Integrated cardiovascular/respiratory control in type 1 diabetes evidences functional imbalance: Possible role of hypoxia.

BACKGROUND: Cardiovascular (baroreflex) and respiratory (chemoreflex) control mechanisms were studied separately in diabetes, but their reciprocal interaction (well known for diseases like heart failure) had never been comprehensively assessed. We hypothesized that prevalent autonomic neuropathy would depress both reflexes, whereas prevalent autonomic imbalance through sympathetic activation would depress the baroreflex but enhance the chemoreflexes. METHODS: In 46 type-1 diabetic subjects (7.0±0.9year duration) and 103 age-matched controls we measured the baroreflex (average of 7 methods), and the chemoreflexes, (hypercapnic: ventilation/carbon dioxide slope during hyperoxic progressive hypercapnia; hypoxic: ventilation/oxygen saturation slope during normocapnic progressive hypoxia). Autonomic dysfunction was evaluated by cardiovascular reflex tests. RESULTS: Resting oxygen saturation and baroreflex sensitivity were reduced in the diabetic group, whereas the hypercapnic chemoreflex was significantly increased in the entire diabetic group. Despite lower oxygen saturation the hypoxic chemoreflex showed a trend toward a depression in the diabetic group. CONCLUSION: Cardio-respiratory control imbalance is a common finding in early type 1 diabetes. A reduced sensitivity to hypoxia seems a primary factor leading to reflex sympathetic activation (enhanced hypercapnic chemoreflex and baroreflex depression), hence suggesting a functional origin of cardio-respiratory control imbalance in initial diabetes.

Mining health care administrative data with temporal association rules on hybrid events.

OBJECTIVE: The analysis of administrative health care data can be helpful to conveniently assess health care activities. In this context temporal data mining techniques can be suitably exploited to get a deeper insight into the processes underlying health care delivery. In this paper we present an algorithm for the extraction of temporal association rules (TARs) on sequences of hybrid events and its application on health care administrative databases. METHODS: We propose a method that extends TAR mining by managing hybrid events, namely events characterized by a heterogeneous temporal nature. Hybrid events include both point-like events (e.g. ambulatory visits) and interval-like events (e.g. drug consumption). The definition of user-defined rule templates can be optionally used to constrain the search only to the extraction of a subset of interesting rules. A TAR post-pruning strategy, based on a case-control approach, is also presented. RESULTS: We analyzed the administrative database of diabetic patients in charge to the regional health care agency (ASL) of Pavia. TAR mining allowed to find patterns specifically related to the diabetic population in comparison with a control group, as well as to check the compliance of the actual clinical careflow with the ASL recommendations. CONCLUSION: The experimental results highlighted the main potentials of the algorithm, such as the opportunity to detect interesting temporal relationships between diagnostic or therapeutic patterns, or to check the adherence of past temporal behaviors to specific expected paths (e.g. guidelines) or to discover new knowledge that could be implicitly hidden in the data.

Bayesian mapping of multiple sclerosis prevalence in the province of Pavia, northern Italy.

The geographical analysis of a disease risk is particularly difficult when the disease is non-frequent and the area units are small. The practical use of the Bayesian modelling, instead of the classical frequentist one, is applied to study the geographical variation of multiple sclerosis (MS) across the province of Pavia, Northern Italy. 464 MS-affected individuals resident in the province of Pavia were identified on December 31st 2000. The overall prevalence was 94 per 100,000 inhabitants. This estimate indicates an increasing MS prevalence in the province, in accordance with the vast majority of the Italian areas where prevalence studies have been repeated. We mapped the geographical variation of MS prevalence across the 190 communes of the province both with a classical approach and a Bayesian approach. The frequentist approach produced an extremely dishomogeneous map, while the Bayesian map was much smoother and more interpretable. Our study underlines the usefulness of Bayesian methods to obtain reliable maps of disease prevalence and to identify possible clusters of disease where to carry out further epidemiological investigations.

The M2DM Project--the experience of two Italian clinical sites with clinical evaluation of a multi-access service for the management of diabetes mellitus patients.

