Oceanic whitetip sharks (Carcharhinus longimanus) have recently been targeted for conservation in the western North Atlantic following severe declines in abundance. Pop-up satellite archival tags were applied to 11 mature oceanic whitetips (10 females, 1 male) near Cat Island in the central Bahamas 1–8 May 2011 to provide information about the horizontal and vertical movements of this species. Another large female was opportunistically tagged in the U.S. Exclusive Economic Zone (EEZ). Data from 1,563 total tracking days and 1,142,598 combined depth and temperature readings were obtained. Sharks tagged at Cat Island stayed within 500 km of the tagging site for ∼30 days before dispersing across 16,422 km2 of the western North Atlantic. Maximum individual displacement from the tagging site ranged from 290–1940 km after times at liberty from 30–245 days, with individuals moving to several different destinations (the northern Lesser Antilles, the northern Bahamas, and north of the Windward Passage). Many sharks returned to The Bahamas after ∼150 days. Estimated residency times within The Bahamas EEZ, where longlining and commercial trade of sharks is illegal, were generally high (mean = 68.2% of time). Sharks spent 99.7% of their time shallower than 200 m and did not exhibit differences in day and night mean depths. There was a positive correlation between daily sea surface temperature and mean depth occupied, suggesting possible behavioral thermoregulation. All individuals made short duration (mean = 13.06 minutes) dives into the mesopelagic zone (down to 1082 m and 7.75°C), which occurred significantly more often at night. Ascent rates during these dives were significantly slower than descent rates, suggesting that these dives are for foraging. The sharks tracked appear to be most vulnerable to pelagic fishing gear deployed from 0–125 m depths, which they may encounter from June to October after leaving the protected waters of The Bahamas EEZ.

CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. In addition, the CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This paper provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM paper in 1983.

Background

Tobacco dependence counseling is recommended to be included as core curriculum for US medical students. To date, there has been little information on students’ self-reported skills and practice opportunities to provide 5A’s (Ask, Advise, Assess, Assist, and Arrange) counseling for tobacco cessation.

Methods

We conducted anonymous surveys of second year and fourth year students at multiple US medical schools between February 2004 and March 2005 (overall response rate 70%). We report on the tobacco control practices of the 860 second year and 827 fourth year students completing the survey.

Measurements and Main Results

Fourth year students reported multiple opportunities to learn tobacco counseling in case-based discussions, simulated patient encounters, and clinical skills courses. They reported more instruction in family medicine (79%) and Internal Medicine (70%) than Pediatrics (54%), Obstetrics/Gynecology (41%), and Surgery clerkships (16%). Compared with asking patients about smoking, advising smokers to quit, and assessing patient willingness to quit, fourth year students were less likely to have multiple practice opportunities to assist the patient with a quit plan and arrange follow-up contact. More than half of second year students reported multiple opportunities for asking patients about smoking but far fewer opportunities for practicing the other 4 As.

Conclusions

By the beginning of their fourth year, most students in this group of medical schools reported multiple opportunities for training and practicing basic 5A counseling, although clear deficits for assisting patients with a quit plan and arranging follow-up care exist. Addressing these deficits and integrating tobacco teaching through tailored specific instruction across all clerkships, particularly in Surgery, Pediatrics, and Obstetrics/Gynecology is a challenge for medical school education.

Anthracycline-based chemotherapy (ABC) is the most effective therapy for diffuse large B-cell lymphoma (DLBCL). The addition of rituximab to ABC in controlled trials has demonstrated superior survival, yet ABC is inconsistently utilized in elderly patients, and little is known about the penetrance or impact of rituximab with other treatments. We analyzed the treatment and survival patterns of 7559 patients with DLBCL over age 66 diagnosed from 1992 to 2002 using a linked Surveillance, Epidemiology and End Results (SEER)–Medicare database. Rituximab use was first detected in 1999 and by 2002 was incorporated in 79% of ABC-treated patients and 71% of patients treated with non-anthracycline chemotherapy, but only 12% of patients not receiving cytotoxic chemotherapy. ABC rates remained constant across time as did rates of no therapy, which were highest among the very old. Rituximab-associated survival improvements were seen among elderly treated with or without anthracyclines. Patients treated with rituximab but not anthracyclines had comparable survival to those treated with anthracycline but not rituximab.

