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Biomedical subjects

L M Fishman

Publications and source records attributed to L M Fishman.

At least 19 recordsLinked to original sources
PubMed2001

Effects of marine sponge extracts on mitogen-activated protein kinase (MAPK/ERK(1,2)) activity in SW-13 human adrenal carcinoma cells.

Some species of marine sponge have been shown to produce metabolites with endocrine-altering and cell growth regulatory properties. Since cell division and differentiation are controlled, in part, by the mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK/ERK) cascade, we tested extracts (1.0mg/ml) from six shallow water marine species obtained in the Florida Keys for effects on MAPK/ERK(l,2) (sub-variant of EC 2.7.1.37) activity in incubations with SW-13 human adrenal carcinoma cells in culture. In these short-term incubations, extracts from two species, the purple bleeding sponge (Iotrochota birotulata) and the West Indian bath sponge (Spongia barbara), significantly inhibited MAPK/ERK(1,2) activity (to 51 and 44% of control levels, respectively) without altering cell survival. Western blots for phosphorylated and total ERK showed that ERK(2) predominated over ERK(1) by a factor of about 4:1 and that the phosphorylated forms of these isozymes were strongly suppressed by active extracts from both sponges. Another species, the green sponge (Haliclona veridis), whose extract has been shown previously to activate guanylate cyclase and to inhibit adenylate cyclase in a variety of mammalian tissues, was found not to affect MAPK/ERK(1,2) in human adrenal carcinoma cultures but did lyse and kill most of these cultured cells. Extracts from the sheepswool sponge (Hippospongia lachne) and the bleeding sponge (Oligoceras hemorrhages) did not significantly affect either MAPK/ERK(1,2) activity or the survival of attached cells. An extract from the fire sponge (Tedania ignis) did not alter MAPK/ERK(1,2) activity but did modestly decrease cell viability. These studies document for the first time species-specifc effects of marine sponge extracts on the MAPK/ERK(1,2) cascade and on the growth and survival of human adrenal carcinoma cells in culture.

Adrenal Gland Neoplasms↗
PubMed2001

Effects of androgens and estrogens and catechol and methoxy-estrogen derivatives on mitogen-activated protein kinase (ERK(1,2)) activity in SW-13 human adrenal carcinoma cells.

We tested the effects of 17beta-estradiol as well as its catechol- and methoxy-derivatives, two androgens (DHEA and testosterone), a glucocorticoid (cortisol), a mineralocorticoid (aldosterone), and progesterone on the activity of ERK(1,2), a key component of the ERK/MAPK enzyme phosphorylation cascade, in SW-13 human adrenal carcinoma cells. After a 24-hour exposure SW-13 cells incubated with 10(-5) M concentrations of 17beta-estradiol, its 2-hydroxy or its 2-methoxy derivative, all had elevated ERK activities (196%, 159%, and 275%, respectively) relative to control cells (p < 0.01). Incubation with testosterone resulted in 162% of control ERK activity (p < 0.01), whereas incubation with the far weaker androgen DHEA or with cortisol, aldosterone, or progesterone had no significant effects. These findings suggest sex steroid-specific influences in the induction or activation of signal transduction pathways known to play a crucial role in cellular proliferation and differentiation.

Adrenal Gland Neoplasms↗
PubMed2000

Alpha1 connexin 43 gap junctions are decreased in human adrenocortical tumors.

Gap junctional communication disorders have been implicated in the etiology of benign and malignant tumors. Understanding the type, distribution, and frequency of gap junctions in adrenal disorders should provide insight into the role of gap junctions in adrenal carcinogenesis as well as information that may be useful in developing improved diagnosis and treatment of adrenal diseases. Using immunocytochemical techniques, we have characterized and compared alpha1 connexins 43 gap junction protein levels in normal adrenal glands to those in benign and malignant adrenocortical human tumors. In addition, gap junction protein levels were studied in a human adrenal cancer cell line (H295). In both normal and neoplastic adrenal tissues, only alpha1 connexin 43 could be detected, whereas beta1 connexin 32 and beta2 connexin 26 were not found. In the normal adrenal gland, the zona fasciculata was demonstrated to have the highest number of gap junctions per cell (mean +/- SEM, 13.78 +/- 1.93). In contrast, in benign adrenocortical adenomas, the number of gap junctions per cell compared to that detected in normal adrenal glands was significantly reduced (mean +/- SEM, 4.6 +/- 1.17; P < or = 0.05), and the lowest number was found in malignant adrenocortical tumors (1.42 +/- 0.58; P < or = 0.05). Similarly, there were few or no alpha1 connexin 43 gap junctions in the H295 population. There was a progressive decrease in gap junction plaques in adrenocortical cancer cell populations compared to those in normal cell populations. Therefore, analysis of gap junction protein may be helpful for the differential diagnosis of benign and malignant adrenal tumors. The induction of gap junctions in malignant cells may provide a novel therapeutic strategy for adrenal cancer.

