Medicine (Northwest Academic Centre) - Research Publications
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ItemGait disorders are associated with non-cardiovascular falls in elderly people: a preliminary study.(Springer Science and Business Media LLC, 2005-12-01)BACKGROUND: The association between unexplained falls and cardiovascular causes is increasingly recognized. Neurally mediated cardiovascular disorders and hypotensive syndromes are found in almost 20 percent of the patients with unexplained falls. However, the approach to these patients remains unclear. Gait assessment might be an interesting approach to these patients as clinical observations suggests that those with cardiovascular or hypotensive causes may not manifest obvious gait alterations. Our primary objective is to analyze the association between gait disorders and a non-cardiovascular cause of falls in patients with unexplained falls. A second objective is to test the sensitivity and specificity of a gait assessment approach for detecting non-cardiovascular causes when compared with intrinsic-extrinsic classification. METHODS: Cross-sectional study performed in a falls clinic at a university hospital in 41 ambulatory elderly participants with unexplained falls. Neurally mediated cardiovascular conditions, neurological diseases, gait and balance problems were assessed. Gait disorder was defined as a gait velocity < 0.8 m/s or Tinetti Gait Score < 9. An attributable etiology of the fall was determined in each participant. Comparisons between the gait assessment approach and the attributable etiology regarding a neurally mediated cardiovascular cause were performed. Fisher exact test was used to test the association hypothesis. Sensitivity and specificity of gait assessment approach and intrinsic-extrinsic classification to detect a non-cardiovascular mediated fall was calculated with 95% confidence intervals (CI95%). RESULTS: A cardiovascular etiology (orthostatic and postprandial hypotension, vasovagal syndrome and carotid sinus hypersensitivity) was identified in 14% of participants (6/41). Of 35 patients with a gait disorder, 34 had a non-cardiovascular etiology of fall; whereas in 5 out of 6 patients without a gait disorder, a cardiovascular diagnosis was identified (p < 0.001). Sensitivity and specificity of the presence of gait disorder for identifying a non-cardiovascular mediated cause was 97.1% (CI95% = 85-99) and 83% (CI95% = 36-99), respectively. CONCLUSION: In community dwelling older persons with unexplained falls, gait disorders were associated with non-cardiovascular diagnosis of falls. Gait assessment was a useful approach for the detection of a non-cardiovascular mediated cause of falls, providing additional value to this assessment.
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ItemSevere hepatitis and prolonged hepatitis B virus-specific CD8 T-cell response after selection of hepatitis B virus YMDD variant in an HIV/hepatitis B virus-co-infected patient(LIPPINCOTT WILLIAMS & WILKINS, 2004-08-20)We describe here a severe flare of hepatitis caused by lamivudine-resistant hepatitis B virus(HBV) in an HIV/HBV co-infected individual.Lamivudine-resistant HBV was detected 6 months before the development of severe hepatitis. Sequencing of the HBV genome isolated from the patients' serum did not identify compensatory mutations in the HBV polymerase that may have restored viral replication. However, a strong HBV-specific CD8 T-cell response was identified and may have resulted in the severe hepatitis.
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ItemImpairment of humoral immunity to Plasmodium falciparum malaria in pregnancy by HIV infection(ELSEVIER SCIENCE INC, 2004-06-05)BACKGROUND: HIV infection increases the risk of malaria infection in pregnant women. Antibodies to variant surface antigens (VSA) on infected erythrocytes might protect against malaria in pregnancy. We postulated that HIV-induced impairment of humoral immunity to VSA mediates the increased susceptibility to malaria. METHODS: We compared serum concentrations of antibodies to VSA by flow cytometry or agglutination, and to merozoite proteins AMA-1 and MSP119 by ELISA, in 298 pregnant Malawian women, and related the findings to malaria and HIV infection, CD4-positive T-cell count, and HIV-1 viral load. FINDINGS: Concentrations of IgG to placental type VSA were lower in HIV-infected women than in HIV-uninfected women (median 8 units [IQR 4-23] vs 20 [12-30]; p<0.0001), among women with malaria (p=0.009) and those without malaria (p=0.0062). The impairment was greatest in first pregnancy. Agglutinating antibodies to placental VSA were present in a lower proportion of HIV-infected than HIV-uninfected women (58 [35.1%] of 165 vs 50 [53.8%] of 93, p<0.001). The degree of antibody binding by flow cytometry was correlated with CD4-positive T-cell count (r=0.16, p=0.019) and inversely with HIV-1 viral load (r=-0.16, p=0.030). Concentrations of antibodies to AMA-1 were lower in HIV infection (p<0.0001) but were not correlated with CD4-positive T-cell count or viral load. Responses to MSP119 were little affected by HIV infection. In multivariate analyses, HIV was negatively associated with amount of antibody to both VSA and AMA-1 (p<0.001 for each) but not MSP119. INTERPRETATION: HIV infection impairs antimalarial immunity, especially responses to placental type VSA. The impairment is greatest in the most immunosuppressed women and could explain the increased susceptibility to malaria seen in pregnant women with HIV infection.
