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PubMed1977

Neuronal depressant effects of diethylester derivatives of excitatory amino acids.

The effect of iontophoretically applied kainic acid diethylester (KDEE) on the firing rate of feline spinal interneurones was investigated and compared with the action of glutamic acid diethyles (GDEE) and aspartic acid diethylester (ADEE). All these esters reversibly reduced spontaneous neuronal firing and increased spike height, KDEE being the most active of this group. KDEE decreased response to glutamate, acetylcholine, and peripheral field stimulation, showing that its depressant action is not due to a selective antagonism of an excitatory putative transmitter.

Acetylcholine↗

PubMed2005

Thermodynamics of membrane elasticity--a molecular level approach to one- and two-component fluid amphiphilic membranes, part II: applications.

The theoretical framework developed in the accompanying publication is applied to a number of experimentally relevant amphiphilic systems. These include the influence of thermodynamic conditions and non-ideal mixing on bending elasticity, ellipsoidal modes of microemulsions and vesicles, hydrocarbon chain coupling in bilayers and the effect of osmotic and hydrostatic pressure on inverse hexagonal (H(II)) phases. It is found that the bending moduli at constant surface tension and constant chemical potentials are markedly different only for two-component membranes and non-ideal mixing with a tendency towards phase separation. The results indicate that non-ideal mixing is the main reason behind the experimentally observed strong compositional dependence of membrane elasticity. It is generally recommended to prefer the bending elastic moduli at constant chemical potentials to those at constant surface tension. A comparison between the area-difference-elasticity (ADE) model and explicit free energy calculations using a molecular model shows a good qualitative agreement for the sphere-to-ellipsoid transition of vesicles. Results for different free energy models of the hydrocarbon chains of amphiphilic molecules suggest that monolayer-monolayer chain coupling is responsible for the relatively higher bending stiffness of bilayers compared to single monolayers. For H(II)-phases an instability at negative pressure differences is predicted.

Computer Simulation↗

PubMed2005

Natural health products and drug disposition.

Botanicals such as herbal products (HPs) and nutraceuticals (NCs) are often regarded as low risk because of their long history of human use. Anecdotal and literature reports of adverse drug events (ADEs) and clinical studies with HPs are increasing, but many of the reports are incomplete and contradictory. These reports need to identify confounding factors and explain contradictory findings if they are to help health care professionals or patients understand what risks are involved. HPs are complex botanicals, not single-active ingredient (SAI) products. Studies can be confounded by different manufacturing processes and formulations, including cosmetics and food supplements; environment; chemotypes; misidentification or adulteration; and factors associated with the patient or user population such as use, total drug load, and genetics. Future studies need to be conducted with characterized product that includes all commercially available related products. Clinical trials should be relevant to the user population and take into account the confounding factors that may influence the interpretation of the findings.

Animals↗

PubMed1992

Effects of a novel prostaglandin, 8-epi-PGF2 alpha, in rabbit lung in situ.

We determined the effects of 8-epiprostaglandin (PG) F2 alpha, a noncyclooxygenase free radical-catalyzed product of arachidonic acid, on pulmonary vascular tone, its potency, and its mechanism of action. 8-Epi-PGF2 alpha (0.5-20 micrograms) was injected into the pulmonary artery (PA) catheter of 10 rabbits whose lungs were perfused in situ with Krebs-Henseleit buffer solution with 3% bovine serum albumin. PA pressure increased from a baseline of 13.5 +/- 0.6 to 25.6 +/- 2.0 cmH2O with 20 micrograms 8-epi-PGF2 alpha. 8-Epi-PGF2 alpha caused a rapid rise in PA pressure followed by a gradual decline over 40-60 min to baseline levels. Double vascular occlusion revealed a twofold increase in arterial resistance at peak rise in PA pressure. The rise in PA pressure with 20 micrograms 8-epi-PGF2 alpha was fivefold greater than with 20 micrograms of the cyclooxygenase-derived prostaglandin PGF2 alpha. The PA pressure response to 8-epi-PGF2 alpha was not altered by either cyclooxygenase block-ade with 150 microM meclofenamate or alpha-receptor blockade with 70 microM phentolamine, but was fully prevented by 40 microM SQ 29548, a thromboxane receptor antagonist. We conclude that in rabbits 8-epi-PGF2 alpha is a potent vasoconstrictor of the pulmonary vasculature, which appears to be due to the activation of SQ 29548-responsive thromboxane receptors.

