Radiographic damage and functional limitations both increase with the duration of ankylosing spondylitis (AS). We examined whether radiographic damage contributed more to functional limitations in late AS than in early AS, and if the strength of association varied with the anatomic region of damage.
In this cross-sectional study of 801 patients with AS, we examined associations of the lumbar modified Stoke AS Spine Score (mSASSS), cervical mSASSS, lumbar posterior fusion, cervical posterior fusion, and hip arthritis with the Bath AS Functional Index (BASFI) and the Health Assessment Questionnaire (HAQ-S).
Higher lumbar and cervical mSASSS were associated with more functional limitations, but there was an interaction between mSASSS and the duration of AS such that the strength of their association with functional limitations decreased with increasing duration of AS. Cervical posterior fusion was associated with worse functioning independent of mSASSS. Hip arthritis was significantly associated with functional limitations independent of measures of spinal damage. Among patients with AS ≥ 40 years, the number of comorbid conditions accounted for most of the variation in functioning. Results were similar for both the BASFI and HAQ-S.
Although both radiographic damage and functional limitations increase over time in AS, the relative contribution of radiographic damage to functional limitations is lower among patients with longstanding AS than early AS, suggesting patients may accommodate to limited flexibility. Damage in different skeletal regions impacts functioning over the duration of AS. Functional limitations due to comorbidity supervene in late AS.
Ankylosing spondylitis; radiographic damage; functional limitations
Recent studies have shown that the transcription factor early growth response-1 (Egr-1) regulates ethanol-induced fatty liver. However, the mechanism(s) through which ethanol oxidation controls Egr-1 is unknown. Here, using recombinant hepatoma (HepG2; VL-17A) cells that metabolize ethanol, we show that alcohol dehydrogenase catalysis of ethanol oxidation and subsequent acetaldehyde production controls Egr-1 expression. Further, the induction of Egr-1 enhances expression of other steatosis-related genes, resulting in triglyceride accumulation. Ethanol exposure increased Egr-1 promoter activity, messenger RNA and Egr-1 protein levels in VL-17A cells. Elevated Egr-1 protein was sustained by an ethanol-induced decrease in proteasome activity, thereby stabilizing the Egr-1 protein. Egr-1 induction depended on ethanol oxidation, as it was prevented when ethanol oxidation was blocked. Ethanol exposure induced Egr-1 and triglyceride accumulation only in alcohol dehydrogenase-expressing cells that produced acetaldehyde. Such induction did not occur in parental, non-metabolizing HepG2 cells or in cells that express only cytochrome P450 2E1. However, direct exposure of HepG2 cells to acetaldehyde induced both Egr-1 protein and triglycerides. Egr-1 over-expression elevated triglyceride levels, which were augmented by ethanol exposure. However, these triglyceride levels did not exceed those in ethanol-exposed cells that had normal Egr-1 expression. Conversely, Egr-1 knockdown by siRNA only partially blocked ethanol-induced triglyceride accumulation and was associated not only with lower Egr-1 expression but also attenuation of SREBP1c and TNF-α mRNAs. Double knockdown of both Egr-1 and SREBP-1c abolished ethanol-elicited steatosis. Collectively, our findings provide important new insights into the temporal regulation by ethanol oxidation of Egr-1 and cellular steatosis.
acetaldehyde; oxidant stress; cytochrome P450 2E1; proteasome; cellular steatosis
Beta-catenin (CTNNB1), a key component of wingless-type mouse mammary tumor virus integration site family (WNT) signaling, participates in follicle stimulated hormone-mediated regulation of estrogen (E2) production. The purpose of these studies was to determine if CTNNB1’s contribution to FSH-mediated steroidogenesis in primary rat granulosa cells was due in part to extracellular stimulation of the canonical WNT signaling pathway. To achieve this purpose, primary cultures of rat granulosa cells were exposed to vehicle or a canonical member of the WNT signaling pathway, WNT3A, before co-culture and in the presence or absence of FSH for 24 h. Activation of the canonical WNT signaling pathway was determined by dose-dependent induction of Axin2 mRNA expression and stimulation of the CTNNB1/T cell factor promoter-reporter TOPflash. WNT pathway induction was demonstrated at doses of 50 and 500 ng/mL of WNT3A. Granulosa cells treated with WNT3A in combination with FSH had enhanced CTNNB1/T cell factor transcriptional activity above cells treated with WNT3A alone. Steroidogenic enzymes and ovarian differentiation factor mRNAs were quantified via quantitative PCR. Expression of steroidogenic enzyme mRNAs aromatase (Cyp19a1), P450 side chain cleavage (Cyp11a1), and steroidogenic acute regulatory protein (Star) were increased following FSH treatment. Co-incubation of WNT3A and FSH reduced the ability of FSH to stimulate steroidogenic enzymes and subsequent E2 and progesterone (P4) production. Concomitant activation of FSH and WNT pathways results in marked reduction of ovarian differentiation factors, LH receptor (Lhcgr) and inhibin-alpha (Inha). Therefore, WNT inhibits FSH target genes and steroid production associated with maturation and differentiation of the ovarian follicle.
