morbidity (26 percent versus 49 percent) (p less than 0.05) were achieved in the latter period. Pylorus preservation, with a mortality and morbidity of 3 percent and 27 percent, respectively, did not increase operative risk or compromise long-term survival in patients with malignant disease. In comparison, relatively high mortality and morbidity rates (14 percent and 59 percent) accompanied total pancreatectomy without improved long-term survival. Five year actuarial survival for nonpancreatic periampullary adenocarcinomas was 58 percent. Thus, we recommend pancreatoduodenectomy with preservation of the pylorus for resection of periampullary tumors. These patients, whose only possibility for cure is a major pancreatic resection, should not be denied this opportunity on the basis of reports from a previous era.


Monotonic change of the mean phenotype in two-locus models.
It is shown that the mean phenotype monotonically approaches the optimum in a class of symmetric, two-locus, two-allele models with stabilizing selection. In this model, mean fitness does not change monotonically. Thus, Fisher's fundamental theorem does not hold, even though another quantity of evolutionary interest, the mean phenotype, can be shown to change monotonically. Using this quantity, it is proven that global stability results for this model.


Successful donor engraftment and repair of the blood-brain barrier in cerebral adrenoleukodystrophy.
Adrenoleukodystrophy (ALD) is caused by mutations within the X-linked ABCD1 gene, resulting in the inability to transport acylated very long chain fatty acids (VLCFAs) into the peroxisome for degradation. VLCFAs subsequently accumulate in tissues, including the central nervous system. Up to 40% of boys develop a severe progressive demyelinating form of ALD, cerebral ALD, resulting in regions of demyelination observed on brain magnetic resonance imaging that are associated with a "garland ring" of gadolinium contrast enhancement. Gadolinium enhancement indicates blood-brain barrier (BBB) disruption and an active inflammatory disease process. Only hematopoietic cell transplant (HCT) has been shown to halt neurologic progression, although the mechanism of disease arrest is unknown. We evaluated imaging- and transplant-related biomarkers in 66 males who underwent HCT. In 77% of patients, gadolinium contrast resolved by 60 days post-HCT. We determined that time to neutrophil recovery and extent of donor chimerism correlated significantly with time to contrast resolution post-HCT. Graft failure was associated with a significantly slower rate of contrast resolution (P < .0001). Time to neutrophil recovery remained significant in multivariate analysis with other biomarkers (P = .03). Our data suggest that robust donor myeloid recovery is necessary for timely repair of the BBB.


Synthesis and conductivity enhancement of Al-doped ZnO nanorod array thin films.
Al-doped ZnO (AZO) nanorod array thin films with various Al/Zn molar ratios were synthesized by chemical bath deposition. The resultant AZO nanorods were well-aligned at the glass substrate, growing vertically along the c-axis [001] direction. In addition, they had an average diameter of 64.7 +/- 16.8 nm and an average length of about 1.0 microm with the structure of wurtzite-type ZnO. Analyses of energy dispersive x-ray spectra and x-ray photoelectron spectra indicated that Al atoms had been doped into the ZnO crystal lattice. The doping of Al atoms did not result in significant changes in the structure and crystal orientation, but the electrical resistivity was found to increase first and then decrease with increasing Al content owing to the increase of carrier concentration and the decrease of mobility. In addition, the transmission in the visible region increased but the increase was reduced at higher Al doping levels. After hydrogen treatment, the morphology of the AZO nanorod array thin films remained unchanged. However, the electrical resistivity decreased significantly due to the formation of oxygen vacancies and interstitial hydrogen atoms. When the real Al/Zn molar ratio was about 3.7%, the conductivity was enhanced about 1000 times and a minimum electrical resistivity of 6.4 x 10( - 4) Omega cm was obtained. In addition, the transmission of the ZnO nanorod array thin film in the visible region was significantly increased but the increase was less significant for the AZO nanorod array thin film, particularly at higher Al doping levels. In addition, the current-voltage curves of the thin film devices with ZnO or AZO nanorod arrays revealed that AZO had a higher current response than ZnO and hydrogen treatment led to a more significant enhancement of current responses (about 100-fold).


