Testing the credibility, feasibility and acceptability of an optimised behavioural intervention (OBI) for avoidant chronic low back pain patients: protocol for a randomised feasibility study.
Chronic back pain continues to be a costly and prevalent condition. The latest NICE guidelines issued in 2009 state that for patients with persistent back pain (of between six weeks and twelve months duration), who are highly distressed and/or disabled and for whom exercise, manual therapy and acupuncture has not been beneficial, the evidence supports a combination of around 100 hours of combined physical and psychological treatment. This is costly, and may prove unacceptable to many patients. A key recommendation of these guidelines was for further randomised controlled trials (RCTs) of psychological treatment and to target treatment to specific sub-groups of patients. Recent trials that have included psychological interventions have shown only moderate improvement at best, and results are not maintained long term. There is therefore a need to test theoretically driven interventions that focus on specific high-risk sub-groups, in which the intervention is delivered at full integrity against a credible control. A feasibility study of a pragmatic randomised controlled trial comparing psychologist-delivered Contextual Cognitive Behavioural Therapy (CCBT) against Treatment As Usual (TAU) physiotherapy delivered by physiotherapists for the treatment of chronic lower back pain in 'avoidant' patients. Ninety-two patients referred for physiotherapy will be recruited and randomised on a 1:1 basis to receive CCBT or TAU. Treatment groups will be balanced by centre and pain interference score. Primary outcomes include assessing the credibility and acceptability of the intervention, and to demonstrate proof of principle through a greater change in pain acceptance in the CCBT arm, measured by the Acceptance and Action -II and the Chronic Pain Acceptance questionnaires. In addition, the feasibility of carrying out a full trial will be explored with reference to recruitment and follow-up rates including the assessment of the burden of outcome measure completion. Secondary patient outcomes include disability, pain, fear of movement, mood, quality of life, and global recovery. Outcomes are measured at three and six months post-randomisation. This paper details the rationale, design, therapist training system and recruitment methods to be used in a feasibility study which will inform the design and efficient implementation of a future definitive RCT. ISRCTN43733490.


Immune privilege and the skin.
This chapter summarizes the evidence that defined compartments of the hair follicle (HF) and nail epithelium maintain an area of relative immune privilege (IP). HF and nail IP is chiefly characterized by absent or very low level of expression of major histocompatibility complex class Ia antigens, complemented by a number of factors, such as the local production of potent immunosuppressive agents, dysfunction of professional antigen-presenting cells and inhibition of natural killer cell activities. In the hair bulb, IP is seen only in the anagen stage of HF cycling, while the nail apparatus continuously maintains an IP site in its proximal nail matrix, since the nail apparatus does not cycle. Possibly, the (non-cycling) bulge area of human scalp HFs also enjoys some relative, stably maintained IP, even though it is not as pronounced as the IP of the anagen hair bulb. A collapse of HF and nail IP likely plays a key role in the pathogenesis of one of the most common organ-specific autoimmune diseases, alopecia areata. Therefore, the therapeutic restoration of IP collapse promises to be a particularly effective future strategy for the treatment of alopecia areata.


The role of verbal memory in regressions during reading is modulated by the target word's recency in memory.
During reading, a number of eye movements are made backward, on words that have already been read. Recent evidence suggests that such eye movements, called regressions, are guided by memory. Several studies point to the role of spatial memory, but evidence for the role of verbal memory is more limited. In the present study, we examined the factors that modulate the role of verbal memory in regressions. Participants were required to make regressions on target words located in sentences displayed on one or two lines. Verbal interference was shown to affect regressions, but only when participants executed a regression on a word located in the first part of the sentence, irrespective of the number of lines on which the sentence was displayed. Experiments 2 and 3 showed that the effect of verbal interference on words located in the first part of the sentence disappeared when participants initiated the regression from the middle of the sentence. Our results suggest that verbal memory is recruited to guide regressions, but only for words read a longer time ago.


Presence of a base line level of sister chromatid exchanges in somatic cells of Drosophila melanogaster in vivo and in vitro.
Sister chromatid exchanges (SCEs) under in vivo and in vitro conditions were examined in ganglion cells of third-instar larvae of Drosophila melanogaster (Oregon-R). In the in vivo experiment, third-instar larvae were fed on synthetic media containing 5-bromo-2'-deoxyuridine (BrdUrd). After two cell cycles, ganglia were dissected and treated with colchicine. In the in vitro experiment, the ganglia were also incubated in media containing BrdUrd for two cell cycles, and treated with colchicine. SCEs were scored in metaphase stained with Hoechst 33258 plus Giemsa. The frequencies of SCEs stayed constant in the range of 25-150 micrograms/ml and 0.25-2.5 micrograms/ml of BrdUrd in vivo and in vitro, respectively. SCEs gradually increased at higher concentrations, strongly suggesting that at least a fraction of the detected SCEs are spontaneous. The constant levels of SCE frequency were estimated, on the average, at 0.103 per cell per two cell cycles for females and 0.101 for males in vivo and at 0.096 for females and 0.091 for males in vitro. No difference was found in the SCE frequency between sexes at any of the BrdUrd concentrations. The analysis for the distribution of SCEs within chromosomes revealed an extraordinarily high proportion of the SCEs at the junctions between euchromatin and heterochromatin; the remaining SCEs were preferentially localized in the euchromatic regions of the chromosomes and in the heterochromatic Y chromosome. These results were largely inconsistent with those of Gatti et al. (1979).


Fine-needle aspiration of cystic lesions of the kidney. Morphologic spectrum and diagnostic problems in 41 cases.
Although imaging studies show the nature of most cystic lesions of the kidney (RCs), many RCs require fine-needle aspiration (FNA) for accurate diagnosis. Interpretation of the FNAs remains challenging. The FNA specimens of 41 RCs were reviewed and correlated with imaging studies. Final diagnoses for 30 cytologically benign lesions were simple cyst (28), acquired cystic kidney (1), and cystic renal carcinoma (1). The fluid from the benign cysts displayed macrophages, epithelial cells from the cyst lining, tubular cells, neutrophils, and Liesegang rings. Fluid from the acquired cystic kidney and the cystic renal cell carcinoma showed features similar to those of the benign cysts. The 9 cases with "suspicious" cytology included 5 complex cystic lesions displaying rare but atypical epithelial cell clusters, 3 low-grade renal cell carcinomas with many mildly atypical papillary clusters of epithelial cells, and 1 simple benign cyst with many tubular cells. The 2 cytologically malignant lesions were cystic renal cell carcinomas with abundant tumor cells with partially clear cytoplasm and atypical nuclei admixed with abundant macrophages and lymphocytes; 1 case developed in a kidney with acquired cystic disease. Simple cysts remain the most frequently aspirated RCs, but complex cystic lesions are increasingly recognized. Since many RCs are composed of independent loculi, a nonrepresentative sample is a potential problem, and cytologic-radiologic correlation becomes mandatory. The "suspicious" patterns identified in this study should serve as diagnostic guidelines and set the foundation for future validation.


Enhancement of Growth and Secondary Metabolites by the Combined Treatment of Trace Elements and Hydrogen Water in Wheat Sprouts.
This study aimed to evaluate the response of Triticum aestivum to hydrogen water (HW) and trace elements treated with HW. A pot experiment was conducted to assess the growth indices, secondary metabolites, and antioxidant levels. The response surface methodology (RSM) approach was used to ascertain the concentrations and significant interaction between treatments. The outcomes demonstrated that the combined treatment of Se acid and Mo oxide exhibited a notable positive effect on the growth and secondary metabolites, when treated with HW as compared to distilled water (DW). Notably, the interaction between these two treatments is significant, and the higher response was observed at the optimal concentration of 0.000005% for Se acid and 0.06% for Mo oxide. Additionally, an in vitro experiment revealed that the mixture treatment inhibits the accumulation of lipids in HepG2 hepatocytes cells. Moreover, metabolic analysis revealed that upregulated metabolites are linked to the inhibition of lipid accumulation. In addition, the analysis emphasizes that the continued benefits of higher plants as a renewable supply for chemicals compounds, especially therapeutic agents, are being expanded and amplified by these state-of-the-art technologies.


S. aureus virulence factors decrease epithelial barrier function and increase susceptibility to viral infection.
Individuals with atopic dermatitis (AD) are highly colonized by Staphylococcus aureus and are more susceptible to severe viral complications. We hypothesized that S. aureus secreted virulence factors may alter keratinocyte biology to enhance viral susceptibility through disruption of the skin barrier, impaired keratinocyte differentiation, and/or inflammation. To address this hypothesis, human keratinocytes were exposed to conditioned media from multiple S. aureus strains that vary in virulence factor production (USA300, HG003, and RN4220) or select purified virulence factors. We have identified the S. aureus enterotoxin-like superantigen SElQ, as a virulence factor of interest, since it is highly produced by USA300 and was detected on the skin of 53% of AD subjects (n = 72) in a study conducted by our group. Treatment with USA300 conditioned media or purified SElQ resulted in a significant increase in keratinocyte susceptibility to infection with vaccinia virus, and also significantly decreased barrier function. Importantly, we have previously demonstrated that keratinocyte differentiation influences susceptibility to viral infection, and our qPCR observations indicated that USA300 S. aureus and SElQ alter differentiation in keratinocytes. CRISPR/Cas9 was used to knock out CD40, a potential enterotoxin receptor on epithelial cells. We found that CD40 expression on keratinocytes was not completely necessary for SElQ-mediated responses, as measured by proinflammatory cytokine expression and barrier function. Together, these findings support that select S. aureus virulence factors, particularly SElQ, enhance the susceptibility of epidermal cells to viral infection, which may contribute to the increased cutaneous infections observed in individuals with AD. IMPORTANCE Staphylococcus aureus skin colonization and infection are frequently observed in individuals with atopic dermatitis. Many S. aureus strains belong to the clonal group USA300, and these strains produce superantigens including the staphylococcal enterotoxin-like Q (SElQ). Our studies highlight that SElQ may play a key role by altering keratinocyte differentiation and reducing barrier function; collectively, this may explain the AD-specific enhanced infection risk to cutaneous viruses. It is unclear what receptor mediates SElQ's effects on keratinocytes. We have shown that one putative surface receptor, CD40, was not critical for its effects on proinflammatory cytokine production or barrier function.


