Comparison of the efficacy and tolerability of simvastatin and atorvastatin in the treatment of hypercholesterolemia.
Simvastatin and atorvastatin are effective statins for treating hypercholesterolemia. The study was undertaken to compare the efficacy and tolerability of simvastatin 20 and 40 mg/day and atorvastatin 10 and 20 mg/day. In this multinational, open-label, crossover study, 258 patients with primary hypercholesterolemia were randomized after 4 weeks of diet plus placebo to once-daily administration of a starting dose sequence of simvastatin (20 mg) or atorvastatin (10 mg), or a higher dose sequence of simvastatin (40 mg) or atorvastatin (20 mg) for 6 weeks. Patients were then switched after a 1-week washout to the corresponding starting or higher dose of the alternate drug for a second 6-week period. The primary endpoint was the mean percent change from baseline to Week 6 in low-density lipoprotein (LDL) cholesterol; percent changes from baseline in total cholesterol, high-density lipoprotein cholesterol, triglycerides, and apolipoprotein B were also compared. Safety was assessed through adverse experiences and laboratory measurements. Both statins produced statistically significant improvements in all measured plasma lipids and lipoproteins. The main treatment comparison showed no statistically significant difference in changes in LDL cholesterol and triglycerides, whereby the overall effects were comparable when doses of 20 mg and 40 mg of simvastatin were compared with atorvastatin 10 mg and 20 mg. The mean percent reductions for LDL cholesterol from baseline to Week 6 ranged from 35-42% for the entire study cohort. An LDL cholesterol level < or = 130 mg/dl (3.4 mmol/l) was achieved in approximately 70% of patients treated with both drugs in this study. Simvastatin and atorvastatin were well tolerated at the doses studied. In patients with hypercholesterolemia, the most commonly used doses of simvastatin and atorvastatin produced similar changes in LDL cholesterol and achieved an LDL cholesterol level < or = 130 mg/dl (3.4 mmol/l) in a similar number of patients. Both statins were well tolerated.


Adolescent gambling and impulsivity: Does employment during high school moderate the association?
The aim of the present study was to examine the potential moderating relationships between adolescent gambling and impulsivity traits (negative urgency, positive urgency, lack of premeditation, lack of perseverance and sensation seeking) with employment status. High-school students (N=400; 69% male; mean age=18.35years; SD=1.16; past year gamblers) were surveyed to provide data on impulsivity and employment. Multiple linear regression analysis was applied to examine associations with gambling and related problems. Positive urgency was associated with stronger scores of both gambling frequency and problem gambling. Students in employment had substantially higher frequency of gambling and greater problem gambling. Moreover, the combination of having a job and low perseverance was associated with a particularly high frequency on gambling. These findings further support the importance of positive urgency and employment status in adolescent gambling. The study highlights unique moderating relationship between gambling and lack of perseverance with employment status. Youth with a low perseverance and having a job may have particular need for interventions to reduce gambling.


Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis.
Colorectal adenomatous polyposis is associated with a high risk of colorectal cancer (CRC) and is frequently caused by germline mutations in APC or MUTYH. However, in about 20-30% of patients no underlying gene defect can be identified. In this study, we tested if recently identified CRC risk variants play a role in patients with >10 adenomas. We analysed a total of 16 SNPs with a reported association with CRC in a cohort of 252 genetically unexplained index patients with >10 colorectal adenomas and 745 controls. In addition, we collected detailed clinical information from index patients and their first-degree relatives (FDRs). We found a statistically significant association with two of the variants tested: rs3802842 (at chromosome 11q23, OR=1.60, 95% CI 1.3 to 2.0) and rs4779584 (at chromosome 15q13, OR=1.50, 95% CI 1.2 to 1.9). The majority of index patients (84%) had between 10 and 100 adenomas and 15% had >100 adenomas. Only two index patients (1%), both with >100 adenomas, had FDRs with polyposis. Forty-one per cent of the index patients had one or more FDRs with CRC. These SNPs are the first common, low-penetrant variants reported to be associated with adenomatous polyposis not caused by a defect in the APC, MUTYH, POLD1 and POLE genes. Even though familial occurrence of polyposis was very rare, CRC was over-represented in FDRs of polyposis patients and, if confirmed, these relatives will therefore benefit from surveillance.


An Lsm2-Lsm7 complex in Saccharomyces cerevisiae associates with the small nucleolar RNA snR5.
Sm-like (Lsm) proteins function in a variety of RNA-processing events. In yeast, the Lsm2-Lsm8 complex binds and stabilizes the spliceosomal U6 snRNA, whereas the Lsm1-Lsm7 complex functions in mRNA decay. Here we report that a third Lsm complex, consisting of Lsm2-Lsm7 proteins, associates with snR5, a box H/ACA snoRNA that functions to guide site-specific pseudouridylation of rRNA. Experiments in which the binding of Lsm proteins to snR5 was reconstituted in vitro reveal that the 3' end of snR5 is critical for Lsm protein recognition. Glycerol gradient sedimentation and sequential immunoprecipitation experiments suggest that the Lsm protein-snR5 complex is partly distinct from the complex formed by snR5 RNA with the box H/ACA proteins Gar1p and Nhp2p. Consistent with a separate complex, Lsm proteins are not required for the function of snR5 in pseudouridylation of rRNA. We demonstrate that in addition to their known nuclear and cytoplasmic locations, Lsm proteins are present in nucleoli. Taken together with previous findings that a small fraction of pre-RNase P RNA associates with Lsm2-Lsm7, our experiments suggest that an Lsm2-Lsm7 protein complex resides in nucleoli, contributing to the biogenesis or function of specific snoRNAs.


[Influenza A from the rational choice theory: proposals for decision making in prevention policies].
This article is a reflection on the social uncertainty caused by Influenza A and on the consequences that it can have on decision making in health promotion policies. We use concepts and metaphors of the Rational Choice Theory, among them, the "in gratitude effect" or the "distrust effect", as we analyse how these can become obstacles for the efficiency of prevention policies. Then, we focus on the information asymmetry of the principal-agent relationship, and we propose measures to diminish the "moral risk" that they cause. We finish by advancing some proposals for designing lines and strategies of action in health promotion policies.


Treatment for acute myocardial infarction. Overview of randomized clinical trials.
This review summarizes the results of several pharmacological interventions that have been evaluated in the management of acute myocardial infarction. Of these, thrombolytic therapy, aspirin, beta-blockers and angiotensin converting enzyme inhibitors have all been proven to reduce mortality risk and the latter three classes of drugs have also been shown to reduce morbidity. Routine use of heparin or nitrates is not recommended although they may be useful in specific circumstances such as post-infarction angina or large infarcts. Drugs that have as yet not been shown to have a role in the routine management of acute myocardial infarction include Class I antiarrhythmic agents, magnesium and calcium antagonists. Management of patients with acute myocardial infarction can now be appropriately based on the evidence generated from well conducted randomized clinical trials and appropriate therapeutic choices based on such information can be expected to reduce their morbidity and mortality risks.


Relationship between an interview-based health promotion program and cardiovascular risk factors at Japanese companies.
The present study investigated the relationship between an interview-based health promotion program and cardiovascular risk factors at manufacturing companies. Excluding insufficient data and the workers who took medication prescribed by a physician in 1993, the subjects were six hundred and twenty-nine 18-55-yr-old employees who had been working at two manufacturing companies in Kyushu from 1993 to 1997. The intervention company introduced an interview-based health promotion program from 1993. The program consisted of health measuring, group education, and health interviewing all employees to help with their behavioral change. We subdivided the subjects into younger (18-34-yr-old) and older (35-55-yr-old) groups. We defined changing degree (Delta) with (the following data in 1997) minus (the initial data in 1993). With agreement of the subject companies, we compared the Delta of each item, including body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), serum total cholesterol (T-cho), serum aspartate aminotransaminase (AST), serum alanine aminotransferase (ALT), and serum gammaglutamyl transpeptidase (GGTP), in the intervention with that in the reference. BMI and SBP decreased significantly after the program in the under 35-yr-old intervention group. On the other hand, T-cho, AST, ALT, and GGTP decreased and HDL increased significantly after the program in the over 34-yr-old intervention group. Our results showed that the worksite health promotion had the potential to improve cardiovascular risk factors of Japanese employees.


Association of leisure-time noise exposure and hearing loss.
The purpose of this study was to investigate the association of noisy leisure activities with hearing loss. Participants (n=3571) were examined in a population-based study of age-related hearing loss conducted in Beaver Dam, Wisconsin. Hearing thresholds were determined by audiometry. Hearing loss was defined as the pure-tone average of the frequencies 500, 1,000, 2,000, and 4,000 Hz greater than 25 dB HL in either ear. Information regarding exposure to leisure-time noise was obtained by interview. After adjusting for potential confounders, individuals who engaged in leisure activities with average sound levels greater than 90 dBA were significantly more likely to have a hearing loss than participants who did not engage in noisy leisure activities (OR=1.11, 95 per cent CI=1.01-1.22). Individuals who engaged in woodworking were 30 per cent more likely to have a hearing loss than those who had never done woodworking. There was a 6 per cent increased risk of hearing loss for each 5-year period of participation. Health care professionals should consider counseling their patients who engage in noisy leisure activities about the risk of noise-induced hearing loss.


Nonuniform Late Pleistocene glacier fluctuations in tropical Eastern Africa.
Today's ice caps and glaciers in Africa are restricted to the highest peaks, but during the Pleistocene, several mountains on the continent were extensively glaciated. However, little is known about regional differences in the timing and extent of past glaciations and the impact of paleoclimatic changes on the afro-alpine environment and settlement history. Here, we present a glacial chronology for the Ethiopian Highlands in comparison with other East African Mountains. In the Ethiopian Highlands, glaciers reached their maximum 42 to 28 thousand years ago before the global Last Glacial Maximum. The local maximum was accompanied by a temperature depression of 4.4° to 6.0°C and a ~700-m downward shift of the afro-alpine vegetation belt, reshaping the human and natural habitats. The chronological comparison reveals that glaciers in Eastern Africa responded in a nonuniform way to past climatic changes, indicating a regionally varying influence of precipitation, temperature, and orography on paleoglacier dynamics.


