Pediatrics and pediatric nephrology lag behind adult medicine in producing randomized controlled trials (RCTs). Physician attitudes have been shown to play a significant role in RCT enrollment.
We surveyed members of the American Society of Pediatric Nephrology regarding beliefs about RCTs and factors influencing decisions to recommend RCT enrollment. Regression analyses were used to identify effects of variables on an aggregate score summarizing attitudes toward RCTs.
130 replies were received. 66% had enrolled patients in RCTs. Respondents in practice >15 years were more likely to have recruited a patient to a RCT than those in practice <5 years. Respondents were more willing to recommend RCT enrollment if the study was multicenter, patients were sicker or had a poorer prognosis, or if the parent or participant received a financial incentive versus the provider. In multiple regression analysis, history of enrolling patients in a RCT was the only significant predictor of higher aggregate RCT-friendly attitude.
Many pediatric nephrologists have never enrolled a patient in a RCT, particularly those in practice <5 years. Respondents who have not enrolled patients in RCTs have a less RCT-friendly attitude. Provision of improved training and resources might increase participation of junior providers in RCTs.
Recruitment of large, diverse populations into genetic studies remains challenging. Potential strategies to overcome limitations include leveraging electronic health data and minimizing patient burden. We sought to describe the overall participation rate and identify characteristics associated with participation in a genetic substudy of patients with type 2 diabetes mellitus, in which patients were identified via electronic hospital data and asked to participate by providing DNA samples by mail.
During a phone interview, participants (n = 455) were asked to take part in a genetic substudy. Subjects verbally consenting were mailed saliva collection kits and written consent forms. We examined demographic and clinical variables associated with verbal consent and DNA kit return using logistic regression.
Overall, 90% (n = 410) verbally consented to the genetic substudy during interviews. However, of those consenting, only 70% returned the DNA kit (n = 287). Among those consenting, after covariate adjustment, male sex (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.09–2.65), African American race (OR, 0.61; 95% CI, 0.39–0.95), hemoglobin A1c (HbA1c) (OR, 0.87; 95% CI, 0.75–1.00), and physical activity (OR, 0.58; 95% CI, 0.37–0.91) were significantly associated with DNA kit return.
To our knowledge, we are the first to demonstrate an inverse association between HbA1c and participation in genetic research, potentially indicating a compliance-related trait needing further exploration. The DNA kit return rate being notably lower than the verbal consent rate suggests that the greater convenience of a telephone/mail-in process did not drastically enhance full participation. Direct comparison to in-person donation may be warranted.
genetics; type 2 diabetes; race; recruitment
Writing clearly is critical to the success of your scientific career. Unfortunately, this skill is not taught in medical school or postgraduate training. This article summarizes our approach to the writing and publication of your research. Here we focus on empirical or experimental reports of translational and clinically oriented research. We review the process of choosing what to write, how to write it clearly, and how to navigate the process of submission and publication.
medical writing; career development
Post-menopausal osteoporosis is associated with estrogen deficiency and
rapid bone loss. The mechanism by which estrogen deficiency results in bone loss
has not been fully explained. Studies in mice rendered acutely estrogen
deficient by ovariectomy have suggested that estrogen deficiency results in an
activated T-lymphocyte phenotype and increased production of pro-osteoclastic
cytokines. The aim of this study was to translate these findings from mouse
models that suggest that the T-lymphocyte plays an important role in the
etiology of post-menopausal osteoporosis. We recruited pre-menopausal women who
underwent ovariectomy (OVX) for benign gynecologic conditions or for prophylaxis
against ovarian cancer and a group of matched control women without OVX.
