Meta-analysis of three observational studies of amlodipine/valsartan in hypertensive patients with additional risk factors.

OBJECTIVES: In this study, the effectiveness of amlodipine/valsartan single-pill combination was assessed in hypertensive patients with diabetes, metabolic risk or overweight. METHODS: Data from 12,265 patients treated with amlodipine/valsartan from three studies were analyzed in a meta-analysis. These studies focused on (i) non-diabetic hypertensive patients suffering from abdominal obesity; (ii) hypertensive patients with at least one metabolic risk factor; and (iii) hypertensive patients with type 2 diabetes mellitus. The observation periods were 16 weeks for the first two and 24 weeks for the latter cohort. RESULTS: At start of observation, the mean blood pressure was 162.3 mmHg (systolic) and 93.5 mmHg (diastolic). A total of 7.4% of patients were aged ≥ 80 years. At end of the observation, a normalized blood pressure was present in 38.8% of patients. No appreciable differences in blood pressure reduction were evident between the study groups. In both age subgroups (< 80 years and ≥ 80 years) blood pressure reduction was comparable. Tolerability was assessed by treating physicians as "very good" (69.3%) and "good" (27.3%). CONCLUSIONS: In daily practice, treatment of hypertensive patients with additional risk factors with amlodipine/valsartan single-pill combinations is well tolerated and associated with effective reduction of blood pressure.

Trends and consequences of lipoprotein(a) testing: Cross-sectional and longitudinal health insurance claims database analyses.

BACKGROUND AND AIMS: Lipoprotein(a) (Lp(a)) is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD). Our goal was to characterize patients undergoing Lp(a) testing and to assess the impact of Lp(a) testing on treatment changes and subsequent ASCVD events. METHODS: A cross-sectional and a longitudinal claims data analysis were performed on 4 million patient records in Germany. Patients were followed up for a maximum of 4 years. RESULTS: In 2015 and 2018, 0.25% and 0.34% of patients were tested, respectively. Testing was more frequent in younger women in the overall population, and in men in the ASCVD population. Patients tested for Lp(a) had more comorbidities and higher ASCVD risk compared to matched control patients. ASCVD hospitalizations were more frequent prior to the first Lp(a) test (5.55 vs 1.42 per 100/person-years). The mortality rate of the Lp(a)-tested cohort and the control group was similar. Mortality was lower in patients with prior ASCVD and Lp(a) testing compared to matched controls with prior ASCVD and no Lp(a) test (2.30 vs 3.64 per 100/person-years, p <0.001). Patients with Lp(a) test received more laboratory examinations and cardiovascular medications and had more visits with specialized physicians. CONCLUSIONS: Lp(a) testing is rarely performed even in patients with very high cardiovascular risk. Patients tested for Lp(a) have more comorbidities and a higher ASCVD risk. Lp(a) testing is associated with more intensive preventive treatment and with positive effects on clinical outcomes and survival. The data support the value of Lp(a) measurements to characterize ASCVD risk and to improve ASCVD prevention.

Detection of H-2 alleles by PCR-RFLP-an alternative to flow cytometry in the screening of transgenic mice.

An increasing number of experimental models is based on well-defined transgenic mice in medical and biological research. Particularly in settings in which transgenic recombinants are used, a fast and reliable method is needed to screen for a defined H-2 background. For this purpose, flow cytometry with specific monoclonal antibodies is the standard procedure. However, epitopes of closely related rodent strains show only minor variations affecting the production of specific discriminating antibodies. Therefore, cross-reactivity of antibodies against specific major histocompatibility complex (MHC) leads to unreliable results in settings with closely related strains. In need of a method with high reliability, we have designed a screening assay based on polymerase chain reaction (PCR) followed by restriction fragment length polymorphisms (RFLP) to discriminate the MHC class I antigens H-2K(d), -K(b), -K(k), which are sequence variants of the H-2K gene. A part of the mus musculus MHC gene coding for H-2K-covering exons 4 and 5 with MHC-differentiating restriction sites-was amplified. Subsequent restriction digest of the PCR products allows to discriminate the three aforementioned alleles and to identify homozygous as well as heterozygous haplotypes. To distinguish transgenic mice defined by certain MHC backgrounds, the PCR-RFLP method is simple, cost-effective, specific, and reliable and can be used independently or in addition to other methods in any laboratory.

