Rifampicin: a glucocorticoid receptor ligand?
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Adrenocorticotropic Hormone↗
Biomedical subjects
J R Davis
Publications and source records attributed to J R Davis.
The outcome of surgery for acromegaly: the need for a specialist pituitary surgeon for all types of growth hormone (GH) secreting adenoma.
OBJECTIVE: Acromegaly is associated with reduced life expectancy, while therapeutic 'cure' (defined by achievement of GH levels < 5 mU/l) is associated with normalization of life expectancy. Surgery remains the treatment of choice but in those in whom operative 'cure' is not achieved, radiotherapy and/or medical treatment are valuable treatment modalities. The chance of subsequent 'cure' with radiotherapy or somatostatin analogue therapy is increased if the post-operative GH level is reduced below 30 mU/l. Using strict criteria for cure and a single dedicated pituitary surgeon, two large European studies reported 'cure' rates of 42% and 56%. In the Manchester region, surgery for these patients has been performed by a number of neurosurgeons, with no specific designated pituitary surgeon dominating the picture. We wished to examine the impact of this surgical strategy on cure rates and the incidence of a post-operative GH level below 30 mU/l. DESIGN: We reviewed the GH results between 1974 and 1997 for every acromegalic who had been referred to the endocrine departments of the two Manchester hospitals responsible for the majority of pituitary disease referrals in Manchester and who had been subsequently referred for pituitary surgery. PATIENTS AND MEASUREMENTS: Seventy-three (33 male) patients had had GH status assessed before and after surgery by an OGTT or GH profile. The patients were aged between 19 and 70 (mean 43) years at surgery. Seventy-one underwent transsphenoidal and 2 transfrontal surgery. Nine surgeons performed operations. RESULTS: Eighteen (24.7%) had microadenomas and 51 (69.9%) macroadenomas. In 4 patients (5.5%) insufficient data were available to size the adenoma. 17.8% of patients were cured by surgery, 38.8% with microadenomas and 11.8% with macroadenomas. In addition, of 52 patients whose GH levels were > 30 mU/l before surgery, only 27 (51.9%) had GH levels below 30 mU/l post-operatively (81.8% of microadenomas, 43.2% of macroadenomas). CONCLUSION: In comparison with other series, the cure rate in this study is significantly lower. The success in reducing GH levels below 30 mU/l post-operatively is difficult to compare with previously published studies, as few groups have analysed their data in this manner. Nonetheless, of our acromegalic patients with a pretreatment GH level in excess of 30 mU/l, nearly 50% have similar GH status postoperatively, thereby rendering them less amenable to cure by alternative therapeutic modalities. This highlights the importance of a specialist pituitary surgeon, not only for GH secreting microadenomas but also for GH secreting macroadenomas. If these patients are not 'cured', the cost of continuing therapy becomes a significant burden on health-care costs. In addition, if the postoperative GH levels remain above 30 mU/l the chances of achieving adequate control of GH levels are greatly reduced, thereby increasing mortality rates as well as morbidity in these patients.
Acromegaly↗
Effects of thermal endometrial ablation. Clinicopathologic correlations.
Electrothermal ablation of endometrium was performed on 207 women for abnormal and sometimes painful uterine bleeding. Recurrence of symptoms or inadequacy of treatment led to hysterectomy in 33 women at intervals of 2 weeks to 60 months. Patterns of uterine tissue destruction, healing and repair, and endometrial regeneration were correlated with the postablation interval. The endometrial thickness was completely destroyed. Necrosis dominated the first month, and a chronic repair-regeneration phase followed. Foreign body giant cells reacted with necrotic eschar, remnants of which were present to 47 months. Intact endometrium regenerated focally in 10 uteri and diffusely in 5. Indications for hysterectomy were attributed directly to ablation failure in 18 of 33 cases. Familiarity with the morphologic effects of ablation will aid in relating ablation failures to direct mechanisms, complications of the procedure, or unrelated events.