Consistent features in the forelimb representation of primary motor cortex in rhesus macaques.
The purpose of this study was to systematically map the forelimb area of primary motor cortex (M1) in rhesus macaques in an effort to investigate further the organization of motor output to distal and proximal muscles. We used stimulus-triggered averaging (StTAing) of electromyographic activity to map the cortical representation of 24 simultaneously recorded forelimb muscles. StTAs were obtained by applying 15 microA stimuli to M1 sites while the monkey performed a reach and prehension task. Motor output to body regions other than the forelimb (e.g., face, trunk, and hindlimb) was identified using repetitive intracortical microstimulation to evoke movements. Detailed, muscle-based maps of M1 revealed a central core of distal (wrist, digit, and intrinsic hand) muscle representation surrounded by a "horseshoe"-shaped zone of proximal (shoulder and elbow) muscle representation. The core distal and proximal zones were separated by a relatively large region representing combinations of both distal and proximal muscles. On the basis of its size and characteristics, we argue that this zone is not simply the result of stimulus-current spread, but rather a distinct zone within the forelimb representation containing cells that specify functional synergies of distal and proximal muscles. Electrode tracks extending medially from the medial arm of the proximal muscle representation evoked trunk and hindlimb responses. No distal or proximal muscle poststimulus effects were found in this region. These results argue against the existence of a second, major noncontiguous distal or proximal forelimb representation located medially within the macaque M1 representation.


Preoperative endovascular embolization of craniospinal hemangioblastomas.
To determine whether hemangioblastomas, highly vascular tumors requiring surgery that is potentially complicated by excessive bleeding, can be embolized safely by using interventional techniques that furnish a more avascular surgical field. Nine hemangioblastomas involving either the cerebellum or the spinal cord were embolized preoperatively. In each case the feeding artery was selectively catheterized with a microcatheter and the hypervascular tumor nidus was devascularized with polyvinyl alcohol particles. Two patients who had undergone recent attempts as surgical resection at another institution had repeat surgery after endovascular embolization rendered the tumor nidus avascular. At surgery, the tumor was completely removed in one case and markedly debulked in the other. In all nine cases, blood loss after embolization was reported to be less than expected by experienced surgeons. In addition, manipulation and removal of the tumor was reported to be subjectively easier in these embolized tumors. The embolization procedure caused no permanent complications; however, one patient with a posterior fossa hemangioblastoma and hydrocephalus worsened clinically within 12 hours of embolization. This event was thought to be caused by obstructive hydrocephalus resulting from tumor swelling. Emergency craniotomy, ventricular decompression, and surgical resection of the tumor produced complete resolution of the signs and symptoms. Our results indicate that preoperative embolization of hemangioblastomas is a safe procedure that is useful in aiding surgical resection of these highly vascular tumors.


Applicant Perspectives on the Otolaryngology Residency Application Process.
It has been nearly 25 years since medical students were queried regarding their perspectives on otolaryngology-head and neck surgery (OHNS) residency selection. Understanding this viewpoint is critical to improving the current application process. To evaluate the perceptions of 2016 OHNS residency applicants regarding the application process and offer suggestions for reform. In this cross-sectional study of anonymous online survey data, a 14-question survey was designed based on resources obtained from a computerized PubMed, Ovid, and GoogleScholar database search of the English language from January 1, 1990, through December 31, 2015, was conducted using the following search terms: (medical student OR applicant) AND (application OR match) AND otolaryngology. The survey was administered to 2016 OHNS residency applicants to examine 4 primary areas: current attitudes toward the match, effect of the new Otolaryngology Program Directors Organization personal statement mandate, sources of advice and information, and suggestions for improvement. In January 2016, an email was sent to 100 program directors asking them to distribute the survey to current OHNS applicants at their institution. One follow-up reminder email was sent in February 2016. A link to the survey was posted on the Otomatch.com homepage on January 28, 2016, with the last response received on March 28, 2016. Survey responses regarding the residency application process. A total of 150 of 370 residency applicants (40.5%) responded to the survey. Of these, 125 respondents (90.6%) noted applying to programs in which they had no specific interest simply to improve their chances of matching. Applicants intended to apply to more programs than they actually did (63.6 vs 60.8; r = 0.19; 95% CI, -0.03 to 0.40). Program directors advised fewer applications than other sources; however, 58 respondents (38.7%) did not receive advice from a program director. A total of 121 respondents (80.7%) found online program information to be insufficient. Finally, 90 of 140 respondents (64.3%) noted that they would agree to a hard cap on applications, among other suggestions for improvement. Several main themes emerged from the data, providing a foundation for process improvement opportunities: careful consideration to applicant mentorship, including peers; uniform set of criteria for residency program websites; and investigating alternative match platforms, which may allow hard caps, flagging programs of higher interest, or wave application cycles. Overall, the otolaryngology applicant provides a unique perspective regarding the current state of the match and potential opportunities for system-wide improvement.