OBJECTIVETo assess the association between diet quality and intake of specific foods with disability and symptom severity in people with multiple sclerosis (MS).
METHODSIn 2015, participants in the ...North American Research Committee on MS (NARCOMS) Registry completed a dietary screener questionnaire that estimates intake of fruits, vegetables and legumes, whole grains, added sugars, and red/processed meats. We constructed an overall diet quality score for each individual based on these food groups; higher scores denoted a healthier diet. We assessed the association between diet quality and disability status as measured using Patient-Determined Disease Steps (PDDS) and symptom severity using proportional odds models, adjusting for age, sex, income, body mass index, smoking status, and disease duration. We assessed whether a composite healthy lifestyle measure, a healthier diet, healthy weight (body mass index <25), routine physical activity, and abstinence from smoking was associated with symptom severity.
RESULTSOf the 7,639 (68%) responders, 6,989 reported physician-diagnosed MS and provided dietary information. Participants with diet quality scores in the highest quintile had lower levels of disability (PDDS; proportional odds ratio OR for Q5 vs Q1 0.80; 95% confidence interval CI 0.69–0.93) and lower depression scores (proportional OR for Q5 vs Q1 0.82; 95% CI 0.70–0.97). Individuals reporting a composite healthy lifestyle had lower odds of reporting severe fatigue (0.69; 95% CI 0.59–0.81), depression (0.53; 95% CI 0.43–0.66), pain (0.56; 95% CI 0.48–0.67), or cognitive impairment (0.67; 95% CI 0.55–0.79).
CONCLUSIONSOur large cross-sectional survey suggests a healthy diet and a composite healthy lifestyle are associated with lesser disability and symptom burden in MS.
Objective
A double‐blind, randomized, controlled study was undertaken to determine whether combined use of interferon β‐1a (IFN) 30μg intramuscularly weekly and glatiramer acetate (GA) 20mg daily is ...more efficacious than either agent alone in relapsing–remitting multiple sclerosis.
Methods
A total of 1,008 participants were randomized and followed until the last participant enrolled completed 3 years. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score, and magnetic resonance imaging (MRI) metrics.
Results
Combination IFN + GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed Expanded Disability Status Scale progression or change in MSFC over 36 months. The combination was superior to either agent alone in reducing new lesion activity and accumulation of total lesion volumes. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity‐free status (DAFS) compared to either single arm, driven by the MRI results.
Interpretation
Combining the 2 most commonly prescribed therapies for multiple sclerosis did not produce a significant clinical benefit over 3 years. An effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. The extension phase for CombiRx will address whether the observed differences in MRI and DAFS findings predict later clinical differences. ANN NEUROL 2013;73:327–340
The production of reactive species contributes to the age-dependent accumulation of dysfunctional mitochondria and protein aggregates, all of which are associated with neurodegeneration. A putative ...mediator of these effects is the lipid peroxidation product 4-hydroxynonenal (4-HNE), which has been shown to inhibit mitochondrial function, and accumulate in the postmortem brains of patients with neurodegenerative diseases. This deterioration in mitochondrial quality could be due to direct effects on mitochondrial proteins, or through perturbation of the macroautophagy/autophagy pathway, which plays an essential role in removing damaged mitochondria. Here, we use a click chemistry-based approach to demonstrate that alkyne-4-HNE can adduct to specific mitochondrial and autophagy-related proteins. Furthermore, we found that at lower concentrations (5-10 μM), 4-HNE activates autophagy, whereas at higher concentrations (15 μM), autophagic flux is inhibited, correlating with the modification of key autophagy proteins at higher concentrations of alkyne-4-HNE. Increasing concentrations of 4-HNE also cause mitochondrial dysfunction by targeting complex V (the ATP synthase) in the electron transport chain, and induce significant changes in mitochondrial fission and fusion protein levels, which results in alterations to mitochondrial network length. Finally, inhibition of autophagy initiation using 3-methyladenine (3MA) also results in a significant decrease in mitochondrial function and network length. These data show that both the mitochondria and autophagy are critical targets of 4-HNE, and that the proteins targeted by 4-HNE may change based on its concentration, persistently driving cellular dysfunction.