To determine whether the “obesity epidemic” could explain the recent rise in the incidence of RA.
Obesity is an under-recognized risk factor for RA. In recent years both the prevalence of obesity and the incidence of RA have been rising.
An inception cohort of Olmsted County, Minnesota residents who fulfilled 1987 American College of Rheumatology criteria for RA in 1980–2007 was compared to population-based controls (matched on age, sex and calendar year). Heights, weights and smoking status were collected from medical records. Obesity was defined as body mass index (BMI) ≥ 30 kg/m2. Conditional logistic regression was used to assess the influence of obesity on developing RA. Population attributable risk was used to estimate the incidence of RA in the absence of obesity.
The study included 813 patients with RA and 813 controls. Both groups had extensive medical history available prior to incidence/index date (mean 32.2 years), and approximately 30% of each group were obese at incidence/index date. The history of obesity was a significantly associated with developing RA (OR:1.24; 95 % CI: 1.01, 1.53 adjusted for smoking status). In 1985–2007 the incidence of RA rose by an increment of 9.2 per 100,000 among women. Obesity accounted for 4.8 per 100,000 (or 52%) of this increase.
Obesity is associated with a modest risk for developing RA. Given the rapidly increasing prevalence of obesity, this has had a significant impact on RA incidence and may account for much of the recent increase in incidence of RA.
rheumatoid arthritis; obesity; incidence; population attributable risk; body mass index
Metastatic malignant melanoma remains one of the most therapeutically challenging forms of cancer. Here we test replication-competent vesicular stomatitis viruses (VSV) on 19 primary human melanoma samples and compare these infections with those of normal human melanocyte control cells. Even at a low viral concentration, we found a strong susceptibility to viral oncolysis in over 70% of melanomas. In contrast, melanocytes displayed strong resistance to virus infection and showed complete protection by interferon. Several recombinant VSVs were compared, and all infected and killed most melanomas with differences in the time course with increasing rates of melanoma infection, as follows: VSV-CT9-M51 < VSV-M51 < VSV-G/GFP < VSV-rp30. VSV-rp30 sequencing revealed 2 nonsynonymous mutations at codon positions P126 and L223, both of which appear to be required for the enhanced phenotype. VSV-rp30 showed effective targeting and infection of multiple subcutaneous and intracranial melanoma xenografts in SCID mice after tail vein virus application. Sequence analysis of mutations in the melanomas used revealed that BRAF but not NRAS gene mutation status was predictive for enhanced susceptibility to infection. In mouse melanoma models with specific induced gene mutations including mutations of the Braf, Pten, and Cdkn2a genes, viral infection correlated with the extent of malignant transformation. Similar to human melanocytes, mouse melanocytes resisted VSV-rp30 infection. This study confirms the general susceptibility of the majority of human melanoma types for VSV-mediated oncolysis.
Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are major causes of blindness. They result from mutations in many genes which has long hampered comprehensive genetic analysis. Recently, targeted next-generation sequencing (NGS) has proven useful to overcome this limitation. To uncover “hidden mutations” such as copy number variations (CNVs) and mutations in non-coding regions, we extended the use of NGS data by quantitative readout for the exons of 55 RP and LCA genes in 126 patients, and by including non-coding 5′ exons. We detected several causative CNVs which were key to the diagnosis in hitherto unsolved constellations, e.g. hemizygous point mutations in consanguineous families, and CNVs complemented apparently monoallelic recessive alleles. Mutations of non-coding exon 1 of EYS revealed its contribution to disease. In view of the high carrier frequency for retinal disease gene mutations in the general population, we considered the overall variant load in each patient to assess if a mutation was causative or reflected accidental carriership in patients with mutations in several genes or with single recessive alleles. For example, truncating mutations in RP1, a gene implicated in both recessive and dominant RP, were causative in biallelic constellations, unrelated to disease when heterozygous on a biallelic mutation background of another gene, or even non-pathogenic if close to the C-terminus. Patients with mutations in several loci were common, but without evidence for di- or oligogenic inheritance. Although the number of targeted genes was low compared to previous studies, the mutation detection rate was highest (70%) which likely results from completeness and depth of coverage, and quantitative data analysis. CNV analysis should routinely be applied in targeted NGS, and mutations in non-coding exons give reason to systematically include 5′-UTRs in disease gene or exome panels. Consideration of all variants is indispensable because even truncating mutations may be misleading.
