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Biomedical subjects

J A Phillips

Publications and source records attributed to J A Phillips.

At least 91 records · Page 5Linked to original sources
PubMed1995

Paediatric treatment costs and the HIV epidemic.

As the AIDS epidemic puts additional strains on the already overburdened health care systems in sub-Saharan Africa, it becomes more important to estimate the cost of the epidemic in terms of health personnel and drug treatments. A retrospective review of 250 randomly selected paediatric admissions to a referral hospital in Malawi was undertaken. Groupings of "possible/probable AIDS" and "probably not AIDS" were used in a comparative analysis of treatment costs. Estimated costs of treatments were significantly lower than those calculated in a study from Zimbabwe using different methodology. Meningitis was the most expensive condition to treat and accounted for a greater percentage of overall cost than either acute respiratory infection, diarrhoeal disease or measles.

Adolescent↗
PubMed1995

Reproductive health in the American workplace.

Helping workers understand their risk of reproductive and developmental hazard exposure can be demanding for the occupational health nurse. The lack of conclusive information about most suspected hazards, as well as concern over job security and advancement, make this issue doubly challenging. Further research is needed to verify or rule out the suspected toxic effects of a hazard. The occupational health nurse must make every effort to keep abreast of new research findings and federal or state requirements related to reproductive hazards. The key to promoting the reproductive health of American workers is primary prevention (Bernhardt, 1990). Educating and counseling workers about reproductive hazards so that they can make informed decisions about their reproductive health, along with implementing engineering controls or ergonomic changes to reduce the risk of exposure, should be the goal of all occupational health programs.

Female↗
PubMed1994

Hemolytically inactive C4B complement allotype caused by a proline to leucine mutation in the C5-binding site.

The fourth component of complement (C4) is encoded by two highly homologous genes, C4A and C4B. Only one hemolytically inactive C4A allotype (C4A6) has been reported. No hemolytically inactive C4B allotype has been described. We report the first hemolytically inactive (hi) allotype of C4B, C4B*1 (hi). This unique variant was first recognized by hemolytic overlay assays and confirmed to segregate in the affected pedigree with the major histocompatibility complex haplotype A28,B35,CW4,DR6, C4A3,C4B1(hi), BFF,C2C. By single strand conformational polymorphism, we detected only a migration variant in exon 12 caused by a C to T transition in the second base of codon 459. This mutation results in a leucine substitution for proline (P459L) 1 residue downstream of a residue known to contribute to the C5-binding site. Allele-specific oligonucleotide analysis of samples demonstrated cosegregation of the mutation with the hemolytically inactive allotype in the affected pedigree. Site-directed mutagenesis and expression studies showed that the P459L mutation causes loss of hemolytic function. C4B*1(hi) is the first example of a circulating C4B protein lacking detectable hemolytic activity and the P459L mutation expands our knowledge of the C5-binding site of C4.

Base Sequence↗
PubMed1994

Genetic mapping of the human growth hormone-releasing factor gene (GHRF) using two intragenic polymorphisms detected by PCR amplification.

We have analyzed the human growth hormone-releasing factor (GHRF) gene by high-resolution restriction mapping of its PCR amplification products. Two intragenic PCR fragment length polymorphisms (PCRFLPs) were detected in introns A and C of the GHRF gene, whose heterozygosities are 40 and 7%, respectively. Linkage analysis using the CEPH panel showed that GHRF is linked to several markers on chromosome 20 and assigned the GHRF locus to a region near the centromere between D20S27 (assigned to 20p12.1-p11.23) and D20S16 (assigned to 20q12). These intragenic PCRFLPs and the tightly linked polymorphisms should provide useful markers for linkage studies of GHRF alleles in familial disorders of growth such as isolated growth hormone deficiency.

Base Sequence↗
PubMed1994

Population screening for carrier status: effects of test limitations on precision of carrier prevalence rates.

