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Biomedical subjects

A Morales

Publications and source records attributed to A Morales.

At least 127 records · Page 7Linked to original sources
PubMed1997

Possible new autosomal recessive syndrome of partial agenesis of the corpus callosum, pontine hypoplasia, focal white matter changes, hypotonia, mental retardation, and minor anomalies.

We describe a brother and sister with severe developmental delay, hypotonia, partial agenesis of the corpus callosum, pontine hypoplasia, focal white matter degenerative abnormalities, macrocrania, frontal bossing, deep-set eyes, and hypertelorism. The brother also had Duane syndrome type II and an ectopic right ureter. The coexistence of these multiple physical and brain abnormalities in a brother and sister suggests a new autosomal recessive syndrome with a slowly progressive course.

Abnormalities, Multiple↗
PubMed1997

Tumor necrosis factor increases hepatocellular glutathione by transcriptional regulation of the heavy subunit chain of gamma-glutamylcysteine synthetase.

Tumor necrosis factor (TNF) is an inflammatory cytokine that causes cell injury by generation of oxidative stress. Since glutathione (GSH) is a key cellular antioxidant that detoxifies reactive oxygen species, the purpose of our work was to examine the regulation of cellular GSH, the expression of heavy subunit chain of gamma-glutamylcysteine synthetase (gamma-GCS-HS), and control of intracellular generation of reactive oxygen species in cultured rat hepatocytes treated with TNF. Exposure of cells to TNF (10,000 units/ml) resulted in depletion of cellular GSH levels (50-70%) and overproduction of hydrogen peroxide (2-3-fold) and lipid peroxidation. However, cells treated with lower doses of TNF (250-500 units/ml) exhibited increased levels of GSH (60-80% over control). TNF treatment increased (70-100%) the levels of gamma-GCS-HS mRNA, the catalytic subunit of the regulating enzyme in GSH biosynthesis. Furthermore, intact nuclei isolated from hepatocytes treated with TNF transcribed the gamma-GCS-HS gene to a greater extent than control cells, indicating that TNF regulates gamma-GCS-HS at the transcriptional level. The capacity to synthesize GSH de novo determined in cell-free extracts incubated with GSH precursors was greater (50-70%) in hepatocytes that were treated with TNF; however, the activity of GSH synthetase remained unaltered by TNF treatment indicating that TNF selectively increased the activity of gamma-GCS. Despite activation of nuclear factor-kappaB (NF-kappaB) by TNF, this transcription factor was not required for TNF-induced transcription of gamma-GCS-HS as revealed by deletion constructs of the gamma-GCS-HS promoter subcloned in a chloramphenicol acetyltransferase reporter vector and transfected into HepG2 cells. In contrast, a construct containing AP-1 like/metal response regulatory elements increased chloramphenicol acetyltransferase activity upon exposure to TNF. Thus, TNF increases hepatocellular GSH levels by transcriptional regulation of gamma-GCS-HS gene, probably through AP-1/metal response element-like binding site(s) in its promoter, which may constitute a protective mechanism in the control of oxidative stress induced by inflammatory cytokines.

Animals↗
PubMed1997

Functional incorporation of P-glycoprotein into Xenopus oocyte plasma membrane fails to elicit a swelling-evoked conductance.

Microinjecton of Xenopus oocytes with P-glycoprotein-containing membranes from multidrug resistant cells following a recently published procedure resulted in the transplantation of the protein to the plasma membrane of the oocytes and was confirmed by Western blot analysis. These oocytes showed a reduced intracellular accumulation of daunomycin, when compared to uninjected oocytes or to those injected with membrane vesicles lacking P-glycoprotein, thus indicating that the protein had been incorporated in a transport-competent form. On the other hand, transplantation of P-glycoprotein to the oocyte membrane did not significantly change either the appearance or the properties of swelling-elicited membrane conductance with respect to those determined in oocytes either uninjected or injected with membranes lacking P-glycoprotein. These results do not support a role for P-glycoprotein as a swelling-activated chloride channel.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Direct effect of ceramide on the mitochondrial electron transport chain leads to generation of reactive oxygen species. Role of mitochondrial glutathione.

