Kenneth McCormick

Neonatal Cord Blood Leptin: Its Relationship to Birth Weight, Body Mass Index, Maternal Diabetes, and Steroids

Leptin is a 16-kD protein encoded by the ob/ob (obesity) gene. In rodents it plays a role in obesity, diabetes, fertility, and neuroendocrine function. In humans serum concentrations of leptin correlate with total body fat in both adults and children. We measured cord blood leptin in 186 neonates that included 82 appropriate for gestational age (AGA), 47 large for gestational age (LGA), 20 infants of diabetic mothers, 52 preterm infants, and 15 intrauterine growth-retarded (IUGR) infants. There were 16 pairs of twins. The mothers of 17 preterm infants were treated with steroids before delivery. Leptin (mean ± SD) concentration in term, AGA infants (39.4 ± 1.1 wk) with birth weight (BW) of 3.2 ± 0.3 kg, body mass index (BMI) of 12.6 ± 1.1 was 4.01 ± 3.5 ng/mL. BW correlated with cord leptin (p = 0.002) in a multivariate analysis controlling for potential confounders. Both LGA infants and infants of diabetic mothers had higher cord leptin concentration 7.3 ± 3.8 and 6.1 ± 4.8 ng/mL, respectively, compared with AGA infants (p < 0.05). Preterm infants had a mean leptin level of 1.8 ± 0.97 ng/mL and a 3-fold elevation was seen if mothers received steroids antenatally (p = 0.006). IUGR infants had increased leptin (6.5 ± 3.9 ng/mL, p= 0.03). Concerning the twin pairs, the smaller had a higher leptin level compared with larger twin (4.1 ± 9.51 versus 2.8 ± 5.14, p = NS). Neonatal cord leptin concentrations correlate well with BW and BMI. No gender differences were found in cord blood leptin. Maternal obesity had no effect on cord leptin, whereas exogenous maternal steroids increased neonatal leptin concentrations.

Evidence That the 11 β-Hydroxysteroid Dehydrogenase (11 β-HSD1) Is Regulated by Pentose Pathway Flux STUDIES IN RAT ADIPOCYTES AND MICROSOMES

11 β-hydroxysteroid dehydrogenase type 1 (11 β-HSD1) catalyzes the interconversion of biologically inactive 11 keto derivatives (cortisone, 11-dehydrocorticosterone) to active glucocorticoids (cortisol, corticosterone) in fat, liver, and other tissues. It is located in the intraluminal compartment of the endoplasmic reticulum. Inasmuch as an oxo-reductase requires NADPH, we reasoned that 11 β-HSD1 would be metabolically interconnected with the cytosolic pentose pathway because this pathway is the primary producer of reduced cellular pyridine nucleotides. To test this theory, 11 β-HSD1 activity and pentose pathway were simultaneously measured in isolated intact rodent adipocytes. Established inhibitors of NAPDH production via the pentose pathway (dehydroandrostenedione or norepinephrine) inhibited 11 β-HSD1 oxo-reductase while decreasing cellular NADPH content. Conversely these compounds slightly augmented the reverse, or dehydrogenase, reaction of 11 β-HSD1. Importantly, using isolated intact microsomes, the inhibitors did not directly alter the tandem microsomal 11 β-HSD1 and hexose-6-phosphate dehydrogenase enzyme unit. Metabolites of 11 β-HSD1 (corticosterone or 11-dehydrocorticosterone) inhibited or increased pentose flux, respectively, demonstrating metabolic interconnectivity. Using isolated intact liver or fat microsomes, glucose-6 phosphate stimulated 11 β-HSD1 oxo-reductase, and this effect was blocked by selective inhibitors of glucose-6-phosphate transport. In summary, we have demonstrated a metabolic interconnection between pentose pathway and 11 β-HSD1 oxo-reductase activities that is dependent on cytosolic NADPH production. These observations link cytosolic carbohydrate flux with paracrine glucocorticoid formation. The clinical relevance of these findings may be germane to the regulation of paracrine glucocorticoid formation in disturbed nutritional states such as obesity.