OBJECTIVES: This paper presents a multi-access service for the management of diabetes mellitus patients and the results of its assessment in two Italian clinical sites. METHODS: The service was evaluated for one year in order to prove the advantages of these kind of systems from different points of view. In this paper the clinical, usability and technical outcomes are presented. RESULTS: The evaluation results show that, thanks to the high flexibility of the implemented service, the telemedicine management of diabetes patients is feasible, well accepted by patients and clinically effective. However, in Italy the problem of quantifying the reimbursement rate of telematic services and the impact they have on the organization are factors that may hamper their introduction in routine clinical practice. CONCLUSIONS: The evaluation study showed that the telemedicine intervention has been satisfactory both for physicians because it allows to constantly monitor the patients' blood glucose level and for patients because it strengthens their motivation to self-monitor the metabolic situation.

Lipoprotein(a), apolipoprotein(a) polymorphism and coronary atherosclerosis severity in type 2 diabetic patients.

BACKGROUND: Few and conflicting data are available in the literature on the association between Lp(a) levels and the severity of coronary artery disease (CAD) in diabetic patients. In addition, no studies took into account the role of apo(a) polymorphism. The purpose of the present study was to analyse the association of the degree of coronary atherosclerosis with Lp(a) levels and apo(a) polymorphism in a large group of type 2 diabetic patients. METHODS: The study population consisted of 227 consecutive type 2 diabetic patients undergoing a routine coronary angiography to evaluate chest pain or suspected CAD. The patients were subdivided into four subgroups according to the number of coronary arteries diseased: normal arteries (n=26), mono-vessel disease (n=67), bi-vessel disease (n=54) and multi-vessel disease (n=80). RESULTS: Lp(a) levels (normal arteries: 14.6+/-19.6 mg/dl; mono-vessel disease: 19.0+/-16.4 mg/dl; bi-vessel disease: 19.3+/-15.1 mg/dl; multi-vessel disease: 26.5+/-16.8 mg/dl; p<0.001) and the percentages of patients with at least one isoform of low molecular weight (normal arteries: 23.1%; mono-vessel disease: 38.8%; bi-vessel disease: 75.9%; multi-vessel disease: 81.2%; p<0.001) were significantly correlated with increasing number of coronary vessels diseased. Multiple logistic regression analysis showed that both Lp(a) levels (OR: 1.31; 95% CI: 1.02-4.11) and apo(a) polymorphism (OR: 3.43; 95% CI: 1.67-7.05) were independent predictors of CAD severity. CONCLUSIONS: Our data suggest that Lp(a) levels and apo(a) polymorphism may be reliable predictors of CAD severity in type 2 diabetic patients.

Extensive use of peripheral angioplasty, particularly infrapopliteal, in the treatment of ischaemic diabetic foot ulcers: clinical results of a multicentric study of 221 consecutive diabetic subjects.

OBJECTIVE: To evaluate the feasibility, technical effectiveness and limb salvage potential of percutaneous transluminal angioplasty (PTA), particularly infrapopliteal, in diabetic subjects with ischaemic foot ulcer. DESIGN: Intervention study with PTA in consecutive series. SETTING: Six Diabetology Foot Centres and one Cardiovascular Catheterization Laboratory in Italy. SUBJECTS: Two hundred and twenty-one consecutive diabetic subjects hospitalized for ischaemic foot ulcer. INTERVENTION: Peripheral arterial occlusive disease (PAOD) was investigated by means of foot pulses assessment, ankle-brachial-index (ABI), transcutaneous oxygen tension (TcPO2) and duplex scanning. If non-invasive parameters suggested PAOD, angiography was performed and a PTA was carried out during the same session. MAIN OUTCOME MEASURES: PTA feasibility, improvement of ABI and TcPO2, limb salvage rate, clinical recurrence. RESULTS: On angiography, two patients had stenoses which were <50% of the vessel diameter. PTA was performed in 191 (85.3%) of the 219 subjects with stenoses >50%, even when longer than 10 cm and/or multiple/calcified. In 11 patients (5.8%) PTA was performed in the proximal axis exclusively, in 81 (42.4%) patients in the infrapopliteal axis exclusively and in 99 (51.8%) in both the femoropopliteal and infrapopliteal axis. Both ABI and TcPO2 improved significantly after PTA (P < 0.0001). Clinical recurrence occurred in 14 subjects: 10 of whom underwent a second successful PTA. Of the 191 patients who underwent PTA, 10 (5.2%) underwent an above-the-ankle amputation. CONCLUSIONS: PTA, including infrapopliteal, is feasible in most diabetic subjects with ischaemic foot ulcer and is effective for foot revascularization. Clinical recurrence was infrequent and the procedure could successfully be repeated in most cases. In subjects treated successfully with PTA the above-the-ankle amputation rate was low. PTA should be considered as the revascularization treatment of first choice in all diabetic subjects with foot ulcer and PAOD.