Animals↗

PubMed2007

Early detection of head and neck cancer: development of a novel screening tool using multiplexed immunobead-based biomarker profiling.

Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease that has been linked to altered immune, inflammatory, and angiogenesis responses. A better understanding of these aberrant responses might improve early detection and prognosis of SCCHN and provide novel therapeutic targets. Previous studies examined the role of multiplexed serum biomarkers in small cohorts or SCCHN sera. We hypothesized that an expanded panel comprised of multiple cytokines, chemokines, growth factors, and other tumor markers, which individually may show some promising correlation with disease status, might provide higher diagnostic power if used in combination. Thus, we evaluated a novel multianalyte LabMAP profiling technology that allows simultaneous measurement of multiple serum biomarkers. Concentrations of 60 cytokines, growth factors, and tumor antigens were measured in the sera of 116 SCCHN patients before treatment (active disease group), 103 patients who were successfully treated (no evidence of disease group), and 117 smoker controls without evidence of cancer. The multimarker panel offering the highest diagnostic power was comprised of 25 biomarkers, including epidermal growth factor, epidermal growth factor receptor, interleukin (IL)-8, tissue plasminogen activator inhibitor-1, alpha-fetoprotein, matrix metalloproteinase-2, matrix metalloproteinase-3, IFN-alpha, IFN-gamma, IFN-inducible protein-10, regulated on activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein-1alpha, IL-7, IL-17, IL-1 receptor-alpha, IL-2 receptor, granulocyte colony-stimulating factor, mesothelin, insulin-like growth factor binding protein 1, E-selectin, cytokeratin-19, vascular cell adhesion molecule, and cancer antigen-125. Statistical analysis using an ADE algorithm resulted in a sensitivity of 84.5%, specificity of 98%, and 92% of patients in the active disease group correctly classified from a cross-validation serum set. The data presented show that simultaneous testing using a multiplexed panel of serum biomarkers may present a promising new approach for the early detection of head and neck cancer.

Adult↗

PubMedDate not supplied

Effect of self-medication with antimalarial drugs on malaria infection in pregnant women in South-Western Nigeria.

OBJECTIVE: To determine the effect of self-medication with chloroquine and pyrimethamine on malaria infection and anaemia during pregnancy. SUBJECTS AND METHODS: The study involved 210 women who attended Ade Oyo Maternity State Hospital, Ibadan, Nigeria. Of these, 156 were pregnant women while 54 were not pregnant (controls). Of the pregnant women, 66 were primigravidae, while 90 were multigravidae. History of treatment of malaria with antimalarial drugs was obtained from the subjects. Gravidity and gestation period were also documented. Two millilitres of blood was withdrawn from each subject, for haematological parameters. Thin and thick films were prepared for malaria parasite identification and quantification. RESULTS: Of the primigravidae and multigravidae 68 and 16.4%, respectively, had taken antimalarial drugs prior to booking. Among primigravidae, only 18% of those with drugs compared with 32% without drugs were malaria-positive. The parasite density was significantly lower among those who took antimalarial drugs than among those who did not (976 +/- 60 versus 2,421 +/- 78, p < 0.05). Similarly, among multigravidae, only 16.4% of those who took antimalarial drugs compared with 34% of those who were not malaria-positive. The parasite density was also significantly lower in multigravidae with drugs than among those without drugs (350 +/- 45 versus 1,000 +/- 65, p < 0.05). The prevalence of anaemia (packed cell volume, PCV < 33) was high, 89% in primigravidae and 70% in multigravidae. Severe anaemia (PCV < 21) was more common in malaria-positive primigravidae and multigravidae than in malaria-negative women. CONCLUSION: The findings indicate that self-medication with chloroquine and pyrimethamine at booking was able to reduce the prevalence of malaria and anaemia in pregnancy.

