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Biomedical subjects

O H Clark

Publications and source records attributed to O H Clark.

At least 145 records · Page 8Linked to original sources
PubMed1991

Thyroid cancer.

There have been important recent advances in our understanding of the biologic nature of thyroid cancer and in the early diagnosis of the disease. Despite these advances, there is still considerable controversy over the management of thyroid cancer, including the extent of surgery, the indications for the use of iodine-131, the effectiveness of thyroid-stimulating hormone suppression, and the prediction of outcome. In this review, the current status of the diagnosis and management of the various types of thyroid cancer are carefully reviewed and extensively documented.

Humans↗
PubMed1991

Increased stimulatory G protein in neoplastic human thyroid tissues.

Prior studies in our laboratory have shown that thyroid neoplasms produce increased amounts of cyclic adenosine monophosphate (cAMP). Thyroid-stimulating hormone receptors act through the stimulatory G protein (Gs) to activate adenylate cyclase, the enzyme responsible for cAMP production. The purpose of this study is to measure the activity and amount of Gs in human normal and neoplastic thyroid tissue to see whether alterations in Gs are responsible for the increased cAMP production seen in thyroid neoplasms. Four tumors with a high TSH-stimulated cyclase activity of 497.6 +/- 71.9 pmol/mg/30 min versus 35.9 +/- 13.5 pmol/mg/30 min for normal tissue from the same patients were studied. In reconstitution studies measuring Gs activity, neoplastic thyroid tissue produced 637 +/- 106 pmol cAMP/mg S49/mg thyroid membrane min versus 363 +/- 133 pmol cAMP/mg 549/mg thyroid membrane/min produced by normal thyroid tissue. Qualitative assessments of the amount of Gs present with cholera toxin-mediated adenosine diphosphate ribosylation showed increased Gs in thyroid tumors. Western blotting with antibodies directed against Gs showed a 3.3 +/- 0.6-fold increase in the amount of Gs in these thyroid tumors. These experiments identify an increase in the amount of an otherwise normal Gs as the biochemical defect responsible for the increased cAMP production in this group of tumors.

Adenocarcinoma↗
PubMed1991

Insulinomas associated with multiple endocrine neoplasia type I: the need for a different surgical approach.

Insulinomas are usually solitary (greater than 90%) benign pancreatic tumors readily cured by enucleation or resection. To determine whether the 4% of insulinomas associated with multiple endocrine neoplasia type 1 (MEN-I) require a different surgical approach, we analyzed our experience in seven patients with MEN-I insulinomas treated during the past 28 years at the University of California, San Francisco, and 53 patients reported in the English literature. We found: (1) MEN-I insulinomas were associated with an antecedent history of other endocrinopathy or a family history of MEN-I in six of our seven patients, allowing preoperative identification of these patients. (2) All seven of our patients had hyperparathyroidism and four had pituitary tumors. Overall 83.6% of patients had hyperparathyroidism and 45.4% had pituitary tumors. (3) In our patients, MEN-I insulinomas were usually multiple (median 3; range 1 to 14). Overall, 76.3% of patients had multiple islet cell tumors. (4) Distal subtotal pancreatectomy with enucleation of any tumors identified in the head of the gland was done in five of our patients. Four are now normoglycemic and one is diabetic. Enucleation alone failed in one patient. The seventh patient was diagnosed at autopsy. Because the diagnosis of MEN-I can generally be made, preoperative strategy can address the unique pathologic features of insulinomas associated with MEN-I. The tumors are usually multiple, so local resection will fail. We recommend subtotal pancreatectomy in addition to enucleation of tumors in the head of the pancreas.

Adolescent↗
PubMed1990

Two G protein oncogenes in human endocrine tumors.

Somatic mutations in a subset of growth hormone (GH)-secreting pituitary tumors convert the gene for the alpha polypeptide chain (alpha s) of Gs into a putative oncogene, termed gsp. These mutations, which activate alpha s by inhibiting its guanosine triphosphatase (GTPase) activity, are found in codons for either of two amino acids, each of which is completely conserved in all known G protein alpha chains. The likelihood that similar mutations would activate other G proteins prompted a survey of human tumors for mutations that replace either of these two amino acids in other G protein alpha chain genes. The first gene so far tested, which encodes the alpha chain of Gi2, showed mutations that replaced arginine-179 with either cysteine or histidine in 3 of 11 tumors of the adrenal cortex and 3 of 10 endocrine tumors of the ovary. The mutant alpha i2 gene is a putative oncogene, referred to as gip2. In addition, gsp mutations were found in 18 of 42 GH-secreting pituitary tumors and in an autonomously functioning thyroid adenoma. These findings suggest that human tumors may harbor oncogenic mutations in various G protein alpha chain genes.

