Absence of age-related changes in venous responsiveness to nitroglycerin in vivo in humans

We have previously demonstrated a progressive loss in the ability of the beta-receptor agonist isoproterenol to relax veins with increasing age. In this study the influence of age on the responsiveness of medium-sized veins to local infusions of nitroglycerin was studied in two groups of 15 healthy male volunteers using the dorsal hand vein compliance technique. A dorsal hand vein was preconstricted with submaximally effective doses of phenylephrine and a dose-response curve with nitroglycerin was established. The nitroglycerin dose that caused a 50% venodilation ranged from 0.7 to 22.4 ng/min (geometric mean 3.6 ng/min) in the younger group (aged 19 to 29 years; mean +/- SD 23 +/- 3 years) and from 0.2 to 17.9 ng/min (geometric mean 3.6 ng/min) in the older subjects (aged 50 to 74 years; mean +/- SD 63 +/- 7 years) (P = 0.49 between geometric means). The mean (+/- SD) maximal venodilation, based on the pretreatment baseline, was 103% +/- 65% in the younger and 125% +/- 64% in the older subjects (P = 0.18). These results indicate that there is no age-related change in venous responsiveness to nitroglycerin.     

In vivo function tests of hepatic drug‐oxidizing capacity in patients with liver disease

Aminopyrine, antipyrine and trimethadione have been widely used for some time as probe drugs to assess non‐selective P450 liver function. They have proved useful in evaluating pre‐ and post‐operative liver function when performing surgery, transplantations, etc., in addition to a general evaluation of liver function and drug interactions. Progress has recently been made both in these non‐selective P450 function tests and in the analysis of drug‐metabolizing enzymes at a molecular level, which has resulted in more selective P450 function tests.
The caffeine (CYP1 A2), chlorzoxazone (CYP2E1), lidocaine (CYP3 A) and midazolam (CYP3 A) function tests and the erythromycin breath test (CYP3 A) are currently being used as specific probes. The future use of these tests needs to be discussed in terms of potential clinical implications.     

多层螺旋CT评估下眼睑增龄性改变

目的 通过多层螺旋CT评估眼轮匝肌厚度与眼眶脂肪脱垂长度的增龄性改变.方法 将148例接受头部多层螺旋CT患者分为青年组(18～44岁)54例、中年组(45～59岁)30例和老年组(≥60岁)64例,于斜矢状位图像上测量右眼眼轮匝肌厚度、眼眶脂肪脱垂长度,分析年龄、性别、眼轮匝肌厚度与眼眶脂肪脱垂长度的关系.结果 青年...     

Neural correlates of age-related changes in cortical neurophysiology

Functional imaging studies of cortical motor systems in humans have demonstrated age-related reorganisation often attributed to anatomical and physiological changes. In this study we investigated whether aspects of brain activity during a motor task were influenced not only by age, but also by neurophysiological parameters of the motor cortex contralateral to the moving hand. Twenty seven right-handed volunteers underwent functional magnetic resonance imaging whilst performing repetitive isometric right hand grips in which the target force was parametrically varied between 15 and 55% of each subject's own maximum grip force. For each subject we characterised two orthogonal parameters, B(G) (average task-related activity for all hand grips) and B(F) (the degree to which task-related activity co-varied with peak grip force). We used transcranial magnetic stimulation (TMS) to assess task-related changes in interhemispheric inhibition from left to right motor cortex (IHIc) and to perform measures relating to left motor cortex excitability during activation of the right hand. Firstly, we found that B(G) in right (ipsilateral) motor cortex was greater with increasing values of age(2) and IHIc. Secondly, B(F) in left ventral premotor cortex was greater in older subjects and in those in whom contralateral M1 was less responsive to TMS stimulation. In both cases, neurophysiological parameters accounted for variability in brain responses over and above that explained by ageing. These results indicate that neurophysiological markers may be better indicators of biological ageing than chronological age and point towards the mechanisms by which reconfiguration of distributed brain networks occurs in the face of degenerative changes.     