Association of lipoprotein(a) levels and apolipoprotein(a) phenotypes with coronary artery disease in Type 2 diabetic patients and in non-diabetic subjects.

AIMS: We investigated whether in Type 2 diabetic patients lipoprotein(a) (Lp(a)) levels and apolipoprotein(a) (apo(a)) polymorphism are associated with angiographically documented coronary artery disease (CAD). We also examined whether there are differences in the distributions of Lp(a) levels and apo(a) phenotypes between CAD patients with and without diabetes. METHODS: A hundred and seven diabetic patients with CAD, 274 diabetic patients without CAD, 201 non-diabetic patients with CAD, and 358 controls were enrolled. RESULTS: Diabetic patients with CAD showed Lp(a) levels (21.2 +/- 17.7 vs. 15.1 +/- 17.8 mg/dl; P = 0.0018) and a percentage of subjects with at least one apo(a) isoform of low molecular weight (MW) (67.2% vs. 27.7%; P = 0.0000) significantly greater than diabetic patients without CAD. Multivariate analysis showed that in diabetic patients Lp(a) levels and apo(a) phenotypes were significantly associated with CAD; odds ratios (ORs) of high Lp(a) levels for CAD were 2.17 (1.28-3.66), while ORs of the presence of at least one apo(a) isoform of low MW were 5.35 (3.30-8.60). Lp(a) levels (30.2 +/- 23.7 vs. 21.2 +/- 17.7 mg/dl; P = 0.0005) and the percentage of subjects with at least one apo(a) isoform of low MW (87.0% vs. 67.2%; P = 0.0001) were significantly higher in CAD patients without than in those with diabetes. CONCLUSIONS: Our data suggest that Lp(a) levels and apo(a) phenotypes are independently associated with CAD in Type 2 diabetic patients; thus both these parameters may be helpful in selecting diabetic subjects at high genetic cardiovascular risk. However, Lp(a) levels and apo(a) polymorphism seem to be cardiovascular risk factors less important in diabetic than in non-diabetic subjects. Diabet. Med. 18, 589-594 (2001)

Association between apolipoprotein(a) phenotypes and coronary heart disease at a young age.

OBJECTIVES: The purpose of this study was to investigate lipoprotein(a) [Lp(a)] levels and apolipoprotein(a) [apo(a)] phenotypes in relation to age of onset of coronary heart disease (CHD). BACKGROUND: Although Lp(a) levels have been extensively analyzed in relation to age of CHD, apo(a) phenotypes have not. METHODS: Three hundred and thirty-five consecutive CHD patients were enrolled and grouped according to their age of CHD onset (<45 years; 45 to 54 years; > or = 55 years). RESULTS: In each patient group Lp(a) levels were higher than in an age-matched control group, but among the patient groups no differences in Lp(a) levels were observed. Apolipoprotein(a) phenotype distributions showed significant differences between patients and age-matched control subjects. Among the patient groups the difference in percentage of subjects with two apo(a) isoforms of low molecular weight (MW) was highly significant (p < 0.001). Multivariate analysis showed that apo(a) phenotypes were the best predictors of early CHD (p < 0.000001). The age-specific odds ratios (ORs) of the presence of at least one apo(a) isoform of low MW for CHD declined with age; in particular apo(a) phenotypes had their highest predictive value in younger persons (OR: 14.62). The OR for the presence of two isoforms of low MW/presence of only isoforms of high MW was 40.88 in the younger age group, 27.17 in age group of 45 to 54 years and 15.83 in the older age group. CONCLUSIONS: The present article reports the first evidence of a strong independent association of apo(a) phenotypes with the age of onset of CHD. Thus, if our data are confirmed by larger studies, apo(a) phenotypes might be used together with Lp(a) levels as powerful genetic markers in assessing the actual risk of developing CHD at a young age.

Cardiovascular autonomic testing in adolescents with type I (insulin-dependent) diabetes mellitus: an 18-month follow-up study.

