Search

BackgroundAn Alternating high- cholesterol dietary regimen has proven to be beneficial when compared to daily high- cholesterol feeding. In the current study we explored whether the same strategy is applicable to a high- fat dietary regimen.ObjectiveTo investigate whether an alternating high- fat dietary regimen can effectively diminish insulin resistance, hepatic and renal inflammation and renal dysfunction as compared to a continuous high- fat diet.DesignFour groups of male ApoE*3Leiden mice (n=15) were exposed to different diet regimens for 20 weeks as follows: Group 1: low- fat diet (10 kcal% fat); Group 2: intermediate- fat diet (25 kcal% fat); Group 3: high- fat diet (45 kcal% fat) and Group 4: alternating- fat diet (10 kcal% fat for 4 days and 45 kcal% fat for 3 days in a week).ResultsCompared to high fat diet feeding, the alternating and intermediate- fat diet groups had reduced body weight gain and did not develop insulin resistance or albuminuria. In addition, in the alternating and intermediate- fat diet groups, parameters of tissue inflammation were markedly reduced compared to high fat diet fed mice.ConclusionBoth alternating and intermediate- fat feeding were beneficial in terms of reducing body weight gain, insulin resistance, hepatic and renal inflammation and renal dysfunction. Thus beneficial effects of alternating feeding regimens on cardiometabolic risk factors are not only applicable for cholesterol containing diets but can be extended to diets high in fat content.

BACKGROUND: Physicians need to inform asymptomatic individuals about personalized outcomes of statin therapy for primary prevention of cardiovascular disease (CVD). However, current prediction models focus on short-term outcomes and ignore the competing risk of death due to other causes. We aimed to predict the potential lifetime benefits with statin therapy, taking into account competing risks. METHODS AND FINDINGS: A microsimulation model based on 5-y follow-up data from the Rotterdam Study, a population-based cohort of individuals aged 55 y and older living in the Ommoord district of Rotterdam, the Netherlands, was used to estimate lifetime outcomes with and without statin therapy. The model was validated in-sample using 10-y follow-up data. We used baseline variables and model output to construct (1) a web-based calculator for gains in total and CVD-free life expectancy and (2) color charts for comparing these gains to the Systematic Coronary Risk Evaluation (SCORE) charts. In 2,428 participants (mean age 67.7 y, 35.5% men), statin therapy increased total life expectancy by 0.3 y (SD 0.2) and CVD-free life expectancy by 0.7 y (SD 0.4). Age, sex, smoking, blood pressure, hypertension, lipids, diabetes, glucose, body mass index, waist-to-hip ratio, and creatinine were included in the calculator. Gains in total and CVD-free life expectancy increased with blood pressure, unfavorable lipid levels, and body mass index after multivariable adjustment. Gains decreased considerably with advancing age, while SCORE 10-y CVD mortality risk increased with age. Twenty-five percent of participants with a low SCORE risk achieved equal or larger gains in CVD-free life expectancy than the median gain in participants with a high SCORE risk. CONCLUSIONS: We developed tools to predict personalized increases in total and CVD-free life expectancy with statin therapy. The predicted gains we found are small. If the underlying model is validated in an independent cohort, the tools may be useful in discussing with patients their individual outcomes with statin therapy.

Inherited and acquired dysregulation of the complement alternative pathway plays an important role in multiple renal diseases. In recent years, the identification of disease-causing mutations and genetic variants in complement regulatory proteins has contributed significantly to our knowledge of the pathogenesis of complement associated glomerulopathies. In these diseases defective complement control leading to the deposition of activated complement products plays a key role. Consequently, complement-related glomerulopathies characterized by glomerular complement component 3 (C3) deposition in the absence of local immunoglobulin deposits are now collectively described by the term “C3 glomerulopathies.” Therapeutic strategies for reestablishing complement regulation by either complement blockade with the anti-C5 monoclonal antibody eculizumab or plasma substitution have been successful in several cases of C3 glomerulopathies. However, further elucidation of the underlying defects in the alternative complement pathway is awaited to develop pathogenesis-specific therapies.

