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Showing papers by "St Bartholomew's Hospital published in 1999"


Journal ArticleDOI
TL;DR: The World Health Organization classification of hematologic malignancies, including lymphoid, myeloid, histiocytic, and mast cell neoplasms, has produced a new and exciting degree of cooperation and communication between oncologists and pathologists from around the world, which should facilitate progress in the understanding and treatment ofhematologicmalignancies.

1,467 citations


Journal ArticleDOI
TL;DR: In patients with prolonged critical illness, high doses of growth hormone are associated with increased morbidity and mortality.
Abstract: Background The administration of growth hormone can attenuate the catabolic response to injury, surgery, and sepsis. However, the effect of high doses of growth hormone on the length of stay in intensive care and in the hospital, the duration of mechanical ventilation, and the outcome in critically ill adults who are hospitalized for long periods is not known. Methods We carried out two prospective, multicenter, double-blind, randomized, placebo-controlled trials in parallel involving 247 Finnish patients and 285 patients in other European countries who had been in an intensive care unit for 5 to 7 days and who were expected to require intensive care for at least 10 days. The patients had had cardiac surgery, abdominal surgery, multiple trauma, or acute respiratory failure. The patients received either growth hormone (mean [±SD] daily dose, 0.10±0.02 mg per kilogram of body weight) or placebo until discharge from intensive care or for a maximum of 21 days. Results The in-hospital mortality rate was higher...

1,085 citations


Journal ArticleDOI
TL;DR: The frequency of postoperative adhesions after abdominal and pelvic surgery in the general population is investigated to provide a basis for the targeting and assessment of new adhesion-prevention measures.

825 citations



Journal ArticleDOI
TL;DR: It is suggested that a significant defect in NHEJ that leads to pronounced radiosensitivity is compatible with normal human viability and does not cause any major immune dysfunction, however, the defect may confer a predisposition to leukaemia.

372 citations


Journal ArticleDOI
11 Dec 1999-BMJ
TL;DR: The quantitative relation between risk factors and screening tests is specified and it is shown how strongly a risk factor needs to be associated with a disease before it is likely to be a useful screening test.
Abstract: One of the most important areas of medical inquiry is the identification of risk factors for specific disorders. Such research is usually aimed at discovering new causes of a disease, but risk factors can also be used as screening tests. The fact that a risk factor must be very strongly associated with a disorder if it is to be a worthwhile screening test is not widely recognised. If this were better understood, fewer risk factors would be proposed unnecessarily as screening tests. Serum cholesterol measurement, for example, would probably never have been considered seriously as a screening test for ischaemic heart disease. Although a high cholesterol concentration is a strong risk factor for ischaemic heart disease in aetiological terms, the association is not sufficiently strong for it to be used as a screening test—in practice, its screening performance is poor.1 In this article we specify the quantitative relation between risk factors and screening tests and show how strongly a risk factor needs to be associated with a disease before it is likely to be a useful screening test. For simplicity, we consider only risk factors with a Gaussian distribution, though the general principles we present can be applied to all frequency distributions. #### Summary points To be a worthwhile screening test, a risk factor must be strongly associated with a disorder The strength of association between a risk factor and a disorder can be quantified by the relative risk or relative odds (odds ratio) A risk factor can also be considered as a screening test, and its association with the disorder can be quantified as the detection rate for a specified false positive rate There is a direct numerical equivalence between the relative odds and the detection rate for specified false positive rate that does not depend on the incidence or prevalence …

332 citations


Journal ArticleDOI
TL;DR: This is the first example of a classically noninvasive bacterial pathogen which elicits a strong mucosal Th1 response and which produces pathology similar to that seen in mouse models of IBD, which is also characterized by a strong Th1 responses.
Abstract: Citrobacter rodentium is a classically noninvasive pathogen of mice that is similar to enteropathogenic Escherichia coli (EPEC) in man. Following oral infection of young mice, the organism colonizes the distal colon, and within 1 week the colonic mucosa doubles in thickness and there is massive epithelial cell hyperplasia. Since T-cell responses in mouse models of inflammatory bowel disease (IBD) also cause epithelial hyperplasia, we have investigated the possibility that C. rodentium promotes similar T-cell responses in the mucosa, thereby increasing epithelial shedding, transmission, and replication of the organism. Beginning 6 days after infection, bacteria were observed to be in close association with the epithelial surface and were also visible scattered throughout the lamina propria and in the submucosa. There was a CD3+-cell infiltrate into the colonic lamina propria and epithelium as well as mucosal thickening and crypt hyperplasia. The majority of CD3+ cells were CD4+ and were not γδ+. Reverse transcription-PCR analysis of cytokines also revealed a highly polarized Th1 response (interleukin-12, gamma interferon, and tumor necrosis factor alpha) in the mucosa and a large increase in the epithelial cell mitogen keratinocyte growth factor. None of the changes were seen in mice inoculated with bacteria lacking intimin (which is necessary for colonization), but they were seen in mice inoculated with C. rodentium complemented with intimin from EPEC. This is the first example of a classically noninvasive bacterial pathogen which elicits a strong mucosal Th1 response and which produces pathology similar to that seen in mouse models of IBD, which is also characterized by a strong Th1 response. These results also suggest that the colonic mucosa responds in a stereotypic way to Th1 responses.

