COVID-19 therapies and their impact on QT interval prolongation: A multicentre retrospective study on 196 patients.

BACKGROUND: SARS-CoV-2 infection has caused a global pandemic. Many of the medications identified to treat COVID-19 could be connected with QTc prolongation and its consequences. METHODS: Non-ICU hospitalized patients of the three centres involved in the study from the 19th of March to the 1st of May were included in this retrospective multicentre study. Relevant clinical data were digitally collected. The primary outcome was the incidence of QTc prolongation ≥ 500 ms, the main secondary outcomes were the Tisdale score ability to predict QTc prolongation and the incidence of ventricular arrhythmias and sudden deaths. RESULTS: 196 patients were analysed. 20 patients (10.2%) reached a QTc ≥ 500 ms. Patients with QTc ≥ 500 ms were significantly older (66.7 ± 14.65 vs 76.6 ± 8.77 years p: 0.004), with higher Tisdale score (low 56 (31.8%) vs 0; intermediate 95 (54.0%) vs 14 (70.0%); high 25 (14.2%) vs 6 (30.0%); p: 0.007) and with higher prognostic lab values (d-dimer 1819 ± 2815 vs 11486 ± 38554 ng/ml p: 0.010; BNP 212.5 ± 288.4 vs 951.3 ± 816.7 pg/ml p < 0.001; procalcitonin 0.27 ± 0.74 vs 1.33 ± 4.04 ng/ml p: 0.003). After a multivariate analysis the Tisdale score was able to predict a QTc prolongation ≥ 500 ms (OR 1,358 95% CI 1,076-1,714p: 0,010). 27 patients died because of COVID-19 (13.7%), none experienced ventricular arrhythmias, and 2 (1.02%) patients with concomitant cardiovascular condition died of sudden death. CONCLUSIONS: In our population, a QTc prolongation ≥ 500 ms was observed in a minority of patients, no suspected fatal arrhythmias have been observed. Tisdale score can help in predicting QTc prolongation.

Patterns of brain structural changes in first-contact, antipsychotic drug-naive patients with schizophrenia.

BACKGROUND AND PURPOSE: Previous studies have suggested that structural changes do occur in the brain of patients with schizophrenia compared with healthy control participants. However, findings from such studies are inconclusive, probably because of the different methodologic approaches, the clinical heterogeneity of patient samples, and also the fact that patients enrolled were treated with antipsychotic drugs. The aim of this study was to investigate brain GM volumes and intrinsic structural WM changes in first-contact, antipsychotic drug-naïve patients with schizophrenia. MATERIALS AND METHODS: A total of 43 first-contact, drug-naïve, patients with schizophrenia and 17 age-matched control participants were studied. All participants underwent T1-weighted MR imaging and DTI scans. Voxel-based morphometry and tract-based spatial statistics were used to compare GM volumes and WM DTI metrics between groups. MR imaging measures were correlated with the duration of the untreated psychosis and the clinical positive and negative symptoms. RESULTS: Compared with control participants, patients with schizophrenia showed smaller volumes of the temporal, parietal, and occipital GM, and a pattern of decreased mean diffusivity and increased fractional anisotropy in the brain stem and cerebellum bilaterally, interhemispheric and cortico-cortical connections bilaterally, and right anterior and posterior limb of the internal capsule. In patients, decreased mean diffusivity and increased fractional anisotropy in several brain regions were related to a longer duration of the untreated psychosis and the severity of positive symptoms. CONCLUSIONS: First-contact, drug-naïve, patients with schizophrenia present with volumetric and DTI changes, which correlated with their clinical features. This study increases our knowledge on the neural networks involved in the pathophysiologic mechanisms of schizophrenia.

Visceral adiposity index is associated with significant fibrosis in patients with non-alcoholic fatty liver disease.

