Roles for endothelial zinc homeostasis in vascular physiology and coronary artery disease.

The discovery of the roles of nitric oxide (NO) in cardiovascular signaling has led to a revolution in the understanding of cardiovascular disease. A new perspective to this story involving zinc (Zn) is emerging. Zn and its associated Zn transporter proteins are important for the integrity and functions of both the large conduit vessels and the microvascular resistance vessels. The Zn and NO pathways are tightly coordinated. Zn ions are required for the dimerization of endothelial nitric oxide synthase and subsequent generation of NO while generation of NO leads to a rapid mobilization of endothelial Zn stores. Labile Zn may mediate important downstream actions of NO including vascular cytoprotection and vasodilation. Several vascular disease risk factors (including aging, smoking and diabetes) interfere with Zn homeostatic mechanisms and both hypozincaemia and Zn transporter protein abnormalities are linked to atherosclerosis and microvascular disease. Some vegetarian diets and long-term use of certain anti-hypertensives may also impact on Zn status. The available evidence supports the existence of a Zn regulatory pathway in the vascular wall that is coupled to the generation and actions of NO and which is compromised in Zn deficiency with consequent implications for the pathogenesis and therapy of vascular disease.

Diabetes-linked zinc transporter ZnT8 is a homodimeric protein expressed by distinct rodent endocrine cell types in the pancreas and other glands.

BACKGROUND AND AIMS: Zinc is abundant in pancreas, being required by endocrine islet cells for hormone secretion and by exocrine acinar cells as pancreatic juice component. ZnT8 is a member of the SLC30A family of zinc transporters whose overexpression in cultured pancreatic beta cells leads to increased insulin secretion in response to glucose, suggesting a possible role in regulating glycemia. ZnT8 was therefore proposed as a therapeutic target for diabetes, and recent genome-wide association studies identified polymorphisms in the ZNT8 gene conferring increased type 2 diabetes risk. METHODS AND RESULTS: As limited information was available on the biochemical properties of ZnT8 and on its endogenous expression, we have raised a specific polyclonal antibody and immunostained protein extracts, cell lines and tissue sections. We show that ZnT8 forms a very stable dimer that requires biological membranes to properly assemble. We demonstrate localization of murine ZnT8 to the secretory granules in pancreatic beta and alpha islet cells. Moreover, we show that ZnT8 is also expressed in other secretory cell types, namely the cubical epithelium that lines thyroid follicles and the cortex of the adrenal gland, suggesting a more widespread role in endocrine secretion. CONCLUSION: We provide novel insights into the features of the ZnT8 transporter, of special relevance in light of its proposed role as therapeutical target for diabetes treatment.

Zinc and its specific transporters as potential targets in airway disease.

The dietary group IIb metal zinc (Zn) plays essential housekeeping roles in cellular metabolism and gene expression. It regulates a number of cellular processes including mitosis, apoptosis, secretion and signal transduction as well as critical events in physiological processes as diverse as insulin release, T cell cytokine production, wound healing, vision and neurotransmission. Critical to these processes are the mechanisms that regulate Zn homeostasis in cells and tissues. The proteins that control Zn uptake and compartmentalization are rapidly being identified and characterized. Recently, the first images of sub-cellular pools of Zn in airway epithelium have been obtained. This review discusses what we currently know about Zn in the airways, both in the normal and inflamed states, and then considers how we might target Zn metabolism by developing strategies to monitor and manipulate airway Zn levels in airway disease.

Transcriptional regulation of the ezrin gene during rat intestinal development and epithelial differentiation.

Polarized intestinal epithelial cells are characterized by the presence of a brush border at their apical surface. The brush border cytoskeleton is assembled during cell differentiation and is composed of parallel actin bundles, held together by specific actin-binding proteins. Using specific cDNA probes we have studied the expression of the mRNAs encoding ezrin and moesin, two members of a class of proteins that connect the microvillar cytoskeleton to the plasma membrane, during the process of enterocyte maturation that occurs both in the embryonic and in the adult small intestine, along the crypt-villus axis. The steady state levels of ezrin mRNA were found to increase in the fetal gut epithelium between day 15 and day 20 of gestation and during the first week after birth, in parallel with the morphogenetic process that leads to cell polarization and brush border assembly. On the contrary, moesin mRNA is expressed at very low levels in the mature small intestine, with a sudden drop in transcription occurring at birth. In the continuously renewing epithelium of adult animals, ezrin mRNA levels are higher in the differentiated villus cells of the distal portions of the gastrointestinal tract and very low in undifferentiated crypt cells. These data demonstrate that the expression of the ezrin gene is regulated at the level of mRNA abundance during development and differentiation of the intestinal epithelium.

