Multifaceted Functions of Rab23 on Primary Cilium-Mediated and Hedgehog Signaling-Mediated Cerebellar Granule Cell Proliferation.

Sonic hedgehog (Shh) signaling from the primary cilium drives cerebellar granule cell precursor (GCP) proliferation. Mutations of hedgehog (Hh) pathway repressors commonly cause medulloblastoma, the most prevalent and malignant childhood brain tumor that arises from aberrant GCP proliferation. We demonstrate that Nestin Cre-driven conditional knock-out (CKO) of a Shh pathway repressor-Rab23 in the mouse brain of both genders caused mis-patterning of cerebellar folia and elevated GCP proliferation during early development, but with no prevalent occurrence of medulloblastoma at adult stage. Strikingly, Rab23-depleted GCPs exhibited upregulated basal level of Shh pathway activities despite showing an abnormal ciliogenesis of primary cilia. In line with the compromised ciliation, Rab23-depleted GCPs were desensitized against Hh pathway activity stimulations by Shh ligand and Smoothened (Smo) agonist-SAG, and exhibited attenuated stimulation of Smo-localization on the primary cilium in response to SAG. These results implicate multidimensional actions of Rab23 on Hh signaling cascade. Rab23 represses the basal level of Shh signaling, while facilitating primary cilium-dependent extrinsic Shh signaling activation. Collectively, our findings unravel instrumental roles of Rab23 in GCP proliferation and ciliogenesis. Furthermore, Rab23's potentiation of Shh signaling pathway through the primary cilium and Smo suggests a potential new therapeutic strategy for Smo/primary cilium-driven medulloblastoma.SIGNIFICANCE STATEMENT Primary cilium and Sonic hedgehog (Shh) signaling are known to regulate granule cell precursor (GCP) proliferation. Aberrant overactivation of Shh signaling pathway ectopically increases GCP proliferation and causes malignant childhood tumor called medulloblastoma. However, the genetic and molecular regulatory cascade of GCP tumorigenesis remains incompletely understood. Our finding uncovers Rab23 as a novel regulator of hedgehog (Hh) signaling pathway activity and cell proliferation in GCP. Intriguingly, we demonstrated that Rab23 confers dual functions in regulating Shh signaling; it potentiates primary cilium and Shh/Smoothened (Smo)-dependent signaling activation, while antagonizes basal level Hh activity. Our data present a previously underappreciated aspect of Rab23 in mediating extrinsic Shh signaling upstream of Smo. This study sheds new light on the mechanistic insights underpinning Shh signaling-mediated GCP proliferation and tumorigenesis.

Progression of atypical femur stress fracture after discontinuation of bisphosphonate therapy.

Atypical femur fracture (AFF) is an uncommon complication of long-term bisphosphonate use, but the risk declines substantially after treatment cessation. We report a case of a 70-year-old woman with osteopenia treated with alendronate for 9 years who presented with right mid-thigh pain and radiographic findings of focal lateral cortical thickening in the right mid-femur and lateral cortex irregularity in the proximal-mid left femur. Alendronate was discontinued, but she remained on estrogen for menopausal symptoms. Four years later, a horizontal linear translucent defect was seen in the right mid-femur area of cortical hypertrophy, consistent with an incomplete AFF. The patient underwent prophylactic intramedullary rodding of the right femur and estrogen was discontinued. Three years later (7 years after initial presentation), the cortical irregularities in the left femur were more prominent and three small horizontal linear translucent defects were now evident, consistent with early incomplete atypical fracture development. The patient also suffered a wrist fracture. She was treated with teriparatide for 1.5 years with resolution of the translucent defects in the left but not the right femur, although abnormal thickening of the lateral cortex persisted in both femurs. Our case demonstrates incomplete atypical femur fracture progression in a patient with long-term bisphosphonate exposure, even after treatment cessation. These findings highlight the importance of follow-up for patients who develop diaphyseal femur stress fractures and the potential for early healing with anabolic therapy. This case also demonstrates the challenge in managing older patients with incomplete AFF at risk for progression to complete AFF and osteoporotic fracture.

