Biomedical subjects
Publications and source records attributed to P Ruiz.
Social and cultural issues may have a profound impact on different populations' responses to the AIDS epidemic. To maximize their own effectiveness, clinicians need to be aware of special needs and concerns.
Cyclosporine A (CyA) nephrotoxicity is associated with impaired renal hemodynamic function and increased production of the vasoconstrictor eicosanoid thromboxane A2 (TxA2). In CyA toxic rats, renal dysfunction can be partially reversed by inhibitors of thromboxane synthase. However, interpretation of these results is complicated since inhibition of thromboxane synthase may cause accumulation of prostaglandin endoperoxides that can act as partial agonists at the TxA2 receptor and may blunt the efficacy of treatment. Furthermore, these endoperoxides may be used as substrate for production of vasodilator prostaglandins causing beneficial effects on hemodynamics which are independent of thromboxane inhibition. To more specifically examine the role of TxA2 in CyA toxicity, we investigated the effects of the thromboxane receptor antagonist GR32191 on renal hemodynamics in a rat model of CyA nephrotoxicity. In this model, administration of CyA resulted in a significant decrease in glomerular filtration rate (GFR) (2.85 +/- 0.26 [CyA] vs 6.82 +/- 0.96 ml/min/kg [vehicle]; p less than 0.0005) and renal blood flow (RBF) (21.65 +/- 2.31 [CyA] vs 31.87 +/- 3.60 ml/min/kg [vehicle]; p less than 0.025). Renal vascular resistance (RVR) was significantly higher in rats given CyA compared to animals treated with CyA vehicle (5.32 +/- 0.55 [CyA] vs. 3.54 +/- 0.24 mm Hg/min/ml/kg [vehicle]; p less than 0.05). These renal hemodynamic alterations were associated with a significant increase in urinary excretion of unmetabolized, "native" thromboxane B2 (TxB2) (103 +/- 18 [CyA] vs 60 +/- 16 pg/hour [vehicle]; p less than 0.05). Only minimal histomorphologic changes were apparent by light microscopic examination of kidneys from both CyA and vehicle treated animals. However, with immunoperoxidase staining, a significantly greater number of cells expressing the rat common leukocyte antigen was found in the renal interstitium of rats given CyA. There was no detectable increase in monocytes/macrophages in the kidneys of CyA toxic animals. In rats treated with CyA, intraarterial infusion of GR32191 at maximally tolerated doses significantly increased GFR and RBF, and decreased RVR. Although both RBF and RVR were restored to levels not different from controls, GFR remained significantly reduced following administration of GR32191. These data suggest that the potent vasoconstrictor TxA2 plays an important role in mediating renal dysfunction in CyA nephrotoxicity. However, other factors may be important in producing nephrotoxicity associated with CyA.
The effects of pre- and posttransplant immunization on graft survival, infiltrate intensity, and host in situ/systemic cellular immune responsiveness were examined for class I MHC-disparate rat renal allograft recipients. Naive, unsensitized PVG (RT1c) recipients of class I MHC disparate PVG.R1 (RT1.Aa on PVG background) orthotopic kidney transplants displayed long-term (greater than 50 days) survival (LTS) in a majority (41/52) of cases. Pretransplant immunization of recipients with a PVG.R1 skin graft most often resulted in rejection (mean survival greater than 21.3 days) with 8/15 rats surviving less than or equal to 2 weeks and only 3/15 with LTS. Pretransplant immunization with a skin graft from a fully MHC-disparate PVG.1A (RT1a on PVG background) donor resulted in acute rejection (mean = 6.1 days) with 0/8 rats surviving greater than or equal to 2 weeks. Donor-specific class I and II disparate (PVG.1A), and third-party (LEW) skin transplants applied on LTS (greater than 50 days) PVG.R1 kidney graft recipients showed typical 1st- and accelerated 2nd-set skin graft rejection, but had no effect on kidney graft survival. In contrast, 6/7 LTS PVG.R1 kidney graft recipients accepted PVG.R1 skin grafts indefinitely following their transient partial rejection. Histologic analysis of kidney allografts revealed the highest degree of mononuclear cell infiltrates in animals specifically sensitized by PVG.1A skin grafts prior to transplant. Donor class I-specific cytotoxic T lymphocyte precursor (pCTL) frequencies, as determined by limiting dilution assays, were increased and equivalent at 1 week posttransplant in kidney allograft cell eluates from nonrejecting naive recipients (1/127-1/2209) and rejecting presensitized animals (1/470-1/7848). LTS animals had decreased intragraft pCTL at greater than 50 days (1/2969-1/61875), as did LTS at greater than 50 days that received PVG.R1, PVG.1A, or LEW skin grafts posttransplant. In all groups, splenocyte pCTL frequencies were significantly lower than the corresponding values within the allograft. By comparison, no significant differences in intragraft or splenic proliferative T lymphocyte (pPTL) precursor frequencies were observed between any groups. These results indicate that unsensitized recipients of class I-disparate renal cells grafts are capable of maintaining graft survival in the early posttransplant period, despite the presence of significant in situ antidonor class I MHC-specific cellular immune responsiveness. These findings also indicate that long-surviving PVG recipients of class I-disparate renal allografts develop specific functional tolerance to donor class I alloantigens, that may be associated with a diminished frequency of anti-class I cytotoxic (but not proliferative) T cell precursors.
