Employment status and perceived health status in younger and older people with multiple sclerosis

This study explores how employment is associated with perceived physical and mental health status in people with multiple sclerosis (MS) adjusted for sociodemographic and clinical variables stratified by age. The sample consisted of 184 MS patients divided into a younger (<45 years) and an older (≥45 years) age group. Respondents underwent an interview, a neurological examination on disability [Expanded Disability Status Scale (EDSS)], and completed the Short Form-36 Health Survey. Of the respondents (mean age 40.5±6.2 years), 43.5% were employed. Significant differences between younger and older patients were found in employment, EDSS, disease duration, and five Short Form-36 Health Survey dimensions. Block-step multiple regression explained 32.4% of the variance in physical health and 14.5% in mental health in the younger group. Being employed was significantly related to good physical health, whereas EDSS diminished the effect of being employed on physical health. The most important variable for mental health was employment status in the younger group. For the older age group, 19.1% of the variance in physical health and 14.0% of the variance in mental health was explained by the studied variables. Male gender and a lower EDSS were significant explanatory variables of better physical health. Male gender significantly explained mental health in the older age group. In conclusion, employment status was an explanatory variable for physical health and mental health in the younger patients. EDSS played a significant role in physical health for all patients. A vocational rehabilitation program could prevent eventual nonemployment and improve health outcomes in older MS people.     

A randomized comparison of paclitaxel-eluting stents versus bare-metal stents for treatment of unprotected left main coronary artery stenosis.

OBJECTIVES: To optimize percutaneous coronary intervention (PCI) strategy for unprotected left main (LM) disease, we performed a randomized study: intravascular ultrasound (IVUS)-guided bare-metal stent (BMS) or paclitaxel-eluting stent (PES) implantation after lesion pre-treatment with cutting balloon (CB) for unprotected LM lesions. BACKGROUND: Recent studies have shown promising results in terms of safety and feasibility for patients with LM disease who underwent PCI with stent implantation. However, comparison of BMS and PES for LM lesions has not yet been evaluated. METHODS: One hundred three patients were randomly assigned to receive BMS (n = 50) or PES (n = 53) implantation. All interventions were IVUS guided, and CB pre-treatment before stenting was performed in all patients. All patients were scheduled for 6-month follow-up. RESULTS: Baseline clinical characteristics were comparable in both cohorts. Stent implantation was successful in all lesions. Follow-up analysis showed binary restenosis in 11 (22%) BMS and in 3 (6%) PES patients (p = 0.021). By IVUS, percentage of neointimal volume obstruction at 6 months was reduced from 25.20 +/- 22.02% with BMS to 16.60 +/- 17.25% with PES (p = 0.02). At 6 months, the major adverse cardiac event-free survival rate was 70% in BMS and 87% in PES patients (p = 0.036). CONCLUSIONS: This study demonstrates that PCI of LM with IVUS guidance and CB pre-treatment is safe and effective. No serious procedure-related complications were observed, and clinical outcomes appeared to be good. Finally, the findings demonstrate that implantation of PES may be superior to BMS in the large-diameter LM vessel at 6 months, warranting the performance of a large-scale randomized trial.     

Endogenous adenosine differentially modulates 5-hydroxytryptamine release from a human enterochromaffin cell model

BACKGROUND & AIMS: The aim was to determine whether adenosine receptors modulate cAMP, intracellular free calcium ([Ca(2+)](i)), and 5-hydroxytryptamine (5-HT) release in human carcinoid BON cells. METHODS: Adenosine receptor (R) mRNA, proteins, and function were identified by Western blots, immunofluorescent labeling, Fluo-4/AM [Ca(2+)](i) imaging, and pharmacologic/physiologic techniques. RESULTS: A1, A2, and A3Rs were present in BON cells and carcinoid tumors. Baseline 5-HT levels increased with adenosine deaminase, activation of A2Rs, and inhibition of A3Rs, whereas A3R activation decreased 5-HT. A2R antagonists or blockade of adenosine reuptake that elevates extracellular adenosine reduced mechanically evoked 5-HT release. In single BON cells, touch elevated [Ca(2+)](i) responses were augmented by adenosine deaminase, A1, and A3R antagonists. CONCLUSIONS: Tonic or mechanically evoked release of endogenous adenosine is a critical determinant of differential activation of adenosine receptors and may have important implications for gut mechanosensory reflexes.     