Ceramide is a sphingolipid that is generated in the signaling of inflammatory cytokines such as tumor necrosis factor (TNF), which exerts many functional roles depending on the cell type where it is produced. Since TNF cytotoxicity is mediated by overproduction of reactive oxygen species from mitochondria, we have examined the role of ceramide in generation of oxidative stress in isolated rat liver mitochondria. The present studies demonstrate that addition of N-acetylsphingosine (C2-ceramide) to mitochondria led to an increase of fluorescence of dihydrorhodamine 123 or dichlorofluorescein-stained mitochondria, indicating formation of hydrogen peroxide. Such effect was significant at 0.25 microM and maximal at 1-5 microM C2, decreasing at greater concentrations. This inductive effect of ceramide was mimicked by N-hexanoylsphingosine at the same concentration range, whereas the immediate precursor of C2, C2-dihydroceramide increased hydrogen peroxide at 1-5 microM. Sphingosine generated hydrogen peroxide at concentrations >/=10 microM, whereas diacylglycerol failed to increase hydrogen peroxide. The increase in hydrogen peroxide induced by C2 was not triggered by mitochondrial permeability transition as C2 did not induce mitochondrial swelling. Blocking electron transport chain at complex I and II prevented the increase in hydrogen peroxide induced by C2; however, interruption of electron flow at complex III by antimycin A potentiated the inductive effect of C2. Depletion of matrix GSH prior to exposure to ceramide resulted in a potentiated increase (2-fold) of hydrogen peroxide generation, leading to lipid peroxidation and loss of activity of respiratory chain complex IV compared with GSH-repleted mitochondria. Mitochondria isolated from TNF-treated cells showed an increase (2-3-fold) in the amount of ceramide compared with mitochondria from untreated cells. These results suggest that mitochondria are a target of ceramide produced in the signaling of TNF whose effect on mitochondrial electron transport chain leads to overproduction of hydrogen peroxide and consequently this phenomena may account for the generation of reactive oxygen species during TNF cytotoxicity.

Animals↗
PubMed1997

Suppression of collagen-induced arthritis through adenovirus-mediated transfer of a modified tumor necrosis factor alpha receptor gene.

OBJECTIVE: To evaluate the efficacy of systemic and intraarticular adenoviral transfer of a modified tumor necrosis factor alpha receptor (TNF alphaR) gene and its expression in rat collagen-induced arthritis (CIA). METHODS: Rats with CIA received injections of replication-deficient adenovirus containing either a TNF alpha inhibitor (TNFI) gene or a control beta-galactosidase (beta-gal) gene. The TNFI gene codes for a fusion protein consisting of the human 55-kd TNF alphaR and a mouse IgG heavy chain. Successful gene transfer was determined by serum TNF alphaR measurements and by histologic examination of injected joints with in situ blue staining. RESULTS: Serum TNF alphaR levels were detectable for 8 days following systemic TNFI gene transfer. CIA severity was significantly suppressed by TNFI gene transfer, both prior to and following arthritis onset (P = 0.0001, by repeated-measures 2-factor analysis of variance). Direct synovial TNFI gene transfer was successful, but induced an inflammatory response without any net TNFI benefit. CONCLUSION: Systemic adenoviral-mediated transfer of the TNFI gene suppressed CIA during its transitory expression. Intraarticular gene transfer was limited by an adenoviral synovitis that was not overcome by delivery of the TNFI gene. TNFI is an excellent protein candidate for further therapeutic study.

Adenoviridae↗
PubMed1997

Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanol-treated rats: effect of membrane physical properties and S-adenosyl-L-methionine.

