Increasing obesity rates in school children in United Arab Emirates.

BACKGROUND: The remarkable socioeconomic changes in United Arab Emirates (UAE) necessitate regular monitoring of obesity in our population. This study explored the epidemiology of obesity in a large cohort of UAE students. METHODS: This population-based study investigated the prevalence of obesity in 44,942 students attending governmental schools in Ras Al-Khaimah. Body-mass-index (BMI) was calculated in 15,532 children (4-12 y) in 2013-2014, and in 29,410 children (3-18 y) in 2014-2015. The International Obesity Task Force, World Health Organization, and Centers for Disease Control (CDC) reference methods were used to identify overweight, obesity, and extremely-obesity. RESULTS: Using CDC interpretation of BMI, from 11 to 14 y, the prevalence of BMI ≥85th percentile was 41.2%, BMI ≥95th percentile 24.3% and BMI ≥99th percentile 5.7%. Obesity increased linearly from 3 to 12 y (R2 ≥ 0.979); each year an additional 2.36% of the students became obese and 0.28% became extremely obese. The rate of extreme-obesity was 9.6-fold higher in boys than girls (0.58% vs. 0.06%). From 15 to 18 y, 10.3% of boys were extremely obese and 3.0% of girls were extremely obese. CONCLUSIONS: These results confirm a steady rise in obesity in children 3-18 y. The rising rate of extreme obesity is also alarming, especially among boys.

Optimal temperature for whole-body hypothermia in the newborn: an in vitro study using foreskin mitochondrial oxygen consumption.

OBJECTIVES: Whole-body hypothermia (to 33.5 ± 0.5°C) is a therapeutic modality that reduces risks of death and neurodevelopmental disability in neonates subjected to hypoxic-ischemic insults. This in vitro study was designed to determine changes in neonatal cellular metabolism with temperature. Its main aim was to compare the metabolic rate at ≤33°C with that at ≥35°C. STUDY DESIGN: Foreskin specimens were used as a source of neonatal tissue. Cellular respiration (mitochondrial O2 consumption) was used as a surrogate biomarker for the metabolic rate. Foreskin specimens from healthy newborns were collected immediately after circumcision and processed within one hour for measuring the rate of O2 consumption at various temperatures (±0.5°C). O2 consumption was determined as function of time from the phosphorescence decay of Pd (II) meso-tetra-(4-sulfonatophenyl)-tetrabenzoporphyrin. RESULTS: In a vial sealed from air and containing foreskin specimen in phosphate-buffered saline supplemented with 5 mM glucose, [O2] decreased linearly with time, confirming its zero-order kinetics. The rate of O2 consumption (µM O2.min-1), thus, was the negative of the slope of [O2] vs. time. Cyanide inhibited O2 consumption, confirming the oxidation occurred in the respiratory chain. Cellular respiration at ≤33°C (n = 25) significantly differed from that at ≥35°C (n = 24), p < 0.001. The rate (µM O2.min-1.mg-1) at 25°C was 0.034 ± 0.006 (n = 11, p = 0.044), at 33°C was 0.029 ± 0.008 (n = 14, reference temperature), at 35°C was 0.062 ± 0.020 (2-fold higher, n = 18, p < 0.001), and at 37°C was 0.061 ± 0.009 (2-fold higher, n = 6, p < 0.001). CONCLUSIONS: Neonatal foreskin cellular respiration is highly sensitive to critical temperatures (33°C vs. 35°C).

Caspase activation by anticancer drugs: the caspase storm.

This study measures the time-dependence of cellular caspase activation by anticancer drugs and compares it with that of cellular respiration. Intracellular caspase activation and cellular respiration were measured during continuous exposure of Jurkat, HL-60, and HL-60/MX2 (deficient in topoisomerase-II) cells to dactinomycin, doxorubicin, and the platinum (Pt) compounds cisplatin, carboplatin, and oxaliplatin. Caspase activation was measured using the fluorogenic compound N-acetyl-asp-glu-val-asp-7-amino-4-trifluoromethyl coumarin (Ac-DEVD-AFC). We show that this substrate rapidly enters cells where it is efficiently cleaved at the aspartate residue by specific caspases, yielding the fluorescent compound 7-amino-4-trifluoromethyl coumarin (AFC). Following cell disruption, released AFC was separated on HPLC and detected by fluorescence. The appearance of AFC in cells was blocked by the pancaspase inhibitor benzyloxycarbonyl-val-ala-asp-fluoromethylketone, thus establishing that intracellular caspases were responsible for the cleavage. Caspase activity was first noted after about 2 h of incubation with doxorubicin or dactinomycin, the production of AFC being linear with time afterward. Caspase activation by doxorubicin was delayed in HL-60/MX2 cells, reflecting the critical role of topoisomerase-II in doxorubicin cytotoxicity. For both drugs, caspase activity increased rapidly between approximately 2 and approximately 6 h, went through a maximum, and decreased after approximately 8 h ("caspase storm"). Cisplatin treatment induced noticeable caspase activity only after approximately 14 h of incubation, and the fluorescent intensity of AFC became linear with time at approximately 16 h. Exposure of the cells to all of the drugs studied led to impaired cellular respiration and decreased cellular ATP, concomitant with caspase activation. Thus, the mitochondria are rapidly targeted by active caspases.