1. Autonomic abnormalities are frequent in adult patients with diabetes mellitus and progress slowly; little is known about frequency and progression of autonomic abnormalities in childhood. 2. To assess whether autonomic abnormalities are already present in childhood, we evaluated the cardiovascular reflexes, the spectral analysis of spontaneous fluctuations in RR interval and blood pressure (low- and high-frequency), and the baroreflex sensitivity at rest, and after vagal (controlled breathing) and sympathetic activation (tilting) in 25 adolescents with Type I diabetes mellitus, aged 10-17 years, at baseline and after 18 months follow-up, and in 20 age- and sex-matched controls. 3. Cardiovascular reflexes were similar in both patients and controls. Similar significant changes in percentage low- and high-frequency (P < 0.005) from rest to tilting and to control breathing were observed in both patients and controls. The baroreflex sensitivity was also similar in patients and controls. Mild and non-systematic correlations were observed between autonomic tests and disease duration or metabolic control. After 18 months follow-up no changes were observed in any of the measured variables. Correlations with metabolic control remained unchanged. 4. These results indicate a substantial stability of cardiovascular autonomic function in childhood diabetes, and suggest that autonomic abnormalities are likely to develop at an older age.

Apolipoprotein(a) phenotypes and their predictive value for coronary heart disease: identification of an operative cut-off of apolipoprotein(a) polymorphism.

BACKGROUND: Apolipoprotein(a) isoforms of low-molecular weight are associated with coronary heart disease. However, because of the high number of apolipoprotein(a) isoforms, it is difficult to assess the cardiovascular risk linked to the apolipoprotein(a) gene of a subject; indeed a cut-off of apolipoprotein(a) polymorphism has not been established. The aim of this investigation was to identify an 'operative' cut-off that discriminates apolipoprotein(a) isoforms associated with high genetic risk for coronary heart disease. METHODS: Two hundred and fifty-one patients with coronary heart disease and 284 controls were recruited. Apolipoprotein(a) isoforms were detected using a high-resolution phenotyping method. RESULTS: Twenty-seven apolipoprotein(a) isoforms with apparent molecular weight varying from 280 to 820 kDa were identified. Several cut-offs of apolipoprotein(a) polymorphism were used in order to compare the frequencies of apolipoprotein(a) isoforms of low and high molecular weight between patients and controls: the cut-off between 640 and 655 kDa had the highest chi 2 (130.40). Even when possible differences in apolipoprotein(a) phenotypes (subjects with at least one isoform of low molecular weight and subjects with only isoforms of high molecular weight) were assessed, the same cut-off showed the highest chi 2 (122.47). Multivariate analysis showed that apolipoprotein (a) isoforms had the greatest predictive value for coronary heart disease (F value = 107.0720), when the cut-off between 640 and 655 kDa was used. CONCLUSIONS: The cut-off between 640 and 655 kDa appears to be the most efficient in identifying subjects at high cardiovascular risk linked to apolipoprotein(a) gene, since this cut-off discriminates apolipoprotein(a) isoforms expressing a greater risk for coronary heart disease.

Apolipoprotein(a) phenotypes as genetic markers of coronary atherosclerosis severity.

We investigated Lp(a) levels and apo(a) polymorphism in relation to the severity of coronary artery disease, expressed both by the number of coronary arteries stenosed and three different coronary scoring systems. In a sample of 267 patients with coronary artery disease, a Mono-, Bi- or Multi-vessel coronary stenosis was documented by angiography. Twenty-five apo(a) isoforms were detected by a high resolution phenotyping method. Lp(a) levels did not show any differences among subgroups of patients. Both the percentage of apo(a) isoforms of low molecular weight (<655 kDa) (P=0.00015) and the percentage of subjects with at least one apo(a) isoform of low molecular weight (P=0.00027) were significantly correlated with increasing number of coronary vessels stenosed. In multivariate analysis, only apo(a) isoforms of low molecular weight were predictors of coronary atherosclerosis severity, when we used as the dependent variable both the '1-2-multi-vessels' categorization (P=0.000067) and the Gensini (P=0.008767), or Green Lane (P= 0.000001) or Dahlen (P=0.000102) coronary scoring system. Our data show that apo(a) isoforms of low molecular weight are associated with a greater severity of coronary atherosclerosis. If these data are confirmed by prospective studies, apo(a) phenotypes might be used as genetic markers of a greater severity of coronary atherosclerotic lesions.

