Rosuvastatin positively changes nerve electrophysiology in diabetic rats.

OBJECTIVE: To examine the effect of rosuvastatin on peripheral nerve function in diabetic rats using electrophysiological measurements. BACKGROUND: Diabetes was induced in 5-day-old male Wistar rats by intraperitoneal (i.p.) injection of streptozotocin (STZ). As many as 45 diabetic rats were randomized to three groups: one treated with rosuvastatin (group R), another with rosuvastatin and mevalonate (group MR) and the other was untreated (group U). The data were compared with a group of normal age-matched rats i.e. control rats (group C). METHODS: Neurophysiological measurements were performed at the age of 3 months (T1) and again at the age of 8 months (T2), after 3 months of treatment. RESULTS: At T1, there was a trend to lower amplitude of compound motor action potential (CMAP) in the three diabetic groups as compared to controls, and no difference for motor nerve conduction velocity (MNCV), amplitude of sensory nerve action potential (SNAP), sensory nerve conduction velocity (SNCV) between diabetic groups and controls. At T2, the amplitude of CMAP was significantly lower in groups R and MR versus group U and control rats. MNCV was significantly and similarly decreased in the three diabetic groups; the latency of the first sensory peak (fastest sensory fibres) was significantly increased in group U but was normal in groups R and MR. CONCLUSIONS: This study shows that: 1.rosuvastatin exerts a beneficial effect on the conduction of the fastest sensory fibres;2.these effects are independent of blood pressure and lipid changes.

Effect of cerivastatin on peripheral capillary permeability to albumin and peripheral nerve function in diabetic rats.

OBJECTIVE: To examine the effect of cerivastatin on capillary permeability to albumin and peripheral nerve function in diabetic rats. ANIMALS: Diabetes was induced in male Wistar rats by i.p. injection of streptozotocin (STZ) at the age of 5 days. Forty diabetic rats were randomized in two groups: one treated by cerivastatin (diabetic treated group, DT) and the other untreated (diabetic untreated group, DU). The data were compared to a group of normal rats. MEASUREMENTS: The peripheral capillary filtration of albumin (CFA) was studied on a limb by a non-invasive isotopic method, and nerve electrophysiological measurements were performed. Rats were followed-up until 6 months. In group DU albumin retention (AR) increased by 3 months and lymphatic uptake of interstitial albumin was impaired at 6 months. None of these disorders was observed in group DT. Motor and sensory nerve conduction velocities (MNCV and SNCV) were significantly slower at 6 months in group DU but not in group DT as compared to control rats. The duration of the sensory nerve action potential (SNAP) was significantly longer in group DU than in control rats at 6 months whereas it did not differ in group DT and in control animals. CONCLUSIONS: This study shows that cerivastatin may prevent the peripheral increase in CFA and lymphatic dysfunction induced by diabetes. These beneficial effects on microcirculation may be involved in the prevention of nerve function deterioration. The underlying mechanisms are likely to be independent of a lipid-lowering effect, but their clarification needs further investigations.

Increased capillary filtration of albumin in diabetic patients--relation with gender, hypertension, microangiopathy, and neuropathy.

The aim of this study was to investigate the factors associated with an increase in capillary filtration of albumin (CFA) in a large series of diabetic patients and its relationship with gender, hypertension, microangiopathy, and neuropathy. One hundred sixty-three unselected diabetic patients, 74 type I and 89 type II, were included. An isotopic test of CFA was performed with 99m technetium-labeled albumin injected intravenously. Radioactivity was counted externally at the forearm with a gamma camera before, during, and after venous compression. After removal of venous compression, interstitial albumin retention (AR) was calculated and the radioactivity disappearance curve was analyzed by the Fast Fourier transform, which provides an index for lymphatic uptake of interstitial albumin (low-frequency to high-frequency amplitude peak ratio [LF/HF]). An increase in AR and LF/HF was found in 65 (39.9%) and 117 (71.7%) patients, respectively. Increased AR was significantly more frequent in women than in men (P=.018) and in patients without microangiopathic complications than in those with them (P=.028). In men, it was significantly more frequent in type I versus type II diabetic patients (P=.004), and AR was significantly higher in patients with peripheral neuropathy than in those without (P=.004). The LF/HF was also significantly higher in men with peripheral neuropathy (P=.045). In women, the AR level correlated negatively with postprandial glycemia (P=.006) and was significantly higher in patients without microangiopathic complications (P=.003). These data suggest the role of hormonal factors, both sex steroids and insulin, and the major role of peripheral neuropathy in the increase in CFA. The highly prevalent increase in CFA before the onset of microangiopathic complications is consistent with the presence of a functional microcirculatory disorder that might contribute to the occurrence of microangiopathic lesions.

Impairment of lymphatic function in women with gynoid adiposity and swelling syndrome.

