Exploring Health Care Disparities in Maternal-Child Simulation-Based Education.

AIM: The purpose of this study was to explore student experiences within a health care disparity simulation, embedded in maternal-child content. BACKGROUND: Health care disparities related to race and ethnicity in the maternal-child population are daunting among African American and Hispanic women. METHOD: Participants completed the Simulation Effectiveness Tool-Modified, a rapid-fire huddle questionnaire, and a demographic instrument. All students participated in structured debriefing. RESULTS: Student responses ( n = 69) demonstrated effectiveness in learning via this scenario. CONCLUSION: The rapid-fire huddle and debriefing are important elements when health care disparities are introduced into nursing curricula.

Genetic analysis of isoform usage in the human anti-viral response reveals influenza-specific regulation of ERAP2 transcripts under balancing selection.

While genetic variants are known to be associated with overall gene abundance in stimulated immune cells, less is known about their effects on alternative isoform usage. By analyzing RNA-seq profiles of monocyte-derived dendritic cells from 243 individuals, we uncovered thousands of unannotated isoforms synthesized in response to influenza infection and type 1 interferon stimulation. We identified more than a thousand quantitative trait loci (QTLs) associated with alternate isoform usage (isoQTLs), many of which are independent of expression QTLs (eQTLs) for the same gene. Compared with eQTLs, isoQTLs are enriched for splice sites and untranslated regions, but depleted of sequences upstream of annotated transcription start sites. Both eQTLs and isoQTLs explain a significant proportion of the disease heritability attributed to common genetic variants. At the ERAP2 locus, we shed light on the function of the gene and how two frequent, highly differentiated haplotypes with intermediate frequencies could be maintained by balancing selection. At baseline and following type 1 interferon stimulation, the major haplotype is associated with low ERAP2 expression caused by nonsense-mediated decay, while the minor haplotype, known to increase Crohn's disease risk, is associated with high ERAP2 expression. In response to influenza infection, we found two uncharacterized isoforms expressed from the major haplotype, likely the result of multiple perfectly linked variants affecting the transcription and splicing at the locus. Thus, genetic variants at a single locus could modulate independent gene regulatory processes in innate immune responses and, in the case of ERAP2, may confer a historical fitness advantage in response to virus.

Catalytic mechanism of the mismatch-specific DNA glycosylase methyl-CpG-binding domain 4.

Thymine:guanine base pairs are major promutagenic mismatches occurring in DNA metabolism. If left unrepaired, these mispairs can cause C to T transition mutations. In humans, T:G mismatches are repaired in part by mismatch-specific DNA glycosylases such as methyl-CpG-binding domain 4 (hMBD4) and thymine-DNA glycosylase. Unlike lesion-specific DNA glycosylases, T:G-mismatch-specific DNA glycosylases specifically recognize both bases of the mismatch and remove the thymine but only from mispairs with guanine. Despite the advances in biochemical and structural characterizations of hMBD4, the catalytic mechanism of hMBD4 remains elusive. Herein, we report two structures of hMBD4 processing T:G-mismatched DNA. A high-resolution crystal structure of Asp560Asn hMBD4-T:G complex suggests that hMBD4-mediated glycosidic bond cleavage occurs via a general base catalysis mechanism assisted by Asp560. A structure of wild-type hMBD4 encountering T:G-containing DNA shows the generation of an apurinic/apyrimidinic (AP) site bearing the C1'-(S)-OH. The inversion of the stereochemistry at the C1' of the AP-site indicates that a nucleophilic water molecule approaches from the back of the thymine substrate, suggesting a bimolecular displacement mechanism (SN2) for hMBD4-catalyzed thymine excision. The AP-site is stabilized by an extensive hydrogen bond network in the MBD4 catalytic site, highlighting the role of MBD4 in protecting the genotoxic AP-site.

A Theory-based Educational Pamphlet With Low-residue Diet Improves Colonoscopy Attendance and Bowel Preparation Quality.

