Gesche Jürgens

Effects of Low-Sodium Diet vs. High-Sodium Diet on Blood Pressure, Renin, Aldosterone, Catecholamines, Cholesterol, and Triglyceride (Cochrane Review)

BACKGROUND The question of whether reduced sodium intake is effective as a health prophylaxis initiative is unsolved. The purpose was to estimate the effects of low-sodium vs. high-sodium intake on blood pressure (BP), renin, aldosterone, catecholamines, and lipids. METHODS Studies randomizing persons to low-sodium and high-sodium diets evaluating at least one of the above outcome parameters were included. Data were analyzed with Review Manager 5.1. RESULTS A total of 167 studies were included. The effect of sodium reduction in: (i) Normotensives: Caucasians: systolic BP (SBP) -1.27 mm Hg (95% confidence interval (CI): -1.88, -0.66; P = 0.0001), diastolic BP (DBP) -0.05 mm Hg (95% CI: -0.51, 0.42; P = 0.85). Blacks: SBP -4.02 mm Hg (95% CI: -7.37, -0.68; P = 0.002), DBP -2.01 mm Hg (95% CI: -4.37, 0.35; P = 0.09). Asians: SBP -1.27 mm Hg (95% CI: -3.07, 0.54; P = 0.17), DBP -1.68 mm Hg (95% CI: -3.29, -0.06; P = 0.04). (ii) Hypertensives: Caucasians: SBP -5.48 mm Hg (95% CI: -6.53, -4.43; P < 0.00001), DBP -2.75 mm Hg (95% CI: -3.34, -2.17; P < 0.00001). Blacks: SBP -6.44 mm Hg (95% CI: -8.85, -4.03; P = 0.00001), DBP -2.40 mm Hg (95% CI: -4.68, -0.12; P = 0.04). Asians: SBP -10.21 mm Hg (95% CI: -16.98, -3.44; P = 0.003), DBP -2.60 mm Hg (95% CI: -4.03, -1.16; P = 0.0004). Sodium reduction resulted in significant increases in renin (P < 0.00001), aldosterone (P < 0.00001), noradrenaline (P < 0.00001), adrenaline (P < 0.0002), cholesterol (P < 0.001), and triglyceride (P < 0.0008). CONCLUSIONS Sodium reduction resulted in a significant decrease in BP of 1% (normotensives), 3.5% (hypertensives), and a significant increase in plasma renin, plasma aldosterone, plasma adrenaline, and plasma noradrenaline, a 2.5% increase in cholesterol, and a 7% increase in triglyceride.

Compared With Usual Sodium Intake, Low- and Excessive-Sodium Diets Are Associated With Increased Mortality: A Meta-Analysis

BACKGROUND The effect of sodium intake on population health remains controversial. The objective was to investigate the incidence of all-cause mortality (ACM) and cardiovascular disease events (CVDEs) in populations exposed to dietary intakes of low sodium (<115 mmol), usual sodium (low usual sodium: 115-165 mmol; high usual sodium: 166-215 mmol), and high sodium (>215 mmol). METHODS The relationship between individual measures of dietary sodium intake vs. outcome in cohort studies and randomized controlled trials (RCTs) measured as hazard ratios (HRs) were integrated in meta-analyses. RESULTS No RCTs in healthy population samples were identified. Data from 23 cohort studies and 2 follow-up studies of RCTs (n = 274,683) showed that the risks of ACM and CVDEs were decreased in usual sodium vs. low sodium intake (ACM: HR = 0.91, 95% confidence interval (CI) = 0.82-0.99; CVDEs: HR = 0.90, 95% CI = 0.82-0.99) and increased in high sodium vs. usual sodium intake (ACM: HR = 1.16, 95% CI = 1.03-1.30; CVDEs: HR = 1.12, 95% CI = 1.02-1.24). In population representative samples adjusted for multiple confounders, the HR for ACM was consistently decreased in usual sodium vs. low sodium intake (HR = 0.86; 95% CI = 0.81-0.92), but not increased in high sodium vs. usual sodium intake (HR = 1.04; 95% CI = 0.91-1.18). Within the usual sodium intake range, the number of events was stable (high usual sodium vs. low usual sodium: HR = 0.98; 95% CI = 0.92-1.03). CONCLUSIONS Both low sodium intakes and high sodium intakes are associated with increased mortality, consistent with a U-shaped association between sodium intake and health outcomes.