Loblolly pine (Pinus taeda L.) is an economically and ecologically important conifer for which a suite of genomic resources is being generated. Despite recent attempts to sequence the large genome of conifers, their assembly and the positioning of genes remains largely incomplete. The interspecific synteny in pines suggests that a gene-based map would be useful to support genome assemblies and analysis of conifers. To establish a reference gene-based genetic map, we performed exome sequencing of 14729 genes on a mapping population of 72 haploid samples, generating a resource of 7434 sequence variants segregating for 3787 genes. Most markers are single-nucleotide polymorphisms, although short insertions/deletions and multiple nucleotide polymorphisms also were used. Marker segregation in the population was used to generate a high-density, gene-based genetic map. A total of 2841 genes were mapped to pine’s 12 linkage groups with an average of one marker every 0.58 cM. Capture data were used to detect gene presence/absence variations and position 65 genes on the map. We compared the marker order of genes previously mapped in loblolly pine and found high agreement. We estimated that 4123 genes had enough sequencing depth for reliable detection of markers, suggesting a high marker conversation rate of 92% (3787/4123). This is possible because a significant portion of the gene is captured and sequenced, increasing the chances of identifying a polymorphic site for characterization and mapping. This sub-centiMorgan genetic map provides a valuable resource for gene positioning on chromosomes and guide for the assembly of a reference pine genome.
loblolly pine; exome sequencing; high-throughput genotyping; high-density genetic map; copy number variation
Men who have sex with men (MSM) who report receptive anal intercourse (RAI) are currently recommended to undergo annual screening for rectal C. trachomatis (CT) and N. gonorrhoeae (GC) infection.
Using standard culture methods, we assessed prevalence of rectal GC/CT among MSM who reported RAI in the last year (n=326) at an urban STD clinic in a midwestern US city. A subset (n=125) also underwent rectal GC/CT screening via nucleic acid amplification testing (NAAT). We examined associations between HIV status and prevalence of rectal GC and rectal CT using unadjusted and adjusted logistic regression models.
Prevalence of rectal GC, rectal CT and either rectal infection was 9%, 9% and 15% by culture and 24%, 23% and 38% by NAAT, respectively. HIV was not associated with rectal GC prevalence in unadjusted or adjusted analyses. HIV-positive status was significantly associated with increased rectal CT prevalence in unadjusted models (odds ratio (OR): 2.18, 95% confidence interval (CI): 1.04, 4.60); this association increased after multivariable adjustment (OR: 3.14, 95% CI: 1.37, 7.19).
MSM reporting RAI had high prevalence of rectal GC and rectal CT. HIV-positive status was significantly associated with prevalent rectal CT, but not with prevalent rectal GC.
Renal dysfunction occurs commonly in patients awaiting orthotopic liver transplantation (OLT) for end-stage liver disease. The use of simultaneous liver-kidney transplantation has increased in the MELD scoring era. As patients may recover renal function after OLT, identifying factors predictive of renal recovery is a critical issue, especially given the scarcity of available organs.
Employing the UNOS database, we sought to identify donor- and patient-related predictors of renal recovery among 1720 patients with pre-OLT renal dysfunction and transplanted from 1989 to 2005. Recovery of renal function post-OLT was defined as a composite endpoint of serum creatinine (SCr) ≤1.5 mg/dL at discharge and survival ≥29 days. Pre-OLT renal dysfunction was defined as any of the following: SCr ≥2 mg/dL at any time while awaiting OLT or need for renal replacement therapy (RRT) at the time of registration and/or OLT.
Independent predictors of recovery of renal function post-OLT were absence of hepatic allograft dysfunction, transplantation during MELD era, recipient female sex, decreased donor age, decreased recipient ALT at time of OLT, decreased recipient body mass index at registration, use of anti-thymocyte globulin as induction therapy, and longer wait time from registration. Contrary to popular belief, a requirement for RRT, even for prolonged periods in excess of 8 weeks, was not an independent predictor of failure to recover renal function post-OLT.
These data indicate that the duration of renal dysfunction, even among those requiring RRT, is a poor way to discriminate reversible from irreversible renal dysfunction.
Little is known about relationships between dietary patterns, n-3 polyunsaturated fatty acids (PUFA) intake and excessive anxiety during pregnancy.
To examine whether dietary patterns and n-3 PUFA intake from seafood are associated with high levels of anxiety during pregnancy.
