Li-Fraumeni Syndrome-related Malignancies Involving the Genitourinary Tract: Review of a Single-institution Experience.
To report a case of pelvic angiosarcoma in a 27-year-old man with Li-Fraumeni Syndrome (LFS) and evaluate the presentation and timeline of genitourinary (GU) tract involvement in LFS patients. We retrospectively identified 39 LFS patients treated at our institution between 2000 and 2014; 7 (18%) had experienced a GU malignancy or an LFS-related malignancy involving the GU tract. Clinical characteristics, including dates of onset of first GU tract malignancies; pathologic findings; multimodal management; and familial history of LFS were reviewed. Median age at first malignancy was 14.0 years (interquartile range [IQR] 5.5-24.0). There was a slight male predominance (4 of 7). Median time between first malignancy and the malignancy involving the GU tract was 10.1 years (IQR 8.0-19.5). Six of the 7 patients (86%) had a form of sarcoma involving the GU tract; 1 developed adrenocortical carcinoma. The cancer pedigree of all patients showed LFS-associated malignancies in family members. Multimodal management included surgical resection in 6 patients with adjuvant chemotherapy or radiotherapy in 1 patient each. One patient received chemotherapy only. Following diagnosis of malignancy involving the GU tract, 5 of the 7 patients developed additional primary malignancies. At a median follow-up of 4.7 years (IQR 3.0-12.1), 2 patients are alive, 3 died of disease, and 1 died of unknown cause. One patient was lost at follow-up. Continued follow-up of LFS cancer patients aimed at the determination of optimal screening, management, and surveillance protocols is recommended and may result in longer survival expectations.


Evaluation of the Utility of Vial Packaging to Reduce Occupational Exposure to Antineoplastic Drugs in Preventing Breakages and Scattering.
The dropping of glass vials because of negligence or accidental events that occur during the preparation or mixing of injectable drugs are examples of instances of occupational exposures occurring in a clinical setting. To reduce such risks, several types of glass vial packaging have been developed. We herein compared the resistance of base- and cup-type packaged vials to breakage and scattering of contents during falls with control vials. The falling heights at which the test products were dropped were set to 70, 135, and 180 cm. Compared with results in the control group, appearance changes were inhibited in the cup-type group. Significant differences were found between the cup-type and control groups at heights of 135 and 180 cm. Next, the resistance of the packaging to spilling and scattering of the solution from the vial was determined. There was no scattering in any types of vials at a height of 70 cm because they were not broken. However, at heights of 135 and 180 cm, the mean scattering distances in the control group were 50 and 70.6 cm, respectively. At these heights, some vials in the base-type and cup-type groups were also cracked, but the solution stayed completely inside the covering packaging, indicating an obvious antiscattering ability. Vials packed in cup- and base-type packaging would lower the risk of the exposure to hazardous drugs during vial breakages. Because the base-type packaging did not show significant antibreakage effects, the cup-type packaging is more suited for hazardous drug packaging. However, cup-type packaging requires equipment investments from pharmaceutical manufacturers. Thus, the cost-effectiveness and the target drug profile should be evaluated, and the use of cup- and base-type packaging as well as control forms should be selected accordingly.


Mechanisms of modal activation of GluA3 receptors.
AMPA receptors are the major excitatory neurotransmitter receptors in the central nervous system and are involved in numerous neurological disorders. An agonist-binding site is present in each of four subunits that form a functional channel. Binding consists of three steps: docking of agonist to the bilobed ligand binding domain (LBD), closure of the LBD, and increased stability of the closed-lobe conformation through interlobe hydrogen bonding. We describe GluA3 single channel currents activated by nitrowillardiine (NO(2)W) and chlorowillardiine (ClW) in the presence of cyclothiazide, in conjunction with crystal structures of GluA2 and GluA3 LBDs bound to fluorowillardiine (FW), ClW, and NO(2)W. When bound to NO(2)W or ClW, the GluA3 channel opens to three conductance levels with comparable open probabilities and displays modal behavior similar to that obtained with glutamate and FW as agonists (Poon et al., 2010). At lower concentrations, ClW evoked an alternate kinetic behavior, consisting of high open probability in lower conductance states. The structure of ClW bound to GluA3 LBD exhibits a unique partially open hydrogen bonding structure that may be associated with these alternative kinetics. NO(2)W evoked longer open times than seen for other agonists in high and very high modes. The structure ofGluA2 LBD bound to NO(2)W exhibits fully closed lobes with additional interlobe interactions mediated by the nitro group. Beyond differences in efficacy between full and partial agonists, the complexities of the single channel behavior of AMPA receptors may also be associated with small interactions that modify the stability of various degrees of closure.


Uterine leiomyosarcoma with myxoid stroma.
Myxoid leiomyosarcomas present a diagnostic problem. They are said to have low mitotic counts and are considered to be exceptions to the general rule that uterine smooth-muscle tumors with a mitotic rate of less than five per ten high-power fields rarely recur. We present two cases of myxoid leiomyosarcoma, both of which show high mitotic counts. In addition, one of the cases presented initially as a typical leiomyosarcoma, but contained abundant myxoid stroma in the metastases. The role of the myxoid stroma in influencing prognosis in leiomyosarcomas is, as yet, uncertain.


Simulated annealing approach to vascular structure with application to the coronary arteries.
Do the complex processes of angiogenesis during organism development ultimately lead to a near optimal coronary vasculature in the organs of adult mammals? We examine this hypothesis using a powerful and universal method, built on physical and physiological principles, for the determination of globally energetically optimal arterial trees. The method is based on simulated annealing, and can be used to examine arteries in hollow organs with arbitrary tissue geometries. We demonstrate that the approach can generate in silico vasculatures which closely match porcine anatomical data for the coronary arteries on all length scales, and that the optimized arterial trees improve systematically as computational time increases. The method presented here is general, and could in principle be used to examine the arteries of other organs. Potential applications include improvement of medical imaging analysis and the design of vascular trees for artificial organs.


Hydrodynamic cavitation-enhanced activation of sodium percarbonate for estrogen removal.
The present paper investigated the potential of hydrodynamic cavitation (HC) as an effective tool for activating sodium percarbonate (SPC). The method's efficiency was demonstrated by effectively removing estrogens, which are pollutants that have adverse impacts on aquatic ecosystems. The effects of the SPC concentration, temperature of solution, and cavitation time were evaluated. After SPC/HC treatment, the removal of estrogens was monitored by liquid chromatography-tandem mass spectrometry (LC -MS/MS). Already after 4 s of treatment and 24 h of reaction time, more than 97% of estrogens (initial concentration of 300 ng/L) were removed. The effect of post-treatment time is not considered in several papers, even though it seems to be crucial and is discussed here. The results were supported by the values of degradation rate constants, which fit the pseudo-first-order kinetic model. We also verified that HC alone was not effective for estrogen removal under the selected conditions. The sustainability of the SPC/HC system was evaluated based on electric energy per order calculation. The combination of SPC and HC is a promising approach for rapidly degrading micropollutants such as estrogenic compounds without the need for additional technological steps, such as pH or temperature adjustment.


Effect of perinatal polybrominated biphenyl exposure on acquisition and performance of an autoshaping paradigm.
Pregnant Sprague-Dawley rats received oral doses of 0, 0.2 or 2 mg/kg/day polybrominated biphenyls (PBB) as fireMaster BP-6 (BP-6) from day 6 of gestation through day 24 postpartum. At approximately 6 months of age male and female offspring were food-deprived to 80% of their free-feeding weights and subjected to four phases of an autoshaping paradigm. Acquisition of Phase I, a VI-90 second schedule of responding, was significantly delayed for female offspring from dams administered 2 mg/kg/day BP-6; a trend toward delayed acquisition was observed in all other PBB-exposed animals. No BP-6-related difference in latency to respond during this phase was observed. Male offspring from dams administered BP-6 appeared to acquire Phase II responding (a FI-90 second contingency) at a faster rate than did control males. In contrast, BP-6-exposed females acquired Phase II responding at a somewhat slower rate than did control females. The sex-related difference in responding may involve a rate-dependent influence, as control females acquired Phase II responding much more quickly than did control males. Control males and females acquired Phase III (FR-20 responding) at approximately the same rate. No BP-6-related deficits were observed during the initial few days of acquisition of FR-20 responding. However, BP-6-exposed male offspring tended to respond more than did control males after this time. BP-6-exposed females tended to respond less than did control females only as the responding of controls approached an asymptote. Phase IV involved FR-20 responding following challenge with d-amphetamine or chloral hydrate; no significant BP-6-related changes in disruption of this behavior were observed.


Alcohol intake and cognitive abilities in old age: the Lothian Birth Cohort 1936 study.
Moderate alcohol consumption has been associated with better cognitive performance in late adulthood, possibly by improving vascular health. Few studies have examined the potentially confounding roles of prior cognitive ability and social class in this relationship. Participants were 922 healthy adults about 70 years old in the Lothian Birth Cohort 1936 study, for whom there are IQ data from age 11. Alcohol consumption was obtained by self-report questionnaire. Cognitive outcome measures included general cognitive ability, speed of information processing, memory, and verbal ability. Moderate to substantial drinking (>2 units/day) was associated with better performance on cognitive tests than low-level drinking (≤2 units/day) or nondrinking in men and women. After adjusting for childhood IQ and adult social class, most of these associations were removed or substantially attenuated. After full adjustment, a small, positive association remained between overall alcohol intake and memory (women and men) and verbal ability (women only). Women's overall alcohol intake was derived almost exclusively from wine. In men, effects differed according to beverage type: wine and sherry-port consumption was associated with better verbal ability, but beer was associated with a poorer verbal ability and spirits intake was associated with better memory. Prior intelligence and socioeconomic status influence both amount and type of alcohol intake and may partly explain the link between alcohol intake and improved cognitive performance at age 70. Alcohol consumption was found to make a small, independent contribution to memory performance and verbal ability, but these findings' clinical significance is uncertain.


