In the present animal model study, the pacemaker Sophós 100 proved fully reliable in a 1 month follow-up period. TVI sensor operation did not interfere with conventional pacemaker functions, opening the way to its implantation in human beings.

In the present animal model study, TVI sensor operation did not interfere with conventional pacemaker functions of implanted Sophós pacemakers. These results look promising since this sensor could play an important part in haemodynamic monitoring: for physiological rate adaptation, for beat-tobeat capture confirmation, in patients with neurocardiogenic syncope, for the follow-up of patients with heart failure, to indicate the best interventricular delay in CRT, and to identify arrhythmias and their haemodynamic impact in implantable cardioverter-defibrillators [10-12].

Diabetic microangiopathy produces widespread small vessel impairment which particularly affects renal glomeruli functions. Microalbuminuria is the earliest marker of microangiopathic kidney disease and has also recently been recognised as a marker of macroangiopathic cardiovascular involvement. To determine correlations between daily microalbuminuria, local microangiopathic kidney damage, systemic macroangiopathic involvement and functional brain microcirculation, 70 Type 2 diabetic subjects who were diagnosed more than 5 years ago underwent carotid (to determine index of macro- and microangiopathy) and interlobar kidney artery color Doppler (to determine microangiopathic involvement), transcranial Doppler (to determine alterations in brain vasomotor reserve), and evaluation of daily albumin excretion rate. All the indices of microcirculatory involvement in the kidney, brain and small vessels downstream-from the carotid arteries were closely related (for all p<0.001) but never correlated with the macroangiopathy index. Daily microalbuminuria correlated with all the micro- (p<0.0001) and macroangiopathic (p<0.005) Doppler indices. These findings confirm that microangiopathy is the main cause of the diabetic increase in the albumin excretion rate and support the view that microalbuminuria can be considered a powerful biomarker of widespread macroangiopathy. Our results suggest microalbuminuria may also identify cerebrovascular diabetic involvement, as it predicts both macroangiopathic carotid alteration and microvascular brain impairment.

AIMS:To determine if apolipoprotein E polymorphism is associated with cardiovascular or all-cause mortality in Italian Type 2 diabetic patients.METHODS:A prospective study of mortality in Type 2 diabetic patients (n = 433) as a function of apolipoprotein E phenotype, which was assessed at entry into the study. During follow up (10 years), 110 (25.4%) patients died of which 66 (15.2%) were the result of cardiovascular causes. Cause of death was established from death certificates and clinical records. The clinical status of the survivors was determined at the end of the study.RESULTS:Apolipoprotein E polymorphisms were not associated with excess cardiovascular or all-cause mortality in the Italian Type 2 diabetic patients either in univariate or multivariate analyses. Age, duration of diabetes and glycated haemoglobin levels at entry were the primary determinants of premature mortality in the diabetic population.CONCLUSIONS:Apolipoprotein E polymorphisms are not markers for premature mortality in Italian Type 2 diabetic patients. The impact of apolipoprotein E mutations may be attenuated by environmental factors, notably a healthier diet, in Italian patients.

We investigated the in vitro effects of therapeutical concentrations of S 21403 (a succinic acid derivative also known as KAD 1229 and mitiglinide) on insulin and glucagon secretion during a metabolic stimulus (glucose rising from 5 to 8.33 mM) or at a stable 2.22 mM glucose using the isolated perfused rat pancreas model, and we compared them with the patterns of repaglinide and glibenclamide. Control perfusions were also performed. During 8.33 mM glucose, insulin release peaked to 339.12+/-22.87 microU/ml in controls. S 21403 enhanced insulin release (first peak 413.02+/-14.90 microU/ml; P<0.03 vs. controls, P=ns vs. repaglinide, P<0.005 vs. glibenclamide). Repaglinide increased glucose-induced first peak secretion to 409.33+/-20.05 microU/ml within the eighth minute (P<0.05 vs. controls, P<0.01 vs. glibenclamide). Glibenclamide did not affect the first phase of glucose-induced insulin release (peak of 338.41+/-29.79 microU/ml) but potentiated and delayed the second phase. No drug affected glucagon release. In conclusion, S 21403 induces a faster, more physiological pattern of insulin release than the other drugs we tested.