Allogeneic adrenocortical transplantation: glucocorticosteroid-independent immunomodulatory properties of adrenal cortex cells.

BACKGROUND: Hormone substitution for the treatment of adrenocortical insufficiency does not adequately substitute the physiologic circadian secretion of corticosteroids and leads to long-term sequelae and reduced quality of life. The lack of adaptation to physical and psychologic stress situations may lead to life-threatening Addison's crises. Allogeneic transplantation of adrenal cortex could offer an intriguing alternative. Adrenocortical grafts were demonstrated to proliferate and produce corticosteroids in physiologic concentrations after transplantation. METHODS: K -transgenic murine lymphocytes and allogeneic adrenal cortex cells were cocultured in mixed lymphocyte reactions to examine the alloimmune response; lymphocytes from T-cell receptor transgenic mice and normal mice, respectively, served as responder cells. The effects of corticosteroids secreted by adrenocortical cells were antagonized by the steroid receptor antagonist mifepristone, whereas the impact of cell-cell interactions was differentiated with transwell culture systems. RESULTS: Coculture of adrenal cortex cells in mixed lymphocyte reactions markedly suppressed lymphocyte proliferation. Transwell cultures demonstrated that adrenocortical cells exerted their effects by a soluble factor that was only partially antagonized by mifepristone. CONCLUSION: In vitro, the presence of adrenocortical cells potently suppressed allogeneic immune responses. This effect was not exclusively the result of the secretion of corticosteroids, indicating an additional immunomodulatory property of adrenocortical cells.

Transplantation of adrenal tissue fragments in a murine model: functional capacities of syngeneic and allogeneic grafts.

Oral hormone substitution for the treatment of Addison's disease inadequately replaces the physiologic circadian secretion of corticosteroids. Alternative therapeutic approaches are reimplantation of healthy autologous adrenal tissue and allogeneic transplantation (Tx), respectively. The aim of our study was to evaluate the functional capacity of adrenal grafts and the influence of intercellular adhesion molecule-1 (ICAM-1) on graft survival. Fragmented adrenal glands of wild-type B10.BR (H-2k) and wild-type or ICAM-1-deficient BALB/c (H-2d) mice were transplanted underneath the kidney capsule of adrenalectomized B10.BR mice [complete major histocompatibility complex (MHC) haplotype disparity in the latter]. Postoperatively, the endocrine function of the adrenal grafts was evaluated by the following parameters: (1) survival analysis of the recipients (termination at day 70 after Tx); (2) reverse transcription-polymerase chain reaction expression analysis of aldosterone synthase (zona glomerulosa-specific) and of 11b-hydroxylase (zona fasciculata-specific); and (3) measurement of basal adrenocorticotropic hormone (ACTH) stimulated serum corticosterone levels. Expression of both enzyme-specific mRNAs was detected in the grafts at any time during the post-Tx period. The adrenal grafts of syngeneic and surviving MHC-disparate mice displayed a similar basal hormone secretion, which was about 60% lower than that in sham-operated animals. In the transplanted mice, ACTH-stimulated corticosterone measurement revealed a 5- to 10-fold decreased functional reserve capacity. ICAM-1 deficiency significantly prolonged the survival of adrenal grafts. Fragmented adrenal grafts are able to maintain physiologic basal corticosterone levels but had markedly reduced reserve capacity. Nevertheless, the results give rise to hopes that autologous or MHC-compatible allogeneic transplantation of adrenal grafts may replace oral hormone substitution in humans.