Effects of antihypertensive treatments on incidence of diabetes: a case-control study.

AIMS: Aim of this case-control study is the assessment of the relationship between antihypertensive treatment and incidence of diabetes in an unselected cohort of subjects participating in a screening program for diabetes. METHODS: A case-control study nested within a cohort of nondiabetic subjects with a mean follow-up of 27.7 ± 11.3 months was performed, comparing 40 cases of incident diabetes and 160 controls matched for age, sex, body mass index, fasting plasma glucose, 2-h post-load glycemia, smoking and alcohol abuse. RESULTS: When considering antihypertensive treatment at enrolment, a lower proportion of cases was exposed to ACE-inhibitors/angiotensin receptor blockers (ACE-i/ARB) in comparison with controls. A non-significant trend toward a higher exposure to diuretics, which were mainly represented by thiazide diuretics, was observed in cases. In a multivariate analysis, including both ACE-i/ARB and diuretics, a protective effect of ACEi/ARB, and an increased risk with diuretics were observed. Similar results were obtained in alternative models, after adjusting for systolic and diastolic blood pressure at enrolment, diagnosis of hypertension, concurrent treatment with ß-blockers or calcium-channel blockers, and number of antihypertensive medications. CONCLUSIONS: Diuretics seem to be associated with a higher incidence of diabetes, whereas treatment with ACEi/ARB could have a protective effect.

Key role of staff competencies for patient and donor safety in a bone marrow transplantation unit: design and implementation of an accredited training and self-assessment program.

Human resources represent at the moment the most critical factor in an hospital setting characterized by a high rate of staff turnover. It is important to ensure a consistent level of expertise and knowledge of professionals who work in health care facilities to provide quality services and simultaneously support the implementation of strategies for patient safety. Unfortunately, the development of effective interventions for training newly added staff and self-evaluation of skills possessed by trained staff are closely related to understanding critical aspects of the organization. At the new Center for Bone Marrow Transplantation and Blood Transfusion Service in Meyer Hospital, during the last year, a group of professional nurses and technicians completed a specific plan to train new staff and, at the same time, a program of self-assessment of skills for experienced staff. The main purpose of this project was to promote skills development by newly added as well as experienced staff, to identify areas of weaknesses, and to correct them with training (organized by the hospital, departmental, or individual) designed to improve performance.

Treatment with insulin secretagogues and cancer-related mortality in type 2 diabetic patients a retrospective cohort study.

BACKGROUND: Recent evidence suggests that some hypoglycemic treatments could affect the incidence of malignancies. This study was aimed at the assessment of cancer-related mortality in type 2 diabetic patients treated with different hypoglycemic drugs. METHODS: A retrospective observational cohort study was performed on a consecutive series of 3002 type 2 diabetic outpatients. Cancer-related death was identified through the City Registry Office. For patients visited for the first time after January 1 (st), 2000, information on incidence of cancer was also available. RESULTS: During a mean follow-up of 4.3+/-2.5 years, 87 cases of cancer-related death were recorded, with a yearly incidence rate of 0.70%. Patients receiving secretagogues showed a significantly higher mortality than the rest of the sample (unadjusted OR [95%CI] 1.76 [1.15-2.69], p=0.009), which was maintained after adjustment for confounders (HR 2.29 [1.21-4.02], p=0.003). Conversely, no significant association of cancer-related mortality was observed with insulin sensitizers or exogenous insulin. In comparison with patients receiving no hypoglycemic treatment, those on secretagogue or insulin monotherapy showed a higher cancer-related mortality (HR 2.25 [1.10-4.78], p=0.034 and HR 2.11 [1.01-4.50], p=0.048, respectively). The effect of treatments on incidence of malignancies was similar to that observed on cancer-related death. CONCLUSIONS: Insulin secretagogues and, to a lesser extent, exogenous insulin, appear to be associated with increased mortality for cancer, even after adjustment for multiple confounders. This issue deserves further investigation through epidemiological studies on larger samples of patients.

