A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery.

BACKGROUND AND METHODS: In the United States, most patients with primary hyperparathyroidism have few or no symptoms. The need for parathyroidectomy to treat all patients with this disorder has therefore been questioned. We studied the clinical course and development of complications for periods of up to 10 years in 121 patients with primary hyperparathyroidism, 101 (83 percent) of whom were asymptomatic. There were 30 men and 91 women (age range, 20 to 79 years). During the study, 61 patients (50 percent) underwent parathyroidectomy, and 60 patients were followed without surgery. RESULTS: Parathyroidectomy in patients with or without symptoms led to normalization of serum calcium concentrations and a mean (+/-SE) increase in lumbar-spine bone mineral density of 8+/-2 percent after 1 year (P=0.005) and 12+/-3 percent after 10 years (P=0.03). Bone mineral density of the femoral neck increased 6+/-1 percent after 1 year (P=0.002) and 14+/-4 percent after 10 years (P=0.002). Bone mineral density of the radius did not change significantly. The 52 asymptomatic patients who did not undergo surgery had no change in serum calcium concentration, urinary calcium excretion, or bone mineral density. However, 14 of these 52 patients (27 percent) had progression of disease, defined as the development of at least one new indication for parathyroidectomy. All 20 patients with symptoms had kidney stones. None of the 12 who underwent parathyroidectomy had recurrent kidney stones, whereas 6 of the 8 patients who did not undergo surgery did have a recurrence. CONCLUSIONS: In patients with primary hyperparathyroidism, parathyroidectomy results in the normalization of biochemical values and increased bone mineral density. Most asymptomatic patients who did not undergo surgery did not have progression of disease, but approximately one quarter of them did have some progression.

DNA damage and repair in central nervous system injury: National Institute of Neurological Disorders and Stroke Workshop Summary.

BACKGROUND AND PURPOSE: DNA damage and repair are areas of research with important implications for stroke and cerebral trauma. DNA damage is present in central nervous system (CNS) injury, and defects in repair mechanisms are associated with neurodegenerative disease. METHODS: A workshop, DNA Damage and Repair in CNS Injury, was organized by the National Institute of Neurological Disorders and Stroke in Bethesda, Md, on September 11, 1995. The objective of this workshop was to promote inquiry and to foster application of research in DNA damage and repair after stroke and trauma. RESULTS: The participants discussed the connection between the fields of DNA damage and repair and stroke and trauma and identified gaps in knowledge to be filled to expand research of DNA damage and repair in CNS injury. Specific recommendations were made targeting research opportunities in the areas of DNA repair and damage in stroke and trauma. CONCLUSIONS: Research in the science of DNA injury and repair will likely provide new and important information on mechanisms of cell damage and provide opportunities for the development of novel and effective therapies to reduce CNS injury in stroke and trauma.

Longitudinal measurements of bone density and biochemical indices in untreated primary hyperparathyroidism.

A large number of patients with primary hyperparathyroidism today do not undergo parathyroidectomy. In this prospective study, we evaluated the effect of untreated disease on biochemical and bone densitometric indices. In 66 patients, seven annual measurements showed no change in serum calcium, phosphorus, PTH, vitamin D, or alkaline phosphatase; in urinary calcium, hydroxyproline or hydroxypyridinium cross-link excretion; or lumbar spine, femoral neck, and radial bone mineral density. The subset of postmenopausal women also showed no change in biochemical indices or bone density at any of the three sites. Twenty-four patients met guidelines for surgery as established by the NIH Consensus Conference, 1990. They differed from those who did not meet these guidelines only by being younger (50 +/- 3 vs. 62 +/- 2 yr; P = 0.0005) and by having higher urinary calcium excretion [7.7 +/- 0.9 vs. 5.4 +/- 0.3 mmol/L (310 +/- 37 vs. 215 +/- 14 mg/g creatinine); P < 0.01]. No longitudinal changes in biochemical profile or bone mineral density at any site were noted in this subgroup. Conservative management of patients with mild primary hyperparathyroidism does not lead to progression of disease, as reflected by biochemical indices. Bone density is maintained over 6 yr of observation at sites reflecting both cortical (radius) and cancellous (lumbar spine) bone.

Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism.

