Membrane flow within the myelin sheath in IDPN neuropathy

This report describes some aspects of beta,beta'-iminodipropionitrile (IDPN) neuropathy in rats as observed by ultrastructural methods and X-ray diffraction. Light microscopy shows gross swelling of the axons in proximal lumbar spinal roots 8 days after intraperitoneal injection of IDPN. Mean axon cross-sectional area and mean axon perimeter increased to 280% and 160% of their control values, respectively. At the same time, myelin membrane packing was not visibly disturbed. In addition, X-ray diffraction patterns, recorded under physiological conditions, demonstrate that the myelin lipid bilayer thickness and widths of the aqueous spaces between bilayers did not change. Related observations are made on posterior tibial nerve (PNS myelin) and ventral spinal cord (CNS myelin). The various observations together are interpreted in terms of a fluid myelin membrane. It is proposed that the myelin membrane flows during axon swelling even though normal membrane-membrane contacts are maintained within the sheath. Membrane flow and slippage between membranes are explained in terms of a molecular model of the myelin multilayer.     

Clinical characteristics of severe peripheral neuropathy induced by docetaxel (Taxotere)

Background: Docetaxel, a semi-synthetic taxane may cause a usuallymild sensory neuropathy. We describe the clinical characteristics of fivepatients who developed a more severe neuropathy following treatment withdocetaxel.Patients and methods: All patients were treated in phase II studieswith 100 mg/m² docetaxel in three weekly cycles, withoutsteroid administration.Results: The clinical picture in these patients was dominated by asensory neuropathy, but in one case severe weakness was present. Anotherpatient developed Lhermitte's sign. Signs and symptoms are usually reversibleafter discontinuation of docetaxel administration, but in three patientssymptoms worsened for some time after the end of treatment before improvementoccurred.Conclusion: Severe docetaxel neuropathy may especially occurfollowing treatment with cumulative dosage over 600 mg/m²; inpatients treated with this dosage a moderate or severe neuropathy may not berare.     

Relative nocturnal hypertension in children with insulin-dependent diabetes mellitus

Twenty-four-hour blood pressure and heart rate measurements were carried out in 14 newly diagnosed diabetics and in 28 diabetics with 5–13 years' duration of the disease; 8 healthy children were used as controls. Mean arterial blood pressure increased at night in 5, decreased slightly (less than 10%) in 5 and decreased markedly (more than 10%) in 18 diabetics with longer duration of the disease. The diurnal-nocturnal differences in heart rates were significantly lower in diabetics with relative "nocturnal hypertension" compared to the control group ( p < 0.05). A significant negative correlation was found between maximal arterial blood pressure during physical exercise and the diurnal-nocturnal differences in mean arterial blood pressure in diabetics ( r =−0.58; p < 0.02). In conclusion, we found elevated nocturnal blood pressure in a subgroup of children with longer duration of diabetes and without increased albumin excretion. However, longitudinal studies of blood pressure profiles are needed to identify the candidates for diabetic vasculopathy among diabetic children.     

Heart rate fluctuations in diabetic patients with cardiac vagal dysfunction: a spectral analysis

The autonomic nervous control of cardiac function during active orthostatic load has been studied by measuring the power spectrum of heart rate fluctuations in 16 insulin-dependent diabetic patients and 14 age-matched control subjects. The patients were subdivided into two groups: 8 with normal respiratory sinus dysrhythmia (RSA+) and 8 with reduced respiratory sinus dysrhythmia (RSA-). In RSA- patients the total power (0.01-0.50 Hz) was significantly reduced compared with control subjects (4.7 versus 15.5 min-2, 2p less than 0.05) and the pattern of heart rate fluctuations was characterized by a relative increase in the low-frequency component (0.01-0.05 Hz) as compared with RSA+ patients and control subjects (45% versus 24% and 27%, both 2p less than 0.01). There was also a significant reduction in the high-frequency component (0.15-0.50 Hz) as compared with RSA+ patients and control subjects (17% versus 36% and 33%, both 2p less than 0.05). During standing, a significant increase in total power was found only in control subjects (2p less than 0.01) and the difference between control subjects, and RSA+ and RSA- patients reached significance (32.2 versus 15.1 and 12.7 min-2, 2p less than 0.02 and 2p less than 0.01). The pattern of heart rate fluctuations in RSA- patients showed no significant change on standing. These results suggest that the reduced overall heart rate variability in diabetic patients with cardiac autonomic neuropathy is associated with a typical heart rate fluctuation pattern.     

