Hypohydration attenuates increases in creatinine clearance to oral protein loading and the renal hemodynamic response to exercise pressor reflex.

Insufficient hydration is prevalent among free living adults. This study investigated whether hypohydration alters 1) renal functional reserve, 2) the renal hemodynamic response to the exercise pressor reflex, and 3) urine-concentrating ability during oral protein loading. In a block-randomized crossover design, 22 healthy young adults (11 females and 11 males) underwent 24-h fluid deprivation (Hypohydrated) or 24-h normal fluid consumption (Euhydrated). Renal functional reserve was assessed by oral protein loading. Renal hemodynamics during the exercise pressor reflex were assessed via Doppler ultrasound. Urine-concentrating ability was assessed via free water clearance. Creatinine clearance did not differ at 150 min postprotein consumption between conditions [Hypohydrated: 246 mL/min, 95% confidence interval (CI): 212-280; Euhydrated: 231 mL/min, 95% CI: 196-265, P = 0.2691] despite an elevated baseline in Hypohydrated (261 mL/min, 95% CI: 218-303 vs. 143 mL/min, 95% CI: 118-168, P < 0.0001). Renal artery vascular resistance was not different at baseline (P = 0.9290), but increases were attenuated in Hypohydrated versus Euhydrated at the end of handgrip (0.5 mmHg/cm/s, 95% CI: 0.4-0.7 vs. 0.8 mmHg/cm/s 95% CI: 0.6-1.1, P = 0.0203) and end occlusion (0.2 mmHg/cm/s, 95% CI: 0.1-0.3 vs. 0.4 mmHg/cm/s 95% CI: 0.3-0.6, P = 0.0127). There were no differences between conditions in free water clearance at 150 min postprotein (P = 0.3489). These data indicate that hypohydration 1) engages renal functional reserve and attenuates the ability to further increase creatinine clearance, 2) attenuates increases in renal artery vascular resistance to the exercise pressor reflex, and 3) does not further enhance nor impair urine-concentrating ability during oral protein loading.NEW & NOTEWORTHY Insufficient hydration is prevalent among free living adults. This study found that hypohydration induced by 24-h fluid deprivation engaged renal functional reserve and that oral protein loading did not further increase creatinine clearance. Hypohydration also attenuated the ability to increase renal vascular resistance during the exercise pressor reflex. In addition, hypohydration neither enhanced nor impaired urine-concentrating ability during oral protein loading. These data support the importance of mitigating hypohydration in free living adults.

Acute kidney injury biomarkers and hydration assessments following prolonged mild hypohydration in healthy young adults.

The high prevalence of inadequate hydration (e.g., hypohydration and underhydration) is concerning given that extreme heat increases excess hospitalizations for fluid/electrolyte disorders and acute kidney injury (AKI). Inadequate hydration may also be related to renal and cardiometabolic disease development. This study tested the hypothesis that prolonged mild hypohydration increases the urinary AKI biomarker product of insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 ([IGFBP7·TIMP-2]) compared with euhydration. In addition, we determined the diagnostic accuracy and optimal cutoffs of hydration assessments for discriminating positive AKI risk ([IGFBP·TIMP-2] >0.3 (ng/mL)2/1,000). In a block-randomized crossover design, 22 healthy young adults (11 females and 11 males) completed 24 h of fluid deprivation (hypohydrated group) or 24 h of normal fluid consumption (euhydrated group) separated by ≥72 h. Urinary [IGFBP7·TIMP-2] and other AKI biomarkers were measured following the 24-h protocols. Diagnostic accuracy was assessed via receiver operating characteristic curve analysis. Urinary [IGFBP7·TIMP-2] [1.9 (95% confidence interval: 1.0-2.8) vs. 0.2 (95% confidence interval: 0.1-0.3) (ng/mL)2/1,000, P = 0.0011] was markedly increased in hypohydrated versus euhydrated groups. Urine osmolality (area under the curve: 0.91, P < 0.0001) and urine specific gravity (area under the curve: 0.89, P < 0.0001) had the highest overall performance for discriminating positive AKI risk. Optimal cutoffs with a positive likelihood ratio of 11.8 for both urine osmolality and specific gravity were 952 mosmol/kgH2O and 1.025 arbitrary units. In conclusion, prolonged mild hypohydration increased urinary [IGFBP7·TIMP-2] in males and females. Urinary [IGFBP7·TIMP-2] corrected to urine concentration was elevated in males only. Urine osmolality and urine specific gravity may have clinical utility for discriminating positive AKI risk following prolonged mild hypohydration.NEW & NOTEWORTHY This study found that prolonged mild hypohydration in healthy young adults increased the Food and Drug Administration approved acute kidney injury (AKI) biomarker urinary insulin-like growth factor-binding protein 7 and tissue inhibitor of metalloproteinase-2 [IGFBP7·TIMP-2]. Urine osmolality and specific gravity demonstrated an excellent ability to discriminate positive AKI risk. These findings emphasize the importance of hydration in protecting renal health and lend early support for hydration assessment as an accessible tool to assess AKI risk.