Prevalence and Variation of Clinically Recognized Inpatient Alcohol Withdrawal Syndrome in the Veterans Health Administration.
No prior study has evaluated the prevalence or variability of alcohol withdrawal syndrome (AWS) in general hospitals in the United States. This retrospective study used secondary data from the Veterans Health Administration (VHA) to estimate the documented prevalence of clinically recognized AWS among patients engaged in VHA care who were hospitalized during fiscal year 2013. We describe variation in documented inpatient AWS by geographic region, hospital, admitting specialty, and inpatient diagnoses using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis and/or procedure codes recorded at hospital admission, transfer, or discharge. Among 469,082 eligible hospitalizations, the national prevalence of documented inpatient AWS was 5.8% (95% confidence interval [CI] 5.2%-6.4%), but there was marked variation by geographic region (4.3%-11.2%), hospital (1.4%-16.1%), admitting specialty (0.7%-19.0%), and comorbid diagnoses (1.3%-38.3%). AWS affected a high proportion of psychiatric admissions (19.0%, 95% CI 17.5%-20.4%) versus Medical (4.4%, 95% CI 4.0%-4.8%) or surgical (0.7%, 95% CI 0.6%-0.8%); though by volume, medical admissions represented the majority of hospitalizations complicated by AWS (n = 13,478 medical versus n = 12,305 psychiatric and n = 595 surgical). Clinically recognized AWS was also common during hospitalizations involving other alcohol-related disorders (38.3%, 95% CI 35.8%-40.8%), other substance use conditions (19.3%, 95% CI 17.7%-20.9%), attempted suicide (15.3%, 95% CI 13.0%-17.6%), and liver injury (13.9%, 95% CI 12.6%-15.1%). AWS was commonly recognized and documented during VHA hospitalizations in 2013, but varied considerably across inpatient settings. This clinical variation may, in part, reflect differences in quality of care and warrants further, more rigorous investigation.


Changes in the serum lipid profile in man during 24 months of arctic residence.
The influence of the severe climate and geographical conditions at the Svalbard archipelago (78-79 degrees N) on serum lipid levels were measured in Caucasian miners who had arrived from the southern part of Ukraine and Russia (48 degrees N). The persons included in the study were randomly divided in five groups according to their time of living (1, 3, 6, 12 and 24 months) at Svalbard. Blood sampling took place during a two week period in January, when the Svalbard archipelago is into its polar night. General elevated levels of triglycerides were found in group I-III (1, 3 and 6 months stay), whereas the values measured in group IV and V (12 and 24 months stay) were somewhat lower. This apparent decline in triglycerides was paralelled by generally elevated levels of HDL cholesterol. The serum level of phospholipids was similar in all groups. All the level of free fatty acids was apparently higher in groups IV and V, particularly 18:3 and 16:1. These results may be indicative of a rise in triglyceride consumption after about a 12 month stay in the archipelago. Besides, the elevated levels of 18:3 and 16:1 fatty acids imply dietary modifications of the serum fatty acids.


Impact of the patient-centered medical home on veterans' experience of care.
A core tenet of the patient-centered medical home is improving patient experiences of care, but evidence is limited on the impact of medical home adoption on patient experiences of care. We conducted a repeated cross-sectional, patient-level analysis in 1 region of the Veterans Health Administration (VHA), which includes 56 primary care sites. Our primary outcomes include 5 domains of patient care experience from the Survey of Healthcare Experiences of Patients (SHEP). We used a linear probability model to test whether changes in medical home implementation are associated with changes in patient experience of care. During the study period, 30,849 SHEP respondents received care. We observed significant increase in medical home implementation: a 10-fold increase in percentage of primary care providers who were part of a medical home, a 7-fold increase in 8 out of 9 structural measures of the medical home, and an increase in overall quality of medical home implementation. Yet, we found no association between medical home adoption and 5 domains of patient experience of care. For example, patients assigned to a medical home provider had a 0.51 percentage point (95% CI, -1.8 to 2.8) higher response in how well they communicate with their provider compared with patients not assigned to a medical provider and with patients in the pre-medical home period. Despite wide implementation of the medical home, we did not see an improvement in patient experiences of care in the VHA. As we focus on primary care transformation, we need to find ways to incorporate the patient's voice and input into these transitions.


[Not Available].
Impact of the French consensus guidlines on the management of colonic and rectal cancer: A population-based study F. Borie, M. El Nasser, A. Herrero, C. Gras-Aygon, CRISAP-LR, J.-P. Daures, B. Tretarre Aim: To compare the management of colorectal cancer (CRC) before and after the French consensus conferences of rectal cancer (RC) in 1994 and colonic cancer (CC) in 1998. From 344 CCR incident cases in 1992 and 545 in 2000, patient characteristics, tumor data, and diagnostic and treatment modalities were collected to compare the management of CRC. Résults: Post-operative mortality did not change significantly (4% in 1992 and 2.8% in 2000). No trends were observed in disease stage at diagnosis or rate of resection. For patients with CC (n=244 in 1992 and n=396 in 2000), the number of resection specimens with at least 12 lymph nodes increased from 11% in 1992 to 27% in 2000 (p<0.001). For CC with Dukes stage C and D, the use of chemotherapy increased significantly: for Dukes Stage C from 45% in 1992 to 55% in 2000; for Dukes Stage D from 37% in 1992 to 67% in 2000. For patients with RC (n=100 in 1992 and n=149 in 2000), no change in use of adjuvant radiotherapy was observed: 59% in 1992 versus 53.4% in 2000. Preoperative radiotherapy for RC was performed in 63% in 1992 and 75% in 2000 (p=0.7). The consensus guidelines appear to have moderately influenced management practices. A better diffusion of guidelines to practitioners and a systematic evaluation of actual practices would be helpful to improve their impact.


Using ecological whole body kinematics to evaluate effects of medication adjustment in Parkinson disease.
Functional motor impairments including mobility are major reasons for clinical intervention and medication adjustment in symptomatic therapy for Parkinson's disease (PD). Outcome measures used to assess the impact of medication are mostly based on patients' memory or diaries which, considering the gaps between visits, are neither objective nor very reliable. Investigating the feasibility of using movement features extracted from ecological whole-body kinematics recordings to measure the quantitative and qualitative changes in multiple aspects of mobility after medication changes in PD. Eleven patients with PD (PwPD) performed mobility tasks in their own home, wearing a full body wireless inertial sensing based motion capture system. Three scripted walking tasks (walking, fast walking, and walk turns) were examined at baseline and two weeks after medication changes. Clinical scales, including investigator-rated clinical global impression of improvement (CGI-I), were collected at both visits. Out of 59 recorded body joint variables, five were identified as pertinent. Changes were represented in vector space as a plot of mean versus peak amplitude. Regression analysis was used to predict clinical improvement or worsening based on these vector features. The predictors were able to explain (>98.5% of variance) patients' clinical global impression of improvement, thus correctly predicting 5 cases of improvement and 2 cases of worsening. This study provided a method of extracting clinically meaningful reports from ecological kinematic data showing changes after drug adjustments. The results are presented using a novel concept called change space that may be more understandable for clinical staff.


Biogenic amine production by wild lactococcal and leuconostoc strains.
Two qualitative and one quantitative HPLC methods were evaluated for the detection of biogenic amine producers among wild dairy lactococcal and leuconostoc strains. High tyramine producers ranging from 370 to 807 mg l-1 were detected by qualitative methods and confirmed by HPLC analysis. Tyramine levels detected throughout the incubation time depended on the concentration of the amino acid precursor available and no tyramine production was observed when strains were grown in milk. However, increasing amounts of tyramine were detected in cultures grown in milk supplemented with different concentrations of tyrosine. Qualitative methods failed to detect weak producers so that tryptamine production (< 7 mg l-1) could only be determined by HPLC. None of the tested strains was able to produce histamine. Simultaneous production of different amines was observed by HPLC although no colour change was observed in the specific decarboxylase media. Thus, it was concluded that the amine forming ability should be taken into account when selecting starters for milk fermentations. Qualitative methods could be used as a first screening step to eliminate the highest amine producers while the quantitative methods would detect any producing strain.


The effects of hyperglycaemia on changes during reperfusion following focal cerebral ischaemia in the cat.
The effects of isosmolar loads of glucose and saline after onset of focal cerebral ischaemia (middle cerebral artery occlusion) were compared in cats. In cats given saline cerebral blood flow (CBF) fell and then rose slightly on the marginal gyrus (infarct penumbra). There was a sustained fall in CBF on the suprasylvian and ectosylvian gyri (infarct core). Reperfusion restored blood flow to preocclusion levels with no overall postischaemic hypoperfusion. Below ischaemic flows of 14 ml/100 g/min brain specific gravity was reduced in a smaller proportion of gyri by contrast with non reperfused cortex, suggesting that in some gyri resolution of cerebral oedema had taken place. GABA uptake was normal in the infarct core, but was reduced within the ischaemic penumbra. In animals given glucose after occlusion, CBF fell on the marginal gyrus during reperfusion. The degree of resolution of cerebral oedema was less than in saline infused cats. GABA uptake showed a pattern of abnormality similar to that seen in saline infused cats, except that uptake values were lower in the infarct core. Pial surface potassium activity remained elevated in the penumbra following reperfusion in glucose infused cats, but returned to normal in saline infused cats. Implications for the management of cerebral ischaemia in man are discussed.


Acyclic cucurbit[n]uril-type molecular containers: influence of glycoluril oligomer length on their function as solubilizing agents.
We present the synthesis of a series of six new glycoluril derived molecular clips and acyclic CB[n]-type molecular containers (1–3) that all feature SO3(−) solubilizing groups but differ in the number of glycoluril rings between the two terminal dialkoxyaromatic sidewalls. We report the X-ray crystal structure of 3b which shows that its dialkoxynaphthalene sidewalls actively define a hydrophobic cavity with high potential to engage in π–π interactions with insoluble aromatic guests. Compounds 1–3 possess very good solubility characteristics (≥38 mM) and undergo only very weak self-association (Ks < 92 M(−1)) in water. The weak self-association is attributed to unfavorable SO3(−)···SO3(−) electrostatic interactions in the putative dimers 12–42. Accordingly, we created phase solubility diagrams to study their ability to act as solubilizing agents for four water insoluble drugs (PBS-1086, camptothecin, β-estradiol, and ziprasidone). We find that the containers 3a and 3b which feature three glycoluril rings between the terminal dialkoxy-o-xylylene and dialkoxynaphthalene sidewalls are less efficient solubilizing agents than 4a and 4b because of their smaller hydrophobic cavities. Containers 1 and 2 behave as molecular clip type receptors and therefore possess the ability to bind to and thereby solubilize aromatic drugs like camptothecin, ziprasidone, and PBS-1086.


