Kenneth L. McCormick

Hypothalamic-Pituitary Dysfunction after Radiation for Brain Tumors

Background Patients with brain tumors who are treated with radiation frequently have growth hormone deficiency, but other neuroendocrine abnormalities are presumed to be uncommon. Methods We studied endocrine function in 32 patients (age, 6 to 65 years) 2 to 13 years after they had received cranial radiotherapy for brain tumors. The doses of radiation to the hypothalamic-pituitary region ranged from 3960 to 7020 rad (39.6 to 70.2 Gy). Nine patients also received 1800 to 3960 rad (18.0 to 39.6 Gy) to the craniospinal axis. Serum concentrations of thyroid, gonadal, and pituitary hormones were measured at base line and after stimulation. Results Nine patients (28 percent) had symptoms of thyroid deficiency, and 20 patients (62 percent) had low serum total or free thyroxine or total triiodothyronine concentrations. Of the 23 patients treated only with cranial radiation, 15 (65 percent) had hypothalamic or pituitary hypothyroidism. Of the nine patients who also received spinal (and thus direct thyroid) radiati...

Normalization of plasma arginine vasopressin concentrations when children with meningitis are given maintenance plus replacement fluid therapy

We hypothesized that plasma arginine vasopressin (AVP) concentrations in children with meningitis are appropriate for the childrens degree of hypovolemia, even though the concentrations were higher than expected for the serum osmolality. A randomized study was conducted to compare the effect on plasma AVP concentrations of giving maintenance fluid requirements plus replacement of any deficit versus restricting fluids to two thirds of maintenance requirements for 24 hours. Plasma AVP concentrations and serum osmolality were measured before fluid therapy was begun and again after 24 hours. Nineteen children, 2 months to 17 years of age, were studied; 13 had bacterial meningitis (12 with Haemophilus influenzae type b). Ten children (seven with bacterial meningitis) received a mean of 1.42 times the calculated maintenance fluid requirements, and nine (six with bacterial meningitis) were restricted to a mean of 0.65 times maintenance. Children in the maintenance group also received significantly more sodium (mean = 6.3 mEq/kg/24 hr) than children in the fluid-restricted group (mean = 2.0 mEq/kg/24 hr). The two groups were comparable for plasma AVP concentration and serum osmolality before fluid therapy was begun. The plasma AVP concentration was significantly lower after 24 hours of maintenance plus replacement fluids than after fluid restriction (p = 0.005), and the change in AVP concentration correlated with the amount of sodium given (p less than 0.02). This study supports the hypothesis that serum AVP concentrations are elevated in patients with meningitis because of hypovolemia and become normal when sufficient sodium is given to facilitate reabsorption of water by the proximal tubule of the kidney. Patients with meningitis can be given maintenance plus replacement fluids but should be monitored for the development of the syndrome of inappropriate secretion of antidiuretic hormone.

Leptin in Children with Newly Diagnosed Type 1 Diabetes: Effect of Insulin Therapy

Leptin, the gene product of adipose tissue that signals caloric plentitude via central nervous system receptors, may also have diverse peripheral metabolic actions. Of paramount interest has been the potential interaction(s) between leptin and insulin. Insofar as insulin alters leptin secretion/action (or vice versa), dysregulation of this system could contribute to disease states such as diabetes. The purpose of this study was to examine the effect of exogenous insulin on serum leptin in children with newly-diagnosed Type 1 diabetes. Since these patients are hypoinsulinemic (insulindeplet. ed) at diagnosis, they present an ideal opportunity to examine the effect of insulin repletion on serum leptin. Seventeen patients were enrolled. At baseline (prior to insulin therapy), leptin levels were 4.3 ± 1.1ng/ml; they were not statistically related to the baseline serum insulin or illness severity. There was no significant change in serum leptin before, shortly (1–6 days) or several weeks (3–26 weeks) after insulin treatment even when the data was corrected for changes in BMI, hemoglobin A1C, and daily insulin dose. Since repletion of the insulin deficiency that is present in non-acidotic, ambulatory patients with new onset Type 1 diabetes did not alter serum leptin, these results argue against an effect of insulin on serum leptin in the absence of the acute diabetic ketoacidosis. Because as the recuperative months following the diagnosis of new onset Type 1 diabetes are marked by weight gain, the absence of a rise in serum leptin might also indicate either an adaptive (weight permissive) or pathologic (impaired secretory) deficit.