Salt appetite and the renin-angiotensin system: effect of oxytocin deficiency

To explore the role of oxytocin in the regulation of salt appetite and blood pressure, we conducted studies in oxytocin gene-knockout mice and determined (1) blood pressure and heart rate during day and night periods, (2) salt appetite after iso-osmotic volume depletion, and (3) salt appetite and blood pressure after central injection of angiotensin II. Long-term arterial catheters were inserted, and blood pressure and heart rate were recorded for 24 hours. There was a modest decrease in blood pressure and heart rate in knockout mice. Salt appetite was measured with a 2- bottle choice (water and 2% NaCl), with measurement of licking activity. Mice were injected subcutaneously with 30% polyethylene glycol (0.5 mL), and voluntary intakes were measured for 24 hours. Knockout mice consumed 3 times the amount of NaCl than did controls, 276+/-77 vs 90+/-38 licks/24 h (P<0.05). Water consumption was similar between groups. Angiotensin II (5, 50, and 200 ng/3 microL) injected intracerebroventricularly produced dose-related increases in intake, with no differences between the groups. The 50-ng dose of angiotensin II elicited salt and water intakes of 151+/-43 vs 160+/-33 licks and 250+/-53 vs and 200+/-51 licks, respectively (control vs knockout). The pressor response to angiotensin II was not different between the groups. Results suggest that oxytocin plays a role in the regulation of blood pressure and salt appetite, specifically as mediated by volume receptors, and that the renin-angiotensin system is not involved in these changes.     

The safety,effectiveness and cost‐effectiveness of cytisine in achieving six‐month continuous smoking abstinence in tuberculosis patients—protocol for a double‐blind,placebo‐controlled randomized trial

Background and aims

Tuberculosis (TB) patients who quit smoking have much better disease outcomes than those who continue to smoke. In general populations, behavioural support combined with pharmacotherapy is the most effective strategy in helping people to quit. However, there is no evidence for the effectiveness of this strategy in TB patients who smoke. We will assess the safety, effectiveness and cost‐effectiveness of cytisine—a low‐cost plant‐derived nicotine substitute—for smoking cessation in TB patients compared with placebo, over and above brief behavioural support.

Design

Two‐arm, parallel, double‐blind, placebo‐controlled, multi‐centre (30 sites in Bangladesh and Pakistan), individually randomized trial.

Setting

TB treatment centres integrated into public health care systems in Bangladesh and Pakistan.

Participants

Newly diagnosed (in the last 4 weeks) adult pulmonary TB patients who are daily smokers (with or without dual smokeless tobacco use) and are interested in quitting (n = 2388).

Measurements

The primary outcome measure is biochemically verified continuous abstinence from smoking at 6 months post‐randomization, assessed using Russell Standard criteria. The secondary outcome measures include continuous abstinence at 12 months, lapses and relapses; clinical TB outcomes; nicotine dependency and withdrawal; and adverse events.

Comments

This is the first smoking cessation trial of cytisine in low‐ and middle‐income countries evaluating both cessation and TB outcomes. If found effective, cytisine could become the most affordable cessation intervention to help TB patients who smoke.     

Perceived health status as measured by the SF-36 in patients with multiple sclerosis: a review

This review of literature gives an overview of recent studies about perceived health status as measured by the Short-Form-36 (SF-36) Health Survey in patients with multiple sclerosis (MS). The SF-36 is one of the tools measuring health status in patients used in international research and clinical practice. It measures two main health concepts – physical and mental. The SF-36 represents a valid instrument able to detect differences in perceived health status in patients. A computer-aided search in Medline and PsycINFO resulted in 504 articles in English published from 1996 to August 2006. After the screening process on the basis of abstracts, eight articles consisting of empirical studies remained in which perceived health status was evaluated using the SF-36 Health Survey. Seven studies focused on disability and perceived health status in the SF-36. Two studies focused on the relationship between depression and perceived health status. These studies showed that MS patients with low disability and minor depression scored significantly better than patients with high disability and major depression in the SF-36 health dimensions. Gender seems to have no influence on perceived health status in MS patients. The longer the disease duration and the more severe the disease, the lower the patients scored in perceived health status. The more disabled, the more depressive and the older the patients, the poorer their perceived health status was. Health providers supporting appropriate treatment might pay more attention to more disabled and more depressive patients, with longer disease duration. Perceived health status can be a predictor of prognosis and intervention outcomes. The study shows the importance of measuring perceived health status in MS patients with implications for their quality of life and provision of care.     

