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Biomedical subjects

D W Cox

Publications and source records attributed to D W Cox.

At least 163 records · Page 9Linked to original sources
PubMed1983

31P-n.m.r. studies on cerebral energy metabolism under conditions of hypoglycaemia and hypoxia in vitro.

A system has been developed for performing 31P-n.m.r. studies on cerebral tissues superfused in vitro, and gives results comparable with those reported from studies in vivo. Under optimal superfusion conditions [10 mM-glucose and O2/CO2 (19:1)] the tissue concentrations of phosphocreatine and ATP were calculated to be approx. 3.1 and 1.3 mumol/g respectively. When the glucose of the superfusing medium was lowered to 0.5 mM, slightly decreased sugar phosphate peaks were observed, but there was no detectable change in [ATP] or [phosphocreatine]. At 0.2 mM-glucose, significantly decreased concentrations of phosphocreatine and ATP were observed. Substitution of pyruvate plus malate for glucose did not decrease levels of phosphocreatine and ATP. When the superfusing medium was gassed with air/CO2 (19:1; 'mild hypoxia'), there was an appreciable fall in sugar phosphates and phosphocreatine with no detectable effect on ATP. In the presence of N2/CO2 (19:1; 'severe hypoxia', since O2 was not completely excluded), concentrations of phosphocreatine fell considerably, but with little effect on ATP. The results demonstrate the feasibility of studying cerebral energy metabolism in vitro using the non-invasive 31P-n.m.r. technique and are discussed in relation to the sensitivity of cerebral tissues to metabolic insults in vitro and in vivo.

Animals↗
PubMed1983

alpha 2-Macroglobulin in patients with obstructive lung disease, with and without alpha 1-antitrypsin deficiency.

Serum alpha 2-macroglobulin concentrations were measured in 178 patients with emphysema and 115 control subjects of similar age and sex distribution. The study group included 59 PI type Z patients with alpha 1-antitrypsin deficiency, five with the rare alpha 1-antitrypsin null genotype (PI Q0 or --), and seven with alpha 1-antitrypsin deficiency of the rare PI types MmaltonZ or MduarteZ. Individuals with all types of alpha 1-antitrypsin deficiency were found to have significantly increased serum concentrations of alpha 2M (p less than 0.001). These increased concentrations were associated with all types of alpha 1-antitrypsin deficiency, not only with the PI type Z. The highest alpha 2-macroglobulin concentrations were found in the PI Q0 patients (5 with emphysema, 2 with no lung disease), and these patients had almost no circulating alpha 1-antitrypsin. Raised concentrations of serum alpha 2-macroglobulin were not due to emphysema: 86 patients with emphysema, of PI type M, and the normal control subjects had similar average concentrations of alpha 2-macroglobulin. One control subject with an average alpha 2-macroglobulin concentration of only 41% of normal was found.

Adult↗
PubMed1983

A new allele of alpha 1-antitrypsin: PI NADELAIDE.

The allele PI NADELAIDE (PI NADE) was named in accord with nomenclature guidelines and specifies a new co-dominant variant of alpha 1AT. Discovery was achieved by IEF and the isoelectric point of NADE is between N and NHAM. Familial inheritance of PI NADE was demonstrated and both PI M2NADE and PI M3NADE phenotypes were observed. The mobility of PI NADE is identical to PI M by both starch and agarose electrophoresis. PI NADE apparently confers normal alpha 1AT serum concentrations and is probably unrelated to disease.

Alleles↗
PubMed1983

Risk for liver disease in adults with alpha 1-antitrypsin deficiency.

Risk for the development of liver disease was estimated in 115 adults with alpha 1-antitrypsin deficiency, most of whom were of PI type (protease inhibitor type) Z. Seventy-one subjects were ascertained through their disease; 44 were ascertained independently of disease. A low concentration of serum prealbumin was sensitive in detecting impaired liver function and may indicate functioning cell mass, a different parameter than is measured by liver enzymes. Liver disease has usually been considered rare in adults with alpha 1-antitrypsin deficiency. However, the risk for the development of liver disease was relatively high for men between 51 and 60 years of age. The risk for women was lower than that for men. Our study indicates that a periodic assessment of liver function may be warranted for patients with alpha 1-antitrypsin deficiency who are over 40 years of age.