Lipoprotein(a) levels and apolipoprotein(a) polymorphism in type 1 diabetes mellitus: relationships to microvascular and neurological complications.

To investigate plasma concentrations of lipoprotein(a) [Lp(a)] and apolipoprotein(a) [apo(a)] polymorphism in relation to the presence of microvascular and neurological complications in type 1 diabetes mellitus, 118 young diabetic patients and 127 age-matched controls were recruited. Lp(a) levels were higher in patients than in controls, but the apo(a) isoforms distribution did not differ between the two groups [higher prevalence of isoforms of high relative molecular mass (RMM) in both groups]. Microalbuminuric patients had Lp(a) levels significantly greater than normoalbuminuric patients, and normoalbuminuric patients showed higher Lp(a) levels than controls. Patients with retinopathy or neuropathy showed similar Lp(a) levels to those without retinopathy or neuropathy. No differences in apo(a) isoforms frequencies were observed between subgroups with and without complications (higher prevalence of isoforms of high RMM in every subgroup). However, among patients with retinopathy, those with proliferative retinopathy had higher Lp(a) levels and a different apo(a) isoforms distribution (higher prevalence of isoforms of low RMM) than those with non-proliferative and background retinopathy (higher prevalence of isoforms of high RMM). Our data suggest that young type 1 diabetic patients without microalbuminuria have Lp(a) levels higher than healthy subjects of the same age. Lp(a) levels are further increased in microalbuminuric patients. High Lp(a) levels and apo(a) isoforms of low RMM seem to be associated with the presence of proliferative retinopathy, but have no relation to neuropathy.

Reduction of 0.1 Hz microcirculatory fluctuations as evidence of sympathetic dysfunction in insulin-dependent diabetes.

OBJECTIVE: Loss of spontaneous fluctuations in resting microcirculatory flow has been described in diabetes mellitus, but its mechanism remains unexplained. METHODS: The autonomic control of forearm skin microcirculation was investigated in 23 insulin-dependent diabetic human subjects (median age 39 years, range 27-50) and in 23 age-matched controls (median age 38 years, range 20-57), by laser-Doppler flowmetry. Using spectral analysis of spontaneous microvascular fluctuations, we measured the power of 0.1 Hz ('10-second rhythm') fluctuations, dependent on sympathetic control, and of respiration-related, high-frequency fluctuations, due to the transmission of mechanical chest activity. Autonomic function abnormalities were assessed by 5 tests of cardiovascular reflexes. RESULTS: Abnormalities in cardiovascular autonomic tests were present in 7/23 patients: deep breathing was abnormal 4 in patients, standing in 2, handgrip in 3, cross-correlation in 4, and Valsalva ratio in 0. The power of 0.1 Hz microcirculatory fluctuations was significantly lower in diabetic than in control subjects (2.57 +/- 0.16 vs 3.48 +/- 0.09 In-mV2, mean +/- s.e.m., P < 0.001), whereas that of respiratory fluctuations was similar (2.60 +/- 0.24 vs 2.56 +/- 0.19 In-mV2, P = n.s.). The 0.1 Hz power was 2 standard deviations below the mean of controls (P < 0.05) in 13/23 diabetic patients; this abnormality was significantly more frequent than abnormalities in any other autonomic test (P < 0.001). CONCLUSIONS: Since the observed reduction was confined to those microvascular fluctuations under autonomic control, but not to those dependent on passive mechanical transmission, the reduction in spontaneous microcirculatory vasomotion appears to be determined mainly by sympathetic dysfunction. Sympathetic impairment of skin microvascular control seems to be a common finding, and is probably an early index of autonomic dysfunction in insulin-dependent diabetes.

Twenty-four-hour pattern of blood pressure and spectral analysis of heart rate variability in diabetic patients with various degrees of autonomic neuropathy. Comparison to standard cardiovascular tests.