293 citations


Journal ArticleDOI
TL;DR: KIMS, the Pharmacia & Upjohn International Metabolic Database, is a long‐term, open, outcomes research programme of hypopituitary adult patients with GHD who are treated in a conventional clinical setting.
Abstract: OBJECTIVE Long-term experience of growth hormone (GH) replacement therapy in a large population of hypopituitary adults with GH deficiency (GHD) is limited, and safety surveillance is clearly essential. KIMS, the Pharmacia & Upjohn International Metabolic Database, is a long-term, open, outcomes research programme of hypopituitary adult patients with GHD who are treated in a conventional clinical setting. PATIENTS The present analysis encompasses data from 1034 hypopituitary adult GHD patients treated with GH for a total of 818 patient years. RESULTS Prior to GH therapy, the KIMS patient population exhibited an increased prevalence of obesity, diabetes mellitus (in females) and hyperlipidaemia, compared with normal populations described in published studies. Quality of life, assessed using a disease-specific questionnaire (QoL-AGHDA), was also reduced in KIMS patients. The maintenance dose of GH was significantly higher in patients who were receiving GH prior to enrolment into KIMS (non-naive patients) compared with patients who commenced GH at the time of enrolment (naive patients). In addition, dose of GH correlated significantly with body weight in the former group of patients. Analysis of serum levels of IGF-I indicated that overtreatment with GH was markedly more common in non-naive than in naive patients. The frequency of adverse events in KIMS patients was no higher than that reported in patients receiving placebo in previous clinical trials. Recurrence of pituitary or CNS tumours was reported in six patients, a rate consistent with data from control series. Three deaths were reported, none of which was obviously associated with GH treatment. CONCLUSIONS Our data, drawn from a large population of hypopituitary adults treated with GH for a total of more than 800 patient years, confirm previous reports that untreated GHD in hypopituitary adults is associated with a number of important clinical problems. In addition, the results suggest that there has been a shift in recent years from determination of GH dose on the basis of body weight to dose titration of individual patients, and indicate that the latter technique has important advantages. The data provide further evidence that GH replacement therapy is well-tolerated in adults. However, it is possible that some adverse events may not become evident over the time scale covered by the present analysis, and continued surveillance therefore remains mandatory.

253 citations


Journal ArticleDOI
TL;DR: In girls, but not in boys, low leptin levels during prepuberty (B1) predicted subsequent gains in the percent body fat during puberty (r = -0.75; P = 0.005), and the sexual dimorphism in leptin Levels during puberty reflects differential changes in body composition.
Abstract: Leptin may have a role in the initiation of puberty and the regulation of subsequent weight gain, but this hypothesis has not been tested by longitudinal study. We report data from 40 normal children (20 boys and 20 girls) followed from 8-16 yr of age with hormone measurements and auxology every 6 months. Before the onset of puberty, leptin levels were similar in boys and girls: G1, mean (95% confidence interval), 2.63 (2.17-3.20) ng/mL; B1, 2.47 (2.08-2.94) ng/mL (P = 0.64) and increased with age in both sexes (B, 0.107 +/- 0.042; P = 0.02). With the onset of puberty, leptin levels increased in girls (B2-B5, P < 0.0005), but decreased in boys (G2-G5, P < 0.0005). Similar positive independent relationships were seen between leptin and fat mass in girls (B, 0.106 +/- 0.022; P < 0.0005) and boys (B, 0.121 +/- 0.020; P < 0.0005), and negative relationships were found with fat-free mass [girls: B, -1.104 +/- 0.381 (P < 0.005); boys: B, -1.288 +/- 0.217 (P < 0.0005)]. Girls gained more fat mass than boys, whereas boys gained more fat-free mass, and this explained the sex difference in leptin levels. Leptin levels correlated significantly with a large number of other hormones, but none was independent of changes in body composition. In girls, but not in boys, low leptin levels during prepuberty (B1) predicted subsequent gains in the percent body fat during puberty (r = -0.75; P = 0.005). The sexual dimorphism in leptin levels during puberty reflects differential changes in body composition. Prepubertal leptin levels in girls also predict gains in the percent body fat.

