BackgroundThe diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity.ObjectiveTo analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus.MethodsRetrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%).ResultsSeropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of ≤ 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades ≤ 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions ≥ 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome.ConclusionThis study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.

Peripheral-blood human T lymphocytes were treated with Staphylococcus aureus alpha-toxin. Membrane permeabilization was assessed by measuring elilux of K+ and Rb+ and influx of Na+, Ca2+, and propidium iodide. Cellular ATP and [3H]thymidine incorporation following lectin stimulation were measured as parameters for cell viability. Internucleosomal cleavage characteristic of programmed cell death was assessed by agarose gel electrophoresis and by quantifying low-molecular-weight, [3H]thymidine-labeled DNA fragments. Nanomolar concentrations of alpha-toxin evoked protracted, irreversible ATP depletion in both activated and resting T lymphocytes. Toxin-damaged cells also lost their ability to incorporate [3H] thymidine upon subsequent stimulation with phytohemagglutinin. These cells carried toxin hexamers, and their plasma membranes became permeable for monovalent ions but not for Ca2+ and propidium iodide. The permeabilization event was followed by internucleosomal DNA degradation characteristic of programmed cell death. Membranes of cells treated with high toxin doses (>300 nM) became permeable to both Ca2+ and propidium iodide. In this case, ATP depletion occurred within minutes and no DNA degradation was observed. When cells were suspended in Na+-free buffer, alpha-toxin applied at low doses still bound and formed hexamers. However, these cells displayed neither DNA degradation nor loss of viability. The data indicate that formation of very small but not of large alpha-toxin pores may trigger programmed cell death in lymphocytes and that uncontrolled flux of Na+ ions may be an important event precipitating the suicide cascade. Alpha-toxin, the major cytolysin of Staphylococcus aureus (3, 7), damages cells by generating pores in the plasma membrane (7, 11, 27, 30). At low concentrations, the 34-kDa toxin monomer binds to susceptible cells by interaction with as-yetunidentified acceptor molecules on the membrane. At high concentrations (>200 nM; 6 jig/ml), binding additionally occurs via nonspecific absorption to the lipid bilayer (9, 16). In rabbit erythrocyte membranes, both modes of binding result in the formation of hexameric pores with an effective diameter of 1 to 2 nm (7, 11). Aqueous pores of similar size have been produced through the action of alpha-toxin on liposomes (17) and planar lipid membranes (2, 20) in endothelial cells (25), polymorphonuclear granulocytes (26), platelets (6), and neuroendocrine cells (1). It is therefore generally assumed that, once formed, alpha-toxin pores will display effective diameters of 1 to 2 nm, allowing passage of mono-and divalent ions and of small macromolecules, including ATP, with molecular weights of .1,000 to 2,000 (7). Recent studies in our laboratories have disclosed, however, that this original concept of homogeneous alpha-toxin pores requires revision. Thus, pores forming in keratinocytes at low toxin doses were found to permit passage of monovalent ions but not of Ca2+ or larger marker molecules such as propidium

To define the location and extent of microvascular damage of the basal lamina after cerebral ischemia and reperfusion in rats, the authors subjected animals (n = 16) to 3 hours of focal cerebral ischemia and 24 hours of reperfusion using the suture middle cerebral artery occlusion model; sham-operated animals served as controls (n = 6). The Western blot technique was used to define the collagen type IV protein content in various brain regions, whereas immunohistochemistry identified microvascular basal lamina loss (anticollagen type IV staining). The extent of damage was quantified by automatic morphometric video-imaging analysis. Statistical analysis was based on the Mann-Whitney test and the paired Student's t-test. The ischemic hemisphere showed a reduction of the collagen type IV protein content after ischemia and reperfusion in the Western blot (reduction compared with the nonischemic side: total hemisphere, 33% +/- 6%; basal ganglia, 25% +/- 7%; cortex 49% +/- 4%; P < 0.01) [corrected]. There was also a decrease in the number of cerebral microvessels between the ischemic and nonischemic hemispheres (20% +/- 2%), cortical (8% +/- 3%), and basal ganglia areas (31% +/- 3%) (P < 0.001). Besides a reduction of the vessel number, there was also a loss in basal lamina antigen-positive stained area in ischemic areas (hemisphere, 16% +/- 3%; cortex, 14% +/- 3%; basal ganglia, 21% +/- 4%; P < 0.01) [corrected]. Cortical areas had a less pronounced basal lamina loss than basal ganglia (P < 0.05). For the first time, microvascular basal lamina damage, indicated by collagen type IV loss, is proven in rats by biochemical and morphometric analysis. These changes are comparable with those found in nonhuman primates. The authors report novel data regarding microvascular ischemic changes in the cortex. These data provide a basis for future experiments to determine the mechanisms of ischemic microvascular damage and to devise new therapeutic strategies.

Our study demonstrates that i) AQP4-Ab-positive NMOSD are more commonly associated with MG in Caucasians than previously thought; ii) MG precedes NMOSD in most cases, often by more than a decade; iii) NMOSD almost exclusively occur in females with juvenile or early-onset MG; and iv) MG frequently takes an unusually mild course in patients with NMOSD. A history of thymectomy could be a possible risk factor for the later development of NMOSD. We recommend testing for AQP4-Ab in MG patients presenting with atypical motor or optic symptoms.

Background and Purpose-Depression may increase the risk for stroke. Few studies have examined whether depression increases the risk for stroke in the very old and among the demented. We examined the relation between depression in 85-year-olds and the 3-year incidence of first-ever stroke. Methods-A representative sample of 494 85-year-olds (147 demented, 347 nondemented) in Gothenburg, Sweden, was examined with psychiatric examinations and key informant interviews. Diagnoses of depression and dementia were made according to the Diagnostic and Statistical Manual of Mental Disorders, Third Revision. The sample was followed for 3 years regarding the incidence of stroke. Information on stroke was obtained from the Swedish Hospital Discharge Register, death certificates, self-reports, and key informants. Those with known stroke history at baseline (nϭ93) were excluded from the incidence study. Results-The prevalence of depression at age 85 was 19%. Depression at baseline (hazard ratio, 2.7; 95% CI, 1.5 to 4.7;Pϭ0.0006) and systolic blood pressure (hazard ratio, 1.014 per 1 mm Hg; 95% CI, 1.00 to 1.03; Pϭ0.019) were related to increased incidence of first-ever stroke during follow-up. Depression increased stroke risk both among demented and nondemented individuals. Among the symptoms of depression, only depressed mood was an independent predictor of incidence first-ever stroke in multivariate analyses. Stroke history at age 85 was not associated with clinical depression. Conclusions-Depression and stroke are both common in elderly populations. The finding that depression increases risk for first-ever stroke indicates that detection and treatment of depression may have implications for stroke prevention.