Cystathionine-synthase-deficient patients do not use the transamination pathway of methionine to reduce hypermethioninemia and homocystinemia

Methionine is supposed to be degraded via two known routes, the transsulfuration and the transamination pathways. In particular, patients with hypermethioninemia, due to a defect in the transsulfuration pathway, may catabolize significant amounts of methionine via the transamination pathway. In this study the relative amount of methionine degraded via the transamination pathway in 17 patients with homozygous homocystinuria, due to cystathionine synthase deficiency, was compared with 23 normal subjects, and with a patient with hypermethioninemia due to a deficiency in methionine adenosyltransferase. The homocystinuric patients and the normal subjects were studied in the fasting state as well as after methionine loading (0.1 g/kg body weight). It is concluded that in cystathionine synthase deficient patients, the transamination pathway is not quantitatively important in methionine degradation despite elevated methionine levels. This is in contrast to the patient with methionine adenosyltransferase deficiency, who catabolizes at least 20% of his dietary methionine via the transamination pathway.     

Staying responsive to the world: modality-specific and -nonspecific contributions to speeded auditory, tactile, and visual stimulus detection

Sustained responsiveness to external stimulation is fundamental to many time-critical interactions with the outside world. We used functional magnetic resonance imaging during speeded stimulus detection to identify convergent and divergent neural correlates of maintaining the readiness to respond to auditory, tactile, and visual stimuli. In addition, using a multimodal condition, we investigated the effect of making stimulus modality unpredictable. Relative to sensorimotor control tasks, all three unimodal detection tasks elicited stronger activity in the right temporo-parietal junction, inferior frontal cortex, anterior insula, dorsal premotor cortex, and anterior cingulate cortex as well as bilateral mid-cingulum, midbrain, brainstem, and medial cerebellum. The multimodal detection condition additionally activated left dorsal premotor cortex and bilateral precuneus. Modality-specific modulations were confined to respective sensory areas: we found activity increases in relevant, and decreases in irrelevant sensory cortices. Our findings corroborate the modality independence of a predominantly right-lateralized core network for maintaining an alert (i.e., highly responsive) state and extend previous results to the somatosensory modality. Monitoring multiple sensory channels appears to induce additional processing, possibly related to stimulus-driven shifts of intermodal attention. The results further suggest that directing attention to a given sensory modality selectively enhances and suppresses sensory processing-even in simple detection tasks, which do not require inter- or intra-modal selection.     

The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus

Most systematic reviews rely substantially on the assessment of the methodological quality of the individual trials. The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of randomized clinical trials (RCTs). The invited participants were experts in the field of quality assessment of RCTs. The initial item pool contained all items from existing criteria lists. Subsequently, we reduced the number of items by using the Delphi consensus technique. Each Delphi round comprised a questionnaire, an analysis, and a feedback report. The feedback report included staff team decisions made on the basis of the analysis and their justification. A total of 33 international experts agreed to participate, of whom 21 completed all questionnaires. The initial item pool of 206 items was reduced to 9 items in three Delphi rounds. The final criteria list (the Delphi list) was satisfactory to all participants. It is a starting point on the way to a minimum reference standard for RCTs on many different research topics. This list is not intended to replace, but rather to be used alongside, existing criteria lists.     

Cystathionine beta-synthase polymorphisms and hyperhomocysteinaemia: an association study

Hyperhomocysteinaemia is generally accepted as an independent and graded risk factor for both arterial occlusive disease and venous thrombosis. The only way of homocysteine degradation is conversion to cysteine in the transsulfuration pathway in which the regulating step is catalysed by cystathionine beta-synthase (CBS). Mild impairment of CBS function could therefore affect homocysteine concentration, in particular after methionine loading, and consequently cardiovascular disease (CVD) risk. We analysed two silent polymorphisms and one short tandem repeat in the CBS gene (ie 699C-->T, 1080C-->T and -5697 (GT) STR) as genetic markers potentially in linkage disequilibrium with a functional polymorphism. We assessed their association with fasting and post-methionine load homocysteine in 190 patients with arterial occlusive disease, and in 381 controls. No differences in CBS genotype frequencies between cases and controls were found, nor was a particular CBS genotype associated with an elevated risk of arterial occlusive disease. Although we did find a high rate of linkage disequilibrium between the two single nucleotide polymorphisms and the GT STR, none of the genotypes defined by the three CBS variants studied showed an association with elevated fasting, post-load or increase upon methionine loading homocysteine concentrations. In conclusion, we did not find any indication that genetic variation in the CBS gene is associated with increased homocysteine concentrations.     

EBV-positive immunodeficiency lymphoma after alemtuzumab-CHOP therapy for peripheral T-cell lymphoma

Chemotherapy with alemtuzumab and the combination of cyclophosphamide, adriamycin, oncovin, and prednisone (CHOP) has become experimental trial therapy for aggressive T-cell lymphoma. Several multicenter phase 3 trials will incorporate this scheme. As part of an ongoing phase 2 trial in which we recently treated 20 patients with 8 cycles of CHOP every 2 weeks with 3 additional doses of 30 mg alemtuzumab per cycle, we observed the development of Epstein-Barr virus (EBV)-positive lymphoproliferative disease, after completion of the immunochemotherapy in 3 patients with peripheral T-cell lymphoma. Because the occurrence of EBV-positive lymphoproliferative disease is rare after alemtuzumab monotherapy, such as is given for chronic lymphocytic leukemia, we think that early reporting of this potential side effect is warranted. It may be caused by intrinsic T-cell defects in patients with T-cell lymphoma, or by the combination of alemtuzumab with CHOP chemotherapy.     

Automated measurement of joint space width in small joints of patients with rheumatoid arthritis

OBJECTIVE: Comparison of performances of 5 (semi)automated methods in measuring joint space width (JSW) in rheumatoid arthritis. METHODS: Change in JSW was determined by 5 measurement methods on 4 radiographs per patient from 107 patients included in the COBRA trial (comparing sulfasalazine alone or in combination with methotrexate and corticosteroids). For each method the number of patients with sufficient available results was assessed (efficiency). An independent repeated measurement was carried out on a random sample of 30 patients' baseline and 1-year radiographs, to evaluate within-method reliability of change scores. Discriminatory ability (DA) of the measurement methods (between the 2 treatment arms) was compared with the DA of the Sharp-van der Heijde score (SHS) and its 2 components (erosion and JSW scores). RESULTS: The overall success rate varied widely between methods. Applying the chosen threshold of a minimum of 50% available joints with a change score per patient resulted in a success rate > 92% in 4/5 methods. Repeatability of measurements was good for most methods (intraclass correlation coefficient > or = 0.80 in 4/5 methods). Almost all measurement methods in 3 followup periods (12/14) showed a lower mean loss of JSW in patients from the intensive treatment group, although this was rarely statistically significant, confirming the known difference in structural damage. JSW as measured by the (semi)automated systems often showed higher DA than the JSW score of the SHS, but was lower than the total SHS and erosion scores. CONCLUSION: Although efficiency of the methods should be improved further, results already show good reliability and encouraging DA of most methods. Optimal information may be obtained with a combination of scoring of erosions and (semi)automated measurement of JSW.