Short-term prediction of secondary progression in a sliding window: A test of a predicting algorithm in a validation cohort.

INTRODUCTION: The Multiple Sclerosis Prediction Score (MSPS, www.msprediction.com) estimates, for any month during the course of relapsing-remitting multiple sclerosis (MS), the individual risk of transition to secondary progression (SP) during the following year. OBJECTIVE: Internal verification of the MSPS algorithm in a derivation cohort, the Gothenburg Incidence Cohort (GIC, n = 144) and external verification in the Uppsala MS cohort (UMS, n = 145). METHODS: Starting from their second relapse, patients were included and followed for 25 years. A matrix of MSPS values was created. From this matrix, a goodness-of-fit test and suitable diagnostic plots were derived to compare MSPS-calculated and observed outcomes (i.e. transition to SP). RESULTS: The median time to SP was slightly longer in the UMS than in the GIC, 15 vs. 11.5 years (p = 0.19). The MSPS was calibrated with multiplicative factors: 0.599 for the UMS and 0.829 for the GIC; the calibrated MSPS provided a good fit between expected and observed outcomes (chi-square p = 0.61 for the UMS), which indicated the model was not rejected. CONCLUSION: The results suggest that the MSPS has clinically relevant generalizability in new cohorts, provided that the MSPS was calibrated to the actual overall SP incidence in the cohort.

Assessing tissue damage in multiple sclerosis: a biomarker approach.

OBJECTIVES: Magnetic resonance imaging (MRI) of the brain and spinal cord is the gold standard for assessing disease activity in multiple sclerosis (MS). MRI is an excellent instrument for determination of accumulated damage to the brain and spinal cord, but tells us little about ongoing tissue damage. In this study, biomarkers of oligodendrocyte, axonal and astrocyte injury were related to MRI and clinical findings and used to assess tissue damage in MS. MATERIALS AND METHODS: Cerebrospinal fluid from 44 patients with relapsing-remitting MS, 20 with secondary progressive MS and 15 controls were investigated with ELISA to determine levels of myelin basic protein (MBP), neurofilament light (NFL) and glial fibrillary acidic protein (GFAp). Patients underwent MRI of the brain and spinal cord, and gadolinium enhancing lesions, T1 lesions and T2 lesions were counted. RESULTS: Patients in clinical relapse and patients with nonsymptomatic gadolinium enhancing lesions had high levels of MBP and NFL, indicating ongoing damage to oligodendrocytes and axons. The level of MBP dropped quickly within a week from the onset of a relapse, whereas NFL remained elevated for several weeks and GFAp slowly rose during the course of a relapse. Relapsing-remitting MS patients without gadolinium enhancing lesions had values of MBP, NFL and GFAp similar to controls, while patients with secondary progressive disease had moderately increased values of all biomarkers. CONCLUSIONS: Analysis of MBP, NFL and GFAp provides direct means to measure tissue damage and is a useful addition to our methods for evaluation of MS.

Normal outcome of pregnancy with ongoing treatment with natalizumab.

BACKGROUND: Treatment of multiple sclerosis (MS) with natalizumab during pregnancy is not recommended due to potential risks for the foetus. Despite strong advice accidental pregnancies occur. CASE: A 32-year old woman with MS since the age of 26 was treated with natalizumab since January 2008. Treatment was stopped April 2011 due to pregnancy plans, but was restarted following an MS relapse. The patient was thoroughly informed about potential foetal risks, but nevertheless she one year later disclosed that she was pregnant in gestational week 15. Treatment was continued, since the first trimester had passed. The pregnancy course was normal and a healthy daughter was born at full gestational term. CONCLUSIONS: This is the second known case where natalizumab treatment continued throughout the whole gestational period.

Time to secondary progression in patients with multiple sclerosis who were treated with first generation immunomodulating drugs.

BACKGROUND: It is currently unknown whether early immunomodulatory treatment in relapsing-remitting MS (RRMS) can delay the transition to secondary progression (SP). OBJECTIVE: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort. METHODS: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995-2004, n = 730) and a historical population-based incidence cohort (onset 1950-64, n = 186). We retrospectively analyzed the difference in time to SP, termed the "period effect" within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis. RESULTS: We found that the "period" affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53). CONCLUSION: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given.