Because of genetic heterogeneity and ambiguity of test results, only rarely will carrier screening identify all carriers of a given autosomal recessive disorder. However, the fraction of carriers identified by the test can be estimated in a case frequency study. The population carrier rate then is the rate observed in a population screening study divided by the fraction of all defective alleles detected by the screening test, estimated in the case frequency study. For example, suppose 3% of a population are found to carry the delta F508 mutation for cystic fibrosis (CF) during population screening. If a case frequency study in this same population finds that 75% of the alleles of CF cases represent the delta F508 mutation, then the estimated population carrier rate is 4% (= .03/.75). The precision of this estimate involves the precision of both the fraction of carriers detected in the case frequency study and the proportion of carriers observed in the population screening study. Standard formulae for estimating the confidence interval and sample size consider only the variability in the population screening study. Since these formulae underestimate the true variability of the estimate of the population carrier rate, the sample size calculated for a population screening study is also underestimated. We present formulae which incorporate the variability in both factors, and illustrate the effect of this additional variability on confidence limits for estimates and sample size when planning a study.

Biometry↗
PubMed1994

Effects of chemical and visual exposure to adults on growth, hormones, and behavior of juvenile green iguanas.

For 1 year, groups of juvenile male green iguanas (Iguana iguana) were housed such that one group was visually exposed to an adult female, a second group was both visually and chemically exposed to an adult female, a third group was visually exposed to an adult male, and a fourth group was both visually and chemically exposed to an adult male. Juvenile males exposed to signals from adult males showed signs of chronic stress, including reduced growth rates, lower testosterone levels, higher corticosterone levels, and decreased frequencies of headbob display. Although visual exposure alone was sufficient to suppress growth, testosterone levels, and rates of display, the addition of chemical exposure strengthened some of these effects. Both chemical and visual exposure to an adult male were necessary to produce elevated corticosterone levels. In contrast, juvenile males exposed to visual and chemical signals from an adult female exhibited growth rates, hormone levels, and behavior patterns typical of juvenile males housed in the absence of adults of either sex. These results suggest that visual and chemical signals from dominants may serve to reinforce social relationships among males through their influence on the physiology and behavior of receivers.

Agonistic Behavior↗
PubMed1994

Angiotensin II type 1 receptor gene abnormality in a patient with Bartter's syndrome.

Administration of a selective angiotensin I type 1 receptor (AT1) antagonist in animals not only nullifies the vasopressor action of angiotensin II, but also induces chloriduria and kaliuria, juxtoglomerular apparatus (JGA) hypertrophy and hyperreninemia, features characteristic of human Bartter's syndrome. We, therefore, explored the possibility that Bartter's syndrome may involve an AT1 abnormality. Using a pair of AT1-specific oligonucleotide primers and two different DNA polymerases (Taq and Pfu), we amplified the approximately 1 kb AT1 coding region of genomic DNA isolated from leukocytes of five patients with Bartter's syndrome by PCR and analyzed the sequence of the product. While the sequence of all clones from four patients were identical to that already reported for the normal human AT1 DNA sequence, 50% of the clones from one patient with Bartter's syndrome were found to have A-->G transition at nucleotide 931 which causes an amino acid substitution (arg-->gly) on the carboxy-terminal cytosolic tail of AT1. This mutation was not found in DNA from 50 normal controls which were screened by restriction enzyme digestion pattern of the PCR products of this region. As PCR-amplified AT1 DNA clones from four other individuals with Bartter's syndrome did not display any abnormality in the coding region, the possibility exists that Bartter's syndrome consists of multiple disease entities, where an AT1 gene abnormality represents a specific subgroup of the syndrome and/or some abnormality includes mutations outside of the coding region.

Animals↗
PubMed1994

DNA mapping in growth and developmental disorders.