247 citations


Journal ArticleDOI
TL;DR: Findings show that leptin has direct, receptor-mediated actions on rodent Leydig cells in culture, at concentrations within the range of obese men, and indicate that leptin action on steroidogenesis occurs downstream of progesterone synthesis.
Abstract: Several studies indicate that the size of body fat stores and the circulating levels of the adipocyte-derived hormone leptin are able to influence the activity of the hypothalamic-pituitary-gonadal axis. The leptin-hypothalamic-pituitary-gonadal interactions have been mainly studied at the level of the central nervous system. In this study, we investigated the possibility that leptin may have direct effects on the rodent Leydig cell function. To probe this hypothesis, we first analyzed the expression of leptin receptors (OB-R) in rodent Leydig cells in culture. RT-PCR studies showed that rat Leydig cells express both the long (OB-Rb) and short isoform (OB-Ra) of leptin receptor, whereas MLTC-1 cells (a murine Leydig tumor cell line) express only the long isoform. Short-term (30 ‐90 min) incubation of rat Leydig cells with increasing concentrations of leptin (2‐500 ng/ml) led to a significant and dose-dependent inhibition of human (h)CGstimulated testosterone (T) production (;60% reduction, IC50 5 20 ng/ml) but no change in basal androgen release. Also, leptin (150 ng/ml) amplified hCG-induced intracellular cAMP formation (1- to 2-fold) without modifying basal cAMP levels. Subsequent experiments showed that leptin inhibited 8Br-cAMP-stimulated T production, indicating that leptin’s effect is exerted beyond cAMP. The inhibitory effect of leptin on hCG-induced T secretion was accompanied by a significant reduction of androstenedione and a concomitant rise of the precursor metabolites pregnenolone, progesterone, and 17-OHprogesterone, conceivable with a leptin-induced lesion of 17,20 lyase activity. Separate experiments performed with the MLTC-1 cells (not expressing cytochrome P450 ‐17a) showed that leptin, though amplifying hCG-stimulated cAMP production, did not modify hCG-stimulated pregnenolone and progesterone release. These results further indicate that leptin action on steroidogenesis occurs downstream of progesterone synthesis. Northern Blot experiments showed no acute effect of leptin on cytochrome P450 ‐17a messenger RNA accumulation in rat Leydig cells in basal and hCG-stimulated conditions, excluding that the rapid changes observed were caused by messenger RNA degradation. In conclusion, these findings, for the first time, show that leptin has direct, receptor-mediated actions on rodent Leydig cells in culture, at concentrations within the range of obese men. (Endocrinology 140: 4939 ‐ 4947, 1999)

245 citations


Journal ArticleDOI
TL;DR: The concordance rate for Type II diabetes in monozygotic twins is very high even in twins initially ascertained discordant for diabetes, a prospective study on 44 non-diabetic subjects each of whom had a sibling twin with diabetes.
Abstract: To determine the concordance rate for Type II (non-insulin-dependent) diabetes mellitus in monozygotic twin pairs, initially ascertained discordant for diabetes, we carried out a prospective study on 44 non-diabetic subjects, each of whom had a sibling twin with diabetes (21 men, 23 women, median age 55 years, interquartile range 47–65). The subjects were referred as discordant for Type II diabetes. The twin pairs were part of the British Diabetic Twin Study and ascertained between May 1968 and January 1998. These subjects underwent an OGTT at time of referral and periodically thereafter. The mean follow-up was 8 years (range 0–18 years) and data were collected until January 1996. The percentage of twins who developed Type II diabetes was assessed by standard actuarial life-table methods and the pairwise concordance rate, that is the proportion of concordant pairs over the sum of concordant and discordant pairs, was calculated. The observed rates of concordance for Type II diabetes at 1, 5, 10, and 15 years follow-up were 17, 33, 57, and 76 %, respectively. The concordance rate for any abnormality of glucose metabolism (either Type II diabetes or impaired glucose tolerance) at 15 years follow-up was 96 %. The concordance rate for Type II diabetes in monozygotic twins is very high even in twins initially ascertained discordant for diabetes. [Diabetologia (1999) 42: 146–150]


Journal ArticleDOI
TL;DR: The pulse wave in man travels in the arteries at a speed of 4 to 10 metres per second, which depends upon the elastic conditions of the arterial wall, which is affected by a variety of factors in health and disease.

