Neuropad as a diagnostic tool for diabetic autonomic and sensorimotor neuropathy.

AIMS: The aim of the present study was to determine the diagnostic accuracy of the Neuropad sudomotor test for diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN), the latter assessed using a multi-level diagnostic approach. METHODS: In 51 diabetic patients, CAN, symptoms and signs of DPN, vibration perception threshold (VPT), cold (CTT) and warm thermal perception thresholds (WTT) were measured. Neuropad response was determined as normal (complete colour change) or abnormal (absent or incomplete colour change). The time until the complete colour change (CCC time) was recorded. RESULTS: CCC time showed significant correlations with all the neurological parameters, the strongest of which were with Valsalva ratio (rho = -0.64, P < 0.0001), symptoms of DPN (rho = 0.66, P < 0.0001), postural hypotension (rho = 0.54, P = 0.0001) and CTT (rho = -0.54, P = 0.0001). CCC time showed moderate diagnostic accuracy for both CAN and DPN: the areas under the receiver operating characteristic (ROC) curves were 0.71 and 0.76, respectively. The diagnostic characteristics of three cut-off values of CCC time, identified by ROC analysis (i.e. 10, 15 and 18 min), were analysed. Compared with 10 min, the 15-min cut-off value provided better specificity (from 27% to 52% and from 31% to 62% for CAN and DPN, respectively) and a better likelihood ratio for negative result (from 0.67 to 0.34 and from 0.58 to 0.33) without lowering sensitivity (from 82% to 82% and from 85% to 80%). CONCLUSIONS: Neuropad is a reliable diagnostic tool for both CAN and DPN, albeit of only moderate accuracy. Extending the observation period to 15 min provides greater diagnostic usefulness.

Usefulness of ambulatory blood pressure monitoring in predicting the presence of autonomic neuropathy in type I diabetic patients.

This study investigated whether nondipping (defined as a day-night change in blood pressure (BP)

Gefitinib inhibits the ability of human bone marrow stromal cells to induce osteoclast differentiation: implications for the pathogenesis and treatment of bone metastasis.

Significant relief of bone pain in patients with bone metastases was observed in a clinical trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib in breast cancer. Osteoclast activation and differentiation are regulated by bone marrow stromal cells (BMSC), a heterogeneous cell compartment that comprehends undifferentiated mesenchymal stem cells (MSC) and their specialized progeny. In this regard, we found that human primary BMSCs express immunoreactive EGFR. Expression of EGFR mRNA and protein was also demonstrated in two human, continuous MSC-like cell lines, HDS-1 and HDS-2 cells. Treatment of HDS cells with EGF produced a significant increase in the levels of activated EGFR which was not observed in the presence of gefitinib. A significant reduction in the basal levels of activation of the EGFR and of Akt was observed in HDS cells following treatment with gefitinib. Treatment of HDS cells with gefitinib produced a significant reduction in the levels of secreted macrophage colony-stimulating factor (M-CSF) and cell-associated receptor activator of NF-kappaB ligand (RANKL) in both cell lines, as assessed by using specific ELISA and Western blotting techniques. Finally, the ability to sustain the differentiation of pre-osteoclasts of conditioned medium from gefitinib-treated HDS cells was reduced by approximately 45% as compared with untreated HDS cells. These data have demonstrated for the first time that the EGFR regulates the ability of BMSCs to induce osteoclast differentiation and strongly support clinical trials of gefitinib in breast cancer patients with bone disease.

The ErbB receptors and their ligands in cancer: an overview.

This review article provides an overview on the most recent advances on the role of ErbB receptors and growth factors of the epidermal growth factor (EGF)-family of peptides in cancer pathogenesis and progression. The ErbB tyrosine kinases and the EGF-like peptides form a complex system. In fact, the interactions occurring between receptors and ligands of these families affect the type and the duration of the intracellular signals that derive from receptor activation. Interestingly, activation of ErbB receptors is also driven by different classes of membrane receptor, suggesting that ErbB kinases can amplify growth promoting signals carried by different pathways. The importance of ErbB receptors and EGF-like peptides in development of organs and tissues has been demonstrated by using different mouse models. In vitro and in vivo studies have also shown that ErbB receptors and their ligands can act as transforming genes. However, evidence suggests that cooperation of different receptors and ligands is necessary to induce a fully transformed phenotype. Indeed, co-expression of different ErbB receptors and EGF-like growth factors is a common phenomenon in human primary carcinomas. This observation suggests that the growth and the survival of carcinoma cells is sustained by a network of receptors/ligands of the ErbB family. In this respect, the contemporary expression of different ErbB tyrosine kinases and/or EGF-like growth factors in human carcinomas might also affect tumor response to target based agents directed against the ErbB receptor/ligand system.

