Substrate topography and size determine the fate of human embryonic stem cells to neuronal or glial lineage

Efficient derivation of neural cells from human embryonic stem cells (hESCs) remains an unmet need for the treatment of neurological disorders. The limiting factors for current methods include being labor-intensive, time-consuming and expensive. In this study, we hypothesize that the substrate topography, with optimal geometry and dimension, can modulate the neural fate of hESCs and enhance the efficiency of differentiation. A multi-architectural chip (MARC) containing fields of topographies varying in geometry and dimension was developed to facilitate high-throughput analysis of topography-induced neural differentiation in vitro. The hESCs were subjected to “direct differentiation”, in which small clumps of undifferentiated hESCs were cultured directly without going through the stage of embryoid body formation, on the MARC with N2 and B27 supplements for 7 days. The gene and protein expression analysis indicated that the anisotropic patterns like gratings promoted neuronal differentiation of hESCs while the isotropic patterns like pillars and wells promoted the glial differentiation of hESCs. This study showed that optimal combination of topography and biochemical cues could shorten the differentiation period and allowed derivation of neurons bearing longer neurites that were aligned along the grating axis. The MARC platform would enable high-throughput screening of topographical substrates that could maximize the efficiency of neuronal differentiation from pluripotent stem cells.     

Bronchodilators in Heart Failure Patients With COPD: Is It Time for a Clinical Trial?

Chronic heart failure (HF) and chronic obstructive pulmonary disease (COPD) commonly coexist, and patients with both diseases fare worse than those with either disease alone. Several factors may contribute to worse outcomes, including an increased burden of care related to greater disease complexity, an overlap of symptoms resulting in misapplication of therapy, and the adverse effects of treatment for one disease on the symptoms and outcomes related to the other. For example, there are conflicting data about the cardiovascular risks of bronchodilators in HF patients who may experience worse outcomes with inhaled beta-2 agonists via arrhythmogenesis, ischemia, and/or attenuation of beta-blocker benefits. In contrast, the long-acting anticholinergic class of bronchodilators has a more reassuring safety profile. Anticholinergic bronchodilators may be the preferred first-line agents for COPD patients with comorbid HF, yet data supporting these recommendations are limited. Therapeutic trials in COPD patients have generally excluded patients with significant HF and vice-versa. This paper reviews bronchodilator therapy in HF and proposes a randomized trial designed to enroll patients with significant COPD and HF to determine the risks and/or benefits of adding a long-acting beta-2 agonist to patients currently taking a long-acting anticholinergic agent.     

The Association of Metabolic Syndrome, Insulin Resistance and Non-alcoholic Fatty Liver Disease in Overweight/Obese Children

Background/Aim:

To study the prevalence of metabolic syndrome (MS), insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) in overweight/obese children with clinical hepatomegaly and/or raised alanine aminotransferase (ALT).

Patients and Methods:

Thirty-three overweight and obese children, aged 2-13 years, presenting with hepatomegaly and/or raised ALT, were studied for the prevalence of MS, IR and NAFLD. Laboratory analysis included fasting blood glucose, serum insulin, serum triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and liver biochemical profile, in addition to liver ultrasound and liver biopsy.

Results:

Twenty patients (60.6%) were labeled with MS. IR was present in 16 (48.4%). Fifteen (44%) patients had biopsy-proven NAFLD. Patients with MS were more likely to have NAFLD by biopsy (P=0.001). Children with NAFLD had significantly higher body mass index, waist circumference, ALT, total cholesterol, LDL-c, TG, fasting insulin, and lower HDL-c compared to patients with normal liver histology (P< 0.05) and fitted more with the criteria of MS (80% vs. 44%). IR was significantly more common among NAFLD patients (73% vs. 28%).

Conclusion:

There is a close association between obesity, MS, IR and NAFLD. Obese children with clinical or biochemical hepatic abnormalities are prone to suffer from MS, IR and NAFLD.     