Somatic mutation patterns at Ig and Non-Ig Loci.
The reverse transcriptase (RT) model of immunoglobulin (Ig) somatic hypermutation (SHM) has received insufficient scientific attention. This is understandable given that DNA deamination mediated by activation-induced deaminase (AID), the initiating step of Ig SHM, has dominated experiments since 2002. We summarise some key history of the RT Ig SHM model dating to 1987. For example, it is now established that DNA polymerase η, the sole DNA repair polymerase involved in post-replication short-patch repair, is an efficient cellular RT. This implies that it is potentially able to initiate target site reverse transcription by RNA-directed DNA repair at AID-induced lesions. Recently, DNA polymerase θ has also been shown to be an efficient cellular RT. Since DNA polymerase θ plays no significant role in Ig SHM, it could serve a similar RNA-dependent DNA polymerase role as DNA polymerase η at non-Ig loci in the putative RNA-templated nucleotide excision repair of bulky adducts and other mutagenic lesions on the transcribed strand. A major yet still poorly recognised consequence of the proposed RT process in Ig SHM is the generation of significant and characteristic strand-biased mutation signatures at both deoxyadenosine/deoxythymidine and deoxyguanosine/deoxycytidine base pairs. In this historical perspective, we highlight how diagnostic strand-biased mutation signatures are detected in vivo during SHM at both Ig loci in germinal centre B lymphocytes and non-Ig loci in cancer genomes. These strand-biased signatures have been significantly obscured by technical issues created by improper use of the polymerase chain reaction technique. A heightened awareness of this fact should contribute to better data interpretation and somatic mutation pattern recognition both at Ig and non-Ig loci.


[Nursing scientific production presented at the annual meetings of the Brazilian Society for the Development of Science].
The authors have analized the scientific production presented by nurses and other professionals associated with the teaching of Nursing, published in the ANNALS of the Yearly Meetings of the Brazilian Society for Science Development (SBPC) from 1949 to 1983. Data showed a prevalence of papers prepared by faculty members over those prepared by Nursing Service Staff, as well a tendency for a quantitative decrease in the scientific production in the last five years.


Recent trends in testing social cognition.
Social cognition refers broadly to the way in which we process social information, and is a critical predictor of social competency. This article provides an overview of some of the assessment approaches that have been developed to assess this construct. A variety of well validated assessment approaches are now available. The most frequently used methods index explicit emotion recognition and/or mental state attribution. There has also been an increasing emphasis on the need to better understand the role of specific perceptual features and cognitive task demands in social cognitive difficulties. In the past 20 years, research on social cognitive function has grown exponentially, reflecting an increased recognition that social cognitive skills are critical for communicative discourse, and in turn mental health and well-being. Accordingly, a large number of measures are now available to quantify social cognitive function. This review shows that many of these measures have good psychometric properties, and appear to have at least moderate sensitivity. However, the review also highlights the importance of using appropriate control tasks to assess the specificity of any observed social cognitive failures, as well as the need for the continued development of measures with greater ecological validity.


Palliative care needs of HIV exposed and infected children admitted to the inpatient paediatric unit in Uganda.
Paediatric palliative care is an emerging subspecialty that focuses on achieving the best possible quality of life for children with life-limiting conditions and also for their families. It is a response to the suffering and unique needs of such children. Globally there is limited documented data available on the palliative care needs of children with HIV. A retrospective review of data of all the HIV exposed and positive children who were admitted to the ward from January to December 2012 was done to document their palliative care needs. A total of 243 children were admitted to the ward during the stated period. Of these, 139 (57.2%) were female and 104 (42.8%) were male. Among them 131 (54%) were aged five years and below whereas 112 (46%) were above five years. Some of the identified palliative care needs documented included physical needs: pneumonia 46 (19%), severe acute malnutrition 38 (16%), mild and moderate acute malnutrition 23 (9.6%), and respiratory tract infections 22 (9.3%). Social needs: poor social support 21 (41%), financial instability 16 (31%), and child neglect 4 (8%). Psychological needs: antiretroviral treatment (ART) counselling 127 (36%), HIV counselling and testing for the child and family 63 (18%), adherence support 53 (15%), and others 11 (3%). Spiritual needs: discontinuing ART because of belief in spiritual healing 18 (81%), loss of hope because of severe ill health 1 (5%), and others 3 (14%). These results emphasise the need for palliative care in children with HIV even in the era of ART. The needs identified are in keeping with studies done elsewhere and are similar to the palliative care needs of children with other life-limiting illnesses such as cancer. HIV positive and exposed children plus their families have vast palliative care needs and a holistic approach is the key in their management.


Molecular cloning of the fMet-Leu-Phe receptor from neutrophils.
The bacterial chemotactic peptide fMet-Leu-Phe (fMLP) activates neutrophils upon binding to surface receptors. In a previous communication we reported the functional reconstitution of the fMLP receptor in Xenopus laevis oocytes (Coats, W. D., and Navarro, J. (1990) J. Biol. Chem. 265, 5964-5966). In this work we report the isolation of the cDNA encoding the fMLP receptor from neutrophils. A rabbit neutrophil cDNA library was screened with an oligonucleotide probe deduced from the nucleotide sequence of G-protein-coupled receptors, and a cDNA encoding the fMLP receptor was isolated. This cDNA was characterized according to the following criteria: 1) Analysis of the deduced amino acid sequence revealed that the clone belongs to a G-protein-coupled receptor. 2) Tissue distribution analysis of the mRNA indicated that the message is only found in neutrophils. 3) In vitro translation of the message revealed a protein corresponding in size to the deglycosylated fMLP receptor. 4) X. laevis oocytes injected with the fMLP receptor message exhibited fMLP-dependent calcium mobilization and specific binding to the fMLP analog 125I-labeled fNle-Leu-Phe-Nle-Tyr-Lys (where Nle is norleucine and fNle is formylnorleucine). The molecular cloning of the fMLP receptor should provide the framework to analyze the relationship between structure, function, and regulation of this receptor.


Trends in hospice discharge, documented inpatient palliative care services and inpatient mortality in ovarian carcinoma.
To investigate the trends in discharge to hospice, documented inpatient palliative care services, and inpatient mortality in metastatic ovarian cancer (mOvCa) patients. Patients≥18years with mOvCa and a non-elective admission between January 1, 2006 and December 31, 2011 were identified from the National Inpatient Sample (NIS). The primary outcome of interest was the temporal trend in the annual proportion of hospitalizations for mOvCa where discharge destination was hospice. Secondary outcomes included temporal trend of inpatient mortality and documented palliative care services. Multivariable logistic regression models were used to ascertain independent factors predictive of hospice discharge and documented palliative services across the clusters of hospitals. A total of 106,203 non-elective hospitalizations were identified. The rate of hospice discharge increased from 9.2% in 2004 to 11.1% in 2011 (ptrend<0.001). Similarly, the rate of documented palliative care services increased from 2.7% in 2004 to 10.4% in 2011 (ptrend<0.001). The inpatient mortality decreased from 9.6% in 2004 to 7.4% in 2011 (ptrend<0.001). In a subset of hospitalizations with extreme risk of dying, 22% were discharged to hospice and 11% received documented palliative care services. One fifth of the patients who died in the hospital received documented palliative care services. The use of hospice as a discharge destination and documented palliative care services is relatively low but appears to be increasing over time for mOvCa patients. Monitoring this data is vital to plan educational programs regarding palliative care approaches in this at-risk population.


Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice.
Liver fibrosis is associated with angiogenesis and leads to portal hypertension. Certain antibiotics reduce complications of liver failure in humans, however, the effects of antibiotics on the pathologic alterations of the disease are not fully understood. The aim of this study was to test whether the non-absorbable antibiotic rifaximin could attenuate fibrosis progression and portal hypertension in vivo, and explore potential mechanisms in vitro. The effect of rifaximin on portal pressure, fibrosis, and angiogenesis was examined in wild type and Toll-like receptor 4 (TLR4) mutant mice after bile duct ligation (BDL). In vitro studies were carried out to evaluate the effect of the bacterial product and TLR agonist lipopolysaccharide (LPS) on paracrine interactions between hepatic stellate cells (HSC) and liver endothelial cells (LEC) that lead to fibrosis and portal hypertension. Portal pressure, fibrosis, and angiogenesis were significantly lower in BDL mice receiving rifaximin compared to BDL mice receiving vehicle. Studies in TLR4 mutant mice confirmed that the effect of rifaximin was dependent on LPS/TLR4 pathway. Fibronectin (FN) was increased in the BDL liver and was reduced by rifaximin administration and thus, was explored further in vitro as a potential mediator of paracrine interactions of HSC and LEC. In vitro, LPS promoted FN production from HSC. Furthermore, HSC-derived FN promoted LEC migration and angiogenesis. These studies expand our understanding of the relationship of intestinal microbiota with fibrosis development by identifying FN as a TLR4 dependent mediator of the matrix and vascular changes that characterize cirrhosis.


Anxiety level and correlates in methamphetamine-dependent patients during acute withdrawal.
Anxiety is often a core element of withdrawal symptoms; however, risk factors associated with anxiety symptoms during the early stage of withdrawal in methamphetamine (METH) users are not well understood. Two hundred ten METH-dependent subjects who had been abstinent for 1 to 7 days were recruited. We used a set of self-administrative questionnaires eliciting information on sociodemographics, detailed drug use history and anxiety. Beck Anxiety Inventory (BAI) was used to measure anxiety symptoms. METH users had a mean BAI score of 6.9; 72 (34.3%) of the study sample had anxiety symptoms during acute METH withdrawal, including 42 (20.0%) with mild anxiety, 25 (11.9%) with moderate anxiety, and 5 (2.4%) with severe anxiety. In addition, gender (female), higher frequency of drug use, and history of polysubstance use were significantly correlated with anxiety symptoms during acute METH withdrawal. Anxiety symptoms appear to be common during the first week of METH abstinence, and several risk factors are identified.