Summary Aims To assess the effects and safety of increasing sulphonylurea dosages or adding metformin in poorly controlled elderly Type 2 diabetic patients.Methods A 18‐month multicentre clinical study was performed on sulphonylurea‐treated diabetic patients over 70 years of age with well‐preserved renal function, steady fasting blood glucose ≥ 200 mg/dl and HbA1c≥ 9%. Patients were randomly assigned to sulphonylurea increased up to its maximum dosage (1st group) or to addition of metformin (2nd group). Glycaemic control, lipid pattern, haemostatic status and safety were monitored during run‐in, at baseline and at scheduled intervals for 18 months. Results[85 patients in the 1st group and 89 patients in the 2nd with complete data. Results Similar improvements in glycaemic levels were observed with both treatments within the first month and a similar decrease in HbA1c within the third month. No further changes occurred in glycaemic control. In the 1st group, fasting glucose (mmol/l, mean ± se) decreased from 14.21 ± 0.49 to 9.88 ± 0.21, average day‐long glucose from 14.87 ± 0.27 to 10.69 ± 0.19 and HbA1c (%) from 10.32 ± 0.13 to 8.66 ± 0.13. In the 2nd treatment group fasting glucose decreased from 14.59 ± 0.61 to 9.05 ± 37.28, average day‐long glucose from 15.09 ± 0.29 to 10.32 ± 0.21 and HbA1c from 10.33 ± 0.13 to 8.77 ± 0.12 (for all P < 0.0005). In this 2nd group, a decrease in LDL‐cholesterol (P < 0.05) and an increase in HDL‐cholesterol levels (P < 0.02) were also observed. In the 1st group, anthrombin III activity increased significantly (P < 0.01). In the 2nd group, significant reductions in markers of platelet function (FP4 and βTG, P < 0.01), thrombin generation (FPA, F1 + 2 and D‐D, P < 0.01), and fibrinolysis inhibition (PAI‐1 activity, PAI‐1 antigen, P < 0.001) were observed. Increases in some fibrinolytic activation markers (t‐PA activity, and AT‐III activity, P < 0.01) occurred. Fasting lactate concentrations were unchanged in the metformin‐treated group. No serious adverse effects were observed in either group. Conclusions These results suggest that either high sulphonylurea dosages or a therapy combining lower sulphonylurea dosages with metformin are effective and safe in an aged but healthy population. Metformin provides additional benefits counteracting several cardiovascular risk factors but must be administered with caution, bearing in mind the general contra‐indications for the drug but not age alone.

Metformin is an oral antihyperglycemic agent used in the therapy of noninsulin-dependent diabetic patients. This biguanide can induce dangerous complications such as lactic acidosis when its plasma concentration is too high. For this reason, the determination of plasma metformin should always be done during treatment. We developed a new HPLC method, for the routine determination of plasma metformin, with good reliability, rapid execution, and low costs. Sample preparation involved precipitation of the plasma proteins containing the internal standard buformin with a mixture of methanol, zinc sulfate, and ethylene glycol; the diluted supernatant was injected into a cation-exchange column. The mobile phase was potassium dihydrogenphosphate buffer-containing acetonitrile. The eluent was monitored at 236 nm. The calibration curve is linear within the range of 20-4000 ng/mL; the within-day coefficients of variation were less than 2.2% for metformin and 1.5% for buformin; the day-to-day coefficients of variation were less than 2.5% for metformin and 1.9% for buformin. The mean recoveries obtained from supplemented samples were included between 99.4 and 104.2% for metformin. Many characteristics make this method useful and easily accessible to all clinical laboratories equipped with HPLC instrumentation.

We assessed the effects of two months gliclazide administration in normal rats on pancreatic alpha- and beta-cell response to a glucose stimulus (11.1 mM) using the standard model of the isolated perfused pancreas. We also determined fasting plasma glucose and pancreatic hormone levels as well as pancreatic and gut hormone tissue concentrations. Twenty-four rats received therapeutic dosages (2.5 mg/kg/daily) gliclazide and 24 received a high, largely supra-therapeutic dosage (15 mg/kg/daily), Twelve rats in each group received one week's post-treatment with placebo, A control group of 12 rats received only placebo throughout the study, In the perfused pancreata of rats on 2.5 mg/kg/daily gliclazide insulin secretory response to a glycaemic stimulus was not significantly reduced. In animals on 15 mg/kg/daily gliclazide the insulin secretory response to the glycaemic stimulus was significantly reduced in both the first and second phases of insulin release (p<0.01 and p<0.002, respectively), Post-treatment with placebo completely reversed gliclazide's inhibition of the beta-cell function, No changes were observed in pancreatic release of glucagon, Although basal glucose and fasting pancreatic hormone levels were not modified by gliclazide at either dosage, pancreatic insulin and glucagon tissue contents were reduced in the rats treated with the 2.5 mg/kg/daily (p<0.05 for both); the reductions were more marked in the group treated with 15 mg/kg/daily (p<0.005 and p<0.01, respectively). The drop in somatostatin never reached statistical significance, All reductions in pancreatic hormone content were fully reversed by placebo treatment, The 2.5 mg/kg/daily gliclazide dosage reduced gut hormone content of glucagon (p<0.025), somatostatin (p<0.025) and vasoactive intestinal peptide (VIP) (p<0.05) and reductions were more marked after administration at high doses. No effect was observed on gut content of gastric inhibitory peptide (GIP) after either dosage of gliclazide, Placebo administration completely reversed all effects of gliclazide, Diab. Nutr. Metab. 11: 104-113, 1998. (C) 1998, Editrice Kurtis.