Bilateral and recurrent optic neuritis in multiple sclerosis.

OBJECTIVE: To assess the frequency of bilateral and recurrent optic neuritis (ON) in multiple sclerosis (MS) and to compare these results with epidemiological data of ON in neuromyelitis optica (NMO) and recurrent ON without other signs of disease. METHODS: We identified 472 patients with diagnosis of MS from the Swedish Multiple Sclerosis Register. These patients were evaluated for the presence of ON and whether the ON was the presenting symptom of MS; unilateral or bilateral; monophasic or recurrent. RESULTS: Twenty-one percent presented with ON as their first manifestation of MS. The proportion of patients developing a second attack of ON before demonstration of other manifestations of MS was 5.5% and the frequency of recurrent bilateral ON as the presenting symptom was 3.8%. Only two patients presented with simultaneously appearing bilateral ON corresponding to 0.42%. CONCLUSION: Recurrent ON, whether unilateral or bilateral, is a common presentation of MS. As MS is a much more common disease than NMO, care must be taken when evaluating the work-up of patients with recurrent ON. In some cases repeated MRI and lumbar punctures are warranted to improve diagnostic accuracy, even in the presence of the serological marker NMO-IgG.

Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation.

BACKGROUND: During the last 15 years, high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HSCT) has globally been performed for severe multiple sclerosis (MS). Most patients have been in progressive phase with long disease duration. As a rule, treatment effect has been minor or moderate. PATIENTS: Since 2004, we have performed HSCT in nine young patients with "malignant" relapsing-remitting MS. Criteria for treatment were short duration of disease; very frequent, severe relapses; recent improvement periods indicating potential for recovery after strong immunosuppression. FINDINGS: Median age at treatment was 27 (range 9-34) years, MS duration 26 (4-100) months, and annualized relapse rate 10 (4-12). Median Disability Status Scale (extended disability status scale, EDSS) at HSCT was 7.0 (3.5-8.0). Median follow-up time April 2008 is 29 (23-47) months. Median EDSS improvement is 3.5 (1.0-7.0), clearly surpassing most previous reports. One patient relapsed mildly with rapid recovery 7 months after HSCT. All patients are otherwise stable, median EDSS being 2.0 (0-6.0). Before HSCT, 61 relapses occurred in 82 patient months; during follow-up, one relapse in 289 patient months. CONCLUSION: This small series of patients with "malignant" relapsing-remitting MS suggests HSCT to be an effective treatment option for this relatively rare disease course. It further suggests that future criteria for HSCT in MS should be close to the present ones.

Sympathetic nerve activity in metabolic control--some basic concepts.

A role for the sympathetic nervous system in hypertension has been looked for in relation to the 'metabolic syndrome' with associations between body weight, insulin sensitivity and hypertension. By use of microneurography human sympathetic responses to hypoglycaemia, normoglycaemic hyperinsulinaemia and food intake have been studied. A strong but differentiated influence of insulin-induced hypoglycaemia comprises increase in muscle sympathetic nerve activity (MSNA) and the sudomotor part of skin sympathetic nerve activity (SSNA), whereas vasoconstrictor SSNA is inhibited. Responses to infusion of 2-deoxy-D-glucose are identical, suggesting central nervous system glucopenia and not insulin to be the causative factor. Insulin infusion during normoglycaemia evokes a moderate increase in MSNA; SSNA and blood pressure does not change. After glucose ingestion MSNA displays a sustained increase, which is only partly elicited by insulin. A significant albeit weaker increase occurs after pure protein or fat meals, and after glucose ingestion in C-peptide-negative diabetic patients, with no insulin secretion. In healthy elderly people the MSNA response to food intake is weak, because of a high outflow already at rest; this is suggested to explain postprandial hypotension in the elderly, a paradoxical mechanism behind clinical autonomic failure. A pathophysiological role of MSNA in the metabolic syndrome with hypertension has been speculated. An association between obesity and elevated level of MSNA at rest is established; observed relationships to chronic insulin levels and hypertension are less unanimous. The adipose tissue regulating hormone leptin has become one focus of interest in ongoing attempts to elucidate a possible role of the human sympathetic nervous system in the 'metabolic syndrome' and hypertension.

