Evidence for nu -bar micro--> nu -bare Oscillations from the LSND Experiment at the Los Alamos Meson Physics Facility.
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Journal Article↗
Biomedical subjects
D Smith
Publications and source records attributed to D Smith.
Exon coconversion biases accompanying intron homing: battle of the nucleases.
Intron homing in phage T4 occurs in the context of recombination-dependent replication, by virtue of intron-encoded endonucleolytic activity. After the td intron endonuclease I-TevI cleaves the intronless recipient 23 and 25 nucleotides upstream of the intron insertion site, exonucleolytic degradation is required for recombination to proceed. This resection process results in coconversion of exon sequences flanking the intron. In a genetic system designed to study coconversion of flanking markers, we demonstrate that although there is a bidirectional polarity gradient, coconversion can be highly asymmetric. Furthermore, we show that the coconversion of flanking markers favors exon I sequences, upstream of the I-TevI cleavage site. These data are consistent with the asymmetric features of the homing pathways that have been invoked for intron mobility in phage T4. Moreover, these results are in accord with the finding that once the td homing-site substrate is cleaved, I-TevI remains bound to the downstream cleavage product, protecting against exonucleolytic degradation, and thereby limiting the extent of coconversion into exon II. The results suggest that recombination events are influenced by a competition between the homing endonuclease and exonucleases for sequences downstream of the I-TevI cleavage site, thereby implying a role for the homing endonuclease in the repair process.
Bacteriophage T4↗
Brain cell membrane Na+,K(+)-ATPase activity following severe hypoxic injury in the newborn piglet.
This study tests the hypothesis that severe brain hypoxia causes decreased Na+,K(+)-ATPase activity, resulting in permanent alterations in the neuronal cell membranes. Seventeen anesthetized piglets (normoxic control (NC), no recovery after hypoxia (Group 1), 6 h normoxic recovery (Group 2), and 48 h normoxic recovery (Group 3)) were studied. Hypoxia was induced by lowering the FiO2 to maintain PCr/Pi ratio at 25% of baseline for 1 h as monitored by 31P-NMR spectroscopy. PCr/Pi returned to 57% of baseline by 6 h and was normal by 48 h. At termination, cortical tissue Na+,K(+)-ATPase activity was determined. Na+,K(+)-ATPase activity was measured in cortical membrane preparations by determining the rate of ATP hydrolysis. NC membranes had Na+,K(+)-ATPase activity of 58.3 +/- 1.3 microM Pi/mg protein/h (mean +/- S.E.M.). Na+,K(+)-ATPase activity was reduced in Groups 1, 2, and 3 (45.8 +/- 1.3, 47.4 +/- 3.6, 48.7 +/- 2.9 microM Pi/mg protein/h) (P < 0.05 compared to NC). There was no difference in enzyme activity among Groups 1, 2, or 3. The data show that in spite of recovery of neuronal oxidative phosphorylation (PCr/Pi) by 48 h, there is a permanent decrease in Na+,K(+)-ATPase activity in cells that have undergone severe hypoxic injury. The persistent decrease in Na+,K(+)-ATPase activity indicates ongoing cell injury following severe cerebral hypoxia, and that recovery of oxidative phosphorylation as indicated by PCr/Pi values cannot be used as an index of recovery of cell function.
Animals↗
The serotonin transporter is a potential susceptibility factor for bipolar affective disorder.
The serotonin transporter is a strong candidate for aetiological involvement in affective disorders and psychosis. We analysed a VNTR in intron 2 of the human serotonin transporter gene (hSERT) for allelic association with bipolar affective disorder, unipolar depression and schizophrenia. An increased frequency of allele 12 of the VNTR was observed in subjects with bipolar affective disorder (n = 191; chi 2 p = 0.00048 by allele) but not unipolar depression (n = 86; chi 2 p = 0.18, ns) or schizophrenia (n = 129; chi 2 p = 0.08, ns), although a trend towards an excess of allele 12 was observed for the latter. There was also a significant difference in the frequency of allele 12 between bipolar affective disorder and unipolar depression (p = 0.0087). The relative risk for bipolar affective disorder with respect to allele 12 was 1.84 (95% CI 0.97-3.56) for heterozygotes, and 3.10 (95% CI 1.60-6.07) for homozygotes, with evidence for a gene-dosage effect. Because allele 12 is common in the population, the attributable risk is 50.8% (95% CI 14.5%-73.3%). We hypothesize that either the VNTR affects regulation of expression of hSERT at the transcriptional level or it is in linkage disequilibrium with another functional polymorphism in the gene, and this results in an increased risk for the development of bipolar affective disorder.