Dosage transmission disequilibrium test (dTDT) for linkage and association detection.

Both linkage and association studies have been successfully applied to identify disease susceptibility genes with genetic markers such as microsatellites and Single Nucleotide Polymorphisms (SNPs). As one of the traditional family-based studies, the Transmission/Disequilibrium Test (TDT) measures the over-transmission of an allele in a trio from its heterozygous parents to the affected offspring and can be potentially useful to identify genetic determinants for complex disorders. However, there is reduced information when complete trio information is unavailable. In this study, we developed a novel approach to "infer" the transmission of SNPs by combining both the linkage and association data, which uses microsatellite markers from families informative for linkage together with SNP markers from the offspring who are genotyped for both linkage and a Genome-Wide Association Study (GWAS). We generalized the traditional TDT to process these inferred dosage probabilities, which we name as the dosage-TDT (dTDT). For evaluation purpose, we developed a simulation procedure to assess its operating characteristics. We applied the dTDT to the simulated data and documented the power of the dTDT under a number of different realistic scenarios. Finally, we applied our methods to a family study of alcohol dependence (COGA) and performed individual genotyping on complete families for the top signals. One SNP (rs4903712 on chromosome 14) remained significant after correcting for multiple testing Methods developed in this study can be adapted to other platforms and will have widespread applicability in genomic research when case-control GWAS data are collected in families with existing linkage data.

CHRNB3 is more strongly associated with Fagerström test for cigarette dependence-based nicotine dependence than cigarettes per day: phenotype definition changes genome-wide association studies results.

AIMS: Nicotine dependence is a highly heritable disorder associated with severe medical morbidity and mortality. Recent meta-analyses have found novel genetic loci associated with cigarettes per day (CPD), a proxy for nicotine dependence. The aim of this paper is to evaluate the importance of phenotype definition (i.e., CPD versus Fagerström test for cigarette dependence (FTCD) score as a measure of nicotine dependence) on genome-wide association studies of nicotine dependence. DESIGN: Genome-wide association study. SETTING: Community sample. PARTICIPANTS: A total of 3365 subjects who had smoked at least one cigarette were selected from the Study of Addiction: Genetics and Environment (SAGE). Of the participants, 2267 were European Americans, 999 were African Americans. MEASUREMENTS: Nicotine dependence defined by FTCD score ≥4, CPD. FINDINGS: The genetic locus most strongly associated with nicotine dependence was rs1451240 on chromosome 8 in the region of CHRNB3 [odds ratio (OR) = 0.65, P = 2.4 × 10(-8) ]. This association was further strengthened in a meta-analysis with a previously published data set (combined P = 6.7 × 10(-16) , total n = 4200). When CPD was used as an alternate phenotype, the association no longer reached genome-wide significance (ß = -0.08, P = 0.0004). CONCLUSIONS: Daily cigarette consumption and the Fagerstrom Test for Cigarette Dependence show different associations with polymorphisms in genetic loci.

A genome-wide association study of DSM-IV cannabis dependence.

Despite twin studies showing that 50-70% of variation in DSM-IV cannabis dependence is attributable to heritable influences, little is known of specific genotypes that influence vulnerability to cannabis dependence. We conducted a genome-wide association study of DSM-IV cannabis dependence. Association analyses of 708 DSM-IV cannabis-dependent cases with 2346 cannabis-exposed non-dependent controls was conducted using logistic regression in PLINK. None of the 948 142 single nucleotide polymorphisms met genome-wide significance (P at E-8). The lowest P values were obtained for polymorphisms on chromosome 17 (rs1019238 and rs1431318, P values at E-7) in the ANKFN1 gene. While replication is required, this study represents an important first step toward clarifying the biological underpinnings of cannabis dependence.

A genome-wide association study of alcohol dependence.

Excessive alcohol consumption is one of the leading causes of preventable death in the United States. Approximately 14% of those who use alcohol meet criteria during their lifetime for alcohol dependence, which is characterized by tolerance, withdrawal, inability to stop drinking, and continued drinking despite serious psychological or physiological problems. We explored genetic influences on alcohol dependence among 1,897 European-American and African-American subjects with alcohol dependence compared with 1,932 unrelated, alcohol-exposed, nondependent controls. Constitutional DNA of each subject was genotyped using the Illumina 1M beadchip. Fifteen SNPs yielded P < 10(-5), but in two independent replication series, no SNP passed a replication threshold of P < 0.05. Candidate gene GABRA2, which encodes the GABA receptor alpha2 subunit, was evaluated independently. Five SNPs at GABRA2 yielded nominal (uncorrected) P < 0.05, with odds ratios between 1.11 and 1.16. Further dissection of the alcoholism phenotype, to disentangle the influence of comorbid substance-use disorders, will be a next step in identifying genetic variants associated with alcohol dependence.

