In the serum of 116 healthy individuals, exogenous bradykinin (BK) half-life (27 +/- 10 s) was lower than that of des-Arg(9)-BK (643 +/- 436 s) and was statistically different in men compared with women. The potentiating effect of an angiotensin-converting enzyme (ACE) inhibitor was, however, more extensive for BK (9.0-fold) than for des-Arg(9)-BK (2.2- fold). The activities of ACE, aminopeptidase P (APP), and kininase I were respectively 44 +/- 12, 22 +/- 9, and 62 +/- 10 nmol x min(-1) x ml(-1). A mathematical model (y = kt(alpha)e(-beta t), t > 0), applied to the BK kinetically released from endogenous high-molecular-weight kininogen (HK) during plasma activation in the presence of an ACE inhibitor, revealed a significant difference in the rate of formation of BK between men and women. For des-Arg(9)-BK, the active metabolite of BK, the rate of degradation was higher in women compared with men, correlating significantly with serum APP activity (r(2) = 0.6485, P < 0.001). In conclusion, these results constitute a basis for future pathophysiological studies of inflammatory processes where activation of the contact system of plasma and the kinins is involved.

This randomized clinical trial compared cognitive-behavioral therapy (CBT), applied relaxation (AR), and wait-list control (WL) in a sample of 65 adults with a primary diagnosis of generalized anxiety disorder (GAD). The CBT condition was based on the intolerance of uncertainty model of GAD, whereas the AR condition was based on general theories of anxiety. Both manualized treatments were administered over 12 weekly 1-hour sessions. Standardized clinician ratings and self-report questionnaires were used to assess GAD and related symptoms at pretest, posttest, and at 6-, 12-, and 24-month follow-ups. At posttest, CBT was clearly superior to WL, AR was marginally superior to WL, and CBT was marginally superior to AR. Over follow-up, CBT and AR were equivalent, but only CBT led to continued improvement. Thus, direct comparisons of CBT and AR indicated that the treatments were comparable; however, comparisons of each treatment with another point of reference (either waiting list or no change over follow-up) provided greater support for the efficacy of CBT than AR.

Angioedema (AE) is a rare but potentially life-threatening side effect of therapy with inhibitors of angiotensin-converting enzyme (ACE), the main bradykinin (BK)-inactivating metallopeptidase in humans. The pathogenesis of ACE inhibitor (ACEi)-associated AE (AEϩ) is presently unknown, although there is increasing evidence of a kinin role. We analyzed the metabolism of endogenous BK (B 2 receptor agonist) and its active metabolite, des-Arg 9 -BK (B 1 receptor agonist), in the presence of an ACEi during in vitro contact activation of plasma from hypertensive patients (n ϭ 39) who presented AEϩ. Kinetic parameters were compared with those measured in a control group (AEϪ) of hypertensive patients (n ϭ 39) who never manifested any acute or chronic side effects while treated with an ACEi. The different kinetic parameters were analyzed using a mathematical model (y ϭ k t ␣ e Ϫ␤ t ) previously applied to a normal, healthy population. The slope of BK degradation, but not its formation from high-molecular-weight kininogen, was lower in AEϩ patients when compared with the AEϪ controls. des-Arg 9 -BK accumulation during the kinetic measurements was significantly higher in AEϩ plasma. This accumulation of the B 1 agonist in AEϩ patients paralleled its half-life of degradation. In conclusion, our results show, for the first time, that an abnormality of endogenous des-Arg 9 -BK degradation exists in the plasma of patients with ACEi-associated AE, suggesting that its pathogenetic mechanism lies in the catabolic site of kinin metabolism.

Among the different enzymes responsible for the metabolism of bradykinin (BK), three peptidases look relevant in vivo: kininase I (KI), which transforms BK into its active metabolite, [des-Arg9]BK; kininase II (KII); and neutral endopeptidase, which inactivate BK and [des-Arg9]BK. The in vitro incubation of BK and [des-Arg9]BK in the serum of four species with or without enalaprilat and the quantification of the immunoreactivity of both peptides at different time intervals allowed the measurement of the kinetic parameters characterizing their metabolic pathways. Highly sensitive chemiluminescent enzyme immunoassays were used to measure the residual concentrations of BK and [des-Arg9]BK. Half-life (t1/2) of BK showed significant difference among species: rats (10 +/- 1 s) = dogs (13 +/- 1 s) < rabbits (31 +/- 1 s) < humans (49 +/- 2 s). t1/2 values of [des-Arg9]BK were also species dependent: rats (96 +/- 6 s) < < rabbits (314 +/- 6 s) = dogs (323 +/- 11 s) = humans (325 +/- 12 s). Enalaprilat significantly prevented the rapid BK and [des-Arg9]BK degradation in all species except that of [des-Arg9]BK in rat serum. Relative amount of BK hydrolyzed by serum KII was given as follows: rabbits (93.7 +/- 14.8%) = rats (83.6 +/- 6.7%) = humans (76.0 +/- 7.5%) > dogs (50.0 +/- 3.9%). Its importance in the hydrolysis of [des-Arg9]BK was 5.2 +/- 0.5% in rats < < 33.9 +/- 1.5% in humans < 52.0 +/- 1.1% in rabbits < 65.1 +/- 3.4% in dogs. The participation of serum KI in the transformation of BK into [des-Arg9]BK was dogs (67.2 +/- 5.3%) > > humans (3.4 +/- 1.2%) = rabbits (1.8 +/- 0.2%) = rats (1.4 +/- 0.3%). Finally, no significant difference on t1/2 values for BK and [des-Arg9]BK could be demonstrated between serum and plasma treated with either sodium citrate or a thrombin inhibitor. These results revealed striking species differences in the serum metabolism of kinins that could address at least partially some of the controversial data related to the cardioprotective role of kinins.

