Search

There is increasing clinical and molecular evidence for the role of hormones and specifically estrogen and its receptor in schizophrenia. A selective estrogen receptor modulator, raloxifene, stimulates estrogen-like activity in brain and can improve cognition in older adults. The present study tested the extent to which adjunctive raloxifene treatment improved cognition and reduced symptoms in young to middle-age men and women with schizophrenia. Ninety-eight patients with a diagnosis of schizophrenia or schizoaffective disorder were recruited into a dual-site, thirteen-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment in addition to their usual antipsychotic medications. Symptom severity and cognition in the domains of working memory, attention/processing speed, language and verbal memory were assessed at baseline, 6 and 13 weeks. Analyses of the initial 6-week phase of the study using a parallel groups design (with 39 patients receiving placebo and 40 receiving raloxifene) revealed that participants receiving adjunctive raloxifene treatment showed significant improvement relative to placebo in memory and attention/processing speed. There was no reduction in symptom severity with treatment compared with placebo. There were significant carryover effects, suggesting some cognitive benefits are sustained even after raloxifene withdrawal. Analysis of the 13-week crossover data revealed significant improvement with raloxifene only in attention/processing speed. This is the first study to show that daily, oral adjunctive raloxifene treatment at 120 mg per day has beneficial effects on attention/processing speed and memory for both men and women with schizophrenia. Thus, raloxifene may be useful as an adjunctive treatment for cognitive deficits associated with schizophrenia. [ABSTRACT FROM AUTHOR]

What is known and objective The thiopurine medications are standard inflammatory bowel disease treatments. Therapeutic failure is observed, however, often because of variable drug metabolism. Allopurinol can enhance the potency of thiopurine treatment. Our objective is to review the relevant literature, and our own experience, to determine if allopurinol enhancement of thiopurine treatment is a reasonable therapeutic strategy. Comment Published reports of, and our own experience using, allopurinol-thiopurine combination therapy indicate that the addition of allopurinol will enhance thiopurine treatment in up to 60% of patients. There are risks to this approach, but with appropriate monitoring, these risks should approximate those observed with thiopurine therapy alone. What is new and conclusion Combination therapy with allopurinol and a thiopurine is a reasonable alternative for inflammatory bowel disease patients not responding to thiopurine monotherapy. Physicians experienced in thiopurine treatment, who have familiarity with thiopurine metabolism, and are willing to engage in appropriate therapeutic monitoring, should consider this strategy. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Pelvic incidence: an anatomic investigation of 880 cadaveric specimens," by D. S. Weinberg\ and colleagues in the December 10, 2015 isssue.

The selective estrogen receptor modulator raloxifene significantly improved memory and attention/processing speed relative to placebo in a 13‐week crossover trial that included both men and women with schizophrenia. Raloxifene did not result in a reduction in symptom severity, however. INSET: précis. [ABSTRACT FROM AUTHOR]

Neurotensin (NT), a brain-gut tridecapeptide, as well as the brain-penetrant NT analog, NT-2, have been shown to elicit a myriad of effects such as hypothermia, analgesia, sedation and suppression of food intake (FI) when administered centrally. These actions are thought to be mediated predominately by NT receptor subtype 1 (NTS1R). The present study examined the effect of NT-2, administered intra-peritoneally (i.p.). DIO mice (50–55g) were treated with either vehicle or NT-2 (0.3 and 3mg/kg; i.p.) and FI and activity were recorded continuously (5min intervals) for 24h. Overnight body weight (BW) was significantly reduced in NT-2-treated mice by more than 2%, FI was significantly reduced by 72–76% at 6h, and by 23–31% at 24h. Moreover, locomotive activities were also transiently reduced. These effects were confirmed in the wild-type mice but not in the NTS1R-deficient mice, supporting the role NTS1R in feeding, weight loss and locomotion. Whether peripheral and/or central activation of NTS1R represent viable approaches to the pharmacotherapy of obesity will require detailed assessment of the relative efficacy and therapeutic index of brain-penetrant and non-brain-penetrant NTS1R agonists. [Copyright &y& Elsevier]