Outcomes and complications of Boston keratoprosthesis type I implantation in unilateral versus bilateral corneal blindness

ObjectiveTo compare the outcomes of Boston keratoprosthesis (KPro) type I implantation between patients who are legally blind versus sighted in the contralateral eye.DesignSingle centre retrospective comparative case series.ParticipantsPatients who underwent Boston KPro type I implantation between 2008 and 2017.MethodsSingle-center retrospective comparative case series. Patients were divided into 2 groups based on the preoperative best-corrected visual acuity (BCVA) in the contralateral eye: group I (>20/200) and group II (20/200).Main outcome measuresPostoperative BCVA, device retention, and complications.ResultsGroup I (56 eyes) and group II (53 eyes) had similar demographics, median preoperative BCVA (hand movements) in the operated eye, and median duration of postoperative follow-up (76.92 vs 85.6 months, respectively). Final postoperative BCVA of the operated eye was statistically better in group I compared with group II (20/400 and hand movements, respectively, p = 0.03). There was no statistical significance in device retention mean survival time. The most common complication in both groups was retroprosthetic membrane. Cystoid macular edema occurred more frequently in group I (p = 0.004), whereas retinal detachment was more common in group II (p = 0.052).ConclusionsMost patients who underwent Boston KPro type I implantation experienced an improvement in their vision, with final BCVA being superior in the unilateral blind group. Despite similar complication rates and device retention, there are additional socioeconomic factors that need to be considered in sighted individuals. Because the prognosis is tied to the underlying etiology, it is important to recognize that some diagnoses may influence a better outcome.     

Early Renal Injury Induced by Caffeine Consumption in Obese,Diabetic ZSF1 Rats

Our previous studies indicate that prolonged caffeine consumption exacerbates renal failure in nephropathy associated with the metabolic syndrome. Reduced activity of the antioxidant defense system and beneficial effects of antioxidant therapy have been reported in diabetic rats and humans. The purpose of this study was to examine the early renal effects of caffeine consumption and the effects of concomitant antioxidant therapy in young obese, diabetic ZSF1 rats. Eleven-week-old male ZSF1 rats were randomized to drink tap water, caffeine (0.1%), tempol (1 mmol/L), or a solution containing caffeine and tempol for nine weeks. Caffeine significantly reduced body weight and glycosuria (weeks 2–9), improved glucose tolerance (week 9), had no effect on elevated plasma triglycerides, plasma cholesterol (week 9) and blood pressure (week 9), and significantly increased plasma cholesterol level (weeks 5 and 9). Yet, as early as after two weeks, caffeine greatly augmented proteinuria and increased renal vascular resistance (RVR) and heart rate (HR: week 9). Tempol had no effects on metabolic status and development of proteinuria, did not alter caffeine-induced metabolic changes and early proteinuria, and attenuated caffeine-induced increase in HR and RVR. Immunohistochemical analysis revealed significant glomerular and interstitial inflammation, proliferation, and fibrosis in control animals. Caffeine augmented the influx of glomerular and interstitial macrophages (ED1+ cells) influx, glomerular and tubular proliferative response, and glomerular collagen IV content. Tempol abolished the exacerbation of renal inflammation, proliferation, and fibrosis induced by caffeine. In conclusion, in nephropathy associated with the metabolic syndrome, caffeine—most likely through the interaction with adenosine receptors and interference with anti-inflammatory and/or glomerular hemodynamic effects of adenosine—augments proteinuria and stimulates some of the key proliferative mechanisms involved in glomerular remodeling and sclerosis. Tempol does not prevent early renal injury (i.e., proteinuria) induced by caffeine, yet abolishes late renal inflammatory, proliferative, and fibrotic change induced by chronic caffeine consumption in obese ZSF1 rats.     

Gender Differences in the Heritability of Musculoskeletal and Body Composition Parameters in Mother-Daughter and Mother-Son Pairs

Bone mass and body composition traits are genetically programmed, but the timing and gender and site specificities of their heritability are unclear. Mother-child correlations of bone mineral density (BMD) and bone mineral content, lean mass, and fat mass were studied in 169 premenopausal mothers and their 239 children. Heritability estimates of lean mass, fat mass, BMD, and area were derived for each gender and pubertal stage. There were significant correlations for most densitometry-derived variables at the spine, hip, femoral neck (FN), and total body (r = 0.192–0.388) in mother-postmenarcheal daughter pairs, for bone areas at all sites in early puberty (r = 0.229–0.508) and for volumetric-derived density at FN and spine (r = 0.238–0.368) in mother-son pairs. Fat mass correlations were significant in both genders after puberty (r = 0.299–0.324) and lean mass in postmenarcheal girls only (r = 0.299). Heritability estimates varied between 21% and 37% for mother-daughter and 18% and 35% for mother-son pairs for density-derived variables and between 26% and 40% for body composition variables. Maternal inheritance of bone traits is expressed in early-pubertal boys for several skeletal site traits but consistently involves most site traits in girls and boys by late puberty. Body composition inheritance is more variable.