Due to advances in treatment, people with HIV are living longer and developing disabilities related to the virus, adverse side effects of medications, and aging. Illness-related uncertainty has been shown to contribute to disablement; however, there is little understanding of the uncertainties related to aging with HIV. The purpose of this research was to describe the contribution of uncertainty to the disability experienced by older adults living with HIV. Forty-nine men and women living with HIV and 50 years or older participated in in-depth qualitative interviews exploring various aspects of social participation and disability. Transcriptions of the interviews were analyzed using a grounded theory approach. Age-related uncertainties were described in the following themes: source of health challenge; health providers' age-related knowledge and skills; financial uncertainty; transition to retirement; appropriate long-term housing, and uncertainty over who would care for them. While not directly attributable to aging, the episodic nature of HIV left many with uncertainties related to when their next episode of illness would occur and often resulted in an inability to plan in advance. Results highlight the need to focus on the notion of successful and positive aging with the view to identifying effective interventions that reduce disability and enhance the overall health of older adults with HIV. This work builds on previous studies highlighting the role of uncertainty in the disability experience by identifying age-related components specific to older adults aging with HIV.

The main goal of this study was to examine the effect of written exposure on generalized anxiety disorder (GAD)-related symptoms in high worriers. Thirty nonclinical high worriers were randomly assigned to either a written exposure condition or a control writing condition. Self-report measures were used to assess worry, GAD somatic symptoms, depression, and intolerance of uncertainty at four time points during the study. Using hierarchical linear modeling (HLM), the authors found that all symptoms (i.e., worry, GAD somatic symptoms, and depression) significantly decreased over time in the written exposure group (although GAD somatic symptoms also decreased in the control group). Moreover, consistent with previous findings that intolerance of uncertainty preceded changes in worry over the course of treatment, intolerance of uncertainty scores predicted subsequent scores on all symptom measures in the experimental group. In contrast, worry and depression scores predicted subsequent intolerance of uncertainty scores in the control group.

Background-Angioedema has been reported during recombinant tissue plasminogen activator (rtPA) treatment of acute ischemic stroke, often with concomitant use of angiotensin I-converting enzyme inhibitor treatment. Angioedema has been partly attributed to the nonapeptide bradykinin (BK), although its precise role has been poorly documented until now. The purposes of this report are 2-fold. First, we sought to define and characterize the in vitro kinin-forming capacity of rtPA when incubated with human plasma at a concentration within the therapeutic concentration range of rtPA attained in blood in vivo during fibrinolysis. Second, we sought to define the mechanism by which rtPA liberates BK from purified human single-chain high-molecular-weight kininogen, a key constituent of the contact system of plasma and the precursor of BK. Summary of Report-When incubated with human plasma, in the presence of an angiotensin I-converting enzyme inhibitor, rtPA generates BK, which is further metabolized to des-Arg 9 -BK. The quantity of kinins generated by rtPA is similar to that observed during the activation of the contact system of plasma with a negatively charged surface, suggesting that it is physiologically relevant. The total amount of des-Arg 9 -BK liberated during the incubation period depends on the aminopeptidase P activity, its main degrading peptidase. Additionally, incubations using purified proteins of the fibrinolytic and the contact system pathways show that the rtPA kinin-forming capacity is mediated by plasmin. Conclusions-We conclude that rtPA used in vitro at a therapeutic concentration has the capacity to generate significant quantities of kinins from human plasma. This kinin-forming activity depends on the activation of the fibrinolytic pathway. These data suggest that angioedema associated with rtPA treatment of ischemic stroke results directly from plasmin-mediated release of BK. Key Words: angioneurotic edema Ⅲ kinins Ⅲ stroke Ⅲ tissue plasminogen activator S erious allergic reactions (anaphylactoid reactions or angioedema) have been observed during thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) (alteplase) used for the treatment of acute ischemic stroke, myocardial infarction, and deep vein thrombosis. 1-8 A substantial number of these patients were simultaneously treated with an angiotensin I-converting enzyme (ACE) inhibitor. Angioedema, a local acute, potentially life-threatening inflammatory reaction, has been reported in patients with acute ischemic stroke treated with rtPA with a frequency of 1.9%. This frequency is higher than that observed in patients treated with an ACE inhibitor for hypertension or heart failure (0.1% to 0.2%). 1,4,9 In these different clinical situations, angioedema has been attributed, at least in part, to bradykinin (BK).BK is the prototype of a family of powerful vasodilatory peptides, the kinins. BK is released from high-molecularweight kininogen (HK) when hydrolyzed by plasma kallikrein. This hydrolysis occurs, at least in vitro, when plasm...

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