Does autonomic neuropathy play a role in erythropoietin regulation in non-proteinuric Type 2 diabetic patients?

AIMS: Erythropoietin (EPO)-deficient anaemia has been described in Type 1 diabetic patients with both severe autonomic neuropathy (AN) and proteinuria. This study was aimed at distinguishing between the effects of AN and nephropathy on haemoglobin and EPO levels in Type 2 diabetic patients at an early stage of diabetic nephropathy. METHODS: In 64 Type 2 diabetic patients (age 52 +/- 10 years, duration 10 +/- 9 years) without overt nephropathy and other causes of anaemia or EPO deficit, we assessed cardiovascular tests of AN, 24-h blood pressure (BP) monitoring, urinary albumin excretion rate (UAE), a full blood count, and serum EPO. RESULTS: Although the Type 2 diabetic patients with AN did not show differences in haemoglobin and EPO when compared with patients without AN, the presence of haemoglobin < 13 g/dl was associated with the presence of AN (chi(2)= 3.9, P < 0.05) and of postural hypotension (chi(2)= 7.8, P < 0.05). In a multiple regression analysis including as independent variables gender, body mass index, duration of diabetes, smoking, creatinine, 24-h UAE, 24-h diastolic BP, ferritin, erythrocyte sedimentation rate, and autonomic score, we found that the only variables independently related to haematocrit were autonomic score, ferritin and erythrocyte sedimentation rate. Finally, the physiological inverse relationship between EPO and haemoglobin present in a control group of 42 non-diabetic non-anaemic subjects was completely lost in Type 2 diabetic patients. The slopes of the regression lines between EPO and haemoglobin of the control subjects and the Type 2 diabetic patients were significantly different (t = 14.4, P < 0.0001). CONCLUSIONS: This study documents an early abnormality of EPO regulation in Type 2 diabetes before clinical nephropathy and points to a contributory role of AN in EPO dysregulation.

Small molecule epidermal growth factor receptor tyrosine kinase inhibitors: an overview.

The epidermal growth factor receptor (EGFR) has been identified as a relevant target for treatment of solid tumors, as it is involved in regulating cellular functions important in the proliferation and survival of cancer cells, is commonly expressed in a range of tumors, and high expression is often related to poor prognosis. Some of the most advanced target based agents in clinical development are the EGFR tyrosine kinase inhibitors (EGFR-TKIs). This brief review summarizes the results of phase II monotherapy trials of EGFR TKIs in cancer patients. The molecular mechanisms involved in regulating the sensitivity/resistance of tumor cells to EGFR-TKIs are also discussed.

Target-based agents against ErbB receptors and their ligands: a novel approach to cancer treatment.

The ErbB receptors and their cognate ligands that belong to the epidermal growth factor (EGF) family of peptides are involved in the pathogenesis of different types of carcinomas. In fact, the ErbB receptors and the EGF-like growth factors are frequently expressed in human tumors. These proteins form a complex system that regulates the proliferation and the survival of cancer cells. Therefore, ErbB receptors and their ligands might represent suitable targets for novel therapeutic approaches in human carcinomas. In this regard, different target-based agents that are directed against the ErbB receptors have been developed in the past two decades. One of these compounds, the humanized anti-ErbB-2 monoclonal antibody trastuzumab has been approved for the treatment of patients with metastatic breast cancer. The anti-EGF receptor (EGFR) antibody C225, as well as EGFR tyrosine kinase inhibitors ZD1839 and OSI-774 are currently in phase III clinical development. Several other ErbB tyrosine kinase inhibitors are in phase I/II studies. These compounds have generally been shown to have an acceptable toxicity profile and promising anti-tumor activity in heavily pretreated patients. The mechanisms of action of these compounds, as well as the potential therapeutic strategies to improve their efficacy are discussed in this review with particular regard to the combinations of anti-ErbB agents with cytotoxic drugs, or combinations of different ErbB-targeting agents.

