Magnetization transfer can predict clinical evolution in patients with multiple sclerosis

The clinical course of multiple sclerosis (MS) is highly variable ranging from benign to aggressive, and is difficult to predict. Since magnetization transfer (MT) imaging can detect focal abnormalities in normal-appearing white matter (NAWM) before the appearance of lesions on conventional MRI, we hypothesized that changes in MT might be able to predict the clinical evolution of MS. We assessed MR data from MS patients who were subsequently followed clinically for 5 years. We computed the mean MT ratio (MTr) in gray matter, in lesions identified on T2-weighted MRI, and in NAWM, as well as in a thick central brain slice for each patient. Patients were divided into stable and worsening groups according to their change in Expanded Disability Status Scale (EDSS) scores over 5 years. We calculated the sensitivity, specificity, predictive value, and odds ratio of the baseline MTr measures in order to assess their prognostic utility. We found significant differences in baseline MTr values in NAWM (p = 0.005) and brain slice (p = 0.03) between clinically stable and worsening MS patients. When these MTr values were compared with changes in EDSS over 5 years, a strong correlation was found between the EDSS changes and MTr values in both NAWM (SRCC = −0.76, p < 0.001) and in the brain slice (SRCC = 0.59, p = 0.01). Baseline NAWM MTr correctly predicted clinical evolution in 15/18 patients (1 false positive and 2 false negatives), yielding a positive predictive value of 77.78 %, a negative predictive value of 88.89 %, and an odds ratio of 28. The relationship between 5-year changes in EDSS and MTr values in T2 weighted MRI lesions was weaker (SRCC = −0.43, p = 0.07). Our data support the notion that the quantification of MTr in the NAWM can predict the clinical evolution of MS. Lower MTr values predict poorer long-term clinical outcome. Abnormalities of MTr values in the NAWM are more relevant to the development of future patient disability than those in the T2-weighted MRI lesions. Received: 3 May 2001, Received in revised form: 11 October 2001, Accepted: 22 October 2001     

Gene targeting of components of the fibrinolytic system

A number of in vitro and in vivo observations have implicated components of the fibrinolytic system in events associated with diverse physiological and pathophysiological processes, ranging from embryo implantation to cancer. Advances in gene targeting technology have led to the generation of mice deficient for components of the fibrinolytic system. Remarkably, these animals survive to adulthood with few spontaneous life threatening events. Thus, these mice are valuable resources for in vivo studies, not only for hemostasis-related research, but also for the relationships of these genes to other disease states associated with cellular growth and mobility, along with angiogenesis, vascular remodeling, inflammation, wound healing, and tumor growth and dissemination.     

Mice with a severe deficiency of the endothelial protein C receptor gene develop,survive, and reproduce normally,and do not present with enhanced arterial thrombosis after challenge

The endothelial cell Protein C receptor (EPCR) functions to enhance activation of anticoagulant Protein C (PC) by the thrombin/ thrombomodulin (Tm) complex on the surface of the endothelium. This overall system functions in anticoagulation, profibrinolytic, and antiinflammatory responses. Mice with a severe targeted deficiency of this receptor have been generated by integration of exogenous DNA elements into the 5'-untranslated region of the EPCR gene. Despite the retention of the entire endogenous EPCR coding sequence in the altered EPCR gene locus, only very low EPCR message contents were detected in mice by quantitative RT-PCR during embryogenesis and up to at least early adulthood. Immunohistochemical analysis of various regions of the arterial tree of mice up to 4 months of age, employing an anti-murine EPCR antibody, confirmed that undetectable levels of this protein were present in arterial regions during these periods. Despite this, these mice are not more prone to arterial thrombosis after challenge in a FeCl3 carotid artery thrombosis model. Small amounts (<10% of wild-type) of this protein were found in other tissues. Matings of mice homozygous for this deficiency led to normal births and survival of the offspring, in contrast to results by others demonstrating early embryonic lethality of a total EPCR deficiency. These data further show that minimal levels of EPCR are able to support male and female virility, as well as embryonic development, birth, and survival to adulthood.     

Ultrasound improves tissue perfusion in ischemic tissue through a nitric oxide dependent mechanism

Ultrasound accelerates enzymatic fibrinolysis in vitro and in animal models and may be used as an adjunct to thrombolytic therapy. Ultrasound can also affect vascular tone directly, and we have now investigated the effect of ultrasound on tissue perfusion in a rabbit model of acute muscle ischemia to characterize the magnitude and temporal course of vasodilation and determine its mechanism. After ligation of the femoral artery of rabbits, tissue perfusion in the gracilis muscle as determined using a laser Doppler probe declined by 53% from 13.7 +/- 0.3 U to 6.4 +/- 0.2 U. The tissue became acidotic as pH declined from normal to 7.05 +/- 0.2. Application of 40 kHz ultrasound at intensities from 0.25 to 0.75 W/cm(2) progressively improved perfusion over 60 min and reversed acidosis, but these effects were both completely blocked by pre-treatment with the nitric oxide synthase inhibitor L-NAME. Nitric oxide synthase activity in muscle was measured using an assay based on the conversion of radiolabeled L-arginine to L-citrulline and demonstrated an increase of 3.6-fold following ultrasound exposure. This effect was greatest at locations close to the transducer and declined progressively away from it. Histologic examination showed greater capillary circumference in ultrasound exposed muscle compared to unexposed tissue with no other histologic changes. We conclude that the application of 40 kHz at low intensity improves perfusion and reverses acidosis in acutely ischemic muscle through a nitric oxide dependent mechanism.     