Alleles↗
A clinical trial of the effects of estrogen in acutely psychotic women.
This study was a preliminary open clinical trial aimed at exploring the hypothesis that estrogen may provide protection against schizophrenia in women. Eleven women with acute psychotic symptoms, as scored on the BPRS, SAPS and SANS, had 0.02 mg estradiol added to neuroleptic treatment for eight weeks. Their response was compared to seven women with similar symptom severity receiving neuroleptic treatment alone. Both groups had baseline hormonal assays of estrogen, progesterone, LH and FSH and underwent regular psychopathology ratings during the eight weeks. The group receiving the estradiol adjunct showed more rapid improvement in psychotic symptoms compared with the group receiving neuroleptics only. This difference was not sustained for the entirety of the trial. Both groups reached similar levels of recovery by the eighth week. These results suggest that estradiol may have antipsychotic properties and/or act as a catalyst for neuroleptic responsiveness in women with schizophrenia.
Acute Disease↗
GDNF signalling through the Ret receptor tyrosine kinase.
Mutational analysis in humans and mice has demonstrated that the Ret, the product of the c-ret proto-oncogene, a member of the receptor tyrosine kinase (RTK) superfamily, is essential for development of the enteric nervous system and kidney. Despite the established role of Ret in mammalian embryogenesis, its cognate ligand(s) is currently unknown. Here we demonstrate, by using a Xenopus embryo bioassay, that glial-cell-line-derived neurotrophic factor (GDNF), a distant member of the transforming growth factor (TGF)-beta superfamily, signals through the Ret RTK. Furthermore, using explant cultures from wild-type and Ret-deficient mouse embryos, we show that normal c-ret function is necessary for GDNF signalling in the peripheral nervous system. Our data strongly suggest that Ret is a functional receptor for GDNF, and that GDNF, in addition to its potential role in the differentiation and survival of central nervous system neurons, has profound effects on kidney organogenesis and the development of the peripheral nervous system.
Animals↗
The activity of a blood type B specific exoglycosidase from Glycine max.
Soluble antigens, enzyme-linked immunosorbent assays (ELISA), and cell suspension assays were used to study the blood group B activity of Glycine max (soybean) alpha-D-galactosidase. The enzyme readily hydrolyzed the terminal alpha-D-galactosyl of the B antigen under a variety of conditions, converting it to H antigen. Conversion of the B antigen to H antigen produces blood type O which is universally transfusable. These preliminary studies are important in determining optimal conditions for enzymatic conversion of blood type B to O erythrocytes if efficient large-scale production of enzymatically converted, universally transfusable red blood cells is to be achieved.
ABO Blood-Group System↗
Rolipram: antidepressant used in Europe and Japan might have promise against TNF, HIV.
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AIDS-Related Opportunistic Infections↗
Identification of the domains of neuronal nitric oxide synthase by limited proteolysis.
Nitric oxide synthase (EC 1.14.13.39) binds arginine and NADPH as substrates, and FAD, FMN, tetrahydrobiopterin, haem and calmodulin as cofactors. The protein consists of a central calmodulin-binding sequence flanked on the N-terminal side by a haem-binding region, analogous to cytochrome P-450, and on the C-terminal side by a region homologous with NADPH:cytochrome P-450 reductase. The structure of recombinant rat brain nitric oxide synthase was analysed by limited proteolyis. The products were identified by using antibodies to defined sequences, and by N-terminal sequencing. Low concentrations of trypsin produced three fragments, similar to those in a previous report [Sheta, McMillan and Masters (1994) J. Biol. Chem. 269, 15147-15153]: that of Mr approx. 135000 (N-terminus Gly-221) resulted from loss of the N-terminal extension (residues 1-220) unique to neuronal nitric oxide synthase. The fragments of Mr 90000 (haem region) and 80000 (reductase region, N-terminus Ala-728) were produced by cleavage within the calmodulin-binding region. With more extensive trypsin treatment, these species were shown to be transient, and three smaller, highly stable fragments of Mr 14000 (N-terminus Leu-744 within the calmodulin region), 60000 (N-terminus Gly-221) and 63000 (N-terminus Lys-856 within the FMN domain) were formed. The species of Mr approx. 60000 represents a domain retaining haem and nitroarginine binding. The two species of Mr 63000 and 14000 remain associated as a complex. This complex retains cytochrome c reductase activity, and thus is the complete reductase region, yet cleaved at Lys-856. This cleavage occurs within a sequence insertion relative to the FMN domain present in inducible nitric oxide synthase. Prolonged proteolysis treatment led to the production of a protein of Mr approx. 53000 (N-terminus Ala-953), corresponding to a cleavage between the FMN and FAD domains. The major products after chymotryptic digestion were similar to those with trypsin, although the pathway of intermediates differed. The haem domain was smaller, starting at residue 275, yet still retained the arginine binding site. These data have allowed us to identify stable domains representing both the arginine/haem-binding and the reductase regions.