GOALS/BACKGROUND: Patients who "no-show" for colonoscopy or present with poor bowel preparation waste endoscopic resources and do not receive adequate examinations for colorectal cancer (CRC) screening. Using the Health Belief Model, we modified an existing patient education pamphlet and evaluated its effect on nonattendance rates and bowel preparation quality. STUDY: We implemented a color patient education pamphlet to target individual perceptions about CRC and changed bowel preparation instructions to include a low-residue diet instead of the previous clear liquid diet. We compared the nonattendance rate over a 2-month period before and after the introduction of the pamphlet, allowing for a washout period during which pamphlet use was inconsistent. We compared the Boston Bowel Preparation Scale (BBPS) in 100 consecutive patients who underwent colonoscopy during each of the 2 periods. RESULTS: Baseline characteristics between the 2 groups were similar, although patients who received the pamphlet were younger (P=0.03). The nonattendance rate was significantly lower in patients who received the pamphlet (13% vs. 21%, P=0.01). The percentage of patients with adequate bowel preparation increased from 82% to 86% after introduction of the pamphlet, although this was not statistically significant (P=0.44). The proportion of patients with a BBPS score of 9 was significantly higher in the pamphlet group (41% vs. 27%, P=0.03). There was no difference in adenoma and sessile serrated adenoma detection rates before and after pamphlet implementation. CONCLUSIONS: After implementing a theory-based patient education intervention with a low-residue diet, our absolute rate for colonoscopy nonattendance decreased by 8% and the proportion of patients with a BBPS score of 9 increased by 14%. The Health Belief Model appears to be a useful construct for CRC screening interventions.

Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics.

Acute myeloid leukemia (AML) is a neoplastic disorder resulting from clonal proliferation of poorly differentiated immature myeloid cells. Distinct genetic and epigenetic aberrations are key features of AML that account for its variable response to standard therapy. Irrespective of their oncogenic mutations, AML cells produce elevated levels of reactive oxygen species (ROS). They also alter expression and activity of antioxidant enzymes to promote cell proliferation and survival. Subsequently, selective targeting of redox homeostasis in a molecularly heterogeneous disease, such as AML, has been an appealing approach in the development of novel anti-leukemic chemotherapeutics. Naphthoquinones are able to undergo redox cycling and generate ROS in cancer cells, which have made them excellent candidates for testing against AML cells. In addition to inducing oxidative imbalance in AML cells, depending on their structure, naphthoquinones negatively affect other cellular apparatus causing neoplastic cell death. Here we provide an overview of the anti-AML activities of naphthoquinone derivatives, as well as analysis of their mechanism of action, including induction of reduction-oxidation imbalance, alteration in mitochondrial transmembrane potential, Bcl-2 modulation, initiation of DNA damage, and modulation of MAPK and STAT3 activity, alterations in the unfolded protein response and translocation of FOX-related transcription factors to the nucleus.

Quantitative analysis of high-resolution microendoscopic images for diagnosis of neoplasia in patients with Barrett's esophagus.

BACKGROUND AND AIMS: Previous studies show that microendoscopic images can be interpreted visually to identify the presence of neoplasia in patients with Barrett's esophagus (BE), but this approach is subjective and requires clinical expertise. This study describes an approach for quantitative image analysis of microendoscopic images to identify neoplastic lesions in patients with BE. METHODS: Images were acquired from 230 sites from 58 patients by using a fiberoptic high-resolution microendoscope during standard endoscopic procedures. Images were analyzed by a fully automated image processing algorithm, which automatically selected a region of interest and calculated quantitative image features. Image features were used to develop an algorithm to identify the presence of neoplasia; results were compared with a histopathology diagnosis. RESULTS: A sequential classification algorithm that used image features related to glandular and cellular morphology resulted in a sensitivity of 84% and a specificity of 85%. Applying the algorithm to an independent validation set resulted in a sensitivity of 88% and a specificity of 85%. CONCLUSIONS: This pilot study demonstrates that automated analysis of microendoscopic images can provide an objective, quantitative framework to assist clinicians in evaluating esophageal lesions from patients with BE. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01384227 and NCT02018367.).

In vivo classification of colorectal neoplasia using high-resolution microendoscopy: Improvement with experience.

