Chest pain is a common symptom in patients with systemic lupus erythematosus, an autoimmune disease that is associated with increased cardiovascular morbidity and mortality. While chest pain ...mechanisms can be multifactorial and often attributed to non-coronary or non-cardiac cardiac etiologies, emerging evidence suggests that ischemia with no obstructive coronary arteries (INOCA) is a prevalent condition in patients with chest pain and no obstructive coronary artery disease. Coronary microvascular dysfunction is reported in approximately half of SLE patients with suspected INOCA. In this mini review, we highlight the cardiovascular risk assessment, mechanisms of INOCA, and diagnostic approach for patients with SLE and suspected CMD.
While autoimmune rheumatic diseases (ARDs) have been linked with coronary microvascular dysfunction (CMD), the relationship between ARD and CMD in women with signs and symptoms of ischemia and no ...obstructive arteries (INOCA) are not well described. We hypothesized that among women with CMD, those with ARD history have greater angina, functional limitations, and myocardial perfusion compromise compared to those without ARD history.
Women with INOCA and confirmed CMD by invasive coronary function testing were included from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) project (NCT00832702). Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI), and cardiac magnetic resonance myocardial perfusion reserve index (MPRI) were collected at baseline. Chart review was performed to confirm self-reported ARD diagnosis.
Of the 207 women with CMD, 19 (9%) had a confirmed history of ARD. Compared to those without ARD, women with ARD were younger (
= 0.04). In addition, they had lower DASI-estimated metabolic equivalents (
= 0.03) and lower MPRI (
= 0.008) but similar SAQ scores. There was a trend towards increased nocturnal angina and stress-induced angina in those with ARD (
= 0.05 for both). Invasive coronary function variables were not significantly different between groups.
Among women with CMD, women with a history of ARD had lower functional status and worse myocardial perfusion reserve compared to women without ARD. Angina-related health status and invasive coronary function were not significantly different between groups. Further studies are warranted to understand mechanisms contributing to CMD among women with ARDs with INOCA.
Glioblastomas (GBMs) are the most aggressive primary brain tumors, with an average survival of less than 15 months. Therefore, there is a critical need to develop novel therapeutic strategies for ...GBM. This study aimed to assess the prognostic value of miR-4516 and investigate its oncogenic functions and the underlying cellular and molecular mechanisms in GBM. To determine the correlation between miR-4516 expression and overall survival of patients with GBM, total RNAs were isolated from 268 FFPE tumor samples, miR expression was assayed (simultaneously) using the nCounter human miRNA v3a assay followed by univariable and multivariable survival analyses. Further, in vitro and in vivo studies were conducted to define the role of miR-4516 in GBM tumorigenesis and the underlying molecular mechanisms. Upon multivariable analysis, miR-4516 was correlated with poor prognosis in GBM patients (HR = 1.49, 95%CI: 1.12-1.99, P = 0.01). Interestingly, the significance of miR-4516 was retained including MGMT methylation status. Overexpression of miR-4516 significantly enhanced cell proliferation and invasion of GBM cells both in vitro and in vivo. While conducting downstream targeting studies, we found that the tumor-promoting function of miR-4516, in part, was mediated by direct targeting of PTPN14 (protein tyrosine phosphatase, non-receptor type 14) which, in turn, regulated the Hippo pathway in GBM. Taken together, our data suggest that miR-4516 represents an independent negative prognostic factor in GBM patients and acts as a novel oncogene in GBM, which regulates the PTPN14/Hippo pathway. Thus, this newly identified miR-4516 may serve as a new potential therapeutic target for GBM treatment.
Poor sleep and obstructive sleep apnea (OSA) have both been associated with worsening neurocognitive function. In the Restoring Insulin Secretion (RISE) Study, we assessed the relationship between ...presence and severity of OSA and cognition in treatment-naïve adults (n=179) with prediabetes or early T2D. A cognitive battery (CogState™ and story recall) assessed 1) psychomotor speed; 2) visual pattern separation; 3) visual attention and working memory; and 4) verbal learning and episodic memory. Wrist accelerometers worn for 7 days measured average sleep duration and efficiency. Other sleep outcomes were measured during one night of laboratory polysomnography. Linear regression models were fit to assess independent relationships between cognition and sleep measures. The cohort consisted of 44% females, 56% males; 53% white, 33% black, 6% Hispanic; age 54.7±8.9 years and BMI 34.7±5.4 kg/m2 (mean±SD). Based on ADA criteria, 73% had prediabetes and 27% had T2D. Sleep duration was 6.5±1.0 h; sleep efficiency was 85.9±7.5%; 26% had moderate OSA, 40% had severe OSA. After adjustment for age, sex, race/ethnicity, education, and BMI, higher sleep efficiency was associated with better visual pattern separation (as measured by the One Card Learning Test; p=0.039) but not with any other neurocognitive assessment. In the RISE cohort, measures of OSA severity (apnea-hypopnea index, oxygen desaturation index, sleep duration below 90% oxygen saturation, microarousal index) were not associated with baseline cognition. This cross-sectional analysis shows a high prevalence of moderate/severe OSA in treatment-naïve adults with prediabetes or early T2D. Although higher sleep efficiency was associated with better visual pattern separation, it was not associated with other measures of cognitive function. Further, OSA severity was not associated with measures of neurocognition.
