Efficacy, safety and acceptability of the new pen needle 33G × 4 mm. AGO 01 study.

OBJECTIVES: Adherence to insulin therapy can be threatened by pain and needle fear. This cross-over randomized non-inferiority trial evaluated a new Pic Insupen 33G × 4 mm needle vs. a 32G × 4 mm needle in terms of metabolic control, safety and acceptability in patients with diabetes treated with insulin. RESEARCH DESIGN AND METHODS: We used a centralized, permuted block randomization, stratified by center and maximum insulin dose per single injection. Subjects used the two needles in two 3 week treatment periods. The primary endpoint was the absolute percentage variation of the blood fructosamine between the two treatments (% |ΔFru|). Additional endpoints were: glycemic variability, total insulin doses, body weight, severe hypoglycemic episodes, leakage at injection sites and pain measured by visual analogue scale. Equivalent glycemic control was defined a priori as % |ΔFru| (including 95% CI) within 20%. RESULTS: Of 87 subjects randomized, 77 completed the study (median age 53.1 [IR 42.3-61.2], median BMI 24.3 Kg/m(2) [IR 21.3-28.5], median duration of insulin therapy [in months] 141.4 (IR 56.3-256.9), median baseline HbA1c 7.9% [IR 7.2-8.8]). The % |ΔFru| was 7.93% (95% CI 6.23-9.63), meeting the non-inferiority criterion. The fasting blood glucose standard deviation was 46.2 (mean 154.6) with the 33G needle and 42.8 (mean 157.3) with the 32G needle (p=0.42). Insulin daily dose and patients' weight did not show any statistically significant variation. We observed 95 episodes of symptomatic hypoglycemia with the 33G needle and 96 with the 32G needle. One episode of severe hypoglycemia was documented in the latter group. As for insulin leakage we observed 37.55 episodes per 100 patient-days with the 33G needle and 32.21 episodes per 100 patient-days with the 32G needle (p=0.31). Patients reported less pain with the 33G × 4 mm needle (p=0.05). STUDY LIMITATIONS: Study sample was mainly composed of adults with type 1 diabetes and study was not blinded. CONCLUSIONS: The 33G needle is not inferior to the 32G needle in terms of efficacy and safety, with reduced pain and no difference in insulin leakage. CLINICAL TRIAL REGISTRATION: NCT01745549.

Effect of stentgraft model on aneurysm shrinkage in 1,450 endovascular aortic repairs.

BACKGROUND: Regression of the aneurysmal sac after endovascular repair of abdominal aortic aneurysm (AAA) is an accepted indicator of aneurysm exclusion. This study evaluated the spontaneous decrease in sac diameter over a 10-year period in patients undergoing endovascular aneurysm repair (EVAR) with different stentgrafts. METHODS: 1,450 patients (mean age 73.1 ± 7.7 years; 1,325 male) undergoing EVAR and with a minimum of 1-year computed tomography (CT) imaging were included. Different implanted stentgrafts (n = 622 [42.9%] Zenith, n = 236 [16.3%] AneuRx, n = 179 [12.3%] Talent, n = 83 [5.7%] Endurant, n = 236 [16.3%] Excluder, n = 36 [2.5%] Fortron, 53 [3.7%] Anaconda, n = 5 [0.3%] others) were employed. "Persisting shrinkage" was measured as ≥ 5 mm AAA diameter regression spontaneously persisting or increasing until the end of follow-up without reintervention. Persisting shrinkage among devices was compared with survival and Cox regression analyses. RESULTS: During a median follow-up of 45 months (interquartile range, IQR, 21-79) persisting shrinkage was detected in 768 (53%) aneurysms. Kaplan-Meier estimates of persisting shrinkage were 25.8% at 1 year, 63% at 3 years and 72.6% at 10 years. Persisting shrinkage rates were significantly higher for Zenith (p < .0001), Endurant (p = .013) and new generation Excluder (p < .0001) devices. Cox analyses confirmed that persisting shrinkage rates were independently associated with Zenith (OR 1.33; 95% CI: 1.176-1.514) and Endurant (OR 1.52; 95% CI: 1.108-2.092) stentgrafts and negatively associated with the AneuRx (OR 0.57; 95% CI: 0.477-0.688) device. Survival rates were higher in the persisting shrinkage group: 84.1% vs. 77.8% at 3 years, and 53% vs. 38.1% at 10 years (p < .0001). Freedom from AAA-related-death rate was 100% at 3 years and 99.7% at 10 years in the persisting shrinkage group. CONCLUSIONS: Aneurysm diameter shrinkage can be achieved in most current EVARs with persisting effect at 10 years from repair and indicates the benefit and safety of treatment. Last generation devices seem to be important factors in inducing aneurysm sac shrinkage with similar clinically relevant effects among single models.

