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Biomedical subjects

J B Hill

Publications and source records attributed to J B Hill.

At least 19 recordsLinked to original sources
PubMed1992

Indium-111 monoclonal antibody B72.3 scintigraphy in colorectal cancer. Correlation with computed tomography, surgery, histopathology, immunohistology, and human immune response.

As part of an open-labeled nonrandomized multi-institutional Phase III study, the authors compared the results of In-111 (In-111) B72.3 glycyl-tyrosyl-n-diethylenetriaminepentaacetic acid lysine (GYK-DTPA) monoclonal antibody scintigraphy with computed tomography (CT), surgery, histopathology, immunohistology, and human antibody response in 23 patients with primary colorectal carcinoma. There were no significant adverse reactions to 1 mg of In-111-labeled antibody. Planar imaging identified 16 of 23 primary colon lesions, whereas single photon emission computer tomography (SPECT) imaging identified 21. SPECT also correctly identified lymphatic involvement in four patients. (There were two false-positive results.) Liver metastases were identified with SPECT imaging. Twenty-six percent of patients developed human anti-mouse antibody (HAMA). These preliminary results demonstrate that In-111 B72.3 GYK-DTPA is a safe monoclonal antibody conjugate that has a high sensitivity for identifying primary colorectal cancer. Regional lymphatic and distant liver metastases also can be imaged, but false-positive results can occur.

Adenocarcinoma↗
PubMed1992

Antithyroid effects of coal-derived pollutants.

Endemic goiter in iodide-sufficient areas of the United States and Colombia has been linked to watersheds rich in coal and shale, which several reports suggest are the source of water-borne goitrogens. In this report the potential antithyroid activities of aqueous coal and shale extracts and of compounds identified in aqueous effluents from coal conversion processes were assayed in thyroid peroxidase (TPO) and thyroid slice systems. Aqueous extracts of coal and black shale were potent inhibitors of TPO or 125I organification by thyroid slices. The most abundant water-soluble compounds derived from coal are dihydroxy-phenols, thiocyanate, disulfides, and hydroxypyridines. The dihydroxyphenols resorcinol, 2-methylresorcinol, and 5-methylresorcinol (orcinol) were 26.7, 22.5, and 7.2 times more potent, respectively, than the antithyroid drug 6-propylthiouracil (PTU). Other dihydroxyphenols and thiocyanate were less potent but comparable in activity to PTU. All dihydroxypyridines and 3-hydroxypyridine produced inhibitory effects comparable to PTU. None of the disulfides inhibited TPO. The antiperoxidase effects of combinations of two dihydroxyphenols or one dihydroxyphenol and SCN were additive, whereas the effects of a combination of four dihydroxyphenols at threshold inhibitory concentrations were synergistic, resulting in net effects equivalent to or greater than the sum of the individual effects. Thus, antithyroid effects may be greatly amplified by exposure to multiple coal-derived goitrogens and could be many times that produced by any one of the contributing pollutants. These results demonstrate that potent water-borne goitrogens are derived from coal and shale and that their contamination of water supplies could pose a serious threat of thyroid disorders.

Animals↗
PubMed1992

Suckling reverses mammotrope responsiveness to TRH.

It is well established that suckling can alter the responsiveness of mammotropes to the prolactin (PRL) releasing actions of thyrotropin-releasing hormone (TRH). The purpose of the present study was to more critically characterize this phenomenon and to determine whether this effect was manifested at the point of TRH receptor binding and effector coupling. Cultured anterior pituitary (AP) cells from suckled and nonsuckled rats were subjected to reverse hemolytic plaque assays for PRL in the absence or presence of TRH. Treatment with TRH (100 nM for 2 h) significantly stimulated PRL secretion by pituitary cells from transiently suckled females (to 147.0 +/- 0.7% of control value; P < 0.05). Surprisingly, this same dose of the secretagogue caused a 30% inhibition (P < 0.05) of PRL release by AP cells obtained from nonsuckled lactators. In order to gain some insight into the possible mechanisms that govern these drastic changes in mammotrope responsiveness to TRH, we evaluated the ability of this secretagogue to activate the phosphoinositidase pathway. To this end, we chose to measure the intracellular accumulation of inositol monophosphate (IP1), a degradative metabolite of the inositol 1,4,5-triphosphate (Ins 1,4,5-P3) second messenger molecule, in the presence of LiCl (10 mM) which prevents further metabolism of IP1. We found that a 2 h exposure to 100 nM TRH resulted in a 3-fold increase in IP1 accumulation by AP cultures derived from both suckled and nonsuckled dams. Our results indicate that TRH effectively activates its receptor and couples to the phosphoinositidase pathway in AP cells from both nonsuckled and suckled females. Thus, we conclude that the suckling-induced increase in mammotrope responsiveness to TRH is regulated subsequent to TRH receptor activation.

