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Biomedical subjects

G Gutierrez

Publications and source records attributed to G Gutierrez.

At least 19 recordsLinked to original sources
PubMed1992

Cinchonine, a potent efflux inhibitor to circumvent anthracycline resistance in vivo.

Circumvention of multidrug resistance is a new field of investigation in cancer chemotherapy, and safe and potent multidrug resistance inhibitors are needed for clinical use. We investigated several analogues of quinine for their ability to increase anthracycline uptake in resistant cancer cells. Cinchonine was the most potent inhibitor of anthracycline resistance in vitro, and its activity was little altered by serum proteins. Serum from rats treated with i.v. cinchonine produced greater uptake of doxorubicin in cancer cells (DHD/K12/PROb rat colon cells and K562/ADM human leukemic cells) than did serum from quinine-treated rats (ex vivo assay). Cinchonine was more effective than quinine in reducing tumor mass and increasing the survival of rats inoculated i.p. with DHD/K12/PROb cells and treated i.p. with deoxydoxorubicin. Moreover, the acute toxicity of cinchonine in rats and mice was lower than that of other quinine-related compounds. The lower toxicity and greater potentiation of in vivo anthracycline activity produced by cinchonine are favorable characteristics for its use as an anti-multidrug resistance agent in future clinical trials.

Animals↗
PubMed1992

Gastric intramucosal pH as a therapeutic index of tissue oxygenation in critically ill patients.

Falls in gastric intramucosal pH (pHi) are associated with morbidity and mortality in patients admitted to intensive-care units (ICU). We tested the hypothesis that ICU outcome can be improved by therapy guided by changes in pHi and aimed at improving systemic oxygen availability. We studied 260 patients admitted to ICUs with APACHE II scores of 15-25. After insertion of a gastric tonometer, each patient was randomly assigned to a control or protocol group within the admission pHi category (normal = 7.35 or higher; low = below 7.35). The control groups were treated according to standard ICU practices. The protocol groups received, in addition, treatment to increase systemic oxygen transport or to reduce oxygen demand, whenever the pHi fell below 7.35 or by more than 0.10 units from the previous measurement. The protocol was used, because pHi fell, in 67 (85%) of the protocol group with normal pHi on admission. There were no significant differences between protocol and control groups in demographic characteristics, admission blood gases or haemoglobin concentration, number or type of organ system failures, or the intensity of ICU care. For patients admitted with low pHi, survival was similar in the protocol and control groups (37% vs 36%), whereas for those admitted with normal pHi, survival was significantly greater in the protocol than in the control group (58% vs 42%; p less than 0.01). Therapy guided by pHi measurements improved survival in patients whose pHi on admission to ICU was normal. pHi-guided resuscitation may help improve outcome in such patients by preventing splanchnic organ hypoxia and the development of a systemic oxygen deficit.

Aged↗
PubMed1992

Autism and tuberous sclerosis.

Autism is a behavior disorder with genetic influences indicated from twin and family studies and from the co-occurrence of autism with known genetic disorders. Tuberous sclerosis complex (TSC) is a known genetic disorder with behavioral manifestations including autism. A literature review of these two disorders substantiates a significant association of autism and TSC with 17-58% of TSC subjects manifesting autism and 0.4-3% of autistic subjects having TSC. In initial data collected on 13 TSC probands and 14 autistic probands in our family study of autism and TSC, we identified 7 TSC subjects with autism. The seven TSC autistic probands are similar to non-TSC autistic probands on the Social and Communication domains of the Autism Diagnostic Inventory (ADI) (Le Couteur et al., 1989), but show fewer Repetitive Rituals. There are more male TSC probands with autism than female, despite an equal sex ratio among TSC probands. The TSC probands with autism have significantly more seizures and mental retardation than those without autism; however, the extent and etiology of associations require further study. Our preliminary findings suggest that a fruitful approach for delineating genetic influences in autism may come from further investigation of possible mechanisms underlying the association of autism and TSC.