We present LyMAS2, an improved version of the 'Lyman- α Mass Association Scheme' aiming at predicting the large-scale 3D clustering statistics of the Lyman- α forest (Ly  α) from moderate-resolution simulations of the dark matter (DM) distribution, with prior calibrations from high-resolution hydrodynamical simulations of smaller volumes. In this study, calibrations are derived from the Horizon-AGN suite simulations, (100 Mpc  h)−3 comoving volume, using Wiener filtering, combining information from DM density and velocity fields (i.e. velocity dispersion, vorticity, line-of-sight 1D-divergence and 3D-divergence). All new predictions have been done at z  = 2.5 in redshift space, while considering the spectral resolution of the SDSS-III BOSS Survey and different DM smoothing (0.3, 0.5, and 1.0 Mpc  h −1 comoving). We have tried different combinations of DM fields and found that LyMAS2, applied to the Horizon-noAGN DM fields, significantly improves the predictions of the Ly  α  3D clustering statistics, especially when the DM overdensity is associated with the velocity dispersion or the vorticity fields. Compared to the hydrodynamical simulation trends, the two-point correlation functions of pseudo-spectra generated with LyMAS2 can be recovered with relative differences of ∼5 per cent even for high angles, the flux 1D power spectrum (along the light of sight) with ∼2 per cent and the flux 1D probability distribution function exactly. Finally, we have produced several large mock BOSS spectra (1.0 and 1.5 Gpc  h −1) expected to lead to much more reliable and accurate theoretical predictions. [ABSTRACT FROM AUTHOR]

The APOGEE Open Cluster Chemical Abundances and Mapping survey is used to probe the chemical evolution of the s-process element cerium in the Galactic disk. Cerium abundances were derived from measurements of Ce ii lines in the APOGEE spectra using the Brussels Automatic Code for Characterizing High Accuracy Spectra in 218 stars belonging to 42 open clusters. Our results indicate that, in general, for ages < 4 Gyr, younger open clusters have higher [Ce/Fe] and [Ce/α-element] ratios than older clusters. In addition, metallicity segregates open clusters in the [Ce/X]–age plane (where X can be H, Fe, or the α-elements O, Mg, Si, or Ca). These metallicity-dependent relations result in [Ce/Fe] and [Ce/α] ratios with ages that are not universal clocks. Radial gradients of [Ce/H] and [Ce/Fe] ratios in open clusters, binned by age, were derived for the first time, with d[Ce/H]/dRGC being negative, while d[Ce/Fe]/dRGC is positive. [Ce/H] and [Ce/Fe] gradients are approximately constant over time, with the [Ce/Fe] gradient becoming slightly steeper, changing by ∼+0.009 dex kpc−1 Gyr−1. Both the [Ce/H] and [Ce/Fe] gradients are shifted to lower values of [Ce/H] and [Ce/Fe] for older open clusters. The chemical pattern of Ce in open clusters across the Galactic disk is discussed within the context of s-process yields from asymptotic giant branch (AGB) stars, gigayear time delays in Ce enrichment of the interstellar medium, and the strong dependence of Ce nucleosynthesis on the metallicity of its AGB stellar sources. [ABSTRACT FROM AUTHOR]

PurposeTo evaluate anti-VEGF and photodynamic therapy (PDT) for juxtafoveal and extrafoveal choroidal neovascularization (CNV) due to age-related macular degeneration (ARMD), ocular histoplasmosis syndrome (OHS), and degenerative myopia.MethodsA total of 10 eyes with juxtafoveal or extrafoveal choroidal neovascularization underwent intravitreal anti-VEGF therapy combined with verteporfin PDT (689 nm). Most treatments consisted of PDT every 12 weeks and either ranibizumab 0.5 mg every 4 weeks or bevacizumab 1.25 mg every 6 weeks, initiated concurrently. Retreatment criteria were persistent exudative signs on optical coherence tomography or fluorescein angiography.ResultsPresenting visual acuity (VA) ranged from 20/20 to 20/60 (mean log MAR±SD, 0.338±0.16 (20/44 equivalent)). After a mean follow-up of 17.5 months, it ranged from 20/15 to 20/40 (mean log MAR±SD, 0.150±0.14 (20/28 equivalent); P=0.027, paired t-test). Six eyes improved by 2 lines and four remained within 2 lines of initial VA. Non-ARMD eyes required much fewer treatments than ARMD eyes. All five non-ARMD eyes and three of five ARMD eyes showed no CNV activity at least 5 months after last treatment.ConclusionsAnti-VEGF therapy and PDT can preserve good visual function and may be suited to some cases of nonfoveal CNV. ARMD eyes require longer courses of treatment than non-ARMD eyes. [ABSTRACT FROM AUTHOR]

