Neurotrophin-3 is increased in skin in human diabetic neuropathy

Although macrolides have been associated with significant pharmacokinetic interactions, clarithromycin is considered to have a low interaction capacity. In this study, six transplant recipients treated with cyclosporin A also received clarithromycin. In all patients, the dose of cyclosporin A had to be reduced by a mean of 33% per day depending on the macrolide dose. Normalization of the dosage parameters began on the fourth day after stopping clarithromycin treatment. Co-administration of cyclosporin A and clarithromycin may lead to increases in whole blood cyclosporin levels, and appropriate dose reductions should be considered.     

Autonomic neuropathy in diabetic children

OBJECTIVE: Evaluate the presence of cardiovascular autonomic nerve dysfunction in children and adolescents with insulin-dependent diabetes mellitus. METHODOLOGY: We studied 110 patients (54 male, 56 female) and 100 healthy sex and age-matched children. Autonomic nerve function was assessed by standard cardiovascular reflex tests: (1) Fall in systolic blood pressure in response to standing. (2) Heart rate in response to standing. (3) Beat-to-beat rate variation during deep breathing. (4) Quotient of heart rate during and after Valsalva manoeuvre. (5) Change in blood pressure response to sustained handgrip. The coefficient of variation of heart rate was determined from 150 systoles using a microcomputer-based technique. The lower limits of normal were defined according to statistical analysis taking into account the relationship between heart rate variability and age. RESULTS: Forty-seven of the 110 diabetic children and adolescents studied showed one or more abnormal tests for cardiovascular autonomic dysfunction; many patients had an abnormality in more than one test. Twenty-two patients showed early involvement, 18 patients had definite and 7 severe involvement. No correlation was found between sex, glycaemic control, duration of diabetes or presence of retinopathy and persistent microalbuminuria and the autonomic nerve function. CONCLUSIONS: In the paediatric age group also, autonomic nerve dysfunction can be present in asymptomatic diabetic patients. Heart rate variation during Valsalva manoeuvre and maximum/minimum 30:15 ratio are the most sensitive indices to detect autonomic abnormalities in children.     

Gait abnormalities in diabetic neuropathy

OBJECTIVE: To investigate the effect of peripheral neuropathy on gait in diabetic patients. RESEARCH DESIGN AND METHODS: Gait analysis was performed in the following groups matched for age, sex, and BMI: 20 normal healthy control subjects (NC), 20 non-neuropathic diabetic control subjects (DC), 20 neuropathic diabetic subjects (DN), and 20 neuropathic diabetic subjects with a history of foot ulceration (DNU). All subjects with orthopedic foot problems were excluded from the study. The following gait parameters were investigated: 1) walking speed; 2) stance phase duration; 3) joint angles and moment arms for the ankle, knee, and hip joints in both sagittal and frontal planes; 4) the components of the ground reaction force (GRF) vector; and 5) the ankle, knee, and hip joint moments originating from the GRF vector in both planes. RESULTS: There were no statistical differences in any of the parameters studied between the NC and DC groups. Walking speed was significantly slower in the DNU group compared with the two control groups (P < 0.02). The maximum knee joint angle was smaller in the sagittal plane for the DNU group compared with the DC group values (P < 0.05). The maximum value of the vertical component of GRF was found to be higher (P < 0.03) in the two control groups compared with the DNU group. The maximum value of the anteroposterior forces was also found to be higher (P < 0.001) in the DC group compared with the DNU group. The maximum frontal plane ankle joint moment was significantly higher (P < 0.05) in the DN compared with the NC group. CONCLUSIONS: Diabetic subjects with peripheral neuropathy demonstrate alterations in some gait parameters during walking. These alterations could facilitate foot injuries, thus contributing to frequent foot ulceration.     