BACKGROUND AND AIMS: High-resolution microendoscopy (HRME) is a novel, low-cost "optical biopsy" technology that allows for subcellular imaging. The study aim was to evaluate the learning curve of HRME for the differentiation of neoplastic from non-neoplastic colorectal polyps. METHODS: In a prospective cohort fashion, a total of 162 polyps from 97 patients at a single tertiary care center were imaged by HRME and classified in real time as neoplastic (adenomatous, cancer) or non-neoplastic (normal, hyperplastic, inflammatory). Histopathology was the gold standard for comparison. Diagnostic accuracy was examined at three intervals over time throughout the study; the initial interval included the first 40 polyps, the middle interval included the next 40 polyps examined, and the final interval included the last 82 polyps examined. RESULTS: Sensitivity increased significantly from the initial interval (50%) to the middle interval (94%, P = 0.02) and the last interval (97%, P = 0.01). Similarly, specificity was 69% for the initial interval but increased to 92% (P = 0.07) in the middle interval and 96% (P = 0.02) in the last interval. Overall accuracy was 63% for the initial interval and then improved to 93% (P = 0.003) in the middle interval and 96% (P = 0.0007) in the last interval. CONCLUSIONS: In conclusion, this in vivo study demonstrates that an endoscopist without prior colon HRME experience can achieve greater than 90% accuracy for identifying neoplastic colorectal polyps after 40 polyps imaged. HRME is a promising modality to complement white light endoscopy in differentiating neoplastic from non-neoplastic colorectal polyps.

In vivo diagnostic accuracy of high-resolution microendoscopy in differentiating neoplastic from non-neoplastic colorectal polyps: a prospective study.

OBJECTIVES: High-resolution microendoscopy (HRME) is a low-cost, "optical biopsy" technology that allows for subcellular imaging. The purpose of this study was to determine the in vivo diagnostic accuracy of the HRME for the differentiation of neoplastic from non-neoplastic colorectal polyps and compare it to that of high-definition white-light endoscopy (WLE) with histopathology as the gold standard. METHODS: Three endoscopists prospectively detected a total of 171 polyps from 94 patients that were then imaged by HRME and classified in real-time as neoplastic (adenomatous, cancer) or non-neoplastic (normal, hyperplastic, inflammatory). RESULTS: HRME had a significantly higher accuracy (94%), specificity (95%), and positive predictive value (PPV, 87%) for the determination of neoplastic colorectal polyps compared with WLE (65%, 39%, and 55%, respectively). When looking at small colorectal polyps (less than 10 mm), HRME continued to significantly outperform WLE in terms of accuracy (95% vs. 64%), specificity (98% vs. 40%) and PPV (92% vs. 55%). These trends continued when evaluating diminutive polyps (less than 5 mm) as HRME's accuracy (95%), specificity (98%), and PPV (93%) were all significantly greater than their WLE counterparts (62%, 41%, and 53%, respectively). CONCLUSIONS: In conclusion, this in vivo study demonstrates that HRME can be a very effective modality in the differentiation of neoplastic and non-neoplastic colorectal polyps. A combination of standard white-light colonoscopy for polyp detection and HRME for polyp classification has the potential to truly allow the endoscopist to selectively determine which lesions can be left in situ, which lesions can simply be discarded, and which lesions need formal histopathologic analysis.

Abiraterone or Enzalutamide for Patients With Metastatic Castration-Resistant Prostate Cancer.