Subjects provided blood samples to characterize T-lymphocyte phenotype by
Fluorescence-activated cell sorting (FACS) and for T-lymphocyte culture and
collection of conditioned media. Bone mineral density at the lumbar spine and
left femoral neck was performed annually for two years and volumetric
measurements by computed tomography (CT) of the thymus were obtained during the
first 6 months. We enrolled 6 OVX and 13 control women. The OVX subjects had a
significant loss of bone mineral density at the lumbar spine and left femoral
neck. The volumetric thymus measurements suggested an increase in thymus size in
the OVX subjects but did not reach statistical significance due to the small
sample size. The T-lymphocyte phenotype in the OVX subjects demonstrated
increased T-lymphocyte activation by FACS compared to the control subjects. Our
preliminary findings support the hypothesis that estrogen deficiency leads to an
activated T-lymphocyte phenotype which may contribute to the bone loss seen in
estrogen deficiency. Larger clinical studies are necessary to confirm these
There is some evidence that bariatric surgery patients who undergo the purely restrictive procedures, such as the gastric banding (GB) or vertical banded gastroplasty surgery, do not meet the dietary reference intakes for several nutrients. Whether dietary counseling improves micro- and macro-nutrient intakes was examined in GB surgery patients.
Twenty-three GB surgery patients received dietary and behavioral counseling for 12 weeks to limit energy intake and improve nutrient intakes. Food intake was assessed by 3-d food record at baseline and 6 and 12 weeks. Post-intervention data were available in 21 patients.
At baseline, more than 50% of the subjects reported inadequate dietary intakes of 13 nutrients but over-consumption of sodium and percent energy from saturated and trans fatty acids. Mixed effects model for repeated measures revealed a significant reduction in energy (p=0.0007), absolute protein (p=0.04), cholesterol (p=0.045), and potassium (p=0.01) intake and an increase in vitamin K (p=0.03) intake and percent energy from protein (p=0.005) over the 12 weeks. McNemar test showed a reduction in the proportion of subjects with an inadequate intake of vitamin K (p=0.008) but an increase in the proportion of subjects with an inadequate intake of thiamin (p=0.03) at 12 weeks. The proportion of subjects who did not meet the nutrient requirements for the remaining 27 nutrients was generally high and remained unchanged.
Dietary intervention improved the intake of some nutrients in GB surgery patients. However, most nutrient intake requirements remained unmet by many subjects. These results indicate that nutritional counseling beyond 12 weeks is warranted in GB surgery patients to improve their dietary nutrient intakes.
gastric banding surgery; dietary intervention; nutrient intake
The American Diabetes Association has called for further research on how patient demographics should determine drug choices for individuals with type 2 diabetes mellitus (T2DM). Here, using in-depth physiology studies, we investigate whether obese patients with T2DM are likely to benefit from thiazolidinediones, medications with a known side effect of weight gain.
Materials and Methods
11 obese and 7 non-obese individuals with T2DM participated in this randomized, placebo-controlled, double-blind, crossover study. Each subject underwent a pair of “stepped” pancreatic clamp studies with subcutaneous adipose tissue biopsies following 21 days of pioglitazone (45 mg) or placebo.
Obese subjects demonstrated significant decreases in insulin resistance and many adipose inflammatory parameters with pioglitazone relative to placebo. Specifically, significant improvements in glucose infusion rates, suppression of hepatic glucose production, and whole fat expression of certain inflammatory markers (IL-6, IL-1b, and iNOS) were observed in obese subjects but not in non-obese subjects. Additionally, adipose tissue from obese subjects demonstrated reduced infiltration of macrophages, dendritic cells, and neutrophils as well as increased expression of factors associated with fat “browning” (PGC-1α and UCP-1).
These findings support the efficacy of pioglitazone to improve insulin resistance and reduce adipose tissue inflammation in obese patients with T2DM.
Type 2 Diabetes; Obesity; Pioglitazone; Adipose Tissue Inflammation; Insulin Resistance
Isoflurane is a volatile anesthetic that is widely used clinically as an inhalational anesthetic. In recent years, several studies have indicated that isoflurane has neuroprotective properties. This has led to the beneficial effects of isoflurane being analyzed in both cell culture and animal models, including various models of brain injury. Neonatal hypoxia ischemia may be characterized as injury that occurs in the immature brain, resulting in delayed cell death via excitotoxicity and oxidative stress. These adverse events in the developing brain often lead to detrimental neurological defects in the future. Currently, there are no well-established effective therapies for neonatal hypoxia ischemia. In line with this, isoflurane, which displays neuroprotective properties in several paradigms and has been shown to improve neurological deficits caused by brain injuries, has the capability to be an extremely relevant clinical therapy for the resolution of deficits concomitant with neonatal hypoxic ischemic brain injuries. This review will therefore seek to explore and analyze the current information on isoflurane, looking at general isoflurane anesthetic properties, and the protection it confers in different animal models, focusing particularly on neuroprotection as shown in studies with neonatal hypoxic ischemic brain injury.
