Stephen D. Simon

High incidence of focal segmental glomerulosclerosis in nephrotic syndrome of childhood.

Abstract In recent adult literature, there have been reports of an increasing incidence of focal segmental glomerulosclerosis (FSGS) among patients with nephrotic syndrome. To examine whether this observation is also relevant to the pediatric population we utilized our hospital computerized database to analyze the data on children with primary nephrotic syndrome seen first between the years 1984 and 1995. A questionnaire was also sent to all metropolitan Kansas City pediatricians to identify possible patients outside the database. The inclusion criteria were clinical nephrotic syndrome or proteinuria with a kidney biopsy. A total of 148 patients (group A) were identified; 86 of them from metropolitan Kansas City (group B). In group A the incidence of minimal change disease (MCD) and FSGS was 52.7% [95% confidence interval (CI) 44%–60%] and 23.0% (95% CI 16–29%), respectively and in group B 54.7% (95% CI 44%–65%) and 24.5% (95% CI 15%–33%), respectively. Those numbers were significantly different from the International Study of Kidney Disease in Children (ISKDC) reported incidence of 76.4% for MCD and 6.9% for FSGS. Similar to the ISKDC, in our population children over 6 years had a higher incidence of FSGS than younger children (32.8% vs. 16.7%, P=0.028). The annual incidence rate for nephrotic syndrome in group B was 2.2 cases/105 children per year, of which MCD comprised 1.22 cases/105 children per year and FSGS 0.5 cases/105 children per year. The annual incidence rates of both primary nephrotic syndrome (3.6) and FSGS (1.6) were significantly higher in African-Americans than Caucasians (1.8 and 0.3 cases/105 children per year, respectively). Our study indicates nearly no change in the annual incidence of pediatric primary nephrotic syndrome, but a higher incidence of FSGS with reciprocal decline in the incidence of MCD. The possibility of primary nephrotic syndrome being caused by a non-MCD entity is further raised among African-Americans and in children over 6 years. We conclude that our perception of primary nephrotic syndrome of childhood as a benign condition has to be carefully reexamined and a more-guarded prognostic approach adopted in our geographic area.

Normal urinary calcium/creatinine ratios in African-American and Caucasian children

A random urine calcium/creatinine ratio (UCa/Cr) is of practical use in screening for hypercalciuria. However, due to worldwide variations, reference values for the pediatric population are not yet well established. Furthermore, no study has been conducted to establish normal UCa/Cr values in young African-American (AA) children. It has also been previously reported that an elevated UCa/Cr is related to a high urine Na/K ratio (UNa/K). The objectives of the present study were: (1) to set normal values of random UCa/Cr by age and race in the pediatric population of Metropolitan Kansas City, (2) to identify potential racial differences in UCa/Cr between Caucasian (CS) and AA children, and (3) to determine the relationship between UCa/Cr and UNa/K in healthy children.A total of 368 healthy children of both genders were enrolled in the study. They were divided into four age groups as follows: (1) <7 months, (2) 8–18 months, (3) 19 months to 6 years, and (4) 7–16 years. Each group was subdivided into AA and CS. A non-fasting random urine specimen from each subject was analyzed for Ca, Na, K and creatinine.The median UCa/Cr values for AA were: (1) 0.13, (2) 0.09, (3) 0.06, and (4) 0.04 and for CS they were (1) 0.26, (2) 0.11, (3) 0.10, and (4) 0.09. The data showed a strong inverse relationship between UCa/Cr and age, the youngest children demonstrating the highest UCa/Cr. In each age group, UCa/Cr in CS exceeded the corresponding value in AA. The age-dependent 95th percentiles of UCa/Cr values for CS were (1) 0.70, (2) 0.50, (3) 0.28, and (4) 0.20 and for AA they were (1) 0.38 and (3) 0.24. Due to outliers, the 95th percentile could not be established for the other two AA subgroups. The relationship between UCa/Cr and UNa/K was found to be extremely weak in both AA (r2=0.00005) and CS (r2=0.02). On the other hand, a strong linear correlation was observed between UNa/K and age (CS r2=0.23, P<0.001, AA r2=0.19, P<0.001), explaining in part the lack of correlation between UNa/K and UCa/Cr.We conclude that the child’s age, ethnicity and geographic location should be taken into consideration when assessing UCa/Cr ratio. Contrary to what has previously been reported in hypercalciuric children, no significant relationship was found between UCa/Cr and UNa/K in healthy children.

