Modification of lymphocyte traffic by vasoactive neurotransmitter substances.

The effects of a number of vasoactive and neurotransmitter substances on lymphocyte traffic were studied by assessing their effects on the release of lymphocytes into primary peripheral (popliteal) nodal efferent lymph of sheep following acute infusion into cannulated afferent nodal lymphatics. In a total of 23 experiments, the output of lymphocytes, small and blast, was increased by serotonin, substance P, bombesin, [met]enkephalin, isoprenaline and phenylephrine and was decreased by vasoactive intestinal peptide (VIP), neurotensin and carbachol. Substances whose actions are modulated by prostaglandins and enhanced by prostaglandin synthesis inhibitors and which elevate blood monocyte and nervous tissue levels of cyclic GMP tended to increase lymphocyte traffic through peripheral lymph nodes in sheep in vivo. The opposite effect tended to be produced by substances whose actions require or are associated with prostaglandins or histamine, and which affect blood monocytic cyclic nucleotide levels by elevation of cyclic AMP or depression of cyclic GMP. Pain and inflammation tended to increase lymphocyte traffic, while analgesics and immunomodulators tended to decrease it.     

Behavioral correlates of renal damage and cardiac changes

The locomotor activity (determined by open-field test) and analgesic response (measured by tail-flick latency) of rats were evaluated during exposure to novel stimuli and again after exposure to shock. The effects of shock stress on hearts and kidneys were evaluated. This study has found that the more active an animal is when exposed to a novel stimuli the more likely it is to develop renal damage or cardiac changes after shock. Shock stress was found to produce changes in locomotor activity and analgesic state, but shock did not correlate as well with cardiac changes as did the animal's response to novel stimuli. A novel system of evaluating renal damage, which correlated to behavioral changes and organ damage, is described.     

Instrumental learning within the spinal cord. II. Evidence for central mediation

Rats spinally transected at the second thoracic vertebra can learn to maintain their leg in a flexed position if they receive legshock for extending the limb. These rats display an increase in the duration of a flexion response that minimizes net shock exposure. The current set of experiments was designed to determine whether the acquisition of this behavioral response is mediated by the neurons of the spinal cord (i.e., is centrally mediated) or reflects a peripheral modification (e.g., a change in muscle tension). Experiment 1 found that preventing information from reaching the spinal cord by severing the sciatic nerve blocked the acquisition of this behavioral response. Spinalized rats also failed to learn if the spinal cord was anesthetized with lidocaine during exposure to response-contingent shock (Experiment 2). Experiment 3 demonstrated that prior exposure to response-contingent shock on one hindleg facilitated acquisition of the response when subjects were later tested on the opposite leg. These findings suggest that acquisition of the instrumental response depends on neurons within the spinal cord.     

Evidence for chloride ions as intracellular messenger substances in astrocytes.

Cultured rat hippocampal astrocytes were used to investigate the mechanism underlying the suppression of Ba2+-sensitive K+ currents by GABAA receptor activation. Muscimol application had two effects on whole cell currents: opening of the well-known Cl- channel of the GABAA receptor and a secondary longer-lasting blockade of outward K+ currents displaying both peak and plateau phases. This blockade was independent of both Na+ (inside and outside) and ATP in the pipette. It also seemed to be independent of muscimol binding to the receptor because picrotoxin application showed no effect on the K+ conductance. The effect is blocked when anion efflux is prevented by replacing Cl- with gluconate (both inside and out) and is enhanced with more permeant anions such as Br- and I-. Moreover, the effect is reproduced in the absence of muscimol by promoting Cl- efflux via lowering of extracellular Cl- levels. These results, along with the requirement for Cl- efflux in muscimol experiments, show a strong dependency of the secondary blockade on Cl- efflux through the Cl- channel of the GABAA receptor. We therefore conclude that changes in the intracellular Cl- concentration alter the outward K+ conductances of astrocytes. Such a Cl--mediated modulation of an astrocytic K+ conductance will have important consequences for the progression of spreading depression through brain tissue and for astrocytic swelling in pathological situations.     