Skeletal involvement in primary hyperparathyroidism is characterized by preferential loss of cortical bone, whereas cancellous bone is relatively spared. Little data are available concerning changes in bone density, particularly at sites containing more cancellous bone, after successful parathyroidectomy. Most patients with primary hyperparathyroidism are asymptomatic, but approximately 50% meet one or more criteria for surgery. In a prospective study of 34 patients who met one or more such criteria, bone density rose at all skeletal sites (lumbar spine, femoral neck, and the radius) in the 4 yr after surgery. The lumbar spine, with most cancellous bone, showed a rapid (mean +/- SE, yr 1, 8.2 +/- 2.0%; P < 0.005) and sustained (yr 4, 12.8 +/- 2.8%; P < 0.001) rise. Post-menopausal patients were similar (by yr 4, 12.5 +/- 2.7%; P < 0.005). At the femoral neck, with intermediate cancellous and cortical composition, a similar increase was noted (12.7 +/- 3.8% by yr 4; P < 0.01). The distal radius, containing mostly cortical bone, rose modestly (4.0 +/- 1.5% by yr 3; P < 0.05), except in patients with lowest preoperative bone density, where the increase was marked (12.3 +/- 2.6% by yr 3; P < 0.05). In patients meeting surgical guidelines, parathyroidectomy is associated with improved bone mineral density.

Laser-Doppler flowmetry in monitoring regulation of rapid microcirculatory changes in spinal cord.

We established a rabbit model for continuous on-line monitoring of spinal cord microcirculation using laser-Doppler flowmetry (LDF). We tested the suitability of this model for studying rapid, nonequilibrium microcirculatory blood flow (BF) states induced by pharmacological treatments, hemorrhage, and asphyxia. Effective BF regulation was observed at systemic arterial pressure levels of 50 mmHg. Autoregulatory vasodilation began 1 min after the onset of severe hypotension, whereas more immediate vasodilation took place after asphyxia (hypercarbia). Pathological situations were studied in a simple model of spinal cord (SC) ischemia-reperfusion after 10 (n = 7) and 25 min (n = 7) of ischemia and 2 h of reperfusion. After 25 min of ischemia, delayed hypoperfusion (BF -35 +/- 7%, P less than 0.01) took place in association with tissue edema. LDF offered sensitive, stable, and reproducible estimates of microcirculation with high temporal resolution, thus permitting on-line evaluation of rapid, nonequilibrium BF responses and delayed states of spinal cord BF dysregulation.

Blood flow and vascular permeability during motor dysfunction in a rabbit model of spinal cord ischemia.

BACKGROUND AND PURPOSE: Delayed deterioration of neurological function after central nervous system ischemia is a well-documented clinical problem. The purpose of our study was to elucidate the role of spinal cord blood flow and spinal cord-blood barrier integrity in the evolution of delayed neurological deterioration after transient spinal cord ischemia in rabbits. METHODS: Anesthetized rabbits were subjected to lumbar spinal cord ischemia (25 minutes) and variable periods of reperfusion (30 minutes to 48 hours after ischemia). Regional spinal cord blood flow was monitored by carbon-14-labeled iodoantipyrine autoradiography; vascular permeability was assessed by quantitative microhistofluorescence of Evans blue-albumin in frozen sections of spinal cord. Hindlimb motor function was assessed by standard scoring system and tissue edema by wet/dry weight method. RESULTS: Hindlimb motor function indicated complete paralysis during ischemia and partial gradual recovery upon reperfusion (up to 8 hours), followed by progressive deterioration to severe deficits over 48 hours. Severe vascular permeability disruption was noticed early (30 minutes) after reperfusion, but almost complete recovery reestablished at 8 hours was followed by a secondary progressive increase in vascular permeability. Blood flow was reduced by 20-30% (p less than 0.01) 4 hours after ischemia in the gray matter, but hyperemia (200-300%, p less than 0.01) was observed 12-24 hours after ischemia. Spinal cord water content increased by 5.7% (p less than 0.05) 24 hours after ischemia. CONCLUSIONS: This study demonstrates that delayed neurological and motor deterioration after spinal cord ischemia is associated with severe progressive breakdown of spinal cord-blood barrier integrity that develops late (hours) after the injury. Our data suggest that no ischemic insult in early or late reperfusion is associated with delayed motor deterioration.