This study assessed the efficacy of 200 mg of aminohexane bisphosphonate (neridronate) administered by intravenous infusion in a single dose or in two separate doses on consecutive days in 32 patients (16 males and 16 females, average age 66 years) affected by active Paget’s disease of bone. Fifteen patients had never been treated with any antiresorptive agent and 17 had had unsatisfactory results from a prior clodronate treatment. All of the latter patients had failed to enter a remission stage (i.e., normalization of bone turnover was not reported at any time during treatment) and had had a full relapse within 6 months after clodronate infusion. In the present study bone-specific alkaline phosphatase (bAp), deoxypyridinoline (dPyr), and N- and C-terminal polypeptide of collagen type 1 (Ntx, Ctx) were determined before neridronate administration and at 1, 3, 6, and 12 months thereafter. Basal values of bAp were 51.7 ± 2.3 μg/L, range 31.7–92.5 (normal range 6.2–23.6). No statistical differences in markers of bone turnover were evident in the basal state between new pagetic patients (bAp = 55.1 ± 4.1) and those suffering a relapse after clodronate (bAp = 48.8 ± 2.6). Neridronate induced an average percent change from baseline in excess bAp of 68.0 ± 4.3 and in excess dPyr, Ntx, and Ctx of 68.1 ± 11, 60.6 ± 8.5, and 86.7 ± 7.8, respectively. Markers of bone resorption declined more slowly in patients treated previously with clodronate, although the average change in percent decrement from baseline in excess bAp as well as in excess of bone resorption markers was not different from that registered in untreated pagetic patients. Response to treatment, defined as a percent decrement from baseline in excess bAp of 50% or more at any time during the 12-month follow-up, was observed in 27 patients (84.4%). Remission (a drop in bAp to within normal range) was achieved in 21 patients (65.6%) and was maintained in 12 at 12-month follow-up, with no significant differences between either 1- or 2-day infusions, or between new pagetic patients and those relapsing after clodronate. In 15 of 21 patients requiring analgesics to alleviate bone pain, pain was reduced or completely alleviated in 8. A slight, short-lived acute phase reaction (fever and/or arthromyalgia) occurred in 6 patients. To summarize, 200 mg of intravenous neridronate, in one or two doses, significantly reduced the biochemical indices of disease activity in the majority of patients, showing a normalization of bAp in more than 60%. We conclude that neridronate can be used safely in the treatment of patients with Paget’s disease of bone either as a first bisphosphonate treatment or as retreatment for patients relapsing after clodronate.

Purpose. To assess whether a screening method based on transcranial Doppler (TCD) examination could detect signs of brain hemodynamic impairment in non-insulin-dependent diabetic patients with retinal microangiopathy of varying severity, asymptomatic for cerebrovascular diseases. Methods. We studied 86 patients stratified according to the presence of proliferative diabetic retinopathy (PDR: 29 cases), background retinopathy (BDR: 32 cases) and no diabetic retinopathy (NDR: 25 patients). TCD was performed to record mean flow velocity and pulsatility index values in the middle cerebral (MCA), anterior cerebral (ACA) and ophthalmic arteries (OA), at rest. It was also employed to evaluate the cerebral vasodilatory response to a breath-holding test: the maximum percentage MCA flow velocity increase during the test was taken as an index of cerebrovascular reactivity. Fifty healthy subjects were studied to establish control values. Analysis of variance was used to test inter-group differences. The regression test was applied to define the relationship between TCD parameters and age and disease duration. Results. No significant differences were found between controls and the whole group of patients with respect to TCD parameters. However, subgroup analysis showed PDR patient had a significantly higher pulsatility index and lower cerebrovascular reactivity than BDR and NDR patients. This difference was not explained by the effect of age or disease duration, being greatest in patients under sixty. Conclusions. These findings seem to confirm the hypothesis of a silent cerebral microangiopathy affecting diabetic patients, with concomitant signs of microangiopathic damage in other districts.

