Pace of Aging in older adults matters for healthspan and lifespan.

As societies age, policy makers need tools to understand how demographic aging will affect population health and to develop programs to increase healthspan. The current metrics used for policy analysis do not distinguish differences caused by early-life factors, such as prenatal care and nutrition, from those caused by ongoing changes in people's bodies due to aging. Here we introduce an adapted Pace of Aging method designed to quantify differences between individuals and populations in the speed of aging-related health declines. The adapted Pace of Aging method, implemented in data from N=13,626 older adults in the US Health and Retirement Study, integrates longitudinal data on blood biomarkers, physical measurements, and functional tests. It reveals stark differences in rates of aging between population subgroups and demonstrates strong and consistent prospective associations with incident morbidity, disability, and mortality. Pace of Aging can advance the population science of healthy longevity.

Validation of a handheld near-infrared spectrophotometer for measurement of chemical intramuscular fat in Australian lamb.

The objective of the study was to independently validate a calibrated commercial handheld near infrared (NIR) spectroscopic device and test its repeatability over time using phenotypically diverse populations of Australian lamb. Validation testing in eight separate data sub-groups (n = 1591 carcasses overall) demonstrated that the NIR device had moderate precision (R2 = 0.4-0.64, RMSEP = 0.70-1.22%) but fluctuated in accuracy between experimental site demonstrated by variable slopes (0.50-0.94) and biases (-0.86-0.02). The repeatability experiment (n = 10 carcasses) showed that time to scan post quartering affected NIR measurement from 0 to 24 h (P < 0.001). On average, NIR IMF% was 0.97% lower (P < 0.001) at 24 h (4.01% ± 0.166), compared to 0 h. There was no difference (P > 0.05) between Time 0 and 1 h or Time 0 and 4 h or between replicate scans within each time point. This study demonstrated the SOMA NIR device could predict lamb chemical IMF% with moderate precision and accuracy, however additional work is required to understand how loin preparation, blooming and surface hydration affect NIR measurement.

Rare bowel emphysema with superior mesenteric artery syndrome after surgery.

Superior mesenteric artery syndrome, a rare cause of duodenal obstruction, occasionally requires surgery. Bowel emphysema might also require surgery and might be an ominous sign of a serious condition. We report the case of a 69-year-old Japanese man with left pneumothorax who was also diagnosed as having bowel emphysema and superior mesenteric artery syndrome simultaneously without serious infection after surgery for the pneumothorax. Following gastric decompression via a nasogastric tube, his general condition resolved quickly with no need for surgical intervention. Prompt and precise diagnosis by computed tomography and both adequate judgment and treatment can avoid surgery in such cases.

Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick1 knockout mice.

NMDA glutamate receptors have key roles in brain development, function and dysfunction. Regulatory roles of D-serine in NMDA receptor-mediated synaptic plasticity have been reported. Nonetheless, it is unclear whether and how neonatal deficits in NMDA-receptor-mediated neurotransmission affect adult brain functions and behavior. Likewise, the role of D-serine during development remains elusive. Here we report behavioral and electrophysiological deficits associated with the frontal cortex in Pick1 knockout mice, which show D-serine deficits in a neonatal- and forebrain-specific manner. The pathological manifestations observed in adult Pick1 mice are rescued by transient neonatal supplementation of D-serine, but not by a similar treatment in adulthood. These results indicate a role for D-serine in neurodevelopment and provide novel insights on how we interpret data of psychiatric genetics, indicating the involvement of genes associated with D-serine synthesis and degradation, as well as how we consider animal models with neonatal application of NMDA receptor antagonists.

P450 oxidoreductase deficiency with maternal virilization during pregnancy.

