High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot.
Prostate cancer (PCa) has a profoundly immunosuppressive microenvironment and is commonly immune excluded with few infiltrative lymphocytes and low levels of immune activation. High-dose radiation has been demonstrated to stimulate the immune system in various human solid tumors. We hypothesized that localized radiation therapy, in the form of high dose-rate brachytherapy (HDRBT), would overcome immune suppression in PCa. To investigate whether HDRBT altered prostate immune context, we analyzed preradiation versus postradiation human tissue from a cohort of 24 patients with localized PCa that received HDRBT as primary treatment (RadBank cohort). We performed Nanostring immune gene expression profiling, digital spatial profiling, and high-throughput immune cell multiplex immunohistochemistry analysis. We also resolved tumor and nontumor zones in spatial and bioinformatic analyses to explore the immunological response. Nanostring immune profiling revealed numerous immune checkpoint molecules (eg, B7-H3, CTLA4, PDL1, and PDL2) and TGFβ levels were increased in response to HDRBT. We used a published 16-gene tumor inflammation signature (TIS) to divide tumors into distinct immune activation states (high:hot, intermediate and low:cold) and showed that most localized PCa are cold tumors pre-HDRBT. Crucially, HDRBT converted 80% of these 'cold'-phenotype tumors into an 'intermediate' or 'hot' class. We used digital spatial profiling to show these HDRBT-induced changes in prostate TIS scores were derived from the nontumor regions. Furthermore, these changes in TIS were also associated with pervasive changes in immune cell density and spatial relationships-in particular, between T cell subsets and antigen presenting cells. We identified an increased density of CD4+ FOXP3+ T cells, CD68+ macrophages and CD68+ CD11c+ dendritic cells in response to HDRBT. The only subset change specific to tumor zones was PDL1- macrophages. While these immune responses were heterogeneous, HDRBT induced significant changes in immune cell associations, including a gained T cell and HMWCK+ PDL1+ interaction in tumor zones. In conclusion, we showed HDRBT converted "cold" prostate tumors into more immunologically activated "hot" tissues, with accompanying spatially organized immune infiltrates and signaling changes. Understanding and potentially harnessing these changes will have widespread implications for the future treatment of localized PCa, including rational use of combination radio-immunotherapy.


Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis.
With the functional demonstration of a role in erythrocyte invasion by Plasmodium falciparum parasites, implications in the aetiology of common conditions that prevail in individuals of African origin, and a wealth of pharmacological knowledge, the stimulatory G protein (Gs) signal transduction pathway presents an exciting target for anti-malarial drug intervention. Having previously demonstrated a role for the G-alpha-s gene, GNAS, in severe malaria disease, we sought to identify other important components of the Gs pathway. Using meta-analysis across case-control and family trio (affected child and parental controls) studies of severe malaria from The Gambia and Malawi, we sought evidence of association in six Gs pathway candidate genes: adenosine receptor 2A (ADORA2A) and 2B (ADORA2B), beta-adrenergic receptor kinase 1 (ADRBK1), adenylyl cyclase 9 (ADCY9), G protein beta subunit 3 (GNB3), and regulator of G protein signalling 2 (RGS2). Our study amassed a total of 2278 cases and 2364 controls. Allele-based models of association were investigated in all genes, and genotype and haplotype-based models were investigated where significant allelic associations were identified. Although no significant associations were observed in the other genes, several were identified in ADORA2A. The most significant association was observed at the rs9624472 locus, where the G allele (approximately 20% frequency) appeared to confer enhanced risk to severe malaria [OR = 1.22 (1.09-1.37); P = 0.001]. Further investigation of the ADORA2A gene region is required to validate the associations identified here, and to identify and functionally characterize the responsible causal variant(s). Our results provide further evidence supporting a role of the Gs signal transduction pathway in the regulation of severe malaria, and request further exploration of this pathway in future studies.


Phase I evaluation of crisnatol (BWA770U mesylate) on a monthly extended infusion schedule.
Crisnatol is an arylmethylaminopropanediol derivative that has shown promise as an antitumor agent in preclinical testing. In a phase I trial using a monthly six-hour infusion schedule the recommended dose for future phase II trials was found to be 388 mg/m2. Neurologic toxicity was dose-limiting in that trial and correlated with the attainment of a threshold plasma concentration of greater than 4.5 micrograms/ml. In this study we treated 15 patients with escalating doses of crisnatol from 450 mg/m2 to 900 mg/m2 administered at a rate of 50 mg/m2/hr over 9, 12, 15, and 18 hours. Toxicity was mild to moderate at all dose levels. However, serious central nervous system effects were noted in one patient at 900 mg/m2 over 18 hours whose plasma level was 6.5 micrograms/ml. This study has demonstrated higher total doses of crisnatol can be given if the drug is administered as a prolonged infusion in an attempt to avoid high plasma levels of the agent.


Traditional processing strongly affects metabolite composition by hydrolysis in Rehmannia glutinosa roots.
The processing of biological raw materials is considered to have an important role in the therapeutic application in Traditional Chinese Medicine. The root of Rehmannia glutinosa has to be processed by nine cycles of rice wine immersing, steaming and drying before using in clinical applications. In order to understand the chemical changes resulting from the processing, a comprehensive analysis of Rehmanniae radix was made using (1)H-NMR and Fourier transform (FT)-mass spectrometry in combination with multivariate data analysis. After (1)H-NMR and principle component analysis, hydrolysis was found to be the major chemical process during the treatments. Catalpol, raffinose and stachyose levels gradually decreased during processing, whereas monosaccharides including galactose and glucose were found to be higher in processed roots. The metabolic profile changed gradually through the processing cycles although the differences became smaller after the fifth processing cycle. The positive and negative ion-mode mass spectra by high resolution FT-MS revealed several series of ion clusters with mass differences of 162.053 Da, indicating a difference of a hexose moiety. During the processing, the number and signal intensity of the smaller glycosides were increased. Therefore, these results indicate that the fresh Rehmanniae radix is rich in polysaccharides, which are hydrolyzed during the processing.


Body size, physical activity and risk of colorectal cancer with or without the CpG island methylator phenotype (CIMP).
We investigated how body size and physical activity influence the risk of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). In the Netherlands Cohort Study (n = 120,852), risk factors were self-reported at baseline in 1986. After 7.3 years of follow-up, 603 cases and 4,631 sub-cohort members were available. CIMP status according to the Weisenberger markers was determined using methylation specific PCR on DNA from paraffin embedded tumor tissue. Hazard rate ratios (HR) and 95% confidence intervals for CIMP (27.7%) and non-CIMP (72.3%) tumors were calculated according to BMI, BMI at age 20, BMI change, trouser/skirt size, height, and physical activity. BMI modeled per 5 kg/m(2) increase was associated with both CIMP and non-CIMP tumors, however, HRs were attenuated when additionally adjusted for trouser/skirt size. Trouser/skirt size, per 2 size increase, was associated with both tumor subtypes, even after adjustment for BMI (CIMP HR: 1.20, 95%CI: 1.01-1.43; non-CIMP HR: 1.14, 95%CI: 1.04-1.28). Height per 5 cm was associated with both tumor sub-types, but HRs were attenuated when adjusted for body weight. BMI at age 20 was positively associated with increased risk of CIMP tumors and the association was significantly less pronounced for non-CIMP tumors (P-heterogeneity = 0.01). Physical activity was inversely associated with both subtypes, but a dose-response association was observed only for non-CIMP tumors (P-trend = 0.02). Body size, especially central adiposity, may increase the risk of both CIMP and non-CIMP tumors. Body fat at young age may differentially influence risk. Physical activity appears to decrease the risk of CRC regardless of these molecular subtypes.


Disability support workers' experience of interaction with a person with profound intellectual disability.
The primary communication partner for many people with profound intellectual disability (PID) who are living in supported accommodation is their disability support worker (DSW). The experiences of DSWs in interacting with people with PID have received limited attention in the literature. The nature of interactions between people with PID and DSWs was explored from the perspective of three DSWs through an analysis of interview data using a phenomenological approach. It was evident from the data that communicating in a way that was perceived to be the preferred style of the person with PID was important to the DSWs. This style, however, was often perceived to be in conflict with their employing organisation's policy and preferred practice. The descriptions in this study have implications for the conceptualisation of best practice in interacting with people with PID. Further research on interactions involving behaviours that may be perceived as inconsistent with concepts of age-appropriate interactions and professional boundaries is recommended.


Thoracoscopic mediastinal lymph node sampling: useful for mediastinal lymph node stations inaccessible by cervical mediastinoscopy.
Cervical mediastinoscopy is useful for the diagnosis of paratracheal lymph node metastasis from bronchogenic carcinoma. Access to adenopathy in the aorticopulmonary window, anterior mediastinal, periazygos, and subcarinal lymph nodes is difficult with this technique. Operative visibility in these locations through anterior mediastinotomy, the Chamberlain procedure, is limited. We have used thoracoscopic mediastinal exploration in 40 patients with computed tomographic scan evidence of enlarged aorticopulmonary window (n = 30) or enlarged right periazygos or subcarinal lymph nodes (n = 10). This procedure was used primarily as an adjunct to cervical mediastinoscopy in the staging of bronchogenic carcinoma. Adjunctive thoracoscopic nodal sampling was 100% sensitive and 100% specific in diagnosing the mediastinal adenopathy. It did not significantly delay thoracotomy in cases of benign adenopathy. Visibility of the ipsilateral pleural space and mediastinum was excellent. Thoracoscopic exploration with mediastinal nodal sampling is a valuable diagnostic adjunct for assessment of adenopathy inaccessible to cervical mediastinoscopy and can overcome many of the limitations of anterior mediastinotomy.


miRNA control of vegetative phase change in trees.
After germination, plants enter juvenile vegetative phase and then transition to an adult vegetative phase before producing reproductive structures. The character and timing of the juvenile-to-adult transition vary widely between species. In annual plants, this transition occurs soon after germination and usually involves relatively minor morphological changes, whereas in trees and other perennial woody plants it occurs after months or years and can involve major changes in shoot architecture. Whether this transition is controlled by the same mechanism in annual and perennial plants is unknown. In the annual forb Arabidopsis thaliana and in maize (Zea mays), vegetative phase change is controlled by the sequential activity of microRNAs miR156 and miR172. miR156 is highly abundant in seedlings and decreases during the juvenile-to-adult transition, while miR172 has an opposite expression pattern. We observed similar changes in the expression of these genes in woody species with highly differentiated, well-characterized juvenile and adult phases (Acacia confusa, Acacia colei, Eucalyptus globulus, Hedera helix, Quercus acutissima), as well as in the tree Populus x canadensis, where vegetative phase change is marked by relatively minor changes in leaf morphology and internode length. Overexpression of miR156 in transgenic P. x canadensis reduced the expression of miR156-targeted SPL genes and miR172, and it drastically prolonged the juvenile phase. Our results indicate that miR156 is an evolutionarily conserved regulator of vegetative phase change in both annual herbaceous plants and perennial trees.