Autistic Disorder↗
PubMed1992

Correction of ischaemic brain acidosis with SQ29,548/1-benzylimidazole.

Thromboxane A2 (TXA2) is a proaggregatory vasoconstrictor that is synthesized and released during reperfusion of ischaemic brain. We administered a TXA2 receptor antagonist, SQ29,548, and a thromboxane A synthase inhibitor, 1-benzylimidazole (1-BI), to rats subjected to 30 min of reversible forebrain ischaemia. Cerebral thromboxane B2 (TXB2), the stable metabolite of TXA2, measured after 60 min of reperfusion was 0.37 +/- 0.08 ng/mg brain protein in animals treated with SQ29,548/1-BI compared with 1.20 +/- 0.16 in ischaemic controls (p < 0.05). Cerebral pH determined by 31P magnetic resonance spectroscopy was higher in treated animals, 7.06 +/- 0.04, than in ischaemic controls, 6.5 +/- 0.01, after 20 min of reperfusion (p < or = 0.01). The significant elevation of cerebral pH in treated animals persisted at 30 (7.17 +/- 0.05 vs. 6.5 +/- 0.01; p < or = 0.01), 35 (7.17 +/- 0.05 vs. 6.44 +/- 0.04; p < or = 0.01), and 40 min of reperfusion (7.06 +/- 0.06 vs. 6.37 +/- 0.01; p < or = 0.05). We conclude that SQ29,548/1-BI reduces thromboxane levels and promotes resolution of tissue acidosis in ischaemic brain. The combination of a TXA2 receptor antagonist with a thromboxane A synthase inhibitor deserves further study as a potential treatment for acute cerebral infarction.

Acidosis↗
PubMed1992

The acrosome reaction-inducing activity of individual human follicular fluid samples is highly variable and is related to the steroid content.

In this study, we have evaluated the relationship between the acrosome reaction-inducing activity of individual human follicular fluid samples and their steroid content. Eighteen samples of follicular fluid were obtained during egg retrieval in six patients undergoing assisted fertilization. Motile spermatozoa were incubated in modified Tyrode's medium (26 mg/ml bovine serum albumin) for 20 h at 1 x 10(7) cells/ml. In a single experiment, aliquots of a semen specimen were simultaneously treated with an aliquot of each follicular fluid sample. The percentage of acrosome reacted spermatozoa was determined using fluorescein isothiocyanate-conjugated Pisum sativum agglutinin (FITC-PSA) lectin. The fluids were also analysed by radioimmunoassay to determine the levels of progesterone, 17 alpha-hydroxy-progesterone, testosterone and oestradiol. The results showed that there was a positive, highly significant correlation between the acrosome reaction-inducing activity and the progesterone level of each follicular fluid sample (r = 0.72, P less than 0.005). Additionally, treatment of the follicular fluid samples with charcoal-dextran caused both a decrease in progesterone concentration and the total loss of the acrosome reaction-inducing activity. The addition of progesterone restored the acrosome reaction-inducing ability in 88% of samples. These data support the idea that progesterone in follicular fluid is the molecule responsible for inducing the acrosome reaction in human spermatozoa.

Acrosome↗
PubMed1992

Comparison of gastric intramucosal pH with measures of oxygen transport and consumption in critically ill patients.

