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Biomedical subjects

J M Adams

Publications and source records attributed to J M Adams.

At least 199 records · Page 11Linked to original sources
PubMed1981

Retrolental fibroplasia: efficacy of vitamin E in a double-blind clinical study of preterm infants.

We performed a double-blind study in 101 preterm infants who weighed less than or equal to 1500 g at birth, who had respiratory distress, and who survived for at least four weeks, to evaluate the efficacy of oral vitamin E in preventing the development of retrolental fibroplasia. Weekly indirect ophthalmologic examinations begun when the infants were three weeks old revealed a significant decrease in the incidence of retrolental fibroplasia greater than or equal to Grade III (P less than 0.03) and greater than or equal to Grade II (P less than 0.05) (McCormick classification) in the 50 infants given 100 mg of vitamin E per kilogram of body weight per day as compared with 51 given 5 mg per kilogram per day (controls). When multivariate analysis was applied to the controls, five risk factors were identified: gestational age, level and duration of administration oxygen, intraventricular hemorrhage, sepsis, and birth weight. When multivariate analysis was applied to both control and treatment groups, the severity of retrolental fibroplasia was found to be significantly reduced in infants given 100 mg of vitamin E (P = 0.012).

Administration, Oral↗
PubMed1981

Recombination events near the immunoglobulin Cmu gene join variable and constant region genes, switch heavy-chain expression, or inactivate the locus.

Immunoglobulin heavy-chain expression is initiated by recombination between a variable region (VH) gene and one of several joining region (JH) genes located near the mu constant region (Cmu) gene, and the active VH gene can subsequently switch to another CH gene. That the general mechanism for CH switching involves recombination between sites within the JH-Cmu intervening sequence and the 5' flanking region of another CH gene is supported here by Southern blot hybridization analysis of eight IgG- and IgA-secreting plasmacytomas. An alternative model requiring successive VH linkage to similar JH clusters near each CH gene is shown to be very unlikely since the mouse genome appears to contain only one complement of the JH locus and no JH gene was detectable within large cloned sequences flanking germline C gamma 3 and C gamma 1 genes. Thus, VH-JH joining and CH switching are mediated by separate regions of "the joining-switch" or J-S element. In each plasmacytoma examined, the J-S element had undergone recombination within both the JH locus and the switch region and was shown to be linked to the functional CH gene in an IgG3, and IgG1, and three IgA secretors. Both JH joining and CH switching occurred by deletion of DNA. Switch recombination occurred at more than one site within the J-S element in different lines, even for recombination with the same CH gene. Significantly, although heavy-chain expression is restricted to one allele ("allelic exclusion"), all rearranged in each plasmacytoma. Some rearrangements were aberrant, involving, for example, deletion of all JH genes from the allele. Hence, an error-prone recombination machinery may account for allelic exclusion in many plasmacytomas.

Animals↗
PubMed1981

Ventilatory responses to hypocapnic vertebral artery perfusion in intact and carotid body denervated dogs.

The ventilatory responses to step changes in vertebral artery PCO2 were investigated in intact and carotid body denervated dogs. The steady-state ventilatory responses of the denervated dogs were less than those of intact dogs. However, when expressed as a ratio to the control ventilation there was no difference between the two groups. While the arterial PCO2 was held at 56 mm Hg by adding CO2 to the inspired air the perfusion of the vertebral arteries was switched from the dog's own arterial supply to hypocapnic blood. The ventilation of the denervated dogs decreased at a faster rate (half time = 130 +/- 9 sec) to a level less than the room air control ventilation. The ventilation in the intact dogs decreased at a slower rate (half time = 184 +/- 23 sec) and was maintained above the room air control level after ten minutes of hypocapnic perfusion. Increasing the medullary blood flow, as measured with radiolabeled microspheres, augmented the rate of decline of ventilation in intact dogs. We conclude, (1) the influence of the peripheral chemoreceptors appears to increase as central drive is decreasing, and (2) the remaining time course of the decrease in ventilation is related to the rate of brain stem perfusion.

Animals↗
PubMed1981

Plasmacytomas with more than one immunoglobulin kappa mRNA: implications for allelic exclusion.