The impact of unemployment on school leavers’ perception of health. Mediating effect of financial situation and social contacts?

Summary Objectives: The main purpose of this paper is to explore whether unemployment influences adolescents’ subjective perception of health and whether perceived financial stress and social contacts can mediate the effect of employment status on health. We are also interested in the differences in financial situation and social contacts between unemployed secondary school leavers and their employed and studying counterparts. Methods: Data were obtained from 844 adolescents (mean age 19.6) from Slovakia. The effect of unemployment on several health indicators was measured and subsequently controlled for perceived financial strain of respondents and their social contacts. Results: The results showed highest financial strain among unemployed, whereas only small differences in social contacts were found between three groups. Negative influence of unemployment on perceived health of respondents was confirmed. Nevertheless, strong influence was found only on long-term well-being and mental health. Financial situation and social contacts contributed to the prediction of almost all health outcomes, and to some extent mediated the effect of unemployment. Conclusions: Although unemployment was found to have a negative impact on health of adolescents, sufficiency of social contacts and good financial situation seem to decrease this effect and protect the health of unemployed people. Submitted: 22 May 2006; Revised: 16 February 2007; Accepted: 27 February 2007     

Bacteremias caused by Escherichia coli in cancer patients - analysis of 65 episodes.

OBJECTIVES: The aims of this study were to evaluate risk factors, clinical presentation, outcome and antimicrobial susceptibility in patients with Escherichia coli bacteremia occurring over seven years in a single cancer hospital. METHODS: Sixty five episodes of bacteremia from E. coli appearing over seven years from 12,301 admissions in a single cancer institution were retrospectively analyzed. RESULTS: The proportion of bacteremia caused by E. coli among Gram-negative bacteremia was 20.8% (the second most common organism after Pseudomonas aeruginosa), and infection-associated mortality was 17%. The incidence in 1989-1995 varied from 14.3 to 24.7%. The most common risk factors were: solid tumors as the underlying disease (70.7%); central venous catheter insertion (32.3%); prior surgery (46.2%), and prior chemotherapy within 48 h (44.4%). Neutropenia and urinary catheters did not place patients at high risk in any of the subgroups. When we compared the two subgroups of 61 cases of bacteremia - monomicrobial and polymicrobial (when E. coli was isolated from blood culture with another microorganism) - we found that acute leukemia and breakthrough (recurrence while receiving antibiotics) bacteremia were more frequently associated with polymicrobial E. coli bacteremia. There was also a difference in infection-associated mortality: monomicrobial bacteremia due to E. coli only had a significantly lower mortality in comparison with polymicrobial E. coli bacteremia (8.9 vs 35.0%, respectively; P<0.03). CONCLUSION: The susceptibility of 115 E. coli strains isolated from 65 episodes of bacteremia was stable. Only two episodes caused by quinolone-resistant strains occurred, both in 1995, after six years of using ofloxacin for prophylaxis in neutropenic patients in our hospital. We found that 85.2-91.3% of all strains were susceptible to aminoglycosides, 97.8% to quinolones, and 90-100% to third generation cephalosporins and imipenems. The patients most commonly infected had solid tumors and the mortality was only 17%.     

Protein misfolding occurs by slow diffusion across multiple barriers in a rough energy landscape