Plaque debulking for femoro-popliteal occlusions: techniques and results.

Although currently there is a trend of using percutaneous transluminal angioplasty (PTA) and stenting for the treatment of long occlusions of superficial femoral artery, many studies reported comparable results in terms of mid- and long-term patency between PTA and stenting and plaque debulking techniques such as remote endarterectomy, directional atherectomy catheter atherectomy and laser guided atherectomy. A successful debulking procedure is strongly associated with patients comorbidities, length of lesions and clinical presentation. In the last decade many new devices have been proposed to improve debulking results. Despite encouraging data about technical feasibility and limb salvage rate, debulking is still associated with a low rate of long-term primary and secondary patency. However, randomized clinical trials are expected and can hopefully provide conclusions on the effective durability of these procedures.

Eczema and food allergy in an Italian pediatric cohort: no association with TLR-2 and TLR-4 polymorphisms.

Recent studies have indicated that Toll-like receptor polymorphisms or their impaired signalling, specifically TLR-2 and TLR-4, were correlated with a higher risk for allergy. The purpose of this study is to evaluate the associations of TRL-2 and TRL-4 single nucleotide polymorphisms (SNP) and atopic traits in a cohort of 159 Italian allergic children (102 affected by eczema and 57 by IgE-mediated food allergy) and 147 healthy controls recruited in Rome, Italy. DNA was isolated from the peripheral blood and TLR-2 R753Q/TLR-4 D299G polymorphisms were determined by TaqMan MGB probes using Real-Time PCR technique. In the control group, the TLR-2 polymorphism R753Q had a prevalence of 2.5% while the frequency of the TLR-4 D299G was 12%. None of the 159 allergic patients showed the R753Q SNP. By contrast, 7/57 patients with food allergy (12%) and 6/102 subjects with eczema (6%) carried the TLR-4 mutation. In our cohort, no evidence of correlation between TLR-2 or TLR-4 polymorphism and eczema and food allergy incidence and/or severity was found. Further studies are needed to clarify the possible role of TLR-2 and TLR-4 polymorphism in allergic disease, in Italian children.

Evaluation of microbial contamination of air in two haematology departments equipped with ventilation systems with different filtration devices.

BACKGROUND: Nosocomial infections (NI) are above all due to health-care workers practices, but also the contamination of the environment could lead to their rise in health-care facilities. Introduction. In the last years, the incidence of NI has increased due to a substantial rise in the number of immuno-compromised patients. These patients are often gathered in hospital areas declared at "high risk" of infection such as Hematology and Bone Marrow Transplant ward. In this study, we evaluated microbial contamination of the air in two divisions with high risk patients, focusing on the validity of the air system with correlation to the presence or not of the HEPA absolute filters. METHODS: An environmental surveillance study has been carried out in two Divisions of Haematology, in two different Hospitals. Investigations have been performed by sampling air and by analyzing bacterial and fungal growth on microbiology plates after an incubation period. RESULTS: Unit A, without HEPA filters in the ventilation systems, showed a gradual increase in the bacterial load 20 and 60 days after cleaning of the ventilation system. Mycetes and Aspergilli were not present in basal conditions, at 20 or 60 days after decontamination. Unit B, equipped with HEPA filters placed at the inlet vents, showed extremely low values of the bacterial load either in basal conditions or upon inspection 60 days after cleaning. No mycetes were present. DISCUSSION: From the results obtained, it was evident that following the cleaning operation, the quality of the air is excellent in both types of equipment, since no mycetes were present and the bacterial load was < 20 CFU/mc in all the sites tested. However, although in subsequent controls mycetes were absent in both types of equipment, a great difference in the suspended bacterial load was found: Unit B was close to sterility whereas in Unit A a progressive increase was observed.