Importance: Abiraterone acetate and enzalutamide are recommended as preferred treatments for metastatic castration-resistant prostate cancer (mCRPC), but differences in their relative efficacy are unclear due to a lack of head-to-head clinical trials. Clear guidance is needed for making informed mCRPC therapeutic choices. Objective: To compare clinical outcomes in patients with mCRPC treated with abiraterone acetate or enzalutamide. Design, Setting, and Participants: This retrospective, multicenter cohort study included patients with mCRPC in the US Department of Veterans Affairs health care system who initiated treatment with abiraterone acetate or enzalutamide between January 1, 2014, and October 30, 2022. Exposures: Abiraterone acetate or enzalutamide. Main Outcomes and Measures: The study used inverse probability of treatment weighting to balance baseline characteristics between patients initiating abiraterone acetate or enzalutamide and evaluated restricted mean survival time (RMST) differences in overall survival (OS), prostate cancer-specific survival (PCS), time to next treatment switching or death (TTS), and time to prostate-specific antigen (PSA) response (TTR) at different time points after treatment initiation. Results: The study included 5779 patients (median age, 74.42 years [IQR, 68.94-82.14 years]). Median follow-up was between 38 and 60 months. Patients initiating enzalutamide on average had longer OS than those initiating abiraterone acetate, with RMSTs of 24.29 months (95% CI, 23.58-24.99 months) and 23.38 months (95% CI, 22.85-23.92 months), respectively, and a difference in RMST of 0.90 months (95% CI, 0.02-1.79 months) at 4 years. Similarly, TTS and TTR were improved in patients initiating enzalutamide, with an RMST at 4 years of 1.95 months (95% CI, 0.92-2.99 months) longer for TTS and 3.57 months (95% CI, 1.76-5.38 months) shorter for TTR. For PCS, the RMST at 2 years was 0.48 months (95% CI, 0.01-0.95 months) longer. An examination of subgroups identified that enzalutamide initiation was associated with longer RMST in OS among patients without prior docetaxel treatment (1.14 months; 95% CI, 0.19-2.10 months) and in those with PSA doubling time of 3 months or longer (2.23 months; 95% CI, 0.81-3.66 months) but not among patients with prior docetaxel (-0.25 months; 95% CI, -2.59 to 2.09 months) or with PSA doubling time of less than 3 months (0.05 months; 95% CI, -1.05 to 1.15 months). Conclusions and Relevance: In this cohort study of patients with mCRPC, initiation of enzalutamide was associated with small but statistically significant improvements in OS, PCS, TTS, and TTR compared with initiation of abiraterone acetate. The improvements were more prominent in short-term outcomes, including TTS and TTR, and in patient subgroups without prior docetaxel or with PSA doubling time longer than 3 months.

WHIM Syndrome: First Reported Case in a Patient of African Ancestry.

Background: Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, primary immunodeficiency syndrome characterized by warts, hypogammaglobulinemia, immunodeficiency, and characteristic bone marrow features of myelokathexis. The pathophysiology of WHIM syndrome is due to an autosomal dominant gain of function mutation in the CXCR4 chemokine receptor resulting in increased activity that impairs neutrophil migration from the bone marrow into the peripheral blood. This results in bone marrow distinctively crowded with mature neutrophils whose balance is shifted towards cellular senescence developing these characteristic, apoptotic nuclei termed myelokathexis. Despite the resultant severe neutropenia, the clinical syndrome is often mild and accompanied by a variety of associated abnormalities that we are just beginning to understand. Case Report. Diagnosis of WHIM syndrome is incredibly difficult due to phenotypic heterogeneity. To date, there are only about 105 documented cases in the scientific literature. Here, we describe the first case of WHIM syndrome documented in a patient of African ancestry. The patient in question was diagnosed at the age of 29 after a comprehensive work-up for incidental neutropenia discovered at a primary care appointment at our center in the United States. In hindsight, the patient had a history of recurrent infections, bronchiectasis, hearing loss, and VSD repair that could not be previously explained. Conclusions: Despite the challenge of timely diagnosis and the wide spectrum of clinical features that we are still discovering, WHIM syndrome tends to be a milder immunodeficiency that is highly manageable. As presented in this case, most patients respond well to G-CSF injections and newer treatments such as small-molecule CXCR4 antagonists.

Baseline correlates of frailty and its association with survival in United States veterans with acute myeloid leukemia.

Frailty is an important construct to measure in acute myeloid leukemia (AML). We used the Veterans Affairs Frailty Index (VA-FI) - calculated using readily available data within the VA's electronic health records - to measure frailty in U.S. veterans with AML. Of the 1166 newly diagnosed and treated veterans with AML between 2012 and 2022, 722 (62%) veterans with AML were classified as frail (VA-FI > 0.2). At a median follow-up of 252.5 days, moderate-severely frail veterans had significantly worse survival than mildly frail, and non-frail veterans (median survival 179 vs. 306 vs. 417 days, p < .001). Increasing VA-FI severity was associated with higher mortality. A model with VA-FI in addition to the European LeukemiaNet (ELN) risk classification and other covariates statistically outperformed a model containing the ELN risk and other covariates alone (p < .001). These findings support the VA-FI as a tool to expand frailty measurement in research and clinical practice for informing prognosis in veterans with AML.