Prevalence of hypovitaminosis D in early infantile hypocalcemia

AIMnTo further define the pathogenesis of infantile hypocalcemia, the prevailing vitamin D status, and treatment outcomes.nnnMETHODS AND RESULTSnOf the 23 infants admitted with infantile hypocalcemia, 21 had biochemical evidence of hypocalcemia and hyperphosphatemia and the other two had isolated hypocalcemia. The majority of these infants had relatively low serum intact parathyroid hormone responses against the backdrop of hypocalcemia. Thirteen (56.5%) of these infants had low 25-hydroxyvitamin D (25-OHD) levels, of whom 69% were Hispanic and 23% were African American. Infantile serum vitamin D status reflected that of the mother in all the 16 instances in which it was measured. Treatment with calcitriol hastened recovery from hypocalcemia in our series.nnnCONCLUSIONSnRelative hypoparathyroidism is the etiology in the majority of cases of late onset and early infantile hypocalcemia. We identified vitamin D deficiency in a significant percentage of infants with hypocalcemia, especially Hispanics and African Americans. Maternal 25-OHD concentrations should be ascertained if the infant has low 25-OHD levels.

Cerebrospinal fluid anion gap in meningitis

CEREBROSPINAL FLUID lactic acid determination can be useful in the rapid differentiation of bacterial from viral meningitis. 1-:~ In patients with bacterial meningitis, CSF lactic acid concentrations are elevated in comparison to those in patients with aseptic meningitis, whose levels are lower but not comparable to those in controls, z Since the enzymatic determination of lactate is not routinely available in many hospitals, CSF anion gaps ([Na § + [K +] -- [C1-] -- [TCO~]) have been correlated in this study with the CSF lactic acid concentrations to determine the value of this readily available test in the rapid diagnosis of bacterial meningitis. MATERIALS AND METHODS Eighty-three CSF samples from 71 patients at the Rhode Island Hospital were tested for lactic acid, sodium, potassium, chloride, and bicarbonate (approximated by TCO:) concentrations. Patients underwent lumbar puncture as part of their clinical evaluation, and included 65 children from one month to 18 years of age, and six adults. In addition, 33 sera from 32 patients were tested for sodium, potassium, chloride, and bicarbonate concentrations. The electrolyte concentrations were determined by standard techniques ([Na +] + [K ~] by the flame photometry method, and [C1-] + [TCO~] with the Beckman analyzer) in the hospitals pediatric chemistry laboratory. For lactate measurements, CSF was precipitated in a 2:1 ratio of 0.6N perchloric acid to sample and was analyzed in triplicate by an enzymatic lactate method, using lactate dehydrogenase and 0.4M hydrazine (Lactate test combination, Boehringer Mannheim, Mannheim, West Germa

Lipid patterns in treated growth hormone deficient children vs. short stature controls.

Abstract Context: Previous studies in adults with growth hormone (GH) deficiency have substantiated an increased risk of cardiovascular events. This risk has been attributed to an unpropitious lipid profile, increased abdominal mass, and higher incidence of metabolic syndrome. In these studies, a collateral observation has been a negative correlation between IGF-1 levels and lipid profiles. Longitudinal studies are lacking in children with GH-deficiency wherein the various lipid subfractions after GH treatment were compared to matched GH-sufficient short stature controls. Our study examined changes in small lipid particles following GH treatment. Objective: The primary objective was to determine the effect of GH treatment on serum lipids in GH-deficient patients vs. short controls. Design, setting, and participants: This was a prospective, unblinded, case-controlled, 6-month trial conducted at a tertiary pediatric referral center. Patients were referred for short stature. Incorporating accepted criteria, the treatment group (n=18) was found to be GH-deficient, whereas the control group (n=13) was GH-sufficient. The two groups had near-identical short stature along in addition to baseline measurements of weight and BMI. Interventions: The treatment arm received 6 months of recombinant GH at standard doses. Main outcome measures: The primary endpoint was the comparison of the lipoprotein subclasses and lipids between the two groups after 6 months. Results: With the exception of the intermediate density lipoprotein (IDL), there were no significant differences at baseline in serum lipid profiles between the GH-deficient children and the controls. After 6 months of therapy, there were statistically significant differences in Apo-B, LDL, and smaller lipoparticles (LDL-3 and non-HDL) in GH-treated children compared to untreated GH-sufficient short children. Conclusions: Our findings indicate that GH replacement may improve cardiovascular outcome by favorably altering lipid profiles.

Cord blood and postnatal serum leptin and its relationship to steroid use and growth in sick preterm infants.

