Characterizing a "Big Data" Cohort of Over 200,000 Low-Income U.S. Infants and Children for Obesity Research: The ADVANCE Early Life Cohort.

Introduction Low-income populations have elevated exposure to early life risk factors for obesity, but are understudied in longitudinal research. Our objective was to assess the utility of a cohort derived from electronic health record data from safety net clinics for investigation of obesity emerging in early life. Methods We examined data from the PCORNet ADVANCE Clinical Data Research Network, a national network of Federally-Qualified Health Centers serving >1.7 million safety net patients across the US. This cohort includes patients who, in 2012-2014, had ≥1 valid body mass index measure when they were 0-5 years of age. We characterized the cohort with respect to factors required for early life obesity research in vulnerable subgroups: sociodemographic diversity, weight status based on World Health Organization (<2 years) or Centers for Disease Control (≥2 years) growth curves, and data longitudinality. Results The cohort includes 216,473 children and is racially/ethnically diverse (e.g., 17.9% Black, 45.4% Hispanic). A majority (56.9%) had family incomes below the Federal Poverty Level (FPL); 32% were <50% of FPL. Among children <2 years, 7.6 and 5.3% had high and low weight-for-length, respectively. Among children 2-5 years, 15.0, 12.7 and 2.4% were overweight, obese, and severely obese, respectively; 5.3% were underweight. In the study period, 79.2% of children had ≥2 BMI measures. Among 4-5 year olds, 21.9% had >1 BMI measure when they were <2 years. Discussion The ADVANCE Early Life cohort offers unique opportunities to investigate early life determinants of obesity in the understudied population of low income and minority children.

The Reference Ability Neural Network Study: Life-time stability of reference-ability neural networks derived from task maps of young adults.

Analyses of large test batteries administered to individuals ranging from young to old have consistently yielded a set of latent variables representing reference abilities (RAs) that capture the majority of the variance in age-related cognitive change: Episodic Memory, Fluid Reasoning, Perceptual Processing Speed, and Vocabulary. In a previous paper (Stern et al., 2014), we introduced the Reference Ability Neural Network Study, which administers 12 cognitive neuroimaging tasks (3 for each RA) to healthy adults age 20-80 in order to derive unique neural networks underlying these 4 RAs and investigate how these networks may be affected by aging. We used a multivariate approach, linear indicator regression, to derive a unique covariance pattern or Reference Ability Neural Network (RANN) for each of the 4 RAs. The RANNs were derived from the neural task data of 64 younger adults of age 30 and below. We then prospectively applied the RANNs to fMRI data from the remaining sample of 227 adults of age 31 and above in order to classify each subject-task map into one of the 4 possible reference domains. Overall classification accuracy across subjects in the sample age 31 and above was 0.80±0.18. Classification accuracy by RA domain was also good, but variable; memory: 0.72±0.32; reasoning: 0.75±0.35; speed: 0.79±0.31; vocabulary: 0.94±0.16. Classification accuracy was not associated with cross-sectional age, suggesting that these networks, and their specificity to the respective reference domain, might remain intact throughout the age range. Higher mean brain volume was correlated with increased overall classification accuracy; better overall performance on the tasks in the scanner was also associated with classification accuracy. For the RANN network scores, we observed for each RANN that a higher score was associated with a higher corresponding classification accuracy for that reference ability. Despite the absence of behavioral performance information in the derivation of these networks, we also observed some brain-behavioral correlations, notably for the fluid-reasoning network whose network score correlated with performance on the memory and fluid-reasoning tasks. While age did not influence the expression of this RANN, the slope of the association between network score and fluid-reasoning performance was negatively associated with higher ages. These results provide support for the hypothesis that a set of specific, age-invariant neural networks underlies these four RAs, and that these networks maintain their cognitive specificity and level of intensity across age. Activation common to all 12 tasks was identified as another activation pattern resulting from a mean-contrast Partial-Least-Squares technique. This common pattern did show associations with age and some subject demographics for some of the reference domains, lending support to the overall conclusion that aspects of neural processing that are specific to any cognitive reference ability stay constant across age, while aspects that are common to all reference abilities differ across age.