The present study analyzed the concentration of renin-like activity and angiotensinogen concentration (AoC) in different brain areas related to cardiovascular control in SHR and Wistar Kyoto (WKY) animals. Male rats of both strains were studied at 8, 16 and 30 weeks of age. The following brain areas were isolated: anterior, medial and posterior hypothalamus, septal area, periaqueductal gray (PG) and the remaining brain stem; nucleus tractus solitarius (NTS) and the remaining medulla oblongata. Plasma renin activity (PRA) and plasma and cerebrospinal fluid (CSF) AoC were determined. Renin-like concentration was higher in SHR than in WKY in the anterior hypothalamus, PG and NTS at different stages of hypertension development. AoC was also higher in some areas of the SHR brain during different periods. PRA, plasma and CSF angiotensinogen concentration showed significant differences between both strain of rats during the development of high blood pressure. Present data support the possibility that the central and peripheral renin-angiotensin system may participate in the maintenance of high blood pressure in the SHR animals.
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Late gestation is associated with insulin resistance in rats and humans. It has been reported that rats at term gestation show active hepatic gluconeogenesis and glycogenolysis, and diminished lipogenesis, despite normal or mildly elevated plasma insulin concentrations, indicating a state of resistance to the hormone action. Since autophosphorylation of the insulin receptor has been reported to play a key role in the hormone signal transduction, we have partially purified plasma-membrane liver insulin receptors from virgin and 22-day-pregnant rats and studied their binding and kinase activities. (1) Insulin binding to partially purified receptors does not appear to be influenced by gestation, as indicated by the observed KD and Bmax. values. (2) The rate of autophosphorylation and the maximal 32P incorporation into the receptor beta-subunit from pregnant rats at saturating concentrations of insulin are markedly decreased with respect to the corresponding values for virgin rats. (3) The diminished autophosphorylation rate was due to a decreased responsiveness of the kinase activity to the action of insulin. (4) Phosphorylation of the exogenous substrates casein and poly(Glu80Tyr20) by insulin-receptor kinase was also less when receptors from pregnant rats were used. These results show the existence of an impairment at the receptor kinase level of the insulin signalling mechanism that might be related to the insulin-resistant state characteristic of term gestation in rats.
To determine the genetic requirements for the development of inflammatory arthritis in MRL-lpr/lpr mice, clinical, serologic, and pathologic features of lpr/lpr and +/+ mice of MRL, B6, C3H, and AKR strains were studied. Arthritis was evaluated by histopathologic examination of the knee joint, while sera were tested for the presence of rheumatoid factor (RF) and anti-DNA activity by ELISA. Of the strains tested to age 7 months, only the MRL-lpr/lpr mice developed histologic evidence of arthritis. All lpr mice, however, produced both IgM RF and IgG RF, although amounts varied among strains. These results indicate that the lpr gene as well as another gene(s) in the MRL background are necessary for the development of inflammatory arthritis and that this lesion may be independent of RF production.
The relative potencies of a series of substance P (6-11) analogues have been determined for spasmogenic activity in the guinea pig ileum in vitro and for potentiation of electrically evoked contractions in the rat vas deferens in vitro. ED50 values were determined for the new analogues. Substance P and its methyl ester were used as standard agonists. Substitution of Gly9 by Pro on [Glu6]SP(6-11) increased four times the activity on the NK-1 receptor. The glycosilation of [Glu6]SP(6-11) by the incorporation of a beta-D-glucopyranosyl amide residue on the gamma-carboxyl group of Glu6 reduced both the activity and selectivity. The simultaneous substitution of Gly9 by Pro and the incorporation of a monosaccharide moiety on the gamma-carboxyl of Glu6 on [Glu6]SP(6-11) yielded an analogue with 60-fold enhanced selectivity relative to substance P for the NK-1 receptor. These results may indicate that the critical factor providing potency to SP(6-11) analogues is mostly related to conformational rather than hydrophilicity aspects of the molecular structure.