Background

We compared aortic stiffness, aortic impedance and pressure from wave reflections in the setting of bicuspid aortic valve (BAV) to the tricuspid aortic valve (TAV) in the absence of proximal aortic dilation. We hypothesized BAV is associated with abnormal arterial stiffness.

Methods

Ten BAV subjects (47 ± 4 years, 6 male) and 13 TAV subjects (46 ± 4 years, 10 male) without significant aortic valve disease were prospectively recruited. Characteristic impedance (Zc) was derived from echocardiographic images and pulse wave Doppler of the left ventricular outflow tract. Applanation tonometry was performed to obtain pulse wave velocity (PWV) at several sites as measures of arterial stiffness and augmentation index (AIx) as a measure of wave reflection.

Results

There were no significant differences between BAV and TAV subjects with regard to heart rate or blood pressure. Zc was similar between BAV and TAV subjects (p=0.25) as was carotid-femoral pulse wave velocity (cf-PWV) and carotid-radial PWV (cr-PWV) between BAV and TAV subjects (p=0.99). Carotid AIx was significantly higher in BAV patients compared with TAV patients (14.3 ± 4.18% versus -3.02 ± 3.96%, p=0.007).

Conclusions

Aortic stiffness and impedance is similar between subjects with BAV and TAV with normal aortic dimensions. The significantly higher carotid AIx in BAV, a proxy of increased pressure from wave reflections, may reflect abnormal vascular function distal to the aorta.

Amphibians have undergone dramatic declines and extinctions worldwide. Prominent among these have been the stream-breeding frogs in the rainforests of eastern Australia. The amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd) has been postulated as the primary cause of these declines. We conducted a capture-mark-recapture study over a 7-year period on the endangered Fleay’s barred frog (Mixophyes fleayi) at two independent streams (30 km apart) in order to assess the stability of these populations. This species had undergone a severe decline across its narrow geographic range. Mark-recapture modelling showed that the number of individuals increased 3–10 fold along stream transects over this period. Frog detection probabilities were frequently above 50% but declined as the populations increased. Adult survival was important to overall population persistence in light of low recruitment events, suggesting that longevity may be a key factor in this recovery. One male and female were present in the capture record for >6 years. This study provides an unambiguous example of population recovery in the presence of Bd.

Whale sharks, Rhincodon typus, are known to aggregate to feed in a small number of locations in tropical and subtropical waters. Here we document a newly discovered major aggregation site for whale sharks within the Al Shaheen oil field, 90 km off the coast of Qatar in the Arabian Gulf. Whale sharks were observed between April and September, with peak numbers observed between May and August. Density estimates of up to 100 sharks within an area of 1 km2 were recorded. Sharks ranged between four and eight metres’ estimated total length (mean 6.92±1.53 m). Most animals observed were actively feeding on surface zooplankton, consisting primarily of mackerel tuna, Euthynnus affinis, eggs.

HIV-associated neurocognitive disorders (HAND) remain prevalent but challenging to diagnose particularly among non-demented individuals. To determine whether a brief computerized battery correlates with formal neurocognitive testing, we identified 46 HIV-infected persons who had undergone both formal neurocognitive testing and a brief computerized battery. Simple detection tests correlated best with formal neuropsychological testing. By multivariable regression model, 53% of the variance in the composite Global Deficit Score was accounted for by elements from the brief computerized tool (p<0.01). These data confirm previous correlation data with the computerized battery, yet illustrate remaining challenges for neurocognitive screening.