Atypical femur fracture incidence in women increases with duration of bisphosphonate exposure.

In a northern California population of older women who were treated with oral bisphosphonate drugs, the incidence of atypical femur fracture, a rare complication of treatment, increased with longer duration of bisphosphonate exposure. These findings align with those previously reported in an independent southern California population. INTRODUCTION: The age-adjusted incidence of atypical femur fracture (AFF) reported in southern California increased with bisphosphonate (BP) exposure, ranging up to 113 per 100,000 person-years for 8-10-year exposure. This study examines the incidence of AFF in a northern California population. METHODS: Women age 45-89 years who initiated oral BP during 2002-2014 in Kaiser Permanente Northern California were followed for AFF outcome, defined by a primarily transverse diaphyseal femur fracture through both cortices, with focal periosteal/endosteal hypertrophy, minimal trauma, and minimal/no comminution. Total BP exposure was determined from dispensed prescriptions. The incidence of AFF, calculated for 2-year BP categories ranging from < 2 to > 10 years, was age-adjusted using the 2000 US Census. RESULTS: Among 94,542 women, 107 experienced an AFF during or < 1 year after BP cessation (mean exposure 6.6 ± 3.0 years and total days' supply 5.7 ± 2.8 years at AFF). A strong relationship between AFF incidence and increasing BP exposure was seen, more than doubling for each 2-year category until 8-10 years. Among women with 2- to < 4-year BP, the crude and age-adjusted incidence was 18 and 9 per 100,000 person-years but increased over 2- and 5-fold for women with 4- to < 6- and 6- to < 8-year BP, respectively. For those receiving ≥ 8-year BP, the crude and age-adjusted incidence peaked at 196 and 112 per 100,000 person-years exposure. CONCLUSION: Incidence of AFF increases markedly after 4-6 years of BP. These trends align with southern California and confirm a strong BP duration-related risk of this rare but serious event.

Recurrence after hospitalization for acute coronary syndrome among HIV-infected and HIV-uninfected individuals.

OBJECTIVES: We evaluated the association of HIV infection and immunodeficiency with acute coronary syndrome (ACS) recurrence, and with all-cause mortality as a secondary outcome, after hospitalization for ACS among HIV-infected and HIV-uninfected individuals. METHODS: We conducted a retrospective cohort study within Kaiser Permanente Northern California of HIV-infected and HIV-uninfected adults discharged after ACS hospitalization [types: ST-elevation myocardial infarction (STEMI), non-STEMI, or unstable angina] during 1996-2010. We compared the outcomes of ACS recurrence and all-cause mortality within 3 years, both overall by HIV status and stratified by recent CD4 count, with HIV-uninfected individuals as the reference group. Hazard ratios (HRs) were obtained from Cox regression models with adjustment for age, sex, race/ethnicity, year, ACS type, smoking, and cardiovascular risk factors. RESULTS: Among 226 HIV-infected and 86 321 HIV-uninfected individuals with ACS, HIV-infected individuals had a similar risk of ACS recurrence compared with HIV-uninfected individuals [HR 1.08; 95% confidence interval (CI) 0.76-1.54]. HIV infection was independently associated with all-cause mortality after ACS hospitalization overall (HR 2.52; 95% CI 1.81-3.52). In CD4-stratified models, post-ACS mortality was higher for HIV-infected individuals with CD4 counts of 201-499 cells/µL (HR 2.64; 95% CI 1.66-4.20) and < 200 cells/µL (HR 5.41; 95% CI 3.14-9.34), but not those with CD4 counts ≥ 500 cells/µL (HR 0.67; 95% CI 0.22-2.08), compared with HIV-uninfected individuals (P trend < 0.001). CONCLUSIONS: HIV infection and immunodeficiency were not associated with recurrence of ACS after hospitalization. All-cause mortality was higher among HIV-infected compared with HIV-uninfected individuals, but there was no excess mortality risk among HIV-infected individuals with high CD4 counts.

Applying ethnic-specific bone mineral density T-scores to Chinese women in the USA.