Disclosure
K.A.Temple: None. A.H.Tjaden: None. D.Ehrmann: None. S.Manchanda: Advisory Panel; Inspire. S.Edelstein: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. S.Craft: None. B.Mokhlesi: None. Rise consortium: n/a.
Funding
American Diabetes Association (1-20-RISE-01 to S.E.); National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; U.S. Department of Veterans Affairs; Kaiser Permanente Southern California
Poor sleep may be associated with reduced β-cell response or decreased insulin sensitivity in youth. We explored whether sleep duration, sleep quality or obstructive sleep apnea (OSA) risk factors ...were associated with measures of β-cell response or insulin sensitivity in youth. At baseline, 88 youth (10-19 yrs of age) with recently diagnosed T2D or prediabetes completed validated questionnaires (Sleep Disturbances Scale and Cleveland Adolescent Sleepiness) in the Restoring Insulin Secretion (RISE) Study. Hyperglycemic clamps measured insulin sensitivity (steady state glucose infusion rate/insulin M/I) and β-cell responses: acute (0-10 min) C-peptide response to glucose (ACPRg), steady-state C-peptide at a glucose of 11.1 mmol/L (SSCP), and arginine-stimulated maximum C-peptide responses at glucose >25 mmol/L (ACPRmax). Linear regression models explored the independent association between sleep variables and clamp measures, adjusted for age, race/ethnicity, sex, Tanner stage, metformin use and BMI. Models including β-cell responses were adjusted for M/I to account for the role of insulin sensitivity in β-cell function. The cohort was 70% female, 28% white, 25% black, 36% Hispanic; age 14.3±2.0 yrs and BMI 36.9±6.4 kg/m2 (mean±SD). Using ADA criteria, 60% had prediabetes and 40% had T2D; 27% reported metformin use. Sleep duration <8 h was reported in 59%; 57% reported daytime sleepiness; 28% reported poor sleep quality; 29% had high risk for OSA. Low sleep duration (<8 h) was associated with a trend for lower ACPRg (p=0.069). No sleep variables (sleep duration or quality, OSA risk) were associated with clamp-derived outcomes in unadjusted or adjusted linear regression models. In youth with prediabetes or T2D, subjective measures of sleep quantity, sleep quality and OSA risk were not independently associated with β-cell response or insulin sensitivity. Further research using objective measures of sleep may better delineate the relationship between sleep and β-cell function in youth.
Disclosure
K.A.Temple: None. A.H.Tjaden: None. S.Manchanda: Advisory Panel; Inspire. D.Ehrmann: None. K.J.Nadeau: None. S.Edelstein: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. B.Mokhlesi: None. Rise consortium: n/a.
Funding
American Diabetes Association (1-20-RISE-01 to S.E.); National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute
Sleep disturbances and circadian misalignment (social jet lag, late chronotype, or shift work) have been associated with worse glycemic control in type 2 diabetes (T2D). Whether these findings apply ...to adults with prediabetes is yet unexplored. We hypothesized that self-reported short sleep, poor sleep quality, and/or circadian misalignment are associated with higher glycemia, BMI, and blood pressure (BP) in adults with prediabetes or recently diagnosed, untreated T2D.
Our cohort included 962 overweight/obese adults ages 20-65 years with prediabetes or recently diagnosed, untreated T2D who completed a 2-h oral glucose tolerance test and validated sleep questionnaires. Independent associations of sleep and circadian variables with glycemia, BMI, and BP were evaluated with regression models.
The multiethnic cohort was 55% men, with mean ± SD age 52.2 ± 9.5 years and BMI 34.7 ± 5.5 kg/m
. Mean sleep duration was 6.6 ± 1.3 h. Poor sleep quality was reported by 54% and high risk for obstructive sleep apnea by 64%. HbA
was significantly higher in those reporting <5 or >8 h sleep per night. Sleep duration >8 h was also associated with higher fasting glucose and <6 h with higher BMI. Shift work was also associated with higher BMI. Social jet lag and delayed chronotype were associated with higher BP.
