Biomedical subjects

E Horvath

Publications and source records attributed to E Horvath.

At least 19 recordsLinked to original sources

PubMed1998

Cytokine gene activity in AML cells in vivo in patients.

The proliferation of acute myelogenous leukemia cells is dependent upon cytokine stimulation. Additionally, there is a body of literature which reports that leukemia cells produce GMCSF, IL6, and other cytokines. The study reported here, using an rt-multiplex polymerase method, determined the presence or absence of transcripts in freshly obtained AML cells for the following cytokine or cytokine-related genes: IL 1beta, IL1ra, TNF alpha, GMCSF, IL6, flt 3, and hSCF. This demonstrated that leukemia cell populations usually contain transcripts for IL1beta, TNF alpha, flt 3 and flt 3 ligand in vivo and that transcripts for the other cytokines only appear after the leukemia cells are processed in vitro. The presence of TNF alpha transcripts appears to be associated with resistance to remission induction therapy. Furthermore, the transcript profile of the leukemia cells can change during remission induction therapy. The data also demonstrate the assessment of cytokine production by leukemia cells after in vitro manipulation should not be extrapolated to the in vivo situation.

Adult↗

PubMed1998

A composite silent corticotroph pituitary adenoma with interspersed adrenocortical cells: case report.

OBJECTIVE AND IMPORTANCE: A case report of an extraordinary sellar pituitary tumor composed of corticotrophs and adrenocortical cells is presented. To our knowledge, this is only the second one reported in the literature. CLINICAL PRESENTATION: An 18-year-old female patient presented with amenorrhea. INTERVENTION: Investigations revealed a sellar mass, which was excised transsphenoidally. Histologically, two cell types could be readily distinguished, i.e., small basophilic cells that were positive for periodic acid Schiff and adrenocorticotropic hormone and large cells with abundant, slightly vacuolated, eosinophilic cytoplasm that were negative for periodic acid Schiff and adrenocorticotropic hormone. The nature of the tumor was revealed by ultrastructural examination, thus highlighting the importance of this technique in the investigation of pituitary adenomas. Immunohistochemistry with a panel of steroidogenic dehydrogenases and hydroxylases was positive in the large cells, confirming these as adrenocortical cells. CONCLUSION: We suggest that the designation "composite silent corticotroph pituitary adenoma with adrenocortical cells" is an appropriate name for this tumor. The explanation for the presence of the two cell types is obscure. Two theories are considered, as were proposed by the authors of the previous case report regarding the same entity, i.e., 1) the possibility of misplaced embryonic adrenocortical cells and 2) the presence of uncommitted stem cells that differentiate into adrenocortical cells.

Adenoma↗

PubMed1998

Pituitary adenoma producing growth hormone and adrenocorticotropin: a histological, immunocytochemical, electron microscopic, and in situ hybridization study. Case report.

The authors report on the morphological features of a pituitary adenoma that produced growth hormone (GH) and adrenocorticotropic hormone (ACTH). This hormone combination produced by a single adenoma is extremely rare; a review of the available literature showed that only one previous case has been published. The tumor, which was removed from a 62-year-old man with acromegaly, was studied by histological and immunocytochemical analyses, transmission electron microscopy, immunoelectron microscopy, and in situ hybridization. When the authors used light microscopy, the tumor appeared to be a bimorphous mixed pituitary adenoma composed of two separate cell types: one cell population synthesized GH and the other ACTH. The cytogenesis of pituitary adenomas that produce more than one hormone is obscure. It may be that two separate cells--one somatotroph and one corticotroph--transformed into neoplastic cells, or that the adenoma arose in a common stem cell that differentiated into two separate cell types. In this case immunoelectron microscopy conclusively demonstrated ACTH in the secretory granules of several somatotrophs. This was associated with a change in the morphological characteristics of secretory granules. Thus it is possible that the tumor was originally a somatotropic adenoma that began to produce ACTH as a result of mutations that occurred during tumor progression.

Acromegaly↗

PubMed1997

A critical role for neutralizing-antibody-producing B cells, CD4(+) T cells, and interferons in persistent and acute infections of mice with lymphocytic choriomeningitis virus: implications for adoptive immunotherapy of virus carriers.