Involvement of D-Asp in P450 aromatase activity and estrogen receptors in boar testis.

Mammalian testis contains D-aspartic acid (D-Asp), which enhances testosterone production. D-Asp, on other hand, also stimulates 17beta-estradiol synthesis in the ovary of some lower vertebrates. We studied boar testis in order to determine if D-Asp intervenes in 17beta-estradiol synthesis in the testis of those mammals which produce significant amounts of estrogens as well as testosterone. The boar testis contains D-Asp (40 +/- 3.6 nmol/g tissue) which, according to immunohistological techniques, is localized mainly in Leydig cells, and, to a lesser extent, in sustentacular (Sertoli), peritubular and some germ cells. The enzyme P450aromatase is present in Leydig cells and few germ cells. In vitro experiments showed that the addition of D-Asp to testicular tissue extracts induced a significant increase of aromatase activity, as evaluated by testosterone conversion into 17beta-estradiol. The enzyme's K(m) was not affected by D-Asp (about 25 nM in both control and D-Asp added tests). On the basis of these results we suggest that, as in the ovary, D-Asp is involved in the local control of aromatase activity of boar testis and, therefore, it intervenes in the 17beta-estradiol production. In the testis, the D-Asp targets are presumably the Leydig cells, which having also a nuclear estrogen receptor are, in turn, one of the putative targets of the 17beta-estradiol that they produce (autocrine effect).

Are sulphonylureas all the same? A cohort study on cardiovascular and cancer-related mortality.

BACKGROUND: Aim of the present study is the comparison of all-cause, cardiovascular and non-cardiovascular mortality, and cardiac morbidity, between patients treated with glibenclamide and gliclazide. METHODS: A retrospective observational cohort study was performed on a consecutive series of 568 outpatients (282 women, 286 men) with type 2 diabetes treated with either glibenclamide (n = 378) or gliclazide (n = 190). Information on all-cause mortality and on causes of death up to 31 December 2004 was obtained by the City of Florence Registry Office. Non-fatal cases requiring hospitalization were identified through the regional hospital discharge system using International Classification of Diseases. RESULTS: Mean follow-up was 5.0 +/- 1.6 and 4.4 +/- 2.0 years for death and cardiac events, respectively; during follow-up, 33 and 11 deaths were observed in the glibenclamide and gliclazide groups, with a yearly mortality rate of 4.3 and 2.2%, respectively (p < 0.05). At Cox regression, after adjustment for potential confounders, including comorbidity, glibenclamide treatment was associated with a significant increase in all-cause mortality [OR 2.1(1.2;2.7), p < 0.05], while the difference in cardiovascular mortality was not statistically significant after adjustment for age and sex. Mortality for malignancies was significantly higher in patients treated with glibenclamide after adjustment for age, sex, BMI, and insulin and metformin treatment, [OR 3.6(1.1;11.9); p < 0.05]. A higher incidence of cardiac events was associated with glibenclamide treatment only in patients with previously known ischaemic heart disease. CONCLUSIONS: Treatment with glibenclamide could be associated with higher mortality for cardiovascular diseases and malignancies, in comparison with gliclazide.

NADPH-d positive neurons of the lizard Podarcis s. sicula oviduct and their relationship to 17beta-estradiol hormone.

The distribution of nicotinamide adenine dinucleotide phosphate reduced diaphorase (NADPH-d) containing neurons was examined in the oviduct of the lizard Podarcis s. sicula and the relationship between these neurons and 17beta-estradiol hormone was studied. NADPH-d-histochemistry and indirect immunofluorescence method were applied to cryostat sections. NADPH-d-nerve structures were found throughout the oviduct. Positive neurons were primarily located in the reproductive oviduct, and were more numerous in the intermuscular and circular muscle layers than in the mucosa. The vagina revealed a reactive nerve population denser than elsewhere. The NADPH-d-positive neurons densities and the 17beta-estradiol plasma levels coincided throughout the lizard sexual cycle. In addition, after 17beta-estradiol treatments, non-reproductive lizards showed an increase of NADPH-d neurons. We suppose that nitric oxide (NO) neurons play an estrogen-dependent role in the oviduct muscle motility.

