Showing papers by "St Bartholomew's Hospital published in 1998"
TL;DR: A differential diagnosis of ACTH-Dependent Cushing’s Syndrome and differentiation from Pseudo-Cushing”s States are presented.
Abstract: I. Introduction II. Definitions and Etiology III. Diagnostic Overview IV. Clinical Features V. Biochemical Diagnosis of Cushing’s Syndrome A. Cardinal features B. Urinary free cortisol (UFC) C. Low-dose dexamethasone testing D. Circadian rhythm assessment E. Cyclical Cushing’s syndrome VI. ACTH-Dependent vs. ACTH-Independent Cushing’s Syndrome VII. Differential Diagnosis of ACTH-Dependent Cushing’s Syndrome A. Overview B. Basal testing C. Dynamic noninvasive testing D. Invasive testing VIII. Other Causes of Cushing’s Syndrome IX. Imaging A. Pituitary B. Adrenal C. Ectopic secretion X. Differentiation from Pseudo-Cushing’s States XI. Conclusions
766 citations
TL;DR: It is attractive to suggest that the anti-inflammatory actions of NSAIDs are due to inhibition of COX-2, whereas the unwanted side-effects, such as irritation of the stomach lining, are dueto inhibition ofCOX-1.
568 citations
TL;DR: The results provide the basis for a molecular-genetic screening approach that will supplement the clinical evaluation and genetic counseling of members of MEN1 families and SSCP was found to be a sensitive and specific mutational screening method that detected >85% of the mutations.
Abstract: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroids, pancreatic islets, and anterior pituitary. The MEN1 gene, on chromosome 11q13, has recently been cloned, and mutations have been identified. We have characterized such MEN1 mutations, assessed the reliability of SSCP analysis for the detection of these mutations, and estimated the age-related penetrance for MEN1. Sixty-three unrelated MEN1 kindreds (195 affected and 396 unaffected members) were investigated for mutations in the 2,790-bp coding region and splice sites, by SSCP and DNA sequence analysis. We identified 47 mutations (12 nonsense mutations, 21 deletions, 7 insertions, 1 donor splice-site mutation, and 6 missense mutations), that were scattered throughout the coding region, together with six polymorphisms that had heterozygosity frequencies of 2%-44%. More than 10% of the mutations arose de novo, and four mutation hot spots accounted for >25% of the mutations. SSCP was found to be a sensitive and specific mutational screening method that detected >85% of the mutations. Two hundred and one MEN1 mutant-gene carriers (155 affected and 46 unaffected) were identified, and these helped to define the age-related penetrance of MEN1 as 7%, 52%, 87%, 98%, 99%, and 100% at 10, 20, 30, 40, 50, and 60 years of age, respectively. These results provide the basis for a molecular-genetic screening approach that will supplement the clinical evaluation and genetic counseling of members of MEN1 families.
415 citations
TL;DR: It is concluded that thin section high resolution MRI on a T2 protocol in the axial and sagittal planes is the imaging investigation of choice in Pendred syndrome.
238 citations
TL;DR: The practical scheme outlined for dose titration of GH replacement resulted in rapid achievement of lower maintenance doses than those achieved using conventional weight-based regimens without loss of efficacy, particularly important in female patients who demonstrated decreased overall sensitivity to GH and required higher doses to achieve the same effects as males.
Abstract: Although growth hormone (GH) replacement therapy is increasingly utilized in the management of adult hypopituitary patients, optimum dosing schedules are poorly defined. The use of weight-based or surface area-based dosing may result in overtreatment, and individual variation in susceptibility on the basis of gender and other factors is now being recognized. To optimize GH replacement and to explore further gender differences in susceptibility, we used a dose titration regimen, starting at the initiation of GH replacement therapy, in 50 consecutive adult-onset hypopituitary patients, and compared the results with those in 21 patients previously treated using a weight-based regimen. Titrated patients commenced GH 0.8 IU/day subcutaneously (0.4 IU/day if hypertensive or glucose tolerance impaired). Serum insulin-like growth factor I (IGF-I) was measured at 0, 2, 4, 6, 8, 10, and 12 weeks in all patients. Serum IGF binding protein 3 and acid labile subunit were measured at the same time points in 17 patients...
235 citations
TL;DR: Langerhans cell histiocytosis in the adult is rare, but it is important to recognize its occurrence, as it must be differentiated from lymphoma, myeloma, and a variety of skin conditions and endocrinopathies.
Abstract: Langerhans cell histiocytosis in the adult is rare, but it is important to recognize its occurrence, as it must be differentiated from lymphoma, myeloma, and a variety of skin conditions and endocrinopathies. It has been reported in patients up to the ninth decade of life, and occurs equally in men and women. Local disease has a good prognosis, but associated diseases--particularly malignancy--may be the cause of death in some adults. The optimal treatment is not known. Coordinated investigation of the epidemiology and therapy of this disease is needed.
228 citations
TL;DR: Molecular heterogeneity for PDS mutations associated with Pendred syndrome is demonstrated and this study would support the use of molecular analysis of the PDS gene in the assessment of families with congenital hearing loss.