PURPOSE: The authors report on a rare case of maternal virilization during pregnancy caused by autosomal recessive P450 oxidore- ductase (POR) deficiency. MATERIALS AND METHODS: A 24-year-old primigravida developed a deepening voice and hirsutism in the second trimester. Prenatal ultrasonography failed to detect any fetal abnormality and fetal growth was normal. POR deficiency was suspected, but the mother declined fetal genetic testing. A female neonate was delivered by cesarean section at 41 weeks' gestation. RESULTS: The neonate had skeletal abnormalities. Mutational analysis of the POR gene demonstrated homozygosity for c.1370 G>A and p.R457H in the patient and heterozygosity in her parents. POR deficiency was confirmed in the neonate. CONCLUSION: POR deficiency should be suspected in cases of maternal virilization. Maternal urinary estriol, fetal magnetic resonance imaging, and parental genetic testing should be performed. Parental consent for fetal genetic testing should be sought to ensure prompt diagnosis and early treatment.

Isoflurane and sevoflurane during reperfusion prevent recovery from ischaemia in mitochondrial KATP channel blocker pretreated hearts.

BACKGROUND AND OBJECTIVE: Inhalation anaesthetics given only during post-ischaemic reperfusion have some protective effect against reperfusion injury in the heart. Adenosine triphosphate-regulated mitochondrial potassium channels have been shown to be an important mediator of cardioprotection. Thus, we investigated whether 5-hydroxydecanoate, a putative mitochondrial potassium channel blocker, prevents the cardioprotective effect of volatile anaesthetics. METHODS: Forty rats were randomly allocated to four groups of equal size: control group, 5-hydroxydecanoate group, 5-hydroxydecanoate + sevoflurane group and 5-hydroxydecanoate + isoflurane group. Seven minutes after the start of perfusion, normal saline (control group) or 5-hydroxydecanoate (the other groups) was administered. Ten minutes after the start of perfusion, the heart was rendered globally ischaemic for 10 min. One minute before the end of the ischaemic period, 2.7% sevoflurane or 1.4% isoflurane were administered in the 5-hydroxydecanoate + sevoflurane or 5-hydroxydecanoate + isoflurane groups respectively. The heart was reperfused for 10 min. RESULTS: Adenosine triphosphate content at the end of reperfusion in the 5-hydroxydecanoate + sevoflurane group was significantly lower (P < 0.05) than those in the control and the 5-hydroxydecanoate + isoflurane groups (19.9 +/- 8.7, 28.1 +/- 3.4 and 30.4 +/- 2.3 micromol g(-1), respectively). In addition, the combination of inhalation anaesthetics and 5-hydroxydecanoate decreased the ratios of recovered hearts from ischaemia (5-hydroxydecanoate + sevoflurane group: 40%, 5-hydroxydecanoate + isoflurane group 50%). CONCLUSION: 5-hydroxydecanoate alone caused no significant changes in haemodynamics and myocardial metabolism. However, the combination of 5-hydroxydecanoate and volatile anaesthetics impaired the recovery from ischaemia. Although animal data cannot be extrapolated to human beings, we suggest that more attention be paid to patients on sulphonylurea drugs, which inhibit potassium channels, when they are anaesthetized with volatile anaesthetics.

Comparison of stepwise and simultaneous estimations of population pharmacokinetics and pharmacodynamics of TS-943.

The prediction performances of population pharmacokinetic-pharmacodynamic analysis of the two methods (a stepwise and a simultaneous estimations) were evaluated with respect to their accuracies and precisions. A study was designed to investigate the safety and efficacy of TS-943 by a 4 hours constant infusion in 36 healthy male subjects. Population analysis was performed using pharmacokinetic and pharmacodynamic models with NONMEM. The mean of the prediction error (MPE) and the root mean squared error (RMSE) served as a measure of accuracy and precision. In addition, a bootstrap validation was also performed. The results indicate that those population pharmacokinetic-pharmacodynamic parameters for the two methods were comparable. The results of simultaneous estimations are similar to those obtained using a stepwise estimation. The mean parameter estimates obtained with the additional 200 bootstrap replicates of data were within 15% of those obtained with the final model in both methods. The present results demonstrated that the accuracy of pharmacodynamic evaluations using a stepwise end a simultaneous estimations was comparable.