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ItemA detrimental role for nitric oxide synthase-2 in the pathology resulting from acute cerebral injury(OXFORD UNIV PRESS INC, 2004-07)Nitric oxide (NO) synthesized from the inducible isoform of nitric oxide synthase (NOS-2) has been suggested to play both beneficial and deleterious roles in various neuropathologies. To define the role of nitric oxide in traumatic brain injury, we subjected male mice lacking a functional NOS-2 gene (NOS-2-/-) and their wild-type littermates (NOS-2+/+) to mild or severe aseptic cryogenic cerebral injury. Expression of NOS-2 mRNA and protein was observed in NOS-2+/+ animals following injury. Lesion volume (as measured by histology and brain imaging) and neurological outcome (using motor and cognitive behavioral paradigms) were assessed at various times after injury. While magnetic resonance imaging revealed the extent of edema of the 2 genotypes to be similar, histology showed a reduced (32%) lesion volume in severely injured NOS-2-/- compared with NOS-2+/+ mice. In addition, NOS-2-/- mice showed significant improvements in both contralateral sensorimotor deficits (grid test: p = 0.011) and cognitive function (Morris water maze: p = 0.009) after severe injury compared to their wild-type littermates. This indicates that lesion volume is reduced and neurological recovery is improved after acute traumatic injury in mice lacking a functional NOS-2 gene, and strongly suggests that the post-trauma production of NO from this source contributes to neuropathology.
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ItemTumour necrosis factor antagonists improve disease activity but not arterial stiffness in rheumatoid arthritis(OXFORD UNIV PRESS, 2005-11)OBJECTIVES: Systemic inflammation may play an important role in the accelerated atherosclerosis and increased cardiovascular mortality of rheumatoid arthritis (RA). Atorvastatin reduced arterial stiffness in RA patients after only 6 weeks, an effect that may be partially mediated by the immunomodulatory effects of this drug. Suppression of inflammation with tumour necrosis factor (TNF) antagonists may therefore also improve vascular function in RA; however, TNF antagonists have also been shown to cause or exacerbate congestive heart failure in patients with RA and heart failure. The aim of the present study was to examine the effect of treatment with TNF antagonists on arterial stiffness in RA patients with active disease. METHODS: Fourteen RA patients (age 55.1 +/- 3.8 yr; disease duration 7.9 +/- 1.3 yr) with high disease activity [disease activity score (DAS28) 7.1 +/- 0.3] commencing treatment with TNF antagonists for the first time were studied. Clinical status and arterial stiffness were measured before and after 6 weeks of TNF antagonist therapy (etanercept, adalimumab or infliximab). RESULTS: Arterial stiffness did not change during the study period (the mean augmentation index was 29.1 +/- 2.2% at baseline vs 30.1 +/- 1.8% at week 6; P = 0.504). The DAS28 improved significantly from 7.1 +/- 0.3 to 4.3 +/- 0.4 (P < 0.0001). The erythrocyte sedimentation rate and C-reactive protein [median (range)] were reduced from 44 (12-85) to 15 (3-82) mm/h (P = 0.02) and from 34 (3-95) to 10 (2-61) mg/l (P = 0.007), respectively. CONCLUSIONS: Despite significant reductions in synovitis and inflammatory markers in these RA patients, arterial stiffness was not improved by 6 weeks of treatment with TNF antagonists. This result is of relevance given recent reports of potential adverse cardiovascular effects of TNF antagonists in some RA patients.