Improving robustness of automatic cardiac function quantification from cine magnetic resonance imaging using synthetic image data.
Although having been the subject of intense research over the years, cardiac function quantification from MRI is still not a fully automatic process in the clinical practice. This is partly due to the shortage of training data covering all relevant cardiovascular disease phenotypes. We propose to synthetically generate short axis CINE MRI using a generative adversarial model to expand the available data sets that consist of predominantly healthy subjects to include more cases with reduced ejection fraction. We introduce a deep learning convolutional neural network (CNN) to predict the end-diastolic volume, end-systolic volume, and implicitly the ejection fraction from cardiac MRI without explicit segmentation. The left ventricle volume predictions were compared to the ground truth values, showing superior accuracy compared to state-of-the-art segmentation methods. We show that using synthetic data generated for pre-training a CNN significantly improves the prediction compared to only using the limited amount of available data, when the training set is imbalanced.


Structures of KaiC circadian clock mutant proteins: a new phosphorylation site at T426 and mechanisms of kinase, ATPase and phosphatase.
The circadian clock of the cyanobacterium Synechococcus elongatus can be reconstituted in vitro by three proteins, KaiA, KaiB and KaiC. Homo-hexameric KaiC displays kinase, phosphatase and ATPase activities; KaiA enhances KaiC phosphorylation and KaiB antagonizes KaiA. Phosphorylation and dephosphorylation of the two known sites in the C-terminal half of KaiC subunits, T432 and S431, follow a strict order (TS-->pTS-->pTpS-->TpS-->TS) over the daily cycle, the origin of which is not understood. To address this void and to analyze the roles of KaiC active site residues, in particular T426, we determined structures of single and double P-site mutants of S. elongatus KaiC. The conformations of the loop region harboring P-site residues T432 and S431 in the crystal structures of six KaiC mutant proteins exhibit subtle differences that result in various distances between Thr (or Ala/Asn/Glu) and Ser (or Ala/Asp) residues and the ATP gamma-phosphate. T432 is phosphorylated first because it lies consistently closer to Pgamma. The structures of the S431A and T432E/S431A mutants reveal phosphorylation at T426. The environments of the latter residue in the structures and functional data for T426 mutants in vitro and in vivo imply a role in dephosphorylation. We provide evidence for a third phosphorylation site in KaiC at T426. T426 and S431 are closely spaced and a KaiC subunit cannot carry phosphates at both sites simultaneously. Fewer subunits are phosphorylated at T426 in the two KaiC mutants compared to phosphorylated T432 and/or S431 residues in the structures of wt and other mutant KaiCs, suggesting that T426 phosphorylation may be labile. The structures combined with functional data for a host of KaiC mutant proteins help rationalize why S431 trails T432 in the loss of its phosphate and shed light on the mechanisms of the KaiC kinase, ATPase and phosphatase activities.


Dopamine supports coupling of attention-related networks.
Attentional processing has been associated with the dorsal attention, default mode, and frontoparietal control networks. The dorsal attention network is involved in externally focused attention whereas the default mode network is involved in internally directed attention. The frontoparietal control network has been proposed to mediate the transition between external and internal attention by coupling its activity to either the dorsal attention network or the default mode network, depending on the attentional demand. Dopamine is hypothesized to modulate attention and has been linked to the integrity of these three attention-related networks. We used PET with 6-[(18)F]fluoro-L-m-tyrosine to quantify dopamine synthesis capacity in vivo and fMRI to acquire stimulus-independent brain activity in cognitively healthy human subjects. We found that in the resting state where internal cognition dominates, dopamine enhances the coupling between the frontoparietal control network and the default mode network while reducing the coupling between the frontoparietal control network and the dorsal attention network. These results add a neurochemical perspective to the role of network interaction in modulating attention.


Seasonal variations affect physical activity and pulmonary rehabilitation outcomes.
Seasonal differences may influence levels of physical activity and outcomes of a pulmonary rehabilitation (PR) program. This study examined the effect of seasonal variations upon baseline measures and outcomes of physical activity, exercise performance, and health status in PR. Stable patients (N = 95) with chronic obstructive pulmonary disease (COPD) were studied and placed into the seasonal group corresponding to when PR commenced: spring (n = 18), summer (n = 23), autumn (n = 34), winter (n = 20). Physical activity was measured by a uniaxial accelerometer, exercise performance by the Incremental Shuttle Walking Test (ISWT), and health status by the Chronic Respiratory Disease Questionnaire-Self Reported. Patients who commenced PR in the winter had lower levels of physical activity at baseline (P = .02) and attained the largest improvements when compared with any other seasonal group (P = .04). No seasonal variation was detected in ISWT scores or health status either prior to or upon completion of PR. The results of this study suggest that levels of daily activity may be vulnerable to seasonal variations and this should be considered when examining physical activity levels in patients with COPD.


[Severe postoperative heart blocks appearing late. 16 cases].
Sixteen patients, aged 4 to 42 years, operated for congenital heart disease, presented, months or years after surgery, complete atrioventricular (11 cases) or sinoatrial block (5 cases). Six patients had transient complete atrioventricular block in the immediate postoperative period, the maximum duration of which was less than 30 days. The late postoperative period was defined as at least 6 months after surgery. The period between surgery and the implantation of a pacemaker varied from 9 months to 19 years, average 6,3 years. Analysis of long term electrocardiographic studies distinguished three types of progression: --group I: alternation of sinus rhythm and conduction defect until definitive block, sometimes presenting with syncope; --group II: sudden, severe conduction defect after a long period of sinus rhythm; --group III: progressive lengthening of the PR interval. Seven patients developed syncope; 4 had dizziness, 2 were short of breath; only 3 were asymptomatic. All underwent permanent pacing. The incidence of late conduction defects appears to be 1 to 2% of operated patients. The causes include progressive fibrosis, slow sclerosis extending over conduction pathways which are congenitally fragile. Most late blocks are of an advanced degree. Some may be responsible for unexplained sudden death. It is therefore desirable to avoid this complication by the judicious and considered implantation of a cardiac pacemaker. Some authors mention the following factors in deciding on the indications for pacing: --complete, transient atrioventricular block during the operation or the immediate postoperative period; --ECG appearances of right bundle branch block and left anterior hemiblock, or trifascicular block; --His bundle studies.(ABSTRACT TRUNCATED AT 250 WORDS)


Triple negative breast cancer: a retrospective study of Hispanics residing in Puerto Rico.
Triple-negative breast cancer (TNBC) demonstrates unique clinicopathological characteristics and survival outcomes. Several studies have documented important disparities in Hispanic women compared to other racial/ethnic groups; nevertheless, data on this entity in a population based Latin country are very limited. Our goal was to assess demographic and clinicopathological characteristics in essentially a pure population of Puerto Rican females with TNBC residing in Puerto Rico, as well as to determine their overall survival and progression-free survival in order to compare with published data. By searching the electronic medical records data base, 54 patients were identified as TNBC. The median follow-up period was 25 months (range, 2-78). Univariate analysis of pretreatment risk factors was conducted. The median age at diagnosis was 55 years. Of 54 cases, 51 had stage I-III presentation. T1/T2 tumors were found in 88.9% and absence of nodal involvement in 68.5%. Prognostic factors for progression free survival (PFS) that were statistically significant were lymph node involvement (p = 0.02), tumor size > 2 cm (p = 0.037) and stage IV (p = 0.00002). The 5-year overall survival and PFS were 81% and 80%, respectively. RESULTS are very similar to published data on females from North America and Europe. Differences in clinical outcome and stage at diagnosis in Hispanic women with TNBC are more likely explained by socioeconomic status and adequate access to care, rather than biological/genetic differences. The association of triple-negative breast cancer with poor prognosis deserves re-evaluation given that patients with negative node involvement and no metastasis appear to be highly


[Individual differences in global vs. local visual perception of hierarchical stimuli under conditions of free and forced recognition].
Sixteen adult subjects were asked to recognize hierarchical letters at either local or global levels. The experiment included two sessions, corresponding to free recognition and forced recognition with the attention directed to a specific level of hierarchy. The analysis of recognition errors and reaction time in the condition of free recognition revealed two individual strategies of visual perception: the "global strategy" (the global level was chosen more frequently) and the "local strategy" (the local level was chosen more frequently). In the condition of forced recognition, the subjects who preferred the "global strategy" demonstrated the expected "global interference effect". The representatives of the "local strategy" showed the inversion of this effect, i.e. their reaction time significantly increased during recognition of the conflict stimuli at the global level.


Roles of Exosomes in Ocular Diseases.
Exosomes, nanoscale vesicles with a diameter of 30 to 150 nm, are composed of a lipid bilayer, protein, and genetic material. Exosomes are secreted by virtually all types of cells in the human body. They have key functions in cell-to-cell communication, immune regulation, inflammatory response, and neovascularization. Mounting evidence indicates that exosomes play an important role in various diseases, such as cancer, cardiovascular diseases, and brain diseases; however, the role that exosomes play in eye diseases has not yet been rigorously studied. This review covers current exosome research as it relates to ocular diseases including diabetic retinopathy, age-related macular degeneration, autoimmune uveitis, glaucoma, traumatic optic neuropathies, corneal diseases, retinopathy of prematurity, and uveal melanoma. In addition, we discuss recent advances in the biological functions of exosomes, focusing on the toxicity of exosomes and the use of exosomes as biomarkers and drug delivery vesicles. Finally, we summarize the primary considerations and challenges to be taken into account for the effective applications of exosomes.


Mineral deposition in diethylstilbestrol- and Synovex-treated steers.
The effects of diethylstilbestrol (DES) and Synovex-S hormonal growth promotants on composition of body ash deposited by feedlot beef steers were studied in two slaughter-balance trials. Trial 1 consisted of three groups of eight Hereford steers averaging 225 kg initial body weight. One group was initially slaughtered (IS) at the beginning of the trial and two groups, control (C) and DES-treated (20 mg/steer daily in diet), were fed for 177 d and then slaughtered. Trial 2 consisted of 28 Hereford steers averaging 310 kg initial body weight. Four steers were IS and 24 steers were assigned to a factorial arrangement of treatments (- or + Synovex-S ear implant and - or + dietary kiln dust), fed for 126 d and slaughtered. Each Synovex-S ear implant contained 200 mg progesterone and 20 mg estradiol benzoate. Kiln dust (KD) was fed as a digestive tract buffer, and the +KD diets contained 1.23% Ca and .37% P compared with .45% Ca and .36% P in -KD diets on an as-fed basis. Mineral concentration in body tissue was greater for IS than for fed steers reflecting deposition of soft tissue, particularly fat, during the feeding period. Mineral concentration in body tissue was similar between C and hormonally-treated steers. Mineral composition of tissue ash in IS, C and hormonally-treated steers and composition of ash deposited during the feeding period for C and treated steers were similar. The results suggest that both DES and Synovex treatments of beef steers do not cause an increased propensity for skeletal growth but that ash deposition is of similar composition in C and treated steers.