First-trimester human trophoblast is class II major histocompatibility complex mRNA+/antigen.

Lack of expression of the polymorphic class I and class II MHC antigens in the cytotrophoblast is one of the major factors determining the privileged immunologic status of the placenta. In this report, we show that first-trimester human placental cytotrophoblast cells display moderate to strong expression of class II MHC (HLA-DR alpha and -DR beta) and Ii chain transcripts, apparently in absence of detectable class II antigens and Ii chain. In addition, DR alpha, DR beta, and Ii mRNAs, but not antigens, are consistently upregulated by IFN-gamma. Constitutive expression and upregulation of mRNAs are detectable in trophoblast cells kept in short term as well as prolonged (2-3 weeks) culture. These results are reminiscent of an analogous mRNA+/antigen- dissociation occurring, in the case of class I MHC gene products, in a subpopulation of first-trimester cytotrophoblast cells. Thus, analogous mechanisms prevent the expression of potentially hazardous class I and II allodeterminants at early stages of semiallogeneic pregnancy.

The "ultraperipheral" revascularization in arteriosclerotic obstruction of tibial vessels. Experimental study.

In arteriosclerotic obstruction of the main tibial arteries, the tibial collateral vessels are usually patent, and about 70% of these arteries are potentially suitable for surgical revascularization. The present study aimed at investigating the practical feasibility of a selective revascularization procedure on these tibial muscular arteries (ultraperipheral revascularization). Six lower limbs amputated at thigh level for arteriosclerotic gangrene with complete obstruction of the main tibial arteries, were studied: the tibial collateral muscular vessels showed patency in 65% of cases. The authors propose a surgical technique for the revascularization of these peripheral vessels with the use of a vascular prosthesis. The "post-operative" angiographic studies showed that revascularization of these peripheral muscular arteries was possible.

The prevalence of endometriosis in premenopausal women undergoing gynecological surgery.

Endometriosis is a disease of the female pelvic mesenchyme in which tissue with epithelial and stromal characteristics of the endometrium develops in a situation other than in the uterus. The aim of this study was to evaluate the prevalence of endometriosis in premenopausal women submitted to laparoscopy and/or laparotomy for infertility, chronic pelvic pain, benign ovarian cysts and uterine myomas. The prevalence of the disease was higher in patients with infertility (30.5%), chronic pelvic (45%) and benign ovarian cysts (43%) than in patients with uterine mvomas (8.5%).

Shrinkage of pituitary PRL-secernent adenoma after short-term treatment with bromocriptine long-acting repeatable injections.

The efficacy, safety and tolerability of a single bromocriptine-LAR injection (50 mg) and of a 6 injection course at 28-day intervals, were evaluated respectively in 13 and in 9 hyperprolactinemic women with radiological signs of PRL-secreting pituitary adenoma. The long-lasting repeatable formulation of bromocriptine induced a rapid and prolonged hypoprolactinemic effect. Side effects related to central activity of the compound were observed only on the first day of compound administration in all subjects except one, whereas no modifications of cardiologic and haematologic parameters were observed. In one subject the occurrence of side effects was observed also during the 6 injection course of treatment. A significant shrinkage of pituitary adenoma was observed at the second CT scan performed in 7 of the 9 subjects treated for 6 months with bromocriptine-LAR. CT scan was not performed in one subject who achieved pregnancy after second bromocriptine-LAR injection, whereas unmodified size of pituitary microadenoma was found in one subject whose PRL secretion did not decrease during the treatment and who referred severe side effects.

[Digestive hemorrhages and intestinal metastases of chorioepithelioma]. / Emorragie digestive e metastasi intestinali da corionepitelioma.