In our cohort, self-reported short and long sleep were both associated with adverse measures of glycemia, and short sleep and shift work were associated with higher BMI. Further research using objective measures of sleep is needed to better delineate the relationship between sleep and glycemia in adults with prediabetes or T2D.
Obstructive sleep apnea (OSA) is associated with insulin resistance and has been described as a risk factor for type 2 diabetes. Whether OSA adversely impacts pancreatic islet β-cell function remains ...unclear. We aimed to investigate the association of OSA and short sleep duration with β-cell function in overweight/obese adults with prediabetes or recently diagnosed, treatment-naive type 2 diabetes.
Two hundred twenty-one adults (57.5% men, age 54.5 ± 8.7 years, BMI 35.1 ± 5.5 kg/m
) completed 1 week of wrist actigraphy and 1 night of polysomnography before undergoing a 3-h oral glucose tolerance test (OGTT) and a two-step hyperglycemic clamp. Associations of measures of OSA and actigraphy-derived sleep duration with HbA
, OGTT-derived outcomes, and clamp-derived outcomes were evaluated with adjusted regression models.
Mean ± SD objective sleep duration by actigraphy was 6.6 ± 1.0 h/night. OSA, defined as an apnea-hypopnea index (AHI) of five or more events per hour, was present in 89% of the participants (20% mild, 28% moderate, 41% severe). Higher AHI was associated with higher HbA
(
= 0.007). However, OSA severity, measured either by AHI as a continuous variable or by categories of OSA severity, and sleep duration (continuous or <6 vs. ≥6 h) were not associated with fasting glucose, 2-h glucose, insulin sensitivity, or β-cell responses.
In this baseline cross-sectional analysis of the RISE clinical trial of adults with prediabetes or recently diagnosed, untreated type 2 diabetes, the prevalence of OSA was high. Although some measures of OSA severity were associated with HbA
, OSA severity and sleep duration were not associated with measures of insulin sensitivity or β-cell responses.
Rapid tumor growth, widespread brain-invasion, and therapeutic resistance critically contribute to glioblastoma (GBM) recurrence and dismal patient outcomes. Although GBM stem cells (GSC) are shown ...to play key roles in these processes, the molecular pathways governing the GSC phenotype (GBM-stemness) remain poorly defined. Here, we show that epigenetic silencing of miR-146a significantly correlated with worse patient outcome and importantly, miR-146a level was significantly lower in recurrent tumors compared with primary ones. Further, miR-146a overexpression significantly inhibited the proliferation and invasion of GBM patient-derived primary cells and increased their response to temozolomide (TMZ), both
and
. Mechanistically, miR-146a directly silenced
and
, two transcription factors that mutually regulated each other, significantly compromising GBM-stemness and increasing TMZ response. Collectively, our data show that miR-146a-POU3F2/SMARCA5 pathway plays a critical role in suppressing GBM-stemness and increasing TMZ-response, suggesting that
and
may serve as novel therapeutic targets in GBM. IMPLICATIONS: miR-146a predicts favorable prognosis and the miR-146a-POU3F2/SMARCA5 pathway is important for the suppression of stemness in GBM.
Abstract
Background
A novel pandemic disease offered the opportunity to create new, disease-specific, symptom rubrics for the homeopathic repertory.
Objective
The aim of this study was to discover ...the relationship between specific symptoms and specific medicines, especially of symptoms occurring frequently in this disease.
Materials and Methods
Worldwide collection of data in all possible formats by various parties was coordinated by the Liga Medicorum Homeopathica Internationalis. As the data came in, more symptoms were assessed prospectively. Frequent analysis and feedback by electronic newsletters were used to improve the quality of the data. Likelihood ratios (LRs) of symptoms were calculated. An algorithm for combining symptom LRs was programmed and published in the form of an app. The app was tested against 18 well-described successful cases from Hong Kong.
Results
LRs of common symptoms such as ‘Fatigue’ and ‘Headache’ provided better differentiation between medicines than did existing repertory entries, which are based only on the narrow presence or absence of symptoms. A mini-repertory for COVID-19 symptoms was published and supported by a web-based algorithm. With a choice of 20 common symptoms, this algorithm produced the same outcome as a full homeopathic analysis based upon a larger number of symptoms, including some that are traditionally considered more specific to particular medicines.
Conclusion
A repertory based on clinical data and LRs can differentiate between homeopathic medicines using a limited number of frequently occurring epidemic symptoms. A Bayesian computer algorithm to combine symptoms can complement a full homeopathic analysis of cases.
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