Acute kidney injury (AKI) is common in premature infants and is associated with poor outcomes. Novel biomarkers can detect AKI promptly. Because premature infants are born with underdeveloped kidneys, baseline biomarker values may differ. We describe baseline values of urinary neutrophil gelatinase associated lipocalin, (NGAL), Interleukin - 18 (IL-18), Kidney Injury Molecule -1 (KIM -1), Osteopontin (OPN), beta-2 microglobulin (B2mG) and Cystatin-C (Cys-C). Next, we test the hypothesis that these biomarkers are inversely related to gestational age (GA). Candidate markers were compared according to GA categories in 123 infants. Mixed linear regression models were performed to determine the independent association between demographics/interventions and baseline biomarker values. We found that urine NGAL, KIM-1, Cys-C and B2mG decreased with increasing GA. With correction for urine creatinine (cr), these markers and OPN/cr decreased with increasing GA. IL-18 (with or without correction for urine creatinine) did not differ across GA categories. Controlling for other potential clinical and demographic confounders with regression analysis shows that, NGAL/cr, OPN/cr and B2mG/cr are independently associated with GA. We conclude that urine values of candidate AKI biomarkers are higher in the most premature infants. These findings should be considered when designing neonatal AKI validation studies.

Objective The literature provides evidence of a strong relationship between greater stress and memory loss, but few studies have examined this relationship with both variables measured over time. The authors sought to determine the prospective association between subjective and objective measures of chronic stress and rate of memory decline in cognitively normal and mildly impaired older adults. Method This longitudinal study was conducted at a university research center and included 61 cognitively normal subjects and 41 subjects with mild cognitive impairment (ages 65–97). Fifty-two subjects were followed for up to 3 years (mean=2 years) and received repeated stress and cognitive assessments. Exclusion criteria were dementia, significant medical or psychiatric conditions, and medication use (e.g., corticosteroids) that might affect cortisol level or cognitive functioning. The main outcome measure was a regression-based slope reflecting performance change on tests of global cognition and episodic memory as a function of baseline diagnosis, recent life events, and salivary cortisol. Examiners were blind to stress ratings and cortisol levels at the time of cognitive testing. Results Higher event-based stress ratings collected over the follow-up period were associated with faster cognitive decline in subjects with mild cognitive impairment but not in cognitively normal subjects. In contrast, higher cortisol levels were associated with slower cognitive decline in subjects with mild cognitive impairment but not in cognitively normal subjects. Conclusions Chronic stress affects cognitive functioning differently in cognitively normal subjects and those with mild cognitive impairment. Cortisol, while likely to have neurotoxic effects over time, may enhance cognitive functioning in older adults compromised by existing cognitive deficits.

The contribution of inflammation to hypertension and target organ damage is under investigation. The matrix metalloproteinase (MMP) enzymes are inflammatory mediators that may contribute to hypertension and its target organ consequences. Here we probe MMPs as inflammatory mediators in hypertension, by studying all three MMP classes in uncomplicated hypertension as well hypertension with profound renal damage, such as hypertensive end-stage renal disease (ESRD). We assayed plasma levels of five MMPs: one collagenase (MMP-1), two gelatinases (MMP-2, MMP-9), and two stromelysins (MMP-3, MMP-10). In hypertension, MMP-9 was elevated versus normotensive controls. Systolic blood pressure (SBP) in all three subject groups positively correlated with MMP-9. In hypertensive-ESRD, MMP-2 and MMP-10 were elevated compared to both hypertensive and normotensive subjects. Several correlations occurred across MMPs, suggesting coordinate biosynthetic control. Our results suggest discrete patterns of MMP overexpression in hypertension, with MMP-9 elevated early, and MMP-2 and MMP-10 linked to target organ damage.

CRP secretion is substantially heritable in humans, demonstrating pleiotropy (shared genetic determination) with other features of the metabolic syndrome, such as BMI, triglycerides or BP. Multiple, common genetic variants in the catecholaminergic/beta-adrenergic pathway contribute to CRP, and these variants (especially at TH and ADRB2) seem to interact (epistasis) to influence the trait. The results uncover novel pathophysiological links between the adrenergic system and inflammation, and suggest new strategies to probe the role and actions of inflammation within this setting.

GTP cyclohydrolase 1 (GCH1) is rate limiting in the provision of the cofactor tetrahydrobiopterin for biosynthesis of catecholamines and NO. We asked whether common genetic variation at GCH1 alters transmitter synthesis and predisposes to disease. Here we undertook a systematic search for polymorphisms in GCH1, then tested variants' contributions to NO and catecholamine release as well as autonomic function in twin pairs. Renal NO and neopterin excretions were significantly heritable, as were baroreceptor coupling (heart rate response to BP fluctuation) and pulse interval (1/heart rate). Common GCH1 variant C+243T in the 3'-untranslated region (3'-UTRs) predicted NO excretion, as well as autonomic traits: baroreceptor coupling, maximum pulse interval, and pulse interval variability, though not catecholamine secretion. In individuals with the most extreme BP values in the population, C+243T affected both diastolic and systolic BP, principally in females. In functional studies, C+243T decreased reporter expression in transfected 3'-UTRs plasmids. We conclude that human NO secretion traits are heritable, displaying joint genetic determination with autonomic activity by functional polymorphism at GCH1. Our results document novel pathophysiological links between a key biosynthetic locus and NO metabolism and suggest new strategies for approaching the mechanism, diagnosis, and treatment of risk predictors for cardiovascular diseases such as hypertension.