Perceptions on the value of bodily functions in multiple sclerosis.

BACKGROUND: In neurological diseases presenting with a plethora of symptoms, the value of bodily functions for a given patient might be a guide for clinical management. Multiple sclerosis (MS) is paradigmatic in this respect, and little is known about the value of different bodily functions of patients and their physicians' perceptions. METHODS: In a multicenter study, 171 patients with relapsing-remitting multiple sclerosis (RRMS), 61% with a clinically active disease within the last 2 years were followed over up to 3 years and yearly patients and their study physician rated on the perceived value of 13 bodily functions via a priority list. Differences between patients and physicians as well as modulating disease demographic factors were analyzed. RESULTS: Patients with RRMS rated visual function followed by thinking and memory and walking highest while physicians stressed mobility, followed by thinking and memory and alertness most. Ratings were independent from disease duration or disability. Strongest value judgment differences were seen in swallowing regarded more relevant by patients and hand function regarded more relevant by physicians. In general, patients' and physicians' ratings through time were quite stable. Collapsing physical items into a physical functioning scale and mental items in a mental function scale, both dimensions were regarded equally important by patients while physicians underscored physical functioning (P = .016). CONCLUSION: There are differences between patients and physicians in value statements of bodily functions in MS. In particular, visual functioning is under-recognized by physicians.

7 Tesla MRI demonstrates vascular pathology in Balo's concentric sclerosis.

Baló's concentric sclerosis (BCS) is an inflammatory demyelinating disease related to multiple sclerosis; its underlying pathology remains unclear. At 7 T MRI in a 19-year-old female BCS patient, microhaemorrhages and ectatic veins were found in T2 hyperintense regions, features which have not been previously reported in conjunction with BCS, and these findings may support the view that vascular pathology plays a role in BCS. MRS data suggest that neuron loss and lipid turnover still took place months after a remission. Plasma exchange was effective in treating a relapse with severe motor deficits, and the off-label use of natalizumab was successful in maintaining remission in this patient.

Gene silencing of MK2 in hard-to-transfect human U937 cells.

Genetic modifications used to answer biological questions in cultured cells are widely used in basic research. Common transfection methods are based on viral components causing cell activation or chemical modifications of small interfering RNA and cytotoxic reagents. Here, we report a rapid and efficient approach to transfect hard-to-transfect human U937 cells via the HVJ Envelope vector system, independent from special transfection media or immobilization of cells. This protocol provides a convenient means of knocking down MAPK-activated kinase 2 in hard-to-transfect cells to study inflammation, cell adhesion, and migration characteristics.

Description of hard-sphere crystals and crystal-fluid interfaces: a comparison between density functional approaches and a phase-field crystal model.

In materials science the phase-field crystal approach has become popular to model crystallization processes. Phase-field crystal models are in essence Landau-Ginzburg-type models, which should be derivable from the underlying microscopic description of the system in question. We present a study on classical density functional theory in three stages of approximation leading to a specific phase-field crystal model, and we discuss the limits of applicability of the models that result from these approximations. As a test system we have chosen the three-dimensional suspension of monodisperse hard spheres. The levels of density functional theory that we discuss are fundamental measure theory, a second-order Taylor expansion thereof, and a minimal phase-field crystal model. We have computed coexistence densities, vacancy concentrations in the crystalline phase, interfacial tensions, and interfacial order parameter profiles, and we compare these quantities to simulation results. We also suggest a procedure to fit the free parameters of the phase-field crystal model. Thereby it turns out that the order parameter of the phase-field crystal model is more consistent with a smeared density field (shifted and rescaled) than with the shifted and rescaled density itself. In brief, we conclude that fundamental measure theory is very accurate and can serve as a benchmark for the other theories. Taylor expansion strongly affects free energies, surface tensions, and vacancy concentrations. Furthermore it is phenomenologically misleading to interpret the phase-field crystal model as stemming directly from Taylor-expanded density functional theory.

Preserved myelin integrity and reduced axonopathy in connexin32-deficient mice lacking the recombination activating gene-1.

