Citations

A growing body of research is investigating the potential contribution of mitochondrial function to the etiology of type 2 diabetes. Numerous in vitro, in situ, and in vivo methodologies are available to examine various aspects of mitochondrial function, each requiring an understanding of their principles, advantages, and limitations. This review provides investigators with a critical overview of the strengths, limitations and critical experimental parameters to consider when selecting and conducting studies on mitochondrial function. In vitro (isolated mitochondria) and in situ (permeabilized cells/tissue) approaches provide direct access to the mitochondria, allowing for study of mitochondrial bioenergetics and redox function under defined substrate conditions. Several experimental parameters must be tightly controlled, including assay media, temperature, oxygen concentration, and in the case of permeabilized skeletal muscle, the contractile state of the fibers. Recently developed technology now offers the opportunity to measure oxygen consumption in intact cultured cells. Magnetic resonance spectroscopy provides the most direct way of assessing mitochondrial function in vivo with interpretations based on specific modeling approaches. The continuing rapid evolution of these technologies offers new and exciting opportunities for deciphering the potential role of mitochondrial function in the etiology and treatment of diabetes.

Recently, several high-impact reviews suggest that regular aerobic exercise is beneficial for maintaining cognitive function in aging adults. Higher cerebral blood flow and/or cerebrovascular reactivity may explain the favorable effect of exercise on cognition. In addition, prostaglandin-mediated vasodilator responses may be influenced by regular exercise. Therefore, our purpose was to evaluate middle cerebral artery (MCA) vasodilator responses in healthy adults before and after cyclooxygenase inhibition. A total of 16 young (26 ± 6 yr; 8 males, 8 females) and 13 older (64 ± 6 yr; 7 males, 6 females) healthy adults participated in the study. Aerobic fitness was determined by maximal aerobic capacity (V̇o2max) on a cycle ergometer. MCA velocity (MCAv) was measured at baseline and during stepped hypercapnia (2%, 4%, and 6% FiCO2) before and after cyclooxygenase inhibition using indomethacin. To account for differences in blood pressure, cerebrovascular conductance index (CVCi) was calculated as MCAv/mean arterial pressure. Cerebrovascular reactivity slopes were calculated from the correlation between either MCAv or CVCi and end-tidal CO2. Young adults demonstrated greater MCAv reactivity (1.61 ± 0.17 vs. 1.06 ± 0.15 cm·s−1·mmHg−1; P < 0.05) and CVCi reactivity (0.015 ± 0.002 vs. 0.007 ± 0.002 cm·s−1·mmHg−1; P < 0.05) compared with the older adults. There was no association between cerebrovascular reactivity and V̇o2maxin the combined group of subjects; however, in older adults MCAv reactivity was correlated with maximal aerobic fitness ( r = 0.64; P < 0.05). Furthermore, the change in MCAv reactivity (between baseline and indomethacin trials) was also associated with V̇o2max( r = 0.59; P < 0.05) in older adults. Cerebral vasodilator responses to hypercapnia were associated with maximal aerobic capacity in healthy older adults. These results may explain the physiological link between regular aerobic exercise and improved cognitive function in aging adults.

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

What's known on the subject? and What does the study add? Variations in the type of urinary diversion exist for patients undergoing radical cystectomy. Although its use has been increasing from 2001 to 2008, patients who are older, female, and primary insured by Medicaid are less likely to receive continent diversions. Furthermore, patients treated surgically at high‐volume and teaching hospitals are more likely to receive continent diversions. Objective To describe the contemporary trends in urinary diversion among patients undergoing radical cystectomy ( RC ) for bladder cancer; and elucidate whether socioeconomic disparities persist in the type of diversion performed in the USA from a population‐based cohort. Patients and Methods Using the Nationwide Inpatient Sample, we identified patients who underwent RC for bladder cancer between 2001 and 2008. Multivariable regression models were used to identify patient and hospital covariates associated with continent urinary diversion and enumerate predicted probabilities for statistically significant variables over time. Results Overall, 55 635 (92%) patients undergoing RC for bladder cancer received incontinent urinary diversion, while 4552 (8%) patients received continent diversion from 2001 to 2008. Receipt of continent urinary diversion increased from 6.6% in 2001–2002 to 9.4% in 2007–2008 ( P < 0.001 for trend). Patients who were older (odds ratio [ OR ] 0.93; P < 0.001), female ( OR 0.52; P < 0.001) and insured by Medicaid ( OR 0.54; P = 0.002) were less likely to receive continent urinary diversion. However, patients treated at teaching ( OR 2.14; P < 0.001) and high‐volume hospitals ( OR 2.39; P = 0.04) had higher odds of continent urinary diversion. Predicted probabilities of continent diversion remained lower for female patients, Medicaid insurance status, and non‐teaching and medium/low‐volume hospitals over time. Conclusions In this nationally representative sample of hospitals from 2001 to 2008, the use of continent diversion in RC gradually increased. Although variations in urinary diversion exist by hospital teaching status, case volume, patient gender and primary health insurance, increased attention in expanding the use of continent diversions may help reduce these disparities for patients undergoing RC for bladder cancer.