Factors determining the 24-h blood pressure profile in normotensive patients with type 1 and type 2 diabetes.

Some controversy still exists about factors involved in the abnormal circadian pattern of blood pressure (BP) in diabetes, while prognostic value of non-dipping condition is being increasingly recognised. This study was aimed at evaluating the relative influence of autonomic neuropathy (AN) and albumin excretion on 24-h BP profile in type 1 and type 2 diabetes. We measured AN cardiovascular tests, 24-h ambulatory BP, and urinary albumin excretion rate (UAE) in 47 type 1 and 34 type 2 normotensive non-proteinuric diabetic patients. In type 1 diabetic patients day-night differences (Delta) in systolic and diastolic BP were lower in those with AN than in those without (3 +/- 9 vs 10 +/- 6%, P < 0.01, and 8 +/- 9 vs 16 +/- 6%, P < 0.001), and in univariate regression analysis they were inversely related to both autonomic score, index of degree of AN (r = -0.61, P < 0.001 and r = -0.65, P < 0.001), and to 24-h UAE (r = -0.39, P < 0.01 and r = -0.46, P < 0.001). In type 1 diabetic patients AN was also associated with lower nocturnal decrease in UAE (patients with AN vs without AN: -37 +/- 214 vs 49 +/- 37%, P < 0.05), and with a stronger relationship between simultaneous 24-h UAE and 24-h BP (for systolic BP patients with AN vs without AN: r = 0.62, P < 0.01 vs r = 0.28, NS). In type 2 diabetic patients Delta systolic BP was reduced in patients with AN compared to those without (4 +/- 7 vs 10 +/- 4%, P < 0.01), and it was related only to autonomic score (r = -0.42, P < 0.01). Using a stepwise regression analysis, in type 1 diabetic patients autonomic score was the variable of primary importance for Delta BP, while in type 2 diabetic patients it was the unique determinant not only of Delta systolic BP but also of 24-h systolic BP. In conclusion, AN is the pivotal factor of blunted nocturnal fall in BP in both type 1 and type 2 diabetic patients. In type 1 diabetic patients AN is associated with attenuated circadian pattern of albuminuria and with a steeper relationship between albuminuria and BP, in type 2 diabetic patients AN is the only factor related to elevated 24-h BP levels. Longitudinal studies are needed to establish the potential role of autonomic dysfunction as a progression promoter for nephropathy and hypertension in type 1 and type 2 diabetes respectively.

Autonomic neuropathy and cardiovascular risk factors in insulin-dependent and non insulin-dependent diabetes.

In 97 IDDM and 64 NIDDM patients aged under 65 years, we evaluated the relationship between autonomic neuropathy (AN) and retinopathy, nephropathy, glycemic control and cardiovascular risk factors. Diabetes duration and HbA1 were significantly higher and body mass index was significantly lower in IDDM patients with AN compared to those without. In NIDDM only age was significantly higher in neuropathic patients. AN was associated with retinopathy in both IDDM (chi2 = 10, P < 0.03) and NIDDM patients (chi2 = 14, P < 0.007), while only in IDDM albumin excretion was significantly higher in patients with AN. Blood pressure (BP) was significantly higher in both IDDM and NIDDM patients with AN compared to those without. There were no differences in smoking and serum lipids between patients with and those without AN. We performed a multiple regression analysis using autonomic score, index of cardiovascular tests impairment, as the dependent variable and age, diabetes duration, body mass index, HbA1, albumin excretion, cholesterolemia, triglyceridemia, systolic BP, and retinopathy as independent variables. With this model in IDDM autonomic score was only related to body mass index (r = -0.29, P < 0.05), to HbA1 (r = 0.46, P < 0.001), and to systolic BP (r = 0.24, P < 0.05), while in NIDDM it was only related to systolic BP (r = 0.54, P < 0.001). In conclusion, AN was related to age in NIDDM, and to diabetes duration and glycemic control in IDDM. AN was associated with retinopathy, with nephropathy (only in IDDM), and with BP levels, but not with dyslipidemia, smoking, or obesity. Excess mortality rate observed in diabetic AN cannot be referred to an association with cardiovascular risk factors.