The function of the clock-associated transcriptional regulator CCA1 (CIRCADIAN CLOCK-ASSOCIATED 1) in Arabidopsis thaliana.
In the model higher plant Arabidopsis thaliana, the CCA1 (CIRCADIAN CLOCK-ASSOCIATED 1) gene plays important circadian clock-associated roles. The CCA1 protein is a member of a small subfamily of single MYB-related transcription factors. This family consists of several homologous CCA1-like transcription factors, including the closest homolog LHY (LATE ELONGATED HYPOCOTYL). To gain insight into the molecular function of CCA1 and its homologs, here we took a unique genetic approach that was recently developed for Arabidopsis thaliana. Through this strategy, referred to as CRES-T (Chimeric REpressor Silencing Technology), a transgenic plant was constructed to produce a dominant negative transcriptional repressor (designated CCA1-SRDX). By employing the resulting transgenic lines, together with previously established cca1 lhy double mutant and CCA1-ox (over-expressing) plants, their circadian clock-associated phenotypes were examined and compared with each other. The observed clock-associated phenotypes of the CCA1-SRDX plants were very similar to those of CCA1-ox, but not to those of cca1 lhy, suggesting that CCA1 acts predominantly as a transcriptional repressor in nature. However, the developmental morphology (or architecture) of adult CCA1-SRDX plants were quite different from that of CCA1-ox, suggesting that CCA1 might also be implicated, directly or indirectly, in an as yet unknown circadian-associated output pathway at a late developmental stage.


Phacolytic glaucoma secondary to ectopia lentis.
This is a report of a 41-year-old woman who presented with a rare complication of congenitally dislocated lenses. Phacolytic glaucoma was found in one eye followed shortly by an attack of phacolytic glaucoma in the opposite eye. although phacolytic glaucoma is an absolute indication for surgery in these patients, surgery in general for dislocated lenses is still thought to be hazardous especially when dealing with a lens fixata as we did here, which is a lens being fixed in the vitreous with attachments to the retina. The cogenital ectopia lentis was believed to be on a hereditary basis since the father of the patient had worn aphakic lenses all his life without surgery and as none of the many other causes of ectopia lentis could be found.


The evolution of sex differences in language, sexuality, and visual-spatial skills.
The evolutionary neurological and physical foundations for human sex differences in language, sexuality, and visual spatial skills are detailed and primate and human studies are reviewed. Trends in the division of labor were established early in evolution and became amplified with the emergence of the "big brained" Homo erectus. A bigger brain necessitated a size increase in the birth canal and female pelvis. These and other physical changes, e.g., the swelling of the breasts and buttocks, may have paralleled the evolution of full-time sexual receptivity, the establishment of the home base, and exaggerated sex differences in the division of labor (hunting vs. gathering), which in turn promoted innate sex differences in visual spatial vs. language skills. For example, female primates produce more social and emotional vocalizations and engage in more tool use and gathering activities, whereas males tend to hunt and kill. Similar labor divisions are evident over the course of human evolution. "Woman's work" such as child rearing, gathering, and domestic tool construction and manipulation contributed to the functional evolution of Broca's speech area and the angular gyrus--which injects temporal sequences and complex concepts into the stream of language and thought. These activities gave rise, therefore, to a female superiority in grammatical (temporal sequential) vocabulary-rich language. Hunting as a way of life does not require speech but requires excellent visual-spatial skills and, thus, contributed to a male visual-spatial superiority and sex difference in the brain. Over the course of evolution males acquired modern human speech through genetic inheritance and because they had mothers who taught them language.


The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease.
Disorders of retinal vascular growth and function are responsible for vision loss in a variety of diseases, including diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity and retinal artery or vein occlusion. Over the past decade, a new signaling pathway that controls retinal vascular development has emerged from the study of inherited disorders - in both humans and mice - that are characterized by retinal hypovascularization. This pathway utilizes a glial-derived extracellular ligand, Norrin, that acts on a transmembrane receptor, Frizzled4, a coreceptor, Lrp5, and an auxiliary membrane protein, Tspan12, on the surface of developing endothelial cells. The resulting signal controls a transcriptional program that regulates endothelial growth and maturation. It will be of great interest to determine whether modulating this pathway could represent a therapeutic approach to human retinal vascular disease.


Expression and regulation of neurotrophins in the nondegenerate and degenerate human intervertebral disc.
The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have been identified in the human intervertebral disc (IVD) and have been implicated in the mechanisms associated with nerve ingrowth and nociception in degeneration of the IVD. The aim of the current study was to investigate an association between neurotrophin expression in the IVD and the severity of disc degeneration, including the effect of disc-related proinflammatory cytokines on neurotrophin and neuropeptide expression in cells derived from the human IVD. Immunohistochemical analysis was performed to examine the expression of NGF, BDNF and their high-affinity receptors Trk-A and Trk-B in human IVD samples, divided into three categories: non-degenerate, moderate degeneration and severe degeneration. In order to study the effect of disc-related cytokines on neurotrophin/neuropeptide gene expression, nucleus pulposus cells derived from non-degenerate and degenerate IVD samples were seeded in alginate and were stimulated with either IL-1beta or TNFalpha for 48 hours. RNA was extracted, cDNA was synthesised and quantitative real-time PCR was performed to examine the expression of NGF, BDNF and substance P. Immunohistochemistry showed expression of NGF and BDNF in the native chondrocyte-like cells in all regions of the IVD and in all grades of degeneration. Interestingly only BDNF significantly increased with the severity of degeneration (P < 0.05). Similar expression was observed for Trk-A and Trk-B, although no association with disease severity was demonstrated. In cultured human nucleus pulposus cells, stimulation with IL-1beta led to significant increases in NGF and BDNF gene expression (P < 0.05). Treatment with TNFalpha was associated with an upregulation of substance P expression only. Our findings show that both the annulus fibrosus and nucleus pulposus cells of the IVD express the neurotrophins NGF and BDNF, factors that may influence and enhance innervation and pain in the degenerate IVD. Expression of Trk-A and Trk-B by cells of the nondegenerate and degenerate IVD suggests an autocrine role for neurotrophins in regulation of disc cell biology. Furthermore, modulation of neurotrophin expression by IL-1beta and modulation of substance P expression by TNFalpha, coupled with their increased expression in the degenerate IVD, highlights novel roles for these cytokines in regulating nerve ingrowth in the degenerate IVD and associated back pain.


Regulatory Effect of Anwulignan on the Immune Function Through Its Antioxidation and Anti-Apoptosis in D-Galactose-Induced Aging Mice.
Aging is a spontaneous and inevitable phenomenon of biology, which can lead to the gradual deterioration of tissues and organs. One of the age-related deterioration processes is immunosenescence, which leads to changes in the function of immune systems, including immune cells and associated cytokines. A proper modulation of immune responses can improve the age-related immunosenescence process and then reach healthy aging. Schisandra sphenanthera, a traditional Chinese medicine, has been used as both a medicine and a nutritional supplement for thousands of years. Anwulignan, a monomer compound of Schisandra sphenanthera lignans, has been reported to possess an immunomodulatory effect. Therefore, this study was designed to further explore whether Anwulignan could also modulate the immune functions in aging model mice and the underlying mechanism. D-galactose (D-gal) is often used as an inducer of immunosenescence in animals. In this study, a mice model was created by subcutaneous D-gal (220 mg kg-1) for successive 42 days. Then, the blood and spleen tissue samples were taken for the analysis and observation of cytokine levels, immunoglobulin levels, leukocyte numbers, and the phagocytic activity of macrophages, as well as the histological changes, the proliferation ability of lymphocytes, and the biochemical parameters in the spleen tissue. Anwulignan significantly increased the serum levels of IL-2, IL-4, IFN-γ, lgG, lgM, and lgA, decreased the content of TNF-α and IL-6 in the aging mice, and increased the blood leukocyte number, the phagocytic activity, the lymphocyte proliferation, and the spleen index in vitro. Anwulignan also significantly increased the activities of SOD and GSH-Px, decreased the contents of MDA and 8-OHdG in the spleen tissue, up-regulated the expressions of Nrf2, HO-1, and Bcl2, down-regulated the expressions of Keap1, Caspase-3, and Bax in the spleen cells, and reduced the apoptosis of spleen lymphocytes. Anwulignan can restore the immune function that is declined in D-gal-induced aging mice partly related to its antioxidant capacity by activating the Nrf2/ARE pathway and downstream enzymes, as well as its anti-apoptotic effect by regulating Caspase-3 and the ratio of Bcl2 to Bax in the spleen.


Effects of hydrological regime and land use on in-stream Escherichia coli concentration in the Mekong basin, Lao PDR.
In the basin of Mekong, over 70 million people rely on unimproved surface water for their domestic requirements. Surface water is often contaminated with fecal matter and yet little information exists on the underlying mechanisms of fecal contamination in tropical conditions at large watershed scales. Our objectives were to (1) investigate the seasonality of fecal contamination using Escherichia coli as fecal indicator bacteria (FIB), and (2) establish links between the fecal contamination in stream water and its controlling factors (hydrology and land use). We present the results of (1) a sampling campaign at the outlet of 19 catchments across Lao PDR, in both the dry and the rainy seasons of 2016, and (2) a 10-day interval monitoring conducted in 2017 and 2018 at three point locations of three rivers (Nam Ou, Nam Suang, and Mekong) in northern Lao PDR. Our results show the presence of fecal contamination at most of the sampled sites, with a seasonality characterized by higher and extreme E. coli concentrations occurring during the rainy season. The highest E. coli concentrations, strongly correlated with total suspended sediment concentrations, were measured in catchments dominated by unstocked forest areas, especially in mountainous northern Lao PDR and in Vientiane province.