Cardiac myxoma cells exhibit embryonic endocardial stem cell features.

The origin of myxoma, the most frequent tumour of the heart, remains uncertain. Previous phenotypic characterizations have shown heterogeneous results and the most recent hypothesis suggests that cardiac myxoma originates from a primitive pluripotential cardiogenic cell. We investigated the expression of actin isoforms in 30 left atrial myxomas by immunohistochemistry and in eight consecutive tumours by RT-PCR. alpha-Smooth muscle actin (alpha-SMA) protein and/or transcripts were detected in all cases, whereas alpha-cardiac actin was observed in few cases and alpha-skeletal actin was always absent. Besides classical features, vessel-like structures were characterized by cells expressing CD34 and, less frequently, alpha-SMA. Confocal microscopy showed focal co-expression of CD34 and alpha-SMA in myxoma cells, suggesting a gradual loss of stem endothelial markers and the acquisition of myocytic antigens. In order to confirm this hypothesis, early cardiac differentiation markers were also investigated. RT-PCR documented the presence of transcripts for Sox9 (100%), Notch1 (87.5%), NFATc1 (37.5%), Smad6, metalloproteinases 1 and 2 alone or in variable combinations and the absence of ErbB3 and WT1. Myxoma cells maintained phenotypic heterogeneity in vitro, including the expression of alpha-SMA and the presence of stress fibres. These findings document in cardiac myxoma cells phenotypic markers of the embryonic endothelial-to-mesenchymal transformation that precedes terminal differentiation of endocardial cushions, supporting the hypothesis that cardiac myxoma cells may derive from adult developmental remnants.

Clinical phenotype and beta-cell autoimmunity in Italian patients with adult-onset diabetes.

OBJECTIVE: To characterize the phenotype of a large population of Italian patients with adult onset (> or =40 years) diabetes who were attending outpatient clinics and who were screened for glutamic acid decarboxylase 65 autoantibodies (GADA), protein tyrosine phosphatase IA-2 (IA-2A) and IA-2beta/phogrin (IA-2betaA). DESIGN AND METHODS: This was a cross-sectional study comprising a total of 881 patients, aged < or = 70 years, diagnosed with type 2 diabetes after the age of 40 years, and consecutively recruited in five clinics located in different geographic areas of Italy (Milan, Florence, Rome, Naples and Catania). Their mean disease duration was 8.1 (6.9; s.d.) years. GADA, IA-2A and IA-2betaA were measured with radiobinding assays with in vitro translated S-methionine-labelled glutamic acid decarboxylase 65 (GAD65) or IA-2 or IA-2beta. Anthropometric and clinical data were collected and compared amongst patients with or without autoantibodies. RESULTS: Sixty-three (7.1%) patients had one or more autoantibodies, 58 (6.6%) had GADA, 22 (2.5%) had IA-2A, six (0.7%) had IA-2betaA and 19 (2.15%) had two or more autoantibodies. IA-2A or IA-2betaA, in the absence of GADA, were found in only five patients. Autoantibody-positive patients were more often female (63.5 vs 36.5%; P < 0.009), had higher glycated haemoglobin (Hb A1c) (P < 0.001), lower body mass index (BMI; P < 0.0005) and waist/hip ratio (WHR; P < 0.01); female gender being the main contributor to BMI and WHR. We did not observe any differences in age at diagnosis or duration of disease with respect to the presence or absence of islet autoantibodies. The proportion of patients on insulin therapy was higher in patients with two or more antibodies, compared with those with one antibody only, and no antibodies (P for trend < 0.001), and among patients with GADA, in those with higher antibody titre (73.9% in those with > 10 units vs 42.0% in those with < or = 10 units; P < 0.007). CONCLUSIONS: Patients with adult onset diabetes characterized by autoimmunity to beta-cells showed a clinical phenotype with anthropometric features that differed from those classically observed in patients with type 2 diabetes. The number and titre of autoantibodies, which reflect the severity of autoimmunity and beta-cell impairment, amplified this difference. The usefulness of autoantibody screening in adult-onset diabetes is further emphasized by these findings.