Safety and Efficacy of Propylene Glycol-Free Melphalan in Patients with AL Amyloidosis Undergoing Autologous Stem Cell Transplantation: Results of a Phase II Study.

Patients with systemic light chain (AL) amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) may develop renal and cardiac toxicities potentially exacerbated by the co-solvent propylene glycol in conventional melphalan formulations. We investigated the safety and efficacy of propylene glycol-free melphalan (PGF-Mel) during HDM/SCT in patients with AL amyloidosis (ClinicalTrials.gov identifier NCT02994784). The primary objective of this phase II, open-label study was evaluation for renal dysfunction, new cardiac arrhythmias, and postural hypotension related to autonomic dysfunction. Secondary objectives included time to neutrophil and platelet engraftment, treatment-related mortality (TRM), overall hematologic response, organ response, and number of peritransplantation hospitalizations. Twenty-eight patients with AL amyloidosis enrolled, of whom 27 underwent HDM/SCT. PGF-Mel at 140 to 200 mg/m2 was administered i.v. in 2 equally divided doses. Patients were monitored for up to 30 days after the last administration of PGF-Mel to assess for treatment-related toxicity. Patients were followed for 12 months from the time of treatment with HDM/SCT for evaluation of hematologic and organ responses. Kaplan-Meier analysis was used to estimate progression-free survival. Two patients (7%) developed renal dysfunction, 5 (19%) experienced new cardiac arrhythmias, and 3 (11%) developed orthostatic hypotension. All patients achieved neutrophil and platelet engraftment, at a median of 10 days and 17 days post-HDM/SCT, respectively. TRM on day +100 was 0%. Peritransplantation hospitalization was required for 23 patients (85%). The most common nonhematologic adverse events were diarrhea (93%), fatigue (82%), and nausea (74%). At 6 months post-HDM/SCT, hematologic complete response or very good partial response occurred in 66% of the patients. At 12 months post-HDM/SCT, renal response occurred in 12 of 23 (52%) patients with renal involvement, and cardiac response occurred in 3 of 11 (27%) patients with evaluable cardiac involvement. Our data indicate that PGF-Mel is safe and efficacious as a high-dose conditioning regimen for autologous SCT in patients with AL amyloidosis.

Asian females without diabetes are protected from obesity-related dysregulation of glucose metabolism compared with males.

OBJECTIVE: The impact of obesity on the risk for type 2 diabetes differs between males and females; however, the underlying reasons are unclear. This study aimed to investigate the effect of sex on obesity-driven changes in the mechanisms regulating glucose metabolism (insulin sensitivity and secretion) among Asian individuals without diabetes in Singapore. METHODS: The study assessed glucose tolerance using oral glucose tolerance test, insulin-mediated glucose uptake using hyperinsulinemic-euglycemic clamp, acute insulin response using an intravenous glucose challenge, and insulin secretion rates in the fasting state and in response to glucose ingestion using mathematical modeling in 727 males and 952 females who had normal body weight (n = 602, BMI < 23 kg/m2 ), overweight (n = 662, 23 ≤ BMI < 27.5), or obesity (n = 415, BMI ≥ 27.5). RESULTS: There were no sex differences among lean individuals. Obesity gradually worsened metabolic function, and the progressive adverse effects of obesity on insulin action and secretion were more pronounced in males than females, such that among participants with obesity, females had greater insulin sensitivity, lower insulin secretion, and lower fasting insulin concentration than males. The increase in waist to hip ratio with increasing BMI was more pronounced in males than females. CONCLUSIONS: The female sex exerts a protective effect on obesity-driven dysregulation of glucose metabolism in Asian individuals without diabetes.

Advanced endoscopic imaging for Barrett's Esophagus: current options and future directions.