Neuropsychological predictors of rapidly progressive Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD), the most common cause of dementia, typically shows a slow clinical progression over time. 'Rapidly progressive' AD, a variant of the disease characterized by an aggressive course, exhibits distinct clinical, biological, and neuropathological features. Here, we investigate neuropsychological predictors of rapid decline in a group of mild patients with AD. METHODS: One hundred fifty-three mild patients with AD admitted to a memory disorder clinic and followed for up to 3 years were included in this study. A comprehensive neuropsychological (NP) battery was performed at the time of enrollment. Patients were defined as 'rapidly progressive' if they exhibited a drop of 6 or more points on the Mini Mental State Examination (MMSE) between two consecutive annual visits. This event defined the main outcome in multiple analyses of variance and Cox proportional hazards models that investigated the impact of NP predictors. Categorical principal component analysis (CATPCA) was also employed in order to delineate clusters of NP tests and to test their effect on the outcome. RESULTS: Of 153 subjects, thirty-seven (24%) were classified as 'rapidly progressive'; those subjects showed younger age of symptoms onset compared to slow decliners (68 vs 71.5 years old). Baseline lower performance on a neuropsychological test of naming predicted a rapid decline over the follow-up (P = 0.001). Three clusters of NP were defined by CATPCA: (i) executive/language, (ii) visuospatial memory, and (iii) verbal memory. The executive/language component predicted a rapid decline over the follow-up (P = 0.016). CONCLUSION: Early executive/language impairment is highly predictive of a rapid progression of AD.

Greater White Matter Hyperintensity Volume Is Associated with the Number of Microhemorrhages in Preclinical Alzheimer's Disease.

BACKGROUND: Increased white matter hyperintensity (WMH) volume visible on MRI is a common finding in Alzheimer's disease (AD). We hypothesized that WMH in preclinical AD is associated with the presence of advanced vessel amyloidosis manifested as microhemorrhages (MCH). OBJECTIVES: 1) To assess the relationship between baseline WMH volume and baseline MCH. 2) To assess the relationship between longitudinal WMH accumulation and last MRI MCH during the double-blind phase of the A4 trial. DESIGN: A multicenter, randomized, double-blind, placebo-controlled, Phase 3 study comparing solanezumab with placebo given as infusions once every 4 weeks over 4.5 years in subjects with preclinical AD, defined as having evidence of elevated brain amyloid before the stage of clinically evident cognitive impairment, with an optional open-label extension period. SETTING: Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. PARTICIPANTS: A sample of 1157 cognitively unimpaired older adults (mean age = 71.9 years [SD = 4.8 years], 59% women, 59% APOE ε4 carriers). MEASUREMENTS: A linear regression model was used to assess the impact of baseline MCH amount (0, 1, 2+) on WMH volume. A linear mixed-effects model was used to assess the impact of last MRI MCH on longitudinal WMH. All models were corrected for age, sex, grey matter volume, cortical amyloid PET, APOE ε4 status, and treatment group. RESULTS: Baseline WMH volume was greater in individuals with more than one MCH compared to those with no MCH (t=4.8, p<0.001). The longitudinal increase in WMH amongst individuals with one (t=2.3, p=0.025) and more than one MCH (t=6.7, p<0.001) at the last MRI was greater than those with no MCH. CONCLUSION: These results indicate a strong association between WMH and MCH, a common manifestation of cerebral amyloid angiopathy and ARIA-H. These results suggest that increased WMH volume may represent an early sign of vessel amyloidosis, likely prior to the emergence of MCH.

Effects of Vascular Risk Factors on the Association of Blood-Based Biomarkers with Alzheimer's Disease.

