Symptomatic peripheral arterial disease: the value of a validated questionnaire and a clinical decision rule

BACKGROUND: If a validated questionnaire, when applied to patients reporting with symptoms of intermittent claudication, could adequately discriminate between those with and without peripheral arterial disease, GPs could avoid the diagnostic measurement of the ankle brachial index. AIM: To investigate the Edinburgh Claudication Questionnaire (ECQ) in general practice and to develop a clinical decision rule based on risk factors to enable GPs to easily assess the likelihood of peripheral arterial disease. DESIGN OF STUDY: An observational study. SETTING: General practice in The Netherlands. METHOD: This observational study included patients of > or =55 years visiting their GP for symptoms suggestive of intermittent claudication or with one risk factor. The ECQ and the ankle brachial index were performed. The prevalence of peripheral arterial disease, defined as an ankle brachial index <0.9, was related to risk factors using logistic regression analyses, on which a clinical decision rule was developed and related to the presence of peripheral arterial disease. RESULTS: Of the 4790 included patients visiting their GP with symptoms suggestive of intermittent claudication, 4527 were eligible for analyses. The prevalence of peripheral arterial disease in this group was 48.3%. The sensitivity of the ECQ was only 56.2%. The prevalence of peripheral arterial disease in a clinical decision rule that included age, male sex, smoking, hypertension, hypercholesterolemia, and a positive ECQ, increased from 14% in the lowest to 76% in the highest category. CONCLUSION: This study indicates that the ECQ alone has an inadequate diagnostic value in detecting patients with peripheral arterial disease. The ankle brachial index should be performed to diagnose peripheral arterial disease in patients with complaints suggestive of intermittent claudication, although our clinical decision rule could help to differentiate between extremely high and lower prevalence of peripheral arterial disease.     

Enhanced number and activity of mitochondria in multiple sclerosis lesions

Mitochondrial dysfunction has been implicated in the development and progression of multiple sclerosis (MS) lesions. Mitochondrial alterations might occur as a response to demyelination and inflammation, since demyelination leads to an increased energy demand in axons and could thereby affect the number, distribution and activity of mitochondria. We have studied the expression of mitochondrial proteins and mitochondrial enzyme activity in active demyelinating and chronic inactive MS lesions. Mitochondrial protein expression and enzyme activity in active and chronic inactive MS lesions was investigated using (immuno)histochemical and biochemical techniques. The number of mitochondria and their co‐localization with axons and astrocytes within MS lesions and adjacent normal‐appearing white matter (NAWM) was quantitatively assessed. In both active and inactive lesions we observed an increase in mitochondrial protein expression as well as a significant increase in the number of mitochondria. Mitochondrial density in axons and astrocytes was significantly enhanced in active lesions compared to adjacent NAWM, whereas a trend was observed in inactive lesions. Complex IV activity was strikingly up‐regulated in MS lesions compared to control white matter and, to a lesser extent, NAWM. Finally, we demonstrated increased immunoreactivity of the mitochondrial stress protein mtHSP70 in MS lesions, particularly in astrocytes and axons. Our data indicate the occurrence of severe mitochondrial alterations in MS lesions, which coincides with enhanced mitochondrial oxidative stress. Together, these findings support a mechanism whereby enhanced density of mitochondria in MS lesions might contribute to the formation of free radicals and subsequent tissue damage. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations

It has previously been shown that, in the heterozygous state, mutations in the SOX9 gene cause campomelic dysplasia (CD) and the often associated autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one recurrent mutation were characterized in one SOX9 allele each, and in one case, no mutation was found. Four missense mutations are all located within the high mobility group (HMG) domain. They either reduce or abolish the DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense and three frameshift mutations identified, two leave the C-terminal transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or almost completely intact. When tested in cell transfection experiments, the recurrent nonsense mutation Y440X, found in two patients who survived for four and more than 9 years, respectively, exhibits some residual transactivation ability. In contrast, a frameshift mutation extending the protein by 70 residues at codon 507, found in a patient who died shortly after birth, showed no transactivation. This is apparently due to instability of the mutant SOX9 protein as demonstrated by Western blotting. Amino acid substitutions and nonsense mutations are found in patients with and without XY sex reversal, indicating that sex reversal in CD is subject to variable penetrance. Finally, none of 18 female patients with XY gonadal dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP assays, providing evidence that SOX9 mutations do not usually result in XY sex reversal without skeletal malformations.      