Post-translational modification on protein Ser/Thr residues by O-linked attachment of ß-N-acetyl-glucosamine (O-GlcNAcylation) is a key mechanism integrating redox signaling, metabolism and stress ...responses. One of the most common neurodegenerative diseases that exhibit aberrant redox signaling, metabolism and stress response is Parkinson's disease, suggesting a potential role for O-GlcNAcylation in its pathology. To determine whether abnormal O-GlcNAcylation occurs in Parkinson's disease, we analyzed lysates from the postmortem temporal cortex of Parkinson's disease patients and compared them to age matched controls and found increased protein O-GlcNAcylation levels. To determine whether increased O-GlcNAcylation affects neuronal function and survival, we exposed rat primary cortical neurons to thiamet G, a highly selective inhibitor of the enzyme which removes the O-GlcNAc modification from target proteins, O-GlcNAcase (OGA). We found that inhibition of OGA by thiamet G at nanomolar concentrations significantly increased protein O-GlcNAcylation, activated MTOR, decreased autophagic flux, and increased α-synuclein accumulation, while sparing proteasomal activities. Inhibition of MTOR by rapamycin decreased basal levels of protein O-GlcNAcylation, decreased AKT activation and partially reversed the effect of thiamet G on α-synuclein monomer accumulation. Taken together we have provided evidence that excessive O-GlcNAcylation is detrimental to neurons by inhibition of autophagy and by increasing α-synuclein accumulation.
Objective:Obstructive sleep apnea (OSA) and primary aldosteronism are common in subjects with resistant hypertension; it is unknown, however, if the two disorders are causally related. This study ...relates plasma aldosterone and renin levels to OSA severity in subjects with resistant hypertension, and in those with equally severe OSA but without resistant hypertension serving as control subjects.
Methods:Seventy-one consecutive subjects referred to the University of Alabama at Birmingham (UAB) for resistant hypertension (BP uncontrolled on three medications) and 29 control subjects referred to UAB Sleep Disorders Center for suspected OSA were prospectively evaluated by an early morning plasma aldosterone concentration (PAC) and renin level, and by overnight, attended polysomnography.
Results:OSA (apnea-hypopnea index AHI ≥ 5/h) was present in 85% of subjects with resistant hypertension. In these subjects, PAC correlated with AHI (ρ = 0.44, p = 0.0002) but not renin concentration. Median PAC was significantly lower in control subjects compared to subjects with resistant hypertension (5.5 ng/dL vs 11.0 ng/dL, p < 0.05) and not related to AHI. In male subjects compared to female subjects with resistant hypertension, OSA was more common (90% vs 77%) and more severe (median AHI, 20.8/h vs 10.8/h; p = 0.01), and median PAC was significantly higher (12.0 ng/dL vs 8.8 ng/dL, p = 0.006).
Conclusion:OSA is extremely common in subjects with resistant hypertension. A significant correlation between PAC and OSA severity is observed in subjects with resistant hypertension but not in control subjects. While cause and effect cannot be inferred, the data suggest that aldosterone excess may contribute to OSA severity.
J Clin Hypertens (Greenwich).