Hypertension Pharmacological Treatment in Adults: A World Health Organization Guideline Executive Summary.
Hypertension is a major cause of cardiovascular disease and deaths worldwide especially in low- and middle-income countries. Despite the availability of safe, well-tolerated, and cost-effective blood pressure (BP)-lowering therapies, <14% of adults with hypertension have BP controlled to a systolic/diastolic BP <140/90 mm Hg. We report new hypertension treatment guidelines, developed in accordance with the World Health Organization Handbook for Guideline Development. Overviews of reviews of the evidence were conducted and summary tables were developed according to the Grading of Recommendations, Assessment, Development, and Evaluations approach. In these guidelines, the World Health Organization provides the most current and relevant evidence-based guidance for the pharmacological treatment of nonpregnant adults with hypertension. The recommendations pertain to adults with an accurate diagnosis of hypertension who have already received lifestyle modification counseling. The guidelines recommend BP threshold to initiate pharmacological therapy, BP treatment targets, intervals for follow-up visits, and best use of health care workers in the management of hypertension. The guidelines provide guidance for choice of monotherapy or dual therapy, treatment with single pill combination medications, and use of treatment algorithms for hypertension management. Strength of the recommendations was guided by the quality of the underlying evidence; the tradeoffs between desirable and undesirable effects; patient's values, resource considerations and cost-effectiveness; health equity; acceptability, and feasibility consideration of different treatment options. The goal of the guideline is to facilitate standard approaches to pharmacological treatment and management of hypertension which, if widely implemented, will increase the hypertension control rate world-wide.


[Stereotaxic thalamotomy in the phantom pain syndrome].
The results of stereotaxic thalamotomy in 18 patients suffering from a severe phantom-pain syndrome are described. It is shown that to achieve a more stable analgetic effect and a reduced emotional background of pain perception it is expedient, parallel with the destruction of the somatotopic zones of the relay posterior ventral nucleus, which have a bearing on pains in the phantom, to also exclude the non-specific afferent systems of the thalamus, that is, the median center, bordering nucleus and oroventral part of the cushion of the optic thalamus. The effects of the electrostimulation of these structures of the thalamus are described in the process of their intraoperational physiological identification. It is shown that the combined destruction of specific and non-specific afferent structures of the optic thalamus in most cases ensures a considerable diminution or disappearance of phantom pain permitting patients to readapt themselves to normal everyday life.


Creating advantages with franchising in healthcare: an explorative mixed methods study on the role of the relationship between the franchisor and units.
Franchising is a promising and increasingly used organizational form to improve strategic, organizational, professional and client-related results in healthcare. However, evidence is scarce regarding how franchises should be operated to actualize such results. This paper aimed to explore the association between the results achieved by healthcare franchises and the working relationships among actors in these franchises. A sequential mixed methods approach was used to obtain both in-depth and broader quantifiable insights into a little-investigated phenomenon. We first employed a qualitative multiple embedded case study. Data were collected through observations, document analyses, and 96 in-depth semi-structured interviews in three Dutch healthcare franchises. Within-case and cross-case comparative analyses were conducted. Subsequently, a cross-sectional survey was developed based on the qualitative study and disseminated among 19 healthcare franchises. 40 franchisors and 346 unit actors filled in the questionnaire. It seems important to have open, committed, cooperative franchise relationships in which professional franchisees and unit managers feel and trust that they have the opportunity to introduce ideas and articulate their needs to the franchisor. Such relationships help ensure satisfaction, survival, and quality of care, because they serve to foster synergy realization and local fit and prevent reinventing the wheel and professional resistance.


Chemoprevention of prostate carcinogenesis by alpha-difluoromethylornithine in TRAMP mice.
Development of effective chemopreventive agents for human consumption requires conclusive evidence of their efficacy in animal models that have relevance to human diseases. Transgenic adenocarcinoma mouse prostate (TRAMP) is an excellent model of prostate cancer that mimics progressive forms of human disease inasmuch as 100% of males develop histological PIN by 8-12 weeks of age that progress to adenocarcinoma with distant site metastases by 24-28 weeks of age. In these animals, ornithine decarboxylase (ODC) activity (>3-fold) as well as protein expression (>4-fold) was found to be markedly higher in the dorsolateral prostate as compared with the nontransgenic littermates, suggesting their suitability to determine the chemopreventive effect of alpha-difluoromethylornithine (DFMO), an enzyme-activated irreversible inhibitor of ODC, against prostate cancer. Using male TRAMP mice, we studied the effect of oral consumption of DFMO on development of prostate carcinogenesis and surrogate end point biomarkers related to prostate cancer progression. In two independent experiments, each consisting of 8 animals on test, the cumulative incidence of prostatic cancer development at 28 weeks of age in 16 untreated TRAMP mice was 100% (16 of 16), whereas 94% (15 of 16) and 69% (11 of 16) of the animals exhibited distant site metastases to lymph nodes and lungs, respectively. Oral consumption of 1% DFMO (w/v) in the drinking water to TRAMP mice from 8 to 28 weeks of age resulted in a significant decrease in (a) weight (59%) and volume (66%) of prostate, (b) genitourinary weight (63%), and (c) ODC enzyme activity (52%) in the dorsolateral prostate. Importantly, in none of the DFMO-fed TRAMP mice were any distant metastases to lymph node and lungs observed. Furthermore, DFMO treatment resulted in the marked reduction in the protein expression of proliferation cell nuclear antigen, ODC, and probasin in the dorsolateral prostate. The protein expression of antimetastases markers, i.e., E-cadherin and alpha- and beta-catenin, was found to be restored in DFMO-fed animals as compared with the non-DFMO-fed mice. These chemopreventive effects of DFMO were further confirmed by immunohistochemical analysis of the dorsolateral prostate. Histological analysis of the dorsolateral prostate of DFMO-fed animals displayed marginal epithelial stratification, a small number of cribriform structures, elongated hyperchromatic epithelial nuclei, and a significant increase in apoptotic index. Non-DFMO-fed animals, on the other hand, displayed extensive epithelial stratification with profound cribriform structures accompanied with marked thickening, remodeling, and hypercellularity of the fibromuscular stroma. In nontransgenic littermates fed with DFMO, no significant alterations in the above parameters were evident. These data demonstrate that ODC represents a promising and rational target for chemoprevention of human prostate cancer and that TRAMP mice are excellent models for screening of novel drugs and chemopreventive regimens for potential human use.


An improved estimator of Variance Explained in the presence of noise.
A crucial part of developing mathematical models of information processing in the brain is the quantification of their success. One of the most widely-used metrics yields the percentage of the variance in the data that is explained by the model. Unfortunately, this metric is biased due to the intrinsic variability in the data. We derive a simple analytical modification of the traditional formula that significantly improves its accuracy (as measured by bias) with similar or better precision (as measured by mean-square error) in estimating the true underlying Variance Explained by the model class. Our estimator advances on previous work by a) accounting for overfitting due to free model parameters mitigating the need for a separate validation data set, b) adjusting for the uncertainty in the noise estimate and c) adding a conditioning term. We apply our new estimator to binocular disparity tuning curves of a set of macaque V1 neurons and find that on a population level almost all of the variance unexplained by Gabor functions is attributable to noise.


Autophagy mediated by endoplasmic reticulum stress enhances the caffeine-induced apoptosis of hepatic stellate cells.
Caffeine has been identified to have beneficial effects against chronic liver diseases, particularly liver fibrosis. Many studies have reported that caffeine ameliorates liver fibrosis by directly inducing hepatic stellate cell (HSC) apoptosis; however, the molecular mechanisms involved in this process remain unclear. The presents study aimed to detect the underlying mechanisms by which caffeine mediates HSC apoptosis and eliminates activated HSCs. For this purpose, the LX-2 cell line was applied in this study and the cells were exposed to various concentrations of caffeine for the indicated times. The effects of caffeine on cell viability and apoptosis were assessed by Cell Counting Kit-8 assay and flow cytometry, respectively. Autophagy and endoplasmic reticulum (ER) stress were explored by morphological assessment and western blotting. In the present study, caffeine was found to inhibit the viability and increase the apoptosis of the LX-2 cells in dose- and time-dependent manners. ER stress was stimulated by caffeine as demonstrated by increased levels of GRP78/Bip, CHOP and inositol‑requiring enzyme 1 (IRE1)-α as well as many enlarged ERs detected by electron microscopy. Caffeine induced autophagy as shown by increased p62 and LC3Ⅱ accumulation and the number of GFP/RFP-LC3 puncta and autophagosomes/autolysosomes. Moreover, IRE1-α knockdown decreased the level of autophagic flux, and inhibition of autophagy protected LX-2 cells from apoptotic death. In conclusion, our study showed that the caffeine-enhanced autophagic flux in HSCs was stimulated by ER stress via the IRE1-α signaling pathway, which further weakened HSC viability via the induction of apoptosis. These findings provide new insight into the mechanism of caffeine's anti-fibrotic effects.


Prevalence, severity and risk factors for depressive symptoms and insomnia in college undergraduates.
Although the college years represent a high-risk period for depressive symptoms and insomnia, little research has explored their prevalence, comorbidities and risk factors within this developmental period. Two studies were conducted; the first evaluated the prevalence and comorbidity of depressive symptoms and insomnia in 1338 students (ages 18-23 years) from a large Southwestern University. Mild depressive symptoms were endorsed by 19% of students and 14.5% reported moderate to severe symptoms. Forty-seven percent of students reported mild insomnia and 22.5% endorsed moderate to severe insomnia severity. A second study investigated perceived stress as a potential mediator of the relation between self-reported childhood adversity and concurrent depressive symptoms and insomnia. Undergraduates (N = 447) from a Southwestern and Southeastern University reported prior childhood adversity, current perceived stress, insomnia and depressive symptoms. Self-reported childhood adversity predicted higher levels of depressive symptoms and insomnia severity, partially mediated by perceived stress. Results support the high prevalence of depressive symptoms and insomnia among undergraduates. The risk for depressive and insomnia symptoms may be increased among students who experienced greater levels of childhood adversity.