This study demonstrates that neutralizing-antibody-producing B cells, CD4(+) T cells, and interferons (IFNs) are of key importance in virus control both in adoptive immunotherapy of persistent infection and in the late phase of acute infection with the WE strain of lymphocytic choriomeningitis virus (LCMV). We report the following results. (i) Clearance of LCMV-WE from C57BL/6 carrier mice by adoptive transfer of memory spleen cells requires B cells and CD4(+) T cells but not necessarily CD8(+) T cells. (ii) At the doses examined, CD8(+) T cells contribute to the initial reduction of viral titers but are alone not sufficient to clear the virus because they are exhausted. (iii) In the presence of functional IFN-gamma, virus clearance correlates well with the generation of neutralizing antibodies in the treated carrier mice. (iv) In the absence of receptors for IFN-gamma, virus clearance is not achieved. (v) Adoptive immunotherapy of mice persistently infected with a distinct virus isolate, LCMV-Armstrong, revealed only low levels of neutralizing antibodies; in this case, CD8(+) T cells were needed for virus clearance in addition to B and CD4(+) T cells. (vi) After low dose infection of C57BL/6 mice with LCMV-WE, virus is eliminated below detectable levels by CD8(+) T cells, but long-term (>2 months) virus control is usually not achieved in the absence of B cells or CD4(+) T cells; reappearance of the virus is paralleled either by exhaustion of virus-specific cytotoxic T lymphocytes or lethal immunopathology. These findings are of importance for adoptive immunotherapy strategies against persistent virus infections in humans.

Animals↗

PubMed1997

Pituitary carcinoma: a clinicopathologic study of 15 cases.

BACKGROUND: Pituitary carcinomas are rare adenohypophysial neoplasms, the definition, diagnosis, therapy, and prognosis of which are controversial. METHODS: Pituitary carcinomas were defined as primary adenohypophysial neoplasms with documented craniospinal and/or systemic metastases. The authors report a clinicopathologic study of 15 examples examined by light microscopy, immunohistochemistry, and image analysis. Both proliferative activity and p53 tumor suppressor gene expression were studied. RESULTS: The study group consisted of 15 patients, including 8 males and 7 females ranging in age from 34-71 years (mean, 56 years). Of these patients, seven had adrenocorticotropic hormone (ACTH)-producing tumors (four in the context of Nelson's syndrome), seven had prolactin-producing tumors, and one had a nonfunctioning tumor. No evidence of diabetes insipidus was seen in any case. Fourteen tumors were initially considered macroadenomas. Of the ten cases for whom tumor extent was known, all had invasive tumors. The interval from the initial diagnosis of adenoma to that of carcinoma ranged from 0.3 to 18.0 years (mean, 6.6 years; median, 5.0 years); the longest mean interval (15.3 years) occurred for patients with Nelson's syndrome. The latency was twice as long for ACTH-producing tumors as for prolactin (PRL) cell tumors (9.5 vs. 4.7 years). All carcinomas showed a greater tendency toward systemic metastasis than craniospinal metastasis; the rate of systemic metastasis was 71% for PRL cell tumors and 57% for ACTH-producing tumors. Thirteen percent of tumors showed both patterns of metastasis. Fully 50% of primary tumors and the majority of metastases showed nuclear pleomorphism and/or hyperchromasia. The mean mitotic, MIB-1, and proliferating cell nuclear antigen indices for primary tumors and metastases were as follows: 2/10 high-power field (hpf), 2.6% and 11%, respectively; 6/10 hpf, 7.8% and 16%, respectively. Staining for p53 protein was noted in 57% of primary tumors and 88% of metastatic tumors; a relative increase in p53 expression in metastases was noted in 83%. All but one of the primary and metastatic tumors were aneuploid. The most common treatments were radiation therapy and, for PRL cell carcinomas, dopamine agonist administration. Both treatments provided only palliation. Eighty percent of the patients died of metastatic disease 7 days to 8 years after the diagnosis of carcinoma; of these, 66% died within 1 year. At last follow-up, 20% of patients were alive with metastases 9-18 months after diagnosis. CONCLUSIONS: Nearly all pituitary carcinomas present as functioning, microscopically atypical or mitotically active, invasive macroadenomas. By definition, after an interval related to their immunotype, all metastasize. The tumors show a greater tendency toward systemic metastasis than craniospinal metastasis and are associated with poor prognosis. Radiation and dopamine agonist therapy generally provide only palliation. Proliferation indices and p53 expression tend to be higher in metastases than in primary tumors. The current definition of pituitary carcinoma requires the demonstration of metastasis; however, high mitotic and MIB-1 labeling indices as well as p53 immunoreactivity suggest the diagnosis and appear to be of prognostic significance. A redefinition of aggressive pituitary tumors is proposed--one that facilitates the recognition of tumors prone to metastasis.

