Stuart A. Chalew

Plasma IGFBP-3 and its relationship with quantitative growth hormone secretion in short children.

OBJECTIVE We assessed the relationship between serum IGFBP‐3 levels with IGF‐I and quantitative GH secretory status in poorly growing children.

GROWTH WITHOUT GROWTH HORMONE: THE "INVISIBLE" GH SYNDROME

Growth hormone (GH) deficiency, diagnosed by radioimmunoassay (RIA) measurements of GH in blood after provocation or in continuous 24 h samples of venous blood, is usually associated with growth failure. 4 non-obese boys have been identified who had normal linear growth despite apparent GH deficiency by standard RIA. All 4 patients had normal GH concentrations as measured with an IM-9 cell radio-receptor assay (RRA). The RRA/RIA ratio of the 4 patients significantly exceeded that of controls. Thus, these patients secrete a molecule with normal GH receptor binding and bioactivity which is invisible to the standard GH RIA. This variant GH is possibly expressed from the human GH-V gene or a mutant allele.

Cardiovascular Reflex Abnormalities in Children and Adolescents With Diabetes Mellitus

OBJECTIVE To assess the usefulness of specific cardiovascular reflex tests in childhood and to estimate the prevalence of cardiovascular reflex abnormalities among children with IDDM. In adults, abnormal cardiovascular reflexes are a frequent complication of diabetes, associated with increased morbidity and mortality. RESEARCH DESIGN AND METHODS We measured heart-rate responses to deep breathing and standing in ambulatory children with and without IDDM between 6–19 yr of age. A subgroup of the IDDM patients was retested after 1 yr. RESULTS We found the best techniques for detecting cardiovascular reflex abnormality in children were as follows: to record heart-rate responses to deep breathing either as the change inheart rate corrected for inspiratory heart rate or as the ratio of R-R intervals during expiration and inspiration; and to use the Maximum-minimum ratio for heart-rate responses to standing. HR-DBC was lower in diabetic than nondiabetic children (28.6 ± 9.2% [n = 248] vs. 33.6 ± 6.8% [n = 60]; P < 0.0005). Similarly, E:I was lower in children with IDDM than control subjects (1.42 ± 0.19 [n = 248] vs. 1.52 ± 0.15 [n = 60]; P < 0.0005). In the IDDM group, 21% of the children had abnormal HR-DBc or E:I responses. HR-STND M/m was lower in children with IDDM than control subjects (1.28 ± 0.20 [n = 167] vs. 1.38 ± 0.22 [n = 45]; P < 0.014). Among children with IDDM, 11.4% had abnormal HR-STND M/m responses. Overall, 29% of IDDM children tested abnormal in either HR-DBC or HR-STND M/m; 3% were abnormal in both tests. We found no correlation of HbA1c levels (n = 74) or duration of diabetes with either HR-DB, expiration to inspiration (n = 248), or HR-STND M/m (n = 167). In patients who were reevaluated after 1 yr we found a high correlation of the first and repeat HR-DBC tests (r = 0.47, n = 75, P < 0.0001), E:I (r = 0.53, n = 75, P < 0.0001), and HR-STND M/m (r = .49, n = 37, P < 0.002), but no evidence of an increased number of children with cardiovascular reflex abnormality. CONCLUSIONS With easily performed HR-DB and HR-STND tests, we detected cardiovascular reflex abnormality in 29% of children with IDDM. We found no correlation of changes in HR-DB and HR-STND with HbA1c or duration of diabetes. These tests provide an objective clinical measurement to monitor autonomic neuropathy in children with diabetes.

Reduction of plasma cortisol levels in childhood obesity

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Late-onset hypocalcemia, rickets, and hypoparathyroidism in an infant of a mother with hyperparathyroidism

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Red blood cell Na+,K+-ATPase in men with newly diagnosed or previously treated essential hypertension.

Alterations of cellular function of Na+,K+-adenosine triphosphatase (ATPase; Na+-K+ pump) have been implicated in the pathophysiology of essential hypertension. Therefore, this aspect of red blood cell (RBC) Na metabolism was studied in black men with newly diagnosed, untreated essential hypertension (NEH) and a normotensive control group. RBC Na content, Na+-K+ pump number (ouabain binding sites), and pump activity were measured. No statistically significant differences were found between the two groups for any of these three parameters. However, a group of previously treated essential hypertensive subjects (PEH) who had been withdrawn from therapy in the preceding 6 weeks were also studied. This group differed significantly from the NEH subjects in regard to all RBC Na+-K+ pump parameters. Their RBC Na content (10.27 +/- 3.23 vs 7.77 +/- 2.52 mmol Na/LRBC; p = 0.006) was higher, and their Na+-K+ pump activity (166 +/- 50 vs 221 +/- 87 nmol inorganic phosphate/mg membrane protein/hr; p = 0.03) and Na+-K+ pump number (213 +/- 40 vs 284 +/- 85 binding sites/RBC; p = 0.001) were lower compared with those in NEH subjects. Although the PEH subjects were older and somewhat less hypertensive than their NEH counterparts, these factors were not found to influence the Na+-K+ pump parameters. These results indicate that chronic diuretic therapy of patients with essential hypertension is associated with a reduced number of RBC Na+-K+ pumps. Since RBCs are not considered target cells for diuretics, the effects of these drugs on RBC electrolyte metabolism may occur at the time of erythropoiesis by the production of RBCs with fewer Na+-K+ pumps.(ABSTRACT TRUNCATED AT 250 WORDS)