Among patients with resistant hypertension (RHTN), there are those whose blood pressure (BP) remains uncontrolled in spite of maximal medical therapy. This retrospective ...analysis aims to characterize these patients with refractory hypertension. Refractory hypertension was defined as BP that remained uncontrolled after ≥3 visits to a hypertension clinic within a minimum 6‐month follow‐up period. Of the 304 patients referred for RHTN, 29 (9.5%) remained refractory to treatment. Patients with refractory hypertension and those with controlled RHTN had similar aldosterone levels and plasma renin activity (PRA). Patients with refractory hypertension had higher baseline BP (175±23/97±15 mm Hg vs 158±25/89±15 mm Hg; P=.001/.005) and heart rate, and higher rates of prior stroke and congestive heart failure. During follow‐up, the BP of patients with refractory hypertension remained uncontrolled (168.4±14.8/93.8±17.7 mm Hg) in spite of use of an average of 6 antihypertensive medications, while those of patients with controlled RHTN decreased to 129.3±11.2/77.6±10.8 mm Hg. Spironolactone reduced the BP by 12.9±17.8/6.6±13.7 mm Hg in patients with refractory hypertension and by 24.1±16.7/9.2±12.0 mm Hg in patients with controlled RHTN. In patients with RHTN, approximately 10% remain refractory to treatment. Similar aldosterone and PRA levels and a diminished response to spironolactone suggest that aldosterone excess does not explain the treatment failure.
To determine the role of race in surgical outcomes of and complications after urethroplasty.
A single institution, retrospective review was conducted from 2011 to 2019 on male patients ≥18 years of ...age who underwent urethroplasty. Exclusion criteria included previous urethral cancer, lack of follow up, or revision urethroplasty. Failure of urethroplasty was defined as requiring revision surgery or recurrence on imaging or cystoscopy. Risk factors for recurrence were determined using descriptive statistics, Wilcoxon comparisons, and multivariate logistic regression.
Three hundred and seven patients were identified with 234 patients meeting inclusion criteria. 63.2% identified as White/Caucasian (CA), 32.5% Black/African American (AA), and 4.3% other race. Mean age was 49.4 years. Between CA and AA patients, there was no difference in mean age, body mass index, smoking status, prior urethroplasty, or prior dilation/DVIU. CAs were more likely to have a fossa navicularis stricture compared to AAs (P = .0094), but there were no significant differences in bulbar, penile, or posterior stricture rates (all P >.05) or length (P = .32). The overall stricture recurrence rate was 15.8% with a median of 242 days to recurrence and no significant difference by race for either outcome (P = .83, P = .64). The only predictor of stricture recurrence was prior dilation/DVIU (P = .0404, OR 2.3, 95% CI 1.0, 5.6). Overall complication rate was 17.5%, with no difference between CA and AAs rates (P = .83) or complication type (P = .62).
There was no significant difference in the rate of surgical failure for urethral stricture repair based on race. The only predictor of surgical failure was having a prior urethral dilation/DVIU.
OBJECTIVE:To evaluate the association between health insurance coverage and disease-modifying therapy (DMT) use for multiple sclerosis (MS).
METHODS:In 2014, we surveyed participants in the North ...American Research Committee on MS registry regarding health insurance coverage. We investigated associations between negative insurance change and (1) the type of insurance, (2) DMT use, (3) use of free/discounted drug programs, and (4) insurance challenges using multivariable logistic regressions.
RESULTS:Of 6,662 respondents included in the analysis, 6,562 (98.5%) had health insurance, but 1,472 (22.1%) reported negative insurance change compared with 12 months earlier. Respondents with private insurance were more likely to report negative insurance change than any other insurance. Among respondents not taking DMTs, 6.1% cited insurance/financial concerns as the sole reason. Of respondents taking DMTs, 24.7% partially or completely relied on support from free/discounted drug programs. Of respondents obtaining DMTs through insurance, 3.3% experienced initial insurance denial of DMT use, 2.3% encountered insurance denial of DMT switches, and 1.6% skipped or split doses because of increased copay. For respondents with relapsing-remitting MS, negative insurance change increased their odds of not taking DMTs (odds ratio OR 1.50; 1.16–1.93), using free/discounted drug programs for DMTs (OR 1.89; 1.40–2.57), and encountering insurance challenges (OR 2.48; 1.64–3.76).