Isoflurane; Long-term neuroprotection; Pre-conditioning; Post-conditioning; Isoflurane mechanism; Neonatal hypoxia ischemia
Following the initial discovery of a natriuretic and diuretic peptide factor present in atrial myocardial tissue homogenates, subsequent elucidation of the natriuretic peptide family has led to substantial advances in the understanding of the autocrine, paracrine, and endocrine regulation of the cardiovascular system. Furthermore, with the development of assays for the measurement of the natriuretic peptides, these important biomarkers have gone from being regarded as biological mediators of the cardiovascular system to now represent important clinical tools for the diagnostic and prognostic evaluation of patients with heart failure, and may have potential as a therapeutic target in this setting as well. An historical perspective on the natriuretic peptides from bench to bedside translation will be discussed.
natriuretic peptides; biology; diagnosis; prognosis; therapy
Although mosaic autosomal chromosomal abnormalities are being increasingly detected as part of high-density genotyping studies, the clinical correlates are unclear. From an electronic medical record (EMR)–based genome-wide association study (GWAS) of peripheral arterial disease, log-R-ratio and B-allele-frequency data were used to identify mosaic autosomal chromosomal abnormalities including copy number variation and loss of heterozygosity. The EMRs of patients with chromosomal abnormalities and those without chromosomal abnormalities were reviewed to compare clinical characteristics. Among 3336 study participants, 0.75% (n = 25, mean age = 74.8 ± 10.7 years, 64% men) had abnormal intensity plots indicative of autosomal chromosomal abnormalities. A hematologic malignancy was present in 8 patients (32%), of whom 4 also had a solid organ malignancy while 2 patients had a solid organ malignancy only. In 50 age- and sex-matched participants without chromosomal abnormalities, there was a lower rate of hematologic malignancies (2% vs 32%, P < .001) but not solid organ malignancies (20% vs 24%, P = .69). We also report the clinical characteristics of each patient with the observed chromosomal abnormalities. Interestingly, among 5 patients with 20q deletions, 4 had a myeloproliferative disorder while all 3 men in this group had prostate cancer. In summary, in a GWAS of 3336 adults, 0.75% had autosomal chromosomal abnormalities and nearly a third of them had hematologic malignancies. A potential novel association between 20q deletions, myeloproliferative disorders, and prostate cancer was also noted.
copy number variation; genome-wide association studies; loss of heterozygosity; mosaic abnormalities; mosaic deletion; myeloproliferative disorders; prostate cancer; unipaternal disomy
Cardiovascular complications are the leading cause of mortality in type II diabetes (T2DM), in which onset and progression of atherosclerosis is linked to chronic inflammation. Activation status of innate immune cells (granulocytes Gc, monocytes Mc), as reflected by increased CD11b, CD66b and other surface markers, increases their endothelial and cytokines/chemokines release. While this inflammatory activation appears inversely related to poor glycemic control, the effect of acute spontaneous hyperglycemia on innate immune cell activation remains unclear. Expression of key markers (CD11b, CD14, CD16, CD62L, and CD66b) was therefore determined by flow cytometry on whole blood of healthy subjects and patients with T2DM with spontaneous, fasting eu- or hyper-glycemia both at baseline and after 30, 90, and 240 min. of room temperature incubation. Hyperglycemic patients with T2DM had significantly higher Gc and Mc CD11b and Gc CD66b surface mean fluorescence intensity (MFI) as compared to euglycemic patients with T2DM whose values were similar to healthy controls. CD16 expression in CD14+CD16+ Mc was elevated in all patients with T2DM, regardless of glycemic levels. Our data suggest that while the presence of diabetes per se may have a pro-inflammatory effect, hyperglycemia seems further acutely exacerbate innate cell inflammatory status, and their consequent endothelial adhesion and vascular damage potential.