Reduced hypertension-induced end-organ damage in mice lacking cardiac and renal angiotensinogen synthesis

Hypertension-induced damage of kidney and heart is of major clinical relevance, but its pathophysiology is only partially understood. As there is considerable evidence for involvement of angiotensin II, we generated a new mouse model by breeding angiotensinogen (AOGEN) deficient mice with transgenic animals expressing the rat AOGEN gene only in brain and liver. This genetic manipulation overcame the hypotension of AOGEN-deficient mice and even caused hypertension indistinguishable in its extent from the parent transgenic mice with an intact endogenous AOGEN gene. In contrast to normal mice, however, crossbred animals lacked detectable expression of AOGEN in kidney and heart. As a consequence they showed markedly reduced cardiac hypertrophy and fibrosis. Furthermore, hypertension-induced alterations in kidney histology and function were less pronounced in crossbred mice than in equally hypertensive animals expressing AOGEN locally. The dysmorphogenesis observed in kidneys from AOGEN-deficient mice was absent in mice expressing this gene only in liver and brain. Our results support an important role of local AOGEN expression in hypertension-induced end-organ damage but not in the development of the kidney.     

Release of vasoactive substances from endothelial cells by shear stress and purinergic mechanosensory transduction

The evidence for release of vasoactive substances from endothelial cells in response to shear stress caused by the viscous drag of passing fluids is reviewed and, in particular, its physiological significance both in short-term regulation of blood vessel tone and in long-term regulation of cell growth, differentiation, proliferation, and cell death in pathophysiological conditions is discussed. A new concept of purinergic mechanosensory transduction, particularly in relation to nociception, is introduced. It is proposed that distension of tubes (including ureter, vagina, salivary and bile ducts, gut) and sacs (including urinary and gall bladders, and lung) leads to release of ATP from the lining epithelium, which then acts on P2X_2/3 receptors on subepithelial sensory nerves to convey information to the CNS.     

Evidence that hepatocytes can phagocytize exogenous substances.

Although the phagocytic action of Kupffer cells is well known, such a phenomenon has not been well documented for hepatocytes. Following the injection of a suspension of egg lecithin-coated silicon particles (0.5-1.5 microns in diameter) into the portal vein of rats, Kupffer cells showed minimal phagocytotic action, which was in contrast to the hepatocytes which displayed numerous phagocytized silicon particles. By comparison, when noncoated silicon particles of the same diameter as those that were coated were injected into the portal vein, the opposite observation was made. There was no uniformity in the ability of the hepatocytes to phagocytize either coated or noncoated particles from one lobule to another. Some showed active phagocytosis, while in others no evidence of such a process was observed. These data provide strong evidence for the selective phagocytic action of liver hepatocytes.     

Evidence for a humoral thymic factor in rabbits

Rabbits thymectomized between 12 and 36 hours after birth subsequently show reduced levels of circulating lymphocytes together with a lowered immunological response to human γ-globulin. These effects of thymectomy can, to a large extent, be prevented by means of intraperitoneal auto-transplants of thymus in a Millipore diffusion chamber. It appears possible that the epithelial-reticular cells of the transplant persist in the diffusion chamber and elaborate a humoral factor, or factors, which take part in the maturation of antibody-producing cells.     

Anxiety sensitivity and impairment: Evidence for a direct association and partial mediation by subclinical anxiety symptoms

Background

Mounting evidence suggests that specific psychological risk factors increase the likelihood for the development of anxiety psychopathology. Anxiety sensitivity (AS), the fear of the consequences of anxiety, is one such risk factor. However, very little is known about the consequences of having elevated AS prior to the development of diagnosable psychopathology. We hypothesized that elevated AS may create impairment among premorbid individuals. The aims of the present study were twofold. The first aim was to examine whether having elevated AS would be predictive of impairment in a nonclinical sample. The second aim was to examine whether subclinical anxiety symptoms would partially mediate the association between AS and impairment in daily life.

Method

These aims were examined in two studies utilizing samples of individuals with elevated levels of AS. Study 1 (N=387) and Study 2 (N=79) were comprised of participants with elevated AS. Participants completed a battery of questionnaires and a diagnostic interview to assess for risk status. Only participants without an anxiety disorder were eligible to participate in the study to ensure that they were in the premorbid stage.

Results

In Study 1, there was a direct effect of AS on impairment. Additionally, there was evidence for anxiety symptoms acting as a partial mediator in the relation between AS and impairment. Study 2 revealed the same pattern of results, with AS having a significant direct effect on impairment that was partially mediated by anxiety symptoms.

Limitations

The samples utilized in the present sample were primarily Caucasian females, thereby potentially limiting the generalizability of these findings.

Conclusions

This study provides evidence that a premorbid risk factor is associated with impairment before the actual development of an anxiety disorder. Implications of the present investigation and future directions are discussed.     