Adult↗
PubMed1983

Restriction fragment length polymorphisms associated with immunoglobulin C gamma genes reveal linkage disequilibrium and genomic organization.

We have demonstrated that restriction fragment length polymorphisms (RFLPs) produced by BamHI can be used as markers for constant (C) region heavy chain genes C psi gamma (C gamma pseudogene), C gamma 2, and C gamma 4. These RFLPs were found nonrandomly associated in the population sample studied. Of the eight combinations (haplotypes) of RFLPs theoretically possible, only two accounted for a total of 88% of the 116 chromosomes examined, a value greater than the total of 25% expected from random segregation of alleles. This indicates considerable linkage disequilibrium between C psi gamma, C gamma 2, and C gamma 4. Quantitative assessment of the degree of association between C gamma gene RFLPs, Gm markers, and switch region RFLPs adjacent to C mu and C alpha 1 revealed that C psi gamma is most tightly associated with C gamma 2 (r = 0.81 and 0.95 for the two common haplotypes), suggesting that C psi gamma maps to a position lying between C alpha 1 and C gamma 2. The association analysis used here should have general applicability for studying the genomic organization of other multigene families.

Alleles↗
PubMed1983

Analysis of a break in chromosome 14 mapping to the region of the immunoglobulin heavy chain locus.

We have detected restriction fragment length polymorphisms associated with the immunoglobulin heavy chain C gamma genes. DNA from both parents of an individual having an unbalanced rearrangement of the long arm of chromosome 14, region q32 [Cox, D. W., Markovic, V. D. & Teshima, I. E. (1982) Nature (London) 297, 428-430], revealed distinctive patterns of BamHI fragments which hybridized with cloned probes from the C gamma 2-C gamma 4 gene cluster. The number of hybridizing fragments in both cases (five) equaled the number of known C gamma genes. Pedigree and densitometric analyses indicated that the proband did not have any maternal complement of C gamma gene-hybridizing fragments. Included on the deleted chromosomal segment was a C gamma gene having properties of the previously reported C gamma pseudogene. We also examined DNA from this family with a probe for the highly polymorphic locus D14S1, which recently was demonstrated to be tightly linked to the C gamma 1 gene locus [Balazs, I., Purrello, M., Rubinstein, P., Alhadeff, B. & Siniscalco, M. (1982) Proc. Natl. Acad. Sci. USA 79, 7395-7399]. EcoRI and EcoRI-BamHI fragments from both parents hybridized with a probe for this locus in DNA from the proband, indicating that, unlike the C gamma gene family, D14S1 was not deleted from the abnormal chromosome. Thus, the chromosomal breakpoint in the proband lies within region 14q32 between the two tightly linked markers, D14S1 and the C gamma 1 heavy chain gene locus. The D14S1 locus must lie proximal to the centromere relative to the C gamma gene family. The genetic variability detected with C gamma gene probes may prove useful for genetic analysis of structural rearrangements involving this region of chromosome 14.

Chromosome Aberrations↗
PubMed1983

Pulmonary function associated with the Mmalton deficient variant of alpha 1-antitrypsin.

We have studied 78 members of a large family in which the Mmalton deficiency allele of alpha 1-antitrypsin (alpha 1AT) is present. Four patients of PI type MmaltonZ (alpha 1AT concentration, 16.4% of normal) had severe emphysema and marked depression in all flow and gas exchange parameters, significantly different from other members of the same family who were normal or had intermediate concentrations of alpha 1AT. Fourteen subjects with PI type MMmalton (alpha 1AT concentration, 63.3% of normal) were compared with 46 PI MM relatives (alpha 1AT, 103.8% of normal) and 14 relatives of PI type MZ (alpha 1AT concentration, 66.5% of normal). Spirometry, flow-volume loops, plethysmography, gas exchange at rest and exercise, and xenon 133 regional lung function were similar in those partially deficient when compared with the normal subjects. There was a trend for impairment of tests of lung function between smoking partially deficient (PI MZ, PI Mmalton) and normal (PI MM) relatives.