Formation of advanced glycation endproducts (AGEs), endothelial dysfunction, and low-grade inflammation are intermediate pathways of hyperglycemia-induced vascular complications. We investigated the effect of benfotiamine on markers of these pathways in patients with type 2 diabetes and nephropathy.Patients with type 2 diabetes and urinary albumin excretion in the high-normal and microalbuminuric range (15-300 mg/24h) were randomized to receive benfotiamine (n = 39) or placebo (n = 43). Plasma and urinary AGEs (N(ε)-(carboxymethyl) lysine [CML], N(ε)-(Carboxyethyl) lysine [CEL], and 5-hydro-5-methylimidazolone [MG-H1]) and plasma markers of endothelial dysfunction (soluble vascular cell adhesion molecule-1 [sVCAM-1], soluble intercellular adhesion molecule-1 [sICAM-1], soluble E-selectin) and low-grade inflammation (high-sensitivity C-reactive protein [hs-CRP], serum amyloid-A [SAA], myeloperoxidase [MPO]) were measured at baseline and after 6 and 12 weeks.Compared to placebo, benfotiamine did not result in significant reductions in plasma or urinary AGEs or plasma markers of endothelial dysfunction and low-grade inflammation.Benfotiamine for 12 weeks did not significantly affect intermediate pathways of hyperglycemia-induced vascular complications. TRIAL REGRISTRATION: ClinicalTrials.gov NCT00565318.

INTRODUCTION: Toll-like receptors (TLRs) are a family of receptors that sense pathogen associated patterns such as bacterial cell wall proteins. Bacterial infections are associated with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Here, we assessed the expression of TLRs 2, 4, and 9 by peripheral blood leukocytes from patients with AAV, and investigated TLR mediated responses ex vivo. METHODS: Expression of TLRs was determined in 38 AAV patients (32 remission, 6 active disease), and 20 healthy controls (HC). Membrane expression of TLRs 2, 4, and 9, and intracellular expression of TLR9 by B lymphocytes, T lymphocytes, NK cells, monocytes and granulocytes was assessed using 9-color flowcytometry. Whole blood from 13 patients and 7 HC was stimulated ex vivo with TLR 2, 4 and 9 ligands and production of cytokines was analyzed. RESULTS: In patients, we observed increased proportions of TLR expressing NK cells. Furthermore, patient monocytes expressed higher levels of TLR2 compared to HC, and in a subset of patients an increased proportion of TLR4(+) monocytes was observed. Monocytes from nasal carriers of Staphylococcus aureus expressed increased levels of intracellular TLR9. Membrane expression of TLRs by B lymphocytes, T lymphocytes, and granulocytes was comparable between AAV patients and HC. Patients with active disease did not show differential TLR expression compared to patients in remission. Ex vivo responses to TLR ligands did not differ significantly between patients and HC. CONCLUSIONS: In AAV, monocytes and NK cells display increased TLR expression. Increased TLR expression by these leukocytes, probably resulting from increased activation, could play a role in disease (re)activation.

The etiology of anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitides (AAV) is unknown, but the association between infections and autoimmunity has been studied extensively. In 2004, a novel theory was proposed that could link infection and autoimmunity. This 'theory of autoantigen complementarity' was based on the serendipitous finding of antibodies against complementary-PR3 (cPR3) in patients with PR3-ANCA-associated vasculitis. cPR3 demonstrated homology to several bacterial proteins, and it was hypothesized that PR3-ANCA develop in response to anti-cPR3 antibodies, as a consequence of the anti-idiotypic network. These data have not been confirmed in other patient cohorts. We investigated the presence of anti-cPR3 antibodies in a Dutch cohort of PR3-ANCA-associated vasculitis patients. Anti-cPR3 reactivity was determined in serum using ELISA. Two separate batches of cPR3 were used to determine reactivity in two separate cohorts of PR3-ANCA-associated vasculitis patients. We found that anti-cPR3-reactivity was not increased in our PR3-ANCA-associated vasculitis patients, in comparison to control groups. Further research will be necessary to prove the concept of autoantigen complementarity in autoimmune diseases.