Myocardial preservation: a comparison of oxygenated crystalloid and blood cardioplegia.
The purpose of this experiment was to compare myocardial protective effect after global ischemia using oxygenated crystalloid (CCcO2) and an oxygenated blood (BCcO2) cardioplegic solutions. Post-ischemic ventricular performance was studied in 2 equal (n = 7) groups of dogs subjected to 120 min of global ischemia induced at average myocardial temperatures of 8 degrees C in the CCcO2 group and 18 degrees C in the BCcO2 group. Left ventricular (LV) function included analysis of LV systolic function (global and regional function), LV diastolic function (chamber and myocardial stiffness) and LV relaxation was measured by sonomicrometry and Millar micrometers. Data were processed with a Dec PDP-11/23 computer. In vitro oxygen content (Vol%) measured 3.2 +/- 1.0 (CCcO2) and 9.5 +/- 0.3 (BCcO2). Percent recoveries of LV global function (LVSP, loop area, % shortening, LV dp/dt, mean VCF and E max) in the CCcO2 group were approximately the same as those in the BCcO2 group. There were no significant differences in LV regional function (loop area and % shortening) after ischemia between the two groups. The chamber and myocardial stiffness after ischemia in the CCcO2 group were almost the same as the baseline values. Values in the BCcO2 group were reduced significantly compared to the baseline level. There were significant differences in post-ischemic chamber and myocardial stiffness between the two groups. Post-ischemic maximum negative LV dp/dt in both groups decreased significantly compared to the baseline values. However, the time constant and diastolic interval after ischemia in both groups were approximately the same as the baseline values. We conclude that there were no significant differences in myocardial protective effect between the CCcO2 and BCcO2 groups, and both methods preserved the ischemic myocardium well.


Characterizing Adult Cochlear Supporting Cell Transcriptional Diversity Using Single-Cell RNA-Seq: Validation in the Adult Mouse and Translational Implications for the Adult Human Cochlea.
Hearing loss is a problem that impacts a significant proportion of the adult population. Cochlear hair cell (HC) loss due to loud noise, chemotherapy and aging is the major underlying cause. A significant proportion of these individuals are dissatisfied with available treatment options which include hearing aids and cochlear implants. An alternative approach to restore hearing would be to regenerate HCs. Such therapy would require a recapitulation of the complex architecture of the organ of Corti, necessitating regeneration of both mature HCs and supporting cells (SCs). Transcriptional profiles of the mature cell types in the cochlea are necessary to can provide a metric for eventual regeneration therapies. To assist in this effort, we sought to provide the first single-cell characterization of the adult cochlear SC transcriptome. We performed single-cell RNA-Seq on FACS-purified adult cochlear SCs from the LfngEGFP adult mouse, in which SCs express GFP. We demonstrate that adult cochlear SCs are transcriptionally distinct from their perinatal counterparts. We establish cell-type-specific adult cochlear SC transcriptome profiles, and we validate these expression profiles through a combination of both fluorescent immunohistochemistry and in situ hybridization co-localization and quantitative polymerase chain reaction (qPCR) of adult cochlear SCs. Furthermore, we demonstrate the relevance of these profiles to the adult human cochlea through immunofluorescent human temporal bone histopathology. Finally, we demonstrate cell cycle regulator expression in adult SCs and perform pathway analyses to identify potential mechanisms for facilitating mitotic regeneration (cell proliferation, differentiation, and eventually regeneration) in the adult mammalian cochlea. Our findings demonstrate the importance of characterizing mature as opposed to perinatal SCs.


Focus on health. Part 2: holistic weight control.
The success of the holistic self-care approach rests with the nurse's and client's commitments to tailoring a new lifestyle which includes permanent weight control. One year of counseling is only a beginning; but the wealth of new-found information that the client can discover about self can be the motivation to continue one day at a time. The only "never" that the client is encouraged to say is, "I'll never go on a diet again." Going on a diet means that one will eventually go off of it. Instead the client is assisted in changing lifestyle by developing different behaviors that will include healthier responses. Nursing implications (integrated throughout this article) include multiple skills, a solid knowledge base, and expert communication skills. Until the nurse experiences or at least simulates the experiences of the yo-yo dieter, he/she cannot be an effective counselor. Unless the nurse practices a self-care approach in his/her life, hypocritical "nursing care" is being practiced. And finally, the nurse must be willing to make a longitudinal commitment to his/her client if the holistic, self-care approach is used. If you as a nurse have these qualifications and choose to adopt the approach, you, as well as the client, will receive rewards and insights about yourself both as nurse and human being.


Cospeciation of termite gut flagellates and their bacterial endosymbionts: Trichonympha species and 'Candidatus Endomicrobium trichonymphae'.
Symbiotic flagellates play a major role in the digestion of lignocellulose in the hindgut of lower termites. Many termite gut flagellates harbour a distinct lineage of bacterial endosymbionts, so-called Endomicrobia, which belong to the candidate phylum Termite Group 1. Using an rRNA-based approach, we investigated the phylogeny of Trichonympha, the predominant flagellates in a wide range of termite species, and of their Endomicrobia symbionts. We found that Trichonympha species constitute three well-supported clusters in the Parabasalia tree. Endomicrobia were detected only in the apical lineage (Cluster I), which comprises flagellates present in the termite families Termopsidae and Rhinotermitidae, but apparently absent in the basal lineages (Clusters II and III) consisting of flagellates from other termite families and from the wood-feeding cockroach, Cryptocercus punctulatus. The endosymbionts of Cluster I form a monophyletic group distinct from many other lineages of Endomicrobia and seem to have cospeciated with their flagellate host. The distribution pattern of the symbiotic pairs among different termite species indicates that cospeciation of flagellates and endosymbionts is not simply the result of a spatial separation of the flagellate lineages in different termite species, but that Endomicrobia are inherited among Trichonympha species by vertical transmission. We suggest extending the previously proposed candidatus name 'Endomicrobium trichonymphae' to all Endomicrobia symbionts of Trichonympha species, and estimate that the acquisition by an ancestor of Trichonympha Cluster I must have occurred about 40-70 million years ago, long after the flagellates entered the termites.


The use of double-J catheter decreases complications of retroperitoneoscopic ureterolithotomy.
To evaluate the retroperitoneoscopic ureterolithotomy in the treatment of ureteral calculi and the need for double-J catheter to reduce the procedure-related complications. We conducted a retrospective study with 47 patients submitted to retroperitoneoscopic ureterolithotomy, of which 31 were selected and divided into two groups: Group 1, whose patients did not have double-J catheter placement, and Group 2, who underwent perioperative double-J catheter implantation. Data collected comprised pre-and post-operative excretory urography, operative time, postoperative analgesia, length of hospital stay and catheter removal. The groups were similar as for age and gender, degree of dilation of the urinary tract, position and average size of the calculi (Group 1 = 15.5 ± 6.6 mm, Group 2 = 16.3 ± 6.1 mm). Operative time was also not significantly different (Group 1 = 130 ± 40.3 min, Group 2 = 136.3 ± 49.3 min). Group 1 had six patients (37.5%) with early (four cases of urinary fistula) and late complications (one case of stenosis of the ureter, one case of functional exclusion of the operated kidney), while Group 2 had no complications. This difference was statistically significant (p = 0.011). The use of double-J catheter was associated with significantly fewer complications in retroperitoneoscopic ureterolithotomy. Surgical time, postoperative analgesia and length of stay were similar between groups with and without catheter.


Optical trap for both transparent and absorbing particles in air using a single shaped laser beam.
Optical trapping of airborne particles is emerging as an essential tool in applications ranging from online characterization of living cells and aerosols to particle transport and delivery. However, existing optical trapping techniques using a single laser beam can trap only transparent particles (via the radiative pressure force) or absorbing particles (via the photophoretic force), but not particles of either type-limiting the utility of trapping-enabled aerosol characterization techniques. Here, we present the first optical trapping technique capable of trapping both transparent and absorbing particles with arbitrary morphology using a single shaped laser beam. Such a general-purpose optical trapping mechanism could enable new applications such as trapping-enabled aerosol characterization with high specificity.


Effect of Preoperative Education using Multimedia on Pain, Uncertainty, Anxiety and Depression in Hysterectomy Patients.
The purpose of this study was to examine the effect of preoperative education using multimedia on level of pain, uncertainty, anxiety and depression in hysterectomy patients. A non-equivalent control group, with a pretest-posttest design was used in this study. The level of post operation pain, pre and post operation uncertainty, anxiety and depression of both the groups was measured. The experimental group was provided with preoperative education using multimedia on the preoperative day at the hospital. The control group was only given usual care. Data were analyzed using SPSS/WIN version 22.0 program. Experimental group showed lower level of post-operation pain in 1 hour (t=-5.08, p<.001) and 24 hours (t=-5.20, p<.001) but not 48 hours (t=-0.91, p=.368). Uncertainty showed significant interaction effect of Group by Time (F=4.16, p=.018). Preoperative education using multimedia for patients with hysterectomy would be effective in lowering patients' level of pain, uncertainty, anxiety and depression.


Bi-fluorescence imaging for estimating accurately the nuclear condition of Rhizoctonia spp.
To simplify the determination of the nuclear condition of the pathogenic Rhizoctonia, which currently needs to be performed either using two fluorescent dyes, thus more costly and time-consuming, or using only one fluorescent dye, thus less accurate. A red primary fluorescence (autofluorescence) of the hyphal cell walls and septa of Rhizoctonia spp. with green excitation is evidenced in Rhizoctonia spp. This property is exploited and combined for the first time with a conventional DAPI fluorescence to accurately determine the nuclear condition of Rhizoctonia. This bi-fluorescence imaging strategy depicted the nuclear condition in Rhizoctonia spp. more accurately than the conventional DAPI fluorescence used alone and was validated against isolates previously genotyped by DNA sequencing. We demonstrated that the bi-fluorescence imaging strategy was safe, accurate and simple to perform and interpret. The developed bi-fluorescence imaging strategy provides a sensitive tool for determining the nuclear condition of Rhizoctonia strains. Its simplicity is a key advantage when there are numerous cultures to be examined.


