Hypertension and sensorimotor peripheral neuropathy in type 2 diabetes.

BACKGROUND: The mechanisms responsible for the onset of sensorimotor peripheral diabetic neuropathy (SMPN) remain largely unknown. To address this issue, we studied the relationship between traditional cardiovascular risk factors, parameters of metabolic control, and the presence of SMPN in patients with type 2 diabetes of relatively short duration. METHODS: Blood pressure, glycated hemoglobin, lipid profile, and the presence of micro- and macrovascular complications were assessed and monitored in 31 consecutive ambulatory patients with type 2 diabetes (age 60.7 +/- 7.5 years, mean +/- SD) within 10 years of diagnosis (mean diabetes duration 6.0 +/- 2.3 years). RESULTS: Clinical and neurophysiological features of SMPN were present in 10 patients (SMPN+, 32%). There were no significant differences in age, gender distribution, diabetes duration, body mass index, metabolic control, and serum cholesterol between SMPN- and SMPN+ patients. However, the prevalence of hypertension (i.e. blood pressure >/=140/90 mm Hg) was higher in SMPN+ patients (10/10 vs. 13/21, chi(2 =) 5.13, p = 0.025). Regression analysis showed that, after correcting for age, gender, duration of diabetes, glycated hemoglobin, and cholesterol, the presence of hypertension was independently associated with SMPN (R(2) = 0.17, p = 0.023). CONCLUSIONS: There is a strong association between hypertension and SMPN in type 2 diabetic patients with relatively short duration of disease. This relationship is independent of other risk factors.

High rate of neoplasia and other co-morbid conditions in type-2 diabetic patients with longer duration of disease and poor metabolic control.

AIM: The aim of the study was to assess the rate of neuroendocrine malignancies in the gastrointestinal tract, other malignancies and mitotic processes, in type-2 diabetic patients. In particular, we tested the hypothesis that a poor metabolic control is associated with a higher rate of neoplasms and other co-morbid conditions, such as hypertension and peripheral neuropathy. METHODS: Forty-one consecutive asymptomatic type-2 diabetic outpatients were followed for 8 years and clustered in 2 groups, according to disease duration, insulin need, and dose of oral antidiabetic agents. Physical examination, blood pressure measurements, and neurophysiologic studies were serially performed during the follow-up. In each subject, a general biochemistry was performed, aspecific and specific antigens (alpha-fetoprotein, carcinoembrionic-antigen and prostate specific antigen PSA and F-PSA) levels were measured, and invasive and non-invasive procedures were carried out, when necessary, to detect a neoplastic process. RESULTS: The rate of malignancies and mitotic processes was significantly higher in patients with longer duration of disease and poor diabetes control (72% vs 13%, p=0.02). Hypertension (83% vs 54%) and peripheral neuropathy (67% vs 21%) were also more common in this group. CONCLUSION: These data, although obtained in a relatively small population, highlight the importance of closely monitoring type-2 diabetic patients with poor diabetes control as this might be associated with the presence of malignancy or other co-morbid conditions. This may be particularly true when the poor glycemic control is characterised by a sudden onset or significant worsening despite streghtening of antidiabetic therapy.

Relative preservation of the renin-angiotensin-aldosterone system response to active orthostatism in type 2 diabetic patients with autonomic neuropathy and postural hypotension.

OBJECTIVE: The pathophysiological mechanisms involved in the progression of autonomic neuropathy (AN) and development of postural hypotension (PH) in type 2 diabetes (T2D) are largely unknown. The aim of this study was to address this issue by investigating the neurohormonal responses during active orthostatism (O) in T2D patients with and without PH. METHODS: Plasma noradrenaline (NA, pmol/L), adrenaline (A, pmol/L), plasma renin activity (PRA, angiotensin I, nmol/L/h) and aldosterone (ALD, pmol/L) were measured in the supine position (baseline) and after 2, 5, and 20 min O in 10 healthy subjects (C), 9 T2D patients without AN (D), 14 T2D patients with AN and without PH (DAN), and 7 T2D patients with AN and PH (DAN-PH). RESULTS: NA concentrations were significantly increased in the C. D and DAN groups during O. In the DAN-PH group, NA increased less markedly with no significant changes at 20 min O (+ 354 +/- 89 pmol/L at 2 min, p < 0.05; + 756 +/- 171 at 5 min, p < 0.05; + 656 +/- 295 at 20 min, p = NS). Absolute NA increments in the DAN-PH group were significantly lower than those in the C, D and DAN groups at 2 and 20 min. Concentrations of A increased significantly in the C and D groups whereas no significant changes were observed in the DAN (+ 27 +/- 27 pmol/L at 2 min, p = NS: + 22 +/- 22 at 5 min, p = NS; + 76 +/- 33 at 20 min, p = NS) and DAN-PH group (+ 16 +/- 11 pmol/L at 2 min, p = NS: + 71 +/- 27 at 5 min, p = NS; + 76 +/- 22 at 20 min, p = NS). Absolute A increments in the DAN and DAN-PH groups were significantly lower than those in controls at 2 and 20 min. By contrast, PRA and ALD increased significantly in all four groups. Absolute PRA increments were similar across the four groups, whereas ALD increments in the D, DAN and DAN-PH groups were significantly lower than those in the C group. CONCLUSIONS: In the DAN-PH group, the renin-angiotensin-aldosterone system response to O was relatively preserved compared with A and NA responses. The impairment of NA response was limited to the DAN-PH group, whereas the reduced A response was a feature of DAN regardless of PH.