Antihypertensive therapy and diabetic microvascular disease

Hypertension is commonly associated with diabetes and may represent either a manifestation or a cause of diabetic vascular injury. The following series of studies have explored the role of hypertension in accelerating diabetic microvascular injury. In addition, the role of various classes of antihypertensive agents in preventing or reversing diabetic vascular abnormalities in the presence and absence of systemic hypertension was assessed in both the experimental and clinical context. The induction of streptozotocin diabetes in SHR leads to accelerated development of nephropathy as assessed by both functional and structural parameters. ACE inhibitors but not dihydropyridine calcium channel blockers favourably influence the progression of experimental diabetic nephropathy even in the setting of a normal blood pressure. More recent studies have shown that the trophic changes in the mesenteric arteries from diabetic rats are also attenuated by ACE inhibition. Preliminary results from the Melbourne Diabetic Nephropathy Study Group suggest that the ACE inhibitor, perindopril, is more effective than the dihydropyridine calcium channel blocker, nifedipine, in retarding the rise in urinary albumin excretion in normotensive insulin and noninsulin dependent diabetic patients with microalbuminuria. In conclusion, ACE inhibitors appear to be the drugs of choice in prevention and treatment of diabetic renal disease and may also act as protective agents at other sites of vascular injury.     

Total cardiac denervation in diabetic autonomic neuropathy

Total loss of the autonomic regulation of heart rate is described in a 28-year-old diabetic with extensive autonomic neuropathy. The patient had an almost fixed heart rate that barely responded to any of the tests that stimulate or inhibit the autonomic nerves. Its behavior was similar to that of the transplanted heart.     

Impaired vasoreactivity to nitric oxide in experimental diabetic neuropathy

Nerve blood flow (NBF) is reduced in experimental diabetic neuropathy (EDN), but the mechanism of its reduction is uncertain. We tested the hypothesis that reduced NBF might be due to alterations of nitric oxide synthase (NOS) and endothelin of microvascular endothelial cells of sciatic nerve. We evaluated epineurial arteriolar vasoreactivity in response to superfused test agents. NBF was measured using microelectrode H2 polarography. Vasoconstrictor responses to endothelin-1 (ET-1; 10(-6), 10(-7), 10(-8), 10(-9), 10(-10) M) showed dose-response curves with similar EC50 values, indicating no change in potency. We applied the NOS inhibitor NG-nitro-L-arginine and observed reduced inhibition of NBF in EDN, correctable with insulin treatment and also with infused L-arginine. We conclude that vasoreactivity is disturbed in EDN, and is due to a combination of an impairment of NOS activity with reduced NO and increased endothelin effect (normal receptor sensitivity and increased plasma values) in EDN. Hyperglycemia is likely to be the mechanism of NOS inhibition since insulin treatment reversed this abnormality.     

Provocation of postural hypotension by insulin in diabetic autonomic neuropathy

The effect of insulin administration on blood pressure has been investigated in eight diabetes with autonomic neuropathy. Systolic and diastolic pressures fell considerably after insulin in all of them. This effect was aggravated by tilting to the vertical position. Five patients fainted when upright with systolic blood pressures less than 50 mm. Hg. This hypotensive effect of insulin occurs whether it is administered intravenously, intramuscularly, or subcutaneously. The onset of the effect is almost immediate after intravenous insulin, is progressive, and may last for several hours. It coincides with a falling blood glucose level and occurs before hypoglycemic levels are reached, and it may be present when the blood glucose level is still elevated. Diurnal variations of postural hypotension have been recorded in some patients, the standing blood pressure falling with the onset of insulin action and rising again as the latter declines. Some of our patients were unable to differentiate between symptoms of hypoglycemia and hypotension. Postural hypotension may account for some episodes of sudden loss of consciousness without warning, usually attributed to hypoglycemia.     

