Exclusion mapping.
The basis for using information against linkage to some loci to support linkage to other loci is discussed and data on cystic fibrosis available up to late July 1985 used as an example.
Biometry↗
Biomedical subjects
J H Edwards
Publications and source records attributed to J H Edwards.
Alprazolam: an antidepressant? Alprazolam, desipramine, and an alprazolam-desipramine combination in the treatment of adult depressed outpatients.
The antidepressant efficacy of alprazolam (ALP) was tested in a double-blind controlled comparison with desipramine (DMI) and an ALP-DMI combination in outpatients diagnosed with major depressive disorder by Research Diagnostic Criteria (90% met criteria for endogenous subtype). Following a placebo period of at least 1 week, subjects who continued to meet severity criteria defined by Hamilton Depression Rating Scale (HDRS) scores were administered oral doses of the active medication (N = 79), in a dose ratio of 1 mg ALP:50 mg DMI:1 mg ALP + 50 mg DMI. Treatment continued for 6 weeks, and all subjects who completed at least 2 weeks (N = 69) were included in endpoint analyses. Following the placebo baseline, symptoms were rated again at day 5 and at the end of weeks 1, 2, 4, and 6. Final doses averaged 4.6 +/- 1.3 mg for the ALP group, 230 +/- 61 mg for the DMI group, and 4.6 +/- 1.2 mg ALP + 229.5 +/- 1.2 mg DMI for the combination group. The final outcome was a comparable degree of improvement at the endpoint among the three treatment groups on measures of depression (HDRS and Beck Depression Inventory), anxiety (Hamilton Anxiety Rating Scale), and global improvement (Global Assessment Scale, and Physician and Patient Global Impressions). A similar outcome was found for the subgroup of patients who completed all 6 weeks (N = 56). Endpoint analyses also showed that ALP-treated subjects responded sooner and continued to show improvement throughout the course of the study on measures of depression, anxiety, and global status. These results suggest that ALP alone is as effective as a standard tricyclic for the acute treatment of patients with major depressive disorder and that significant improvement may occur within the first week of medication. Side effect profiles were compared among treatment groups and are discussed, as are other clinical studies that have investigated ALP's potential antidepressant efficacy.
Adolescent↗
The estimation of risks from the induction of recessive mutations after exposure to ionising radiation.
Since recent assessments of genetic risks from radiation have concentrated on harmful dominant effects, a quantitative assessment of risks from recessives is needed. Presumably, harmful recessives can arise at all loci coding for essential proteins (perhaps 10 000), but mutation to dominant alleles is likely to be a property of relatively few loci. While many recessives doubtless remain to be discovered, those known at present tend to have earlier and more severe effects than dominants. Induced recessive mutations can cause harm by partnership with a defective allele already established in the population; partnership with another recessive mutation induced at the same locus; the formation of homozygous descendants, that is, identity by descent; and heterozygous effects. Calculations based on a combination of data from observations on human populations and from mouse experiments suggest that an extra genetically significant dose of 1 cGy (centiGray, equivalent to 1 rad) X or gamma irradiation received by each parent in a stable population with a million liveborn offspring would induce up to 1200 extra recessive mutations. From partnership effects, about one extra case of recessive disease would be expected in the following 10 generations. Homozygosity resulting from identity by descent could not normally occur until the fourth generation after exposure but, on certain assumptions, about ten extra cases of recessive disease would be expected from this cause by the tenth generation. In the same period, about 250 recessive alleles would be eliminated in heterozygotes (that is, Muller's 'genetic deaths') given 2.5% heterozygous disadvantage. These deleterious heterozygous effects should not be combined with those of dominants, as has been done in some previous risk estimates. It is considered unlikely that many radiation induced recessives would show heterozygous advantage. Certain dominants (combined frequently at least 10(-3)) should be excluded from calculations of mutational risk because they are unlikely to be maintained by mutation.
Abnormalities, Radiation-Induced↗
The population genetics of Duchenne: natural and artificial selection in Duchenne muscular dystrophy.