Adrenocorticotropic Hormone↗

PubMed1997

Antiproliferative effect of the somatostatin analogue octreotide on growth hormone-producing pituitary tumors: results of a multicenter randomized trial.

OBJECTIVE: To determine and quantify the in vivo effects of octreotide on the cell cycle kinetics of growth hormone-producing pituitary adenomas. DESIGN: A multicenter randomized trial had been conducted to assess the clinical efficacy of octreotide, and we studied tissue specimens from pituitary macroadenomas in 32 patients with acromegaly from that trial-16 of whom had received 4 months of octreotide therapy before surgical resection and 16 of whom had undergone surgical resection only. MATERIAL AND METHODS: All tumors had been fully characterized on the basis of their immunophenotypic profile and their ultrastructural morphologic features. Included were 16 densely and 16 sparsely granulated somatotroph adenomas. In each case, immunostaining for the cell cycle-specific nuclear antigen Ki-67 was performed with use of the MIB-1 antibody. The staining reaction was manually quantified, and a tumor growth fraction was derived in each case. RESULTS: The mean growth fraction of tumors exposed to octreotide was suppressed by 83% in comparison with untreated surgical controls (0.011+/-0.004% versus 0.065+/-0.016%, respectively; P = 0.0068). The association between octreotide treatment and lower tumor growth fractions was statistically independent of tumor subtype, being evident among both sparsely and densely granulated somatotroph adenomas. CONCLUSION: Octreotide exerts a significant antineoplastic effect on somatotroph adenomas, one readily reflected at the level of the cell cycle. This antiproliferative response provides insight into several clinicopathologic issues surrounding octreotide therapy for these neoplasms.

Acromegaly↗

PubMed1997

Salivary gland-like tumors of the sellar region.

Herein we present a group of rare tumors of the sella region that have not been previously recognized. Although clinically and radiographically the tumors resemble nonfunctioning pituitary adenomas, their histologic, immunohistochemical, and ultrastructural features differ and indicate a salivary gland origin. The lesions cover a morphologic spectrum that includes cellular pleomorphic adenoma, monomorphic adenoma, oncocytoma, and low-grade adenocarcinoma of the salivary gland. All tumors except the oncocytoma were immunoreactive for cytokeratin and were negative for pituitary hormones and synaptophysin. Ultrastructural characteristics in the cases examined include hypodense stromal material, basal lamina, and tonofilament bundles. The single oncocytoma was packed with mitochondria and lacked membrane-bound secretory granules. DNA ploidy based on image analysis and MIB-1 labeling indices showed diversity within this group of tumors, with labeling indices ranging from 0.06% to 15%. The presumed origin of these rare neoplasms is from salivary gland rests related to the normal pituitary gland. Despite their varied morphology, such tumors are easily confused with pituitary adenoma. Although rare, tumors of salivary gland origin should be considered in the differential diagnosis of unusual adenohypophyseal tumors.

Adenocarcinoma↗

PubMed1997

In vitro antiviral drug sensitivity of the Kaposi's sarcoma-associated herpesvirus.