Amino Acid Sequence↗
PubMed1990

Results of surgical treatment for hyperparathyroidism associated with renal disease.

Recently, the role and timing of surgery for treating secondary and tertiary hyperparathyroidism (HPT) have been questioned. In order to delineate the indications for surgery in these patients, a retrospective analysis of 53 consecutive patients treated with parathyroidectomy was conducted. Subtotal thyroidectomy was done in 37 of 45 patients undergoing their initial operations for HPT. Eight additional patients were referred after failed operations. Of 33 patients with preoperative bone pain, 70% improved. Joint pain improved in 87% of 30 patients, pruritus improved in 81% of 27 patients, and preoperative malaise improved in 73% of 33 patients after parathyroidectomy. Abdominal pain and irritated eyes were unlikely to improve. The best predictors of a successful outcome were a markedly elevated preoperative immunoreactive parathyroid hormone (mid-region) level and an elevated alkaline phosphatase level. There were no perioperative deaths. One patient (1.6%) had a recurrent laryngeal nerve injury, and one patient required reoperation for a neck hematoma. No patient had permanent hypoparathyroidism, but transient hypocalcemia (less than 7 mg/dL) occurred in 22%. Postoperative hypocalcemia correlated with elevated preoperative alkaline phosphatase levels (r2 = 0.247).

Adult↗
PubMed1990

Iodide-induced hypothyroidism in patients after thyroid resection.

The purpose of this investigation was to determine whether an intrinsic defect in thyroid hormone production is required for the development of iodide-induced hypothyroidism or does it also develop in TSH-stimulated normal thyroid tissue. To answer this question, we studied the response to iodine administration (180 mg iodide daily for 3-4 months) in eight euthyroid patients who had had partial thyroidectomies 2 months to 10 years previously for benign thyroid nodules, and in three euthyroid control subjects. In all 11 euthyroid patients, basal serum TSH concentrations increased during iodide administration. In six of the eight patients who had previous thyroid operations and in two of the three control patients, basal serum TSH concentrations increased into the abnormal range (greater than 6 U ml-1). Increased serum TSH concentrations were noted as early as 1 week after potassium iodide had been started and the increased levels persisted during the period of iodide administration. Although basal values for serum TSH concentration were initially within the normal range, those patients with highest basal serum TSH values developed the greatest increase in TSH in response to potassium iodine. Among the eight patients treated by partial thyroidectomy, serum T4 concentrations decreased in five, serum T3 concentration decreased in three and all five developed mild symptoms of hypothyroidism while receiving iodide. Serum T4 concentrations also decreased slightly in two of the three control patients. Serum total iodine levels increased from 7.0 +/- 0.5 to 315.7 +/- 108.6 g dl-1 (mean-+/- standard error) during potassium iodide administration, but there was no correlation between the level of serum iodide concentration achieved and inhibition of thyroid function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Persistent and recurrent hyperparathyroidism: assessment with gadopentetate dimeglumine-enhanced MR imaging.

The effect of gadopentetate dimeglumine on signal intensity of abnormal parathyroid glands was assessed in 14 patients with persistent and recurrent hyperparathyroidism. Non-contrast material-enhanced T1- and T2-weighted spin-echo images were compared with T1-weighted images obtained 1 minute and 10 minutes after administration of gadopentetate dimeglumine. Percentage of contrast between the abnormal gland and surrounding tissue was determined with the use of skeletal muscle, subcutaneous fat, and thyroid gland as reference tissues. All 11 abnormal parathyroid glands showed low to intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Gadopentetate dimeglumine significantly increased the signal intensity enhancement ratio of all abnormal parathyroid glands, causing increased percentage of contrast relative to the thyroid gland and skeletal muscle on T1-weighted images. However, the percentage of contrast relative to these tissues was even greater on nonenhanced T2-weighted images. Thus, gadopentetate dimeglumine can substantially enhance the signal intensity of abnormal parathyroid glands and improve differential contrast with some neighboring tissues on T1-weighted images, but it does not improve contrast with surrounding tissue beyond that achieved on T2-weighted images.