Turkish Validity and Reliability Study of "Intensive Care Nurses" Attitude Scale Toward Brain Death and Organ Transplantation.
This study was carried out to analyze the validity and reliability of the Turkish adaptation of the "Intensive Care Nurses" Attitude Scale towards Brain Death and Organ Transplantation". The research was carried out as a methodological study and 256 nurses were included in the study. Language, content validity, explanatory and confirmatory factor analyzes were used to analyze data. Twenty-one point 5% of nurses stated that they had an organ donation card. It was determined that the Cronbach alpha coefficient of scale was .85, and item-total score correlations were between .143 and .700. It was established that the scale showed three-factor structure and the first factor was named as "Approving Organ Donation", the second factor as "Discomfort" and the third factor as "Improving The Quality of Life". The Turkish version of the scale was found to be an valid and reliable measurement tool.


The Gazayerli knot-tying instrument or ligator for use in diverse laparoscopic surgical procedures.
An instrument for accurately and expeditiously tightening extracorporeal knots during laparoscopic surgery is presented. This instrument has been used successfully in a variety of laparoscopic procedures such as herniorrhaphy, cholecystectomy, oophorectomy, and others in which sutures were required to complete the operation.


[Comparative characteristics of the lipoprotein spectrum in hypercholesterolemia in 40- to 59-year-old men living in Moscow and Kharkov].
Total cholesterol, triglycerides and high- and low-density lipoprotein cholesterol were measured in a study of 40-59-years-old male populations in Moscow and Kharkov. Hypercholesterolemic individuals were identified, using standard criteria, in both cities. Although mean lipid parameters were similar in individuals with second-type hyperlipoproteinemia from Moscow and Kharkov, the pattern of hypercholesterolemia was different in terms of the lipoprotein spectrum. It is concluded that detailed differentiation of second-type hyperlipoproteinemia is essential for the identification of major mechanisms of the atherogenic potential of hypercholesterolemia in different populations.


Autoimmune Hepatitis and Autoimmune Hepatitis Overlap With Sclerosing Cholangitis: Immunophenotype Markers in Children and Adolescents.
The pathophysiology of autoimmune hepatitis (AIH) may involve the activation of immune cells and changes in the expression of cellular markers. The aim of the present study was to characterize the immunophenotype markers of lymphocytes and monocytes in the peripheral blood of children and adolescents with type 1 AIH and AIH overlap with sclerosing cholangitis (overlap syndrome [OS]). This is a cross-sectional study of 20 children and adolescents diagnosed with type 1 AIH and 19 with OS. Fifteen healthy subjects were included as controls. Flow cytometric analysis was used to identify markers of inflammation and autoimmunity. The total number of CD4 T cells was higher in the AIH patients compared with the controls. The number of CD4 T cells expressing CCR3 and CD28 was higher in the AIH group than in the control group. CD45RO was more highly expressed in the AIH group, whereas CD45RA was more highly expressed in the OS group. In regard to CD8 T lymphocytes, the CCR3 expression was higher in both groups of patients. Patients with OS had the highest expression of CD45RA and CD25. In monocytes, human leukocyte antigen DR (HLA-DR) was less expressed in both groups of patients. Complex phenotype features may be involved in the pathophysiology of AIH, accounting for changes in immune system regulation mechanisms. In conclusion, even after good response to treatment, patients still have immune activity signals at the cellular level.


An analysis of the spatio-temporal occurrence of anthelmintic veterinary drug residues in groundwater.
Anthelmintics are antiparasitic drugs used to control helminthic parasites such as nematodes and trematodes in animals, particularly those exposed through pasture-based production systems. Even though anthelmintics have been shown to be excreted into the environment in relatively high amounts as unmetabolized drug or transformation products (TPs), there is still only limited information available on their environmental occurrence, particularly in groundwater, which has resulted in them being considered as potential emerging contaminants of concern. A comprehensive study was carried out to investigate the occurrence of 40 anthelmintic residues (including 13 TPs) in groundwaters (and associated surface waters) throughout the Republic of Ireland. The study focused on investigating the occurrence of these contaminants in karst and fractured bedrock aquifers, with a total of 106 sites (88 groundwaters and 18 surface waters) samples during spring 2017. Seventeen anthelmintic compounds consisting of eight parent drugs and nine TPs were detected at 22% of sites at concentrations up to 41 ng L-1. Albendazole and its TPs were most frequently detected residues, found at 8% of groundwater sites and 28% of surface water sites. Multivariate statistical analysis identified several source and pathway factors as being significantly related to the occurrence of anthelmintics in groundwater, however there was an evident localised effect which requires further investigation. An investigation of the temporal variations in occurrence over a 13 month period indicated a higher frequency and concentration of anthelmintics during February/March and again later during August/September 2018, which coincided with periods of increased usage and intensive meteorological events. This work presents the first detections of these contaminants in Irish groundwater and it contributes to broadening our understanding of anthelmintics in the environment. It also provides insight to seasonal trends in occurrence, which is critical for assessing potential future effects and implications of climate change.


The Hox cooperativity motif of the chimeric oncoprotein E2a-Pbx1 is necessary and sufficient for oncogenesis.
E2a-Pbx1 chimeric oncoproteins result from fusion of the E2A and PBX1 genes at the sites of t(1;19) chromosomal translocations in a subset acute lymphoblastic leukemias. Experimentally, E2a-Pbx1 transforms a variety of cell types, including fibroblasts, myeloid progenitors, and lymphoblasts. Structure-function studies have shown that contributions from both E2a and Pbx1 are necessary for oncogenesis, but the Pbx1 homeodomain is dispensable and the required portion of Pbx1 has not been delineated. In this study, we used deletional and site-directed mutagenesis to identify portions of Pbx1 necessary for oncogenic and transcriptional activities of E2a-Pbx1. These studies defined a motif (named the Hox cooperativity motif [HCM]) carboxy terminal to the Pbx homeodomain that is required for cooperative DNA binding, cellular transcriptional activity, and the oncogenic potential of E2a-Pbx1. The HCM is highly conserved throughout the Pbx/exd subfamily of divergent homeodomain proteins and functions in DNA-binding assays as a potential contact site for Hox dimerization. E2a-Pbx1 proteins with interstitial deletion or single-point mutations in the HCM could neither activate transcription in cellular assays nor transform NIH 3T3 cells. An E2a-Pbx1 mutant containing 50 amino acids of Pbx1b spanning the HCM but lacking the homeodomain was capable of inducing fibroblast transformation. Thus, the HCM is a necessary and sufficient contribution of Pbx1 for oncogenesis induced by E2a-Pbx1 and accounts for its homeodomain-independent transforming properties. Since subtle alterations of the Pbx HCM result in complete abrogation of transforming activity whereas the homeodomain is entirely dispensable, we conclude that interactions mediated by the HCM are more important for transformation by E2a-Pbx1 than interactions with cognate Pbx DNA sites.


Video brochures in a mailed fecal immunochemical test outreach program provide cancer screening information in a user-friendly format for rural Appalachian community members.
Colorectal cancer (CRC) screening is recommended for average-risk adults, yet many adults are not up-to-date with screening. One recommended CRC screening approach is the annual completion of a fecal immunochemical test (FIT). However, usually, fewer than half of mailed FIT tests are returned. To address barriers to FIT return, a video brochure was developed providing targeted CRC screening information and step-by-step FIT instructions as a component in a mailed FIT program. This pilot study occurred in 2021-2022 and partnered with a federally qualified health center in Appalachian Ohio to send a FIT to patients who were 50-64 years old, of average risk, and not up-to-date on CRC screening. Patients were randomly assigned to 1 of 3 groups that differed on materials sent with the FIT: usual care (manufacturer's instructions), a video brochure (video instructions, disposable gloves, disposable stool collection device), or an audio brochure (audio instructions, disposable gloves, disposable stool collection device). Overall, 16 of 94 patients (17%) returned the FIT, and return was higher among those sent the video brochure (28%) compared to the other 2 groups (OR: 3.1; 95% CI: 1.02, 9.2; P = .046). Two patients had positive tests and were referred for colonoscopy. Patients sent the video brochure reported the content was important, relevant, and made them think about completing the FIT. Using a video brochure to provide understandable information in a mailed FIT kit is a promising strategy to improve CRC screening outreach programs in rural regions.


Toward Customized Care Comment on "(Re) Making the Procrustean Bed? Standardization and Customization as Competing Logics in Healthcare".
Patients want their personal needs to be taken into account. Accordingly, the management of care has long involved some degree of personalization. In recent times, patients' wishes have become more pressing in a moving context. As the population ages, the number of patients requiring sophisticated combinations of longterm care is rising. Moreover, we are witnessing previously unvoiced demands, preferences and expectations (eg, demand for information about treatment, for care complying with religious practices, or for choice of appointment dates). In view of the escalating costs and the concerns about quality of care, the time has now come to rethink healthcare delivery. Part of this reorganization can be related to customization: what is needed is a customized business model that is effective and sustainable. Such business model exists in different service sectors, the customization being defined as the development of tailored services to meet consumers' diverse and changing needs at near mass production prices. Therefore, its application to the healthcare sector needs to be seriously considered.


[Cushing's syndrome: clinical study of fifteen cases].
To study the epidemiological and clinical features and diagnostic tests of Cushing's syndrome (CS) of non-iatrogenic etiology, because of there are few similar studies in the last ten years. Fifteen cases of CS were diagnosed from 1992 to 1997 at our hospital. We describe the epidemiological, clinical, biochemical, radiologic, therapeutic and evolutive characteristics. Both diabetes mellitus and hypertension were observed in 40% of patients. The frequency of etiologies was: Cushing's disease, 66.6%; ectopic ACTH syndrome, 13.3%; adrenal adenoma, 6.6%; adrenal carcinoma, 6.6%; and undiagnosed, 6.6%. The 24-hour urine free cortisol (UFC) and the overnight 1 mg oral dexamethasone suppression test yielded 93.3 and 100% diagnostic sensitivity for CS, respectively. The overnight 8 mg oral dexamethasone suppression test, the metyrapone test and the 7 mg intravenous dexmethasone test had 75, 50 and 60% diagnostic sensitivity for Cushing's disease, respectively. Ketoconazole treatment had success in to normalize the 24-hour UFC in all patients, except for the case of adrenal carcinoma. The Cushing's disease was the most common form of CS. The 24-hour UFC and overnight 1 mg oral dexamethasone suppression test were good screening studies. Ketoconazole was successful in normalizing the adrenal cortex function.