The hepatic defect in glycogen synthesis in chronic diabetes involves the G-component of synthase phosphatase.
Hepatocytes from normal fed rats and from chronically (90 h) alloxan-diabetic rats were compared. The rate and the extent of activation of glycogen synthase in response to 60 mM-glucose were greatly decreased in diabetes. During incubation of gel-filtered extracts from broken hepatocytes, diabetes only decreased the rate of the activation, which became ultimately complete in either preparation. Synthase phosphatase activity, as measured by the activation of purified hepatic synthase b, was decreased in chronic diabetes. The decrease was proportional to the severity of the diabetes, and reached 90% when the plasma glucose concentration was greater than or equal to 55 mM. In contrast, phosphorylase phosphatase activity was not decreased. Synthase phosphatase activity was progressively restored by treatment with insulin for 20-68 h. During the induction of diabetes and during insulin treatment there was a good correlation between the activity of synthase phosphatase and the maximal activation of synthase in glucose-stimulated hepatocytes from the same livers. The decreased activity of synthase phosphatase in diabetes cannot be explained by an inhibitor. The decrease was much less marked when synthase phosphatase was assayed by the dephosphorylation of 32P-labelled synthase from muscle. This observation suggested a loss of only one component of synthase phosphatase. Cross-combination of subcellular fractions from control rats and from diabetic rats showed a preferential loss of G-component, with little or no loss of S-component. No G-component could be detected in severe diabetes. The concentration of G-component is therefore of critical importance in the glucose-induced activation of glycogen synthase in the liver.


IETS management of the challenges associated with embryo pathogen interaction.
One of the very first challenges the International Embryo Transfer Society (IETS) addressed was concern about disease transmission via the transfer of in vivo -derived (IVD) bovine embryos. IETS commissioned its Import/Export Committee, later named Health and Safety Advisory Committee (HASAC), to resolve this matter, with the assistance of the Data Retrieval Committee following its formation in 1991. Since its first meeting in 1984, considerable achievements have been made, including meeting the numerous challenges created by the many innovations in this industry. Based on research studies and their designs, the IETS HASAC developed a system for categorising pathogens and diseases potentially susceptible to interaction with IVD embryos. This has been instrumental in defining safe operating protocols and ultimately leading to the development of the now universally accepted techniques for certification of embryo health. The close cooperation of IETS/HASAC with the World Organization of Animal Health (WOAH, formerly OIE) has facilitated the establishment of guidelines for regulators worldwide, thus ensuring the safety of international trade with embryos, while avoiding unjustified regulatory measures. In addition, IETS/HASAC produced and published the IETS Manual: A Procedural Guide and General Information for the Use of Embryo Transfer Technology Emphasising Sanitary Procedures for the embryo transfer industry (1st edition, 1987; 5th edition, 2023). This manual and its updates were designed to provide the industry world-wide with a source of information on safe and sanitary handling procedures for embryos, to describe the procedures necessary to ensure that the transfer of embryos does not result in transmission of pathogenic agents or disease, and to ensure consistent and accurate identification of embryos. The result of these 40years of IETS/HASAC involvement is that embryo transfer technology is recognised as having a comparative advantage in international movement of germplasm.


Increased pro-inflammatory cytokines, glial activation and oxidative stress in the hippocampus after short-term bilateral adrenalectomy.
Bilateral adrenalectomy has been shown to damage the hippocampal neurons. Although the effects of long-term adrenalectomy have been studied extensively there are few publications on the effects of short-term adrenalectomy. In the present study we aimed to investigate the effects of short-term bilateral adrenalectomy on the levels of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α; the response of microglia and astrocytes to neuronal cell death as well as oxidative stress markers GSH, SOD and MDA over the course of time (4 h, 24 h, 3 days, 1 week and 2 weeks) in the hippocampus of Wistar rats. Our results showed a transient significant elevation of pro-inflammatory cytokines IL-1β and IL-6 from 4 h to 3 days in the adrenalectomized compared to sham operated rats. After 1 week, the elevation of both cytokines returns to the sham levels. Surprisingly, TNF-α levels were significantly elevated at 4 h only in adrenalectomized compared to sham operated rats. The occurrence of neuronal cell death in the hippocampus following adrenalectomy was confirmed by Fluoro-Jade B staining. Our results showed a time dependent increase in degenerated neurons in the dorsal blade of the dentate gyrus from 3 days to 2 weeks after adrenalectomy. Our results revealed an early activation of microglia on day three whereas activation of astroglia in the hippocampus was observed at 1 week postoperatively. A progression of microglia and astroglia activation all over the dentate gyrus and their appearance for the first time in CA3 of adrenalectomized rats hippocampi compared to sham operated was seen after 2 weeks of surgery. Quantitative analysis revealed a significant increase in the number of microglia (3, 7 and 14 days) and astrocytes (7 and 14 days) of ADX compared to sham operated rats. Our study revealed no major signs of oxidative stress until 2 weeks after adrenalectomy when a significant decrease of GSH levels and SOD activity as well as an increase in MDA levels were found in adrenalectomized compared to sham rats. Our study showed an early increase in the pro-inflammatory cytokines followed by neurodegeneration and activation of glial cells as well as oxidative stress. Taking these findings together it could be speculated that the early inflammatory components might contribute to the initiation of the biological cascade responsible for subsequent neuronal death in the current neurodegenerative animal model. These findings suggest that inflammatory mechanisms precede neurodegeneration and glial activation.


Laparoscopic ultrasound enhances diagnostic laparoscopy in the staging of intra-abdominal neoplasms.
Routine laparoscopy and laparoscopic ultrasound (LUS) for staging intra-abdominal malignancies remains controversial. Thus, we undertook a prospective study to assess the value of preoperative laparoscopy with LUS for patients with intra-abdominal tumors judged resectable by preoperative studies. Laparoscopy was successfully performed in 76 of 77 patients, and 60 underwent LUS. Of 33 patients with presumed pancreatic cancer, laparoscopic findings changed the operative management of 11 patients, and LUS altered the management of an additional 6 patients. Laparotomy was avoided in 9 patients (27%). Among 14 patients with hepatobiliary tumors, laparotomy was avoided in 9 patients in whom laparoscopy and/or LUS revealed either benign or advanced disease. Operative management was altered in 4 of 18 patients with gastric or esophageal cancer by laparoscopic findings. LUS did not add to the management of these patients. Of 12 patients with presumed intra-abdominal lymphoma, 9 were diagnosed with lymphoma and 3 with benign disease, without laparotomy in all but 1 case. Laparoscopy and LUS are valuable tools for evaluating the resectability of pancreatic and hepatobiliary tumors. Laparoscopy, and to a lesser degree LUS, greatly facilitates diagnosing patients with intra-abdominal lymphomas and spares an occasional patient with esophagogastric carcinoma from undergoing laparotomy.


Threat management priorities for conserving Antarctic biodiversity.
Antarctic terrestrial biodiversity faces multiple threats, from invasive species to climate change. Yet no large-scale assessments of threat management strategies exist. Applying a structured participatory approach, we demonstrate that existing conservation efforts are insufficient in a changing world, estimating that 65% (at best 37%, at worst 97%) of native terrestrial taxa and land-associated seabirds are likely to decline by 2100 under current trajectories. Emperor penguins are identified as the most vulnerable taxon, followed by other seabirds and dry soil nematodes. We find that implementing 10 key threat management strategies in parallel, at an estimated present-day equivalent annual cost of US$23 million, could benefit up to 84% of Antarctic taxa. Climate change is identified as the most pervasive threat to Antarctic biodiversity and influencing global policy to effectively limit climate change is the most beneficial conservation strategy. However, minimising impacts of human activities and improved planning and management of new infrastructure projects are cost-effective and will help to minimise regional threats. Simultaneous global and regional efforts are critical to secure Antarctic biodiversity for future generations.


Structural changes in epidermal scale and appendages as indicators of defective TGM1 activity.
Defective transglutaminase 1 (TGM1) is a causative factor in some cases of lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE) despite large differences in the phenotype between these conditions. In some of these individuals, defective cornified envelopes (CEs) have been reported by light or electron microscopic examination in epidermal scale, nail and/or hair. These findings suggest that assessment of such defects could have a diagnostic utility in distinguishing TG1-deficient versus non-deficient cases of autosomal recessive ichthyosis (ARI) . Present work (a) examines the integrity of CEs in epidermal scale and appendages in a case of TGM1-deficient CIE, (b) assesses the utility of hair/nail versus scale analysis in the diagnosis of TGM1 deficiency in vivo and (c) helps characterize the consequences of the V518M mutation in TGM1, about which conflicting reports have appeared. To this end, epidermal scale or callus, nail and hair samples from a patient with TGM1-deficient CIE, his asymptomatic family members and control subjects were extracted vigorously in sodium dodecyl sulfate and dithiothreitol and examined by light (phase contrast) and electron microscopy. Both epidermal scale and nail from the index case lacked the prominent cell borders that were visible by phase contrast microscopy after detergent extraction of control samples. (By contrast, abundant envelope structures were visible in extracted epidermal scale from patients with ichthyosis vulgaris, loricrin keratoderma and epidermolytic hyperkeratosis.) Electron microscopy confirmed the paucity of intact CEs, and revealed further that hair cuticle cells from the same subject also lacked the marginal bands that are visible in control hair samples. Such aberrations were evident neither in the samples from asymptomatic relatives of the index case nor in the hair-cuticle cells of numerous normal individuals, evidence that this defect is not a common polymorphism. These studies extend our prior work on TGM1-deficient LI to the full spectrum of TGM1-deficient patients, showing that the CIE phenotype, when attributable to a V518M heterozygous mutation in TGM1 in combination with an inactive allele, confers a cross-linking deficiency in a variety of keratinizing epithelia, as previously shown for TGM1-negative LI. These results further suggest that a non-invasive assessment of scale, nail and hair could be of diagnostic utility in distinguishing patients across a full range of phenotypes with deficiency in TGM1-encoded transglutaminase activity from other causes of ARI.