Animals↗
PubMed1991

Treatment of advanced-stage massive mediastinal Hodgkin's disease: the case for combined modality treatment.

In the initial series of 198 patients treated at the National Cancer Institute (NCI) with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy for Hodgkin's disease, a review of presenting chest radiographs available on 192 of these patients showed 49 patients with mediastinal masses greater than one third the greatest posteroanterior chest diameter. Five patients had stage IIB disease, and 44 had stage III or IV disease. Thirty-five (71%) patients achieved a complete remission with MOPP chemotherapy. Fourteen (40%) of the complete responders relapsed, but four of these achieved durable remissions in response to subsequent therapy. Thirty (61%) patients have died (14 induction failures, nine relapsed patients, seven complete responders in remission). Thus, with a median follow-up of 20 years (range, 15 to 23), the overall survival for the group is 39%, and the disease-free survival for the complete responders is 60%. A subset of 10 patients received mantle radiation therapy after maximal response to MOPP. One of these patients failed to achieve complete remission, but among the nine complete responders only one has relapsed. In contrast, 13 of 26 (50%) patients achieving a complete response to MOPP alone have relapsed (P2 = .0536). Although MOPP alone was not prospectively compared with MOPP plus radiation therapy in the treatment of advanced-stage massive mediastinal Hodgkin's disease in this series, the retrospective analysis shows a nearly significant difference in disease-free survival favoring combined modality treatment. The difference in tumor mortality between MOPP-treated (44%) and combined modality-treated patients (80%) was also nearly significant (P2 = .055). However, overall survival differences between patients treated with MOPP alone and those treated with combined modality therapy were not significantly different (P2 = 0.23) because of the mortality related to late complications of combined modality treatment.

Adolescent↗
PubMed1991

Suckling unmasks the stimulatory effect of dopamine on prolactin release: possible role for alpha-melanocyte-stimulating hormone as a mammotrope responsiveness factor.

Mounting evidence indicates that dopamine (DA) can stimulate as well as inhibit PRL release when given in appropriately low doses. In the present study, we investigated whether the suckling stimulus could influence this response. Pituitary cultures from suckled or nonsuckled rats were exposed to DA (10(-16) - 10(-6) M) during a reverse hemolytic plaque assay for PRL. Pituitary cells from nonsuckled rats exhibited only the inhibitory response to DA; exposure to high-dose DA (10(-6) M) reduced plaque area to 42.3 +/- 7.2% (mean +/- SEM) of control. A low dose of DA (10(-12) M) had no effect on PRL secretion (79.3 +/- 13.3% of control). In striking contrast, a brief suckling stimulus (10 min) rendered the mammotropes responsive to stimulation by low-dose DA (to 152.7 +/- 12.5% of control). Thus, suckling appears to be a requirement for expression of the stimulatory effect of DA in lactators. In a subsequent series of experiments we explored the possibility that a hypophysial factor, released during nursing, might mimic the effects of suckling on mammotrope responsiveness. Accordingly, we tested the effects of alpha-melanocyte-stimulating hormone (10(-7) M) and low-dose DA, alone or in combination, on pituitary cells from nonsuckled rats. Although neither agent alone had a dramatic effect on PRL secretion, concurrent administration of both of these significantly stimulated PRL release to 130.0 +/- 4.2% of control. Taken together, these results demonstrate that suckling renders mammotropes responsive to the stimulatory effects of DA. Moreover, our data indicate that alpha-melanocyte-stimulating hormone could function as a responsiveness factor in this phenomenon.