BACKGROUND: Metabolic factors have been associated with liver damage in patients with non-alcoholic fatty liver disease (NAFLD). AIMS: To test a new marker of adipose dysfunction, the visceral adiposity index (VAI), in NAFLD patients to assess whether or not it is associated with host factors, and to investigate a potential correlation with histological findings. METHODS: One hundred and forty-two consecutive NAFLD patients were evaluated by liver biopsy, and clinical and metabolic measurements, including insulin resistance with the homeostasis model assessment (HOMA), and VAI by using waist circumference, body mass index, triglycerides and HDL. Serum levels of TNFα, IL-6, adiponectin and leptin were also assessed. All biopsies were scored for NAFLD activity score (NAS) and its components, and for staging (Kleiner). RESULTS: By multiple linear regression analysis, VAI was independently associated with higher HOMA (P = 0.04), and fibrosis (P = 0.04). In addition, an independent association was found between higher VAI and lower adiponectin levels (P = 0.002). Higher HOMA (OR 1.149, 95% CI 1.003-1.316, P = 0.04), higher VAI (OR 1.446, 95% CI 1.023-2.043, P = 0.03), lobular inflammation (OR 3.777, 95% CI 1.771-8.051, P = 0.001), and ballooning (OR 2.884, 95% CI 1.231-6.757, P = 0.01) were correlated with significant fibrosis (F2-F4) on multiple logistic regression analysis. In particular, the prevalence of significant fibrosis progressively increased from patients with a VAI ≤ 2.1 and HOMA ≤ 3.4 (26%) to those with a VAI > 2.1 and HOMA > 3.4 (83%). CONCLUSIONS: In NAFLD patients, visceral adiposity index is an expression of both qualitative and quantitative adipose tissue dysfunction and, together with insulin resistance, is independently correlated with significant fibrosis.

Cornea in acromegalic patients as a possible target of growth hormone action.

BACKGROUND: GH exerts its effects on many organs and the eye also seems to be a target site, although few authors have investigated the corneal thickness in patients with acromegaly. AIM: To perform a detailed ophthalmological evaluation in acromegalic patients, in relation to disease activity. MATERIAL AND METHODS: Twenty-eight acromegalic patients (11 males, 17 females) and 22 voluntary healthy subjects underwent complete metabolic and ophthalmological evaluation, including retinal thickness (RT), central corneal thickness (CCT), and intraocular pressure values (IOP). RESULTS: Significantly greater CCT values were found in all acromegalic patients in comparison with controls (567 vs 528.5 µm; p<0.001), without concomitant greater corrected IOP. No difference was found for RT. Analyzing these data according to disease activity, uncontrolled patients showed greater CCT values (573.5 vs 559 µm; p=0.002) and corrected IOP (17.4 vs 16 mmHg; p=0.001) than the controlled ones. CCT also correlated with basal and nadir GH after oral glucose load levels, IGF-I levels, and duration of active disease. CONCLUSIONS: Acromegaly is characterized by greater CCT values, supporting the hypothesis that GH excess may have stimulatory effects on the cornea as well as on other target organs. Higher GH levels, disease control status and duration of active disease seem to be the main causes of increased corneal thickness. We suggest a careful and detailed corneal evaluation in acromegalic patients to prevent the potential risk of increased IOP, in addition to the already-known complications.

Outcome of pregnancy in type 1 diabetic patients treated with insulin lispro or regular insulin: an Italian experience.

Some studies have shown that fetal outcome observed in patients using insulin lispro is much the same as in pregnant women using regular insulin. This study aims to analyze the Italian data emerging from a multinational, multicenter, retrospective study on mothers with type 1 diabetes mellitus before pregnancy, comparing those treated with insulin lispro for at least 3 months before and 3 months after conception with those treated with regular insulin. The data collected on pregnant women with diabetes attending 15 Italian centers from 1998 to 2001 included: HbA1c at conception and during the first and third trimesters, frequency of severe hypoglycemic episodes, spontaneous abortions, mode and time of delivery, fetal malformations and mortality. Seventy-two diabetic pregnancies treated with lispro and 298 treated with regular insulin were analyzed, revealing a trend towards fewer hypoglycemic episodes in the former, who also had a significantly greater reduction in HbA1c during the first trimester. The rate of congenital malformations was similar in the offspring of the two groups of women treated with insulin lispro or regular insulin. These findings suggest that insulin lispro could be useful for the treatment of hyperglycemia in type 1 diabetic pregnant women.

Markers of inflammation and prevalence of vascular disease in patients with metabolic syndrome.