The current study sought to investigate the factors, in particular anthropometric parameters, associated with an impairment of capillary permeability and lymphatic function in a large series of women complaining of a swelling syndrome. One hundred ninety-seven women with a swelling syndrome were investigated, 43 of whom were obese (body mass index [BMI]>30 kg/m2), 77 overweight (BMI=25 to 30 kg/m2). Thirty-five of the 197 women had abdominal adiposity (waist-to-hip ratio [WHR]>0.85). Capillary filtration of albumin and lymphatic function were studied by means of an isotopic test using 99mtechnetium-labeled albumin and venous compression. This test allowed measurement of interstitial albumin retention (AR) and the evaluation of lymphatic function by analyzing the radioactivity disappearance curve after removal of venous compression with the fast Fourier transform (low frequency/high frequency [LF/HF]). Body composition was studied by the bioelectrical impedance method. WHR correlated with fasting blood glucose (P=.03), serum triglyceride (P<.0001), and apoprotein B (P=.008) levels. AR was increased (> or =8 %) in 117 women (59.4%) and LF/HF (> or =1 %) in 149 cases (75.6%). Extracellular water (ECW) was increased (>107% of the theoretical value) in 144 cases (73.1%). LF/HF correlated negatively with age (P=.001), BMI (P=.006), WHR (P<.0001), and fat mass (P=.002). In the multivariate analysis taking age, BMI, and WHR as independent variables, LF/HF correlated significantly with WHR (P<.005). There was a trend to a higher prevalence of an increase in AR in the women with an increase in ECW (61.8 %) as compared with those without an increase in ECW (52.8%). We conclude that abdominal adiposity is associated with metabolic disorders secondary to insulin resistance as previously demonstrated, whereas lymphatic dysfunction is mainly associated with gynoid adiposity. Besides microcirculatory disorders, changes in the secretory regulation of hormones involved in salt and water retention are likely to play an important role in ECW excess.

In vivo sequential study of skeletal muscle capillary permeability in diabetic rats: effect of anthocyanosides.

Alterations in the capillary filtration of macromolecules are well documented in diabetic patients and experimental diabetes. Various flavonoids including anthocyanosides and ginkgo biloba extracts have been shown to be effective against experimentally induced capillary hyperfiltration. The aim of the present study was to test the effects of anthocyanosides on capillary filtration in diabetic rats. For this purpose, we have validated the use of our previously described in vivo method for measurement of the capillary filtration of albumin (CFA) in rats. Male Wistar rats with streptozotocin (STZ)-induced diabetes were randomized in 3 groups to receive either ginkgo biloba (group A), Vaccinium myrtillus (group B), or no treatment (group C). The isotopic test of CFA consisted of intravenously injecting 99mtechnetium-labeled albumin, inducing venous compression on a hindquarter, and measuring radioactivity externally on the limb before, during, and after removal of venous compression. After removal of the tourniquet, the radioactivity curve decreased. Interstitial albumin retention (AR) and the ratio of the amplitudes of the low- and high-frequency peaks (LF/HF ratio), an index of lymphatic function obtained by the fast Fourier transform of the last part of the radioactivity curve, were calculated. In STZ-treated animals, the isotopic test was performed at a mean age of 97 days (time 1) and after 6 weeks (time 2) and 12 weeks (time 3) of treatment, ie, 6 and 12 weeks after time 1. At time 1, AR was significantly higher in the 3 diabetic groups than in the control rats, without a significant difference between these groups. In group B, AR decreased significantly (P = .015) at times 2 and 3. In group C, AR increased significantly (P < .0005) from time 1 to time 3. In group A, AR increased slightly (NS) between time 1 and time 3. In groups A and C, the LF/HF ratio significantly increased with time (P < .0005) and the levels at time 3 were significantly higher versus control rats (P < .0001). In group B, the LF/HF ratio remained unchanged from time 1 to time 3 and similar to the values found in the control rats. In conclusion, these data show that (1) this new in vivo noninvasive method can be used to study CFA in skeletal muscle in diabetic rats, (2) it is reproducible and may be repeated over several months to evaluate spontaneous microcirculatory changes, and (3) anthocyanosides appear to be effective in preventing the increase in CFA and the failure of lymphatic uptake of interstitial albumin in diabetic animals.

In vivo kinetics of 123 iodine-labelled insulin in skeletal muscle of patients with type 2 diabetes. Effect of metformin.