Glucose; Granulocytes; Monocytes; Type II Diabetes
In scientific teams as in life, conflicts arise. This paper aims to provide an introduction to tools and skills to help in managing conflicts in practice. Using a structured approach enables the concerns and interests of all involved to be identified and clarified. It also permits a better understand yourself and others and will help empower those in conflict to find acceptable and workable resolutions.
sCD40L is a pro-atherogenic cytokine, part of the TNF superfamily and consistently associated with obesity, diabetes, and increased cardiovascular (CV) risk. While the role of sCD40L in the onset/progression of CV complications of dysmetabolic diseases may be modulated by acute and/or chronic fluctuations of plasma insulin and glucose, very little has been done to clarify this interaction. The kinetic profile of sCD40L (and, in an exploratory manner, of several immuno-modulatory factors), were measured during hyperglycemia and euglycemic-hyperinsulinemia in a group of ten healthy young males (26.8±1.4 yrs). After an overnight fast, i.v. catheters were placed in antecubital veins of both arms for blood drawing and dextrose/insulin i.v. infusions. Procedures lasted 240 min, including baseline (t = 0–60), hyperglycemia (t = 60–150; plasma glucose ~220 mg/dL via i.v. dextrose infusion); and euglycemic-hyperinsulinemia (t = 150–240; glucose infusion continued to clamp glycemic levels between 80 and 110 mg/dL; constant insulin infusion @ 1.5 mU/kg/min).
Plasma for cytokine assays was sampled at 12 separate time-points. Plasma levels of sCD40L were significantly reduced (p<0.01) during hyperglycemia and euglycemic-hyperinsulinemia, paralleling the kinetic profiles of FFA and ketone bodies. This pattern was also observed in other immuno-moduatory factors (notably cortisol and EGF), while (IL-1α, -4, -6, -9, -10, TNF-α, Eotaxin) did not change significantly. Significant reductions of the pro-atherogenic cytokine sCD40L were observed during endogenous and exogenous hyperinsulinemia, independent of prevailing glucose concentration, in young healthy males. Our data suggest a mechanism by which correct insulin action may exert a beneficial protective role against inflammation independent of its immediate glucose-lowering effect.
sCD40L; cytokines; insulin; healthy; young males
Mind-body practices are increasingly used to provide stress reduction for posttraumatic stress disorder (PTSD). Mind-body practice encompasses activities with the intent to use the mind to impact physical functioning and improve health.
This is a literature review using PubMed, PsycINFO, and PILOTS to identify the effects of mind-body intervention modalities, such as yoga, taichi, qigong, mindfulness-based stress reduction, meditation, and deep breathing, as interventions for PTSD.
The literature search identified 92 articles, only 16 of which were suitable for inclusion in this review. We reviewed only original, full text articles that met the inclusion criteria. Most of the studies have small sample size, but findings from the 16 publications reviewed here suggest that mind-body practices are associated with positive impacts on PTSD symptoms. Mind-body practices incorporate numerous therapeutic effects on stress responses, including reductions in anxiety, depression, and anger, and increases in pain-tolerance, self-esteem, energy levels, ability to relax, and ability to cope with stressful situations. In general, mind-body practices were found to be a viable intervention to improve the constellation of PTSD symptoms such as intrusive memories, avoidance, and increased emotional arousal.
Mind-body practices are increasingly employed in the treatment of PTSD and are associated with positive impacts on stress-induced illnesses such as depression and PTSD in most existing studies. Knowledge about the diverse modalities of mind-body practices may provide clinicians and patients with the opportunity to explore an individualized and effective treatment plan enhanced by mind-body interventions as part of ongoing self-care.
mindfulness; exercise; breathing; yoga; taichi; posttraumatic stress disorder
Injection drug use remains a significant risk for acquiring HIV infection. The mechanisms by which morphine enhances HIV infection of human immune cells are largely unknown.
In this study, we sought to determine the possible mechanisms by which morphine upregulates HIV infection of human blood monocyte-derived macrophages (MDM).
In this study, MDM were infected with the R5, X4, and R5X4 HIV strains. HIV replication was determined by performing reverse transcriptase activity assays. HIV receptors were determined by performing reverse transcriptase polymerase chain reactions and flow cytometry assays. β-chemokines were analyzed by performing enzyme-linked immunosorbent assays. In addition, HIV R5 strain and murine leukemia virus envelope-pseudotyped HIV infection was performed to determine whether morphine affects HIV infection of macrophages at entry level.