Screening efforts led to the identification of PI-8182 (1), an inhibitor of the chymotrypsin-like (CT-L) activity of the proteasome. Compound 1 contains a hydronaphthoquinone pharmacophore with a thioglycolic acid side chain at position 2 and thiophene sulfonamide at position 4. An efficient synthetic route to the hydronaphthoquinone sulfonamide scaffold was developed and compound 1 was synthesized in-house to confirm the structure and activity (IC50 = 3.0 ± 1.6 μM [n=25]). Novel hydronaphthoquinone derivatives of the hit 1 were designed, synthesized and evaluated as proteasome inhibitors. The structure activity relationship (SAR) guided synthesis of more than 170 derivatives revealed that the thioglycolic acid side chain is required and the carboxylic acid group of this side chain is critical to the CT-L inhibitory activity of compound 1. Furthermore, replacement of the carboxylic acid with carboxylic acid isosteres such as tetrazole or triazole greatly improves potency. Compounds with a thio-tetrazole or thio-triazole side chain in position 2, where the thiophene was replaced by hydrophobic aryl moieties were the most active compounds with up to 20-fold greater CT-L inhibitory than compound 1 (compounds 15e, 15f, 15h 15j, IC50 values around 200 nM and compound 29, IC50 = 150 nM). The synthetic iterations described here not only led to improving potency in vitro but also resulted in the identification of compounds that are more active such as 39 (IC50 = 0.44 to 1.01 μM) than 1 (IC50 = 3.54 to 7.22 μM) at inhibiting the proteasome CT-L activity in intact breast cancer cells. Treatment with 39 also resulted in the accumulation of ubiquitinated cellular proteins and inhibition of tumor cell proliferation of breast cancer cells. The hit 1 and its analog 39 inhibited proteasome CT-L activity irreversibly.

Background

The US CDC estimates over 2 million foodborne illnesses are annually caused by 4 major enteropathogens: non-typhoid Salmonella spp., Campylobacter spp., Shigella spp. and Yersinia enterocoltica. While data suggest a number of costly and morbid chronic sequelae associated with these infections, pathogen-specific risk estimates are lacking. We utilized a US Department of Defense medical encounter database to evaluate the risk of several gastrointestinal disorders following select foodborne infections.

Methods

We identified subjects with acute gastroenteritis between 1998 to 2009 attributed to Salmonella (nontyphoidal) spp., Shigella spp., Campylobacter spp. or Yersinia enterocolitica and matched each with up to 4 unexposed subjects. Medical history was analyzed for the duration of military service time (or a minimum of 1 year) to assess for incident chronic gastrointestinal disorders. Relative risks were calculated using modified Poisson regression while controlling for the effect of covariates.

Results

A total of 1,753 pathogen-specific gastroenteritis cases (Campylobacter: 738, Salmonella: 624, Shigella: 376, Yersinia: 17) were identified and followed for a median of 3.8 years. The incidence (per 100,000 person-years) of PI sequelae among exposed was as follows: irritable bowel syndrome (IBS), 3.0; dyspepsia, 1.8; constipation, 3.9; gastroesophageal reflux disease (GERD), 9.7. In multivariate analyses, we found pathogen-specific increased risk of IBS, dyspepsia, constipation and GERD.

Conclusions

These data confirm previous studies demonstrating risk of chronic gastrointestinal sequelae following bacterial enteric infections and highlight additional preventable burden of disease which may inform better food security policies and practices, and prompt further research into pathogenic mechanisms.

Objective

Magnetic resonance imaging (MRI) often demonstrates brain lesions in neuropsychiatric systemic lupus erythematosus (NPSL). The present study compared post-mortem histopathology with pre-mortem MRI in NPSL.

Methods

200 subjects with NPSLE were studied prospectively with MRI over a 10-year period during which 22 subjects died. In 14 subjects, a brain autopsy with histopathology that permitted direct comparison with pre mortem MRI was successfully obtained. Surface anatomy was used to determine the approximate location of individual lesions.

Results

Pre mortem MRI findings in fatal NPSLE were small focal white matter lesions (100%), cortical atrophy (64%), ventricular dilation (57%), cerebral edema (50%), diffuse white matter abnormalities (43%), focal atrophy (36%), cerebral infarction (29%), acute leukoencephalopathy (25%), intracranial hemorrhage (21%), and calcifications (7%). Microscopic findings in fatal NPSLE included global ischemic changes (57%), parenchymal edema (50%), microhemorrhages (43%), glial hyperplasia (43%), diffuse neuronal/axonal loss (36%), resolved cerebral infarction (33%), microthomboemboli (29%), blood vessel remodeling (29%), acute cerebral infarction (14%), acute macrohemorrhages (14%), and resolved intracranial hemorrhages (7%). Cortical atrophy and ventricular dilation seen by MRI predicted brain mass at autopsy (r = -0.72, p = 0.01, and r = -0.77, p =0.01, respectively). Cerebral autopsy findings, including infarction, cerebral edema, intracranial hemorrhage, calcifications, cysts, and focal atrophy were also predicted accurately by pre mortem MRI.