Serum stem cell growth factor for monitoring hematopoietic recovery following stem cell transplantation.

Stem cell growth factor (SCGF) is a novel cytokine for primitive hematopoietic progenitor cells. Although it has burst-promoting activity and granulocyte/macrophage colony-promoting activity in vitro, its significance in hematopoiesis in vivo has not been elucidated. In this study, we have established enzyme-linked immunosorbent assay (ELISA) to quantify human SCGF and measured serum cytokines in normal volunteers and 27 patients undergoing stem cell transplantation (SCT), including six autologous and 21 allogeneic transplants. SCGF levels gradually increased after SCT regardless of graft-versus-host disease or type of transplant. The maximum level of SCGF was observed during the rapid granulocyte recovery phase in patients subjected to an autologous transplantation, and during the granulocyte stabilization phase in allogeneic patients. SCGF levels in PBSCT patients began to rise earlier than in BMT patients. Two patients with no increment of SCGF after SCT showed delayed engraftment. The source of SCGF was further analyzed by RT-PCR and we found that SCGF was highly expressed in bone marrow (BM) CD34(+) and CD34(-)CD33(+) cells, but not in BM CD34(-)CD33(-) cells, BM stromal cells and peripheral blood cells. The cell population expressing SCGF in BM possess the colony-forming cell activity. Therefore, serum SCGF can be an indicator of hematopoietic recovery following SCT.

Pharmacokinetic and pharmacodynamic analysis of TS-943, a selective non-peptide platelet glycoprotein-IIb/IIIa (GPIIb/IIIa) receptor antagonist, using a nonlinear mixed effect model in dogs.

A simultaneous analysis of the pharmacokinetics and pharmacodynamics of TS-943, a selective nonpeptide platelet glycoprotein-IIb/IIIa (GPIIb/IIIa) receptor antagonist, was made in dogs using a nonlinear mixed effect model. Plasma concentrations of TS-943 were determined after bolus intravenous injection, constant infusion and bolus plus constant infusion. Pharmacokinetic/pharmacodynamic data were fitted using NONMEM software. The pharmacokinetics of TS-943 fitted a two-compartment open model with first-order elimination. The pharmacodynamic model that best fitted platelet aggregation was an inhibitory sigmoid Emax model. The final estimates for E0 (baseline effect), Emax (maximum effect), IC50 (50% inhibitory concentration) and gamma (Hill coefficient) were 66.3%, 64.3%, 104 ng mL(-1) and 1.37, respectively. Correlations between TS-943 plasma concentration and extension of template bleeding time were examined by fitting with an exponential model. The TS-943 plasma concentration necessary to double bleeding time (C2-BTE) was approximately 209 ng mL(-1). The model estimated that the C2-BTE/IC50 (inhibition of platelet aggregation) ratio was approximately 2.0-fold in dogs. Our results suggest that the ratio values for dogs and man are comparable. A nonlinear mixed effect model was a useful tool for exploring the concentration-effect relationship for both efficacy and safety of TS-943 in dogs and man. In this study, the dog was found to be a useful model for screening of efficacy and safety of TS-943 in man.

Effects of nicorandil on myocardial function and metabolism in the post-ischaemic reperfused heart with or without inhalation anaesthetics.