BACKGROUND: The capillary filtration of albumin (CFA) is often increased in diabetic patients. However, the transcapillary transfer of insulin is considered to be a key stage in insulin action. The aim was to study the in vivo kinetics of 123I-labelled human insulin in the skeletal muscle of type 2 diabetic patients with an increase in CFA and to evaluate the effect of metformin, using a noninvasive method. METHODS: Ten type 2 diabetic patients and 6 healthy control subjects were investigated. After an i.v injection of 123I-labelled insulin, venous samples were drawn during 75 minutes and radioactivity was counted externally by a gammacamera on the contralateral forearm before, during and after venous compression. The changes in the serum percentages of bound and free 123I were followed during the entire test and the forearm iodine bound to insulin was estimated by multiplying the forearm counted radioactivity by the serum percentage of bound iodine at the same time. RESULTS: In the diabetic patients the maximal increase in the forearm iodine bound to insulin during venous compression was lower (p=0.06), and 10 minutes after removal of venous compression the forearm retention of labelled insulin was significantly lower (p<0.0005) than in controls. After one month of metformin treatment, retention of labelled insulin significantly increased (p<0.001) but was still significantly lower than in the controls (p<0.001). CONCLUSION: The in vivo kinetics of (123) I-labelled insulin procedure allows the study of skeletal muscle metabolism provided venous compression is exerted. In type 2 diabetic patients a reduction of insulin transfer from capillary to tissue despite an increase in CFA, and a reduction of the time spent by insulin in the tissues contribute to insulin resistance. The latter disorder may be improved by metformin.

Application of in vivo activation analysis to the compartmental study of sodium in the hand.

Sodium kinetics were studied in the hands of 14 subjects by local in vivo neutron activation analysis. Hands were irradiated with 252 Cf sources giving absorbed doses of 8 cGy. The variation in 24Na radioactivity was plotted against time, and each curve fitted to a function that was the sum of two exponentials. Two pools were identified, one corresponding to fast turnover, with a half-life of about one hour, the other to a slower turnover process with a half-life averaging 79 h if the calcium concentration of the hand bones is normal, and 35 h if it is subnormal. The mean ratio of calcium to slowly exchangeable sodium is estimated to be 47.7, and the ratio of quickly exchangeable sodium to slowly exchangeable sodium to be 0.65. These various parameters should be of interest in bone pathology.

Chernobyl three years later: radiobiologic evaluation of a radioactive contamination.

On April 26, 1986, after partial fusion and confining loss by explosion of a nuclear reactor, 5 x 10(7) Ci of radionuclides escaped from Chernobyl. Three years later, maps show contamination by radioactive isotopes (formed during that period) of 21,000 km2 of Soviet soil, mainly in Byelorussia and part of the Ukraine. Decontamination measures have not been effective to date and 135,000 persons are being followed medically, taking into account the radioactive doses they received. An initial excess of morbidity from solid tumors has been noted much sooner than in the case of Hiroshima and Nagasaki, but its significance is in dispute. Three years later, only the extent of the ecologic disaster caused by the radioactive contamination can be confirmed. It is too early to draw conclusions about radiation-induced carcinogenesis for the contaminated population.

Study of capillary filtration by double labelling I131-albumin and Tc99m red cells. Application to the pharmacodynamic activity of Daflon 500 mg.

The Tc99m albumin test can be used to confirm idiopathic cyclic oedema (ICO) syndrome by a pathological retention of albumin of more than 8% of the maximum level, following release of the tourniquet (results obtained in 420 patients compared with 100 healthy women). This test was completed by a study involving double labelling using I131-albumin and Tc99m red cells in ten healthy subjects and ten female patients with untreated ICO syndrome. The tests were repeated at a six week interval. Evaluation of retention levels after tourniquet release showed nil retention of red cells in both populations and nil albumin retention in the healthy subjects whilst it was pathological in the patients with ICO. The curve of decreasing radioactivity was often marked by irregular oscillations after tourniquet removal. Study of these oscillations by the Fast Fourier Transform revealed reproducible abnormalities in the low frequency zone only, between 37 and 28 mHz in the ICO patients. These abnormalities took the form of more frequent peaks with higher amplitudes than in the healthy subjects and were linked--in the case of excessive leak of albumin from capillaries--to lymphatic resorption. In the high frequency zone between 630 and 39 mHz, results corresponding to variations related to arteriovenous compliance were similar in both populations and by both tests. A double blind placebo-controlled trial in 30 patients with ICO was carried out to study the pharmacodynamic activity of a flavonoid, Daflon 500 mg (2 tabs daily for 6 weeks), which revealed a decrease in the degree of retention--initially high--of labelled albumin (p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Capillary filtration and lymphatic resorption in diabetes. Application to the pharmacodynamic activity of Daflon 500 mg.