Enhancement of indomethacin-induced gastric damage by mouth breathing in rabbits

Previous studies have reported that mouth breathing is associated with respiratory acidosis. Regarding to the reports that renal elimination of weak acids such as indomethacin is pH dependent, this study was carried out to evaluate the role of mouth breathing on plasma level of indomethacin and indomethacin-induced gastric damage in rabbits. Mouth breathing was induced by surgical ligation of nostrils under general anesthesia. One day after the operation, arterial blood samples were collected for acid–base balance analysis and indomethacin was administered intraperitoneally in a single dose of 40 mg/kg. The animals were killed 4 h after indomethacin administration and blood samples were collected for spectrofluorometric determination of indomethacin in plasma. The results showed that indomethacin induces more severe gastric damage in nose obstructed rabbits compared with sham and unoperated (UNOP) animals. Acid–base analysis revealed a respiratory acidosis in nose obstructed rabbits and indomethacin level of plasma was significantly higher in nose obstructed animals in comparison with control rabbits. The study shows that mouth breathing can increase the potentiation of indomethacin-induced gastric mucosal damage that may be due to higher level of indomethacin in plasma of nose obstructed animals.     

Pulmonary damage caused by fluoride in rabbits during experimental fluorosis

The effect of fluoride on lung tissue was assessed in rabbits during experimental fluorosis. Sodium fluoride as 5, 10, 20 and 50 mg/kg body weight/day was injected subcutaneously for 100 days into rabbits of both sexes. The control animals were given 1 cc distilled water/kg body weight/day for the same period. Histological studies showed alveolar hemorrhage, necrosis of alveolar epithelium and bronchiolitis, followed by progressive exudation of oedema fluid, congestion, and hyperplasia of alveolar cell nuclei in treated animals. In animals of the 50 mg fluoride group, lung parenchyma had a distorted appearance with loss of alveolar architecture. The structural manifestations in pulmonary tissue were more progressive with the subsequent increase in the dosage of fluoride.     

大豆低聚糖和低聚肽对高脂血症大鼠血管活性物质和血液流变学的影响

目的探讨大豆低聚糖(SOS)和大豆低聚肽(SOP)对高脂血症大鼠血管活性物质和血液流变学的影响。方法60只健康成年SD大鼠随机分为5组:分别饲喂正常饲料(正常对照组,NCG),高脂饲料(高血脂模型组,HCG),高脂饲料 2%SOS(SOS组)、高脂饲料 3%SOP(SOP组)、高脂饲料 2%SOS 3%SOP(SOSP组)8周,测定大鼠血脂、血管活性物质PG I2、TXA2、NO和血液流变学指标。结果各实验组均能显著降低高脂血症大鼠血清TC、TG、LDL-C,升高HDL-C,改善血脂水平。同时升高PG I2、NO,降低TXA2和TXA2/PG I2比值,还能降低血黏度和红细胞压积,并以复合干预组效果最佳。结论SOS和SOP具有良好的调节血脂、影响血管活性物质生成和改善血液流变学的作用,以联合使用效果最为显著。     

Evidence of neuronal oxidative damage in Alzheimer's disease.

Oxidative stress has been proposed as a pathogenetic mechanism in Alzheimer's disease. One mechanism of oxidative damage is the nitration of tyrosine residues in proteins, mediated by peroxynitrite breakdown. Peroxynitrite, a reaction product of nitric oxide and superoxide radicals, has been implicated in N-methyl-D-aspartate receptor-mediated excitotoxic damage. Reported evidence of oxidative stress in Alzheimer's disease includes increased iron, alterations in protective enzymes, and markers of oxidative damage to proteins and lipids. In this report, we demonstrate the presence of nitrotyrosine in neurofibrillary tangles of Alzheimer's disease. Nitrotyrosine was not detected in controls lacking neurofibrillary tangles. Immunolabeling was demonstrated to be specific nitrotyrosine in a series of control experiments. These observations link oxidative stress with a key pathological lesion of Alzheimer's disease, the neurofibrillary tangle, and demonstrate a pathogenetic mechanism in common with the other major neurodegenerative diseases of aging, Parkinson's disease and amyotrophic lateral sclerosis. These findings further implicate nitric oxide expression and excitotoxicity in the pathogenesis of cell death in Alzheimer's disease.     

Evidence of genotoxic damage in human cataractous lenses.

Lens epithelial fragments (tags) recovered from individuals during routine cataract extraction have been assessed for cellular changes reflective of genotoxic damage. A high percentage of tags exhibited a population of micronucleated and polyploid cells. The presence and number of micronuclei (MN) in the epithelia of cataract patients appears to be independent of age and sex. However, a large number of MN in the epithelial cells of some individuals strongly suggests a history of compromised genomic integrity. While the study was not designed to define the role of DNA damage in the development of cataracts or to monitor human populations at risk of exposure to exogenous mutagens/cataractogens, the potential of the methodology to address each is demonstrated.