CONCLUSIONS:Insurance coverage affects DMT use for persons with MS, and use of free/discounted drug programs is substantial and makes economic analysis that ignores these supplements potentially inaccurate. The rising costs of drugs and changing insurance coverage adversely affect access to treatment for persons with MS.
To evaluate associations between a broad range of approaches to classifying diet and incident type 2 diabetes in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study.
This ...study included 8,750 Black and White adults without diabetes at baseline. Diabetes was defined according to fasting glucose ≥70 mmol/L, random glucose ≥111 mmol/L, or use of diabetes medications. The exposures were diet scores for Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND), dietary inflammatory index (DII), dietary inflammation score (DIS), and empirical dietary patterns (plant-based and Southern) determined using data collected with use of the Block98 food-frequency questionnaire. Modified Poisson regression was used to assess association of dietary measures with risk of incident type 2 diabetes, with models adjusted for total energy intake, demographics, lifestyle factors, and waist circumference.
There were 1,026 cases of incident type 2 diabetes during follow-up (11.7%). Adherence to the Southern dietary pattern was most strongly associated with risk of incident type 2 diabetes after adjustment for demographics and lifestyle (quintile Q5 vs. lowest Q1: risk ratio RR 1.95; 95% CI 1.57, 2.41). Of the diet scores, DIS (Q5 vs. Q1 RR 1.41) and MIND (Q1 vs. Q5 RR 1.33), demonstrated anti-inflammatory diets, had strongest associations with lower diabetes incidence.
We found associations of several dietary approaches with incident type 2 diabetes. Investigation into mechanisms driving the association with the Southern dietary pattern is warranted. Further research into use of DIS, DII, and MIND diet score should be considered for dietary recommendations for diabetes prevention.
The safety and effectiveness of live virus vaccines, such as the varicella-zoster vaccine, are unknown in patients with inflammatory diseases receiving immunomodulatory therapy such as tumor necrosis ...factor inhibitors (TNFis).
To evaluate the safety and immunogenicity of the live attenuated zoster vaccine (ZVL) in patients receiving TNFis.
Randomized, blinded, placebo-controlled trial. (ClinicalTrials.gov: NCT02538341).
Academic and community-based rheumatology, gastroenterology, and dermatology practices.
Adults aged 50 years or older receiving TNFis for any indication.
Random assignment to ZVL versus placebo.
Glycoprotein enzyme-linked immunosorbent assay (gpELISA) and enzyme-linked immunosorbent spot (ELISpot) from serum and peripheral blood mononuclear cells measured at baseline and 6 weeks after vaccination. Suspected varicella infection or herpes zoster was clinically assessed using digital photographs and polymerase chain reaction on vesicular fluid.
Between March 2015 and December 2018, 617 participants were randomly assigned in a 1:1 ratio to receive ZVL (
= 310) or placebo (
= 307) at 33 centers. Mean age was 62.7 years (SD, 7.5); 66.1% of participants were female, 90% were White, 8.2% were Black, and 5.9% were Hispanic. The most common TNFi indications were rheumatoid arthritis (57.6%) and psoriatic arthritis (24.1%); TNFi medications were adalimumab (32.7%), infliximab (31.3%), etanercept (21.2%), golimumab (9.1%), and certolizumab (5.7%). Concomitant therapies included methotrexate (48.0%) and oral glucocorticoids (10.5%). Through week 6, no cases of confirmed varicella infection were found; cumulative incidence of varicella infection or shingles was 0.0% (95% CI, 0.0% to 1.2%). At 6 weeks, compared with baseline, the mean increases in geometric mean fold rise as measured by gpELISA and ELISpot were 1.33 percentage points (CI, 1.17 to 1.51 percentage points) and 1.39 percentage points (CI, 1.07 to 1.82 percentage points), respectively.
Potentially limited generalizability to patients receiving other types of immunomodulators.
This trial informs safety concerns related to use of live virus vaccines in patients receiving biologics.
The National Institute of Arthritis and Musculoskeletal and Skin Diseases and the American College of Rheumatology.
PDF