Ethanol intake depletes the mitochondrial pool of reduced glutathione (GSH) by impairing the transport of GSH from cytosol into mitochondria. S-Adenosyl-L-methionine (SAM) supplementation of ethanol-fed rats restores the mitochondrial pool of GSH. The purpose of the current study was to determine the effect of ethanol feeding on the kinetic parameters of mitochondrial GSH transport, the fluidity of mitochondria, and the effect of SAM on these changes. Male Sprague-Dawley rats were fed ethanol-liquid diet for 4 weeks supplemented with either SAM or N-acetylcysteine (NAC). SAM-supplementation of ethanol-fed rats restored the mitochondrial GSH pool but NAC administration did not. Kinetic studies of GSH transport in isolated mitochondria revealed two saturable, adenosine triphosphate (ATP)-stimulated components that were affected significantly by chronic ethanol feeding: lowering Vmax (0.22 and 1.6 in ethanol case vs. 0.44 and 2.7 nmol/15 sec/mg protein in controls) for both low and high affinity components with the latter showing an increased Km (15.5 vs. 8.9, mmol/L in ethanol vs. control). Mitochondria from SAM-supplemented ethanol-fed rats showed kinetic features of GSH transport similar to control mitochondria. Determination of membrane fluidity revealed an increased order parameter in ethanol compared with control mitochondria, which was restricted to the polar head groups of the bilayer and was prevented by SAM but not NAC supplementation of ethanol-fed rats. The changes elicited in mitochondria by ethanol were confined to the inner membrane; mitoplasts from ethanol-fed rats showed features similar to those of intact mitochondria such as impaired transport of GSH and increased order parameter. A different mitochondrial transporter, adenosine diphosphate (ADP)/ATP translocator, was unaffected by ethanol feeding. Furthermore, fluidization of mitochondria or mitoplasts from ethanol-fed rats by treatment with a fatty acid derivative restored their ability to transport GSH to control levels. Thus, ethanol-induced impaired transport of GSH into mitochondria is selective, mediated by decreased fluidity of the mitochondrial inner membrane, and prevented by SAM treatment.

Acetylcysteine↗
PubMed1997

Membrane currents in immature oocytes of the Rana perezi frog.

Immature oocytes of the Rana perezi frog were studied electrophysiologically to see if some of the unusual ionic channels found in Xenopus oocytes were also expressed in these cells. Growing oocytes showed a fairly linear current/voltage relationship (from -200 to +60 mV), whereas fully grown cells had several voltage-dependent conductances. Depolarizing pulses elicited a potassium current blocked by tetraethylammonium (TEA) and two kinetically different Ca2+-dependent Cl- currents (ICl(Ca)), both sensitive to niflumic acid. ICl(Ca), which have not been previously observed in Rana immature oocytes, were also found in response to acetylcholine or rabbit serum superfusion or intracellular injection of Ca2+. In addition, three different Cl- currents were activated in these cells by hyperpolarization: (1) a transient inward current dependent on a critical intracellular Ca2+ concentration; (2) an inward rectifier Cl- current, which was Ca2+ independent; and (3) a high threshold (over -140 mV), slow Cl- current, blocked by several divalent cations, 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and 4-acetamido-4-isothiocyanatostilbene-2, 2'-disulphonic acid (SITS). The presence of most of these infrequent currents in immature oocytes of several frogs and toads suggests that they are not merely the result of random genomic expression but a programmed decision, probably related to a definite functional role.

Animals↗
PubMed1997

Testosterone supplementation for hypogonadal impotence: assessment of biochemical measures and therapeutic outcomes.