DNA mapping techniques are being increasingly applied to familial and acquired disorders affecting growth and development. To understand the potential applications of these techniques, one must first have a good understanding of the components and basic structure of DNA, the genetic code, the basic structure of genes and the roles that various components of gene structure play in regulating gene expression. Following review of this basic information, a variety of DNA mapping techniques including in situ hybridization, Southern blotting, polymerase chain reaction amplification, DNA sequencing and linkage analysis will be covered. Applications of these techniques can enable mapping of unknown genes by detection of loss of allelic heterozygosity or use of linkage analysis and genetic maps. With increasing ease, mutations such as deletions, expansions, rearrangements and point mutations can be detected in diseases such as congenital adrenal hyperplasia, cystic fibrosis, diabetes insipidus, growth hormone deficiency, fragile X syndrome, Laron dwarfism and Turner syndrome. From this discussion, a better understanding of methods of gene localization, uses of genetic maps and rapid, convenient methods to detect a variety of molecular derangements causing familial disorders affecting growth and development will be gained.

Blotting, Southern↗
PubMed1994

Exclusion of growth hormone (GH)-releasing hormone gene mutations in familial isolated GH deficiency by linkage and single strand conformation analysis.

The molecular basis and the locus responsible for most familial cases of isolated GH deficiency (IGHD) are still unknown. The GH-releasing hormone (GHRH) gene has been evaluated as a possible candidate in 23 unrelated families with IGHD, 14 of whom were classified as having autosomal recessive IGHD type IB and 9 of whom had autosomal dominant IGHD type II. Three highly polymorphic microsatellites (dinucleotide repeats), mapped close to GHRH on chromosome 20 by previous linkage studies, were analyzed as markers for the GHRH locus. All available family members were genotyped for D20S44 [no recombination with GHRH at a LOD (logarithm of the odds) score of 3.6]. Noninformative families were also genotyped for D20S45 and/or D20S54 (located at approximately 1 and 3 centiMorgan of genetic distance from GHRH, respectively). Twenty families were informative for linkage analysis with 1 or more of these markers. We found at least 1 obligate recombinant with discordance between phenotype and genotype in 19 of the 23 families (83%). There is only a very small chance (1-3% or less) that the discordances observed are due to recombination between the GHRH locus and the marker tested. Concordant segregation was seen in only 1 type IB family (4%). When probands from this and the 3 noninformative families were screened for sequence variants in the 5 exons of the GHRH gene by single strand conformation analysis, no abnormal patterns were observed. We conclude that mutations responsible for IGHD are not within or near the structural gene for GHRH on chromosome 20 in the 23 families studied. As linkage to the GH-1 gene has also been previously excluded in 65% of these families, mutations in a locus or loci unlinked to GH-1 and GHRH must be responsible for the majority of these IGHD families.

Base Sequence↗
PubMed1994

Familial growth hormone deficiency: a model of dominant and recessive mutations affecting a monomeric protein.

Two families with familial isolated GH deficiency (IGHD) were studied, type II (autosomal dominant) and type I (autosomal recessive), whose GH1 genes exhibit cosegregation with IGHD. DNA sequencing of the GH1 genes of the first family (IGHD II) demonstrated heterozygosity for a T-->C transition in the sixth base of the donor splice site of intron III. The GH1 gene mutation in the second family (IGHD I) was found, in a previous study, to be a G-->C transversion altering the first base of the donor splice site of intron IV. Interestingly, analysis of the transcripts derived from the mutant IGHD II allele revealed that the sequences corresponding to exon III were absent due to an exon skip that causes the loss of amino acids 32-71 from the mature GH protein. In contrast, the IGHD I mutation activates a cryptic donor splice site 73 bases upstream of the normal exon IV donor splice site causing loss of amino acids 103-126 of exon IV followed by a reading frameshift and synthesis of 94 novel amino acids before chain termination 88 nucleotides downstream of the normal GH stop codon. It is hypothesized that, because of the loss of protein sequences derived from exons IV and V, the IGHD I mutation products are not transported to secretory granules and thus cannot perturb secretion of the normal monomeric GH protein. In contrast the T-->C IGHD II mutant allele product retains these sequences and is transported to secretory granules where it can interact with the normal allele product producing a dominant-negative effect at the protein level.

Adolescent↗
PubMed1994

Evidence that the Saethre-Chotzen syndrome locus lies between D7S664 and D7S507, by genetic analysis and detection of a microdeletion in a patient.