Background: Comorbidities may influence the levels of blood-based biomarkers for Alzheimer's disease (AD). We investigated whether differences in risk factors or comorbid conditions might explain the discordance between clinical diagnosis and biomarker classifications in a multi-ethnic cohort of elderly individuals. Aims: To evaluate the relationship of medical conditions and other characteristics, including body mass index (BMI), vascular risk factors, and head injury, with cognitive impairment and blood-based biomarkers of AD, phosphorylated tau (P-tau 181, P-tau 217), in a multi-ethnic cohort. Methods: Three-hundred individuals, aged 65 and older, were selected from a prospective community-based cohort for equal representation among three racial/ethnic groups: non-Hispanic White, Hispanic/Latino and African American/Black. Participants were classified into four groups based on absence (Asym) or presence (Sym) of cognitive impairment and low (NEG) or high (POS) P-tau 217 or P-tau 181 levels, determined previously in the same cohort: (Asym/NEG, Asym/POS, Sym/NEG, Sym/POS). We examined differences in individual characteristics across the four groups. We performed post-hoc analysis examining the differences across biomarker and cognitive status. Results: P-tau 217 or P-tau 181 positive individuals had lower BMI than P-tau negative participants, regardless of symptom status. Symptomatic and asymptomatic participants did not differ in terms of BMI. BMI was not a mediator of the effect of P-tau 217 or P-tau 181 on dementia. Frequencies of other risk factors did not differ between the four groups of individuals. Conclusions: Participants with higher levels of P-tau 217 or P-tau 181 consistent with AD had lower BMI regardless of whether the individual was symptomatic. These findings suggest that weight loss may change with AD biomarker levels before onset of cognitive decline. They do not support BMI as a confounding variable. Further longitudinal studies could explore the relationship of risk factors with clinical diagnoses and biomarkers.

Increased Diameters of the Internal Cerebral Veins and the Basal Veins of Rosenthal Are Associated with White Matter Hyperintensity Volume.

BACKGROUND AND PURPOSE: White matter hyperintensities on T2-weighted MR imaging are typical in older adults and have been linked to several poor health outcomes, including cognitive impairment and Alzheimer disease. The presence and severity of white matter hyperintensities have traditionally been attributed to occlusive arteriopathy, but recent evidence also implicates deep medullary venule collagenosis and associated vasogenic edema. Historically, postmortem analyses have been the sole way to analyze cerebral veins, but SWI can be now used to examine cortical veins in vivo. The aim of the current study was to determine whether there is an association between the diameters of the large draining cerebral veins/sinuses and white matter hyperintensity volume. MATERIALS AND METHODS: T2-weighted FLAIR and SWI were performed in 682 older adults without dementia (mean age, 73.9 ± 5.9 years; 59.1% women). Total and regional white matter hyperintensity volume was derived. We measured the diameters of 5 regions of the cerebral venous draining system: internal cerebral veins, basal veins of Rosenthal, superior sagittal sinus, vein of Galen, and straight sinus terminus. RESULTS: Increased diameter of the internal cerebral veins was associated with greater total white matter hyperintensity volume (ß = 0.09, P = .02) and regionally in the parietal (ß = 0.10, P = .006), frontal (ß = 0.09, P = .02), and temporal (ß = 0.09, P = .02) lobes. Increased diameter of the basal veins of Rosenthal was associated with greater total (ß = 0.10, P = .01), frontal (ß = 0.11, P = .003), and temporal (ß = 0.09, P = .02) white matter hyperintensity volume. CONCLUSIONS: Our results suggest that the caliber of the internal cerebral veins and of the basal veins of Rosenthal relates to regional white matter disease.

changes in serum and urinary calcium during treatment with hydrochlorothiazide: studies on mechanisms.