Electrical spinal-cord stimulation for painful diabetic peripheral neuropathy

BACKGROUND: Conventional treatment for painful peripheral diabetic neuropathy is largely symptomatic and often ineffective, with unacceptable side-effects. We tested electrical spinal-cord stimulation for the management of chronic neuropathic pain. METHODS: Ten diabetic patients who did not respond to conventional treatment (mean age 51 [SD 9.3] years, six with type II diabetes, mean duration of diabetes 12 [6.3] years, mean duration of neuropathy 5 [2.1] years) were studied. The electrode was implanted in the thoracic/lumbar epidural space. Immediate neuropathic pain relief was assessed by visual analogue scale (VAS) after connecting the electrode, in a random order, to a percutaneous electrical stimulator or to a placebo stimulator. Exercise tolerance was assessed on a treadmill. FINDINGS: Eight subjects had statistically significant pain relief with the electrical stimulator (p < 0.02) and were therefore converted to a permanent system. Statistically significant relief of both background and peak neuropathic pain was achieved at 3 months (n = 7, p = 0.016), at 6 months (n = 7, p = 0.03), and at the end of the study (14 months, n = 7, background pain p = 0.06, peak pain p = 0.03). One patient died 2 months after the start of the study of unrelated cause while continuing to benefit from treatment and another patient ceased to benefit at 4 months. McGill pain questionnaire scores with the stimulator turned off did not change significantly from baseline scores, indicating that the severity of the underlying pain was unaltered. However, with the stimulator turned on, there was a statistically significant (p < 0.05) improvement in all four components of the score, by the end of the study. At the end of the study, six patients continued to gain significant pain relief and used the stimulator as the sole treatment for their neuropathic pain. For example, median background and peak pain scores at the end of study, were, respectively, 77 and 81 with the stimulator off and 23 and 20 with the stimulator on. Exercise tolerance significantly improved at 3 months (n = 7, median % increase 85 [IQR, 62-360], p = 0.015) and at 6 months (n = 6, 163 [61-425], p = 0.0007). Electrophysiological tests, vibration perception-threshold, and glycaemic control were unchanged. INTERPRETATION: Electrical spinal-cord stimulation offers a new and effective way of relieving chronic diabetic neuropathic pain and improves exercise tolerance. The technique should be considered in patients with neuropathic pain who do not respond to conventional treatment.     

A model of human microvascular exchange

A compartmental model consisting of the circulation, a general interstitium, and the lymphatics, is formulated to describe the transport and distribution of fluid and plasma proteins (albumin) in the human microvascular exchange system. Transcapillary mass exchange is assumed to occur via a coupled Starling mechanism. Unknown or poorly quantified model parameters are estimated by statistical fitting of simulation predictions to five different sets of experimental data. The data consist of steady-state and transient plasma and interstitial volumes and colloid osmotic pressures measured under laboratory or clinical conditions for normal humans and for patients with nephrotic syndrome or mild heart disease. In all cases, it is assumed that the system response to perturbations imposed either artificially or through illness is due to changes in the Starling driving forces. The three best-fit parameters were found to be normal capillary hydrostatic pressure, Pc,o = 11.0 mm Hg; albumin reflection coefficient, sigma = 0.99; and lymph flow sensitivity, LS = 43.1 ml/mm Hg.hr. Three other parameters, which were unknown but related to the estimated parameters through steady-state mass balance equations, were determined to be fluid filtration coefficient, KF = 121.1 ml/mm Hg.hr; albumin permeability-surface area product, PS = 73.0 ml/hr; and normal lymph flow, JL,o = 75.7 ml/hr. The fully described model was validated by comparisons between (1) simulation predictions and data used in parameter estimation, (2) estimated transport parameters and available literature values, and (3) model predictions and an additional set of experimental data.     