Journal ArticleDOI
TL;DR: The accurate diagnosis of ACTH-dependent CS and localization of an intrapituitary microadenoma requires bilateral IPSCS with CRH stimulation, provided that the appropriate technical experience is available, and when IPSG and MRI findings were contradictory, IPSG was more often correct than MRI scanning.
Abstract: The clinical, biochemical, and radiological features of pituitary ACTH-dependent Cushing's syndrome (CS) [Cushing's disease (CD)] are often indistinguishable from those of occult ectopic ACTH-dependent CS (oEAS). We have evaluated, retrospectively, the results of simultaneous bilateral inferior petrosal sinus (IPS) ACTH sampling before and after CRH stimulation in 128 patients with ACTH-dependent CS: 107 patients with CD, 6 with oEAS, 1 with an adrenal adenoma, 1 with a pituitary gangliocytoma, and 1 with Nelson's syndrome; while, in the remaining 12, the source remains unclear. One hundred seven patients received human-sequence CRH (hCRH), and 11 received ovine CRH; another 6 patients underwent stimulation with desmopressin and hCRH, and 4 with desmopressin alone. A successful bilateral IPS catheterization and sampling (IPSCS) rate of 87.5% was obtained only after considerable experience had been gained. Sixty-nine patients with CD underwent successful bilateral IPSCS: the IPS-to-peripheral ratio of plasma ACTH value (IPS/P) rose from 9.5 +/- 1.4 to a maximum ratio of 55.8 +/- 7.5 in 67 patients, after CRH stimulation. The maximum ratio was obtained at 5 min in 60 of the 69 patients with CD; however, all 69 patients obtained a ratio of more than 2, at that time. In contrast, the 6 patients with occult ACTH-secreting neoplasms had a maximal IPS/P ratio of 1.3 +/- 0.16, and this did not change after CRH stimulation. A bilateral IPS/P ratio more than 2, obtained 5 min after CRH stimulation, had a sensitivity of 97% and a specificity of 100% in diagnosing CD. Two patients with proven active CD had an IPS/P ratio of less than 2. After successful bilateral IPSCS, the gradients between the IPS ACTH concentrations [IPS ACTH gradient (IPSG)] of more than 1.4, at 5 min after CRH stimulation, had a sensitivity of 83% in correctly lateralizing the pituitary microadenoma, compared with 72% sensitivity for magnetic resonance imaging (MRI) scanning. Furthermore, when IPSG and MRI findings were contradictory, IPSG was more often correct than MRI scanning. Although oEAS is a relatively uncommon cause of ACTH-dependent hypercortisolism (5.5% in our series), the accurate diagnosis of ACTH-dependent CS and localization of an intrapituitary microadenoma requires bilateral IPSCS with CRH stimulation, provided that the appropriate technical experience is available. hCRH is as effective a secretagogue as ovine CRH, and either may be used. The value of the combination of CRH and desmopressin stimulation requires more detailed investigation.

Journal ArticleDOI
TL;DR: The study demonstrated that five weekly intra-articular injections of sodium hyaluronate (Hyalgan) were superior to placebo and well tolerated in patients with osteoarthritis of the knee with a symptomatic benefit which persisted for 6 months.
Abstract: Objectives. We examined the eYcacy, safety and patient satisfaction of intra-articular hyaluronic acid (HA) in patients with osteoarthritis of the knee. Methods. One hundred patients with mild to moderate osteoarthritis of the knee entered a randomized blind-observer trial of 6 months HA vs placebo. Primary eYcacy criteria were pain on walking, measured with a visual analogue scale, and the Lequesne Index. Results. For pain on walking, a significant diVerence in favour of HA was found for completed patients at week 5, the end of the course of injections, and at month 6, the end of the study (P= 0.0087 and P= 0.0049, respectively). Further analysis using the Last Observation Carried Forward (LOCF ) also showed a significant benefit favouring HA at month 6 (P= 0.0010). For the Lequesne Index, a significant diVerence in favour of HA was found at week 5 (P= 0.030) and at month 2 (P= 0.0431), but this was only of borderline significance at month 4 (P= 0.0528). Patients’ global assessment of eYcacy favoured HA at month 6 (P= 0.012). Improvement in other secondary criteria was generally superior in the HA group compared to placebo both at week 5 and month 6. Adverse events, mainly local injection site reactions, occurred in both groups with equal frequency. Conclusions. The study demonstrated that five weekly intra-articular injections of sodium hyaluronate (HyalganA) were superior to placebo and well tolerated in patients with osteoarthritis of the knee with a symptomatic benefit which persisted for 6 months. Osteoarthritis (OA) of the knee is very common and toms in patients with OA of the knee [3‐5]. This type very important. Population surveys have shown that of action is characteristic of a group of compounds radiographically determined OA of the knee is present called ‘slow acting symptomatic drug for osteoarthritis’ in between 15 and 30% of subjects aged over 45 yr, and [6 ] to distinguish them from NSAIDs. thereafter increases steadily with age [1, 2]. Current HyalganA, used in this study, is a highly purified, treatment is usually disappointing and most rheuma- concentrated (10 mg/ml ), viscous solution of natural tologists do not follow-up patients once the diag- HA with a molecular weight in the range of 500‐ nosis is made. Non-steroidal anti-inflammatory drugs 730 kDa, extracted from rooster combs. In studies (NSAIDs) have been the mainstay of drug treatment in reported to date [3‐5], HyalganA has been very well knee OA, as in other types of arthritis, but have obvious tolerated with no significant side-eVects apart from the limitations. The elderly are most at risk from serious possibility of transient localized pain after the injection. adverse eVects of these drugs, particularly peptic ulcer- While most studies have found HyalganA to be eVective, ation, bleeding or perforation. Intra-articular steroids Henderson et al. [7] failed to show a diVerence in a are used in OA, but their long-term eYcacy is not well placebo-controlled study. This 6 month study of 91 established. patients had a high percentage of withdrawals (38%) Intra-articular sodium hyaluronate (hyaluronic acid; and local adverse eVects (pain and/or swelling: 47% in HA) oVers the prospect of another approach to the the HA group and 22% with placebo). This may have treatment of OA. Studies have shown that a course of resulted in an insuYcient power to detect a diVerence five injections of HA provides prolonged relief of symp- in the completed patients. The question, therefore,

