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Biomedical subjects

I Willis

Publications and source records attributed to I Willis.

At least 55 records · Page 3Linked to original sources
PubMed1984

Mutations affecting excision of the intron from a eukaryotic dimeric tRNA precursor.

The nucleotide sequences of a Schizosaccharomyces pombe opal suppressor serine tRNA gene (sup9-e) and of 12 in vivo-generated mutant genes, which have lost the ability to suppress UGA mutations, have been determined. Analysis of the expression of these genes in Saccharomyces cerevisiae in vitro and in vivo systems has revealed defects in tRNA gene transcription and precursor tRNA processing. Single base changes in the D-loop, the intron and the extra arm affect the efficiency of splicing of the tRNA precursors while an anti-codon stem mutation may affect the accuracy of this process. Two mutations which occur in the intervening sequence of the sup9-e gene allow an alternate tRNA base pairing configuration. Transcription of the sup9-e gene and of the adjacent tRNAMet gene (located 7 bp downstream) is essentially abolished in vivo by a G----A19 mutation in the tRNASer gene, suggesting that tRNAMet may be derived solely via processing of the tRNASer-tRNAMet dimeric precursor.

Ascomycota↗
PubMed1984

The sup8 tRNALeu gene of Schizosaccharomyces pombe has an unusual intervening sequence and reduced pairing in the anticodon stem.

We have cloned and sequenced the wild-type and suppressor alleles of the S. pombe sup8 tRNA gene. The wild-type allele has a leucine UAA anticodon and the suppressor (sup8-e) carries the opal suppressor anticodon UCA. The gene has a 16 base pair intervening sequence that, in the RNA, is predicted to form a secondary structure which involves base pairing to the 5', rather than the usual 3' side of the 5' splice site. When incubated in Saccharomyces cerevisiae cell-free extracts both alleles are efficiently transcribed, the 5' leader and 3' trailer sequences are removed and CCA is added to the 3' processed end; however, the intervening sequence is not excised. This finding implies that the structural requirements of the splicing endonucleases in the two yeasts have diverged. No other tRNA genes with related sequences were detected in S. pombe DNA by hybridization, suggesting that other UUA isoacceptors may be structurally dissimilar to sup8 or that the UUA codon may be decoded by a UUG leucine isoacceptor.

Alleles↗
PubMed1984

Psoralens: a search for more effective derivatives for photochemotherapeutic regimens.

The objective of our studies under the National Toxicology Program on psoralens was to evaluate a new furocoumarin derivative that would be highly efficacious and yet possess little or no systemic toxicity while also having a short effective biologic half-life. In addition, this work allowed for the development of a test system for compound evaluation of various psoralen derivatives. A guinea pig model was used first, followed by definitive studies in hairless mice for evaluation of the phototoxic potentialities of 32 furocoumarins and 4 benzofuran derivatives. Rank order depends on whether the derivative is administered topically or orally; methyl furocoumarins were the most potent topical photosensitizers, but they were weak when orally administered. On the other hand, aminomethyl derivatives as a group were most potent of all the derivatives when orally administered but were mediocre topical photosensitizers. The standard for these studies, 8-methoxypsoralen (8-MOP), was mediocre in topical and oral regimens. Specific dose-response studies revealed the 5'-aminomethyl-4,4',8-trimethylpsoralen derivative to be six times more potent than 8-MOP. Moreover, the dose-response curve indicated that the response of the 5'-aminomethyl derivative is eliminated three to four times faster than is 8-MOP. No straightforward relationship between molecular structure and photosensitizing power was found. These results underscore the need for oral and topical evaluation of a given test sensitizer as well as for determination of the chemical nature, temporal distribution, and metabolic fate of its photochemically active form.

Animals↗
PubMed1983

Effect of varying dose of UV radiation on mammalian skin: simulation of decreasing stratospheric ozone.

To better understand the dependence of the incidence of squamous cell carcinoma on changes in solar spectral distribution and dose regimen, we exposed SK-1 hairless mice to solar-simulating radiation (290-400 nm). Selective UV filtration was accomplished by passing this radiation through Schott WG-320 cutoff filters of 0, 0.5, 1.0, 2.0, and 3.0 mm thickness. Minimal erythema doses (MED) were determined for each filter combination. Starting with 0.5 and with 0.9 MED, groups of 20 mice were irradiated 5 days per week; this was increased by 20% increments (of the original dose) every 6th day for 40 days ("0.5 MED" and "0.9 MED" experimental groups, respectively). Other groups of mice were irradiated with the same incremental increases, starting at 6.5 J/cm2 ("equal dose" regimen). The salient results were: (1) shorter wavelength components appear to preferentially produce tumors; (2) resultant observable dose-response behavior for each regimen is a complicated function of concurrent "light" and "dark" reactions; (3) time-dose reciprocity is absent; and (4) there are no straightforward relationships among tumor efficiency, dose fractionation, and spectral distribution of excitation radiation. These results indicate that photocarcinogenesis is a dynamic process, in which events that result in tumor growth compete with those that cause tumor regression.