Heart Rate Modeling and Prediction Using Autoregressive Models and Deep Learning.
Physiological time series are affected by many factors, making them highly nonlinear and nonstationary. As a consequence, heart rate time series are often considered difficult to predict and handle. However, heart rate behavior can indicate underlying cardiovascular and respiratory diseases as well as mood disorders. Given the importance of accurate modeling and reliable predictions of heart rate fluctuations for the prevention and control of certain diseases, it is paramount to identify models with the best performance in such tasks. The objectives of this study were to compare the results of three different forecasting models (Autoregressive Model, Long Short-Term Memory Network, and Convolutional Long Short-Term Memory Network) trained and tested on heart rate beats per minute data obtained from twelve heterogeneous participants and to identify the architecture with the best performance in terms of modeling and forecasting heart rate behavior. Heart rate beats per minute data were collected using a wearable device over a period of 10 days from twelve different participants who were heterogeneous in age, sex, medical history, and lifestyle behaviors. The goodness of the results produced by the models was measured using both the mean absolute error and the root mean square error as error metrics. Despite the three models showing similar performance, the Autoregressive Model gave the best results in all settings examined. For example, considering one of the participants, the Autoregressive Model gave a mean absolute error of 2.069 (compared to 2.173 of the Long Short-Term Memory Network and 2.138 of the Convolutional Long Short-Term Memory Network), achieving an improvement of 5.027% and 3.335%, respectively. Similar results can be observed for the other participants. The findings of the study suggest that regardless of an individual's age, sex, and lifestyle behaviors, their heart rate largely depends on the pattern observed in the previous few minutes, suggesting that heart rate can be reasonably regarded as an autoregressive process. The findings also suggest that minute-by-minute heart rate prediction can be accurately performed using a linear model, at least in individuals without pathologies that cause heartbeat irregularities. The findings also suggest many possible applications for the Autoregressive Model, in principle in any context where minute-by-minute heart rate prediction is required (arrhythmia detection and analysis of the response to training, among others).


[Thyroid carcinoma found incidentally after thyroidectomy: postoperative strategy].
Completion operations after thyroid surgery due to incidental postoperative diagnosis of thyroid cancer are indicated in differentiated thyroid cancer with tumor size > 1 cm, extrathyroidal invasion, multifocality, angioinvasion or metastases. By thorough preoperative clinical work-up of nodular goiter (ultrasonography, fine needle aspiration cytology the frequency of completion thyroidectomies are aimed to be less than 10% of all thyroid cancer operations. To facilitate postoperative radioiodine ablation prophylactic completion operations can be postponed to 3 months postoperatively to minimize surgical morbidity, if not performed during the early postoperative period. Prophylactic central node dissection as part of the completion operation is reserved for papillary (PTC) and medullary carcinomas (MTC) but not for follicular cancer. Lateral node dissection is recommended in nodal-positive MTC and in PTC with more than 5 lymph node metastases in the central compartment.


Clinical Outcomes of Metastatic Poor Prognosis Germ Cell Tumors: Current Perspective From a Referral Center.
Survival estimates with first-line treatment for patients with metastatic poor prognosis germ cell tumors (GCT) are still suboptimal in the literature. We conducted a retrospective study to evaluate the outcome of patients referred to our tertiary cancer center. A retrospective analysis was conducted on patients who received at least first-line chemotherapy at our center. Distribution of clinical characteristics was evaluated in the periods < 1997, 1997 to 2001, 2001 to 2006, and 2007 to 2013. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall survival (OS). Univariable and multivariable Cox models with prespecified clinical variables were undertaken for PFS and OS. All tests and confidence intervals were 2-sided and set at a P = .05 level of significance. Between 1982 and 2013, 168 patients were identified. The median age was 27 years (interquartile range [IQR], 22-34). The presence of liver, bone, or brain metastases trended to greater incidence from 1997 onward (27.5% < 1997 to 55.6% in 2007-2013; χ(2)P = .054). Median follow-up was 102 (IQR, 63-166) months. Global 5-year PFS was 48.5% (95% confidence interval [CI], 41.5-56.8) and OS was 63.2% (95% CI, 56.0-71.2). In multivariable analysis, treatment period was not significantly associated with either PFS (overall P = .229) or OS (overall P = .216). In this single-center series of consecutive poor prognosis GCT we could observe greater PFS and OS than the historical estimates. This observation was independent from the period of treatment. Based on the present results, studies focused on improving the outcome in the sole poor-risk cohort should be discouraged. Results were biased by their retrospective quality.


Efficacy of neuropsychological rehabilitation for mild-moderate traumatic brain injury.
The growing literature on cognitive rehabilitation is increasingly demanding more evaluation related to the validity of such therapy. The current research addresses some of the criticisms of previous efficacy studies and provides support for the effectiveness of cognitive rehabilitation according to a specific treatment protocol employed at an outpatient rehabilitation program. Stringent subject selection criterion were utilized to maximize the validity of the statistical comparisons of selected pre- and post- rehabilitation neuropsychological test scores and cognitive level of functioning. Results supported improvement in performance on selected neuropsychological test scores and cognitive functioning following cognitive rehabilitation. Limited validating evidence for behavioral indicators of level of cognitive functioning were obtained through correlations of behavioral ratings to their corresponding neuropsychological test scores. Results suggest that traditional measures of efficacy of cognitive rehabilitation may be insensitive to the cognitive sequalae of mild head injury due, in part, to compensatory strategies invoked by the subjects.


Tobacco smoking and mortality among Aboriginal and Torres Strait Islander adults in Australia.
Despite generally high smoking prevalences, stemming from colonization, the relationship of smoking to mortality has not been quantified reliably in an Indigenous population. We investigate smoking and mortality among Aboriginal and Torres Strait Islander adults in Australia, where current adult daily smoking prevalence is 40.2%. A prospective study of 1388 cardiovascular disease- and cancer-free Aboriginal adults aged ≥45 years, of the 267 153 45 and Up Study participants randomly sampled from the New South Wales general population over 2006-09. Questionnaire and mortality data were linked (through the Centre for Health Record Linkage) to mid-2019. Adjusted hazard ratios (called relative risks, RRs) for all-cause mortality-among current- and past- versus never-smokers-were estimated overall, by smoking intensity and by age at cessation. Smoking-attributable fractions and associated deaths were estimated. Over 14 586 person-years' follow-up (median 10.6 years), 162 deaths accrued. Mortality RRs [95% confidence interval (CI)] were 3.90 (2.52-6.04) for current- and 1.95 (1.32-2.90) for past- versus never-smokers, with age heterogeneity. RRs increased with smoking intensity, to 4.29 (2.15-8.57) in current-smokers of ≥25 cigarettes/day. Compared with never-smokers, RRs were 1.48 (0.85-2.57) for those quitting at <45 years of age and 2.21 (1.29-3.80) at 45-54 years. Never-smokers lived an average >10 years longer than current-smokers. Around half of deaths among adults aged ≥45 years were attributable to smoking, exceeding 10 000 deaths in the past decade. In this population, >80% of never-smokers would survive to 75 years, versus ∼40% of current-smokers. Quitting at all ages examined had substantial benefits versus continuing smoking; those quitting before age 45 years had mortality risks similar to never-smokers. Smoking causes half of deaths in older Aboriginal and Torres Strait Islander adults; Indigenous tobacco control must receive increased priority.


Comprehensive transcriptome analysis of phytohormone biosynthesis and signaling genes in microspore/pollen and tapetum of rice.
To investigate the involvement of phytohormones during rice microspore/pollen (MS/POL) development, endogenous levels of IAA, gibberellins (GAs), cytokinins (CKs) and abscisic acid (ABA) in the mature anther were analyzed. We also analyzed the global expression profiles of genes related to seven phytohormones, namely auxin, GAs, CKs, brassinosteroids, ethylene, ABA and jasmonic acids, in MS/POL and tapetum (TAP) using a 44K microarray combined with a laser microdissection technique (LM-array analysis). IAA and GA(4) accumulated in a much higher amount in the mature anther compared with the other tissues, while CKs and ABA did not. LM-array analysis revealed that sets of genes required for IAA and GA synthesis were coordinately expressed during the later stages of MS/POL development, suggesting that these genes are responsible for the massive accumulation of IAA and GA(4) in the mature anther. In contrast, genes for GA signaling were preferentially expressed during the early developmental stages of MS/POL and throughout TAP development, while their expression was down-regulated at the later stages of MS/POL development. In the case of auxin signaling genes, such mirror-imaged expression observed in GA synthesis and signaling genes was not observed. IAA receptor genes were mostly expressed during the late stages of MS/POL development, and various sets of AUX/IAA and ARF genes were expressed during the different stages of MS/POL or TAP development. Such cell type-specific expression profiles of phytohormone biosynthesis and signaling genes demonstrate the validity and importance of analyzing the expression of phytohormone-related genes in individual cell types independently of other cells/tissues.


Effectiveness of different resin composite materials for repairing noncarious amalgam margin defects.
The specific objective of this in vitro study was to determine whether the current flowable resin composites can establish an effective seal in repairing noncarious amalgam margin defects. A total of 30 freshly extracted caries-free human third molars were used for this investigation. Class I preparations with a standardized 160-μ marginal defect were made by condensing amalgam against a Mylar strip. Accelerated aging and corrosion protocols were then applied to simulate oral conditions. The prepared teeth were randomly divided into five groups (n = 6 per group) according to the repair material employed as follows: (1) no treatment (control); (2) self-adhering flowable resin composite (Vertise Flow); (3) flowable resin composite (Filtek Ultimate Flowable); (4) sonic-activated resin composite (SonicFill); and (5) self-adhesive cement (SmartCem2). Specimens were thermocycled again and then immersed in 5% methylene blue at 37°C for 24 h. For dye-leakage measurements, specimens were sliced longitudinally using a low-speed diamond disk. The results indicated that the flowable resin composite material significantly reduced marginal microleakage compared to the control and SonicFill (P < 0.05). Current flowable resin composites were found to be adequate materials for repairing noncarious amalgam margin defects.