Anemia↗

PubMed2006

Heritability of refractive error and ocular biometrics: the Genes in Myopia (GEM) twin study.

PURPOSE: A classic twin study was undertaken to assess the contribution of genes and environment to the development of refractive errors and ocular biometrics in a twin population. METHODS: A total of 1224 twins (345 monozygotic [MZ] and 267 dizygotic [DZ] twin pairs) aged between 18 and 88 years were examined. All twins completed a questionnaire consisting of a medical history, education, and zygosity. Objective refraction was measured in all twins, and biometric measurements were obtained using partial coherence interferometry. RESULTS: Intrapair correlations for spherical equivalent and ocular biometrics were significantly higher in the MZ than in the DZ twin pairs (P < 0.05), when refraction was considered as a continuous variable. A significant gender difference in the variation of spherical equivalent and ocular biometrics was found (P < 0.05). A genetic model specifying an additive, dominant, and unique environmental factor that was sex limited was the best fit for all measured variables. Heritability of spherical equivalents of 88% and 75% were found in the men and women, respectively, whereas, that of axial length was 94% and 92%, respectively. Additive genetic effects accounted for a greater proportion of the variance in spherical equivalent, whereas the variance in ocular biometrics, particularly axial length was explained mostly by dominant genetic effects. CONCLUSIONS: Genetic factors, both additive and dominant, play a significant role in refractive error (myopia and hypermetropia) as well as in ocular biometrics, particularly axial length. The sex limitation ADE model (additive genetic, nonadditive genetic, and environmental components) provided the best-fit genetic model for all parameters.

Adolescent↗

PubMed1971

Studies of human sera with cytotoxic activity.

42 human sera showing in vitro cytotoxic activity of restricted or broad HL-A specificities with test human lymphocytes were studied for the molecular and immunoglobulin class of cytotoxic antibody using sucrose gradient separations, DEAE-cellulose chromatography, and Sephadex G-200 gel filtration. Sera originated from patients with previous multiple pregnancies (19), multiply transfused patients (8), subacute bacterial endocarditis (4), systemic lupus (2), and human umbilical cord sera (9). In 32 of 42 instances, predominant cytotoxic activity was found in high molecular weight gradient fractions; however, DEAE chromatographic separations revealed cytotoxic activity in initial buffer fractions containing primarily gammaG globulin. Gradient separations of cytotoxic activity within initial gammaG DEAE fractions showed localization of cytotoxicity only in high molecular weight materials. Confirmation of high molecular weight gammaG cytotoxic activity was obtained by resistance to mercaptoethanol treatment, abolition of activity after absorption only with specific anti-gammaG antisera, and by the finding that high molecular weight cytotoxic activity in gradients or gel filtration run at neutral pH 7.4 became 7S when separations were rerun at an acidic pH of 4.0. Such 7S activity again became rapidly sedimenting when the same fractions were again rerun in gradients at neutral pH.19S gammaM cytotoxic activity was documented in a panel of 15 human sera containing anti-"I" cold agglutinins. In this instance the cytotoxic activity appeared to be related to the cold agglutinin antibody since it was mercaptoethanol sensitive and could be demonstrated in monoclonal antibody eluates containing primarily gammaM. No in vitro protection again cytotoxic effect was demonstrated when isolated human 19S anti-gamma-globulins were aded to the lymphocytotoxic assay system. With the exception of cold agglutinins, human cytotoxic antibodies appear to be primarily gammaG producing in vitro lymphocyte killing either as 7S gammaG globulin or as rapidly sedimenting aggregates or complexes of gammaG molecules.