Studies were undertaken in man to evaluate the roles of volume depletion and of the parathyroid glands in mediating the changes in serum and urinary calcium which follow the administration of hydrochlorothiazide, 100 mg twice daily, for 4 days, 42 studies were carried out in 16 normal subjects, 9 patients with hyperparathyroidism, and 7 vitamin D-treated subjects with hypoparathyroidism. In six studies in normal subjects, daily sodium losses during thiazide administration were quantitatively replaced, and in six other studies the effect of equivalent sodium losses produced by furosemide was evaluated. Although the magnitude of sodium losses was similar in three groups during therapy with thiazides, urinary calcium fell and urinary phosphorus increased significantly only in normal subjects and those with hyperparathyroidism; no change occurred in patients with hypoparathyroidism. With the replacement of the thiazide-induced sodium losses by NaCl in normals, urinary calcium did not change as urinary sodium increased 4- to 5-fold. Furosemide administration produced similar sodium losses while urinary calcium remained at or above control levels. After correction for changes in plasma protein concentration caused by thiazide-induced hemoconcentration, mean levels of serum calcium were significantly increased only in subjects with hyperparathyroidism and vitamin D-treated patients with hypoparathyroidism. The results indicate that both depletion of extracellular fluid volume and the presence of the parathyroid glands are necessary for the decrease in urinary calcium in response to thiazide therapy. Both the reduction in urinary calcium and increase in urinary phosphate after the use of thiazides may be due, in part, to potentiation of the action of the parathyroid hormone on the nephron. The rise in serum calcium could be due to thiazide-induced release of calcium from bone into extracellular fluid, particularly in states where bone resorption may be augmented, i.e., vitamin D therapy or hyperparathyroidism.

Resistance to symptomatic insulin reactions after fasting.

This study was carried out to determine if, in fasting, an adaptation to utilization of ketones could prevent cerebral dysfunction during periods of acute, insulin-induced glucopenia. In the course of standard insulin tolerance tests (0.1-0.2 U/kg), nine obese subjects manifested frank hypoglycemic reactions resulting in an increase in urinary catecholamine excretion from 61 to 113 mug/24 hr (P < 0.01). After fasting 2 months, administration of weight-adjusted doses of insulin produced identical maximum insulin concentrations and disappearance curves. However, no insulin reactions nor significant rises in catecholamine excretion occurred despite equal extent and rate of glucose fall. Glucose concentrations as low as 0.5 mmoles/liter (9 mg/100 ml) failed to precipitate hypoglycemic reactions. During the postfast insulin tolerance tests, mean plasma 2-hydroxybutyrate (beta-OHB) decreased from 8.02 to 6.69 mmoles/liter (P < 0.01). In another five fasting subjects tested, the A-V difference for beta-OHB across brain increased progressively from 0.21 to 0.70 mmoles/liter whereas across the forearm no consistent uptake could be demonstrated. Simultaneously, the A-V difference across the brain for glucose decreased from 0.24 to 0.07 mmoles/liter of plasma. In addition to insulin-induced suppression of hepatic ketogenesis, the augmented cerebral ketone uptake during insulin hypoglycemia contributes to the net fall in plasma beta-OHB. Ketoacids, extracted by the fast-adapted brain, supplant glucose as a metabolic substrate preventing overt hypoglycemic reactions during acute glucopenia.

Comparison of effects of 1 alpha-hydroxy-vitamin D3 and 1,25-dihydroxy-vitamin D3 in man.

The effects of short-term treatment with 1,25-dihydroxy-vitamin D3 [1,25(0H)2D3] or 1 alpha-hydroxy-vitamin D3 [1 alpha(OH)D3] on intestinal absorption of 47Ca were compared in 41 experiments in normals and 72 experiments in patients with chronic renal failure. 11 patients were studied a second time after treatment for 2-5 mo. Doses varied from 0.14 to 5.4 mug/day to establish dose-response relationships. Urinary calcium was monitored in normal subjects, nine of whom received a constant calcium intake on a metabolic unit. There was an increase in intestinal absorption of 47Ca and urinary calcium in normals receiving 1,25 (OH)2D3, 0.14 mug/day or greater, and 0.28 mug/day or greater augmented intestinal absorption of 47Ca in chronic renal failure. In contrast, 2.6 mug/day of 1 alpha (OH) D3 was required to increase intestinal absorption of 47Ca in both groups. The increase in urinary calcium to maximal levels was delayed during treatment with 1 alpha (OH) D3, 5-10 days vs. 2-5 days with 1,25 (OH)2D3. Moreover, half times for urinary calcium to decrease to pretreatment levels after stopping treatment were greater after 1 alpha-(OH) D3 (1.5-2.7 days) than 1,25(OH)2D3 (1.1-2.0 days). With long-term administration there was a progressive increase in intestinal absorption of 47Ca in the patients receiving 1 alpha (OH)D3; this was not observed with 1,25(OH)2D3. The pharmacologic differences between 1 alpha(OH) D3 and 1,25(OH)2D3 may be explained by the requirement for 25-hydroxylation of 1alpha(OH) D3 before biologic effects occur; at low doses (less than 1 mug/day), 1 alpha(OH) D3 competes with vitamin D3 for 25-hydroxylation. With prolonged treatment or larger doses (greater than 2 mug/day),, 1alpha(OH) D3 could accumulate and then be hydroxylated resulting in production of higher levels of 1,25(OH)2D3.