Morphine significantly enhanced HIV R5 strain infection of MDM but had little effect on X4 strain infection. The macrophage-tropic R5 strain envelope-pseudotyped HIV infection was markedly increased by morphine, whereas murine leukemia virus envelope-pseudotyped HIV infection was not significantly affected. Furthermore, morphine significantly upregulated CCR5 receptor expression and inhibited the endogenous production of β-chemokines in MDM. The opioid receptor antagonist naltrexone blocked the effects of morphine on the production of β-chemokines.
Opiates enhance HIV R5 strain infection of macrophages through the downregulation of β-chemokine production and upregulation of CCR5 receptor expression and may have an important role in HIV immunopathogenesis.
CCR5; β-chemokines; macrophages; morphine; opioid
Low density lipoprotein cholesterol (LDL-C) has been clearly associated with the risk of developing coronary heart disease (CHD). The best and most convenient method for determining LDL-C has come under increased scrutiny in recent years. We present comparisons of Friedewald’s calculated LDL-C (C-LDL-C) and direct LDL-C (D-LDL-C) using three different homogenous assays. This highlights differences between the two methods of LDL-C measurement, and how this affects the classification of samples into different LDL-C treatment goals as determined by NCEP ATP III guidelines thus potentially affecting treatment strategies.
Lipid profiles of a total of 2,208 clinic patients were retrieved from the Central Arkansas VA Healthcare System (CAVHS) clinical laboratory database. Samples studied were of one week period of time during the 3 periods studied, 2000 (period 1), 2002 (period 2) and 2005 (period 3). Different homogenous assays for D-LDL-C measurement were used for each of the 3 periods.
There is a fundamental disagreement between D-LDL-C and C-LDL-C, even though Pearson’s correlation coefficients are 0.93, 0.97 and 0.98 for periods 1, 2 and 3 respectively. Using the model for period 1, when C-LDL-C is 70 mg/dl, the predicted D-LDL-C is 95 mg/dl (36% higher). The differences between C-LDL-C and predicted D-LDL-C progressively decrease at higher LDL-C cut points. In the assay used in period 3, there are 290 samples with D-LDL-C values between 100–130 mg/dl. Of these, only 182 samples show agreement with C-LDL-C values whereas 90 samples with a D-LDL-C in the 100–130 mg/dl range are in 70–100 mg/dl range using the C-LDL-C assay. While the kappa statistics suggests the LDL-C measures have relatively high levels of agreement, the significant generalized McNemar tests (p<0.01) provide additional evidence of disagreement between C-LDL-C and D-LDL-C during all the 3 periods.
Our results highlight D-LDL-C measurements using 3 different assays during 3 different time periods. In all assays there is substantial lack of agreement between D-LDL-C and C-LDL-C which in most cases resulted in higher D-LDL-C values than C-LDL-C. This leads to clinically significant misclassification of patient’s LDL-C to a different LDL-C treatment goal which would potentially result in more drug usage; thus exposing patients to more potential side effects and at a much greater cost with little evidence of benefit.
direct LDL; calculated LDL; cholesterol
Effects of neighborhood contextual features have been found for many diseases, including bone fractures in adults. Our study objective was to evaluate the association between neighborhood characteristics and pediatric bone fracture rates. We hypothesized that neighborhood indices of deprivation would be associated with higher fracture rates. Pediatric bone fracture cases treated at a tertiary, academic, urban pediatric emergency department between 2003 – 2006 were mapped to census block groups using geographical information systems software. Fracture rates were calculated as fractures per 1,000 children in each census block. Exploratory factor analysis of socioeconomic indicators was performed using 2000 census block data. Factor scores were used to predict odds of bone fracture at the individual level while adjusting for mean age, gender composition, and race/ethnicity composition at census block level using our sample data. We analyzed 3764 fracture visits in 3557 patients representing 349 distinct census blocks groups. Fracture rates among census blocks ranged from 0 to 207 per 1,000 children/study period. Logistic regression modeling identified two factors (race/education and large families) associated with increased fracture risk. Census variables reflecting African American race, laborer/service industry employment, long term block group residence and lower education levels strongly loaded on the race/education factor. The large families factor indicated the children-to-families ratio within the block group. The poverty factor was not independently associated with fracture risk. Thus, neighborhood characteristics are associated with risk for fractures in children. These results can help inform translational efforts to develop targeted strategies for bone fracture prevention in children.