Anemia, Hemolytic↗

PubMed1978

Effects of alpha adrenergic blockade upon coronary hemodynamics.

The effect of alpha adrenergic block-ade on coronary blood flow regulation at rest was studied in 11 normally innervated patients and 8 cardiac allograft recipients by measuring arterial pressure and coronary sinus blood flow by thermodilution before and after alpha adrenergic blockade with phentolamine. Coronary vascular resistance was calculated by using coronary sinus blood flow and mean arterial pressure, and metabolic demand was estimated by the product of systolic arterial pressure and heart rate. In addition, the coronary sinus blood flow response to tachycardia was examined in 9 innervated patients and 12 denervated patients, with measurements repeated after phentolamine in 8 of the 9 innvervated patients and 6 of the 12 denervated patients. There was a 7.3+/-4.4% increase in coronary sinus blood flow in the innervated patients in response to alpha blockade, whereas the transplanted patients had an 8.2+/-1.8% fall in coronary sinus blood flow, despite equivalent changes in rate pressure product. The innervated patients also demonstrated a significantly greater increase in coronary sinus blood flow than did the transplanted patients during the first 5 s of an abrupt increase in heart rate (26+/-4 vs. 8+/-2.5 ml/min, P <0.001). This early response was blunted after alpha adrenergic blockade. We conclude that there is basal alpha adrenergic tone present on the coronary vasculature in man that is withdrawn by a sudden increase in heart rate.

Adolescent↗

PubMed1995

A simple, safe and efficient anaesthetic breathing system for universal use in rural environments.

A new simple, safe and efficient anaesthetic breathing system, the Humphrey ADE system, is described for universal use on adults and children. Specialist knowledge is not required as it has been designed to be easy to use. Requiring low fresh gas flows of only three to four litres per minute, the system is efficient for spontaneous, manually assisted respiration, and for controlled ventilation with an automatic ventilator. These multiple functions are dependent on only two positions of a single lever. Easy to follow instructions are permanently engraved on the main block.

Anesthesia, Inhalation↗

PubMed1989

The influence of CO2 production and physiological deadspace on end-tidal CO2 during controlled ventilation: a study using a mechanical model.

A mechanical lung model was used to investigate the effect of varying carbon dioxide production and deadspace on the end-tidal carbon dioxide levels achieved during mechanical ventilation when using the Bain, Humphrey ADE, and circle systems. Both factors had significant influence on end-tidal carbon dioxide concentration and could result in values in excess of those considered acceptable in clinical practice. The implications of the results are discussed.

Anesthesia, Closed-Circuit↗

PubMed2003

Controversial treatment of spasticity: exploring alternative therapies for motor function in children with cerebral palsy.

The treatment and management of children with cerebral palsy is an ever-evolving story. In the past 20 years, a number of exciting innovations in treatment have expanded the opportunities to help children. At the same time, the field has experienced a remarkable proliferation of "alternative" therapies-approaches based on ideas about the biologic basis of neurodevelopmental disabilities and their management that differ considerably from conventional thinking in Western medicine. Professionals working with children with cerebral palsy and their families are frequently asked for an opinion about or even endorsement of these new and "promising" approaches to therapy. These can be very difficult to provide when the evidence is limited, peer-reviewed reports are scarce, and the primary source of information is the World Wide Web. The purposes of this article are to discuss briefly why it can be difficult to ascertain whether any treatment--conventional or alternative--does more harm than good, and to consider what rules of evidence can be applied to make a sound judgment about a new treatment. The article then discusses several current controversial alternative therapies, reviewing the available literature and offering a critical appraisal of each. Topics addressed include hyperbaric oxygen therapy, conductive education, the Adeli suit, and therapeutic (subthreshold) electrical stimulation because these approaches have been applied to children with cerebral palsy.

Cerebral Palsy↗

PubMed2006

Twin study on heritability of activity, attention, and impulsivity as assessed by objective measures.