Conclusion

Brain lesions in NPSLE detected by MRI accurately represent serious underlying cerebrovascular and parenchymal brain injury on pathology.

Background

Buprenorphine/naloxone (BUP/NX) is not licensed for use in China or Thailand and there was little clinical experience with this drug combination in these countries at the inception of HIV Prevention Trial Network (HPTN) 058, a randomized trial comparing risk reduction counseling combined with either short-term or long-term medication assisted treatment with BUP/NX to prevent HIV infection and death among opioid-dependent injectors.

Methods

We conducted a safety phase that included the first 50 subjects enrolled at each of the three initial study sites (N=150). Clinical and laboratory assessments were conducted at baseline and weekly for the first 4 weeks. Changes in laboratory parameters were estimated with random effects models.

Results

BUP/NX was well tolerated by study subjects and opioid withdrawal scores decreased substantially during the 3-day induction. Two participants experienced grade 3 clinical adverse events, which were categorized as probably not related to the study drug. Grade 2 or 3 increases in alanine aminotransferase (ALT) occurred in 25 (17%) subjects. The magnitude of ALT increase over 4-week follow-up was strongly associated with baseline ALT elevation.

Conclusions

In Chinese and Thai opioid-dependent injectors, we found BUP/NX to be effective in reducing opioid withdrawal symptoms and safe during short-term use. ALT increases were observed over 4-week-follow-up, which are consistent with reports from Western populations. Long-term safety and efficacy evaluations are indicated.

Among peripheral regulatory T cells, CD8+ T cells also play an important role in the maintenance of immune homeostasis. A subset of CD8+ Treg that express αβTCR and CD8αα homodimers can recognize TCR-derived peptides in the context of the class Ib MHC molecule Qa-1. To gain a better understanding of the nature and phenotype of CD8αα+TCRαβ+ Treg, a global gene expression profiling using microarray, real-time quantitative PCR, and flowcytometry analysis was performed using functional Treg clones and lines. Our data show that CD8+ Treg shared gene profile expressed by innate-like lymphocytes, including murine intraepithelial lymphocytes and thymic CD8αα+TCRαβ+ T cell populations. Additionally, this subset displays differential expression of several key regulatory molecules, including CD200. CD8αα+ Treg expressed higher levels of a number of NK cell related receptors and molecules belonging to the TNF superfamily. Collectively, peripheral class Ib-reactive CD8αα+TCRαβ+ T cells represent a unique regulatory population different from class Ia MHC-restricted conventional T cells. These studies have important implications for the regulatory mechanisms mediated by the CD8+ Treg population in general.

We assessed the relationship of insulin resistance with cognitive decline and brain atrophy over two years in early Alzheimer’s disease (AD, n=48) and nondemented controls (n=61). Intravenous glucose tolerance tests were conducted at baseline to determine insulin area-under-the-curve (AUC). A standard battery of cognitive tasks and MRI were conducted at baseline and 2-year follow-up. In nondemented controls, higher baseline insulin AUC was associated with 2-year decline in global cognitive performance (beta=−0.36, p=0.005). In early AD, however, higher insulin AUC was associated with less decline in global cognitive performance (beta=0.26, p=0.06), slower global brain atrophy (beta=0.40, p=0.01) and less regional atrophy in the bilateral hippocampi and cingulate cortices. While insulin resistance is associated with cognitive decline in nondemented aging, higher peripheral insulin may have AD-specific benefits or insulin signaling may be affected by systemic physiologic changes associated with AD.

In a sample of urban youth (N = 1,070), we examined the links between primary caregiver affect (i.e., warmth and hostility) and two measures of sexual behavior in adolescence – early sexual initiation and sex with multiple partners. We also examined the extent to which neighborhood disadvantage moderated associations between caregiver affect and adolescent sexual behavior. We found that caregiver hostility was positively associated with early sex and sex with multiple partners in neighborhoods characterized by high levels of disadvantage, but inversely associated with both sex outcomes in neighborhoods characterized by low levels of disadvantage. Caregiver warmth, on the other hand, was inversely associated with early sexual initiation and sex with multiple partners in all neighborhoods regardless of neighborhood disadvantage.