Abstract: Pendred syndrome is an autosomal recessive disorder characterized by the association between sensorineural hearing loss and thyroid swelling or goitre and is likely to be the most common form of syndromic deafness. Within the thyroid gland of affected individuals, iodide is incompletely organified with variable effects upon thyroid hormone biosynthesis, whilst the molecular basis of the hearing loss is unknown. The PDS gene has been identified by positional cloning of chromosome 7q31, within the Pendred syndrome critical linkage interval and encodes for a putative ion transporter called pendrin. We have investigated a cohort of 56 kindreds, all with features suggestive of a diagnosis of Pendred syndrome. Molecular analysis of the PDS gene identified 47 of the 60 (78%) mutant alleles in 31 families (includes three homozygous consanguineous kindreds and one extended family segregating three mutant alleles). Moreover, four recurrent mutations accounted for 35 (74%) of PDS disease chromosomes detected and haplotype analysis would favour common founders rather than mutational hotspots within the PDS gene. Whilst these findings demonstrate molecular heterogeneity for PDS mutations associated with Pendred syndrome, this study would support the use of molecular analysis of the PDS gene in the assessment of families with congenital hearing loss.
224 citations
TL;DR: In this paper, multivariate regression was used to identify known components within very noisy data, permitting the rapid detection of explosive materials in the presence of overlying media for security screening applications, and the error associated with the prediction is consistent from statistically reliable data (106 integrated counts) down to spectra containing in the region of 103 counts.
Abstract: Energy dispersive x-ray diffraction (EDXRD) has been developed as a tool for the detection of explosives in passenger baggage. The measured spectra result from the combined diffraction from each of the materials within a scattering volume. Multivariate regression was used to identify known components within very noisy data, permitting the rapid detection of explosive materials in the presence of overlying media for security screening applications. Explosives can be positively identified in spectra containing as few as several hundred counts and the error associated with the prediction is consistent from statistically reliable data (106 integrated counts) down to spectra containing in the region of 103 counts. This analysis can be employed in any situation where qualitative information is required from poor quality spectral data. © 1998 John Wiley & Sons, Ltd.
181 citations
TL;DR: The data suggest that a significant inverse relation exists between presumed atherosclerotic load and aortic compliance determined noninvasively based on aorti pulse wave velocity measurements, and if these findings are confirmed by prospective, longitudinal follow-up studies, such measurements may prove useful as a noninvasive marker of vascular risk.
Abstract: —The aim of this study was to establish the relation between noninvasive Doppler ultrasound assessments of aortic compliance, based on “foot-to-foot” aortic pulse wave velocity measurements, and presumed atherosclerotic load in patients with vascular disease and/or diabetes mellitus. One hundred ten patients with vascular disease and/or diabetes mellitus (arteriopaths) underwent measurement of in vivo aortic compliance using Doppler ultrasound. Demographic data on these subjects were recorded along with details of cardiovascular risk factors and events. Aortic compliance values were compared with data from 51 age-matched healthy, asymptomatic subjects putatively free of vascular disease (controls). Data are expressed as mean±SD. Arteriopaths were aged 64.1±8.4 years and had total cholesterol levels of 5.9±1.1 mmol/L and aortic compliance of 0.78±0.42%/10 mm Hg [1.33 kPa]. Most arteriopaths had 2 or more cardiovascular risk factors and events: diabetes (n=41), hypertension (n=45), smoking (n=86), cerebrovascular/transient ischemic event (n=13), myocardial infarction (n=44), angina (n=51), and/or peripheral vascular disease (n=33). Controls were aged 64.3±12.1 years with total cholesterol of 6.1±1.1 mmol/L and aortic compliance of 1.14±0.46%/10 mm Hg [1.33 kPa] ( P P
172 citations
TL;DR: Five PTEN mutations were identified in 37 primary prostatic tumours analysed and it was found that 70% of tumours showed loss or alteration of at least one PTEN allele, supporting the evidence for PTEN involvement in prostate tumour progression.
Abstract: The chromosomal region 10q23-24 is frequently deleted in a number of tumour types, including prostate adenocarcinoma and glioma. A candidate tumour-suppressor gene at 10q23.3, designated PTENor MMAC1, with putative actin-binding and tyrosine phosphatase domains has recently been described. Mutations in PTEN have been identified in cell lines derived from gliomas, melanomas and prostate tumours and from a number of tumour specimens derived from glial, breast, endometrial and kidney tissue. Germline mutations in PTEN appear to be responsible for Cowden disease. We identified five PTEN mutations in 37 primary prostatic tumours analysed and found that 70% of tumours showed loss or alteration of at least one PTEN allele, supporting the evidence for PTEN involvement in prostate tumour progression. We raised antisera to a peptide from PTEN and showed that reactivity occurs in numerous small cytoplasmic organelles and that the protein is commonly expressed in a variety of cell types. Northern blot analysis revealed multiple RNA species; some arise as a result of alternative polyadenylation sites, but others may be due to alternative splicing.