An unusual case of digestive haemorrhage due to colic metastasis of choriocarcinoma is reported. Reference is made to the fact that the literature contains only three other cases of intestinal metastasis from choriocarcinoma and one from haemorrhagic destructive mole. Note is taken of the fact that the multiplicity of secondary sites may lead to haemorrhage in other districts, particularly the brain. Even so, the digestive haemorrhage is often the introductory sign of the primary neoplasia. The various ways of preoperatively diagnosing its nature and site are discussed. It is also shown that surgical management can be combined with suitable chemotherapy to achieve encouraging results.

[The choice of operation in perforated gastroduodenal ulcer]. / La scelta dell'intervento nell'ulcera gastro duodenale perforata.

The main point for a surgeon treating a perforated peptic ulcer is to choose between a simple treatment of the complication and a treatment both of complication and ulcer disease. So, the A. have analysed their series of 58 patients with perforated peptic ulcer: one patient underwent nasogastric suction as suggested by Taylor, 16 patients underwent suture plication of the perforation, 41 underwent immediate gastrectomy. A fully follow-up was performed: in the suture-plication group only 28.5% was symptonfree, the remaining 71.5% had recurrent dyspepsia or underwent definitive gastrectomy. Follow-up results of the immediate gastrectomy patients and elective gastrectomy patients are the same. The A. discuss the different procedures of treatment and their specific indications. Surgical treatment is the selected one and simple suture and immediate gastrectomy are not opposite.

[A difficult diagnosis: retroperitoneal rupture of the duodenum caused by closed trauma of the abdomen]. / Una diagnosi difficile: la rottura retroperitoneale del duodeno da trauma chiuso nell'addome.

The Authors report two cases of sub-peritoneal rupture of the duodenum following blunt abdominal trauma. The diagnostic difficulties are explained in detail. Emphasis is placed on the importance of prompt recognition of the duodenal injury and early surgical treatment to ensure a successful outcome.

[Primary lymphoma of the rectum]. / Il linfoma primitivo del retto.

Observation of a case of primary rectal lymphoma (123 cases described) led to a discussion of certain aspects of the condition. Although the clinical picture points to a straightforward general diagnosis of cancer, it is possible to achieve correct diagnosis using deep and multiple perendoscopic biopsy, considering the submucous origin of the lymphomas. The therapeutic approach should allow for correct staging which is only obtained by means of diagnostic studies aimed at excluding multicentric localisations. Surgery must be considered elective in stage I and II or in cases of need. Sensitivity to radiotherapy has led some authors to propose it as a primary treatment. Chemotherapy is indicated alone or in association with radiotherapy or surgery. It is also pointed out that treatment modalities are still debated because data are not homogeneous and so few cases have been reported.

[Long-term evaluation of the treatment of perforated gastroduodenal ulcer using a median suture]. / Valutazione a distanza del trattamento dell'ulcera gastro-duodenale perforata mediante rafia.

Simple suture associated with treatment using H2-antagonists has replaced gastroduodenal resection in the treatment of peptic ulcer. Forty-four patients were submitted to rafia suture for perforated gastric or duodenal ulcer (1972-1986). Fourteen were treated in the pre-H2-antagonist period and 30 in the post-H2 antagonist period. Patients were followed up: Vissick classes I and II represent 58.3% of cases in the pre-H2-antagonist period and 95.8% in the post-H2-antagonist period. Two patients from the first period were subjected to gastroduodenal resection. In no patient of the second period was further ulcer therapy necessary. In patients of the first period, oesophagogastroduodenoscopy evidenced duodenal ulcer in one case and erosive duodenitis in two cases; erosive duodenitis was present in one patient of the second period. The choice of rafia would appear to be a valid one. Follow-up after a longer period should provide confirmation.

[Embolism of the superior mesenteric artery. A clinical experience]. / L'embolia dell'arteria mesenterica superiore. Un'esperienza clinica.

The Authors report their clinical experience in superior mesenteric artery embolism: 10 arterial embolisms (71%) collected from a series of 14 obstructions of the superior mesenteric artery. The main interval from the beginning of the symptomatology to hospital admission was 48 h. Laparotomy was performed in all ten patients; gangrenous bowel was resected in 2 and 2 had an embolectomy of the superior mesenteric artery without intestinal resection. The remaining 6 patients had laparotomy alone and died. The Authors emphasize the difficulty in recognizing the disease at an early stage and suggest to contemplate in patients at risk with a persistent abdominal pain, the possibility of a superior mesenteric artery embolism.

[Complementary profundoplasty. Clinical experience]. / Profundoplastica "complementare". Esperienza clinica.