Role of neuropathy and high foot pressures in diabetic foot ulceration

OBJECTIVE: High plantar foot pressures in association with peripheral neuropathy have been ascertained to be important risk factors for ulceration in the diabetic foot. Most studies investigating these parameters have been limited by their size and the homogeneity of study subjects. The objective of this study was therefore to ascertain the risk of ulceration associated with high foot pressures and peripheral neuropathy in a large and diverse diabetic population. RESEARCH DESIGN AND METHODS: We studied a cross-sectional group of 251 diabetic patients of Caucasian (group C) (n=121), black (group B) (n=36), and Hispanic (group H) (n=94) racial origins with an overall age of 58.5+/-12.5 years (range 20-83). There was an equal distribution of men and women across the entire study population. All patients underwent a complete medical history and lower extremity evaluation for neuropathy and foot pressures. Neuropathic parameters were dichotomized (0/1) into two high-risk variables: patients with a vibration perception threshold (VPT) > or =25 V were categorized as HiVPT (n=132) and those with Semmes-Weinstein monofilament tests > or =5.07 were classified as HiSWF (n=190). The mean dynamic foot pressures of three footsteps were measured using the F-scan mat system with patients walking without shoes. Maximum plantar pressures were dichotomized into a high-pressure variable (Pmax6) indicating those subjects with pressures > or =6 kg/cm2 (n=96). A total of 99 patients had a current or prior history of ulceration at baseline. RESULTS: Joint mobility was significantly greater in the Hispanic cohort compared with the other groups at the first metatarsal-phalangeal joint (C 67+/-23 degrees, B 69+/-23 degrees, H 82+/-23 degrees, P=0.000), while the subtalar joint mobility was reduced in the Caucasian group (C 21+/-8 degrees, B 26+/-7 degrees, H 27+/-11 degrees, P=0.000). Maximum plantar foot pressures were significantly higher in the Caucasian group (C 6.7+/-2.9 kg/cm2, B 5.7+/-2.8 kg/cm2, H 4.4+/-1.9 kg/cm2, P=0.000). Univariate logistic regression for Pmax6 on the history of ulceration yielded an odds ratio (OR) of 3.9 (P=0.000). For HiVPT, the OR was 11.7 (P=0.000), and for HiSWF the OR was 9.6 (P=0.000). Controlling for age, diabetes duration, sex, and race (all P < 0.05), multivariate logistic regression yielded the following significant associations with ulceration: Pmax6 (OR=2.1, P=0.002), HiVPT (OR=4.4, P=0.000), and HiSWF (OR=4.1, P=0.000). CONCLUSIONS: We conclude that both high foot pressures (> or =6 kg/cm2) and neuropathy are independently associated with ulceration in a diverse diabetic population, with the latter having the greater magnitude of effect. In black and Hispanic diabetic patients especially, joint mobility and plantar pressures are less predictive of ulceration than in Caucasians.     

Ambulatory blood pressure measurement in type-II diabetic patients with autonomic neuropathy

The aim of our study was to access the 24-hr ambulatory blood pressure (BP) in diabetic patients with autonomic neuropathy (AN). Twenty-two NIDDM patients without hypertension, being treated with sulfonylureas, were studied. The 24-hr ambulatory blood pressure recordings were performed using portable non-invasive automatic system. Autonomic neuropathy was assessed by standard cardiovascular reflex tests. There were ten patients with and 12 without AN, matched for age, body mass index, duration of diabetes and glycemic control. Mean BP increased at night in four of the subjects with AN and decreased in the remaining 18 patients. The group of subjects with nocturnal increases in BP had more severe autonomic nerve dysfunction compared with those with decreases in nocturnal BP. No significant difference between clinical and ambulatory day-time measurements was found. In three patients with AN after 5 weeks intensified therapy. 24-hr BP did not show any significant difference.     

Transperineurial capillary abnormalities in the sural nerve of patients with diabetic neuropathy

Morphometric techniques were employed to assess perineurial capillary abnormalities in the sural nerve of 20 diabetic patients with neuropathy and 10 normal control subjects. Structural abnormalities were related to quantitative neurophysiological and neuropathological measures of neuropathy. Perineurial capillary endothelial cell area (P < 0.001) and endothelial cell profile number (P < 0.01) were increased and luminal area (P < 0.001) was reduced in diabetic patients when compared with control subjects. A significant relationship was observed between endothelial cell hyperplasia and measures of neuropathic severity. These findings provide evidence for perineurial capillary luminal occlusion due primarily to both endothelial cell hypertrophy and hyperplasia. Such a reduction in luminal size is expected to reduce transperineurial and hence endoneurial blood flow, resulting in endoneurial hypoxia and hence human diabetic neuropathy.     