Background: Studies have suggested that women with previous diagnoses of gynecologic cancer (cervical, endometrial, or ovarian) have an increased risk for colorectal cancer.Objective: To quantify risk for colorectal cancer after gynecologic cancer, both overall and for subgroups defined by age at diagnosis, cancer stage at diagnosis, ethnicity, and duration of follow-up.Design: Retrospective cohort analysis of the Surveillance, Epidemiology, and End Results (SEER) program database from 1974 through 1995.Setting: U.S. cancer registry.Patients: 21,222 patients with cervical cancer, 51,680 patients with endometrial cancer, and 28,832 patients with ovarian cancer.Measurements: Standardized incidence ratios (SIRs) were calculated for each gynecologic cancer site and for subgroups to represent the relative risk for colorectal cancer in women with previously diagnosed gynecologic cancer compared with women without gynecologic cancer. Poisson regression methods adjusting simultaneously for all study variables were used to estimate relative risks for colorectal cancer across subgroups with each gynecologic cancer.Results: Overall, risk for colorectal cancer was elevated among women with previous ovarian cancer (SIR, 1.36 [95% CI, 1.21 to 1.53]). Risk was greatest in women who received a diagnosis before 50 years of age (SIR, 3.67 [CI, 2.74 to 4.80]) but was also elevated in women who received a diagnosis between 50 and 64 years of age (SIR, 1.52 [CI, 1.25 to 1.83]). The risk for colorectal cancer after endometrial cancer was also elevated substantially if endometrial cancer was diagnosed before the age of 50 (SIR, 3.39 [CI, 2.73 to 4.17]). No apparent risk elevation was associated with previous cervical cancer.Conclusions: Previous endometrial or ovarian cancer, particularly when diagnosed at an early age, increases subsequent risk for colorectal cancer. Greater emphasis on colorectal cancer screening in these populations may be necessary. [ABSTRACT FROM AUTHOR]

The circumgalactic medium (CGM) is fed by galaxy outflows and accretion of intergalactic gas, but its mass, heavy element enrichment, and relation to galaxy properties are poorly constrained by observations. In a survey of the outskirts of 42 galaxies with the Cosmic Origins Spectrograph onboard the Hubble Space Telescope, we detected ubiquitous, large (150-kitoparsec) halos of ionized oxygen surrounding star-forming galaxies; we found much less ionized oxygen around galaxies with little or no star formation. This ionized CGM contains a substantial mass of heavy elements and gas, perhaps far exceeding the reservoirs of gas in the galaxies themselves. Our data indicate that it is a basic component of nearly all star-forming galaxies that is removed or transformed during the quenching of star formation and the transition to passive evolution. [ABSTRACT FROM AUTHOR]

There is sparse evidence on community practice patterns in treating women with breast cancer. This study compared care of women with breast cancer with evidence from meta-analyses and US National Comprehensive Cancer Network (NCCN) clinical guidelines. Records of 4395 women with breast cancer were abstracted from practices of 19 surgeon oncologists in six specialty practices in the Philadelphia region during 1995-1999. Patients were followed through December 2001. Low-frequency data were obtained on all patients. All other data were from a random sample of 464 women, minimum of 50 patients per practice. Actual care provided was compared to NCCN guidelines and results of meta-analyses. Fewer than half the women received treatments reflecting meta-analysis results or NCCN guidelines, by disease stage/TNM status. Adherence to either standard varied from 0% for LCIS to 87% for stages IIA or IIB node positive. There are multiple interactive reasons for low adherence to guidelines or meta-analyses results, including insufficient health system supports to clinicians, inadequate organisation and delivery systems and ineffective continuing medical education. The paucity of written information from patient records on physician/patient interactions limits the understanding of treatment decisions.British Journal of Cancer (2004) 90, 26-30. doi:10.1038/sj.bjc.6601439 www.bjcancer.com [ABSTRACT FROM AUTHOR]

The melanocortin system is involved in the regulation of several diverse physiologic pathways. Recently we have demonstrated that replacing His6 by Pro6 in the well-known antagonist SHU-9119 resulted in a potent agonist at the hMC5R (EC50 = 0.072 n m) with full antagonist activity at the hMC3R and the hMC4R. We have designed, synthesized, and pharmacologically characterized a series of peptide analogs of MT-II and SHU-9119 at the human melanocortin receptors MC3R, MC4R and MC5R. All these peptides were modified at position 6 with a Pro instead of a His residue. In this study, we have identified new scaffolds which are antagonists at the hMC4R and hMC3R. Additionally, we have discovered a new selective agonist at the hMC4R, Ac-Nle-c[Asp-Pro-D-Phe-Arg-Trp-Lys]-Pro-Val-NH2 ( 6, PG-931) which will be useful in further biologic investigations of the hMC4R. PG-931 was about 100-fold more selective for the hMC4R vs. the hMC3R (IC50 = 0.58 and 55 n m, respectively). Some of these new analogs have exceptional biologic potencies at the hMC5R and will be useful in further efforts to differentiate the substructural features responsible for selectivity at the hMC3R, hMC4R, and hMC5R. [ABSTRACT FROM AUTHOR]