[Cardiac tumors]. / I tumori cardiaci.

Primary cardiac tumors are rare and their subdivision often difficult because of their unknown origin. In the most recent classification, cardiac tumors are divided into benign (about 75% and malignant neoplasms in relationship to their tissue differentiation (rhabdomyoma, haemangioma, etc.) or uncertain aetiology (myxoma, papillary fibroelastoma). Primary malignant tumors are maimly represented by sarcomas. The most frequent tumor is cardiac myxoma, which by itself represents about 50% of all primary cardiac neoplasms. Although non-invasive technologies as trans-esophageal ecocardiography allow the detection and exact localization of cardiac mass, clinical diagnosis is often tardive. This is due, besides the intrinsic rarity, to two main factors: first, the tumor is often asymptomatic (incidental autopic finding) or; alternatively, it may show aspecif symptoms mimicking heart failure or other pathologies. In this article, clinicopathological features of main primary cardiac tumors are presented. Investigation of the histogenesis of some of these neoplasms is still a primary field of research.

Unusual cardiac tumour with perivascular myoid differentiation: a case report.

A previously healthy 70 year old woman was admitted for fatigue and dyspnoea on exertion and cough. A two dimensional echocardiography revealed a mass in the right atrium, which obstructed filling and infiltrated the cardiac chamber wall. Postsurgical histological examination revealed an unusual tumour with prevalent myoid glomangiopericytoma-type and haemangiopericytoma-like patterns. Mitosis and necrosis were absent. A computed tomography scan excluded the presence of metastasis to distant organs or, conversely, metastatic involvement of the heart. Therefore, a diagnosis of tumour with perivascular myoid differentiation was made. This new entity, recently described in soft tissues, can easily recur. Its recognition helps to differentiate from metastasis and other primitive cardiac tumours sharing some morphological features but a different clinical behaviour, with consequent improvement to the management of patient care.

Cellular retinol-binding protein-1 expression in endometrial stromal cells: physiopathological and diagnostic implications.

AIMS: Cellular retinol-binding protein-1 (CRBP-1) contributes to the maintenance of the differentiated state of the endometrium through retinol bioavailability regulation. The aim was to analyse CRBP-1 expression in endometrial stromal cells at eutopic and ectopic sites in different physiopathological conditions. METHODS AND RESULTS: Antibodies to CRBP-1, CD10 and alpha-smooth muscle actin were applied to proliferative (n = 10), secretory (n = 9) and atrophic (n = 7) endometrium, decidua (n = 4), adenomyosis (n = 5), endometriosis (n = 10), endometrial polyps (n = 9), simple endometrial hyperplasia (n = 6), well-differentiated endometrioid carcinoma (n = 6) and submucosal leiomyomas (n = 5). In some cases, Western blotting and reverse transcription-polymerase chain reaction were also applied. CRBP-1 was expressed by eutopic and ectopic endometrial stromal cells more markedly during the late secretory phase and in decidua of pregnancy. CRBP-1 expression was low in the stroma of atrophic endometrium and absent in myometrium, leiomyomas and cervical stroma. CD10 immunoreactivity was weak in atrophic endometrium and in decidua. CONCLUSIONS: CRBP-1 expression characterizes endometrial stromal cells at eutopic and ectopic sites and appears to be more specific than CD10. The level of CRBP-1 varies in intensity according to hormonal variations, reaching its maximum in predecidua and decidua. Thus, immunodetection of CRBP-1 may help to elucidate the physiopathological changes which occur in endometrial stroma and can also be applied as an adjuvant stromal marker.