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.

Relationship between autonomic neuropathy, 24-h blood pressure profile, and nephropathy in normotensive IDDM patients.

OBJECTIVE: To evaluate the relationship between autonomic neuropathy, nephropathy, and 24-h blood pressure (BP) pattern in insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: We studied 30 normotensive IDDM patients without overt nephropathy, divided into two groups and matched for age, duration of diabetes, and HbA1, according to the presence of cardiovascular autonomic neuropathy. We simultaneously measured 24-h BP and urinary albumin excretion rate (UAE) on urine collections timed overnight and at 2-h intervals during the day. RESULTS: Mean day and night systolic and diastolic BP values did not significantly differ between the groups. Mean night albuminuria was significantly higher in patients with autonomic neuropathy than in those without (61.4 +/- 104.6 [mean +/- SD] vs. 16 +/- 25.2 micrograms/min, P < 0.04). The percentages day-night changes in systolic BP, diastolic BP, and UAE were significantly lower in neuropathic patients (systolic BP: 2.4 +/- 7.7 vs. 9.6 +/- 4.2%, P < 0.001; diastolic BP: 8.4 +/- 6.9 vs. 15.5 +/- 5.4%, P < 0.002; UAE: -8 +/- 99.4 vs. 49.3 +/- 29.4%, P < 0.02) and were inversely related to autonomic score, index of autonomic neuropathy degree (r = -0.54, P < 0.002; r = -0.58, P < 0.001; and r = -0.53, P < 0.005, respectively). In patients with autonomic neuropathy, 2-h day periods and day and night UAE were more strongly related, respectively, to mean 2-h day periods (r = 0.58, P < 0.0001), day systolic BP (r = 0.67, P < 0.04), and night systolic BP (r = 0.69, P < 0.04) than in patients without autonomic neuropathy (2-h day periods: r = 0.32, P < 0.001; day: r = 0.37, NS; night: r = 0.35, NS). CONCLUSIONS: Autonomic neuropathy in IDDM patients is associated with reduced nocturnal falls in BP and UAE and with a stronger relationship of UAE to systolic BP. We suggest a pathogenetic role of autonomic neuropathy in the development of diabetic nephropathy through changes in nocturnal glomerular function and by enhanced kidney vulnerability to hemodynamic effects of BP.

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)

Increased left ventricular mass in normotensive diabetic patients with autonomic neuropathy.

The possible relationship between diabetic autonomic neuropathy, circadian blood pressure changes, and echocardiographic parameters was investigated in 27 normotensive diabetic patients (10 with and 17 without autonomic neuropathy) who underwent 24 h noninvasive ambulatory blood pressure monitoring and M-mode echocardiographic recording. The two groups were comparable for age, sex, duration of diabetes, body mass index, and metabolic control. There were no significant differences in 24 h average and diurnal values of systolic, diastolic, or mean blood pressure. The percent changes from day to night of systolic, diastolic, and mean blood pressures were significantly lower in diabetics with neuropathy than in those without (P < .04 or less). Increased left ventricular mass index (LVMI) (135.4 +/- 10.2 v 102.9 +/- 6.3; P < .005), septal wall thickness, and posterior wall width were observed in neuropathic patients. Fractional shortening, peak velocity of early left ventricular filling (E), peak velocity of late ventricular filling (A), and their ratio (E/A) were similar in the two groups. The increased LVMI we observed may represent a possible link between diabetic autonomic neuropathy, nocturnal blood pressure levels, and higher cardiovascular mortality rate.

Twenty-four hours blood pressure and heart rate profiles in diabetics with and without autonomic neuropathy.

Previous studies have shown an increased incidence of sudden deaths and lower survival in diabetics with autonomic neuropathy. In hypertensive non diabetic patients a direct correlation has been found between nocturnal blood pressure levels and left ventricular hypertrophy. We have shown in diabetics with autonomic neuropathy a flattening in nocturnal blood pressure reduction and increased 24 hours blood pressure values compared to diabetics without autonomic neuropathy and controls. Our results suggest that abnormalities in 24 hours blood pressure profile might play a role in the increased incidence of cardiovascular morbidity and mortality in diabetics with autonomic neuropathy.

