Biomedical subjects

L Whittaker

Publications and source records attributed to L Whittaker.

14 recordsLinked to original sources

PubMed2001

Do patients with critical limb ischaemia undergo multiple amputations after infrainguinal bypass surgery?

BACKGROUND: it has been suggested that an aggressive policy of bypass for limb salvage in critical ischaemia may result in patients subsequently undergoing multiple amputations. The aim of this study was to test this suggestion in the context of a dedicated Vascular Surgical Unit in a U.K. teaching hospital. METHODS: three hundred and sixty-eight patients undergoing lower limb bypass operations for critical limb ischaemia between April 1991 and March 1999 were studied retrospectively. Their median age was 69 years (IQR 64--75) and 243 (66%) were men. RESULTS: seventy-five operations were followed by one or more amputation (20%). Only 2% were multiple amputations. Age and sex had no effect on amputation rates, but emergency bypass operations led to a higher rate of amputation in those with critical limb ischaemia. CONCLUSION: patients with critical limb ischaemia who undergo lower limb bypass surgery rarely have subsequent multiple amputation.

Aged↗

PubMed2000

The measurement of pupil cycling time.

PURPOSE: To assess the influence of pupil size on pupil cycling time (PCT), a measure which may be elongated in cases of neurological disease. METHOD: Clinically, pupil "cycling" is produced by focusing a slit-lamp beam on the pupil margin. A rhythmic contraction and dilation of the pupil is produced, as changes in pupil size alternately prevent and allow the light beam to reach the retina. In this study, however, the light beam was controlled electronically so that cycling could be produced around different pupil sizes. Measurements of the variation of PCT with pupil size were taken from 22 young normal subjects. RESULTS: PCT was seen to depend upon pupil size, increasing monotonically but non-linearly as size increased. The wave-form of pupil cycling is typically sawtooth, contraction being much faster than dilation. There was considerable variation amongst subjects in the range of pupil sizes where pupil cycling could be elicited. CONCLUSIONS: The results point to the need for a standardised procedure for the measurement of cycling time, because differences in clinical conditions will themselves influence pupil size, as will other external variables such as ambient light level. The results also bring into question neurological explanations for increased PCT in those diseases where pupil size is affected, because normal subjects have PCTs well beyond the accepted limits of normality when their pupils are enlarged.

Adolescent↗

PubMed1998

HIV protease genotype and viral sensitivity to HIV protease inhibitors following saquinavir therapy.

OBJECTIVE: To examine the relationship between HIV protease genotype and altered protease inhibitor sensitivity of isolates from patients after therapy with saquinavir (SQV) in its hard gelatin formulation. DESIGN: Forty-one post-therapy isolates and corresponding baseline samples were obtained from 37 patients in four different clinical trials after therapy with SQV for 16-147 weeks. Post-therapy isolates were selected on the basis of preliminary sequence or drug sensitivity data. RESULTS: Fifteen out of 17 isolates without detectable Val-48 or Met-90 mutations retained sensitivity to SQV. (The remaining isolates showed only a marginal increase in median inhibitory concentration.) In addition, three out of 15 isolates with Met-90 retained sensitivity to all other protease inhibitors tested (indinavir, ritonavir, amprenavir, nelfinavir). Of the isolates showing reduced sensitivity to SQV, six out of 22 retained sensitivity to all other protease inhibitors, whereas only four out of 22 showed broad cross-resistance to all protease inhibitors tested. The reduction in sensitivity correlated closely with the presence of Val-48 or Met-90. Subsequent accessory substitutions were also linked to reduced sensitivity. However, significant linkage was observed only between mutations at residues 48 and 82 and between those at residues 82 and 74. CONCLUSIONS: Recruitment of Val-48/Met-90 mutations was not found to be synonymous with cross-resistance. Indeed, the majority of isolates with these mutations retained sensitivity to at least one protease inhibitor (Val-48, 86%; Met-90, 77%). The recruitment of accessory mutations may occur only after the selection of key resistance mutations. Furthermore, Met-90 was found to be a poor marker of cross-resistance in SQV-treated patients.