Pregnant women enrolled from 1991–1992 in ALSPAC (n 9,530). Dietary patterns were established from a food frequency questionnaire using principal component analysis. Total intake of n-3 PUFA (grams/week) from seafood was also examined. Symptoms of anxiety were measured at 32 weeks of gestation with the Crown-Crisp Experiential Index; scores ≥9 corresponding to the 85th percentile was defined as high anxiety symptoms. Multivariate logistic regression models were used to estimate the OR and 95% CI, adjusted by socioeconomic and lifestyle variables.
Multivariate results showed that women in the highest tertile of the health-conscious (OR 0.77; 0.65–0.93) and the traditional (OR 0.84; 0.73–0.97) pattern scores were less likely to report high levels of anxiety symptoms. Women in the highest tertile of the vegetarian pattern score (OR 1.25; 1.08–1.44) were more likely to have high levels of anxiety, as well as those with no n-3 PUFA intake from seafood (OR 1.53; 1.25–1.87) when compared with those with intake of >1.5 grams/week.
The present study provides evidence of a relationship between dietary patterns, fish intake or n-3 PUFA intake from seafood and symptoms of anxiety in pregnancy, and suggests that dietary interventions could be used to reduce high anxiety symptoms during pregnancy.
Cytoplasmic lipid droplets (CLD) are organelle-like structures that function in neutral lipid storage, transport and metabolism through the actions of specific surface-associated proteins. Although diet and metabolism influence hepatic CLD levels, how they affect CLD protein composition is largely unknown. We used non-biased, shotgun, proteomics in combination with metabolic analysis, quantitative immunoblotting, electron microscopy and confocal imaging to define the effects of low- and high-fat diets on CLD properties in fasted-refed mice. We found that the hepatic CLD proteome is distinct from that of CLD from other mammalian tissues, containing enzymes from multiple metabolic pathways. The hepatic CLD proteome is also differentially affected by dietary fat content and hepatic metabolic status. High fat feeding markedly increased the CLD surface density of perilipin-2, a critical regulator of hepatic neutral lipid storage, whereas it reduced CLD levels of betaine-homocysteine S-methyltransferase, an enzyme regulator of homocysteine levels linked to fatty liver disease and hepatocellular carcinoma. Collectively our data demonstrate that the hepatic CLD proteome is enriched in metabolic enzymes, and that it is qualitatively and quantitatively regulated by diet and metabolism. These findings implicate CLD in the regulation of hepatic metabolic processes, and suggest that their properties undergo reorganization in response to hepatic metabolic demands.
Vesicular stomatitis virus (VSV) has shown considerable promise both as an immunization vector and as an oncolytic virus. In both applications, an important concern is the safety profile of the virus. To generate a highly attenuated virus, we added two reporter genes to the 3′ end of the VSV genome, thereby shifting the NPMGL genes from positions 1 to 5 to positions 3 to 7. The resulting virus (VSV-12′GFP) was highly attenuated, generating smaller plaques than four other attenuated VSVs. In one-step growth curves, VSV-12′GFP displayed the slowest growth kinetics. The mechanism of attenuation appears to be due to reduced expression of VSV genes downstream of the reporter genes, as suggested by a 10.4-fold reduction in L-protein RNA transcript. Although attenuated, VSV-12′GFP was highly effective at generating an immune response, indicated by a high-titer antibody response against the green fluorescent protein (GFP) expressed by the virus. Although VSV-12′GFP was more attenuated than other VSVs on both normal and cancer cells, it nonetheless showed a greater level of infection of human cancer cells (glioma and melanoma) than of normal cells, and this effect was magnified in glioma by interferon application, indicating selective oncolysis. Intravenous VSV-12′GFP selectively infected human gliomas implanted into SCID mice subcutaneously or intracranially. All postnatal day 16 mice given intranasal VSV-12′GFP survived, whereas only 10% of those given VSV-G/GFP survived, indicating reduced neurotoxicity. Intratumoral injection of tumors with VSV-12′GFP dramatically suppressed tumor growth and enhanced survival. Together these data suggest this recombinant virus merits further study for its oncolytic and vaccine potential.
A significant number of mania patients fail to respond to current pharmacotherapy, thereby there is need for novel augmentation strategies. The results of some early studies showed the effectiveness of cholinomimetics in the treatment of mania. One open case series suggested the efficacy of donepezil in the treatment of bipolar disorder. Our aim was to explore whether an oral cholinesterase inhibitor, donepezil, administered during a 4-week treatment period, would benefit patients with acute mania.