Global burden of inflammatory bowel disease 1990-2019: A systematic examination of the disease burden and twenty-year forecast.
Inflammatory bowel disease (IBD) is an idiopathic intestinal disease with various levels and trends in different countries and regions. Understanding the current burden and trends of IBD in various geographical locations is essential to establish effective strategies for prevention and treatment. We report the average annual percentage change (AAPC) and estimated annual percentage change (EAPC) in age-standardized rates (ASR) of IBD in different regions based on the Global Burden of Disease (GBD) study from 1990-2019, and the relationships between IBD and the human development index (HDI) and socio-demographic index (SDI). The prevalence trends of IBD were predicted by gender from 2019-2039. To comprehensively investigate IBD data, providing further insights into the management of this chronic disease. We collected the information on the incidence of IBD from the GBD study from 1990-2019 to calculate the AAPC and EAPC in ASR of IBD in different regions. The relationships between IBD, HDI, and SDI were analyzed. The Nordpred and Bayesian age-period-cohort models were used to predict the prevalence trends of IBD by gender from 2019-2039, and the reliability of the results was validated. Statistics of all the data in this study were performed using R software (version 4.2.1). North America consistently had the highest IBD ASR, while Oceania consistently had the lowest. East Asia had the fastest average annual growth in ASR (2.54%), whereas Central Europe had the fastest decline (1.38%). Countries with a low age-standardized incidence rates in 1990 showed faster growth in IBD while there was no significant correlation in 2019. Additionally, IBD increased faster in countries with a low age-standardized death rates in 1990, whereas the opposite was true in 2019. Analysis of SDI and IBD ASR showed that countries with a high SDI generally had a higher IBD ASR. Finally, the projections showed a declining trend in the incidence of IBD from 2019-2039, but a gradual increase in the number of cases. As the global population increases and ages, early monitoring and prevention of IBD is important to reduce the disease burden, especially in countries with a high incidence of IBD.


Prediction of Carotid Intraplaque Hemorrhage Using Adventitial Calcification and Plaque Thickness on CTA.
Carotid intraplaque hemorrhage is associated with stroke, plaque thickness, stenosis, ulceration, and adventitial inflammation. Conflicting data exist on whether calcification is a marker of plaque instability, and no data exist on adventitial calcification. Our goal was to determine whether adventitial calcification and soft plaque (a rim sign) help predict carotid intraplaque hemorrhage. This was a retrospective cohort study of 96 patients who underwent carotid MRA and CTA within 1 month, from 2009 to 2016. We excluded occlusions (n = 4) and near occlusions (n = 0), leaving 188 carotid arteries. Intraplaque hemorrhage was detected by using MPRAGE. Calcification, adventitial pattern, stenosis, maximum plaque thickness (total, soft, and hard), ulceration, and intraluminal thrombus on CTA were recorded. Atherosclerosis risk factors and medications were recorded. We used mixed-effects multivariable Poisson regression, accounting for 2 vessels per patient. For the final model, backward elimination was used with a threshold of P < .10. Receiver operating characteristic analysis determined intraplaque hemorrhage by using the area under the curve. Our final model included the rim sign (prevalence ratio = 11.9, P < .001) and maximum soft-plaque thickness (prevalence ratio = 1.2, P = .06). This model had excellent intraplaque hemorrhage prediction (area under the curve = 0.94), outperforming the rim sign, maximum soft-plaque thickness, NASCET stenosis, and ulceration (area under the curve = 0.88, 0.86, 0.77, and 0.63, respectively; P < .001). Addition of the rim sign performed better than each marker alone, including maximum soft-plaque thickness (area under the curve = 0.94 versus 0.86, P < .001), NASCET stenosis (area under the curve = 0.90 versus 0.77, P < .001), and ulceration (area under the curve = 0.90 versus 0.63, P < .001). The CTA rim sign of adventitial calcification with internal soft plaque is highly predictive of carotid intraplaque hemorrhage.


Nature and distribution of vascular resistance in hypoxic pig lungs.
We used the vascular occlusion technique in pig lungs isolated in situ to describe the effects of hypoxia on the distribution of vascular resistance and to determine whether the resistive elements defined by this technique behaved as ohmic or Starling resistors during changes in flow at constant outflow pressure, changes in outflow pressure at constant flow, and reversal of flow. During normoxia, the largest pressure gradient occurred across the middle compliant region of the vasculature (delta Pm). The major effect of hypoxia was to increase delta Pm and the gradient across the relatively noncompliant arterial region (delta Pa). The gradient across the noncompliant venous region (delta Pv) changed only slightly, if at all. Both delta Pa and delta Pv increased with flow but delta Pm decreased. The pressure at the arterial end of the middle region was independent of flow and, when outflow pressure was increased, did not increase until the outflow pressure of the middle region exceeded 8.9 Torr during normoxia and 18.8 Torr during hypoxia. Backward perfusion increased the total pressure gradient across the lung, mainly because of an increase in delta Pm. These results can be explained by a model in which the arterial and venous regions are represented by ohmic resistors and the middle region is represented by a Starling resistor in series and proximal to an ohmic resistor. In terms of this model, hypoxia exerted its major effects by increasing the critical pressure provided by the Starling resistor of the middle region and the ohmic resistance of the arterial region.


A comparison of digitally scanned radiographs with conventional film for the detection of small endodontic instruments.
The use of computers in dentistry is becoming common as a practice tool for a diverse number of tasks, including the storage and enhancement of intra-oral radiographs. Several systems of digital radiography are available to produce a digital image including irradiation of a charged-couple device and scanning conventional radiographs. This study compared various digital images of scanned periapical radiographs with the original radiographs to determine whether the digitized images offered any advantage when viewing small files at the radiographic apex. Twenty extracted permanent molar teeth were prepared by gaining straight line access to the root canals and a ISO size 06 K-file was introduced into one of the canals until the tip was flush with the apical foramen. Using a standardized technique, radiographs were taken of the teeth using E-speed film. The radiographs were scanned and five digital images: original, enhanced, negative to positive conversion, zoom and zoom of negative to positive were produced. Three evaluators compared each of the images with the radiograph for clarity of the endodontic file in relation to the radiographic apex. Results were analysed using the Wilcoxon signed rank test and the Kappa (kappa) test was used to measure the level of agreement between the three evaluators. The results revealed that all the digital images produced by this scanner were inferior to the radiograph (P < 0.001) and that there was high agreement between evaluators.


Ca2+ transport by the luminal membrane of the distal nephron: action and interaction of protein kinases A and C.
We previously reported that parathyroid hormone and calcitonin increase Ca2+ uptake by purified distal luminal membranes. This effect is mimicked by high concentrations of cAMP. However, both hormones stimulate adenylate cyclase and phospholipase C. The purpose of the present study was to investigate the role of the phospholipase C pathway in the hormone action, and the interrelationship between the two messengers. Distal tubules from rabbit kidneys were incubated with dibutyryl cAMP (dbcAMP) or PMA, or both, and Ca2+ uptake by purified luminal membranes was measured by the rapid filtration technique. Incubation of the distal tubules with 1 mM dbcAMP significantly increased Ca2+ transport by the luminal membranes. A dose-response curve showed a half-maximal stimulation with 0.82 mM dbcAMP. In contrast, treatment of the tubules with 10 nM, 100 nM or 1 microM PMA did not influence Ca2+ uptake by these membranes. However, the addition of 100 nM PMA to low concentrations of dbcAMP strongly increased this uptake. The presence of cAMP or protein kinase C inhibitors prevented the effects of either a high concentration of dbcAMP alone or a low concentration of dbcAMP combined with 100 nM PMA. Our laboratory has already reported that Ca2+ uptake by the distal luminal membranes displays two-component kinetics. dbcAMP increased the Vmax of the low-affinity component, whereas a combination of the two messengers stimulated the Vmax of both the low- and high-affinity components. From these results, we conclude that: (1) in the distal tubule cells, activation of both protein kinases A and C is necessary for the stimulation of Ca2+ transport by the luminal membrane; (2) the combined effect of protein kinases A and C involves both components of the Ca2+-transport kinetics.


Selective estrogen receptor modulators and pharmacogenomic variation in ZNF423 regulation of BRCA1 expression: individualized breast cancer prevention.
The selective estrogen receptor modulators (SERM) tamoxifen and raloxifene can reduce the occurrence of breast cancer in high-risk women by 50%, but this U.S. Food and Drug Administration-approved prevention therapy is not often used. We attempted to identify genetic factors that contribute to variation in SERM breast cancer prevention, using DNA from the NSABP P-1 and P-2 breast cancer prevention trials. An initial discovery genome-wide association study identified common single-nucleotide polymorphisms (SNP) in or near the ZNF423 and CTSO genes that were associated with breast cancer risk during SERM therapy. We then showed that both ZNF423 and CTSO participated in the estrogen-dependent induction of BRCA1 expression, in both cases with SNP-dependent variation in induction. ZNF423 appeared to be an estrogen-inducible BRCA1 transcription factor. The OR for differences in breast cancer risk during SERM therapy for subjects homozygous for both protective or both risk alleles for ZNF423 and CTSO was 5.71.


Use of a noncycloplegic autorefractor to perform vision screening in preschools.
Early detection and treatment of vision disorders in children are important to avoid lifelong visual impairment; however, preschool vision-screening rates are low. Traditional methods of screening lack the precision of objective tests and are difficult to administer in preschoolers. This study adopted a method using school nurses to conduct vision screening in preschoolers with a portable autorefractor. In addition, the effectiveness of the school nurse in conducting follow-up was evaluated. In a sample of 600 children, more than 98% completed the screening, and 7% were referred for follow-up evaluation. Seventeen percent of parents had plans to follow-up after receiving a brochure indicating that their child would benefit from a comprehensive eye exam. However, after a conversation with the school nurse, 86% had plans to schedule an evaluation with an eye care professional. Of the 15 students with known follow-up, 10 received glasses. The described method is effective in identifying young children with potential vision problems and facilitating their correction after contact made by the school nurse.