The Authors report a 68% overall success rate in a three years follow-up study of 45 "complementary" profundoplasties. The key factors with a significant prognostic effect on the clinical surgical results are the early postoperative increase of the resting ankle pressure index (I.W.) and the angiographic preoperative patency of the tibial arteries. An early postoperative increase of I.W. has been always associated with good results whereas an unchanged postoperative I.W. has always been associated with poor results; an angiographic tibial run-off (one or two or three patient tibial arteries) has been associated with significant better clinical results (p less than 0.001).

[Endarterectomy of the internal carotid. Clinical experience]. / La disostruzione della carotide interna. Esperienza clinica.

The authors report a clinical experience on 37 internal carotid endarterectomies of 33 patients classified as: group A (asymptomatic patients); 4 patients (13%), group B (RIA); 9 patients (27%), group C (stabilized neurological lesions); 19 patients (56%), group D (acute cerebral ischemia): 1 patient (3%). Sixteen thromboendarterectomies (43%) were carried on for the prophylaxis of neurological lesions, 20 (54%) to increase and balance the cerebral blood flow in patients with stable neurological lesions, 1 (3%) for acute cerebral ischemia. The overall operative mortality was 6%, the operative morbidity was 22%. The clinical follow-up concerned 26 patients: the overall mortality was 19%: in survivors the late results were excellent. The rate of postoperative stenosis was 18%: 80% of these arteries had been treated without a patch angioplasty.

[Endoscopic retrograde cholangiography in the diagnosis of hepatic hydatidosis]. / La colangiografia retrograda endoscopica nella diagnostica dell'idatidosi epatica.

The Authors studied the role of E.R.C.P. in the presurgical investigations of hepatic hydatid cyst in a consecutive series of 24 patients. The reasons for admission and presurgical investigation (blood test, chest X-ray, plain abdominal X-ray, intravenous cholangiography, ultrasonography, liver scintigraphy, C.T., E.R.C.P.) are evaluated and compared. The results showed a good correlation, as related to the cyst and biliary tree relationship between operative findings and E.R.C.P. The E.R.C.P. provided an etiological diagnosis in obstructive jaundice and showed a biliary tract involvement by the cyst both in patients with a complication at admission or in the past history and in 25% of the asymptomatic patients (pericystic bilioma, exterior compression of bile ducts, direct communications between cyst and biliary tree).

[The incidence of 1,2-dimethylhydrazine-induced colonic neoplasms in the rat: the effect of constipation]. / Incidenza delle neoplasie coliche indotte da 1,2-dimetilidrazina nel ratto: influenza della stipsi.

The authors studied the role of slow bowel transit in the development of colonic neoplasias in rats treated with 1,2-dimethylhydrazine (DMH). Forty Sprague-Dawley male rats, weighing 400 g, were used in the experiment and were divided into 4 groups of 10 rats each. The first and the second group were given, weekly, subcutaneous injections of DMH at a dose of 25 mg/kg for 25 and 27 weeks respectively; in these groups constipation was obtained by reducing water intake throughout the period of the experiment. The third and the fourth group (control groups) received DMH at the dose of 25 mg/kg for 25 and 27 weeks respectively and water "ad libitum". The rats were weighed once a week and stool output, weight, and number of scybala/day were recorded once every four weeks. Rats were sacrificed one week after the final injection of DMH and every intestinal lesion macroscopically identified was histologically examined. All rats showed weight loss from the 22nd week to the sacrifice. The mean stool weight/day was 21.2 g +/- 1.47 in the groups A and B; while for the groups C and D it was 23.6 g +/- 1.81 (p = 0.019). The number of scybala/day was 26 +/- 3 in the groups A and B, whereas in the groups C and D was 34 +/- 4 (p = 0.05). An increased number of cancers per rat was recorded in the groups A and B compared to control groups, respectively from 0.66 to 1.4 at 25 weeks (p = 0.02) and from 0.9 to 2.44 at 27 weeks (p = 0.07). A corresponding increase in the number of polyps after 25 weeks was demonstrated, taking into account the possible polyp-cancer sequence. Our study suggests that the slow bowel transit induced an increased number of colonic neoplasia in relation to the prolonged contact of the carcinogen with the mucosa or to its greater concentration in the colonic lumen due to the fecal output reduction.