The dynamics of X linkage was derived by Haldane in 1935. It is clear that the majority of mutations to an X linked lethal are new and that methods of control based on relatives of known cases can have limited impact on future incidence. The ability to define and track neighbouring loci allows some carriers who are daughters of carriers to be detected, and possible carriers to be excluded, with high reliability. Fetal diagnosis may also be made in the same way, but not without a substantial casualty rate. The precision of such diagnosis by proxy is limited both by the estimate of the recombination fraction and its variance, and can rarely exceed 1/s where the recombinational data are based on s informative meioses. Bracketing loci provide greater security from failure to diagnose cases but may involve substantial casualty rates. The estimation of both failure rates and casualty rates is discussed.
Female↗
In vitro release of arachidonic acid and in vivo responses to respirable fractions of cotton dust.
It was considered that the fall in lung function seen after exposure to cotton dust may be attributable in part to the activity of arachidonic acid metabolites, such as leucotrienes as well as to the more established release of histamine by cotton dust. However, we found that cotton and barley dusts elicited poor release of arachidonic acid from an established macrophage like cell line compared with that observed with other organic dusts. In the experimental animal, pulmonary cellular responses to both cotton and barley dust were similar to those evoked by moldy hay and pigeon dropping dusts, although after multiple doses a more severe response was seen to cotton and barley. Since both moldy hay and pigeon droppings elicit a greater arachidonic acid release than cotton or barley, a role for arachidonic acid in inducing the cellular response is less likely than other factors. There are limitations to our conclusions using this system, i.e., the arachidonic acid may be released in a nonmetabolized form, although it is noted that the two dusts with the greatest arachidonic acid release produce their clinical responses in humans largely by hypersensitivity mechanisms.
Animals↗
DNA polymorphism of the C2 and factor B genes. Detection of a restriction fragment length polymorphism which subdivides haplotypes carrying the C2C and factor B F alleles.
Factor B and the second component of complement (C2) in man are encoded within the major histocompatibility complex by single loci that are less than 1 kb apart. A 2.3 kb factor B-specific cDNA probe has been used to examine, by Southern blot analysis, the genomic DNA of individuals typed for C2 and factor B by protein electrophoresis. We have identified a restriction fragment length polymorphism using the endonuclease Taq I, which subdivides haplotypes carrying both the common variant of C2 (C2C) and the fast (F) variant of factor B. This DNA polymorphism has been mapped to lie in the C2 gene and represents a new genetic marker not defined by protein electrophoresis. This polymorphism may serve as a useful marker in the genetic analysis of diseases that are related to the major histocompatibility complex.
Alleles↗
Skin-test reactivity to egg protein--exposure by inhalation compared with ingestion.
Of two hundred and sixty-seven subjects exposed to egg by ingestion only, forty-eight were skin (prick)-test positive to egg material. All forty-eight subjects also reacted to other allergens on skin testing, forty-seven (98%) to allergens associated with respiratory allergy. Of thirteen subjects exposed to egg by inhalation in their workplace (and ingestion) two were skin-test-positive to egg, both also reacting to respirable allergens. Thus, inhalation of egg antigen does not greatly influence skin-test reactivity to eggs as determined by comparing the ratio of egg skin-test-positives to total skin-test-positives in the egg groups ingesting and inhaling egg antigen, i.e. 48:218 vs 2:6. In terms of the pulmonary response to inhaled eggs there were equal numbers of symptomatics with positive skin tests to common allergens as there were symptomatics with negative skin tests. Thus, an allergic predisposition shown by a positive skin test to common allergens does not predict nor preclude development of a pulmonary reaction to inhaled egg material.
Allergens↗
Report of the Committee on Methods of Linkage Analysis and Reporting.