Adult↗
Vernix caseosa peritonitis: report of two cases with antenatal onset.
Maternal peritonitis secondary to fetal vernix caseosa is considered an infrequent complication of cesarean section in which commonly spilled amniotic fluid is incompletely lavaged. Nine of the 10 reported cases have been diagnosed in the postpartum period after an uneventful cesarean section. Characteristically, vernix elicits granulomatous inflammation, occasionally with a mass lesion simulating bowel perforation and leading to colectomy. One case of antenatal leakage of amniotic fluid has been reported, also with granulomatous inflammation. We report two additional cases of antenatal leakage, both with acute inflammation lacking granulomatous features or mass lesions. The interval between amniotic fluid contamination and histopathologic evaluation is the basis for variations in the inflammatory pattern.
Adult↗
Dynamic changes in prolactin promoter activation in individual living lactotrophic cells.
The firefly luciferase gene has become widely used as a convenient reporter for studies of gene promoter regulation. Very recently, the development of ultralow-light imaging cameras has enabled the quantitative digital imaging of light signals resulting from luciferase activation in the presence of luciferin substrate. We have applied this technology to the study of PRL promoter activation in individual pituitary tumor cells to study the temporal and spatial characteristics of the expression of a well-characterized pituitary hormone gene. Rat pituitary GH3 cells were transfected by lipofection with a luciferase reporter gene linked to 5000 bp from the human PRL gene 5'-flanking region. A series of stably transfected cell clones were generated, and one of these was chosen for detailed study on the basis of appropriate regulation of high-level luciferase expression by a series of known stimuli including TRH, forskolin, the calcium channel agonist Bay K8644, and basic fibroblast growth factor (bFGF). These cells were subjected to direct imaging of luciferase activity using a Hamamatsu photon-counting camera linked to a Zeiss Axiovert microscope with an Argus-50 image processor. Cells were exposed to 1 mM luciferin, and images were integrated over 30-min periods for up to 72 h. The total photon count over a given field settled to steady levels within 10 h and then remained constant for over 55 h. Addition of forskolin, TRH, or bFGF increased the total photon count of fields of 20-100 cells by 2- to 4-fold consistent with previous data from transient expression assays using the human PRL promoter. Individual cells, on the other hand, showed marked marked temporal and spatial heterogeneity and variability of luciferase expression when studied at 3-h intervals. Unstimulated cells showed variable luciferase expression with up to 40-fold excursions in photon counts per single cell area within 12-h periods. Stimulation of cells with either TRH, forskolin, or bFGF resulted in smooth increases in photon output over fields of 20-100 cells, but again individual cell responses differed widely, with some cells showing slow progressive rises in photon output, others showing phasic or transient responses, and yet others showing no response. In conclusion, we found a surprising degree of heterogeneity and temporal variability in the level of gene expression in individual living pituitary tumor cells over long periods of time, with markedly divergent responses to hormonal or intracellular stimulation. The use of stably transfected clonal cell lines with extended periods of reporter gene imaging offers a valuable insight into control of gene expression in living cells in real time.
Animals↗
Medical issues for a mission to Mars.
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Aerospace Medicine↗
Depletion of EBV-infected cells in donor marrow by counterflow elutriation.
Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disease (PTLD) is a well-recognized complication of T cell-depleted (TCD) allogeneic bone marrow transplantation (BMT). Certain methods of TCD, such as counterflow elutriation (CE), have not been associated with an increased incidence of PTLD. Since CE depletes B cells as well as T cells, the hypothesis that CE depletes donor marrow of EBV-infected cells was tested in this study. Marrow samples from 70 donors were assayed by qualitative and semi-quantitative polymerase chain reaction (PCR) amplification to detect EBV DNA in four cellular fractions produced by elutriation: a small cell fraction (F70), two intermediate-sized cell fractions (F110 and F140), and a large cell (hematopoietic precursor-enriched, lymphocyte-depleted) rotor-off (R/O) fraction. The distribution of B cells in elutriation fractions was 21% (F70), 59% (F110), 18% (F140), and 2% (R/O). Qualitatively, the frequency of EBV DNA detected in fractions was 49% (F70), 57% (F110), 73% (F140), and 44% (R/O). The relative concentration of EBV DNA in each fraction was determined by semiquantitative PCR. The mean number of EBV DNA copies per 150,000 cells was 0.57 (F70), 4.6 (F110), 5.7 (F140), and 0.61 (R/O). Relative EBV DNA load in each fraction was calculated by multiplying the mean concentration of EBV DNA per fraction and mean mononuclear cell content in each fraction. The relative distribution of EBV DNA was 0.5, 58, 40, and 1.5% in the F70, F110, F140, and R/O fractions, respectively. No correlation between the amount of EBV in the graft and development of PTLD could be made, because only one of the 70 recipients developed PTLD and this was following autologous hematopoietic recovery. Although these results demonstrate that the majority of EBV-infected cells in marrow are separated from the TCD graft by counterflow elutriation, further studies are required to differentiate the role of this phenomenon from that of other potential factors, such as the amount of T cell depletion and recovery of EBV immunity in the pathogenesis of PTLD after BMT.
Bone Marrow Cells↗
Cell proliferation and death in the irradiated pituitary gland and its modification by growth stimulants.
PURPOSE: This study was undertaken to show whether the rate of expression of radiation injury in the rat pituitary gland could be accelerated by the use of growth stimulants. METHODS AND MATERIALS: Rat pituitary glands were irradiated in situ with a range of single doses up to 20 Gy. The rats were then given subcutaneous slow-release implants containing 17beta-estradiol (E2) and sulpiride (S) to stimulate lactotroph proliferation. Two sequential cycles were used, each consisting of stimulation (3 weeks) and withdrawal (2 weeks). Measurements were made of gland weight; BrdU-labeled, giant, and apoptotic cells; lactotrophs; as well as pituitary prolactin content, in response to exogenous thyroid-releasing hormone (TRH). RESULTS: The two cycles of stimulation/withdrawal resulted in marked changes in gland weight, BrdU-labeling index, and serum prolactin (PRL) levels in unirradiated rats. The proportion of immunopositive growth-hormone-producing (GH) cells increased after irradiation. Radiation inhibited the hypertrophic response to E2 + S and also inhibited increases in BrdU-labeling index and serum PRL levels. Also, giant lactotrophs were observed in the irradiated pituitaries. However, they were not seen in the unirradiated rats or in the irradiated rats treated with E2 + S. TRH promoted PRL secretion in the unirradiated rat. In contrast, TRH inhibited PRL secretion in the irradiated rat and in all treatment groups receiving E2 + S. Apoptosis was induced by irradiation and was substantially increased in lactotrophs and in other cell types by withdrawal of the E2 and S stimulus, although the highest observed incidence was only 7 per 10,000 cells. CONCLUSION: Both irradiation and E2 + S treatment removed the hypothalamic control of PRL secretion, which reveals this important inhibitory action of TRH upon PRL secretion. This suggests that it is not suitable as a dynamic test of pituitary PRL reserves in such abnormal situations, where there may also be damage to the hypothalamic-pituitary vasculature. The increasing proportion of GH cells after irradiation indicates that lactotrophs respond more rapidly to irradiation. The stimulation by E2 + S somehow prevented the radiation-damaged lactotrophs from becoming giant cells. Also, the ratio of apoptotic cells to BrdU-labeled cells was increased by the E2 + S treatment, indicating that the E2 + S did enhance radiation-induced cell death relative to cell renewal. However, overall, the E2 + S stimulus protocol did not promote a dramatic increase in cell death (apoptosis) nor a marked decrease in residual gland weight after irradiation. Hence, its use would probably not be beneficial in the treatment of slow-responding prolactinomas, if malignant lactotrophs respond similarly to the normal pituitary lactotrophs. However, the observation of induced apoptosis after hormone and drug withdrawal suggests that agents which promote tumor shrinkage may be effective by causing rapid apoptosis of tumor cells in vivo.