Studies on mechanisms of hypocalcemia of magnesium depletion.

Studies were carried out to evaluate the mechanism of hypocalcemia in magnesium depletion. Day old chicks fed a magnesium deficient diet developed marked hypocalcemia, with a direct relation between serum calcium (y) and magnesium (x): y = 2.68 x + 4.24, r = 0.84 (both in mg/100 ml). Injections of parathyroid extract that increased serum calcium 2-3 mg/100 ml in normals had no effect in Mg-depleted birds. Very large dietary supplements of calcium or vitamin D(3) increased mean serum calcium only from 5.3 to 7.7 and 7.8 mg/100 ml, respectively, while a normal magnesium diet for 3 days increased calcium from 5.3 to 9.9 mg/100 ml despite absence of dietary calcium. Intestinal calcium transport, studied in vitro, and the calcium concentration of the carcass was significantly increased in magnesium-depleted chicks, making it unlikely that reduced intestinal absorption of calcium caused the hypocalcemia. In magnesium-deficient chicks, the bone content of magnesium was decreased by 74%, the calcium content was unchanged, and the cortical thickness of bone was markedly increased. After 3 days of magnesium-repletion, cortical thickness was reduced with increased endosteal resorption. There was an increase in unmineralized osteoid tissue in the magnesium-depleted chicks. Parathyroid gland size and histology did not differ in magnesium-depleted and control birds. The results suggest that hypocalcemia develops due to altered equilibrium of calcium between extracellular fluid and bone, favoring increased net movement into the latter. Failure of parathyroid gland function could also exist, and unresponsiveness to parathyroid hormone (PTH) may also contribute to the hypocalcemia. However, failure of PTH action is probably due to the presence of excess osteoid tissue rather than a primary event leading to hypocalcemia.

Striatal size and relative glucose metabolic rate in schizotypal personality disorder and schizophrenia.

BACKGROUND: Schizotypal personality disorder (SPD) shares social deficits and cognitive impairment with schizophrenia, but is not typically characterized by frank psychosis. Because striatal size and functional activity have both been shown to be associated with psychotic symptoms, we carried out the first study of SPD to assess the caudate and putamen for comparison with findings in schizophrenia. METHODS: Patients with SPD (n = 16), schizophrenic patients (n = 42), and age- and sex-matched normal control subjects (n = 47) were assessed with magnetic resonance imaging. All of the patients with SPD and subsamples of the schizophrenic patients (n = 27) and control subjects (n = 32) were also assessed with positron emission tomography using fluorodeoxyglucose F-18. RESULTS: The relative size of the putamen in controls was significantly larger than in patients with SPD and significantly smaller than in schizophrenic patients, while the relative size of the caudate was similar in all 3 groups. Compared with control values, relative glucose metabolic rate in the ventral putamen was significantly elevated in patients with SPD and reduced in schizophrenic patients. When subsamples of schizophrenic patients (n = 10) and patients with SPD (n = 10) both of whom never received medication were compared, this pattern was more marked, with the highest value for the putamen being found in patients with SPD for the ventral slice and the lowest value for the right dorsal putamen. CONCLUSIONS: Patients with SPD showed reduced volume and elevated relative glucose metabolic rate of the putamen compared with both schizophrenic patients and controls. These alterations in volume and activity may be related to the sparing of patients with SPD from frank psychosis.

Effects in vivo of vitamin D metabolites and 17 beta-estradiol on parathyroid hormone-dependent formation of adenosine 3',5'-monophosphate in rat bone.