A survey of genome-wide association studies, polygenic scores and UK Biobank highlights resources for autoimmune disease genetics.
Autoimmune diseases share a general mechanism of auto-antigens harming tissues. Still. they are phenotypically diverse, with genetic as well as environmental factors contributing to their etiology at varying degrees. Associated genomic loci and variants have been identified in numerous genome-wide association studies (GWAS), whose results are increasingly used for polygenic scores (PGS) that are used to predict disease risk. At the same time, a technological shift from genotyping arrays to next generation sequencing (NGS) is ongoing. NGS allows the identification of virtually all - including rare - genetic variants, which in combination with methodological developments promises to improve the prediction of disease risk and elucidate molecular mechanisms underlying disease. Here we review current, publicly available autoimmune disease GWAS and PGS data based on information from the GWAS and PGS catalog, respectively. We summarize autoimmune diseases investigated, respective studies conducted and their results. Further, we review genetic data and autoimmune disease patients in the UK Biobank (UKB), the largest resource for genetic and phenotypic data available for academic research. We find that only comparably prevalent autoimmune diseases are covered by the UKB and at the same time assessed by both GWAS and PGS catalogs. These are systemic (systemic lupus erythematosus) as well as organ-specific, affecting the gastrointestinal tract (inflammatory bowel disease as well as specifically Crohn's disease and ulcerative colitis), joints (juvenile ideopathic arthritis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis), glands (Sjögren syndrome), the nervous system (multiple sclerosis), and the skin (vitiligo).


Obstructive gastric foreign body in a rhesus monkey (Macaca mulatta).
Weight loss and depression were the principal signs in a case of obstructive gastric foreign body resulting from the ingestion of pine wood fragments by a rhesus monkey. This was the second case of its kind to occur in a short period. Replacement of the monkeys' pine wood resting platforms with platforms made of oak eliminated the problem.


Using live videography observation and Bayesian isotope mixing model to identify food composition and dietary contribution to inorganic mercury and methylmercury intake by songbird nestlings.
Mercury (Hg) exposure is increasing in terrestrial birds; however, studies on its sources are scarce. In the present study, we elucidated the food composition of green-backed tit nestlings from three urban forest parks (CPL, AHL, and LCG) using live videography observation (LVO). Furthermore, the daily dietary intakes of inorganic Hg (IHg) (MDIIHg) and methylmercury (MeHg) (MDIMeHg) were determined using the Bayesian isotope mixing model (BIMM) to uncover the nestlings' specific dietary Hg contribution. Both LVO and BIMM indicated that Lepidoptera (primarily caterpillar) constituted the primary food source for the nestlings in the three forests, accounting for approximately 60% of their diet in all three forest parks. The estimated MDI of Hg revealed that lepidopterans and spiders primarily contributed to IHg exposure, with a co-contribution ratio of 71.8%-97.7%. Unexpectedly, dietary MeHg was mostly derived from spiders; the highest contribution ratio of 93.6% was recorded at CPL, followed by another peak ratio of 92.9% at LCG. However, the dietary exposure was primarily IHg, accounting for 69.8% (AHL), 62.0% (LCG), and 61.3% (CPL) of the nestlings. Our study findings highlight the importance of dietary IHg transfer in evaluating the effects of Hg in nestlings. LVO, coupled with BIMM, is an effective tool for determining the food compositions of songbird nestlings and estimating the contribution of specific diets.


Isolation of human oncogene sequences (v-fes homolog) from a cosmid library.
To define the human homolog (or homologs) of transforming sequences (v-fes gene) common to Gardner (GA) and Snyder Theilen (ST) isolates of feline sarcoma virus (FeSV), a representative library of human lung carcinoma DNA in a cosmid vector system was constructed. Three cosmid clones were isolated containing GA/ST FeSV v-fes homologous cellular sequences, within 32- to 42-kilobase cellular inserts representing 56 kilobases of contiguous human cellular DNA. Sequences both homologous to, and colinear with, GA or ST FeSV v-fes are distributed discontinuously over a region of up to 9.5 kilobases and contain a minimum of three regions of nonhomology representing probable introns. A thymidine kinase selection system was used to show that, upon transfection to RAT-2 cells, the human c-fes sequence lacked detectable transforming activity.


Structure of Pseudomonas aeruginosa populations analyzed by single nucleotide polymorphism and pulsed-field gel electrophoresis genotyping.
Pseudomonas aeruginosa has a wide ecological distribution that includes natural habitats and clinical settings. To analyze the population structure and distribution of P. aeruginosa, a collection of 111 isolates of diverse habitats and geographical origin, most of which contained a genome with a different SpeI macrorestriction profile, was typed by restriction fragment length polymorphism based on 14 single nucleotide polymorphisms (SNPs) located at seven conserved loci of the core genome (oriC, oprL, fliC, alkB2, citS, oprI, and ampC). The combination of these SNPs plus the type of fliC present (a or b) allowed the assignment of a genetic fingerprint to each strain, thus providing a simple tool for the discrimination of P. aeruginosa strains. Thirteen of the 91 identified SNP genotypes were found in two or more strains. In several cases, strains sharing their SNP genotype had different SpeI macrorestriction profiles. The highly virulent CHA strain shared its SNP genotype with other strains that had different SpeI genotypes and which had been isolated from nonclinical habitats. The reference strain PAO1 also shared its SNP genotype with other strains that had different SpeI genotypes. The P. aeruginosa chromosome contains a conserved core genome and variable amounts of accessory DNA segments (genomic islands and islets) that can be horizontally transferred among strains. The fact that some SNP genotypes were overrepresented in the P. aeruginosa population studied and that several strains sharing an SNP genotype had different SpeI macrorestriction profiles supports the idea that changes occur at a higher rate in the accessory DNA segments than in the conserved core genome.


[Alzheimer's disease and caregivers experience in home care].
The aim of this study is to investigate the experience of primary caregivers (men and women) of Alzheimer Disease dementia, in order to tailor program and project to avoid care giving burden. A qualitative phenomenological method was used and the sample was defined by data saturation. Interviews were carried out and recorded in a day care Centre, transcribed verbatim. The analysis was conducted coding common themes and phrases. Six main themes emerged. Our results are similar to those existing in literature, showing care givers as individual in great danger physically and mentally. In the light of the study it is possible to tailor a nursing model in order to improve quality of life and decrease the burden of caregivers, this model should be implemented and analyzed.


NTP Toxicology and Carcinogenesis Studies of Nalidixic Acid (CAS No. 389-08-2) in F344/N Rats and B6C3F1 Mice (Feed Studies).
Nalidixic acid is an antimicrobial agent to treat bacterial infections of the urinary tract. NTP Toxicology and Carcinogenesis studies were conducted by feeding diets containing nalidixic acid (approximately 99% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. Thirteen-Week Studies: Nalidixic acid was administered at dietary concentrations ranging from 1,000 to 16,000 ppm. One female rat that received 16,000 ppm nalidixic acid died before the end of the studies; no other compound-related deaths occurred in rats and mice. The final mean body weights of rats that received 8,000 or 16,000 ppm were 23% or 49% lower than those of controls for males and 11% or 31% lower for females. Feed consumption by rats receiving 16,000 ppm was approximately two-thirds that by controls. Liver weight to body weight ratios for male rats that received 2,000 ppm or more and female rats that received 8,000 ppm or more were significantly greater than those for controls. Degeneration of the germinal epithelium in the seminiferous tubules of the testis was observed in 10/10 male rats that received 16,000 ppm; no other compound-related histopathologic effects were observed in rats. The final mean body weights of mice that received 8,000 or 16,000 ppm were 10%-20% lower than those of controls. Feed consumption by dosed mice was similar to that by controls. Liver weight to body weight ratios were significantly greater for male mice receiving 2,000, 8,000, or 16,000 ppm and for female mice receiving 4,000, 8,000, or 16,000 ppm than for the controls. No compound-related histopathologic effects were observed in mice. Based on these results, 2-year studies of nalidixic acid were conducted by feeding diets containing 0, 2,000, or 4,000 ppm nalidixic acid to groups of 50 male and 50 female F344/N rats and 50 male and 50 female B6C3F1 mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose rats were 7%-23% lower than those of controls, and those of low dose male rats were 6%-11% lower than those of controls. The average daily feed consumption by dosed rats ranged from 89% to 96% that by controls. The average amount of nalidixic acid consumed per day was approximately 80 or 175 mg/kg for low dose or high dose rats. Mean body weights of high dose male mice were 1%-8% lower than those of controls throughout the study. Mean body weights of dosed female mice were 5%-17% lower than those of controls. Average daily feed consumption by dosed mice was within 3% of that by controls. The estimated average amount of nalidixic acid consumed per day was approximately 220 or 475 mg/kg for low dose or high dose mice. No significant differences in survival were seen between any groups of rats or mice of either sex after 2 years (male rats: control, 27/50; low dose, 28/50; high dose, 27/50; female rats: 22/50; 31/50; 29/50; male mice: 33/50; 34/50; 31/50; female mice: 40/50; 43/50; 32/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The incidences of preputial gland neoplasms in dosed male rats and of clitoral gland neoplasms in dosed female rats were significantly greater than those in controls (male--preputial gland adenomas, papillomas, or carcinomas, combined: control, 3/49; low dose, 19/49; high dose, 20/47; female--clitoral gland adenomas, papillomas, or carcinomas, combined: 5/46; 15/46; 16/47). A squamous cell carcinoma of the tongue was seen in two high dose male rats. The historical incidence of oral cavity neoplasms in untreated control male F344/N rats is 7/1,596 (0.4%). There were decreased incidences of leukemia (20/50; 9/50; 7/50) and mammary gland neoplasms (10/50; 7/50; 2/50) in dosed female rats and of pituitary gland neoplasms (11/49; 2/50; 2/50) in dosed male rats. Retinal degeneration and cataracts of the eye were observed at increased incidences in dosed rats (degeneration--male: 4/48; 41/48; 47/49; female: 2/47; 40/48; 46/50; cataracts--malee observed at increased incidences in dosed rats (degeneration--male: 4/48; 41/48; 47/49; female: 2/47; 40/48; 46/50; cataracts--male: 11/48; 23/48; 38/49; female: 0/47; 18/48; 14/50). The cause of these cataracts and retinal degeneration is uncertain because cages were not rotated and low and high dose groups of rats may have been exposed to greater light intensity than were the controls. Subcutanous tissue fibrosarcomas and fibromas or fibrosarcomas (combined) were increased in dosed male mice (fibromas or fibrosarcomas, combined: 5/50; 9/50; 14/50). There were no increased incidences of neoplasms in dosed female mice. Genetic Toxicology: Nalidixic acid was not mutagenic in any of several in vitro short-term tests. No gene reversion was observed in S. typhimurium strains TA97, TA98, TA100, or TA1535 after exposure to nalidixic acid in either the presence or absence of exogenous metabolic activation. Results of tests for induction of trifluorothymidine resistance in mouse L5178Y/TK lymphoma cells were negative with or without metabolic activation. In CHO cells, nalidixic acid did not induce sister chromatid exchanges or chromosomal aberrations in either the presence or absence of activation. Conclusions: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of nalidixic acid for F344/N rats, as indicated by increased incidences of preputial gland neoplasms in males and clitoral gland neoplasms in females. There was equivocal evidence of carcinogenic activity for male B6C3F1 mice fed diets containing nalidixic acid, as indicated by marginally increased incidences of subcutaneous tissue neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice fed diets containing 2,000 or 4,000 ppm nalidixic acid for 2 years. Synonym: 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid Trade Names: NegGram®.; Dixiben®.; Nalidixan®.; Nalurin®.; Nogram®.; UroNeg®.; Uralgin®.; Urisal®.