TrkA and TrkC neurotrophin receptor-like proteins in the lizard gut.

The tyrosine kinase proteins (Trk), encoded by the trk family of proto-oncogenes, mediate, in mammals, the action of neurotrophins, a family of growth factors acting on the development and maintenance of the nervous system. Neurotrophins and their specific receptors, TrkA, TrkB and TrkC, seem to be phylogenetically well preserved but, in reptiles, data regarding the occurrence of Trk-like proteins are very scarce, especially in non-nervous organs. Western blot analysis demonstrated that the lizard gut contains TrkA- and TrkC-like, but not TrkB-like, proteins. Consistently, TrkA- and TrkC-like immunoreactivity were both observed in neurons of the anterior intestine, whereas endocrine cells of the stomach and anterior intestine only displayed TrkA-like immunoreactivity. These results demonstrate for the first time the occurrence of Trk-like proteins in non-neuronal tissues of reptilians and provide further evidence for the evolutionary preservation of the molecular mass and cell distribution of Trk neurotrophin receptor-like proteins in the gut of vertebrates.

The relationships of nicotinamide adenine dinucleotide phosphate-d to nitric oxide synthase, vasoactive intestinal polypeptide, galanin and pituitary adenylate activating polypeptide in pigeon gut neurons.

The distribution of nicotinamide adenine dinucleotide phosphate (NADPH)-d neurons and their relationship with nitric oxide synthase (NOS), vasoactive intestinal polypeptide (VIP), pituitary adenylate activating polypeptide (PACAP) and galanin (Gal) were examined in the gastrointestinal (GI) tract of the pigeon Columbia livia. NADPH-d-histochemistry, indirect immunofluorescence and confocal analysis were applied to cryosections. Western blot analysis was also applied on pigeon gut. NADPH-d neurons were found throughout the pigeon GI tract and they were evident in the myenteric, circular muscle and submucous plexuses. Positive varicose nerve fibres were also distributed within the longitudinal muscle layers and in the lamina propria of the mucosa. The stomach was the segment richest in positivities. The copresence VIP/Gal/NOS as well as PACAP/VIP were revealed in some NADPH-d-neurons. We suppose that the nitrergic nerve population of the pigeon GI tract belong to the muscle motility regulation as an inhibitory descending nerve pathway. Moreover the presence of VIP, Gal and PACAP in some NADPH-d-containing neurons enhances the inhibitory actions of these neurotransmitters whereas PACAP and Gal role is actually unknown.

The distribution and colocalisation of nicotinamide adenine dinucleotide phosphate reduced-diaphorase (NADPH-d)-/nitric oxide synthase (NOS)-containing neurons in the innervation of the duck ureter.

ensp;The distribution and colocalisation of nicotinamide adenine dinucleotide phosphate reduced-diaphorase (NADPH-d)-/nitric oxide synthase (NOS)-containing (nitrergic) neurons in the innervation of the duck ureter have been studied using histochemistry and immunohistochemistry. Quantitative analysis showed that nitrergic neurons made up 60% and 70% of the total intramural and adventitial neuronal populations, respectively. About 40% of intramural nitrergic neurons expressed VIP-immunoreactivity, and about 75% of nitrergic adventitial neurons expressed TH-immunoreactivity. The density of nitrergic adventitial neurons was significantly greater in the lower tract than in the upper and intermediate tracts. Nerve lesioning experiments showed that the majority of ureteral nitrergic innervation was extrinsic in origin; nitrergic adventitial neurons primarily projected caudocranially, whereas NOS-immunoreactive and NOS-/VIP-immunoreactive intramural neurons primarily projected craniocaudally. These findings suggest that, in birds, the nitrergic innervation plays a role in ureteral functions such as epithelial mucosecretion, muscular motility, and the closing and/or opening of the ureteral papilla.