Helicobacter pylori prevalence in patients with diabetes and its relationship to dyspeptic symptoms.

As available data on Helicobacter pylori infection in patients with diabetes are scattered and discordant, we evaluated the prevalence of H. pylori and its relationship to dyspeptic symptoms in adult patients with diabetes and subjects with dyspepsia. H. pylori infection (evaluated using the 13C urea breath test) and dyspeptic symptoms (nausea, bloating, and epigastric distress) were investigated in 71 consecutive diabetic outpatients; the presence of gross lesions, histologic gastritis, and Helicobacter was verified in the patients with a positive urea test who agreed to undergo upper gastrointestinal tract endoscopy. Seventy-one age- and gender-matched subjects with dyspepsia were used as controls. Helicobacter pylori infection was detected in 49 (69%) patients with diabetes and in 33 (46%) subject with dyspepsia (p = 0.007). Helicobacter pylori was present in 27 (77%) of 35 patients with diabetes with dyspeptic symptoms and in 22 (61%) of 36 patients without dyspeptic symptoms. Endoscopy revealed peptic ulcers in 13 of 23 patients; H. pylori infection was histologically confirmed in the gastric antrum of all patients with diabetes, and in the body of the stomach in 74%. The significantly higher prevalence of H. pylori infection in the patients with diabetes may partially explain their dyspeptic symptoms. The high prevalence of H. pylori infection, esophagitis, and peptic ulcers found in our patients with diabetes (with or without dyspepsia) suggests that this population should be considered "at risk" for H. pylori infection and suitable candidates for treatment.

[Study of the onset and progression of peripheral neuropathy and hypertension in NIDDM]. / Studio dell'esordio e della progressione della neuropatia periferica e dell'ipertensione nei NIDDM.

BACKGROUND: Diabetic neuropathy is the most common pathology affecting the peripheral nervous system. In prognostic terms, it is the most devastating complication of diabetes. About 50% of diabetics suffer from neuropathy between 25-30 years after the diagnosis of diabetes, even if over the past few decades there has been a considerable improvement in the diagnostic methods and criteria used to classify peripheral neuropathies, many of which are related to the development of neurophysiology. However, we still do not know enough about the incidence, prevalence and natural history of peripheral neuropathy diagnosed using clinical and electrophysiological criteria in non-insulin dependent diabetic patients. METHODS: The authors carried out a randomized study of the relationship between glucose intolerance, hyperglycemia, hyperinsulinemia, hypertension and early and manifest forms of peripheral neuropathy in 32 patients with NIDDM (aged 41-72 years old, duration of diabetes 1-27 years) over a 24-month period. In 11 patients diabetes was almost at onset (Group 1): 8 cases with diabetes for 1-2.5 years (4 hypertensives and 4 normotensives) and 3 cases with diabetes for 4 years (all normotensive). Twenty-one patients (Group 2) had had diabetes for longer (5-27 years): 5 were hypertensive and 16 normotensive. A full longitudinal neurophysiological study (EMG and ENG) was performed. In 11 NIDDM in Group 1, at basal conditions carpal tunnel syndrome (right CTS) was revealed in 1 case, right CTS with diffuse radiculopathy in 1 case, diffuse radiculopathy in 2 cases, lumbosacral radiculopathy in 1 case, and 1 right CTS with "mixed" symptoms. EMG-ENG were normal in 2 patients. RESULTS: The following developments were noted during the follow-up: rapid deterioration due to the onset of motor sensitive polyneuropathy (MSPN) in 1 patient, 3 cases of chronic neurogenic disorder with active denervation, 2 cases of "mixed" type symptoms. The results were only comparable in 2 cases. In 3 NIDDM with diabetes for 4 years, 1 patient presented MSPN and 2 were affected by chronic neurogenic disorders; during the follow-up the conduction of MSPN and active denervation deteriorated into chronic neurogenic syndrome. Moreover, 6 initially normotensive NIDDM developed hypertension. In 21 NIDDM of Group 2, 7 of the 16 who were initially normotensive became hypertensive. Three new cases of polyneuropathy were also reported in this group, and 5 already had MSPN but showed a deterioration of conduction during the follow-up in 1 case. One patient presented active denervation in chronic neurogenic symptoms and chronic neurogenic symptom was comparable in 1 case. One patient presented a normal EMG-ENG at both the start and end of the study. "Mixed" type of symptoms were recorded at the basal level in 11 patients (defined as the presence on the EMG of muscular areas with multiphase potentials of brief duration and low amplitude, first recruited under slight voluntary effort, isolated or mixed with areas of neurogenic potentials). Over the course of 12-24 months, eight patients deteriorated with chronic neurogenic symptoms without active denervation in 5 and present in 2 cases. One case also showed a deterioration of carpal tunnel syndrome. CONCLUSIONS: These results show that 1) metabolic control and a complete neurophysiological examination are essential for preventing and identifying the onset and progress of neuromuscular damage; 2) the onset or deterioration of these two complications mainly had a less well known common cause which was less studied and described.