Specialized patterns of vascular differentiation antigens in the pregnant mouse uterus and the placenta.
The success of pregnancy depends on the ability of trophoblast cells to infiltrate the maternal decidua and breach uterine vessels. To ask whether the antigenic phenotype of maternal endothelial cells (EC) in the vascular zone and central decidua basalis may reflect a specialized programming of these vessels for interaction with the trophoblast, we did a survey of several mouse EC differentiation antigens, including MECA-32, MECA-99, and endoglin. Our results revealed striking differences in the phenotype of endothelial lining of vessels in the distinct compartments of the pregnant uterus during Day 9 of pregnancy and at midgestation. Vessels in the central decidua basalis and the vascular zone showed strong expression of MECA-99 but only weak expression of MECA-32, contrasting with the MECA-99(lo), MECA-32(hi) vessels in the capsularis. The vascular zone in addition stained brightly with anti-endoglin. Importantly, invading trophoblast as well as trophoblast cells lining maternal blood spaces were MECA-99(+), MECA-32(-), and endoglin(-), suggesting that the expression of MECA-99 may reflect a specialized co-programming of these trophoblast and EC for future interaction, but also that trophoblast cells may mimic selected antigenic characteristics of endothelium in association with their role in lining maternal blood spaces. In the term pregnant uterus the expression of all differentiation antigens decreased dramatically, suggesting that trophoblast cells as well as maternal EC lose their selected antigenic characteristics when the process of placentation is complete.


Supplying commercial biomedical companies from a human tissue bank in an NHS hospital--a view from personal experience.
NHS histopathology laboratories are well placed to develop banks of surgically removed surplus human tissues to meet the increasing demands of commercial biomedical companies. The ultimate aim could be national network of non-profit making NHS tissue banks conforming to national minimum ethical, legal, and quality standards which could be monitored by local research ethics committees. The Nuffield report on bioethics provides ethical and legal guidance but we believe that the patient should be fully informed and the consent given explicit. Setting up a tissue bank requires enthusiasm, hard work, and determination as well as coordination between professionals in the NHS trust and in the commercial sector. The rewards are exiting new collaborations with commercial biomedical companies which could help secure our future.


Involvement of HIF-1α in MLCK-dependent endothelial barrier dysfunction in hypoxia.
The mechanisms of endothelial barrier dysfunction induced by hypoxia are incompletely understood. Hypoxia-inducible factor-1 alpha (HIF-1α) is a key transcription factor partially responsible for hypoxia-related responses, but its role in regulation of hypoxia-induced endothelial barrier dysfunction is unclear. The aim of this study was to determine the molecular mechanism by which HIF-1α regulates endothelial barrier function during hypoxia. Endothelial cell monolayers exposed to normoxia or hypoxia were used for physiological, morphological, and biochemical analyses. The results showed that hypoxia disrupts endothelial barrier function by upregulating protein expression of myosin light chain (MLC) kinase (MLCK) and MLC phosphorylation. Hypoxia also induces HIF-1 activation by increasing HIF-1α expression, nuclear accumulation, DNA binding activity and target gene expression of HIF-1 in endothelial cells. Knockdown of HIF-1α attenuates endothelial barrier dysfunction and the increased MLCK protein expression induced by hypoxia. Inhibiting the transcription activity of HIF-1 by overexpressing factor inhibiting HIF-1(FIH) prevents the increased MLC phosphorylation and also attenuates endothelial barrier dysfunction in hypoxia. The results suggest that HIF-1α is involved in the MLCK-dependent endothelial barrier dysfunction induced by hypoxia.


Healthy older observers show equivalent perceptual-cognitive training benefits to young adults for multiple object tracking.
The capacity to process complex dynamic scenes is of critical importance in real life. For instance, traveling through a crowd while avoiding collisions and maintaining orientation and good motor control requires fluent and continuous perceptual-cognitive processing. It is well documented that effects of healthy aging can influence perceptual-cognitive processes (Faubert, 2002) and that the efficiency of such processes can improve with training even for older adults (Richards et al., 2006). Here we assess the capacity of older participants to improve their tracking speed thresholds in a dynamic, virtual reality environment. Results show that this capacity is significantly affected by healthy aging but that perceptual-cognitive training can significantly reduce age-related effects in older individuals, who show an identical learning function to younger healthy adults. Data support the notion that learning in healthy older persons is maintained for processing complex dynamic scenes.


Mental health recovery on care farms and day centres: a qualitative comparative study of users' perspectives.
Mental health services increasingly incorporate the vision of recovery. This qualitative study analysed and compared experiences of recovery on prevocational services, in order to assess if users make progress towards recovery, relative to a staged recovery model. Data were collected through semi-structured interviews with participants on care farms (n = 14), work (n = 7) and creative projects (n = 5). The transition from past to current lives was described as a progressive, non-linear process, with different stages guided by different goals. Participants on creative projects lacked clear goals, presented less interest in peers and high need for emotional support. Participants on work projects aimed for occupational rehabilitation, but struggled with the patient culture of the peer community. Participants on care farms aimed for daytime occupations and closer contact with society. They experienced care farms as open, real-life work settings where they could exercise responsibility and connect with people. Participants progressed towards recovery, as care farms, work- and creative projects empowered them to leave behind inactive, isolated or disorganized living. In day centres, users focused on self-reflection and personal development (creative projects) or on occupational performance (work projects), whereas on care farms, users fulfilled worker roles in a real-life, open community environment. Organized as open communities in real-life settings, care farms facilitate the reflection on personal and social responsibility, and therefore have the potential to help users internalize worker identities and improve their motivation to progress towards recovery. Supervisors on care farms are regarded by users as close contacts within the social networks they develop on the service, a position that allows supervisors to actively engage and promote users' progress towards recovery. Elements of the farm environment (such as the "normal life", presence of family members and visitors, and nature) can serve as anchors for supporting the progress towards recovery.


Detection of rotavirus in horses with and without diarrhea by electron microscopy and Rotazyme test.
A total of 142 equine fecal samples (93 field fecal and 49 experimental fecal specimens) were examined for rotavirus using direct electron microscopy (EM) and the Rotazyme test. Eighty-six stool specimens were diarrhea samples. The Rotazyme test sensitivity and accuracy as compared to EM was determined by the visual (color reaction) and spectrophotometric methods. The overall agreement was 94.8% and 92.3% between EM and Rotazyme visual and spectrophotometric methods, respectively when suspect reactions (1 + color reaction or net absorbance between 0.05 and 0.1) were not included. The Rotazyme test is a quick, simple, and accurate diagnostic test for detection of rotavirus in equine fecal samples. It could be used by the equine practitioner with a minimum of laboratory facilities and by diagnostic and research laboratories.


[A chamber for evaluating the free choice by laboratory rats and mice of a space containing tobacco smoke].
An original experimental setup has been designed that allows evaluation of the free preference of space containing tobacco smoke by small laboratory animals. For the laboratory mice (C57B1/6 and BALB/c) and rats (MNRA and MR) placed every day into this box, no emotional-stress reaction (ESR) caused by the environment novelty was observed on the 19th day of experiment. A difference in the free preference of space containing tobacco smoke was observed between inbred animals with active and passive ESR phenotypes.


12-lipoxygenase activity plays an important role in PAR4 and GPVI-mediated platelet reactivity.
Following initial platelet activation, arachidonic acid is metabolised by cyclooxygenase-1 and 12-lipoxygenase (12-LOX). While the role of 12-LOX in the platelet is not well defined, recent evidence suggests that it may be important for regulation of platelet activity and is agonist-specific in the manner in which it regulates platelet function. Using small molecule inhibitors selective for 12-LOX and 12-LOX-deficient mice, the role of 12-LOX in regulation of human platelet activation and thrombosis was investigated. Pharmacologically inhibiting 12-LOX resulted in attenuation of platelet aggregation, selective inhibition of dense versus alpha granule secretion, and inhibition of platelet adhesion under flow for PAR4 and collagen. Additionally, 12-LOX-deficient mice showed attenuated integrin activity to PAR4-AP and convulxin compared to wild-type mice. Finally, platelet activation by PARs was shown to be differentially dependent on COX-1 and 12-LOX with PAR1 relying on COX-1 oxidation of arachidonic acid while PAR4 being more dependent on 12-LOX for normal platelet function. These studies demonstrate an important role for 12-LOX in regulating platelet activation and thrombosis. Furthermore, the data presented here provide a basis for potentially targeting 12-LOX as a means to attenuate unwanted platelet activation and clot formation.


