Conditional inactivation of the Men1 gene leads to pancreatic and pituitary tumorigenesis but does not affect normal development of these tissues

Mutations of the MEN1 gene, encoding the tumor suppressor menin, predispose individuals to the cancer syndrome multiple endocrine neoplasia type 1, characterized by the development of tumors of the endocrine pancreas and anterior pituitary and parathyroid glands. We have targeted the murine Men1 gene by using Cre recombinase-loxP technology to develop both total and tissue-specific knockouts of the gene. Conditional homozygous inactivation of the Men1 gene in the pituitary gland and endocrine pancreas bypasses the embryonic lethality associated with a constitutional Men1(-/-) genotype and leads to beta-cell hyperplasia in less than 4 months and insulinomas and prolactinomas starting at 9 months. The pituitary gland and pancreas develop normally in the conditional absence of menin, but loss of this transcriptional cofactor is sufficient to cause beta-cell hyperplasia in some islets; however, such loss is not sufficient to initiate pituitary gland tumorigenesis, suggesting that additional genetic events are necessary for the latter.

Endothelin axis expression is markedly different in the two main subtypes of renal cell carcinoma

BACKGROUND. The endothelin axis has been implicated in cancer growth, angiogenesis, and metastasis, but to the authors' knowledge the expression of endothelin genes has not been defined in renal cell carcinoma (RCC). METHODS. Tissue specimens were harvested from both normal and tumor-affected regions at the time of radical nephrectomy from 35 patients with RCC (22 with clear cell RCC [ccRCC] and 13 with papillary RCC [PRCC]). Real-time reverse transcriptase-polymerase chain reaction analysis determined the expression profile of the preproendothelins (PPET-1, PPET-2, and PPET-3), the endothelin receptors (ETA and ETB), and the endothelin-converting enzymes (ECE-1 and ECE-2). RESULTS. PPET-1 was found to be up-regulated in ccRCC tumor specimens and down-regulated in PRCC tumor specimens. ETA was significantly down-regulated in PRCC tumor specimens. ECE-1 was expressed in all tissue specimens at comparable levels, with moderate but significant elevation in normal tissue specimens associated with PRCC. Of the other genes, PPET-2 and ETB were expressed in all tissue specimens and no differences were observed between tumor subtypes or tumor-affected and normal tissue specimens, whereas PPET-3 and ECE-2 were present in all tissue specimens but were barely detectable. CONCLUSIONS. The endothelin axis was expressed differently in the two main subtypes of RCC and appeared to match macroscopic features commonly observed in these tumors (i.e., high expression of PPET-I in hypervascular ccRCC contrasted against low PPET-1 and ETA expression in hypovascular PRCC). The presence of ECE-1 mRNA in these tissue specimens suggested that active endothelin ligands were present, indicating endothelin axis activity was elevated in ccRCC compared with normal kidney, but impaired in PRCC. The current study provided further evidence that it is not appropriate to consider ccRCC and PRCC indiscriminately in regard to treatment. (C) 2004 American Cancer Society.

Personality disorders in the community: Results from the Australian National Survey of Mental Health and Well-Being Part III - Relationships between specific type of personality disorder, Axis 1 mental disorders and physical conditions with disability and health consultations

Background The aims of this study were threefold. First, to ascertain whether personality disorder (PD) was a significant predictor of disability (as measured in a variety of ways) over and above that contributed by Axis I mental disorders and physical conditions. Second, whether the number of PD diagnoses given to an individual resulted in increasing severity of disability, and third, whether PD was a significant predictor of health and mental health consultations with GPs, psychiatrists, and psychologists, respectively, over the last 12 months. Method Data were obtained from the National Survey of Mental Health and Wellbeing, conducted between May and August 1997. A stratified random sample of households was generated, from which all those aged 18 and over were considered potential interviewees. There were 10 641 respondents to the survey, and this represented a response rate of 78%. Each interviewee was asked questions indexing specific ICD-10 PD criteria. Results Five measures of disability were examined. It was found that PD was a significant predictor of disability once Axis I and physical conditions were taken into account for four of the five disability measures. For three of the dichotomously-scored disability measures, odds ratios ranged from 1.88 to 6.32 for PD, whilst for the dimensionally-scored Mental Summary Subscale of the SF-12, a beta weight of -0.17 was recorded for PD. As regards number of PDs having a quasi-linear relationship to disability, there was some indication of this on the SF-12 Mental Summary Subscale and the two role functioning measures, and less so on the other two measures. As regards mental consultations, PD was a predictor of visits to GPs, psychiatrists and psychologists, over and above Axis I disorders and physical conditions. Conclusion The study reports findings from a nationwide survey conducted within Australia and as such the data are less influenced by the selection and setting bias inherent in other germane studies. However, it does support previous findings that PD is a significant predictor of disability and mental health consultations independent of Axis I disorders and physical conditions.

