PubMed Health⌕ Search

Biomedical subjects

C Stanley

Publications and source records attributed to C Stanley.

At least 37 records · Page 2Linked to original sources
PubMed1996

Sherpa brain glucose metabolism and defense adaptations against chronic hypoxia.

The brain of hypoxia-tolerant vertebrates is known to survive extreme oxygen limitation at least in part because of very low rats of ATP utilization and ATP production. To asses whether similar adaptations are involved in healthy humans during hypoxia adaptation over generational time, we initially used positron-emission tomography measurements of glucose metabolic rates in the brain of Quechuas, whose ancestors have been indigenous to the Andes at altitudes between approximately 3,300 and 4,500 m for several hundred years. Workers in this field generally believe that the lineage of Sherpas has been indigenous to the Himalayas for even longer and that Sherpas and other peoples indigenous to the Tibetan plateau are perhaps the most exquisitely hypoxia adapted of all humans. For this reason, in this study we extended our database to include Sherpas. With the use of the same protocol as before, two metabolic states were analyzed: 1) the presumed normal (hypoxia-adapted) state, monitored as soon as possible after subjects left the Himalayas and 2) the deacclimated state, monitored after 3 wk at low altitudes. Positron-emission tomography measurements of 2-[18F]deoxy-2-fluoro-D-glucose metabolic rates, quantified in 26 regions of the brain, indicated that the Sherpas' brain metabolism differed significantly from that of Quechuas but was essentially identical to that of lowlanders. Region-by-region patterns were similar in all three groups, indicating that the regional organization of glucose metabolism in the brain is a conservative, relatively constant characteristic.

Adaptation, Physiological↗
PubMed1996

Effects of hypocarbia on the development of cystic periventricular leukomalacia in premature infants treated with high-frequency jet ventilation.

BACKGROUND AND OBJECTIVE: Previous data from our institution indicate that mechanically ventilated premature infants are at increased risk for cystic periventricular leukomalacia (CPVL), particularly if hypocapnia occurs. High-frequency jet ventilation (HFJV) may produce substantial hypocapnia. We sought to investigate whether hypocapnia during HFJV is associated with the development of CPVL. METHODS: Sixty-seven premature infants (mean gestational age, 27.2 weeks; mean birth weight, 1001 g) underwent HFJV for a mean of 44 (range, 8 to 70) hours during the first 3 days of life. All infants were followed with serial neurosonograms at least weekly until 6 to 8 weeks of age and every 2 to 4 weeks thereafter until discharge. To assess the cumulative effects of hypotension, acidosis, hypoxemia, and hypocarbia during the first 3 days of life on the development of PVL, we developed a quantitative assessment in which we assigned threshold levels at particular critical values of these parameters (such as a mean PaCO2 of 20 mm Hg) and calculated an area above the curve between longitudinally connected values of these parameters and the threshold levels. RESULTS: Nine of the 67 infants died before 21 days of life. Of the 58 who survived beyond 21 days, large CPVL (> 5 mm in size) developed in 18 infants. Infants with cysts were similar in birth weight, gestational age, and virtually all other antepartum, intrapartum, and postpartum parameters compared with the 40 neonates in whom CPVL did not develop. However, infants with CPVL were significantly more likely to have moderate or severe periventricular echodensities preceding development of CPVL and periventricular echodensities that persisted for a longer period. We did not find an effect of hypotension, acidosis, or hypoxemia on the development of CPVL. There were no differences in the mean PaCO2, the absolute low PaCO2 values, the ranges of low PaCO2 between groups, or area above the curve measurements at threshold levels of 15 and 20 mm Hg, respectively. However, logistic regression analysis revealed that infants with CPVL were independently significantly more likely to have greater cumulative hypocarbia below a threshold level of 25 mm Hg during the first day of life (odds ratio, 5.43; 95% confidence interval, 1.33 to 22.2). CONCLUSIONS: Hypocarbia produced by treatment with HFJV during the first 3 days of life is associated with the subsequent development of CPVL. The mechanisms for the development of CPVL among premature infants treated with HFJV need to be established.

Carbon Dioxide↗
PubMed1995

Enhanced cardiac metabolism of plasma glucose in high-altitude natives: adaptation against chronic hypoxia.