We performed four cardiovascular tests of autonomic function (deep breathing, lying to standing, Valsalva manoeuvre, postural hypotension) and simultaneous 24h recordings of blood pressure (BP) and ECG in 35 normotensive diabetic subjects. Autoregressive power spectrum analysis of RR interval variability was applied to 24h ECG recordings to obtain for day and night periods power of low- (0.03-0.15 Hz, LF) and high-frequency (0.18- 0.40 Hz, HF) components, relative markers of sympathetic and vagal activity respectively, and their ratio (LF/HF), assumed as index of sympathovagal balance. Eighteen patients showed normal cardiovascular tests, 6 patients one abnormal heart rate test, 5 patients two abnormal heart rate tests, and 6 patients also abnormal postural hypotension test. In diabetic patients with increasing degree of autonomic neuropathy, there was a progressive reduction of day-night change in systolic BP (p < 0.01), of LF during the day (p < 0.01), of HF during the night (p < 0.04), of day-night change in HF (p < 0.02), and of day-night change in HF/LF (p < 0.03). Day-night change in systolic BP was related to postural hypotension (p < 0.001) and to deep breathing (p < 0.01). Day LF was related to lying to standing (p < 0.001), to postural hypotension (p < 0.005) and to deep breathing (p < 0.007). Night HF was related to deep breathing (p < 0.0002) and to lying to standing (p < 0.02). Day-night change in HF/LF was slightly related to deep breathing, lying to standing, and to postural hypotension (p < 0.04). In a multiple regression analysis including age, diabetes duration, and cardiovascular tests as independent variables, day-night change in BP and day LF were only related to postural hypotension, whereas night HF was related to deep breathing. In conclusion, in diabetic patients with increasing autonomic damage, there is a progressive impairment of nocturnal fall of BP and of sympathetic activity during the day, blunted nocturnal increase of vagal activity and lower circadian variation in sympathovagal balance. The significant but not very close correlation of day-night pattern of BP and sympathovagal activity to standard cardiovascular reflex tests, supports the independent usefulness of 24h BP monitoring and spectral analysis of heart rate variability in diabetic neuropathy.

IDDM in the province of Pavia, Italy, from a population-based registry.A descriptive study.

OBJECTIVE: To report the incidence of insulin-dependent diabetes mellitus (IDDM) in the Province of Pavia, Italy, in the 0- to 29-year-old age-group between 1988 and 1992. Urban versus rural residence, socioeconomic level, and family size of IDDM cases were also investigated. RESEARCH DESIGN AND METHODS: A prospective register was established in 1988 to collect all newly diagnosed IDDM patients with onset before 30 years of age. The primary data source was based on notification of new cases by hospitals, out-patient clinics, family doctors, and pediatricians. The secondary and independent data source consisted of the registries of prescriptions for insulin syringes in the health districts of the province. RESULTS: In 5 years (1988-1992), 66 cases of IDDM in the 0- to 29-year-old age-group were identified. The completeness of ascertainment was 100% for the combined sources. Age-adjusted (world-standardized) incidence rates per 100,000 (95% confidence interval) were 9.52 (6.42-13.61), 6.72 (4.68-9.34), and 8.27 (6.42-10.58), respectively, for the age-groups 0-14, 15-29, and 0-29. The rates were higher for residents in urban areas. The number of children in the families of IDDM patients was significantly higher than in the reference population. CONCLUSIONS: Our data indicate the concordance of IDDM incidence rates with the North-Italian rates and a possible association of the disease with environmental factors. These factors might enhance the susceptibility to IDDM in genetically predisposed individuals.

Relationship between the circadian rhythms of blood pressure and sympathovagal balance in diabetic autonomic neuropathy.

In diabetic autonomic neuropathy, abnormal circadian patterns of blood pressure and sympathovagal balance with reduced fall of blood pressure and prevalence of sympathetic activity during the night have been described. To correlate the abnormalities of blood pressure to those of sympathovagal balance, we simultaneously performed 24-h noninvasive monitoring of blood pressure and ECG in 25 diabetic patients (45.6 +/- 13.6 yr of age with a 17.6 +/- 9.1 yr duration of diabetes) with various degrees of cardiovascular reflex impairment. Autoregressive power spectrum analysis of RR interval variability was applied to 24-h ECG recordings to obtain for day and night periods the mean power of low- (0.03-0.15 Hz) and high-frequency (0.18-0.40 Hz) components, which are relative markers of sympathetic and vagal activity, respectively, and their ratio (low frequency/high frequency), assumed as index of sympathovagal balance. Diabetic patients showed a lower percentage of day-night change in systolic blood pressure (9 +/- 5.48 vs. 11.6 +/- 4.78%, P < 0.037), a lower day low frequency (5.9 +/- 0.81 vs. 6.62 +/- 0.73 In-ms2, P < 0.001), a lower night high frequency (6.06 +/- 0.71 vs. 6.52 +/- 0.85 In-ms2, P < 0.05), a lower day low frequency:high frequency ratio (1.82 +/- 1.77 vs. 3.05 +/- 1.82, P < 0.01), and a lower percentage of day-night change in low-frequency:high frequency ratio (-13.4 +/- 109.9 vs. 28.7 +/- 29.7%, P < 0.05), when compared with control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of apo(a) polymorphism by a modified immunoblotting technique in an Italian population sample.