Evaluation of random plasma cortisol and the low dose corticotropin test as indicators of adrenal secretory capacity in critically ill patients: A prospective study

It is unclear whether a random plasma cortisol measurement and the corticotropin (ACTH) test adequately reflect glucocorticoid secretory capacity in critical illness. This study aimed to determine whether these tests provide information representative of the 24 hour period. Plasma cortisol was measured hourly for 24 hours in 21 critically ill septic patients followed by a corticotropin test with 1 μ g dose administered intravenously. Serum and urine were analysed for ACTH and free cortisol respectively. Marked hourly variability in plasma cortisol was evident (coefficient of variation 8-30%) with no demonstrable circadian rhythm. The individual mean plasma cortisol concentrations ranged from 286 59 nmol/l to 796 &PLUSMN; 83 nmol/l. The 24 hour mean plasma cortisol was strongly correlated with both random plasma cortisol (r(2) 0.9, P< 0.0001) and the cortisol response to corticotropin (r(2) 0.72, P< 0.001). Only nine percent of patients increased their plasma cortisol by 250 nmol/l after corticotropin (euadrenal response). However, 35% of non-responders had spontaneous hourly rises > 250 nmol/l thus highlighting the limitations of a single point corticotropin test. Urinary free cortisol was elevated (865&PLUSMN; 937 nmol) in both corticotropin responders and non-responders suggesting elevated plasma free cortisol. No significant relationship was demonstrable between plasma cortisol and ACTH. We conclude that although random cortisol measurements and the low dose corticotropin tests reliably reflect the 24 hour mean cortisol in critical illness, they do not take into account the pulsatile nature of cortisol secretion. Consequently, there is the potential for erroneous conclusions about adrenal function based on a single measurement. We suggest that caution be exercised when drawing conclusions on the adequacy of adrenal function based on a single random plasma cortisol or the corticotropin test.

Developmental vitamin D (DVD) deficiency in the rat alters adult behaviour independently of HPA function

Developmental vitamin D deficiency (DVD) has been shown to alter the orderly pattern of brain development. Even though the period of vitamin D deficiency is restricted to gestation this is sufficient to induce behavioural abnormalities in the adult offspring consistent with those seen in many animal models of schizophrenia. Given that some of these behavioural alterations could also be an indirect result of either impaired maternal hypothalamic pituitary axis (HPA) function (which in turn could influence maternal care) or the result of a permanent alteration in HPA function in the adult offspring we have examined HPA status in both maternal animals and adult offspring. In this study we have established that HPA function is normal in the maternally vitamin D deficient rat. We replicate the behavioural phenotype of hyperlocomotion whilst establishing that HPA function is also unchanged in the adult mate offspring. We conclude that the behavioural alterations induced by DVD deficiency are due to some adverse event in brain development rather than via an alteration in stress response. (c) 2006 Elsevier Ltd. All rights reserved.

Cloning and sequence analysis of pituitary prolactin cDNA from the northern brown bandicoot (Isoodon macrourus)

The nuclectide sequence for pituitary prolactin cDNA from the marsupial bandicoot (Isoodon macrourus) was determined by reverse transcription-polymerase chain reaction and 5'/3' rapid amplification of cDNA ends. The deduced amino acid sequence showed high sequence identity with brushtail possum prolactin (95%) and all of the expected structural features of a quadruped prolactin. A prolactin gene tree was constructed and rates of evolution calculated for bandicoot, possum, opossum and several mammalian and non-mammalian prolactins. Bootstrap analysis provided strong support for marsupials as a sister group with eutherian mammals and weak support for opossum and bandicoot as an independent grouping from the brushtail possum. The rates of molecular evolution for marsupial prolactins were comparable to the slow rate seen in the majority of quadruped prolactins that have been sequenced. (c) 2005 Elsevier Inc. All rights reserved.

Variability of cortisol assays can confound the diagnosis of adrenal insufficiency in the critically ill population

Objective: To compare the total plasma cortisol values obtained from three widely used immunoassays and a high pressure liquid chromatography (HPLC) technique on samples obtained from patients with sepsis. Design and setting: Observational interventional in the general intensive care unit of a metropolitan hospital. Patients and participants: Patients admitted to the intensive care unit with a diagnosis of sepsis and fulfilling criteria of systemic inflammatory response syndrome. Interventions: Standard short synacthen test performed with 250 mu g cosyntropin. Measurements and results: Two of the three immunoassays returned results significantly higher than those obtained by HPLC: Immulite by 95% (95%CI 31-188%) and TDx by 79% (21-165%). The limits of agreement for all three immunoassays with HPLC ranged from -62% to 770%. In addition, by classifying the patients into responders and non-responders to ACTH by standard criteria there was concordance in all assays in only 44% of patients. Conclusions: Immunoassay estimation of total plasma cortisol in septic patients shows wide assay related variation that may have significant impact in the diagnosis of relative adrenal insufficiency.