Adenoma↗
PubMed2000

Biosynthesis and metabolism of steroid hormones by human adrenal carcinomas.

Over a 15-year period, our university-based laboratory obtained 125 adrenal tumors, of which 15 (12%) were adrenal cortical carcinomas. Of these, 6 (40% of the carcinomas) occurred in patients with clear clinical manifestations of steroid hormone excess. Adrenal cortical carcinoma cells derived from the surgically resected tumors in 4 of these patients were isolated and established in primary culture. Radiotracer steroid interconversion studies were carried out with these cultures and also on mitochondria isolated from homogenized tissues. Large tumors had the lowest steroidogenic activities per weight, whereas small tumors had more moderately depressed enzyme activities relative to cells from normal glands. In incubations with pregnenolone as substrate, 1 mM metyrapone blocked the synthesis of corticosterone and cortisol and also the formation of aldosterone. Metyrapone inhibition was associated with a concomitant increase in the formation of androgens (androstenedione and testosterone) from pregnenolone. Administration of metyrapone in vivo before surgery in one patient resulted in a similar increase in plasma androstenedione, though plasma testosterone levels were not significantly affected. In cultures of two of four tumors examined, dibutyryl cAMP stimulated 11ss-hydroxylase activity modestly; ACTH also had a significant stimulatory effect in one of these tumors. Unlike results obtained with normal or adenomatous adrenal cortical tissues, mitochondria from carcinomatous cells showed a lack of support of either cholesterol side-chain cleavage enzyme complex or steroid 11ss-hydroxylase activity by Krebs cycle intermediates (10 mM isocitrate, succinate or malate). This finding is consistent with the concept that these carcinomas may tend to function predominantly in an anaerobic manner, rather than through the oxidation of Krebs cycle intermediates.

Adrenal Cortex Hormones↗
PubMed1998

Studies of the neuronal transdifferentiation process in cultured human pheochromocytoma cells: effects of steroids with differing functional groups on catecholamine content and cell morphology.

The neuronal differentiation of adrenal pheochromocytoma cells from human subjects was studied in vitro for periods of up to 65 days. Changes with time in culture were observed in both intracellular catecholamine content (progressive decreases in epinephrine, norepinephrine, and dopamine, except for a possible transient early increase in the latter) and in morphology (increases in neurite outgrowth) of cells cultured in control medium; supplementation of cultures with nerve growth factor resulted in a substantial increase in neurite formation. The effects on these changes of the presence in the culture medium of various steroids were examined. The addition of 11-oxygenated steroids (aldosterone, corticosterone, cortisol, or dexamethasone) at 10(-5) M concentrations caused at least 2.5-fold increases in mean intracellular dopamine and norepinephrine levels; with dexamethasone, 9-10-fold increases were observed. Intracellular epinephrine content was also enhanced by 11,17-oxygenated steroids (dexamethasone and cortisol), but not by the other 11-oxygenated compounds studied. These two 11,17-oxygenated glucocorticoids also inhibited the morphologic changes seen with extended periods in culture, decreasing the outgrowth of neurite projections and causing cells to attain a vacuolated and granular appearance; the presence of dexamethasone strongly inhibited the morphologic changes induced by nerve growth factor. 11-Deoxy steroid intermediates (pregnenolone, 11-deoxycorticosterone, and 11-deoxycortisol) had little or no effect on catecholamine content or on morphology. Preliminary observations suggest that C-18 and C-19 sex steroid hormones (17 beta-estradiol and testosterone) may have morphologic effects opposite to those of the 11-oxygenated compounds, showing a slight stimulatory influence on the formation of neurite projections, but no significant effect on catecholamine content.

Adrenal Cortex Hormones↗
PubMed1997

The management of diabetes insipidus in adults.

The management of patients with diabetes insipidus can be confusing because of the disorder's variable pathophysiology, the numerous medications used, and the possible complications related to their use. Nevertheless, the primary care physician, rather than the subspecialist, will increasingly be called on to manage patients with such relatively uncommon conditions in the future. If a few basic facts and principles are kept in mind, the care of most patients with diabetes insipidus can be successful. A comprehensive, practical review of the short- and long-term therapy for patients with diabetes insipidus, including central diabetes insipidus, nephrogenic diabetes insipidus, and the "excessive vasopressinase syndrome," is presented. The use of single and multidrug regimens, and of the newly marketed oral formulation of desmopressin acetate, is described for common clinical settings.