BACKGROUND AND OBJECTIVE: Simulation-based medical education (SBME) is used to teach residents. However, few studies have evaluated its clinical impact. The goal of this study was to evaluate the impact of an SBME session on pediatric interns’ clinical procedural success. METHODS: This randomized trial was conducted at 10 academic medical centers. Interns were surveyed on infant lumbar puncture (ILP) and child intravenous line placement (CIV) knowledge and watched audiovisual expert modeling of both procedures. Participants were randomized to SBME mastery learning for ILP or CIV and for 6 succeeding months reported clinical performance for both procedures. ILP success was defined as obtaining a sample on the first attempt with &lt;1000 red blood cells per high-power field or fluid described as clear. CIV success was defined as placement of a functioning catheter on the first try. Each group served as the control group for the procedure for which they did not receive the intervention. RESULTS: Two-hundred interns participated (104 in the ILP group and 96 in the CIV group). Together, they reported 409 procedures. ILP success rates were 34% (31 of 91) for interns who received ILP mastery learning and 34% (25 of 73) for controls (difference: 0.2% [95% confidence interval: –0.1 to 0.1]). The CIV success rate was 54% (62 of 115) for interns who received CIV mastery learning compared with 50% (58 of 115) for controls (difference: 3% [95% confidence interval: –10 to 17]). CONCLUSIONS: Participation in a single SBME mastery learning session was insufficient to affect pediatric interns’ subsequent procedural success.

Objective— Endothelial outgrowth cells (EOC) decrease inflammation and improve endothelial repair. Inflammation aggravates kidney injury in renal artery stenosis (RAS), and may account for its persistence upon revascularization. We hypothesized that EOC would decrease inflammatory (M1) macrophages and improve renal recovery in RAS. Approach and Results— Pigs with 10 weeks of RAS were studied 4 weeks after percutaneous transluminal renal angioplasty (PTRA+stenting) or sham, with or without adjunct intrarenal delivery of autologous EOC (10×10 6 ), and compared with similarly treated normal controls (n=7 each). Single-kidney function, microvascular and tissue remodeling, inflammation, oxidative stress, and fibrosis were evaluated. Four weeks after PTRA, EOC were engrafted in injected RAS-kidneys. Stenotic-kidney glomerular filtration rate was restored in RAS+EOC, RAS+PTRA, and RAS+PTRA+EOC pigs, whereas stenotic-kidney blood flow and angiogenesis were improved and fibrosis attenuated only in EOC-treated pigs. Furthermore, EOC increased cell proliferation and decreased the ratio of M1 (inflammatory)/M2 (reparative) macrophages, as well as circulating levels and stenotic-kidney release of inflammatory cytokines. Cultured-EOC released microvesicles in vitro and induced phenotypic switch (M1-to-M2) in cultured monocytes, which was inhibited by vascular endothelial growth factor blockade. Finally, a single intrarenal injection of rh-vascular endothelial growth factor (0.05 μg/kg) in 7 additional RAS pigs also restored M1/M2 ratio 4 weeks later. Conclusions— Intrarenal infusion of EOC after PTRA induced a vascular endothelial growth factor–mediated attenuation in macrophages inflammatory phenotype, preserved microvascular architecture and function, and decreased inflammation and fibrosis in the stenotic kidney, suggesting a novel mechanism and therapeutic potential for adjunctive EOC delivery in experimental RAS to improve PTRA outcomes.