Superhydrophobic and Recyclable Cellulose-Fiber-Based Composites for High-Efficiency Passive Radiative Cooling.
Passive daytime radiative cooling (PDRC) involves cooling down an object by simultaneously reflecting sunlight and thermally radiating heat to the cold outer space through the Earth's atmospheric window. However, for practical applications, current PDRC materials are facing unprecedented challenges such as complicated and expensive fabrication approaches and performance degradation arising from surface contamination. Herein, we develop scalable cellulose-fiber-based composites with excellent self-cleaning and self-cooling capabilities, through air-spraying ethanolic poly(tetrafluoroethylene) (PTFE) microparticle suspensions embedded partially within the microsized pores of the cellulose fiber to form a dual-layered structure with PTFE particles atop the paper. The formed superhydrophobic PTFE coating not only protects the cellulose-fiber-based paper from water wetting and dust contamination for real-life applications but also reinforces its solar reflectivity by sunlight backscattering. It results in a subambient cooling performance of 5 °C under a solar irradiance of 834 W/m2 and a radiative cooling power of 104 W/m2 under a solar intensity of 671 W/m2. The self-cleaning surface of composites maintains their good cooling performance for outdoor applications, and the recyclability of the composites extends their life span after one life cycle. Additionally, dyed cellulose-fiber-based paper can absorb appropriate visible wavelengths to display specific colors and effectively reflect near-infrared lights to reduce solar heating, which synchronously achieves effective radiative cooling and esthetic varieties.


CO(2) response element and corresponding trans-acting factor of the promoter for ribulose-1,5-bisphosphate carboxylase/oxygenase genes in Synechococcus sp. PCC7002 found by an improved electrophoretic mobility shift assay.
We analyzed the promoter of the genes encoding the ribulose-1,5-bisphosphate carboxylase/oxygenase (rbc) in the cyanobacterium Synechococcus sp. PCC7002 and localized the CO(2)-regulatory element. Cyanobacterial transformants were constructed with several DNA segments of the rbc promoter fused to the chloramphenicol acetyltransferase (CAT) gene, and their acetyltransferase activities were analyzed under 0.03% and 1% CO(2) conditions. We found that the AT-rich element localized from -262 to -291 relative to the rbc translation-starting site was required for CO(2)-dependent repression. Fluorescent-labeled oligonucleotide probes of identical sequence to the AT-rich element were reacted with protein extracts from cells cultured under conditions of low and high CO(2) atmospheric content. We detected a gel retardation complex of a strong signal intensity in extracts from cells cultured under 15% CO(2), but only a weak signal from cells cultured under 1% CO(2). Moreover, a DNA affinity precipitation assay identified a 16-kDa protein that bound to nucleotide sequences within the AT-rich element. The partial amino acid sequence of the protein was similar to the deduced protein sequences of ORF129 and ORF155 from Synechocystis 6803. Our findings suggest that the AT-rich element plays a role as a negative CO(2)-regulatory element and its trans-acting factor possibly regulates the rbc transcription in response to CO(2) levels.


[Atherogenic lipoprotein remnants in humans].
Remnant lipoproteins (RLPs) are the lipolytic product of triglycerides transported by very low density lipoproteins (VLDL) of hepatic and intestinal origin and intestinal chylomicrons. Lipoprotein lipase activity hydrolyse triglycerides in several steps, producing heterogeneous particles. Fasting plasma concentration in normolipidemic subjects is low, but it increases in post-prandial states. Genetic alterations in Apo-E subtypes increases RLPs plasma concentration and produce dyslipoproteinemia phenotype. RLPs atherogenicity depends on their role as endothelial injuring factors, their impaired recognition by lipoprotein receptors, and their susceptibility to oxidative stress. They also promote the circulation of molecular adhesion molecules, the internalization in subendothelial macrophages via scavenger receptors and the accumulation in foam cells, all of them early mechanisms of atheromatosis. RLPs metabolism has been a subject of controversial studies. Their origin from different lipoproteins may explain their structural heterogeneity, therefore increasing the methodological difficulties to include RLPs in the atherogenic lipoprotein profile in the epidemiological studies of the field. Last advances on metabolism of RLPs and their emergent clinical role justifies an up dated revision of RLPs.


A novel mutation, of the Bacillus subtilis hut operon that relieves both catabolite repression and amino acid repression.
A mutation, designated hutCR11, which resulted in high expression of the hut operon and release of the catabolite repression and amino-acid repression of hut expression, was isolated and determined to be a T-to-G transversion at position +30 (+1 indicates the transcription-initiation site). In the hutCR11 mutant, levels of hutP mRNA were 5-fold higher than those in wild-type cells under conditions of non-induction and induction and 11-fold higher under conditions of catabolite repression and amino-acid repression. Mutation analysis showed that two types of base change (T-->A and T-->C) at position +30 did not cause high expression of the hut operon, indicating that this was specifically caused by the single base substitution (T-->G) at position +30. The base substitution of A for T at position +30 also led to partial relief of both catabolite repression and amino-acid repression. These results indicate that the nucleotide sequence at +30 is important for regulation of both catabolite repression and amino-acid repression of the hut operon.


The murine SP-C promoter directs type II cell-specific expression in transgenic mice.
Genomic DNA from the mouse pulmonary surfactant protein C (SP-C) gene was analyzed in transgenic mice to identify DNA essential for alveolar type II cell-specific expression. SP-C promoter constructs extending either 13 or 4.8 kb upstream of the transcription start site directed lung-specific expression of the bacterial chloramphenicol acetyl transferase (CAT) reporter gene. In situ hybridization analysis demonstrated alveolar cell-specific expression in the lungs of adult transgenic mice, and the pattern of 4.8 SP-C-CAT expression during development paralleled that of the endogenous SP-C gene. With the use of deletion constructs, lung-specific, low-level CAT activity was detected in tissue assays of SP-C-CAT transgenic mice retaining 318 bp of the promoter. In transient and stable cell transfection experiments, the 4.8-kb SP-C promoter was 90-fold more active as a stably integrated gene. These findings indicate that 1) the 4.8-kb SP-C promoter is sufficient to direct cell-specific and developmental expression, 2) an enhancer essential for lung-specific expression maps to the proximal 318-bp promoter, and 3) the activity of the 4.8-kb SP-C promoter construct is highly dependent on its chromatin environment.


Single-cell transcriptome profiling of the Ciona larval brain.
The tadpole-type larva of Ciona has emerged as an intriguing model system for the study of neurodevelopment. The Ciona intestinalis connectome has been recently mapped, revealing the smallest central nervous system (CNS) known in any chordate, with only 177 neurons. This minimal CNS is highly reminiscent of larger CNS of vertebrates, sharing many conserved developmental processes, anatomical compartments, neuron subtypes, and even specific neural circuits. Thus, the Ciona tadpole offers a unique opportunity to understand the development and wiring of a chordate CNS at single-cell resolution. Here we report the use of single-cell RNAseq to profile the transcriptomes of single cells isolated by fluorescence-activated cell sorting (FACS) from the whole brain of Ciona robusta (formerly intestinalis Type A) larvae. We have also compared these profiles to bulk RNAseq data from specific subsets of brain cells isolated by FACS using cell type-specific reporter plasmid expression. Taken together, these datasets have begun to reveal the compartment- and cell-specific gene expression patterns that define the organization of the Ciona larval brain.


Origin and diversification of Hibiscus glaber, species endemic to the oceanic Bonin Islands, revealed by chloroplast DNA polymorphism.
Abstract Two woody Hibiscus species co-occur in the Bonin Islands of the northwestern Pacific Ocean: Hibiscus glaber Matsum. is endemic to the islands, and its putative ancestral species, Hibiscus tiliaceus L., is widely distributed in coastal areas of the tropics and subtropics. To infer isolating mechanisms that led to speciation of H. glaber and the processes that resulted in co-occurrence of the two closely related species on the Bonin Islands, we conducted molecular phylogenetic analyses on chloroplast DNA (cpDNA) sequences. Materials collected from a wide area of the Pacific and Indian Oceans were used, and two closely related species, Hibiscus hamabo Siebold Zucc. and Hibiscus macrophyllus Roxb., were also included in the analyses. The constructed tree suggested that H. glaber has been derived from H. tiliaceus, and that most of the modern Bonin populations of H. tiliaceus did not share most recent ancestry with H. glaber. Geographic isolation appears to be the most important mechanism in the speciation of H. glaber. The co-occurrence of the two species can be attributed to multiple migrations of different lineages into the islands. While a wide and overlapping geographical distribution of haplotypes was found in H. tiliaceus, localized geographical distribution of haplotypes was detected in H. glaber. It is hypothesized that a shift to inland habitats may have affected the mode of seed dispersal from ocean currents to gravity and hence resulted in geographical structuring of H. glaber haplotypes.


Acute alcohol intoxication-induced microvascular leakage.
Alcohol intoxication can increase inflammation and worsen injury, yet the mechanisms involved are not clear. We investigated whether acute alcohol intoxication increases microvascular permeability and investigated potential signaling mechanisms in endothelial cells that may be involved. Conscious rats received a 2.5 g/kg alcohol bolus via gastric catheters to produce acute intoxication. Microvascular leakage of intravenously administered fluorescein isothiocyanate (FITC)-conjugated albumin (FITC-albumin) from the mesenteric microcirculation was assessed by intravital microscopy. Endothelial-specific mechanisms were studied using cultured endothelial cell monolayers. Transendothelial electrical resistance (TER) served as an index of barrier function, before and after treatment with alcohol or its metabolite acetaldehyde. Pharmacologic agents were used to test the roles of alcohol metabolism, oxidative stress, p38 mitogen-activated protein kinase (MAPK), myosin light-chain kinase (MLCK), rho kinase (ROCK), and exchange protein activated by cAMP (Epac). VE-cadherin localization was investigated to assess junctional integrity. Rac1 and RhoA activation was assessed by ELISA assays. Alcohol significantly increased FITC-albumin extravasation from the mesenteric microcirculation. Alcohol also significantly decreased TER and disrupted VE-cadherin organization at junctions. Acetaldehyde significantly decreased TER, but inhibition of alcohol dehydrogenase or application of a superoxide dismutase mimetic failed to prevent alcohol-induced decreases in TER. Inhibition of p38 MAPK, but not MLCK or ROCK, significantly attenuated the alcohol-induced barrier dysfunction. Alcohol rapidly decreased GTP-bound Rac1 but not RhoA during the drop in TER. Activation of Epac increased TER, but did not prevent alcohol from decreasing TER. However, activation of Epac after initiation of alcohol-induced barrier dysfunction quickly resolved TER to baseline levels. Our results suggest that alcohol intoxication increases microvascular permeability to plasma proteins. The data also suggest the endothelial-specific mechanism involves the p38 MAPK, Rac1, and reorganization of VE-cadherin at junctions. Last, activation of Epac can quickly resolve alcohol-induced endothelial barrier dysfunction.