The locus for Saethre-Chotzen syndrome, a common autosomal dominant disorder of craniosynostosis and digital anomalies, was previously mapped to chromosome 7p between D7S513 and D7S516. We used linkage and haplotype analyses to narrow the disease locus to an 8-cM region between D7S664 and D7S507. The tightest linkage was to locus D7S664 (Z = 7.16, theta = .00). Chromosomes from a Saethre-Chotzen syndrome patient with t(2;7) (p23;p22) were used for in situ hybridization with YAC clones containing D7S664 and D7S507. The D7S664 locus was found to lie distal to the 7p22 breakpoint, and the D7S507 locus was deleted from the translocation chromosomes. These genetic and physical mapping data independently show that the disease locus resides in this interval.

Acrocephalosyndactylia↗
PubMed1993

DNA analysis of cystic fibrosis in Brazil by direct PCR amplification from Guthrie cards.

A 3 bp deletion of codon 508 (phenylalanine) of the cystic fibrosis (CF) gene constitutes the mutation of most CF chromosomes. The frequency of this mutation (referred to as delta F508), varies considerably between populations, ranging from 26% of the CF mutations in Turkey to 88% in Denmark. To determine the frequency of the delta F508 mutation in Brazilian Caucasoid CF patients, we used direct polymerase chain reaction (PCR) amplification of DNA obtained from dried blood spots on Guthrie cards, followed by ethidium bromide staining of gels. Although the overall frequency of the delta F508 mutation was 47% of 380 CF chromosomes from Brazilian Caucasoids born in five different states, significant interstate differences were observed, ranging from a delta F508 frequency of 27% to 53%. While our method could be used to screen patients and their relatives for carrier testing and prenatal diagnosis, the efficacy of screening only for the delta F508 mutation would be low, and would vary from state to state. Screening for a panel of local mutations will be needed to increase the mutation detection rate and optimize genetic counseling.

Base Sequence↗
PubMed1993

Differential resource use, growth, and the ontogeny of social relationships in the green iguana.

Growth rates, resource use, and ontogeny of behavior patterns were examined in captive groups of juvenile green iguanas (Iguana iguana). Four groups were housed in large arenas where supplemental heat and perch sites were limited, whereas two control groups were housed in similar arenas without limited resources. Growth, frequency and types of displays, behavioral interactions, and the use of resources were monitored. By 35-70 days of age, male hatchlings in arenas with limited resources could be classified into two groups: rapid growing dominant individuals and slow growing subordinate individuals. Growth and dominance were not correlated with size of individuals at hatching. Digestive efficiency of males was related to dominance and access to limited resources, but all lizards exhibited a similar digestive efficiency when maintained at a constant ambient temperature. Dominant males used the resources, especially supplemental heat sources, twice as often as subordinate males. The dominant/subordinate relationships and accompanying skew in body size were not evident in the control groups, or in females of any group. At 105 days, control groups were introduced to conditions with limited resources, resulting in increased aggressive interactions and divergence in growth rates. Onset of adult behavioral patterns was related to body size, and the species-specific signature display was observed in dominant males up to several months before subordinate males. These results indicate that male green iguanas establish a dominance hierarchy immediately posthatching when resources are limited, and as a consequence, both physiological and behavioral maturation are delayed in subordinate individuals.

Age Factors↗
PubMed1993

Optimizing prehospital triage criteria for trauma team alerts.

Although scores and other prehospital triage schema effectively identify injured patients who will benefit from trauma center care, those tools are relatively nonspecific. One consequence is overtriage--transport of less severely injured patients to trauma centers--with resulting expenditure of scarce resources on patients who do not benefit from an emergent and intensive response. We developed a tool that, during the prehospital phase, can sort inner-city trauma victims into those who will require ICU/OR services and those who will not. Beginning with the trauma triage criteria promulgated by the American College of Surgeons, we created two tiers of personnel response based on vital signs, mechanism of injury, and limited anatomic information ordinarily reported by prehospital providers. Based on our initial experience with the two-tier response, the sorting criteria were revised and refined. The sensitivity of the current version of the two-tier criteria for predicting which trauma patients will require ICU/OR services during the first 24 hours of hospitalization approaches 95% (excluding misapplications of the tool) while avoiding urgent trauma team mobilization in 57% of patients triaged to our trauma center. Two-tiered trauma responses appear to be safe and may represent an important strategy for more effective distribution of increasingly scarce and costly resources.