Objective

Despite behavioral differences between genetic subtypes of Prader-Willi syndrome, no studies have been published characterizing brain structure in these subgroups. Our goal was to examine differences in the brain structure phenotype of common subtypes of Prader-Willi syndrome (PWS) [chromosome 15q deletions and maternal uniparental disomy 15 (UPD)].

Methods

Fifteen individuals with PWS due to a typical deletion ((DEL) Type I; n=5, Type II; n=10), 8 with PWS due to UPD, and 25 age-matched healthy-weight individuals (HWC) participated in structural magnetic resonance imaging (MRI) scans. A custom voxel-based morphometry processing stream was used to examine regional differences in gray and white matter volume between groups, covarying for age, sex, and body mass index (BMI).

Results

Overall, compared to HWC, PWS individuals had lower gray matter volumes that encompassed the prefrontal, orbitofrontal and temporal cortices, hippocampus and parahippocampal gyrus, and lower white matter volumes in the brain stem, cerebellum, medial temporal and frontal cortex. Compared to UPD, the DEL subtypes had lower gray matter volume primarily in the prefrontal and temporal cortices, and lower white matter in the parietal cortex. The UPD subtype had more extensive lower gray and white matter volumes in the orbitofrontal and limbic cortices compared to HWC.

Conclusions

These preliminary findings are the first structural neuroimaging findings to support potentially separate neural mechanisms mediating the behavioral differences seen in these genetic subtypes.

ABSTRACT

Purpose: To analyze weekend physiotherapy services in acute-care community hospitals across Canada. Method: Questionnaires were mailed to acute-care community hospitals (institutions with >100 inpatient beds, excluding psychiatric, mental health, paediatric, rehabilitation, tertiary, and long-term care facilities) across Canada from January to April 2010. The questionnaire collected information on patient referral criteria, staffing, workload, and compensation for weekend physiotherapy services and on the availability of other rehabilitation health professionals. Results: Of 146 community hospitals deemed eligible, 104 (71%) responded. Weekend physiotherapy was offered at 69% of hospitals across Canada, but this rate varied: ≥75% in all regions except Quebec (30%). Hospitals with a high proportion of acute-care beds were more likely to offer weekend physiotherapy services (logistic regression, p=0.021). Services differed among Saturdays, Sundays, and holidays in terms of the numbers of both physiotherapists and physiotherapy assistants working (Kruskal–Wallis, p<0.02 for each). Physiotherapists were predominantly compensated via time off in lieu. Of hospitals not offering weekend physiotherapy, 53% reported that it would benefit patients; most perceived staffing and financial barriers. Social-work services were offered on the weekend at 24% of hospitals and occupational therapy at 16%. Conclusions: Substantial regional variation exists in access to weekend physiotherapy services in acute-care community hospitals. To address the importance of this variation, research on the efficacy and cost-effectiveness of such services is required.

OBJECTIVE

Impaired insulin sensitivity is linked to cognitive deficits and reduced brain size. However, it is not yet known whether insulin sensitivity involves regional changes in gray matter volume. Against this background, we examined the association between insulin sensitivity, cognitive performance, and regional gray matter volume in 285 cognitively healthy elderly men and women aged 75 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.

RESEARCH DESIGN AND METHODS

Insulin sensitivity was calculated from fasting serum insulin and plasma glucose determinations using the homeostasis model assessment of insulin resistance (HOMA-IR) method. Cognitive performance was examined by a categorical verbal fluency. Participants also underwent a magnetic resonance imaging (MRI) brain scan. Multivariate analysis using linear regression was conducted, controlling for potential confounders (sex, education, serum LDL cholesterol, mean arterial blood pressure, and abdominal visceral fat volume).

RESULTS

The HOMA-IR was negatively correlated with verbal fluency performance, brain size, and temporal lobe gray matter volume in regions known to be involved in speech production (Brodmann areas 21 and 22, respectively). No such effects were observed when examining diabetic (n = 55) and cognitively impaired (n = 27) elderly subjects as separate analyses.

CONCLUSIONS

These cross-sectional findings suggest that both pharmacologic and lifestyle interventions improving insulin signaling may promote brain health in late life but must be confirmed in patient studies.