To elucidate the molecular basis of the interaction of the native dodecapeptide γ-MSH with the melanocortin receptors, we performed a structure-activity study in which we systematically replaced L-Ala in each position of this peptide. Here we report the binding affinity and agonist potency on human MC3R, MC4R and MC5R. Intracellular cAMP concentration was measured on CHO cells, and binding assays were carried out using membranes prepared from these cell lines which stably express hMC3R, hMC4R and hMC5R. Our results indicate that the last four amino acids in the C-terminal region of γ-MSH are not important determinants of biological activity and selectivity at human melanocortin receptors. Interesting results were obtained when L-Ala was substituted for His[sup 6], Phe[sup 7], Arg[sup 8] and Trp[sup 9]. For these peptides, the affinity and activity at all three human receptors (MC3R, MC4R and MC5R) decreased significantly, demonstrating that the His-Phe-Arg-Trp sequence in γ-MSH is important for activity at these three melanocortin receptors. Similar results were obtained when Met³ was replaced with L-Ala, suggesting the importance of this position in the interaction with all three receptors. This study highlights the role played by the His-Phe-Arg-Trp sequence in receptor binding and in agonist activity of γ-MSH. [ABSTRACT FROM AUTHOR]

Background: Patients with stage II colorectal cancer and no histologic evidence of lymph node invasion develop recurrent disease, presumably because of undetected micrometastases. Guanylyl cyclase C is expressed by intestinal and colorectal cancer cells but not by extraintestinal tissues or tumors.Objective: To examine the expression of guanylyl cyclase C messenger RNA (mRNA) in lymph nodes of patients with node-negative colorectal cancer who did and did not have recurrent disease.Design: Case-control study.Setting: Tertiary care academic medical center.Patients: Paraffin-embedded lymph nodes were obtained from 21 patients with histologically confirmed node-negative colorectal cancer who had undergone resection. Controls included 11 patients without disease recurrence 6 or more years after resection, and case-patients included 10 patients whose disease recurred up to 3 years after resection.Measurements: Sections of paraffin-embedded lymph nodes were obtained from each patient and were pooled, and their RNA was analyzed by reverse transcriptase polymerase chain reaction (RT-PCR).Results: Guanylyl cyclase C mRNA was expressed in lymph nodes from all patients with recurrent disease but not in those from patients without recurrent disease (P = 0.004). Nested RT-PCR that used primers for carcinoembryonic antigen, a marker for colorectal cancer, identified carcinoembryonic antigen mRNA in lymph nodes from only 1 of 10 patients with recurrent disease and those from 0 of 11 patients without recurrent disease. The odds ratio for death associated with expression of guanylyl cyclase C mRNA in regional lymph nodes was 15.0 (95% CI, 1.1 to 756.7).Conclusions: Expression of guanylyl cyclase C mRNA in lymph nodes is associated with recurrence of colorectal cancer in patients with stage II disease. Analysis of guanylyl cyclase mRNA expression by RT-PCR may be useful for colorectal cancer staging. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect, if any, of histamine type 2 receptor antagonists (H2RAs) on serum alcohol levels under various conditions including type of H2RA receptor antagonist, alcohol dose, and fed status of the subject.Study Design: Meta-analysis of the published literature.Data Sources: Studies were identified by MEDLINE (January 1982 through December 1997) using the key words H2 receptor antagonists and alcohol. Other studies were identified by reviewing bibliographies of retrieved articles and by discussion with colleagues.Study Selection: Studies were selected if they involved the coadministration of H2RAs and alcohol in healthy, human volunteers. Studies that may have addressed this goal but were performed in another context, for instance the measurement of ulcer healing, were excluded.Data Extraction: Data were extracted on the design, number of participants, participant characteristics, type and dose of H2RA administered, serum alcohol levels (measured as Cmax) along with standard deviations, dose of alcohol received, and fed or fasted status of participants. Alcohol dose was arbitrarily divided into low dose (< or = 0.5 g/kg body weight) versus high dose (> 0.5 g/kg body weight). In addition, studies involving ranitidine and cimetidine were stratified by sample size into small (n < or = 10) versus not small (n > 10).Measurements and Main Results: Twenty-four trials met selection criteria. Small elevations in Cmax were noted when cimetidine (2.71 mg/DL; 95% confidence internal [CI] 1.60, 3.83) or ranitidine (6.95 mg/DL; 95% CI 5.83, 8.08) were coadministered with alcohol. No such differences were noted for famotidine (0.28 mg/DL; 95% CI -1.24, 1.80) or nizatidine (2.33 mg/DL;, 95% CI -0.06, 4.72). The elevation detected with cimetidine and ranitidine was most pronounced in smaller studies (n < 10). Separate analyses investigating the effect of alcohol dose and fed or fasted status of participants revealed no clinically important differences.Conclusions: Cimetidine and ranitidine, but not the other H2RAs, can cause small elevations of serum alcohol level when alcohol and drug are administered concurrently. Studies with larger numbers of participants were less likely to demonstrate this effect. Relative to accepted, legal definitions of intoxication, the effect of any H2RA on blood alcohol level is unlikely to be clinically relevant. [ABSTRACT FROM AUTHOR]