Lower frequency of sister chromatid exchanges and altered frequency of HLA B-region alleles among individuals with sporadic dysplastic nevi.

Sister chromatid exchanges (SCE) were analyzed in peripheral blood lymphocytes of 24 individuals, following diagnosis, and prior to surgical removal, of a sporadic dysplastic nevus (DN). Lower SCE values and variability were found in 23 sporadic DN individuals compared with controls (2.52 +/- 0.12 and 3.76 +/- 0.22 SCE/cell, respectively). These DN individuals, contrarily to healthy controls and some types of tumor patients whose cells are hypersensitive to mutagenic agents, did not show increased SCE rates as a consequence of cigarette smoking, alcohol consumption and diagnostic radiation treatments. These observations are in contrast with clinical evidence that similar lesions are both markers or risk and precursors of malignancy in individuals with multiple nevi, affected by the dysplastic nevus syndrome (DNS) or belonging to FMM (familial malignant melanoma) families. Three HLA class I alleles out of 72 tested were found more frequently in sporadic DN individuals compared with controls: B37 (p < 0.05), B52 (p < 0.01) and B70 (p < 0.01). Whether the greater chromosomal stability (as shown by the SCE analysis), and/or the altered frequency of some HLA alleles could influence the chance of developing cutaneous malignancy in DN individuals is yet to be evaluated.

The in vitro production of thromboxane B2 by platelets of diabetic patients is normal at physiological concentrations of ionized calcium.

Platelets of patients with diabetes and no evidence of macroangiopathy produce normal amounts of thromboxane (Tx) B2 in vivo, whereas they usually show increased production in vitro. Since in vitro studies have been usually performed in citrated PRP, we tested the hypothesis that the discrepancy between in vivo and in vitro studies is due to the low concentration of plasma ionized calcium ([Ca2+]o) that is present in citrated PRP. In fact, low [Ca2+]o artifactually potentiates the platelet TxB2 production in vitro. Forty patients with diabetes mellitus and 37 matched controls were studied. Blood was anticoagulated with citrate, the thrombin inhibitor D-phenylalanyl-l-prolyl-l-chloromethylketone (PPACK) or both anticoagulants. Platelet aggregation, release of 14C-serotonin and TxB2 production were induced in platelet rich plasma (PRP) by several agonists. The following results were obtained: i) Citrated PRP: Arachidonic acid induced aggregation (p < 0.01) and TxB2 production (p < 0.02) were significantly greater in patients than in controls. No statistically significant differences were found with other agonists. ii) PPACK PRP: No statistically significant difference was found between diabetic platelets and controls. iii) PPACK plus citrate PRP: The results were not different from those obtained with citrate alone. Therefore, our results show that diabetic platelets produce normal amounts of TxB2 in vitro when the [Ca2+]o is physiological.

Sister chromatid exchange analysis in familial groups of malignant melanoma patients.