The timescale for the microscopic dynamics of proteins during conformational transitions is set by the intrachain diffusion coefficient, D. Despite the central role of protein misfolding and aggregation in many diseases, it has proven challenging to measure D for these processes because of their heterogeneity. We used single-molecule force spectroscopy to overcome these challenges and determine D for misfolding of the prion protein PrP. Observing directly the misfolding of individual dimers into minimal aggregates, we reconstructed the energy landscape governing nonnative structure formation. Remarkably, rather than displaying multiple pathways, as typically expected for aggregation, PrP dimers were funneled into a thermodynamically stable misfolded state along a single pathway containing several intermediates, one of which blocked native folding. Using Kramers’ rate theory, D was found to be 1,000-fold slower for misfolding than for native folding, reflecting local roughening of the misfolding landscape, likely due to increased internal friction. The slow diffusion also led to much longer transit times for barrier crossing, allowing transition paths to be observed directly for the first time to our knowledge. These results open a new window onto the microscopic mechanisms governing protein misfolding.The formation of intricate 3D structures by proteins is a complex physical process. Such “folding” is typically described in terms of energy landscape theory (1) as a thermally driven diffusive search over an energy landscape in conformational space for the minimum-energy structure. In this picture, whereas the rates at which structural transitions take place are dominated by the presence of energy barriers in the landscape (2), it is the coefficient of diffusion over the landscape, D, that encapsulates the microscopic dynamics of the protein chain, setting the characteristic timescale for molecular motions. Knowledge of D provides insight into the internal friction in the protein chain as it undergoes conformational fluctuations (3) and sets the ultimate speed limit at which changes in structure can take place (4).Given the fundamental importance of the diffusion coefficient in protein folding, there has been much interest in measuring D under different conditions. Conformational diffusion has been studied extensively in peptides and unfolded proteins (5–10), using fluorescence probes such as fluorophore quenching or Förster resonant energy transfer to measure reconfiguration times. Typically, D ∼10⁷–10⁸ nm²/s was found, although values as low as 10⁵ nm²/s have been reported (10). Because the diffusion coefficient is inversely proportional to friction, measurements of D have been important for investigating the role and origin of internal friction along the folding pathway (6, 9). Possible links between the value of D and aggregation propensity have also been explored in intrinsically disordered proteins (5). However, it has proven challenging to measure the diffusion coefficient during barrier crossing via fluorescence, owing to the very brief transition time for barrier crossing (11).Recently, an alternate approach using single-molecule force spectroscopy (SMFS), whereby force is applied to induce structural changes in an isolated molecule, has been applied to measure D for barrier crossings (12–15). This approach takes advantage of the powerful ability of force spectroscopy to measure energy landscapes by analyzing the statistics of conformational fluctuations (16), using the landscape profile and rates to recover D from Kramers’ theory (17). The ability to probe barrier crossings opens up the exciting possibility of investigating the microscopic differences between native structure formation and what happens when folding goes awry, producing nonnative structures. Such misfolding is a feature of many diseases, with misfolded proteins characteristically aggregating into insoluble amyloid fibers rich in β-sheets (18). The value of D should be particularly important in misfolding, because the outcome of misfolding and aggregation processes is thought in many cases to be dominated by kinetics (19). Although in silico studies have begun to probe the energy landscapes for protein misfolding and aggregation (20), these landscapes have not yet been reconstructed experimentally. A direct comparison between diffusion in native folding and misfolding of the same protein has therefore not yet been made.An important challenge in studying misfolding and aggregation is that they are typically very heterogeneous processes, involving various transient species along multiple pathways leading to different types of aggregates (21). Despite recent advances including solving the structures of some native-like aggregation precursor states (22, 23) and small oligomers (24), a full picture of the sequence of molecular events in aggregation remains elusive. Single-molecule assays are well suited to overcome this challenge, through their ability to distinguish and characterize even transient subpopulations with high sensitivity (25). Previous studies have investigated phenomena ranging from transient, metastable misfolding events (26–28) to various stages in the growth of aggregates (29, 30), but complete misfolding pathways leading to stable misfolded states have not yet been elucidated (25).Here we use SMFS to reconstruct the energy landscape for misfolding of the prion protein PrP and thereby recover D for misfolding. PrP is particularly interesting as a model for investigating protein misfolding, because even though PrP folds rapidly into its native structure (PrP^C) under normal conditions (31), it has a stable misfolded form, PrP^Sc, which can convert PrP^C to form more PrP^Sc, thereby acting as an infectious agent to transmit prion diseases (32). The structure of PrP^Sc remains unknown, as does the mechanism for conversion of PrP^C, although a variety of structural models (33) and mechanisms (32, 34) have been proposed. Previous single-molecule studies of PrP misfolding (35) have characterized properties such as the kinetics of oligomerization (30) and the dependence of aggregation pathways on metal ions (36), suggesting that the conversion of PrP features several phases starting with dimerization, but detailed pathways were not resolved. SMFS measurements of isolated PrP monomers found that they frequently sampled various misfolded conformations, but they were not thermodynamically stable, consistent with the view that misfolded PrP is stable only within aggregates (27).Because the conversion of PrP may start with dimerization (30, 37), here we have focused on dimers as the smallest form of aggregate. Using optical tweezers to apply tension and thereby unfold and refold single PrP dimers, we found that dimers readily misfold into stable aggregates. A single misfolding pathway was observed and characterized in detail, revealing several exceptional features that set PrP apart from other proteins studied to date. Reconstruction of the energy landscape for dimer misfolding, along with the previously measured landscape for native folding (15), was then used to make the first comparison of D for native folding versus misfolding in the same protein, showing that diffusion is much slower during misfolding than during native folding.