BACKGROUND: Alternate day calorie restriction (CR) has been shown to be almost as beneficial as daily CR. The question arises whether this concept is also applicable to alternating dietary composition. OBJECTIVE: To seek evidence that alternating high cholesterol (HC)-cholesterol-free (CON) Western diet can effectively diminish hepatic and renal inflammation and cardiovascular risk factors as compared with daily HC-supplemented Western diet. DESIGN: Four groups of ApoE*3Leiden mice, a humanized model for atherosclerosis, were subjected to different feeding treatments for 16 weeks. Mice were fed CON diet; CON diet with 1% w/w cholesterol (HC); alternate (ALT) diet regimen of CON (4 days) and HC (3 days); or CON diet supplemented with 0.43% (w/w) cholesterol (MC), with overall dietary cholesterol intake equal to ALT. Plasma was analyzed for cardiovascular risk factors, aorta for atherosclerotic lesion formation, and liver and kidney for inflammation. RESULTS: ALT diet but not MC was almost as effective as daily CON feeding in preventing disease development. Compared to HC, the ALT group showed 62% lower hepatic nuclear factor kappa B (NF-κB) activity (P

TRPC6, encoding a member of the transient receptor potential (TRP) superfamily of ion channels, is a calcium-permeable cation channel, which mediates capacitive calcium entry into the cell. Until today, seven different mutations in TRPC6 have been identified as a cause of autosomal-dominant focal segmental glomerulosclerosis (FSGS) in adults.Here we report a novel TRPC6 mutation that leads to early onset FSGS. We identified one family in whom disease segregated with a novel TRPC6 mutation (M132T), that also affected pediatric individuals as early as nine years of age. Twenty-one pedigrees compatible with an autosomal-dominant mode of inheritance and biopsy-proven FSGS were selected from a worldwide cohort of 550 families with steroid resistant nephrotic syndrome (SRNS). Whole cell current recordings of the mutant TRPC6 channel, compared to the wild-type channel, showed a 3 to 5-fold increase in the average out- and inward TRPC6 current amplitude. The mean inward calcium current of M132T was 10-fold larger than that of wild-type TRPC6. Interestingly, M132T mutants also lacked time-dependent inactivation. Generation of a novel double mutant M132T/N143S did not further augment TRPC6 channel activity.In summary, our data shows that TRPC6 mediated FSGS can also be found in children. The large increase in channel currents and impaired channel inactivation caused by the M132T mutant leads to an aggressive phenotype that underlines the importance of calcium dose channeled through TRPC6.

The identification of recessive disease-causing genes by homozygosity mapping is often restricted by lack of suitable consanguineous families. To overcome these limitations, we apply homozygosity mapping to single affected individuals from outbred populations. In 72 individuals of 54 kindred ascertained worldwide with known homozygous mutations in 13 different recessive disease genes, we performed total genome homozygosity mapping using 250,000 SNP arrays. Likelihood ratio Z-scores (ZLR) were plotted across the genome to detect ZLR peaks that reflect segments of homozygosity by descent, which may harbor the mutated gene. In 93% of cases, the causative gene was positioned within a consistent ZLR peak of homozygosity. The number of peaks reflected the degree of inbreeding. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations within a single ZLR peak of homozygosity as short as 2 Mb, containing an average of only 16 candidate genes. As many specialty clinics have access to cohorts of individuals from outbred populations, and as our approach will result in smaller genetic candidate regions, the new strategy of homozygosity mapping in single outbred individuals will strongly accelerate the discovery of novel recessive disease genes.

