Understanding who benefits most from cognitive rehabilitation for multiple sclerosis: A secondary data analysis.

BACKGROUND: Up to 70% of people with multiple sclerosis (MS) experience cognitive difficulties. Cognitive rehabilitation is a type of therapy that helps manage cognitive problems. OBJECTIVE: The Cognitive Rehabilitation for Attention and Memory in MS (CRAMMS) trial showed some evidence of effectiveness of cognitive rehabilitation in improving cognitive function, with some participants benefitting more than others. We therefore conducted a secondary analysis of the CRAMMS data to understand who benefits most. METHODS: We grouped baseline data into four categories of possible predictors. We used regression models to identify specific factors/characteristics that could predict the likelihood that an individual will benefit from cognitive rehabilitation. RESULTS: The models predicted whether a participant improved or did not improve in neuropsychological function following cognitive rehabilitation in up to 86% of participants. Results suggest that younger participants with medium to high education, diagnosed with relapsing-remitting multiple sclerosis (RRMS) and primary-progressive multiple sclerosis (PPMS) who have not experienced any recent relapses, with mild to moderate cognitive difficulties were most likely to benefit from cognitive rehabilitation. CONCLUSION: We can predict which participants are most likely to demonstrate significant improvements in neuropsychological function following group-based cognitive rehabilitation. Clinically, this allows us to optimise limited neuropsychology resources by offering such cognitive rehabilitation to those most likely to benefit.

American health care paradox-high spending on health care and poor health.

BACKGROUND: For decades, US taxpayers have been lamenting the high cost of health care. Since the mid-1980s, Americans have had double-digit spending on health care. Despite this investment, Americans are less healthy than their European and Scandinavian counterparts across an array of health measures. AIM: We sought to explore how inadequate attention to the social, behavioral and environmental determinants of health may contribute to the American health care paradox of high health care spending and poor health outcomes. DESIGN: Mixed methods. METHODS: We report previous findings related from a 10-year analysis of national-level health and social service spending and health outcome data from the Organization of Economic and Cooperation and Development (OECD). We also put forth case studies representing different socioeconomic strata to illustrate the relationship between health care and social service spending and health. RESULTS: Although the US spending more of its GDP on health care than any other country, it is not a high spender when one sums spending on both health care and social services. The U.S. however has the lowest ratio of our social service spending to health care spending in the OECD, and countries with lower ratios on average have worse health outcomes. Cases from diverse socioeconomic strata demonstrate how limited attention to the social determinants of health can result in extremely high health care costs and poor health outcomes. CONCLUSIONS: Greater investment in addressing the social, behavioral and environmental determinants of health may foster better health without accelerating health care costs in America.

Comparative analyses of tooth wear in free-ranging and captive wild equids.

REASONS FOR PERFORMING STUDY: Captive breeding has played a crucial role in the conservation of threatened equid species. Grazing ruminants and rhinoceros in captivity have less abrasion-dominated tooth wear than their free-ranging conspecifics, with potential negative consequences for their health. However, a similar study on wild equids in captivity is missing. OBJECTIVES: The aim was to establish if different tooth wear patterns are exhibited by free-ranging and captive equids. STUDY DESIGN: Cross-sectional study of museum specimens comparing free-ranging and captive equids. METHODS: Dental casts of maxillary cheek teeth of 228 museum specimens (122 from free-ranging and 106 from captive individuals) of 7 wild equid species were analysed using the extended mesowear method. Although teeth showing specific abnormalities were not scored, the presence of focal overgrowths (hooks) of the rostral premolars (106, 206) was recorded. RESULTS: Captive Equus ferus przewalskii, E. grevyi, E. hemionus, E. quagga boehmi and E. zebra hartmannae have less abrasion-dominated tooth wear on their premolars than their free-ranging conspecifics (P<0.001). Fewer differences were exhibited between populations in the molars. No differences were exhibited in the distal cusp of the molars (110, 210) between populations, except in a small sample of E. kiang. Captive equids exhibited more homogeneous wear along the tooth row whereas free-ranging equids exhibited a tooth wear gradient, with more abrasion on premolars than molars. There were more rostral hooks on the premolars (106, 206) in the captive than the free-ranging population (P = 0.02). CONCLUSIONS: Captive equids did experience less abrasion-dominated tooth wear than their free-ranging conspecifics, but the differences in tooth wear were less pronounced than those between captive and free-ranging wild ruminant and rhinoceros species. This indicates that feeding regimes for captive equids deviate less from natural diets than those for captive ruminants and rhinoceros but that factors leading to hook formation, in particular feeding height, should receive special attention. The Summary is available in Chinese - see Supporting information.