Context

California is the first and only state to implement a patient-to-nurse ratio mandate for hospitals. Increasing nurse staffing is an important organizational intervention for improving patient outcomes. Evidence suggests that staffing improved in California hospitals after the mandate was enacted, but the outcome for hospitals bearing a disproportionate share of uncompensated care—safety-net hospitals—remains unclear. One concern was that California’s mandate would burden safety-net hospitals without improving staffing or that hospitals would reduce their skill mix, that is, the proportion of registered nurses of all nursing staff. We examined the differential effect of California’s staffing mandate on safety-net and non-safety-net hospitals.

Methods

We used a time-series design with Annual Hospital Disclosure data files from the California Office of Statewide Health Planning and Development (OSHPD) for the years 1998 to 2007 to assess differences in the effect of California’s mandate on staffing outcomes in safety-net and non-safety-net hospitals.

Findings

The mandate resulted in significant staffing improvements, on average nearly a full patient per nurse fewer (−0.98) for all California hospitals. The greatest effect was in those hospitals with the lowest staffing levels at the outset, both safety-net and non-safety-net hospitals, as the legislation intended. The mandate led to significantly improved staffing levels for safety-net hospitals, although there was a small but significant difference in the effect on staffing levels of safety-net and non-safety-net hospitals. Regarding skill mix, a marginally higher proportion of registered nurses was seen in non-safety-net hospitals following the mandate, while the skill mix remained essentially unchanged for safety-net hospitals. The difference between the two groups of hospitals was not significant.

Conclusions

California’s mandate improved staffing for all hospitals, including safety-net hospitals. Furthermore, improvement did not come at the cost of a reduced skill mix, as was feared. Alternative and more targeted designs, however, might yield further improvement for safety-net hospitals and reduce potential disparities in the staffing and skill mix of safety-net and non-safety-net hospitals.

This study examined racial/ethnic differences in the rates of HIV risk behaviors and whether the relationship between HIV risk factors and HIV risk behaviors varies by race/ethnicity in clients participating in NIDA Clinical Trials Network multi-site trials. The sample was 41% non-Hispanic White, 32% non-Hispanic Black, and 27% Hispanic (N=2,063). HIV risk behaviors and measures of substance and psychosocial HIV risk factors in the past month were obtained. Non-Hispanic Blacks engaged in less HIV sexual risk behaviors overall than non-Hispanic Whites. While non-Hispanic Whites were the most likely to report any injection drug use, Hispanics engaged in the most HIV drug risk behaviors. Specific risk factors were differentially predictive of HIV risk behavior by race/ethnicity. Alcohol use severity was related to engaging in higher sex risk behaviors for non-Hispanic Blacks and non-Hispanic Whites. Greater psychiatric severity was related to engaging in higher sex risk behaviors for non-Hispanic Whites. Drug use severity was associated with engaging in higher risk drug behaviors for non-Hispanic Whites and Hispanics with the magnitude of the relationship stronger for Hispanics. These findings highlight the need for further research testing HIV risk prevention interventions within racial/ethnic groups to identify target behaviors or risk factors that are salient for certain groups to inform HIV prevention interventions.

Relative free energy calculations based on molecular dynamics simulations were combined with available experimental binding free energies to predict unknown binding affinities of acyclic Cucurbituril complexes in the blind SAMPL3 competition. The predictions showed good agreement with experimental results, yielding root mean square errors of about 2.6 kcal/mol for seven host-guest systems. However, the standard deviations found in our simulations were ranging up to 2.4 kcal/mol, which indicates the need for better sampling. We compare the performance of three different approaches: Bennett’s Acceptance Ratio Method and Thermodynamic Integration based on both the trapezoidal and Simpson’s rule. Surprisingly, both Bennett’s Acceptance Ratio Method and Thermodynamic Integration with trapezoidal rule lead to the same root mean square error. We also evaluate the influence of the protonation states of the amine groups of the guest molecules, showing that the deprotonated forms exhibit a poorer correspondence to experimental results with a root mean square error of 5.2 kcal/mol. In addition, we demonstrate that a decrease of the buffer concentration by about 20mM in our simulations can raise the root mean square error to 3.8 kcal/mol.