Adipose Tissue↗
PubMed1990

Actin architecture of cultured human thyroid cancer cells: predictor of differentiation?

The actin cytoskeleton is important for cell structure and motility. A disordered actin architecture has been correlated with a high metastatic potential in melanoma, fibrosarcoma, and colon cancer models. Thyrotropin is known to induce growth and differentiation in cultured thyroid cells, whereas the carcinogenic phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) causes dedifferentiation and malignant transformation in many cell lines. We therefore assessed the effect of thyrotropin and TPA on the actin architecture of FTC-133 human follicular thyroid cancer cells in continuous culture. Staining of filamentous actin with rhodamine phalloidin showed that 1 mU/ml or 30 mU/ml thyrotropin-induced actin polymerization was detectable at 1 hour but more notable at 24 hours. Similarly TPA (0.008 to 10 mumol/L) caused rapid actin fiber disruption and redistribution to the cell periphery. Secondary antibody staining for alpha-actinin, a protein that binds and crosslinks actin, was more prominent after treatment with thyrotropin but decreased after TPA. These findings indicate that the actin cytoskeleton has a dynamic response to trophic factors. Thyrotropin promoted actin polymerization, but TPA caused depolymerization. These effects may correlate with cellular alpha-actinin levels. Actin architecture may therefore reflect the state of differentiation of thyroid tumor cells.

Actin Cytoskeleton↗
PubMed1990

Surgery in the treatment of thyroid cancer.

Patients with thyroid cancers offer a clinical challenge to the physician and surgeon for both treatment and research. It is evident that preoperative, intraoperative, and postoperative management can all favorably affect the clinical outcome. This demands close cooperation among internist, endocrinologist, radiotherapist, and surgeon. As surgeons, we advocate total thyroidectomy for most thyroid cancers, when it can be done safely, because recurrences will be minimized and the subsequent use of radioactive iodine treatment is facilitated. In the hands of an experienced thyroid surgeon, total thyroidectomy can be accomplished with a minimum of risk. In the future we hope to be able to identify patients at highest risk for aggressive tumor behavior and select these patients for the most aggressive treatment plans. In other cases early detection by surveillance of patients at risk for thyroid cancer, particularly medullary thyroid cancer, has already favorably affected prognosis by allowing treatment at an earlier stage of disease.

Adenocarcinoma↗
PubMed1989

Increased serum levels of a parathyroid hormone-like protein in malignancy-associated hypercalcemia.

STUDY OBJECTIVE: To measure the serum levels of a newly described parathyroid hormone-like protein (PLP) which was isolated from malignant tumors associated with hypercalcemia, and determine whether PLP is a humoral factor in malignancy-associated hypercalcemia. DESIGN: A cross-sectional study of serum levels of PLP using a newly developed radioimmunoassay. SETTING: A university-affiliated Veterans Administration hospital in San Francisco, California, a University hospital in Hong Kong, and a private hospital in Danville, Pennsylvania. PATIENTS: Patients with hypercalcemia (calcium greater than 2.65 mmol/L) and a diagnosis of malignancy were studied. Control groups included normocalcemic patients with malignancy, patients with hyperparathyroidism, and normal subjects. MEASUREMENTS AND MAIN RESULTS: Serum immunoreactive PLP (iPLP) levels in normal subjects were less than 2.5 pmol eq/L (10 pg/mL), and 68% of subjects had undetectable levels. The serum concentration of iPLP was normal in 15 of 16 hypercalcemic patients with hyperparathyroidism. Serum iPLP was increased (greater than 2.5 pmol eq/L) in 36 of 65 (55%) patients with malignancy-associated hypercalcemia, with a mean value of 6.1 +/- 0.9 pmol eq/L (24 pg/mL). In a subgroup of patients with solid tumors serum iPLP was increased in 30 (71%) of 42 hypercalcemic patients, with a mean value of 6.5 +/- 0.9 pmol eq/L. Serum iPLP was elevated in only 3 of 23 normocalcemic patients with cancer. In patients with solid malignancies (n = 59), levels of iPLP were positively correlated with the total serum calcium (r = 0.43, P less than 0.01). CONCLUSION: The data indicate a relation between the serum concentration of iPLP and the presence of hypercalcemia in solid malignancies. The results support a role for PLP as a humoral mediator of hypercalcemia in most patients with solid tumors. Measurement of iPLP should be useful in the differential diagnosis of hypercalcemia.