AIM: The aim of this study was to determine the prevalence of carotid atherosclerosis and coronary heart disease and cerebrovascular disease in subjects with metabolic syndrome and to investigate the relationship between atherosclerosis and C-reactive protein (CRP) levels. METHODS: We studied 568 ambulatory subjects, referred to our Center for the study of atherosclerosis and cardiovascular prevention by general practitioner, for the presence of traditional cardiovascular risk factors. Subjects were divided in two groups: those with metabolic syndrome (n=163), and those with 0-2 metabolic abnormalities (n=405). All subjects underwent carotid artery ultrasound and blood tests including high sensitivity-CRP measurement. RESULTS: Prevalence of carotid lesions, previous cardiac or cerebrovascular events was higher in patients with metabolic syndrome. CRP levels were higher in patients with metabolic syndrome (0.6+/-0.23 vs 0.42+/-0.2, P<0.01). An increased relative risk for carotid atherosclerosis, coronary heart disease and cerebrovascular disease was not associated with each single component of the metabolic syndrome, but it was significantly associated with the coexistence of three or more of these. Patients with the metabolic syndrome had a higher incidence of carotid and coronary disease, if CRP levels were above 0.3 mg/dL. CONCLUSION: Patients with metabolic syndrome are at increased risk for cardiovascular events. Strategy to treat these patients is not well clarified. Life style changes are mandatory, but in very high-risk subgroups secondary prevention strategies may be advisable. These may be identified by using CRP levels as a marker.

Metabolic parameters and adipokine profile during GH replacement therapy in children with GH deficiency.

OBJECTIVE: GH replacement therapy in children with GH deficiency (GHD) mainly promotes linear growth. Not only have very few studies fully analyzed the metabolic consequences of GH therapy, but also the question as to whether GH may affect adipokine secretion has been insufficiently investigated. Our aim was to study the effects of GH replacement therapy on auxological data, lipid and glycemic profiles, insulin homeostasis (HOMA-IR) and serum adipokines in children. METHODS: This was a 1-year prospective study. Thirty-four GHD children (11.6 +/- 2.6 years) and thirty healthy matched controls were enrolled. Children affected by GHD were studied both before beginning continuous GH replacement therapy and again at 12 months. RESULTS: At the beginning of the study, total and LDL cholesterol were higher in GHD children than in controls (P<0.001), whereas HDL cholesterol, triglycerides, insulin, HOMA-IR, leptin, and adiponectin were similar. At 12 months of continuous GH replacement therapy in the GHD group, there was a significant increase in both auxological data and IGF-I (P<0.001); total cholesterol (P<0.001), LDL (P<0.001), triglycerides (P<0.005), and leptin (P<0.001) decreased significantly; HDL (P<0.003), insulin (P<0.001), HOMA-IR (P<0.001) increased while adiponectin was unmodified. Furthermore, IGF-IDelta showed an inverse correlation with leptin Delta (rho = -0.398, P = 0.02). CONCLUSIONS: In GHD children, the evaluation of metabolic parameters proves to be a useful tool for the evaluation of auxological parameters during GH replacement therapy. In our study, GH replacement therapy in GHD children improved final height, restored IGF-I levels, reduced leptin levels, and improved the lipid profile, without producing any unfavorable effects on glucose metabolism.

[Role of MR cholangiopancreatography in the evaluation of biliary disease]. / II ruolo della colangiopancreatografia a risonanza magnetica nello studio della patologia biliare.

PURPOSE: To evaluate the diagnostic accuracy of MR cholangiopancreatography (MRCP) in biliary tree patology in comparison with percutaneous transhepatic cholangiography (PTC), endoscopic retrograde cholangiopancreatography (ERCP) and surgical findings. MATERIALS AND METHODS: Forty-six patients , with clinical and laboratory findings suggestive of biliary tree pathology, and after an abdominal US, underwent MRCP with a 1.5 T superconductive magnet equipped with a phased-array body coil. MR exam was performed with baseline sequences for the examination of the upper abdomen, followed by specific MRCP sequences and, in cases of suspected neoplastic disease, completed with abdominal sequences after a bolus injection of paramagnetic contrast. RESULTS: MRCP showed normal findings in 16/46 patients, biliary duct dilatation in 25/46 patients (7 choledocolithiasis, 10 benign obstructions and 8 neoplastic stenoses) and stenoses without dilatation of biliary tree in 5/46 patients. In 25 patients with biliary duct dilatation, CPRM correctly identified the level of in 100% of patients (25/25) and the nature in 88% of patients (22/25). In 5 patients with stenosis without dilatation of biliary tree, CPRM identified 2 true positives (sclerosing cholangitis), 2 false positives and 1 patient is still in follow-up. CONCLUSIONS: In our experience MRCP proved to be highly accurate as fundamental diagnostic step in patients with clinical and laboratory findings suggestive of biliary disease. The workload of ERCP, invasive method with risk of complications, in the diagnosis stage could therefore be reduced and its use be reserved for therapeutic indications.

