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Biomedical subjects

R Willis

Publications and source records attributed to R Willis.

At least 37 records · Page 2Linked to original sources
PubMed1990

Lovastatin decreases coenzyme Q levels in humans.

Lovastatin is clinically used to treat patients with hypercholesterolemia and successfully lowers cholesterol levels. The mechanism of action of lovastatin is inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme involved in the biosynthesis of cholesterol from acetyl-CoA. Inhibition of this enzyme could also inhibit the intrinsic biosynthesis of coenzyme Q10 (CoQ10), but there have not been definitive data on whether lovastatin reduces levels of CoQ10 as it does cholesterol. The clinical use of lovastatin is to reduce a risk of cardiac disease, and if lovastatin were to reduce levels of CoQ10, this reduction would constitute a new risk of cardiac disease, since it is established that CoQ10 is indispensable for cardiac function. We have conducted three related protocols to determine whether lovastatin does indeed inhibit the biosynthesis of CoQ10. One protocol was done on rats, and is reported in the preceding paper [Willis, R. A., Folkers, K., Tucker, J. L., Ye, C.-Q., Xia, L.-J. & Tamagawa, H. (1990) Proc. Natl. Acad. Sci. USA 87, 8928-8930]. The other two protocols are reported here. One involved patients in a hospital, and the other involved a volunteer who permitted extraordinary monitoring of CoQ10 and cholesterol levels and cardiac function. All data from the three protocols revealed that lovastatin does indeed lower levels of CoQ10. The five hospitalized patients, 43-72 years old, revealed increased cardiac disease from lovastatin, which was life-threatening for patients having class IV cardiomyopathy before lovastatin or after taking lovastatin. Oral administration of CoQ10 increased blood levels of CoQ10 and was generally accompanied by an improvement in cardiac function. Although a successful drug, lovastatin does have side effects, particularly including liver dysfunction, which presumably can be caused by the lovastatin-induced deficiency of CoQ10.

Adolescent↗
PubMed1989

The fate of the non-operated ear in otosclerosis.

Records of 300 consecutive patients who had only one ear operated on by stapedectomy and who received long-term followup were studied. These cases came from 3036 stapedectomy operations performed between January 1961 and April 1969. In general, the two ears behaved the same: if a "flat" sensorineural loss occurred in one ear, it was likely to develop in the other. Similarly, if one ear developed a high-tone loss, the other would do likewise. With the exception of acute fistula, there is no suggestion that the operation of stapedectomy predisposes an ear to late sensorineural problems. Patients with bone-conduction thresholds that are depressed at all frequencies when first examined should be advised that progressive sensorineural hearing loss may occur later in both ears. Accordingly, the benefit gained by stapedectomy may ultimately need to be supplemented by hearing aids. This study also revealed that a patient with clinical conductive otosclerosis in only one ear at first presentation had only a 50% chance of long-term benefit from stapedectomy.

Female↗
PubMed1989

Betamethasone and the human fetal ductus arteriosus.

We used a sensitive Doppler echocardiographic technique to evaluate in utero the effects of betamethasone on the human ductus arteriosus. Transient, mild constriction of the ductus arteriosus 4-5 hours after the first injection of betamethasone occurred in two of 11 trials. The relatively mild and brief effects on the human ductus of betamethasone in usual doses are probably not clinically significant in most instances. Hence, they do not appear to contraindicate the use of glucocorticoids to promote fetal lung maturation.

Betamethasone↗
PubMed1989

Nasal obstruction in the neonate.

At birth, the neonate is an obligate nasal breather and any compromise of the nasal passages is potentially life threatening. It is important for the otorhinolaryngologist to quickly recognize and manage even subtle constrictions or obstructions of the nasal passages in this age group. Many times the nasal airway is disregarded as the source of airway difficulty if small catheters can be passed. Conversely, the inability to pass nasal catheters is often arbitrarily diagnosed as choanal atresia or stenosis. This limited outlook can delay appropriate therapy. The differential diagnosis of nasal obstruction in the neonate is presented wit emphasis on evaluation of nasal obstruction in anatomically normal appearing noses.

Airway Obstruction↗
PubMed1988

Missense mutations in an infectious human immunodeficiency viral genome: functional mapping of tat and identification of the rev splice acceptor.

Single nucleotide alterations were introduced into an infectious clone of human immunodeficiency virus type 1 to create a series of missense mutants in the tat coding region. Although mutations in a proline-rich region and a basic lysine-arginine-rich region resulted in wild-type phenotypes, five of six mutations in a cysteine-rich domain completely abolished tat activity and virus replication. One cysteine mutant retained tat activity but was negative for virus expression. Surprisingly, this mutant could not be complemented by tat, and virus expression was restored only by cotransfection with a plasmid expressing the rev gene. Another mutant with an alteration toward the C-terminal region showed significantly reduced tat activity and required complementation by a combination of tat and rev for virus replication. Further analysis revealed that a previously unrecognized splice acceptor site within this region, apparently used to generate the rev mRNA, had been altered. We provide evidence suggesting that tat and rev proteins are encoded by distinct mRNA species.

Amino Acid Sequence↗
PubMed1988

Teratogenic effects of first-trimester cyclophosphamide therapy.

Intravenous cyclophosphamide was administered for severe exacerbation of systemic lupus erythematosus to a patient not known to be in the first trimester of pregnancy. The patient received no other medication except prednisone. Her neonate was born with multiple anomalies, including absent thumbs, cleft palate, low-set ears, and multiple eye abnormalities. These anomalies probably reflect teratogenic effects of cyclophosphamide, and indicate that judgment is required before its use in the first trimester. Furthermore, this case illustrates the need for effective contraception and repetitive pregnancy testing when potentially teratogenic agents are administered to presumably nonpregnant women in the reproductive age group.