OBJECTIVE: Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8, has been implicated as the causative agent of Kaposi's sarcoma. Retrospective studies show that the risk of development of Kaposi's sarcoma is significantly lower in AIDS patients who received ganciclovir or phosphonoformic acid (PFA) therapy. Therefore, in vitro antiviral drug sensitivity of KSHV was studied. METHODS: The KSHV genome is a latent episome in lymphoma cells such as the BCBL-1 cell line. Lytic KSHV DNA synthesis is induced by the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate in BCBL-1 cells; this system was used to evaluate the effects of antiviral drugs on KSHV DNA synthesis. RESULTS: Linear (lytic) KSHV DNA synthesis and virus secretion was inhibited in BCBL-1 cell cultures by cidofovir (median inhibitory concentration, 0.05 microM), ganciclovir (5.1 microM) and PFA (97 microM), and by aciclovir (75 microM). Prolonged incubation of BCBL-1 cells with antiviral drugs had no effect on episomal KSHV DNA synthesis. CONCLUSIONS: The antiviral drug assay developed shows that KSHV is very sensitive to cidofovir, moderately sensitive to ganciclovir and PFA, and weakly sensitive to aciclovir. Therefore, low doses of cidofovir, or high doses of PFA or ganciclovir could suppress clinical reactivation of KSHV. Antiviral drugs did not inhibit episomal virus DNA synthesis, suggesting that the latent form of viral DNA is replicated by host DNA polymerases. Consequently, no benefit can be expected from antiviral drugs in KSHV-positive B-cell lymphomas or during latency.

Acyclovir↗

PubMed1996

The World Health Organization classification of adenohypophysial neoplasms. A proposed five-tier scheme.

BACKGROUND: Although numerous attempts have been made, the classification of pituitary neoplasms remains controversial. METHODS: The present proposal is based on correlative clinical and pathologic (histologic, immunocytochemical, and electron microscopic) studies of more than 8000 surgically removed human pituitary tumors. RESULTS: Anterior pituitary tumors have been variously classified on the basis of their clinical presentation, biochemical findings, histology (growth pattern, tinctorial characteristics), proliferation indices, immunocytochemical profile, and ultrastructural features. Herein we propose a five-tier classification, clinicopathologic in nature, which focuses on endocrine activity, imaging, operative findings, histology, immunocytochemistry, and ultrastructure. The integration of these five complementary approaches into what is fundamentally a pathologic classification is as practical as it is novel. Its importance lies in the fact that the collected data provide valuable information to the clinical endocrinologist, neurosurgeon, and oncologist involved in the assessment of a tumor's biologic behavior, growth potential, therapeutic responsiveness, and prognosis. Due to financial restraints, lack of facilities, and unavailability of well trained personnel, we realize that at present the five approaches cannot be fully implemented in all institutions. Nonetheless, clinical and biochemical data, imaging, and operative findings, as well as basic histologic parameters are generally readily available. Collectively they are indispensable in establishing the correct diagnosis and in directing patient management. Conversely, the cost-effectiveness of immunocytochemistry and electron microscopy is debatable in that their performance and interpretation requires time, financial resources, and expertise. Nonetheless, it should be clear that any correlation between endocrine activity, growth potential, morphologic features, immunocytochemical profile, and ultrastructural features provides greater insight into the pathobiology of adenohypophysial tumors than is gained by routine histology alone. Thus we feel justified in including immunocytochemical and ultrastructural investigation of pituitary tumors in a modern classification. At present, more sophisticated molecular biologic methods represent investigative tools that play no significant role in the classification. CONCLUSIONS: A five-tier classification of adenohypophysial neoplasms based on clinical and biochemical results, imaging, operative findings, histology, immunocytochemistry, and electron microscopy is proposed. It is recommended to the World Health Organization for acceptance.

Humans↗

PubMed1996

Heat shock proteins and experimental autoimmune encephalomyelitis (EAE): I. Immunization with a peptide of the myelin protein 2',3' cyclic nucleotide 3' phosphodiesterase that is cross-reactive with a heat shock protein alters the course of EAE.