Up-regulation of c-FLIPshort and reduction of activation-induced cell death in T-cells from patients with Type 1 diabetes.

AICD of T-cells is an efficient way of removing activated T-lymphocytes. In this study we investigated the molecular basis of AICD upon reactivation in peripheral T-lymphocytes from newly diagnosed T1DM patients and age-matched healthy controls. In an in vitro model system, PHA-stimulated T-cells, upon prolonged culture in IL-2, acquire a sensitive phenotype to Fas-mediated apoptosis. This phenomenon is less pronounced in T1DM T-cells. Moreover, the restimulation of activated T-cells via TCR/CD3 and/or via CD28 inhibits Fas-mediated apoptosis in T1DM in comparison to control T-cells. After Fas triggering, the generation of the active sub-units of caspase-8 is significantly reduced in T1DM T-cells restimulated via TCR/CD3 and/or CD28. In parallel, we found that the amount of c-FLIPshort protein is significantly increased in the DISC only in T1DM T-cells restimulated via TCR/CD3 and via CD28. These data suggest that increased levels of c-FLIPshort may prevent recruitment of pro-caspase-8 in T1DM CD3-treated T-cells and provide new insight into the molecular mechanisms of apoptosis resistance in stimulated T-cells from T1DM patients.

Importance of premeal injection time in insulin therapy: Humalog Mix25 is convenient for improved post-prandial glycemic control in type 2 diabetic patients with Italian dietary habits.

We investigated the use, in a short period, of Humalog Mix25 (Mix25) in a twice-daily administration regimen compared to a twice-daily injection therapy with Humulin 30/70 (30/70) in diabetic patients with Italian dietary habits. We studied 33 type 2 diabetic patients aged 59.1 +/- 8.1 years, BMI 29.8 +/- 2.7 kg/m2, duration of diabetes and insulin therapy of 14.4 +/- 9.8 and 4.2 +/- 4.6 years, respectively. After a 4-day lead-in period of twice-daily human insulin 30/70 treatment, patients were randomized to one of two treatment sequences: (1) a twice-daily regimen with Mix25 just 5 minutes before the morning and evening meals for 12 days, followed by a twice-daily therapy with human insulin 30/70 given 30 minutes before the morning and evening meals for an additional 12 days; or (2) the alternate sequence. Each patient underwent a mixed meal test: Humulin 30/70 was administered 30 minutes before the meal, while Mix25 was given 5 minutes before. The 2-hour post-prandial glucose concentration after breakfast was significantly lower during treatment with Mix25 than with Humulin 30/70 (157 +/- 43.2 vs. 180 +/- 43.2 mg/dl, p<0.05). The glycemic excursion after dinner on Mix25 treatment was significantly lower than with Humulin 30/70 (12.2 +/- 48.01 vs. 35.5 +/- 36.92 mg/dl, p<0.05). AUCglucose after Mix25 was lower than after Humulin 30/70. Glycemia after test meal was significantly lower with Mix25 than with Humulin 30/70. Insulin and free insulin concentrations after the test meal were significantly higher with Mix25 in comparison to Humulin 30/70. AUC serum insulin and free insulin curves after Mix25 were significantly higher than after Humulin 30/70 (p=0.028 and p=0.005, respectively). Twice-daily injections of Humalog Mix25, compared to human insulin 30/70 in type 2 diabetic patients with Italian dietary habits, provide improved and lasting post-prandial glycemic control, with the great convenience of the injection just before the meal.

Regulation of apoptosis in endocrine autoimmunity: insights from Hashimoto's thyroiditis and Graves' disease.