Caucasian reference data are used to classify bone mineral density in US women of all races. However, use of Chinese American reference data yields lower osteoporosis prevalence in Chinese women. The reduction in osteoporosis labeling may be relevant for younger Chinese women at low fracture risk. INTRODUCTION: Caucasian reference data are used for osteoporosis classification in US postmenopausal women regardless of race, including Asians who tend to have lower bone mineral density (BMD) than women of white race. This study examines BMD classification by ethnic T-scores for Chinese women. METHODS: Using BMD data in a Northern California healthcare population, Chinese women aged 50-79 years were compared to age-matched white women (1:5 ratio), with femoral neck (FN), total hip (TH), and lumbar spine (LS) T-scores calculated using Caucasian versus Chinese American reference data. RESULTS: Comparing 4039 Chinese and 20,195 white women (44.8 % age 50-59 years, 37.5 % age 60-69 years, 17.7 % age 70-79 years), Chinese women had lower BMD T-scores at the FN, TH, and LS (median T-score 0.29-0.72 units lower across age groups, p < 0.001) using Caucasian reference data. Using Chinese American BMD reference data resulted in an average +0.47, +0.36, and +0.48 units higher FN, TH, and LS T-scores, respectively, reducing the prevalence of osteoporosis (T-score ≤ -2.5) in Chinese women at the FN (16.7 to 6.6 %), TH (9.8 to 3.2 %), and LS (23.2 to 8.9 %); osteoporosis prevalence at any one of three sites fell from 29.6 to 12.6 % (22.4 to 8.1 % for age 50-64 years and 43.2 to 21.0 % for age 65-79 years). CONCLUSION: Use of Chinese American BMD reference data yields higher (ethnic) T-scores by 0.4-0.5 units, with a large proportion of Chinese women reclassified from osteoporosis to osteopenia. The reduction in osteoporosis labeling with ethnic T-scores may be relevant for younger Chinese women at low fracture risk.

Comparing US paediatric and adult weight classification at the transition from late teenage to young adulthood.

BACKGROUND: Although paediatric growth charts are recommended for weight assessment prior to age 20, many teenagers transition earlier to adult care where absolute body mass index (BMI) is used. This study examines concordance of weight classification in older teenagers using paediatric percentiles and adult thresholds. METHODS: BMI from 23 640 US teens ages 18-19 years were classified using paediatric BMI percentile criteria for underweight (< 5th), normal (5th to < 85th), overweight (85th to < 95th), obesity (≥ 95th) and severe obesity (≥ 120% × 95th percentile) and adult BMI (kg m(-2) ) criteria for underweight (< 18.5), normal (18.5-24.9), overweight (25-29.9) and obesity: class I (30-34.9), class II (35-39.9) and class III (≥ 40). Concordance was examined using the kappa (κ) statistic. Blood pressure (BP) from the same visit was classified hypertensive for BP ≥ 140/90. RESULTS: The majority of visits (72.8%) occurred in adult primary care. Using paediatric/adult criteria, 3.4%/5.2% were underweight, 66.6%/58.8% normal weight, 15.7%/21.7% overweight, 14.3%/14.3% obese and 4.9%/6.0% severely/class II-III obese, respectively. Paediatric and adult classification for underweight, normal, overweight and obesity were concordant for 90.3% (weighted κ 0.87 [95% confidence interval, 0.87-0.88]). For severe obesity, BMI ≥ 120% × 95th percentile showed high agreement with BMI ≥ 35 kg m(-2) (κ 0.89 [0.88-0.91]). Normal-weight males and moderately obese females by paediatric BMI percentile criteria who were discordantly classified into higher adult weight strata had a greater proportion with hypertensive BP compared with concordantly classified counterparts. CONCLUSIONS: Strong agreement exists between US paediatric BMI percentile and adult BMI classification for older teenagers. Adult BMI classification may optimize BMI tracking and risk stratification during transition from paediatric to adult care.

Racial/ethnic differences in hip and diaphyseal femur fractures.

