A chronic mouse model of Parkinson's disease has a reduced gait pattern certainty

The purpose of this investigation was to determine if a chronic Parkinson's disease mouse model will display less certainty in its gait pattern due to basal ganglia dysfunction. A chronic Parkinson's disease mouse model was induced by injecting male C57/BL mice with 10 doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg) (MPTP) and probenecid (250 mg/kg) (P) over 5 weeks. This chronic model produces a severe and persistent loss of nigrostriatal neurons resulting in dopamine depletion and locomotor impairment. The control mice were treated with probenecid alone. Fifteen weeks after the last MPTP/P treatment, the mice were videotaped in the sagittal plane with a digital camera (60 Hz) as they ran on a motorized treadmill at a speed of 10 m/min. The indices of gait and gait variability were calculated. Stride length was significantly (p = 0.016) more variable in the chronic MPTP/P mice. Additionally, the chronic MPTP/P mice had a statistically less certain gait pattern when compared to the control mice (p = 0.02). These results suggest that variability in the gait pattern can be used to evaluate changes in neural function. Additionally, our results imply that disorder of the basal ganglia results in less certainty in modulating the descending motor command that controls the gait pattern.     

MCP-1-dependent signaling in CCR2(-/-) aortic smooth muscle cells

Monocyte chemoattractant protein-1 (MCP-1, CCL2) is a mediator of inflammation that has been implicated in the pathogenesis of a wide variety of human diseases. CCR2, a heterotrimeric G-coupled receptor, is the only known receptor that functions at physiologic concentrations of MCP-1. Despite the importance of CCR2 in mediating MCP-1 responses, several recent studies have suggested that there may be another functional MCP-1 receptor. Using arterial smooth muscle cells (SMC) from CCR2(-/-) mice, we demonstrate that MCP-1 induces tissue-factor activity at physiologic concentrations. The induction of tissue factor by MCP-1 is blocked by pertussis toxin and 1,2-bis(O-aminophenyl-ethane-ethan)-N,N,N',N'-tetraacetic acid-acetoxymethyl ester, suggesting that signal transduction through the alternative receptor is G(alphai)-coupled and dependent on mobilization of intracellular Ca(2+). MCP-1 induces a time- and concentration-dependent phosphorylation of the mitogen-activated protein kinases p42/44. The induction of tissue factor activity by MCP-1 is blocked by PD98059, an inhibitor of p42/44 activation, but not by SB203580, a selective p38 inhibitor. These data establish that SMC possess an alternative MCP-1 receptor that signals at concentrations of MCP-1 that are similar to those that activate CCR2. This alternative receptor may be important in mediating some of the effects of MCP-1 in atherosclerotic arteries and in other inflammatory processes.     

Characterization of Brucella abortus Soluble Antigen Employed in Immunoassay

A soluble antigen extract of Brucella abortus (BASA) has been prepared by the National Veterinary Services Laboratories and furnished to a number of workers who are examining antibody-mediated and cell-mediated immune responses of cattle infected with B. abortus. Three lots of BASA were examined. There were quantitative but not qualitative differences among lots by content of protein, total carbohydrate, hexose, fatty acid, and 2-keto-3-deoxyoctonic acid. The presence of smooth lipopolysaccharide was demonstrated by the presence of 2-keto-3-deoxyoctonic acid and lipid, by Limulus lysate gelation activity, and by formation of characteristic lipopolysaccharide precipitates in immunoelectrophoresis. A polysaccharide antigen as well as two nonsurface antigens, A2 and C, were also identified. BASA is a satisfactory antigen for use in the enzyme-linked immunosorbent assay since the smooth lipopolysaccharide component bound to polystyrene and functioned in the test. Normal murine spleen cells showed a mitogenic response to BASA similar to that produced by purified smooth lipopolysaccharide. BASA has been used in other laboratories to stimulate peripheral blood leukocytes from cattle infected with B. abortus. Because BASA is a mixture of antigenic components shown to have mitogenic effects in the mouse system, questions on the nature of its stimulatory effect on bovine cells are raised.     