Factors Influencing Infant Visits to Emergency Departments

Objectives. To follow the 1995 birth cohort of infants, born in the State of Missouri, through their first birthday to: 1) examine their rates of visits to emergency departments (EDs), 2) identify predictors of any ED visit, 3) examine rates of nonurgent ED visits, and 4) identify predictors of nonurgent visits. Methods. This was a retrospective population cohort study. Using deterministic linkage procedures, 2 databases at the Missouri Department of Health (DOH; (the patient abstract database and the birth registry database) were linked by DOH personnel. International Classification of Diseases, Ninth Revision-Clinical Modification codes for ED visits were classified as emergent, urgent, or nonurgent by 2 researchers. Eight newborn characteristics were chosen for analysis. Negative binomial regression was used to examine the rates and predictors of both total and nonurgent ED visits. Results. There were 935 total ED visits and 153 nonurgent ED visits per 1000 infant years. The average number of visits was .94, with 59% of infants having no visits, 21% having 1 ED visit, and 20% having 2 or more visits. Factors associated with increases in both total and nonurgent ED visits were Medicaid, self-pay, black race, rural region, presence of birth defects, and a nursery stay of >2 days. Significant interactions were found between Medicaid and race and Medicaid and rural regions on rates of ED use and nonurgent use. The highest rate of ED use, 1.8 per person year, was seen in white, rural infants on Medicaid, and the lowest rate (.4 per person year) was seen in urban white infants not on Medicaid. The highest rates of nonurgent use, .3 per person year, were among urban and rural Medicaid infants of both races and among black infants on commercial insurance. The lowest nonurgent rate, .04 per person year, was seen in white urban infants on commercial insurance. Conclusion. Infants in the State of Missouri have high rates of ED visits. Nonurgent visits are only a small portion of ED visits and cannot explain large variations in ED usage. Increased ED use by Medicaid patients may reflect continuing difficulties in accessing primary care.

X chromosome gene expression in human tissues: Male and female comparisons

About 25% of X-linked genes may escape inactivation at least to some degree. However, in vitro results from somatic cell hybrids may not reflect what happens in vivo. Therefore, we analyzed the female/male (F/M) gene fold expression ratio for 299 X-linked and 7795 autosomal genes from 11 different tissues from an existing in vivo microarray database. On average 5.1 and 4.9% of genes showed higher expression in females compared with 7.4 and 7.9% in males, respectively, for X-linked and autosomal genes. A trend was found for F/M gene fold ratios greater than 1.5 for several X-linked genes indicating overexpression in females among multiple tissues. Nine X-linked genes showed overexpression in females in at least 3 of the 11 studied tissues. Of the 9 genes, 6 were located on the short arm and 3 on the long arm of the X chromosome. Six of the 9 genes have previously been reported to escape X inactivation. However, in general, no consistent pattern was seen for the expression of X-linked genes between in vitro and in vivo systems. This study indicates that factors other than the X-inactivation process may impact on the expression of X-linked genes resulting in an overall similar gender expression for both X-linked and autosomal genes.

HIV gp120- and methamphetamine-mediated oxidative stress induces astrocyte apoptosis via cytochrome P450 2E1