The Diagnostic Value of Integrated Growth Hormone Secretion Studies Shorter than 24 Hours in Normal- and Short-Growing Children

Spontaneous growth hormone (GH) secretion is evaluated by measurement of the 24-hour integrated concentration of GH (24-hour IC-GH), a major diagnostic procedure, or by shorter protocols such as monitoring 6 h during sleep. We have evaluated several possibilities for shortening the procedure by comparing the results of an abbreviated procedure to the 24-hour IC-GH studies. The study population consisted of 50 children with classic GH deficiency (group GHD), determined by provocative testing, and 45 children who had a subnormal secretion of GH (group N), determined by low 24-hour IC-GH but normal GH provocative tests. Twenty-two children of normal height and stature served as a control group. All the children were prepubertal, while there was no overlap between the lower 5th percentile of the 24-hour IC-GH of the control subjects (3.3 micrograms/l) and the upper 97th percentile of the 24-hour IC-GHs of the N and GHD groups (2.9 and 2.7 micrograms/l, respectively), there was a considerable overlap between the IC-GH of control subjects and that of the GHD and N groups measured in all the abbreviated blood withdrawal protocols, except for the 10-hour daytime and the 12-hour nighttime protocols of the GHD patients. It should be noted that there was only a small overlap between the control and the GHD groups during the 12-hour daytime protocol. We have found that the longer the blood collection period the greater the sensitivity and the specificity. We conclude that the 24-hour IC-GH test is the best diagnostic tool for identifying children with subnormal GH secretion.

Linogliride fumarate, representing a new class of oral hypoglycemic agent for diabetes

This study presents the first multiday therapy trial of linogliride fumarate, a representative of a new class of oral hypoglycemie agents. Linogliride demonstrated a significant hypoglycémie activity in 26 patients with non‐insulin‐dependent diabetes mellitus receiving 1 week of therapy. In a dose range of 150 to 400 mg b.i.d., fasting glucose levels fell from 237 ± 52 mg to 199 ± 59 mg by day 7 (P < 0.01). Eight‐hour glucose AUCs fell from 2121 ± 617 mg/dl/8 hr baseline to 1781 ± 631 mg/dl/8 hr on day 7 of treatment (P < 0.01). This was associated with a significant increase in insulin AUC from 380 ± 327 to 610 ± 417 on day 7 (P < 0.01). Thus its initial action appears to be by an insulin secretagogue mechanism. No patient had any major adverse effect. This initial study indicates that linogliride fumarate is an effective hypoglycemic agent that significantly lowers fasting and postprandial glucose levels with short‐term use. Linogliride fumarate represents a new group of hypoglycemic agents that may be shown to have therapeutic utility.

Effect of age on the response to parathyroid hormone

Serum phosphate (PO4) levels and the tubular threshold for PO4 corrected for glomerular filtration (TP/GF) are age-dependent, being higher in children than in adults. We evaluated the effect of age on the response to infusion of parathyroid hormone(1-34) (PTH) in healthy children (n = 8) and adults (n = 12). In addition, six patients with pseudohypoparathyroidism (PHP) and two with PTH deficiency (hypoparathyroidism [HP]) were also studied. At baseline, TP/GF in normal subjects was inversely correlated with urinary cyclic adenosine monophosphate corrected for glomerular filtration (UcAMP/GF) (P < .0359). After PTH administration in the controls, UcAMP/GF was inversely correlated with TP/GF (P < .0007) and directly correlated with maximal fractional extraction of PO4 (FEP) (P < .0002). The slope of the regression of TP/GF (P < .0076) and FEP (P < .0034) with UcAMP/GF was steeper in children than in adults. Two HP patients had high PTH-stimulated UcAMP/GF levels, but stimulated TP/GF and FEP were not changed commensurate with levels that would expected from the normative data. In six patients with PHP, PTH-stimulated TP/GF was also correlated with peak UcAMP/GF (r = .96, P < .002). PHP patients could be distinguished from normal controls based on the combination of low peak FEP or high TP/GF together with low peak UcAMP/GF. Thus, in normal subjects, the phosphaturic response to PTH is correlated with the increase in urinary cAMP and is age-dependent, with a greater decrease of TP/GF in children than in adults.

The Relationship of Growth Rate, Plasma Growth Hormone (GH) Concentration, and GH-Binding Protein

Growth hormone (GH)-binding protein (GHBP) and GH secretion are potential mediators of linear growth in children. To study the relationship between these variables, we measured GHBP activity, peak stimulated GH (PKGH), and 24-hour integrated GH concentration (ICGH) in 76 children referred for evaluation of growth. Linear growth was expressed as an age- and sex-specific growth rate standard deviation score (GRSD), which was calculated from sequential height measurements in the 6-month period immediately before GH testing. Using multiple regression models, we found that the relationship between GHBP and growth (GRSD) depended on height (height standard deviation [HGTSD] expressed as an age- and sex-specific z score) controlling for ICGH or PKGH. In further analysis of this relationship, we divided the subjects by HGTSD in subsequent analyses. In 19 children of normal stature (HGTSD > -2), GRSD increased with GH concentration (measured both as PKGH and ICGH: P <.013,R2 = .56) but decreased with higher levels of GHBP (P < .005,R2 = .62). In contrast, for 57 subjects with severe short stature (HGTSD < or = -2), GRSD could not be predicted from GHBP, GH secretion, HGTSD, or interaction involving these variables. These data suggest the hypothesis that under normal conditions, GHBP and GH level may be important predictors of growth rate in children.