Carbohydrate response element binding protein (ChREBP) is a transcription factor involved in hepatic lipogenesis. Its function is in part under the control of AMP-activated protein kinase (AMPK) and protein phosphatase 2A (PP2A). Given known effects of ethanol on AMPK and PP2A, it is plausible that ethanol might enhance fatty acid synthesis by increasing the activity of ChREBP. We hypothesized that another potential pathway of ethanol-induced hepatic steatosis is mediated by activation of ChREBP.
The effects of ethanol on ChREBP were assessed in hepatoma cells and in C57BL/6J mice fed with the Lieber-DeCarli diet.
When the cells were exposed to ethanol (50 mM) for 24 hrs, the activity of a liver pyruvate kinase (LPK) promoter-luciferase reporter was increased by ~4-fold. Ethanol feeding of mice resulted in the translocation of ChREBP from cytosol to the nucleus. PP2A activity was increased in the liver of ethanol-fed mice by 22%. We found no difference in the levels of hepatic Xu-5-P between ethanol-fed mice and controls. Transfection of a constitutively active AMPK expression plasmid suppressed the basal activity of the LPK luciferase reporter and abolished the effect of ethanol on the reporter activity. However, transfection of rat hepatoma cells with a dominant negative AMPK expression plasmid induced basal LPK luciferase activity by only ~20%. The effect of ethanol on ChREBP was attenuated in the presence of okadaic acid, an inhibitor of PP2A.
The effects of ethanol on AMPK and PP2A may result in activation of ChREBP, providing another potential mechanism for ethanol-induced hepatic steatosis. However, additional okadaic acid-insensitive effects appear to be important as well.
ChREBP; ethanol; AMPK; Protein phosphatase 2A
Diabetes mellitus is one of the most prevalent diseases and is associated with increased incidence of structural and functional derangements in the kidneys, eventually leading to end-stage renal disease in a significant fraction of afflicted individuals. The renoprotective effects of renin-angiotensin system (RAS) blockade have been established; however, the mechanistic pathways have not been fully elucidated. In this review article, the cardinal role of an activated RAS in the pathogenesis of diabetic nephropathy is discussed with a focus on 4 themes: 1) Introduction to RAS cascade, 2) Intrarenal RAS in diabetes, 3) Clinical outcomes of RAS blockade in diabetic nephropathy, and 4) Potential of urinary angiotensinogen (AGT) as an early biomarker of intrarenal RAS status in diabetic nephropathy. This review article provides a mechanistic rational supporting the hypothesis that an activated intrarenal RAS contributes to the pathogenesis of diabetic nephropathy, and that urinary AGT levels provide an index of intrarenal RAS activity.
diabetic nephropathy; renin-angiotensin system; angiotensinogen; kidney
Insulin resistance or its sequelae may be the common etiology of maladies associated with metabolic syndrome (e.g., hypertension, type 2 diabetes, atherosclerosis, heart attack, stroke and kidney failure). It is thus important to understand those factors that affect insulin sensitivity. This review stems from the surprising discovery that interference with angiotensin signaling improves insulin sensitivity and it provides a general overview of insulin action and factors that control insulin sensitivity.
The blood-brain barrier (BBB) is a physical and metabolic barrier that separates the CNS from the peripheral circulation. CNS drug delivery across the BBB is challenging, primarily due to the physical restriction of paracellular diffusion between the endothelial cells that comprise the microvessels of the BBB and the activity of efflux transporters that quickly expel back into the capillary lumen a wide variety of xenobiotics. Therapeutic manipulation of protein trafficking is emerging as a novel means of modulating protein function, and in this mini-review, the targeting of the trafficking of two key BBB proteins, P-glycoprotein and occludin, is presented as a novel, reversible means of optimizing CNS drug delivery.
blood-brain barrier; CNS drug delivery; protein trafficking; protein-protein interaction; oxidative stress; peripheral inflammatory pain; P-glycoprotein; occludin