166 citations
TL;DR: Hepatic steatosis occurs commonly in patients receiving 5-FU and folinic acid and can be severe, which can make hepatic metastases difficult to assess and if its benign nature is not appreciated treatment may be inappropriately altered.
Abstract: The frequency and severity of fatty infiltration of the liver in patients receiving 5-fluorouracil (5-FU) and folinic acid has not been documented systematically. Its development can result in difficulty assessing disease progression, and treatment may be altered inappropriately. Twenty-seven patients with colon cancer and liver metastases receiving 5-FU and folinic acid were studied with computerized tomography (CT) before treatment and after six or 12 cycles of chemotherapy. Forty-seven per cent of patients developed hepatic steatosis during treatment. There was no correlation between development of hepatic steatosis and the dose of chemotherapy or the liver function tests. Hepatic steatosis occurs commonly in patients receiving 5-FU and folinic acid and can be severe. Its development can make hepatic metastases difficult to assess and if its benign nature is not appreciated treatment may be inappropriately altered.
TL;DR: It is indicated that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%.
Abstract: Purpose: The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery Methods and Materials: This quantitative meta-analysis included updated individual patient data from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials Results: With a median follow-up of 9 years, the hazard ratio (HR) of 089 (95% CI 078–101) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years This result is not conventionally statistically significant ( p = 0062) No clear differences in the size of the effect by sex, age, or tumor location were apparent Conclusion: Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4% Trials or a meta-analysis of around 2000 patients would be needed to reliably detect such an improvement (15→20%)
TL;DR: Overall survival and PFS have now ceased to be significant, because most patients have ultimately succumbed to their disease, and the benefits of interferon should be confirmed in larger multi‐centre studies in the setting of minimal residual disease following autologous transplantation.
Abstract: High-dose chemotherapy (melphalan) with autologous marrow stem cell support (AMSCS) results in high response rates in multiple myeloma (MM), with up to 50% of patients achieving complete remission. However, these remissions are generally not durable. As the cytokine interferon alpha has been shown to prolong partial response following conventional chemotherapy, this trial was conducted to evaluate its role following high-dose chemotherapy. 85 patients were randomly assigned to maintenance treatment with interferon alpha, 3 x 10(6) units/m2 subcutaneously three times weekly until relapse or no further treatment following recovery from high-dose chemotherapy (melphalan 140-200 mg/m2 or busulphan 16 mg/kg) combined with AMSCS. At 5.8 years following the accrual of the last patient in this trial, 38 patients had died, 17 in the interferon arm and 21 in the control arm. The median progression-free survival (PFS) in the 42 patients randomized to interferon alpha was 46 months versus 27 months in the controls. Both overall survival and PFS, which were highly significant at median follow-up of 52 months, have now ceased to be significant, because most patients have ultimately succumbed to their disease. Interferon was tolerated by the majority of patients with very good compliance. Toxicity consisted mainly of flu-like symptoms and malaise which were usually self-limiting. The results of such a pilot study should be carefully interpreted and the benefits of interferon should be confirmed in larger multicentre studies in the setting of minimal residual disease following autologous transplantation.
TL;DR: Infecton imaging is a new diagnostic tool that is specific for detecting sites of bacterial infection in the body and the high positive predictive value displayed by the technique is clinically important because a positive image strongly supports a diagnosis ofacterial infection.
Abstract: AIMS: To determine the sensitivity and specificity of 99mTc-Infecton (Infecton), a novel ciprofloxacin based imaging agent, in detecting sites of infection. METHODS: Ninety patients thought to be suffering from a variety of infections were administered 300-400 MBq of Infecton intravenously. Whole body images were taken one and four hours later. Appropriate specimens were taken for microbiological investigations. Statistical analysis was performed using a computer statistical package. RESULTS: Ninety eight Infecton images were produced. Forty one of these were positive, including three false positives, where the patients had non-infective conditions. Fifty seven negative images were obtained, of which 41 were true negatives and 16 were false negatives, having definite evidence of infection. Thus, Infecton imaging has a sensitivity of 70.3% and a specificity of 93.1% for detecting infective foci. The positive and negative predictive values were 92.6% and 71.9%, respectively. CONCLUSION: Infecton imaging is a new diagnostic tool that is specific for detecting sites of bacterial infection in the body. The high positive predictive value displayed by the technique is clinically important because a positive image strongly supports a diagnosis of bacterial infection. A negative result does not rule out an infection, and may be a result of previous or current antibiotic treatment and/or infection with organisms that do not take up Infecton. Infecton imaging has major advantages over well established imaging techniques, including radiolabelled leucocytes, and may prove to be a superior method for localising bacterial infections.
TL;DR: Comment on the acceptable limits of informed consent in medical research is revisited by Len Doyal and Jeffrey Tobias and three people who are not doctors, researchers, or medical ethicists.