The need for accredited training in gynaecological oncology: a report from the European Network of Young Gynaecological Oncologists (ENYGO).

BACKGROUND: Primary data on training experiences of European gynaecological oncology trainees are lacking. This study aims to evaluate trainee profile, satisfaction and factors affecting the training experience in gynaecological oncology in Europe. PATIENTS AND METHODS: A web-based anonymous survey sent to ENYGO members/trainees in July 2011. It included sociodemographic information and a 22-item (1-5 Likert scale) questionnaire evaluating training experience in gynaecological oncology. Chi-square tests were used for evaluating the independence of categorical variables and t-test (parametric)/Mann-Whitney (non-parametric) tests for differences between two independent groups on continuous data. Cluster analysis was used to identify groupings in multivariate data and Cronbach's-alpha for questionnaire reliability. A multivariable linear regression model was used to assess the effect of variables on training satisfaction. RESULTS: One hundred and nineteen gynaecological-oncology trainees from 31 countries responded. The mean age was 37.4 (S.D, 5.3) years and 55.5% were in accredited training posts. Two clusters identified in the cohort (Calinski-Harabasz, CH = 47.35) differed mainly by accredited training (P = 0.003). The training-satisfaction score (TSS) had high reliability (Cronbach's alpha, 0.951) and was significantly associated with accredited posts (P < 0.0005), years of training (P = 0.001) and salary (P = 0.002). The TSS was independent of age (P = 0.360), working hours (P = 0.620), overtime-pay (P = 0.318), annual leave (P = 0.933), gender (P = 0.545) and marital status (P = 0.731). Accredited programme trainees scored significantly higher than others in 17 of 22 aspects of training. The areas of greater need included advanced laparoscopic/urological/colorectal surgery, radiation oncology, palliative-care, cancer genetics and research opportunities. CONCLUSIONS: Our data demonstrate the importance of accredited training and the need for harmonisation of gynaecological oncology training within Europe.

Character and spatial distribution of OH/H2O on the surface of the Moon seen by M3 on Chandrayaan-1.

The search for water on the surface of the anhydrous Moon had remained an unfulfilled quest for 40 years. However, the Moon Mineralogy Mapper (M3) on Chandrayaan-1 has recently detected absorption features near 2.8 to 3.0 micrometers on the surface of the Moon. For silicate bodies, such features are typically attributed to hydroxyl- and/or water-bearing materials. On the Moon, the feature is seen as a widely distributed absorption that appears strongest at cooler high latitudes and at several fresh feldspathic craters. The general lack of correlation of this feature in sunlit M3 data with neutron spectrometer hydrogen abundance data suggests that the formation and retention of hydroxyl and water are ongoing surficial processes. Hydroxyl/water production processes may feed polar cold traps and make the lunar regolith a candidate source of volatiles for human exploration.

Social stress alters expression of large conductance calcium-activated potassium channel subunits in mouse adrenal medulla and pituitary glands.