Acute Disease↗
PubMed1996

Ambulatory parathyroidectomy for primary hyperparathyroidism.

OBJECTIVE: To evaluate whether the combined application of preoperative localization and intraoperative monitoring of intact parathyroid hormone (iPTH) levels could facilitate safe outpatient parathyroidectomy. DESIGN: Consecutive patients, who had no antecedent social or medical conditions mandating hospitalization, were prospectively offered ambulatory parathyroidectomy with a mean follow-up of 7 months (range, 1-25 months). SETTING: Tertiary care referral center PATIENTS: From 85 patients who had primary hyperparathyroidism with hypercalcemia and elevated iPTH levels, 57 were offered outpatient parathyroidectomy. Nineteen patients were asymptomatic, 3 had hypercalcemic crisis, and the others gave a history of renal stones or had complaints consistent with bone disease. INTERVENTIONS: Technetium Tc 99m sestamibi scintiscans were used for preoperative localization. Monitoring iPTH levels during parathyroidectomy quantitatively assured the surgeon (G.L.I. only) when all hyperfunctioning glands were excised. MAIN OUTCOME MEASURE: The number of patients without complications and with short operative times who were discharged without hospital admission or overnight stay. RESULTS: The combination of preoperative localization of abnormal parathyroid glands and a decline in circulating iPTH levels predicting postoperative normocalcemia after excision of all hyperfunctioning glands resulted in successful parathyroidectomy in 84 of 85 patients. A decreased operative time (average, 52 minutes) with minimal neck dissection permitted outpatient parathyroidectomy in 42 of 57 eligible patients. CONCLUSIONS: The combination of preoperative parathyroid scintiscan localization and iPTH level monitoring during surgery permitted successful parathyroidectomy in an ambulatory setting in half of a consecutive series of patients with primary hyperparathyroidism. The safety, success, and likely cost savings of this approach suggest wider application.

Adolescent↗
PubMed1996

Tyrosine hydroxylase gene expression in varying forms of human pheochromocytoma.

We performed a comparative study of catecholamine content, tyrosine hydroxylase (TH) activity, and TH mRNA levels in normal human adrenals and various clinical forms of human pheochromocytoma. We studied sporadic, benign intra-adrenal chromaffin tumors and other non-malignant intra-adrenal tumors associated with multiple endocrine neoplasia type 2B (MEN 2B) and von Hippel-Lindau disease along with one extra-adrenal malignant pheochromocytoma. Our findings suggest substantial differences in TH transcriptional rates or the stability of TH mRNA or both may contribute to altered TH expression in human chromaffin cells associated with "normal" adrenal tissues and various forms of pheochromocytoma and distinctive patterns of expression in the different settings in which these tumors arise.

Adrenal Gland Neoplasms↗
PubMed1996

Ultrastructural dynamics of mitochondrial morphology in varying functional forms of human adrenal cortical adenoma.

Adrenal cortical mitochondria display an extensive capacity to adapt morphologically to the functional state of the adrenal cortical cell. In the present study, we have used transmission electron microscopy to analyze cortical tissues from 3 normal human adrenal glands (zona fasciculata and zona glomerulosa), and from 8 steroid-secreting adrenal cortical adenomas (3 cortisol-producing, 4 aldosterone-producing, and 1 progesterone-producing tumor), correlating both clinical and biochemical features with cellular ultrastructure. The morphology of mitochondria was related to the enzyme activity and steroid-biosynthetic capacity of each tumor. Cells from aldosterone-producing adenomas demonstrated a large number of elongated tubular mitochondria with characteristic bridging of inner membranes, producing a lamellar-type pattern. Cells from cortisol-producing adenomas showed large round mitochondria with vesicular or tubulovesicular inner membranes surrounded by a characteristic dilated smooth endoplasmic reticulum. A highly unusual progesterone-producing adenoma, in which a deficiency of 21 alpha-hydroxylase activity was demonstrated, showed a peculiar type of enlarged lamellar mitochondria with bright inner matrix and a reduced number of inner membranes. Therefore, the ultrastructural characteristics of adrenal cortical mitochondria appear to be potential markers for the differentiation of steroid-producing adenomas. These studies point to the possibility of a broader use of electron microscopy in the study of adrenal tumors.