Journal Article
TL;DR: Targeting OX40 shows considerable promise as a new strategy to inhibit ongoing T cell reactions in the gut, as evidenced by a reduction in tissue myeloperoxidase; reduced transcripts for TNF-alpha,IL-1, IL-12, and IFN-gamma; and a reduction the T cell infiltrate.
Abstract: OX40 is a member of the TNFR superfamily, and is found predominantly on activated CD4-positive T cells. In vitro an OX40-IgG fusion protein inhibits mitogen- and Ag-driven proliferation and cytokine release by splenocytes and lymph node T cells. In contrast, an OX40 ligand-IgG fusion protein enhanced proliferative responses. In normal mice, OX40-positive cells are observed only in lymphoid tissues, including Peyer's patches of the gut. In mice with hapten-induced colitis or IL-2 knockout mice with spontaneous colitis, OX40-positive cells are found infiltrating the lamina propria. Administration of the OX40-IgG fusion protein to mice with ongoing colitis (but not the OX40 ligand-IgG) ameliorated disease in both mouse models of inflammatory bowel disease. This was evidenced by a reduction in tissue myeloperoxidase; reduced transcripts for TNF-alpha, IL-1, IL-12, and IFN-gamma; and a reduction in the T cell infiltrate. Targeting OX40 therefore shows considerable promise as a new strategy to inhibit ongoing T cell reactions in the gut.

Journal ArticleDOI
TL;DR: Patients treated with 106Ru had a significantly greater risk of local tumor recurrence than did those patients treated with either 125I or PBRT in the treatment of choroidal melanoma.

Journal ArticleDOI
TL;DR: It is concluded that pituitary adenomas show a lower level of p 27 protein expression than the normal cells from which they are derived, with malignant transformation leading to complete loss of p27 immunoreactivity.
Abstract: The cell cycle is regulated by a number of inhibitors, including p27 Kip1 (p27), which belongs to the kip1 family. By binding to the cyclin/cyclin-dependent kinase complexes, it regulates progression of G1 to S phase in the cell cycle. It has been reported that p27 knockout mice develop multiorgan hyperplasia and intermediate lobe pituitary tumors secreting ACTH. Previously, we and others have been unable to show any consistent change in messenger RNA expression or genomic mutations for p27 in human corticotroph adenomas. However, dysregulation at the protein level has been reported in nonendocrine tumors, and we, therefore, investigated the expression of p27 in a range of benign and metastatic pituitary tumors. We studied a total of 107 pituitaries, including normal pituitary (n 5 20), Cushing’s disease (n 5 21), acromegaly (n 5 19), nonfunctioning adenomas (n 5 18), prolactinomas (n 5 7), TSH-omas (n 5 2), FSH-omas (n 5 6), aggressive tumors showing invasiveness and recurrence (n 5 9), and metastatic pituitary carcinomas (n 5 5). Using standard immunohistochemical techniques with a highly specific monoclonal antibody, p27 expression was determined quantitatively as the percentage of cells showing strongly positive, weak, or negative staining. In each sample, ;500 cells were analyzed. We also analyzed normal pituitaries using double-labeling for p27 and each of the pituitary hormones to characterize the expression of p27 in each cell type. p27 was expressed in normal pituitary cells; in tumors expressing GH, prolactin, TSH, and FSH; and in aggressive tumors, but markedly reduced expression of p27 was seen in corticotroph tumors and pituitary carcinomas. In the normal pituitary, somatotroph, lactotroph, and thyrotroph cells showed strong p27 staining, whereas normal corticotroph cells showed a much lower level of p27 staining (P , 0.001). Somatotroph, lactotroph, gonadotroph, and thyrotroph adenomas showed a lower level of p27 expression compared with normal somatotrophs (P 5 0.02), lactotrophs (P 5 0.03), gonadotrophs (P 5 0.01), and thyrotrophs, respectively, whereas the lower level of p27 expression present in normal corticotrophs virtually disappeared in corticotroph adenomas (P 5 0.001). We conclude that pituitary adenomas show a lower level of p27 protein expression than the normal cells from which they are derived, with malignant transformation leading to complete loss of p27 immunoreactivity. Corticotrophs are quite different to other pituitary cell types in terms of p27 immunoreactivity because both normal and tumorous corticotrophs have low p27 staining, and we speculate that this may relate to their inherent control mechanisms. (J Clin Endocrinol Metab 84: 3823‐3830, 1999)