High prevalence of asymptomatic deep vein thrombosis on admission in a medical unit among elderly patients

The prevention of venous thromboembolism in medical patients remains questioned. All consecutive outpatients admitted in our medical unit were considered for inclusion in this study which aimed to estimate the prevalence of asymptomatic venous thrombosis on admission and the incidence during hospital stay. Exclusion criteria were: age <18 years, suspicion of venous thromboembolism, stay <4 days, ongoing anticoagulant therapy. Venous compression ultrasonography of the lower limbs was performed within 48 h. 234 patients were included. The prevalence of asymptomatic deep vein thrombosis on admission and the incidence during hospital follow-up were respectively 5.5% (95% confidence interval, 3.1 to 9.5%) and 2.6 per 1,000 person-days (95% confidence interval, 0.0 to 5.2). The prevalence and the incidence reached respectively 17.8% (95% confidence interval, 8.5 to 32.6%) and 6.0 per 1,000 person-days (95% confidence interval, 0.0 to 12.7) among patients over 80 years. A high prevalence of asymptomatic deep vein thrombosis on admission was suggested particularly among elderly medical patients.     

A new locus for spinocerebellar ataxia (SCA21) maps to chromosome 7p21.3-p15.1

We investigated a French family with a new type of autosomal dominant spinocerebellar ataxia that was excluded from all previously identified genes and loci. The patients exhibited a slowly progressive gait and limb ataxia variably associated with akinesia, rigidity, tremor, and hyporeflexia. A mild cognitive impairment also was observed in some cases. We performed a genomewide search and found significant evidence for linkage to chromosome 7p21.3-p15.1. Analysis of key recombinants and haplotype reconstruction traced this novel spinocerebellar ataxia locus to a 24cM interval flanked by D7S2464 and D7S516.     

The ketogenic diet: a review of the experience at Connecticut Children's Medical Center

We undertook a retrospective analysis of epilepsy patients referred and treated for more than 6 months with the ketogenic diet during 1994-1999 at Connecticut Children's Medical Center. Outcome measures included antiepileptic drug number, seizure frequency, electroencephalogram background/paroxysmal activity, and adverse effects at 6 months and 1 year on the ketogenic diet. The final cohort included 24 of 48 referred patients (mean age, 6.5 years; range = 1-15 years of age). The etiology of epilepsy was equally divided between idiopathic and cryptogenic epilepsy and symptomatic epilepsy. Intention to treat analysis revealed that 35% (17 of 48) achieved more than 50% reduction in seizure frequency, and 8.5% (four of 48) were seizure-free by 6 months. A sustained 50% or greater reduction at 1 year was observed in 23% (11 of 48), and the same 8.5% (four of 48) remained seizure-free. None of these improvements were statistically related to age (P = 0.97), sex (P = 0.78), or epilepsy etiology (P = 0.80). The number of antiepileptic drugs used per patient decreased. Electroencephalogram at 1 year demonstrated an improvement in background in 31% (five of 16 patients) and a reduction in paroxysmal features in 37.5% (6 of 16 patients). Most adverse effects were mild, self-limited, and occurred early. Hyperuricemia (more than 6 mg/dL) was more persistent in three patients.     

Postmortem serotoninergic correlates of cognitive decline in Alzheimer's disease

Serotonin1A receptor density and serotonin concentration were measured in the postmortem neocortex of 17 AD patients who had been prospectively assessed every four months with the Mini-Mental State Examination (MMSE) for a mean of 2.6 years till death. In the frontal cortex, serotonin levels correlated negatively with the annual rate of MMSE decline, while serotonin1A receptor density was positively correlated with the rate of MMSE decline. Our study suggests that reduced serotonin levels and increased serotonin1A receptor density are markers for accelerated cognitive decline in AD, and provides support for the use of serotonin1A antagonists in the treatment of AD.     

The fate of stable femoral components retained during isolated acetabular revision: a six-to-twelve-year follow-up study

BACKGROUND: The decision as to whether to revise a well-fixed femoral component in hips requiring isolated acetabular revision is challenging. The purpose of the present study was to determine the long-term results of, and the complications associated with, retention of a stable and well-fixed femoral component during isolated acetabular revision. METHODS: We retrospectively reviewed the clinical and radiographic results for thirty-one patients (thirty-two hips) who underwent isolated revision acetabuloplasty without removal of a well-fixed femoral component. The reason for acetabular revision was aseptic loosening in thirty-one hips and malposition in one hip. Of the thirty-two femoral components, twenty-one were cemented and eleven were cementless. The average duration of follow-up from the time of the index revision was 8.1 years (range, 6.4 to 12.5 years), and the average duration of total service of the femoral component was seventeen years (range, seven to twenty-five years) from time of the initial implantation. The average age of the patients at the time of the index revision was sixty-six years (range, twenty-nine to eighty-seven years). RESULTS: Thirty-one (97%) of the primary femoral components were judged to be stable and well fixed at the latest follow-up evaluation. One femoral component (3%) was revised because of aseptic loosening, eight years after the index acetabular revision and seventeen years after the initial total hip arthroplasty. Radiographic evaluation of the thirty-one femoral components that were not revised demonstrated no evidence of loosening or subsidence. There were no dislocations, nerve palsies, or intraoperative fractures associated with retention of the femoral component. Twenty-seven (84%) of the acetabular components were judged to be stable at the latest follow-up evaluation. CONCLUSION: In hips treated with isolated acetabular revision, a well-fixed femoral component can be retained successfully without adversely affecting the acetabular exposure; the placement, position, or stability of the acetabular component; or the ability to restore bone stock. The data from the present study support the decision to retain a well-fixed femoral component when the acetabular component needs to be revised.