OBJECTIVE: To determine the relationship of tonometrically measured gastric intramucosal pH to clinically accepted indices of systemic oxygenation. DESIGN: Prospective, nonintervention study. SETTING: Medical and surgical ICUs of a university hospital. PATIENTS: Critically ill patients (n = 22) with pulmonary artery catheters in place who also required nasogastric suctioning. MEASUREMENTS AND MAIN RESULTS: Tonometric measurements of gastric intramucosal pH were compared with concurrently obtained systemic indices of tissue oxygenation. These variables included oxygen delivery (DO2), oxygen consumption (VO2), oxygen extraction ratio, arterial lactate concentrations, mixed venous PO2, and mixed venous pH. The study period ranged from the time of insertion of the pulmonary artery catheter to the time of its removal. We classified patients who were alive by the end of the study as survivors and those patients who died with the pulmonary artery catheter in place as nonsurvivors. Both groups had similar levels of DO2 during the study period, but nonsurvivors had greater levels of VO2, oxygen extraction ratio, and serum lactate concentrations than survivors. Gastric intramucosal pH, mixed venous pH, and mixed venous PO2 values were lower in nonsurvivors. Both groups demonstrated the phenomenon of oxygen supply dependency. When the final measurements taken before the removal of the pulmonary artery catheter or death were compared, only gastric intramucosal pH and mixed venous pH showed differences between the groups, being lower in nonsurvivors. All the patients who died, except for one, had final gastric intramucosal pH values of less than 7.32. CONCLUSIONS: In this group of patients, death was associated with increased tissue needs for oxygen that were not adequately satisfied by the available levels of oxygen supply. We also conclude that tonometrically measured gastric intramucosal pH is a useful noninvasive adjunct to current methods of monitoring systemic oxygenation.

Adult↗
PubMed1992

Role of tissue hypoxia as the mechanism of lactic acidosis during E. coli endotoxemia.

We compared the hemodynamic and metabolic alterations produced in rabbits by similar decreases in cardiac output created by inflating a balloon placed in the right ventricle (n = 6) with those produced by an intravenous bolus of Escherichia coli lipopolysaccharide (LPS; SEP group; n = 6). We measured O2 consumption (VO2), O2 transport (TO2), and O2 extraction ratio (ERO2) for the whole animal and also for the left hindlimb. Both groups experienced similar decreases in cardiac output, systemic TO2, and VO2 and similar increases in ERO2. For the hindlimb, TO2 was similar, but VO2 and ERO2 were lower for the SEP group 30 min after LPS administration (P less than 0.05); however, this difference disappeared during the remainder of the experiment. Arterial lactate concentration was greater (P less than 0.05) for the SEP group. There were no differences in skeletal muscle PO2, measured with a multiwire surface electrode, or in cardiac and skeletal muscle concentrations of high-energy phosphates. We hypothesize that a direct effect of LPS on cellular metabolism may have resulted in greater arterial lactate concentration for the SEP group.

Acidosis, Lactic↗
PubMed1992

Gastric intramucosal pH: a noninvasive method for the indirect measurement of tissue oxygenation.

BACKGROUND: Monitoring the adequacy of tissue oxygenation is an important goal in the care of the critically ill patient. Global alterations in tissue oxygenation are inferred from changes in systemic oxygen transport (defined as the product of cardiac output and arterial oxygen content) and total oxygen consumption. These parameters, however, cannot measure the level of oxygenation of specific tissue beds, in particular those that are first affected by hypoxia, such as the gastrointestinal tract and the kidneys. DISCUSSION: Gastrointestinal tonometry is a new method for measuring the partial pressure of carbon dioxide of the gastrointestinal mucosa. This information can be used in conjunction with the arterial blood bicarbonate to calculate the pH of the mucosa. Mucosal acidosis correlates well with the onset of anaerobic metabolism in response to hypoxia or sepsis. This review discusses the basic principles of tonometry, the results of experimental and clinical studies, and the practical aspects related to the implementation and use of tonometers in patients in the critical care unit. CONCLUSION: Gastrointestinal tonometry is a relatively noninvasive device that appears capable of measuring metabolic changes produced by hypoxia. Because of the sensitive nature of the gastrointestinal mucosa, these changes often occur well in advance of other, more common, indices of hypoxia. The use of the tonometer may become a routine procedure in the overall monitoring of critically ill patients.

Anaerobic Threshold↗
PubMed1991

Cellular energy metabolism during hypoxia.