IGFBPs modulate IGF-I- and high glucose-controlled growth of human retinal endothelial cells.

Insulin-like growth factor binding proteins (IGFBPs) are important local factors in the development of proliferative diabetic retinopathy. We investigated the effects of IGF-I and increased glucose concentrations on the release of IGFBPs and the growth of human retinal endothelial cells (HRECs). HRECs secrete IGFBPs-2 to -5. IGF-I stimulated thymidine incorporation and modified the pattern of IGFBPs, decreasing the inhibitory IGFBP-4 through down-regulation of its mRNA, and increasing IGFBP-5 which, per se, was able to modulate HREC growth, exerting post-transcriptional control. Studies using an antibody (alpha IR3) against the IGF-I receptor, and compounds with low affinity for IGFBPs, such as insulin and des(1-3)IGF-I, showed that an interaction between IGF-I and IGFBP-5 was necessary to detach this IGFBP from its binding sites. The dose of IGF-I that significantly decreased the IGFBP-4/IGFBP-5 ratio was the same that stimulated HREC growth. Chronic exposure to high concentrations of glucose was able to reduce HREC mitogenesis, interacting with the IGF system through a decrease in the stimulatory IGFBPs-2, -3 and -5, leaving the concentration of the inhibitory IGFBP-4 constant. These results extend our previous observations in endothelial cells and suggest that the IGFBP-4/IGFBP-5 ratio regulates IGF-I-induced growth of HRECs, whereas a general decrease in IGFBPs (except for IGFBP-4) was the anti-proliferative effect of chronic exposure to high glucose concentrations.

Apoptotic events in a human ovarian cancer cell line exposed to anthracyclines.

Cytotoxic drugs commonly used in cancer therapy promote tumor cell death by inducing apoptosis, but the cell death pathway(s) is likely dependent on the mechanism of drug action. In the present study, we investigated the mechanisms of cell death induced by doxorubicin (DXR) and the novel disaccharide anthracycline MEN 10755, in a human ovarian cancer cell line (A2780). Exposure to either anthracycline induced the up-regulation of several genes known to promote cell cycle arrest and DNA repair (WAF1/p21, GADD45) or apoptosis (bax, Fas). Although the expression of Fas was increased, an antagonistic anti-Fas antibody ZB4 did not inhibit anthracycline-induced apoptosis, suggesting that the stimulation of the Fas receptor did not play a critical role in the induction of apoptosis in this cell line. We also observed that neither MEN 10755 nor DXR were able to induce apoptosis in A2780 cells deprived of the nucleus but retaining an intact mitochondrial function (cytoplasts) and that apoptosis induced by either anthracycline was inhibited by cycloheximide, indicating that it is an active process requiring new protein synthesis. Both the caspases inhibitors, ZVAD-fmk and DEVD-cho, inhibited at similar extent apoptosis induced by either DXR or MEN 10755, suggesting an involvement of caspase-3 in this response. We conclude that, in a tumor cell line of epithelial origin, the apoptosis following exposure to anthracyclines is an active process requiring protein synthesis and drug interaction with nuclear structures. The pathway was Fas-independent but likely involved bax and caspase-3 as effectors of the cascade culminating in apoptosis.

Comparison of capillary electrophoresis with HPLC for diagnosis of factitious hypoglycemia.