Quantitative MRI: hidden age-related changes in brain tissue

The advent of MRI has made a remarkable progress in the understanding of age-related brain changes providing a noninvasive tool to study in vivo the normally aging individuals at multiple time points. However, conventional MRI techniques are unable to detect and quantify age-related microstructural changes that have been documented at the post-mortem examination of brain tissues. More sophisticated, quantitative MR techniques such as magnetization transfer imaging, diffusion tensor imaging, and proton MR spectroscopy have been shown to be sensitive to microstructural and metabolic changes that occur in gray and white matter over the course of life span. This review highlights some of these innovative, quantitative MR techniques that are particularly relevant for the study of occult age-related brain tissue changes. Characterization of the in vivo patterns of molecular and cellular changes that occur in the normal aging brain is of crucial importance to understand the pathophysiology of normal cognitive decline and to interpret observed changes in neurodegenerative diseases.     

Cancer in the older adult: understanding age-related changes

As the population ages, nurses will be working with increased numbers of elderly cancer patients. It is imperative that nurses gain an understanding of the aging process and an appreciation of the cancer experience in the older adult. By aggravating or influencing cancer-related symptoms and their treatments, or by inducing non-cancer related symptoms, concurrent health problems may inadvertently be thought to be associated with malignancy progression. An in-depth investigation of a patient's history may reveal a vast number of actual and potential health problems; the areas that pose special concerns for the elderly are nutrition, pain, and psychosocial aspects, such as depression and confusion.     

Neurophysiological correlates of age-related changes in working memory updating

Normal aging is associated with a gradual decline in executive functions such as set-shifting, inhibition, and updating, along with a progressive decline of neurotransmitter systems including the dopamine system. Modulation from the dopamine system is thought to be critical for the gating of information during working memory. Given the known relationships between executive aging, cognition, and dopamine, this study aims to explore the neurobiology underlying age-related changes in working memory updating using fMRI with healthy subjects from across the adult age spectrum. Our results indicate that older age is associated with poorer performance, reduced meso-cortico-striatal activation, and reduced functional coupling between the caudate and the VLPFC during the updating task. Additionally, caudate activation is associated with improved accuracy and VLPFC activation with faster reaction times in the full sample. Thus, older subjects' under-recruitment of and reduced functional coupling between these regions may specifically underlie age-related changes in working memory updating. These results are consistent with computational models of executive cognition and dopamine-mediated age-related cognitive decline.     

Role of hepatic autoregulation in defense against hypoglycemia in humans.

To assess the role of hepatic autoregulation in defense against hypoglycemia, we compared the effects of complete blockade of glucose counterregulation with those of blockade of only neurohumoral counterregulation during moderate (approximately 50 mg/dl) and severe (approximately 30 mg/dl) hypoglycemia induced by physiologic hyperinsulinemia during subcutaneous infusion of insulin in normal volunteers. Compared with observations in control experiments, neurohumoral counterregulatory blockade (somatostatin, propranolol, phentolamine, and metyrapone), during which identical moderate hypoglycemia was achieved using the glucose clamp technique, resulted in suppressed glucose production (0.62 +/- 0.08 vs. 1.56 +/- 0.07 mg/kg per min at 12 h, P less than 0.01) and augmented glucose utilization (2.17 +/- 0.18 vs. 1.57 +/- 0.07 mg/kg per min at 12 h, P less than 0.01). Complete blockade of counterregulation (neurohumoral blockade plus prevention of hypoglycemia) did not further enhance the suppressive effects of insulin on glucose production. However, when severe hypoglycemia was induced during neurohumoral counterregulatory blockade, glucose production was nearly two times greater (1.05 +/- 0.05 mg/kg per min at 9 h) than that observed during complete counterregulatory blockade (0.58 +/- 0.08 mg/kg per min at 9 h, P less than 0.01) and that observed during mere neurohumoral blockade with moderate hypoglycemia (0.59 +/- 0.06 mg/kg per min at 9 h, P less than 0.01). These results demonstrate that glucose counterregulation involves both neurohumoral and hepatic autoregulatory components: neurohumoral factors, which require only moderate hypoglycemia for their activation, augment glucose production and reduce glucose utilization; hepatic autoregulation requires severe hypoglycemia for its activation and may thus serve as an emergency system to protect the brain when other counterregulatory factors fail to prevent threatening hypoglycemia.     

