Classification of outcomes events in the Dutch TIA trial: prognostic value of accepted and rejected events

OBJECTIVE: In large multicentre clinical trials adjudication of outcome events most often is done centrally. Some of these events would eventually be judged not to meet the criteria and hence would be rejected. If the classification procedures work correctly one would expect a higher risk of future vascular events after an 'accepted' rather than after a 'rejected event. In the present study we aimed at testing the adequacy of a classification procedure in a trial of patients with a transient ischemic attack (TIA) or minor ischemic stroke by comparing the further outcome between patients in whom a possible event was either rejected or accepted for the final analysis in this trial. RESEARCH DESIGN AND METHODS : The vascular outcome events were analysed in 3150 patients with TIA or minor stroke who participated in the Dutch TIA trial. We identified the patients with a first 'accepted' or 'rejected' non-fatal stroke or myocardial infarction (MI). In these two groups of patients we determined the occurrence of the subsequent vascular events (vascular death, stroke or MI). The incidence was compared with survival analysis techniques. RESULTS: Among 308 patients with a first nonfatal 'accepted' event in 81 (26.3%) a new vascular event occurred; among the 51 patients with a 'rejected' event there were 12 (23.5%) such events. The hazard ratio for new vascular events was 1.22 (95% CI 0.67-2.22). After multivariate adjustment for age, type of qualifying event, history of smoking, angina pectoris and myocardial infarction, and Rankin score > or = 3, the hazard ratio was 1.49 (95% CI 0.78-2.84). CONCLUSION: our study suggested that the adjudication process of outcome events in the Dutch TIA trial was done correctly because a trend towards a higher recurrence rate of vascular events among patients with 'accepted' outcome events was found.     

The immunodominant epitope of lipocalin allergen Bos d 2 is suboptimal for human T cells

We have proposed earlier that the poor capacity of the lipocalin allergen Bos d 2 to stimulate highly allergic subjects' peripheral blood mononuclear cells could be ascribed to endogenous lipocalins and could be related to the allergenic potential of the molecule. Here, we have characterized the proliferative and cytokine responses of human T cell clones against the immunodominant epitope of Bos d 2. We observed, for clone F1-9, that a substitution of aspartic acid for asparagine in the core region of the epitope increased the stimulatory capacity of the peptide about 100-fold in comparison with the natural peptide. For clone K3-2, from a different patient, the substitution of lysine for glutamine or isoleucine for leucine in the core region resulted in about 30-fold and 10-fold increases in the stimulatory capacity of the peptides, respectively. The clones also recognized self-protein-derived peptides but not the peptides derived from other lipocalins. We suggest that the poor recognition of the immunodominant epitope of Bos d 2 can be a factor accounting for Bos d 2-allergic subjects' weak cellular responses. Suboptimal recognition of self and allergen epitopes by T cells may be of significance for the allergenicity of proteins.     

Increased pregnancy loss in young women with aortoiliac disease

BACKGROUND: During clinical evaluation of young women with peripheral arterial occlusive disease, we were surprised by the high prevalence of pregnancy loss in women with segmental stenosis confined to the aortoiliac segment. We wondered if increased occurrence of miscarriage is the result of high expression of vascular and obstetrical risk factors in these patients, or if it is related to localization of disease. In a case-control study designed to investigate risk factors for peripheral arterial occlusive disease in young women, we assessed the risk of miscarriage in these patients according to level of obstruction. METHODS: A total of 202 female patients, aged 18-49 years and 466 healthy control women from a population based case-control study, donated venous blood samples and filled out a structured questionnaire concerning classical cardiovascular risk factors and obstetrical history. In all patients, diagnosis of peripheral arterial occlusive disease was confirmed by intra-arterial angiography. Patients were classified into two groups: those with and those without stenosis of the aortoiliac segment (aortoiliac disease). RESULTS: In 77 of the 202 patients (38%) with peripheral arterial occlusive disease, the obstruction was confined to the aortoiliac segment. The occurrence of miscarriage was high (42%) in young women with aortoiliac disease. Compared to healthy controls, the risk of miscarriage increased 3-fold (OR 3.1; 95% CI 1.8-5.6) in these patients. Adjustment for obstetrical and vascular risk factors did not affect the risk estimate. CONCLUSION: This is the first study that identifies aortoiliac disease as a risk factor for pregnancy loss in young women. The risk of miscarriage is increased 3-fold in women with aortoiliac disease. The presence of vascular and obstetrical risk factors did not affect the strength of the association. Pregnancy loss could be the first sign of insufficient aortic circulation in these patients.     

Hypomagnesemia after aneurysmal subarachnoid hemorrhage

OBJECTIVE: Hypomagnesemia frequently occurs in hospitalized patients, and it is associated with poor outcome. We assessed the frequency and time distribution of hypomagnesemia after aneurysmal subarachnoid hemorrhage (SAH) and its relationship to the severity of SAH, delayed cerebral ischemia (DCI), and outcome after 3 months. METHODS: Serum magnesium was measured in 107 consecutive patients admitted within 48 hours after SAH. Hypomagnesemia (serum magnesium <0.70 mmol/L) at admission was related to clinical and initial computed tomographic characteristics by means of the Mann-Whitney U test. Hypomagnesemia at admission and during the DCI onset period (Days 2-12) was related to the occurrence of DCI and hypomagnesemia at admission, and hypomagnesemia that occurred any time during the first 3 weeks after SAH was related to outcome. RESULTS: Hypomagnesemia at admission was found in 41 patients (38%) and was associated with more cisternal (P = 0.006) and ventricular (P = 0.005) blood, a longer duration of unconsciousness (P = 0.007), and a worse World Federation of Neurosurgical Societies scale score at admission (P = 0.001). The crude hazard ratio for DCI with hypomagnesemia at admission was 2.4 (95% confidence interval, 1.0-5.6), and after multivariate adjustment it was 1.9 (95% confidence interval, 0.7-4.7). The hazard ratio of hypomagnesemia from Days 2 to 12 for patients with DCI was 3.2 (range, 1.1-8.9) after multivariate adjustment. The crude odds ratio for poor outcome (Glasgow Outcome Scale score, 1-3) with hypomagnesemia at admission was 2.5 (range, 1.1-5.5). Hypomagnesemia at admission did not contribute to the prediction of outcome in the multivariate model. CONCLUSION: Hypomagnesemia is frequently present after SAH and is associated with severity of SAH. Hypomagnesemia occurring between Days 2 and 12 after SAH predicts DCI.     