The metabolism of glucose in mammalian heart is 25-50% more O2 efficient than the metabolism of free fatty acids. To assess the role of substrate preference in adaptations to chronic hypoxia, positron emission tomographic measurements of heart regional glucose uptake rates after an overnight fast were made in volunteer Quechua subjects and in Sherpa subjects, both indigenous to altitudes of over 3,000 m, and in a group of lowlander volunteers. Highest uptake rates were found in the Quechuas on arrival and in the Sherpas after a 3-wk period at low altitude, intermediate rates in Quechuas after a 3-wk period at low altitude and in the lowlanders, and lowest rates in Sherpas on arrival. These low values were probably related to the stress of travel to the site of the experiments. Measured plasma catecholamines, hormones, and substrates indicated that glucose concentrations correlated best with observed variations in glucose uptake, with a negative correlation for the control subjects and a positive correlation for the Quechuas and Sherpas. Uptake values in Quechuas declined significantly after a 3-wk period at low altitude, but the positive correlation with glucose levels persisted. We conclude that an elevated glucose preference in heart is a true metabolic adaptation in humans adapted over generations to chronic hypoxia.

Adaptation, Physiological↗
PubMed1995

Sequence-specific purification of nucleic acids by PNA-controlled hybrid selection.

Using an oligohistidine peptide nucleic acids (oligohistidine-PNA) chimera, we have developed a rapid hybrid selection method that allows efficient, sequence-specific purification of a target nucleic acid. The method exploits two fundamental features of PNA. First, that PNA binds with high affinity and specificity to its complementary nucleic acid. Second, that amino acids are easily attached to the PNA oligomer during synthesis. We show that a (His)6-PNA chimera exhibits strong binding to chelated Ni2+ ions without compromising its native PNA hybridization properties. We further show that these characteristics allow the (His)6-PNA/DNA complex to be purified by the well-established method of metal ion affinity chromatography using a Ni(2+)-NTA (nitrilotriactic acid) resin. Specificity and efficiency are the touchstones of any nucleic acid purification scheme. We show that the specificity of the (His)6-PNA selection approach is such that oligonucleotides differing by only a single nucleotide can be selectively purified. We also show that large RNAs (2224 nucleotides) can be captured with high efficiency by using multiple (His)6-PNA probes. PNA can hybridize to nucleic acids in low-salt concentrations that destabilize native nucleic acid structures. We demonstrate that this property of PNA can be utilized to purify an oligonucleotide in which the target sequence forms part of an intramolecular stem/loop structure.

Base Composition↗
PubMed1994

The brain at high altitude: hypometabolism as a defense against chronic hypoxia?

The brain of hypoxia-tolerant vertebrates is known to survive extreme limitations of oxygen in part because of very low rates of energy production and utilization. To assess if similar adaptations may be involved in humans during hypoxia adaptation over generational time, volunteer Quechua natives, indigenous to the high Andes between about 3,700 and 4,900 m altitude, served as subjects in positron emission tomographic measurements of brain regional glucose metabolic rates. Two metabolic states were analyzed: (a) the presumed normal (high altitude-adapted) state monitored as soon as possible after leaving the Andes and (b) the deacclimated state monitored after 3 weeks at low altitudes. Proton nuclear magnetic resonance spectroscopy studies of the Quechua brain found normal spectra, with no indication of any unusual lactate accumulation; in contrast, in hypoxia-tolerant species, a relatively large fraction of the glucose taken up by the brain is released as lactate. Positron emission tomographic measurements of [18F]2-deoxy-2-fluoro-D-glucose (FDG) uptake rates, quantified in 26 regions of the brain, indicated systematically lower region-by-region glucose metabolic rates in Quechuas than in lowlanders. The metabolic reductions were least pronounced in primitive brain structures (e.g., cerebellum) and most pronounced in regions classically associated with higher cortical functions (e.g., frontal cortex). These differences between Quechuas with lifetime exposure to hypobaric hypoxia and lowlanders, which seem to be expressed to some degree in most brain regions examined, may be the result of a defense adaptation against chronic hypoxia.

