Diagnostic value of D-dimer in patients with suspected pulmonary embolism: results from a multicentre outcome study

BACKGROUND: D-dimer tests are used in various diagnostic strategies to exclude pulmonary embolism (PE). However, their role as an exclusionary first-line test is still uncertain, mainly because accuracy of the test varies according to the assay and the studied population. METHODS: The aim of this multicentre study was to evaluate the accuracy of D-dimer testing in patients with suspected PE. Diagnosis of PE was based on pre-test clinical probability (PCP) evaluation and both single-detector spiral CT (CT) and lower limbs compression ultrasonography (CUS). Lung scanning and/or pulmonary angiography was mandatory when CT or CUS was inconclusive and when both CT and CUS were normal in a patient with a high PCP. All patients were followed-up for 3 months, looking for VTE recurrence. D-dimers were collected within 24 h of inclusion and stored in each local hematology unit, to be analyzed at the end of all inclusions; physicians in charge of the patient were blinded to D-dimer results. RESULTS: Three hundred and fifty two patients were included in 4 centres. Prevalence of PE was 38.6%. PCP was low in 82 (23.3%), intermediate in 176 (50%) and high in 94 (26.7%) patients. Sensitivity of D-dimer was 96.3% (95% CI: 93-99) and negative predictive value reached 94.4% (95% CI: 90-99). Five patients with a confirmed PE had a D-dimer level below 500 ng/ml (two patients with a high PCP). Among 258 patients with low or intermediate PCP, 80 (31%) had a negative D-dimer test result; three of them had a false negative result and the number needed to test was 3.3. Among 94 patients with a high PCP, 9 had a negative D-dimer test result; two of them had a false negative result and the number needed to test was 13.5. CONCLUSION: These results confirm that rapid assays used in this study can safely exclude PE in first-line testing only in non-high CP patients.     

From dichotic listening to the irrelevant sound effect: a behavioural and neuroimaging analysis of the processing of unattended speech

The assumption that ignoring irrelevant sound in a serial recall situation is identical to ignoring a non-target channel in dichotic listening is challenged. Dichotic listening is open to moderating effects of working memory capacity (Conway et al., 2001) whereas irrelevant sound effects (ISE) are not (Beaman, 2004). A right ear processing bias is apparent in dichotic listening, whereas the bias is to the left ear in the ISE (Hadlington et al., 2004). Positron emission tomography (PET) imaging data (Scott et al., 2004, submitted) show bilateral activation of the superior temporal gyrus (STG) in the presence of intelligible, but ignored, background speech and right hemisphere activation of the STG in the presence of unintelligible background speech. It is suggested that the right STG may be involved in the ISE and a particularly strong left ear effect might occur because of the contralateral connections in audition. It is further suggested that left STG activity is associated with dichotic listening effects and may be influenced by working memory span capacity. The relationship of this functional and neuroanatomical model to known neural correlates of working memory is considered.     

Regional variations in the prevalence of multiple sclerosis in French farmers

Background

Studies on the prevalence of multiple sclerosis have been carried out worldwide, showing a heterogeneous distribution between countries and even between the different regions of the same country.

Methods

We estimated the regional and national prevalence of multiple sclerosis in France on 1 January 2003, based on the computerised database of the national farmer health insurance system (“Mutualité Sociale Agricole”).

Results

There were 2667 cases of multiple sclerosis registered on the prevalence date, out of 4 098 477 affiliates. After standardisation on age, estimates for the national prevalence of multiple sclerosis in French farmers were 65.0 per 100 000 inhabitants (95% confidence interval 62.5 to 67.5), 41.9 per 100 000 in men (39.1 to 44.7) and 96.3 per 100 000 in women (92.0 to 100.6). The prevalence of multiple sclerosis was significantly higher in the north eastern regions (approximately 100 per 100 000 inhabitants) compared with the south western regions (around 50 per 100 000 inhabitants).

Conclusion

Our study is the first to evaluate the overall prevalence of multiple sclerosis in France and its 22 regions using the same methodology. Our results may be generalised to the whole French population as there is no convincing evidence of an increased or decreased susceptibility to multiple sclerosis among farmers or persons living in the countryside. This places France among the countries of medium to high prevalence. Confirming the uneven distribution of multiple sclerosis that correlates with latitude, raises once more the question of the role of genetic and environmental factors in the susceptibility to multiple sclerosis.Studies on the prevalence of multiple sclerosis (MS) have been carried out worldwide, showing a heterogeneous distribution of cases between countries. This heterogeneity seems to correlate with latitude, with an increasing south to north gradient in the Northern hemisphere. Whether this gradient is caused by genetic or environmental factors remains a matter of debate.^1,2,3 France is considered a country of medium to high prevalence for MS.^4,5,6,7,8 To date, there has been no overall estimate of the prevalence of MS in France using the same methodology for all regions. The Mutualité Sociale Agricole is the second health insurance system in France. It has exclusive coverage of farmers and farm workers, as well as their spouses and children, provided they do not work outside the farm. Our objective was to estimate the overall prevalence of MS in France and in each of its 22 administrative regions.     