BACKGROUND: Nicorandil, which is an ATP-sensitive K channel opener, has been reported to protect the ischaemic myocardium. However, its interaction with inhalation anaesthetics on the ischaemic myocardium has not been well elucidated. So, we have investigated whether isoflurane or sevoflurane modify the effects of nicorandil on cardiac function and metabolism in the rat heart-lung preparation. METHODS: Animals were allocated to 4 groups as follows: Control group, no drug; Nic group, nicorandil; Nic+Iso group, nicorandil and isoflurane; Nic+Sev group, nicorandil and sevoflurane. Seven minutes after the start of perfusion, nicorandil was administered and 10 min after the start of perfusion, the heart was rendered globally ischaemic for 10 min, and then the heart was reperfused for 10 min. RESULTS: LVdP/dt max in the Nic group was higher than those in the other groups. Right atrial pressure in the Nic+Iso and Nic+Sev groups was significantly higher than in the Control and Nic groups. Myocardial ATP in the Nic group was higher than in the other groups. DHBA levels in the perfusate in the Nic and Nic+Iso groups were lower than those in the Control and Nic+Sev groups, but those in the Nic+Sev group were higher than those in the other groups. CONCLUSIONS: Nicorandil improved post-ischaemic cardiac function and preserved high-energy phosphates. However, these beneficial effects of nicorandil were abolished by the combination with isoflurane or sevoflurane. In addition, sevoflurane increased hydroxyl radical formation in the post-ischaemic reperfused heart.

Effects of glibenclamide on hydroxyl radical formation in the postischaemic reperfused heart with or without inhalation anaesthetics.

BACKGROUND AND OBJECTIVE: We investigated whether glibenclamide (glyburide) affects myocardial metabolism and hydroxyl radical formation in the rat heart-lung preparation with or without inhalation anaesthetics. METHODS: Thirty-seven male Wistar rats were allocated to four groups: (a) control group (C), received vehicle only; (b) group G, received glibenclamide 10 microM L-1; (c) group I, received glibenclamide 10 microM L-1 and 1.4% isoflurane during perfusion; (d) group S, received glibenclamide 10 microM L-1 and 2.7% sevoflurane during perfusion. Glibenclamide was administered 7 min after the start of perfusion. Ten minutes later, the heart was rendered globally ischaemic for 10 min by reducing the preload and afterload to zero, and then the heart was reperfused for 10 min. The formation of hydroxyl radicals in perfusate blood and heart was measured with high performance liquid chromatography using salicylic acid. Hydroxyl radicals react with salicylic acid, yielding dihydroxybenzoic acids. RESULTS: The recovery time from ischaemia in group G was significantly longer than the other groups. However, there were no differences in myocardial metabolites and dihydroxybenzoic acids concentrations in the perfusate and heart among the four groups. CONCLUSIONS: Glibenclamide prolonged recovery time from ischaemia, but did not affect hydroxyl radical formation in the postischaemic reperfused heart. In addition, isoflurane and sevoflurane shortened this time. These facts suggest that mechanisms other than effects of volatile anaesthetics on hydroxyl radical formation are responsible for their protective effects in this model.

[Anesthetic management of a child with congenital sensory neuropathy with anhydrosis].

Congenital sensory neuropathy with anhydrosis is a rare disorder characterized by insensitivity to pain with normal tactile perception, self-mutilation, anhydrosis, recurrent unexplained fever, mental retardation and variable autonomic abnormality. We managed a 14-year-old boy with this syndrome who underwent repair of right femur fracture. Anesthesia was induced with propofol and ketamine. Adequate depth of anesthesia was carefully controlled by processed electroencephalogram, and core body temperature was maintained at 37.0 degrees C during the surgery. The patient was well sedated, and nausea and vomiting were not noted postoperatively. Use of droperidol and propofol may be beneficial for anesthetic management of this syndrome, because droperidol exerts residual hypnotic effect postoperatively, and both drugs have antiemetic property.

Stimulation of RNA polymerase II elongation by hepatitis delta antigen.

Transcription elongation by RNA polymerase II (RNAPII) is negatively regulated by the human factors DRB-sensitivity inducing factor (DSIF) and negative elongation factor (NELF). A 66-kilodalton subunit of NELF (NELF-A) shows limited sequence similarity to hepatitis delta antigen (HDAg), the viral protein required for replication of hepatitis delta virus (HDV). The host RNAPII has been implicated in HDV replication, but the detailed mechanism and the role of HDAg in this process are not understood. We show that HDAg binds RNAPII directly and stimulates transcription by displacing NELF and promoting RNAPII elongation. These results suggest that HDAg may regulate RNAPII elongation during both cellular messenger RNA synthesis and HDV RNA replication.