Diminished in Situ Glucose-6-Phosphate Flux in Permeabilized Adipocytes From Streptozocin-Induced Diabetic Rats

With metabolically active, saponin-permeabilized adipocytes, in situ pathway metabolism, which was distal to glucose transport, was examined in acute streptozocin-induced diabetic (STZ-D) rats. Metabolic reactions were initiated with selectively radiolabeled glucose-6-phosphate (G6P), an otherwise inert substrate with intact cells. Thus, the membrane pores permitted a direct comparison of cellular flux between control and STZ-D adipocytes at identical initial substrate concentrations. Three metabolic pathways were studied: 1) proximal glycolysis through the triosephosphates ([3-3H]G6P to 3H2O), 2) glycolysis-Krebs ([6-14C]G6P) oxidation, and 3) lipogenesis ([6-14C]G6P incorporation into triglyceride). The extent of membrane porosity was assessed by both propidium iodide staining and lactate dehydrogenase leakage to assure that porosity was comparable between the cell groups. Porous adipocytes from STZ-D rats had markedly attenuated rates of G6P metabolism compared with controls. At enzyme-saturating concentrations of G6P (4 mM), this deficit ranged from 44% for glycolysis-Krebs oxidation to 88% for lipogenesis. The reduction in glycolysis-Krebs oxidation was also evident between 0.5 and 6 mM G6P. These porous-cell data were compared with parallel studies of glucose metabolism and clearance in intact adipocytes. Finally, several glycolytic enzymes and acetyl-CoA carboxylase were measured in cell-free (sonicated) extracts with traditional in vitro methods under Vmax conditions. Overall, the in situ porous-cell flux measurements uncovered larger deficits in posttransport cellular metabolism than were apparent in the cell-free, in vitro assays. We conclude that, in actively metabolizing porous rat adipocytes, there exists a striking and unequivocal transport-independent defect in intermediary metabolism after acute STZ-D.

Carnitine Palmitoyltransferase: Effects of Diabetes, Fasting, and pH on the Reaction That Generates Acyl CoA

Although carnitine palmitoyltransferase (CPT) has received considerable attention, particularly its regulation by malonyl CoA, most studies have monitored the forward reaction, ie, the formation of acylcarnitine. We examined the opposite or reverse reaction, in which palmitoyl CoA is generated, in osmotically-disrupted rat hepatic mitochondria. Specifically, the effects of pH, fasting, and untreated recent-onset diabetes were investigated. As with the forward (f) reaction, the CPT reverse (r) velocity v pH curve was somewhat parabolic with a pH maximum at approximately 7.2 (except the CPT that was from the diabetic rats). However, as the pH rose, the CPT reverse and forward curves diverged due to a precipitous decline in the forward reaction. This discordance in rates in the alkaline range was apparent in all three groups of CPT but was most prominent in the diabetic preparation (for example, as the pH increased from 7.3 to 8.8, the respective declines in the f and r velocities were 74% and 2%). In addition, under our assay conditions the CPTr from diabetic rats not only had a higher velocity (55.4 +/- 1.4 nmol/min/mg protein) than that from the fed (32.1 +/- 3.1) or fasted (43.1 +/- 3.4) animals, but also the Vmax was found to be twofold greater, even though there was no difference in the Km for palmitoylcarnitine. In summary, diabetes affects the kinetics of the reverse reaction and, regardless of the animals premortem condition, but more so in the diabetes, this reaction is less attenuated than the forward one as the pH rises.