Large conductance calcium-activated potassium (BK) channels are very prominently expressed in adrenal chromaffin and many anterior pituitary cells, where they shape intrinsic excitability complexly. Stress- and sex-steroids regulate alternative splicing of Slo-alpha, the pore-forming subunit of BK channels, and chronic behavioural stress has been shown to alter Slo splicing in tree shrew adrenals. In the present study, we focus on mice, measuring the effects of chronic behavioural stress on total mRNA expression of the Slo-alpha gene, two key BK channel beta subunit genes (beta2 and beta4), and the 'STREX' splice variant of Slo-alpha. As a chronic stressor, males of the relatively aggressive SJL strain were housed with a different unfamiliar SJL male every 24 h for 19 days. This 'social-instability' paradigm stressed all individuals, as demonstrated by reduced weight gain and elevated corticosterone levels. Five quantitative reverse transcriptase-polymerase chain assays were performed in parallel, including beta-actin, each calibrated against a dilution series of its corresponding cDNA template. Stress-related changes in BK expression were larger in mice tested at 6 weeks than 9 weeks. In younger animals, Slo-alpha mRNA levels were elevated 44% and 116% in the adrenal medulla and pituitary, respectively, compared to individually-housed controls. beta2 and beta4 mRNAs were elevated 162% and 194% in the pituitary, but slightly reduced in the adrenals of stressed animals. In the pituitary, dominance scores of stressed animals correlated negatively with alpha and beta subunit expression, with more subordinate individuals exhibiting levels that were three- to four-fold higher than controls or dominant individuals. STREX variant representation was lower in the subordinate subset. Thus, the combination of subunits responding to stress differs markedly between adrenal and pituitary glands. These data suggest that early stress will differentially affect neuroendocrine cell excitability, and call for detailed analysis of functional consequences.

Toxicity and bioconcentration potential of the agricultural pesticide endosulfan in phytoplankton and zooplankton.

Agricultural pesticide runoff in southeastern coastal regions of the United States is a critical issue. Bioconcentration of pesticides by phytoplankton and zooplankton at the base of the aquatic food web may increase the persistence of pesticides in aquatic ecosystems and cause effects at higher trophic levels. This study examined the toxicity of a widely used agricultural pesticide, endosulfan, to Pseudokirchneriella subcapitatum (freshwater green alga) and Daphnia magna (freshwater cladoceran). We then investigated the potential of both plankton species to sequester endosulfan from their surrounding media. We also assessed the degree to which endosulfan is accumulated by D. magna via food (endosulfan-contaminated P. subcapitatum). A 96-h growth rate EC50 of 427.80 microg/L endosulfan was determined for P. subcapitatum, whereas a 24-h immobilization EC50 of 366.33 microg/L endosulfan was determined for D. magna. The 5-h EC50s for filtration and ingestion in D. magna were 165.57 microg/L and 166.44 microg/L, respectively. An average bioconcentration factor (BCF) of 2,682 was determined for P. subcapitatum exposed to 100 microg/L endosulfan for 16 h. An average BCF of 3,278 was determined for D. magna in a 100 microg/L endosulfan water-only exposure. There was negligible uptake of endosulfan by D. magna feeding on contaminated algae in clean water (BCF approximately 0). Different proportions of parent isomers (endosulfan I and II) and the primary degradation product (endosulfan sulfate) were detected among treatments. Endosulfan was rapidly accumulated and concentrated from water by P. subcapitatum and D. magna neonates. Endosulfan contained in phytoplankton, however, was not bioaccumulated by zooplankton. These findings may prove useful in assessing ecosystem risk, because uptake from the water column appears to be the dominant route for bioconcentration of endosulfan by zooplankton.

Memory training for children with Down syndrome.

One well-established fact concerning cognitive and language development in individuals with Down syndrome is that working memory is particularly poor, with auditory working memory worse than visual working memory. Working memory serves the functions of control, regulation, and active maintenance of information and is critical in daily complex cognitive activities. Thus, there is a strong need to find effective and practical interventions targeted at improving working memory in individuals with Down syndrome. The present paper reviews research on rehearsal training and concludes that it can be used successfully to increase working memory in individuals with Down syndrome. However, there are still questions about whether auditory working memory can be improved reliably, whether improvement can be maintained over the long term, and whether improvement exists beyond any effect of increased attention. We describe our in-progress study which addresses these concerns.

Oxygen isotopes and the moon-forming giant impact.

We have determined the abundances of 16O, 17O, and 18O in 31 lunar samples from Apollo missions 11, 12, 15, 16, and 17 using a high-precision laser fluorination technique. All oxygen isotope compositions plot within +/-0.016 per mil (2 standard deviations) on a single mass-dependent fractionation line that is identical to the terrestrial fractionation line within uncertainties. This observation is consistent with the Giant Impact model, provided that the proto-Earth and the smaller impactor planet (named Theia) formed from an identical mix of components. The similarity between the proto-Earth and Theia is consistent with formation at about the same heliocentric distance. The three oxygen isotopes (delta17O) provide no evidence that isotopic heterogeneity on the Moon was created by lunar impacts.