Abstract: # Informed consent in medical research {#article-title-2}
In the issue of 12 April 1997 the BMJ invited comment on the acceptable limits of informed consent in medical studies. In view of the large correspondence this generated, we invited the two original commentators, Len Doyal and Jeffrey Tobias, to revisit the subject. We also invited comments from three people who are not doctors, researchers, or medical ethicists: two of them represent the views of patients and potential patients
# Informed consent—a response to recent correspondence {#article-title-3}
Editorial by Smith and Personal views pp 1026-7
The publication of the debate between myself and Jeffrey Tobias about the acceptable limits of informed consent in medical research has generated an immense and varied number of letters to the BMJ .1–4 This in itself is gratifying, whether or not correspondents agree with my arguments. It provides ample evidence of widespread and serious deliberation about the moral boundaries of the rights of participants in research.
Previous articles and comment on informed consent are available on our website (see Collections)
Many correspondents either explicitly or implicitly endorse the hard line that I take in my paper on the right of competent people to an acceptable level of information before agreeing to participate in medical research. Other contributions confirm my emphasis on the moral importance of the principle of informed consent but, in light of the highly specific circumstances where I argue that the principle must be qualified, question the degree or clarity of my own commitment to it. What is important here is our shared belief in the moral imperative of respecting human autonomy in almost all circumstances.
I still disagree with those authors who argue that it is not necessary to obtain informed consent if this will lead to the methodological compromise, or possible cancellation, of potentially beneficial studies involving clinical interventions that carry minimal risks. What these …
TL;DR: Infection with the nematode Trichinella spiralis in mice defective for cytokines or their receptors is used to investigate cytokine regulation of both immunopathlogy and parasite rejection and it is found that parasite expulsion is IL‐4 dependent.
Abstract: The relationship between intestinal pathology and immune expulsion of gastrointestinal nematodes remains controversial. Parasite expulsion is associated with intestinal pathology in several model systems and both of these phenomena are T cell dependent. Immune expulsion of gastrointestinal helminth parasites is usually associated with Th2 responses, but the effector mechanisms directly responsible for parasite loss have not been elucidated. In contrast, the intestinal pathology observed in many other disease models closely resembles that seen in helminth infections, but has been attributed to Th1 cytokines. We have used infection with the nematode Trichinella spiralis in mice defective for cytokines or their receptors to investigate cytokine regulation of both immunopathlogy and parasite rejection. Consistent with previous findings, we found that parasite expulsion is IL-4 dependent. Contrary to expectations, however, the enteropathy is not regulated by IFN-γ but by IL-4. Moreover, abrogation of severe pathology in TNF receptor-defective animals does not prevent parasite expulsion. TNF is therefore involved in intestinal pathology in nematode infections, apparently under regulation by IL-4- and Th2-mediated responses. This work therefore not only reveals a novel interplay between IL-4 and TNF, but also that the IL-4-dependent protective response against the parasite operates by a mechanism other than merely the gross degradation of the parasite's environment brought about by the immune enteropathy.
TL;DR: The various patterns of neurophysiological abnormalities which may complicate prolonged critical illness and possible aetiological factors are described to lead to further insights into the causes of neuromuscular weakness in the critically ill and ultimately to measures for their prevention and treatment.
Abstract: Objective
To describe the various patterns of neurophysiological abnormalities which may complicate prolonged critical illness and identify possible aetiological factors.
TL;DR: The data suggest that the menstrual irregularity in Cushing's disease appears to be the result of hypercortisolemic inhibition of gonadotropin release acting at a hypothalamic level, rather than raised circulating androgen levels.
Abstract: Menstrual irregularity is a common complaint at presentation in women with Cushing's syndrome, although the etiology has been little studied. We have assessed 45 female patients (median age, 32 yr; range, 16-41 yr) with newly diagnosed pituitary-dependent Cushing's syndrome. Patients were subdivided into 4 groups according to the duration of their menstrual cycle: normal cycles (NC; 26-30 days), oligomenorrhea (OL; 31-120 days), amenorrhea (AM; > 120 days), and polymenorrhea (PM; < 26 days). Blood was taken at 0900 h for measurement of LH, FSH, PRL, testosterone, androstenedione, dehydroepiandrosterone sulfate, estradiol (E2), sex hormone-binding globulin (SHBG), and ACTH; cortisol was sampled at 0900, 1800, and 2400 h. The LH and FSH responses to 100 micrograms GnRH were analyzed in 23 patients. Statistical analysis was performed using the nonparametric Mann-Whitney U and Spearman tests. Only 9 patients had NC (20%), 14 had OL (31.1%), 15 had AM (33.3%), and 4 had PM (8.8%), whereas 3 had variable cycles (6.7%). By group, AM patients had lower serum E2 levels (median, 110 pmol/L) than OL patients (225 pmol/L; P < 0.05) or NC patients (279 pmol/L; P < 0.05), and higher serum cortisol levels at 0900 h (800 vs. 602 and 580 nmol/L, respectively; P < 0.05) and 1800 h (816 vs. 557 and 523 nmol/L, respectively; P < 0.05) and higher mean values from 6 samples obtained through the day (753 vs. 491 and 459 nmol/L, respectively; P < 0.05). For the whole group of patients there was a negative correlation between serum E2 and cortisol at 0900 h (r = -0.50; P < 0.01) and 1800 h (r = -0.56; P < 0.01) and with mean cortisol (r = -0.46; P < 0.05). No significant correlation was found between any serum androgen and E2 or cortisol. The LH response to GnRH was normal in 43.5% of the patients, exaggerated in 52.1%, and decreased in 4.4%, but there were no significant differences among the menstrual groups. No differences were found in any other parameter. In summary, in our study 80% of patients with Cushing's syndrome had menstrual irregularity, and this was most closely related to serum cortisol rather than to circulating androgens. Patients with AM had higher levels of cortisol and lower levels of E2, while the GnRH response was either normal or exaggerated. Our data suggest that the menstrual irregularity in Cushing's disease appears to be the result of hypercortisolemic inhibition of gonadotropin release acting at a hypothalamic level, rather than raised circulating androgen levels.