Adenoma↗
PubMed1996

The piriformis syndrome.

Piriformis syndrome is an often misdiagnosed cause of sciatica, leg, or buttock pain, and disability. The sciatic nerve may be compressed within the buttock by the piriformis muscle, with pain increased by muscular contraction, palpation, or prolonged sitting. A thorough medical history and physical examination are essential to proper diagnosis. Diagnostic testing may be used to differentiate piriformis syndrome from other causes of sciatica, lower extremity weakness, and pain. This article reviews the pathophysiology and management of piriformis syndrome.

Buttocks↗
PubMed1995

Heparin-induced aldosterone suppression and hyperkalemia.

PURPOSE: To review the effects of heparin and heparinoid compounds on aldosterone physiology and associated induction of hyperkalemia. MATERIALS AND METHODS: A comprehensive literature search (of human and animal data) was carried out by computer and by using reference citations from primary sources. RESULTS: Heparin and its congeners are predictable, potent inhibitors of aldosterone production. This inhibitory effect is specific for the zona glomerulosa; other corticosteroids are not affected. Aldosterone suppression occurs within a few days of initiation of therapy, is reversible, and is independent of either anticoagulant effect or route of administration. Decreases in aldosterone levels may occur with heparin dosages as low as 5,000 U BID. The most important, but probably not the only mechanism of aldosterone inhibition appears to involve reduction in both the number and affinity of the angiotensin-II receptors in the zona glomerulosa. Prolonged use of heparin causes marked reduction in the width of the adrenal zona glomerulosa. CONCLUSIONS: Aldosterone suppression results in natriuresis and less predictably in decreased excretion of potassium. Greater than normal serum potassium levels occur in about 7% of patients, but marked hyperkalemia generally requires the presence of additional factors perturbing potassium balance (in particular, renal insufficiency, diabetes mellitus, or the use of certain medications). Heparin-induced increases in serum potassium need to be better anticipated by clinicians. Serum potassium levels should be monitored periodically in patients being given heparin for 3 or more days, and in patients at relatively high risk for hyperkalemia, the monitoring interval should probably be no greater than 4 days.

Adrenal Glands↗
PubMed1995

Review of the literature: severe hyperphosphatemia.

A patient with a markedly elevated serum phosphorus level (23.9 mg/dL) is described, followed by a brief review of severe hyperphosphatemia. Elevated serum phosphorus levels may be artifactual or true. True hyperphosphatemia is usefully subdivided according to (a) whether phosphorus is added to the extracellular fluid from a variety of exogenous or endogenous sources, or (b) whether the urinary excretion of phosphorus is reduced from either decreased glomerular filtration or increased tubular reabsorption. Severe hyperphosphatemia, defined herein as levels of 14 mg/dL or higher, is almost invariably multifactorial--usually resulting from addition of phosphorus to the extracellular fluid together with decreased phosphorus excretion. The hyperphosphatemia of the patient described herein appeared to result from a combination of dietary phosphorus supplementation, acute renal failure, acute pancreatitis, and ischemic bowel disease, complicated by lactic acidosis.

Acid-Base Equilibrium↗
PubMed1994

Edema control in the management of disabling chronic venous insufficiency.

This study was undertaken to assess the biomedical and socioeconomic rationale of edema control in disabling chronic venous insufficiency (CVI). In this 15-year retrospective survey (1974 through 1988) edema control was achieved by use of Unna's boot for leg ulcerations and by compressive hosiery for prevention of ulcerations. The study included 2,317 self- or physician-referred patients with disabling CVI, of whom 998 presented with venous stasis ulcers, many with recurrent ulcerations. Two hundred thirty-six patients were seen and treated only once and never returned. They were listed as not healed. Including patients who never returned after the first visit, the overall healing rate was 60.9%. Excluding the nonreturning patients, the overall rate of verified healing was 73.3%. The healing rate was 91% for first ulcers of complaint patients (patients treated at least 12 times in 32 weeks). The Unna's boot, being a functional substitute for the failing muscle pump in CVI, is a noninvasive and ambulatory method of controlling edema and treating ulcers in CVI. It does not interfere with patients' activities, it is inexpensive, and it is adaptable to middle aged and elderly ambulatory populations.

Administration, Topical↗
PubMed1992

Electrophysiologic evidence of piriformis syndrome.