Adaptation, Physiological↗
PubMed1994

The metabolic effects of surface cooling neonates prior to cardiac surgery.

Neonates undergoing cardiac surgery at The Children's Hospital of Philadelphia frequently developed metabolic acidemia as they passively cooled prior to the start of cardiopulmonary bypass. This study was performed in an attempt to identify the mechanism for this acidemia. After receiving an initial dose of fentanyl (10 micrograms/kg) and pancuronium, 22 neonates were randomly assigned to maintain normothermia by active warming (Group I), or to permit passive cooling (Group II) before surgery. Arterial blood samples were obtained prior to, and at 10 and 45 min after entering the operating room for the analysis of pH, gas tensions, lactate, pyruvate, plasma free fatty acids, acetoacetate, beta-hydroxybutyrate, total CO2, and glucose concentrations. In the last 11 patients studied, the observation period was extended to 75 min at which time another arterial blood sample was obtained. There was a steady decrease in heart rate as the Group II patients cooled; however, arterial blood pressure did not change in either group. There were no changes in blood values measured in Group I neonates. In the Group II patients, there was a progressive decline in calculated base excess, total CO2, and an increase in serum lactate as the patients cooled. The metabolic acidemia that develops in neonates represents lactate accumulation as a consequence of surface cooling prior to surgery and the institution of cardiopulmonary bypass. Whether lactate accumulates as a result of anaerobic metabolism in underperfused tissue beds or reduced hepatic clearance could not be distinguished in this study. Since neither clinically significant hemodynamic changes nor differences in outcome were found between the two groups, the authors believe this mild lactic acidemia is inconsequential and does not require therapy.

Acidosis↗
PubMed1993

Single base pair mutation analysis by PNA directed PCR clamping.

A novel method that allows direct analysis of single base mutation by the polymerase chain reaction (PCR) is described. The method utilizes the finding that PNAs (peptide nucleic acids) recognize and bind to their complementary nucleic acid sequences with higher thermal stability and specificity than the corresponding deoxyribooligonucleotides and that they cannot function as primers for DNA polymerases. We show that a PNA/DNA complex can effectively block the formation of a PCR product when the PNA is targeted against one of the PCR primer sites. Furthermore, we demonstrate that this blockage allows selective amplification/suppression of target sequences that differ by only one base pair. Finally we show that PNAs can be designed in such a way that blockage can be accomplished when the PNA target sequence is located between the PCR primers.

Alleles↗
PubMed1993

Developmental data on individuals with the Brachmann-de Lange syndrome.

One hundred twenty-two patients with clinically confirmed Brachmann-de Lange syndrome (BDLS) were evaluated developmentally. Recruitment was made from our genetics department and through meetings of the Cornelia de Lange Syndrome Foundation parent support group. Developmental information was obtained from records of physicians, schools and developmental centers, or from parents on each of the 122 individuals, allowing division into four groups for study: group 1 (n = 48) underwent formal developmental assessments, which generated intelligence or developmental quotients, and had a completed parental questionnaire with specific developmental questions regarding ages of skills mastered; group II (n = 23) had additional developmental records available without formal testing, as well as the questionnaire; group III (n = 22) had only a completed questionnaire; and group IV (n = 29) had formal developmental testing or other developmental records but no available questionnaire. These data were analyzed in order to be able to predict attainable psychomotor development. Average scores on formal testing were found to be in the mild to moderate level of mental retardation, ranging from below 30 to 85, with an average intelligence quotient of 53, higher than previously reported. Visual-spatial memory and perceptual organization skills were found to be strengths. Younger individuals born before 1980 demonstrated higher scores on testing. Early intervention appears to play a major role in the level of developmental achievement.

Adolescent↗
PubMed1993

Nephrolithiasis, hypocitraturia, and a distal renal tubular acidification defect in type 1 glycogen storage disease.