Relationships between liver testosterone receptor isoforms and aromatase activity in female green frog, Rana esculenta.

Testosterone receptors (AR) are present in the liver of the female green frog, Rana esculenta, which resolve into two fractions (A and B) by ion-exchange chromatography. Fraction A is primarily located in the nuclei, fraction B predominates in the cytosols, and both fractions show a high affinity and specificity for testosterone. Liver AR fraction levels vary dramatically during the frog sexual cycle. Fraction A levels are high only when the liver is engaged in vitellogenin production and the plasma testosterone levels are high: they are maximal when aromatase activity is most intense. Fraction B levels are high when the liver is not producing vitellogenin and the plasma testosterone levels are minimal. In addition, in vivo experiments carried out on ovariectomized females treated with testosterone show that testosterone induces both fraction A and liver aromatase activity. This induction may be a step in the process that allows the liver to obtain estrogen from plasma testosterone which induces vitellogenin synthesis.

Trk-neurotrophin receptor-like immunoreactivity in the gut of teleost species.

Neurotrophins, acting through their high-affinity signal-transducing Trk receptors, are involved in the development, differentiation and maintenance of discrete neuron populations in the higher vertebrates. Furthermore, the presence of Trk receptors in some non-neuronal tissues, including the endocrine cells of the gut, could indicate an involvement of neurotrophins also in these tissues. Recently, neurotrophins and neurotrophin receptor proteins have been identified in the lower vertebrates and invertebrates, whose amino acid sequences are highly homologous with those found in mammals. The present study investigates the occurrence and distribution of Trk-like proteins in the neurons and gut endocrine cells in five species of teleost. Single and double immunolabeling was carried out on fresh and paraffin-embedded tissue using commercially available antibodies against sequences of the intracytoplasmic domain of the mammalian Trk. Western-blot analysis, carried out on samples of stomach and intestine of bass, identified proteins whose estimated molecular masses (140 kDa, 145 kDa and 143-145 kDa) were similar to those reported for full-length TrkA, TrkB and TrkC in the higher vertebrates. TrkA-like immunoreactivity was found in the enteric nervous system plexuses of three fish species. Trk-like immunoreactivity was observed in the endocrine cells as follows: sparse TrkA-like immunoreactive endocrine cells were detected only in the intestine: TrkB-like immunoreactive cells were detected only in the stomach; and TrkC-like immunoreactive cells were found both in the intestine of the carp and in the stomach of the bass, where they also showed TrkB-like immunoreactivity. These findings confirm the occurrence and distribution of Trk-like proteins in teleosts. These proteins are closely related to the Trk neurotrophin receptors of mammals. The functional significance of Trk-like proteins in both neuronal and non-neuronal cells of teleosts is still not clear.

Galanin in the lizard oviduct: its distribution and relationships with estrogen, VIP and oviposition.

The distribution of neurons containing galanin immunoreactivity (Gal/IR) has been detected in the oviduct of the lizard Podarcis s. sicula during the main phases of its sexual cycle and after 17beta-estradiol treatment. Indirect immunofluorescence technique was applied both to cryostatic sections and whole mount preparations, and Western blot analysis, with an antibody directed against mammalian galanin (Gal), was performed with lizard oviduct extracts. Colocalization of Gal with vasoactive intestinal polypeptide (VIP) was also studied as well as Gal effects on egg deposition. In the quiescent oviduct of non-reproductive females, scanty Gal/IR fibres were found in the uterine-vaginal segment. During the reproductive period a gradual increase of positive nerve fibres and cell bodies were found distally in the lizard oviduct and the vagina revealed a reactive nerve population denser than elsewhere. Gal-IR nerve structures were present either in the musculature or mucosa and in the intermuscular layer they were organized in a nerve network. In the oviduct of non-reproductive females, 17beta-estradiol administration induced a significant increase of neurons containing Gal/IR. This hormone could be involved in the egg laying by means of galanin action and this hypothesis is supported by the induction of premature oviposition in pre-ovulatory females after Gal administration. Western blot analysis validates this peptide as true Gal, recognising one protein band with a molecular weight (3.2 kDa), similar to that of porcine Gal. Double labelling studies showed the co-presence of Gal and VIP in some neurons.