Mexiletine. A review of its therapeutic use in painful diabetic neuropathy

Mexiletine is an orally active local anaesthetic agent which is structurally related to lidocaine (lignocaine) and has been used for alleviating neuropathic pain of various origins. Mexiletine has been evaluated in several randomised, placebo-controlled trials in patients with painful diabetic neuropathy. The drug decreased mean visual analogue scale (VAS) pain ratings in all studies that used this measure, although in only 2 studies was this effect significantly greater than the often substantial responses seen with placebo. The clinical significance of these decreases is not clear. Statistically significant (vs placebo) reductions in VAS pain ratings were observed in 16 patients receiving mexiletine 10 mg/kg/day for 10 weeks in 1 study and in nocturnal (but not diurnal) pain in 31 patients receiving mexiletine 675 mg/day for 3 weeks in another. Retrospective analysis of another study revealed that mexiletine recipients (225 to 675 mg/day) who described their pain as stabbing, burning or formication on the pain-rating-index-total instrument of the McGill Pain Questionnaire, experienced statistically significant reductions in VAS pain scores after 5 weeks, compared with placebo recipients. Mexiletine generally did not have a significant influence on the quality of sleep in patients with diabetic neuropathy. In Japanese patients, statistically significant reductions in subjective pain ratings were achieved with mexiletine 300 mg/day in 1 study and with 450 mg/day in a further study. In controlled trials, the frequency of adverse events in patients receiving mexiletine for painful diabetic neuropathy ranged from 13.5 to 50%. Gastrointestinal complaints, of which nausea was the most frequent, were the most common adverse events in mexiletine recipients. Central nervous system complaints were uncommon, but included: sleep disturbance, headache, shakiness, dizziness and tiredness. Serious cardiac arrhythmias have not been reported in patients receiving mexiletine for painful diabetic neuropathy; however, transient tachycardia and palpitations have been reported. There are significant differences in the metabolism of mexiletine between people who have cytochrome P450 2D6 [CYP2D6; extensive metabolisers (EMs)] and those who lack this isoenzyme [poor metabolisers (PMs)]. EMs, but not PMs, are susceptible to drug interactions between mexiletine and drugs that inhibit CYP2D6 (e.g. quinidine). Moreover, mexiletine inhibits CYP2D6-mediated metabolism of metoprolol and cytochrome P450 1A2-mediated metabolism of theophylline. Phenytoin and rifampicin (rifampin) induce the metabolism of mexiletine. Clearance of mexiletine is impaired in patients with hepatic, but not renal, dysfunction. Hence, dosage adjustments may be necessary in patients with liver disease. CONCLUSIONS: Tricyclic antidepressants (TCAs) are the agents of choice for painful diabetic neuropathy; however, they are ineffective in approximately 50% of patients and are generally not well tolerated. Mexiletine is an alternative agent for the treatment of painful diabetic neuropathy in patients who have not had a satisfactory response to, or cannot tolerate, TCAs and/or other drugs.     

Corrected QT interval in relation to the severity of diabetic autonomic neuropathy

The aim of this study was to investigate to what extent the existence of objective signs of diabetic autonomic neuropathy affects the corrected QT interval (QTc) in diabetic subjects. A total of 105 diabetic subjects (type 1, n = 53; type 2, n = 52) as well as 40 matched (by age and sex) control subjects were studied. All subjects underwent the battery of five Ewing tests. Autonomic neuropathy was diagnosed if two of the five tests were abnormal. In addition, the result of each test was considered as normal (grade = 0), borderline (grade = 1) or abnormal (grade = 2), and on the basis of the sum of the scores we calculated a total score for autonomic neuropathy. The QTc interval was measured at rest, and a value > 440 ms was considered abnormal. The QTc interval was significantly more prolonged in diabetic persons with autonomic neuropathy than in those without neutopathy and in control subjects: 408.4 +/- 24.2 ms vs. 394.6 +/- 27.9 ms and 393.6 +/- 25.5 ms respectively (P = 0.001). Furthermore, multivariate analysis controlling for age, sex, systolic and diastolic blood pressure, body mass index (BMI), waist-hip ratio (WHR), smoking, type and duration of diabetes, type of treatment, HBA1c and total score of autonomic neuropathy eliminated the role of all these factors as potential confounders except for the total score of autonomic neuropathy, which was found to affect QTc interval independently and significantly (P = 0.012). In summary, the present study confirmed the well-known relation between autonomic neuropathy and QTc interval; in addition, it showed that QTc prolongation is associated with major degrees of autonomic neuropathy.     