Renal stones containing calcium can occur in patients with type 1 glycogen storage disease. We studied 11 patients with glycogen storage disease. Five patients had renal calculi, nephrocalcinosis, or both, and five had hypercalciuria. Serum levels of calcium, phosphorus, parathyroid hormone, and urate were normal. Serum levels of 1,25-dihydroxyvitamin D were elevated in each patient. None of the patients had a metabolic acidosis, but all nine who were tested had evidence of impaired acid excretion. In response to an acid load, eight of the nine patients had subnormal titratable acid excretion, and nine had subnormal ammonia excretion; six of nine patients were unable to secrete hydrogen ions in response to bicarbonate administration. These data indicate that patients with type 1 glycogen storage disease have an incomplete form of distal renal tubular acidosis. This may be the cause of hypercalciuria and nephrocalcinosis in these patients.

Acidosis, Renal Tubular↗
PubMed1993

UV-A-mediated activity of p-methoxymethylcinnamate.

Methyl esters of hydroxycinnamic acids are photobiologically active. Cis(Z) and trans(E) p-methoxymethyl-cinnamate photosensitize Escherichia coli and Chinese hamster ovary cells. They also produce sister chromatid exchanges. Photosensitization is oxygen independent, and the cinnamates are not genetically active in the absence of light in the Ames Salmonella typhimurium test.

Animals↗
PubMed1992

The influence of orientation and number of copies of T and B cell epitopes on the specificity and affinity of antibodies induced by chimeric peptides.

CBA and TO mice were immunized with chimeric peptide immunogens consisting of B cell (residues 404-414) and T cell (residues 288-302) epitopes from the F protein of measles virus. The chimeras were co-linearly synthesized to contain one or two copies of the T cell epitope linked to one or two copies of the B cell epitope via a glycine.glycine spacer. Two orientations were synthesized such that the T cell epitope(s) were located at either the amino or carboxyl terminus of the B cell epitope(s). The levels of antibody induced following immunization with the chimeras were assessed by enzyme-linked immunosorbent assay using microtiter plates coated with either the homologous chimera or the B cell epitope sequence. The affinities of the anti-chimera antibodies for the B cell epitope were assessed by a fluid-phase double-isotope radioimmunoassay. All the chimeras induced good antibody responses in both strains of mice with specificity for the B cell epitope. Chimeras containing two copies of the T cell epitope induced antibodies with higher affinity for the B cell epitope than did chimeras containing one copy of the T cell epitope or two copies of the B cell epitope. Furthermore, the amino terminal location of the T cell epitope in relation to the B cell epitope in the chimera induced higher affinity anti-B cell antibody than did the reverse orientation. These results suggest that orientation of epitopes and amino acid composition of chimeric peptides affect antigen processing and presentation to T cells which govern both the specificity and affinity of antibody produced. Thus, for the production of synthetic peptide immunogens with vaccine potential, attention needs to be given to the number and orientation of the component epitopes required to produce highest affinity antibody.

Animals↗
PubMed1992

The effect of orientation of epitopes on the immunogenicity of chimeric synthetic peptides representing measles virus protein sequences.

We have studied the influence of the orientation of T- and B-cell epitopes on the immunogenicity of chimeric synthetic peptides in terms of the ability of the T-cell epitope to provide help for the production of antibody to the B-cell epitope. A T-cell epitope from the fusion protein of measles virus (288-302), previously shown to act as a T-helper epitope in a panel of six inbred mouse strains, was co-linearly synthesized at either the amino- or carboxyl- terminus of a B-cell epitope from the haemagglutinin of the virus (188-199) with or without the inclusion of a glycine-glycine spacer. The four chimeric peptides were used to immunize a panel of five mouse strains and induced good anti-chimera antibody responses. In general, the chimeras in which the T-cell epitope was amino-terminal to the B-cell epitope induced antibodies which bound well to the B-cell epitope whereas the carboxyl-terminal orientation of the T-cell epitope with respect to the B-cell epitope failed to induce such antibody. These latter chimeras induced the production of antibodies which preferentially bound to the T-cell epitope. The inclusion of the gly-gly spacer in the chimeras did not enhance their immunogenicity nor did it increase antibody titres to the B-cell epitope. The affinity of the anti-peptide antibodies was markedly influenced by the orientation of the epitopes in the chimeras. The antibody elicited by the peptide in which the T-cell epitope was amino terminal to the B-cell epitope had significantly higher affinity for the B-cell epitope than that induced by immunization with the peptide in the reverse orientation.