Apo(a), the specific lipoprotein(a) (Lp(a)) apolipoprotein, is characterized by different isoforms (from 6 to 11 on SDS-PAGE) encoded by a system of autosomal codominant alleles. Electrophoresis on agarose gel displays a better resolving power than SDS-PAGE (a larger number of apo(a) isoforms is detected). The aim of this work was to set up a simple technique that uses a capillary blotting apparatus and a polyvinylidene difluoride membrane for protein transfer. We tested an Italian population sample of 202 healthy subjects (123 men and 79 women) and we detected 22 apo(a) isoforms varying from 280 to 775 kDa. In our sample, 135 subjects (66.5%) had a single-band phenotype, 64 (31.7%) had a double-band phenotype and 3 subjects (1.5%) had no detectable bands ('null' phenotype). This simple and reproducible technique could be applied in the genetic screening of apo(a) polymorphisms and for clinical investigations of the risk of developing cardiovascular diseases.

Impaired circadian modulation of sympathovagal activity in diabetes. A possible explanation for altered temporal onset of cardiovascular disease.

BACKGROUND: Diabetic subjects have a high incidence of cardiovascular accidents, with an altered circadian distribution. Abnormalities in the circadian rhythm of autonomic tone may be responsible for this altered temporal onset of cardiovascular disease. METHODS AND RESULTS: To assess circadian changes of sympathovagal balance in diabetes, we performed 24-hour power spectral analysis of RR interval fluctuations in 54 diabetic subjects (age, 44 +/- 2 years) with either normal autonomic function or mild to severe autonomic neuropathy and in 54 age-matched control subjects. The power in the low-frequency (LF, 0.03-0.15 Hz) and high-frequency (HF, 0.18-0.40 Hz) bands was considered an index of relative sympathetic and vagal activity, respectively. Diabetic subjects with autonomic abnormalities showed a reduction in LF compared with control subjects (5.95 +/- 0.12 In-msec2 versus 6.73 +/- 0.11, p < 0.001) and an even greater reduction in LF, particularly during the night and the first hours after awakening (5.11 +/- 0.18 In-msec2 versus 6.52 +/- 0.14, p < 0.001). Day-night rhythm in sympathovagal balance was reduced or absent in diabetic subjects compared with control subjects. CONCLUSIONS: Diabetic subjects with or without signs of autonomic neuropathy have a decreased vagal activity (and hence a relatively higher sympathetic activity) during night hours and at the same time of the day, during which a higher frequency of cardiovascular accidents has been reported. These observations may provide insight into the increased cardiac risk of diabetic patients, particularly if autonomic neuropathy is present.

High plasma levels of catecholamines during insulin-induced hypoglycemic stress do not cause beta-adrenergic receptor sequestration.

In the present investigation insulin-induced hypoglycemia was used as a powerful stimulus to rapidly release epinephrine from the adrenal medulla. Insulin injection raised epinephrine 16-fold and doubled norepinephrine plasma levels. The aim of this attempt was to induce beta-adrenergic receptors (beta-ARs) sequestration in vivo on mononuclear leukocytes (MNLs). The number of total and surface beta-ARs was significantly increased 30 minutes after insulin administration, with only partial recovery at 90 minutes. No detectable receptor sequestration was observed: surface receptors were about 90% of total receptors in all the conditions examined. Isoproterenol-stimulated cyclic adenosine monophosphate (cAMP) accumulation was also increased after 30 minutes (+66%) and 90 minutes (+65%) of insulin injection. Basal and forskolin-stimulated intracellular cAMP values were unchanged. We conclude that, even after a strong release of catecholamines, beta-AR redistribution cannot be demonstrated on MNLs.