Piriformis syndrome (PS) is defined by a loose cluster of symptoms arising from entrapment of one or both divisions of the sciatic nerve as they pass the sciatic notch. This paper presents a method of using the H-reflex as an aid in the diagnosis of PS. Forcible pressure from the piriformis muscle on the sciatic nerve can be induced by internal rotation of an affected limb in an adducted, flexed position. This pressure is reflected in a delay of the H-reflex. The length of delay seen in 39 legs of 34 patients who met the criteria for PS is compared with that seen in 13 unaffected contralateral limbs and 14 limbs from able-bodied subjects. Mean delay of H-reflex was 2.66 msec for affected legs and .36 msec for the combined control groups (t = 7.45, p less than .001). There were no differences in the H-reflexes themselves between groups. Physical therapy aimed at reducing mechanical impingement was successful in 11 of 12 patients on followup at three to nine months.

Adolescent↗
PubMed1989

Biosynthesis of androgens by pheochromocytomas.

Homogenates from four adrenal pheochromocytomas converted 4-14C-labeled pregnenolone, 17-hydroxyprogesterone, and dehydroepiandrosterone into androstenedione and testosterone. In addition to these androgens, labeled pregnane substrates were also transformed into corticosteroids, as previously reported, and this conversion occurred in even higher yield. The formation of labeled metabolites of either pathway was greater in homogenates from intraadrenal pheochromocytomas than in those derived from an extraadrenal tumor, but less than in preparations of hyperplastic adrenal cortex. Incubations of subcellular fractions isolated from an adrenal pheochromocytoma showed that the enzyme activities involved in androgen formation from the radioactive substrates studied were associated with the microsomes and required exogenous cofactors. In contrast to adrenocortical tissue, chromaffin cell preparations uniformly failed to convert substrate [4-14C] cholesterol into either androgens or corticosteroids. The data available demonstrate the presence in chromaffin tissue of all of the enzyme activities required for the biosynthesis of androgens and corticosteroids except for those involved in the side-chain scission of cholesterol.

Adrenal Cortex↗
PubMed1989

Pheochromocytoma. Lateral versus anterior operative approach.

The possibility of bilateral, extra-adrenal, and malignant tumors has dictated a thorough abdominal exploration through an anterior incision in the management of patients with pheochromocytomas. Careful visualization or palpation of the sites known to harbor secondary tumors is still recommended by many surgeons. The present study contrasts the results and morbidity of the retroperitoneal approach with that of the intraperitoneal operative approach for resection of pheochromocytoma. In the last 14 years, 37 patients had successful total resections of their pheochromocytomas, excluding one patient with metastasis to the liver at the time of surgery who died 10 years after operation. After preoperative localization of their tumors, 17 patients were explored anteriorly and 20 underwent resection using a lateral approach. Thirty-one patients have been followed from 2 to 141 (average 56) months. All patients have either returned to a normotensive state on no medication (27 patients) or, while requiring medication (9 patients), have had normal urinary metanephrine/catecholamine levels, except for the one patient with metatastic disease. There were substantial differences in morbidity rates between the two groups, however. Four patients (20%) had minor postoperative complications, following retroperitoneal resection that included pleural effusion, urinary retention, pulmonary congestion, and fever. Nine patients (53%) had complications when the anterior approach was used, including splenectomy in two, pneumonia, and postoperative fever. Postoperative hospital stay averaged 9.8 days (range, 4 to 21 days) for the anterior group and 6.1 days (range, 4 to 12 days) when a lateral approach was used (p = 0.002). Our data suggest that, with accurate unilateral localization, the flank, retroperitoneal approach for resection of pheochromocytoma can be used successfully with less morbidity.

Adolescent↗
PubMed1989

Influence of ethanol on fetal brain cholinergic enzyme activities.

Cultured brain cells from rat fetuses of ethanol-treated mothers demonstrated more than 2-fold elevations in choline acetyltransferase (ChAT) activity relative to those of control (saline-exposed) fetal brain cells. When cells from control animals were incubated in vitro for 5 days with 0.1% ethanol, ChAT activity was found to increase more than 4-fold. Brain cells from in utero ethanol-treated animals further exposed to ethanol in vitro for 5 days demonstrated significantly higher ChAT activity compared to cells exposed to ethanol only in vivo. These levels were more than 6 times greater than those of central nervous system cells never exposed to ethanol. Acetylcholinesterase (AChE) activity was significantly elevated (greater than 4-fold) in fetal brain cells when ethanol was present both in vivo and in vitro, but neither treatment alone resulted in any significant changes in AChE. These effects of ethanol on enzymes involved in acetylcholine metabolism may contribute to the different developmental neurologic abnormalities associated with fetal alcohol exposure.

Acetylcholinesterase↗