The effects of anthelmintic treatments on the development of gastrointestinal parasitism in calves.
Fortnightly treatment of susceptible calves with 1-tetramisole during the first two months of continuous exposure to pastures residually heavily-infected with Ostertagia ostertagi, Cooperia oncophora and Nematodirus helvetianus did not prevent the development of clinical parasitic gastroenteritis, although the infections were not as severe as in nontreated calves. Development of resistance in treated calves was manifested by significantly smaller numbers of Cooperia eggs in utero (which were reflected by reduced fecal egg counts) and by significantly smaller Nematodirus worm burdens than in susceptible calves that commenced grazing coincident with cessation of treatment. The findings also indicated that resistance to Nematodirus helvetianus was slower in developing in treated than in nontreated infected calves.


Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer.
Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.


Low-dose carperitide (α-human A-type natriuretic peptide) alleviates hemoglobin concentration decrease during prolonged oral surgery: a randomized controlled study.
Surgical injury stimulates the renin-angiotensin-aldosterone system (RAAS) and causes antidiuresis, leading to postoperative oliguria. Carperitide (α-human A-type natriuretic peptide) is a cardiac peptide hormone secreted from the atrium. This peptide hormone enhances diuresis by suppressing the RAAS. In our experience, carperitide alleviates decreased hemoglobin (Hb) concentration during elective surgery. In the current study, we investigated the relationship between low-dose carperitide (0.01 µg/kg/min) and Hb concentration during oral surgery. Patients (ASA-PS: I-II, 40-80 years old) undergoing oral maxillofacial surgery (duration of operation >8 h) were enrolled in this study. Patients were divided into two groups: the carperitide group received carperitide at 0.01 µg/kg/min and the control group received normal saline. Body fluid water [including total body water (TBW), extracellular water (ECW), and intracellular water (ICW)], urine volume, and chemical parameters such as Hb concentration, PaO2, and serum electrolytes were evaluated every 2 h. In the carperitide group (n = 15), Hb decreased from 12.6 ± 1.1 to 10.8 ± 1.5 g/dl, while it decreased from 12.6 ± 1.4 to 9.5 ± 1.3 g/dl in the control group (n = 15) (p < 0.05). Urine volume (2557.3 ± 983.5 mL) in the carperitide group was significantly more than it was in the control group (1108.8 ± 586.4 mL; p < 0.001). There were no significant differences in clinical characteristics, body fluid water, PaO2, and serum electrolytes between the two groups. In addition, there were no perioperative clinical respiratory and hemodynamic complications in the groups. The Hb concentration in the group administered low-dose carperitide at 0.01 µg/kg/min remained higher than that in the control group during surgery. Administration of low-dose carperitide may therefore reduce the risk of blood transfusion during surgery.


[Novel treatments for hepatitis C virus infection in chronic kidney disease].
Recent evidence has been accumulated showing a negative impact of chronic hepatitis C virus infection on survival in patients with chronic kidney disease. Moreover, it appears that anti-HCV positive status has been associated with an increased risk of developing chronic kidney disease in the adult general population. These reports have emphasized the need for safe and effective therapies for hepatitis C virus infection in the chronic kidney disease population. Treatment of HCV has made considerable progress with the approval of interferon-free, direct-acting antiviral drug-based combination therapies among patients with intact kidneys; but a paucity of information exists regarding chronic kidney disease patients. The first published report on the antiviral treatment of hepatitis C among patients with chronic kidney disease (stage 4-5) and HCV genotype 1 concerns the combination of grazoprevir (NS3/4A protease inhibitor) and elbasvir (NS5A inhibitor); excellent safety and efficacy (sustained viral response, 94.3% 115/122) have been reached. In another study, the 3-D regimen (ombitasvir/ paritaprevir/ ritonavir/ dasabuvir with or without ribavirin) has been administered to CKD (stage 4-5) patients with genotype 1 (n=20); the rate of sustained viral response was excellent (90%, 18/20) and no patients discontinued treatment due to adverse events. Preliminary data on the combined treatment of sofosbuvir (NS5B inhibitor) and simeprevir (NS3/4A inhibitor) has given a viral response of 89% (34/38), but the size of the study group (n=38 patients with end-stage renal disease) was small. Thus, the evidence in the medical literature concerning use of DAAs in CKD population is encouraging even if it has a preliminary nature. Also, several points need to be addressed regarding the use of DAAs in CKD population including their impact on survival, costs, and drug-drug interactions.


Impact of site of tumor recurrence upon survival for children with recurrent or progressive medulloblastoma.
The object of this study was to identify prognostic factors for survival among children with recurrent medulloblastoma. Postprogression survival and patient, tumor, and treatment factors were examined in 46 cases of recurrent medulloblastoma (mean age of patients at diagnosis 6.5 years, mean age at progression 8.4 years). Differences were calculated by Kaplan-Meier log-rank analysis. Multivariate analysis was performed using the Cox proportional hazard model. The probability of 5-year survival was 26.3%. Forty-one patients received salvage therapy and five patients received hospice care only. Log-rank analysis showed an association between prolonged patient survival and recurrence limited to the primary site (p = 0.008), initial therapy including the Pediatric Oncology Group (POG) regimen for the treatment of brain tumors in infants ("Baby POG;" p = 0.037), and treatment with radiation therapy (RT) following initial progression (p = 0.015). Cox regression analysis showed a significant association between prolonged survival and only one variable--tumor recurrence restricted to the primary site (p = 0.037). There was no significant association between prolonged survival and any other variables, including patient sex, age at progression, interval from tumor diagnosis to progression, initial tumor stage, and salvage treatment with chemotherapy. Subgroup analysis revealed that site of tumor progression was also prognostic for survival among the subgroup of patients older than 3 years of age at diagnosis who were initially treated with RT and chemotherapy (p = 0.017, log-rank test). Some children with recurrent medulloblastoma will be long-term survivors, and certain features are associated with likelihood of survival. Patients whose tumors recur at only the primary tumor site have an increased chance of prolonged survival.


Comparison of two techniques used for the recovery of nematode infective larvae from pasture.
The recovery of gastrointestinal nematode infective larvae from herbage collected manually was compared with the recovery from herbage ingested by sheep with oesophageal fistulae, on five occasions during the grazing season. At least three times more larvae were recovered from the oesophageal fistulates than by manual collection. There was no significant variation between the numbers of larvae collected at 09.00, 12.00 and 15.00, nor was there any difference in the distribution of genera recovered by the two methods. The worm burdens of tracer lambs and the larval counts from the fistulated sheep were used to estimate the rate of larval establishment.


[Endovascular repair for an acute traumatic aortic transection: a case report].
A thirty-eight-year-old male patient who suffered from 10th and 11th thoracal vertebrae fractures, paraplegia and acute traumatic aortic transection because of accidental fall was referred to our hospital. Open surgical repair carried a very high risk due to severe coexisting injuries. Transection was treated with 30x100 mm Valiant thoracic endograft, which was deployed just distal to the ostium of the left carotid artery. The patient was transferred to the neurosurgery clinic for treatment of paraplegia after an uneventful recovery. Endovascular repair of acute transection confers substantial advantages in mortality and morbidity compared to surgical repair. However, the long-term durability of thoracic endografts remains unknown. If the long-term results are as satisfactory as the promising mid-term results, this technique may become the gold standard approach for the treatment of acute transection.


Epidemiological studies of rubella virus in a tropical African community.
The single-radial-haemolysis test for antibody to rubella virus provides a simple rapid method for carrying out large serological surveys. The availability of a collection of sequential serum samples from inhabitants of two Gambian villages, Manduar and Keneba, made it possible to determine the pattern of rubella epidemics in these communities between 1966 and 1976. The serological findings indicated that an epidemic had occurred approximately two years before the commencement of the study. There was no further evidence of rubella infection until approximately 1973 when a large-scale epidemic occurred. Although the communities were monitored throughout the period of study there was no clinical evidence of infection and no cases of congenital rubella syndrome.


Silane Effects on Adhesion Enhancement of 2K Polyurethane Adhesives.
With excellent properties such as great flexibility, outstanding chemical resistance, and superb mechanical strength, two-part polyurethane (2K PU) adhesives have been widely applied in many applications, including those in transportation and construction. Despite the extensive use, their adhesion to nonpolar polymer substrates still needs to be improved and has been widely studied. The incorporation of silane molecules and the use of plasma treatment on substrate surfaces are two popular methods to increase the adhesion of 2K PU adhesives, but their detailed adhesion enhancement mechanisms are still largely unknown. In this research, sum frequency generation (SFG) vibrational spectroscopy was used to probe the influence of added or coated silanes on the interfacial structure at the buried polypropylene (PP)/2K PU adhesive interface in situ. How plasma treatment on PP could improve adhesion was also investigated. To achieve maximum adhesion, two methods to involve silanes were studied. In the first method, silanes were directly mixed with the 2K PU adhesive before use. In the second method, silane molecules were spin-coated onto the PP substrate before the PU adhesive applied. It was found that the first method could not improve the 2K PU adhesion to PP, while the second method could substantially enhance such adhesion. SFG studies demonstrated that with the second method silane molecules chemically reacted at the interface to connect PP and 2K PU adhesive to improve the adhesion. With the first method, silane molecules could not effectively diffuse to the interface to enhance adhesion. In this research, plasma treatment was also found to be a useful method to improve the adhesion of the 2K PU adhesive to nonpolar polymer materials.