Mice heterozygously deficient for myelin protein zero (P0) mimicking human Charcot-Marie-Tooth (CMT) disease 1B show T-lymphocyte and macrophage upregulation in peripheral nerves, which aggravates and modulates the genetically mediated demyelinating neuropathy. In connexin32 (cx32)-deficient (cx32(def)) mice, which mimic the X-linked dominant form of CMT (CMTX), T-lymphocyte and macrophage numbers are also significantly elevated in peripheral nerves. To test the hypothesis that immune cells are indeed pathogenic in this model, we cross-bred cx32(def) mice with recombination activating gene-1 (RAG-1)-deficient mice, which lack mature T- and B-lymphocytes. In these immunoincompetent double mutants, the number of endoneurial macrophages was reduced. Furthermore, features indicative of myelin degeneration and axonopathic changes were mitigated in the RAG-1-deficient double mutants, whereas enlarged periaxonal Schwann cell collars, a hallmark specific for cx32-mutants, were not reduced. Since both cx32- and P0 deficiency lead to similar immunopathogenic processes, we conclude that immune-mediated demyelination may be a feature common to many CMT-like neuropathies independent of the genetic origin.

A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3.

Autosomal recessive Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of disorders affecting the peripheral nervous system. The axonal form of the disease is designated as "CMT type 2" (CMT2), and one locus (1q21.2-q21.3) has been reported for the autosomal recessive form. Here we report the results of a genomewide search in an inbred Costa Rican family (CR-1) affected with autosomal recessive CMT2. By analyzing three branches of the family we detected linkage to the 19q13.3 region, and subsequent homozygosity mapping defined shared haplotypes between markers D19S902 and D19S907 in a 5.5-cM range. A maximum two-point LOD score of 9.08 was obtained for marker D19S867, at a recombination fraction of.00, which strongly supports linkage to this locus. The epithelial membrane protein 3 gene, encoding a PMP22 homologous protein and located on 19q13.3, was ruled out as being responsible for this form of CMT. The age at onset of chronic symmetric sensory-motor polyneuropathy was 28-42 years (mean 33.8 years); the electrophysiological data clearly reflect an axonal degenerative process. The phenotype and locus are different from those of demyelinating CMT4F, recently mapped to 19q13.1-13.3; hence, the disease affecting the Costa Rican family constitutes an axonal, autosomal recessive CMT subtype (ARCMT2B).

Abnormal vasoreaction to arousal stimuli--an early sign of diabetic sympathetic neuropathy demonstrated by laser Doppler flowmetry.

Early diagnosis of diabetic autonomic neuropathy contributes to the prevention of serious complications and improves the prognosis of patients with diabetes. Common tests of peripheral autonomic function are the quantitative sudomotor axon reflex test or the sympathetic skin response (SSR). Quantitative sudomotor axon reflex test is quantifiable but technically demanding. Sympathetic skin response cannot be quantified easily. To study whether measurement of skin vasomotion is suited to assess early sympathetic peripheral neuropathy, we monitored skin blood flow at the index finger pulp using laser Doppler flowmetry before and after electrical stimulation. We assured that the stimulus was sufficient to elicit an efferent sympathetic response by monitoring palmar SSR ipsilateral to the flow measurement. In 21 diabetic patients with at least stage one polyneuropathy and 21 age-matched controls, SSR was recorded from one palm and sole following electrical stimulation at the contralateral wrist. Sympathetic skin response was present at the palms in all patients and controls and absent at the sole of two patients only. Eight patients (38.9%) had abnormal SSR, with absent plantar responses in two patients, prolonged plantar latencies in six patients, and prolonged volar SSR latencies in two patients. Skin blood flow responses were more often abnormal (46.1%) than SSR (P < 0.05), responses were delayed in two patients and absent in another 8 patients. Skin blood flow retest reliability was high with a repeatability coefficient of 10.64% in controls and 12.34 % in patients. Skin blood flow monitoring after sympathetic stimulation provides a reproducible parameter of sympathetic vasomotor control and complements the diagnostic value of SSR testing.

Neural and endothelial control of the microcirculation in diabetic peripheral neuropathy.