Although only one allele of an immunoglobulin gene is thought to be expressed as a polypeptide by a given lymphocyte ("allelic exclusion"), three murine plasmacytomas were found to contain more than one kappa light chain mRNA species, as evidenced by the sequences of distinct kappa cDNA clones. Two different kappa cDNA sequences were cloned from BFPC 61 microsomal mRNA, two from MOPC 173, and three from S107. One cDNA sequence from each tumor matches the known secreted polypeptide, while the variant sequences differ in the variable (V) region. Hence fusion of a V kappa gene to a joining (J kappa) gene has occurred independently on separate homologous chromosomes and each allele is transcriptionally competent. The BFPC 61 variant sequence contained a normal V kappa sequence linked out of phase to J kappa 2; hence allelic exclusion in this line is accounted for by an error in DNA rearrangement. One S107 variant cDNA has an untranslatable sequence linked to J kappa--C kappa and may derive from a non-V kappa or pseudo-V kappa gene fused to J kappa. Another S107 variant cDNA, however, has a proper V kappa linked in phase to J kappa (albeit missing the first two germ-line J kappa codons) and the MOPC 173 variant sequence also contains a proper V kappa--J kappa join, although it does not encode a tryptophan residue common to all immunoglobulin chains. The presence of two potentially expressible kappa mRNAs in both S107 and MOPC 173 suggests that allelic exclusion does not hold in all lymphocytes, or that it sometimes reflects events subsequent to mRNA production, such as inability of certain kappa chains to assemble properly with the heavy chain. These observations are compatible with a stochastic model for allelic exclusion in which productive and nonproductive V--J recombination events occur at a certain frequency for each allele.

Alleles↗
PubMed1981

An association between retinopathy of prematurity and intraventricular hemorrhage in very low birth weight infants.

An association between cicatricial retinopathy of prematurity and intraventricular hemorrhage in very low birth weight infants was investigated retrospectively. Newborns were studied who weighed less than or equal to 1500 g at birth, who were less than or equal to 32 weeks gestational age and appropriate by weight, and admitted in the first 24 hours of life to our Neonatal Intensive Care Unit. Diagnosis of retinopathy of prematurity was made by retinal examination at approximately 4 weeks of age. Diagnosis of intraventricular hemorrhage was made by computerized tomography and clinical findings. A total of 138 infants were studied and divided into two groups: (A) birth weight less than or equal to 1000 g (31); (B) birth weight 1001--1500 g (107). There was a statistically significant association between cicatricial retinopathy of prematurity and intraventricular hemorrhage in both groups. There were no statistical differences between birth weight, gestational age, duration of oxygen therapy, highest oxygen concentration received, Apgar scores, incidence of hyaline membrane disease and patent ductus arteriosus between cicatricial retinopathy of prematurity and no retinopathy of prematurity patients in either group. This association may be an important consideration in the pathogenesis of both vascular diseases.

Cerebral Hemorrhage↗
PubMed1981

Sets of immunoglobulin V kappa genes homologous to ten cloned V kappa sequences: implications for the number of germline V kappa genes.

To count V kappa genes homologous to particular V kappa nucleotide sequences, thereby permitting estimates for the total V kappa repertoire, we hybridized 10 cloned V kappa cDNA sequences to restriction fragments of mouse embryo DNA (Southern blots). Particular probes labeled up to 17 fragments, of which up to 8 were strongly labeled. This indicates that the germline contains sets of related V kappa genes. Only 4 nonoverlapping gene sets of 16-22 genes each were found. Assuming that the probes used are a random sample of the V kappa pool, the pattern repetitions suggest that the germline contains a total of about 5 distinct V kappa gene sets and about 90 V kappa genes. Correlating sets of strongly labeled genes with V kappa groups having similar N-terminal sequences led to an estimate of about 300 germline V kappa genes, while extrapolation from the number of genes in the VK-21 group gave an estimate of 90-140 genes. Since the three independent estimates fell between 90 and 320 genes, the germline V kappa repertoire, at least as expressed in myelomas, probably lies in that range. The V kappa fragment patterns given by three probes did not differ detectably between BALB/c, NZB, and A/J DNA but all three patterns differed in AKR DNA, indicating that there is limited polymorphism within the mouse V kappa locus. Somatic mutation must expand the number of expressed V kappa sequences, since the 8-12 VK-21 genes estimated for BALB/c and for NZB is significantly less than the 22 known NZB VK-21 polypeptides.