Symptom management in older primary care patients: feasibility of an experimental, written self-disclosure protocol.

BACKGROUND: Distress-driven symptoms are prevalent among older primary care patients and account for a large percentage of office visits and increased medical costs. An experimental written self-disclosure protocol has been shown to reduce symptoms and use of health care services in healthy adults. Written self-disclosure as a method for reducing symptoms has not been evaluated in the primary care setting. OBJECTIVE: To evaluate the feasibility of adapting an experimental written self-disclosure protocol for the primary care setting. DESIGN: Randomized, single-blind feasibility study. SETTING: University-based geriatric and internal medicine primary care clinics. PATIENTS: 45 patients 66 years of age or older without a psychiatric diagnosis. INTERVENTION: Three 20-minute writing sessions focusing on distressing experiences (in the intervention group) or health behaviors (in the control group). MEASUREMENTS: The feasibility outcomes were patient recruitment, protocol logistics, and patient and provider satisfaction. The clinical outcomes were somatic and distress symptoms, health care utilization, and associated costs. RESULTS: One third of patients screened were recruited; 96% of patients recruited completed the protocol. Clinic contact time was an average of 55 minutes per patient. Patients and providers reported high levels of satisfaction with the protocol. Reductions in symptoms were minimal for both groups. Use of outpatient services and associated costs decreased in both groups, but the reduction was twice as great in the treatment group as in the control group. CONCLUSIONS: Findings support the feasibility of implementing the protocol as a primary care intervention.

Monolayers of derivatized poly(L-lysine)-grafted poly(ethylene glycol) on metal oxides as a class of biomolecular interfaces.

We report on the design and characterization of a class of biomolecular interfaces based on derivatized poly(l-lysine)-grafted poly(ethylene glycol) copolymers adsorbed on negatively charged surfaces. As a model system, we synthesized biotin-derivatized poly(l-lysine)-grafted poly(ethylene glycol) copolymers, PLL-g-[(PEGm)((1-x)) (PEG-biotin)(x)], where x varies from 0 to 1. Monolayers were produced on titanium dioxide substrates and characterized by x-ray photoelectron spectroscopy. The specific biorecognition properties of these biotinylated surfaces were investigated with the use of radiolabeled streptavidin alone and within complex protein mixtures. The PLL-g-PEG-biotin monolayers specifically capture streptavidin, even from a complex protein mixture, while still preventing nonspecific adsorption of other proteins. This streptavidin layer can subsequently capture biotinylated proteins. Finally, with the use of microfluidic networks and protein arraying, we demonstrate the potential of this class of biomolecular interfaces for applications based on protein patterning.

Noninvasive blood pressure performance: a reproducible method for quantifying motion artifact tolerance in oscillometry.

Motion artifact tends to degrade oscillometric noninvasive blood pressure measurement (NIBP) accuracy and other aspects of performance (measurement time, patient comfort, false-positive readings). Medical personnel generally have not fully appreciated the extent of these degradations, in part because NIBP provides no waveform display to allow visualization of artifact disruption (unlike the electrocardiography (ECG) and pulse oximetry (SpO2) patient channels). More importantly, the magnitude and frequency of NIBP errors has also gone unappreciated because the auditory noise produced by transport vibration prevents accurate quantification of NIBP accuracy by the traditional auscultatory method. To overcome these problems, a commercially available NIBP simulator was modified to permit the superimposition of repeatable motion artifact waveforms from a function generator onto known patient blood pressure profiles available in the NIBP simulator. The superimposed artifact waveforms had been collected under transport conditions. This methodology enabled comparisons between artifact-free NIBP readings, on the one hand, and artifact-contaminated readings on the other. Monitors under test were subjected to multiple combinations of patient and artifact profiles. Measurement errors were expressed as a percent deviation of the artifact-contaminated readings from the expected (artifact-free) readings. Statistical analyses of the data compared the performance of the different monitor types with nonparametric tests of inference (Kruskal-Wallis H test, Mann-Whitney U test, and chi-squared test). These analyses demonstrated statistically significant differences in performance including accuracy, yield (incidence of values within various error categories), retries, measurement time, and false-positive readings under artifact-only conditions. The method further demonstrated that the monitor using ECG synchronization to filter motion artifact achieved statistically and clinically significant improvements in accuracy without compromising clinical expectations for measurement time. This approach provided a reproducible and quantifiable method by which to assess and differentiate the artifact tolerance of different NIBP technologies.