UNLABELLED: Contemporary femur fracture rates were examined in northern California women and compared by race/ethnicity. During 2006-2012, hip fracture rates declined, but diaphyseal fracture rates increased, especially in Asians. Women with diaphyseal fracture were younger and more likely to be bisphosphonate-treated. These disparities in femur fracture should be further examined. INTRODUCTION: The epidemiology of diaphyseal femur fracture differs from proximal femur (hip) fracture, although few studies have examined demographic variations in the current era. This study examines contemporary differences in low-energy femur fracture by race/ethnicity in a large, diverse integrated health-care delivery system. METHODS: The incidence of hip and diaphyseal fracture in northern California women aged ≥50 years old during 2006-2012 was examined. Hip (femoral neck and pertrochanteric) fractures were classified by hospital diagnosis codes, while diaphyseal (subtrochanteric and femoral shaft) fractures were further adjudicated based on radiologic findings. Demographic and clinical data were obtained from health plan databases. Fracture incidence was examined over time and by race/ethnicity. RESULTS: There were 10,648 (97.3 %) hip and 300 (2.7 %) diaphyseal fractures among 10,493 women. The age-adjusted incidence of hip fracture fell from 281 to 240 per 100,000 women and was highest for white women. However, diaphyseal fracture rates increased over time, with a significant upward trend in Asians (9 to 27 per 100,000) who also had the highest rate of diaphyseal fracture. Women with diaphyseal fracture were younger than women with hip fracture, more likely to be of Asian race and to have received bisphosphonate drugs. Women with longer bisphosphonate treatment duration were also more likely to have a diaphyseal fracture, especially younger Asian women. CONCLUSION: During 2006 to 2012, hip fracture rates declined, but diaphyseal fracture rates increased, particularly among Asian women. The association of diaphyseal fracture and bisphosphonate therapy should be further investigated with examination of fracture pattern.

Prevalence of obesity and extreme obesity in children aged 3-5 years.

BACKGROUND: Early childhood adiposity may have significant later health effects. This study examines the prevalence and recognition of obesity and severe obesity among preschool-aged children. METHODS: The electronic medical record was used to examine body mass index (BMI), height, sex and race/ethnicity in 42,559 children aged 3-5 years between 2007 and 2010. Normal or underweight (BMI < 85th percentile); overweight (BMI 85th-94th percentile); obesity (BMI ≥ 95th percentile); and severe obesity (BMI ≥ 1.2 × 95th percentile) were classified using the 2000 Centers for Disease Control and Prevention growth charts. Provider recognition of elevated BMI was examined for obese children aged 5 years. RESULTS: Among 42,559 children, 12.4% of boys and 10.0% of girls had BMI ≥ 95th percentile. The prevalence was highest among Hispanics (18.2% boys, 15.2% girls), followed by blacks (12.4% boys, 12.7% girls). A positive trend existed between increasing BMI category and median height percentile, with obesity rates highest in the highest height quintile. The prevalence of severe obesity was 1.6% overall and somewhat higher for boys compared with girls (1.9 vs. 1.4%, P < 0.01). By race/ethnicity, the highest prevalence of severe obesity was seen in Hispanic boys (3.3%). Among those aged 5 years, 77.9% of obese children had provider diagnosis of obesity or elevated BMI, increasing to 89.0% for the subset with severe obesity. CONCLUSIONS: Obesity and severe obesity are evident as early as age 3-5 years, with race/ethnic trends similar to older children. This study underscores the need for continued recognition and contextualization of early childhood obesity in order to develop effective strategies for early weight management.

Risk of preterm delivery in non-diabetic women with polycystic ovarian syndrome.