Dysregulation of apoptosis is associated with the pathogenesis of organ-specific autoimmune diseases, through altered target organ susceptibility. Apoptosis signaling pathways can be initiated through activation of death receptors such as Fas. A comparative analysis of the expression of Fas and FasL, the antiapoptotic molecule Bcl-2, and apoptosis in both thyrocytes and thyroid-infiltrating lymphocytes (TILs) from patients with either Graves' disease (GD) or Hashimoto's thyroiditis (HT) was performed. GD thyrocytes expressed less Fas than HT thyrocytes, whereas GD TILs had higher levels of Fas and FasL than HT TILs. GD thyrocytes expressed higher levels of Bcl-2 compared with HT thyrocytes. The opposite pattern was observed in GD (low Bcl-2) and HT (high Bcl-2) TILs. Consistently, thyrocyte apoptosis was marked in HT and poor in GD thyroids, and TIL apoptosis was marked in GD and poor in HT. Our findings suggest that in GD thyroid the regulation of Fas/FasL/Bcl-2 favors apoptosis of infiltrating lymphocytes. Moreover, the reduced levels of Fas/FasL and increased levels of Bcl-2 should favor thyrocyte survival and hypertrophy associated with stimulatory thyroid-stimulating hormone receptor antibodies. In contrast, the regulation of Fas/FasL/Bcl-2 expression in HT can promote thyrocyte apoptosis via homophylic Fas-FasL interactions, and a gradual reduction in thyrocyte numbers leading to hypothyroidism. Fas-mediated apoptosis may be a general mechanism of cell damage in destructive organ-specific autoimmunity.

Preprandial combination of lispro and NPH insulin improves overall blood glucose control in type 1 diabetic patients: a multicenter randomized crossover trial.

BACKGROUND AND AIM: While lispro insulin has been reported to lower postprandial blood glucose concentrations, less consistent effects have been shown for glycosylated hemoglobin (HbA1c) levels. Aim of this study was to determine whether pre-meal association of NPH, an intermediate-acting insulin, with lispro improves overall glycemic control in type 1 diabetic patients. METHODS AND RESULTS: Eighty-five type 1 diabetic patients were studied in a multicenter randomized comparative (human regular vs lispro insulin) crossover (3-month) study in which NPH insulin was given as a dinner or bedtime injection and at breakfast and lunch if necessary. The number of injections was kept constant: 42% and 58% of patients injected insulin 3 and 4 times per day, respectively. Fasting and preprandial blood glucose levels were similar, while postprandial levels improved after lispro compared to human regular insulin (breakfast: 8.28 +/- 2.39 vs 9.28 +/- 2.72 mmol/l; lunch: 8.33 +/- 2.67 vs 9.06 +/- 2.67 mmol/l, dinner: 8.06 +/- 2.72 vs 9.28 +/- 2.44 mmol/l, ANOVA: p = 0.003). HbA1c also improved after lispro: 8.1 +/- 0.9 vs 8.3 +/- 0.8%, p < 0.05. The rate of hypoglycemia was similar. Patients showed better acceptance of lispro treatment (p < 0.001). CONCLUSIONS: Lispro improves overall blood glucose control in type 1 diabetic patients without increasing the incidence of hypoglycemia. This can be achieved by an optimal combination of lispro insulin with NPH whenever the time intervals between meals are too long.

Differential regulation of Fas-mediated apoptosis in both thyrocyte and lymphocyte cellular compartments correlates with opposite phenotypic manifestations of autoimmune thyroid disease.

Several mechanisms are probably involved in determining the evolution of autoimmune thyroid disease (AITD) towards either hypothyroidism and the clinical syndrome known as Hashimoto's thyroiditis (HT) or toward hyperthyroidism and the symptoms of Graves' disease (GD). To gain further insight into such mechanisms we performed an exhaustive comparative analysis of the expression of key molecules regulating cell death (Fas, Fas ligand [FasL], Bcl-2) and apoptosis in both thyrocytes and thyroid infiltrating lymphocytes (TILs) from patients with either GD or HT. GD thyrocytes expressed less Fas/FasL than HT thyrocytes, whereas GD TILs had higher levels of Fas/FasL than HT TILs. GD thyrocytes expressed increased levels of the antiapoptotic molecule Bcl-2 compared to the low levels detected in HT thyrocytes. The opposite pattern was observed in GD (low Bcl-2) and HT (high Bcl-2) TILs. The patterns of apoptosis observed were consistent with the regulation of Fas, FasL, and Bcl-2 described above. Our findings suggest that in GD thyroid the regulation of Fas/FasL/Bcl2 favors apoptosis of infiltrating lymphocytes, possibly limiting their autoreactive potential and impairing their ability to mediate tissue damage. Moreover, the reduced levels of Fas/FasL and increased levels of Bcl-2 should favor thyrocyte survival and favor the thyrocyte hypertrophy associated with immunoglobulins stimulating the thyrotropin (TSH) receptor. In contrast, the regulation of Fas/FasL/Bcl2 expression in HT promotes thyrocyte apoptosis, tissue damage, and a gradual reduction in thyrocyte numbers leading to hypothyroidism. These findings help define key molecular mechanisms contributing to the clinical outcome of thyroid autoimmunity.