Aging and prefrontal functions: dissociating orbitofrontal and dorsolateral abilities

This study aimed to determine whether age differentially affects performance on tasks tapping orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC). We administered prefrontal measures to healthy younger ( n=23; age= 28.4+/-5.9, education = 15.7+/-2.6, MMSE=29.5+/-0.6 ) and older participants ( n=20; age=69.1+/-5.0, education =15.5+/-3.4, MMSE =28.9+/-1.5). Groups did not differ on education or mental status, P>0.05. Tasks thought to involve greater OFC processing included the Iowa Gambling Task and Delayed Match and Non-Match to Sample Tasks. Tasks requiring greater DLPFC processing included Petrides' Self-Ordered Pointing, WAIS-R Digit Span Backward, Letter Fluency, and Months Backward from the Boston Revision of WMS-Mental Control. Composite z-scores were calculated for OFC and DLPFC tasks. A 2 x 2 ANOVA revealed a Group x Task interaction: F(1,41) =5.55, P=0.02, and a Group main effect: F(1,41)= 12.16, P=0.001. Follow-up analyses revealed younger adults outperformed older adults on OFC tasks only ( younger = 0.37+/-0.46, older= -0.43+/-0.70; t(41) =4.5, P<0.001 ). Post-hoc analyses of individual tasks confirmed that despite age differences on Petrides' Self-Ordered Pointing, measures requiring relatively greater OFC involvement showed larger effect sizes for age differences. Thus, tasks emphasizing OFC functions appear more sensitive to age effects when directly compared to measures of DLPFC functioning. Reasons for this difference in magnitude may stem from differential aging of prefrontal cortex or differential recruitment of alternative brain regions for successful task completion.     

Expression of the cytoplasmic tail of LMP1 in mice induces hyperactivation of B lymphocytes and disordered lymphoid architecture

The oncogenic EBV protein LMP1 mimics a dysregulated CD40 receptor in vitro. To compare CD40 and LMP1-mediated events in vivo, transgenic mice were engineered to express mouse CD40 (mCD40tg) or a protein with extracellular mCD40 and cytoplasmic LMP1 (mCD40-LMP1tg). Transgenic and CD40(-/-) mice were bred so that only the transgenic CD40 molecule is expressed in B cells, macrophages, and dendritic cells. mCD40-LMP1tg mice had normal lymphocyte subsets, and immunization elicited an antibody response featuring normal isotype switching, affinity maturation, and germinal center (GC) formation. However, unimmunized mCD40-LMP1tg mice had expanded immature and germinal center B cells, produced autoantibodies, exhibited marked splenomegaly and lymphadenopathy, and elevated serum IL-6. Thus, signaling through the LMP1 cytoplasmic tail results in amplified and abnormal mimicry of CD40 functions in vivo, indicating possible ways in which LMP1 contributes to the pathogenesis of EBV-associated human disease.     

Effects of digoxin in infants with congested circulatory state due to a ventricular septal defect

Digoxin alone was used to treat a congested circulatory state in 21 infants (mean age, 2.7 months; mean weight, 3.8 kg) with a ventricular septal defect. The dose was adjusted on the basis of pharmacokinetics to achieve a mean steady-state concentration of 1.6 +/- 0.3 ng of digoxin per milliliter of serum. The mean red-cell level of sodium-potassium ATPase fell from 23.1 +/- 7.0 to 12.6 +/- 5.2 nmol per milligram per minute with treatment. Only 6 of the 21 patients had an inotropic response, as reflected by echocardiographic measurements, but the drug was of clinical benefit to 12 infants (including these 6). These results show that not all infants with a congested circulatory state due to a ventricular septal defect benefit from digoxin therapy. Furthermore, in some subjects clinical improvement occurs in the absence of a measurable inotropic response.     

Fibrinogen stabilizes placental-maternal attachment during embryonic development in the mouse

In humans, maternal fibrinogen (Fg) is required to support pregnancies by maintaining hemostatic balance and stabilizing uteroplacental attachment at the fibrinoid layer found at the fetal-maternal junction. To examine relationships between low Fg levels and early fetal loss, a genetic model of afibrinogenemia was developed. Pregnant mice homozygous for a deletion of the Fg-gamma chain, which results in a total Fg deficiency state (FG(-/-)), aborted the fetuses at the equivalent gestational stage seen in humans. Results obtained from timed matings of FG(-/-) mice showed that vaginal bleeding was initiated as early as embryonic day (E)6 to 7, a critical stage for maternal-fetal vascular development. The condition of afibrinogenemia retarded embryo-placental development, and consistently led to abortion and maternal death at E9.75. Lack of Fg did not alter the extent or distribution pattern of other putative factors of embryo-placental attachment, including laminin, fibronectin, and Factor XIII, indicating that the presence of fibrin(ogen) is required to confer sufficient stability at the placental-decidual interface. The results of these studies demonstrate that maternal Fg plays a critical role in maintenance of pregnancy in mice, both by supporting proper development of fetal-maternal vascular communication and stabilization of embryo implantation.