We conducted a 4-week double-blind, placebo-controlled trial of donepezil as an adjunctive treatment to lithium in patients with acute mania. Eligible subjects were randomly assigned to receive donepezil or placebo in addition to lithium. Donepezil was started at 5 mg/day, and increased to 10 mg/day in the first week. Patients were rated with the Young Mania Rating Scale (YMRS) and Brief Psychiatric Rating Scale (BPRS) at baseline, day 1, week 1, week 2, and week 4.
Out of the 30 patients who were enrolled, 15 were on donepezil and 15 were on placebo. All patients completed the 4-week trial. On the first day, there was a difference of 1.97 units on the psychomotor symptoms scale of the YMRS in the donepezil group as compared to the placebo group (t = 2.39, P = 0.02). There was a difference of 0.57 units (t = 2.09, P = 0.04) in the speech item and a difference of 0.29 units in the sexual interest item (t = 2.11, P = 0.04) in the donepezil group as compared to the placebo group. The total YMRS difference on the first day approached the conventional significance level (1.97 units, t = 1.84, P = 0.07). Over the course of 4 weeks, we failed to find that donepezil produced any significant difference in the YMRS (6.71 units difference, t = −1.44, P = 0.16) or the BPRS scale (1.29 units difference, t = −0.33, P = 0.75) as compared to placebo. Ten subjects (66.67%) in both groups met the criteria for clinical response (Fisher’s exact P = 1.00). Five subjects (33.33%) in the donepezil group met the criteria for clinical remission while nine subjects (60.00%) in the placebo group met the remission criteria (Fisher’s exact P = 0.27).
Use of the oral anticholinergic donepezil had some benefit in the augmentation of lithium treatment on the first day, but did not provide any significant benefits in the long-term.
acute mania; cholinesterase inhibitors; donepezil; lithium
There remains a need for biomarkers to guide therapy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Our objective was to determine whether measures of platelet activation or inflammation are associated with disease activity in Wegener’s granulomatosis (WG).
Study subjects were participants in a clinical trial. Soluble CD40 ligand (sCD40L), C-reactive protein, interleukin 6 (IL-6), IL-8, monocyte chemoattractant protein 1 (MCP-1), P-selectin, vascular endothelial growth factor, and proteinase 3 (PR3)-specific ANCA were measured by ELISA using plasma samples obtained at baseline (active disease), at remission, and prior to, during, and after first flares. Disease activity was assessed by the Birmingham Vasculitis Activity Score for WG (BVAS/WG). Association of biomarkers with disease activity was determined with conditional logistic and linear regression.
Over a mean followup of 27 months, 180 subjects underwent 2044 visits; markers were measured in 563 samples. Longitudinally, all markers other than IL-6 were associated with disease activity. The strongest associations for active disease at baseline versus remission were observed for sCD40L (OR 4.72, 95% CI 2.47–9.03), P-selectin (OR 6.26, 95% CI 2.78–14.10), PR3-ANCA (OR 9.41, 4.03–21.99), and inversely for MCP-1 (OR 0.36, 95% CI 0.22–0.57). BVAS/WG increased by 0.80 (95% CI 0.44–1.16), 0.83 (95% CI 0.42–1.25), and 0.81 (95% CI 0.48–1.15) per unit-increase in PR3-ANCA, sCD40L, and P-selectin, respectively; and decreased by 1.54 (95% CI 0.96–2.12) per unit-increase in MCP-1.
Cytokines arising from within the circulation, including those of platelet activation, correlate with disease activity in WG.
VASCULITIS; BIOMARKERS; DISEASE ACTIVITY; WEGENER’S GRANULOMATOSIS
Previous work demonstrated that the transcription factor, early growth response-1 (Egr-1) participates in the development of steatosis (fatty liver) after chronic ethanol administration. Here, we determined the extent to which Egr-1 is involved in fatty liver development in mice subjected to acute ethanol administration.
In acute studies, we treated both wild type and Egr-1 null mice with either ethanol or phosphate-buffered saline (PBS) by gastric intubation. At various times after treatment, we harvested sera and livers and quantified endotoxin, indices of liver injury, steatosis, and hepatic Egr-1 content. In chronic studies, groups of mice were fed liquid diets containing either ethanol or isocaloric maltose-dextrin for 7-8 weeks.