OBJECTIVEnTo study the effect of prenatal and postnatal glucocorticoids use on serum leptin and weight gain in sick preterm infants and its correlation with caloric intake.nnnMETHODSnSerum leptin was measured in 24 neonates at day 1 (cord), 14 and 28 by radioimmunoassay. Total caloric intake (enteral and parenteral) and weight were measured on days 14 and 28 of life.nnnRESULTSnMean birth weight and gestational age of study infants were 864 +/- 273 g (mean +/- SD) (range 520-1755 g), and 26.6 +/- 2.4 weeks (23-32 weeks) respectively. Cord blood leptin was greater in infants whose mothers received antenatal steroids (1.98 +/- 1.05 ng/ml vs 0.94 +/- 0.39 ng/ml, p=0.004). Serum leptin increased postnatally from 1.52 +/- 1.0 ng/ml at birth to 2.2 +/- 1.3 ng/ml on day 28 of life (p=0.03). Mean serum leptin had an inverse exponential relationship with postnatal weight gain by day 28 of life (R2=0.56). Total caloric intake on days 14 and 28 of life did not correlate with postnatal weight gain.nnnCONCLUSIONSnIncreased serum concentration of leptin following glucocorticoids may be associated with poor weight gain in sick preterm infants.

Hyperthyroxinemia in Newborns Due to Excess Thyroxine-Binding Globulin

NORMALLY, the bulk of total serum thyroxine (T4), approximately 80 per cent, is bound to T4-binding globulin, a glycoprotein synthesized in the liver. An elevation in the serum concentration of thi...

Hypomagnesemia due to two novel TRPM6 mutations.

Abstract Background: Although most hypocalcemia with hypomagenesemia in the neonatal period is due to transient neonatal hypoparathyroidism, magnesium channel defects should also be considered. Case: We report a case of persistent hypomagnesemia in an 8-day-old Hispanic male who presented with generalized seizures. He was initially found to have hypomagnesemia, hypocalcemia, hyperphosphatemia and normal parathyroid hormone. Serum calcium normalized with administration of calcitriol and calcium carbonate. Serum magnesium improved with oral magnesium sulfate. However, 1 week after magnesium was discontinued, serum magnesium declined to 0.5 mg/dL. Magnesium supplementation was immediately restarted, and periodic seizure activity resolved after serum magnesium concentration was maintained above 0.9 mg/dL. The child was eventually weaned off oral calcium and calcitriol with persistent normocalemia. However, supraphysiologic oral magnesium doses were necessary to prevent seizures and maintain serum magnesium at the low limit of normal. Methods and results: As his clinical presentation suggested primary renal magnesium wastage, TRPM6 gene mutations were suspected; subsequent genetic testing revealed the child to be compound heterozygous for TRPM6 mutations. Conclusion: Two novel TRPM6 mutations are described with a new geographic and ethnic origin. This case highlights the importance of recognizing disorders of magnesium imbalance and describing new genetic mutations.

Osteomalacia with hypophosphatemia and hypercalciuria: A possible new variant of osteomalacia

A 12-year-old girl had a severe genu valgum deformity and osteomalacia with hypophosphatemia, hypercalciuria, and modestly elevated levels of 1,25-dihydroxyvitamin D3 and intact parathyroid hormone. This patient seems to have a different type of hypophosphatemic osteomalacia from that previously described.

Growth hormone-IGF-I axis and growth velocity in Chinese children with type 1 diabetes mellitus.

OBJECTIVEnTo elucidate hormonal disturbances in patients with type 1 diabetes mellitus (DM1) with and without growth retardation.nnnMETHODSnPatients with DM1 were divided into two groups, group A consisted of 14 patients with poor growth, and group B consisted of 24 patients with normal growth. Serum IGF-I, IGFBP-3, basal and stimulated GH, and HbA1c were measured.nnnRESULTSnSerum IGF-I and IGFBP-3 concentrations were significantly decreased in group A versus both groups B and controls in Tanner stages I-III; in addition, these measurements in group B were significantly lower compared to controls in Tanner stages II and III, but there was no significant difference in prepuberty. Both basal and peak serum GH were attenuated significantly in group A versus group B. Basal serum GH in group B (normal growth DM1) was significantly elevated versus the controls. There was an unambiguous negative linear regression between IGF-I and mean HbA1c in patients with DM1.nnnCONCLUSIONSnGrowth retardation in patients with DM1 is associated with an abnormal GH-IGF-I axis and poor glycemic control.