The common C-terminal sequences of substance P and neurokinin A contact the same region of the NK-1 receptor

AbstractAlthough neurokinin A (NKA), a tachykinin peptide with sequence homology to substance P (SP), is a weak competitor of radiolabeled SP binding to the NK-1 receptor (NK-1R), more recent direct binding studies using radiolabeled NKA have demonstrated an unexpected high-affinity interaction with this receptor. To document the site of interaction between NKA and the NK-1R, we have used a photoreactive analogue of NKA containing p-benzoyl-L-phenylalanine (Bpa) substituted in position 7 of the peptide. Peptide mapping studies of the receptor photolabeled by 125I-iodohistidyl1-Bpa7NKA have established that the site of photoinsertion is located within a segment of the receptor extending from residues 178 to 190 (VVCMIEWPEHPNR). We have previously shown that 125I-BH-Bpa8SP, a photoreactive analogue of SP, covalently attaches to M181 within this same receptor sequence. Importantly, both of these peptides (125I-iodohistidyl1-Bpa7NKA and 125I-BH-Bpa8SP) have the photoreactive amino acid in an equivalent position within the conserved tachykinin carboxyl-terminal tail. In this report, we also show that site-directed mutagenesis of M181 to A181 in the NK-1R results in a complete loss of photolabeling of both peptides to this receptor site, indicating that the equivalent position of SP and NKA, when bound to the NK-1R, contact the same residue

Capacity building for evidence-based decision making in local health departments: Scaling up an effective training approach

Abstract Background There are few studies describing how to scale up effective capacity-building approaches for public health practitioners. This study tested local-level evidence-based decision making (EBDM) capacity-building efforts in four U.S. states (Michigan, North Carolina, Ohio, and Washington) with a quasi-experimental design. Methods Partners within the four states delivered a previously established Evidence-Based Public Health (EBPH) training curriculum to local health department (LHD) staff. They worked with the research team to modify the curriculum with local data and examples while remaining attentive to course fidelity. Pre- and post-assessments of course participants (n = 82) and an external control group (n = 214) measured importance, availability (i.e., how available a skill is when needed, either within the skillset of the respondent or among others in the agency), and gaps in ten EBDM competencies. Simple and multiple linear regression models assessed the differences between pre- and post-assessment scores. Course participants also assessed the impact of the course on their work. Results Course participants reported greater increases in the availability, and decreases in the gaps, in EBDM competencies at post-test, relative to the control group. In adjusted models, significant differences (p < 0.05) were found in ‘action planning,’ ‘evaluation design,’ ‘communicating research to policymakers,’ ‘quantifying issues (using descriptive epidemiology),’ and ‘economic evaluation.’ Nearly 45% of participants indicated that EBDM increased within their agency since the training. Course benefits included becoming better leaders and making scientifically informed decisions. Conclusions This study demonstrates the potential for improving EBDM capacity among LHD practitioners using a train-the-trainer approach involving diverse partners. This approach allowed for local tailoring of strategies and extended the reach of the EBPH course.http://deepblue.lib.umich.edu/bitstream/2027.42/109528/1/13012_2014_Article_124.pd

Expression of p16 and HPV E4 on biopsy samples and methylation of FAM19A4 and miR124-2 on cervical cytology samples in the classification of cervical squamous intraepithelial lesions

The decision to treat a cervical squamous intraepithelial lesion (SIL) by loop electrosurgical excision procedure (LEEP) relies heavily on a colposcopy-directed biopsy showing high-grade (H)SIL. Diagnosis is often supported by p16, an immunohistochemical (IHC) biomarker of high-risk (hr)HPV E7 gene activity. Additional potential markers include methylation of tumor suppressor genes FAM19A4/miR124-2 in cervical cytology for advanced transforming HSIL and the IHC marker HPV E4 for productive, potentially regressing lesions. In 318 women referred for colposcopy, we investigated the relationship between staining patterns of p16 and E4 IHC in the worst biopsy, and the relation of these to FAM19A4/miR124-2 methylation status in cytology. E4-positive staining decreased with increasing SIL/CIN grade from 41% in LSIL to 3% in HSIL/CIN3. E4 positivity increased with grade of p16 when p16 expression was limited to the lower two third of the epithelium (r = 0.378), but fell with expression over. Loss of E4 expression in the worst lesion was associated with the methylation of FAM19A4/miR124-2. We also examined whether these biomarkers can predict the histological outcome of the LE