Common Variants at VRK2 and TCF4 Conferring Risk of Schizophrenia

Common sequence variants have recently joined rare structural polymorphisms as genetic factors with strong evidence for association with schizophrenia. Here we extend our previous genome-wide association study and meta-analysis (totalling 7 946 cases and 19 036 controls) by examining an expanded set of variants using an enlarged follow-up sample (up to 10 260 cases and 23 500 controls). In addition to previously reported alleles in the major histocompatibility complex region, near neurogranin (NRGN) and in an intron of transcription factor 4 (TCF4), we find two novel variants showing genome-wide significant association: rs2312147[C], upstream of vaccinia-related kinase 2 (VRK2) [odds ratio (OR) = 1.09, P = 1.9 × 10(-9)] and rs4309482[A], between coiled-coiled domain containing 68 (CCDC68) and TCF4, about 400 kb from the previously described risk allele, but not accounted for by its association (OR = 1.09, P = 7.8 × 10(-9)).

Expanding the range of ZNF804A variants conferring risk of psychosis

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10−8) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10−7, and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10−8. In this study, using 5164 schizophrenia cases and 20 709 controls, we replicated the association with schizophrenia (odds ratio OR=1.08, P=0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N=609, OR=1.09, P=0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]—common and with low relative risk—may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39 481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P=0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P=0.0016 for association with the larger set of psychiatric disorders).

Similar Effects of Disease-Modifying Antirheumatic Drugs, Glucocorticoids, and Biologic Agents on Radiographic Progression in Rheumatoid Arthritis: Meta-Analysis of 70 Randomized Placebo-Controlled or Drug-Controlled Studies, Including 112 Comparisons

OBJECTIVE To define the differences in effects on joint destruction in rheumatoid arthritis (RA) patients between therapy with single and combination disease-modifying antirheumatic drugs (DMARDs), glucocorticoids, and biologic agents. METHODS Randomized controlled trials in RA patients, investigating the effects of drug treatment on the percentage of the annual radiographic progression rate (PARPR) were included in a meta-analysis performed with the use of Review Manager 5.0 software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. RESULTS Data from 70 trials (112 comparisons, 16 interventions) were summarized in 21 meta-analyses. Compared with placebo, the PARPR was 0.65% smaller in the single-DMARD group (P < 0.002) and 0.54% smaller in the glucocorticoid group (P < 0.00001). Compared with single-DMARD treatment, the PARPR was 0.62% smaller in the combination-DMARD group (P < 0.001) and 0.61% smaller in the biologic agent plus methotrexate (MTX) group (P < 0.00001). The effect of a combination of 2 DMARDs plus step-down glucocorticoids did not differ from the effect of a biologic agent plus MTX (percentage mean difference -0.07% [95% confidence interval -0.25, 0.11]) (P = 0.44). CONCLUSION Treatment with DMARDs, glucocorticoids, biologic agents, and combination agents significantly reduced radiographic progression at 1 year, with a relative effect of 48-84%. A direct comparison between the combination of a biologic agent plus MTX and the combination of 2 DMARDs plus initial glucocorticoids revealed no difference. Consequently, biologic agents should still be reserved for patients whose RA is resistant to DMARD therapy. Future trials of the effects of biologic agents on RA should compare such agents with combination treatments involving DMARDs and glucocorticoids.

A large replication study and meta-analysis in European samples provides further support for association of AHI1 markers with schizophrenia

The Abelson helper integration site 1 (AHI1) gene locus on chromosome 6q23 is among a group of candidate loci for schizophrenia susceptibility that were initially identified by linkage followed by linkage disequilibrium mapping, and subsequent replication of the association in an independent sample. Here, we present results of a replication study of AHI1 locus markers, previously implicated in schizophrenia, in a large European sample (in total 3907 affected and 7429 controls). Furthermore, we perform a meta-analysis of the implicated markers in 4496 affected and 18,920 controls. Both the replication study of new samples and the meta-analysis show evidence for significant overrepresentation of all tested alleles in patients compared with controls (meta-analysis; P = 8.2 x 10(-5)-1.7 x 10(-3), common OR = 1.09-1.11). The region contains two genes, AHI1 and C6orf217, and both genes-as well as the neighbouring phosphodiesterase 7B (PDE7B)-may be considered candidates for involvement in the genetic aetiology of schizophrenia.