OBJECTIVE: To examine the risk and etiology of preterm delivery in women with polycystic ovary syndrome (PCOS). STUDY DESIGN: Retrospective cohort study comparing preterm delivery rate among non-diabetic PCOS and non-PCOS women with singleton pregnancy. Multivariable logistic regression was used to identify predictors of preterm delivery among PCOS women. RESULT: Among 908 PCOS women with singleton pregnancy, 12.9% delivered preterm compared with 7.4% among non-PCOS women (P<0.01). Causes of preterm delivery among PCOS women included preterm labor (41%), cervical insufficiency (11%), hypertensive complications (20%), preterm premature rupture of membranes (15%), fetal-placental concerns (9%) and intrauterine fetal demise (5%). Maternal age, race/ethnicity and nulliparity were significant predictors of preterm delivery in PCOS, whereas body mass index and fertility medications were not. CONCLUSION: A higher proportion of PCOS women delivered preterm (12.9%) compared with non-PCOS women, with the majority of cases due to spontaneous preterm birth. Future studies should explore etiologies and strategies to improve pregnancy outcomes in PCOS.

The impact of subtrochanteric fracture criteria on hip fracture classification.

SUMMARY: Hospital diagnosis codes are useful for assessing hip fracture rates in large populations. However, these codes do not reliably differentiate hip fractures that occur in the subtrochanteric region. Identification of subtrochanteric fractures requires review of radiographic images to distinguish these fractures from the more commonly occurring trochanteric fractures. PURPOSE: This study examines the accuracy of coded hospital diagnoses for hip fracture compared to fracture site verification based on operative and radiologic data. The variability in subtrochanteric fracture assignment was also examined using different anatomic criteria. METHODS: This retrospective study includes female members of Kaiser Permanente Northern California age 60 years and older with nontraumatic hip fracture during 2007-2008. Anatomic site was verified by operative and radiologic records, including radiographic image review for fractures occurring in the subtrochanteric region. Two different criteria were compared for subtrochanteric fracture. RESULTS: We identified 2,824 women with incident hip fracture during the 2-year period. The average age was 82.9 ± 8.2 years and 15% were non-White. International Classification of Diseases, Ninth Revision (ICD-9) coding was accurate for femoral neck and trochanteric fractures (>90% confirmed by operative/radiologic reports), compared to only 26% for subtrochanteric fractures using the Orthopedic Trauma Association (OTA) criteria for subtrochanteric fracture. Using OTA classification, 1.3% of hip fractures were assigned as subtrochanteric compared to 4.2% when the criteria were broadened to include the lesser trochanter. Both femoral neck and pertrochanteric fracture rates increased exponentially with age, while age-related rates in subtrochanteric fracture differed by diagnostic classification method; the broader criteria including the lesser trochanter produced age-related trends that mirrored femoral neck and pertrochanteric fractures. CONCLUSION: Unlike femoral neck and pertrochanteric fractures, epidemiologic studies of subtrochanteric fractures cannot rely on ICD-9 codes alone. Review of radiologic images using OTA criteria is required for identification of subtrochanteric fractures occurring below the lesser trochanter.

Cesarean births in Taiwan.

OBJECTIVE: To evaluate the use of cesarean delivery in Taiwan by comparing local clinical indications with those in international cohorts. METHODS: In-patient claims from the National Health Insurance (NHI) in Taiwan were analyzed. Indications for cesarean delivery were evaluated with primary diagnosis codes and procedure codes from the NHI dataset. To produce a stable numerator for cesarean section, 3 years (1998-2000) of claims for cesarean delivery were abstracted and annualized. RESULTS: Rates ranged between 27.3% and 28.7% for primary cesarean delivery and were below 5% for vaginal birth after a cesarean section (VBAC). Compared with rates in other countries, rates for overall and primary cesarean section as well as for VBAC were significantly higher in medical centers in Taiwan (P<0.001). However, the clinics contributed the most to the difference in both overall and primary cesarean rates. The most common indication for cesarean section was prior cesarean section (43.3%-45.5%), followed by malpresentation (19.6%-23.4%). The proportion of fetuses with malpresentation delivered by cesarean section in Taiwan was 7.9%, almost twice the upper limit expected for all pregnancies as indicated in international studies. CONCLUSION: It is important to use appropriately documented data and to compare them with international data when monitoring local obstetric practices. The disproportionately high cesarean delivery rates in Taiwan may hold major lessons for the many countries contemplating or having universal health insurance coverage with a similar mix of providers.

Persistence with weekly alendronate therapy among postmenopausal women.