Critical stages of tumor growth regulation in transgenic mice harboring a hepatocellular carcinoma revealed by distinct patterns of tumor necrosis factor-alpha and transforming growth factor-beta mRNA production

There is now good evidence that cytokines contribute to the regulation of tumor growth. The cytokine-driven modulation of tumor growth was investigated during the progression of a hepatocellular carcinoma (HCC) in SV40 large T tumor antigen transgenic mice. In vivo, an increased rate of liver growth correlated with increased transforming growth factor (TGF)-beta 1 mRNA expression, while the greatest amounts of tumor necrosis factor (TNF)-alpha mRNA were detected earlier during tumor development. Conversely, no particular alteration of IL-1 alpha, IL-1 beta, IL-6, IL-2, IL-4 and IFN-gamma mRNA production could be reported. In vitro, hepatocyte-like tumor cell lines established at two stages, either before or after HCC differentiation, were characterized. The early-stage-derived cell line produced TNF-alpha mRNA, but had barely detectable expression of TGF-beta 1 mRNA, while later-stage- derived cell lines showed the reciprocal pattern. All cell lines displayed a lack of sensitivity to TNF-alpha, although some degree of sensitivity to TNF-alpha could be observed in the presence of actinomycin-D or after treatment with IFN-gamma. The early-stage- derived cell line was sensitive to the growth inhibitory effects of TGF- beta 1, but late-stage-derived tumor cell lines displayed a loss of sensitivity to TGF-beta 1 which correlated with the increased expression of TGF-beta 1 mRNA. Altogether, this suggests that tumor cells contribute to the discrete TNF-alpha and TGF-beta 1 expression patterns during HCC progression. This model of HCC could be of valuable interest to assess the impact of various immunotherapeutic strategies on modulation of tumor growth.      

<Emphasis Type="Italic">TCF7L2</Emphasis>variant genotypes and type 2 diabetes risk in Brazil: significant association,but not a significant tool for risk stratification in the general population

Background  

Genetic polymorphisms of the TCF7L2 gene are strongly associated with large increments in type 2 diabetes risk in different populations worldwide. In this study, we aimed to confirm the effect of the TCF7L2 polymorphism rs7903146 on diabetes risk in a Brazilian population and to assess the use of this genetic marker in improving diabetes risk prediction in the general population.     

Superficial temporal artery as an external landmark for deeper-lying brain structures

Additional localizing superficial landmarks for intracranial structures can be of use to the neurosurgeon. This study was performed to evaluate the usefulness of the superficial temporal artery (STA) as an external landmark for deeper brain structures. Thirteen adult cadavers (26 sides) underwent latex injection of their STA bilaterally. Dissections were next carried out to identify this vessel. Once the STA and its frontal and parietal branches were skeletonized, craniectomies were performed and the underlying dura mater excised. Measurements were made between the frontal and parietal branches of the STA and deeper brain structures. The STA was found to branch on average 3 cm superior to the tragus. The bifurcation of the STA was found to commonly bifurcate at the level of the floor of the middle cranial fossa or superior temporal gyrus. The Sylvian fissure was found at a mean of 2 cm superior to the STA bifurcation. The angle between the frontal branch of the STA and the zygomatic arch had a mean of 37 degrees. The angle between the frontal and parietal branches of the STA had a mean of 87 degrees. At the level of the glabella, the frontal branch of the STA was on average 3 cm posterior to the frontal pole. The temporal tip was located a mean of 3.2 cm anterior to the frontal branch of the STA. The plane of the foramen of Monro was found to lie at a mean distance of 2.3 cm posterior to the frontal branch of the STA. The parietal branch of the STA was noted to travel more or less parallel with the central sulcus in all specimens and to travel an average of 2 cm posterior to this sulcus. At the level of the lateral attachment of the tentorium cerebelli, the parietal branch of the STA was found to travel a mean of 4.8 cm anterior to the entrance of the vein of Labbé into the transverse sinus. The parietal branch of the STA was also found to travel a mean of 4.2 cm anterior to the angular gyrus and 3.9 cm anterior to the supramarginal gyrus. Palpation or Doppler identification of the STA and its branches with subsequent mapping on the lateral cranium may prove useful as an additional superficial landmark for the neurosurgeon.