NADPH-diaphorase and NOS enzymatic activities in some neurons of reptilian gut and their relationships with two neuropeptides.

The distribution of neurons containing the enzymes NADPH-diaphorase (NADPH-d) and nitric oxide synthase (NOS) has been studied in the gastrointestinal tract of lizard (Podarcis s. sicula) and snake (Thamnophis sirtalis). The techniques employed were the NADPH-d/nitroblue tetrazolium histochemical method, and the indirect immunofluorescence applied to cryostat sections and to whole-mount preparations. The colocalization of NADPH-d with NOS, with vasoactive intestinal polypeptide (VIP) and with galanin (Gal) was also studied, and a Western blot analysis using an antibody directed against mammalian Gal was performed on lizard stomach extracts. NADPH-d positive nerve cell bodies and fibres were found in the myenteric and submucous plexuses throughout the gastrointestinal tract of both reptiles. These nerve structures were also present in the other intramural nerve plexuses, although in smaller quantities. Both in lizard and snake, the stomach revealed a positive nerve population that was more dense than elsewhere in the gut. The population of the NADPH-d-positive neurons observed in the lizard was larger than that observed in the snake. The distribution of both populations was similar to those that have been described in the gut of several mammalian and non-mammalian vertebrates. Both in lizard and snake, a one-to-one correspondence was noted between NOS- and NADPH-d-containing nerve cell bodies, and the nitrergic neurons containing Gal appeared to be more numerous than those containing VIP. Western blot analysis recognised a single band with a molecular weight (3.4 kDa) very similar to that of porcine Gal. It is hypothesised that at least some of the nitrergic neurons of the lizard and snake gut are inhibitory motor neurons innervating the circular smooth musculature. In addition, the colocalization of NOS and VIP in neurons enhances their inhibitory action. The role of the neurons containing both NOS and Gal remains unknown.

Neuronal and non-neuronal Trk neurotrophin receptor-like proteins in Eisenia foetida (Annelida Oligochaeta).

The occurrence and distribution of Trk proteins, which are the high-affinity signal-transducing receptors for neurotrophins, have been investigated in earthworms (Eisenia foetida) using polyclonal antibodies which map within their catalytic domain. Western-blot analysis identified major protein bands whose estimated molecular masses were consistent with those of the full-length Trk proteins in vertebrates. Specific immunoreactivity for TrkA-, TrkB-, and TrkC-like was observed in neuronal populations of the dorsal cerebral, subpharyngeal and ventral cord ganglia. Furthermore, TrkA-like immunoreactivity was observed in subcutaneous neurons and nerve fibers between muscle layers in the peripheral nervous system. TrkB- and TrkC-like immunoreactivity was observed in the gut innervation. Non-neuronal expression of TrkB and TrkC proteins was found in epidermal cells, and TrkC-like immunoreactivity was detected in the gut epithelium.

NADPH-diaphorase-, nitric oxide synthase- and VIP-containing nerve structures in the hen oviduct: a histochemical and immunohistochemical study.