Effect of vascular cell adhesion molecule 1 on fibroblasts in human eosinophilic chronic rhinosinusitis.
The pathogenesis of eosinophilic chronic rhinosinusitis (ECRS) is still unclear. Paranasal mucosa inflammation is thought to be related to eosinophilic infiltration. This infiltration seems to induce changes in the expression of cell adhesion molecules such as vascular cell adhesion molecule 1 (VCAM-1). The E-cadherin-beta-catenin complex maintains the integrity of the epithelium. Downregulation of beta-catenin and E-cadherin is a pivotal factor for progressive cell growth. This study aimed to assess which cytokines regulate the expression of the adhesion molecule E-cadherin and the multi-functional protein beta-catenin, which plays a key role in cadherin-mediated anchoring in ECRS. Cultured ECRS specimens were incubated with human VCAM-1. After a period of up to 72 h, expression of E-cadherin and beta-catenin was determined using cytokine immunoassay and immunohistochemistry. In ECRS, significant increases in E-cadherin expression were found in fibroblast cell cultures. Stimulation with VCAM-1 did not produce a significant alteration in the expression of the adherens junction protein beta-catenin. In addition, VCAM-1 did not decrease the levels of membrane staining for adherens junction proteins. The selective increase in E-cadherin expression in eosinophilic fibroblast cultures might be explained by a higher concentration of the Th2-type cytokines in these cultures. The tissue remodelling observed during chronic eosinophilic inflammation offers new insight into the pathogenesis of ECRS.


Layer-by-Layer Polymer Functionalization Improves Nanoparticle Penetration and Glioblastoma Targeting in the Brain.
Glioblastoma is characterized by diffuse infiltration into surrounding healthy brain tissues, which makes it challenging to treat. Complete surgical resection is often impossible, and systemically delivered drugs cannot achieve adequate tumor exposure to prevent local recurrence. Convection-enhanced delivery (CED) offers a method for administering therapeutics directly into brain tumor tissue, but its impact has been limited by rapid clearance and off-target cellular uptake. Nanoparticle (NP) encapsulation presents a promising strategy for extending the retention time of locally delivered therapies while specifically targeting glioblastoma cells. However, the brain's extracellular structure poses challenges for NP distribution due to its narrow, tortuous pores and a harsh ionic environment. In this study, we investigated the impact of NP surface chemistry using layer-by-layer (LbL) assembly to design drug carriers for broad spatial distribution in brain tissue and specific glioblastoma cell targeting. We found that poly-l-glutamate and hyaluronate were effective surface chemistries for targeting glioblastoma cells in vitro. Coadsorbing either polymer with a small fraction of PEGylated polyelectrolytes improved the colloidal stability without sacrificing cancer cell selectivity. Following CED in vivo, gadolinium-functionalized LbL NPs enabled MRI visualization and exhibited a distribution volume up to three times larger than liposomes and doubled the retention half-time up to 13.5 days. Flow cytometric analysis of CED-treated murine orthotopic brain tumors indicated greater cancer cell uptake and reduced healthy cell uptake for LbL NPs compared to nonfunctionalized liposomes. The distinct cellular outcomes for different colayered LbL NPs provide opportunities to tailor this modular delivery system for various therapeutic applications.


The analgesic effect of combined treatment with intranasal S-ketamine and intranasal midazolam compared with morphine patient-controlled analgesia in spinal surgery patients: a pilot study.
Ketamine is a well-known analgesic and dose-dependent anesthetic used in emergency and disaster medicine. Recently, a new formulation of S-ketamine, as an intranasal spray, was developed and tested in our institution in healthy volunteers. The authors investigated the effect of intranasal S-ketamine spray combined with midazolam intranasal spray in postoperative spinal surgery patients. In this prospective, computer-randomized, double-blinded noninferiority study in spinal surgery patients, the effects of intranasal S-ketamine and midazolam were compared with standard morphine patient-controlled analgesia (PCA). The primary end point was the numeric rating scale pain score 24 hours after surgery. Twenty-two patients finished this study, eleven in each group. There were similar numeric rating scale scores in the morphine PCA and the S-ketamine-PCA groups at 1, 2, 4, 24, 48, and 72 hours after surgery during rest as well as in motion. There were no differences in the satisfaction scores at any time between the groups. The number of bolus demands and deliveries was not significantly different. In our study, we found that an S-ketamine intranasal spray combined with intra-nasal midazolam was similar in effectiveness, satisfaction, number of demands/deliveries of S-ketamine and morphine, and number/severity of adverse events compared with standard intravenous PCA with morphine. S-ketamine can be regarded as an effective alternative for a traditional intravenous morphine PCA in the postoperative setting.


Identification of active-site residues in Bradyrhizobium japonicum malonamidase E2.
Malonamidase (MA) E2 was previously purified and characterized from Bradyrhizobium japonicum USDA 110. The gene encoding this enzyme has been cloned, sequenced and expressed in Escherichia coli. The recombinant MAE2 was purified to homogeneity from the transformed E. coli. The biochemical properties of the recombinant enzyme are essentially identical to those from wild-type B. japonicum. A database search showed that the MAE2 protein has a high sequence similarity with the common signature sequences of the amidase family. The only exception is that the aspartic residue in these signature sequences is replaced by a glutamine residue. In order to identify amino acid residues essential for enzyme activity, a series of site-directed mutagenesis studies and steady-state kinetic experiments were performed. Gln(195), Ser(199), Cys(207) and Lys(213) of the common signature sequences were selected for site-directed mutagenesis. Among the mutants, Q195D, Q195E and S199C showed less than 0.02% of the k(cat) value of the wild-type enzyme, and S199A, Q195L and Q195N exhibited no detectable catalytic activities. Mutants (K213L, K213R and K213H) obtained by replacement of the only conserved basic residue, Lys(213), in the signature sequences, also displayed significant reductions (approx. 380-fold) in k(cat) value, whereas C207A kept full activity. These results suggest that MAE2 may catalyse hydrolysis of malonamate by a novel catalytic mechanism, in which Gln(195), Ser(199) and Lys(213) are involved.


Hydrogel crosslinking density regulates temporal contractility of human embryonic stem cell-derived cardiomyocytes in 3D cultures.
Systematically tunable in vitro platforms are invaluable in gaining insight to stem cell-microenvironment interactions in three-dimensional cultures. Utilizing recombinant protein technology, we independently tune hydrogel properties to systematically isolate the effects of matrix crosslinking density on cardiomyocyte differentiation, maturation, and function. We show that contracting human embryonic stem cell-derived cardiomyocytes (hESC-CMs) remain viable within four engineered elastin-like hydrogels of varying crosslinking densities with elastic moduli ranging from 0.45 to 2.4 kPa. Cardiomyocyte phenotype and function was maintained within hESC embryoid bodies for up to 2 weeks. Interestingly, increased crosslinking density was shown to transiently suspend spontaneous contractility. While encapsulated cells began spontaneous contractions at day 1 in hydrogels of the lowest crosslinking density, onset of contraction was increasingly delayed at higher crosslinking densities up to 6 days. However, once spontaneous contraction was restored, the rate of contraction was similar within all materials (71 ± 8 beats/min). Additionally, all groups successfully responded to electrical pacing at both 1 and 2 Hz. This study demonstrates that encapsulated hESC-CMs respond to 3D matrix crosslinking density within elastin-like hydrogels and stresses the importance of investigating temporal cellular responses in 3D cultures.


Fast spectroscopic imaging for non-invasive thermometry using the Pr[MOE-DO3A] complex.
The praseodymium complex of 10-(2-methoxyethyl)-1,4,7,10-tetraaza-cyclododecane-1,4,7-tr iacetate) was evaluated as a temperature-sensitive contrast agent using the temperature dependence (approximately 0.12 ppm degrees C(-1)) of the chemical shift of its methoxy side group signal. Pr[MOE-DO3A] was employed in combination with spectroscopic imaging (SI) methods for the determination of spatially resolved 2D and 3D temperature distributions in phantoms. Conventional SI and fast echo planar SI sequences (EPSI) were implemented on a 4.7 T MR imaging system fulfilling the demands for non-invasive thermometry (NIT) with respect to thermal and temporal resolution, being <1 degree C and <20 s total measuring time, respectively. The sequences are based on a fast spin echo SI method taking into account the very short relaxation times of the Pr complex methoxy group (T1 = 28 ms, T2 = 13 ms) and its chemical shift difference (-24 ppm) from water. Calibration curves were measured in a uniformly heated water phantom and 2D SI methods were applied to dynamic heating experiments. The average differences between the temperatures measured via fibreoptic thermometer and those derived from the spectroscopic methods were < or =0.2 degrees C. Furthermore, 3D EPSI experiments with a 16 x 16 x 16 matrix size yielded temperature measurements within 17 s from voxels of size 3 x 3 x 3 mm3.


Influence of Dietary Supplementation of Probiotic Pediococcus acidilactici MA18/5M During the Transition From Freshwater to Seawater on Intestinal Health and Microbiota of Atlantic Salmon (Salmo salar L.).
The aim of this study was to assess the effect of the transfer from freshwater to seawater on the distal intestinal bacterial communities of Atlantic salmon (Salmo salar L.) and to evaluate the effect of dietary inclusion of Pediococcus acidilactici MA18/5M (at 1.19 × 106 CFU/g). In this context, fish health and antiviral response were also investigated. A 12-week feeding trial was conducted in a flow-through rearing system involving 6 weeks in freshwater and 6 weeks in seawater. Fish received a control and probiotic diet. The composition of the salmon gut bacterial communities was determined by high-throughput sequencing of digesta and mucosa samples from both the freshwater and seawater stage. The main phyla detected during both freshwater and seawater stages were Firmicutes, Proteobacteria, Fusobacteria, and Actinobacteria. Significant differences were observed between the intestinal microbiota in the digesta and the mucosa. Both probiotic supplementation and the seawater transfer (SWT) had a substantial impact on the microbial communities, with most pronounced changes detected in the mucosal communities after SWT. This last finding together with a significantly higher antiviral response (mx-1 and tlr3 gene expression) in the distal intestine of fish fed the probiotic diet suggest a causal link between the microbiota modulation and activation of antiviral response. Feeding probiotics during the freshwater stage did not significantly increase survival after infectious pancreatic necrosis virus (IPNV) challenge after SWT, although higher survival was observed in one out of two replicate challenge tanks. In conclusion, this study demonstrated that both dietary probiotic supplementation and transfer from freshwater to seawater have an important role in modulating the bacterial communities in the distal intestine of Atlantic salmon. Furthermore, supplementation of the diet with P. acidilactici MA18/5M can modulate antiviral response.