Effects of cibenzoline on cardiac function and metabolism in the rat heart--lung preparation.

BACKGROUND AND OBJECTIVE: Although there is concern that cibenzoline, an antidysrhythmic drug for the treatment of ventricular and supraventricular dysrhythmias, may be associated with dose-dependent inhibition of myocardial contractility there are few reports about the relationship between myocardial metabolism and cardiac function when it is used. The present study was designed to investigate the effects of cibenzoline on cardiac function and metabolism. The effects of cibenzoline on cardiac function and myocardial metabolism were assessed in the isolated rat heart-lung preparation. METHODS: Thirty-two male Wistar-ST rats were divided into four groups: control, and those to receive cibenzoline, either 300, 900 or 3000 ng mL(-1). The cibenzoline was administered into the perfusate 5 min after the start of perfusion. Heart rates in the 3000 ng mL(-1) group were significantly lower than those in the control group. Cardiac output in the 3000 ng mL(-1) group at 15 and 30 min was significantly lower than in the control group. In all groups, values for %LV dP/dt max (the ratio of values at each time to those at 5 min) at 20, 25, 30 min were significantly higher than at 5 min. Myocardial adenosine triphosphate concentration in the 3000 ng mL(-1) group was significantly lower than in controls. There was no difference between groups in the lactate/pyruvate ratio. CONCLUSION: The therapeutic range of cibenzoline has few effects on cardiac function and metabolism, although concentrations 10 times greater may cause a deterioration in myocardial metabolism.

Intravenous ketamine attenuates arterial pressure changes during the induction of anaesthesia with propofol.

BACKGROUND AND OBJECTIVE: To investigate whether the administration of ketamine before induction with propofol produces a smaller decrease in arterial pressure. METHODS: Twenty-two patients were assigned to one of two groups to receive either propofol with ketamine (n = 11) or propofol alone (n = 11, control). Anaesthesia was induced with 2 mg kg-1 propofol and 0.5 mg kg-1 ketamine or 2 mg kg-1 propofol alone. Ketamine was administered 1 min prior to induction with propofol. Immediately after induction with propofol, vecuronium (0.15 mg kg-1) was administered. Four minutes after administration of vecuronium, tracheal intubation was performed. Anaesthesia was maintained using sevoflurane (0.5%) in 66% nitrous oxide until 3 min after intubation. Systolic, diastolic and mean arterial pressure and heart rate were recorded on arrival, directly before induction with propofol, prior to tracheal intubation, immediately after intubation and at 3 min after intubation. RESULTS AND CONCLUSIONS: Administration of ketamine before induction with propofol preserved haemodynamic stability compared with induction with propofol alone.

Ultrastructural fragility and type IV collagen abnormality of the anterior lens capsules in a patient with Alport syndrome.

PURPOSE: To investigate ultrastructural and immunohistological abnormalities of the lens capsules in a patient with Alport syndrome. METHODS: Two anterior lens capsules were obtained at phacoemulsification from a 43-year-old female patient with bilateral lenticonus who was affected by Alport syndrome. The right capsule was examined by transmission electron microscopy and the left capsule was stained with two monoclonal antibodies against the triple-helical domains of type IV collagen alpha2 and alpha5 chains. RESULTS: Numerous vertical dehiscences with many disrupted interdigitations were observed in the right anterior lens capsule. Decreased reactivity of monoclonal antibodies against type IV collagen alpha5 chain and normal reactivity against the alpha2 chain were shown in the left anterior lens capsule. CONCLUSION: The ultrastructural fragility of the anterior lens capsules in this patient with Alport syndrome appears to be associated with the abnormality of the type IV collagen molecules including the alpha5 chain.

T-cell-specific expression of kinase-defective Eph-family receptor protein, EphB6 in normal as well as transformed hematopoietic cells.