INTRODUCTION: Although clinical trials indicate that oral bisphosphonates reduce osteoporotic fracture risk, compliance with bisphosphonate therapy in practice is suboptimal, with 1-year discontinuation rates exceeding 50%. METHODS: We conducted a retrospective cohort study among female members of a large integrated health care delivery system (Kaiser Permanente of Northern California), age 45 years and older, to determine their persistence with weekly alendronate (defined as continuous use, allowing for a refill gap of 60 days), predictors of discontinuation, and subsequent osteoporosis therapy. We also examined the effect of varying the refill gap from 30 to 120 days on the discontinuation rate. From 2002 through 2003, we identified 13,455 women (age 68.8+/-10.4 years) who initiated weekly oral alendronate therapy. RESULTS: Using a 60-day refill gap, the 1-year discontinuation rate was 49.6% [95% confidence interval (CI) 48.8-50.4%]; this increased to 58.0% (CI 57.2-58.8%) with a 30-day gap and decreased to 42.2% (CI 41.1-43.0%) with a 120-day gap. Among those who discontinued therapy, about one-third restarted alendronate or another osteoporosis drug within 6 months. Baseline factors associated with alendronate discontinuation included prior bone mineral density testing [adjusted odds ratio (OR) 0.64, CI 0.60-0.69], prior postmenopausal hormone therapy (OR 0.78, CI 0.73-0.84), prior high-dose oral glucocorticoid therapy (OR 1.26, CI 1.05-1.51), prior gastrointestinal diagnoses (OR 1.21, CI 1.09-1.36), and high number of therapeutic classes of prescriptions filled in the prior year (OR 1.21, CI 1.10-1.32), although the final model had limited explanatory power. CONCLUSIONS: We conclude that apparent discontinuation rates are high within 1 year after treatment initiation, although a subset of women appears to restart bisphosphonate or other osteoporosis therapy. Because intermittent use and/or poor adherence is common, discontinuation rates based on data from administrative databases are sensitive to the refill gap length. In addition, we identified no clinical factors highly predictive of discontinuation.

The regulation of T cell homeostasis and autoimmunity by T cell-derived LIGHT.

Costimulatory molecules on antigen-presenting cells (APCs) play an important role in T cell activation and expansion. However, little is known about the surface molecules involved in direct T-T cell interaction required for their activation and expansion. LIGHT, a newly discovered TNF superfamily member (TNFSF14), is expressed on activated T cells and immature dendritic cells. Here we demonstrate that blockade of LIGHT activity can reduce anti-CD3-mediated proliferation of purified T cells, suggesting that T cell-T cell interaction is essential for this proliferation. To test the in vivo activity of T cell-derived LIGHT in immune homeostasis and function, transgenic (Tg) mice expressing LIGHT in the T cell lineage were generated. LIGHT Tg mice have a significantly enlarged T cell compartment and a hyperactivated peripheral T cell population. LIGHT Tg mice spontaneously develop severe autoimmune disease manifested by splenomegaly, lymphadenopathy, glomerulonephritis, elevated autoantibodies, and severe infiltration of various peripheral tissues. Furthermore, the blockade of LIGHT activity ameliorates the severity of T cell-mediated diseases. Collectively, these findings establish a crucial role for this T cell-derived costimulatory ligand in T cell activation and expansion; moreover, the dysregulation of T cell-derived LIGHT leads to altered T cell homeostasis and autoimmune disease.

The critical role of LIGHT, a TNF family member, in T cell development.

Negative selection refers to the selective deletion of autoreactive thymocytes but its molecular events have not been well defined. In this study, we demonstrate that a cellular ligand for herpes virus entry mediator and lymphotoxin receptor (LIGHT), a newly identified member of the TNF superfamily, may play a critical role in negative selection. Using TCR transgenic mice, we find that the blockade of LIGHT signaling in vitro and in vivo prevents negative selection induced by peptide and intrathymically expressed Ags, resulting in the rescue of thymocytes from apoptosis. Furthermore, the thymi of LIGHT transgenic mice show severe atrophy with remarkably reduced CD4(+)CD8(+) double-positive cells caused by increased apoptosis, suggesting that LIGHT can delete immature T cells in vivo. Taken together, these results demonstrate a critical role of LIGHT in thymic negative selection of the T cell repertoire.