Hemodynamic and metabolic changes in hepatic transplantation

In this study, we retrospectively analyzed the intraoperative hemodynamic, laboratory, and coagulation data on the first 83 patients who underwent an initial liver transplantation procedure at our institution. The major hemodynamic changes at the time of reperfusion of the donor liver were significant decreases in arterial blood pressure, systemic vascular resistance, and pulmonary artery temperature and significant increases in cardiac output and pulmonary capillary wedge pressure. The alterations in laboratory values reflected intraoperative therapeutic manipulations. Citrate toxicity is a concern, and the amount of calcium chloride administered reflected the volume of blood transfused. On reperfusion, the fibrinogen concentration decreased and both the prothrombin time and the activated partial thromboplastin time increased. This coagulopathy was also evident in the thromboelastographic values. Aggressive monitoring and prompt intervention are necessary to maintain hemodynamic and metabolic homeostasis in these patients.     

Influence of atherosclerosis on age-related changes in renal size and function

BACKGROUND: Renal size and function reflect the health of the kidney. These parameters are associated with age, gender and body weight. The kidneys are also influenced by micro- and macrovascular diseases. Atherosclerotic markers and risk factors may influence the age-related changes of renal size and function. METHODS: Data of 1056 patients who entered the SMART-study (Second Manifestations of ARTerial disease) were used to assess the effect of atherosclerosis on the relationship between age and renal size and function and to study the effect of atherosclerosis on renal size and function. Patients who were newly referred to the hospital with manifestations of vascular disease were screened for asymptomatic atherosclerosis with noninvasive tests. The carotid intima-media thickness (IMT) and albuminuria were used as estimates for the atherosclerotic burden. Renal size was defined as the mean pole-to-pole length of both kidneys measured by ultrasonography. Renal function was represented by serum creatinine. RESULTS: Intima-media thickness was a significant effect modifier of the age-renal size relationship (P = 0.041). The increase of serum creatinine with age was more pronounced in the highest tertile of IMT (P = 0.048). Renal size decreased equally with age in patients with and without hypertension or diabetes mellitus (DM). The same held true for the age-renal function relationship. Albuminuria and DM were independent predictors of renal size and function. CONCLUSION: Atherosclerosis accelerates the decrease of renal size and the increase of serum creatinine with age. Renal size and function are determined by albuminuria and DM.     

Radioimmunoassay for pancreatic polypeptide, and its age-related changes in concentration

Pancreatic polypeptide (PP), a recently discovered pancreatic hormone, is potentially a marker for endocrine tumors. Consequently, we devised a radioimmunoassay for it, using antisera (raised in rabbits) to bovine PP, 125I-labeled bovine PP (purified by anion-exchange chromatography), and human PP standards. Concentrations circulating in fasting, normal subjects were measured. Statistical analysis of the results revealed a skewed distribution. An age-related increase was also observed. Evaluating PP concentrations in sera from 23 patients with endocrine tumors, we found increased values in a few cases of Zollinger-Ellison syndrome, medullary carcinoma of the thyroid, carcinoid syndrome, and one tumor producing vasoactive intestinal polypeptide (VIPoma). In contrast, values from five insulinomas and one glucagonoma were within the normal reference interval. Thus, an increased value for PP in a fasting individual may suggest the diagnosis of an endocrine tumor but is not a diagnostic prerequisite.     

