The effects of spinal anesthesia on the circulation in normal unoperated man with reference to the autonomy of the arterioles and especially those of the renal circulation

The present study, comprising observations on 21 subjects given high spinal anesthesia, is an investigation of the effects of anesthetic denervation in normal man, uncomplicated by surgical intervention, on the circulation with particular reference to the vascular bed of the kidney. It is concluded that the renal arterioles are distinctly autonomous, in the sense that under basal conditions the renal vascular tone is not affected by anesthetic denervation. Our observations further suggest that the arteriolar bed generally (apart from the skin) possesses considerably more autonomy than is usually attributed to it-sufficient, in fact, in the normal supine individual at rest, to maintain an essentially normal arterial pressure. We find no evidence of significant arteriolar dilatation during high spinal anesthesia, such reduction in blood pressure as occurs being attributable, we believe, to diminished circulating blood volume in consequence of dilatation of the capillaries, venules, and veins. Part I deals with the following topics: (1) Methods; (2) the effects of spinal anesthesia on renal blood flow; (3) on the arterial pressure, and (4) on the reflex responses to posture, hypercapnia, and anoxemia. Part II consists of a review of the evidence on (5) the existence of tonic vasoconstrictor activity and on (6) the existence of autonomy in the peripheral arterioles generally, and (7) in the kidney in particular, and (8) the peripheral effects of hypercapnia and anoxemia. In (5) it is brought out that the notion of tonic vasoconstrictor activity in the sympathetic nervQus system, apart from the skin, is based largely upon animal experiments which are seriously complicated by general anesthesia, venous dilatation, etc., and that the information so obtained cannot be transferred with confidence to normal animals, and certainly not to man. PART I Methods The subjects were male convalescent patients ranging in age from 18 to 50 years who, with a single exception, presented no abnormal signs contraindicating selection for this study. They were examined in the morning in the basal, fasting condition, and were prepared for the measurement of renal blood flow and filtration rate by the clearance method, as described by Smith, Goldring, and Chasis (93). In the earlier observations the phenol red and inulin (35) clearances were followed, but after the introduction of the diodrast clearance (93), all three clearances were used. The phenol red clearance serves as a check on the diodrast clearance, the constancy of the phenol red/diodrast clearance ratio before and after anesthesia demonstrating that procaine per se has no effect upon the tubular excretory mechanism. The infusions corresponded to the typical infusion cited by Chasis, Ranges, Goldring, and Smith (18). Zero time was taken as the beginning of the priming infusion, which occupied about 10 minutes; the infusion was then changed to the sustaining infusion, the first urine collection period being started at about 30 minutes. The sustaining infusion was usually interrupted momentarily to permit injection of the anesthetic, and a short washout period was allowed to reestablish blood levels of diodrast, etc. before the next urine collection period was started. The urine collection periods (10 to 15 minutes in length) were timed to 15 seconds, and all urine samples were collected by catheter with sterile precautions, the bladder being washed out with 20 cc. of saline. (In our opinion, single urine collection periods obtained by voluntary voiding, or even by catheterization without rinsing the bladder, may be highly inaccurate; we have made nearly 3000 catheterized and rinsed collections, and we recognize that it is impossible even by this method to empty the bladder completely every time.) All our observations have been made on the descending limb of water diuresis, and to prevent an excessive reduction of urine flow we have 31

Immunoregulatory Mechanisms Underlying Prevention of Colitis-Associated Colorectal Cancer by Probiotic Bacteria

Background: Inflammatory bowel disease (IBD) increases the risk of colorectal cancer. Probiotic bacteria produce immunoregulatory metabolites in vitro such as conjugated linoleic acid (CLA), a polyunsaturated fatty acid with potent anticarcinogenic effects. This study aimed to investigate the cellular and molecular mechanisms underlying the efficacy of probiotic bacteria in mouse models of cancer. Methodology/Principal Findings: The immune modulatory mechanisms of VSL#3 probiotic bacteria and CLA were investigated in mouse models of inflammation-driven colorectal cancer. Colonic specimens were collected for histopathology, gene expression and flow cytometry analyses. Immune cell subsets in the mesenteric lymph nodes (MLN), spleen and colonic lamina propria lymphocytes (LPL) were phenotypically and functionally characterized. Mice treated with CLA or VSL#3 recovered faster from the acute inflammatory phase of disease and had lower disease severity in the chronic, tumor-bearing phase of disease. Adenoma and adenocarcinoma formation was also diminished by both treatments. VSL#3 increased the mRNA expression of TNF-a, angiostatin and PPAR c whereas CLA decreased COX-2 levels. Moreover, VSL#3-treated mice had increased IL-17 expression in MLN CD4+ T cells and accumulation of Treg LPL and memory CD4+ T cells. Conclusions/Significance: Both CLA and VSL#3 suppressed colon carcinogenesis, although VSL#3 showed greater anticarcinogeni

Murine and Bovine γδ T Cells Enhance Innate Immunity against Brucella abortus Infections

γδ T cells have been postulated to act as a first line of defense against infectious agents, particularly intracellular pathogens, representing an important link between the innate and adaptive immune responses. Human γδ T cells expand in the blood of brucellosis patients and are active against Brucella in vitro. However, the role of γδ T cells in vivo during experimental brucellosis has not been studied. Here we report TCRδ−/− mice are more susceptible to B. abortus infection than C57BL/6 mice at one week post-infection as measured by splenic colonization and splenomegaly. An increase in TCRγδ cells was observed in the spleens of B. abortus-infected C57BL/6 mice, which peaked at two weeks post-infection and occurred concomitantly with diminished brucellae. γδ T cells were the major source of IL-17 following infection and also produced IFN-γ. Depletion of γδ T cells from C57BL/6, IL-17Rα−/−, and GMCSF−/− mice enhanced susceptibility to B. abortus infection although this susceptibility was unaltered in the mutant mice; however, when γδ T cells were depleted from IFN-γ−/− mice, enhanced susceptibility was observed. Neutralization of γδ T cells in the absence of TNF-α did not further impair immunity. In the absence of TNF-α or γδ T cells, B. abortus-infected mice showed enhanced IFN-γ, suggesting that they augmented production to compensate for the loss of γδ T cells and/or TNF-α. While the protective role of γδ T cells was TNF-α-dependent, γδ T cells were not the major source of TNF-α and activation of γδ T cells following B. abortus infection was TNF-α-independent. Additionally, bovine TCRγδ cells were found to respond rapidly to B. abortus infection upon co-culture with autologous macrophages and could impair the intramacrophage replication of B. abortus via IFN-γ. Collectively, these results demonstrate γδ T cells are important for early protection to B. abortus infections