Nighttime heart rate and survival in depressed patients post acute myocardial infarction.

OBJECTIVES: To determine if: 1) depressed patients with a recent acute myocardial infarction (AMI) have higher nighttime heart rate (HR) than nondepressed patients, and 2) elevated nighttime HR is associated with decreased survival post AMI. Depression is a risk factor for mortality post AMI. It is also associated with sleep disturbances and with elevated HR, which may be more pronounced at night. Resting and 24-hour HR have been found to predict mortality in patient and community samples. METHODS: Ambulatory electrocardiographic data were obtained from 333 depressed patients and 383 nondepressed patients with recent AMI. They were followed for up to 30 months (median = 24 months). RESULTS: Depressed patients had higher nighttime HR (70.7 +/- 0.7 versus 67.7 +/- 0.6 beats per minute (bpm); p = .001), and daytime HR (76.4 +/- 0.7 versus 74.2 +/- 0.6 bpm; p = .02) than nondepressed patients, even after adjusting for potential confounds. Depression (hazard ratio (Haz R) = 2.19; p = .02) and nighttime HR (Haz R = 1.03; p = .004), but not daytime HR, predicted survival after adjusting for other major predictors and for each other. The interaction between nighttime HR and depression on survival approached, but did not achieve, significance (p = .08). CONCLUSIONS: Mean day and nighttime HR values are higher in depressed patients than in nondepressed patients post AMI. Depression and elevated nighttime HR, but not daytime HR, are independent predictors of survival in these patients. Although depressed patients have a higher nighttime HR than nondepressed patients, nighttime HR predicts mortality in both depressed and nondepressed patients.

Heart rate turbulence, depression, and survival after acute myocardial infarction.

OBJECTIVE: Depression is a risk factor for mortality after acute myocardial infarction (AMI), possibly as a result of altered autonomic nervous system (ANS) modulation of heart rate (HR) and rhythm. The purposes of this study were to determine: a) whether depressed patients are more likely to have an abnormal HR response (i.e., abnormal turbulence) to premature ventricular contractions (VPCs), and b) whether abnormal HR turbulence accounts for the effect of depression on increased mortality after AMI. METHODS: Ambulatory electrocardiographic data were obtained from 666 (316 depressed, 350 nondepressed) patients with a recent AMI; 498 had VPCs with measurable HR turbulence. Of these, 260 had normal, 152 had equivocal, and 86 had abnormal HR turbulence. Patients were followed for up to 30 (median = 24) months. RESULTS: Depressed patients were more likely to have abnormal HR turbulence (risk factor adjusted odds ratio = 1.8; 95% confidence interval [CI] = 1.0-3.0; p = .03) and have worse survival (odds ratio = 2.4; 95% CI = 1.2-4.6; p = .02) than nondepressed patients. When HR turbulence was added to the model, the adjusted hazard ratio for depression decreased to 1.9 (95% CI = 0.9-3.8; p = .08), and to 1.6 (95% CI = 0.8-3.4; p = .18) when a measure of HR variability (LnVLF) was added. The hazard was found to differ over time with depression posing little risk for mortality in year 1 but greater risk in years 2 and 3 of the follow up. CONCLUSION: ANS dysregulation may partially mediate the increased risk for mortality in depressed patients with frequent VPCs after an AMI.

Depression and obstructive sleep apnea in patients with coronary heart disease.

OBJECTIVE: Depression is a risk factor for cardiac events in patients with coronary heart disease (CHD). Obstructive sleep apnea/hypopnea syndrome (OSAHS) is frequently comorbid with depression and is also a risk factor for cardiac events. Undetected OSAHS could help explain the increased risk associated with depression. METHODS: Medically stable patients with CHD and major (MD, n = 53), minor (md, n = 36), or no depression (ND, n = 43) were evaluated for 2 nights in a sleep medicine laboratory. RESULTS: The prevalence of OSAHS did not differ across groups (MD 66%, md 69%, ND 77%; p > .05). Patients with MD had a significantly greater frequency of apneic episodes, a significantly longer duration of apneas and hyponeas, and more oxygen desaturations per hour than those with md, but there were no differences between MD and ND in frequency of apneic episodes or oxygen desaturations. However, males with MD tended to have more obstructive episodes per hour than did ND males, whereas females with MD had fewer episodes than did ND females. Apnea duration was longer in patients with MD compared with patients with no ND. There was no difference in the mean duration of apnea per hour between the md and ND groups. CONCLUSIONS: Although OSAHS is not more common in depressed patients with CHD, MD is associated with longer obstructive sleep apneic episodes in both men and women and with a higher frequency of episodes in men.