The effects of recombinant human growth hormone on body composition and glucose metabolism in HIV-infected patients with fat accumulation.

GH has been proposed as a therapy for patients with HIV-associated fat accumulation, but the pharmacological doses (6 mg/d) used have been associated with impaired fasting glucose and hyperglycemia. In contrast, physiologic doses of GH ( approximately 1 mg/d) in HIV-negative men reduced visceral adiposity and eventually improved insulin sensitivity, despite initially causing insulin resistance. We conducted an open-label study to evaluate the effects of a lower pharmacologic dose of GH (3 mg/d) in eight men with HIV-associated fat accumulation. Oral glucose tolerance, insulin sensitivity, and body composition were measured at baseline, and 1 and 6 months. Six patients completed 1 month and 5, 6 months of GH therapy. IGF-I levels increased 4-fold within 1 month of GH treatment. Over 6 months, GH reduced buffalo hump size and excess visceral adipose tissue. Total body fat decreased (17.9 +/- 10.9 to 13.5 +/- 8.4 kg, P = 0.05), primarily in the trunk region. Lean body mass increased (62.9 +/- 6.4 to 68.3 +/- 9.1 kg, P = 0.03). Insulin-mediated glucose disposal, measured by a euglycemic hyperinsulinemic clamp, declined at month 1 (49.7 +/- 27.5 to 25.6 +/- 6.6 nmol/kg(LBM).min/pmol(INSULIN)/liter, P = 0.04); values improved at month 6 (49.2 +/- 22.6, P = 0.03, compared with month 1) and did not differ significantly from baseline. Similarly, the integrated response to an oral glucose load worsened at month 1 (glucose area under the curve 20.1 +/- 2.3 to 24.6 +/- 3.7 mmol.h/liter, P < 0.01), whereas values improved at month 6 (22.1 +/- 1.5, P = 0.02, compared with month 1) and did not differ significantly from baseline. One patient developed symptomatic hyperglycemia within 2 wk of GH initiation; baseline oral glucose tolerance testing revealed preexisting diabetes despite normal fasting glucose. In conclusion, GH at 3 mg/d resulted in a decrease in total body fat and an increase in lean body mass in this open-label trial. While insulin sensitivity and glucose tolerance initially worsened, they subsequently improved toward baseline. However, the dose of GH used in this trial was supraphysiologic and led to an increase in IGF-I levels up to three times the upper normal range. Because there are known adverse effects of long-term GH excess, the effectiveness of lower doses of GH should be studied. We also recommend a screening oral glucose tolerance test be performed to exclude subjects at risk for GH-induced hyperglycemia.

Metabolic effects of indinavir in healthy HIV-seronegative men.

BACKGROUND: Therapy with HIV protease inhibitors (PI) has been associated with hyperglycemia, hyperlipidemia and changes in body composition. It is unclear whether these adverse effects are drug related, involve an interaction with the host response to HIV or reflect changes in body composition. METHODS: Indinavir 800 mg twice daily was given to 10 HIV-seronegative healthy men to distinguish direct metabolic effects of a PI from those related to HIV infection. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance (OGTT), insulin sensitivity by hyperinsulinemic euglycemic clamp, and body composition were measured prior to and after 4 weeks of indinavir therapy. RESULTS: Fasting glucose (4.9 +/- 0.1 versus 5.2 +/- 0.2 mmol/l; P = 0.05) insulin concentrations (61.7 +/- 12.2 versus 83.9 +/- 12.2 pmol/l; P < 0.05), insulin : glucose ratio (12.6 +/- 1.7 versus 15.9 +/- 1.9 pmol/mmol; P < 0.05) and insulin resistance index by homeostasis model assessment (1.9 +/- 0.3 versus 2.8 +/- 0.5;P < 0.05) all increased significantly. During OGTT, 2 h glucose (5.1 +/- 0.4 versus 6.5 +/- 0.6 mmol/l; P < 0.05) and insulin levels (223.1 +/- 48.8 versus 390.3 +/- 108.8 pmol/l;P =0.05) also increased significantly. Insulin-mediated glucose disposal decreased significantly (10.4 +/- 1.4 versus 8.6 +/- 1.2 mg/kg x min per microU/ml insulin; 95% confidence interval 0.6--.0;P < 0.01). There was no significant change in lipoprotein, triglycerides or free fatty acid levels. There was a small loss of total body fat (15.8 +/- 1.4 versus 15.2 +/- 1.4 kg;P = 0.01) by X-ray absorptiometry without significant changes in weight, waist : hip ratio, and visceral or subcutaneous adipose tissue by computed tomography. CONCLUSIONS: In the absence of HIV infection, treatment with indinavir for 4 weeks causes insulin resistance independent of increases in visceral adipose tissue or lipid and lipoprotein levels.