Animals↗
A yeast artificial chromosome (YAC) contig encompassing the critical region of the X-linked lymphoproliferative disease (XLP) locus.
X-linked lymphoproliferative disease (XLP) is characterized by a marked vulnerability to Epstein-Barr virus (EBV) infection. Infection of XLP patients with EBV invariably results in fatal mononucleosis, agammaglobulinemia, or malignant lymphoma. Initially the XLP gene was assigned to a 10-cM region in Xq25 between DXS42 and DXS37. Subsequently, an interstitial, cytogenetically visible deletion in Xq25 was identified in one XLP family, 43. In this study we estimated the deletion in XLP patient 43-004 by dual-laser flow karyotyping to involve 2% of the X chromosome, or approximately 3 Mb of DNA sequence. From a human chromosome Xq25-specific yeast artificial chromosome (YAC) sublibrary, five YACs containing DNA sequences deleted in patient 43-004 have been isolated. Sequence-tagged sites (STSs) from these YACs have been used to identify interstitial deletions in unrelated XLP patients. Three more families with interstitial deletions were found. Two of the patients (63-003 and 73-032) carried an interstitial deletion of 3.0 Mb overlapping the 43-004 deletion. In one XLP patient (30-011) who exhibited the characteristic postinfectious mononucleosis phenotype of XLP with hypogammaglobulinemia and malignant lymphoma, a deletion of approximately 250 kb was detected overlapping the deletion detected in patients 43-004, 63-003, and 73-032. A YAC contig of 2.2 Mb spanning the XLP critical region, whose orientation on chromosome X was determined by double-color fluorescence in situ hybridization and which consists of 15 overlapping YAC clones, has been constructed. A detailed restriction enzyme map of the region has been constructed. YAC insert sizes were determined by counter-clamped homogenous electric field gel electrophoresis. Chimerism of YACs was determined by FISH and restriction mapping. On the basis of lambda subclones, YAC end-derived plasmids, and STSs with an average spacing of 100 kb, a long-range physical map was constructed using 5 rare-cutter restriction enzymes. The STSs and lambda subclones were used in Southern hybridization and PCR analyses. The work presented here substantially refines the critical region for XLP. The YAC contig with the overlapping interstitial deletions constitutes the basis for the construction of a transcriptional map of the critical region and facilitates the identification of the XLP gene.
Chromosomes, Artificial, Yeast↗
Telepathology: a ten-year progress report.
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Feasibility Studies↗
Diagnostic accuracy of an international static-imaging telepathology consultation service.
Static-image and dynamic- (real-time) image telepathology are competing technologies. Although some studies suggest that the diagnostic accuracy of the dynamic-image telepathology approaches the accuracy of light microscopy, few reports have documented the diagnostic accuracy of static-image telepathology as used in the setting of an actual surgical pathology consultation practice. We report the results of an analysis of 171 telepathology consultation cases submitted to the Arizona-International Telemedicine Network (AITN). Digital images were submitted by pathologists from six participating institutions in Arizona, Mexico, and China. Telepathologists could render a telepathology diagnosis (TP) or defer rendering a diagnosis to obtain additional video images, glass slides for detailed analysis, or to obtain tissue blocks for special studies such as immunohistochemistry. The telepathologists rendered diagnoses for 144 cases and deferred 27 cases. Two pathologists retrospectively evaluated-glass slides from each case and rendered a consensus glass slide (GS) "truth" diagnosis. There was 88.2% concordance between TP and GS diagnoses (127 of 144 diagnoses). Concordance of 96.5% was achieved for clinically important diagnoses (139 of 144 diagnoses). Telepathologists deferred making a diagnosis to obtain glass slides for conventional light microscopy in 14 cases (8.1%) and for results of immunohistochemistry studies in 13 cases (7.6%). Thus, correct diagnoses were rendered by static-image telepathology in 127 of 171 cases (74.3%) at the time of telepathology diagnostic sessions. Inappropriate field selection and sampling biases of referring pathologists, as well as a tendency of static-image telepathologists to underestimate the complexity of some cases, may reduce the value of consultations based on the viewing of static images.