OBJECTIVE: To examine the role played by endothelium-dependent and endothelium-independent vasodilation of the cutaneous microcirculation and their relationship to neural microcirculatory control in type 1 and type 2 diabetic patients. METHODS: Acetylcholine and sodium nitroprusside were iontophoresed using a dose-response technique. Endothelium-dependent, endothelium-independent, and C-fiber-mediated vasodilation were measured with a laser Doppler device. RESULTS: Endothelium-dependent vasodilation of the forearm cutaneous microcirculation was attenuated in diabetic subjects. The response was less in type 2 diabetic subjects than in controls (p < 0.005). In contrast, there was no significant difference between type 1 diabetic subjects and controls. There was no significant abnormality in endothelium-independent vasodilation in either diabetic group. The C-fiber-mediated axon reflex in the forearm was impaired in both type 1 and type 2 diabetics, which is consistent with a small-fiber neuropathy (p < 0.005). The duration of diabetes in type 2 diabetics was a significant predictor of the maximum endothelium-mediated vasodilation. CONCLUSION: Changes in cutaneous blood flow are seen relatively early in the course of diabetic peripheral neuropathy and are characterized by endothelial and neural but not smooth muscle dysfunction. The presence of significant C-fiber impairment in both diabetic groups, together with significantly greater dysfunction in endothelium-dependent vasodilation in type 2 diabetics, suggests that the endothelial function and nitric oxide may play a greater role in the pathogenesis of diabetic peripheral neuropathy in type 2 diabetic patients.

[Low-flow anesthesia with desflurane]. / Niedrigflussnarkosen mit Desfluran.

OBJECTIVES: Due to its low solubility and negligible metabolism, desflurane is assumed to be especially suitable for application by low-flow anaesthetic techniques. The aim of this clinical investigation was the development of a standardised dosing scheme for low-flow and minimal-flow desflurane anaesthesia. METHODS: One hundred six ASA status I-II patient were assigned to six groups according to the duration of the initial high-flow phase, fresh gas flow, and fresh-gas desflurane concentration. The median age, height, body weight, and constitution of the groups was comparable. After an initial high-flow phase using 4.4 l/min, the fresh gas flow was reduced to 0.5 l/min (minimal-flow anaesthesia) or 1.0 1/min (low-flow anaesthesia). Inspired nitrous oxide concentrations were maintained at 60% to 70%. Using different standardised schemes of vaporizer settings, inspired desflurane concentrations were applied in the range from 3.4% to 8.7%, i.e., between 1 and 1.5 MAC. Inspired and expired desflurane concentrations were measured continuously by the side-stream technique and recorded on-line. Venous blood samples were taken immediately prior to induction and 45 min after flow reduction for measurement of carboxyhaemoglobin (COHb) concentration). RESULTS: In the 10- to 15-min initial phase during which a high fresh gas flow of 4.4 l/min was used, the inspired desflurane concentration reached values in the range of 90%-95% of the fresh gas concentration. In low-flow anaesthesia this concentration could be maintained without any alteration of the vaporizer setting, whereas in minimal-flow anaesthesia with flow reduction the fresh gas concentration had to be increased by 1% to 2%: The quotient calculated by division of the inspired desflurane concentration by its fresh gas concentration (Q = CI/CF) ranges between 0.65 and 0.75 in animal-flow and between 0.80 and 0.85 in low-flow anaesthesia. If use was made of the wide output range of the desflurane vaporizer, the inspired concentration could be increased rapidly by about 5% in 8 min, although the flow was kept constant at 0.5 l/min. Compared with its value prior to induction (2.13 +/- 1.05%), the COHb concentration decreased statistically significantly by about 0.7% during the 1st hour of minimal-flow anaesthesia (1.42 +/- 1.01%). In no case was a COHb concentration observed that exceeded threatening or even toxic values, although the soda lime was changed routinely only once a week. CONCLUSIONS: The pharmacokinetic properties of desflurane, resulting in especially low individual uptake, and the wide output range of the vaporizer facilitate the use of low-flow anesthetic techniques in routine clinical practice. Even in minimal-flow anesthesia, the duration of the initial high-flow phase can be shortened to min. If the flow is reduced to 1 l/min, the inspired desflurane concentration achieved in the initial high-flow phase can be maintained without any alteration of the vaporizer setting. In minimal-flow anesthesia, however, with flow reduction to 0.5 l/min, the fresh gas concentration has to be increased to a value 1%-2% higher than the inspired nominal value. Due to the wide dialing range of the desflurane vaporizer, the amount of vapour delivered into the breathing system can be increased to about 110 ml/min even at a flow of 0.5 l/min. The large amount of agent that can be delivered into the system even under low-flow conditions, together with the very low individual uptake, results in a time-constant that is sufficient short for the clinically required rapid increase in inspired desflurane concentrations. The short time-constant of low-flow desflurane anaesthesia improves the control of the anaesthetic concentration. If all measures are taken to safely avoid inadvertent drying out of the soda lime, there is no evidence that low-flow anaesthesia with desflurane is liable to increase the risk of accidental carbon monoxide poisoning. (ABSTRACT TRUNCATED)