Quetiapine dosage in bipolar disorder episodes and mixed states

OBJECTIVE: Although the maximal quetiapine doses in the published studies were restricted to 800 mg/day, higher quetiapine doses are not unusual in clinical practice. The aim of the present study was to evaluate the effectiveness, tolerability and clinical reasons associated to the use of high dosage of quetiapine (>800 mg), when used under routine clinical conditions, in a sample of bipolar disorder and schizoaffective bipolar inpatients. METHODS: Charts of all bipolar and schizoaffective adult inpatients, who had received quetiapine for a mood episode between 1999 and 2005 were retrospectively reviewed. These charts also included the assessment of manic and depressive symptoms on admission and at discharge using the Beck-Rafaelsen Mania Scale (MAS) and the Montgomery Asberg depression rating scale (MADRS), respectively. RESULTS: Data of 50 patients were analyzed. The overall F in repeated measures ANOVA revealed a significant MAS scores reduction between admission and discharge. MAS scores reduction did not differ between the high and low quetiapine groups. Similarly, a significant MADRS reduction was found. Again, no differences between the high and the low dose group were found. Logistic regression analysis of the 50 patients revealed only mixed episodes predicted high quetiapine dosage. CONCLUSIONS: The present study confirms quetiapine efficiency and tolerability in the treatment of bipolar episodes, even in doses > to 800 mg and found a link between quetiapine doses and mixed episodes.     

Dynamic history of low-grade gliomas before and after temozolomide treatment

OBJECTIVE: To evaluate the natural progression and the impact of temozolomide in low-grade gliomas and to correlate these changes with the profile of genetic alterations. METHODS: The mean tumor diameter (MTD) of low-grade gliomas was evaluated on serial magnetic resonance images before (n = 39), during, and after (n = 107) treatment with neoadjuvant temozolomide. MTD growth curves were correlated with chromosomes 1p-19q loss and p53 overexpression in the tumors. RESULTS: Before temozolomide onset, MTD increased linearly over time, indicating a continuous growth that was significantly slower in 1p-19q deleted tumors (3.4 vs 5.9mm/year; p = 0.0016) and in tumors that did not overexpress p53 (4.2 vs 6.3mm/year; p = 0.05). During temozolomide treatment, almost all patients (92%) experienced initial decrease of MTD. Subsequently, some tumors started to resume growth despite continuous administration of temozolomide, with a lower rate of relapse in 1p-19q deleted tumors (16.6 vs 58%; p = 0.0004) and in tumors that did not overexpress p53 (26 vs 68%; p = 0.003). When temozolomide was discontinued in the absence of tumor progression, a majority of tumors resumed their progressive growth within a year. INTERPRETATION: Untreated low-grade gliomas grow continuously at a rate that is influenced by the genetic alterations of the tumors. Temozolomide reverses this pattern at the onset, but this effect is often brief in patients whose tumors overexpress p53 and do not harbor the 1p-19q codeletion, suggesting acquired chemoresistance. A majority of tumors will resume their growth when treatment is discontinued, raising the issue of the optimal duration of treatment in continuously responding patients.     

Cognitive behavioural therapy for weight gain associated with antipsychotic drugs

Schizophrenia patients with the deficit syndrome (DS) may represent a homogeneous subgroup. To increase the practicability of diagnosing the DS, Kirkpatrick et al. [Kirkpatrick, B., Buchanan, RW., Breier, A. Carpenter, WT., 1993. Case identification and stability of the deficit syndrome of schizophrenia. Psychiatry Res. 47, 47-56.] proposed the use of a 'proxy' case identification tool using standardized symptom ratings instead of the Schedule for the Deficit Syndrome (SDS) which requires an independent clinical assessment. The Proxy for the Deficit Syndrome (PDS) is based on the extraction of symptoms that are essentially equivalent or overlap substantially with the restricted affect and diminished emotional range on the SDS. Kirkpatrick et al. [Kirkpatrick, B., Buchanan, RW., Breier, A. Carpenter, WT., 1993. Case identification and stability of the deficit syndrome of schizophrenia. Psychiatry Res. 47, 47-56.] reported good sensitivity and specificity in a comparison of SDS and PDS assessments among 100 chronic schizophrenia outpatients. The present investigation involves the comparison of the deficit syndrome as assessed by the "gold standard" Schedule for the Deficit Syndrome with the ratings of the same symptoms embodied in the "proxy instrument" the PANSS, within the same group of 156 inpatients. Forty-four patients were assessed by the SDS to have the deficit syndrome. Patients with and without the DS, as defined by the SDS, did not differ for age, education, age at illness onset and duration of illness. The two main 'proxy' measures PDS1 and PDS2 discriminated across the SDS groups. The direct dichotomous comparison of the actual SDS and the 'proxy' derived PDS groups demonstrated good specificity (78.6% and 79.5%) and moderate to very good sensitivity (61.4% and 86.4%) and there was a moderately low rate of false positive cases (21.4% and 20.5%). For the two main 'proxy' measures (PDS1 and PDS2) kappas were .38 and .59, representing poor to good agreement. In our sample of rigorously diagnosed schizophrenia inpatients, the use of a 'proxy' case identification tool for the deficit syndrome would appear to be a viable alternative in identifying a subgroup of schizophrenia patients with the deficit syndrome when the use of the actual SDS is not feasible. Further study is indicated before the PDS as extracted from the PANSS can be used in lieu of the SDS for identifying patients with this syndrome.     