The enzyme NADPH-diaphorase (NADPH-d; a marker of NO producing or nitrergic neurons) and the neuropeptide VIP have been detected in the nerve structures of the hen oviduct by histochemical and immunohistochemical techniques performed on cryostatic sections and whole mount preparations. In the upper four segments of the oviduct, i.e. the infundibulum, magnum, isthmus and shell gland, nitrergic and VIP-positive nerve structures were particularly numerous in the intermuscular and mucosal layers, and were represented by fibres and cell bodies showing mainly a perivascular distribution. Functionally, such perivascular structures were related to the blood flow regulation. Different types of nitrergic pyrenophora were recognized in the walls of the shell gland on the basis of their peculiar morphology. In the distal zone of the oviduct, the vagina, nitrergic and VIP-positive nerve fibres were widely diffused in the circular muscle, which was particularly thick in this segment. The source of at least part of such fibres was probably represented by large nerve cell bodies scattered in the layer and containing NO and VIP colocalized. Functionally these cells retained inhibitory motor neurons causing relaxation of the vaginal smooth muscle.

[A peculiar anomaly of the main biliary duct: choledochal cystic dilatation]. / Una particolare anomalia della V.B.P.: la dilatazione cistica del coledoco.

The Authors report a case of choledochal cystic dilatation and examine this particular anomaly of the main biliary duct analysing the complex classification. After a brief review of the embryology of the hepato-pancreatic ring, etiopathogenetic theories, clinic characteristics, as well as diagnostic and therapeutic possibilities for this affection are taken into account. It is concluded that the best therapeutic choice should be always based on an accurate evaluation of the anatomo-pathological conditions in each single case.

Characterization of uterine growth response to cholera toxin in hamsters and test of heat-labile enterotoxin from Escherichia coli.

Cholera toxin (CT) and the heat-labile enterotoxin from Escherichia coli, when injected intraperitoneally into cycling hamsters but not rats or mice, induced a massive uterine growth similar to that normally induced by the implanting blastocyst during pregnancy. CT and heat-labile enterotoxin are the only known agents that have this action in any species. Uterine weight reached a maximal sixfold increase 48 h after injection of CT. Concurrent injection of estrogen, progesterone, and CT increased the maximal response to eightfold and eliminated differences in the response to CT injected on different days of the 4-day hamster estrous cycle. The dose response for CT, heat-labile enterotoxin, and CT plus estrogen plus progesterone was most linear (r greater than 0.93) when the logarithm of uterine weight was plotted against the dose of toxin. The hamster uterine weight response can serve as a simple, highly precise, and highly specific bioassay for CT and heat-labile enterotoxin.

Induction of estrogen and progesterone receptors and decidualization in the hamster uterus by cholera toxin.

Cholera toxin (CT) injected ip on day 1 (day of ovulation) of the 4-day hamster estrous cycle, when circulatory progesterone is high and estrogen low, induced a massive uterine decidual reaction, a progesterone-dependent growth normally triggered by the implanting blastocyst. However, CT injected ip on day 3, when circulatory estrogen is high and progesterone low, did not induce a decidual reaction but, instead, intensified the effects of estrogen (stromal edema and stimulation of the mucosa). These cycle day effects were reproduced in one uterine horn injected intraluminally with CT, but not in the other horn of the same animal given solvent alone as a control. The intrauterine injection of CT had no effect on the concentration of serum estrogen or progesterone. The decidual reaction resulting from intrauterine injection of CT on day 1 was accompanied by increases in estrogen receptor (femtomoles per mg DNA) in both cytoplasm and nucleus. In long term ovariectomized hamsters, an ip or intrauterine injection of CT induced only histological effects of estrogen (stromal edema and mucosal mitosis) without affecting circulatory estrogen. These estrogenic effects were accompanied by increases in receptors for estrogen and progesterone in both cytoplasm and nucleus. CT injected ip into ovariectomized hamsters primed with estrogen intensified the stromal edema and mucosal mitosis and resulted in progesterone and estrogen receptor levels equal to or greater than those after the administration of CT or estrogen alone. When progesterone was included in the priming (estrogen + progesterone + CT), all receptor levels were decreased, and a massive decidual reaction resulted. Thus, the induction of estrogen receptor by CT may have been the primary event that triggered the decidual reaction. Whether CT-induced estrogen receptor is mediated by cAMP, a known mediator of CT, remains to be determined.