Segmentation of age-related white matter changes in a clinical multi-center study

Age-related white matter changes (WMC) are thought to be a marker of vascular pathology, and have been associated with motor and cognitive deficits. In the present study, an optimized artificial neural network was used as an automatic segmentation method to produce probabilistic maps of WMC in a clinical multi-center study. The neural network uses information from T1- and T2-weighted and fluid attenuation inversion recovery (FLAIR) magnetic resonance (MR) scans, neighboring voxels and spatial location. Generalizability of the neural network was optimized by including the Optimal Brain Damage (OBD) pruning method in the training stage. Six optimized neural networks were produced to investigate the impact of different input information on WMC segmentation. The automatic segmentation method was applied to MR scans of 362 non-demented elderly subjects from 11 centers in the European multi-center study Leukoaraiosis And Disability (LADIS). Semi-manually delineated WMC were used for validating the segmentation produced by the neural networks. The neural network segmentation demonstrated high consistency between subjects and centers, making it a promising technique for large studies. For WMC volumes less than 10 ml, an increasing discrepancy between semi-manual and neural network segmentation was observed using the similarity index (SI) measure. The use of all three image modalities significantly improved cross-center generalizability compared to neural networks using the FLAIR image only. Expert knowledge not available to the neural networks was a minor source of discrepancy, while variation in MR scan quality constituted the largest source of error.     

Structural basis for reduced glomerular filtration capacity in nephrotic humans.

Previous studies have established that in a variety of human glomerulopathies the reduced glomerular filtration rate (GFR) is due to a marked lowering of the ultrafiltration coefficient (Kf). To identify the factors which lower Kf, we measured the filtering surface area per glomerulus, filtration slit frequency, basement membrane thickness, and GFR and its determinants in patients with minimal change and membraneous nephropathies and in age-matched healthy controls. Overall values of Kf for the two kidneys were calculated from GFR, renal plasma flow rate, systemic colloid osmotic pressure, and three assumed values for the transcapillary pressure difference. "Experimental" values of the glomerular hydraulic permeability (kexp) were then calculated from Kf, glomerular filtering surface area, and estimates of the total number of nephrons of the two kidneys. Independent estimates of the glomerular hydraulic permeability (kmodel) were obtained using a recent mathematical model that is based on analyses of viscous flow through the various structural components of the glomerular capillary wall. Individual values of basement membrane thickness and filtration slit frequency were used as inputs in this model. The results indicate that the reductions of Kf in both nephropathies can be attributed entirely to reduced glomerular hydraulic permeability. The mean values of kexp and kmodel were very similar in both disorders and much smaller in the nephrotic groups than in healthy controls. There was good agreement between kexp and kmodel for any given group of subjects. It was shown that, in both groups of nephrotics, filtration slit frequency was a more important determinant of the water flow resistance than was basement membrane thickness. The decrease in filtration slit frequency observed in both disorders caused the average path length for the filtrate to increase, thereby explaining the decreased hydraulic permeability.     

Direct muscarinic cholinergic inhibition of hepatic glucose production in humans.

To explore the potential role of the parasympathetic nervous system in human glucoregulatory physiology, responses to the muscarinic cholinergic agonist bethanechol (5.0 mg s.c.) and antagonist atropine (1.0 mg i.v.) were measured in normal humans. There were no changes in the plasma glucose concentration or rates of glucose production or utilization following atropine administration. After bethanechol administration there were no changes in the plasma glucose concentration or fluxes despite increments in plasma glucagon (75 +/- 7 to 103 +/- 10 pg/ml, P less than 0.02). There were no changes in insulin or C-peptide levels. To test the hypothesis that direct muscarinic inhibition of glucose production was offset by an indirect action of the agonist, specifically increased glucagon secretion with consequent stimulation of glucose production, bethanechol was administered while glucagon levels were held constant with the islet clamp technique (somatostatin infusion with insulin, glucagon and growth hormone replacement at fixed rates). Under that condition the muscarinic agonist induced a 25% decrement in the plasma glucose concentration (101 +/- 8 to 75 +/- 8 mg/dl, P less than 0.05). When compared with separate clamp control studies (with placebo rather than bethanechol injection) both the rate of glucose production and the glucose concentration were reduced (P less than 0.05) following bethanechol injection; the rate of glucose utilization was unaltered. Thus, we conclude: Withdrawal of parasympathetic tone does not appear to be an important glucoregulatory process in humans. Direct muscarinic cholinergic inhibition of hepatic glucose production occurs in humans but during generalized muscarinic activation this is offset by an indirect muscarinic action, increased glucagon secretion with consequent stimulation of glucose production. Thus, particularly if regional neuronal firing occurs, the parasympathetic nervous system may play an important role in human glucoregulatory physiology.     