Journal ArticleDOI
TL;DR: Weak correlations were observed between the maintenance dose of GH and the change in IGF-I in men and women receiving sex steroid replacement, but not in patients with untreated hypogonadism or an intact gonadotropin reserve.
Abstract: Data from 665 adults with GH deficiency (GHD; 332 women; 169 childhood-onset GHD; mean age, 44 yr) were analyzed to determine the efficacy of and individual responsiveness to GH replacement therapy. GH replacement was started at enrolment into KIMS (Pharmacia & Upjohn, Inc. International Metabolic Database). Mean maintenance doses of GH after 6 and 12 months were 0.43 and 0.53 mg/day (1.3 and 1.6 IU/day) for men and women, respectively. Serum insulin-like growth factor I (IGF-I) sd score increased from −2.2 and− 4.2 in men and women, respectively, to 1.8 and −0.9 at 6 months and 0.8 and −0.7 at 12 months. The waist/hip ratio decreased after 6 and 12 months, with the changes more pronounced in men. The waist/hip ratio was not influenced by age of onset of GHD, severity of hypopituitarism, or gonadal status. Total cholesterol decreased significantly in men, and high density lipoprotein cholesterol increased in women. Systolic blood pressure was unchanged during GH therapy, but diastolic blood pressure decre...

Journal ArticleDOI
TL;DR: There was a significant alteration in the normal set-point of F to E interconversion toward E, and the fall in the urinary tetrahydrocortisols/tetrahydocortisone ratio (THF+allo-THF/THE) bu...
Abstract: The interconversion of hormonally active cortisol (F) and inactive cortisone (E) is catalyzed by two isozymes of 11beta-hydroxysteroid dehydrogenase (11betaHSD), an oxo-reductase converting E to F (11betaHSD1) and a dehydrogenase (11betaHSD2) converting F to E. 11betaHSD1 is important in mediating glucocorticoid-regulated glucose homeostasis and regional adipocyte differentiation. Earlier studies conducted with GH-deficient subjects treated with replacement GH suggested that GH may modulate 11betaHSD1 activity. In 7 acromegalic subjects withdrawing from medical therapy (Sandostatin-LAR; 20-40 mg/month for at least 12 months), GH rose from 7.1 +/- 1.5 to 17.5 +/- 4.3 mU/L (mean +/- SE), and insulin-like growth factor I (IGF-I) rose from 43.0 +/- 8.8 to 82.1 +/- 13.7 nmol/L (both P < 0.05) 4 months after treatment. There was a significant alteration in the normal set-point of F to E interconversion toward E. The fall in the urinary tetrahydrocortisols/tetrahydocortisone ratio (THF+allo-THF/THE; 0.82 +/- 0.06 to 0.60 +/- 0.06; P < 0.02) but unaltered urinary free F/urinary free E ratio (a marker for 11betaHSD2 activity) suggested that this was due to inhibition of 11betaHSD1 activity. An inverse correlation between GH and the THF+allo-THF/THE ratio was observed (r = -0.422; P < 0.05). Conversely, in 12 acromegalic patients treated by transsphenoidal surgery (GH falling from 124 +/- 49.2 to 29.3 +/- 15.4 mU/L; P < 0.01), the THF+allo-THF/THE ratio rose from 0.53 +/- 0.06 to 0.63 +/- 0.07 (P < 0.05). Patients from either group who failed to demonstrate a change in GH levels showed no change in the THF+allo-THF/THE ratio. In vitro studies conducted on cells stably transfected with either the human 11betaHSD1 or 11betaHSD2 complementary DNA and primary cultures of human omental adipose stromal cells expressing only the 11betaHSD1 isozyme indicated a dose-dependent inhibition of 11betaHSD1 oxo-reductase activity with IGF-I, but not GH. Neither IGF-I nor GH had any effect on 11betaHSD2 activity. GH, through an IGF-I-mediated effect, inhibits 11betaHSD1 activity. This reduction in E to F conversion will increase the MCR of F, and care should be taken to monitor the adequacy of function of the hypothalamo-pituitary-adrenal axis in acromegalic subjects and in GH-deficient, hypopituitary patients commencing replacement GH therapy. Conversely, enhanced E to F conversion occurs with a reduction in GH levels; in liver and adipose tissue this would result in increased hepatic glucose output and visceral adiposity, suggesting that part of the phenotype currently attributable to adult GH deficiency may be an indirect consequence of its effect on tissue F metabolism via 11betaHSD1 expression.

Journal ArticleDOI
23 Jul 1999-Science
TL;DR: Mutation of cysteine-937 of intimin to alanine reduced costimulatory activity in vitro and prevented immunopathology in vivo and enables the bacteria to promote conditions that are favorable for increased microbial colonization.
Abstract: Enteropathogenic Escherichia coli (EPEC) cells adhere to gut epithelial cells through intimin α: the ligand for a bacterially derived epithelial transmembrane protein called the translocated intimin receptor. Citrobacter rodentium colonizes the mouse colon in a similar fashion and uses a different intimin: intimin β. Intimin α was found to costimulate submitogenic signals through the T cell receptor. Dead intimin β+ C. rodentium , intimin α–transfected C. rodentium or E. coli strain K12, and EPEC induced mucosal hyperplasia identical to that caused by C. rodentium live infection, as well as a massive T helper cell–type 1 immune response in the colonic mucosa. Mutation of cysteine-937 of intimin to alanine reduced costimulatory activity in vitro and prevented immunopathology in vivo. The mucosal changes elicited by C. rodentium were interferon-γ–dependent. Immunopathology induced by intimin enables the bacteria to promote conditions that are favorable for increased microbial colonization.