Compared with controls, acute ethanol-treated mice showed a rapid, transient elevation in serum endotoxin beginning 30 minutes after treatment. One hour post-gavage, livers from ethanol-treated mice exhibited a robust elevation of both Egr-1 mRNA and protein. By three hours post-gavage, liver triglyceride increased in ethanol-treated mice as did lipid peroxidation. Acute ethanol treatment of Egr-1-null mice showed no Egr-1 expression, but these animals still developed elevated triglycerides, although significantly lower than ethanol-fed wild-type littermates. Despite showing decreased fatty liver, ethanol-treated Egr-1 null mice exhibited greater liver injury. After chronic ethanol feeding, steatosis and liver enlargement were clearly evident, but there was no indication of elevated endotoxin. Egr-1 levels in ethanol-fed mice were equal to those of pair-fed controls.
Acute ethanol administration induced the synthesis of Egr-1 in mouse liver. However, despite its robust increase, the transcription factor had a smaller, albeit significant, function in steatosis development after acute ethanol treatment. We propose that the rise in Egr-1 after acute ethanol is an hepatoprotective adaptation to acute liver injury from binge drinking that is triggered by ethanol metabolism and elevated levels of endotoxin.
alcoholic liver injury; fatty liver; oxidant stress; transcription factors; glutathione
Assess a generic measure of health-related quality of life (HRQOL) as an outcome measure in granulomatosis with polyangiitis (Wegener's, GPA)
Subjects were participants in the Wegener’s Granulomatosis Etanercept Trial (WGET) or the Vasculitis Clinical Research Consortium Longitudinal Study (VCRC-LS). HRQOL was assessed with the Short Form 36 Health Survey (SF-36) that includes physical and mental component summary scores (PCS and MCS). Disease activity was assessed with the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis (BVAS/WG).
Data from 180 subjects in the WGET (median follow-up = 2.3 years, mean number of visits = 10) and 237 subjects in the VCRC-LS (median follow-up = 2.0 years, mean number of visits = 8) were analyzed. One unit increase in BVAS/WG corresponded to a 1.15 unit (95%CI: 1.02; 1.29) decrease in PCS and a 0.93 (95%CI: 0.78; 1.07) decrease in MCS in the WGET and by 1.16 for PCS (95%CI: 0.94; 1.39) and 0.79 for MCS (95%CI: 0.51; 1.39) in the VCRC-LS. In both arms of the WGET study, SF-36 measures improved rapidly during the first 6 weeks of treatment followed by gradual improvement among patients achieving sustained remission (0.5 improvement in PCS per three months), but worsened slightly (0.03 decrease in PCS per three months) among patients not achieving sustained remission (p = 0.005).
HRQOL, as measured by SF-36, is reduced among patients with GPA. SF-36 measures are modestly associated with other disease outcomes and discriminate between disease states of importance in GPA.
vasculitis; health-related quality of life; outcome measures
Lersivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with a unique resistance profile exhibiting potent antiviral activity against wild-type HIV and several clinically relevant NNRTI-resistant strains. Lersivirine, a weak inducer of the cytochrome P450 (CYP) enzyme CYP3A4, is metabolized by CYP3A4 and UDP glucuronosyltransferase 2B7 (UGT2B7). Two open, randomized, two-way (study 1; study A5271008) or three-way (study 2; study A5271043) crossover phase I studies were carried out under steady-state conditions in healthy subjects. Study 1 (n = 17) investigated the effect of oral rifampin on the pharmacokinetics (PKs) of lersivirine. Study 2 (n = 18) investigated the effect of oral rifabutin on the PKs of lersivirine and the effect of lersivirine on the PKs of rifabutin and its active metabolite, 25-O-desacetyl-rifabutin. Coadministration with rifampin decreased the profile of the lersivirine area under the plasma concentration-time curve from time zero to 24 h postdose (AUC24), maximum plasma concentration (Cmax), and plasma concentration observed at 24 h postdose (C24) by 85% (90% confidence interval [CI], 83, 87), 83% (90% CI, 79, 85), and 92% (90% CI, 89, 94), respectively, versus the values for lersivirine alone. Coadministration with rifabutin decreased the lersivirine AUC24, Cmax, and C24 by 34% (90% CI, 29, 39), 25% (90% CI, 16, 33), and 58% (90% CI, 52, 64), respectively, compared with the values for lersivirine alone. Neither the rifabutin concentration profile nor overall exposure was affected following coadministration with lersivirine. Lersivirine and rifabutin reduced the 25-O-desacetyl-rifabutin AUC24 by 27% (90% CI, 21, 32) and Cmax by 27% (90% CI, 19, 34). Lersivirine should not be coadministered with rifampin, which is a potent inducer of CYP3A4, UGT2B7, and P-glycoprotein activity and thus substantially lowers lersivirine exposure. No dose adjustment of rifabutin is necessary in the presence of lersivirine; an upward dose adjustment of lersivirine may be warranted when it is coadministered with rifabutin.