Increased production of thromboxane (TX) by rejecting renal allografts results in significant and partially reversible renal vasoconstriction. In this study, we evaluated the potential benefit of chronically administering the TX synthetase inhibitor OKY-046 from the time of transplantation in a rat model of acute renal allograft rejection. In animals which received 75 mg/kg/day of OKY-046 by intermittent i.p. injection, allograft function was not improved, but renal thromboxane production was not significantly inhibited. However, animals which received an equivalent dose of OKY-046 by continuous intra-arterial infusion for four days maintained clearances of inulin (4.46 +/- 0.79 ml/min/kg) and PAH (23.86 +/- 1.81 ml/min/kg) at normal levels not different from non-rejecting isografts (4.83 +/- 0.93 and 18.33 +/- 2.55 ml/min/kg, respectively). In contrast, animals which received continuous infusion of saline vehicle alone developed a significant reduction in renal function (CIn: 1.58 +/- 0.27 ml/min/kg; CPAH: 9.12 +/- 1.51 ml/min/kg) by the fourth day after transplantation. Intra-arterial infusion of OKY-046 significantly reduced four-day allograft TXB2 production, as well as urinary TXB2 excretion, but had no effect on allograft production of PGE2 or 6-keto-PGF1 alpha. Despite the beneficial effects on allograft function, OKY-046 neither altered the morphologic appearance of the cellular infiltrate nor the systemic proliferative and cytotoxic anti-donor cellular immune responses. Six days following transplantation, renal TXB2 production was only partially inhibited in animals given continuous infusions of OKY-046, and remained markedly elevated. This partial inhibition of TX production resulted in a slight but insignificant functional improvement.(ABSTRACT TRUNCATED AT 250 WORDS)
The aims of this work were to investigate the possible effect of several antimicrobial agents alone and in combinations against 190 clinical isolates of Mycobacterium tuberculosis and 30 isolates of Mycobacterium avium, 30 Mycobacterium fortuitum and 30 Mycobacterium chelonei. The susceptibility was determined in Müller-Hinton agar and Middlebrook 7H 10 agar. For interpretation of the results the minimum inhibitory concentration (MIC) was determined and for the combinations of antimicrobials we used the Fractional Inhibitory Concentration Index (FIC). The possible clinical efficacy was determined by the Inhibitory Quotient. The synergistic effect of several combinations of these compounds was demonstrated.
Psychiatric disorders associated with human immunodeficiency virus (HIV) infection are increasingly prevalent. The psychologic, sociocultural, and medicolegal dimensions of HIV disease further fragment and complicate the care of these individuals. This article reviews the psychiatric aspects of HIV disease and suggests practical approaches to management and patient care.
A linear specular reflection simulating a membrane was visualized along the back of the neck on sonograms of ten normal fetuses ranging in age from 10 to 14 menstrual weeks. Follow-up ultrasound studies of eight of the fetuses and postpartum clinical examinations of all subjects were normal, revealing no evidence of neck abnormalities. Although this pseudomembrane is similar in appearance to published examples of early cystic hygroma, it is a normal finding that can be distinguished from early cystic hygroma on the basis of its less bulbous appearance and the absence of underlying septations. This structure corresponds in distribution to the skin along the back of the fetus and likely represents a specular reflection from the skin surface.
Acquired immune deficiency syndrome (AIDS) and related disorders are increasingly and unsettlingly prevalent. The authors describe neuropsychiatric, psychosocial, and ethical-legal problems associated with HIV infections that are commonly encountered in a consultation-liaison psychiatry setting. Because of HIV's potential for undermining cognitive function, they recommend a systematic neurobehavioral assessment for the differential diagnosis of emotional disturbance, including a test battery that also identifies neurotoxic effects of pharmacological agents. Among significant psychosocial and ethical-legal problems are patient's reactions to AIDS, their fears of social abandonment, staff burn-out, antibody testing, confidentiality, and the use of life-support measures. The consultation-liaison psychiatrist's awareness of the complexities of HIV-related neuropsychiatric symptoms and psychosocial issues can be of enormous benefit to medical caregivers and to the patients themselves.
The aim of this study was to evaluate the components of the renin-angiotensin system in the periphery and in the central nervous system (CNS) of the spontaneous hypertensive rats (SHR). On the other hand, the norepinephrine (NE) content of the different areas and of the mesenteric artery were also measured. Sixteen SHR and 9 Wistar Kyoto (WKY) control animals were used at about 6 months of age. Blood and cerebrospinal fluid (CSF) samples were collected. The brain was dissected into several areas and the mesenteric artery was excised. Plasma renin activity (PRA), plasma angiotensinogen concentration (P1AoC), brain renin (RC) and angiotensinogen concentrations (AoC) were evaluated by radioimmunoassay. NE was determined in all the tissues by a fluorimetric technique. PRA, P1AoC and NE concentration in the mesenteric artery were similar in both groups. An increase in the NE content of the cerebellum was detected in the SHR without changes in the other areas of the CNS. AoC was decreased in the CSF and in the brain stem of the SHR animals. RC was evaluated in the hypothalamus, brain stem, cerebral cortex and cerebellum of the same strain of rats. These results seem to indicate the some alteration of the peptidergic system in the CNS is present in the hypertensive animals.
Linitis plastica carcinoma of the colon and rectum is a relatively rare primary colorectal malignancy. The initial diagnosis of this disease is often difficult, and its eventual prognosis is poor. In this report, we describe a case of primary linitis plastica of the rectum in a 57-yr-old American Indian. This case is unique since it represents the first documentation of a primary rectal lesion with metastases to the stomach. The current literature is reviewed with examination of the clinicopathologic features of this neoplasm.
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