HIV-1 glycoprotein 120 (gp120) is known to cause neurotoxicity via several mechanisms including production of proinflammatory cytokines/chemokines and oxidative stress. Likewise, drug abuse is thought to have a direct impact on the pathology of HIV-associated neuroinflammation through the induction of proinflammatory cytokines/chemokines and oxidative stress. In the present study, we demonstrate that gp120 and methamphetamine (MA) causes apoptotic cell death by inducing oxidative stress through the cytochrome P450 (CYP) and NADPH oxidase (NOX) pathways. The results showed that both MA and gp120 induced reactive oxygen species (ROS) production in concentration- and time-dependent manners. The combination of gp120 and MA also induced CYP2E1 expression at both mRNA (1.7±0.2- and 2.8±0.3-fold in SVGA and primary astrocytes, respectively) and protein (1.3±0.1-fold in SVGA and 1.4±0.03-fold in primary astrocytes) levels, suggesting the involvement of CYP2E1 in ROS production. This was further confirmed by using a selective inhibitor of CYP2E1, diallylsulfide (DAS), and CYP2E1 knockdown using siRNA, which significantly reduced ROS production (30–60%). As the CYP pathway is known to be coupled with the NOX pathway, including Fenton–Weiss–Haber (FWH) reaction, we examined whether the NOX pathway is also involved in ROS production induced by either gp120 or MA. Our results showed that selective inhibitors of NOX, diphenyleneiodonium (DPI), and FWH reaction, deferoxamine (DFO), also significantly reduced ROS production. These findings were further confirmed using specific siRNAs against NOX2 and NOX4 (NADPH oxidase family). We then showed that gp120 and MA both induced apoptosis (caspase-3 activity and DNA lesion using TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling) assay) and cell death. Furthermore, we showed that DAS, DPI, and DFO completely abolished apoptosis and cell death, suggesting the involvement of CYP and NOX pathways in ROS-mediated apoptotic cell death. In conclusion, this is the first report on the involvement of CYP and NOX pathways in gp120/MA-induced oxidative stress and apoptotic cell death in astrocytes, which has clinical implications in neurodegenerative diseases, including neuroAIDS.

Readmission of breastfed infants in the first 2 weeks of life.

OBJECTIVE: Readmission of breastfeeding infants for hyperbilirubinemia and/or dehydration has been increasing in recent years. The purpose of the current study was to characterize the indications for and condition of these infants at readmission, and to determine factors present prior to initial hospital discharge which might have identified them to be at risk.STUDY DESIGN: The records of 125 breastfeeding infants who were admitted to Childrens Mercy Hospital from 1995 to 1997 in the first 2 weeks of life with diagnoses of hyperbilirubinemia, dehydration, or feeding problems were reviewed. Infants with hemolytic disease, infection, or other underlying causes were excluded.At readmission, 80 infants had total bilirubin levels >342 μmol/l (20 mg/dl) and gestational age ≥38 weeks or total bilirubin levels >308 μmol/l (18 mg/dl) and gestational age <38 weeks. Forty-nine infants had a weight loss ≥12% from birth weight or a serum sodium concentration ≥145 mmol/l. Twenty-six infants had both hyperbilirubinemia and excessive weight loss or hypernatremia.RESULTS: The mean gestational age of all infants was 38.6 weeks, 95% CI, 38.3 to 38.9 weeks. Mean length of initial hospital stay was 1.8 days (SD 1.03) for vaginally delivered infants compared with 3.4 days (SD 2.1) for those delivered by C-section (p=0.003). The Cesarean birth rate (9%) was disproportionally low in infants readmitted compared with overall C-section rate in Kansas City, MO (17%) (p=0.03). There was a significantly lower rate of readmission for infants whose initial hospital stay was ≥3 days (p=<0.002), but not for infants whose initial stay was ≥2 days (p=0.1). Infants admitted for hyperbilirubinemia only were at 38.3±1.6 weeks gestation compared with infants admitted for excessive weight loss or hypernatremia, 39.2±1.3 (p=0.06), and 1 day older, 5.4±1.9 days vs. 4.4±2.5 days (p=0.05).CONCLUSION: This study confirms that prematurity and short hospital stays are risk factors for readmission of breastfeeding infants with hyperbilirubinemia and/or excessive weight loss and hypernatremia. An initial hospital stay ≥3 days was associated with a reduced risk for readmission of these infants.

Assessment of HIV-related stigma in a US faith-based HIV education and testing intervention

The African American church is a highly influential institution with the potential to greatly increase the reach of HIV prevention interventions and address HIV‐related stigma in US African American communities. However, there are few studies on HIV‐related stigma and African American church populations. This study explored HIV‐related stigma among church and community members participating in an HIV education and testing intervention pilot study in African American churches, named Taking It to the Pews.