Amino Acid Sequence↗
Levels of 5-hydroxymethyl-2'-deoxyuridine in DNA from blood as a marker of breast cancer.
BACKGROUND: Oxidative DNA damage can result from numerous endogenous metabolic processes as well as from exposure to environmental and dietary oxidants. One important type of oxidative DNA damage is the formation of hydroxylated DNA bases. This type of DNA damage may have a role in carcinogenesis. METHODS: We examined the levels of a hydroxylated thymine residue, 5-hydroxy-methyl-2'-deoxyuridine, in DNA obtained from the peripheral blood of breast cancer patients and control women. The isolated DNA was analyzed for levels of 5-hydroxymethyl-2'-deoxyuridine by gas chromatography with mass spectral detection. RESULTS: The levels of this modified base were significantly higher in 25 breast cancer patients compared with 38 controls, with levels of 0.112 +/- 0.046 in the cancer patients versus 0.083 - 0.025 in the controls, given as pg 5-hydroxymethyl-2'-deoxyuridine/ng thymidine, mean +/- standard deviation (P = 0.019). After controlling for various covariates, the adjusted mean levels of oxidative DNA damage were still significantly higher in women with breast cancer relative to controls. CONCLUSIONS: These results indicate that the levels of 5-hydroxymethyl-2'-deoxyuridine in DNA from peripheral nucleated blood may be potentially useful as a marker of breast cancer.
Biomarkers, Tumor↗
Long-term benefits of aggressive treatment for primary colorectal cancer.
The long-term follow up of 128 colorectal cancer patients is reported. Seventy-nine percent (101/128) of the patients had curative resections: 70 patients had radical lymphadenectomies with wide removal of tumor-adjacent nodes, and 31 patients had standard resections. The 5-year overall survival rates for Dukes' stage B and C patients and for all rectosigmoid cancer patients significantly favored radical resection (60% vs. 38%, 57% vs. 29%, respectively, P < 0.05). Tumor-free survival rates were also higher after radical lymphadenectomy but did not reach statistical significance. Eleven percent (14/128) of the patients required multiorgan resections, and/or preoperative radiation to render fixed cancers resectable, and these patients had a 10-year tumor-free survival rate of 45%, compared to zero % 5-year survival for the 27 patients who underwent palliative procedures (P < 0.01). These results confirm that many colorectal cancer patients will be cured with aggressive treatment and they support the need for a controlled trial for evaluation of lymphadenectomy for this disease.
Adult↗
Massive gastrointestinal hemorrhage from AIDS-related Kaposi's sarcoma confined to the small bowel managed with radiation.
A > 50% incidence of Kaposi's sarcoma (KS) of the gastrointestinal tract has been seen in acquired immunodeficiency syndrome (AIDS) patients with cutaneous KS. Although gastrointestinal Kaposi's sarcoma (GIKS) is usually asymptomatic, hemorrhages from the oral cavity, esophagus, stomach, and large bowel have occurred in this disease. We describe a patient with acute, massive gastrointestinal hemorrhage from GIKS confined to the small bowel who was treated with chemotherapy, surgery, and radiation. To the best of our knowledge, this is the first reported case of AIDS-related GIKS limited to the small bowel. Although chemotherapy is generally used successfully to palliate diffuse GIKS, we report that radiation was an effective modality that rapidly resulted in resolution of considerable local bleeding and could be used in such cases as an alternative to surgery. Details of this case history, including radiographs, are presented.
Acquired Immunodeficiency Syndrome↗
Effect of allowing for ethnic group in prenatal screening for Down's syndrome.