Origin of Strong Hydrogen Bonding and Preferred Orientation of Water at Uncharged Polyethylene Glycol Polymer/Water Interface.
Polyethylene glycol (PEG), a water-soluble non-ionic polymer, finds diverse applications from Li-ion batteries to drug delivery. The effectiveness of PEG in these contexts hinges on water's behavior at PEG/water interfaces. Employing heterodyne-detected vibrational sum frequency generation and Raman spectroscopy along with a novel analytical approach, termed difference spectroscopy with simultaneous curve-fitting analysis, we observed that water exhibits both "hydrogen-up" and "hydrogen-down" orientations at PEG(≥400u)/water interfaces. As the molar mass of PEG increases, the contribution of the strongly hydrogen-bonded and H-up-oriented water rises. We propose that the PEG-affected interfacial water originates from the asymmetrical hydration of the surface-adsorbed PEG, as evidenced by the resemblance between the water spectra in the hydration shell of PEG and those at the PEG/water interface. These findings elucidate the molecular mechanism underlying PEG's catalytic role in water splitting at membrane interfaces.


Influence of orientation on the evolution of small perturbations in compressible shear layers with inflection points.
We investigate the influence of orientation on the evolution of small perturbations in compressible shear layers with inflection points. By using linear analysis, we demonstrate that perturbations along the shear plane are most affected by compressibility. The influence of compressibility gradually diminishes with increasing obliqueness of the perturbations with respect to the shear plane. It is demonstrated that the effective gradient Mach number is an appropriate compressibility parameter. We establish that spanwise perturbations, orthogonal to the shear plane, are impervious to compressibility effects. Direct numerical simulations of compressible mixing layers subject to the perturbations at various obliqueness angles verify the analytical findings.


Neuroanatomy of complex social emotion dysregulation in adolescent offenders.
Social emotions require the correct integration of emotional, cognitive, and social processes and are critical for complex social interactions. Adolescent criminal offenders (AOs) show abnormalities in the experience of basic emotions. However, most research has focused solely on basic emotions, neglecting complex social emotions that could be critical for social reintegration. The purpose of this study was to investigate the behavioral and neural correlates of social emotions (envy and Schadenfreude) in AOs. We explored the experience of complex social emotions, as well as their anatomical correlates, in AOs (n = 19) and a nonoffenders control group (NOs, n = 20). Additionally, we assessed the relationship between social emotions, executive functions (EFs), and fluid intelligence (FI). Structural brain imaging was obtained in all participants. The results showed that AOs had significantly lower envy and Schadenfreude ratings and exhibited lower performance in EFs compared with NOs. The measurement of EFs relied on the INECO frontal screening (IFS). Experiencing fewer social emotions was associated with diminished EFs but not with FI. Moreover, in AOs, reduced levels of envy and Schadenfreude were linked with reduced gray matter volumes in regions subserving mentalizing abilities (inferior parietal lobe and precuneus) and socioemotional processing (inferior and middle temporal regions), as well as key hubs of the executive frontoparietal network (inferior parietal lobule, orbital and rectus gyri). Additional analysis on the AOs revealed no associations between the type of crime and our variables of interest (EFs, FI and social emotions). Our findings are the first to provide evidence on abnormalities in the experience of social emotions in AOs that are associated with neurocognitive markers of social cognition and EFs. Understanding social emotions and their abnormalities (under-experience) as complex intertwined processes may have important future translational implications, including risk prediction for social adaptation/reintegration, sociocognitive targeted interventions, and skill training for social emotions in vulnerable populations.


Modelling diffuse nutrient flow in eutrophication control scenarios.
The Swedish Water Management Research Programme (VASTRA) focuses on the development and demonstration of tools for more efficient eutrophication control when implementing the EU water framework directive in Sweden. During the first half of the programme, models for nitrogen flow were developed, and at present, similar models for phosphorus are under construction (e.g. HBV-P). The programme is interdisciplinary, and scientists are collaborating in actor-games and focus group evaluations including scenario analysis. The scenarios modelled in VASTRA phase I, show that (i) changed agricultural practices can be the most effective and least expensive way to reduce nitrogen transport from land to the sea; (ii) constructed agricultural wetlands may only have small impact on riverine nitrogen transport in some regions, due to natural hydrometeorological dynamics; (iii) removing planktivorous fish may be an efficient way of reducing the algal concentrations in lakes without the undesired side-effect of increased nutrient load to the down-stream river system. In VASTRA phase II, one of the highlights will be interdisciplinary scenario-modelling of different measure strategies in a pilot catchment of southern Sweden (Rönne å).


Two-year outcome of intravitreal injections of ranibizumab for myopic choroidal neovascularization.
To evaluate the 2-year outcome, efficacy, and safety of intravitreal ranibizumab injections for myopic choroidal neovascularization (CNV). We retrospectively reviewed the medical records of 28 consecutive eyes that received intravitreal injections of ranibizumab for myopic CNV with a 24-month follow-up. Retreatment was performed as needed in eyes with persistent or recurrent CNV. Patient demographic data, best-corrected visual acuity (BCVA), CNV findings on fluorescent angiography, central macular thickness on optical coherence tomography, total number of treatments, and complications were recorded. Mean baseline BCVA was 0.53±0.32 logMAR [Snellen equivalent (SE), 6/20], and improved significantly to 0.28±0.32 logMAR (SE, 6/11) at 1 year and 0.29±0.28 logMAR (SE, 6/12) at 2 years (both P<0.01, Wilcoxon signed-rank test). The average number of total injections over 2 years was 3.32 (SD 2.13). A mean of 2.82 injections were performed in the first year, and 0.50 in the second year. Twenty-three eyes (82.1%) had no need for treatment during the second year of follow-up. Mean improvement from the baseline was 2.57 Snellen lines (SD 2.35) at 1 year, and 2.29 lines (SD 2.69) at 2 years. At 2 years, 11 eyes (39.3%) showed a gain of at least 3 lines after treatment. No complications were noted after treatment. Intravitreal ranibizumab injection was safe and effective in treating myopic CNV, with visual improvement maintained over 2 years.


Analysis of Serum Interleukin (IL)-1β and IL-18 in Systemic Lupus Erythematosus.
Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by biological and clinical heterogeneity. The interleukin (IL)-1 superfamily is a group of innate cytokines that contribute to pathogenesis in many autoimmune diseases. IL-1β and IL-18 are two members that have been shown to play a role in murine lupus-like models, but their role in human SLE remains poorly understood. Here, IL-1β and IL-18 were quantified by enzyme-linked immunosorbent assay in the serum of healthy controls (HCs) and SLE patients from a prospectively followed cohort. Disease activity and organ damage were assessed using SLE disease activity index 2000 (SLEDAI-2K) and SLE damage index scores (SDI), respectively. 184 SLE patients (mean age 44.9 years, 91% female, 56% double-stranded deoxyribonucleic acid positive) were compared to 52 HC. SLE patients had median [IQR] SLEDAI-2K of 4 [2,6], and SDI of 1 [0-2]. Serum IL-18 levels were statistically significantly higher in SLE patients compared to HCs. Univariable linear regression analyses showed that patients with active renal disease or irreversible organ damage had statistically significantly elevated serum IL-18 levels. The association between serum IL-18 and active renal disease was confirmed in multivariable analysis after adjusting for ethnicity and organ damage. High baseline serum IL-18 levels were associated with organ damage at the subsequent visit. Serum IL-1β levels were not significantly elevated in SLE patients when compared to HCs and had no association with overall or organ-specific disease activity or organ damage in cross-sectional and longitudinal analyses. Our data suggest that serum IL-18 and IL-1β have different clinical implications in SLE, with IL-18 being potentially associated with active renal disease.


A pilot study combining individual-based smoking cessation counseling, pharmacotherapy, and dental hygiene intervention.
Dentists are in a unique position to advise smokers to quit by providing effective counseling on the various aspects of tobacco-induced diseases. The present study assessed the feasibility and acceptability of integrating dentists in a medical smoking cessation intervention. Smokers willing to quit underwent an 8-week smoking cessation intervention combining individual-based counseling and nicotine replacement therapy and/or bupropion, provided by a general internist. In addition, a dentist performed a dental exam, followed by an oral hygiene treatment and gave information about chronic effects of smoking on oral health. Outcomes were acceptability, global satisfaction of the dentist's intervention, and smoking abstinence at 6-month. 39 adult smokers were included, and 27 (69%) completed the study. Global acceptability of the dental intervention was very high (94% yes, 6% mostly yes). Annoyances at the dental exam were described as acceptable by participants (61% yes, 23% mostly yes, 6%, mostly no, 10% no). Participants provided very positive qualitative comments about the dentist counseling, the oral exam, and the resulting motivational effect, emphasizing the feeling of oral cleanliness and health that encouraged smoking abstinence. At the end of the intervention (week 8), 17 (44%) participants reported smoking abstinence. After 6 months, 6 (15%, 95% CI 3.5 to 27.2) reported a confirmed continuous smoking abstinence. We explored a new multi-disciplinary approach to smoking cessation, which included medical and dental interventions. Despite the small sample size and non-controlled study design, the observed rate was similar to that found in standard medical care. In terms of acceptability and feasibility, our results support further investigations in this field. ISRCTN67470159.


Head injuries in Leeds: changes in epidemiology and survival over 12 years.
To map the pattern of survival and epidemiology of patients admitted to accident and emergency, at a regional neurosciences unit with an isolated head injury, over a 12 year period. The TARN database of a regional neuroscience referral centre was analysed to identify patients who where admitted after a significant, isolated head injury between January 1990 and December 2001. Demographic data about the patient and nature and cause of the injury were extracted and survival was mapped over the time period. Statistical analysis was performed to identify change in survival. There were 810 eligible patients. The most common cause of injury was road traffic accident (47%) with an average of 42.6% patients transferred from other hospitals. The most common disposal of patients was to an intensive care unit (35%). There was an overall increase in the number of patients but survival did not increase over the time period. Mean survival was 81.8% and overall survival decreased from 95.0% in 1990 to 81.6% in 2001, although this did not represent significant change (p = 0.990). Short term survival after significant head injury has not changed significantly over the 12 year period studied. No subset of patients is having a disproportionate effect on survival but in patients aged over 75, survival increased significantly. Further multicentre work is indicated to map a more accurate clinical picture of head injury survival.