We used an in vivo infusion technique to assess the hypothesis that vitamin D metabolites and estrogens modulate tissue responsiveness to parathyroid hormone via effects on the adenylate cyclase-cAMP system. After treatment with these agents for 3-4 days, rats were thyroparathyroidectomized. Twenty-four hours later, parathyroid extract (PTE) was infused, and cAMP in calvaria was measured. The response to PTE was achieved by 2 min and represented a 4-fold increase in the tissue concentration of cAMP at the highest dose of hormone tested. Treatment with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], did not affect cAMP levels in bone. However, 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3], either 0.25 or 1.25 micrograms daily, led to a major increase in PTE-stimulated cAMP formation, a result which persisted when carried out in chronically thyroparathyroidectomized animals. This effect did not reflect direct stimulation of adenylate cyclase or inhibition of cyclic nucleotide phosphodiesterase from bone by the vitamin metabolite, nor did it operate via the 1,25-(OH)2D3 receptor. 24,25-(OH)2D3 treatment also increased cAMP concentrations in renal cortical slices, but not in liver. Adenylate cyclase activity in kidneys from 24,25-(OH)2D3-treated rats was not different from that found in control tissue, but total cytosol phosphodiesterase activity was diminished. 17 beta-Estradiol, over a daily dose range of 2.5 micrograms to 5.0 mg, lowered basal cAMP levels but did not alter PTE-stimulated cAMP production. We conclude that modulation of PTH action in bone by estrogen does not involve modification of the acute cAMP response to PTH. Further, the results support the concept that there are unique actions of 24,25-(OH)2D3 on bone and kidney which are not duplicated by 1,25(OH)2D3.

Hypercalcemia in rats bearing growth hormone- and prolactin-secreting transplantable pituitary tumors.

We evaluated the effects of chronic massive elevations of serum GH and PRL on calcium metabolism in rats bearing the MStT/W15 and 7315a transplantable pituitary tumors. MStT/W15 tumor rats manifest elevated serum GH and PRL levels, hypercalcemia, hypercalciuria, and elevated serum levels of PTH and 1,25-dihydroxyvitamin D. The hypercalcemia was not reversed by dexamethasone or propranolol treatment, but was ameliorated by starvation. Parathyroidectomy produced hypocalcemia in the MStT/W15 tumor rats, confirming the parathyroid dependence of the hypercalcemia. The 7315a tumor produced a milder degree of hypercalcemia, along with elevated serum levels of PRL, ACTH, and corticosterone; serum GH was normal. In high concentrations, PRL and/or GH may stimulate the secretion of PTH as well as enhance dietary calcium absorption, in part through the mediation of 1,25-dihydroxyvitamin D.

Desensitization of vascular tissue to parathyroid hormone and parathyroid hormone-related protein.

Although PTH and PTH-related protein (PTHrP) are vasodilators, prolonged exposure to elevated levels of PTH is often associated with hypertension. We investigated the effects of prolonged incubation with PTH or PTHrP on arterial segments and cultured vascular smooth muscle cells (VSMC). PTH or PTHrP transiently relaxed precontracted arterial segments within 10 min. Additional PTH or PTHrP added after 40-min exposure to these peptides had little effect on vascular tone, whereas forskolin, isoproterenol, isobutylmethyl-xanthine, or acetylcholine were still potent. In fura 2-loaded VSMC, 5-min incubation with PTH or PTHrP attenuated angiotensin II (Ang II)-induced calcium mobilization, an effect that was reduced by preincubation of VSMC with PTH for 1.5 h. Similarly, 1.5-h preincubation with PTH or PTHrP decreased the cAMP response to these peptides but not to forskolin or NaF. Ang II potentiated the cAMP response to PTH and PTHrP but was also subject to desensitization. Nle8, 18Tyr34 bovine PTH(3-34) amide did not desensitize vascular tissue to PTH or PTHrP. Our results suggest that homologous desensitization to PTH or PTHrP in vascular tissue requires receptor stimulation, occurs proximal to G stimulatory protein, and impairs attenuation of calcium mobilization by PTH or PTHrP. This may be a mechanism by which vasodilator effects of these peptides are decreased with prolonged elevation of PTH levels.