We conducted a study to investigate ethnic group differences in levels of serum markers used in screening for Down's syndrome [serum alpha-fetoprotein (AFP), unconjugated oestriol (uE3), total human chorionic gonadotrophin (hCG), free alpha- and free beta-hCG, and dimeric inhibin-A], to estimate the extent to which maternal weight differences between ethnic groups explain these differences, and to estimate the effect of adjusting for ethnic group and maternal weight on screening performance. Serum measurements were taken from women who were screened prenatally for Down's syndrome. AFP, uE3, and hCG concentrations were available from 9462 white, 4215 black, and 4392 South Asian women with singleton pregnancies without Down's syndrome or neural tube defects between 15 and 22 weeks' gestational age. Frozen serum samples were available from a subset of 922 white, 449 black, and 135 South Asian women and were used for measurement of free alpha-hCG, free beta-hCG, and inhibin. Values were expressed as multiples of the median (MOM) for women of the same gestational age. There were statistically significant differences in the serum marker levels between ethnic groups that were not explained by differences in maternal weight. The main differences were found in black women compared with white women; black women had serum AFP levels 22 per cent higher (95 per cent confidence interval 20-24 per cent), total hCG levels 19 per cent higher (16-22 per cent), and free beta-hCG levels 12 per cent (3-21 per cent) higher. The other differences were less than 10 per cent. Adjusting for ethnic group only had a small estimated effect on screening performance: a maximum of about 0.5 per cent extra detection at a 5 per cent false-positive rate. At a fixed risk cut-off level, the false-positive rate will not be materially different between different ethnic groups. Adjusting serum markers for ethnic groups improves Down's syndrome screening performance to a very small extent. It is worthwhile because of its established value in AFP screening for open neural tube defects.
Asian People↗
The novel selected-ion flow tube approach to trace gas analysis of air and breath.
We present an overview of the development and use of our selected-ion flow tube (SIFT) technique as a sensitive, quantitative method for the rapid, real-time analysis of the trace gas content of atmospheric air and human breath, presenting some pilot data from various research areas in which this method will find valuable application. We show that it is capable of detecting and quantifying trace gases, in complex mixtures such as breath, which are present at partial pressures down to about 10 parts per billion. Following discussions of the principles involved in this SIFT method of analysis, of the experiments which we have carried out to establish its quantitative validity, and of the air and breath sampling techniques involved, we present sample data on the detection and quantification of trace gases on the breath of healthy people and of patients suffering from renal failure and diabetes. We also show how breath ammonia can be accurately quantified from a single breath exhalation and used as an indicator of the presence in the stomach of the bacterium Helicobacter pylori. Health and safety applications are exemplified by analyses of the gases of the gases of cigarette smoke and on the breath of smokers. The value of this analytical method in environmental science is demonstrated by the analyses of petrol vapour, car exhaust emissions and the trace organic vapours detected in town air near a busy road. Final examples of the value of this analytical method are the detection and quantification of the gases emitted from crushed garlic and from breath following the chewing of a mint, which demonstrate its potential in food and flavour research. Throughout the paper we stress the advantages of this SIFT method compared to conventional mass spectrometry for trace gas analysis of complex mixtures, emphasizing its selectivity, sensitivity and real-time analysis capability. Finally, we note that whilst the current SIFT is strictly laboratory based, both transportable and portable instruments are under construction and development. These instruments will surely extend the application of this analytical technique into more areas and allow greater exploitation of their on-line and real-time features.
Air↗
Effects of Outward Bound Experience as an adjunct to inpatient PTSD treatment of war veterans.
There is a paucity of studies on Outward Bound Experiences (OBE) with adult psychiatric populations and, more notably, with trauma victims. This study evaluates the efficacy of OBE as an adjunct to specialized inpatient PTSD treatment with survivors of chronic combat-related PTSD (N = 219) at two Veterans Administration Medical Centers. On several measures of PTSD and general adaptation, results showed that the five-day OBE did not differ from standard treatment of PTSD survivors. Two other issues were addressed: identification of successful and non-successful subjects as a result of OBE, and exploration of objective versus subjective measures among this chronic group. Finally, as a post-study analysis, inferred curative components of the OBE were discussed as each appeared to impact on the participants.
Adult↗
Cell kinetics in vivo of human breast cancer.