PURPOSE: Although hypogonadism is a rare cause of erectile failure, impotent men are frequently treated with supplemental androgens. The results of such treatment and the individual merits of available formulations remain controversial. A series of hypogonadal men participated in a trial of oral testosterone undecanoate to assess the effectiveness of the medication, and use of biochemical and clinical outcome measures. MATERIALS AND METHODS: A consecutive sample of 23 hypogonadal impotent men received testosterone undecanoate orally for no less than 60 days. Serum levels of gonadotropins, testosterone, estrogens and sex hormone-binding globulin were measured before, during and after the trial. Sexual response and feeling of well-being were measured by daily diaries and visual analogue scales. RESULTS: Testosterone undecanoate produced restoration of plasma testosterone levels in all patients but a measurable improvement in sexual attitudes and performance in only 61%. Visual analogue scores were effective discriminants of the therapeutic response but none of the conventional biochemical measures predicted or correlated with clinical outcome. CONCLUSIONS: Testosterone undecanoate is an effective agent for treating hypogonadism. In hypogonadal impotent patients the most appropriate outcome measure for androgen supplementation is individual response to therapy, while conventional biochemical hormone determinations lack predictive value and fail to correlate with response.

Adult↗
PubMed1997

Rapid detection of bladder cancer: a comparative study of point of care tests.

PURPOSE: We assessed sensitivity, specificity, accuracy, positive predictive value and negative predictive value of the bladder tumor antigen (Bard BTA), fibrinogen/fibrin degradation products (AuraTek FDP), urinary cytology and hemoglobin dipstick tests in the urine of patients presenting to a urology clinic. MATERIALS AND METHODS: A total of 130 patients (60 with bladder cancer) provided a urine sample, which was divided into appropriate aliquots for each of the tests cited above. The endoscopist, pathologist, cytologist and the person performing the BTA/FDP/hemoglobin dipstick were blinded as to the results of the other tests, and the tests were read independently by a second blinded evaluator. RESULTS: Comparative results demonstrate a clear superiority of FDP in sensitivity (81%) and overall accuracy in bladder cancer detection (p = 0.0001) while cytology and BTA were marginally better than FDP in specificity. CONCLUSIONS: The anticipated lack of specificity of the hemoglobin dipstick was confirmed as well as the inadequacy of urinary cytology, particularly in the well differentiated tumors. Our findings with BTA were disappointing. The superiority of the FDP, first demonstrated here, was particularly striking in its ability to detect even well differentiated tumors. The simplicity and significantly better overall performance of FDP make it a reliable test for detection of transitional cell carcinoma of the bladder and a potential alternative to urinary cytology with important implications for clinical practice and health economics.

Aged↗
PubMed1997

An uncommon urologic presentation of a supernumerary breast.

Polythelia and polymastia are common developmental abnormalities of the breast and nipple which usually present as small lesions along the mammary line, an embryologic line that extends bilaterally from the axillary regions to the inguinal ligaments. These lesions have been reported in various locations outside the mammary line. We report an unusual location of polymastia in the perineum of a newborn male. A brief discussion of the clinical relevance of such lesions is also included.

Breast↗
PubMed1997

Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis.

OBJECTIVES: On the assumption that interstitial cystitis (IC) is the result of a defective mucous lining of the bladder epithelium, a study was carried out to investigate the activity of hyaluronic acid (HA) in the treatment of IC. HA is an important glycosaminoglycan (GAG) present in all connective tissues, including the GAG layer of the vesical mucosa. It exhibits a variety of pharmacologic properties that enhance its appeal for the therapy of IC. METHODS: A total of 25 patients, with the characteristic picture of IC and refractory to other medical treatments, participated in a trial of HA. Patients received 40 mg of HA intravesically on a weekly basis for 4 weeks, then monthly. Response to therapy was evaluated by symptom score, voiding diaries, and visual analog scales. RESULTS: An initial positive (complete+partial) response of 56% at week 4 increased to 71% by week 12. This response was maintained until week 20; beyond week 24 there appears to be a moderate decrease in the effectiveness of the medication. There was no significant toxicity attributable to the presence of HA in the bladder. CONCLUSIONS: The response of refractory IC patients to the intravesical administration of HA was gratifying. In the past, many therapies for IC that were initially considered promising failed the test of a controlled study. Further studies will establish the effectiveness of this particular preparation of HA in the treatment of IC.