Barrett's esophagus is the precursor to esophageal adenocarcinoma, one of the most rapidly increasing cancers in the United States. Given the poor prognosis of late-stage adenocarcinoma, endoscopic surveillance is recommended for subjects with Barrett's esophagus to detect early neoplasia. Current guidelines recommend "random" four-quadrant biopsies taken every 1-2 cm throughout the Barrett's segment. However, this only samples a minority of epithelium and has been shown to miss areas of endoscopically- inapparent neoplasia (high grade dysplasia or cancer). Recent efforts have focused on developing novel diagnostic imaging technologies to detect the subtle epithelial changes associated with dysplasia and neoplasia in Barrett's esophagus. Some of these modalities serve as "red flag" technologies designed to detect areas of abnormality within large surface areas. Other technologies serve to characterize areas of visible abnormality, offering a higher spatial resolution to confirm/exclude the presence of neoplasia. This review summarizes several available and evolving imaging technologies used in the endoscopic diagnosis and surveillance of Barrett's associated neoplasia.

Small cell lung cancer in young patients: trends in sociodemographic factors, diagnosis, treatment, and survival.

Background: Small cell lung cancer (SCLC) in patients <50 years old has unique socioeconomic and clinical implications. We aimed to examine the demographics, treatment patterns, and survival of young patients with SCLC and compared them to older adults. Methods: The National Cancer Database (NCDB) was queried to identify SCLC cases diagnosed from 2004 to 2016. Patients were divided into three age groups: ≥18-<50, ≥50-<70, and ≥70 years. Patient characteristics were evaluated for survival within each age group. Kaplan-Meier and Cox regression analyses were used to assess survival. Results: Of the 172,453 evaluated SCLC patients (median age 66 years), 8,792 were ≥18-<50 years old. Compared to the older groups, patients under 50 were more likely to be Black, uninsured or on Medicaid, have household income <$30,000, and present with stage III or IV disease (P<0.0001 for all). While young patients were more likely to receive guideline-concordant care (GCC), the hazard of death increased to 1.96 (95% CI: 1.80-2.14; P<0.0001) with receipt of nonstandard therapy. Private insurance, female gender, non-White race, Hispanic ethnicity, and higher income were associated with better survival. The youngest cohort had significantly better survival overall when compared to the older patients (P<0.0001), but the survival advantage was reduced with the advancing stage. Conclusions: SCLC patients under 50 years old represent a socioeconomically disadvantaged group with advanced disease at presentation. Despite having fewer comorbidities and being offered guideline-concordant treatment, younger patients with SCLC have only marginally better survival than older patients in advanced stages.

Dynamic assessment of insulin secretion and insulin resistance in Asians with prediabetes.

AIMS/HYPOTHESIS: Prediabetes and type 2 diabetes are highly prevalent in Asia. Understanding the pathophysiology of abnormal glucose homeostasis in Asians will have important implications for reducing disease burden, but there have been conflicting reports on the relative contributions of insulin secretion and action in disease progression. In this study, we aimed to assess the contribution of ß-cell dysfunction and insulin resistance in the Asian prediabetes phenotype. METHODS: We recruited 1679 Asians with prediabetes (n = 659) or normoglycemia (n = 1020) from a multi-ethnic population in Singapore. Participants underwent an oral glucose tolerance test, an intravenous glucose challenge, and a hyperinsulinemic-euglycemic clamp procedure to determine glucose tolerance, ß-cell responsivity, insulin secretion, insulin clearance and insulin sensitivity. RESULTS: Participants with prediabetes had significantly higher glucose concentrations in the fasting state and after glucose ingestion than did normoglycemic participants. Insulin sensitivity (M/I ratio) was ~15% lower, acute insulin response (AIR) to intravenous glucose and ß-cell responsivity to oral glucose were ~35% lower, but total insulin secretion rate in the fasting state and after glucose ingestion was ~10% greater in prediabetic than in normoglycemic participants. The decrease in ß-cell function with worsening glucose homeostasis in Asians with prediabetes was associated with progressively greater defects in AIR rather than M/I. However, analysis using static surrogate measures (HOMA indices) of insulin resistance and ß-cell function revealed a different pattern. CONCLUSIONS: Lower AIR to intravenous glucose and ß-cell responsivity to oral glucose, on a background of mild insulin resistance, are the major contributors to the dysregulation of glucose homeostasis in Asians with prediabetes.

Heredity of type 2 diabetes confers increased susceptibility to oxidative stress and inflammation.