OBJECTIVE: The purpose of this study was to assess heritability of activity, attention, and impulsivity by comparing young monozygotic (MZ) twins with dizygotic (DZ) twins using objective measures. METHOD: The OPTAx test is an infrared motion analysis to record the movement pattern during a continuous performance test. Seventeen MZ and 12 same sexed DZ twin pairs in the range of 6 to 12 years were tested. The zygosity was determined by DNA-fingerprinting. The measures under investigation were activity (microevents and spatial scaling), impulsivity (errors of commission), and attention (accuracy and variability). For statistical analyses, the classical model of Falconer and the ACE and ADE genetic model for twin data were applied in order to estimate the proportion of the variance in activity, impulsivity and attention that is due to genetic effects. RESULTS: The respective coefficients of intraclass correlations in MZ twins ranged between .35 and .65 whereas for DZ twins the correlations were between .12 and .88. The heritability estimates resulting from both models were about 30% for 4 of the 5 measures, but none of these was significantly different from 0. CONCLUSION: We found no significant influence of genetic factors for activity, attention, and impulsivity. The authors conclude that further investigation of heritability of ADHD is necessary using larger sample sizes and objective measures.

Attention↗

PubMed2004

The exceptionally high rate of spontaneous mutations in the polymerase delta proofreading exonuclease-deficient Saccharomyces cerevisiae strain starved for adenine.

BACKGROUND: Mutagenesis induced in the yeast Saccharomyces cerevisiae by starvation for nutrilites is a well-documented phenomenon of an unknown mechanism. We have previously shown that the polymerase delta proofreading activity controls spontaneous mutagenesis in cells starved for histidine. To obtain further information, we compared the effect of adenine starvation on mutagenesis in wild-type cells and, in cells lacking the proofreading activity of polymerase delta (phenotype Exo-, mutation pol3-01). RESULTS: Ade+ revertants accumulated at a very high rate on adenine-free plates so that their frequency on day 16 after plating was 1.5 x 10(-4) for wild-type and 1.0 x 10(-2) for the Exo- strain. In the Exo- strain, all revertants arising under adenine starvation are suppressors of the original mutation, most possessed additional nutritional requirements, and 50% of them were temperature sensitive. CONCLUSIONS: Adenine starvation is highly mutagenic in yeast. The deficiency in the polymerase delta proofreading activity in strains with the pol3-01 mutation leads to a further 66-fold increase of the rate of mutations. Our data suggest that adenine starvation induces genome-wide hyper-mutagenesis in the Exo- strain.

Adenine↗

PubMed2001

Development of Dengue virus type 2 replicons capable of prolonged expression in host cells.

BACKGROUND: As part of a program to develop a Dengue virus vaccine which avoids the deleterious effects of antibody dependent enhancement (ADE) of infection mediated by antibodies to Dengue virus structural proteins, we have begun to investigate the possibility of designing Dengue vaccines based on non-structural proteins. RESULTS: Dengue constructs which lack major structural proteins replicate intracellularly in tissue culture. These replicons are capable of prolonged expression of Dengue virus non-structural proteins for at least seven days in culture. CONCLUSIONS: Dengue virus genomes lacking major structural proteins can, like other flaviviruses, replicate intracellularly and express virus non-structural proteins with minimal toxicity to host cells. These findings pave the way for the development of dengue virus replicons as a form of live, attenuated virus vaccine.

Animals↗

PubMed2004

A unifying mechanism in the initiation of cancer and other diseases by catechol quinones.