We describe sequence similarity and immunologic cross-reactivity between a peptide of the mycobacterial hsp, HSP65, and the myelin protein 2',3' cyclic nucleotide 3' phosphodiesterase (CNP). We demonstrate that immunization with the homologous cross-reactive CNP peptide (hsp-CNP peptide) has significant biological consequences. Rats immunized with hsp-CNP peptide in either complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA) produce large amounts of peptide-specific antibody. Isotypes of antibodies in animals immunized with peptide in CFA are IgG1 and IgG2a. Isotypes of antibodies in rats immunized with peptide in IFA are predominantly IgG1, with low titers of IgG2a. T cell proliferative responses to HSP65 are present in rats immunized with peptide in CFA. T cell responses to HSP65 initially are absent in rats immunized with peptide in IFA but develop over time. T cell proliferative responses to hsp-CNP peptide were not detected. None of the groups of rats developed clinical or histologic evidence of experimental autoimmune encephalomyelitis (EAE). To induce EAE, rats preimmunized with hsp-CNP peptide were challenged with guinea pig spinal cord (GPSC) emulsified in CFA. Rats preimmunized with peptide in CFA developed severe EAE. Rats preimmunized with hsp-CNP peptide in IFA were protected from EAE, with both a lower incidence and severity of disease. Injecting the murine monoclonal antibody recognizing the shared HSP65 and CNP epitope did not protect against EAE. Our data suggest that a Th2 pattern of immune response to a CNP peptide that itself is non-encephalitogenic protects against EAE. Immune responses to either hsp or myelin proteins cross-reactive with hsp may play an important role in the development of EAE.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed1996

Pituitary choristoma composed of corticotrophs and adrenocortical cells in the sella turcica.

A pituitary tumour composed of well-differentiated corticotrophs and adrenocortical cells is reported. Sections of the tumour revealed a mixture of small round cells with amphophilic or basophilic periodic acid-Schiff (PAS)-positive cytoplasm and large spherical and oval cells with abundant, granular, partly vacuolated PAS-negative cytoplasm. The small cells contained type 1 cytokeratin-positive microfilaments, numerous 250-500 nm endocrine-type secretory granules immunoreactive for adenocorticotropic hormone (ACTH) and beta-lipotropin. The large cells possessed ample cytoplasm filled with abundant vesicular smooth endoplasmic reticulum, numerous mitochondria possessing tubulovesicular cristae and frequent dense bodies. They lacked the features of pituitary endocrine cells or folliculostellate cells and were found to contain a panel of steroidogenic dehydrogenases and hydroxylases. The tumour was classified as a choristoma, in which two distinct cells types, corticotrophs and adrenocortical cells, were mixed. We suggest that, under continued ACTH stimulation, umcommitted stem cells may differentiate into adrenocortical cells. Alternatively, the presence of adrenocortical cells may be the result of heterotopia.

Adolescent↗

PubMed1996

Gonadotroph adenoma of the pituitary gland: a clinicopathologic analysis of 100 cases.

OBJECTIVE: To determine the clinical and pathologic features in a large cohort of randomly selected patients with gonadotroph pituitary adenomas. DESIGN: We retrospectively reviewed clinical, surgical, and pathologic findings in 100 patients (79 men and 21 women, 30 to 82 years old) with this tumor. RESULTS: Diagnosis of a pituitary tumor was prompted by visual loss (43%), symptoms of hypopituitarism (22%), headache (8%), or a combination of these findings (10%); 17% of the patients were asymptomatic. Visual field defects were present in 68% of the study group, and complete or partial anterior pituitary failure was present in 77%. Serum prolactin concentrations were increased (maximum, 110 ng/mL) in 33% of patients. Hypersecretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) was documented in 11 and 5 patients, respectively. The serum level of alpha-subunit was increased in 1 of 29 patients in whom it was measured. All patients had pituitary macroadenomas, only 21% of which were grossly invasive. The surgical approach was transsphenoidal in all but two patients, who underwent transfrontal craniotomy; gross total tumor resection was achieved in 90%. By definition, all tumors had at least 10% immunoreactivity for LH, FSH, or both. All tumors were chromophobic. Ultrastructurally, the tumors were characterized as gonadotroph adenomas of "male" (45%) or "female" (9%) type as well as null-cell adenomas of the oncocytic (35%) or nononcocytic (11%) type. After a median follow-up of 4.3 years, 69% of the patients who had had visual field defects noted normalization or improvement. Persistent or clinically recurrent pituitary tumor tissue was present in 42%. A second pituitary surgical procedure was required in eight patients. CONCLUSION: Most patients with clinically evident gonadotroph pituitary tumors have loss of vision and hypopituitarism. Hypersecretion of FSH or LH is unusual, and no distinct hormone-dependent clinical phenotype is present. Transsphenoidal surgical treatment generally yields normalization or improvement of visual field defects.

Adenoma↗

PubMed1996

The effect of interferon-alpha on the pituitary-adrenal axis.