Bone Neoplasms↗
PubMed1989

The reasons for failure in parathyroid operations.

Primary hyperparathyroidism occurs in about 1 in every 700 individuals. We analyzed our experience with 81 patients with persistent or recurrent hyperparathyroidism who were treated at the University of California, San Francisco, and the Veterans Administration Medical Center, San Francisco, from January 1979 through September 1988. In the 89 reoperations performed, the following six reasons or combination of reasons were responsible for the failed initial operation: (1) in 50 patients, there were multiple abnormal glands (30 hyperplastic and 20 second adenoma); (2) in 40 patients, the tumor was located in an ectopic position (22 mediastinal, 9 deep-seated cervical, 7 intrathyroidal, and 2 undescended); (3) in 17 patients, there were supernumerary parathyroid glands; (4) in 12 patients, the abnormal parathyroid glands were found in normal locations and the tumors were missed because of surgeon inexperience; (5) in 4 patients, failure was due to metastatic parathyroid cancer; and (6) in 4 patients, failure was due to errors on frozen section examinations. Preoperative localization studies usually identified the abnormal parathyroid tumor(s) prior to reoperations and were helpful in these patients. Knowledge of the reasons for failed parathyroid operations and the usual and unusual sites where parathyroid tumors are situated as well as a complete exploration should decrease the frequency of failed parathyroid operations. Localization studies are helpful for identifying these often elusive tumors.

Choristoma↗
PubMed1989

Medullary thyroid carcinoma. The need for early diagnosis and total thyroidectomy.

Forty patients with medullary thyroid carcinoma and 3 patients with C-cell hyperplasia were studied. Seventeen (40%) cases were sporadic and 26 (60%) were hereditary. Eight patients had type lla multiple endocrine neoplasia, 7 patients had type llb multiple endocrine neoplasia, and 11 patients had familial nonmultiple endocrine neoplasia medullary thyroid carcinoma. Mean follow-up was 6.3 years, with actuarial survival of 88% and 78% at 5 and 10 years (22 and 13 patients), respectively. Seven patients died 1.5 to 10 years after the initial operation; all had advanced disease at presentation (6 with distant, 1 with lymph node metastasis). No deaths occurred in patients with familial nonmultiple endocrine neoplasia medullary thyroid carcinoma, C-cell hyperplasia, or medullary thyroid carcinoma limited to the thyroid gland. Nineteen (68%) of 28 patients diagnosed without screening had regional or distant metastases, whereas only 6 (40%) of 15 patients diagnosed by screening had metastases. Twenty-six patients treated initially with total thyroidectomy and central neck clearance required an average of one reoperation, whereas those with lesser initial procedures required an average of two reoperations. We concluded that (1) familial nonmultiple endocrine neoplasia medullary thyroid carcinoma, early medullary thyroid carcinoma or C-cell hyperplasia, and asymptomatic patients have a good prognosis; (2) screening for medullary thyroid carcinoma by measuring serum calcitonin levels results in earlier diagnosis; and (3) total thyroidectomy and central neck clearance is the procedure of choice for medullary thyroid carcinoma.

Adult↗
PubMed1989

Inhibition of endogenous lactate turnover with lactate infusion in humans.

The extent to which lactate infusion may inhibit endogenous lactate production, though previously considered, has never been critically assessed. To examine this proposition, single injection tracer methodology (U-14C Lactate) has been used for the estimation of lactate kinetics in 12 human subjects under basal conditions and with the infusion of sodium lactate. The basal rate of lactate turnover was measured on a day before the study with lactate infusion, and averaged 63.7 + 5.5 mg/kg/h. Six of these individuals received a stable lactate infusion at an approximate rate of 160 mg/kg/h, while the remaining six individuals were infused at the approximate rate of 100 mg/kg/h. It has been found that stable lactate infused at rates approximating 160 mg/kg/h consistently produced a complete inhibition of endogenous lactate production. Infusion of lactate at 100 mg/kg/h caused a lesser and more variable inhibition of endogenous lactate production (12% to 64%). In conclusion, lactate infusion significantly inhibits endogenous lactate production.