Animals↗
PubMed1981

Organization of genes and spacers within the mouse immunoglobulin VH locus.

The germline organization of mouse immunoglobulin VH genes has been investigated using cloned VH sequences. Hybridization studies with VH probes from plasmacytomas HPC76 (H76), S107, HOPC1 (H1), and lymphoma ABLS-8 (A8) demonstrated that the VH locus contains at least three distinct VH gene families. Comparison with other results suggests a total of about 10 such families, and of the order of 160 germline VH genes. Nucleotide sequencing revealed that the H76 family includes anti-inulin VH sequences, and the S107 family is known to encode antiphosphorylcholine sequences. The three VH gene families studied were mapped in the order H76-S107-A8/H1-CH by determining which VH genes had been deleted from several plasmacytomas by VH rearrangement events. Nine genomic clones from athe H76 family, and one each from the S107 and A8/H1 families, were characterized; collectively they span 103 kilobases (kb). Two clones from the H76 family and one from the S107 family each bore a pair of VH genes separated by approximately 14 kb, suggesting that related VH genes in these families are clustered with a typical spacing of approximately 14 kb. No other VH genes were detected within the spacers, arguing against intermingling of different families. Within the VH76 family cluster, however, two closely homologous VH genes were shown not to be adjacent. While spacer sequences were strongly conserved in the A8/H1 family, the H76 family had minimal conservation and that was restricted to regions immediately surrounding the genes. Hence conservation of spacer sequences cannot be essential for VH gene function, nor for maintenance of a VN family. Spacers in both the H76 and S108 family contained small repeat elements, some of which behaved like mobile DNA sequences.

Animals↗
PubMed1980

Cloned embryonic DNA sequences flanking the mouse immunoglobulin C gamma 3 and C gamma 1 genes.

To investigate the DNA surrounding genes for immunoglobulin heavy chain constant (CH) regions, we have isolated two clones bearing a C gamma 3 gene and two bearing a C gamma 1 gene from a library of mouse embryo DNA fragments. The C gamma 3 clones span 8.6 kilobase pairs (kb) on the 5' side of the gene and 6.7 kb on its 3' side, while the C gamma 1 clones together span 13 kb of 5' flanking sequence and 2.5 kb of 3' flanking sequence. Restriction mapping of the C gamma 3 gene indicates that intervening sequences divide the gene into segments of domain size, as in other CH genes. Hybridization of clone fragments to restriction digests of mouse DNA indicates that both the C gamma 1 and C gamma 3 genes probably occur as single copies in the genome. Moreover, the entire cloned sequences on the 5' side of both genes appear to be unique in the genome, indicating that no large common sequences flank CH genes. Restriction data suggest that the C gamma 3 gene is 37-40 kb 5' to the C gamma 1 gene.

Animals↗
PubMed1980

Organization of the sequences flanking immunoglobulin heavy chain genes and their role in class switching.

We have used heteroduplex analysis to investigate the sequences surrounding the germline C gamma 1 and C gamma 3 genes, and to compare them with those surrounding the C mu gene. We detected an inverted pseudogene 5' to the C gamma 3 gene and 50-65% homologous to it. A 400 bp region of the C gamma 1 and C gamma 3 3' flanking sequences was conserved as strongly as the genes (65-80%), suggesting it may have a specific function. The sequences 5' to the C gamma 1 and C gamma 3 genes and possibly also the C mu gene are composed of tandem partially homologous repeats of a similar 250 bp unit, arranged in the case of the C gamma 1 gene, in 2-5 kb blocks of alternating orientation. These repeats comprised over 13 kb of the spacer region separating the C gamma 3 and C gamma 1 genes. Recombination sites for heavy chain class switching fell within these repeated sequences, suggesting that recombination between partially homologous blocks of repeat sequences 5' to CH genes generates the deletion responsible for class switching. This hypothesis was strongly supported by an examination of published nucleotide sequences around the recombination sites of rearranged C gamma 1 and C gamma 2b genes (1,2).