Effects of a Case Management Program on Self-efficacy, Depression and Anxiety in Pregnant Women with Gestational Diabetes Mellitus.
To examine the effects of a case management program on self-efficacy, depression and anxiety in pregnant women with gestational diabetes mellitus. Thirty-seven patients who enrolled in a diabetes outpatient clinic were randomly assigned to either an experimental group (n=19) or a control group (n=18). The experimental group received a 2-week intervention composed of a series of one face-to-face interactive interview and five telephone interviews based on the National standards for diabetes self-management education and Bandura's self-efficacy resources of performance accomplishment, vicarious experience, verbal persuasion, and emotional arousal. The effects of the intervention were assessed by completion of a 9-item self-efficacy questionnaire, a 20-item depression questionnaire and a 20-item anxiety questionnaire prior to, and after the intervention. The statistical significances were examined using t-test. The change in self-efficacy was significantly greater in the experimental group than in the control group. Depression and anxiety changes in the experimental group were significantly greater compared to those in the control group. The results of study suggest that a case management program improves self-efficacy, and decreases depression and anxiety in pregnant women with gestational diabetes mellitus.


MUC4 and ERBB2 expression in major and minor salivary gland mucoepidermoid carcinoma.
Peptide sequence homology between the gene product of human MUC4 and rat sialomucin complex (SMC) has recently been reported. Each contains a mucin subunit with antiadhesive activity linked to the plasma membrane by means of a transmembrane subunit with two epidermal growth factor (EGF)-like domains that act as ligand for ErbB2. This study investigates MUC4 and ErbB2 receptor expression in major and minor salivary gland mucoepidermoid carcinoma and correlates patterns of expression with clinical outcomes. MUC4 antigens and ErbB2 receptor expression are localized by immunohistochemical studies that use archival formalin-fixed and paraffin-embedded tissue. Clinical outcomes are determined by retrospective chart review of all patients (n = 28) with available archived pathologic specimens at the University of Miami-affiliated hospitals treated between 1994 and 2000. Median survival time was 24 months (range, 2-60 months) among the nine patients who died, whereas median follow-up time in the remaining 19 patients is 33.4 months (range, 4.7-73 months). A trend toward a reduction in MUC4 antigen expression in high-grade tumors (55% expression) compared with low-grade (91% expression) and intermediate-grade (100% expression) tumors is identified (chi square, p =.0975). Patients with tumors expressing MUC4 antigens are at reduced risk of death (hazard ratio [HR], 0.20; p =.0531). Adjustment for pathologic grade, T stage, and age results in a much higher risk of death for patients whose tumors do not express MUC4 antigens, although this does not meet statistical significance (HR, 26.6; p =.1). Analysis of recurrence adjusting for T stage reveals that patients whose tumors do not express MUC4 antigens are at increased risk of recurrence compared with patients whose tumor expresses MUC4 antigens (HR, 6.37; p =.03). ErbB2 receptor staining is noted in seven of 28 patients, with five of these seven showing 2+ and 3+ membrane-staining patterns. Adjustment for pathologic grade and age suggests that patients whose tumors express high levels of ErbB2 (2+, 3+) are at increased risk of death compared with patients with low or no expression of ErbB2 (HR, 2.29; p =.32). MUC4 antigen positivity is seen in two of the five cases with 2+ and 3+ staining for ErbB2. CONCLUSIONS.: These findings suggest MUC4 antigen positivity is associated with reduced risk of death and reduced risk of recurrence and may identify a subset of patients with more favorable prognosis. Although limited by small sample size, analysis reveals ErbB2 overexpression is not consistently associated with MUC4 antigen positivity and might be associated with increased risk of death.


Estimating exotic gene flow into native pine stands: zygotic vs. gametic components.
Monitoring contemporary gene flow from widespread exotic plantations is becoming an important problem in forest conservation genetics. In plants, where both seed and pollen disperse, three components of exotic gene flow with potentially unequal consequences should be, but have not been, explicitly distinguished: zygotic, male gametic and female gametic. Building on a previous model for estimating contemporary rates of zygotic and male gametic gene flow among plant populations, we present here an approach that additionally estimates the third (female gametic) gene flow component, based on a combination of uni- and biparentally inherited markers. Using this method and a combined set of chloroplast and nuclear microsatellites, we estimate gene flow rates from exotic plantations into two Iberian relict stands of maritime pine (Pinus pinaster) and Scots pine (Pinus sylvestris). Results show neither zygotic nor female gametic gene flow but moderate (6-8%) male gametic introgression for both species, implying significant dispersal of pollen, but not of seeds, from exotic plantations into native stands shortly after introduced trees reached reproductive maturity. Numerical simulation results suggest that the model yields reasonably accurate estimates for our empirical data sets, especially for larger samples. We discuss conservation management implications of observed levels of exposure to nonlocal genes and identify research needs to determine potentially associated hazards. Our approach should be useful for plant ecologists and ecosystem managers interested in the vectors of contemporary genetic connectivity among discrete plant populations.


Depletion of miR-96 Delays, But Does Not Arrest, Photoreceptor Development in Mice.
Abundant retinal microRNA-183 cluster (miR-183C) has been reported to be a key player in photoreceptor development and functionality in mice. However, whether there is a protagonist in this cluster remains unclear. Here, we used a mutant mouse model to study the role of miR-96, a member of miR-183C, in photoreceptor development and functionality. The mature miR-96 sequence was removed using the CRISPR/Cas9 genome-editing system. Electroretinogram (ERG) and optical coherence tomography (OCT) investigated the changes in structure and function in mouse retinas. Immunostaining determined the localization and morphology of the retinal cells. RNA sequencing was conducted to observe retinal transcription alterations. The miR-96 mutant mice exhibited cone developmental delay, as occurs in miR-183/96 double knockout mice. Immunostaining of cone-specific marker genes revealed cone nucleus mislocalization and exiguous Opn1mw/Opn1sw in the mutant (MT) mouse outer segments at postnatal day 10. Interestingly, this phenomenon could be relieved in the adult stages. Transcriptome analysis revealed activation of microtubule-, actin filament-, and cilia-related pathways, further supporting the findings. Based on ERG and OCT results at different ages, the MT mice displayed developmental delay not only in cones but also in rods. In addition, a group of miR-96 potential direct and indirect target genes was summarized for interpretation and further studies of miR-96-related retinal developmental defects. Depletion of miR-96 delayed but did not arrest photoreceptor development in mice. This miRNA is indispensable for mouse photoreceptor maturation, especially for cones.


Constituents and antimicrobial activity of the essential oils from flower, leaf and stem of Helichrysum armenium.
The chemical constituents from the flower, leaf and stem of Helichrysum armenium DC. (Asteraceae) growing in Iran were obtained by hydrodistillation and analyzed by GC and GC/MS. The oil of flower was characterized by higher amount of limonene (21.2%), alpha-cadinol (18.2%), borneol (11.9%), delta-cadinene (9.0%), bornyl acetate (8.0%) and alpha-humulene (7.3%). Twenty one constituents representing 96.2% of the chromatographical leaf oil were identified of which limonene (29.2%), alpha-pinene (14.4%), caryophyllene oxide (6.5%), alpha-gurjunene (6.3%), bornyl acetate (5.5%) and torreyol (5.2%) were the major components. The main components of the stem oil were limonene (23.6%), alpha-pinene (13.4%), spathulenol (6.4%), alpha-gurjunene (6.3%), caryophyllene oxide (5.3%), bornyl acetate (5.2%), beta-cubebene (4.8%) and delta-cadinene (4.3%). The composition of the oils is different, although the most abundant components are identical in leaf oil (96.2%). The antimicrobial effect of flower, leaf and stem essential oils from Helichrysum armenium was studied according to the agar diffusion cup method. The essential oils had a moderate effect on the Gram-positive and Gram-negative bacteria and had a substantial fungicidal effect on the fungi under study.


Surgical management of an ethmoid cyst in a horse.
A 2-year old Thoroughbred filly was examined for a 1-month history of persistent nasal discharge. Contrast radiography revealed a circumscribed mass within the right maxillary sinus which extended to the frontal sinus and ethmoid labyrinth. A discrete attachment of the mass to the ethmoid labyrinth was identified at surgery. Surgical removal of the mass eliminated the nasal discharge. On gross examination, the external structure of the mass was similar to a turbinate with a thin bony wall covered by a smooth mucosal membrane. The internal structure of the lesion had a lining membrane with multiple 1-3 cm in diameter fluid filled cystic structures. The histological appearance of the multiloculated structure was similar to the ethmoid labyrinth. This, combined with the single site of attachment to the ethmoid labyrinth, suggested that the cyst was ethmoidal in origin.


Psychometric Properties of the Persian Translation of Video Gaming Addiction Test.
The current study aims to measure the validity, reliability, and psychometric properties of the Persian translation of the Video Gaming Addiction Test (VAT). A total of 280 young men (14-20 years old) (Mean±SD age: 17.22±1.8 years), including excessive gamers and normal subjects, entered the study. They answered VAT, Visual Analog Scale (VAS), and Conner-Davidson Resilience Scale (CD-RISC). The VAT was translated and then back-translated. For testing reliability, we used the Cronbach alpha, split-half method, and Guttman method. Also, convergent and discriminant validity were tested to examine the construct validity of the translated version of VAT. The Cronbach alpha for the total scale was 0.81. Also, after splitting questions in half, the Cronbach alpha values for these halves were 0.71 and 0.69. Six Guttman lambdas were calculated with 0.75 minimum and 0.82 maximum, all showing good reliability of the test. Convergent validity was tested by testing the correlation between VAT and VAS. The Pearson correlation was fond 0.73, showing a strong relationship between the two factors (P<0.001). For testing discriminant validity, the association of VAT with CD-RISC was tested, showing no correlation between these scales (r=-0.157; P=0.09). The Persian translation of the VAT is valid and reliable, and it is appropriate for research and clinical use with acceptable properties, similar to the original version.


Electrophile-induced ether transfer: stereoselective synthesis of 2,6-disubstituted-3,4-dihydropyrans.
Stereoselective synthesis of trans-2,6-disubstituted-3,4-dihydropyrans has been achieved from a simple homoallylic alkoxyether via a three-step sequence: electrophile-induced ether transfer, cyclization, and functionalization, which is highlighted by a rare example of Ferrier rearrangement of allylic ether. This methodology was successfully implemented for the asymmetric synthesis of a C7-C17 fragment of swinholide A.