Carbon Radioisotopes↗
PubMed1989

MR signal intensity of parathyroid adenomas: correlation with histopathology.

Recent experience has shown that parathyroid adenomas vary in their MR signal intensity, which raises the question of whether the signal intensity is related to different histologic characteristics. In order to address this question, 10 patients who had MR imaging studies (four at 0.35 T, six at 1.5 T) showing large- to medium-sized parathyroid adenomas and who subsequently underwent surgery with histologic proof of the lesion were evaluated. The MR appearance was compared with histologic characteristics. The adenomas were classified into three groups according to the MR appearance: group I, low signal intensity on short TR/TE images, high signal intensity on long TR/TE images (n = 5); group II, low signal intensity on short and long TR/TE images (n = 3); group III, high signal intensity on short and long TR/TE images (n = 2). Histologic analysis revealed that the major features of each group were different. High cellularity without degeneration or fibrosis was observed for all five adenomas from group I. In group II, all three adenomas showed cellular degenerative changes, old hemorrhage with hemosiderin-loaded macrophages, and/or fibrosis. In group III, both adenomas showed evidence of acute hemorrhage without significant degenerative or fibrotic changes. These data suggest that the signal intensity of parathyroid adenomas on T1- and T2-weighted images corresponds at least in part to differences in histologic composition.

Adenoma↗
PubMed1989

Total gastrectomy and small intestinal cholesterol synthesis in diabetic rats.

Cholesterol synthesis is increased two- to threefold in the small intestine of diabetic rats. We have observed, in three separate experiments, that the characteristic increase in small intestinal cholesterol synthesis (SICS) in diabetic rats was prevented by total gastrectomy. Food intake was increased twofold, and the small intestine hypertrophied in the gastrectomized diabetic animals. In normal animals, total gastrectomy resulted in only a very small increase in intestinal cholesterol synthesis. In hyperphagic lactating animals, total gastrectomy did not prevent the characteristic increase in SICS that is usually observed in this hyperphagic model. These results indicate that the effects of total gastrectomy on preventing an increase in SICS are relatively specific for the diabetic state. The mechanism by which total gastrectomy prevents the increase in intestinal cholesterol synthesis in diabetic animals is unknown. Vagotomy did not prevent the typical increase in intestinal synthesis in diabetic animals. Additionally, selectively removing either the antrum or fundus of the stomach did not prevent the increase in SICS in diabetic animals, indicating that the inhibition requires the removal of the entire stomach. It can be speculated that the stomach produces a substance that induces the increase in SICS observed in diabetic animals and that total gastrectomy removes this stimulatory substance.

Animals↗
PubMed1989

A new experimental model for secondary hyperparathyroidism.

We have developed an animal model to study the pathogenesis of secondary hyperparathyroidism by inducing stable uremia in Sprague-Dawley rats by selective microligation of terminal branches of the left renal artery, followed by right nephrectomy. After 4 weeks the animals were killed, the parathyroid glands were removed and weighed, and blood samples were obtained. Of 30 rats, uremia developed in 22 (73%; uremic group) and eight (27%) died or did not become uremic. A sham-operated group of 15 rats served as control (control group). Creatinine levels were 1.8 +/- 0.5 mg/dl in the uremic group versus 0.5 +/- 0.1 mg/dl in the control group (p less than 0.0001). Parathyroid glands were hyperplastic in all rats with uremia and were heavier than parathyroid glands of control animals (70.3 +/- 26 vs 19.1 +/- 8 micrograms; p less than 0.0001). In the group with uremia, parathyroid hormone levels were increased over those of the control group (112.6 +/- 13 vs 28.9 +/- 6.2 pg/ml; p less than 0.0001), whereas osteocalcin levels were similar (36.6 +/- 11 vs 37.5 +/- 1 ng/ml). Serum calcium, phosphate, and alkaline phosphatase levels were similar in both groups. Our model can be used to test hypotheses concerning the treatment of secondary hyperparathyroidism and the relative pathogenetic relevance of vitamin D deficiency and phosphate retention.

Alkaline Phosphatase↗