Journal Article•
TL;DR: One of the ways in which TNF-alpha causes tissue injury in the gut is by stimulating mucosal mesenchymal cell to secrete matrix-degrading metalloproteinases, and neutrality of this activity should help maintain tissue integrity.
Abstract: Anti-TNF-alpha Ab therapy has been shown to be of benefit in the treatment of active Crohn's disease, but the tissue-injuring processes in the gut mediated by TNF-alpha that might be inhibited by neutralizing Ab are unknown. In this work, we have used a p55 TNF receptor-human IgG fusion protein (TNFR-IgG) to prevent the severe mucosal injury that ensues when lamina propria T cells in explant cultures of human fetal small intestine are directly activated with the lectin PWM. Following T cell activation and associated with mucosal injury, there is a marked elevation of soluble TNF-alpha in organ culture supernatants and a large increase in TNF-alpha mRNA transcripts. The addition of TNFR-IgG at the onset of cultures greatly reduced PWM-induced tissue injury, without inhibiting the increase in TNF-alpha and IFN-gamma transcripts seen following T cell activation. Mucosal injury in this model is mediated by endogenously-produced matrix metalloproteinases (MMPs). When TNFR-IgG was added to PWM-stimulated explants, there was a reduction in MMPs in the explant culture supernatants, especially stromelysin-1. Recombinant TNF-alpha and IL-1beta added directly to mucosal mesenchymal cell lines also caused an increase in MMP production, but only the former was inhibited by the TNFR-IgG. These results suggest that one of the ways in which TNF-alpha causes tissue injury in the gut is by stimulating mucosal mesenchymal cell to secrete matrix-degrading metalloproteinases. Neutralization of this activity should help maintain tissue integrity.
TL;DR: It is concluded that APT produces greater change in anxiety, adjustment to cancer and use of coping strategies than a non‐directive, supportive intervention over an 8 week period of treatment.
Abstract: This study compared the effectiveness of two psychological treatments in a group of 57 patients with various types of cancer attending the Royal Marsden Hospital. Patients referred for psychiatric assessment who met criteria for an abnormal adjustment reaction were randomly allocated to either 8 weeks of Adjuvant Psychological Therapy (APT), a problem-focused, cognitive behavioural treatment programme, or 8 weeks of a comparison treatment of supportive counselling. At 8 weeks from the baseline assessment, APT had produced a significantly greater change than the counselling intervention on fighting spirit, helplessness, coping with cancer, anxiety, and self-defined problems. At 4 months from baseline, APT had produced a significantly greater change than counselling on fighting spirit, coping with cancer, anxiety and self defined problems. It is concluded that APT produces greater change in anxiety, adjustment to cancer and use of coping strategies than a non-directive, supportive intervention over an 8 week period of treatment. This difference persists at follow up 4 months after baseline assessment.
TL;DR: It is concluded that mutations of the p27/kip1 gene, deletions of the 12p13 area or changes in expression, are not a general feature of corticotroph tumours, even those with intermediate lobe characteristics; however, other mechanisms of p27 / kip1 inactivation may be related to more aggressive histological subtypes of ACTH-secreting and possibly other pituitary tumours.