The increase in sympathetic nerve activity after glucose ingestion is reduced in type I diabetes.

Food intake is followed by an increase in baroreflex-governed sympathetic outflow to muscle vessels. It is established that insulin contributes to this stimulation; however, the increase occurs (to a lesser degree) even in the absence of enhanced insulin secretion. To further elucidate the role of insulin, muscle nerve sympathetic activity was recorded by microneurography, and the increase after an oral 100-g glucose load in eight C-peptide-negative patients with type I diabetes without any signs of neuropathy was compared with that in 16 healthy control subjects. The level of sympathetic activity at rest was similar in the two groups (type I diabetes patients, 19.5+/-2.4 bursts/min; controls, 20.4+/-4.8 bursts/min; means+/-S.D.). Following glucose intake there was a significant increase in activity in both groups, with maximum values at 30 min of 24.3+/-3.7 bursts/min for type I diabetes patients and 34.4+/-9.1 bursts/min for controls. The summarized response (during 90 min) of the diabetic patients was less than half that of the control subjects (P=0.0003). It is concluded that the response of muscle nerve sympathetic activity to glucose ingestion is reduced to about half of its normal strength in the absence of insulin, and that there is no difference in sympathetic outflow at rest between healthy subjects and diabetic patients without polyneuropathy.

Sympathetic vasoconstrictor outflow to extremity muscles in cluster headache. Recordings during spontaneous and nitroglycerin-induced attacks.

To search for evidence of sympathetic dysregulation during cluster headache attacks, microneurographic recordings of muscle nerve sympathetic activity (MSA) were obtained from the peroneal nerve. In three recordings commenced after the onset of spontaneous attacks, MSA was about twice as high during the attack as afterwards. In four nitroglycerin-induced attacks, MSA showed a rise paralleling the pain, preceded by an initial peak. The latter accompanied hypotension, whereas the rise coinciding with cluster headache was associated with rising blood pressure. The normal baroreflex-governed pulse synchrony of MSA was preserved both during spontaneous and provoked attacks. In seven cluster headache patients in whom nitroglycerin did not cause an attack, only an initial peak in MSA occurred. Nor was any late nitroglycerin-induced rise in MSA observed in nine healthy subjects; the initial peak in MSA and heart rate was followed by a rapid return to normal despite a falling blood pressure. It is concluded that cluster headache attacks are associated with an increase in MSA that elevates blood pressure by causing vasoconstriction, and that this increase, rather than indicating sympathetic dysregulation, is a normal pain-evoked secondary phenomenon. The findings in healthy subjects support the notion that nitroglycerin has a central sympatho-inhibitory effect.

Increase in muscle nerve sympathetic activity after glucose intake is blunted in the elderly.

Muscle nerve sympathetic activity (MSA; involved in blood pressure regulation) was recorded by microneurography in the peroneal nerve for 90 min after ingestion of 100 g D-glucose in three groups of healthy subjects: young subjects (mean age 26 years) and 70-year-old men with normal and reduced insulin sensitivity as assessed by euglycaemic insulin clamp. Muscle nerve sympathetic activity at rest was lowest in the young and highest in the insulin-resistant subjects (burst frequencies 19.8 +/- 6.0, 47.7 +/- 7.0 and 55.1 +/- 11.5 bursts/min for the three groups, respectively). The young subjects responded to glucose intake with a pronounced increase in MSA, a response that was blunted in the elderly and weakest in the insulin-resistant subjects. A similar relationship was observed during a Valsalva manoeuvre, indicating that the blunted response in the elderly is a generalized phenomenon. Blood pressure remained stable in the young subjects but fell slightly and significantly in the elderly subjects. It is concluded that old subjects utilize their total capacity for MSA close to maximum at rest. Thus, the reserve for response to stimuli normally evoking a strong increase in MSA is restricted. This restriction may contribute to postprandial hypotension in the healthy elderly.

Effect of noxious stimulation on sympathetic vasoconstrictor outflow to human muscles.