Endogenous vasoconstrictor prostanoids: role in serotonin and vasopressin-induced coronary vasoconstriction.
A vasoconstrictor-induced prostacyclin (PGI2) production in a perfused rat heart was found, suggesting a mitigating role of PGI2 on coronary vasoconstriction. Treatment of the heart with cyclooxygenase inhibitors (aspirin or indomethacin) decreased PGI2 production by more than 90% and paradoxically reduced the vasoconstriction response. The attenuating effect of cyclooxygenase blockade suggested that endogenous prostanoids contribute to serotonin-, vasopressin- or U46619-induced vasoconstriction. Two prostaglandin (PG) H2/thromboxane A2 (TXA2) receptor antagonists, i.e., 13-azaprostanoic acid (13-APA) and SQ 29,548 were used to investigate putative endogenous vasoconstrictor prostanoids on the exogenously induced vasoconstriction. Retrogradely perfused (5-6 ml/min) rat hearts were rendered guiescent, yet responsive to stimuli, by local injection of lidocaine to the atrioventricular node. Changes in coronary vascular resistance (i.e., perfusion pressure at constant flow) were monitored and the cardiac effluent was collected for analysis of 6-keto PGF1 alpha (the stable metabolite of PGI2) as well as PGF2 alpha by radioimmunoassay. Three vasoconstrictors, i.e., serotonin, vasopressin and the TXA2/PGH2 analog U46619, as well as authentic PGD2, PGE2 and PGF2 alpha were infused. PGD2, PGE2 and PGF2 alpha exerted a dose-related coronary vasoconstriction, as did U46619, serotonin and vasopressin. Treatment with 13-APA (100 microM) or SQ 29,548 (100 nM) almost abolished U46619-induced vasoconstriction. The addition of PGH2/TXA2 receptor antagonists also significantly reduced the pressor effect of exogenously administered PGs, serotonin and vasopressin, with the exception that SQ 29,548 did not significantly antagonize PGE2-induced vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)


Challenging stereotypes and changing attitudes: Improving quality of care for people with hepatitis C through Positive Speakers programs.
Positive Speakers programs consist of people who are trained to speak publicly about their illness. The focus of these programs, especially with stigmatised illnesses such as hepatitis C (HCV), is to inform others of the speakers' experiences, thereby humanising the illness and reducing ignorance associated with the disease. This qualitative research aimed to understand the perceived impact of Positive Speakers programs on changing audience members' attitudes towards people with HCV. Interviews were conducted with nine Positive Speakers and 16 of their audience members to assess the way in which these sessions were perceived by both speakers and the audience to challenge stereotypes and stigma associated with HCV and promote positive attitude change amongst the audience. Data were analysed using Intergroup Contact Theory to frame the analysis with a focus on whether the program met the optimal conditions to promote attitude change. Findings suggest that there are a number of vital components to this Positive Speakers program which ensures that the program meets the requirements for successful and equitable intergroup contact. This Positive Speakers program thereby helps to deconstruct stereotypes about people with HCV, while simultaneously increasing positive attitudes among audience members with the ultimate aim of improving quality of health care and treatment for people with HCV.


Impact of an advertising campaign on condom use in urban Pakistan.
This study describes an assessment of the impact on condom use in urban Pakistan of the second phase of an intensive condom advertising campaign conducted as part of a social marketing program. Between April and June 2009, advertisements for Touch condoms appeared on private television channels and on radio stations. To assess the impact of the campaign, a nationally representative panel survey of men married to women aged 15-49 was conducted, collecting information on behaviors related to condom use and recall of contraceptive advertisements. We employed conditional change regression analysis to determine whether awareness of the Touch ad at follow-up was associated with improved attitudes toward condoms and condom use. Respondents with confirmed awareness of the Touch campaign experienced significant improvements in indicators related to condom use, even after controlling for region, socioeconomic and demographic characteristics, the values of the indicators at baseline, and exposure to the first phase of the campaign. They experienced increases in the following: perceived availability of condoms; discussion of family planning; approval of family planning; procurement of condoms; and ever use, current use, and consistent use of condoms with wife. The study indicates that condom advertising can be effective in increasing condom use in urban Pakistan.


Assessing the risks of trace elements in environmental materials under selected greenhouse vegetable production systems of China.
The risk assessment of trace elements of different environmental media in conventional and organic greenhouse vegetable production systems (CGVPS and OGVPS) can reveal the influence of different farming philosophy on the trace element accumulations and their effects on human health. These provide important basic data for the environmental protection and human health. This paper presents trace element accumulation characteristics of different land uses; reveals the difference of soil trace element accumulation both with and without consideration of background levels; compares the trace element uptake by main vegetables; and assesses the trace element risks of soils, vegetables, waters and agricultural inputs, using two selected greenhouse vegetable systems in Nanjing, China as examples. Results showed that greenhouse vegetable fields contained significant accumulations of Zn in CGVPS relative to rice-wheat rotation fields, open vegetable fields, and geochemical background levels, and this was the case for organic matter in OGVPS. The comparative analysis of the soil medium in two systems with consideration of geochemical background levels and evaluation of the geo-accumulation pollution index achieved a more reasonable comparison and accurate assessment relative to the direct comparison analysis and the evaluation of the Nemerow pollution index, respectively. According to the Chinese food safety standards and the value of the target hazard quotient or hazard index, trace element contents of vegetables were safe for local residents in both systems. However, the spatial distribution of the estimated hazard index for producers still presented certain specific hotspots which may cause potential risk for human health in CGVPS. The water was mainly influenced by nitrogen, especially for CGVPS, while the potential risk of Cd and Cu pollution came from sediments in OGVPS. The main inputs for trace elements were fertilizers which were relatively safe based on relevant standards; but excess application caused trace element accumulations in the environmental media.


Comparison of Quality of Life, Depression, Anxiety, Suicide, Social Anxiety and Obsessive-Compulsive Symptoms Between Adolescents with Acne Receiving Isotretinoin and Antibiotics: A Prospective, Non-randomised, Open-Label Study.
The effects of isotretinoin on suicide, social anxiety and obsessive-compulsive symptoms in adolescents with acne have not been sufficiently investigated. This study aimed to evaluate the quality of life, depression, anxiety, suicide, social anxiety, and obsessive-compulsive symptoms of adolescents receiving systemic isotretinoin and antibiotic treatments at baseline and at 3 months. The study included a total of 102 adolescents using isotretinoin (n = 60) and antibiotics (n = 42). The Acne Quality of Life Scale (AQLS), Hospital Anxiety and Depression Scale (HADS), Suicide Probability Scale (SPS), Liebowitz Social Anxiety Scale (LSAS), and Maudsley Obsessive-Compulsive Question List (MOCQL) were administered to both groups at baseline and at 3 months. In order to exclude patients with comorbid psychiatric disorders, the patients were evaluated at the beginning of the study with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL). There were no significant differences in the mean age, gender distribution, educational level, and family history of mental illness between the two groups. There were significant decreases in the Global Acne Grading System scores, visual analogue scale scores, AQLS scores, total and subscale scores of LSAS, and total and subscale scores of MOCQL at 3 months compared with baseline in both groups. However, there were no significant changes in the total and subscale scores of HADS and total and subscale scores of SPS at 3 months compared with baseline in both groups. We found that neither isotretinoin nor antibiotic treatment affected the levels of depression, anxiety, and suicide in acne patients. Moreover, both isotretinoin and antibiotic treatment were shown to improve the quality of life, social anxiety, and obsessive-compulsive symptoms in acne patients. However, clinicians should be careful about psychiatric side effects in patients using isotretinoin. Further studies with a larger number of cases and with a longer follow-up period are needed to investigate the complex effects of isotretinoin on the central nervous system.


Difficulty in establishing a diagnosis in an uncommon presentation of a minor salivary gland tumour.
We report the case of a man presenting with a large, airway obstructing, minor salivary gland tumour arising from the right tonsillar base. Clinically, the tumour behaved in a malignant way. A firm diagnosis of malignancy could not be made histologically. The differential diagnosis included polymorphous low-grade adenocarcinoma, basal cell adenoma and adenoid cystic carcinoma. However, on balance, based on the clinical presentation, a diagnosis of malignancy was favoured and appropriate treatment was considered. Because of the patient's co-morbidities, further surgery was not an option and it was agreed that the patient should undergo radiotherapy instead. While he was waiting for radiotherapy, the tumour went into remission.


Increased cyclooxygenase-2 (COX-2): a potential role in the pathogenesis of lymphoma.
B cell lymphomas are a diverse group of clinicopathologic diseases with an increasing incidence. As with other malignancies, the accumulation of genetic abnormalities are required for malignant transformation of human lymphocytes. Cyclooxygenase-2 (COX-2) is a key biosynthetic enzyme in prostaglandin synthesis and has been implicated in the pathogenesis of numerous malignancies including colon, breast, and lung cancer. There is little data on the potential role of COX-2 in lymphoma pathogenesis. In this study, several B lymphoma cell lines and primary B cells obtained from normal volunteer controls were examined for COX-2 protein expression. Immunoblot analysis demonstrated between an approximately 2.2-4.3-fold increase in COX-2 protein expression relative to primary B cells in all lymphoma cell lines examined. Increased COX-2 phosphorylation was found in the BJAB, BL41, and Raji cells whereas the levels in Daudi, Namalwa, and Ramos did not differ from that of primary B cells. Treatment with 25-100 microM celecoxib (CEL) resulted in decreased proliferation as measured by [3H]thymidine in all cell lines examined, and the effect was dose-dependent, and not significantly enhanced by chlorambucil (CHL). The effect of COX-2 inhibition on apoptosis in lymphoma cells was examined and revealed apoptotic induction of greater than 85% in all cell lines examined at 50 microM celecoxib. The pro-apoptotic effect was dose-dependent, and was not significantly enhanced by chlorambucil. Examination of apoptosis-related proteins by immunoblot analysis revealed levels of BCL-2, BCL-X(L), and Bax to be unaffected by celecoxib. In contrast, levels of Akt, MCL-1, and phosphorylated SAP-kinase were all decreased after incubation with 50 microM celecoxib. These findings suggest that increased COX-2 expression and activity, contributes to the pathogenesis of B cell lymphomas and point to a possible role for COX-2 inhibition in their treatment.


Impact of Magnesium Supplementation in Muscle Damage of Professional Cyclists Competing in a Stage Race.
Magnesium is a cofactor of different enzymatic reactions involved in anabolic and catabolic processes that affect muscular performance during exercise. In addition, it has been suggested that magnesium could participate in maintaining muscle integrity during demanding effort. The main purpose of this study was to analyze the effects of magnesium supplementation in preventing muscle damage in professional cyclists taking part in a 21-day cycling stage race. Eighteen male professional cyclists (n = 18) from two teams were recruited to participate in the research. They were divided into 2 groups: the control group (n = 9) and the magnesium-supplemented group (n = 9). The supplementation consisted of an intake of 400 mg/day of magnesium during the 3 weeks of competition. Blood samples were collected according to World Anti-Doping Agency rules at three specific moments during competition: immediately before the race; mid competition; and before the last stage. Levels of serum and erythrocyte magnesium, lactate dehydrogenase, creatinine kinase, aspartate transaminase, alanine transaminase, myoglobin, aldolase, total proteins, cortisol and creatinine were determined. Serum and erythrocyte magnesium levels decreased during the race. Circulating tissue markers increased at the end of the race in both groups. However, myoglobin increase was mitigated in the supplemented group compared with the controls. We conclude that magnesium supplementation seems to exert a protective effect on muscle damage.