The role of axonal ion conductances in diabetic neuropathy: a review

Diabetic neuropathy is a common complication in diabetes mellitus. Diabetic neuropathy is accompanied by alterations in axonal excitability, which can lead to either "positive" (paresthesia, dysesthesia, pain) and/or "negative" (hypesthesia, anesthesia) symptoms. The mechanisms underlying these alterations in axonal excitability are not well understood. Clinical tests reveal reduced nerve conduction velocity and axonal loss, but fail to explain nerve excitability. Many different factors have been suggested in relation to the pathophysiology of diabetic neuropathy. There are probably as many factors as there are different clinical pictures in diabetic neuropathy. Nevertheless, it seems that hyperglycemic hypoxia is mainly responsible for the electrophysiological changes seen in damaged diabetic nerves. This article summarizes experimental data indicating that a dysfunction of ion conductances, especially voltage-gated ion channels, could contribute to abnormalities in the generation and/or conduction of action potentials in diabetic neuropathy.     

Association of relative nocturnal hypertension and autonomic neuropathy in insulin-dependent diabetic children

Twenty-four hour BP and heart rate measurements were carried out in fourteen newly diagnosed-, and in twenty-eight diabetics with 5-13 years of duration; and in eight healthy control children. Mean arterial BP rose at night in five-, fell slightly (less than 10%) in five- and fall markedly (more than 10%) in eighteen diabetics with longer duration of the disease. The diurnal-nocturnal difference of mean arterial pressure was significantly lower in the groups with nocturnal BP rise and slight nocturnal BP fall, compared to the control group (< 0.001; p < 0.01, respectively). The diurnal-nocturnal differences of heart rates were significantly lower in diabetics with relative "nocturnal hypertension" compared to the control group (p < 0.05). The presence of subclinical signs of diabetic autonomic neuropathy was significantly higher in patients with nocturnal BP rise and slight nocturnal BP fall compared to patients with marked nocturnal BP fall and newly diagnosed diabetics (chi squared p = 0.02 and p = 0.01, respectively). In conclusion, the prevalence of autonomic symptoms in diabetic children could be related to change in diurnal/nocturnal arterial BP, however longitudinal studies of ABPM are needed to define, whether patients with abnormal BP profiles are candidates for the development of diabetic vascular disease.     

Reproducibility of different methods for diagnosing and monitoring diabetic neuropathy

The subspecialty of allergy and immunology, like all medical specialties, has been dramatically impacted by the managed care revolution. Many of the changes that have been imposed by our environment are likely to persist, including increased emphasis on efficiency of practice and cost-effectiveness of treatment modalities. It is predicted that these changes will decrease the involvement of allergists and immunologists in the primary treatment of patients with allergic rhinitis and mild asthma, in favor of management by generalists with subspecialty consultation. Conversely, outcomes studies demonstrate the cost-effectiveness of management of moderate to severe asthma by an allergy and immunology subspecialist. It is thought probable that HMOs will recognize this fact and implement it as a pattern of practice. The allergist and immunologist will continue to offer, uniquely, expertise in allergic history taking, patient education, environmental control, and management of allergic inflammation. He or she will also be afforded an opportunity for practice expansion, particularly as an expert consultant, into other areas of immune inflammation, such as autoimmunity and graft rejection. Potentially new and increasingly specific products of the pharmaceutical and biotechnology industries will enhance these opportunities for practice expansion by physicians who combine intellectual understanding with practical expertise in patient management. Realization of these new opportunities will require us to work together as teachers and role models to communicate the excitement of our subspecialty to new physicians. Allergy and immunology is a subspecialty with a bright future, provided that we have the will and the insight to deal effectively with our challenges and to master opportunities that our science presents to us.