BACKGROUND: The diagnosis of "factitious hypoglycemia" is essentially based on the disclosure of hypoglycemic agents in blood or urine. The aim of this study was to evaluate the performance of capillary electrophoresis (CE) as a quantitative method for determination of chlorpropamide, tolbutamide, glipizide, gliclazide, and glibenclamide in serum. METHODS: Serum samples (1 mL), with internal standard added, were purified by solid-phase extraction on OASIS(TM) HLB cartridges (Waters), dried under reduced pressure, and reconstituted with 30-60 microL of acetonitrile:H(2)O. Analysis was carried out by micellar electrokinetic capillary chromatography in 5 mmol/L borate, 5 mmol/L phosphate, 75 mmol/L sodium cholate, pH 8.5, containing 25 mL/L methanol. Separation was accomplished in a 20 cm x 50 microm (i.d.) silica capillary at 25 degrees C and a constant voltage of +10 kV. Pharmacokinetics of gliclazide (80-mg tablet) in a diabetic patient were assayed by both HPLC and CE. Two hypoglycemic patients positive by HPLC analysis for unreported gliclazide and tolbutamide overdose were also screened by CE. RESULTS: Separation of six drugs (including the internal standard) was accomplished in 5 min plus 5 min rinsing. The between-day CV of the ratio of the areas of the sulfonylurea drugs to internal standard was <1% (n = 10). Linearity (r(2) > or =0.998) and recovery (> or =80%) were good for all sulfonylurea drugs tested. Pharmacokinetic curves for gliclazide by CE and HPLC were superimposable. CE analysis confirmed the HPLC diagnosis of surreptitious abuse of gliclazide and tolbutamide. CONCLUSION: CE is a useful tool in the clinical chemistry and toxicology laboratory for drug monitoring and pharmacokinetic investigations.

Protective effect of the tachykinin NK2 receptor antagonist nepadutant in acute rectocolitis induced by diluted acetic acid in guinea-pigs.

We have evaluated the potential protective activity of nepadutant, a selective tachykinin NK2 receptor antagonist, in a model of acute rectocolitis induced by an enema with 7.5% acetic acid in guinea-pigs. The injury was quantified visually by using a macroscopic injury score, and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil infiltration, and plasma protein extravasation were evaluated. The injury caused by 7.5% acetic acid was mild, affecting the superficial layers and producing a strong edema of the submucosa. A single administration of nepadutant (0.3-10 mg/kg s.c., 1 h before acetic acid) markedly reduced the macroscopic damage and necrosis score and the increase in plasma protein extravasation induced by 7.5% acetic acid in the early phase of the injury. Single administration of nepadutant (3 mg/kg s.c.) reduced the macroscopic score and myeloperoxidase activity at the top (24 h) of inflammation. Repeated administration (3 mg/kg s.c. three times during 24 h) or co-administration of the tachykinin NK1 receptor antagonist MEN 11467 (3 mg/kg s.c.) did not enhance the antiulcer effect obtained with the single treatment with nepadutant. These data suggest the involvement of tachykinin NK2 receptors in the first phases of inflammation induced by acetic acid.

Value of a simple echocardiographic linear predictor of left ventricular mass in systemic hypertension.

The need for calculations limits the clinical use of left ventricular (LV) mass. Because LV mass is strictly dependent on wall thickness for every given value of LV external dimension, we tested the clinical value of the sum of LV external dimension plus ventricular septal thickness plus posterior wall thickness as predictors of standard LV mass. We studied 295 healthy normotensive subjects and 1,686 subjects with systemic hypertension, followed up for 1 to 9 years. In the normotensive group, the predictor of LV mass showed a very close association with standard LV mass according to an allometric model (LV mass [g] = 0.230 x LV mass predictor [cm]3.01), with 99.7% of LV mass variability explained by the model. Also, in the hypertensive group, the LV mass predictor showed a very close allometric relation to standard LV mass (R2 = 0.998). During follow-up there were 154 cardiovascular morbid events and 50 deaths from all causes. The risk of cardiovascular morbid events and that of death increased to a similar extent with LV mass normalized by body surface area, height or height2.7, as well as with the LV mass predictor. The risk estimates for cardiovascular morbidity and all-cause mortality provided by models including either LV mass predictor or LV mass uncorrected or corrected by height, body surface area, or height2.7 did not show any statistical differences between the different models. In conclusion, the sum of LV external dimension plus ventricular septum thickness plus posterior wall thickness, easily measurable from the M-mode echocardiographic tracing, very closely predicts standard LV mass in adult hypertensive subjects. The prognostic value of this measure does not differ from that of standard LV mass.