Outcome of Benign Acute Childhood Myositis: The Experience of 2 Large Tertiary Care Pediatric Hospitals.
The aims of the study were to determine the evolution of benign acute childhood myositis in children and to assess the relationship between creatine phosphokinase (CPK) values and myoglobinuria. A retrospective study of patients with benign acute childhood myositis seen in 2 tertiary care university-affiliated pediatric hospitals during overlapping 4-year periods. Demographic data, historical details, clinical, and laboratory results were extracted from the charts of children younger than 16 years with a CPK greater than 3 times normal. Complications, treatments, and outcomes were recorded. Fifty-four children were included, 43 (80%) were male, and mean age was 7.3 years (median [range], 6 [3-16] years), none showed abnormal neurological findings, manifested hematuria, or developed renal failure. Mean CPK level at presentation was 1872 IU/L (range, 511-8086 IU/L). None developed renal failure, and there were no adverse outcomes on follow-up. Acute childhood myositis is a predominantly benign disease. Neurological examination is usually normal and rhabdomyolysis is rare. Although severe pathological comorbid conditions must be excluded, a complete history and examination, coupled with simple blood and urine tests, can help minimize unnecessary diagnostic investigations.


Toxic isolectins from the mushroom Boletus venenatus.
Ingestion of the toxic mushroom Boletus venenatus causes a severe gastrointestinal syndrome, such as nausea, repetitive vomiting, diarrhea, and stomachache. A family of isolectins (B. venenatus lectins, BVLs) was isolated as the toxic principles from the mushroom by successive 80% ammonium sulfate-precipitation, Super Q anion-exchange chromatography, and TSK-gel G3000SW gel filtration. Although BVLs showed a single band on SDS-PAGE, they were further divided into eight isolectins (BVL-1 to -8) by BioAssist Q anion-exchange chromatography. All the isolectins showed lectin activity and had very similar molecular weights as detected by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis. Among them, BVL-1 and -3 were further characterized with their complete amino acid sequences of 99 amino acids determined and found to be identical to each other. In the hemagglutination inhibition assay, both proteins failed to bind to any mono- or oligo-saccharides tested and showed the same sugar-binding specificity to glycoproteins. Among the glycoproteins examined, asialo-fetuin was the strongest inhibitor. The sugar-binding specificity of each isolectin was also analyzed by using frontal affinity chromatography and surface plasmon resonance analysis, indicating that they recognized N-linked sugar chains, especially Galbeta1-->4GlcNAcbeta1-->4Manbeta1-->4GlcNAcbeta1-->4GlcNAc (Type II) residues in N-linked sugar chains. BVLs ingestion resulted in fatal toxicity in mice upon intraperitoneal administration and caused diarrhea upon oral administration in rats.


Are the washout values currently accepted for lesion characterization in dedicated adrenal CT adequate for diagnosis?
We aimed to investigate the accuracy of density characteristics and washout values of lesions detected on computed tomography (CT) at the cutoff values obtained from the literature by taking the pathological results of adrenalectomy specimens as reference and to determine the cutoff values of parameters evaluated on CT for the differentiation of adenoma and nonadenoma lesions in the study group. Hospital records and standard CT imaging data (noncontrast early phase [65 s] and late phase [15 min] ) of 84 patients with 87 lesions who underwent adrenalectomy between January 2012 and December 2018 were retrospectively reevaluated by two radiologists in consensus. The patients were categorized as having adenoma and nonadenoma lesions according to the pathology results. The sensitivity, specificity and diagnostic accuracy of CT parameters (density values and washout percentages) were evaluated. Differences in the CT parameters (size, noncontrast and early-late enhancement density and absolute and relative washout values) were investigated. The optimal cutoff values of CT parameters were determined by ROC analysis. Noncontrast CT had a specificity of 87.75% and 95.9%, sensitivity of 60% and 48.6%, diagnostic accuracy of 77.7% and 89.47% for adenomas, at the cutoff values of ≤10 HU and ≤0 HU, respectively. For absolute washout value ≥ 60%, the sensitivity, specificity and accuracy were 64.7%, 52.38% and 56.75%, respectively; while these rates were 76.47%, 56.52% and 62.16%, respectively, for relative washout value ≥40%. Adenomas and nonadenomas showed significant difference in terms of size (p < 0.0001), unenhanced attenuation (p < 0.0001), relative washout (p = 0.020) and delay enhancement (p < 0.001). But there were no differences in terms of absolute washout (p = 0.230) and early enhancement (p = 0.264). The cutoff values for the differentiation of adenomas and nonadenomas were as follows: size ≤44 mm, noncontrast density <20 HU, early-phase density ≥45 HU, delayed-phase density ≤44 HU, absolute washout 74.83% and relative washout 57.76%. The current washout criteria used in the differentiation of adenoma and nonadenoma lesions in dynamic CT imaging can give false negative and positive results. According to the existing criteria, the most reliable parameter in adenoma-nonadenoma differentiation is ≤ 0 HU noncontrast CT density value.


A primary meningioma of the lumbar spine with neck metastasis.
Context: Approximately 25% of all primary spinal cord tumors are meningiomas, and 80% of these tumors occur in the thoracic region. Few meningiomas of the lumbar spine have been presented. Extracranial metastasis of meningioma occurs extremely rare, only in about 0.1% of meningiomas. Even metastasis, the sites are seldom seen in deep soft tissue. We reported a woman original meningioma in the lumbar spine with distal deep neck metastasis. Findings: A 59-year-old patient suffered from severe right drop foot, numbness, and radicular pain for the previous 6 months. Computed tomography (CT) disclosed a huge, macrolobulated retroperitoneal soft-tissue lesion with a size of 14.9 × 10.8 × 17.7 cm. Magnetic resonance imaging (MRI) further revealed a solid spinal intracanal tumor with moderate enhancement involving the right paraspinal region at the L2∼L5 level and the right iliac fossa. A meningioma was diagnosed with histological proof. Four months later, another metastatic meningioma in her left neck. She was managed conservatively without neurologic dysfunction. Conclusions: To the best of our knowledge, such a large meningioma of the lumbar spine has not previously been reported in the literature. In this study, we demonstrated a rare spinal meningioma located in the lumbar spine primarily with secondary soft tissue metastasis.


Oxidation of carbohydrates and palmitate by intact cultured neonatal rat heart cells.
The rates of uptake and oxidation of glucose, lactate, pyruvate, and palmitate were measured for "mixed" cultures of rat heart cells that exhibit a myocyte-to-fibroblast ratio similar to that observed in vivo. Glucose uptake and conversion to lactate were also measured using enriched cultures of myocytes and fibroblasts. The metabolism of mixed cultures, which contain 70-80% myocytes, closely resembles that of enriched myocyte cultures. The energy production and substrate oxidation rates of cultured neonatal heart cells, adult myocytes, and perfused hearts are compared. It appears that the energy requirements of cultured heart cells are much lower than that of whole tissue. The results suggest that the metabolism of cultured heart cells may be basically the same as those in vivo but appears to be different because of reduced energy requirements in culture.


Cholinergic facilitation of trace eyeblink conditioning in aging rabbits.
The hippocampus is importantly involved in learning and memory, and is severely impacted by aging. In in vitro hippocampal slices, both the post-burst afterhyperpolarization (AHP) and spike-frequency accommodation are reduced in hippocampal pyramidal neurons after hippocampally-dependent trace eyeblink conditioning, indications of increased cellular excitability. The AHP results from the activation of outward potassium currents, including sI(AHP) and muscarine-sensitive I(M). The AHP is significantly increased in aging hippocampal neurons, potentially contributing to age-associated learning deficits. Compounds which reduce the AHP and spike-frequency accommodation could facilitate learning in normal aging or in age-associated dementias such as Alzheimer's disease. The cholinesterase inhibitor metrifonate enhances trace eyeblink conditioning by aging rabbits and reduces the AHP and accommodation in hippocampal CA1 neurons in a dose-dependent manner. These reductions are mediated by muscarinic cholinergic transmission as they are blocked by atropine. Hippocampal neurons from metrifonate treated but behaviorally naive rabbits were more excitable and not desensitized to the effects of metrifonate since the AHP and accommodation were further reduced when metrifonate was bath applied to the neurons. These observations suggest that the facilitating effect of chronic metrifonate on acquisition of hippocampally dependent tasks is mediated at least partially by increasing the baseline excitability of CA1 pyramidal neurons. The issue of whether learning can be facilitated with muscarinic cholinergic agonists, in addition to cholinesterase inhibitors, was addressed by training aging rabbits during intravenous treatment with the M1 agonist CI1017. A dose-dependent enhancement of acquisition was observed, with rabbits receiving 1.0 or 5.0 mg/ml CI1017 showing comparably improved learning rates as those receiving 0.5 mg/ml or vehicle. Sympathetic side effects, mainly excess salivation, were seen with the 5.0 mg/ml dose. Post-training evaluations suggested that the effective doses of CI1017 were enhancing responsivity to the tone conditioned stimulus. These studies suggest that muscarinic cholinergic neurotransmission is importantly involved in associative learning; that learning in aging animals may be facilitated by enhancing cholinergic transmission; and that the facilitation may be mediated through actions on hippocampal neurons.