Abstract: The molecular mechanisms leading to Cushing’s diseaseare unclear. Inhibitors of cyclin-cyclin dependent kinase(CDK) complexes are regulators of the cell cycle andmay function as tumour suppressor genes, many of whichhave been involved in the pathogenesis of several humanmalignancies. A member of this family, the p27/kip1gene, maps to chromosome 12p13 and encodes aninhibitor of several cyclin-CDK complexes; these controlthe progression of the cell cycle from G1 to S-phase.Complete lack of p27/kip1 function, as occurs in thep27/kip1 ‘knockout’ mouse, produces a complex pheno-type associated with the development of pituitarytumours, specifically those of the intermediate lobecorticotrophs. We therefore investigated whether struc-tural and functional abnormalities of the p27/kip1 geneand loss at the chromosome 12p13 region were present inhuman corticotrophin (ACTH)-secreting pituitary tu-mours. We studied 21 pituitary tumours, of which 20were ACTH-secreting (two of these had biochemical andhistological features of ‘intermediate-lobe’ tumours andone was malignant) while the remaining tumour was aprolactinoma; three ectopic secretors of ACTH (twobronchial and one thymic carcinoid); and a non-secretorythymic carcinoid. The whole coding region of the p27/kip1 gene was screened for mutations by PCR–SSCPanalysis and/or direct sequencing, while tumour mRNAexpression was analysed by means of a semi-quantitativeduplex PCR. Three polymorphic microsatellite markersof the 12p13 region were used to assess loss ofheterozygosity (LOH) in 12 samples. Finally, tumourp27/kip1 protein expression was assessed by immunohis-tochemistry using a monoclonal antibody in 12 samplessuitable for analysis. No sequence abnormalities werefound in any of the samples other than a previously-described polymorphism. No LOH was observed in thetumours analysed. p27/kip1 mRNA expression wassimilar in tumour samples in comparison with normalpituitaries. Seven of the eight corticotroph tumoursanalysed by immunohistochemistry stained positive forp27/kip1, including the intermediate lobe. The onlymalignant pituitary tumour in the original series showedan absence of staining for p27/kip1. In addition, thethree carcinoid tumours studied were negative onimmunohistochemistry. Of a further three malignantpituitary tumours assessed, two (including a prolactino-ma) were essentially negative, while the third wasmoderately positive. We conclude that mutations of thep27/kip1 gene, deletions of the 12p13 area or changes inexpression, are not a general feature of corticotrophtumours, even those with intermediate lobe character-istics. However, other mechanisms of p27/kip1 inactiva-tion, such as an abnormality at the post-translationallevel, may be related to more aggressive histologicalsubtypes of ACTH-secreting and possibly other pituitarytumours.Keywords: Cushing’s disease; ACTH-tumour; p27-kip1;mutation; carcinoid; cell cycle inhibitor; pituitarytumourIntroductionThe molecular pathogenesis of pituitary tumours is asyet unclear. Attempts to identify genes related tospecific pituitary growth have so far been disappoint-ing, as non-specific oncogenes and tumour suppressorgenes, as well as genes related to pituitary physiologicalregulation, have been found to be structurally normalin the majority of such tumours (Herman et al., 1993;Levy et al., 1994; Dahia et al., 1996).It has recently been reported that mice with agenomic ‘knockout’ of the p27/kip1 gene developmulti-organ hyperplasia resulting in increased animalsize and pituitary tumours that originate fromintermediate lobe corticotrophs, but no other neo-plasms (Fero et al., 1996; Nakayama et al., 1996;Kyiokawa et al., 1996). Such tumours immunostain forcorticotrophin (ACTH). The p27/kip1 gene maps tochromosome 12p13 and encodes for a 27 kd proteinthat is a member of the cyclin-kinase inhibitor proteins(CKIs) family, including cyclin-cyclin dependent kinase(CDK) complexes with CDK 2,3,4, and 6 (Poliak et al.,1994a; Poliak et al., 1994b; Toyoshima et al., 1994).Some of these complexes, formed between D-typecyclins and CDK4/CDK6, mediate the phosphoryla-tion of the retinoblastoma (Rb) protein and, throughits inactivation, allow the progression of cell cycle frommid-G1. Another target for p27 regulation is the cyclinE/CDK2 complex, required for entry into S-phasefrom late G1 (Kato et al., 1994). The p27 product isinvolved in pathways that sense both mitogenic andantiproliferative extrinsic signals: its activity is high inquiescent cells and declines during cell cycle progres-sion (Polyak et al., 1994a). There is evidence suggestingthat p27 mediates G1 arrest induced by transforminggrowth factor-b, contact inhibition, or serum depriva-
TL;DR: It is believed that these cytokines may play an important role in the successful establishment of the pregnancy; the evidence for this belief is examined in this review.
TL;DR: The effect of GH on urinary cortisol, cortisone and cortisol metabolites in hypopituitary adults at increasing doses of hydrocortisone replacement is examined.