Journal ArticleDOI
TL;DR: Good prognosis parameters are: progression-free interval of > 2 years, CR to induction treatment and normal or low serum markers at relapse and the results of high-dose salvage chemotherapy should be interpreted on the background of these prognostic factors.
Abstract: The aim of this study was to define prognostic parameters for survival in patients with malignant germ cell tumours progressing after platinum-based induction chemotherapy with or without surgery. A total of 164 progressing patients (testicular: 83%, extragonadal: 17%) were identified out of 795 patients treated with platinum-based induction chemotherapy for metastatic germ cell malignancy with or without surgery. 'Progressive disease' included patients who had progressed after a previous partial or complete remission as well as patients who failed primary therapy. Salvage chemotherapy consisted of 'conventional' platinum-based chemotherapy. Prognostic factors for survival were assessed by uni- and multivariate analyses. The resulting prognostic model was validated in an independent data set of 66 similar patients. For all 164 patients the median time from start of induction chemotherapy to progression was 10 months (range: 0-99). Thirty-eight (23%) patients relapsed after 2 years. The 5-year survival rate for all progressing patients was 30% (95% confidence interval 23-38%). In the univariate analysis the following factors most importantly predicted a poor prognosis: progression-free interval 100 kU l(-1) or hCG >100 IU l(-1)) formed a poor prognosis group of 30 patients, none of whom survived after 3 years. Patients with at most two of these three risk factors formed a good prognosis group of 94 patients (76%) with a 47% (37-56%) 5-year survival. Thirty-eight patients from the good prognosis group with a progression-free interval of >2 years had a 2-year survival of 74% (60-88%) and 5-year survival of 61%. These prognostic groups were validated in the independent data set, in which 5-year survival rates in the good and poor risk groups were 51% and 0% respectively. One-third of patients progressing during or after platinum-based induction chemotherapy for metastatic germ cell malignancy may be cured by repeated 'conventional' platinum-based chemotherapy. Good prognosis parameters are: progression-free interval of > 2 years, CR to induction treatment and normal or low serum markers at relapse (hCG < 100 IU l(-1) and AFP < 100 kU l(-1)). The results of high-dose salvage chemotherapy should be interpreted on the background of these prognostic factors.

Journal ArticleDOI
TL;DR: The role of surgery in malignant bowel obstruction needs careful evaluation, using validated outcome measures on symptom control and quality of life scores.

Journal ArticleDOI
TL;DR: There is an urgent need for an intervention which could be used in rural hospitals, thus preventing the hazardous and expensive emergency transfer of patients to the capital.
Abstract: Deliberate self-harm is an important problem in the developing world. Ingestion of yellow oleander seeds (Thevetia peruviana) has recently become a popular method of self-harm in northern Sri Lanka -- there are now thousands of cases each year. These seeds contain cardiac glycosides that cause vomiting, dizziness, and cardiac dysrhythmias such as conduction block affecting the sinus and AV nodes. This paper reports a study of the condition's mortality and morbidity conducted in 1995 in Anuradhapura General Hospital, a secondary referral centre serving 750 000 people in Sri Lanka's north central province. 415 cases were admitted to the hospital during 11 months; 61% were women and 46% were less than 21 years old. A prospective study of 79 patients showed that 6% died soon after admission. 43% presented with marked cardiac dysrhythmias which necessitated ther transfer to the coronary care unit in Colombo for prophylactic temporary cardiac pacing. The reasons for the acts of self-harm were often relatively trivial, particularly in children; most denied that they wished to die. Unfortunately, the case fatality rate for oleander poisoning in Sri Lanka is at least 10%. This epidemic is not only causing many unnecessary deaths, it is also putting immense stress on the already stretched Sri Lankan health services. There is an urgent need for an intervention which could be used in rural hospitals, thus preventing the hazardous and expensive emergency transfer of patients to the capital.

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TL;DR: Primary healthcare professionals require education about the importance of ocular symptoms, especially squint, in paediatric patients.
Abstract: BACKGROUND Delay in diagnosis of retinoblastoma causes considerable parental distress; however, the primary healthcare professional (PHP) may have difficulty detecting the most common presenting symptom—leucocoria. Alternatively, the PHP may not appreciate that retinoblastoma is the pathology underlying more common ocular symptoms in infants and young children. METHOD The parents of 100 recently diagnosed patients with retinoblastoma were interviewed to establish the extent of diagnostic delay, ascertain any associated risk factors, and to determine whether or not delay influenced treatment outcome. RESULTS Although nearly 50% of patients were referred to an ophthalmologist within 1 week of first consulting a PHP, one quarter waited more than 8 weeks. There was a significantly increased risk of diagnostic delay in younger patients, those presenting with squint rather than leucocoria, and those first presenting to a health visitor rather than to a general practitioner. The risk of local tumour invasion was significantly increased by diagnostic delay. Treatment with primary enucleation was not increased by diagnostic delay. There were no deaths during the study period. CONCLUSION Primary healthcare professionals require education about the importance of ocular symptoms, especially squint, in paediatric patients.