Chemosensory and cholinergic stimulation of fictive respiration in isolated CNS of neonatal opossum.
1. The aim of the present experiments was to characterize the central chemical drive of fictive respiration in the isolated CNS of the newborn opossum, Monodelphis domestica. This opossum preparation, in contrast to those of neonatal rats and mice, produces respiratory rhythm of high frequency in vitro. 2. Fictive respiration was recorded from C3-C5 ventral roots of the isolated CNS of 4- to 14-day-old opossums using suction electrodes. At room temperature (21-23 degrees C) the frequency of respiration was 43 +/- 5.3 min-1 (mean +/- S.E.M., n = 50) in basal medium Eagle's medium (BMEM) equilibrated with 5% CO2-95% O2, pH 7.37-7.40. Respiratory discharges remained regular throughout 8 h experiments and continued for more than 20 h in culture. 3. Superfusion of the brainstem confirmed that solutions of pH 6.3-7.2 increased both the amplitude and frequency of respiration. High pH solutions (7.5-7.7) had the opposite effect and abolished the rhythm at pH 7.7. Addition of ACh (50-100 microM) or carbachol (0.01-10 microM) to the brainstem superfusion also increased the amplitude and frequency of respiratory activity, as did physostigmine (50-100 microM) or neostigmine (20-50 microM). Conversely, scopolamine (50-100 microM) reduced the amplitude and frequency of the basal respiratory rhythm by about 30%. 4. H(+)- and cholinergic-sensitive areas on the surface of the isolated CNS were explored with a small micropipette (outer tip diameter, 100 microns) filled with BMEM (pH 6.5) or 1 microM carbachol. Carbachol applied to H(+)- and cholinergic-sensitive areas in the ventral medulla mimicked the changes of respiratory pattern produced by low pH application. Responses to altered pH and carbachol were abolished by scopolamine (50 microM). Histochemistry demonstrated several medullary groups of neurons stained for acetylcholinesterase. The superficial location of one of these groups coincided with a functional and anatomically well-defined pH- and carbachol-sensitive area placed medial to the hypoglossal roots. 5. Exploration of chemosensitive areas revealed that application of drugs or solutions of different pH to a single well-defined spot could have selective and distinctive effects upon amplitude and frequency of respiratory activity. 6. These results show that fictive respiration in the isolated CNS of the newborn opossum is tonically driven by chemical- and cholinergic-sensitive areas located on the ventral medulla, the activity of which regulates frequency and amplitude of respiration. They suggest that a cholinergic relay, although not essential for rhythm generation, is involved in the central pH chemosensory mechanism, or that cholinergic and chemical inputs converge upon the same input pathway to the respiratory pattern generator.


Coding characteristics of spiking local interneurons during imposed limb movements in the locust.
The performance of adaptive behavior relies on continuous sensory feedback to produce relevant modifications to central motor patterns. The femoral chordotonal organ (FeCO) of the legs of the desert locust monitors the movements of the tibia about the femoro-tibial joint. A ventral midline population of spiking local interneurons in the metathoracic ganglia integrates inputs from the FeCO. We used a Wiener kernel cross-correlation method combined with a Gaussian white noise stimulation of the FeCO to completely characterize and model the output dynamics of the ventral midline population of interneurons. A wide range of responses were observed, and interneurons could be classified into three broad groups that received excitatory and inhibitory or principally inhibitory or excitatory synaptic inputs from the FeCO. Interneurons that received mixed inputs also had the greatest linear responses but primarily responded to extension of the tibia and were mostly sensitive to stimulus velocity. Interneurons that received principally inhibitory inputs were sensitive to extension and to joint position. A small group of interneurons received purely excitatory synaptic inputs and were also sensitive to tibial extension. In addition to capturing the linear and nonlinear dynamics of this population of interneurons, first- and second-order Wiener kernels revealed that the dynamics of the interneurons in the population were graded and formed a spectrum of responses whereby the activity of many cells appeared to be required to adequately describe a particular stimulus characteristic, typical of population coding.


Polarized distribution of mRNAs encoding a putative LDL receptor adaptor protein, xARH (autosomal recessive hypercholesterolemia) in Xenopus oocytes.
The Xenopus homologue of hARH (human autosomal recessive hypercholesterolemia) was identified in a screen for vegetally localized RNAs. xARH contains a N-terminal phosphotyrosine binding (PTB) domain that is 91% identical to that of the human gene, a domain previously shown to bind the LDL receptor family members. Maternal xARH, unlike hARH, is present as two transcripts that differ in their 3' UTRs. The large transcript, xARH-alpha, primarily localizes to the oocyte vegetal cortex. The small transcript, xARH-beta, is not localized. During embryogenesis, xARH RNA is found redistributed in a perinuclear pattern. Similar to hARH, xARH is found in the adult liver, but at low levels compared to oocytes. Downstream of the PTB domain is a conserved clathrin box and a C terminal region 50% identical to that of hARH. Previous in vitro studies from this lab have shown xARH can bind the LDLR as well as the vitellogenin (VTG) receptor. We find that injection of the C terminal region missing the PTB domain significantly reduces the internalization of VTG in early stage oocytes, an event that requires the VTG receptor. The data strongly suggest that xARH encodes an adaptor protein that functions in the essential receptor-mediated endocytosis of nutrients during oogenesis. Because xARH protein is found uniformly distributed along the animal/vegetal axis in oocytes, we propose that the localization of xARH-alpha to the vegetal cortex while xARH-beta remains unlocalized, facilitates the uniform distribution of the protein in this extraordinarily large cell.


Pax2 in development and renal disease.
Pax genes are associated with a variety of developmental mutations in mouse and man that are gene dosage sensitive, or haploinsufficient. The Pax2 gene encodes a DNA binding, transcription factor whose expression is essential for the development of the renal epithelium. Both gain and loss of function mutants in the mouse demonstrate a requirement for Pax2 in the conversion of metanephric mesenchymal precursor cells to the fully differentiated tubular epithelium of the nephron. However, Pax2 expression is down-regulated as cells leave the mitotic cycle. Humans carrying a single Pax2 mutant allele exhibit renal hypoplasia, vesicoureteric reflux, and optic nerve colobomas. Conversely, persistent expression of Pax2 has been demonstrated in a variety of cystic and dysplastic renal diseases and correlates with continued proliferation of renal epithelial cells. Thus, Pax2 misexpresssion may be a key determinant in the initiation and progression of renal diseases marked by increased or deregulated cell proliferation.


CDKN2a/p16INK4a mutations and lack of p19ARF involvement in familial melanoma kindreds.
Germline mutations in the cyclin-dependent kinase inhibitor 2a (CDKN2a) gene, which maps to the 9p21 chromosomal region and encodes the cyclin-dependent kinase inhibitor p16INK4a, have been detected in a proportion of familial melanoma kindreds, suggesting that it is the putative 9p21-linked melanoma susceptibility gene. The p19ARF transcript, an alternative spliced form of the CDKN2a gene, has recently been shown to inhibit, like the p16INK4a protein, cell cycle progression, raising the possibility that it might constitute an additional melanoma tumor suppressor gene at the 9p21 locus. To determine the contribution of these candidate genes to familial melanoma genetic predisposition, we screened 10 such kindreds for germline mutations in the p16INK4a and p19ARF genes. Four independent germline missense mutations, mapping in exon 1alpha (Gly23Asp; Arg24Pro) and exon 2 (Asn71Ileu; Pro114Leu) of the CDKN2a gene, were identified. Two previously described polymorphisms were also detected, Ala148Thr in exon 2 and a base change in the 3' untranslated region of exon 3. No disease-associated mutations in exon 1beta of the p19ARF gene were found. Our data support the hypothesis that the CDKN2a is a melanoma susceptibility gene in familial melanoma, whereas the p19ARF gene does not seem to play a significant role.


Hematopoietic stem cell-derived exosomes promote hematopoietic differentiation of mouse embryonic stem cells in vitro via inhibiting the miR126/Notch1 pathway.
Cell-derived exosomes (EXs) can modulate target cell differentiation via microRNAs (miRs) that they carried. Previous studies have shown that miR126 is highly expressed in hematopoietic stem cells (HSCs) and plays a role in hematopoiesis via modulating the Notch pathway that participates in progenitors' cell fate decisions. In this study we investigated whether HSC-derived EXs (HSC-EXs) could affect the differentiation of mouse embryonic stem cells (ESCs) into HSCs. We prepared HSC-EXscon, HSC-EXssc and HSC-EXsmiR126 from control HSCs and the HSCs transfected with scramble control or miR126 mimics, respectively. HSC-EXs were isolated by ultracentrifugation and analyzed using nanoparticle tracking analysis. We incubated the collected EXs with mouse ESCs over a 10-d differentiation induction period, during which HSC-EXs and a Notch pathway activator (Jagged1, 100 ng/mL) were added to the cultures every 3 d. After the 10-d differentiation period, the expression levels of miR126, SSEA1, CD117, Sca1, Notch1 and Hes1 in ESCs were assessed. The generated HSCs were validated by flow cytometry using antibodies against HSC markers (CD117, CD34 and Sca1). Our results revealed that: (1) transfection with miR126 mimics significantly increased miR126 levels in HSC-EXsmiR126. (2) HSC-EX co-culture promoted mouse ESCs differentiation into HSCs with the most prominent effect found in the HSC-EXsmiR126 co-culture. (3) HSC differentiation was verified by reduced SSEA1 expression and increased CD117 and Sca1 expression. (4) All the effects caused by HSC-EXs were accompanied by significant reduction of Notch1 and Hes1 expression, thus inhibition of the Notch1/Hes1 pathway, whereas activation of Notch by Jagged1 abolished the effects of HSC-EXsmiR126. In conclusion, HSC-EXs promote hematopoietic differentiation of mouse ESCs in vitro by inhibiting the miR126/Notch1 pathway.


Accumulation of misfolded SOD1 in dorsal root ganglion degenerating proprioceptive sensory neurons of transgenic mice with amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease affecting upper and lower motoneurons (MNs). Although the motor phenotype is a hallmark for ALS, there is increasing evidence that systems other than the efferent MN system can be involved. Mutations of superoxide dismutase 1 (SOD1) gene cause a proportion of familial forms of this disease. Misfolding and aggregation of mutant SOD1 exert neurotoxicity in a noncell autonomous manner, as evidenced in studies using transgenic mouse models. Here, we used the SOD1(G93A) mouse model for ALS to detect, by means of conformational-specific anti-SOD1 antibodies, whether misfolded SOD1-mediated neurotoxicity extended to neuronal types other than MNs. We report that large dorsal root ganglion (DRG) proprioceptive neurons accumulate misfolded SOD1 and suffer a degenerative process involving the inflammatory recruitment of macrophagic cells. Degenerating sensory axons were also detected in association with activated microglial cells in the spinal cord dorsal horn of diseased animals. As large proprioceptive DRG neurons project monosynaptically to ventral horn MNs, we hypothesise that a prion-like mechanism may be responsible for the transsynaptic propagation of SOD1 misfolding from ventral horn MNs to DRG sensory neurons.


Adverse reactions to herbal therapy in dermatology.
There are many herbal therapies available for dermatological diseases that patients have already begun to discover. Dermatologists must be educated not only in the benefits of these therapies, but must also be aware of some of the risks and adverse effects. They need information about the effects of herbal remedies in order to better serve their patients who may be using herbs to treat their dermatological conditions. This brief review summarizes some of the more common herbal therapies used by many dermatology patients for their skin diseases, and the adverse reactions and drug interactions that may occur.