Acute hypoxia and cytochrome P450–mediated hepatic drug metabolism in humans

Our objective was to investigate the effect of acute hypoxia on the activity of hepatic cytochrome P450 (CYP) enzymes.

Effect of growth hormone on hepatic cytochrome P450 activity in healthy elderly men

Our objective was to study the effect of recombinant human growth hormone (rhGH) on hepatic cytochrome P450 (CYP) activity in 30 healthy elderly men.

The Significance of Duration and Amount of Sodium Reduction Intervention in Normotensive and Hypertensive Individuals: A Meta-Analysis

The purpose of this meta-analysis was to establish the time for achievement of maximal blood pressure (BP) efficacy of a sodium reduction (SR) intervention and the relation between the amount of SR and the BP response in individuals with hypertension and normal BP. Relevant studies were retrieved from a pool of 167 randomized controlled trials (RCTs) published in the period 1973-2010 and integrated in meta-analyses. Fifteen relevant RCTs were included in the maximal efficacy analysis. After initiation of sodium reduction (range: 55-118 mmol/d), there were no significant differences in systolic blood pressure (SBP) or diastolic blood pressure (DBP) between measurements at weeks 1 and 2 (∆SBP: -0.18 mmHg/∆DBP: 0.12 mmHg), weeks 1 and 4 (∆SBP: -0.50 mmHg/∆DBP: 0.35 mmHg), weeks 2 and 4 (∆SBP: -0.20 mmHg/∆DBP: -0.10 mmHg), weeks 2 and 6 (∆SBP: -0.50 mmHg/∆DBP: -0.42 mmHg), and weeks 4 and 6 (∆SBP: 0.39 mmHg/∆DBP: -0.22 mmHg). Eight relevant RCTs were included in the dose-response analysis, which showed that within the established usual range of sodium intake [<248 mmol/d (5700 mg/d)], there was no relation between the amount of SR (range: 136-188 mmol) and BP outcome in normotensive populations [∆SBP: 0.99 mm Hg (95% CI: -2.12, 4.10 mm Hg), [corrected] P = 0.53; ∆DBP: -0.49 mm Hg (95% CI: -4.0, 3.03), P = 0.79]. In contrast, prehypertensive and hypertensive populations showed a significant dose-response relation (range of sodium reduction: 77-140 mmol/d) [∆SBP: 6.87 mmHg (95% CI: 5.61, 8.12, P < 0.00001); ∆DBP: 3.61 mmHg (95% CI: 2.83, 4.39, P < 0.00001)]. Consequently, the importance of kinetic and dynamic properties of sodium reduction, as well as baseline BP, should probably be considered when establishing a policy of sodium reduction.

Does Pharmacogenetic Testing for CYP450 2D6 and 2C19 Among Patients with Diagnoses within the Schizophrenic Spectrum Reduce Treatment Costs

The effect of pharmacogenetic testing for CYP450 2D6 and 2C19 on treatment costs have not yet been documented. This study used Danish patient registers to calculate healthcare costs of treating patients with diagnoses within the schizophrenic spectrum for 1 year with or without pharmacogenetic testing for polymorphisms in the genes for the CYP2D6 and CYP2C19 enzymes. In a randomized, controlled trial, stratified with respect to metabolizer genotype, 104 patients were assigned to treatment based on pharmacogenetic testing and 103 patients to treatment as usual. Random exclusion of extensive and intermediate metabolizers was used to increase the frequency of extreme metabolizers (poor metabolizers and ultrarapid metabolizers for CYP2D6) to 20% in both groups. Cost differences were analysed at several levels including (i) overall healthcare expenditure, (ii) psychiatric hospital cost (iii) nonpsychiatric hospital cost, (iv) primary care spending and (v) pharmaceuticals. Statistically significant differences in costs of psychiatric care dependent on metabolizer status were found between intervention groups. Pharmacogenetic testing significantly reduced costs among the extreme metabolizers (poor metabolizers and ultrarapid metabolizers) to 28%. Use of primary care services and pharmaceuticals was also affected by the intervention.This study confirms earlier findings that extreme metabolizers (poor and ultrarapid metabolizers) incur higher costs than similar patients with a normal metabolizer genotype. However, this study shows that these excess costs can be reduced by pharmacogenetic testing. Pharmacogenetic testing for CYP2D6 and CYP2C19 could thus be considered as a means of curtailing high psychiatric treatment costs among extreme metabolizers.