Joyce M. Lee

Continuous glucose monitoring and intensive treatment of type 1 diabetes

BACKGROUND The value of continuous glucose monitoring in the management of type 1 diabetes mellitus has not been determined. METHODS In a multicenter clinical trial, we randomly assigned 322 adults and children who were already receiving intensive therapy for type 1 diabetes to a group with continuous glucose monitoring or to a control group performing home monitoring with a blood glucose meter. All the patients were stratified into three groups according to age and had a glycated hemoglobin level of 7.0 to 10.0%. The primary outcome was the change in the glycated hemoglobin level at 26 weeks. RESULTS The changes in glycated hemoglobin levels in the two study groups varied markedly according to age group (P=0.003), with a significant difference among patients 25 years of age or older that favored the continuous-monitoring group (mean difference in change, -0.53%; 95% confidence interval [CI], -0.71 to -0.35; P<0.001). The between-group difference was not significant among those who were 15 to 24 years of age (mean difference, 0.08; 95% CI, -0.17 to 0.33; P=0.52) or among those who were 8 to 14 years of age (mean difference, -0.13; 95% CI, -0.38 to 0.11; P=0.29). Secondary glycated hemoglobin outcomes were better in the continuous-monitoring group than in the control group among the oldest and youngest patients but not among those who were 15 to 24 years of age. The use of continuous glucose monitoring averaged 6.0 or more days per week for 83% of patients 25 years of age or older, 30% of those 15 to 24 years of age, and 50% of those 8 to 14 years of age. The rate of severe hypoglycemia was low and did not differ between the two study groups; however, the trial was not powered to detect such a difference. CONCLUSIONS Continuous glucose monitoring can be associated with improved glycemic control in adults with type 1 diabetes. Further work is needed to identify barriers to effectiveness of continuous monitoring in children and adolescents. (ClinicalTrials.gov number, NCT00406133.)

MicroRNA Expression, Survival, and Response to Interferon in Liver Cancer

BACKGROUND Hepatocellular carcinoma is a common and aggressive cancer that occurs mainly in men. We examined microRNA expression patterns, survival, and response to interferon alfa in both men and women with the disease. METHODS We analyzed three independent cohorts that included a total of 455 patients with hepatocellular carcinoma who had undergone radical tumor resection between 1999 and 2003. MicroRNA-expression profiling was performed in a cohort of 241 patients with hepatocellular carcinoma to identify tumor-related microRNAs and determine their association with survival in men and women. In addition, to validate our findings, we used quantitative reverse-transcriptase-polymerase-chain-reaction assays to measure microRNAs and assess their association with survival and response to therapy with interferon alfa in 214 patients from two independent, prospective, randomized, controlled trials of adjuvant interferon therapy. RESULTS In patients with hepatocellular carcinoma, the expression of miR-26a and miR-26b in nontumor liver tissue was higher in women than in men. Tumors had reduced levels of miR-26 expression, as compared with paired noncancerous tissues, which indicated that the level of miR-26 expression was also associated with hepatocellular carcinoma. Moreover, tumors with reduced miR-26 expression had a distinct transcriptomic pattern, and analyses of gene networks revealed that activation of signaling pathways between nuclear factor kappaB and interleukin-6 might play a role in tumor development. Patients whose tumors had low miR-26 expression had shorter overall survival but a better response to interferon therapy than did patients whose tumors had high expression of the microRNA. CONCLUSIONS The expression patterns of microRNAs in liver tissue differ between men and women with hepatocellular carcinoma. The miR-26 expression status of such patients is associated with survival and response to adjuvant therapy with interferon alfa.

Prevalence and Determinants of Insulin Resistance Among U.S. Adolescents A population-based study

OBJECTIVE—We sought to examine the distribution of insulin and homeostasis model assessment of insulin resistance (HOMA-IR) and associations of HOMA-IR with sex, race/ethnicity, age, and weight status, as measured by BMI, among U.S. adolescents. RESEARCH DESIGN AND METHODS—Of 4,902 adolescents aged 12–19 years who participated in the National Health and Nutrition Examination Survey 1999–2002, analysis was performed for a nationally representative subsample of 1,802 adolescents without diabetes who had fasting laboratory measurements. The main outcome measure was HOMA-IR, calculated from fasting insulin and glucose and log transformed for multiple linear regression analyses. RESULTS—In adjusted regression models that included age and weight status, girls had higher HOMA-IR than boys and Mexican-American children had higher HOMA-IR levels than white children. There were no significant differences in adjusted HOMA-IR between black and white children. Obese children (BMI ≥95th percentile) had significantly higher levels of HOMA-IR compared with children of normal weight (BMI <85th percentile) in adjusted comparisons (mean HOMA-IR 4.93 [95% CI 4.56–5.35] vs. 2.30 [2.21–2.39], respectively). Weight status was by far the most important determinant of insulin resistance, accounting for 29.1% of the variance in HOMA-IR. The prevalence of insulin resistance in obese adolescents was 52.1% (95% CI 44.5–59.8). CONCLUSIONS—Obesity in U.S. adolescents represents the most important risk factor for insulin resistance, independent of sex, age, or race/ethnicity. The prevalence of insulin resistance in obese children foreshadows a worrisome trend for the burden of type 2 diabetes in the U.S.