Human glomerular endothelial cells IGFBPs are regulated by IGF-I and TGF-beta1.

The release of insulin-like growth factor binding proteins (IGFBPs) and their regulation in human glomerular endothelial cells (GENC) was characterised. GENC produce IGFBP-4, IGFBP-2 and IGFBP-3 and express mRNA for IGFBP-2 to IGFBP-5. Due to the fact that IGF-I and TGF-beta1 modulate glomerular hypertrophy, their action on IGFBP release and GENC growth was studied. IGF-I increased IGFBP-3, IGFBP-2 and decreased IGFBP-4, while TGF-beta1 decreased IGFBP-3 and apparently increased IGFBP-4. All of the IGFBPs, except the TGF-beta1-regulated IGFBP-4, were modulated at mRNA level. IGF-I stimulated GENC proliferation, while TGF-beta1 inhibited their growth. It was demonstrated that an IGFBP-3 antibody reduced GENC proliferation. However, rhIGFBP-3 alone had no effect on GENC, but after 48 h pre-incubation the IGF-I stimulated GENC growth was increased, suggesting that IGFBP-3 could modulate the IGF-I induced GENC proliferation. It was concluded that the stimulatory IGFBP-3 and the inhibitory IGFBP-4 could regulate GENC growth, although the IGFBP-3 seems to have a predominant effect in this control.

Circulating insulin and insulin growth factor-1 are independent determinants of left ventricular mass and geometry in essential hypertension.

BACKGROUND: It is unclear whether insulin and insulin-like growth factor-1 (IGF-1) are independent determinants of left ventricular (LV) mass in essential hypertension. METHODS AND RESULTS: We studied 101 never-treated nondiabetic subjects with essential hypertension. All had 24-hour noninvasive ambulatory blood pressure (ABP) monitoring and a 75-g oral glucose tolerance test. We determined fasting glucose, insulin, and IGF-1 and postload glucose and insulin 2 hours after glucose. Insulin resistance was estimated by the homeostasis model assessment (HOMA(IR)) formula. LV mass showed an association with body mass index (BMI) (r=0.47; P<0.01), postload insulin (r=0.54; P<0.01), HOMA(IR) (r=0.39; P<0.01), and IGF-1 (r=0. 43; P<0.01) and a weaker association with average 24-hour systolic and diastolic ABPs (r=0.29 and r=0.26; P<0.05) and basal insulin (r=0.31; P<0.05). Relative wall thickness was positively related to IGF-1 (r=0.39; P<0.01) but not to fasting or 2-hour postload insulin, HOMA(IR), and glucose. In a multiple regression analysis, the final LV mass model (R(2)=0.64) included IGF-1, postload insulin, average 24-hour systolic ABP, sex, and BMI. IGF-1 and postload insulin accounted for >40% of variability of LV mass. The final model (R(2)=0.36) for relative wall thickness included IGF-1 (16% total explained variability), average 24-hour systolic ABP, sex, BMI, and age but not insulin and HOMA(IR). CONCLUSIONS: These data indicate that insulin and IGF-1 are powerful independent determinants of LV mass and geometry in untreated subjects with essential hypertension and normal glucose tolerance.

Effect of MEN 11467, a new tachykinin NK1 receptor antagonist, in acute rectocolitis induced by acetic acid in guinea-pigs.