Abstract: Objective Growth hormone (GH) replacement therapy in hypopituitary adults has been associated with a decreased urinary ratio of 11-hydroxy/11-oxo-cortisol metabolites (CoM). This could result from GH regulation of the activity of hepatic or renal 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD1 and 2), the enzymes responsible for cortisol-cortisone interconversion, or alternatively it might reflect decreased cortisol availability. To elucidate this, we examined the effect of GH on urinary cortisol, cortisone and cortisol metabolites in hypopituitary adults at increasing doses of hydrocortisone replacement. Design Patients received increasing twice daily doses of hydrocortisone (HC) (10/10, 20/10, 40/20 mg) each week, before and during 2 months of GH replacement (0.25 U/kg/week). Patients Seven hypopituitary adults (three men and four women, age range 47-64 years) with combined GH and ACTH deficiency. Three additional patients with GH deficiency, but intact ACTH reserve, were also studied. Measurements Urine steroid metabolite profiles were measured in 24-hour urine collections by gas chromatography after each week of treatment. Urinary free cortisol and free cortisone were measured by radioimmunoassay as a measure of renal 11 beta-HSD-2 activity. Results Total urinary CoM increased with rising doses of HC, but at each particular HC dose, were unchanged after GH (before versus after GH, median (range): 9.67 (7.86-12.59) versus 9.93 (8.31-14.08); 15.87 (12.37-31.39) versus 17.07 (12.64-23.81); 26.68 (19.07-42.14) versus 26.77 (8.01-37.62) mg/24 hours). The urine ratio 11-hydroxy/11-oxo-CoM decreased significantly with GH treatment, at each HC dose schedule (1.22 (1.02-1.96) versus 0.92 (0.83-1.63) P = 0.018; 1.53 (1.30-2.23) versus 1.23 (0.93-1.46) P = 0.018; 1.87 (1.45-2.70) versus 1.56 (1.22-1.79) P = 0.018). The urinary ratio tetrahydrocortisols/tetrahydrocortisone, an alternative index of 11 beta-HSD activity, also fell with GH therapy at each HC dose (P = 0.049; P = 0.018; P = 0.043). In contrast, the urinary 20-hydroxy/20-oxo-CoM ratio exhibited a small increase with GH, suggesting that the changes observed above were not simply due to changes in redox status. The patients with GH deficiency, but intact ACTH reserve, demonstrated changes in urine steroid profiles similar to the group receiving hydrocortisone replacement. Urinary free cortisone and urinary free cortisol/free cortisone ratios did not change with GH therapy, but the serum cortisol/ cortisone ratio fell significantly with GH therapy at each hydrocortisone dose. Conclusions GH therapy decreases the urinary ratios 11-hydroxy/11-oxo-cortisol metabolites and tetrahydrocortisols/tetrahydrocortisone, but not urinary free cortisone or the urinary free cortisol/free cortisone ratio. This effect is not secondary to reduced cortisol availability. These findings provide further evidence for direct or indirect modulation of cortisol metabolism by growth hormone and suggest that this occurs at hepatic or an alternative site of 11 beta-hydroxysteroid dehydrogenase-1 activity.
TL;DR: In the Centenary year of Wertheim's hysterectomy for the treatment of invasive cervical cancer, it is appropriate to look at less radical methods of managing early stage disease, with careful selection within strict criteria.
TL;DR: The peritoneum is the largest and most complexly arranged serous membrane in the body as discussed by the authors, and the peritoneal ligaments, mesenteries and omenta also serve as boundaries for disease processes and conduits for disease spread.
Abstract: The peritoneum is the largest and most complexly arranged serous membrane in the body. The potential peritoneal spaces, the peritoneal reflections forming peritoneal ligaments, mesenteries, omenta and the natural flow of peritoneal fluid determine the route of spread of intraperitoneal fluid and, consequently, disease processes within the abdominal cavity. The peritoneal ligaments, mesenteries and omenta also serve as boundaries for disease processes and conduits for disease spread. The peritoneal cavity and its reflections are frequently involved by infectious, inflammatory, neoplastic and traumatic processes. Before the introduction of cross-sectional imaging, the peritoneum and its reflections could only be imaged with difficulty, often requiring invasive techniques. Computed tomography and, to a lesser extent, sonography and MR imaging allow the accurate examination of the complex anatomy of the peritoneal cavity, which is the key to understanding the pathological processes affecting it. This article reviews the normal peritoneal anatomy and its disease processes.
TL;DR: Findings are in keeping with currently held hypotheses of hyperactivity and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis in depression and chronic fatigue syndrome respectively.
TL;DR: Until another more specific form of treatment is available, chemotherapy may still be of some value in patients with highly aggressive and malignant pituitary tumors, at least in achieving a temporary remission or delay in progression.
Abstract: Pituitary tumors are mostly benign lesions, although 5-35% are locally invasive. A small number exhibit a more aggressive course, infiltrating dura, bone and sinuses, and are designated highly aggressive. However, the presence of metastases separate from the pituitary in the central nervous system or at a distance is necessary to designate pituitary tumors as carcinomas, i.e. truly malignant. When conventional therapeutic modalities fail, systemic chemotherapy remains the last option. We report seven such patients, three with highly aggressive and four with malignant pituitary tumors (n=4) four women; median age, 32 yr; range, 23-48 yr), who received one or more courses of chemotherapy with lomustine and 5-fluorouracil (median, two courses; range, one to six courses). Three patients with systemic metastatic disease had a shorter survival (median, 5 months; range, 1-14 months) than the one patient with central nervous system metastases alone (10 yr). A patient with an aggressive nonmetastatic prolactinoma who initially responded to chemotherapy died from another nondisease-associated cause. Two patients, one with an aggressive and one with a metastatic tumor, achieved symptomatic improvement with a median duration of 6 months. A hormonal reduction greater than 50% was observed in two of seven patients; only one patient who had an aggressive tumor obtained an objective tumor response. The median survival from the time of initiation of chemotherapy in patients with malignant tumors ranged from 3-65 months. Two patients with malignant tumors developed disease progression while receiving chemotherapy; no patient with extracranial metastases showed a response. Treatment was well tolerated, with minimal individual side-effects. Three patients with no response to initial treatment received different chemotherapeutic regimens with no additional response. All patients with metastatic malignant tumors eventually died. Treatment with cytotoxic chemotherapy is noncurative, and current experience is limited. Until another more specific form of treatment is available, chemotherapy may still be of some value in patients with highly aggressive and malignant pituitary tumors, at least in achieving a temporary remission or delay in progression. The combination of lomustine/5-fluorouracil proved easy to administer with minimal toxicity, although the response rate was only 14%. Until a more specific treatment is found, an optimal chemotherapeutic regimen needs to be established.