1. In fifteen healthy volunteers, muscle nerve sympathetic activity (MSA) was recorded from the peroneal nerve using microneurography. Blood pressure and electrocardiogram were also recorded. 2. Painful stimuli, adjusted to the subject's tolerance level, were delivered over 30-60 s via (a) pressure to the nail-bed of different digits, and to the trigeminal region, (b) electrical stimulation (5 Hz) of digital nerves and of the supraorbital nerve, or (c) instillation of soap solution into one eye. Non-painful ocular pressure was also applied. 3. All procedures except electrical stimulation of digital nerves caused a marked increase in MSA (mean, 160-248%) with preserved pulse synchrony and a rise in blood pressure. Stimulation of digits induced tachycardia, whereas stimulation of the trigeminal region tended to cause bradycardia. 4. Despite similar pain ratings, electrical stimulation of digital nerves caused a smaller MSA response than the other stimuli (mean increase, 40%). 5. It is concluded that sustained noxious stimulation in awake humans evokes a generalized MSA increase; the activity is still under baroreflex control, but the inhibitory level is reset. Both spinal and brainstem reflexes may contribute; a defence reaction is an unlikely explanation. It is suggested that the number of afferent C fibres activated by electrical stimulation of digital nerves was insufficient to induce any marked MSA response. 6. The non-painful oculo-cardiac reflex is associated with a strong increase in MSA.

Human sympathetic nerve activity to glabrous skin does not increase during simulated diving.

In humans, cardiovascular adjustment to simulated diving causes a marked increase in sympathetic outflow to intramuscular vessels and muscle vasoconstriction. Skin vasoconstriction in the hand also occurs during diving in humans. Skin nerve sympathetic activity (SSA), containing vasoconstrictor signals to glabrous skin, unexpectedly was reduced during diving in a previous study of SSA recorded in the peroneal nerve. SSA was recorded by microneurography in the median nerve in 13 healthy volunteers during simulated diving. Skin blood flow in the hand and one finger was monitored. The typical SSA response, irrespective of duration of diving and water temperature, was an increase during the control period immediately prior to immersion of the face and a sudden reduction of SSA when the face was immersed. The increase in SSA preceding the dive was accompanied by vasoconstriction, which continued during the dive, but re-dilation regularly occurred before the end of the dive. Inhibition of SSA was not total. Mental arithmetic during diving evoked strong bursts of SSA, similar to those seen normally during mental stress. It is concluded that the true response of SSA to simulated diving is an inhibition of the immediately preceding outflow, in agreement with observations of cutaneous blood flow in animals. The skin vasoconstriction recorded during simulated diving is a consequence of an SSA increase before the procedure, suggested to be a stress response before the forthcoming manoeuvre. The SSA response during simulated diving is the opposite to that of sympathetic outflow to muscle, which emphasizes the diversity of sympathetic regulation of different organ systems.

Increase in muscle nerve sympathetic activity in humans after food intake.

1. The influence of the intake of different nutrients on muscle nerve sympathetic activity was studied by use of microneurography. Muscle nerve sympathetic activity, heart rate, blood pressure and the insulin response were monitored for 90 min in 39 healthy, lean, normotensive subjects (mean age 26 years) who received 100 g of glucose in 300 ml of water (n = 8), 50 g of fat in 250 ml of water (n = 8), 100 g of lean meat corresponding to 40 g of protein with 250 ml of water (n = 8), 300 ml of water only (n = 7) or a mixed meal (1750 kJ) (n = 8). 2. All types of food evoked an increase in muscle nerve sympathetic activity whereas water caused no change. The increase in muscle nerve sympathetic activity was already significant at 15-30 min and was still strongly significant at 90 min. The effect of glucose was significantly greater than that of fat and protein; the mixed meal caused an intermediate response. Blood pressure changes were minor. 3. It is concluded that a sustained increase in muscle nerve sympathetic activity occurs regularly after any type of food intake. A rise in muscle nerve sympathetic activity takes place in the absence of an insulin response, and insulin contributes to only part of the increase after ingestion of glucose or a mixed meal. The muscle nerve sympathetic activity response is thought to be of importance for the redistribution of blood to the splanchnic region after a meal. Lack of this response is likely to explain postprandial hypotension in autonomic failure.