Adult↗
PubMed1983

A systematic controlled study of pulmonary abnormalities in rheumatoid arthritis.

We have conducted a prospective comparison of 155 rheumatoid patients and 95 control subjects. Both groups were selected without regard to respiratory status, but were comparable in age, sex and smoking experience. The prevalence of respiratory symptoms, of past respiratory illnesses and of pulmonary function findings of airway obstruction was similar in both groups. However, the rheumatoids showed an increased frequency of chest crackles and abnormal chest radiographs, and had pulmonary function changes suggestive of a restrictive ventilatory defect. These pulmonary abnormalities were associated with smoking, the presence of nonpulmonary extraarticular features, the level of rheumatoid disease activity and treatment with oral corticosteroid or gold.

Adult↗
PubMed1982

Attenuation of evoked field potentials from dentate granule cells by low glucose, pyruvate + malate, and sodium fluoride.

Extracellular field potentials were evoked from granule cells of the dentate gyrus by stimulation of the perforant path of the hippocampal slice, superfused with medium containing 10 mM glucose. Decreasing the glucose concentration to 2 mM caused a large but reversible attenuation of the rate of rise of population excitatory postsynaptic potential (EPSP) and of the population spike amplitude. Similar behaviour was observed in the presence of 5 mM glucose, although the decrease in EPSP was much less marked. Substitution of pyruvate + malate (2 mM, 0.2 mM) for glucose in the superfusion medium strongly depressed both EPSP and population spike. Sodium fluoride (1 mM) attenuated the population spike without affecting the EPSP. It is suggested that the behaviour of the evoked granule cell responses in the presence of lowered glucose or alternative substrates does not correlate with the energy state of the tissue.

Animals↗
PubMed1982

The HLAB*18,BF*F1 in haplotype in type 1 diabetes.

We have investigated the properdin factor B (BF) locus as a possible marker for Type 1 diabetes. The frequencies of the four BF alleles were determined among 70 Type 1 diabetics with onset before age 18 years. The frequency of BF F1 among the diabetics was increased compared with 206 controls (15.7 vs 3.4%). The relative risk (RR) associated with BF F1 was 5.30. The suggestion that BF is most strongly associated with onset of diabetes under 10 years of age was not supported. HBLA 18 was increased (RR = 4.91) and B7 was decreased in frequency (RR = 0.41) among the 62 diabetics tested compared with 238 controls. An association was observed between HLAB 18 and BF F1 among the diabetics. A study of 12 families in which BF*F1 was segregating suggested that BF*F1 and HLAB*18 are components of a haplotype associated with Type 1 diabetes in this population and that both haplotypes of an affected parent may contribute to the development of Type 1 diabetes.

Adolescent↗
PubMed1982

Functional assessment of genetic variants of alpha 1-antitrypsin.

The specific activity of thirteen genetic variants of the protease inhibitor alpha 1-antitrypsin (alpha 1AT) has been determined. Elastase inhibitor activity was assayed protein substrates (elastin and gelatin) and the synthetic substrate N-tert-butoxy-carbonyl-L-alanine p-nitrophenyl ester. The synthetic substrate alpha-N-benzoyl-DL-arginine p-nitroanilide HCl was used to assay trypsin inhibitor activity. The specific activity of alpha 1AT was expressed as serum inhibition/immunological concentration of alpha 1AT. Sera of PI type FM had reduced specific activity with elastase, but not with trypsin. With the possible exception of MP, no other variants showed significant differences in specific activity when compared with normal PI type M.

Elastin↗
PubMed1982

Three new rare variants of alpha 1-antitrypsin.

Three new rare genetic variants of the serum protein alpha 1-antitrypsin (alpha 1-protease inhibitor) have been identified in a Caucasian population. The new alleles in the PI system are PI*EFRA, PT*PCAS, and PI*XALB. When compared with the normal type M by isolectric focusing in polyacrylamide, Efranklin (EFRA) is anodal, and Pcastoria (PCAS) and Xalban (XALB) are cathodal. These variants have been compared with previously described variants by isoelectric focusing and by electrophoresis in agarose and acid starch gels. All three variant alleles appear to be associated with normal amounts of alpha 1-antitrypsin, assayed both by functional and immunological methods.