Abnormalities in free fatty acid (FFA) metabolism are an intrinsic feature of type II diabetes mellitus and may even play a role in the development of glycaemic imbalance. This study investigated whether the anti-diabetic drug metformin can reduce FFA levels in clinical practice and whether this correlates with its anti-diabetic effect. For 6 months metformin was added to sulfonylurea therapy in 68 type II diabetic outpatients with poor glycaemic control, being administered before meals and at bed-time. Basal and daily area-under-the-curve (AUC) glucose levels dropped (both P < 0.0005) like basal and daily AUC FFA levels (P < 0.004 and P < 0.001 respectively) reductions were all correlated (P < 0.001 and P < 0.003 respectively). Reductions in fasting and daily AUC glucose correlated more closely with body fat distribution, expressed by waist-hip ratio (WHR) (P < 0.006 and P < 0.004 respectively), than with the body mass index (BMI) (P < 0.02 and P < 0.04 respectively). Similarly fasting and daily AUC FFA correlated with WHR (P < 0.007 and P < 0.01 respectively) but not with BMI (both P = ns). Subdividing male and female diabetic patients into groups with low and high WHRs, fasting and daily AUC glucose were reduced in men (P < 0.01 and P < 0.02) and in women (P < 0.02 and P < 0.04 respectively) with low WHRs less than in men and in women with higher WHRs (for each gender P < 0.0001 and P < 0.0002, respectively). Decreases in fasting and daily AUC FFA, which did not reach significance in either men or women with low WHRs, were statistically significant in men (P < 0.03 and P < 0.01 respectively) and in women (P < 0.02 and P < 0.005 respectively) with high WHRs. These findings suggest that an improvement in FFA plasma levels might contribute to metformin's anti-diabetic activity which appears to be more marked in patients with high WHRs. Moreover adding a bed-time dosage to the standard administration at meal times seems to be an effective therapeutical strategy.

Ninety-four diabetic patients, asymptomatic for cerebrovascular disease, stratified according to the presence of proliferative retinopathy (PDR), background retinopathy (BDR) and no diabetic retinopathy (NDR) underwent transcranial Doppler evaluation. Impairment in neither blood flow velocity and pulsatility index recorded at the ophthalmic and intracranial arteries, nor in the vasodilatory response to a breath-holding test was found in patients, when compared to age-matched controls. The subgroup analysis showed that PDR patients had significantly higher pulsatility index and lower cerebrovascular reactivity values than BDR and NDR patients. Such a difference was not just due to age or disease duration, being greatest in patients under the sixties. In asymptomatic diabetic patients, PDR may be a predictor of early cerebral vessel involvement and should lead to investigate brain hemodynamics by screening procedures.

The effects of glimepiride, the newest sulphonylureic compound, on pancreatic insulin and glucagon secretion were studied using the classical, isolated, perfused rat pancreas model. The influence of four different environmental glucose conditions (during a glycaemic stimulus with glucose increasing from 5 to 8.33 mM and at stable 0, 5 and 2.22 mM glucose levels) on the effects of glimepiride was also assessed. At a pharmacological concentration glimepiride strongly stimulated beta-cell activity, producing a characteristic biphasic insulin release with a sharp first-phase secretory peak, followed by a prolonged and sustained second phase. Environmental glucose concentrations markedly influenced the extent, but not the pattern of glimepiride-induced insulin secretion, as hormone release dropped significantly when the glucose level was reduced. Glimepiride failed to influence alpha-cell activity at any of the environmental glycaemic levels.

The first part of the paper deals with the relationship between two inhibiting factors of the complex enzyme cascade regulating fibrinolysis, namely plasminogen activator inhibitor type-1 (PAI-1) and lipoprotein(a) (Lp(a)). Blood concentrations of Lp(a), PAI-1 antigen (PAI-1 AG) and activity (PAI-1 AT), and the main parameters of lipo- and glyco-metabolic balance were studied in 80 type II diabetic patients. Roughly hyperbolic patterns have been found between PAI-1 and Lp(a). Negative statistically significant linear correlation can be elicited when Log PAI-1 AG and Log PAI-1 AT values are plotted versus Lp(a) values, the first one being particularly tight. These findings suggest a nearly on/off control of the two parameters, limiting the risk of hypofibrinolysis. The second part of the paper was aimed at verifying this hypothesis. A group of 30 diabetic patients were treated for 3 months with metformin, an antidiabetic biguanide compound which has been reported to reduce PAI-1 levels both in diabetic and in non-diabetic patients. Metformin significantly reduced PAI-1 AG and PAI-1 AT but did not influence plasma Lp(a) levels. A clear linear correlation between the basal Lp(a) values and the changes in PAI-1 AG levels was found. An even tighter correlation was elicited between the decrease in PAI-1, and PAI-1 pretreatment values.

Malignant external otitis (MEO) is an infection of the external auditory meatus, that affects elderly diabetic patients. As this disease results in a high percentage of deaths, especially if the diagnosis is delayed, we thought that it would be useful to cite a recent case study that was resolved in a positive way, in spite of the extent of the disease.