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Chromosome Mapping↗
0.6 T magnetic resonance imaging of the orbit.
Magnetic resonance (MR) imaging of the orbit was performed with a 0.6 T superconducting imaging system in 100 patients with normal orbits who were being evaluated for brain pathology and in 21 additional patients with a variety of orbital lesions to determine the efficacy of MR imaging in displaying orbital abnormalities. Usually, MR studies were performed using a multislice technique with multiple spin-echo pulse sequences and 30, 60, and 90 msec echo times and 500, 1500, and 2000 msec repetition times. Using section thicknesses of about 8 mm, imaging was performed in the transaxial, coronal, and sagittal projections. Pixel size was 0.9 X 1.8 mm, and the examination took about 30 min. The MR findings were compared with computed tomographic (CT) findings in all cases. Either combined axial and coronal studies of 5-mm-thick sections or a thin axial study of 1-mm-thick sections followed by reformatting techniques to obtain multiplanar images was used. Contrast enhancement was used in the CT studies. Both MR and CT clearly demonstrated the soft-tissue abnormality in all cases except two, in which MR failed to detect the abnormality. In one, MR failed to detect a small retrobulbar hemorrhage that occurred after a surgical procedure for retinal detachment. In the second case, rather extensive calcification in the posterior choroidal layers and lens was not detected by MR imaging. In several other cases, MR provided information beyond that obtained with CT. MR has the advantage of providing exquisite anatomic detail in multiplanar images, and it appears to be more sensitive than CT in detecting small, subacute and chronic hemorrhage within soft-tissue masses in the orbit and in detecting ischemia of the globe. CT is superior to MR imaging in portraying fine bone detail.
Adult↗
Detection of mutations.
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Cells, Cultured↗
Methods for reducing particle concentrations of Aspergillus fumigatus conidia and mouldy hay dust.
The effectiveness of commercially available domestic air purifiers to reduce airborne Aspergillus fumigatus conidia and mouldy hay dust was investigated. It was found that the rate of particle clearance is a function of the volume of air passing through the purifiers but that the low throughflow of air makes their use of little value in clearing particles from a normal sized room. Vacuum cleaners were more effective than air purifiers because of their higher air throughput, so too were high volume fan systems in conjunction with simple filtration units. Ionizers had no effect but steam condensation was very efficient at clearing airborne particles.
Air Conditioning↗
Population genetics of C4 with the use of complementary DNA probes.
The C4 system is unusually variant both in the number of expressed genes and in the variety of those expressed. It is also closely linked to other two complement loci (C2 and Bf), which are structurally distinct but not linked to the two complement loci (C3 and C5) which are structurally similar. The C2, Bf, C4 segment lies within the MHC system, and their closeness to one another, and to the surrounding recognition loci (HLA-A, -B, -C, -DR) makes it difficult to attribute benefit or handicap, in relation to any disease, to any single locus by simple comparisons. The variation at the protein level, expressed by specificity, or charge, or size, or haemolytic activity, can now be supplemented by variation at restriction sites, or in the length of DNA between sites. The latter may be either causally or coincidentally related to the variant proteins. These data provide information on the evolutionary relations of the variants, both within the between species, and on the determinants related to inadequate or inappropriate defence against disease. They also provide evidence relevant to the sufficiency of the classical explanations of mutation, recombination and misalignment with recombination, and selection as explanations for what exists now.
Alleles↗
Locus for cystic fibrosis.
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Chromosomes, Human, 13-15↗
Chromosome maps of man and mouse II.
Chromosome displays and listings are presented showing loci whose position is known in both man and mouse, in similar manner to our previous report (Dalton et al. 1981). There is now evidence for at least 27 conserved autosomal segments with two or more loci in the two species. The human and mouse chromosome maps show the location of homologous genes. The mouse map also shows the positions of translocations used in gene location and of some other genes used in linkage studies on them.
Animals↗
Byssinosis. Inhalation challenge with polyphenol.
Most studies designed to determine the etiologic agent in byssinosis have relied on in vitro test for normal volunteers to assess the effects of components isolated from cotton plants, cotton factory dust, or their associated organisms. In one of the few studies directly on byssinotic subjects, symptoms were reproduced on inhalation challenge with a condensed polyphenol isolated from bracts of cotton plants. The results were highly significant, with only byssinotic workers responding; however, when we repeated the investigation with 29 subjects, no individual responded to challenge with symptoms such as those experienced returning to work at the cotton mill after a weekend break. Tests of pulmonary function could not detect differences between polyphenol and saline challenges. Compared with groups of workers not exposed to cotton dust and matched for age and smoking habits, significant differences in pulmonary function were observed, confirming the detrimental effects of long-term exposure to cotton dust, particularly in combination with cigarette smoke.
Adult↗
Spina bifida trials.
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Human Experimentation↗