Reducing the sexual risk behaviors of HIV+ individuals: Outcome of a randomized controlled trial

Testing behavioral interventions to increase safer sex practices of HIV+ individuals has the potential to significantly reduce the number of new infections. This study evaluated a behavioral intervention designed to reduce the sexual risk behaviors of HIV+ individuals. HIV+ individuals (N = 387) who reported engaging in unprotected sex with HIV- or partners of unknown serostatus were randomly assigned to (a) a single counseling session targeting problem areas identified by the participant in 3 possible intervention domains (i.e., condom use, negotiation, disclosure); (b) a single-session comprehensive intervention that covered all 3 intervention domains; (c) the same comprehensive intervention, plus 2 monthly booster sessions; or (d) a 3-session diet and exercise attention-control condition. The median number of unprotectedsex acts decreasedfrom 14 at baseline to6, 6, and4 at 4-, 8-, and 12-month follow-ups, respectively. A repeated measures analysis of variance revealed a significant decrease in unprotected sex acts across all groups across time. A significant Group x Time interaction revealed that the comprehensive-with-boosters group had the most unprotected sex at 8-month follow-up as compared to the other 3 groups. These findings suggest that a brief intervention can result in large reductions in HIV transmission risks among HIV+ individuals, but the relative benefit of one intervention approach over another remains unclear. Support for this work was provided, in part, by the National Institute of Mental Health (NIMH) Grant 5 R01 MH56264 (Brief Targeted Behavior Intervention for HIV+ Persons, T. L. Patterson, P.I.), NIMH Center Grant 2 P50 MH45294 (HIV Neurobehavioral Research Center, I. Grant, P.I.), and the Department of Veterans Affairs. We thank all of the project staff, in particular Duane Stanton, who participated in data collection and the conduct of the intervention.     

Coping and psychological distress among symptomatic HIV+ men who have sex with men

This study evaluated relations among indicators of latent coping factors and psychological distress while incorporating measures of life stress and HIV illness related factors simultaneously among 211 symptomatic, HIV+ men who have sex with men (MSM). Participants were all assessed at a single time point. A structural equations model with latent factors for approachoriented coping, avoidant-oriented coping, and psychological distress showed adequate fit. Furthermore, significant associations were identified among latent factors for approach-oriented coping, avoidance coping, and psychological distress; specifically, greater use of approach-oriented coping strategies and less use of avoidant-oriented coping were associated with lower levels of psychological distress. The model was revised to incorporate variables significantly associated with psychological distress (i.e., personal loss-total events, personal loss-controllability, and HIV-related symptoms). Relations among the coping and psychological distress latent factors remained significant. The results suggest that HIV+ MSM who do not have the coping skills or resources necessary to use adequate coping strategies to face the chronic burdens associated with HIV illness are likely to experience higher levels of psychological distress, independent of life stress and ongoing HIV-related symptoms. This work was supported by grants from the National Institute of Mental Health, including PO1 MH49548, and T32 MH18917.     

Determination of cystathionine beta-synthase activity in human plasma by LC-MS/MS: potential use in diagnosis of CBS deficiency

Cystathionine β-synthase (CBS) deficiency is usually confirmed by assaying the enzyme activity in cultured skin fibroblasts. We investigated whether CBS is present in human plasma and whether determination of its activity in plasma could be used for diagnostic purposes. We developed an assay to measure CBS activity in 20 μL of plasma using a stable isotope substrate - 2,3,3-²H serine. The activity was determined by measurement of the product of enzyme reaction, 3,3-²H-cystathionine, using LC-MS/MS. The median enzyme activity in control plasma samples was 404 nmol/h/L (range 66–1,066; n = 57). In pyridoxine nonresponsive CBS deficient patients, the median plasma activity was 0 nmol/ho/L (range 0–9; n = 26), while in pyridoxine responsive patients the median activity was 16 nmol/hour/L (range 0–358; n = 28); this overlapped with the enzyme activity from control subject. The presence of CBS in human plasma was confirmed by an in silico search of the proteome database, and was further evidenced by the activation of CBS by S-adenosyl-L-methionine and pyridoxal 5′-phosphate, and by configuration of the detected reaction product, 3,3-²H-cystathionine, which was in agreement with the previously observed CBS reaction mechanism. We hypothesize that the CBS enzyme in plasma originates from liver cells, as the plasma CBS activities in patients with elevated liver aminotransferase activities were more than 30-fold increased. In this study, we have demonstrated that CBS is present in human plasma and that its catalytic activity is detectable by LC-MS/MS. CBS assay in human plasma brings new possibilities in the diagnosis of pyridoxine nonresponsive CBS deficiency.