Hypothalamic-Pituitary Dysfunction After Radiation for Brain Tumors

BACKGROUND Patients with brain tumors who are treated with radiation frequently have growth hormone deficiency, but other neuroendocrine abnormalities are presumed to be uncommon. METHODS We studied endocrine function in 32 patients (age, 6 to 65 years) 2 to 13 years after they had received cranial radiotherapy for brain tumors. The doses of radiation to the hypothalamic-pituitary region ranged from 3960 to 7020 rad (39.6 to 70.2 Gy). Nine patients also received 1800 to 3960 rad (18.0 to 39.6 Gy) to the craniospinal axis. Serum concentrations of thyroid, gonadal, and pituitary hormones were measured at base line and after stimulation. RESULTS Nine patients (28 percent) had symptoms of thyroid deficiency, and 20 patients (62 percent) had low serum total or free thyroxine or total triiodothyronine concentrations. Of the 23 patients treated only with cranial radiation, 15 (65 percent) had hypothalamic or pituitary hypothyroidism. Of the nine patients who also received spinal (and thus direct thyroid) radiation, three (33 percent) had evidence of primary thyroid injury. Seven of the 10 postpubertal, premenopausal women (70 percent) had oligomenorrhea, and 5 (50 percent) had low serum estradiol concentrations. Three of the 10 men (30 percent) had low serum testosterone concentrations. Overall, 14 of the 23 postpubertal patients (61 percent) had evidence of hypogonadism. Mild hyperprolactinemia was present in 50 percent of the patients. Responses to stimulation with corticotropin-releasing hormone and corticotropin were normal in all patients except one, who had panhypothalamic dysfunction. However, serum 11-deoxycortisol responses to the administration of metyrapone were low in 11 of the 31 patients (35 percent) tested. Three of the 32 patients, (9 percent) had no endocrine abnormalities, 9 (28 percent) had an abnormal result on tests of thyroid, gonadal, prolactin, or adrenal function, 8 (25 percent) had abnormalities in two axes, 8 (25 percent) in three axes, and 4 (12 percent) in all four axes. CONCLUSIONS Cranial radiotherapy in children and adults with brain tumors frequently causes abnormal hypothalamic-pituitary function. The most frequent changes are hypothyroidism and gonadal dysfunction, although subtle abnormalities in adrenal function may also be present.

Fluid Management in Bacterial Meningitis (BM)

Elevated plasma arginine vasopressin concentrations [AVP] and cerebral edema occur in BM. Therefore fluid restriction has been recommended in early management. However dehydration may also increase [AVP] and fluid restriction may decrease cerebral perfusion. A randomized, prospective study is in progress to establish the relationship between initial hydrastatus and [AVP], and to determine the effect of rehydration or fluid restriction on subsequent [AVP]. Six children with BM have been studied to date (table). Hydration was estimated clinically and determined by bromide space. [AVP] was measured at presentation, 24 hours later, and at the end of antibiotic therapy. No patient developed hyponatremia, SIADH, or fluid overload.Results to date suggest that children with BM are often dehydrated at the time of presentation and that replacement fluid therapy results in the normalization of [AVP].

Biochemical Profiles following Aspirin Administration in Reye's Syndrome Patients and Controls

Is aspirin an important factor in the pathogenesis of Reyes syndrome (RS)? We have challenged 11 control individuals (C), 5 first degree relatives of RS patients (FR) and two patients who have recovered from RS (RS-1 & RS-2) with standard doses of aspirin for 12 hrs. (600 mg. q 4 hrs.) while fasting. There were no differences in the preaspirin and postaspirin concentrations of ammonia, glucose, AST, or LDH in the RS patients compared to the controls. However, both RS patients showed increased lactate, decreased pyruvate, and decreased β-hydroxybutyrate concentrations following the aspirin challenge while controls showed an opposite trend as illustrated below:These biochemical differences in the RS patients compared to controls suggest an altered cytosolic redox state which is also an indirect index of mitochondrial function. One interpretation of these preliminary observations is that individuals who develop RS may be susceptible to mitochondrial injury when exposed to aspirin during fasting.