Microcirculatory disorders are often a complication of diabetes. They are associated with an increased capillary permeability which can be assessed by the Landis test using 99mTc-labelled albumin. Labelled albumin retention is measured by external detection (residual radioactivity after removal of venous tourniquet). The Fast Fourier Transform of the radioactivity disappearance graph reflects the lymphatic albumin resorption. Thirteen out-patients with diabetes from 1 to 19 years suffering from evident microcirculatory disorders were treated with a micronized flavonoid fraction: Daflon 500 mg (2 tablets per day) during a month. Antihypertensive and/or antidiabetic treatment were continued during the study if they were given before starting. A test was performed before, and at the end of the treatment. In 10 of the 13 patients, the test was carried out a third time 5.5 +/- 1.0 months later, after treatment withdrawal. Results were as follows: 1) labelled albumin retention was abnormal (greater than or equal to 8%) at the start and became normal in the patients and improved in 1 patient. After treatment withdrawal, the results of the third test were again abnormal, in the patients who had been normalized beforehand; 2) the initially abnormal lymphatic resorption became normal in six of the 13 patients at the end of the treatment and became abnormal again in all patients after treatment withdrawal. In a parallel group of 15 patients with abnormal test lymphatic fluctuations and not being treated with a vasculo-protector agent, the initially abnormal test remained abnormal 5 to 48 months later in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in capillary permeability in diabetic patients.

Microangiopathic disorders, characterized by capillary vasodilation and increases in capillary blood flow and permeability, are common in diabetes and can occur before the development of microangiopathic complications. In a study of 163 diabetic patients, capillary permeability, measured by albumin retention (AR), was increased in 39% of patients. AR was increased more frequently in women than in men, and in patients without microangiopathic complications than in patients with complications. Increased AR was significantly associated with insulin-dependent diabetes in male patients. Lymphatic function was abnormal in 72% of patients; this abnormality was often present before AR increased. The pathophysiology of microangiopathy is complex and involves metabolic, haemodynamic, neurological and hormonal factors. Improved control of glycaemia and blood pressure can reduce capillary permeability. In addition, studies with a flavonoid fraction and n-3 polyunsaturated fatty acids suggest that these agents may also be beneficial.

Nerve electrophysiological changes in rats with early induced diabetes.

In rats with diabetes induced at weaning, pathological examinations have shown that the reduction of myelin thickness occurs earlier than axon size reduction. The aim of this study was to provide a detailed description of neurophysiological changes during nerve growth and maturation in rats with streptozotocin-induced diabetes in prepubertal stage. Five-day male Wistar rats received an injection of streptozotocin. Motor and sensory conduction velocities increased until 6.5 months in diabetic and control rats and at this age it became lower in diabetic rats. In diabetic rats, the amplitudes of the compound motor action potentials (CMAP) were lower by the 3 months and did not increase later. The amplitudes and areas of sensory action potentials (SNAP) increased until 9 months in both groups. SNAP duration decreased with ageing. Sensory peak 1 and peak 2 latencies became longer from 6.5 to 9 months in diabetic rats, with a longer latency difference between the 2 sensory peaks by 4 months. At 3 and 4 months of age, peak 1 and peak 2 latencies correlated with SNAP amplitude and duration in control rats but not in diabetic rats. In conclusion, in rats with early induced diabetes, the earliest electrophysiological impairments consist of lower CMAP amplitudes, and longer difference between latencies of sensory peaks 1 and 2. These sequential neurophysiological changes should be considered when testing new therapeutic approaches in diabetic neuropathy.

Chernobyl, four years on.

It is still too soon to make a full assessment of the Chernobyl disaster, but one should be begun, and practical inferences, with particular reference to the prevention of radiation-induced cancers, may be drawn.

Extra cellular water and increase in capillary permeability to albumin in overweight women with swelling syndrome.

OBJECTIVE: To evaluate extracellular water (ECW) in the recumbent and the upright position, in overweight and lean women with swelling syndrome, and to correlate the excess in ECW with an increase in capillary filtration of albumin (CFA). PATIENTS: Fifty-one women with a swelling syndrome were investigated, 26 of whom were overweight. MEASUREMENTS: ECW was measured by the bioelectrical impedance method, in the recumbent position and again after a postural test which consisted of walking around for 30 min. CFA was studied by an isotopic test using 99m technetium-labelled albumin. RESULTS: ECW increased (>107% of the theoretical value) in 22 of the 26 overweight patients and 23 of the 25 lean patients. The CFA isotopic test was abnormal in half (11/22) of the overweight patients with increased ECW and in three of the four overweight patients with a normal ECW value. It was abnormal in 18 of the 23 lean patients with increased ECW and in the two lean patients with a normal ECW value. During the postural test, a significant (by> or =4%) increase in ECW occurred in a higher proportion of overweight patients tested (14/22) than among the lean women tested (0/5; P=0. 04). CONCLUSIONS: The swelling syndrome is indeed related to an increase in ECW in lean and overweight subjects and to a further increase in ECW after a postural test only in the overweight patients. It is also associated with microcirculatory disorders in most of the lean patients who complain of swelling and in only half of the overweight patients with the same complaints, which suggests that other factors (e.g. hormonal disorders) may be involved in the overweight patients. International Journal of Obesity (2000)24, 126-130