Animals↗
PubMed1980

Deletions are associated with somatic rearrangement of immunoglobulin heavy chain genes.

The organization of mouse immunoglobulin heavy chain genes has been investigated by hybridization with cloned mu and alpha cDNA probes. Restriction endonuclease fragments bearing mu and alpha constant region genes and two types of variable region (VH) genes were compared in BALB/c embryos, liver and nine plasmacytomas synthesizing IgM, IgA, IgG1, IgG2a, IgG2b and IgG3. Embryo DNA was found to contain a single copy of the C mu gene per haploid genome. In contrast, one VH probe (HPC 76) detected at least six related VH genes, while the other (S107) detected a separate set of at least four genes, indicating that the germline contains distinct sets of multiple related VH genes. Most VH genes within the two subsets remained in germline context in different plasmacytomas, providing no evidence for somatic reassortment of VH genes. One plasmacytoma was devoid of specific VH genes, including some related to the expressed VH sequence. This may mean that the translocation event creating an active heavy chain gene involves deletion of the DNA between the expressed VH and CH sequences. The context of C mu sequences in DNA from a plasmacytoma secreting IgM differed from that in embryo DNA, as did C alpha sequences in two IgA- and several IgG-secreting plasmacytomas. Unlike heavy chain expression, rearrangement was not confined to one allele and often took different forms within a single cell line, presumably varying on different homologous chromosomes. Each rearrangement, whether resulting in an active C gene or not, appeared to change sequences upstream but not downstream from the CH gene. Significantly, the eight IgG and IgA plasmacytomas examined had undergone deletions of at least half and often all C mu sequences while retaining the embryo level of C alpha sequences. Hence a deletion mechanism may be responsible for the switch in expression from one CH gene to another which occurs during differentiation of a lymphocyte clone.

Alleles↗
PubMed1980

Enrichment of specific genes from genomic DNA or from clone library DNA, using R-looping.

We have developed a procedure for enriching DNA for specific sequences that is based on R-looping (Thomas et al., 1976). R-loops are formed with the DNA using mRNAs containing the sequence of interest and then isolated on poly(U)-sepharose via the poly(A) tail of the mRNA. Model experiments showed that plasmid DNA containing a cDNA copy of an immunoglobulin kappa chain mRNA could be selectively retrieved using this procedure. Approx. 5-10% of the kappa sequences in mouse embryo DNA could be recovered by R-looping, while non-specific binding of mouse DNA to the poly(U)-sepharose column was 0.03-0.04%. This represents a 100-200-fold enrichment of mouse genomic kappa sequences. We have also used the procedure to rapidly screen a mouse clone library for immunoglobulin heavy chain genes. DNA from the clone library was enriched 100-200-fold using immunoglobulin heavy chain mRNAs, and the enriched DNA repackaged in vitro to recover the phage.

Animals↗
PubMed1980

Intervening sequences divide the gene for the constant region of mouse immunoglobulin mu chains into segments, each encoding a domain.

To elucidate the structure of the gene for the constant region of immunoglobulin mu chains, we have cloned a 9.9-kilobase-pair fragment of mouse DNA bearing a gene for the constant region of the mu chain (C mu gene) from an IgM-secreting mouse plasmacytoma. The sequence around this gene has apparently undergone somatic rearrangement; the gene occurs in an EcoRI restriction endonuclease fragment of a different size from that in embryo or liver DNA and no C mu-bearing fragment of embryo size remains in the plasmacytoma. The cloned sequence lacks a variable region gene; hence, if this C mu gene is active, its position within the clone indicates that the gene for the variable region of a heavy chain (VH gene) must be more than 3.7 kilobase pairs away. The C mu gene is divided by three intervening sequences into four coding segments, each of which encodes one of the domains (homology units) of the polypeptide. The nucleotide sequence coding for amino acids near the V-C junction is not present within the C mu clone or clones bearing homologous embryonic VH genes. This suggests that an immunoglobulin heavy chain, in common with light chains, is encoded not only by a V and C gene, but also by an independent joining region (JH) gene.

Animals↗