Anti-Inflammatory Effect of Angelica gigas via Heme Oxygenase (HO)-1 Expression.
Angelica gigas (AG) is effective against various medical conditions such as bacterial infection, inflammation, and cancer. It contains a number of coumarin compounds and the group of interest is the pyranocoumarin, which comprises decursin and decursinol angelate. This group has an effect on controlling inflammation, which is caused by excessive nitric oxide (NO) production. Heme oxygenases (HOs), particularly HO-1, play a role in regulating the production of NO. Thus, this study aimed to investigate the anti-inflammatory effects of AG by measuring HO-1 expression. Treatments with CH2Cl2 layer and Angelica gigas extract (AGE) showed the highest NO inhibition effects. Decursin, decursinol angelate, and nodakenin were isolated from the CH2Cl2 layer of AGE. Decursin also demonstrated the highest anti-oxidative effect among the coumarins. Although decursin had the best NO inhibition and anti-oxidative effects, the effects of AGE treatment far surpassed that of decursin. This is owing to the combination effect of the coumarins present within AGE, which is a solvent extract of AG. The expression of HO-1 is an effective indicator of the anti-inflammatory effects of AG. Based on the results of the coumarin compounds, HO-1 expression was found to be dose dependent and specific to decursin.


A Plasmodium berghei putative serine-threonine kinase 2 (PBANKA_0311400) is required for late liver stage development and timely initiation of blood stage infection.
In Plasmodium, protein kinases govern key biological processes of the parasite life cycle involved in the establishment of infection, dissemination and sexual reproduction. The rodent malaria model P lasmodium berghei encodes for 66 putative eukaryotic protein kinases (ePKs) as identified through modelling domain signatures and are highly conserved in Plasmodium falciparum We report here the functional characterisation of a putative serine-threonine kinase P BANKA_0311400 identified in this kinome analysis and designate it as Pbstk2 To elucidate its role, we knocked out Pbstk2 locus and performed a detailed phenotypic analysis at different life cycle stages. The Pbstk2 knockout (KO) was not compromised in asexual blood stage propagation, transmission and development in the mosquito vector. The Pbstk2 KO produced viable salivary gland sporozoites that successfully transformed into exo-erythrocytic forms (EEFs) and were morphologically indistinguishable from wild-type GFP (WT GFP) with regard to size and shape until 48 h. An intravenous dose of 1×103 Pbstk2 KO sporozoites in C57BL/6 mice failed to establish blood stage infection and a higher dose of 5X103 showed a 2-3 day delay in prepatency as compared to WT GFP parasites. Consistent with such an observation, analysis of in vitro EEF development at 62 h revealed that the hepatic merozoite numbers were reduced to nearly 40% as compared to WT GFP and showed meagre expression of MSP1. Our studies provide evidence for the role of PbSTK2 in late liver stage development and for the successful establishment of a timely blood stage infection.


[New chemotherapy approaches to psychoses].
Particular features are involved in the atypical antipsychotic concept: efficacity on refractory patients and negative symptoms, less or no extrapyramidal side effects, less tardive dyskinesia and less increase in prolactinemia. The imprecision of the atypical neuroleptic class must be underlined. In fact, the pharmacological agents who are included in this class potentially induce few neurological side effects. These effects appearing in doses very much higher than in the therapeutical range. In this case, atypical should refer to a particularity in the links between doses, efficacy and side effects more than to a definition in a specific category. Dopaminergic hypothesis is explained more and more by a dopaminergic system dysregulation than by a simple dopaminergic hyperactivity. This dysregulation might be autonomous or linked to other monoaminergic systems. These new antipsychotics show affinity for different monoaminergic receptors. After clozapine, several agents are now available (risperidone) or just about to be (olanzapine, seroquel, sertindole, ziprasidone, zotépine). Therapeutical effects are probably linked with a dual antagonist effects on 5HT2 and D2 receptors. The atypical antipsychotic efficacy on negative symptoms remains controversial. While very few patients are found to be "purely" negative, most of the schizophrenic patients will show sooner or later some negative symptoms mixed with positive ones. The obvious difficulties in methodological and clinical evaluation of negative symptoms are at least dual: depressive symptoms; extrapyramidal side effects. Secondary negative symptoms usually don't last, while primary negative symptoms are more permanent. Kraepelin describes them as the avolutionnal syndrome of dementia praecox. Usually negative symptoms improve during therapeutic trials, including those using classical neuroleptics. This should not lead us to the conclusion that we have today at our disposal pharmacological agents effective on avolutionnal syndrome or primary negative symptoms. More studies are still necessary. Similarities and differences between the new antipsychotic are not yet evaluated, except partly for clozapine and risperidone. Some new neuroleptics might simplify greatly the therapeutic range. Studies concerning risperidone clearly prove its efficacity on a daily dose of 6 +/- 2 mg. A daily dose of 10 mg doesn't bring any additional improvement. This aspect must be underlined while the efficacy-dose ratio of the classical neuroleptics are still questioned. Consequently too many patients might be given insufficient doses and others excessive doses resulting in side effects and no additional benefits. These new antipsychotics must add a positive modification in schizophrenic care. They might lead to a limited use of additional therapeutics and a better observance thus allowing less relapses and less rehospitalisations.


Spherocentric arthroplasty of the knee. A long-term and final follow-up evaluation.
The spherocentric knee was designed as an intrinsically stable prosthesis to manage the problems of deformity, instability, and metaphyseal bone loss in joints too severely involved to use resurfacing arthroplasty. Follow-up information has been obtained on 58 of the first 82 knees requiring spherocentric arthroplasty. After an average eight-year followup period, the results are gratifying with respect to pain, ambulatory ability, deformity, and instability. The infection and reoperation rates of 5% and 15% seem satisfactory when one considers the severely disabled patient and pathologic conditions of the knee joint.


A population-based study in Ghana to investigate inter-individual variation in plasma t-PA and PAI-1.
Susceptibility to arterial thrombosis has a significant genetic component that is partly due to the expression of two proteins, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1), that directly influence thrombus formation and degradation. We have initiated a large-scale population-based study to characterize the genetic architecture of plasma t-PA and PAI-1 in Blacks from Sunyani, Ghana. The design of the study is based on the recruitment of 2000 unrelated subjects who are ascertained without regard to chronic disease status. The analyses of the results will be done by dividing the data into two parts, a modeling set and a validation data set. This study design will facilitate the identification of genetic, environmental, and demographic factors that contribute to inter-individual variation in plasma levels of t-PA and PAI-1 in the population at-large. We report the specifics of the study design, as well as phenotype information on the first 1000 subjects. Our results show that females and males differ significantly in several key measures, including PAI-1, BMI, total cholesterol, and systolic blood pressure. The data collected from this population-based study demonstrate significant sex differences in PAI-1 and critical factors that may influence risk of thrombosis. These samples will serve to inform the genetic analyses of t-PA and PAI- levels.


The Human Central Pattern Generator for Locomotion: Does It Exist and Contribute to Walking?
The ability of dedicated spinal circuits, referred to as central pattern generators (CPGs), to produce the basic rhythm and neural activation patterns underlying locomotion can be demonstrated under specific experimental conditions in reduced animal preparations. The existence of CPGs in humans is a matter of debate. Equally elusive is the contribution of CPGs to normal bipedal locomotion. To address these points, we focus on human studies that utilized spinal cord stimulation or pharmacological neuromodulation to generate rhythmic activity in individuals with spinal cord injury, and on neuromechanical modeling of human locomotion. In the absence of volitional motor control and step-specific sensory feedback, the human lumbar spinal cord can produce rhythmic muscle activation patterns that closely resemble CPG-induced neural activity of the isolated animal spinal cord. In this sense, CPGs in humans can be defined by the activity they produce. During normal locomotion, CPGs could contribute to the activation patterns during specific phases of the step cycle and simplify supraspinal control of step cycle frequency as a feedforward component to achieve a targeted speed. Determining how the human CPGs operate will be essential to advance the theory of neural control of locomotion and develop new locomotor neurorehabilitation paradigms.


The relationship between incontinence, breathing disorders, gastrointestinal symptoms, and back pain in women: a longitudinal cohort study.
Recent studies suggest a relationship between incontinence, respiratory disorders, gastrointestinal (GI) symptoms, and back pain (BP). However, causality is difficult to infer. This longitudinal study aimed to determine whether the presence or development of one disorder increases risk for the development of another. Women from the Australian Longitudinal Study on Women's Health were divided into subgroups; those with no BP (n=7259), no incontinence (n=18,480), no breathing problems (including allergy) (n=15,096), and no GI symptoms (n=17,623). Each subgroup was analyzed to determine the relationship between the development of the absent condition and the presence or development of the other conditions. Factors with a previously identified relationship with BP were included in analysis. Women with pre-existing and/or newly developed incontinence (prevalence ratios [PR]: 1.26 to 2.12) and breathing problems (PR: 1.38 to 2.11) had an increased risk for the development of BP, and women with pre-existing and newly developed BP were more likely to develop incontinence and breathing problems (PR: 1.18 to 2.44 and 1.53 to 2.62, respectively). The presence of GI symptoms was also identified as a risk factor for the development of these conditions. This study provides evidence of a relationship between BP, incontinence, respiratory problems, and GI symptoms in which the presence of one symptom is associated with the development of another. This suggests that common factors may contribute to the development of symptoms across this range of conditions.


Activation of Trk neurotrophin receptors in the absence of neurotrophins.
Neurotrophins regulate neuronal cell survival and synaptic plasticity through activation of Trk receptor tyrosine kinases. Binding of neurotrophins to Trk receptors results in receptor autophosphorylation and downstream phosphorylation cascades. Here, we describe an approach to use small molecule agonists to transactivate Trk neurotrophin receptors. Activation of TrkA receptors in PC12 cells and TrkB in hippocampal neurons was observed after treatment with adenosine, a neuromodulator that acts through G protein-coupled receptors. These effects were reproduced by using the adenosine agonist CGS 21680 and were counteracted with the antagonist ZM 241385, indicating that this transactivation event by adenosine involves adenosine 2A receptors. The increase in Trk activity could be inhibited by the use of the Src family-specific inhibitor, PP1, or K252a, an inhibitor of Trk receptors. In contrast to other G protein-coupled receptor transactivation events, adenosine used Trk receptor signaling with a longer time course. Moreover, adenosine activated phosphatidylinositol 3-kinase/Akt through a Trk-dependent mechanism that resulted in increased cell survival after nerve growth factor or brain-derived neurotrophic factor withdrawal. Therefore, adenosine acting through the A(2A) receptors exerts a trophic effect through the engagement of Trk receptors. These results provide an explanation for neuroprotective actions of adenosine through a unique signaling mechanism and raise the possibility that small molecules may be used to elicit neurotrophic effects for the treatment of neurodegenerative diseases.