Altered fat distribution in HIV-positive men on nucleoside analog reverse transcriptase inhibitor therapy.

To determine whether HIV infection, the wasting syndrome, or nucleoside analog reverse transcriptase inhibitor (NRTI) or protease inhibitor (PI) therapy uniquely affect fat distribution in men, we performed manual regional analysis of total, appendicular, trunk, and central abdominal fat measured by dual-energy X-ray absorptiometry (DEXA). Five groups of study subjects were identified for this cross-sectional analysis: HIV-negative controls (HIV-; N = 44) and four groups of HIV-positive subjects: antiretroviral (ARV)-naive or with limited prior use of NRTIs (ARV-; N = 23); on NRTIs for > or =6 months but PI-naive (NRTI; N = 30); on an NRTI/PI regimen for > or =6 months but with no complaints of abnormal fat distribution (NRTI/PI; N = 26); and those on NRTIs but PI-naive with the wasting syndrome (NRTI/WS; N = 40). Total, appendicular, trunk, and central abdominal fat was significantly lower in NRTI/WS. The ratio of trunk fat to appendicular fat was virtually identical in HIV- and ARV-. This ratio was significantly higher in the NRTI, NRTI/PI, and NRTI/WS groups, and values in these three groups were similar. These cross-sectional data suggest that HIV-infected men receiving NRTIs have an altered pattern of fat distribution, compared with HIV-negative men and HIV-positive men who are not receiving antiretroviral therapy. This effect was independent of the concomitant use of a PI or a diagnosis of the wasting syndrome. We saw no evidence of a unique effect of HIV infection per se on regional fat distribution. Although the fat ratio is increasingly employed, its physiologic significance is unclear. Our results, which have been obtained retrospectively, are intended to provide the impetus for prospective, controlled studies of the interactions among drug and host factors in the development of fat distribution abnormalities.

Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia.

Although low fertility rates have traditionally been reported among women with classic CAH and especially among women with the salt-wasting variant, more recent data suggest that fertility rates are significantly improved, largely owing to earlier treatment of CAH, improved compliance with therapy, and surgical advances in genital reconstruction. Furthermore, ovulation induction and assisted reproductive techniques are now available to women who remain infertile despite effective adrenal androgen suppression. Although the pregnancy experience in women with classic CAH remains limited, it is apparent that, once pregnant, these women have a high probability of successful outcome. Key issues should be emphasized in the management of CAH during gestation, including the need for assessing adrenal steroid replacement and adrenal androgen suppression, particularly in light of the interplay between maternal hyperandrogenism and the protective effect of placental aromatase activity, which provides a relatively large margin of safety for the female fetus. Maternal hormone levels should be evaluated in the context of laboratory-specific reference ranges for pregnancy. The infant should be examined for ambiguous genitalia and monitored for evidence of adrenal insufficiency. Although an affected female infant with classic CAH has not been reported as a pregnancy outcome of a mother with classic virilizing CAH, these concerns should be discussed during preconception counseling. Patients should also be aware of the importance of medication compliance and careful hormonal monitoring during the entire pregnancy. In most cases, successful gestational management requires the close coordination of care between the obstetrician and endocrinologist.