[Can the Body Mass Index and the waist:hips ratio (WHR) affect the correlation between impedance measurement and anthropometry in the evaluation of body composition?]. / Possono il Body Mass Index (BMI) ed il rapporto vita/fianchi (WHR) influenzare la correlazione tra impedenziometria ed antropometria nella valutazione della composizione corporea?

Among the numerous techniques used to measure body composition, this study utilised anthropometric methods (weight, height, circumference and skin folds) and impedance measurement (measurement of bioelectric impedance). Results from the two methods were compared in order to assess whether BMI parameters and the waist/hips ratio (WHR) influenced this correlation. One hundred and eighty patients (133 F, 47 M) were included in the study. Patients were divided into groups according to the degree of obesity expressed as BMI and WHR. Body composition was evaluated using anthropometric methods (according to Garrow Webster, Durnin-Womersley, modified Durnin-Womersley and Jackson-Pollock) and impedance measurement in which resistive bioelectric impedance is measured using a tetrapolar technique. A good correlation was generally observed in the female population between impedance assessment and anthropometric methods, and this correlation was not influenced by either BMI or WHR. In the male group, on the other hand, the correlation between the two methods was limited by BMI greater than 30 and WHR greater than 1. In conclusion, impedance measurement and plicometric methods are generally compatible, but areas of uncertainty arise in the male population with BMI greater than 30 and WHR greater than 1.

Autonomic neuropathy and secondary hyperparathyroidism in uremia.

To evaluate the relationship between autonomic neuropathy, and biochemical and radiological parameters of secondary hyperparathyroidism, we examined 19 predialysis and 24 hemodialysis non-diabetic uremic patients. Autonomic neuropathy was assessed using four cardiovascular tests. Ten predialysis and 15 hemodialysis patients showed abnormalities in one or more autonomic tests. Ca, Ca2+, P, alkaline phosphatase, immunoreactive parathyroid hormone and osteocalcin did not significantly differ in uremic patients with and without abnormal autonomic test results. Radiological markers of hyperparathyroidism such as acro-osteolysis (score A) and subperiosteal resorption (score B) were more common in patients with abnormalities in autonomic tests than in patients without. When predialysis and hemodialysis patients were considered separately, the correlation between score A, score B and autonomic neuropathy was confirmed only in hemodialysis patients. In conclusion, autonomic neuropathy is not related to biochemical parameters of hyperparathyroidism, while it appears correlated with radiological signs of osteodystrophy, suggesting a possible pathogenetic link between autonomic neuropathy and secondary hyperparathyroidism.

Autonomic neuropathy and secondary hyperparathyroidism in uraemia.

To evaluate the relationship between autonomic neuropathy, and biochemical and X-ray parameters of secondary hyperparathyroidism, we examined 19 predialysis and 24 haemodialysis non-diabetic uraemic patients. Autonomic neuropathy was assessed using four tests: deep breathing, Valsalva manoeuvre, lying to standing, and postural hypotension. Serum Ca, Ca2+, P, Mg, alkaline phosphatase, iPTH, and osteocalcin were assayed. Hand X-ray was obtained to evaluate acro-osteolysis (score A) and subperiosteal resorption (score B). Ten predialysis patients (52%) and 15 haemodialysis patients (62%) showed one or more abnormal autonomic tests. Age, dialysis duration, and biochemical parameters of secondary hyperparathyroidism did not differ significantly in uraemic patients with and without abnormal autonomic tests. Furthermore, there was no significant relation between autonomic tests and iPTH or osteocalcin. Score A and score B was significantly greater in patients with abnormal tests than in patients without (P less than 0.009 and P less than 0.025). When predialysis and haemodialysis patients were considered separately the correlation between score A, score B, and autonomic neuropathy was confirmed only in haemodialysis patients. In conclusion, autonomic neuropathy does not seem to be related to the biochemical parameters of secondary hyperparathyroidism, while it appears significantly associated with the radiological signs of osteodystrophy, suggesting a possible pathogenetic linkage between autonomic neuropathy and secondary hyperparathyroidism.