Tissue hypoxia is frequently seen in critically ill patients and it perhaps predisposes these patients to development of multiple system organ failure. In cellular terms, hypoxia is characterized by decreases in the intracellular concentration of oxygen, leading to a decline in aerobically produced adenosine triphosphate (ATP). The deficit arising from unequal levels of cellular ATP requirements and aerobic ATP production is partially satisfied by anaerobic sources of ATP, including glycolysis, the creatine kinase reaction, and the adenylate kinase reaction. These reactions can set in motion cellular mechanisms that ultimately may lead to cellular dysfunction and death. A clear understanding of the relative importance of these reactions is impossible to acquire from global measures of oxygen delivery and oxygen consumption; therefore, the clinical monitoring of tissue oxygenation also should include the measurement of metabolically relevant, organ-specific variables.

Adenine Nucleotides↗
PubMed1991

Gastric mucosal pH as a prognostic index of mortality in critically ill patients.

OBJECTIVE: To determine if measurements of gastric intramucosal pH have prognostic implications regarding ICU mortality. DESIGN: Prospective comparison of outcome. SETTING: General adult ICUs in two teaching hospitals. PATIENTS: Eighty consecutive patients age 18 to 84 yrs (mean 63.4), 50 men and 30 women, 55% in the medical and 45% in the surgical services. METHODS: Gastric intramucosal pH was measured on ICU admission and again 12 hrs later. A value of greater than or equal to 7.35 was used to differentiate between normal and low gastric intramucosal pH. MEASUREMENTS AND MAIN RESULTS: Fifty-four patients had a normal gastric intramucosal pH and 26 patients had a low gastric intramucosal pH on ICU admission. The mortality rate was greater in the low gastric intramucosal pH group (65.4% vs. 43.6%; p less than .04). The frequency of sepsis and the presence of multisystem organ failure also were greater in the low gastric intramucosal pH group (p less than .01). Further stratification of patients according to gastric intramucosal pH measured 12 hrs after admission showed a greater mortality rate in patients with persistently low gastric intramucosal pH when compared with patients with normal gastric intramucosal pH during the first 12 hrs (86.7% vs. 26.8%; p less than .001). CONCLUSIONS: Measurements of gastric intramucosal pH on ICU admission, and again 12 hrs later, have a high specificity for predicting patient survival in this ICU patient population (77.8% to 80.6%). Furthermore, given its relative noninvasive nature, tonometrically measured gastric intramucosal pH may be a useful addition to patient monitoring in the ICU.

Critical Care↗
PubMed1991

Oxygen supply and utilization relationships. A reevaluation.

The relationship between oxygen transport (TO2) and oxygen consumption (VO2) has been studied in patients with a number of acute and chronic disorders. Many of these patients have been shown to have a linear relationship between these two variables over a wide range of TO2, which has been considered as evidence of pathologic supply dependency. This supply dependency contrasts with animal studies that have clearly demonstrated a biphasic relationship between TO2 and VO2. This review of the available data concerning the relationship between oxygen transport and supply under conditions of increased oxygen requirements and reduced oxygen transport suggests the possibility that the observed interaction in patients may, in many cases, represent the normal physiologic behavior of the system rather than an abnormal manifestation of impaired oxygen extraction.

Biological Transport↗
PubMed1991

Rabbit skeletal muscle PO2 during hypodynamic sepsis.

