Characteristic Metabolism of Free Amino Acids in Cetacean Plasma: Cluster Analysis and Comparison with Mice

From an evolutionary perspective, the ancestors of cetaceans first lived in terrestrial environments prior to adapting to aquatic environments. Whereas anatomical and morphological adaptations to aquatic environments have been well studied, few studies have focused on physiological changes. We focused on plasma amino acid concentrations (aminograms) since they show distinct patterns under various physiological conditions. Plasma and urine aminograms were obtained from bottlenose dolphins, pacific white-sided dolphins, Risso's dolphins, false-killer whales and C57BL/6J and ICR mice. Hierarchical cluster analyses were employed to uncover a multitude of amino acid relationships among different species, which can help us understand the complex interrelations comprising metabolic adaptations. The cetacean aminograms formed a cluster that was markedly distinguishable from the mouse cluster, indicating that cetaceans and terrestrial mammals have quite different metabolic machinery for amino acids. Levels of carnosine and 3-methylhistidine, both of which are antioxidants, were substantially higher in cetaceans. Urea was markedly elevated in cetaceans, whereas the level of urea cycle-related amino acids was lower. Because diving mammals must cope with high rates of reactive oxygen species generation due to alterations in apnea/reoxygenation and ischemia-reperfusion processes, high concentrations of antioxidative amino acids are advantageous. Moreover, shifting the set point of urea cycle may be an adaption used for body water conservation in the hyperosmotic sea water environment, because urea functions as a major blood osmolyte. Furthermore, since dolphins are kept in many aquariums for observation, the evaluation of these aminograms may provide useful diagnostic indices for the assessment of cetacean health in artificial environments in the future

Global, regional, and national burden of congenital heart disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017

BACKGROUND: Previous congenital heart disease estimates came from few data sources, were geographically narrow, and did not evaluate congenital heart disease throughout the life course. Completed as part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017, this study aimed to provide comprehensive estimates of congenital heart disease mortality, prevalence, and disability by age for 195 countries and territories from 1990 to 2017. METHODS: Mortality estimates were generated for aggregate congenital heart disease and non-fatal estimates for five subcategories (single ventricle and single ventricle pathway congenital heart anomalies; severe congenital heart anomalies excluding single ventricle heart defects; critical malformations of great vessels, congenital valvular heart disease, and patent ductus arteriosus; ventricular septal defect and atrial septal defect; and other congenital heart anomalies), for 1990 through to 2017. All available global data were systematically analysed to generate congenital heart disease mortality estimates (using Cause of Death Ensemble modelling) and prevalence estimates (DisMod-MR 2·1). Systematic literature reviews of all types of congenital anomalies to capture information on prevalence, associated mortality, and long-term health outcomes on congenital heart disease informed subsequent disability estimates. FINDINGS: Congenital heart disease caused 261 247 deaths (95% uncertainty interval 216 567-308 159) globally in 2017, a 34·5% decline from 1990, with 180 624 deaths (146 825-214 178) being among infants (aged <1 years). Congenital heart disease mortality rates declined with increasing Socio-demographic Index (SDI); most deaths occurred in countries in the low and low-middle SDI quintiles. The prevalence rates of congenital heart disease at birth changed little temporally or by SDI, resulting in 11 998 283 (10 958 658-13 123 888) people living with congenital heart disease globally, an 18·7% increase from 1990 to 2017, and causing a total of 589 479 (287 200-973 359) years lived with disability. INTERPRETATION: Congenital heart disease is a large, rapidly emerging global problem in child health. Without the ability to substantially alter the prevalence of congenital heart disease, interventions and resources must be used to improve survival and quality of life. Our findings highlight the large global inequities in congenital heart disease and can serve as a starting point for policy changes to improve screening, treatment, and data collection. FUNDING: Bill & Melinda Gates Foundation

A SHORT-TERM STUDY OF THE SAFETY, PHARMACOKINETICS, AND EFFICACY OF RITONAVIR, AN INHIBITOR OF HIV-1 PROTEASE

Background. Reverse-transcriptase inhibitors have only moderate clinical efficacy against the human immunodeficiency virus type 1 (HIV-1). Ritonavir is an inhibitor of HIV-1 pretease with potent in vitro anti-HIV properties and good oral bioavailability. Methods. We evaluated the antiviral activity and safety of ritonavir in a double-blind, randomized, placebo-controlled phase 1 and 2 study of 84 HIV-positive patients with 50 or more CD4+ lymphocytes per cubic millimeter. The patients were randomly assigned to one of four regimens of ritonavir therapy, or to placebo for four weeks and then (by random assignment) to one of the ritonavir regimens. Results. During the first 4 weeks, increases in CD4+ lymphocyte counts and reductions in the log number of copies of HIV-1 RNA per milliliter of plasma were similar among the four dosage groups, but in the three lower-dosage groups there was a return to base-line levels by 16 weeks. After 32 weeks, in the seven patients in the highest-dosage group (600 mg of ritonavir every 12 hours), the median increase from base line in the CD4+ lymphocyte count was 230 cells per cubic millimeter, and the mean decrease in the plasma concentration of HIV-1 RNA (as measured by a branched-chain DNA assay) was 0.81 log (95 percent confidence interval, 0.40 to 1.22). In a subgroup of 17 patients in the two higher-dosage groups, RNA was also measured with an assay based on the polymerase chain reaction, and after eight weeks of treatment there was a mean maximal decrease in viral RNA of 1.94 log (95 percent confidence interval, 1.37 to 2.51). Adverse events included nausea, circumoral paresthesia, elevated hepatic aminotransferase levels, and elevated triglyceride levels. Ten withdrawals from the study were judged to be related to ritonavir treatment. Conclusions. In this short-term study, ritonavir was well tolerated and had potent activity against HIV-1, but its clinical benefits remain to be established