Abnormalities, Drug-Induced↗
PubMed1988

Significance of biological parameters of human blood levels of CoQ10.

Ninety-one men and 143 women who were so-called normal subjects were tested for cardiac performance at rest and their blood levels of co-enzyme Q10 (CoQ10) were determined. In males, a negative relationship between progression of age and cardiac performance, and a positive relationship between progression of age and blood levels of CoQ10 were revealed. In females, a positive relationship between age and blood levels of CoQ10 was found. The mean CoQ10 blood level for both sexes was the same (0.79 +/- 0.20 micrograms/ml for males and 0.79 +/- 0.23 for females). Cardiac performance declines with age in the male population. A decreased biosynthesis and/or incorporation of CoQ10 into mitochondrial structures of muscle cells may occur with age in a normal population.

Adult↗
PubMed1987

Unesterified cholesterol in Schnyder's corneal crystalline dystrophy.

We examined a 51-year-old woman who had bilateral corneal crystalline deposits unassociated with xanthelasma or systemic involvement. Her son had similar corneal lesions. Plasma cholesterol and apolipoprotein A-I and B levels were normal in both patients. Histopathologic examination of the corneal button in the mother obtained at the time of keratoplasty disclosed lipid deposits that stained with oil red O as well as with filipin, a fluorescent probe that specifically detects unesterified cholesterol. Electron microscopy showed abnormal accumulation of lipid and cholesterol in the central and paracentral basal epithelium, Bowman's layer, and superficial stroma.

Cholesterol↗
PubMed1987

Digiscan activity: automated measurement of thigmotactic and stereotypic behavior in rats.

Visual measures of stereotypy, margin time (thigmotaxis or wall-hugging), and center time were correlated with automated measures using a revised 16 beam version of the Digiscan Animal Activity Monitor System. Rats were injected with d-amphetamine (1.25, 2.5, 5.0 and 10.0 mg/kg), scopolamine (1.25 and 2.5 mg/kg) or saline and drugs were found to increase center time and decrease margin time in a dose-dependent manner, with the maximum effect occurring with 1.25 and 2.5 mg/kg, respectively. At higher doses, an opposite effect was observed. Extremely high correlations between visual and automated recordings of both margin time and center time were found. Since thigmotaxic or wall-hugging behavior has been used as an indicator of emotionality in rats, the results of the present study suggest that these two locomotor variables may be useful additions to the Digiscan multivariate analysis of locomotor behavior. It was also found that a redefinition of stereotypic behavior improved its correlation with visual measurements compared to earlier studies.

Animals↗
PubMed1987

Epitope insertion into the human hypoxanthine phosphoribosyltransferase protein and detection of the mutant protein by an anti-peptide antibody.

The translational stop codon TAA of the human hypoxanthine phosphoribosyltransferase (HPRT) cDNA has been changed to GAA by site-specific mutagenesis. This modification extends the open reading frame to a downstream stop codon and results in the addition of a unique negatively charged hexapeptide to the C terminus of human HPRT protein. The mutated cDNA was transferred into HPRT-deficient rodent cells by retroviral vector infection, and the expressed enzyme was found to be fully active. An antibody against a synthetic octapeptide corresponding to the mutated HPRT C terminus precipitated the HPRT protein specifically from cells infected with the mutant virus and not infected with the wild-type HPRT virus. The technique of inserting a novel epitope into a protein by site-directed mutagenesis should be generally applicable in studies of the regulation of gene expression in vitro and in vivo.

Epitopes↗
PubMed1985

Otitis media and the Australian aboriginal.

Australia's aboriginal population, which numbers 150,000 persons, suffers much more from otitis media than does the nonaboriginal population, which numbers 15,000,000. Moreover, the clinical presentation, course, and pathology of otitis media in aboriginals have features that differ from what are considered usual. Problems of isolation, communication, and socioeconomic circumstances require that specially designed treatment projects be set up. Debate continues as to why aboriginal otitis media behaves so differently, and theories cover the full range: genetic factors, environment, protein-calorie malnutrition and immunity mechanisms, allergies, different microbiology, and so on. Current research may point up a link to ocular trachoma. The process of spontaneous healing of drum perforations is being studied in an attempt to identify those factors that may delay or prevent such healing.

Australia↗
PubMed1984

The biochemistry of vitamin B6 is basic to the cause of the Chinese restaurant syndrome.

The concept of this basic research was that monosodium L-glutamate could reveal a deficiency of vitamin B6 by the neurological reactions known as the Chinese Restaurant Syndrome. An other amino acid, tryptophan, administered to subjects, is known to reveal a deficiency of vitamin B6 by the excretory xanthurenic acid, etc. The presence and degree of a deficiency of vitamin B6 in 155 students on no supplemental B6 was determined by the differential assay of aspartate transaminase of erythrocytes which also allows each subject to be a control. Twenty-seven of 155 students had extraordinarily low basal specific activities of the transaminase, less than 0.26 mumol pyruvate/(h X 10(8) erythrocytes). These 27 were challenged with glutamate and a placebo. Twelve of 27 revealed the Chinese Restaurant Syndrome, and 15 did not. By double blind trials, the 12 "responders" were treated with pyridoxine and a placebo for twelve weeks, and then were rechallenged with glutamate and a placebo. Decoding showed 3 of 12 received placebo to pyridoxine and then revealed the symptoms of the syndrome again to glutamate; 9 of 12 received pyridoxine and then 8 of 9 failed to respond to glutamate. These results show, p less than 0.01, that the symptoms of the Chinese Restaurant Syndrome to oral glutamate fail to reoccur after treatment which pyridoxine, and that the biochemistry of vitamin B6 is basic to the cause of the Chinese Restaurant Syndrome.

Aspartate Aminotransferases↗