Microtensile and tensile bond strength of single-bottle adhesives: a new test method.
To evaluate the tensile and microtensile bond strength of five single-bottle adhesives to dentine, extracted human molar teeth were used. For each tooth dentine was exposed on the occlusal surface by cutting with an isomet saw and the remaining part was mounted in a plastic ring using dental stone. The tested adhesive materials were: Scotchbond 1, Syntac SC, One-Step, Prime & Bond 2.1 and Clearfil SE Bond. The adhesive was applied to either 1 mm(2) of dentine or a circular area with a diameter of 3.9 mm. Composite resin Clearfil AP-X was placed to the adhesives using a Teflon split mould 3.9 mm in diameter and 2.5 mm in height. Tensile and microtensile bond strengths were measured using a universal testing machine at a crosshead speed of 0.5 mm min(-1). Under tensile mode, the bond strengths were 16.7 +/- 3.5, 15.2 +/- 2.5, 11.5 +/- 3.2, 13.7 +/- 2.6, 20.9 +/- 4.2 MPa for each material. Under microtensile mode, the bond strengths were 52.5 +/- 9.5, 55.3 +/- 8.3, 40.5 +/- 5.2, 37.5 +/- 8.7, 60 +/- 6.21 MPa. Fracture pattern of bonded specimens showed 66% cohesive dentine failure in samples tested for tensile bond strength. For the microtensile test, failures were mainly adhesive at the interface between adhesive and dentine (94%).


Stress echocardiography.
Stress echocardiography is the combination of 2D echocardiography with a physical, pharmacological or electrical stress. The diagnostic end point for the detection of myocardial ischemia is the induction of a transient worsening in regional function during stress. Stress echocardiography provides similar diagnostic and prognostic accuracy as ra-dionuclide stress perfusion imaging, but at a substantially lower cost, without environmental impact, and with no biohazards for the patient and the physician. Among different stresses of comparable diagnostic and prognostic accuracy, semisupine exercise is the most used, dobutamine the best test for viability, and dipyridamole the safest and simplest pharmacological stress. The additional clinical benefit of myocardial contrast echo-cardiography, tissue Doppler imaging and real time 3-D echocardiography has been inconsistent and disappointing, whereas the potential of adding coronary flow reserve evaluation of left anterior descending coronary artery by transthoracic Doppler echocardiography adds another important dimension to stress echocardiography. In spite of its dependence upon operator's training, stress echocardiography is today the best possible imaging choice to achieve the still elusive target of sustainable cardiac imaging in the field of noninvasive diagnosis of coronary artery disease.


Biapenem American Cyanamid Co.
Biapenem is an injectable carbapenem antibiotic with activity against a broad spectrum of bacteria [155679]. It has been submitted for marketing approval in Japan by Lederle Japan, a joint venture between Cyanamid and Takeda. Biapenem is in phase III trials in Germany, South Africa, Spain, Australia and New Zealand for skin infections, and phase I trials in the UK and the US.


Immunohistologic c-myc protein in benign breast disease and cancer.
We have studied the histopathology and differential distribution of the c-myc protein (Myc) in human breast tissues including 17 cases of infiltrating mammary carcinoma, 4 cases of fibroadenoma, 5 cases with fibrocystic changes, and 1 case of reduction mammoplasty (as a control). Using a sensitive immunohistochemical method on frozen tissue sections, both a rabbit polyclonal anti-c-myc antibody and a mouse monoclonal anti-c-myc antibody, H51C116, produced high levels of Myc staining in the nuclei of epithelial cells of infiltrating mammary carcinomas (30-90% of cells stained). In contrast, the nuclei of epithelial cells of fibroadenomas, and breast tissues with fibrocystic changes stained infrequently. We studied benign tissue surrounding the tumors in four cases; three were essentially negative, and one showed nuclear epithelial cell staining throughout the lobules. Sixteen of the tumors were examined in parallel, using formalin-fixed, paraffin-embedded samples. Immunohistological procedures for Myc produced uniform, intense epithelial cell cytoplasmic staining (8 cases); light epithelial cell cytoplasmic staining (5 cases) or were unstained (3 cases). We argue that the differences between frozen and paraffin sections are incompatible with the notion of simple displacement of nuclear Myc to the cytoplasm during fixation. Elevated levels of nuclear Myc in tumor cells and subsets of benign tissue are consistent with a role for Myc in mammary cell proliferation and tumorigenesis.


Wildfire response to changing daily temperature extremes in California's Sierra Nevada.
Burned area has increased across California, especially in the Sierra Nevada range. Recent fires there have had devasting social, economic, and ecosystem impacts. To understand the consequences of new extremes in fire weather, here we quantify the sensitivity of wildfire occurrence and burned area in the Sierra Nevada to daily meteorological variables during 2001–2020. We find that the likelihood of fire occurrence increases nonlinearly with daily temperature during summer, with a 1°C increase yielding a 19 to 22% increase in risk. Area burned has a similar, nonlinear sensitivity, with 1°C of warming yielding a 22 to 25% increase in risk. Solely considering changes in summer daily temperatures from climate model projections, we estimate that by the 2040s, fire number will increase by 51 ± 32%, and burned area will increase by 59 ± 33%. These trends highlight the threat posed to fire management by hotter and drier summers.


Clinical outcomes following atrophic alveolar ridge reconstruction using collagenated xenogeneic bone block or autogenous bone block: One-year follow-up of a randomized controlled clinical.
This investigation aimed to evaluate the 1-year survival of implants placed after staged lateral alveolar ridge augmentation using equine-derived collagenated xenogeneic bone blocks (CXBBs) or autogenous bone block (ABB). Fifty patients who underwent lateral augmentation in a previous trial were included. The primary outcome measure was implant survival at the 1-year follow-up, and secondary outcomes included implant success, peri-implant clinical and volumetric parameters, pink aesthetic scores (PES) and patient-reported outcome measures. Data analysis involved Fisher's exact test, the Mann-Whitney U-test and the Wilcoxon signed-rank test. In this study, no late implant failures were observed. The cumulative survival rates were 78.6% for the CXBB group and 90.9% for the ABB group, with no difference between the groups. Similarly, the success rates were 53.6% and 63.6%, respectively, showing no significant difference. Peri-implant clinical and volumetric parameters indicated the presence of healthy peri-implant tissues surrounding implants placed in both CXBB- and ABB-augmented sites. PES were 8.5 and 11.0 for implants placed in CXBB- and ABB-augmented sites, respectively. Furthermore, patient satisfaction rates were high and similar between the groups. Dental implants placed in both CXBB- and ABB-augmented ridges demonstrated no statistically significant differences in clinical, volumetric and aesthetic outcomes, along with high patient satisfaction rates.


Stress and well-being at work: A century of empirical trends reflecting theoretical and societal influences.
In various forms, research on stress and well-being has been a part of the Journal of Applied Psychology (JAP) since its inception. In this review, we examine the history of stress research in JAP by tracking word frequencies from 606 abstracts of published articles in the journal. From these abstracts, we define 3 eras: a 50 year-era from 1917 to 1966, a 30-year era from 1967 to 1996, and a 20-year era from 1997 to the present. Each era is distinct in terms of the number of articles published and the general themes of the topic areas examined. We show that advances in theory are a major impetus underlying research topics and the number of publications. Our review also suggests that articles have increasingly tended to reflect broader events occurring in society such as recessions and workforce changes. We conclude by offering ideas about the future of stress and well-being research. (PsycINFO Database Record


[Serum concentrations and factors affecting the blood bioavailability of chloramphenicol in bovine (author's transl)].
Serum concentrations and factors affecting the blood bioavailability of chloramphenicol in bovineThe authors have compared the serum concentrations and the factors affecting blood bioavailability of chloramphenicol after intramuscular administration of canadian commercial preparations containing 500 mg/mL of antibiotic. The animals (dairy cows and heifers) received each drug (20 mg/kg) in one or two injection sites. The serum samples, analysed by colorimetric or microbiological methods, showed that considerable differences in concentration exist between the two methods. The evolution of biodisponibility factors proved identical in both cases. It appears that therapeutic levels of chloramphenicol are reached only by drug A for four to five hours. The usual dosage (2-10 mg/kg), by intramuscular route, is not sufficient to attain these active concentrations using the other drugs. However, the important variability obtained during the experiment and reflected in the standard deviation values, has not proved that drug A has a better bioavailability based on the criteria of the only microbiological analysis.


Association of Genetic Variation at AQP4 Locus with Vascular Depression.
Despite its substantial clinical importance, specific genetic variants associated with depression have not yet been identified. We sought to identify genetic variants associated with depression by (a) focusing on a more homogenous subsample (vascular depression) and (b) applying a three-stage approach. First, we contacted 730 participants with a confirmed atherosclerotic disease (coronary artery disease) from a population-based study population (German Myocardial Infarction Family Study IV) for psychiatric assessment with the Mini International Neuropsychiatric Interview. Second, we genotyped these patients using genome-wide single nucleotide polymorphism (SNP) arrays. Third, we characterized the SNP via in-silico analysis. The final sample consisted of 342 patients (78.3% male, age = 63.2 ± 9.9 years), 22.8% with a severe depressive disorder. Variant rs528732638 on chromosome 18q11.2 was a genome-wide significant variant and was associated with 3.6-fold increase in the odds of lifetime depression. The locus belongs to a linkage disequilibrium block showing expression quantitative trait loci effects on three putative cis-regulated genes, including the aquaporin 4 (AQP4) locus. AQP4 is already known to mediate the formation of ischemic edema in the brain and heart, increasing the size and extent of resulting lesions. Our findings indicate that AQP4 may also play a role in the etiopathology of vascular depression.


Bevel direction and postdural puncture headache: a meta-analysis.
The effect of lumbar puncture needle bevel direction on the incidence of postdural puncture headache (PDPH) is somewhat controversial. We performed a meta-analysis of available trials to determine if bevel direction during lumbar puncture would influence the incidence of PDPH. Studies were identified primarily by searching the National Library of Medicine's PubMed database (1966 to November 29, 2004) and abstracts from several national meetings (American Society of Anesthesiology, International Anesthesia Research Society, American Society of Regional Anesthesia, Society of Obstetric Anesthesia and Perinatology) for terms related to needle and bevel direction. Inclusion criteria were assessment of the incidence of PDPH after lumbar puncture with a cutting needle (eg, Quincke, Tuohy), comparison of a "parallel" (bevel oriented in a longitudinal or cephalad to caudad direction) to "perpendicular" (bevel oriented in a transverse direction) orientation during needle insertion, randomized trials, and trials primarily in adult populations. Data on study characteristics and incidence of PDPH were abstracted from qualified studies and subsequently analyzed. The search resulted in 52 abstracts from which the original articles were obtained and data abstracted, with ultimately a total of 5 articles meeting all inclusion criteria. Insertion of a non-pencil-point/cutting needle with the bevel oriented in a parallel/longitudinal fashion resulted in a significantly lower incidence of PDPH compared with that oriented in a perpendicular/transverse fashion (unadjusted rates of 10.9% versus 25.8%; odds ratio = 0.29 [95% CI = 0.17-0.50]). Our meta-analysis indicates that with use of a cutting needle, insertion in a parallel/longitudinal fashion may significantly reduce the incidence of PDPH, although the reasons for this decrease are unclear.