Administration, Intravesical↗
PubMed1997

Intralesional administration of biological response modifiers in the treatment of localized cancer of the prostate: a feasibility study.

OBJECTIVES: The primary aims of this pilot study were to establish the feasibility of intraprostatic administration of biological response modifiers (BRMs) and to investigate the toxicity and side effects of recombinant interferon (IFN)-alpha-2b injected into prostate glands harboring cancer. A secondary goal was to perform a preliminary assessment of the antitumor effect of this treatment. METHODS: Nine patients with histologically documented carcinoma of the prostate participated in the study. IFN was administered weekly for 5 weeks, under transrectal ultrasound visualization, with a modified gun that permitted the controlled injection of small volumes initially into the area of the tumor and later into the whole gland. Total doses of IFN ranged between 15 and 100 MU. RESULTS: The procedure resulted in minor local discomfort, comparable to a prostatic biopsy. Side effects from the drug were those anticipated from most BRMs (chills, fever, malaise, headache, fatigue), and in every case they were minor and self-limiting to several hours. Local adverse events were limited to gross hematuria (2 patients [22%]) and hematospermia (1 patient [11%]) and resolved spontaneously within 2 weeks. Antitumor activity, a secondary goal of the study, was noted in 3 (33%) patients with limited follow-up (mean 22.5 months). CONCLUSIONS: The results of this pilot study indicate that the intraprostatic administration of IFN-alpha-2b can be readily accomplished by the method described here and is associated with minor, self-limited toxicity. With the regimen and doses used, IFN demonstrated modest antineoplastic activity. Modifications of the schedule, routes, and amounts administered may result in enhanced therapeutic value.

Aged↗
PubMed1997

Vascular control mechanisms in penile erection: phylogeny and the inevitability of multiple and overlapping systems.

A co-ordinated series of vascular events underlie the generation of a penile erection. The control and regulation of this simple event is, in fact, a complex of interactions occurring at multiple levels. Many of these individual pathways and responses have been studied extensively. The understanding of the necessity of the integration between the individual pathways into a complex of series and parallel coupled mechanisms provides a rationale for the development of a framework of multiple and overlapping systems. This paper sets out some of the principles of integrated and balanced control of vasodilation and vasoconstriction in the penis. In addition, the role of growth induction and regression and the importance of time as a factor in studying penile structure and function is discussed.

Animals↗
PubMed1997

A therapeutic taxonomy of treatments for erectile dysfunction: an evolutionary imperative.

AIM OF THE STUDY: A functional classification of treatments for erectile dysfunction is important but none exists at present. Advances in the understanding of the mechanisms of drug action and of the mechanisms of penile erection suggest that there is now a rational basis for a therapeutic classification, with the expectation that a logical diagnostic classification will follow. METHODS: The currently available treatments for erectile function and the known relevant basic science were reviewed and assessed. From this, and analysis of classification systems in other fields, a classification was proposed and evaluated with respect to existing treatments. RESULTS: The treatments for erectile dysfunction were classified into five major classes by their mode of action: (I) Central Initiators, (II) Peripheral Initiators, (III) Central Conditioners, (IV) Peripheral Conditioners and (V) Other. Drugs in these classes are further subdivided by the routes of administration and the mechanisms of specificity. CONCLUSIONS: It is possible to analyze all known treatments using this classification. The principles of this scheme should be sufficiently clear as to enable knowledgeable specialists to arrive at similar conclusions about a drug. The classification proposed is general enough such that most new drugs should fall within a class. However, it should be modified if necessary, if new therapeutic agents can not be appropriately classified. It is our conclusion that with such endeavours the specialty itself and national regulatory bodies will find it easier to define and control how to apply new drugs, how to evaluate new drugs, and how to establish reasonable equivalences among agents and in whom these drugs and devices should be used.

Erectile Dysfunction↗
PubMed1997

A multicenter trial evaluation of the fibrin/fibrinogen degradation products test for detection and monitoring of bladder cancer.