Autoimmune reactions in patients with M-component and peripheral neuropathy.

A study of 17 patients with autoimmune axonal or demyelinating peripheral neuropathy in combination with M-component is described. The M-component was associated with MGUS (monoclonal gammopathy of undetermined significance) in 12 patients, CLL in one patient, WaldenstrÖm's disease in one patient, and myeloma in three patients. Immunohistological examination with direct and indirect fluorescence showed binding of antibodies to nerve structures of the same class and light chain as seen in the M-component. In five cases of IgM M-component, the demyelinating neuropathy was caused by binding of the IgM M-protein and complement C3b to myelin-associated glycoproteins (MAG). In 12 cases with axonal neuropathy, binding of IgG to the connective tissue of the peri- and endoneurium was found in 50% of cases, IgM in five cases, and IgD in one case. None of the patients had central nervous system (CNS) symptoms. The clinical and therapeutic difficulties are discussed; only two patients with an acute course responded to immunosuppression. A marked co-expression of other autoimmune phenomena is interpreted in the light of cross-reactions between the autoantibody and similar tissue autoantigens.     

Nerve biopsy findings in Niemann-Pick type II (NPC)

The severe infantile form of Niemann-Pick disease type II was diagnosed in a 4-year-old girl and confirmed by demonstrating in cultured skin fibroblasts a deficiency of low-density lipoprotein-stimulated cholesterol ester synthesis of < 5% of normal. Electrodiagnostic studies revealed changes of a predominantly demyelinating motor and sensory polyneuropathy. Light microscope and ultrastructural examination of a peroneal nerve biopsy showed unique changes. Compacted myelin sheaths were disproportionately thin with marked globular irregularities in single teased nerve fibres and evidence of chronic demyelination. The majority of axons were preserved but axonal spheroids and cytoskeletal abnormalities akin to neuroaxonal dystrophy were noted. Membrane-bound multilobulated lysosomal inclusions of floccular and electron-dense material were present in Schwann cells (SC), endoneurial fibroblasts, macrophages, pericytes and endothelial cells. SC of myelinated fibres were stuffed with whorls of concentric osmiophilic membranous profiles and electron-lucent material. The findings are diagnostic and differ from those of classical Niemann-Pick disease.     

Activity and distribution of phosphoinositidase C in rat sciatic nerve.

The hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2) by rat sciatic nerve cytosolic phosphoinositidase C [phosphoinositide-specific phospholipase C (PIC)] was studied at neutral pH and at ionic concentrations that approximate intracellular conditions. The principal water-soluble product formed was shown to be inositol trisphosphate by anion exchange chromatography. The maximum hydrolysis rate (2.5 nmol/min/mg protein) was achieved at less than 100 nM Ca2+. Hydrolysis was markedly increased to 15 nmol/min/mg protein by inclusion of K+ in the reaction mixture. In the presence of 200 mM K+, the optimum Ca2+ was increased to approximately 600 nM. Higher Ca2+ concentrations progressively inhibited PIP2 hydrolysis. Mg2+ also inhibited the reaction, but the presence of equimolar amounts of ATP and Mg2+ had no effect. Appreciable degradation of phosphatidylinositol-4-phosphate (PIP) also occurred in the nanomolar Ca2+ range, whereas breakdown of phosphatidylinositol (PI) required millimolar Ca2+. The presence of PIP but not PI inhibited PIP2 hydrolysis. Upon subcellular fractionation of nerve, more than 50% of recovered PIC activity was in the cytosol and about 20% was located in a myelin-enriched fraction. Using PIP2 as substrate, PIC activities in nerves from normal and streptozotocin-induced diabetic animals were not different. However, the myelin-associated enzyme from diabetic animals was more labile to freezing and thawing.