Inhibitory control of the human dorsolateral prefrontal cortex during the anti-saccade paradigm--a transcranial magnetic stimulation study

In the anti-saccade paradigm, subjects are instructed not to make a reflexive saccade to an appearing lateral target but to make an intentional saccade to the opposite side instead. The inhibition of reflexive saccade triggering is under the control of the dorsolateral prefrontal cortex (DLPFC). The critical time interval at which this inhibition takes place during the paradigm, however, is not exactly known. In the present study, we used single-pulse transcranial magnetic stimulation (TMS) to interfere with DLPFC function in 15 healthy subjects. TMS was applied over the right DLPFC either 100 ms before the onset of the visual target (i.e. -100 ms), at target onset (i.e. 0 ms) or 100 ms after target onset (i.e. +100 ms). Stimulation 100 ms before target onset significantly increased the percentage of anti-saccade errors to both sides, while stimulation at, or after, target onset had no significant effect. All three stimulation conditions had no significant influence on saccade latency of correct or erroneous anti-saccades. These findings show that the critical time interval at which the DLPFC controls the suppression of a reflexive saccade in the anti-saccade paradigm is before target onset. In addition, the results suggest the view that the triggering of correct anti-saccades is not under direct control of the DLPFC.     

Voxel-based morphometry of auditory and speech-related cortex in stutterers

Stutterers demonstrate unique functional neural activation patterns during speech production, including reduced auditory activation, relative to nonstutterers. The extent to which these functional differences are accompanied by abnormal morphology of the brain in stutterers is unclear. This study examined the neuroanatomical differences in speech-related cortex between stutterers and nonstutterers using voxel-based morphometry. Results revealed significant differences in localized grey matter and white matter densities of left and right hemisphere regions involved in auditory processing and speech production.     

Ascorbic acid inhibits PMP22 expression by reducing cAMP levels

Charcot-Marie-Tooth [CMT] syndrome is the most common hereditary peripheral neuropathy. CMT1A, which accounts for 50% of all CMT cases, usually results from triploidy of the PMP22 gene. Preclinical trials using an animal model show that disabled mice force-fed with high doses of ascorbic acid partially recover muscular strength after a few months of treatment, and suggest that high doses of ascorbic acid repress PMP22 expression. In this study, we demonstrated that ascorbic acid represses PMP22 gene expression by acting on intracellular cAMP levels and adenylate cyclase activity. This action is dose dependent and specific to ascorbic acid, since repression is not observed after treatment with other antioxidants. The new properties of ascorbic acid are discussed, along with the implications of these findings for CMT disease treatment.     

High hepatic glutathione stores alleviate Fas-induced apoptosis in mice

BACKGROUND/AIMS: The agonistic Jo2 anti-Fas antibody reproduces human fulminant hepatitis in mice. We tested the hypothesis that enhancing hepatic glutathione (GSH) stores may prevent Jo2-induced apoptosis. METHODS: We fed mice with a normal diet or a sulfur amino acid-enriched (SAA(+)) diet increasing hepatic GSH by 63%, and challenged these mice with Jo2. RESULTS: The SAA(+) diet markedly attenuated the Jo2-mediated decrease in hepatic GSH and the increase in the oxidized glutathione (GSSG)/GSH ratio in cytosol and mitochondria. The SAA(+) diet prevented protein kinase Czeta (PKCzeta) and p47(phox) phosphorylations, Yes activation, Fas-tyrosine phosphorylation, Bid truncation, Bax, and cytochrome c translocations, the mitochondrial membrane potential collapse, caspase activation, DNA fragmentation, hepatocyte apoptosis, and mouse lethality after Jo2 administration. The protective effect of the SAA(+) diet was abolished by a small dose of phorone decreasing hepatic GSH back to the levels observed in mice fed the normal diet. Conversely, administration of GSH monoethyl ester after Jo2 administration prevented hepatic GSH depletion and attenuated toxicity in mice fed with the normal diet. CONCLUSIONS: The SAA(+) diet preserves GSSG/GSH ratios, and prevents PKCzeta and p47(phox) phosphorylations, Yes activation, Fas-tyrosine phosphorylation, mitochondrial permeabilization, and hepatic apoptosis after Fas stimulation. GSH monoethyl ester is also protective, suggesting possible clinical applications.