Background: Nationally representative data are critical for understanding the causes, costs and consequences of dementia and MCI in the US and can better inform policies aimed at reducing their impact on patients, families, and public programs. Because research on dementia is often based on highly selected samples of older adults who are disproportionately White, college‐educated, and high‐income, the nationally representative Health and Retirement Study (HRS) has become an essential resource for US population‐level information on dementia prevalence and incidence. However, the original HRS substudy providing dementia diagnostic information was fielded more than 20 years ago. We developed the Harmonized Cognitive Assessment Protocol (HCAP) to provide national estimates of the prevalence of MCI and dementia in the US and to examine differences by age, race and ethnicity, and gender. Method: A random sample of 3,496 HRS participants age 65+ completed a comprehensive neuropsychological test battery and a standard informant interview. Dementia and MCI were classified using an algorithm based on standard diagnostic criteria and comparing test performance to a robust normative sample. National prevalence was estimated using population weights. Result: A total of 393 (9.8%) individuals [mean (SD) age, 82.3 (7.4); 243 women (62%) and 150 men (38%)] were classified as having dementia, and 804 (22%) individuals were classified as having MCI [mean (SD) age, 76.8 (7.8) years, 243 women (62%) and 150 men (38%)]. People with dementia and MCI were more likely to be older, had fewer years of school, and were more likely to be non‐Hispanic Black or Hispanic than non‐Hispanic White. No differences in prevalence were found between women and men. Conclusion: Using a comprehensive, harmonized neuropsychological test battery and large substudy sample to derive national estimates, we found the prevalence of dementia and MCI among people age 65 and older was similar to that of other Western countries. Cognitive impairment is common among older adults, and shows significant patterning along racial, ethnic, and socioeconomic lines. Updated dementia prevalence estimates for the United States from 2016 show that the disproportionate burden of dementia and MCI among Black and Hispanic older adults and people with lower educational attainment persists. [ABSTRACT FROM AUTHOR]

Background: Bilingualism is increasingly common in older adults in the US and may impact the expression and course of Alzheimer's Disease and related dementias (ADRD). Optimal methods for assessing cognition in population‐based studies of bilingual older adults are not established. Given that declines in semantic fluency are associated with declines in episodic memory in ADRD, we examined the degree to which animal naming in English and Spanish is associated with memory performance in a sample of bilingual Mexican American (MA) older adults. Method: The Brain Attack Surveillance in Corpus Christi‐Cognitive study is a population‐based study of cognition in MA and non‐Hispanic white adults 65+ in south Texas. We included US‐born, bilingual MA participants who completed in‐person neuropsychological assessment in their preferred language (English) with the Harmonized Cognitive Assessment Protocol. We added a Spanish animal naming trial to the standard animal naming trial in English. We used the delayed recall score from a word list as the indicator of memory performance. We performed a series of regression analyses with delayed recall as the dependent variable and the English and Spanish animal naming scores as the independent variables, with age, sex, years of education, and a self‐reported bilingualism index score to account for level of bilingualism (range 0–1; 0 indicates monolingual Spanish; 1 indicates monolingual English) as covariates. Result: Ninety‐six participants were included (Mage = 73yrs±6; Meducation = 11±4; 60% women; Table 1). In separate regression models including covariates, English animal naming (b = 0.25, p<.0001) and Spanish animal naming (b = 0.20, p <.05) were each associated with delayed recall. When considered together, English animal naming (b = 0.24, p = <.0001) and not Spanish animal naming (b = 0.03, p =.69) was associated with delayed recall, after accounting for age, sex, years of education, and level of bilingualism (Table 2). Results were consistent when the analysis was restricted to balanced bilinguals (Table 3). Conclusion: Semantic fluency in English and Spanish were each related to episodic memory among bilingual MA older adults assessed in English, although the Spanish trial did not add unique information in its association with episodic memory. Future studies should evaluate how bilingual semantic fluency is associated with longitudinal cognitive decline in ADRD. [ABSTRACT FROM AUTHOR]

Background: In 2019, more than 16 million U.S. family members and friends provided 18.6 billion hours of unpaid care to people with cognitive impairment. Mexican Americans (MAs) make up two thirds of the Latinx population and research shows that MA caregivers report more caregiver burden compared to non‐Hispanic Whites (NHW). The purpose of this study is to examine the underlying mechanisms influencing caregiver burden on the physical and mental health of caregivers by ethnicity and familism. Method: We recruited adults 65 and older with cognitive impairment (Montreal Cognitive Assessment score>25), and their caregivers living in Nueces County, Texas. Caregiver burden was measured using the Zarit Burden Interview. Familism was measured using a 18‐item scale. Caregiver's mental and physical health were derived from the 36‐Item Short Form Survey. Covariates included caregiver's age, sex, ethnicity, education and care recipient's cognitive function and physical impairment, including the ability to eat, dress or go to the toilet without assistance. We used weighted path analysis to test effects of ethnicity, familism and caregiver burden on caregiver's mental and physical health. Covariates with p‐values>0.15 were excluded to attain a parsimonious reduced model. Result: We included data from 516 caregivers and those they cared for. MA caregivers were younger, female, had less education and scored higher on the familism scale compared to NHW (Table 1). Figure 1 includes results from our reduced weighted path model which presented a good model fit. Increased caregiver burden was associated with worse mental (B = ‐0.53;p<0.001) and physical health (B = ‐0.14;p = 0.003). Familism had indirect positive effects on mental and physical health outcomes mediated by lowering caregiver burden (B = ‐0.15;p = 0.001). Being a MA caregiver was associated with a stronger level of familism (B = 0.49;p<0.001). Findings indicate that MA caregivers have better physical and mental health due to reduced caregiver burden because of stronger family relations. Conclusion: Results show that increased caregiver burden is associated with worse caregiver's mental and physical health. However, among MA, familism can be a protective factor against caregiver burden. Findings can contribute to early identification, intervention and coordination of services to help reduce caregiver burden, particularly in the growing MA informal caregiver population. [ABSTRACT FROM AUTHOR]