Adult↗
PubMed1993

Heterogeneous growth hormone (GH) gene mutations in familial GH deficiency.

The GH1 genes of probands of two families with familial isolated GH deficiency (IGHD) were sequenced. Double stranded sequencing of the polymerase chain reaction (PCR) amplification products from genomic DNA of two affected cousins in a consanguineous Turkish family revealed a G-->A transition in the 20th codon of the GH1 signal peptide. This substitution converts a TGG (Trp) to a TAG (stop) codon and generates a new AluI recognition site. PCR amplification of the GH1 alleles of family members, followed by AluI digestion, revealed that the G-->A transition segregated with the IGHD phenotype. In a Saudi Arabian family, a G-->C transversion was found that alters the first base of the donor splice site of intron IV. This substitution should perturb mRNA splicing, resulting in an altered protein product which should be unstable or bioinactive. This transversion also destroys an HphI site, which was used to assay samples from relatives. Digestion of PCR amplification products with HphI demonstrated cosegregation of the G-->C transversion with IGHD. These results demonstrate that familial IGHD is a heterogeneous disease that perturbs different steps in the expression of the GH1 gene.

Base Sequence↗
PubMed1993

Detection of a novel arginine vasopressin defect by dideoxy fingerprinting.

Autosomal dominant neurohypophyseal diabetes insipidus is a familial form of diabetes insipidus. This disorder is associated with variable levels of arginine vasopressin (AVP) and diabetes insipidus of varying severity, which responds to exogenous AVP. To determine the molecular basis of autosomal dominant neurohypophyseal diabetes insipidus, the AVP genes of members of a large kindred were analyzed. A new method, called dideoxy fingerprinting, was used to detect an AVP mutation that was characterized by DNA sequencing. The novel defect found changes the last codon of the AVP signal peptide from alanine to threonine, which should perturb cleavage of mature AVP from its precursor protein and inhibit its secretion or action.

Arginine Vasopressin↗
PubMed1992

A human interleukin 3 analog with increased biological and binding activities.

Human interleukin 3 (IL-3) variants generated by site-directed mutagenesis were analyzed in multiple biological and binding assays to identify residues critical for IL-3 activity. Two mutants carrying substitutions in the predicted hydrophilic region within the first alpha-helix, [Ala21,Leu22]IL-3 and [Ala21,Leu22,Ala25]IL-3 showed loss of biological activity and high-affinity binding. Mutants in a second predicted hydrophilic region, [Ala44,Leu45,Ala46]IL-3 and [Ala44,Ala46]IL-3, however, showed similar biological and binding activities to wild-type IL-3. Mutations in a C-terminal hydrophilic region that overlaps the fourth predicted alpha-helix led to either loss or gain of function. IL-3 analogs [Glu104,Asp105]-, [Leu108]-, [Asn108]-, [Thr108]-, and [Ala101,Leu108]IL-3 were less active than wild-type IL-3, whereas [Ala101]IL-3 and [Val116]IL-3 were 2- to 3-fold more potent. Significantly, the double mutant [Ala101,Val116]IL-3 exhibited a 15-fold greater potency than native IL-3. Receptor binding studies showed that [Ala101,Val116]IL-3 exhibited increased binding to the high- and low-affinity receptors of monocytes. These results show the generation of an IL-3 analog with increased biological and binding activities and support a model where the C terminus of IL-3 interacts with the alpha chain of the IL-3 receptor, making this region a useful focus for the development of more potent IL-3 agonists or antagonists.

Amino Acid Sequence↗