Amino Acid Sequence↗
PubMed1992

Enzyme mechanisms for pyruvate-to-lactate flux attenuation: a study of Sherpas, Quechuas, and hummingbirds.

During incremental exercise to fatigue under hypobaric hypoxia, Andean Quechua natives form and accumulate less plasma lactate than do lowlanders under similar conditions. This phenomenon of low lactate accumulation despite hypobaric hypoxia, first discovered some half century ago, is known in Quechuas to be largely unaffected by acute exposure to hypoxia or by acclimatization to sea level conditions. Earlier Nuclear Magnetic Resonance (NMR) spectroscopy and metabolic biochemistry studies suggest that closer coupling of energy demand and energy supply in Quechuas allows given changes in work rate with relatively modest changes in muscle adenylate and phosphagen concentrations, thus tempering the activation of glycolytic flux to pyruvate--a coarse control mechanism operating at the level of overall pathway flux. Later studies of enzyme activities in skeletal muscles of Quechuas and of Sherpas have identified a finely-tuned control mechanism which by adaptive modifications of a few key enzymes apparently serves to specifically attenuate pyruvate flux to lactate.

Adaptation, Physiological↗
PubMed1992

Neurodevelopment of preterm infants: neonatal neurosonographic and serum bilirubin studies.

In this study of 249 preterm infants of less than 34 weeks' gestation, the relationships between maximal serum total bilirubin concentrations during the neonatal period, neonatal cranial ultrasonographic abnormalities, and severe neurodevelopmental sequelae are described. The subjects, who were selected on the basis of serial cranial ultrasonographic findings, had repeated neurologic and developmental examinations during late infancy and early childhood that established the presence (n = 45) or absence (n = 204) of spastic forms of cerebral palsy. Of the 204 subjects without cerebral palsy, 23 scored abnormally low on standardized developmental testing during early childhood. All but seven of the subjects with cerebral palsy had grade III/IV intracranial hemorrhage or moderate to severe periventricular echogenicity or both, ultrasonographic abnormalities that probably reflect a disruption in the blood-brain barrier as well as extravasation of blood into brain tissue; however, analysis of the data did not suggest that these cranial ultrasonographic abnormalities increased either the maximum serum bilirubin concentration during the neonatal period or the susceptibility of the subjects to neurologic damage from hyperbilirubinemia. Also, there was no evidence to suggest that bilirubinemia in the range studied (2.3 to 22.5 mg/100 mL total serum bilirubin) was causally related to cerebral palsy, early developmental delay, or the development of periventricular cysts in this population of preterm infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Apgar Score↗
PubMed1992

Mechanical ventilation in preterm infants: neurosonographic and developmental studies.

Surviving preterm infants of less than 34 weeks' gestation who were selected on the basis of serial cranial ultrasonographic findings during their nursery course had repeated neurologic and developmental examinations during late infancy and early childhood that established the presence (n = 46) or absence (n = 205) of spastic forms of cerebral palsy. Of the 205 infants without cerebral palsy, 22 scored abnormally low on standardized developmental testing during early childhood. The need for mechanical ventilation beginning on the first day of life (n = 92) was significantly related to gestational age, birth weight, Apgar scores, patent ductus arteriosus, grade III/IV intracranial hemorrhage, large periventricular cysts, and the development of cerebral palsy. In the 192 mechanically ventilated infants, vaginal bleeding during the third trimester, low Apgar scores, and maximally low PCO2 values during the first 3 days of life were significantly related to large periventricular cysts (n = 41) and cerebral palsy (n = 43), but not to developmental delay in the absence of cerebral palsy (n = 18). The severity of intracranial hemorrhage in mechanically ventilated infants was significantly associated with gestational age and maximally low measurements of PCO2 and pH, but not with Apgar scores or maximally low measurements of PO2. Logistic regression analyses controlling for possible confounding variables disclosed that PCO2 values of less than 17 mm Hg during the first 3 days of life in mechanically ventilated infants were associated with a significantly increased risk of moderate to severe periventricular echodensity, large periventricular cysts, grade III/IV intracranial hemorrhage, and cerebral palsy. Neurosonographic abnormalities were highly predictive of cerebral palsy independent of PCO2 measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Diseases↗