Cytokine profiles in drug-naive schizophrenic patients.

A large body of evidence concerning immunological abnormalities in schizophrenic patients seems to suggest a role of the immune system in the multifactorial pathogenesis of schizophrenia. We investigated the production of various cytokines [interleukin (IL)-2, IL-4, IL-10, interferon (INF)-gamma] in drug-free (n=26) and drug-naive (n=7) schizophrenic patients and in healthy controls (n=33). Production of IL-2 and INF-gamma was significantly higher (respectively P=0.021 and P=0.001) in patients than in controls. These findings provide further evidence that immunological abnormalities are present in some schizophrenic patients.

Possible pathogenetic relevance of interleukin-1 beta in "destructive" organ-specific autoimmune disease (Hashimoto's thyroiditis).

Thyroid follicular cells (TFC) abundantly express a variety of immunologically relevant surface molecules in Hashimoto's thyroiditis (HT), for example, MHC antigens and adhesion molecules such as ICAM-1. Cytokines produced by infiltrating type 1 helper and cytotoxic T cells are importantly involved in de novo expression or up-regulation of such molecules. We recently demonstrated that TFC from HT patients almost invariably bear on their surface two additive functional molecules: Fas/Apo1/CD95, an important participant in apoptosis, and B7.1, a member of a family of "co-stimulatory" molecules that are crucial for efficient antigen presentation. To date, 12 out of 14 surgical HT thyroid specimens that we studied by immunohistochemistry showed B7.1-positive TFC, and all showed Fas-positive TFC, different from Graves' disease (GD) or nonautoimmune specimens. We have investigated the role of a number of cytokines (IL-1 beta, TNF-alpha, IL-4, IL-6, IL-10, IL-12, TGF-beta 1, IFN-gamma) in regulating B7.1 and Fas expression. The experiments were performed by immunofluorescence flow cytometry on TFC purified from nontoxic goiter specimens which were Fas- and B7.1-negative at baseline, and one B7.1/Fas-positive HT specimen. IFN-gamma (500 U/mL) and TNF-alpha (200 ng/mL) were unable to induce de novo expression of B7.1 or Fas on cultured TFC. At higher doses (2000 U/mL and 800 ng/mL, respectively), they were unable to induce B7.1, but potentiated the spontaneous expression of Fas. Type 2 cytokines (IL-4 and IL-10) were unable to induce Fas or B7.1 on TFC at all, or to down-regulate Fas or B7.1 when expressed. On the other hand, IL-1 beta was the only cytokine able to induce Fas expression on Fas-negative TFC at doses ranging from 100 to 1000 pg/mL. Moreover, at a dose of 400 pg/mL, it was also able to induce B7.1. We demonstrated by immunohistochemistry that IL-1 beta is abundantly present on HT thyroids, including follicular structures. It is conceivable that IFN-gamma, or other cytokines secreted by infiltrating T-lymphocytes, are able to promote IL-1 beta secretion by TFC. In conclusion, a crucial role of IL-1 beta in "destructive" organ-specific autoimmunity may be suggested both for the perpetuation of the autoimmune reaction (induction of efficient autoantigen presentation by TFC, via co-stimulatory molecules) and in induction of tissue damage via "suicide" Fas/FasL-mediated TFC interaction.

Nitric oxide primes pancreatic beta cells for Fas-mediated destruction in insulin-dependent diabetes mellitus.

Fas is an apoptosis-inducing surface receptor involved in controlling tissue homeostasis and function at multiple sites. Here we show that beta cells from the pancreata of newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients express Fas and show extensive apoptosis among those cells located in proximity to Fas ligand-expressing T lymphocytes infiltrating the IDDM islets. Normal human pancreatic beta cells that do not constitutively express Fas, become strongly Fas positive after interleuken (IL)-1beta exposure, and are then susceptible to Fas-mediated apoptosis. NG-monomethyl-L-arginine, an inhibitor of nitric oxide (NO) synthase, prevents IL-1beta-induced Fas expression, whereas the NO donors sodium nitroprusside and nitric oxide releasing compound (NOC)-18, induce functional Fas expression in normal pancreatic beta cells. These findings suggest that NO-mediated upregulation of Fas contributes to pancreatic beta cell damage in IDDM.