Animals↗
PubMed1990

Is the mammosomatotrope a transitional cell for the functional interconversion of growth hormone- and prolactin-secreting cells? Suggestive evidence from virgin, gestating, and lactating rats.

Serum concentrations of PRL and GH increase and decrease, respectively, during the progression from nonpregnancy through lactation. However, it is unknown whether the secretory capacities and/or relative abundance of cells that release PRL or GH are altered during these physiological states. In the present study anterior pituitaries from adult virgin, gestating, and early or late lactating female rats were dispersed with trypsin and subsequently assayed for PRL and GH release using reverse hemolytic plaque assays. We found that the relative abundance of PRL-secreting cells was greater and that of GH cells lower in pituitaries from lactating females than in those from virgins. Moreover, the relative amounts of both PRL and GH released per cell were diminished in gestating and lactating females. For PRL, this decrease could be accounted for by an increase in the number of cells that released small quantities of hormone. We then performed simultaneous plaque assays to determine whether the shifts in the relative proportions of PRL and GH secretors were due to changes in the percentages of cells that secrete each hormone alone or in the fraction that releases both PRL and GH concurrently. Variations in both single and dual hormone-secreting cells appear to contribute to the overall fluctuations in the relative abundance of PRL and GH cells during these physiological transitions. We conclude that the additional PRL secretors present during lactation may arise from cells that previously released only GH, and that this functional interconversion of GH and PRL secretors might involve an intermediate cell type, the mammosomatotrope.

Animals↗
PubMed1989

Relative importance of newly synthesized and stored hormone to basal secretion by growth hormone and prolactin cells.

It is generally accepted that under basal conditions there is preferential release of newly synthesized hormone by a number of endocrine cell type, including those that secrete GH or PRL. However, the cellular basis for this phenomenon along with the relative contribution of stored hormone to basal secretion has yet to be clearly established. In the present study, we employed reverse hemolytic plaque assays to monitor basal and stimulated release of GH and PRL from individual cells in which de novo protein synthesis had been blocked. Monodispersed pituitaries from adult male rats were cultured for 21 h in the absence or presence of maximally effective doses of puromycin (100 microM) or cycloheximide (36 microM) and were then subjected to separate plaque assays for GH or PRL. Treatment with puromycin reduced the percentage of GH or PRL secretors (plaque formers) by about half. Coincubation with stimulatory secretagogues did not increase the percentages of GH or PRL secretors in control cultures, but returned the proportion in puromycin-treated cells to normal, demonstrating that cells which failed to secrete basally could still release hormone from their stored pools when stimulated. Very similar results were obtained when these experiments were repeated with cycloheximide. Taken together, these results demonstrate that only a fraction of the cells that release GH or PRL are dependent upon newly synthesized hormone for basal secretion; the remainder appear capable of mobilizing stored hormone for this purpose even in the absence of stimulation.

Animals↗
PubMed1988

Evaluation of fludarabine phosphate in small cell carcinoma. A Southwest Oncology Group Study.

Fludarabine phosphate was given as a 5 day bolus infusion to eleven evaluable patients with recurrent small cell lung carcinoma. Patients had failed on one prior treatment regimen. There were no responses in the eleven evaluable patients. Severe neurologic toxicity occurred in one patient. Fludarabine phosphate as given in this protocol was not an effective agent in recurrent small cell lung carcinoma.

Adult↗
PubMed1986

Lethal multiple pterygium syndrome: three consecutive cases in one family.