Rates of cell proliferation within tumours may provide prognostic information and help in the rational administration of chemotherapy and radiotherapy. In vivo labelling with 5-bromo-2'-deoxyuridine (BrdU) was used in 89 women with breast cancer to determine the labelling index for BrdU (BLI), the length of S phase (TS) and the potential doubling time of the tumour (Tpot). Kinetic data were obtained in 84 patients. The median BLI was 3.2 per cent, TS 12 h, and Tpot 12.5 days. There was no systematic difference in the labelling index determined by flow cytometry and by manual counting on sections. Labelling indices were significantly higher in aneuploid tumours, and in tumours not expressing oestrogen receptors, but were not correlated with tumour size, nodal status, or expression of c-erbB2. In vivo measurement of tumour cell kinetics can be made rapidly and reliably in the majority of human breast cancers, and may have a role to play in planning therapy.
Breast Neoplasms↗
Silicon and silicone levels in patients with silicone implants.
Although a potential link between silicone gel breast implants and autoimmune connective tissue disease has been suggested, none has been proven. The potential role of silicone as an immune adjuvant remains very controversial. Currently available techniques do not easily allow precise measurements of silicone in tissues. However, all compounds containing silicon (which would include silicone) can be measured accurately. The present study was designed to measure silicon levels in the fibrous capsules of patients with silicone-gel breast implants, saline breast implants and silicone inflatable penile prostheses. Baseline control silicon levels were obtained from the breast tissue of patients undergoing breast reduction, who had no exposure to breast implants. All silicon measurements were carried out using atomic absorption spectrometry with a graphite furnace. The mean silicon levels in 16 breast tissue control samples from 8 patients undergoing breast reduction varied from 0.046 to 0.742 micrograms/g dry weight, with the median mean being 0.0927. The median silicon level in capsules from 6 patients with saline implants was 7.7 micrograms/g (range 36.6). The median silicon level in capsules from 5 patients with silicone inflatable penile prostheses was 19.5 micrograms/g (range 34.8). Although the levels of silicon in capsules of patients with saline breast prostheses and penile implants were higher than in control samples, they were much lower than those from the capsules of the 58 gel implants (median 9979 micrograms/g). Of the 58 silicone gel breast implants (from 20 patients with bilateral implant removal and 18 patients with unilateral removal) which had been inserted from 1974 to 1990, 28 were intact, 8 had pinhole leaks, and 22 were ruptured. Median capsule silicon levels and ranges for all 58 implants, for intact only, for leaking, and for ruptured were: 9979 (152,000), 10,477 (88,703), 6592 (65,396), and 9922 (152,387) micrograms/g respectively. There were no significant differences in silicon levels associated with implant status, duration in situ, or year of implantation. Capsule contracture was not associated with higher levels of capsule silicon. Capsule silicon levels were about 10(6) times higher than previously assayed blood silicon levels. This may be because silicone released from implants remains localized in capsular tissue, or because blood-borne silicone is quickly excreted. Using 29Si nuclear magnetic resonance spectroscopy, no detectable silicone was found in the blood of 7 control women and 7 women with silicone-gel implants (5 with known implant rupture).
Breast Implants↗
An analysis of the cost of clinical surveillance after primary therapy for women with early stage invasive breast cancer.
Routine surveillance for distant metastases in women with early stage breast cancer has limited clinical utility and can result in large medical care costs. In order to estimate breast cancer surveillance costs, we used the results of a survey administered to a random sample of physician members of the American Society of Clinical Oncology. The survey measured the frequency in which radiographic and laboratory tests are ordered for postmenopausal women with stage I or II breast cancer after the completion of surgery and radiation or adjuvant chemotherapy if indicated. There were 209 completed surveys representing a response rate of 48%. The volume of tests ordered was expressed in terms of Medicare's relative value units (RVUs) and 1993 cost equivalents. The mean total RVUs over 5 years post-diagnosis was 43.8 (interquartile range 30.1-54.2) which represents a cost of $1369 using the 1993 Medicare conversion factor of $31.249. A cumulative logistic regression model categorized RVUs according to intensity of care (minimal, average, and intensive). While medical oncologists compared to surgeons and radiation oncologists, and physicians practicing in the Northeast and Midwest, compared to those practicing in the South and West, were more likely to adopt an intensive practice style, these differences were not statistically significant (p = 0.1). None of the other provider characteristics evaluated, including gender, prior experience, and practice type, had a significant effect on physician practice in a multivariate model. The data showed a wide variation among providers in surveillance practice patterns that was largely unexplained by physician demographics. These results are consistent with the physician practice style hypothesis which suggests that wide variations in treatment patterns result from uncertainty regarding effectiveness of care.
Breast Neoplasms↗