Diphenyl sulfoxides as selective antagonists of the muscarinic M2 receptor.

Structure activity studies on [4-(phenylsulfonyl)phenyl]methylpiperazine led to the discovery of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl(S)-sufinyl]phenyl]-1-pi perazineacetonitrile, 1, an M2 selective muscarinic antagonist. Affinity at the cloned human M2 receptor was 2.7 nM; the M1/M2 selectivity is 40-fold.

Diphenylsulfone muscarinic antagonists: piperidine derivatives with high M2 selectivity and improved potency.

Piperidine analogues of our previously described piperazine muscarinic antagonists are described. Piperidine analogues show a distinct structure-activity relationship (SAR) that differs from comparable piperazines. Compounds with high selectivity and improved potency for the M2 receptor have been identified. The lead compound, 12b, increases acetylcholine release in vivo. Compounds of this class may be useful for the treatment of cognitive disorders such as Alzheimer's disease (AD).

Host gene regulation during coxsackievirus B3 infection in mice: assessment by microarrays.

Host genetic responses that characterize enteroviral myocarditis have not yet been determined. The injurious and inflammatory process in heart muscle may reflect host responses of benefit to the virus and ultimately result in congestive heart failure and dilated cardiomyopathy. On the other hand, host responses within the myocardium may secure the host against acute or protracted damage. To investigate the nature of modified gene expression in comparison with normal tissue, mRNA species were assessed in myocardium using cDNA microarray technology at days 3, 9, and 30 after infection. Of 7000 clones initially screened, 169 known genes had a level of expression significantly different at 1 or more postinfection time points as compared with baseline. The known regulated genes were sorted according to their functional groups and normalized expression patterns and, subsequently, interpreted in the context of viremic, inflammatory, and healing phases of the myocarditic process.

Cost-effectiveness of the conventional papanicolaou test with a new adjunct to cytological screening for squamous cell carcinoma of the uterine cervix and its precursors.

OBJECTIVE: To estimate costs and outcomes of conventional annual Papanicolaou (Pap) test screening compared with biennial Pap test plus speculoscopy (PPS) screening for cervical neoplasms. DESIGN: A Markov model compared cost-effectiveness and outcomes of annual Pap tests with biennial PPS. The model includes direct costs of screening, diagnostic testing, and treatment for squamous intraepitheial lesions and invasive cancers; indirect costs (eg, lost productivity because of cervical cancer); and newer management practices, including human papillomavirus DNA testing. PATIENTS: Women aged 18 to 64 years. INTERVENTION: Screening for cervical neoplasms with either annual Pap smear test or biennial PPS. MAIN OUTCOME MEASURE: Marginal cost per life-year gained. RESULTS: The probability of women having squamous intraepithelial lesions, cervical cancer, or death from cervical cancer was lower among women undergoing PPS biennially. A total of 12 additional days of life per woman was gained with biennial PPS during the 47-year model period. Total average cumulative direct medical costs per patient were $1419 for biennial PPS compared with $1489 for annual Pap tests. Total costs, including direct medical costs and indirect costs, were $2185 for PPS compared with $3179 for Pap tests alone. Increased savings and patient outcomes were observed in high-risk populations. CONCLUSION: Our simulations indicate that biennial screening with PPS is expected to provide cost savings for women older than 18 years compared with annual Pap test screening, especially for those in high-risk populations.

Whiskers amiss, a new vibrissae and hair mutation near the Krt1 cluster on mouse chromosome 11.