Variation and Trends in ED Use of Radiographs for Asthma, Bronchiolitis, and Croup in Children

OBJECTIVES: The objectives were (1) to determine trends in radiograph use in emergency department (ED) care of children with asthma, bronchiolitis, and croup; and (2) to examine the association of patient and hospital factors with variation in radiograph use. METHODS: A retrospective, cross-sectional study of National Hospital Ambulatory Medical Care Survey data between 1995 and 2009 on radiograph use at ED visits in children aged 2 to 18 years with asthma, aged 3 months to 1 year with bronchiolitis, and aged 3 months to 6 years with croup. Odds ratios (ORs) were calculated and adjusted for all factors studied. RESULTS: The use of radiographs for asthma increased significantly over time (OR: 1.06; 95% confidence interval [CI]: 1.03–1.09; P < .001 for trend) but were unchanged for bronchiolitis and croup. Pediatric-focused EDs had lower use for asthma (OR: 0.44; 95% CI: 0.29–0.68), bronchiolitis (OR: 0.37; 95% CI: 0.23–0.59), and croup (OR: 0.34; 95% CI: 0.17–0.68). Compared with the Northeast region, the Midwest and South had statistically higher use of radiographs for all 3 conditions. The Western region had higher use only for asthma (OR: 1.67; 95% CI: 1.07–2.60), and bronchiolitis (OR: 2.94; 95% CI: 1.48–5.87). No associations were seen for metropolitan statistical area or hospital ownership status. CONCLUSIONS: The ED use of radiographs for children with asthma increased significantly from 1995 to 2009. Reversing this trend could result in substantial cost savings and reduced radiation. Pediatric-focused EDs used significantly fewer radiographs for asthma, bronchiolitis, and croup. The translation of practices from pediatric-focused EDs to all EDs could improve performance.

Effect of mild-to-moderate smoking on viral load, cytokines, oxidative stress, and cytochrome P450 enzymes in HIV-infected individuals

Mild-to-moderate tobacco smoking is highly prevalent in HIV-infected individuals, and is known to exacerbate HIV pathogenesis. The objective of this study was to determine the specific effects of mild-to-moderate smoking on viral load, cytokine production, and oxidative stress and cytochrome P450 (CYP) pathways in HIV-infected individuals who have not yet received antiretroviral therapy (ART). Thirty-two human subjects were recruited and assigned to four different cohorts as follows: a) HIV negative non-smokers, b) HIV positive non-smokers, c) HIV negative mild-to-moderate smokers, and d) HIV positive mild-to-moderate smokers. Patients were recruited in Cameroon, Africa using strict selection criteria to exclude patients not yet eligible for ART and not receiving conventional or traditional medications. Those with active tuberculosis, hepatitis B or with a history of substance abuse were also excluded. Our results showed an increase in the viral load in the plasma of HIV positive patients who were mild-to-moderate smokers compared to individuals who did not smoke. Furthermore, although we did not observe significant changes in the levels of most pro-inflammatory cytokines, the cytokine IL-8 and MCP-1 showed a significant decrease in the plasma of HIV-infected patients and smokers compared with HIV negative non-smokers. Importantly, HIV-infected individuals and smokers showed a significant increase in oxidative stress compared with HIV negative non-smoker subjects in both plasma and monocytes. To examine the possible pathways involved in increased oxidative stress and viral load, we determined the mRNA levels of several antioxidant and cytochrome P450 enzymes in monocytes. The results showed that the levels of most antioxidants are unaltered, suggesting their inability to counter oxidative stress. While CYP2A6 was induced in smokers, CYP3A4 was induced in HIV and HIV positive smokers compared with HIV negative non-smokers. Overall, the findings suggest a possible association of oxidative stress and perhaps CYP pathway with smoking-mediated increased viral load in HIV positive individuals.

Creatinine excretion rates for renal clearance studies.

Abstract  A total of 637 timed-urine collections for creatinine excretion rates obtained from 295 children over 14 years have been analyzed. The children ranged in age from 2.8 to 21.7 years at the time of the clearance study. The data analyzed included only one study from a child during any 6-month period. The objective is to provide data defining the expected range of creatinine excretion for renal clearance studies. One hundred forty-two studies were conducted on children not pretreated with cimetidine and 495 on those pretreated with cimetidine. Analysis showed that pretreatment with cimetidine for creatinine clearance studies does not alter creatinine excretion rates (P=0.080; 95% CI –0.03 to 1.61). Creatinine excretion rates in urine collections obtained at home (roughly 24-h collections) were compared with 2-h supervised collections in the Children’s Kidney Center. The supervised urine collections resulted in creatinine excretion rates 1.38 mg/kg/24 h greater than home collections (P=0.001; 95% CI 0.76–2.00). Using regression equations for creatinine excretion rate with age, tables have been prepared showing the expected rate of creatinine excretion for renal clearance studies in children 3–21 years of age.