Family history information on essential tremor: potential biases related to the source of the cases.
The proportion of essential tremor (ET) cases that can be attributed to genetic factors is unknown; estimates range from 17--100%. One possible reason for this variability is that clinic and community cases may differ with regard to family history of ET. This is because clinic patients are self-selected and represent as few as 0.5% of all ET cases. Our goal was to determine whether ET cases ascertained from a clinic differed from those ascertained from a community in terms of the family history information that they provided. Subjects (57 clinic, 64 community) underwent a family history interview. Clinic cases were 4.73 times more likely to report an affected relative than were community cases. We conclude that there was a substantial difference between our clinic and community ET cases in terms of the information they provided regarding their family history. Selection and reporting biases could have accounted for this difference. Because of these biases, the source of the cases must be taken into consideration when investigators are trying to synthesize the widely variable results of studies that have estimated the genetic contribution to ET.


White and Red Sorghum as Primary Carbohydrate Sources in Extruded Diets of Felines.
The research objectives were to evaluate the effect of dietary supplementation of white (WSH) and red (RSH) sorghum grains on gastrointestinal health of felines through the determination of apparent total tract macronutrient digestibility (ATTD), fecal characteristics, fermentative end-products, and microbiota, compared with a traditional corn-based diet. We hypothesize that inclusion of RSH and WSH, respectively, would be well-accepted by cats, and the RSH and WSH diets would be comparable to corn when added as the main carbohydrate source in extruded diets. Three diets containing 30% corn, 30% WSH, or 30% RSH were formulated to meet or exceed the AAFCO (2018) nutrient profiles for cats during growth. Nine male cats (0.8 ± 0.00 yr) were randomly assigned to one of the three dietary treatments using a triplicated 3 × 3 Latin square design. Experimental periods consisted of 14 d (10 d of diet adaption and 4 d of total and fresh fecal collections). The ATTD of dry matter (DM) did not differ amongst treatments, organic matter was greatest (P < 0.05) for both sorghum diets (86.4%) and lowest for the corn diet (84.2%), crude protein was comparable among diets ranging from 84.5 to 86.6%, acid hydrolyzed fat was high among diets varying between 91.4 and 92.8%, and total dietary fiber was greatest (P < 0.05) for the WSH diet (56.0%) with the corn diet being lowest (44.7%). Digestible energy was greatest (P < 0.05) for the WSH diet (4.66 kcal/g) and lowest for the corn diet (4.54 kcal/g), with the RSH diet being intermediate (4.64; P > 0.05). Fecal pH (6.3-6.5) and most fecal metabolites did not differ among diets except for phenol/indole concentrations that were significantly lower (P < 0.05) in cats fed the RSH diet (1.5 μmole/g DM) than for cats fed the corn diet (2.1 μmole/g DM). Bacteroidetes, Firmicutes, Fusobacteria, and Proteobacteria were the major phyla observed in the microbiota of feces of cats fed the three experimental diets, with no differences seen amongst all treatments. Data indicate that dietary supplementation of these varieties of WSH and RSH as carbohydrate sources were well-tolerated by the cat.


Ultrasensitive interplay between ferromagnetism and superconductivity in NbGd composite thin films.
A model binary hybrid system composed of a randomly distributed rare-earth ferromagnetic (Gd) part embedded in an s-wave superconducting (Nb) matrix is being manufactured to study the interplay between competing superconducting and ferromagnetic order parameters. The normal metallic to superconducting phase transition appears to be very sensitive to the magnetic counterpart and the modulation of the superconducing properties follow closely to the Abrikosov-Gor'kov (AG) theory of magnetic impurity induced pair breaking mechanism. A critical concentration of Gd is obtained for the studied NbGd based composite films (CFs) above which superconductivity disappears. Besides, a magnetic ordering resembling the paramagnetic Meissner effect (PME) appears in DC magnetization measurements at temperatures close to the superconducting transition temperature. The positive magnetization related to the PME emerges upon doping Nb with Gd. The temperature dependent resistance measurements evolve in a similar fashion with the concentration of Gd as that with an external magnetic field and in both the cases, the transition curves accompany several intermediate features indicating the traces of magnetism originated either from Gd or from the external field. Finally, the signatures of magnetism appear evidently in the magnetization and transport measurements for the CFs with very low (<1 at.%) doping of Gd.


Plant Immunity Is Compartmentalized and Specialized in Roots.
Roots are important organs for plant survival. In recent years, clear differences between roots and shoots in their respective plant defense strategies have been highlighted. Some putative gene markers of defense responses usually used in leaves are less relevant in roots and are sometimes not even expressed. Immune responses in roots appear to be tissue-specific suggesting a compartmentalization of defense mechanisms in root systems. Furthermore, roots are able to activate specific defense mechanisms in response to various elicitors including Molecular/Pathogen Associated Molecular Patterns, (MAMPs/PAMPs), signal compounds (e.g., hormones) and plant defense activator (e.g., β-aminobutyric acid, BABA). This review discusses recent findings in root defense mechanisms and illustrates the necessity to discover new root specific biomarkers. The development of new strategies to control root disease and improve crop quality will also be reviewed.


Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis.
Aryl hydrocarbon receptor (AhR), a transcription factor of the bHLH/PAS family, is well characterized to regulate the biochemical and toxic effects of environmental chemicals. More recently, AhR activation has been shown to regulate the differentiation of Foxp3(+) Tregs as well as Th17 cells. However, the precise mechanisms are unclear. In the current study, we investigated the effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR ligand, on epigenetic regulation leading to altered Treg/Th17 differentiation, and consequent suppression of colitis. Dextran sodium sulphate (DSS) administration induced acute colitis in C57BL/6 mice, as shown by significant weight loss, shortening of colon, mucosal ulceration, and increased presence of CXCR3(+) T cells as well as inflammatory cytokines. Interestingly, a single dose of TCDD (25 µg/kg body weight) was able to attenuate all of the clinical and inflammatory markers of colitis. Analysis of T cells in the lamina propria (LP) and mesenteric lymph nodes (MLN), during colitis, revealed decreased presence of Tregs and increased induction of Th17 cells, which was reversed following TCDD treatment. Activation of T cells from AhR(+/+) but not AhR (-/-) mice, in the presence of TCDD, promoted increased differentiation of Tregs while inhibiting Th17 cells. Analysis of MLN or LP cells during colitis revealed increased methylation of CpG islands of Foxp3 and demethylation of IL-17 promoters, which was reversed following TCDD treatment. These studies demonstrate for the first time that AhR activation promotes epigenetic regulation thereby influencing reciprocal differentiation of Tregs and Th17 cells, and amelioration of inflammation.


Effects of landscape simplicity on crop yield: A reanalysis of a global database.
Ecological theory on diversity suggests that agriculture requires sufficient biodiversity, ecological function, and critical ecosystem services to remain sustainable and resilient. As such, research related to the effect of ecosystem services and diversity on crop yields has increased significantly in the past decade. One such study by Dainese and colleagues that presented a global synthesis of a compiled database of 1,475 crop experiments related to pollination and pest control ecosystem services and crop yields quickly garnered attention in the literature with more than 540 citations since its publication in 2019. Given the strong influence of this study on the research on diversity and agricultural production, we conduct a reanalysis on the publicly available dataset from the global synthesis study to test the robustness of findings to modeling approach and assumptions. In our reanalysis we apply ordinary least squares regression methods rather than Bayesian path analysis to the same data to examine the robustness of observed field-scale landscape diversity-ecosystem services-crop yield relationships. The result of our reanalysis supports the findings of Dainese and colleagues, illustrating the robustness of findings that suggest that increasing landscape simplicity is associated with lower rates of pollination and pest control ecosystem service provisioning and lower crop yields. However, our analyses also suggest that provisioning of pollination and pest control services account for only a small fraction of the total effect of landscape simplicity on crop yields. Furthermore, we find that management and soil health may mediate the effects of landscape simplicity on ecosystem services and crop yields. While our results complement previous findings for landscape simplicity and ecosystem services, they also indicate that above and below ground ecosystem services are not mutually exclusive but concurrently contribute to support crop production in agriculture.


Reducing terminals of urinary chondroitin sulfate.
Human urinary chondroitin sulfate isolated from the cetylpyridinium chloride-complex of the non-dialyzable fraction of the pooled urine was subjected to ethanol fractionation, successive enzymic digestion with neuraminidase and mucopolysaccharidases, and anion exchange chromatography. The gas liquid chromatographic analyses of the acetyl and butaneboronic acid ester derivatives of the reduced terminal sugar units after treatment with sodium borohydride plus hydrolysis revealed that 42% of the urinary chondroitin sulfate was bound to peptide through xylose. The reducing terminal sugar units of the peptide-free form consisted of 34.6% of xylose, 22.4% of galactose, 16.4% of glucose of unknown origin and 26.6% of glucuronic acid. These observations showed that the xyloside, galactoside and glucuronide linkages at non-terminal sites of carbohydrate chains of chondroitin sulfate were cleaved in tissues. It was thus suggested that the endo-types of beta-xylosidase, beta-galactosidase and beta-glucuronidase, which act on proteochondroitin sulfate are present in tissues.