The first step in cancer initiation is the reaction of chemical carcinogens with DNA to form stable adducts, which remain in DNA unless removed by repair, and depurinating adducts, which detach from DNA following destabilization of the glycosyl bond. Depurinating DNA adducts of polycyclic aromatic hydrocarbons play a major role in the initiation of cancer, as shown by the correlation between depurinating adducts and oncogenic mutations of the H-ras oncogene in mouse skin. Following these results, experiments on the metabolism of estrogens, formation of depurinating DNA adducts, carcinogenicity, mutagenicity, and cellular transformation have led us to the hypothesis that certain metabolites of endogenous estrogens--in particular, estradiol(estrone)-3,4-quinones--can react with DNA to form depurinating adducts at the N-3 of Ade and the N-7 of Gua. Depurination of these adducts can generate critical mutations by error-prone repair to initiate breast, prostate, and other cancers. The oxidation mechanism of catechols to quinone compounds includes not only natural estrogens, but also synthetic estrogens, such as hexestrol and the human carcinogen diethylstilbestrol, which react with DNA to form N3Ade and N7Gua adducts, presumably to initiate cancer. Furthermore, the initiating mechanism of the leukemogen benzene involves oxidation of catechol to catechol quinone, which reacts with DNA to form N3Ade and N7Gua adducts. The quinone of the neurotransmitter dopamine can also react with DNA to form N3Ade and N7Gua adducts. The subsequent mutations could be at the origin of Parkinson's and other neurodegenerative diseases. In summary, the apurinic sites produced in DNA from the loss of these depurinating adducts can be converted into mutations by error-prone repair, which may initiate cancer and other diseases.

Animals↗

PubMed2005

A yeast artificial chromosome-splitting vector designed for precise manipulation of specific plant chromosome region.

A yeast artificial chromosome (YAC) splitting vector, pKI01, was constructed for manipulating plant chromosome fragments cloned as YACs in order to transfer specific regions of the fragments into plant cells. Vector pKI01 consists of Km(r) and ADE2 genes (selective markers for plant and yeast transformants, respectively), inverted telomeric repeats Tr and CEN4. To demonstrate the utility of pKI01, YAC CIC9e2 harboring a 590-kb fragment from Arabidopsis thaliana chromosome 5 was split into specific fragments. A 1-kb target region positioned 100 kb from the right end of the 590 kb fragment was cloned into pKI01. The resultant plasmid, pKY03, was introduced into Saccharomyces cerevisiae harboring YAC CIC9e2. The Ade+ transformants were found to contain two new YACs of 490 and 100 kb, and to lack the original 590 kb YAC, consistent with the expected splitting event. To release the desired middle region of YAC CIC9e2, two additional splitting vectors were constructed, pKY11 and pKY14. By conducting two rounds of splitting, i.e., the first round 100 kb from the right end of YAC CIC9e2 with pKY11 to generate 490 and 100 kb YACs and a second round 50 kb from the right end of the new 490 kb YAC to generate 440 and 50 kb YACs, the middle 50 kb region of a plant chromosome fragment harboring Km(r) was successfully released as a split YAC. These results indicate that YAC splitting vectors as constructed in this study are useful for generating any desired plant chromosome fragment as a YAC for eventual re-introduction into plant cells.

Arabidopsis↗

PubMed2001

Adenine deaminase activity of the yicP gene product of Escherichia coli.

During previous work on deriving inosine-producing mutants of Escherichia coli, we observed that an excess of adenine added to the culture medium was quickly converted to hypoxanthine. This phenomenon was still apparent after disruption of the known adenosine deaminase gene (add) on the E. coli chromosome, suggesting that, like Bacillus subtilis, E. coli has an adenine deaminase. As the yicP gene of E. coli shares about 35% identity with the B. subtilis adenine deaminase gene (ade), we cloned yicP from the E. coli genome and developed a strain that overexpressed its product. The enzyme was purified from a cell extract of E. coli harboring a plasmid containing the cloned yicP gene, and had significant adenine deaminase [EC 3.5.4.2] activity. It was deduced to be a homodimer, each subunit having a molecular mass of 60 kDa. The enzyme required manganese ions as a cofactor, and adenine was its only substrate. Its optimum pH was 6.5-7.0 and its optimum temperature was 60 degrees C. The apparent Km for adenine was 0.8 mM.

Aminohydrolases↗