Development of a murine model of cerebral aspergillosis

Central nervous system (CNS) Aspergillus infection has a mortality rate in humans that approaches 95%. Because no animal models are available for studying this infection, we sought to develop a murine model of CNS aspergillosis. Inconsistent data were obtained for nonimmunosuppressed CD-1, C57BL/6, and DBA/2N mice after infection by midline intracranial injection of Aspergillus fumigatus. CD-1 mice given cyclophosphamide to produce immunosuppression had continuous pancytopenia. Dose-finding studies in CD-1 mice showed that infection with 5 x 106 conidia/mouse consistently caused 100% mortality by day 5-8; no mice died before day 3. Histologic examination of samples of brain tissue showed focal abscesses containing Aspergillus hyphae. Fungus burdens in brain were higher than those in other organs, although Aspergillus disseminated to the kidneys and the spleen. The model we established provides an opportunity to study immune responses to and therapeutic options for CNS disease in an immunologically defined, genetically manipulable, and inexpensive species.     

Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64)

BACKGROUND: The progression of nephropathy from diagnosis of type 2 diabetes has not been well described from a single population. This study sought to describe the development and progression through the stages of microalbuminuria, macroalbuminuria, persistently elevated plasma creatinine or renal replacement therapy (RRT), and death. METHODS: Using observed and modeled data from 5097 subjects in the UK Prospective Diabetes Study, we measured the annual probability of transition from stage to stage (incidence), prevalence, cumulative incidence, ten-year survival, median duration per stage, and risk of death from all-causes or cardiovascular disease. RESULTS: From diagnosis of diabetes, progression to microalbuminuria occurred at 2.0% per year, from microalbuminuria to macroalbuminuria at 2.8% per year, and from macroalbuminuria to elevated plasma creatinine (>or=175 micromol/L) or renal replacement therapy at 2.3% per year. Ten years following diagnosis of diabetes, the prevalence of microalbuminuria was 24.9%, of macroalbuminuria was 5.3%, and of elevated plasma creatinine or RRT was 0.8%. Patients with elevated plasma creatinine or RRT had an annual death rate of 19.2% (95% confidence interval, CI, 14.0 to 24.4%). There was a trend for increasing risk of cardiovascular death with increasing nephropathy (P < 0.0001), with an annual rate of 0.7% for subjects in the stage of no nephropathy, 2.0% for those with microalbuminuria, 3.5% for those with macroalbuminuria, and 12.1% with elevated plasma creatinine or RRT. Individuals with macroalbuminuria were more likely to die in any year than to develop renal failure. CONCLUSIONS: The proportion of patients with type 2 diabetes who develop microalbuminuria is substantial with one quarter affected by 10 years from diagnosis. Relatively fewer patients develop macroalbuminuria, but in those who do, the death rate exceeds the rate of progression to worse nephropathy.     

Level of kidney function as a risk factor for cardiovascular outcomes in the elderly

BACKGROUND: There is a high prevalence of both reduced kidney function as well as cardiovascular disease (CVD) in the elderly. We evaluated whether the level of kidney function is an independent risk factor for CVD outcomes in the Cardiovascular Health Study (CHS), a cohort of subjects whose age at baseline was 65 years old or older. METHODS: Cox proportional-hazards regression was used to evaluate the association of predicted glomerular filtration rate (GFR) with CVD after adjustment for the major CVD risk factors. We searched for nonlinear relationships between GFR and CVD, as well as interactions between level of kidney function and major CVD risk factors on CVD. RESULTS: A total of 4893 subjects with predicted GFR of 15 to 130 mL/min/1.73 m2 were included in the analysis. Fifty-six percent were female and the mean age was 73.4 years. Of the subjects, 549 (11.2%) died and 1229 (25.1%) experienced CVD events in 5.05 years of follow-up. Each 10 mL/min/1.73 m2 lower GFR was associated with an adjusted hazard ratio for CVD, de novo CVD, recurrent CVD and all-cause mortality of 1.05 (1.02, 1.09), 1.07 (1.01, 1.12), 1.04 (0.99, 1.09), and 1.06 (1.00, 1.12), respectively. There was no significant interaction between level of GFR and other traditional CVD risk factors on CVD outcomes. A linear model best described the relationship between GFR and CVD. CONCLUSION: The level of GFR is an independent risk factor for CVD, de novo CVD, and all-cause mortality in the elderly.     

Extensive experience with dural sinus thrombosis

OBJECTIVE: Dural sinus thrombosis (DST) is an uncommon cause of stroke. The safest and most effective therapy for DST has not been conclusively identified. METHODS: A retrospective chart review of data for 31 patients who were treated for DST at our institution between 1992 and 2001 was performed. Four treatment strategies were identified, i.e., 1). medical observation only, 2). systemic anticoagulation (AC) therapy with heparin, 3). endovascular chemical thrombolysis with urokinase or tissue plasminogen activator and concurrent systemic AC therapy, and 4). mechanical endovascular clot thrombolysis with concurrent systemic AC therapy. Complications and clinical outcomes were assessed for each group. RESULTS: Patients treated solely with medical observation fared the worst; four of five patients experienced intracranial hemorrhagic complications, and only two of five exhibited clinical improvement. Patients who received systemic AC therapy experienced no hemorrhagic complications, even when pretreatment hemorrhage was present; 75% (six of eight patients) exhibited improvement with AC therapy alone. Chemical thrombolysis was very effective in restoring sinus patency (90% of patients); however, 30% of patients (3 of 10 patients) experienced hemorrhagic complications. Sixty percent of patients (6 of 10 patients) who underwent chemical thrombolysis exhibited clinical improvement. Patients who underwent mechanical thrombectomies demonstrated a low hemorrhagic complication rate, and most (88%) made good recoveries. CONCLUSION: Therapy directed at the underlying clot in DST must begin without delay. Our results suggest that supportive medical management of DST, without therapy directed at the clot or clotting process, is not effective. Systemic AC therapy, even in the presence of intracerebral hemorrhage, seems to be safe. Heparin can be safely titrated to yield partial thromboplastin times of 60 to 70 seconds. Chemical clot thrombolysis is efficacious in opening occluded sinuses but may cause intracranial hemorrhage. We currently recommend either systemic AC therapy or systemic AC therapy in conjunction with mechanical clot thrombectomy as a safe effective treatment for DST.     

