Patient reported outcomes in a secondary progressive MS cohort related to cognition, MRI and physical outcomes.

BACKGROUND: Patient-reported outcomes (PROs) are increasingly being used as outcomes in secondary progressive multiple sclerosis (SPMS) trials. We examined how PROs reflect disease burden in SPMS. METHODS: In this observational prospective study, 65 SPMS patients were examined by five different PROs (Fatigue Scale Motor Cognition (FSMC), Multiple Sclerosis Impact Scale version 2 (MSIS-29v2), 36-Item Short Form Health Survey version 2 (SF-36v2), EQ-5D-5L and Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis version 2.0 (WPAI:MS)); two different rating scales, Multiple Sclerosis Impairment Scale (MSIS) and Expanded Disability Status Scale (EDSS); functional tests of mobility (Timed-25-Foot Walk (T-25FW), 6-Spot Step Test (6-SST) and (9-Hole Peg Test (9-HPT)); cognitive tests (Symbol Digital Modalities Test (SDMT) and Brief Visuospatial Memory Test-Revised (BVMT-R)); and multimodal Magnetic Resonance Imaging (MRI). RESULTS: When the PROs were divided into physical and psychological subscores, the PRO physical subscores of FSMC, MSIS-29v2 and SF-36v2 correlated with physical rating scales (EDSS, MSIS) and physical measures of upper (9-HPT) and lower extremity function (T-25FW and 6-SST)) (p = 0.04-0.0001). 9-HPT correlated the least with physical subscores of PROs but showed the strongest correlation with activity impairment (subscore of WPAI:MS). In contrast, psychological PRO subscores of FSMC, MSIS-29v2 and SF-36v2 did not reflect the cognitive outcomes (SDMT and BVMT-R), although the cognitive scores correlated with disease burden indicated by MRI lesion volumes. The psychological PRO subscores did not correlate with fatigue, physical and MRI outcomes either. CONCLUSION: Correlation between PRO physical subscores and physical outcomes supports PROs as potentially useful clinical endpoints in SPMS. The results of this study indicate that patients with SPMS highly perceive their mobility on function of their lower extremities, while they perceive their daily activities highly dependent on function of the upper extremities. Psychological subscores of MS specific PROs may be less suitable as surrogate markers for the cognitive status and should be considered as a mental quality of life measurement independent of disease burden.

Antibody response against gastrointestinal antigens in demyelinating diseases of the central nervous system.

BACKGROUND: Antibodies against gastrointestinal antigens may indicate altered microbiota and immune responses in the gut. Recent experimental data suggest a connection between gastrointestinal immune responses and CNS autoimmunity. METHODS: Antibodies against gliadin, tissue transglutaminase (tTG), intrinsic factor (IF), parietal cells (PC) and Saccharomyces cerevisiae (ASCA) were screened in the sera of 45 patients with AQP4-seropositive neuromyelitis optica (NMO) and NMO spectrum diseases (NMO/NMO-SD), 17 patients with AQP4-seronegative NMO, 85 patients with clinically definite multiple sclerosis (MS), and 48 healthy controls (HC). RESULTS: Thirty-seven percentages of patients with AQP4-seropositive NMO/NMO-SD and 28% of patients with MS had at least one particular antibody in contrast to 8% of HC (P < 0.01, respectively). Antibodies were most common (46%) in AQP4-seropositive myelitis (P = 0.01 versus HS, P = 0.05 versus MS). Anti-gliadin and ASCA were more frequent in the AQP4-seropositive NMO-spectrum compared to controls (P = 0.01 and P < 0.05, respectively). CONCLUSION: Antibody responses against gastrointestinal antigens are common in MS and AQP4-seropositive NMO/NMO-SD, especially in longitudinally extensive myelitis.

Treatment for Helicobacter pylori infection and risk of Parkinson's disease in Denmark.

BACKGROUND AND PURPOSE: It has been speculated that gastrointestinal infection with Helicobacter pylori (HP) contributes to the development of Parkinson's disease (PD). We used nationwide Danish registers to investigate this hypothesis. METHODS: We identified 4484 patients with a first time PD diagnosis between 2001 and 2008 from the Danish National Patient Register (DNPR) and 22, 416 population controls from the Danish Civil Registration System (CRS). Information on drug use was obtained from the National Prescription Registry (NPR). We used logistic regression to compute odds ratios (OR) for the association between treatment for HP and risk of PD. RESULTS: Prescriptions for HP-eradication drugs and proton pump inhibitors (PPI) 5 or more years prior to the diagnosis of PD were associated with a 45% and 23% increase in PD risk, respectively. Hospitalizations and outpatient visits for gastritis and peptic/duodenal ulcers, however, were not associated with PD. CONCLUSIONS: Our population-based study suggests that chronic HP infections and/or gastritis contribute to PD or that these are PD-related pathologies that precede motor symptoms.

Axonal lesion-induced microglial proliferation and microglial cluster formation in the mouse.