We report on three sib fetuses with the lethal multiple pterygium syndrome (LMPS), one case occurring in a twin pregnancy. All three fetuses had a cystic hygroma and hydrops was detected by ultrasound. The classification scheme for LMPS proposed by Hall [1984] is examined. With our present state of knowledge of this syndrome, subdivision on bone-fusion types does not appear to be justified. Antenatal detection by ultrasound is possible in most pregnancies with a second affected fetus because of cystic hygroma and hydrops. In the term or near-term infant in which ultrasound has not shown cystic hygroma or hydrops, a diagnosis of Pena-Shokeir type I syndrome should be considered because pterygia are a component of that syndrome but cystic hygroma and hydrops are not.

Abnormalities, Multiple↗
PubMed1979

Oxidative metabolites of [2-14C]propylthiouracil in rat thyroid.

The identities and relative amounts of the major metabolites in rat thyroids 6 h after the administration of [14C]propylthiouracil ([14C]PTU) have been investigated. Rat thyroid extracts were chromatographed on columns of Bio-Gel P-2 and DEAE-Sephadex and in various thin layer chromatography systems. The extracts contained protein-bound PTU metabolites; an unknown peak 3; peak 1, which was chromatographically similar to PTU--SO2H; peak 2, which was similar to PTU--SO3H; PTU; and small amounts of 6-n-propyluracil (PU). The major metabolites were isolated and purified by column chromatograpy. On the basis of chromatographic properties identical to cochromatographed standards in seven different systems and the products formed after treatment with various reagents, peak 1 was identified as PTU-SO2H and peak 2 as PTU--SO3H. Peak 3 was seen only on Bio-Gel P-2 columns, was very unstable, and was not similar to any known PTU standard. The properties of this compound suggest that it may be a thiolsulfonic ester (formula:see text), but the data are insufficient for positive identification. Approximately 85% of the radioactivity in the protein peak was bound to thyroglobulin. HCl converted 86.5% of the protein-bound radioactivity to PU, and H2S converted 91% to PTU, indicating that an oxidized S was involved in the linkage to protein. Dithiothreitol released 23.6% of the protein-bound radioactivity as PTU, and mercaptoethanol released 32.5%, indicating that 25-35% of the PTU is bound in disulfide linkage. Approximately 50% of the radioactivity released by mercaptoethanol was S-ethanol PTU, which suggests a PTU-protein bond similar to a thiolsulfonic ester. Quantitation of the metabolites revealed that protein-bound metabolites accounted for 21-29% of the total radioactivity, unknown peak 3 accounted for 7.1%, PTU--SO2H for 48-50%, PTU--SO3H for 8-10%, and PTU for 10.7-16.5%. Only traces of PU were observed. The data demonstrate that PTU--SO2H is the major PTU metabolite in rat thyroid and must be the compound X observed by other investigators and that all metabolites identified are oxidative products of PTU. These findings support the earlier conclusion of Taurog and Riesco that protein binding of PTU occurs as a consequence of oxidation.

Animals↗
PubMed1976

Efficacy of activated charcoal hemoperfusion in removing lethal doses of barbiturates and salicylate from the blood of rats and dogs.

Rats were injected intraperitoneally with lethal doses of sodium pentobarbital (115 mg/kg) or a lethal mixture of sodium salicylate (500 mg/kg) and sodium acetazolamide (25 mg/kg). Within about 20 min, part of each group was connected to an extracorporeal circuit containing uncoated activated charcoal and part to an empty control circuit. After a 90-min hemoperfusion, the treated groups showed a significantly decreased mortality (58% to 14% for pentobarbital; 100% to 0% for salicylate). Dogs were injected intravenously with lethal doses of sodium phenobarbital (175 mg/kg). One group was treated by hemoperfusion through an empty device in a control extracorporeal circuit, a second group was treated with loose-bed activated charcoal devices, and a third group with fixed-bed activated charcoal devices. For both the fixed and loose-bed devices, a 5-h hemoperfusion markedly decreased mortality (100% to less than or equal to 15%). The lethal combination of salicylate and closed-circuit methoxyflurane anesthesia was also successfully treated in dogs. This study clearly demonstrates the lifesaving potential of uncoated activated charcoal hemoperfusion.

Animals↗