INTRODUCTION AND OBJECTIVE: Heredity of type 2 diabetes mellitus (T2DM) is associated with greater risk for developing T2DM. Thus, individuals who have a first-degree relative with T2DM (FDRT) provide a natural model to study factors of susceptibility towards development of T2DM, which are poorly understood. Emerging key players in T2DM pathophysiology such as adverse oxidative stress and inflammatory responses could be among possible mechanisms that predispose FDRTs to develop T2DM. Here, we aimed to examine the role of oxidative stress and inflammatory responses as mediators of this excess risk by studying dynamic postprandial responses in FDRTs. RESEARCH DESIGN AND METHODS: In this open-label case-control study, we recruited normoglycemic men with (n=9) or without (n=9) a family history of T2DM. We assessed plasma glucose, insulin, lipid profile, cytokines and F2-isoprostanes, expression levels of oxidative and inflammatory genes/proteins in circulating mononuclear cells (MNC), myotubes and adipocytes at baseline (fasting state), and after consumption of a carbohydrate-rich liquid meal or insulin stimulation. RESULTS: Postprandial glucose and insulin responses were not different between groups. Expression of oxidant transcription factor NRF2 protein (p<0.05 for myotubes) and gene (pgroup=0.002, ptime×group=0.016), along with its target genes TXNRD1 (pgroup=0.004, ptime×group=0.007), GPX3 (pgroup=0.011, ptime×group=0.019) and SOD-1 (pgroup=0.046 and ptime×group=0.191) was upregulated in FDRT-derived MNC after meal ingestion or insulin stimulation. Synergistically, expression of target genes of inflammatory transcription factor nuclear factor kappa B such as tumor necrosis factor alpha (pgroup=0.001, ptime×group=0.007) was greater in FDRT-derived MNC than in non-FDRT-derived MNC after meal ingestion or insulin stimulation. CONCLUSIONS: Our findings shed light on how heredity of T2DM confers increased susceptibility to oxidative stress and inflammation. This could provide early insights into the underlying mechanisms and future risk of FDRTs for developing T2DM and its associated complications.

Cerebral ischemia and neuroregeneration.

Cerebral ischemia is one of the leading causes of morbidity and mortality worldwide. Although stroke (a form of cerebral ischemia)-related costs are expected to reach 240.67 billion dollars by 2030, options for treatment against cerebral ischemia/stroke are limited. All therapies except anti-thrombolytics (i.e., tissue plasminogen activator) and hypothermia have failed to reduce neuronal injury, neurological deficits, and mortality rates following cerebral ischemia, which suggests that development of novel therapies against stroke/cerebral ischemia are urgently needed. Here, we discuss the possible mechanism(s) underlying cerebral ischemia-induced brain injury, as well as current and future novel therapies (i.e., growth factors, nicotinamide adenine dinucleotide, melatonin, resveratrol, protein kinase C isozymes, pifithrin, hypothermia, fatty acids, sympathoplegic drugs, and stem cells) as it relates to cerebral ischemia.

Optical visualisation of thermogenesis in stimulated single-cell brown adipocytes.

The identification of brown adipose deposits in adults has led to significant interest in targeting this metabolically active tissue for treatment of obesity and diabetes. Improved methods for the direct measurement of heat production as the signature function of brown adipocytes (BAs), particularly at the single cell level, would be of substantial benefit to these ongoing efforts. Here, we report the first application of a small molecule-type thermosensitive fluorescent dye, ERthermAC, to monitor thermogenesis in BAs derived from murine brown fat precursors and in human brown fat cells differentiated from human neck brown preadipocytes. ERthermAC accumulated in the endoplasmic reticulum of BAs and displayed a marked change in fluorescence intensity in response to adrenergic stimulation of cells, which corresponded to temperature change. ERthermAC fluorescence intensity profiles were congruent with mitochondrial depolarisation events visualised by the JC-1 probe. Moreover, the averaged fluorescence intensity changes across a population of cells correlated well with dynamic changes such as thermal power, oxygen consumption, and extracellular acidification rates. These findings suggest ERthermAC as a promising new tool for studying thermogenic function in brown adipocytes of both murine and human origins.