Whiskers amiss (wam) is a new spontaneous recessive mutation in the SELH/Bc strain of mice that causes a phenotype of askew, sometimes kinked or curled, breakable whiskers and disheveled-appearing body hair, apparently owing to disoriented guard hairs. Heterozygotes on three genetic backgrounds are indistinguishable from normal. Using informative SSLPs in the F2 generation after crosses to two normal strains, we have mapped wam to the region of the type I keratin cluster on Chromosome (Chr) 11, within an approximately 6-cM segment according to the current Mouse Genome Database (MGD) map position of flanking SSLPs. Although several other hair mutations also map to the Krt1 region (Re, Rim3, Bdai, Bsk), none has a hair and whisker phenotype similar to that of wam, and, because all are transmitted as dominants, interpretable complementation tests could not be done. Scabbing and tissue loss occur on the rims of the pinnae and tail tip in some aging wam homozygotes, suggesting that wam may be an animal model of a genetic ectodermal disorder. The SELH/Bc strain background appears to have an unusually high rate of spontaneous mutation; wam is the sixth mutation to be described.

Preparation and storage characteristics of white cell-reduced high-concentration platelet concentrates collected by anapheresis system for transfusions in utero.

BACKGROUND: Important concerns with regard to in utero platelet transfusions are avoidance of volume overload and the immunomodulatory effects of residual white cells (WBCs). This study evaluated a modification of a leukocyte-reduction system (LRS, Spectra, COBE BCT) for apheresis, which collects high-concentration WBC-reduced platelets (HCPs) for in utero transfusion. STUDY DESIGN AND METHODS: The LRS procedure was modified by running the platelet collection pump at specified low flow rates (Q(col)) for the first part of the procedure, collecting HCPs by gently purging them from the LRS chamber into a designated collection bag and then restoring the original LRS procedure settings to collect a second standard apheresis platelet concentrate (PC). Two centers carried out 32 procedures. Platelet yield, residual WBCs, and in vitro platelet function studies were evaluated. RESULTS: Platelet concentrations in 60 mL of HCPs were predictable according to Q(col) (r(2) = 0.735). HCP yields varied from 0.9 to 3.2 x 10(11), depending on the desired final platelet concentrations in 60 mL, with an overall average of 1. 92 x 10(11) (n = 32). Apheresis PCs had a mean platelet yield of 2.9 x 10(11) (1.3-4.4 x 10(11), n = 20) and 3.9 x 10(11) (2.2-5.8 x 10(11), n = 12) at concentrations of 1.3 x 10(12) per L for single-needle and dual- needle procedures, respectively. Median WBC counts were 5.6 x 10(3) for HCPs and 2.0 x 10(4) for apheresis PCs, with >99 percent expected to be less than 1 x 10(6). HCP in vitro characteristics were equivalent to those of apheresis PCs at 24 hours after collection. In vitro performance declined over storage as a function of HCP yield. HCP pH at 22(o)C was maintained at a level of >6.2 for more than 3 days for yields >1.6 x 10(11), less than 2 days for yields 1.6 to 2.2 x 10(11), and less than 24 hours for yields >2.2 x 10(11). HCPs showed good in vitro characteristics and could be stored for 1 to 3 days, depending on the total number of platelets collected. CONCLUSION: A standard apheresis PC and an HCP requiring no secondary processing can be collected with the Spectra LRS. The platelet concentration may be determined by clinical need. HCPs meet the requirements for components that are transfused in utero.

SCH 57790: a novel M2 receptor selective antagonist.

As a decrease in cholinergic neurons has been observed in Alzheimer's Disease (AD), therapeutic approaches to AD include inhibition of acetylcholinesterase to increase acetylcholine levels. Evidence suggests that acetylcholine release in the CNS is modulated by negative feedback via presynaptic M2 receptors, blockade of which should provide another means of increasing acetylcholine release. Structure-activity studies of [4-(phenylsulfonyl)phenyl]methylpiperazines led to the synthesis of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl]sulfinyl]-phenyl]-1-piperazin eacetonitrile. This compound, SCH 57790, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 2.78 nM; the affinity at M1 receptors is 40-fold lower. SCH 57790 is an antagonist at M2 receptors expressed in CHO cells, as the compound blocks the inhibition of adenylyl cyclase activity mediated by the muscarinic agonist oxotremorine. This compound should be useful in assessing the potential of M2 receptor blockade for enhancement of cognition.