Blood thiols following amifostine and mesna infusions, a pediatric oncology group study.

The Pediatric Oncology Group study for metastatic Ewing's sarcoma used amifostine and mesna with the alkylating agents. To determine the fate of combined drug thiols, we measured thiol levels in plasma, red blood cells (RBC), and peripheral blood mononuclear cells (PBMC) of four patients. We also conducted analogous measurements on two patients who received mesna alone and a volunteer's blood following in vitro treatment. Thiols were labeled with monobromobimane, separated on high-pressure liquid chromatography, and detected by fluorescence. Incubation of a volunteer's blood with mesna, WR-1065, or both revealed that cellular uptake of total reducible drug was approximately 10% of plasma level for mesna but approximately 60% for WR-1065. Cellular drugs were mainly the thiol form, whereas half of the plasma drugs were disulfides. Combined incubation with both thiols did not change the extent or form of uptake. WR-1065 and mesna prevented glutathione depletion by 4-hydroperoxycyclophosphamide. Results from patients were similar. WR-1065 and mesna appeared in the cells by the end of the drug infusions, although WR-1065 uptake was more efficient than mesna. The concentration-time profiles of mesna in RBC paralleled those in plasma. Amifostine administration during mesna infusion caused transient increase in mesna levels. Both agents increased blood cysteine and decreased total reducible cysteine. Mesna alone and mesna plus amifostine prevented cellular glutathione depletion. In conclusion, mesna is imported by RBC and PBMC, but less efficiently than WR-1065. When present at equal levels, these thiols do not influence each other's uptake. Adequate dosing of either drug is necessary for protecting the cells from toxic effects of alkylating agents.

Classic Kaposi's sarcoma associated with human herpesvirus 8 infection in a 13-year-old male: a case report.

PURPOSE: Classic Kaposi's sarcoma (KS) is rare in children. Although its etiology is not fully understood, human herpesvirus 8 (HHV-8) is present in the angiogenic lesions. We report an HIV-negative, 13-year-old patient of Sicilian descent with HHV-8-associated classic KS to facilitate the diagnosis and treatment of this entity in children. EXPERIMENTAL DESIGN: DNA was extracted from the skin specimen of the patient and analyzed via PCR assay and Southern blot hybridization for HHV-8 DNA. The amplified HHV-8 DNA was cloned, sequenced, and compared with the prototype HHV-8-KS330/BAM. RESULTS: The patient presented with purpuric lesions on the distal lower extremities and the tip of his nose, associated with thrombocytopenia and leukopenia, suggesting an immune-mediated cytopenia. While on prednisone, he developed marked vascular proliferation in the groins. Biopsy of the skin lesions showed KS, and HHV-8 was detected in the tissues by PCR. Sequence analysis of the amplified DNA was homologous to the prototype HHV-8-KS330/BAM. His HHV-8 strain was the A subgroup, the type associated with Mediterranean classic KS. Stopping prednisone and treatment with IFN-alpha and IgG resulted in regression of the groin lesions. CONCLUSIONS: This report emphasizes the importance of recognizing classic KS in children and avoiding immunosuppressive therapies in indolent classic KS. The diagnostic and therapeutic strategies were effective and well tolerated.

Palpable spongy mass over the clavicle, an underutilized sign of clavicular fracture in the newborn.

This prospective study emphasizes the importance of an early physical finding of neonatal clavicular fracture, termed "the palpable spongy mass sign." Of the 1,661 term neonates examined at our tertiary center over a 20-month period, 24 had clinical signs of a clavicular fracture. In 22 of the 24 neonates, the fractures were documented by positive radiographs or callus formation. None of the fractures was recognized because of an asymmetric Moro reflex, visible swelling, or bruising. The palpable spongy mass was present in 18 of the 22 fractures (82%), crepitus in 10 (45%), angulation deformity in two (9%), and localized tenderness in one (5%). Any combination of crepitus, deformity, and localized tenderness was detected in 11 of the 22 (50%) fractures. When the palpable spongy mass sign was added to these three signs, all but one fracture was clinically detected (95%), emphasizing the importance of using all physical findings. We conclude that "the clavicular spongy mass sign" is highly sensitive and predictive of neonatal clavicular fractures.