The effect of continuous glucose monitoring in well-controlled type 1 diabetes.

OBJECTIVE The potential benefits of continuous glucose monitoring (CGM) in the management of adults and children with well-controlled type 1 diabetes have not been examined. RESEARCH DESIGN AND METHODS A total of 129 adults and children with intensively treated type 1 diabetes (age range 8–69 years) and A1C <7.0% were randomly assigned to either continuous or standard glucose monitoring for 26 weeks. The main study outcomes were time with glucose level ≤70 mg/dl, A1C level, and severe hypoglycemic events. RESULTS At 26 weeks, biochemical hypoglycemia (≤70 mg/dl) was less frequent in the CGM group than in the control group (median 54 vs. 91 min/day), but the difference was not statistically significant (P = 0.16). Median time with a glucose level ≤60 mg/dl was 18 versus 35 min/day, respectively (P = 0.05). Time out of range (≤70 or >180 mg/dl) was significantly lower in the CGM group than in the control group (377 vs. 491 min/day, P = 0.003). There was a significant treatment group difference favoring the CGM group in mean A1C at 26 weeks adjusted for baseline (P < 0.001). One or more severe hypoglycemic events occurred in 10 and 11% of the two groups, respectively (P = 1.0). Four outcome measures combining A1C and hypoglycemia data favored the CGM group in comparison with the control group (P < 0.001, 0.007, 0.005, and 0.003). CONCLUSIONS Most outcomes, including those combining A1C and hypoglycemia, favored the CGM group. The weight of evidence suggests that CGM is beneficial for individuals with type 1 diabetes who have already achieved excellent control with A1C <7.0%.

Weight Status in Young Girls and the Onset of Puberty

OBJECTIVE. We sought to examine the association between weight status in early childhood and onset of puberty. PATIENTS AND METHODS. The study included 354 girls from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development. Girls were followed longitudinally with height and weight measurements at 36 and 54 months and grades 1, 4, 5, and 6 and with assessment of pubertal stage by physical examination and maternal report in grades 4 through 6. The main outcome was the presence of early puberty, indexed as follows: (a) breast development at or more than Tanner stage 2 by physical examination at grade 4; (b) breast development at or more than Tanner stage 3 by physical examination at grade 5; (c) maternal report of breast development at or more than Tanner stage 3 at grade 5; and (d) maternal report of menarche having already occurred (yes versus no) at grade 6. Multiple logistic regression models predicting early versus late puberty were constructed by using the covariate BMI z score at 36 months, rate of change of BMI and accelerated BMI between 36 months and grade 1, race, maternal education, and maternal age of menarche. RESULTS. BMI z score at 36 months, rate of change of BMI between 36 months and grade 1, an earlier age of maternal menarche, and nonwhite race were each consistently and positively associated with an earlier onset of puberty across the various measures of puberty. CONCLUSIONS. Higher BMI z score in girls as young as 36 months of age and higher rate of change of BMI between 36 months old and grade 1, a period well before the onset of puberty, are associated with earlier puberty, which suggests that increasing rates of obesity in the United States may result in an earlier average age of onset of puberty for US girls.

Vitamin D Deficiency in a Healthy Group of Mothers and Newborn Infants

Plasma 25-hydroxyvitamin D was measured in 40 healthy, mostly Black, mother-infant pairs. Although a majority of mothers received a daily prenatal multivitamin, vitamin D deficiency (<30 nmol/L), was found in 50% of mothers and 65% of their newborn infants, with a positive correlation between maternal and infant plasma 25-hydroxyvitamin D concentrations. Maternal vitamin D deficiency may represent an important risk factor for the development of rickets in children.

Metabolic Syndrome and Growth Hormone Deficiency in Adult Survivors of Childhood Acute Lymphoblastic Leukemia

The purpose of the study was to determine the prevalence of metabolic syndrome, growth hormone deficiency, and cardiovascular risk factors among adult survivors of childhood acute lymphoblastic leukemia (ALL) treated with or without cranial irradiation.