Animals↗
PubMed1982

Photochemotherapy: a new promising chemical derivative.

A new synthetic psoralen (5'aminomethyl-4,4',8-trimethylpsoralen) is presented which possesses potential superior photochemotherapeutic efficacy. Results of studies conducted on the guinea pig and hairless mouse in our laboratories reveal that following oral administration there is a more rapid onset of photosensitization, a more rapid loss of photosensitization indicating apparent chemical inactivation or excretion, and a lower systemic toxicity on a milligram to milligram basis when compared to conventional psoralen derivatives. These results indicate that the use of this new derivative will minimize potential side effects such as ocular complications and inadvertent additional photosensitization that might lead to premature aging and carcinogenesis due to the slow onset and prolonged photosensitization following administration that are characteristic of conventional psoralen derivatives.

Animals↗
PubMed1981

The rapid induction of cancers in the hairless mouse utilizing the principle of photoaugmentation.

We report a method for rapidly inducing cancer in the hairless mouse utilizing regimen in which an exposure to highly erythemogenic, but otherwise clinically noninjurious, dose of broad spectrum (290-400 nm) ultraviolet light is increased by 20% every 6th day. Clinical and histological observations reveal the presence of squamous cell cancer after as little as 18 days of irradiation. The rate of cancer induction is enhanced by the 320-400 nm component and this enhancement is shown to be a photoaugmentative effect. The results support the idea that stratum corneum and/or malpighian layer thickening produced in early stages of tumor induction tends to protect against the detrimental effects of UV radiation. Strict monitoring of both the spectral distribution and output of the radiation source is imperative for reproducible rates of tumor induction.

Animals↗
PubMed1980

The interaction of L-DOPA melanin with p-tert-butylcatechol.

The interaction between the skin depigmenter 4-tert-butylcatechol (tBC) and L-DOPA melanin was qualitatively studied by means of spectroscopically monitoring the binding of tBC melanin as well as the oxidation of tBC in the presence and absence of melanin. Additionally, we assessed the quantitative effect of tBC on melanin's chemical reactivity by using the reduction of potassium ferricyanide as a redox marker. The kinetics of ferricyanide reduction in the ternary (melanin/tBC/ferricyanide) system are essentially different from those in each of the binary components (i.e., melanin/ferricyanide and tBC/ferricyanide). The experiments indicate that tBC can bind to melanin (KB = 3.8 X 10(3) M-1) and that melanin can act as a "catalyst-like" electron transfer agent which couples ferricyanide reduction with tBC oxidation (k' = 1.3 X 10(-6) mole min-1). These kinetic and thermodynamic parameters may provide a means of quantitatively comparing melanins obtained from different biological and pathological situations, and they may make possible an understanding of cutaneous depigmentation processes on the molecular level.

Catechols↗
PubMed1980

Potential ocular complications from PUVA therapy and their prevention.

During the last decade psoralens have become increasingly popular in treating psoriasis. The well-known photosensitizing action of these drugs has led to increasing concern regarding potential ocular complications, particularly in patients receiving prolonged psoralen therapy. We have demonstrated that this drug can be found in lenses of rats injected (intraperitoneally) with 4-8 mg/kg of 8-methoxypsoralen (8-MOP) and that its presence can lead to a photosensitized enhancement of lenticular fluorescence. Our experiments suggest one mechanism regarding the photosensitizing properties of 8-MOP within the ocular lens. Photo-addition products are generated with certain amino acid residues in the lens proteins which may result in the permanent retention of this compound within the ocular lens. We have recently shown that free 8-MOP can also be detected in human lenses for at least 12 hr following oral ingestion. Since the free 8-MOP tends to diffuse out of the lens during this period of time (as long as photic stimulation is prevented) it may be possible to prevent these photochemical reactions if the patient avoid exposure to ambient light for 12-24 hr immediately following ingestion of the drug. It may also be possible to protect these patients with special glasses which are capable of reflecting all UV radiation (up to 400 nm) while completely transmitting the visible radiation (400-750 nm).

Adult↗
PubMed1979

Zebra-like hyperpigmentation in an infant with multiple congenital defects.

An unusual pattern of zebra-like hyperpigmentation was observed in a black male infant with congenital defects that included an atrial septal defect, dextrocardia, auricular atresia, deafness, and growth retardation. The hyperpigmentation was strikingly linear and symmetrical and followed a dermatomal distribution, with involvement of the trunk and extremities. Results of histological, histochemical, and electron microscopic studies were normal except for an increase in the number of melanocytes in the bands of hyperpigmentation. This pigmentary anomaly appears to be transient and has faded to 50% of its original intensity. A review of the literature has not disclosed any similar cases.