Blunted plasma cyclic adenosine monophosphate response to isoproterenol in pseudohypoparathyroidism.

Plasma cAMP, serum glucose, and cardiovascular responses to isoproterenol infusion were examined in seven normal subjects and seven patients with pseudohypoparathyroidism (PHP), type I (three with deficiency of the hormone receptor-cyclase coupling protein (N-protein) and four who were N-protein replete). Although plasma cAMP responses were blunted in both subgroups of PHP patients, the cardiovascular and glucose responses to isoproterenol were normal. We conclude that the blunted plasma cAMP response to isoproterenol in PHP does not depend on deficient N-protein coupling of adenylate cyclase to the beta-adrenergic receptor and that the cardiovascular and glucose responses to isoproterenol are not reflected in changes in plasma cAMP.

Circadian blood pressure and renin, aldosterone, cortisol, and prolactin levels in hypertensive pseudohypoparathyroid patients.

We investigated the relation between 24-h recumbent blood pressure levels and secretory patterns of PRA, aldosterone, cortisol, and PRL in four hypertensive pesudohypoparathyroid (PsHP) males and nine age- and weight-matched males with essential hypertension. Although both groups had PRA and aldosterone circadian rhythms, the variability and concentrations of these hormones over 24 h were considerably less in PsHP patients. Plasma cortisol concentrations demonstrated a well defined circadian rhythm in both groups, with no discernable differences between the PsHP patients and the patients with essential hypertension. All patients with essential hypertension had circadian rhythms of PRL secretion, but the PsHP patients failed to demonstrate a circadian variation in PRL secretion. These results suggest that factors other than those investigated in this study are responsible for the maintenance of elevated blood pressures in PsHP patients. The absence of circadian secretion of PRL may be related to altered dopaminergic control mechanisms in PsHP patients.

Altered red cell sodium transport in hypoparathyroidism: relation to serum calcium.

We studied Na transport in red blood cells (RBC) from six patients with hypoparathyroidism (HYPO; 3 postsurgical and 3 idiopathic) and 13 normal subjects. In HYPO, the effect of treatment-induced increases in serum Ca2+ on RBC Na transport also was examined. Na efflux mediated by the ouabain-sensitive Na,K pump and furosemide-sensitive Na,K cotransport (CoT) was examined by flux methodology in RBCs Na loaded to 5 levels of intracellular Na (Nai; 5-90 mM/liter cells) by the p-chloromercuribenzene method. The pump-mediated Na efflux was similar in untreated HYPO patients and normal subjects. Correction of hypocalcemia by vitamin D and oral calcium produced a mean increase in serum Ca2+ from 6.62 +/- 0.23 (+/- SEM) to 8.73 +/- 0.32 mg/dl. In HYPO patients treated with vitamin D and oral calcium, an increasing serum Ca2+ level was associated with significant (P less than 0.01) reductions in pump activity. Further, there was an inverse correlation (r = 0.813; P less than 0.001) between serum Ca2+ and pump-mediated Na efflux rate. RBC Na efflux through the CoT pathway was markedly reduced (P less than 0.05-0.01) in HYPO patients compared to normal subjects at all levels of Nai. Treatment-induced increases in serum Ca2+ had no effect on the reduced RBC CoT function in HYPO. Thus, changes in ambient serum Ca2+ can modulate the activity of the RBC Na,K pump in HYPO, with increases in Ca2+ inhibiting pump function. The markedly decreased RBC CoT activity was not related to associated hypertension or altered renal function and may represent a primary phenomenon in HYPO. These alterations in RBC Na transport may account for the higher Na, in RBCs of HYPO patients.

Responses to glucagon infusion in pseudohypoparathyroidism.