Humans↗
Psychological distress in patients with hyperprolactinaemia.
OBJECTIVE: In addition to the physical symptoms of galactorrhoea and amenorrhoea, hyperprolactinaemia in women is also reported to be associated with psychological symptoms. Previous studies have found an increased incidence of depression, anxiety and hostility in female patients with hyperprolactinaemia. In this study, psychological symptoms were assessed in a large population of patients and symptom scores were compared between patients with definite evidence of pituitary adenoma on high-resolution CT scanning and those without, who were presumed to have idiopathic or 'functional' hyperprolactinaemia. DESIGN: Postal survey: population-control study of female patients with hyperprolactinaemia. PATIENTS: Sixty-five women with hyperprolactinaemia were compared with a control group of 26 women with normoprolactinaemic pituitary disease (acromegaly or nonfunctioning pituitary adenoma). The hyperprolactinaemic patients were subdivided according to whether a pituitary adenoma was visible on high-resolution CT scanning (39 patients) or whether they had normal CT scans, in which case they were categorized as having idiopathic or 'functional' hyperprolactinaemia (26 patients). MEASUREMENTS: Patients were sent 2 questionnaires, the Hospital Anxiety and Depression (HAD) Scale and the 90-item Symptom Checklist (SCL-90), to assess psychological wellbeing. RESULTS: Overall, 54% of hyperprolactinaemic patients were found to have definite or borderline anxiety as judged by HAD scores, compared with 27% of normoprolactinaemic control patients. Those with normal CT scans were significantly more likely to have definite or borderline anxiety (73% of patients) than those with CT evidence of a pituitary tumour causing their hyperprolactinaemia (41%, P < 0.003), despite similar levels of serum prolactin. A similar increased proportion of hyperprolactinaemic patients scored highly on the anxiety component of the SCL-90, although mean scores were not different from controls. No differences were seen in scores for depression, but both subgroups of hyperprolactinaemic patients scored more highly than controls for hostility on the SCL-90 questionnaire. CONCLUSION: These findings confirm the presence of significant anxiety in a proportion of women with hyperprolactinaemia. Hyperprolactinaemic women with no abnormality on CT scans displayed more psychological distress than those with definite pituitary microadenomas. These results may provide insight into the pathogenesis of 'functional' hyperprolactinaemia.
Adenoma↗
Clinical manifestations of Plasmodium falciparum malaria experimentally induced by mosquito challenge.
To determine the characteristics of clinical illness accompanying Plasmodium falciparum infection induced by controlled exposure to infected mosquitoes, records of 118 volunteers participating in studies conducted between 1985 and 1992 were reviewed. One hundred fourteen volunteers (97%) reported at least one symptom attributable to malaria, with fatigue, myalgias or arthralgias, headache, and chills most commonly reported. The median duration of symptoms was 3 days. Fever was recorded in 61% of volunteers; 4 volunteers had temperatures >40 degrees C. Neutropenia and thrombocytopenia were present in 9% and 12% of volunteers, respectively. Despite counts as low as 658/microL (neutrophils) or 73,000/microL (platelets), no secondary infectious or hemorrhagic complications occurred. In all cases, volunteers recovered completely and laboratory values returned to baseline after specific antimalarial therapy. Recrudescence did not occur in any volunteer. In this model, mosquito inoculation of P. falciparum is a reliable, safe, and well-tolerated method of experimental challenge.