Abnormalities, Multiple↗
PubMed1978

Biological changes of human cutaneous nerves caused by ultraviolet irradiation: an ultrastructural study.

Three white male volunteers were irradiated by long wave ultraviolet (UV-A) and by solar simulating radiation (SSR). An acute change of cutaneous nerves was found following a single exposure of UV-A irradiation. Non-myelinated Schwann cells and perineural cells in the papillary and reticular dermis were degenerated. Axoplasms appeared to be electron-dense, but were less affected than Schwann cells. After long-term repeated exposure, many free nerve endings were found in the dermo-epidermal junction above the basal lamina and some of them made a terminal enlargement. In one instance an axon made a swelling. Dermal free nerve endings also seemed to be increased in number and some of them were situated immediately beneath the melanocytes which were active in melanogenesis. Multiplication of basal lamina of the Schwann cells and perineural cells was observed. Amorphous material was precipitated around the non-myelinated Schwann cells. After a single exposure of SSR irradiation the degeneration of Schwann cells and axons in the dermo-epidermal junction was less severe than after UV-A and changes were minor in the reticular dermis. After repeated exposure, intra-epidermal proliferation of free nerve endings was detected. Dermal nerves were slightly affected. No intra-epidermal free nerve endings were observed in controls. The intra-epidermal proliferation of free nerve endings was confirmed following repeated UV exposures. Melanocyte-nerve association is suggested to be the cause of stimulating melanocyte activity.

Dose-Response Relationship, Radiation↗
PubMed1978

Psoralen-UVA-treated psoriatic lesions. Ultrastructural changes.

Psoralen-ultraviolet light (PUVA)-treated psoriatic lesions were studied for ultrastructural changes. In early stages of treatment, sunburn cells in the epidermis and bizarre giant cells in the dermis were more frequently observed. When clinical improvement was apparent, these changes had subsided. Dermal abnormality in long-term therapy consisted of a thick perivascular coat of amorphous substance. No abnormality was found in the epidermal keratinocytes in long-term therapy, except a clustering and giant cell formation of melanocytes, a heavy melanization of keratinocytes, and hyperkeratosis. Low-dose initiation and slow increment of both 8-methoxypsoralen and UVA is probably a reasonable regimen for benign dermatoses such as psoriasis because it will allow enough time for the skin to become more protected, while the therapeutic results are as satisfactory as in a high-dose schedule.

Aged↗
PubMed1977

UVA erythema in skin: is it a sunburn?

Specimens obtained from human skin following the induction of erythema responses with long ultraviolet (UVA) and with middle ultraviolet (UVB) radiation alone were compared histologically to determine whether the effects of these two portions of the electromagnetic spectrum were the same. It was found that, except for similar dermal inflammatory changes, the effects of UVA were not the same as those of UVB; characteristic epidermal sunburn damage was induced by the latter, but not by the former.

Erythema↗
PubMed1977

Biologic changes due to long-wave ultraviolet irradiation on human skin: ultrastructural study.

Alteration of the skin induced by single and repeated long-wave ultraviolet (UVA) exposures was studied. Following a single exposure to relatively large doses of UVA, pronounced dermal damage was observed. In the papillary dermis, superficial dermal vessels showed widely open endothelial gaps and extravasation of blood cells. Marked changes of fibroblasts were also seen in the superficial dermis. In the reticular dermis, extravascular fibrin deposition was seen. After repeated exposures to UVA the formation of cross-banded filamentous aggregations ("Zebra bodies") was observed in the superficial and reticular dermis. These were often found in amorphous masses surrounding the blood vessels. These striking dermal alterations were absent in skin irradiated by solar stimulating radiation and in control skin. Dyskeratotic "sunburn cells" were occasionally seen in the epidermis after single as well as repeated exposures to UVA. The number of these cells was less than that seen after a single exposure to solar simulating radiation.

Adult↗
PubMed1976

Factors influencing methoxsalen phototoxicity in vitiliginous skin.

A series of experiments were conducted to determine the optimum conditions required to induce methoxsalen phototoxicity in vitiliginous skin. The results revealed that optimum phototoxicity could be obtained only when a lapse of at least 15 minutes was allowed between the application of the drug and exposure to long-wave ultraviolet light (UVA). The duration of methoxsalen's phototoxic potentially, after its application to skin, varied in direct proportion to chemical concentration. Although a high chemical concentration and low dosage of UVA was a less time-consuming method of inducing phototoxicity, our results indicate that lower concentration and longer UVA exposure were less likely to induce undersirable blistering reactions.

Administration, Topical↗
PubMed1975

Photosensitivity.

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Age Factors↗