WR-2721 (amifostine) infusion in patients with Ewing's sarcoma receiving ifosfamide and cyclophosphamide with mesna: drug and thiol levels in plasma and blood cells, a Pediatric Oncology Group study.

PURPOSE: Previous WR-2721 human pharmacokinetic studies were limited to plasma levels in patients receiving platinum-based compounds, and none includes the effects of WR-2721 on endogenous thiols. In the present study (Pediatric Oncology Group study no. 9457), we measured the levels of WR-2721, its active metabolites, as well as cysteine and glutathione in whole blood, plasma, and blood cells in patients receiving high-dose alkylating agents with mesna. METHODS: WR-2721 was administered (15 min intravenous infusion of 825 mg/m(2) per dose x2) to five patients with metastatic Ewing's sarcoma receiving ifosfamide and cyclophosphamide with mesna. Intracellular and extracellular blood thiols were labeled with monobromobimane (mBBr) at the time of collection, and the low molecular weight (LMW) thiols were subsequently separated by HPLC and detected by fluorescence. RESULTS: The active metabolite of the drug, WR-1065, peaked at 100 microM in plasma and blood cells at the end of WR-2721 infusion and decayed with a rapid initial half-life. Detectable levels of WR-1065 and its LMW disulfides were present in plasma and blood cells at approximately 1 h after the WR-2721 infusion. By the end of the first WR-2721 infusion (prior to mesna infusion), the mean cysteine level more than doubled and the mean Cys-SS-LMW (cystine and the mixed LMW disulfides) level decreased by approximately 50% in both plasma and blood cells. In four of five patients, reduced glutathione levels in blood cells increased by the end of the first WR-2721 infusions, the average increment being approximately 36%. CONCLUSIONS: (1) WR-1065 is rapidly formed from WR-2721 and equilibrates between plasma and blood cells; (2) WR-1065 decays in plasma and blood cells with similar rapid initial half-lives of approximately 16 min; (3) WR-2721 treatment increases cysteine in plasma and blood cells, an effect similar to that of mesna; (4) WR-2721 treatment appears to increase glutathione levels in blood cells; (5) Mesna does not have a substantial effect on the fate of WR-2721 in patients.

Determination of the cytoprotective agent WR-2721 (Amifostine, Ethyol) and its metabolites in human blood using monobromobimane fluorescent labeling and high-performance liquid chromatography.

PURPOSE: WR-2721 [S-2-(3-aminopropylamino)ethylphosphorothioic acid] is a chemoprotective agent that is currently in pediatric clinical trials. It is a prodrug that is dephosphorylated by alkaline phosphatase to the active free thiol form, WR-1065 [S-2-(3-aminopropylamino)ethanethiol]. It is likely that adequate and sustained cellular levels of the drug are necessary for optimum cytoprotection. To date, a method to measure both plasma and cellular levels of WR-2721 and its metabolites in clinical samples has not been available. METHODS: In the study reported here the monobromobimane (mBBr) fluorescent labeling method was used to measure these levels when drug was added in vitro to blood samples from normal volunteers. In addition, we present pharmacokinetic data from a pediatric patient receiving WR-2721 (825 mg/m2 x 2). RESULTS: The results can be summarized as follows: (1) WR-2721 was detected in the patient's plasma with a half-life of about 10 min; (2) the WR-1065 concentration in the blood cellular fraction was similar to that of plasma; (3) both WR-1065 and WR-SS-low molecular weight (WR-SS-LMW) metabolites disappeared from plasma and the cellular fraction by 3.6 h after WR-2721 infusion; (4) a large proportion of WR-1065 was oxidized in plasma to WR-SS protein and WR-SS-LMW; (5) a large proportion of WR-1065 in the cellular fraction was oxidized to WR-SS-protein; (6) the WR-SS-LMW concentration in the cellular fraction was low; and (7) saturation of plasma and cellular protein binding sites was possible. CONCLUSIONS: The pharmacokinetic data that were generated with this technique could guide clinical trials using WR-2721.

Munchausen syndrome by proxy.

Munchausen syndrome by proxy is the most difficult form of child abuse. It carries substantial morbidity and mortality. The diagnosis relies on appropriate suspicion and careful investigation. The psychological illness/need of the perpetrator is the main clinical feature. Early recognition and appropriate intervention prevent further abuse and criminal actions.

Interleukin 1beta mediated calciotropic activity in serum of children with juvenile rheumatoid arthritis.