Metabolic regulation of sympathetic nervous system activity: lessons from intraneural nerve recordings.

Intraneural recordings of sympathetic nerve discharge give access to two subdivisions of the sympathetic nervous system: muscle nerve sympathetic activity and skin nerve sympathetic activity. Muscle nerve sympathetic activity (MSA) involves baroreceptor-controlled vasoconstrictor impulses to the resistance vessels in skeletal muscles. MSA is time-locked to the heart rhythm, correlates at rest to plasma noradrenaline concentrations and increases with age, but displays large inter-individual variations, the causes of which are poorly understood. Skin nerve sympathetic activity (SSA) is irregular with no relation to the pulse, is composed of sudomotor and cutaneous vasoconstrictor impulses and is practically absent in relaxed subjects in a thermoneutral environment. MSA and the sudomotor component of SSA are stimulated by acute insulin-induced hypoglycaemia, whereas the vasoconstrictor component of SSA is inhibited. MSA is stimulated by oral D-glucose but not by intravenous D-glucose or water. Under euglycaemia, insulin stimulates MSA in a dose-dependent fashion. Neither oral glucose nor insulin stimulate SSA. Exposure to carbohydrate intake and insulin have variable influences on the sympathetic nerve discharge. Various mechanisms are likely to operate in these interactions, including stimulation of central sympathetic motoneurons, baroreceptor control, and input from peripheral receptors in the vasculature or the gastrointestinal tract.

Long-term variability and reproducibility of resting human muscle nerve sympathetic activity at rest, as reassessed after a decade.

Human muscle nerve sympathetic activity measured by microneurography during supine rest is known to vary considerably between healthy subjects, whereas in a given individual the level of muscle nerve sympathetic activity is stable over weeks and months. To further characterize long-term variability or reproducibility microneurographic recordings of muscle nerve sympathetic activity were performed in 15 healthy, normotensive subjects (mean age 51 years) who had undergone the same procedure between 10 and 14 years earlier (mean 12 years). The range of muscle nerve sympathetic activity was 9-59 in the first and 13-61 bursts/min in the second recording. Subjects maintained the level of muscle nerve sympathetic activity displayed previously, although with a slight but significant tendency to a higher outflow with increasing age. It is concluded that muscle nerve sympathetic activity is characterized by large inter-individual differences and strong intra-individual reproducibility over many years, with a tendency to increase with age. The age relationship is only in a minor part responsible for the variability, the cause of which remains unexplained. Because of the marked difference between individuals, strict normality criteria are difficult to define when comparing groups of subjects. There remains the risk of either obtaining spurious differences or obscuring a true abnormality. This is unlikely to apply when results in individual subjects are compared.

The sympathetic response to euglycaemic hyperinsulinaemia. Evidence from microelectrode nerve recordings in healthy subjects.

Sympathetic nervous system activation by insulin has been suggested as a mechanism explaining the association between insulin resistance and hypertension. We further examined the effect of insulin by direct microneurographic muscle and skin nerve sympathetic activity recordings during euglycaemic insulin clamps in healthy subjects. The mean plasma insulin level was elevated from 5.3 +/- 0.7 to 92.2 +/- 2.2 mU/l in seven subjects during a 90-min one-step clamp. In six other subjects plasma insulin was further raised from 85.7 +/- 4.0 mU/l to 747 +/- 53 mU/l between 45-90 min (two-step clamp). Four of the latter subjects received a sham clamp with NaCl infusions only on a second recording session. At the low dose of insulin muscle nerve sympathetic activity increased from a resting level of 22.7 +/- 5.0 bursts per min to 27.7 +/- 5.0 bursts per min at 15 min (p less than 0.05). The increases in muscle nerve sympathetic activity were significant (p less than 0.001; ANOVA) throughout insulin infusion, with a slight further increase (from 29.2 +/- 1.6 to 32.3 +/- 1.9 bursts per min) at the supraphysiological insulin concentration. During sham clamps muscle nerve sympathetic activity did not increase. Both insulin clamps induced minor, but significant, increases in forearm venous plasma noradrenaline concentrations. Skin nerve sympathetic activity (n = 3) did not change during insulin infusions. Heart rate increased slightly but significantly (p less than 0.005), during the insulin clamps. Blood pressure was not notably affected. In conclusion, hyperinsulinaemia was associated with increased vasoconstrictor nerve activity to skeletal muscle and with no change of sympathetic outflow to skin.