Residual effects of a traumatic brain injury on locomotor capacity: a first study of spatiotemporal patterns during unobstructed and obstructed walking

OBJECTIVES: To understand the residual locomotor effects of a traumatic brain injury (TBI) on unobstructed and obstructed walking. PARTICIPANTS: Eight young, high-functioning adults with TBI and 4 healthy subjects. MAIN OUTCOME MEASURES: Spatiotemporal gait parameters and their relation to specific clinical measures of severity and locomotor and balance abilities. RESULTS: Subjects with TBI walked slower and showed a tendency for greater foot clearances in all conditions. Slower walking was due to decreased stride lengths and not cadence, while higher foot clearances were due to placing the trailing foot farther from the obstacle and increasing hip flexion angles during avoidance. CONCLUSIONS: The results suggest that this highly functional TBI population used increased caution. Measures of injury severity did not provide simple predictions of locomotor ability, but the one-legged stance test with eyes closed correlated to walking capacity.     

Subchondral fractures in osteonecrosis of the femoral head: comparison of radiography,CT, and MR imaging

OBJECTIVE: Our objective was to compare the sensitivity of unenhanced radiography, CT, and MR imaging in revealing subchondral fractures. SUBJECTS AND METHODS: Forty-five subjects with stage I and stage II osteonecrosis of the femoral head were included in the study as part of a multicenter clinical trial to evaluate the effectiveness of recombinant human bone morphogenetic protein as an adjuvant treatment to core decompression. Patients were evaluated with radiography, CT, and MR imaging 6 and 12 months after surgery. RESULTS: At 6 months, 18 fractures were shown on CT scans, but only 12 were detected on radiographs and six, on MR images. At 12 months, 20 subchondral fractures were detected on CT scans, but only 17 were seen on radiographs and 11, on MR images. Compared with CT, MR imaging has a sensitivity and specificity of 38% and 100%, and unenhanced radiography has a sensitivity and specificity of 71% and 97%, respectively. On T2-weighted MR images, the subchondral fractures were visualized as crescentic high-signal-intensity lines, and in all patients, on the corresponding CT scans, the fracture clearly breached the femoral cortex. CONCLUSION: CT reveals more subchondral fractures in osteonecrosis of the femoral head than unenhanced radiography or MR imaging. The high-signal-intensity line seen on T2-weighted MR images appears to represent fluid accumulating in the subchondral fracture, which may indicate a breach in the overlying articular cartilage.     

Iliac artery stenting versus surgical reconstruction for TASC (TransAtlantic Inter-Society Consensus) type B and type C iliac lesions

OBJECTIVE: The TransAtlantic Inter-Society Consensus (TASC) document did not define the best treatment for moderately severe iliac artery lesions, ie, TASC type B and type C iliac lesions, because of insufficient solid evidence to make firm recommendations. The purpose of this study was to evaluate the influence of risk factors on outcome of iliac stenting and operative procedures used to treat TASC type B and type C lesions. METHODS: Over the 5 years from 1996 to 2001, 188 endovascular and direct aortoiliac surgical reconstruction procedures were performed in 87 women and 101 men with TASC type B and type C iliac lesions and chronic limb ischemia. The criteria prepared by the Ad Hoc Committee on Reporting Standards (Society for Vascular Surgery/International Society for Cardiovascular Surgery (SVS/ISCVS) were followed to define variables. Both univariate analysis (Kaplan-Meier method) and multivariate analysis (Cox proportional hazards model) were used to determine the association between variables, cumulative patency rate, limb salvage, and survival. RESULTS: Indications for revascularization were disabling claudication (73%), limb salvage (25%), and blue toe syndrome (2%). Patients in the surgery group (n = 52) had significantly higher primary patency rates compared with patients in the stent group (n = 136) at univariate analysis (Kaplan-Meier method, log-rank test; P =.015). Primary patency rates at 1, 3, and 5 years were 85%, 72%, and 64% after iliac stenting, and 89%, 86%, and 86% after surgical reconstruction, respectively. Univariate and multivariate Cox regression analysis enabled identification of poor runoff (ie, runoff score >5 for unilateral procedures or >2.5 for bilateral outflow procedures; relative risk, 2.5; 95% confidence interval [CI], 1.4-4.2; P =.001) as the only independent predictor of decreased primary patency in all patients. However, stratified analysis including only patients with poor runoff revealed that patients undergoing iliac stenting had significantly lower primary patency rates compared with those undergoing surgical reconstruction (Kaplan-Meier method, log-rank test; P =.05). External iliac artery disease and female gender were also identified as independent predictors of decreased primary stent patency. CONCLUSIONS: Poor infrainguinal runoff is the main risk factor for decreased primary patency after surgical reconstruction and iliac stenting to treat TASC type B and type C iliac lesions. However, primary patency is less affected by poor runoff in patients undergoing surgical procedures. The presence of poor runoff, external iliac artery disease, and female gender are independent predictors of poor outcome after iliac stenting, and therefore these risk factors should determine the need for surgical reconstruction.