This study evaluates the early and long-term clinical and echocardiographic outcome of edge-to-edge (E2E) mitral valve repair (MVr) concomitant to septal myectomy (SM) in patients with symptomatic hypertrophic obstructive cardiomyopathy (HOCM). A retrospective single-center analysis was performed of patients who underwent isolated SM or SM with E2E MVr from 2011 to 2022. Exclusion criteria were primary mitral valve (MV) disease or concomitant valve surgery. Early and long-term safety, functional and echocardiographic outcomes were compared between groups. Between January 2011 and April 2022, 76 consecutive patients underwent SM for HOCM: 42 patients (55%) underwent SM without additional E2E MVr (Group 1) and 34 patients (45%) underwent SM with additional E2E MVr (Group 2). At latest follow-up, 87% of patients were in New York Heart Association (NYHA) class I-II with no significant differences in NYHA class between groups. Incidence of safety events was comparable between groups. Echocardiographic relief of left ventricular outflow tract (LVOT) obstruction was comparable at early follow-up (P = 0.68), with a significant but small difference in maximum LVOT pressure gradient at latest follow-up in favor of E2E MVr (P = 0.04). Furthermore, patients who underwent SM with E2E MVr showed less residual systolic anterior motion at early and latest follow-up (P = 0.020; P = 0.178). Reintervention on the MV was absent in both groups at 1 year and equally low at follow-up (P = 0.27). This study demonstrates that adding E2E MVr to septal myectomy is as safe as isolated myectomy for the treatment of HOCM. Moreover, the addition of E2E MVr is associated with similar excellent functional improvement and freedom from MV reintervention. [ABSTRACT FROM AUTHOR]

Objective: To estimate associations of lifetime traumatic brain injury (TBI) characteristics with prospective suicide attempt among US Army soldiers. Method: The Army STARRS (Study to Assess Risk and Resilience in Servicemembers) Pre/Post Deployment Study surveyed 3 Brigade Combat Teams that were deployed to Afghanistan in 2012. Lifetime TBI and past-month postconcussive/post-TBI symptoms were evaluated at predeployment baseline. Recency and number of TBIs were quantified, and TBI severity was classified on the basis of reports of alteration/loss of consciousness and memory lapse. Suicide attempt data came from administrative records and surveys administered after return from deployment. Logistic regression models estimated associations of TBI characteristics with prospective suicide attempt among baseline respondents who were deployed (n = 7677), adjusting for other risk factors including lifetime mental disorder. Results: One hundred three soldiers made a suicide attempt over a median follow-up period of 30 months (weighted prevalence = 1.31% [0.14%]). In the final model estimating joint associations of TBI severity/recency and past-month postconcussive/post-TBI symptoms, only postconcussive/post-TBI symptoms were associated with a higher risk of suicide attempt (per standard score increase: AOR [adjusted odds ratio] = 1.31; 95% CI, 1.05-1.63; P = .012). Conclusions: Among the lifetime TBI characteristics evaluated at predeployment baseline, only past-month postconcussive/post-TBI symptoms were prospectively associated with an increased risk of suicide attempt following deployment. Detection of postconcussive/post-TBI symptoms could facilitate targeting of Army suicide prevention programs. [ABSTRACT FROM AUTHOR]