Network-based drug repositioning.
Network-based computational biology, with the emphasis on biomolecular interactions and omics-data integration, has had success in drug development and created new directions such as drug repositioning and drug combination. Drug repositioning, i.e., revealing a drug's new roles, is increasingly attracting much attention from the pharmaceutical community to tackle the problems of high failure rate and long-term development in drug discovery. While drug combination or drug cocktails, i.e., combining multiple drugs against diseases, mainly aims to alleviate the problems of the recurrent emergence of drug resistance and also reveal their synergistic effects. In this paper, we unify the two topics to reveal new roles of drug interactions from a network perspective by treating drug combination as another form of drug repositioning. In particular, first, we emphasize that rationally repositioning drugs in the large scale is driven by the accumulation of various high-throughput genome-wide data. These data can be utilized to capture the interplay among targets and biological molecules, uncover the resulting network structures, and further bridge molecular profiles and phenotypes. This motivates many network-based computational methods on these topics. Second, we organize these existing methods into two categories, i.e., single drug repositioning and drug combination, and further depict their main features by three data sources. Finally, we discuss the merits and shortcomings of these methods and pinpoint some future topics in this promising field.


Actions without consequences: injury-related messages in children's programs.
To characterize children's television programs in terms of their unintentional injury-related messages. Content analysis. Episodes representing a total of 216 unique television programs were coded for the presence of imitable unsafe behaviors without consequences. A census of all children's programming airing in a northeastern city during the first week of December 1996. Exactly 47.0% of children's programming depicted at least 1 instance of unsafe, imitable behavior without consequences; one third had more than 3 instances. Exactly 51.0% of the programs targeted to school-age children and 33.4% of the programs targeted to preschoolers contained these unsafe behaviors. The majority (56.8%) of children's programs on basic cable television depicted unsafe behavior as compared with 23.1% of programs shown on public television. Cartoon programs depicted the most unsafe behaviors (60.3%), as compared with live-action programs (33.4%) and other genres (23.3%). Children's television programs depict too many unsafe behaviors without consequences. Future work should explore the role of these programs in the development of unsafe behaviors in children.


Social Competence with Peers in Third Grade: Associations with Earlier Peer Experiences in Child Care.
The early developmental antecedents of individual differences in children's social functioning with peers in third grade were examined using longitudinal data from the large-scale NICHD Study of Early Child Care. In a sample of 1364 children, with family and child factors controlled, the frequency of positive and negative peer interactions in child care between 24 and 54 months and the number of hours spent in child-care peer groups of different sizes (alone; dyad; small; medium; large), predicted third graders' peer competence at three levels of analysis: individual social skills, dyadic friendships, and peer group acceptance. Children who had more positive experiences with peers in child care had better social and communicative skills with peers in third grade, were more sociable and cooperative and less aggressive, had more close friends, and were more accepted and popular. Children with more frequent negative experiences with peers in child care were more aggressive in third grade, had lower social and communicative skills, and reported having fewer friends. When children spent more time in small-sized peer groups in child care (4 or fewer children at 24 months of age, up to 7 or fewer at 54 months), they were more sociable and cooperative in third grade, but their teachers rated them as more aggressive suggesting that such children may be more socially outgoing and active both positively and negatively. Like those who spent more time in small peer groups, children who spent more hours in medium-sized groups received higher ratings for peer aggression by their third grade teachers. Children who spent more time with one other child in child care or in small peer groups had fewer classroom friends in third grade as reported by the teacher but not according to maternal report or self report. There were no significant associations between the amount of time children spent in large child-care based peer groups and third grade peer social competence.


SUMO E3 ligase AtMMS21 regulates drought tolerance in Arabidopsis thaliana(F).
Post-translational modifications of proteins by small ubiquitin-like modifiers (SUMOs) play crucial roles in plant growth and development, and in stress responses. The MMS21 is a newly-identified Arabidopsis thaliana L. SUMO E3 ligase gene aside from the SIZ1, and its function requires further elucidation. Here, we show that MMS21 deficient plants display improved drought tolerance, and constitutive expression of MMS21 reduces drought tolerance. The expression of MMS21 was reduced by abscisic acid (ABA), polyethylene glycol (PEG) or drought stress. Under drought conditions, mms21 mutants showed the highest survival rate and the slowest water loss, and accumulated a higher level of free proline compared to wild-type (WT) and MMS21 over-expression plants. Stomatal aperture, seed germination and cotyledon greening analysis indicated that mms21 was hypersensitive to ABA. Molecular genetic analysis revealed that MMS21 deficiency led to elevated expression of a series of ABA-mediated stress-responsive genes, including COR15A, RD22, and P5CS1 The ABA and drought-induced stress-responsive genes, including RAB18, RD29A and RD29B, were inhibited by constitutive expression of MMS21. Moreover, ABA-induced accumulation of SUMO-protein conjugates was blocked in the mms21 mutant. We thus conclude that MMS21 plays a role in the drought stress response, likely through regulation of gene expression in an ABA-dependent pathway.


Acute and chronic effects of polystyrene microplastics on juvenile and adult Daphnia magna.
We investigate the distribution and effects of polystyrene microplastic (MP) particles in exposure experiments with the ecotoxicology model organism Daphnia magna. The aim was to investigate the short and long-term toxicity of MP at different concentrations. To achieve this goal, the effects of 6 μm commercially available polystyrene beads on two different life-stages of D. magna: < 24 h old juveniles and 9 days old adults was assessed. The following end points in test animals were measured: (1) survival, (2) growth, (3) individual and population fecundity, (4) age at maturation and (5) body size of newborn offspring. These response variables were followed in two acute and two chronic experiments. The acute experiments showed that MP is not acutely toxic to D. magna within 48 h, but cause added mortality within 120 h. The juveniles were about 50% more sensitive than the adults tested. In life-cycle experiments testing chronic exposure to MP, again, animals exposed as juveniles at relatively high concentrations, i.e. > 30 μg ml-1 showed higher sensitivity. We observed slightly increased mortality, reduced growth and stimulation of early reproduction at the cost of later reproduction. Animals exposed after reaching adulthood did not show increased mortality and showed a stimulation response with higher reproductive rates than the control group. However, both the growth rate of mother animals and the body size of newborn declined with increasing dose of MP. We conclude that these effects indicate a role of MP in mechanical interaction/interference with the animal on the level of feeding (clogging filtering functions), digestion (gut filled with plastic particles), and/or other animal behavior. The study also illustrates how MP with slow break-down rates may accumulate in the environment and enter the food-chain as obstructing non-food particles in filter-feeding organisms.


The false fame illusion in people with memories about a previous life.
The present study examined whether individuals with full-blown memories of highly implausible events are prone to commit source monitoring errors. Participants reporting previous-life memories and those without such memories completed a false fame task. This task provides an index of source monitoring errors (i.e., misclassifying familiar non-famous names as famous names). Participants with previous-life memories had a greater tendency to judge the names of previously presented non-famous people as famous than control participants. The two groups did not differ in terms of correct recognition of new non-famous names and famous names. Although dissociation, cognitive failures, sleep-related experiences, depressive symptoms, and signs of psychological distress were all significantly higher in participants with previous-life memories than in controls, these variables did not predict the false fame illusion.


Carboxymethylcellulose Mediates the Transport of Carbon Nanotube-Magnetite Nanohybrid Aggregates in Water-Saturated Porous Media.
Carbon-metal oxide nanohybrids (NHs) are increasingly recognized as the next-generation, promising group of nanomaterials for solving emerging environmental issues and challenges. This research, for the first time, systematically explored the transport and retention of carbon nanotube-magnetite (CNT-Fe3O4) NH aggregates in water-saturated porous media under environmentally relevant conditions. A macromolecule modifier, carboxymethylcellulose (CMC), was employed to stabilize the NHs. Our results show that transport of the magnetic CNT-Fe3O4 NHs was lower than that of nonmagnetic CNT due to larger hydrodynamic sizes of NHs (induced by magnetic attraction) and size-dependent retention in porous media. Classical Derjaguin-Landau-Verwey-Overbeek (DLVO) theory can explain the mobility of NHs under varying experimental conditions. However, in contrast with colloid filtration theory, a novel transport feature-an initial lower and a following sharp-higher peaks occurred frequently in the NHs' breakthrough curves. The magnitude and location of both transport peaks varied with different experimental conditions, due to the interplay between variability of fluid viscosity and size-selective retention of the NHs. Promisingly, the estimated maximum transport distance of NHs ranged between ∼0.38 and 46 m, supporting the feasibility of employing the magnetically recyclable CNT-Fe3O4 NHs for in situ nanoremediation of contaminated soil, aquifer, and groundwater.


Does Lipocalin-2 Affect Metabolic Syndrome in Hepatic Infections?
Background and objective Lipocalin-2 (LCN-2) is an adipokine that plays a protective role in various inflammatory disorders and regulates innate immune response to acute and chronic infections. However, scant information is available regarding the relationship between serum LCN-2 levels and type 2 diabetes mellitus (T2DM) occurring concurrently with chronic hepatic infections. The present study sought to investigate the association of LCN-2 with T2DM patients with hepatic infections. Methods The association of LCN-2 with T2DM, hepatic steatosis, and inflammation was tested in 37 non-T2DM noninfectious individuals (group A, control group) and 55 age-matched patients with T2DM and chronic infection (group B). Anthropometric data were measured and the body-fat percentage was calculated using bioelectrical impedance analysis (BIA). Hemoglobin (Hb), fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), liver function enzymes (LFEs), lipid profile, and total leukocyte count (TLC) were measured. Serum LCN-2 levels were measured using a commercially available sandwich enzyme-linked immunosorbent assay method. Results Levels of LCN-2 were significantly elevated in group B (1896.90 ± 73.13 ng/ml) versus control group A (263.58 ± 15.66 ng/mL; p<0.001). LCN-2 correlated moderately with alanine aminotransferase (ALT) (r=0.369), alkaline phosphatase ALP (r=0.419), and HbA1c (r=0.341) (p<0.01). All correlations were lost when adjusted for the presence of hepatitis, indicating that liver infection exacerbates insulin resistance. Conclusion Based on our findings, circulating LCN-2 is elevated in T2DM subjects with hepatitis B co-infection and may contribute towards deranged inflammatory response.