Sister chromatid exchange (SCE) analysis was carried out on peripheral blood lymphocytes of 20 familial malignant melanoma (FMM) and 39 sporadic malignant melanoma (SMM) untreated patients, belonging to 10 and 39 families, respectively. The study was extended to 39 unaffected close relatives of FMM patients, to 187 unaffected close relatives of SMM patients, and to 20 unaffected unrelated individuals (control group), all examined under the same conditions. The mean SCE rates/cell were significantly higher in MM families than in the control group, and in melanoma patients than in their close relatives. The mean SCE levels of FMM and SMM patients, (8.4 +/- 0.8 and 8.0 +/- 0.3, respectively) were similar, and so were the distributions of individuals in classes of increasing SCE values (with a modal value at 7-8 SCEs/cell). The mean SCE levels of close relatives of FMM and SMM patients were also similar (5.4 +/- 0.2 and 5.4 +/- 0.1, respectively, with a modal value at 4-5 SCEs/cell), and slightly higher than in the control group (4.7 +/- 0.2 SCEs/cell). More than 7 SCEs/cell were observed in the majority (41 of 59) of FMM or SMM patients, in a smaller fraction (25 of 227) unaffected relatives, and in none of 20 unrelated unaffected individuals. These observations favor the hypothesis that higher SCE levels may be an expression of constitutional lesions predisposing to this neoplastic disease.

HLA study of 21 families with two or more members affected by febrile convulsions.

21 Italian families with at least two members who had had febrile convulsions (FC) were HLA-typed for class I antigens. A total of 49 subjects and 43 close relatives (parents or sibs) were examined. No single antigen or haplotype was statistically more frequent among pooled FC subjects. The study, however, is not conclusive regarding a relationship between FC and HLA region because of the possible genetic heterogeneity of proneness to FC. In a significant proportion of cases two FC affected sibs had unaffected parents: besides the models of inheritance so far proposed for this pathology, the involvement of two complementary dominant factors was also considered. The report includes uncommon cases: a family where one FC affected parent transmitted the same HLA haplotype to all three affected sibs; two more families, with both parents and progeny affected by FC. The HLA typing of all members of these unusual families, although not furnishing relevant information at present, may be of value to other investigators.

Double minute chromosomes and a homogeneously staining chromosome region in C3H10T1/2 murine cells transformed "in vitro" by proton radiation.

Four foci (type II or type III) of transformed cells, isolated from the murine line C3H10T1/2 after exposure to proton radiations, were expanded and cytogenetically examined. While the overall numerical chromosome distributions were similar, there were some differences between the various cell lines with regard to the presence and frequency of specific-marker chromosomes and to the colony-forming efficiency in soft-agarose medium. No association between any of these markers and the transformed phenotype could be established. However, in the line F4, derived from a type II focus, numerous double-minute chromosomes (DM) were observed after passage 22, and the phenomenon became more pronounced in the subclone C2. The finding of DMs in radiation-transformed cells is unusual. The DMs were observed in long-term subcultures, and in one of them they were partially replaced by a homogeneously staining chromosome region (HSR). DNAs from transformed cells of the line F4 and subclone C2 was digested with restriction enzymes and analyzed by Southern blotting with probes for seven oncogenes commonly amplified in cancer cells (c-myc, N-myc, N-ras, Ki-ras, Ha-ras, c-myb, c-abl) and with probes for the mouse MHC class I region. None of the regions tested was structurally altered or amplified in these transformed cells. The origin of the genetic material carried by DMs or homogeneously staining intrachromosomal regions (HSR) in cells of the line F4 and subclone C2, where it is believed to provide a selective advantage for in vitro growth, remains unknown.

Sister chromatid exchange in methotrexate resistant and sensitive C3H10T1/2 mouse cells.

Sister chromatid exchange (SCE) induction by methotrexate (MTX) was analyzed in C3H10T1/2 clone 8 mouse cells and in two MTX-resistant subclones with numerous double minute chromosomes (DM) present in the majority of cells. Significantly higher SCE levels were found, as expected, in sensitive cells after treatments with 10(-2) or 10(-5) M MTX but not in resistant cells permanently growing in the presence of a high concentration of MTX (2 x 10(-3) M) and characterized by a markedly lower cell cycle replication index (R.I.), i.e. in conditions that are known to otherwise favour SCE induction. These observations suggest, for the MTX-resistant cells under study, the existence of conditions limiting SCE formation.

[Afterload changes in diabetic dysautonomia evaluated using echocardiography]. / Alterazioni del post carico nella disautonomia diabetica valutate ecocardiograficamente.