OBJECTIVE: To detect the presence and source of calciotropic activity in the serum of children with juvenile rheumatoid arthritis (JRA). METHODS: Metabolic evaluation of an adolescent with polyarticular JRA and hypercalcemia/hypercalciuria included testing with a bone disc bioassay. The bioassay detects calciotropic activity (increased bone resorption or reduced bone formation) in serum. Interleukin 1 receptor antagonist (IL-1RA) was added to patient sera to test the role of IL-1beta. The results in this index case prompted additional study in 9 children with JRA. Correlation of calciotropic activity with disease activity score, erythrocyte sedimentation rate (ESR), and urinary calcium excretion was by Spearman rank correlation. RESULTS: Calciotropic activity was found in 2 consecutive samples from the index patient. This activity was eliminated by addition of IL-1RA (p < 0.001 compared to serum alone). Testing of the other 9 children showed calciotropic activity at least once in 7/9 and 10/15 samples studied. Addition of IL-1RA completely (6/8) or partially (2/8) neutralized calciotropic activity (p < 0.001 compared to serum alone) in the specimens available for testing. Calciotropic activity did not significantly correlate with disease activity score, ESR, or urine calcium. CONCLUSION: Our data indicate the presence of IL-1beta mediated calciotropic activity in the sera of children with JRA, and suggest a role for IL-1beta in JRA associated osteopenia.

Nontuberculous Mycobacteria subcarinal lymphadenitis and severe airway obstruction.

This report has emphasized the importance of a careful evaluation of the chest roentgenogram for lymphadenopathy in children with wheezing, cough, or other symptoms of lower airway disease. This patient report also illustrates that intrathoracic lymphadenitis caused by nontuberculous mycobacteria should be considered in children with unexplained airway obstruction.

Energetics of ATP dissociation from the mitochondrial ATPase during oxidative phosphorylation.

The dissociation constant (KdATP) for ATP bound in the high affinity catalytic site of membrane-bound beef heart mitochondrial ATPase (F1) was calculated from the ratio of the rate constants for the reverse dissociation step (k-1) and the forward binding step (k+1). k-1 for ATP bound to submitochondrial particles or to submitochondrial particles washed with KCl so as to activate ATPase activity was accelerated by about five orders of magnitude during respiratory chain-linked oxidations of NADH. In the presence of NADH and 0.1 mM ADP, k-1 increased more than six orders of magnitude. These energy-dependent dissociations of ATP were sensitive to the uncoupler carbonyl cyanide p-trifluoromethyloxyphenylhydrazone. Only small changes in k+1 were observed in the presence of NADH or NADH and ADP. KdATP at 23 degrees C in the absence of NADH and ADP was 10(-12) M, in the presence of NADH, 3 microM, and in the presence of NADH and 0.1 mM ADP, 60 microM. Thus, the dissociation of ATP during the transition from non-energized to energized states was, under these conditions, accompanied by observed free energy changes of 8 and 9.7 kcal/mol, respectively.

Mechanism of ATP synthesis by mitochondrial ATP synthase from beef heart.

Previous studies of the rate constants for the elementary steps of ATP hydrolysis by the soluble and membrane-bound forms of beef heart mitochondrial F1 supported the proposal that ATP is formed in high-affinity catalytic sites of the enzyme with little or no change in free energy and that the major requirement for energy in oxidative phosphorylation is for the release of product ATP. The affinity of the membrane-bound enzyme for ATP during NADH oxidation was calculated from the ratio of the rate constants for the forward binding step (k+1) and the reverse dissociation step (k-1). k-1 was accelerated several orders of magnitude by NADH oxidation. In the presence of NADH and ADP an additional enhancement of k-1 was observed. These energy-dependent dissociations of ATP were sensitive to the uncoupler FCCP. k+1 was affected little by NADH oxidation. The dissociation constant (KdATP) increased many orders of magnitude during the transition from nonenergized to energized states.

Phase I trial of continuous infusion carboplatin and etoposide in children with refractory acute leukemia: a Pediatric Oncology Group study.

PURPOSE: The purpose of this phase I study was to determine the toxicities and response to continuous infusion carboplatin in combination with a fixed dose of etoposide (VP-16) in children with refractory acute leukemia. PATIENTS AND METHODS: From January 1989 to February 1992, 20 patients received 28 courses of treatment. Each course of treatment consisted of a 1-hour intravenous (IV) infusion of VP-16 100 mg/m2/d for 5 days, followed by a 23-hour IV infusion of carboplatin each day. The initial, total 5-day dose of carboplatin (1,000 mg/m2) was escalated by 250- to 375-mg increments to a final, total dose of 1,875 mg/m2 over 5 days. RESULTS: Significant marrow suppression was observed in all patients, with prolonged marrow aplasia at the 1,875-mg/m2 dose level. Grade III diarrhea occurred in three patients; 10 patients experienced life-threatening infection and three had severe thrombocytopenic bleeding. Major marrow responses (two complete remissions and two partial remissions) occurred in four patients (20%). CONCLUSION: In view of the apparent antileukemic efficacy and minimal extramedullary toxicity, carboplatin deserves further study in a phase II trial.