Biphasic Anaphylactic Reactions in Pediatrics

Objectives. The objectives of this study were to: 1) determine the incidence of biphasic reactions in children with anaphylaxis; 2) establish what risk factors can predict progression to a biphasic reaction; and 3) assess the utility of inpatient observation for patients whose anaphylaxis appears to have resolved. Methods. We performed a retrospective analysis of all children admitted to Childrens Hospital inpatient service between 1985 and 1999 with acute anaphylaxis. Data were collected from the medical records regarding past medical history, presenting signs and symptoms, treatment, and hospital course. Patients were considered to have resolution of anaphylaxis if they were documented to have cessation of all symptoms and needed no therapy for at least 1 hour. Biphasic reactions were defined as a worsening of symptoms requiring new therapy after resolution of anaphylaxis. Significant biphasic reactions were defined as those requiring oxygen, vasopressors, intubation, subcutaneous epinephrine, or unscheduled bronchodilator treatments. Patients were considered to benefit from a 24-hour observation period if they had a significant biphasic reaction within 24 hours of admission. Results. Of 108 anaphylactic episodes, 2 (2%) were fatal, and 1 (1%) was a protracted anaphylactic reaction. Among the remaining 105 children with resolution of anaphylaxis, 6 (6%) [95% confidence (CI): 2, 12] had biphasic reactions, of which 3 (3%) [95% CI: .6, 8] were significant. Of those who had a biphasic reactions, the median time from the onset of symptoms to the initial administration of subcutaneous epinephrine was 190 minutes, versus 48 minutes for those without a biphasic reaction. Patients with or without biphasic reactions did not differ significantly in the incidence of initial epinephrine use, initial steroid use, or serious respiratory or cardiovascular symptoms on initial presentation. Two of 105 (2%) [95% CI: .2, 7] patients clinically benefitted from a 24-hour observation period. Conclusions. We found an overall incidence of biphasic reactions of 6%, and an incidence of significant biphasic reactions of 3%, among pediatric patients admitted with anaphylaxis. Delayed administration of subcutaneous epinephrine was associated with an increased incidence of biphasic reactions. Approximately 2% of patients with anaphylaxis potentially benefitted from a 24-hour period of observation after symptoms had resolved.

Enhancer of zeste homolog 2 epigenetically silences multiple tumor suppressor microRNAs to promote liver cancer metastasis

Epigenetic alterations and microRNA (miRNA) deregulation are common in hepatocellular carcinoma (HCC). The histone H3 lysine 27 (H3K27) tri‐methylating enzyme, enhancer of zeste homolog 2 (EZH2) mediates epigenetic silencing of gene expression and is frequently up‐regulated in human cancers. In this study we aimed to delineate the implications of EZH2 up‐regulation in miRNA deregulation and HCC metastasis. Expressions of a total of 90 epigenetic regulators were first determined in 38 pairs of primary HCCs and their corresponding nontumorous livers. We identified EZH2 and its associated polycomb repressive complex 2 (PRC2) as one of the most significantly deregulated epigenetic regulators in primary HCC samples. Up‐regulation of EZH2 was next confirmed in 69.5% (41/59) of primary HCCs. Clinicopathologically, EZH2 up‐regulation was associated with HCC progression and multiple HCC metastatic features, including venous invasion (P = 0.043), direct liver invasion (P = 0.014), and absence of tumor encapsulation (P = 0.043). We further demonstrated that knockdown of EZH2 in HCC cell lines reduced the global levels of tri‐methylated H3K27, and suppressed HCC motility in vitro and pulmonary metastasis in a nude mouse model. By interrogating the miRNA expression profile in EZH2‐knockdown cell lines and primary HCC samples, we identified a subset of miRNA that was epigenetically suppressed by EZH2 in human HCC. These included well‐characterized tumor‐suppressor miRNAs, such as miR‐139‐5p, miR‐125b, miR‐101, let‐7c, and miR‐200b. Pathway enrichment analysis revealed a common regulatory role of these EZH2‐silenced miRNAs in modulating cell motility and metastasis‐related pathways. Our findings suggest that EZH2 exerts its prometastatic function by way of epigenetic silencing of multiple tumor suppressor miRNAs. Conclusion: Our study demonstrated that EZH2 epigenetically silenced multiple miRNAs that negatively regulate HCC metastasis. (HEPATOLOGY 2012)

Microvessel Density, Vascular Endothelial Growth Factor and Its Receptors Flt-1 and Flk-1/KDR in Hepatocellular Carcinoma

Assessment of angiogenesis may yield important information for an effective antiangiogenic treatment for hepatocellular carcinoma (HCC) because HCC is characteristically hypervascular We examined the relationship of microvessel density (MVD), vascular endothelial growth factor (VEGF), and VEGF receptors Flt-1 and Flk-1/KDR in 50 patients with HCC and in 3 hepatoma cell lines. VEGF messenger RNA (mRNA) was overexpressed in 26 tumors (52%), and the 3 VEGF isoforms (121, 165, and 189) were present in high frequencies. Flt-1 mRNA was overexpressed in 34 tumors (68%), with levels significantly increased in HCCs compared with the nontumorous livers. Tumor Flt-1 mRNA significantly correlated with tumor VEGF mRNA levels. Within the group of tumors 8.5 cm or less in diameter, tumors with intrahepatic metastasis in the form of tumor microsatellite formation had significantly higher VEGF mRNA levels. MVD assessed by immunohistochemical analysis with CD34 antibody was inversely related to tumor size. Angiogenesis as assessed by MVD and tumor VEGF expression seems to have a more important role in tumor growth and intrahepatic metastasis in smaller HCCs. The differential up-regulation of Flt-1 suggests that it may have an important role in angiogenesis in HCC.