Objective: While all second-generation antipsychotics (SGAs) are promoted for having a low risk of extrapyramidal side effects (EPS), clinical observations suggest differences between the various agents. Nevertheless, this question has never been examined in a systematic review and meta-analysis of head-to-head comparisons. Methods: We searched the register of the Cochrane schizophrenia group (last search May 2007), supplemented by MEDLINE (last search July 2009) for randomized, blinded studies comparing the following SGAs in the treatment of schizophrenia or related disorders: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, and zotepine. At least 3 reviewers extracted the data independently. The primary outcome was “use of antiparkinson medication.” The results were combined in a meta-analysis. Results: We included 54 studies with 116 arms. Risperidone was associated with more use of antiparkinson medication than clozapine, olanzapine, quetiapine, and ziprasidone. Ziprasidone showed more use of antiparkinson medication than olanzapine and quetiapine and zotepine more than clozapine. There was no significant difference between amisulpride and its comparators (olanzapine, risperidone, or ziprasidone). Quetiapine showed significantly less use of antiparkinson medication than the 3 other SGAs it was compared with (olanzapine, risperidone, and ziprasidone). Scale-derived data (Barnes Akathisia Scale and Simpson Angus Scale) were limited. Conclusions: Our meta-analysis demonstrates that there are differences between the SGAs in their ability to induce EPS that clinicians consider warrant treatment with antimuscarinic drugs. Even though the differences were relatively small, they might be important for individual patients and should be taken into account in drug choice.
antiparkinson medication; akathisia; classification of antipsychotics
The past decade has brought important advances in the understanding of rheumatoid arthritis and its management and treatment. New classification criteria for rheumatoid arthritis, better definitions of treatment outcome and remission, and the introduction of biologic response-modifying drugs designed to inhibit the inflammatory process have greatly altered the approach to managing this disease. More aggressive management of rheumatoid arthritis early after diagnosis and throughout the course of the disease has resulted in improvement in patient functioning and quality of life, reduction in comorbid conditions, and enhanced survival.
ACPA, anti–citrullinated protein antibody; ACR, American College of Rheumatology; BeSt, Behandel-Strategieën [trial]; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; CTLA-4:Ig, cytotoxic T lymphocyte–associated antigen 4:immunoglobulin fusion protein; DAS28, Disease Activity Score in 28 joints; DMARD, disease-modifying antirheumatic drug; EULAR, European League Against Rheumatism; HCQ, hydroxychloroquine; MTX, methotrexate; SDAI, Simplified Disease Activity Index; SSZ, sulfasalazine; TEAR, Treatment of Early Aggressive Rheumatoid Arthritis [study]; TNF, tumor necrosis factor
HIV/AIDS and its treatment often alter body composition and result in poorer physical functioning. The aim of this study was to determine the effects of a moderate-intensity exercise program on body composition and the hormones and cytokines associated with adverse health outcomes. HIV-infected males (N = 111) were randomized to an exercise group (EX) who completed 6 weeks of moderate-intensity exercise training, or to a nonintervention control group (CON). In pre- and postintervention, body composition was estimated via DXA, peak strength was assessed, and resting blood samples were obtained. There was a decrease in salivary cortisol at wake (P = 0.025) in the EX and a trend (P = 0.07) for a decrease 1 hour after waking. The EX had a significant increase in lean tissue mass (LTM) (P < 0.001) following the intervention. Those in the EX below median body fat (20%) increased LTM (P = 0.014) only, while those above 20% decreased fat mass (P = 0.02), total fat (N = 0.009), and trunk fat (P = 0.001), while also increasing LTM (P = 0.027). Peak strength increased between 14% and 28% on all exercises in the EX group. These data indicate that 6 weeks of moderate-intensity exercise training can decrease salivary cortisol levels, improve physical performance, and improve body composition in HIV-infected men.
Standard treatment for severe granulomatosis with polyangiitis (GPA, previously Wegener’s granulomatosis) is daily oral cyclophosphamide (CYC), a cytotoxic agent associated with ovarian failure. In this study we assessed the rate of diminished ovarian reserve in women with GPA who received CYC versus methotrexate (MTX).
Patients in the Wegener’s Granulomatosis Etanercept Trial received either daily CYC or weekly MTX and were randomized to etanercept or placebo. For all women under 50, plasma samples taken at baseline or early in the study were evaluated against samples taken later in the study to compare levels of anti-Müllerian hormone (AMH) and follicle stimulating hormone (FSH), endocrine markers of remaining egg supply. Diminished ovarian reserve was defined as AMH<1.0ng/ml.