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ItemDifferential regulation of gastric tumor growth by cytokines that signal exclusively through the coreceptor gp130(W B SAUNDERS CO-ELSEVIER INC, 2005-09)BACKGROUND & AIMS: We have shown that mice with a mutation in gp130 (gp130(757F/F)), the signal transducing receptor for interleukin (IL)-6 family cytokines, have chronic gastric inflammation and develop distal stomach tumors associated with deregulated phosphorylated STAT3 expression. This model recapitulates many characteristics of intestinal-type gastric cancer in humans. METHODS: To evaluate the role of IL-6 and IL-11 as ligands regulating tumor growth and submucosal invasion, we compared tumor characteristics of gp130(757F/F) mice with gp130(757F/F) mice lacking IL-6 or mature T and B cells. RESULTS: As a result of the gp130(757F/F) mutation, expression of IL-6 and IL-11 was greatly up-regulated concomitant with activation of STAT3 and development of tumors. However, the lack of IL-6 or T and B cells did not impact on tumor growth. While IL-6 did not regulate tumor growth or tumor vascularization, gp130(757F/F)/IL-6(-/-) mice showed approximately 10-20-fold more submucosal tumor invasion, reduced mononuclear inflammatory cell infiltrate, and greater IL-11 and matrix metalloproteinase (MMP)-13 and MMP-9 synthesis than gp130(757F/F) mice. Expression of MMP-13 was largely restricted to tumor-associated stroma, but MMP-9 was also expressed in polymorphonuclear cells and a subset of epithelial cells. In addition, treatment with recombinant IL-11 stimulated expression of MMP-13 and MMP-9 in stomachs of wild-type mice. CONCLUSIONS: Increased submucosal invasion in gp130(757F/F)/IL-6(-/-) mice could not be explained by increased vascularization or reduced immunosurveillance but was most likely facilitated by augmented metalloproteinase activity driven by elevated IL-11 levels.
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ItemHeterochromatin silencing and locus repositioning linked to regulation of virulence genes in Plasmodium faiciparum(CELL PRESS, 2005-04-08)The malaria parasite Plasmodium falciparum undergoes antigenic variation to evade host immune responses through switching expression of variant surface proteins encoded by the var gene family. We demonstrate that both a subtelomeric transgene and var genes are subject to reversible gene silencing. Var gene silencing involves the SIR complex as gene disruption of PfSIR2 results in activation of this gene family. We also demonstrate that perinuclear gene activation involves chromatin alterations and repositioning into a location that may be permissive for transcription. Together, this implies that locus repositioning and heterochromatic silencing play important roles in the epigenetic regulation of virulence genes in P. falciparum.
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ItemThe neuroprotective effect of progesterone after traumatic brain injury in male mice is independent of both the inflammatory response and growth factor expression(WILEY, 2005-03)Previous studies suggest that progesterone may possess neuroprotective properties after traumatic insult but, with the exception of reduced formation of cerebral oedema, limited experimental evidence has been presented to support this claim. In the present study we focused on the effect of progesterone treatment on structural and functional deficits in an experimental model of traumatic brain injury. Female mice exhibited significantly (P = 0.0445) reduced lesion volumes compared with males after aseptic cryogenic cerebral injury (ACI), suggesting that female sex steroids provide protection against this injury. In male mice, progesterone treatment after injury (three intraperitoneal doses of 8 mg/kg) reduced lesion volume (P = 0.0429) and improved performance in a spatial cognitive task (Morris water maze; P = 0.0014). However, progesterone had no demonstrable effect on the formation of oedema as measured using T2-weighted magnetic resonance imaging, nor did it affect brain water content. The pro-inflammatory cytokines TNF-alpha and IL-1beta, and growth factors BDNF and G-CSF, were all strongly transcriptionally activated after ACI. However, progesterone administration did not affect expression of these genes. This study provides strong evidence that progesterone possesses neuroprotective properties in a mouse model of traumatic brain injury, but suggests that the steroid achieves this effect through mechanism(s) independent of the inflammatory response or growth factor up-regulation.
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ItemAntagonism of the interleukin-1 receptor following traumatic brain injury in the mouse reduces the number of nitric oxide synthase-2-positive cells and improves anatomical and functional outcomes(WILEY, 2005-07)Interleukin (IL)-1beta plays an important role in the inflammatory response that results from traumatic brain injury and antagonism of the actions of this cytokine can affect outcome. We subjected male mice to aseptic cryogenic injury and assessed recovery through anatomical, histological and functional measures following treatment with recombinant mouse IL-1 receptor antagonist (IL-1ra). A single dose (1 microg, i.c.v.) at the time of injury reduced lesion volume 3 days later, as assessed by Nissl staining, and also the number (30%) of FluoroJade-positive degenerating neurones. Mice treated with IL-1ra performed better on the beam balance and in the grid test as compared with vehicle-treated animals. Furthermore, IL-1ra-treated animals showed fewer (40%) nitric oxide synthase-2-positive cells in and around the lesion. These data suggest that activation of the IL-1 receptor following trauma contributes to the pathology and that antagonism can reduce both anatomical and functional consequences of neuroinflammation.