We have studied echocardiographic morpho-functional alterations in 34 male subjects with diabetes, aged 31-73 years, with and without autonomic nervous system failure. The subjects are grouped following the tests "deep breathing", "Valsalva manoeuver", "lying to standing" and "active standing" in: D-I (10 normal subjects); D-II (16 subjects with parasympathetic failure); D-III (8 subjects with orthosympathetic failure). The D-III subjects showed significantly lower parietal systolic stress (PSS) compared to normal subjects, 115.6 +/- 17.4 vs 163.1 +/- 13.1 10(3) dynes/cm2 (mean +/- 1SD), and significantly lower end isovolumetric systolic stress, 67.8 +/- 7.8 vs 98.6 +/- 7.1 10(3) dynes/cm2 ("afterload" indexes). In D-III group, the subjects with noradrenaline levels greater than 300 pg/ml, with an hypothetical peripheral resistance to noradrenaline (or receptor "down regulation"), showed higher blood pressure levels and higher parietal stress (PSS: 141.3 +/- 25.3 vs 98.5 +/- 20.7 10(3) dynes/cm2; EISS: 74.1 +/- 17.8 vs 63.6 +/- 8.6 10(3) dynes/cm2). Thus, cardiovascular signs of autonomic failure, like the stress index variation, related to a modification of the afterload, may be observable in diabetic patients.

An unusually large 5q duplication in an adult female subject: spreading of inactivation and in vitro instability of the derivative Xp/5q chromosome.

An unbalanced translocation resulting in an unusually large partial 5q trisomy (5q11-5qter) and partial Xp monosomy (Xp11-Xpter) is reported in a 24 yr old woman with phenotypic abnormalities including gonadal dysgenesis and mental retardation. The karyotypes of the parents and the brother were found normal. Peripheral blood stimulated lymphocytes and cutaneous fibroblasts of the proband exhibited constantly, after BrdU incorporation, selective inactivation of the derivative X;5 chromosome spreading to the 5q duplicate segment. A variety of numerical and structural changes involving the derivative chromosome were observed in about 10% of cells of the cultured lymphoblastoid line established from the subject's lymphocytes. The extended 5q duplication, according to the literature, is generally accompanied by a severe phenotype and by developmental failure; it is therefore believe that genetic inactivation of the 5q duplicated region permitted the proband's development to adult age, despite the profound chromosomal imbalance.

Sister chromatid exchange and proliferation pattern in stimulated lymphocytes of cutaneous malignant melanoma patients.

Sister chromatid exchange (SCE) and the proliferative pattern of phytohemagglutinin-stimulated lymphocytes were examined in 36 nonfamilial cutaneous malignant melanoma (CMM) patients. One close relative of each of 27 CMM patients was also examined. All the patients had undergone surgical treatment for the neoplasm, but had received no chemotherapy or radiotherapy. The SCE rates were found to be higher and more variable in a significant fraction of CMM patients, and in relatively fewer unaffected relatives, which is in contrast to findings in unrelated subjects taken as controls. Also, variable and higher proportions of cells in metaphase of the first cell cycle (M1), after 72-hr culture in the presence of bromodeoxyuridine, were more often found among the CMM patients than in the controls; however, no effect of clinical progression of the neoplastic disease on SCE rates or on the lymphoproliferative pattern was observed. The present study indicates heterogeneity among subjects who develop CMM and suggests that the peculiarities of SCE rates and of the lymphoproliferative patterns observed in some of the CMM patients and in a few of their close relatives may be connected with the mechanism of onset of the neoplasm.

Malignant melanoma: sister chromatid exchange analysis in three families.

Sister chromatid exchange (SCE) was analyzed in stimulated lymphocytes and skin fibroblasts in members of three families with cutaneous malignant melanoma (CMM). Two of these families were characterized by familial CMM; the other family had one patient affected by CMM and two others with other cutaneous melanocytic lesions. All the patients had undergone surgery but no chemotherapy. Higher and differing SCE rates were found in lymphocytes and in fibroblasts of all patients. A wide range of SCE distribution was found in patients with high SCE rate. A few healthy close relatives also showed relatively high SCE rates and wide range distributions. These subjects may be regarded as a subset of family members at high risk for developing cancer. The variability of SCE rates and distribution may reflect genetic heterogeneity of CMM.

Reciprocal translocations in couples with spontaneous abortions.

A sample of 87 couples addressed to cyto-genetic analysis after the occurrence of one or more spontaneous abortions was studied. Reciprocal translocations were found in three couples. In reviewing the literature, the data were broken down and reassembled in order to estimate the translocation frequency in homogeneous samples. The conclusions of this re-examination is that for those couples with a history of frequent spontaneous abortions, a cytogenetic investigation is advisable, even if there have been no cases of still-borns or malformed children.