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TL;DR: MR imaging appears accurate in the prediction of myometrial tumor involvement and in showing the relationship of cervical carcinoma to the internal os and, hence, the patient's suitability for trachelectomy.
Abstract: PURPOSE: To assess whether magnetic resonance (MR) imaging can be used for reliable prediction of proximal extension of cervical carcinoma into the myometrium MATERIALS AND METHODS: Thirty patients with early cervical carcinoma underwent MR imaging with use of a 15-T magnet prior to surgery The MR images were analyzed by two radiologists, unaware of the histopathologic findings, for the relationship of the tumor to the internal os and extension of the tumor into the myometrium Findings at MR imaging were compared with those at histopathologic examination RESULTS: At MR imaging, 24 patients were considered not to have tumor extension proximal to the internal os and into the myometrium All tumors were confirmed histopathologically In six patients thought to have myometrial tumor invasion at MR imaging, five tumors were confirmed histopathologically; in one, tumor extended up to the internal os but did not involve the myometrium CONCLUSION: This is a small study, but MR imaging appears accurate in th

Journal ArticleDOI
TL;DR: T helper 1-type immune reactions in the gut cause important human diseases, such as Crohn's disease and coeliac disease, and it is suggested that the tissue injury is mediated not by the immune cells, but by cytokine-induced changes in keratinocyte growth factor and matrix metalloproteinase production by resident gut myofibroblasts.

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TL;DR: There is a need for larger studies to provide clear evidence as to whether specialist palliative care services provide improvements in patients' quality of life, and the possibility that models of care might be justifiable on other grounds such as patient preference or cost-effectiveness is excluded.
Abstract: This study set out to systematically review the research evidence about the impact of alternative models of specialist palliative care on the quality of life of patients. Eighty-six relevant papers were identified and reviewed, including 22 descriptive and 27 comparative studies. We found few comparative trials of reasonable quality. There was some evidence that in-patient palliative care provided better pain control than home care or conventional hospital care, but this research was dated and open to criticism. Research on palliative home care teams and co-ordinating nurses has demonstrated limited impact on quality of life over conventional care for patients dying at home. These negative findings may be due to the limitations of the assessment tools used. There is a need for larger studies to provide clear evidence as to whether specialist palliative care services provide improvements in patients' quality of life. This review does not exclude the possibility that models of care might be justifiable on o...

Journal ArticleDOI
TL;DR: Results show that the selection of the labelling approach as well as the right choice of the peptide structure are crucial for labelling peptides with 99mTc to achieve complexes with favourable biodistribution and could play a role in imaging tumours that do not bind octreotide derivatives.
Abstract: In this paper the preclinical evaluation of the somatostatin analogue RC160 labelled with technetium-99m using bifunctional chelators (BFCs) based on the hydrazinonicotinamide (HYNIC) and N(3)S system is described and a comparison made with [Tyr(3)]-octreotide (TOC). Conjugates of both peptides with HYNIC, and of RC160 with benzoyl-MAG(3) and an N(3)S-adipate derivative were prepared and radiolabelling performed at high specific activities using tricine, tricine/nicotinic acid and ethylenediamine-N,N'-diacetic acid (EDDA) as co-ligands for HYNIC conjugates. All conjugates and (99m)Tc-labelled peptides showed preserved binding affinity for the somatostatin receptor (IC50, Kd<5 nM). The biodistribution was markedly dependent on the BFC and co-ligand used, with the amidothiol ligands showing a greater degree of hepatobiliary clearance, the HYNIC/tricine complex higher blood levels and the HYNIC/EDDA complex the highest level of renal excretion and lowest blood levels. All peptide conjugates showed receptor-mediated uptake in tumour xenografts, but tumour uptake was significantly lower for the (99m)Tc-RC160 derivatives compared with (99m)Tc-EDDA/HYNIC-[Tyr(3)]-octreotide (0.2%-3.5%ID/g vs 9.7%ID/g) and correlated well with the reduced internalisation rate for RC160 derivatives. Our results show that the selection of the labelling approach as well as the right choice of the peptide structure are crucial for labelling peptides with (99m)Tc to achieve complexes with favourable biodistribution. Despite the relatively low tumour uptake compared with (99m)Tc-EDDA/HYNIC-[Tyr(3)]-octreotide, (99m)Tc-RC160 could play a role in imaging tumours that do not bind octreotide derivatives.

Journal ArticleDOI
TL;DR: In primary Raynaud's syndrome, topical application of a nitric-oxide-generating system can stimulate an increase in both microcirculatory volume and flux, which may be secondary to impaired synthesis of, or impaired sensitivity to, nitric oxide.