Stereotaxic implantation of autologous adrenal medulla into caudate nucleus in four patients with parkinsonism. One-year follow-up.

Four patients with levodopa-responsive parkinsonism (aged 26, 35, 45, and 49 years) received autologous adrenal medullary implants into or near the left caudate nucleus by stereotaxic implantation after flank adrenalectomy. All patients had an immediate response to implantation lasting several days, during which parkinsonian signs and symptoms decreased. This period was followed by a gradual reappearance of symptoms in all but one patient. This patient had had a dramatic increase in "on" time without dyskinesias and a decrease in the severity and duration of "off" time. He died of multifocal glioblastoma 1 year after transplantation. Autopsy revealed no surviving adrenal cells. In one case, the stereotaxic implantation missed the basal ganglia, resulting in the placement of the adrenal medullary tissue into the medial thalamus and near the third ventricle; the patient did not improve. In the other two cases, a modest but definite increase in "on" time without dyskinesia and a reduction in the severity and duration of "off" time has been observed. The role of autologous adrenal medullary transplantation in patients with parkinsonism remains to be determined. Patients with a family history of cerebral malignancy may be at increased risk for the development of transplant-induced malignancy.

Nephrolithiasis and bone involvement in primary hyperparathyroidism.

PURPOSE: The purpose of this study was to compare patients with primary hyperparathyroidism with and without nephrolithiasis with regard to (1) biochemical profile, and (2) presence and extent of bone involvement. PATIENTS AND METHODS: Of 70 unselected patients enrolled in a longitudinal study on the natural history of primary hyperparathyroidism, 62 who underwent complete bone densitometry evaluation were considered. The patients had mild hypercalcemia (2.77 +/- 0.02 mmol/L), as well as elevated parathyroid hormone levels by mid-molecule, N-terminal, and immunoradiometric assays. Bone densitometry was assessed by dual-photon absorptiometry of the lumbar spine and femoral neck, and single-photon absorptiometry of the forearm. RESULTS: Eleven of the 62 patients (18%) had nephrolithiasis. There was no difference in serum parathyroid hormone levels, calcium, phosphorus, serum 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D3 between those with and without kidney stones. Total daily urinary calcium excretion was higher among those who formed stones (8.2 +/- 1.0 mmol versus 6.1 +/- 0.4 mmol, p less than 0.05), but not when expressed per mmol of creatinine (0.72 +/- 0.07 versus 0.69 +/- 0.04). Urinary hydroxyproline was also higher in patients who formed stones (58 +/- 11 mg/24 hours versus 37 +/- 2 mg/24 hours; p less than 0.05). Hypercalciuria occurred in 39% of the entire cohort (n = 24), and in 33% (n = 17) of those without stones. Only 29% (n = 7) of those with hypercalciuria had nephrolithiasis. Calcium excretion correlated positively with serum 1,25-dihydroxyvitamin D3 (r = +0.32, p less than 0.05), and negatively with forearm bone mineral density (all patients: r = -0.34, p less than 0.05; hypercalciuric patients: r = -0.53, p less than 0.05). Circulating 1,25-dihydroxyvitamin D3 levels were elevated in a similar proportion of (1) all patients (31%, n = 19); (2) those with nephrolithiasis (27%); and (3) those without stones (31%). Bone mineral density was less than 80% of normal in 61% of patients, but forearm, femoral neck, and lumbar spine density were indistinguishable among those with and without stones. CONCLUSIONS: Cortical bone demineralization occurs to the same extent and frequency in patients with and without nephrolithiasis, and these two subgroups share similar biochemical and bone densitometric profiles. The pathophysiologic events leading to renal and skeletal involvement in primary hyperparathyroidism may be less selective than previously believed, as evidenced by: (1) increased urinary hydroxyproline in patients with nephrolithiasis, and (2) documentation that urinary calcium excretion reflects not only vitamin D status, but bone resorption was well.

Effect of systemic platelet-activating factor (PAF) on the rabbit spinal cord microcirculation.