Critical Exponents of the Fully Frustrated 2-D Xy Model

We present a detailed study of the critical properties of the 2-D XY model with maximal frustration in a square lattice. We use extensive Monte Carlo simulations to study the thermodynamics of the spin and chiral degrees of freedom, concentrating on their correlation functions. The gauge invariant spin-spin correlation functions are calculated close to the critical point for lattice sizes up to $240\times 240$; the chiral correlation functions are studied on lattices up to $96\times 96$. We find that the critical exponents of the spin phase transition are $\nu=0.3069$, and $\eta=0.1915$, which are to be compared with the unfrustrated XY model exponents $\nu=1/2$ and $\eta=0.25$. We also find that the critical exponents of the chiral transition are $\nu_{\chi}=0.875$, $2\beta=0.1936$, $2\gamma= 1.82$, and $2\gamma\>\prime=1.025$, which are different from the expected 2-D Ising critical exponents. The spin-phase transition occurs at $T_{U(1)}=0.446$ which is about 7\% above the estimated chiral critical temperature $T_{Z_{2}}= 0.4206$. However, because of the size of the statistical errors, it is difficult to decide with certainty whether the transitions occur at the same or at slightly different temperatures. Finally, the jump in the helicity modulus in the fully frustrated system is found to be about 23\% below the unfrustrated universal value. The most important consequence of these results is that the fully frustrated XY model appears to be in a novel universality class. Recent successful comparisons of some of these results with experimental data are also briefly discussed. (TO APPEAR IN PRB)Comment: 47 pages (PHYZZX

Study on COgnition and Prognosis in the Elderly (SCOPE)

Blood Press. 1999;8(3):177-83. Study on COgnition and Prognosis in the Elderly (SCOPE). Hansson L, Lithell H, Skoog I, Baro F, Bánki CM, Breteler M, Carbonin PU, Castaigne A, Correia M, Degaute JP, Elmfeldt D, Engedal K, Farsang C, Ferro J, Hachinski V, Hofman A, James OF, Krisin E, Leeman M, de Leeuw PW, Leys D, Lobo A, Nordby G, Olofsson B, Zanchetti A, et al. University of Uppsala, Department of Public Health, Sweden. Abstract The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multicentre, prospective, randomized, double-blind, parallel-group study designed to compare the effects of candesartan cilexetil and placebo in elderly patients with mild hypertension. The primary objective of the study is to assess the effect of candesartan cilexetil on major cardiovascular events. The secondary objectives of the study are to assess the effect of candesartan cilexetil on cognitive function and on total mortality, cardiovascular mortality, myocardial infarction, stroke, renal function, hospitalization, quality of life and health economics. Male and female patients aged between 70 and 89 years, with a sitting systolic blood pressure (SBP) of 160-179 mmHg and/or diastolic blood pressure (DBP) of 90-99 mmHg, and a Mini-Mental State Examination (MMSE) score of 24 or above, are eligible for the study. The overall target study population is 4000 patients, at least 1000 of whom are also to be assessed for quality of life and health economics data. After an open run-in period lasting 1-3 months, during which patients are assessed for eligibility and those who are already on antihypertensive therapy at enrolment are switched to hydrochlorothiazide 12.5 mg o.d., patients are randomized to receive either candesartan cilexetil 8 mg once daily (o.d.) or matching placebo o.d. At subsequent study visits, if SBP remains >160 mmHg, or has decreased by 85 mmHg, study treatment is doubled to candesartan cilexetil 16 mg o.d. or two placebo tablets o.d. Recruitment was completed in January 1999. At that time 4964 patients had been randomized. All randomized patients will be followed for an additional 2 years. If the event rate is lower than anticipated, the follow-up will be prolonged. PMID: 10595696 [PubMed - indexed for MEDLINE

Exercise therapy in adults with serious mental illness: a systematic review and meta-analysis

Background: Individuals with serious mental illness are at a higher risk of physical ill health. Mortality rates are at least twice those of the general population with higher levels of cardiovascular disease, metabolic disease, diabetes, and respiratory illness. Although genetics may have a role in the physical health problems of these patients, lifestyle and environmental factors such as levels of smoking, obesity, poor diet, and low levels of physical activity also play a prominent part.&lt;p&gt;&lt;/p&gt; Objective: To conduct a systematic review and meta-analysis of randomised controlled trials comparing the effect of exercise interventions on individuals with serious mental illness.&lt;p&gt;&lt;/p&gt; Methods: Searches were made in Ovid MEDLINE, Embase, CINAHL, PsycINFO, Biological Abstracts on Ovid, and The Cochrane Library (January 2009, repeated January 2013) through to February 2013.&lt;p&gt;&lt;/p&gt; Results: Eight RCTs were identified in the systematic search. Six compared exercise versus usual care. One study assessed the effect of a cycling programme versus muscle strengthening and toning exercises. The final study compared the effect of adding specific exercise advice and motivational skills to a simple walking programme. Exercise programmes were noted by their heterogeneity in terms of the type of exercise intervention, setting, and outcome measures. The review found that exercise improved levels of exercise activity (n=13, standard mean difference [SMD] 1.81, CI 0.44 to 3.18, p = 0.01). No beneficial effect was found on negative (n = 84, SMD = -0.54, CI -1.79 to 0.71, p = 0.40) or positive symptoms of schizophrenia (n = 84, SMD = -1.66, CI -3.78 to 0.45, p = 0.12). No change was found on body mass index compared with usual care (n= 151, SMD = -0.24, CI -0.56 to 0.08, p = 0.14), or body weight (n = 77, SMD = 0.13, CI -0.32 to 0.58, p = 0.57). No beneficial effect was found on anxiety and depressive symptoms (n = 94, SMD = -0.26, CI -0.91 to 0.39, p = 0.43), or quality of life in respect of physical and mental domains. One RCT measured the effect of exercise on exercise intensity, attendance, and persistence at a programme. No significant effect was found on these measures.&lt;p&gt;&lt;/p&gt; Conclusions: This systematic review showed that exercise therapies can lead to a modest increase in levels of exercise activity but overall there was no noticeable change for symptoms of mental health, body mass index, and body weight.&lt;p&gt;&lt;/p&gt