The aim of this study was to evaluate the effect of MEN 11467 (1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N{N-(p-tolylacetyl)-N-(meth yl)-D-3(2-Naphthyl)alanyl}diaminocyclohexane), a new potent tachykinin NK1 receptor antagonist, in an experimental model of acute rectocolitis induced by an enema with 7.5% acetic acid in guinea-pigs. This effect was compared to that of mesalazine (5-amino-2-hydroxybenzoic acid). The injury was quantified visually by using a macroscopic injury score and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil infiltration, and plasma protein extravasation were evaluated. The injury caused by 7.5% acetic acid was mild, affecting the superficial layers and producing a strong edema of the submucosa. A single administration of MEN 11467 (0.3-10 mg/kg s.c., I h before acetic acid) reduced the macroscopic damage and necrosis score and the increase in plasma protein extravasation induced by 7.5% acetic acid in the early acute phase of the injury (death at 2.5 h). Mesalazine (100 mg/kg p.o., 1 h before) reduced the macroscopic score but not the plasma protein extravasation. Repeated administration of MEN 11467 (1-3 mg/kg s.c., -1, +6 and +23 h after 7.5% acetic acid) reduced the macroscopic score and myeloperoxidase activity but not the plasma protein extravasation induced in the late phase of acute injury (death at 24 h). At this time mesalazine markedly reduced the macroscopic score, myeloperoxidase activity and plasma protein extravasation induced by 7.5% acetic acid. These results suggest a greater involvement of tachykinin NK1 receptors in the early phase than in the late phase of colonic inflammation in response to chemical injury.

Left ventricular hypertrophy in daily dialysis.

Cardiac hypertrophy, a well-known independent risk factor for cardiovascular death, is a very frequent complication in ESRD patients. Its frequency tends to be even higher in dialyzed patients due to the fact that the current dialytic treatments are unable to keep under a satisfactory control the various responsible factors and particularly the blood pressure, which is largely the most important. Daily hemodialysis, a more frequent schedule consisting of 6-7 sessions/week lasting 2 or more hours, has definitely proved its superiority in controlling blood pressure and in improving anemia, and thus has the requisites for positively influencing cardiac hypertrophy. In fact, a series of studies, both retrospective and prospective, performed during the last years by our group, have confirmed that this new, more frequent and thus more physiological schedule, is able not only to stop the progression of the cardiac hypertrophy in uremic patients but also to revert toward the normality, in a relatively short time. This appears to be essentially a consequence of the excellent blood pressure control, which in turn derives from the easier control of the true dry weight, achievable with this type of dialytic treatment.

Calcium antagonists and cardiovascular risk in patients with hypertension and Type 2 diabetes mellitus: evidence from the PIUMA Study. Progetto Ipertensione Umbria Monitoraggio Ambulatoriale.

We conducted a retrospective analysis of all subjects with essential hypertension and Type 2 diabetes mellitus enrolled in the PIUMA (Progetto Ipertensione Umbria Monitoraggio Ambulatoriale) registry, in order to evaluate whether the use of calcium antagonists is associated with an increase in cardiovascular risk in these subjects. One hundred and sixty-four consecutive subjects with no previous cardiovascular morbid events and coexistence of essential hypertension and Type 2 diabetes mellitus were studied before therapy and followed for up to 12 years (mean 5). There were periodical contacts with family doctors and patients in order to ascertain the occurrence of major cardiovascular events. The use of calcium antagonists that preceded the event was considered for classification. None of the patients was lost to follow-up. At entry, the patients who were subsequently given calcium antagonists (n=50) had a higher clinical (174/98 vs 161/92 mmHg, both p<0.01) and 24-hr ambulatory blood pressure (150/90 vs 141/84 mmHg, both p<0.01) than those who were not. During follow-up there were 53 major cardiovascular morbid events (6.46 per 100 person-years). The rate of total cardiovascular events [5.6 vs 6.8 events per 100 person-years, relative risk 0.88 (95% CI: 0.47-1.61)] and that of cardiac events [4.0 vs 3.3 events per 100 person-years, relative risk 1.33 (95% CI: 0.62-2.89)] did not differ between users of calcium antagonists and non-users. The use of angiotensin converting enzyme inhibitors (n=66) was unrelated to the risk of cardiovascular events (relative risk 1.24, 95% CI: 0.71-2.16). In a Cox multivariate analysis, only age (p=0.002) and 24-hr pulse pressure (p=0.04) were independent predictors of cardiovascular events. In conclusion, this cohort study does not support the hypothesis that use of calcium antagonists is associated with an excess risk of adverse cardiovascular events in uncomplicated subjects with essential hypertension and Type 2 diabetes mellitus.