Of 42 women in this analysis (mean age 35), 24 had CYC exposure prior to enrollment and 28 received the drug during the study. At study entry, women with prior CYC exposure had significantly lower AMH, higher FSH, and a higher rate of early menstruation cessation. For women with normal baseline ovarian function, 6/8 who received CYC during the trial developed diminished ovarian reserve, compared to 0/4 who did not receive CYC (p<0.05). Changes in AMH correlated inversely with cumulative CYC dose (p=0.01), with a 0.74ng/ml decline in AMH for each 10g of CYC.
Daily oral CYC, even when administered for less than 6 months, causes diminished ovarian reserve, as indicated by low AMH levels. These data highlight the need for alternative treatments for GPA in women of childbearing age.
Granulomatosis with polyangiitis; fertility; cyclophosphamide; anti-Müllerian hormone; ovarian function
Granulosa cell tumors (GCTs) are the most common ovarian estrogen producing tumors, leading to symptoms of excessive estrogen such as endometrial hyperplasia and endometrial adenocarcinoma. These tumors have malignant potential and often recur. The etiology of GCT is unknown. TGFα is a potent mitogen for many different cells. However, its function in GCT initiation, progression and metastasis has not been determined. The present study aims to determine whether TGFα plays a role in the growth of GCT cells. KGN cells, which are derived from an invasive GCT and have many features of normal granulosa cells, were used as the cellular model. Immunohistochemistry, Western blot and RT-PCR results showed that the ErbB family of receptors is expressed in human GCT tissues and GCT cell lines. RT-PCR results also indicated that TGFα and EGF are expressed in the human granulosa cells and the GCT cell lines, suggesting that TGFα might regulate GCT cell function in an autocrine/paracrine manner. TGFα stimulated KGN cell DNA synthesis, cell proliferation, cell viability, cell cycle progression, and cell migration. TGFα rapidly activated EGFR/PI3K/Akt and mTOR pathways, as indicated by rapid phosphorylation of Akt, TSC2, Rictor, mTOR, P70S6K and S6 proteins following TGFα treatment. TGFα also rapidly activated the EGFR/MEK/ERK pathway, and P38 MAPK pathways, as indicated by the rapid phosphorylation of EGFR, MEK, ERK1/2, P38, and CREB after TGFα treatment. Whereas TGFα triggered a transient activation of Akt, it induced a sustained activation of ERK1/2 in KGN cells. Long-term treatment of KGN cells with TGFα resulted in a significant increase in cyclin D2 and a decrease in p27/Kip1, two critical regulators of granulosa cell proliferation and granulosa cell tumorigenesis. In conclusion, TGFα, via multiple signaling pathways, regulates KGN cell proliferation and migration and may play an important role in the growth and metastasis of GCTs.
G-protein coupled estrogen receptor 1 (GPER) plays an important role in mediating estrogen action in many different tissues under both physiological and pathological conditions. G-1 (1-[4-(6-bromobenzo[1,3]dioxol-5yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl]-ethanone) has been developed as a selective GPER agonist to distinguish estrogen actions mediated by GPER from those mediated by classic estrogen receptors. In the present study, we surprisingly found that G-1 suppressed proliferation and induced apoptosis of KGN cells (a human ovarian granulosa cell tumor cell line), actions that were not blocked by a selective GPER antagonist G15 or siRNA knockdown of GPER. G-1 also suppressed proliferation and induced cell apoptosis in GPER-negative HEK-293 cells and MDA-MB 231 breast cancer cells. Our results demonstrate that G-1 suppresses proliferation of ovarian and breast cancer cells in a GPER-independent manner. G-1 may be a candidate for the development of drugs against ovarian and breast cancer.
GPR30/GPER; G-1; G15; ovarian cancer; breast cancer; estrogen receptors
Persons with rheumatoid arthritis (RA) suffer a high burden of infections, but currently no biomarkers are available to identify individuals at greatest risk. A prospective longitudinal study was therefore conducted to determine the association between the responsiveness of ex vivo cytokine production and 6-month risk of infections. Infections were identified by billing codes and validated by medical record review. At baseline, the release of 17 cytokines by peripheral blood mononuclear cells in response to stimulation, or media alone, was measured using multiplexed cytokine analysis. Production of IL-2, IL-8, IL-10, IL-17, TNF-α, IFN-γ, and GM-CSF, induced by various conditions, was significantly associated with the occurrence of infections. A multivariable prediction model based on these data provided new information on the risk of infection beyond standard assessments of disease activity, severity, and treatment. Future studies could utilize this information to devise new biomarkers for the prediction of infection in patients with RA.
Immune signature; immune response; peripheral blood mononuclear cells