Adolescent↗
PubMed1982

alpha 2-Macroglobulin production by cultured human fibroblasts.

Alpha 2-macroglobulin (alpha 2M), a high-molecular-weight plasma protease inhibitor has been shown, by both immunological and functional methods, to be produced by cultured adult lung fibroblasts. Cultured skin fibroblasts synthesized approximately one tenth as much alpha 2M as lung fibroblasts. This quantitative difference in alpha 2M production was also demonstrated in fibroblasts of isogenic origin. There was no difference in the amount of alpha 2M produced between adult and fetal fibroblasts of the same tissue type (i.e., of lung or of skin origin). alpha 2M was produced in culture during log-phase growth as well as at confluence. Two other plasma protease inhibitors, C1-esterase inhibitor and a substance immunologically crossreacting with human inter-alpha-trypsin inhibitor, were also made by the cultured fibroblasts. Plasma protease inhibitors not detectable in culture supernatants were alpha 1-antitrypsin, alpha 1-antichymotrypsin, and antithrombin III.

Cell Line↗
PubMed1982

Apolipoprotein and lipoprotein concentrations in familial apolipoprotein C-II deficiency.

Lipoprotein and apolipoprotein concentrations were determined in 11 homozygous and 9 heterozygous subjects for familial apolipoprotein C-II (Apo C-II) deficiency. Apo C-II was not detectable in the homozygotes, with the exception of 1 subject who possessed immunochemically detectable quantities in one of two samples. Apolipoproteins C-III (Apo C-III) and E (Apo E) were elevated 2-3-fold in 9 of 11 homozygotes. Apo C-III, but not Apo E, correlated with triglyceride levels (1500-4100 mg/dl). However, both Apo C-III and Apo E correlated with the cholesterol levels and one another. Apolipoproteins A-I (Apo A-I), A-II (Apo A-II) and B (Apo B) were reduced to approximately 50-60% of normal values in association with very low levels of cholesterol in high density (HDL; 11 +/- 2 mg/dl) and low density (LDL; 19 +/- 6 mg/dl) lipoproteins in the homozygous subjects. These alterations were associated with a marked decrease in the proportion of plasma Apo C-III associated with HDL. The levels of apolipoprotein D (Apo D) were within the normal range. Nine obligate heterozygotes had Apo C-II concentrations (mean 1.8 +/- 0.5 mg/dl; range 1.2-2.7 mg/dl) which were approximately 40-50% of normal values (mean 2.9 +/- 0.9 mg/dl; range 1.7-5.6 mg/dl). The reduction in absolute amounts of Apo C-II was also reflected in a reduction of the ratio Apo C-II/Apo C-III in very low density lipoproteins (VLDL) and in a reduction in the ability of the sera to activate skim milk lipoprotein lipase. The concentrations of Apo A-II, Apo B, Apo C-III and Apo E were normal. Apo A-I concentrations were normal or slightly low in association with slightly reduced concentrations of HDL cholesterol and a low proportion of plasma Apo C-III in HDL in relation to LDL and VLDL in some heterozygotes. It is concluded that the marked alterations in the apolipoprotein levels in homozygous subjects are primarily a reflection of the deficiency of Apo C-II which results in severe hypertriglyceridemia. In heterozygotes, the partial deficiency of Apo C-II appears to result in a minor disturbance of the clearance of the triglycerides and Apo C-III rich particles but no marked changes in the concentrations of total lipids, lipoproteins and apolipoproteins in fasting plasma.

Adolescent↗
PubMed1981

New variants of alpha 1-antitrypsin: comparison of Pi typing techniques.

Four new rare inherited variants (Pi types) of alpha 1-antitrypsin (alpha 1-protease inhibitor) are described. Each variant has been compared with previously reported genetic variants by several techniques used for Pi typing: isoelectric focusing in polyacrylamide gel, starch gel electrophoresis, and agarose gel electrophoresis. Some variants are identical or very similar by one technique but can be clearly distinguished by another technique. Crossed immunoelectrophoresis and gel immunofixation have been used to identify the gel bands as alpha 1-antitrypsin.

Adolescent↗