Platelet-activating factor (PAF) is an endogenous phospholipid mediator with pro-inflammatory and vasoactive properties. Since PAF has been implicated in ischemic neuroinjury, we determined its effects on rabbit spinal cord microcirculation (SCM). Using laser-Doppler flow measurements, we monitored mean arterial pressure and SCM continuously on-line during and after i.v. infusion (1 min) of 0.5 nmol/kg of PAF (n = 20) and measured thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in arterial blood 1.5 min after the infusion. Responses were compared to those after indometacin pretreatment (4 mg/kg, n = 11). During the infusion, spinal cord blood flow (SCBF) decreased by 14 +/- 5% (P less than 0.05) paralleling the systemic hypotensive changes (17 +/- 5%, P less than 0.01) with no changes in vascular resistance (SCVR). However, immediately after termination of PAF infusion, SCVR decreased by 17 +/- 5% (P less than 0.01) while SCBF rapidly recovered. Plasma levels of both TXB2 and 6-keto-PGF1 alpha were significantly elevated. TXB2 release was correlated with the degree of hypotension during the PAF infusion (r greater than 0.72; P less than 0.05) while 6-keto-PGF1 alpha release correlated well with the decrease in SCVR during the infusion period (r greater than 0.64; P less than 0.05). Indomethacin blocked both the hemodynamic events and the eicosanoid release induced by PAF. Our data suggest that PAF modulates SCM through eicosanoid-mediated mechanism.

Skeletal disease in primary hyperparathyroidism.

Most patients with primary hyperparathyroidism in the 1980s do not have evidence of bone disease when they are evaluated by conventional radiography. We sought to determine whether skeletal involvement can be appreciated when more sensitive techniques, such as bone densitometry and bone biopsy, are utilized. We investigated 52 patients with primary hyperparathyroidism. They had mild hypercalcemia, 2.8 +/- 0.03 mmol/liter (11.1 +/- 0.1 mg/dl), low normal phosphorus, 0.9 +/- 0.03 mmol/liter (2.8 +/- 0.1 mg/dl), and no symptoms or specific radiological signs of skeletal involvement. The greatest reduction in bone mineral density was found at the site of predominantly cortical bone, the radius (0.54 +/- 0.1 g/cm; 79 +/- 2% of expected), whereas the site of predominantly cancellous bone, the lumbar spine (1.07 +/- 0.03 g/cm2), was normal (95 +/- 3% of expected). The site of mixed composition, the femoral neck (0.78 +/- 0.14 g/cm2), gave an intermediate value (89 +/- 2% of expected). Preferential involvement of cortical bone with apparent preservation of cancellous bone in primary hyperparathyroidism was confirmed by percutaneous bone biopsy. Over 80% of patients had a mean cortical width below the expected mean, whereas cancellous bone volume in over 80% of patients was above the expected mean. The results indicate that the majority of patients with asymptomatic primary hyperparathyroidism have evidence by bone densitometry and bone biopsy for cortical bone disease. The results also indicate that the mild hyperparathyroid state may be protective of cancellous bone. The therapeutic implications of these observations await further longitudinal experience with this study population.

Parathyroid function in Paget's disease of bone.

In order to determine the prevalence of secondary hyperparathyroidism in patients with Paget's disease of bone, we measured serum parathyroid hormone levels (N-terminal assay) in 39 patients with a wide range of pagetic activity. All patients had normal serum calcium levels. A total of 30 patients were either untreated or had received no treatment for 6 months or longer when studied; the other 9 were receiving either salmon calcitonin (3) or EHDP (6). The results showed that in 7 of the 39 patients (18%) parathyroid hormone levels were increased above normal. These were among the most severely affected cases, as manifested by the degree of elevation of three pagetic biochemical indices: serum alkaline phosphatase, plasma bone Gla protein, and 24 h urinary hydroxyproline-creatinine ratios. Levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 were normal. We examined the relationships between parathyroid hormone and each of the three pagetic indices as well as serum calcium for the entire group of 39 patients. Parathyroid hormone values did not correlate with serum calcium measurements (r = -0.241, p = NS) but did correlate significantly with serum alkaline phosphatase (r = 0.496, p less than 0.001), plasma bone Gla protein (r = 0.537, p less than 0.001), and urinary hydroxyproline (r = 0.450, p less than 0.011). We conclude that relative or absolute increases in parathyroid hormone may occur in moderately active Paget's disease, possibly in the setting of greater calcium demands during periods of increased pagetic new bone formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Addisonian crisis while taking high-dose glucocorticoids. An unusual presentation of primary adrenal failure in two patients with underlying inflammatory diseases.