PURPOSE: Presently there is a lack of effective, noninvasive tests for the detection and monitoring of bladder cancer. Measurement of fibrin/fibrinogen degradation products in urine has been shown to be a useful indicator of bladder carcinoma. The objective of this study was to evaluate the AuraTek FDP rapid immunoassay device for the detection of urinary fibrin/ fibrinogen degradation products associated with bladder cancer. MATERIALS AND METHODS: A prospective multicenter study was conducted to compare AuraTek FDP with urinary cytology and hemoglobin dipstick for the detection of bladder cancer in 192 patients with a history of bladder cancer. RESULTS: AuraTek FDP was significantly more sensitive (68%) than conventional urinary cytology (34%, p < 0.001) or hemoglobin dipstick (41%, p < 0.001) in the detection of bladder tumors, particularly for low stage low grade disease. In subjects with invasive disease (T2-T4) the AuraTek FDP test had a sensitivity of 100%. Specificity of AuraTek FDP was 96% for healthy subjects, 86% in patients with urological disease other than bladder cancer and 80% for patients under surveillance for bladder cancer but with a negative cystoscopic finding at the time of assay. CONCLUSIONS: This simple, rapid (less than 7 minutes) point of care test is superior to conventional urine cytology and hemoglobin dipstick as an aid in the detection of bladder cancer.

Aged↗
PubMed1997

GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect.

Mitochondria generate reactive oxygen species (ROS) as byproducts of molecular oxygen consumption in the electron transport chain. Most cellular oxygen is consumed in the cytochrome-c oxidase complex of the respiratory chain, which does not generate reactive species. The ubiquinone pool of complex III of respiration is the major site within the respiratory chain that generates superoxide anion as a result of a single electron transfer to molecular oxygen. Superoxide anion and hydrogen peroxide, derived from the former by superoxide dismutase, are precursor of hydroxyl radical through the participation of transition metals. Glutathione (GSH) in mitochondria is the only defense available to metabolize hydrogen peroxide. A small fraction of the total cellular GSH pool is sequestered in mitochondria by the action of a carrier that transports GSH from the cytosol to the mitochondrial matrix. Mitochondria are not only one of the main cellular sources of ROS, they also are a key target of ROS. Mitochondria are subcellular targets of cytokines, especially tumor necrosis factor (TNF); depletion of GSH in this organelle renders the cell more susceptible to oxidative stress originating in mitochondria. Ceramide generated during TNF signaling leads to increased production of ROS in mitochondria. Chronic ethanol-fed hepatocytes are selectively depleted of GSH in mitochondria due to a defective operation of the carrier responsible for transport of GSH from the cytosol into the mitochondrial matrix. Under these conditions, limitation of the mitochondrial GSH pool represents a critical contributory factor that sensitizes alcoholic hepatocytes to the prooxidant effects of cytokines and prooxidants generated by oxidative metabolism of ethanol. S-adenosyl-L-methionine prevents development of the ethanol-induced defect. The mitochondrial GSH carrier has been functionally expressed in Xenopus laevis oocytes microinjected with mRNA from rat liver. This critical carrier displays functional characteristics distinct from other plasma membrane GSH carriers, such as its ATP dependency, inhibitor specificity, and the size class of mRNA that encode the corresponding carrier, suggesting that the mitochondrial carrier of GSH is a gene product distinct from the plasma membrane transporters.

Animals↗
PubMed1997

Left anterior descending coronary artery bridge. A cause of early death after cardiac transplantation.

Immediately following orthotopic transplantation, a patient suffered left pump failure, which resulted in death. Autopsy of the donor heart revealed a proximal left anterior descending artery bridge with a thrombus causing segmental distal anteroseptal infarction. In this case report, myocardial coronary bridges and their clinical implications are reviewed. Myocardial bridging and acute coronary obstruction should be considered in the differential diagnosis of patients with acute pump dysfunction following orthotopic cardiac transplantation.

Coronary Thrombosis↗