This report concerns the use of a minimum stress animal model for evaluating the neuromodulatory effects of interferon-alpha (IFN-alpha). Male Sprague-Dawley rats, 350-450 g, received jugular catheters and were habituated to handling and sampling arenas. These procedures will minimize stress usually associated with i.v. injections and blood sampling. Natural rat IFN-alpha/beta (RaIFN-alpha/beta) endotoxin free (Lee Biomolecular Research Laboratories, San Diego, CA) or recombinant human IFN-alpha, (rHuIFN-alpha) (a gift from Hoffman La Roche, Nutley, NJ) was injected into rats via catheter at various IFN concentrations. Controls were injected with either (1) vehicle (saline), (2) human or bovine serum albumin in saline, or (3) heat-denatured RaIFN-alpha/beta. Experiments were begun (0 h) at about 0900 h, and blood samples were withdrawn at intervals up to 2 h after IFN or control injections and replaced by the same volume of saline. The concentrations of corticosterone and ACTH in peripheral plasma were measured by radioimmunoassay. Both IFN, when injected at concentrations of 300 or 600 U/g body weight (U/gbw), stimulated an increase above 0 h levels of both hormones in the same animals. Additionally, the stimulation was also evident when compared with plasma hormone levels in animals injected with control substance in a parallel time course. After administration of 150 U/gbw of either IFN, only the increase in the blood corticosterone was significant. These studies demonstrate that both homospecific (RaIFN-alpha/beta) and heterospecific (rHuIFN-alpha) IFN preparations are capable of stimulating the pituitary-adrenal axis.

Adrenal Cortex↗

PubMed1996

Proliferative activity and invasiveness among pituitary adenomas and carcinomas: an analysis using the MIB-1 antibody.

Although histologically benign, one-third of all pituitary tumors will be invasive of surrounding structures. In this study, the relationship between the proliferative activity in pituitary adenomas and their invasiveness was investigated. Invasion was defined as gross, operatively or radiologically apparent infiltration of dura or bone. Using the recently developed MIB-1 monoclonal antibody, which recognizes the Ki-67 cell cycle-specific nuclear antigen, the growth fractions of 37 noninvasive adenomas, 33 invasive adenomas, and 7 primary pituitary carcinomas were determined. All tumors were fully classified by histology, immunohistochemistry, and electron microscopy. The mean Ki-67 -derived growth fractions for noninvasive adenomas, invasive adenomas, and pituitary carcinomas were 1.37 +/- 0.15%, 4.66 +/- 0.57%, and 11.91 +/- 3.41%, respectively (mean +/- standard error of the mean). An analysis of variance and then individual pairwise comparisons confirmed significant differences in the mean Ki-67 labeling index between each of the three tumor groups (P < 0.01). The mean growth fraction of hormonally active pituitary adenomas (3.25 +/- 0.26%) was significantly higher than that for nonfunctioning adenomas (2.06 +/- 0.23%) (P = 0.03). Establishing a threshold labeling index of 3% served to distinguish invasive from noninvasive adenomas with 97% specificity and 73% sensitivity and was associated with positive and negative predictive values of 96 and 80%, respectively. Although invasive pituitary tumors exhibited significantly higher growth fractions than did noninvasive tumors, there were individual exceptions, indicating that in a subpopulation of invasive pituitary tumors, factors other than proliferative activity determine invasive potential.

Adult↗

PubMed1996

GYKI-46 903, a non-competitive antagonist for 5-HT3 receptors.

The effects of GYKI-46 903 ((+)endo-4-propionyloxy-6-(4-fluorophenyl)-1-azabicyclo [3.3.1]non-6-ene HCl), on 5-HT3 receptors have been studied and compared with ondansetron in peripheral organs in vitro and in vivo, and in a receptor binding assay in membranes prepared from rat cerebral cortex. GYKI-46 903 was found to be a non-competitive antagonist at 5-HT3 receptors present in non-stimulated longitudinal muscle strip of guinea-pig ileum (pD2' against serotonin = 5.54), and also in 5-methoxytryptamine-pretreated electrically stimulated ileal preparations (pD2' against serotonin = 5.26). On the contrary, ondansetron was found to be a competitive antagonist for 5-HT3 receptors; the pA2 value against serotonin was 7.40 in non-stimulated ileum, and it was 7.08 in electrically stimulated ileal preparation pretreated with 5-methoxytryptamine. In displacement studies, the pIC50 values of GYKI-46 903 and ondansetron against [3H]granisetron binding to rat cerebral cortex membranes were 6.91 and 8.58 respectively. GYKI-46 903, when administered by intravenous infusion, antagonized the decrease in heart rate evoked by serotonin (Bezold-Jarisch reflex) in anaesthetized rats, and the maximal reversal was less than 50%. This was in striking contrast with ondansetron, which, after intravenous injection, completely antagonized the serotonin-induced bradycardia with an ID50 value of 3.28 ug/kg. These data classify GYKI-46 903 as a non-competitive antagonist for 5-HT3 receptors.