Microglia are innate immune cells and form the first line of defense of the CNS. Proliferation is a key event in the activation of microglia in acute pathology, and has been extensively characterized in rats, but not in mice. In this study we investigated axonal-lesion-induced microglial proliferation and surface antigen expression in C57BL/6 mice. Transection of the entorhino-dentate perforant path projection results in an anterograde axonal and a dense terminal degeneration that induces a region-specific activation of microglia in the dentate gyrus. Time-course analysis showed activation of microglial cells within the first week post-lesion and cell counting demonstrated a significant 1.6-fold increase in microglial numbers 24 h post-lesion reaching a maximal 3.8-fold increase 3 days post-lesion compared with controls. Double staining for the microglial macrophage antigen-1 and the proliferation marker bromodeoxyuridine, injected 1 h prior to perfusion, showed that lesion-reactive microglia accounted for the vast majority of proliferating cells. Microglia proliferated as soon as 24 h after lesion and 25% of all microglial cells were proliferating 3 days post-lesion. Immunofluorescence double staining showed that most activated, proliferating microglia occurred in multicellular clusters and co-expressed the intercellular adhesion molecule-1 and the hematopoietic stem cell marker cluster of differentiation 34. In conclusion, this study extends observations of axonal lesion-induced microglial proliferation in rats to mice, and provides new information on early microglial proliferation and microglial cluster formation and surface antigen expression in the mouse.

Purification and characterization of cathepsin D from herring muscle (Clupea harengus).

Cathepsin D was purified and concentrated 469-fold from a homogenate of Clupea harengus muscle. The purified enzyme is a monomer with a molecular weight of 38000-39000. It is inhibited by pepstatin and has optimal activity at pH 2.5 with hemoglobin as the substrate. The isoelectric point is at pH 6.8. Glycosidase treatment and binding to Concanavalin A indicated that the enzyme contains one N-linked carbohydrate moiety of the high-mannose type per molecule. The first 21 amino acid residues of the N-terminal showed high similarity to cathepsin D from antarctic icefish liver (Chionodraco hamatus) and trout ovary (Oncorhynchus mykiss). Digestion of the beta-chain of oxidized insulin resulted in preferential cleavage at Leu(15)-Tyr(16), (47%), Tyr(16)-Leu(17) (34%) and Ala(14)-Leu(15) (18%). Incubation with myofibrils from herring muscle at pH 4.23 showed that the enzyme mainly degraded myosin, actin and tropomyosin.

Purification and characterization of two chymotrypsin-like proteases from the pyloric caeca of rainbow trout (Oncorhynchus mykiss).

1. Two chymotrypsins, called chymotrypsin I and II, were purified from the pyloric caeca of rainbow trout, by (NH4)2SO4 fractionation, hydrophobic interaction chromatography (phenyl-Sepharose) and ion-exchange chromatography (DEAE-Sepharose). 2. The approximate molecular weights of chymotrypsin I and II were 28,200 (+/- 1200) and 28,800 (+/- 900), respectively, as determined by SDS-PAGE and their isoelectric points were about 5. 3. The pH optima of the enzymes were centered around nine, when assayed for succinyl-L-Ala-L-Ala-L-Pro-L-Phe-p-nitroanilide (Suc-AAPF-NA) as substrate and both enzymes were unstable at pH values below 5. 4. The amidase activity of both enzymes increased with temperature up to about 55 degrees C. Chymotrypsin I was found to be more heat stable than chymotrypsin II, an effect most likely explained by stronger calcium binding of the former. 5. The trout chymotrypsins were significantly more active than bovine alpha-chymotrypsin when assayed against Suc-AAPF-NA at 25 degrees C and casein at low temperatures (10-20 degrees C), indicating an adaptation of the activities of the trout chymotrypsins to the habitation temperatures of the fish.

Salicylate- and aspirin-induced uncoupling of oxidative phosphorylation in mitochondria isolated from the mucosal membrane of the stomach.

The hypothesis that the damaging effect on the stomach mucosa of salicylic acid and its derivatives is ascribable to an uncoupling of oxidative phosphorylation has been investigated by testing of mitochondria isolated from the corpus gland area of mini-pig gastric mucosa. Mitochondria, influenced by salicylate or acetylsalicylate (0.7-5.6 mmol/l), demonstrated increased respiration rate, decreased respiratory control ratio, and decreased P/O ratio when tested in vitro. Uncoupling of oxidative phosphorylation occurred at a salicylate concentration between 3.5 and 5.6 mmol/l.

Preservation of kidneys for transplantation. Assessment of ischemic damage by renal autoperfusion.

Autoperfusion of canine kidneys was investigated as an alternative method to determinate the ischmic organ damage following various preservation procedures. As a compromise between implantation of the donor kidney and normotherimic isolated perfusion, autoperfusion is shown to offer some advantages in the study of the pathophysiology of the ischemic damaged kidney. Within 3 hours of autoperfusion, we obtained detailed information about the immediate regenerative ability of the glomerular, tubular, and vascular functions following various sorts of ischemic trauma.