We measured skeletal muscle tissue PO2 (PtO2) in anesthetized rabbits (n = 7) following infusion of an intravenous bolus of E coli endotoxin. An array of surface PO2 microelectrodes was placed over the hindlimb biceps femoris muscle and sufficient readings were obtained to construct a PtO2 histogram. Changes in the histogram standard deviation were used to characterize micro-circulatory maldistribution. Systemic O2 consumption (VO2) was measured by the expired gas method. Cardiac output (Q) and systemic O2 transport (TO2) were calculated. Samples of arterial, right atrial (ra), and hindlimb venous blood, from a catheter placed in the infrarenal portion of the vena cava, were simultaneously obtained for measurement of blood gases and saturations. Following the administration of endotoxin, there were decreases in Q and TO2 of approximately 50 percent. The VO2 initially decreased 23 percent, but returned to baseline levels 30 minutes after endotoxin administration. Systemic O2 extraction ratio (ERO2 = VO2/TO2) increased from 0.32 +/- .03 to 0.54 +/- .07 (p less than 0.01), whereas hindlimb ERO2 increased from 0.42 +/- .03 to 0.60 +/- .02 (p less than 0.01). The arithmetic mean of the PtO2 histograms decreased after endotoxin infusion (43 +/- 4 to 7 +/- 2 mm Hg; p less than 0.01), but PLO2 remained at baseline levels (35 +/- 2 vs. 33 +/- 2 mm Hg; p = NS). The standard deviation of the PtO2 histograms remained constant during the experiment. This finding supports the notion that skeletal muscle microcirculatory heterogeneity does not increase during endotoxin induced hypodynamic sepsis.

Animals↗
PubMed1990

Skeletal muscle PO2 during hypoxemia and isovolemic anemia.

We subjected anesthetized mechanically ventilated rabbits (n = 6) to sequential exchanges of blood for a 6% dextran solution and compared their responses with those obtained in a previous study on progressive hypoxemia (n = 7). Right atrial PO2 (PVO2)RA and hindlimb PO2 (PVO2)limb, measured at the level of the iliac bifurcation, were compared with tissue PO2 (PtiO2) histograms obtained with an array of surface microelectrodes placed over the biceps femoris muscle. Systemic O2 consumption (VO2) was measured with the expired gas method. Cardiac output and systemic O2 transport (TO2) were calculated. Six exchanges of blood for dextran produced decreases in hemoglobin from 10.8 +/- 0.4 to 2.7 +/- 0.2 g/dl (P less than 0.001). Critical TO2 (TO2crit), defined as the level of TO2 associated with initial decreases in control VO2, was similar for anemia and hypoxemia (40.5 +/- 5.6 and 40.1 +/- 5.3 ml.min-1.kg-1, respectively). At any given TO2 other than control TO2, the levels of (PVO2)RA and (PVO2)limb were greater in anemia than in hypoxemia (P less than 0.01), but the mean and the distribution of the PtiO2 histograms were similar in both conditions. Mean PtiO2 was significantly less than (PVO2)RA or (PVO2)limb, except for those values obtained during the control period. These results confirm our previous finding that PVO2 is not an accurate index of PtiO2 under conditions of tissue hypoxia. Furthermore, similar PtiO2 levels during anemia and hypoxemia suggest that VO2 is limited by decreases in O2 diffusion from the capillaries to the cells.

Anemia↗
PubMed1989

Sodium azide mutagenesis in mammals: inability of mammalian cells to convert azide to a mutagenic intermediate.

Sodium azide is unique among mutagens. It is highly mutagenic in many plant and bacterial species but marginally mutagenic in mammalian cells. A possible explanation for this difference in mutagenic efficiency may lie in the inability of mammalian cells to convert azide to the putative ultimate mutagen. Normal human fibroblasts and Chinese hamster cells or cell-free extracts from these cell lines were treated with azide and the sonicates tested for mutagenicity in Salmonella strain TA1530. The data suggest that neither cell line was capable of converting azide to a mutagenic intermediate. In addition, both cell lines expressed the enzyme O-acetylserine(thio)-lyase which is responsible for the conversion of azide to azidoalanine, the putative mutagenic intermediate. Although mammalian cells possess the enzyme responsible for the conversion of azide to azidoalanine, they appear incapable of converting azide into a mutagenic intermediate in appreciable quantities. Further, the data support the conclusion that azide may be further modified in mammalian cells to an intermediate that is not genotoxic.

Animals↗