Model of spontaneous obesity in aging male Wistar rats.
We analyzed retrospectively data from 148 chow-fed male Wistar rats killed between the age of 6 wk and 2 yr while varying in body weight from 136 to 917 g. The purpose of this study was to clarify the relationship of body weight and body lipid content with the composition and cellularity of the epididymal and retroperitoneal fat depots. A positive linear association was found between body weight and body water or fat-free dry residue, whereas total body lipid exhibited a curvilinear relationship with body weight. The weight of the epididymal pads was linearly related to body weight but not to body lipid. In contrast, retroperitoneal pad weight was exponentially related to body weight and paralleled total body lipid. A strong linear correlation was found between total body lipid and weight (r = 0.959) or depot lipid content (r = 0.967) of the retroperitoneal fat pads. In this rat model of aging and spontaneous obesity, significant regional differences exist in adipose depot composition and cellularity. A practical outcome of this study is a simple and accurate prediction of body lipid content from the gravimetric determination of the retroperitoneal fat depots.


A comparison between older persons with down syndrome and a control group: clinical characteristics, functional status and sensorimotor function.
The increase in life expectancy within the general population has resulted in an increasing number of elderly adults with intellectual disability, and this is reflected in the increased life expectancy in persons with Down syndrome, currently about 56 years. The aim of this study was to study the clinical characteristics, the functional status and sensori-motor function of 10 older persons with Down syndrome (mean age 59 years), 13 younger persons with Down syndrome (mean age 44 years) and compare them with 38 adults with intellectual disability without Down syndrome and a control group of people without intellectual disability. All the persons with Down syndrome and intellectual disability resided in two residential living centres in Israel, while the 31 older persons without intellectual disability (mean age 75 years), who served as the control group, lived in an independent living facility. The study considered demographic data, medical backgrounds, physical and functional tests. The results showed that the older persons with Down syndrome in the study were more obese, shorter and had more medical problems than both the older persons with intellectual disability and the control group. The functional performance of the older adults with Down syndrome was more impaired in comparison with both other groups. It is postulated that their slower responses may be explained by a less physically active lifestyle, that may accelerate the onset of disease, resulting in symptoms associated with aging that are detrimental to health.


Optimizing pediatric histrelin implantation to improve success rates in clinic without sedation.
The purpose of this study was to review our success rate performing the histrelin implant procedure in clinic without sedation. A retrospective study was performed for histrelin implant procedures done at our institution from 2008 to 2020. Wilcoxon rank-sum test or Fisher's exact test was utilized to identify significant differences (p<0.05). A total of 73 patients underwent 184 histrelin implant procedures from 2008 to 2020. In the past few years, there has been a decrease in procedures for precocious puberty and an increase for gender dysphoria. The majority of procedures were performed in clinic without sedation (82%). The only risk factor associated with requiring sedation was younger age (median 9 vs. 10 years; p<0.003). Complications (i.e. implant fracture or need for counter-incision) were noted in 10 of the procedures (5%). The only risk factor identified for a procedural complication during implant removal/replacement was interval time from insertion (21 vs. 13 months; p<0.01). The only documented wound problem reported was dermatitis in 1 patient (no suture granuloma, dehiscence, or implant extravasation). Procedural refinements and distraction therapy have enabled us to perform the majority of procedures in clinic without sedation. In our experience, procedural difficulty and complications appear to increase with prolonged implant duration. Histrelin implantation is increasingly being performed for gender dysphoria.


Utility of the Movement Disorders Society Criteria for Progressive Supranuclear Palsy in Clinical Practice.
When the 2017 Movement Disorders Society Criteria for progressive supranuclear palsy is applied, patients may appear to have multiple phenotypes. The maximum allocation extinction rules were developed to provide a consistent method for applying the criteria and reaching a single diagnostic label. In this study, we apply both to a neuropathologic cohort of progressive supranuclear palsy and other parkinsonian conditions. An autopsy cohort of 54 patients with progressive supranuclear palsy and 56 patients with other neuropathologic diseases was selected. Clinical data were retrospectively abstracted, and the diagnostic criteria for progressive supranuclear palsy were applied. All possible phenotypes applicable were listed and maximum allocation extinction rules were applied to assess reduction in the number of phenotypes ascribed per patient. In the progressive supranuclear palsy group, 52 patients met the criteria for multiple phenotypes, with an average of 7 phenotypes per patient. In the nonprogressive supranuclear palsy group, all 56 patients had features of more than one phenotype, up to 3 per patient. After application of maximum allocation extinction rules, the majority of the patients in both groups had a single predominant phenotype. Freezing of gait, supranuclear gaze palsy, and frontal behavioral syndrome were more common in the progressive supranuclear palsy group. The diagnostic criteria for progressive supranuclear palsy identify many clinical features, thereby leading to assignment of multiple phenotypes per patient. We demonstrate that the maximum allocation extinction rules can effectively lead to a single consensus phenotype, maintaining a uniform diagnostic label for clinical and research applications.


Metastatic Prostate Adenocarcinoma Masquerading as Invasive Fungal Sinusitis.
A 58 year old male with a history of prostate adenocarcinoma presented with diplopia, severe headaches, and eye pain, consistent with sinusitis. Imaging was concerning for invasive fungal sinusitis (IFS) and an urgent ENT consultation was requested. Endoscopic sinus surgery was performed revealing metastatic prostate adenocarcinoma to the sinuses and anterior cranial fossa. The distinctive imaging features in this case are very useful when considering the divergent management options of IFS and metastatic sinus disease. These entities are likely to be encountered more frequently as immunomodulating therapies expand and prostate cancer continues to be a leading cause of death in males.


Epilepsy and non-organic non-affective psychosis. National epidemiologic study.
This study tests the hypothesis that epilepsy increases the risk of developing schizophrenia and other non-affective functional psychoses using a nationwide sample of people with epilepsy. A record linkage study between a sample from the National Patient Register, consisting of 67,116 people with epilepsy, and the Danish Psychiatric Register identified all people with non-affective psychoses with onset after the first epilepsy diagnosis. The relation between risk of psychiatric disorder in people with epilepsy and the general Danish population was estimated. The incidences of the spectrum of non-organic non-affective psychosis, non-affective psychosis and schizophrenia were significantly increased both for men and women, even after exclusion of people diagnosed as suffering from a learning disability or substance misuse. This study supports the notion of an association between epilepsy and the risk of subsequent non-affective psychosis.


Evaluating alternatives to dual-energy x-ray absorptiometry for assessing bone quality in patients undergoing spine surgery.
The purpose of this study was to compare and contrast lumbar bone quality and osteoporosis/osteopenia screening results via dual-energy x-ray absorptiometry (DEXA), CT, and MRI. A consecutive series of 426 candidates screened for lumbar disc replacement over a 5-year period beginning in 2018 was reviewed. Patients with a preoperative lumbar spine DEXA scan and a CT and/or MRI scan were included. The primary outcome measures included the bone mineral density (BMD) and osteoporosis or osteopenia classification from DEXA scans, Hounsfield units (HUs) for CT, and vertebral bone quality (VBQ) assessment for MRI. Patients were included if they had a DEXA scan within 1 year of an MRI or CT scan. DEXA BMD scores from composite or level-by-level reports were recorded. Asynchronous MRI and CT measurements were conducted using PACS. Interrater and intrarater reliability scores were generated for both CT and MRI measurements and ranged from 1.000 for MRI L1-4 scans to 0.683 for MRI VBQ. All 3 types of scans were statistically significantly correlated with one another; however, CT was more strongly correlated with the lumbar DEXA value (r = 0.439, p < 0.001). The correlation between MRI VBQ and DEXA was -0.103, (p < 0.045). The CT level-by-level measurements correlate with the corresponding level-by-level DEXA BMD values (correlation ranging from 0.531 to 0.289, p < 0.001 to p = 0.007). CT HU values were more strongly related to osteoporosis/osteopenia classification based on DEXA T-scores than were MRI VBQ values. Receiver operating characteristic analyses found that the area under the curve was 0.817 for CT and 0.539 for MRI. These results demonstrate that CT HUs more closely correlate to DEXA scores than MRI VBQ in this population of patients undergoing surgery for symptomatic disc degeneration. Thus, CT may be an alternative to DEXA for assessing VBQ in this population.


Critical analysis of reduction mammaplasty techniques in combination with conservative breast surgery for early breast cancer treatment.
Although reduction mammaplasty is a well-described technique for aesthetic purposes, there are few previous reports regarding its application and clinical outcome following conservative breast surgery reconstruction. The purpose of this study was to analyze the feasibility of the technique and its outcome following conservative breast surgery. Oncologic data and information on age, body mass index, smoking history, and comorbid conditions were collected. Reconstructed and opposite breast complications were evaluated. Reduction mammaplasty was indicated to reconstruct moderate breast defects in patients with enough remaining breast tissue. Mean follow-up was 22 months. Seventy-four patients underwent immediate reduction mammaplasty following breast-conserving surgery. In 55.4 percent of patients, tumors measured 2 cm or less (T1) and in 47.2 percent they were located in the upper outer quadrants. Breast complications occurred in 13 patients (17.6 percent), with skin necrosis in six (8.1 percent), infection in two (2.7 percent), partial areola necrosis in two (2.7 percent), dehiscence in two, and total areola necrosis in one (1.35 percent). Late complications represented by skin lesions and fat necrosis were observed in five patients (6.8 percent). Obese patients and smokers had a significantly higher rate of reconstructed breast complications compared with the normal/overweight patients (p = 0.002) and nonsmokers (p = 0.043). No significant association between complications and age, hypertension, diabetes, axillary lymph node dissection, or chemotherapy was found. Reduction mammaplasty is a consistent technique for reconstruction following breast-conserving surgery. Complications are more often observed in the reconstructed breast, and obese patients and smokers are higher risk patients.