TL;DR: Endogenous cortisol secretion was abolished by parenteral etomidate, allowing serum cortisol levels to be controlled with an iv infusion of hydrocortisone over an 8-week period in intensive care before definitive pancreatic surgery.
Abstract: We report the emergency and prolonged use of etomidate to control circulating cortisol levels in a patient with Cushing’s syndrome secondary to ectopic ACTH production from a pancreatic islet cell tumor. Duodenal perforation and peritonitis complicated an episode of salmonella septicemia, precluding the use of conventional oral medical adrenolytic therapy. Endogenous cortisol secretion was abolished by parenteral etomidate, allowing serum cortisol levels to be controlled with an iv infusion of hydrocortisone over an 8-week period in intensive care before definitive pancreatic surgery.
TL;DR: Although GHS-R messenger RNA is abundant in human somatotroph adenomas, it is also present in other pituitary adenoma, particularly ACTH-secreting tumors, and it appears from this study that G HS-R may be expressed in other neuroendocrine tumors.
Abstract: Synthetic GH secretagogues (GHSs; GH-releasing peptides and their nonpeptide mimetics) stimulate GH release, activate the hypothalamo-pituitary-adrenal axis, and release PRL in vivo. Patients with acromegaly show an exuberant GH response to GHSs, whereas patients with pituitary-dependent ACTH-secreting tumors show an exaggerated rise in ACTH and cortisol. We, therefore, studied the presence of GHS receptor (GHS-R) messenger ribonucleic acid (RNA) in 38 human pituitary tumors of different cell types, 3 ectopic ACTH-secreting tumors, a pancreatic gastrinoma, 3 insulinomas, and a nonsecreting thymic carcinoid as well as in 7 normal pituitary glands. Certain pituitary tumors were also studied by in vitro cell culture with measurement of secreted GH, ACTH, PRL, FSH, LH,α -subunit, and TSH. RNA was extracted from tissue samples and, after RT, a duplex PCR reaction with primers for the GHS-R gene and for the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase was performed, allowing semiquantitation of GH...
TL;DR: In this model of chronic inflammation, aspirin, more selective for the inhibition ofCOX-1 is more effective than the selective COX-2 inhibitors nimesulide and NS-398 at inhibiting granuloma dry weight, vascularity and COX activity.
Abstract: Objective and Design: The anti-inflammatory effects of therapeutic dosing of drugs with greater selectivity for the inhibition of the constitutive (COX-1) or inducible isoform (COX-2) of cyclooxygenase were assessed in a model of chronic inflammation.¶Methods: The murine chronic granulomatous tissue air pouch model involves the subcutaneous injection of air into the dorsum of mice followed 24 h later by the intrapouch injection of an inflammatory stimulus (0.5 ml of Freund's complete adjuvant containing 0.1% croton oil). Aspirin, more selective in vitro for the inhibition of COX-1 (10,200 mg/kg) and nimesulide, a selective in vitro inhibitor of COX-2 (0.5, 5 mg/kg) were dosed p.o. daily from 3 days after injection of the inflammatory stimulus. Granuloma dry weight, vascularity and COX activity (measured as PGE2) were assessed at various time points throughout the inflammatory lesion to resolution at day 28. A second COX-2 inhibitor, NS 398 (0.1, 1, 10 mg/kg), was dosed p.o. daily from 3 days after the injection of the inflammatory stimulus and its effects on granuloma dry weight, vascularity and COX activity were measured at 7 days.¶Results: Aspirin (200 mg/kg) significantly inhibited levels of PGE2 throughout the time course and at the lower dose (10 mg/kg) from day 14. Nimesulide (5 mg/kg) however, significantly increased levels of PGE2 at days 5 and 21, but at 0.5 mg/kg was without effect. Aspirin (200 mg/kg) significantly reduced granuloma dry weight at day 14 but had no effect on granuloma vascularity at day 7. In contrast, nimesulide (5 mg/kg) significantly increased granuloma vascularity at day 7 and granuloma dry weight at day 14. NS-398 at all doses had no effect on granuloma dry weight, vascularity or COX activity 7 days after the injection of the inflammatory stimulus.¶Conclusion: In this model of chronic inflammation, aspirin, more selective for the inhibition of COX-1 is more effective than the selective COX-2 inhibitors nimesulide and NS-398 at inhibiting granuloma dry weight, vascularity and COX activity.