Sex differences in hepatic gluconeogenic capacity after chronic alcohol consumption

Alcohol-induced hypoglycemia has traditionally been attributed to the amount of ethanol consumed rather than any inherent decline in glucose output capacity by the gluconeogenic organs and/or an increase in skeletal muscle glucose uptake. Further, while the potential for sex differences that might impact glucose homeostasis following chronic alcohol consumption has been recognized, direct evidence has been noticeably absent. This paper will provide a brief review of past and present reports of the potential for sex differences in glucose homeostasis following chronic ethanol consumption. This paper will also provide direct evidence from our laboratory demonstrating sex differences from chronic alcohol consumption resulting in a decrement in glucose appearance and more importantly, a specific decline in hepatic gluconeogenic (HGN) capacity in the absence and presence of ethanol. All our studies involved 8 weeks of chronic alcohol consumption in male and female Wistar rats, as well as a 24 to 48 hour fast to deplete hepatic glycogen stores. Under the conditions of chronic alcohol consumption and an acute dose of ethanol, we provide in vivo evidence of an early decline in whole body glucose appearance in females fed an ethanol diet compared to controls. While the decline was also observed in males fed the alcohol diet, it occurred much later compared to ethanol fed females. The site for the decline in whole body glucose production (i.e., either the kidneys or the liver) was beyond the scope of our prior in vivo study. In a follow-up study using the in situ perfused liver preparation, we provide additional evidence for a specific reduction in HGN capacity from lactate in ethanol fed females compared to ethanol fed males in the absence of alcohol in the perfusion medium. Finally, employing the isolated hepatocyte technique, we report decrements in HGN from lactate in ethanol fed females compared to ethanol fed males in the presence of ethanol in the incubation medium. The mechanism for the specific decline in HGN within the liver of ethanol fed females remains to be determined. To the extent that our observations in animals can be extrapolated to humans, we conclude that alcoholic women are more susceptible to ethanol-induced hypoglycemia compared to alcoholic men.     

The effects of oral nifedipine on hepatic blood flow in humans

Duplex ultrasonography was used to measure changes in hepatic blood flow in 13 healthy volunteers after they received single doses of 10 mg oral nifedipine and placebo. Blood flow was measured in the hepatic artery and branches of the portal and hepatic veins at baseline and 0.3, 0.6, 1, 1.5, 2, 3, 4, and 5 hours after drug administration. Cardiac output was also measured at baseline and 1, 2, and 3 hours after dosing. Blood flow initially increased in all three vessels 0.6 hour after administration of nifedipine (29%, 56%, and 31% in the hepatic artery, hepatic vein, and portal vein, respectively) compared with placebo. Flow rapidly returned to baseline in the hepatic artery and hepatic vein, whereas it appeared to remain elevated through 3 hours in the portal vein. Nifedipine administration resulted in an increase in cardiac output of 26%, 22%, and 14% above placebo at 1, 2, and 3 hours, respectively. No significant differences were detected in the systolic, diastolic, or mean arterial blood pressures after nifedipine or placebo. This study demonstrates that nifedipine increases hepatic blood flow in a transient nature and systemic hemodynamic parameters do not necessarily reflect specific organ responses. The nifedipine-induced change in blood flow should be considered when nifedipine is coadministered with high-clearance drugs, because systemic availability may be increased.