Low heart rate variability and the effect of depression on post-myocardial infarction mortality.

BACKGROUND: Depression is associated with an increased risk for mortality after acute myocardial infarction (MI). The purpose of this study was to determine whether low heart rate variability (HRV) mediates the effect of depression on mortality. METHODS: Twenty-four-hour ambulatory electrocardiograms were obtained from 311 depressed patients with a recent acute MI who were enrolled in the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial and from 367 nondepressed patients who met the ENRICHD medical inclusion criteria. Standard HRV indexes were extracted from the recordings. RESULTS: The log of very low-frequency (LnVLF) power, an index of HRV derived from power spectral analysis of the electrocardiogram signal (0.0033-0.04 Hz [in milliseconds squared]), was lower in the depressed than in the nondepressed patients (P<.001). There were 47 deaths (6.1%) during a 30-month follow-up. After adjusting for potential confounders, the depressed patients remained at higher risk for all-cause mortality compared with the nondepressed patients (hazard ratio, 2.8; 95% confidence interval [CI], 1.4-5.4; P<.003). When LnVLF power was entered into the model, the hazard ratio for depression dropped to 2.1 (95% CI, 1.1-4.2; P = .03). The proportion of the risk for depression attributable to LnVLF power was 0.27 (95% CI, 0.23-0.31; P<.001). CONCLUSIONS: Low HRV partially mediates the effect of depression on survival after acute MI. This finding helps to clarify the physiological mechanisms underlying depression's role as a risk factor for mortality in patients with coronary heart disease. It also raises the possibility that treatments that improve both depression and HRV might also improve survival in these patients.

Extramedullary leukemia in children with newly diagnosed acute myeloid leukemia: a report from the Children's Cancer Group.

OBJECTIVES: To describe features of patients with acute myeloid leukemia presenting with extramedullary leukemic tumors (EML). METHODS: Among 1,832 patients entered on Children's Cancer Group's chemotherapy trials with acute myeloid leukemia, 199 patients had EML, defined as any leukemic collection outside the bone marrow cavity. Three patient groups were denoted: group 1 (n=109) with EML involving skin (with or without other sites of EML), group 2 (n=90) with EML in sites other than skin, and group 3 (n=1,633) without EML. RESULTS: The incidence of EML was 10.9%. Group 1 patients tended to be younger, had higher white blood cell counts, were more often CNS positive, had FAB M4 or M5 subtypes, and possessed more abnormalities of chromosome 11 than group 3 patients. Group 2 patients were younger, more often had the FAB M2 subtype, and had a higher incidence of t(8;21)(q22;q22) abnormality than group 3, but had similar white blood cell counts and incidence of CNS positivity at diagnosis. For group 1 the 5-year event-free survival was 26%, significantly worse than for group 3 at 29%. Event-free survival was better for group 2 patients (5-year estimate 46%), which remained a favorable prognostic factor by multivariate analysis. The authors retrospectively determined whether 118 (59%) of the EML patients received localized radiotherapy to the site of EML: 42 did and 76 did not. There were no differences in estimated event-free survival between patients who did and did not receive radiotherapy. CONCLUSIONS: Non-skin (group 2) EML appeared to be an independent favorable prognostic factor. Localized radiotherapy to the site of EML at the end of induction chemotherapy did not improve outcome.

Ascertainment of a mid-western US female adolescent twin cohort for alcohol studies: assessment of sample representativeness using birth record data.

Female twin pairs were identified from birth records, and their families invited to participate in a prospective study of the determinants of alcohol problems in women. We investigated sampling biases arising because of failure to locate families, or non-cooperation of families. Out of 2644 families with a live-born pair (born between July 1975 and December 1986) who survived beyond infancy, contact was established and a brief screening interview completed with 90% (N = 2380). Fewer than 6% of located families declined to participate in the initial screening interview. Predictors of failure to locate a family or to obtain a screening interview were identified from information recorded in birth records, and from neighborhood characteristics identified from 1990 US Census block group data for the family residence when the twins were born. African-American families were under-represented in the final sample, but this effect was barely significant when other variables were controlled for. Under-represented were families where the mother was 19 or younger at the birth of the twins, where the mother herself was born out-of-state, or where information about biological father was not reported in the birth record. Non-participating families on average came from neighborhoods with a higher proportion of residents living in poverty, and with a higher proportion of African-American residents. Sampling biases were however small. The unusual cooperativeness in research of families with twins persists.