Although most kinase-defective growth factor receptor proteins are associated with pathogenic conditions, a kinase-defective Eph-family receptor protein, EphB6, is expressed in normal human tissues. We generated monoclonal antibodies specific for human EphB6 to characterize its expression on human hematopoietic cells. A very small population of normal human peripheral white blood cells (0.57 +/- 0.07%, n = 12) expressed EphB6. The EphB6-positive cells were CD2+, CD7+, CD3+ and CD4+ or CD8+ lymphocytes, but they did not express CD19 or CD11b. In human bone marrow, only 1.5 +/- 0.19% of lymphocytes expressed EphB6. Compared with the expression in peripheral lymphocytes, prominent expression of EphB6 protein was demonstrated in CD4+CD8+ double-positive mouse thymocytes. The T-cell lineage-specific expression was strictly conserved in human leukemia/lymphoma cells. Among T-cell-derived leukemia cells, the expression level of EphB6 seemed to decrease with maturation of the cells. These results suggest that EphB6 expression is regulated in T-cell development.

ELISA for urinary trehalase with monoclonal antibodies: a technique for assessment of renal tubular damage.

BACKGROUND: alpha,alpha-Trehalase, located on renal proximal tubules, is a glycoprotein that hydrolyses alpha,alpha-trehalose to two glucose molecules. Urinary trehalase reflects damage to renal proximal tubules, but its activity has not been measured routinely because measurement of catalytic activity is rather complicated and because conventional assays for enzyme activity might not reflect all of the trehalase protein because of enzyme inactivation in urinary samples. METHODS: We established novel monoclonal antibodies for human trehalase and a sandwich ELISA for quantification of urinary trehalase. We determined the urinary trehalase protein concentration with this ELISA and trehalase catalytic activity, and the results of these two methods were compared. RESULTS: The ELISA system was more sensitive than the detection of enzyme activity and could detect a subtle difference in the amount of trehalase present in renal diseases. The within- and between-assay CVs in the ELISA were 6.7-7.6% and 6.2-8.2%, respectively. Highly significant increases in both the quantity and activity were seen in patients with nephrotic syndrome (acute phase), Lowe syndrome, and Dent disease. The quantities were 70- to 200-fold greater, whereas enzyme activities were, at most, 10-fold higher than those of control subjects. In the detection of small amounts of trehalase in patients with chronic glomerulonephritis and renal anomalies, quantities were better than enzyme activities. CONCLUSIONS: We have established an ELISA system for quantification of urinary trehalase that uses novel monoclonal antibodies. Our ELISA system is simpler and more sensitive than a conventional activity assay and reflects trehalase protein. This ELISA can be a useful as a common tool for clinical assessment of renal proximal tubular damage.

Population pharmacokinetics and pharmacodynamics of TS-943 for selective nonpeptide platelet glycoprotein IIb/IIIa receptor antagonist in normal healthy subjects.

The pharmacokinetics and pharmacodynamics of TS-943 were evaluated with use of NONMEM in 36 healthy male subjects after constant infusion of five different single-dose regimens. Population analysis showed the plasma concentration-time profiles of TS-943 to be best-fit characterized by a two-compartment open model with constant infusion and first-order elimination. The pharmacodynamic model that best fitted the platelet aggregation was a sigmoid Emax model. The final estimates for baseline effect, 50% inhibitory concentration (IC50), and the Hill coefficient were 79.4%, 23.4 ng/mL and 1.63, respectively. The maximum effect (Emax) was fixed at 80% (submaximal aggregation response). In addition, correlations between TS-943 plasma concentration and extension of template bleeding time were examined by fitting with an exponential model. The model estimates that the TS-943 plasma concentration necessary to double template bleeding time is approximately 63 ng/mL (ie, 2.7-fold greater than the IC50). The population approaches for pharmacokinetic-pharmacodynamic investigation can be useful for the analysis of concentration-effect relationships and concentration-adverse event relationships for a platelet glycoprotein IIb/IIIa receptor antagonist.