Quantum Interference in Superconducting Wire Networks and Josephson Junction Arrays: Analytical Approach based on Multiple-Loop Aharonov-Bohm Feynman Path-Integrals

We investigate analytically and numerically the mean-field superconducting-normal phase boundaries of two-dimensional superconducting wire networks and Josephson junction arrays immersed in a transverse magnetic field. The geometries we consider include square, honeycomb, triangular, and kagome' lattices. Our approach is based on an analytical study of multiple-loop Aharonov-Bohm effects: the quantum interference between different electron closed paths where each one of them encloses a net magnetic flux. Specifically, we compute exactly the sums of magnetic phase factors, i.e., the lattice path integrals, on all closed lattice paths of different lengths. A very large number, e.g., up to $10^{81}$ for the square lattice, exact lattice path integrals are obtained. Analytic results of these lattice path integrals then enable us to obtain the resistive transition temperature as a continuous function of the field. In particular, we can analyze measurable effects on the superconducting transition temperature, $T_c(B)$, as a function of the magnetic filed $B$, originating from electron trajectories over loops of various lengths. In addition to systematically deriving previously observed features, and understanding the physical origin of the dips in $T_c(B)$ as a result of multiple-loop quantum interference effects, we also find novel results. In particular, we explicitly derive the self-similarity in the phase diagram of square networks. Our approach allows us to analyze the complex structure present in the phase boundaries from the viewpoint of quantum interference effects due to the electron motion on the underlying lattices.Comment: 18 PRB-type pages, plus 8 large figure

Study on COgnition and Prognosis in the Elderly (SCOPE): baseline characteristics

Blood Press. 2000;9(2-3):146-51. Study on COgnition and Prognosis in the Elderly (SCOPE): baseline characteristics. Hansson L, Lithell H, Skoog I, Baro F, Bánki CM, Breteler M, Castaigne A, Correia M, Degaute JP, Elmfeldt D, Engedal K, Farsang C, Ferro J, Hachinski V, Hofman A, James OF, Krisin E, Leeman M, de Leeuw PW, Leys D, Lobo A, Nordby G, Olofsson B, Opolski G, Prince M, Reischies FM. University of Uppsala, Department of Public Health, Clinical Hypertension Research, Sweden. Abstract The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multi-centre, prospective, randomized, double-blind, parallel-group study. The primary objective of SCOPE is to assess the effect of the angiotensin II type 1 (AT1) receptor blocker, candesartan cilexetil 8-16 mg once daily, on major cardiovascular events in elderly patients (70-89 years of age) with mild hypertension (DBP 90-99 and/or SBP 160-179 mmHg). The secondary objectives of the study are to test the hypothesis that antihypertensive therapy can prevent cognitive decline (as measured by the Mini Mental State Examination, MMSE) and dementia, and to assess the effect of therapy on total mortality, myocardial infarction (MI), stroke, renal function, and hospitalization. A total of 4964 patients from 15 participating countries were recruited during the randomization phase of SCOPE, exceeding the target population of 4000. The mean age of the patients at enrolment was 76 years, the ratio of male to female patients was approximately 1:2, and 52% of patients were already being treated with an antihypertensive agent at enrolment. The majority of patients (88%) were educated to at least primary school level. At randomization, mean sitting blood pressure values were SBP 166 mmHg and DBP 90 mmHg, and the mean MMSE score was 28. Previous cardiovascular disease in the study population included myocardial infarction (4%), stroke (4%) and atrial fibrillation (4%). Men, more often than women, had a history of previous MI, stroke and atrial fibrillation. A greater percentage of men were smokers (13% vs 6% in women) and had attended university (11% vs 3% of women). Of the randomized patients, 21% were 80 years of age. In this age group smoking was less common (4% vs 10% for 70-79-year-olds) and fewer had attended university (4% vs 7% for 70-79-year-olds). The incidence of MI was similar in both age groups. However, stroke and atrial fibrillation had occurred approximately twice as frequently in the older patients. The patients' mean age at baseline was similar in the participating countries, and most countries showed the approximate 1:2 ratio for male to female patients. There was also little inter-country variation in terms of mean SBP, DBP or MMSE score. However, there was considerable regional variation in the percentage of patients on therapy prior to enrolment. PMID: 10855739 [PubMed - indexed for MEDLINE