Impulse control disorders (ICDs), including disordered gambling, can occur in a significant number of patients with Parkinson’s disease (PD) receiving dopaminergic therapy. The neurobiology underlying susceptibility to such problems is unclear, but risk likely results from an interaction between dopaminergic medication and a pre-existing trait vulnerability. Impulse control and addictive disorders form part of a broader psychopathological spectrum of disorders, which share a common underlying genetic vulnerability, referred to as externalizing. The broad externalizing risk factor is a continuously varying trait reflecting vulnerability to various impulse control problems, manifested at the overt level by disinhibitory symptoms and at the personality level by antecedent traits such as impulsivity and novelty/sensation seeking. Trait “disinhibition” is thus a core endophenotype of ICDs, and a key target for neurobiological investigation. The ventral striatal dopamine system has been hypothesized to underlie individual variation in behavioral disinhibition. Here, we examined whether individual differences in ventral striatal dopamine synthesis capacity predicted individual variation in disinhibitory temperament traits in individuals with PD. Eighteen early-stage male PD patients underwent 6-[18F]Fluoro-l-DOPA (FDOPA) positron emission tomography scanning to measure striatal dopamine synthesis capacity, and completed a measure of disinhibited personality. Consistent with our predictions, we found that levels of ventral, but not dorsal, striatal dopamine synthesis capacity predicted disinhibited personality, particularly a propensity for financial extravagance. Our results are consistent with recent preclinical models of vulnerability to behavioral disinhibition and addiction proneness, and provide novel insights into the neurobiology of potential vulnerability to impulse control problems in PD and other disorders.

Background

Non-motor symptoms are present in Parkinson's disease (PD) and a key determinant of quality of life. The Non-motor Symptoms Scale (NMSS) is a validated scale that allows quantifying frequency and severity (burden) of NMS. We report a proposal for using NMSS scores to determine levels of NMS burden (NMSB) and to complete PD patient classification.

Methods

This was an observational, cross-sectional international study of 935 consecutive patients. Using a distribution of NMSS scores by quartiles, a classification based on levels from 0 (no NMSB at all) to 4 (very severe NMSB) was obtained and its relation with Hoehn and Yahr (HY) staging, motor and health-related quality of life scales was analyzed. Concordance between NMSB levels and grouping based on clinician's global impression of severity, using categorical regression, was determined. Disability and HRQoL predictors were identified by multiple regression models.

Results

The distribution of motor and QoL scales scores by HY and NMSB levels was significantly discriminative. The difference in the classification of cases for both methods, HY and NMSB, was significant (gamma = 0.45; ASE = 0.032). Concordance between NMSB and global severity-based levels from categorical regression was 91.8%, (kappaw = 0.97). NMS score was predictor of disability and QoL.

Conclusions

Current clinical practice does not address a need for inclusion of non-motor scores in routine assessment of PD in spite of the overwhelming influence of NMS on disability and quality of life. Our data overcome the problems of “pure motor assessment” and we propose a combined approach with addition of NMSB levels to standard motor assessments.

Background

Prior research has shown that removing occupational asthmatics from exposure does not routinely lead to significant improvements in respiratory impairment. These studies were of limited duration and factors determining recovery remain obscure. Our objective was to evaluate residual respiratory impairment and associated sputum and blood biomarkers in subjects with Western red cedar asthma after exposure cessation.

Methods

Subjects previously diagnosed with cedar asthma, and removed from exposure to cedar dust for at least one year, were recruited. Subjects completed a questionnaire and spirometry. PC20 (methacholine concentration that produces 20% fall in FEV1 (forced expiratory volume at 1 second)) sputum cellularity and select Th1/Th2 (T helper cells 1 and 2) cytokine concentrations in peripheral blood were determined. The asthma impairment class was determined and multivariate analyses were performed to determine its relationship with sputum cell counts and serum cytokines.

Results

40 non-smoking males (mean age 62) were examined at a mean interval of 25 years from cedar asthma diagnosis and 17 years from last cedar exposure. 40% were in impairment class 2/3. On average, the PC20 had increased by 2.0 mg/ml; the FEV1 decreased by 1.5 L, with greater decrease in those with greater impairment. Higher impairment was associated with serum interferon-gamma (mean = 1.3 pg/ml in class 2/3 versus 0.62 pg/ml in class 0/1, p = 0.04), mainly due to the FEV1 component (correlation with interferon-gamma = −0.46, p = 0.005).

Conclusion

Years after exposure cessation, patients with Western red cedar asthma have persistent airflow obstruction and respiratory impairment, associated with systemic inflammation.