Rapid resetting of human baroreflex working range: insights from sympathetic recordings during acute hypoglycaemia.

1. Human muscle nerve sympathetic activity (MSA), which is governed by baroreflexes and involved in blood pressure homeostasis, is increased during acute insulin-induced hypoglycaemia. 2. To elucidate the detailed relationship between MSA and blood pressure during hypoglycaemia, 0.15 i.u. (kg body weight)-1 regular human insulin was given intravenously to eight fasting, healthy volunteers. Microneurographic recording of MSA in the peroneal nerve was made with simultaneous monitoring of arterial blood pressure by a finger cuff (Finapres). The course of MSA and blood pressure was monitored for 30 min before and 60 min after insulin injection. In three subjects control recording without insulin injection was made for the same duration. 3. Stimulus-response regression lines were constructed by plotting diastolic blood pressure against the occurrence frequency of MSA for the period of initial rest, the period of maximal MSA outflow during hypoglycaemia and the period of glucose counter-regulation. The control experiments were analysed for the corresponding periods. 4. The stimulus-response line was stable throughout the control experiments, whereas it was shifted either to the left or to the right during hypoglycaemia, and regularly shifted to the left (i.e. towards a lower blood pressure) during glucose counter-regulation, without change of slope. 5. It is concluded that the changes in MSA during acute hypoglycaemia are not secondary to baroreflex regulation but instead are characterized by acute resetting of the baroreflex working range without change of sensitivity.

Low ambient temperature increases baroreflex-governed sympathetic outflow to muscle vessels in humans.

Microelectrode multi-unit recordings of muscle nerve sympathetic activity, primarily involved in blood pressure regulation, were made from the right peroneal nerve in 10 healthy subjects during exposure to cold inside a box used for hypothermic surgery. Blood pressure was monitored by an automatic cuff applied to the left arm. Heart activity (ECG) and the temperature inside the box were monitored. Muscle nerve sympathetic activity outflow and blood pressure were stable during 15 minutes initial rest at 22.7 +/- 0.3 degrees C (mean +/- SEM). All subjects increased muscle nerve sympathetic activity and blood pressure with lowering of ambient temperature. The box temperature was 10.5 +/- 0.3 degrees C at the end of the cooling period. With rewarming the changes in muscle nerve sympathetic activity and blood pressure were reversed. Mean outflows of muscle nerve sympathetic activity during initial rest, final phase of cooling period, and post-rewarming were 20.3 +/- 2.7, 26.6 +/- 3.2 and 20.2 +/- 2.8 burst min-1, respectively. Systolic blood pressure during the same periods was 118 +/- 3, 131 +/- 4 and 120 +/- 4 mmHg, respectively, whereas corresponding values for diastolic blood pressure were 73 +/- 2, 82 +/- 2 and 75 +/- 2 mmHg (P less than 0.001 for all variables; (ANOVA). It is concluded that muscle nerve sympathetic activity, while not regarded as being involved in body temperature regulation, is under the influence of ambient temperature and contributes to blood pressure elevation in a cold environment.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspects of autonomic neurophysiology in diabetic polyneuropathy: a brief review.

The autonomic nervous system is a very diverse system, governing many organs according to endogenous and environmental demands. Consequently autonomic dysfunction in diabetic polyneuropathy is many faceted. Assessment of autonomic nerve function, by testing the reflex responses of autonomic effector organs, should preferably take this differentiation into account. Microneurography allows direct study of the normal and disturbed physiology of two subdivisions of the sympathetic nervous system: signals in muscle nerve fascicles involved in cardiovascular homeostasis, and impulses in skin nerve fascicles involved in body thermoregulation. Observations made with this research tool emphasize the functional differentiation of the autonomic nervous system, and the technique can be used to elucidate pathophysiological mechanisms in disorders such as diabetic polyneuropathy.