The diagnosis of acute hypoadrenalism seldom is considered in patients without known adrenal insufficiency who are taking supraphysiologic amounts of glucocorticoids. We report two patients who presented in acute addisonian crisis on more than one occasion while taking high doses of glucocorticoids (30 to 40 mg of prednisone daily) for underlying inflammatory disease (recurrent pleuropericarditis and sarcoidosis). Evidence of severe mineralocorticoid deficiency was present in each patient, and the conditions of both improved remarkably when mineralocorticoid was added to their regimens. The cause of primary adrenal failure and its acute presentation was unclear in both patients but is presumed to be related to the underlying inflammatory disease.

Deteriorating stroke model: histopathology, edema, and eicosanoid changes following spinal cord ischemia in rabbits.

Secondary motor dysfunction is often observed following ischemic episodes in the central nervous system. To study potential mechanisms of postischemic motor deterioration, we developed a rabbit spinal cord ischemia model that has characteristics similar to the clinical condition termed deteriorating stroke. In this model, 70% of the rabbits regained substantial motor function by 4 hours after complete hindlimb paralysis during lumbar spinal cord ischemia; however, over the next 20 hours motor function steadily declined to the point where only 30% of the rabbits had minimal hopping function. The role of eicosanoids in spinal cord ischemia was studied by radioimmunoassay of several prostaglandins (6-keto-PGF1 alpha, PGE2, and TxB2) in the spinal cord. After 5 minutes of reperfusion, TxB2 levels were markedly elevated (p less than 0.05) while 6-keto-PGF1 alpha levels did not change. The TxB2:6-keto-PGF1 alpha ratio was also significantly increased. After 30 minutes of reperfusion, PGE2 levels were also elevated (p less than 0.05). Tissue edema measured by microgravimetry was also increased after 30 minutes of reperfusion in both gray and white matter. By 4 hours of reperfusion, rabbits regained near-normal hindlimb motor function while PGE2, 6-keto-PGF1 alpha, TxB2, and tissue water content were back to normal. However, by 18 hours of reperfusion, when hindlimb function was deteriorating, TxB2 levels were elevated again, and edema in gray and white matter was increased as was the number of necrotic neurons observed by light microscopy. These results suggest that the secondary deterioration of motor neurologic function was due to the excess formation of TxA2 primarily in the late reperfusion phase. However, further studies are necessary to elucidate the relation of TxA2 with ischemic neural injury.

Increased thromboxane A2 and 5-HETE production following spinal cord ischemia in the rabbit.

Ischemia was induced for 25 min in the spinal cord of rabbits followed by a long term period of recirculation. At various time points of recirculation (5, 30 min, 4, 18 hr and 1 wk) slices were taken from the ischemic region and incubated for 45 min in Krebs-Ringer solution. The levels of the eicosanoids, PGE2, PGD2, PGF2 alpha, TXB2, 6-keto-PGF1 alpha and 5-HETE accumulated in the incubation medium were measured by radioimmunoassay. TXB2, release was found to be increased at an early (5 min) and late (1 wk) period of reperfusion. A seven-fold increase in the release of 5-HETE was found 5 min after reperfusion that tended to stay elevated at 18 hr and 1 week of recirculation. PGI2 synthetase activity decreased by 40% at 30 min, with return to normal at later time points. The ratio of TXA2/PGI2 was significantly higher than control at 30 min and 1 wk. The synthesis of PGE2, PGD2 and PGF2 alpha was maintained at normal levels throughout the complete course of reperfusion. No changes in eicosanoid synthesis were noted in remote spinal cord regions. The significant increase of TXA2 synthesis at 5 min and 1 wk of reperfusion may point to a role of this arachidonate metabolite in the acute events and in the later stages of neurological dysfunction. The enhanced release of 5-HETE, a metabolite of 5-HETE, suggest an enhanced formation of leukotriene B4 and peptide leukotrienes and a potential role for these 5-lipoxygerase metabolites of arachidonate in ischemia injury to the brain and the spinal cord.