A review of current treatment strategies for restless legs syndrome (Willis-Ekbom disease).
Restless legs syndrome (RLS), recently renamed Willis-Ekbom disease (WED), is a common movement disorder. It is characterised by the need to move mainly the legs due to uncomfortable, sometimes painful sensations in the legs, which have a diurnal variation and a release with movement. Management is complex. First, centres should establish the severity of RLS using a simple 10-item RLS severity rating scale (IRLS). They should also exclude secondary causes, in particular ensuring normal iron levels. Mild cases can be managed by lifestyle changes, but patients with a IRLS score above 15 usually require pharmacological treatment. Dopaminergic therapies remain the mainstay of medical therapies, with recent evidence suggesting opioids may be particularly effective. This article focuses on the different treatment strategies in RLS, their associated complications and ways to manage them.


[Role of the surgeon in the hospital infections control committees].
Hospital-acquired infections are the ones that develop within hospital stay or appear after discharge. These infections are associated with an increased rate of morbidity and mortality, longer hospital stay and higher hospital costs and Hospital Infections Control Committees have been founded to prevent it. In this review, we intended to investigate the role of the surgeon in this committee.


Influence of controlled encoding and retrieval facilitation on memory performance in patients with different profiles of mild cognitive impairment.
Memory tests able to differentiate encoding and retrieval processes from the memoranda storing ones should be used to differentiate patients in a very early phase of AD. In fact, individuals with mild cognitive impairment (MCI) can be characterized by two different memory profiles: a pure amnestic one (with poor learning and retrieval and poor improvement when encoding is assisted and retrieval is facilitated) and a dysexecutive one (with inefficient encoding and/or poor retrieval strategies and improvement with assisted encoding and retrieval). The amnestic profile characterizes subjects affected by medio-temporal atrophy typical of AD. In this study, a Grober-Buschke memory procedure was used to evaluate normal controls and MCI patients with different cognitive profiles: pure amnestic (aMCIsd), amnestic plus other cognitive impairments (aMCImd) and non-amnestic (naMCI). An index of sensitivity of cueing (ISC) measured the advantage passing from free to cued recall. Results showed that both strategic and consolidation abilities were impaired in the aMCIsd and aMCImd groups and were preserved in the naMCI group. aMCImd, however, compensated the memory deficit with assisted encoding and retrieval, but aMCIsd performed very poorly. When MCI subjects were defined according to the ISC value, subjects with poor ISC were primarily in the aMCIsd group and, to a lesser extent, in the aMCImd group and the naMCI group. Finally, patients with a poor ISC showed cerebral atrophy documented in the precocious phase of AD and the retrosplenial cerebral areas seemed to be the most useful areas for identifying patients in the early phase of AD.


Reduced occurrence of severe visual impairment after introduction of anti-Vascular Endothelial Growth Factor in wet age-related macular degeneration - a population- and register-based study from northern Sweden.
To study the occurrence of severe visual impairment (SVI) and treatment outcome at 12 months in patients treated for wet age-related macular degeneration (AMD) by use of data from the Swedish Macula Register (SMR) and referrals to the regional low vision clinics in five northern counties. Referrals to low vision clinics during 2005, 2009 and 2013 and treatment outcome at 12 months from the SMR database from 2008 until 2013 in patients >65 years of age in five northern counties were included in the survey. The rate of referral due to AMD was significantly reduced during the time period (-48%; p < 0.001). At 12 months, a significant slight mean improvement in logMAR visual acuity (VA) was observed (-0.01, SD 0.37; p < 0.001) after a mean of 5.0 ± 2.3 anti-vascular endothelial growth factor (VEGF)-injections were administered. Age and low baseline VA was associated with less favourable visual outcome (p < 0.001). Referral rate to low vision clinic is a valuable tool for estimating occurrence of SVI and fell between the years 2005 until 2013. Data from the SMR showed improvement in visual acuity on the whole, but also identified patients at high risk for developing SVI during anti-VEGF-treatment.


Thrombopoietin and its receptor, c-mpl, are constitutively expressed by mouse liver endothelial cells: evidence of thrombopoietin as a growth factor for liver endothelial cells.
Present data suggest that the primary site of thrombopoietin (TPO) mRNA is the liver. Previously, we reported that specific murine liver endothelial cells (LEC-1) located in the hepatic sinusoids support in vitro megakaryocytopoiesis from murine hematopoietic stem cells suggesting that these cells may be a source of TPO. We report here that TPO and its receptor, c-mpl, are coexpressed on cloned LEC-1. Enzyme-linked immunosorbent assay (ELISA), biological assay, and flow cytometry studies confirmed the expression of both TPO and its receptor, respectively, at the protein level. TPO activity was enhanced in supernatants from LEC-1 treated with tumor necrosis factor (TNF)-alpha and gamma-interferon (INF). Our results show that TPO through its receptor stimulated the growth of LEC-1 in vitro. These observations establish LEC-1 as a novel source of TPO in the liver. To our knowledge, this is the first report that liver endothelial cells express both TPO and its receptor, c-mpl, and our findings indicate that this cytokine constitutes a growth factor for liver endothelial cells in vitro.


Epidemiological studies of oats consumption and risk of cancer and overall mortality.
A review of epidemiological studies on the intake of oats and oat-based products and its effect on the risk of chronic disease and deaths was performed. Seven studies were identified of cancer risk (two each on prostate and colorectal cancer, and one each on pancreatic, breast and endometrial cancer), and one study on overall mortality. With the exception of a case-control study of pancreatic cancer, all studies were of cohort design: five studies were based on a single cohort from Denmark. The results of most cohort studies suggest a weak protective effect of a high intake of oats on cancer risk (relative risks in the order of 0·9). Potential limitations of the studies are dietary exposure misclassification, low statistical power because of limited exposure contrast and residual confounding. Despite the evidence from experimental and mechanistic studies of a protective effect of oats intake on CVD and diabetes, no epidemiological studies have been conducted on these conditions.


Genetic diversity and population structure of Trypanosoma brucei in Uganda: implications for the epidemiology of sleeping sickness and Nagana.
While Human African Trypanosomiasis (HAT) is in decline on the continent of Africa, the disease still remains a major health problem in Uganda. There are recurrent sporadic outbreaks in the traditionally endemic areas in south-east Uganda, and continued spread to new unaffected areas in central Uganda. We evaluated the evolutionary dynamics underpinning the origin of new foci and the impact of host species on parasite genetic diversity in Uganda. We genotyped 269 Trypanosoma brucei isolates collected from different regions in Uganda and southwestern Kenya at 17 microsatellite loci, and checked for the presence of the SRA gene that confers human infectivity to T. b. rhodesiense. Both Bayesian clustering methods and Discriminant Analysis of Principal Components partition Trypanosoma brucei isolates obtained from Uganda and southwestern Kenya into three distinct genetic clusters. Clusters 1 and 3 include isolates from central and southern Uganda, while cluster 2 contains mostly isolates from southwestern Kenya. These three clusters are not sorted by subspecies designation (T. b. brucei vs T. b. rhodesiense), host or date of collection. The analyses also show evidence of genetic admixture among the three genetic clusters and long-range dispersal, suggesting recent and possibly on-going gene flow between them. Our results show that the expansion of the disease to the new foci in central Uganda occurred from the northward spread of T. b. rhodesiense (Tbr). They also confirm the emergence of the human infective strains (Tbr) from non-infective T. b. brucei (Tbb) strains of different genetic backgrounds, and the importance of cattle as Tbr reservoir, as confounders that shape the epidemiology of sleeping sickness in the region.


Contribution of KCNQ and TREK Channels to the Resting Membrane Potential in Sympathetic Neurons at Physiological Temperature.
The ionic mechanisms controlling the resting membrane potential (RMP) in superior cervical ganglion (SCG) neurons have been widely studied and the M-current (IM, KCNQ) is one of the key players. Recently, with the discovery of the presence of functional TREK-2 (TWIK-related K+ channel 2) channels in SCG neurons, another potential main contributor for setting the value of the resting membrane potential has appeared. In the present work, we quantified the contribution of TREK-2 channels to the resting membrane potential at physiological temperature and studied its role in excitability using patch-clamp techniques. In the process we have discovered that TREK-2 channels are sensitive to the classic M-current blockers linopirdine and XE991 (IC50 = 0.310 ± 0.06 µM and 0.044 ± 0.013 µM, respectively). An increase from room temperature (23 °C) to physiological temperature (37 °C) enhanced both IM and TREK-2 currents. Likewise, inhibition of IM by tetraethylammonium (TEA) and TREK-2 current by XE991 depolarized the RMP at room and physiological temperatures. Temperature rise also enhanced adaptation in SCG neurons which was reduced due to TREK-2 and IM inhibition by XE991 application. In summary, TREK-2 and M currents contribute to the resting membrane potential and excitability at room and physiological temperature in the primary culture of mouse SCG neurons.


Alcohol use disorder in an Israeli general hospital: sociodemographic, ethnic and clinical characteristics.
Alcohol consumption in Israel has increased over the last 20 years. Patients with alcohol use disorder (AUD) who present at a hospital enable early intervention. To examine, for the first time, the characteristics of AUD patients in an Israel general hospital, and whether their alcohol use was documented in their files. A group of 178 consecutive patients referred for psychiatric consultation was compared to a second group of 105 hospitalized patients who were not referred. These two groups were studied to compare risk factors for AUD. Patients in both groups were prospectively interviewed using a CAGE questionnaire, demonstrated as an effective screening instrument for AUD. Patients' files in both groups were examined for documentation of alcohol use. There was no significant difference between the prevalence of AUD in the two groups. The groups were then merged since no significant difference in the risk factor effects between the two groups was found. The risk factors for AUD in the final statistical analysis were lower educational status, living alone, being born in the Former Soviet Union and weaker religious observance. Post-traumatic stress disorder (PTSD), cigarette smoking and substance use were found to be independent risk factors. Soldier status was associated with significant alcohol misuse and AUD (CAGE1-4). Alcohol consumption was documented in the files of AUD patients in 48% of the first group and 21% of the second. Physicians often neglect to take a history of alcohol consumption. Routine use of the CAGE questionnaire is recommended in Israeli general hospitals. Special attention should be given to PTSD patients and to soldiers.