Single or graded doses of glucagon (Eli Lilly) were given to patients with pseudohypoparathyroidism (PsHP) type I to examine the possible presence of hormone resistance. The doses of glucagon ranged from 0.25-15 micrograms/kg. The following individuals were studied: 13 normal subjects, 5 patients with low erythrocyte N-protein activity (PsHP type Ia), and 7 patients with normal erythrocyte N-protein activity (PsHP type Ib). Two additional patients with treated primary hypothyroidism who were relatives of a patient with PsHP type Ib were also studied. The patients with PsHP type Ia had blunted plasma cAMP responses to all glucagon doses. In contrast, the patients with PsHP type Ib had normal cAMP responses to glucagon infusion. However, the 2 relatives of the patient with PsHP type Ib had clearly decreased cAMP responses to glucagon infusion; both had normal renal responses to PTH and were clinically and biochemically euthyroid at the time of study. Glucose responses to glucagon were normal in both PsHP groups; the glucose response per unit cAMP response was slightly, but not significantly, enhanced in PsHP type Ia patients. Glucagon resistance appears to be a common finding in patients with PsHP type Ia, but not in those with PsHP type Ib. However, the observation of reduced glucagon responsivity in association with familial hypothyroidism in a kindred with PsHP type Ib suggests the possibility that this disorder may also cause disturbances in several hormone systems.

Parathyroid hormone, platelet calcium, and blood pressure in normotensive subjects.

Relations between platelet cytosolic calcium, parathyroid hormone, and blood pressure were investigated in 91 normotensive subjects: 47 men and 44 women ranging in age from 24 to 70 years. The men had higher mean arterial blood pressure, serum creatinine, and body mass index than the women. Serum total calcium, plasma ionized calcium, and parathyroid hormone (measured as both intact hormone and mid-molecule fragment) were not different between men and women; however, serum phosphate was higher in women than in men. Basal platelet cytosolic calcium was higher in men than in women (113.7 +/- 1.9 versus 105.9 +/- 1.7, respectively; p less than 0.01), but there was no difference in the peak platelet cytosolic calcium responses to thrombin between the two groups. In the combined group of male and female subjects, platelet cytosolic calcium correlated with diastolic blood pressure and mean arterial pressure (r = 0.37, p less than 0.001 and r = 0.32, p less than 0.01, respectively). Intact parathyroid hormone correlated with systolic and mean arterial blood pressure (r = 0.41, p less than 0.001 for both). Age correlated with both systolic blood pressure (r = 0.40, p less than 0.001) and intact parathyroid hormone (r = 0.51, p less than 0.001). When multiple regression analysis was performed using mean arterial pressure as the dependent variable, platelet cytosolic calcium and intact parathyroid hormone maintained significant correlations with mean arterial pressure. Platelet cytosolic calcium did not correlate with intact parathyroid hormone. These results suggest that both platelet cytosolic calcium and intact parathyroid hormone are associated with blood pressure regulation in normotensive subjects. However, the influences of these two factors on blood pressure are not interrelated.

Deficient activity of receptor-cyclase coupling protein is transformed lymphoblasts of patients with pseudohypoparathyroidism, type I.

Erythrocytes of many patients with pseudohypoparathyroidism, type 1 (PHP-I) exhibit quantitatively reduced activity of the N protein, the guanine nucleotide-binding regulatory component of adenylate cyclase. We have designated this group of patients PHP-Ia to distinguish them from PHP-Ib patients, in whom erythrocyte N activity is quantitatively normal. In virus-transformed lymphoblasts of three normal, three PHP-Ia, and two PHP-Ib subjects, we compared N and adenylate cyclase activities, as well as cAMP accumulation and susceptibility to radiolabeling in the presence of [32P]NAD and cholera toxin. In comparison to normal lymphoblasts, N activities were reduced by approximately 50% in lymphoblasts of the PHP-Ia patients, but were not reduced in lymphoblasts from the PHP-Ib patients. Toxin-catalyzed radiolabeling of the 42,000 molecular weight subunit of the N protein was also reduced in lymphoblasts of the PHP-Ia patients. These results are consistent with the hypothesis that N deficiency is generalized in tissues of PHP-Ia patients. Deficient lymphoblast N activity in PHP-Ia was not associated with decreases in adenylate cyclase activity or cAMP accumulation, probably because these activities involve many potential regulable cellular components in addition to the N protein.