5-Methoxytryptamine↗

PubMed1995

In vivo release of interleukin-1 beta into hypothalamic extracellular fluid in rats: effects of repeated sampling.

Interleukin-1 beta (Il-1 beta) concentrations in extracellular fluid (ECF) withdrawn at 10-min intervals through a push-pull cannula (PPC) located in the hypothalamus were studied in freely behaving male rats for 1 h at 24 and 72 h and again at 7 days after PPC implantation. Il-1 beta concentrations in ECF were similar in the latter. However, when ECF was sampled at 3 h and again 7 days after PPC implantation, Il-1 beta concentrations were greatly elevated at 7 days when compared to all other intervals. These results demonstrate how the relationships between Il-1 beta measured in ECF and the conditions of measurement appear to be integral parts of a whole intracerebral system: cytokine concentrations appear to be inextricably bound to intrahypothalamic conditions created by the sampling device presence and frequency of use.

Animals↗

PubMed1995

Cushing's disease due to female gonadotroph adenoma of the pituitary.

A 39-year-old woman presented with amenorrhoea, hyperprolactinaemia and sellar mass. Bromocriptine normalized PRL levels but failed to suppress tumour growth. Subsequently, she developed clinical signs and elevated blood cortisol levels consistent with a diagnosis of Cushing's disease. A pituitary tumour was removed which was immunoreactive for ACTH. Electron microscopic examination, however, revealed a female gonadotroph adenoma indicating that adenoma cells regarded as gonadotrophs by ultrastructural analysis may occasionally secrete ACTH and cause Cushing's disease.

Adenoma↗

PubMed1995

Clinical case seminar: lymphocytic hypophysitis: clinicopathological findings.

This report describes the clinicopathological features of 16 patients with lymphocytic hypophysitis and compares the results with the published literature. There were 2 males and 14 females in this series. In 10 of the 14 females (71%), the presentation was associated with pregnancy. Nine patients (56%) presented with symptoms of an expanding pituitary sellar mass, 10 (63%) had anterior pituitary hypofunction, 3 had diabetes insipidus (19%). Progressive undiagnosed hypopituitarism led to the demise of 3 patients (19%). Hyperprolactinemia was encountered in 6 patients (38%), and elevated growth hormone levels (GH) resulted in IGF-1 excess in one patient. Computed tomography (CT) and magnetic resonance (MR) imaging revealed features of a pituitary mass mimicking an adenoma in 10 cases (83%). Four patients (25%) had associated autoimmune thyroiditis. Morphologic examination of the pituitary and immunohistochemistry showed a polyclonal lymphoplasmacytic infiltrate as well as occasional neutrophils, eosinophils, and macrophages; the chronic inflammatory process resulted in focal or diffuse adenohypophysial destruction of variable severity with associated fibrosis. The inflammatory infiltrate involved the neurohypophysis in 2 cases and one of these patients had diabetes insipidus; the posterior lobe of two other patients with diabetes insipidus was not examined morphologically. We conclude that lymphocytic hypophysitis should be considered in the differential diagnosis of females with pituitary enlargement presenting in the peripartum period as well as those patients in whom pituitary hormone deficiency and/or excess is noted in association with a co-existing autoimmune disorder. This clinical suspicion should probably also be extended to include patients presenting with rapidly growing pituitary masses associated with compressive symptoms with or without pituitary hormone dysfunction. Because of the transient endocrine and compressive features of this condition in many instances, conservative treatment on the basis of clinical suspicion alone may obviate the need for aggressive pituitary surgery.

Adult↗