Management of Vocal Fold Scars by Concurrent Nanofat and Microfat Grafting.
Vocal fold scarring is the cause of severe dysphonia and represents a therapeutic challenge; dysphagia can also be present in case of soft tissue defect due to previous oncological surgery. The ideal surgical solution should concurrently provide vocal fold augmentation and re-establishment of tissue elasticity. Nanofat technique has given so far promising results in remodeling skin scars and improving tissue pliability. The present paper describes for the first time the use of nanofat injected into the vocal fold cover for pliability restoration, combined with traditional microfat for vocal fold augmentation. Seven patients (aged 23-77 years) affected by severe dysphonia, related to extensive vocal fold scarring (3 of them were also affected by dysphagia for liquid consistencies), underwent a single procedure of concurrent microfat and nanofat vocal fold injection under direct microlaryngoscopy in general anesthesia. Results were evaluated by objective outcome measures and auto evaluation performed by questionnaires concerning the phonatory and swallowing efficiency. The voice quality and the perceived swallowing capability of all patients improved after surgery and are stable at follow-up (4-8 months). The reported preliminary data show that nanofat, due to its regenerative potential related to adipose-derived stem cells and growth factors, can be a promising adjunct to traditional fat augmentation to improve elasticity of the delicate multilayered structure of the vocal fold and to enhance its vibratory capabilities. Further experience on a wider number of patients and long-term follow-up are necessary to confirm the validity of this technique.


History of endoscopic skull base surgery: its evolution and current reality.
The history of the endoscope exemplifies the manner in which technological advances influence medicine and surgery. Endoscopic systems have evolved and improved, and they currently provide detailed visualization of a variety of deep organ structures. Otorhinolaryngological surgeons have used the endoscope for more than 30 years. In the 1990s, a number of influential neurosurgeons and otorhinolaryngological surgeons began performing purely endoscopic pituitary surgery. Endoscopic transsphenoidal operations are now extending beyond the sella. The collaboration between otorhinolaryngologists and neurosurgeons has produced a new subspecialty of "endoscopic skull base surgery." There is a great deal of progress still to be made in developing skills, instruments, and improving skull base repair. The extended skull base approaches allow surgical exposures from the olfactory groove to C-2 and to the infratemporal region and jugular fossa laterally. This article discusses the history of the endoscope, the pivotal technological advances, and the key figures in the burgeoning field of endoneurosurgery.


Perceived racial/ethnic discrimination, smoking and alcohol consumption in the Multi-Ethnic Study of Atherosclerosis (MESA).
To examine the association of perceived racial/ethnic discrimination with smoking and alcohol consumption in adults participating in the Multi-Ethnic Study of Atherosclerosis. Data on 6680 black, Chinese, Hispanic and white adults aged 45 to 84 years of age recruited from Illinois, New York, Maryland, North Carolina, Minnesota and California during 2000 and 2002 were used for this analysis. Logistic regression was used to estimate the association of perceived racial/ethnic discrimination with smoking status and alcohol consumption for each racial/ethnic group separately. Blacks were more likely to experience racial/ethnic discrimination (43%) than Hispanics (19%), Chinese participants (10%) or whites (4%, P<0.0001). In the fully-adjusted model, blacks reporting racial/ethnic discrimination had 34% and 51% greater odds of reporting smoking and drinking, respectively, than blacks who did not report racial/ethnic discrimination. Hispanics reporting racial/ethnic discrimination had 62% greater odds of heavy drinking. Whites reporting racial/ethnic discrimination had 88% greater odds of reporting being current smokers than whites who did not report racial/ethnic discrimination. Our findings suggest that the experience of discrimination is associated with greater prevalence of unhealthy behaviors. Specifically, the use of smoking and alcohol may be patterned by experience of discrimination.


Assessment of dysmyelination with RAFFn MRI: application to murine MPS I.
Type I mucopolysaccharidosis (MPS I) is an autosomal recessive lysosomal storage disorder with neurological features. Humans and laboratory animals with MPS I exhibit various white matter abnormalities involving the corpus callosum and other regions. In this study, we first validated a novel MRI technique, entitled Relaxation Along a Fictitious Field in the rotating frame of rank n (RAFFn), as a measure of myelination and dysmyelination in mice. We then examined differences between MPS I mice and heterozygotes using RAFF5 and histology. RAFF5 (i.e., RAFFn with n = 5) relaxation time constants were highly correlated with histological myelin density (R2 = 0.68, P<0.001), and RAFF5 clearly distinguished between the hypomyelinated and dysmyelinated shiverer mouse and the wild-type mouse. Bloch-McConnell theoretical analysis revealed slower exchange correlation times and smaller exchange-induced relaxation rate constants for RAFF4 and RAFF5 compared to RAFF1-3, T1ρ, and T2ρ. These data suggest that RAFF5 may assess methylene protons in myelin lipids and proteins, though other mechanisms (e.g. detection of myelin-bound water) may also explain the sensitivity of RAFF5 to myelin. In MPS I mice, mean RAFF5 relaxation time constants were significantly larger for the striatum (P = 0.004) and internal capsule (P = 0.039), and marginally larger for the fornix (P = 0.15). Histological assessment revealed no differences between MPS I mice and heterozygotes in myelin density or corpus callosum thickness. Taken together, these findings support subtle dysmyelination in the brains of mice with MPS I. Dysmyelination may result from myelin lipid abnormalities caused by the absence of α-L-iduronidase. Our findings may help to explain locomotor and cognitive deficits seen in mice with MPS I.


Release of decay-accelerating factor into stools of patients with colorectal cancer by means of cleavage at the site of glycosylphosphatidylinositol anchor.
The expression of decay-accelerating factor (DAF), a cell-membrane-complement regulator, is enhanced in colorectal cancer, and DAF is detected in the stools of patients with colorectal cancer. In this study, to elucidate mechanisms whereby DAF is released into the colonic lumen, we analyzed and compared the properties of DAF in stools and colorectal-cancer tissues. Stool specimens taken before surgery and tissue samples from surgically resected colorectal cancers were obtained from 21 patients. We analyzed DAF in stool and tissue specimens using immunoblotting, ultracentrifugation, and phase separation with Triton X-114. We analyzed the expression profile of DAF mRNA in cancer tissues using reverse transcription-polymerase chain reaction to determine whether DAF transcripts for a secretory form of DAF were present. With the use of immunoblotting, stool DAF was detected as a broad band with a molecular weight of around 70,000 kDa that migrated slightly more slowly than cancer-tissue DAF. About 90% of stool DAF was present as a soluble form that remained in the 100,000 g supernatant after ultracentrifugation. On phase separation with Triton X-114, the soluble stool DAF was partitioned mainly into the aqueous phase, indicating its hydrophilic nature and lack of the fatty-acid glycosylphosphatidylinositol anchor component. In colorectal cancer tissues, reverse transcription-polymerase chain reaction experiments revealed a nonspliced DAF messenger RNA that encodes a secretory form of DAF in just 2 of the 21 specimens examined. These data suggest that DAF is released from colorectal cancer cells by way of cleavage of membrane-bound DAF at the site of the glycosylphosphatidylinositol anchor.


Cellular origin of the chemokinetic inhibitor of polymorphononuclear leucocytes found in sera from patients with chronic lymphocytic leukaemia.
In a previous study, we demonstrated the existence in serum from patients with chronic lymphocytic leukaemia (CLL) of a cell-directed, heat-labile chemokinetic inhibitor of polymorphonuclear leucocytes (PMN). The aim of this investigation was to study the cellular origin of this inhibitor. Supernatants from short term cultured lymphocytes from 3 healthy persons and 5 patients with CLL, and from 16 different established human non-haematopoietic and haematopoietic cell lines were analyzed. Only the leukaemic B-lymphocytes from the CLL patients produced the inhibitor. The presence of the inhibitor was also demonstrated in supernatants from the fresh CLL cells from one CLL patient and a leukaemic cell line established from these cells using Epstein-Barr virus as the immortalizing agent. A lymphoblastoid cell line derived from the normal B-cells of the same CLL patient did not produce the chemokinetic inhibitor. We therefore conclude that the cellular origin of the heat-labile, cell-directed chemokinetic inhibitor of PMN migration is the CLL cell.


Asymmetry of cilia and of mice and men.
Evidence is given for the opinion that cilia in the early embryo, by their work, determine the laterality of the body; without ciliary work body laterality would be randomized. More exactly, monocilia in the primitive node are responsible for this determination. They have been described as being of the 9+0 type, but with dynein arms and with a gyrating movement. The orientation of the monocilia on the epithelium is of no importance but the direction of their gyration is, as may also be the shape of the node. The chirality of the cilia is thus reflected directly in the asymmetry of the body. The dynein arms go clockwise as seen from the base to tip and the ciliary rotation is in the same direction. The resulting waterflow is towards the left and so is the movement of the forming heart. In most subgroups of the immotile-cilia syndrome this mechanism does not work and equally many individuals will be born with situs inversus as with situs solitus. An exception is the immotile-cilia subgroup, named 'microtubule transposition', which is characterized by all cilia having a 9+0 structure throughout most of their length.


The Influence of Sensorineural Hearing Loss on the Relationship Between the Perception of Speech in Noise and Dysarthric Speech.
The ability to understand speech under adverse listening conditions is highly variable across listeners. Despite this, studies have found that listeners with normal hearing display consistency in their ability to perceive speech across different types of degraded speech, suggesting that, for at least these listeners, global skills may be involved in navigating the ambiguity in speech signals. However, there are substantial differences in the perceptual challenges faced by listeners with normal and impaired hearing. This study examines whether listeners with sensorineural hearing loss demonstrate the same type of consistency as normal-hearing listeners when processing neurotypical (i.e., control) speech that has been degraded by external noise and speech that is neurologically degraded such as dysarthria. Listeners with normal hearing (n = 31) and listeners with sensorineural hearing loss (n = 36) completed an intelligibility task with neurotypical speech in noise and with dysarthric speech in quiet. Findings were consistent with previous work demonstrating a relationship between the ability to perceive neurotypical speech in noise and dysarthric speech for listeners with normal hearing, albeit at a higher intelligibility level than previously observed. This relationship was also observed for listeners with hearing loss, although listeners with more severe hearing losses performed better with dysarthric speech than with neurotypical speech in noise. This study demonstrated a high level of consistency in intelligibility performance for listeners across two different types of degraded speech, even when those listeners were further challenged by the presence of sensorineural hearing loss. Clinical implications for both listeners with hearing loss and their communication partners with dysarthria are discussed.