Optical imaging innovations for atherosclerosis research: multiphoton microscopy and optical nanoscopy.
Cardiovascular disease is the leading cause of death and morbidity worldwide. Improving vascular prevention and therapy based on a refined mechanistic pervasion of atherosclerosis as the underlying pathology could limit the effect of vascular disease in aging societies. During the past decades, microscopy has contributed greatly to a better understanding of vascular physiology and pathology by allowing imaging of living specimen with subcellular resolution and high specificity. An important advance has been accomplished through the application of multiphoton microscopy in the vascular domain, a technological development that enabled multidimensional and dynamic imaging deep into the cellular architecture of intact tissue under physiological conditions. To identify and validate new targets for treating atherosclerosis, novel imaging strategies with nanoscale resolution will be essential to visualize molecular processes in intracellular and extracellular compartments. This review will discuss the current use of 2-photon microscopy and will provide an overview and outlook on options for introducing nanoscopic optical imaging modalities in atherosclerosis research.


KLF11 deficiency enhances chemokine generation and fibrosis in murine unilateral ureteral obstruction.
Progression of virtually all forms of chronic kidney disease (CKD) is associated with activation of pro-inflammatory and pro-fibrotic signaling pathways. Despite extensive research, progress in identifying therapeutic targets to arrest or slow progression of CKD has been limited by incomplete understanding of basic mechanisms underlying renal inflammation and fibrosis in CKD. Recent studies have identified Kruppel-like transcription factors that have been shown to play critical roles in renal development, homeostasis, and response to injury. Although KLF11 deficiency has been shown to increase collagen production in vitro and tissue fibrosis in other organs, no previous study has linked KLF11 to the development of CKD. We sought to test the hypothesis that KLF11 deficiency promotes CKD through upregulation of pro-inflammatory and pro-fibrogenic signaling pathways in murine unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis. We found that KLF11-deficiency exacerbates renal injury in the UUO model through activation of the TGF-β/SMAD signaling pathway and through activation of several pro-inflammatory chemokine signaling pathways. Based on these considerations, we conclude that agents increase KLF11 expression may provide novel therapeutic targets to slow the progression of CKD.


POLYPOIDAL CHOROIDAL VASCULOPATHY ASSOCIATED WITH CENTRAL SEROUS CHORIORETINOPATHY: Pachychoroid Spectrum of Diseases.
To study multimodal imaging features of polypoidal choroidal vasculopathy (PCV) associated with central serous chorioretinopathy (CSC) in the same eye. A retrospective observational study of cases of suspected PCV which underwent indocyanine green angiography, fundus fluorescein angiography and optical coherence tomography was done, to look for simultaneous typical CSC-like active leak in the same eye. The relevant history, best-corrected visual acuity, optical coherence tomography, fundus fluorescein angiography, and indocyanine green angiography findings were analyzed. From 226 patients reviewed, 195 patients had PCV from which 6 eyes (3.07%) with features of PCV associated with typical CSC-like active leak in the same eye were identified; 3 men and 3 women with a mean age of 62.6 years. Optical coherence tomography showed notched pigment epithelial detachment in two and irregular peaked pigment epithelial detachment in four cases with subretinal fluid and/or subretinal haemorrhage over a thick choroid with dilated outer choroidal vessels. Fundus fluorescein angiography showed stippled hyperfluorescence at polyp area and a separate typical CSC-like active leak-Inkblot in three and Smokestack in three cases. On indocyanine green angiography, multiple polyps were noted with choroidal hyperpermeability in late phase at the site of CSC leak. The coexistence of PCV with typical CSC-like active leaks and a thick choroid in the same eye simultaneously provides strong evidence that these diseases have an association and support the hypothesis that these conditions may originate from predisposed thick choroid.


Neuroprotective strategies in Parkinson's disease : an update on progress.
In spite of the extensive studies performed on postmortem substantia nigra from Parkinson's disease patients, the aetiology of the disease has not yet been established. Nevertheless, these studies have demonstrated that, at the time of death, a cascade of events had been initiated that may contribute to the demise of the melanin-containing nigro-striatal dopamine neurons. These events include increased levels of iron and monoamine oxidase (MAO)-B activity, oxidative stress, inflammatory processes, glutamatergic excitotoxicity, nitric oxide synthesis, abnormal protein folding and aggregation, reduced expression of trophic factors, depletion of endogenous antioxidants such as reduced glutathione, and altered calcium homeostasis. To a large extent, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) animal models of Parkinson's disease confirm these findings. Furthermore, neuroprotection can be afforded in these models with iron chelators, radical scavenger antioxidants, MAO-B inhibitors, glutamate antagonists, nitric oxide synthase inhibitors, calcium channel antagonists and trophic factors. Despite the success obtained with animal models, clinical neuroprotection is much more difficult to accomplish. Although the negative studies obtained with the MAO-B inhibitor selegiline (deprenyl) and the antioxidant tocopherol (vitamin E) may have resulted from an inappropriate choice of drug (selegiline) or an inadequate dose (tocopherol), the niggling problem that still remains is why these drugs, and others, do work in animals while they fail in the clinic. One reason for this may be related to the fact that in normal human brains the number of dopaminergic neurons falls by around 3-5% every decade, while in Parkinson's disease this decline is greater. Brain autopsy studies have shown that by the time the disease is identified, some 70-75% of the dopamine-containing neurons have been lost. More sensitive reliable methods and clinical correlative markers are required to discern between confoundable symptomatic effects versus a possible neuroprotective action of drugs, namely, the ability to delay or forestall disease progression by protecting or rescuing the remaining dopamine neurons or even restoring those that have been lost.A number of other possibilities for the clinical failure of potential neuroprotectants also exist. First, the animal models of Parkinson's disease may not be totally reflective of the disease and, therefore, the chemical pathologies established in the animal models may not cause, or contribute to, the progression of the disease clinically. Second, because of the series of events occurring in neurodegeneration and our ignorance about which of these factors constitutes the primary event in the pathogenic process, a single drug may not be adequate to induce neuroprotection and, as a consequence, use of a cocktail of drugs may be more appropriate. The latter concept receives support from recent complementary DNA (cDNA) microarray gene expression studies, which show the existence of a gene cascade of events occurring in the nigrostriatal pathway of MPTP, 6-OHDA and methamphetamine animal models of Parkinson's disease. Even with the advent of powerful new tools such as genomics, proteomics, brain imaging, gene replacement therapy and knockout animal models, the desired end result of neuroprotection is still beyond our current capability.


Incompatibility between E colicin plasmids.
We have tested the ability of pairs of colicin E plasmids to replicate stably in the same cell line. Although many of the pairs of E colicin plasmids were compatible, plasmids ColE3-CA38, ColE7-K317 and ColE8-J were mutually incompatible, as were ColE5-099, ColE6-CT14 and ColE9-J. Incompatibility between ColE6-CT14 and ColE5-099 or ColE9-J was asymmetrical, whereas incompatibility between the other plasmid pairs was symmetrical.


Expression of the rhesus glycoproteins, ammonia transporter family members, RHCG and RHBG in male reproductive organs.
The rhesus glycoproteins, Rh B glycoprotein (RHBG) and Rh C glycoprotein (RHCG), are recently identified ammonia transporters. Rhcg expression is necessary for normal male fertility, but its specific cellular expression is unknown, and Rhbg has not been reported to be expressed in the male reproductive tract. This study sought to determine the specific cellular expression of Rhcg, to determine whether Rhbg is expressed in the male reproductive tract, and, if so, to determine which cells express Rhbg using real-time RT-PCR, immunoblot analysis, and immunohistochemistry. Both Rhbg and Rhcg were expressed throughout the male reproductive tract. In the testis, high levels of Rhbg were expressed in Leydig cells, and Rhcg was expressed in spermatids during the later stages of their maturation (steps 13-16) in stages I-VIII of the seminiferous epithelium cycle. In the epididymis, basolateral Rhbg was present in narrow cells in the initial segment, in principal cells in the upper corpus, and in clear cells throughout the epididymis. Apical Rhcg immunolabel was present in principal cells in the caput and upper corpus epididymidis and in clear cells in the middle and lower corpus and cauda epididymidis. In the vas deferens, apical Rhcg immunolabel and basolateral Rhbg immunolabel were present in some principal cells and colocalized with H(+)-ATPase immunolabel. We conclude that both Rhbg and Rhcg are highly expressed in specific cells in the male reproductive tract where they can contribute to multiple components of male fertility.


Bacteriophage endolysin Lyt μ1/6: characterization of the C-terminal binding domain.
The gene product of orf50 from actinophage μ1/6 of Streptomyces aureofaciens is a putative endolysin, Lyt μ1/6. It has a two-domain modular structure, consisting of an N-terminal catalytic and a C-terminal cell wall binding domain (CBD). Comparative analysis of Streptomyces phage endolysins revealed that they all have a modular structure and contain functional C-terminal domains with conserved amino acids, probably associated with their binding function. A blast analysis of Lyt μ1/6 in conjunction with secondary and tertiary structure prediction disclosed the presence of a PG_binding_1 domain within the CBD. The sequence of the C-terminal domain of lyt μ1/6 and truncated forms of it were cloned and expressed in Escherichia coli. The ability of these CBD variants fused to GFP to bind to the surface of S. aureofaciens NMU was shown by specific binding assays.


Retinoic acid regulation of homoeostatic synaptic plasticity and its relationship to cognitive disorders.
There is increasing interest in retinoic acid (RA) as a regulator of the complex biological processes underlying the cognitive functions performed by the brain. The importance of RA in brain function is underlined by the brain's high efficiency in converting vitamin A into RA. One crucial action of RA in the brain is dependent on RA receptor α (RARα) transport out of the nucleus, where it no longer regulates transcription but carries out non-genomic functions. RARα, when localised in the cytoplasm, particularly in neuronal dendrites, acts as a translational suppressor. It regulates protein translation as a crucial part of the mechanism maintaining homoeostatic synaptic plasticity, which is characterised by neuronal changes necessary to restore and balance the excitability of neuronal networks after perturbation events. Under normal conditions of neurotransmission, RARα without ligand suppresses the translation of proteins. When neural activity is reduced, RA synthesis is stimulated, and RA signalling via RARα derepresses the translation of proteins and synergistically with the fragile X mental retardation protein allows the synthesis of Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors that re-establish normal levels of synaptic activity. Homoeostatic synaptic plasticity underlies many cognitive processes, so its impairment due to dysregulation of RA signalling may be involved in neurodevelopmental disorders such as autism, which is also associated with FMRP. A full understanding of RA signalling control of homoeostatic synaptic plasticity may point to treatments.