Adolescent↗
Monochromatic microtomographic imaging of osteoporotic bone.
A monochromatic beam obtained from laboratory based instrumentation has been used for the first time to carry out a microtomographic x-ray scan of a small segment of osteoporotic bone. The resulting tomograph provides an accurate map of the x-ray linear attenuation coefficient at the characteristic energy for Cu K alpha x-rays. The bone segment was imaged in a variety of ways which are common to microtomography in order to compare the efficacy of different experimental configurations. A Si crystal monochromator was placed before the x-ray detector in order to reject radiation scattered by the sample. In addition, polychromatic scans were compared with monochromatic scans. The effects of multiple scatter can be seen upon comparison of scans with and without the second monochromator. The results indicate that beam-hardening and x-ray scattering can significantly alter an image, thereby distorting the interpretation of what is physically present in the specimen. An accurate, monochromatic tomographic scanning facility is being developed in an attempt to map meaningful physical constants for various materials.
Bone and Bones↗
Full presence of Epstein-Bar virus (EBV)-encoded latent proteins in tissues from a patient with severe chronic active EBV infection syndrome.
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Adult↗
Glucocorticoid receptor structure and function in glucocorticoid-resistant small cell lung carcinoma cells.
Human small cell lung carcinomas (SCLCs) frequently express the adrenocorticotrophin precursor gene proopiomelanocortin. Glucocorticoids usually fail to inhibit this ectopic adrenocorticotrophin production, in contrast to their effects in the pituitary. We have shown three human SCLC cell lines to be globally resistant to glucocorticoid action; in two of these lines this occurs despite the presence of glucocorticoid receptors (GR+). Accordingly, we have cloned and sequenced the GR coding region from one of these two GR+, SCLC cell lines, COR L24, and identified compound heterozygous mutations. One allele had a single nucleotide substitution of A to G in the NH2-terminal domain, which altered Asp to Ser at amino acid 363. The other allele contained a trinucleotide insertion at the 5' boundary of exon 4, which introduced an additional amino acid, Arg453, between the two zinc fingers of the DNA binding domain. In cotransfection studies using the glucocorticoid responsive mouse mammary tumor virus-luciferase Ser363 did not alter receptor function. In contrast, Arg453 encoded a GR with 48% Vmax activity compared to wild-type receptor (P < 0.001), with an unchanged EC50. Thus, GR mutations may contribute to the glucocorticoid-resistant phenotype of GR+ COR L24 cells, which could confer survival advantage to this highly malignant neuroendocrine tumor.
Amino Acid Sequence↗
Molecular biology techniques in endocrinology.
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Endocrinology↗
Hyperreactio luteinalis associated with pregnancy: a case report and review of the literature.
Hyperreactio luteinalis is a condition associated with bilateral and, in rare cases, unilateral ovarian enlargement due to theca lutein cysts. Hyperreactio luteinalis is a benign condition, usually found incidentally at cesarean section, which can appear anaplastic and lead to unnecessary ovarian resection. A 21-year-old Hispanic woman, G2P1, presented at 19 weeks with a singleton pregnancy, bilaterally enlarged ovaries, and a normal beta hCG. Over the next four months, her ovaries increased 75% in size with the right ovary becoming entrapped in the pelvis. The patient underwent a primary low transverse cesarean section. The ovaries had an anaplastic appearance and on frozen section revealed multiple benign theca lutein cysts. There are 51 reported cases of hyperreactio luteinalis associated with a normal pregnancy in the literature. It is estimated that approximately 60% of the cases of hyperreactio luteinalis unassociated with trophoblastic disease occur with normal singleton pregnancy. There are multiple benign ovarian lesions including hyperreactio luteinalis that can mimic ovarian neoplasms. Accordingly, it is important to exclude these from the differential diagnosis via a wedge biopsy and frozen section to avoid unnecessary surgical excision.
Adult↗