Amino Acid Substitution↗

PubMed1998

A randomized clinical trial of cryotherapy, laser vaporization, and loop electrosurgical excision for treatment of squamous intraepithelial lesions of the cervix.

OBJECTIVE: To compare cryotherapy, laser vaporization, and loop electrical excision for treatment of squamous intraepithelial lesions (SILs). METHODS: Women at least 18 years old with biopsy-proven SIL, negative pregnancy tests, negative findings on endocervical curettage, satisfactory colposcopy examinations, and congruent Papanicolaou smear and biopsy results were assigned randomly to treatment after stratification by SIL grade, endocervical gland involvement, and lesion size; they were evaluated 1, 4, 8, 12, 16, 20, and 24 months after treatment. Data were analyzed using chi2 statistics, logistic regression analysis, and the Cox proportional hazards model. RESULTS: Of 498 patients assigned, 108 were excluded (most because of inadequate follow-up), leaving 390 (139 cryotherapy, 121 laser vaporization, 130 loop excision) for analysis. All were followed 6-37 months (mean 16). There were no statistically significant differences in complications, persistence (disease present less than 6 months after treatment), or recurrence (disease present more than 6 months after treatment). Risk of persistent disease was higher among women with large lesions (risk ratio [RR], 18.9; 95% confidence interval [CI], 3.2, 110.6). Recurrence risk was higher among women aged 30 years and older (RR, 2.1; 95% CI, 1.2, 4.3), those with human papillomavirus type 16 or 18 (RR, 2.1; 95% CI, 1.1, 4.0), and those who had had prior treatment (RR, 2.1; 95% CI, 1.1, 3.9). CONCLUSION: The data support a high success rate with all three modalities. No significant difference in success rates was observed between the three treatments in our population. Additional attention and research should be directed toward the higher risk patients identified above.

Adolescent↗

PubMed1996

Clinical applications of genetic testing: implications for the family physician.

Genetic testing may be applied in a variety of clinical situations, including preconception counseling, prenatal diagnosis and postnatal determination of genetic predisposition to disease. The family physician needs to become familiar with the full range of genetic testing possibilities in all phases of the human life cycle. Cystic fibrosis, Huntington's disease and cancer are three diseases for which genetic testing has become a reality, and they serve to illustrate the clinical and ethical dilemmas that arise with this type of testing.

Ethics, Medical↗

PubMed1996

Endometrial hyperplasia and endometrial cancer.

Endometrial cancer is the most frequently seen gynecologic neoplasm, but it fortunately has low mortality, which is due largely to its presentation with abnormal bleeding and its subsequent early diagnosis. The morbidity associated with therapy for early lesions is moderate. Hyperplasia with atypia should be treated as early cancers. Many molecular markers are currently under study. Markers may soon help us identify invasive lesions at higher risk of recurring and thus more suitable for adjunct therapy. Screening in the general population is not recommended, but a high-risk group that is more suitable for screening could be identified, including obese and nulliparous women, those treated with unopposed estrogen or tamoxifen, or those with family or past histories of breast or colon cancer. Development of chemoprevention with an oral contraceptive during the reproductive years is under way, and there may be a role for chemoprevention in the reversal of hyperplasias.

Biomarkers, Tumor↗

PubMed1996

Uterine sarcoma.

Sarcomas are rare tumors with unpredictable prognosis. They are treated similarly to endometrial cancers. Little is known of epidemiologic risk factors for sarcoma; similarly, little work has been performed assessing molecular alterations in sarcomas. Because of their rarity, uterine sarcomas are not suitable for screening. Chemoprevention studies might target those at risk for recurrence or a second neoplasm.

Biomarkers, Tumor↗

PubMed1996

Ovarian intraepithelial neoplasia and ovarian cancer.

Ovarian cancer accounts for only 4% of cancers in women, but it is the leading cause of death from gynecologic malignancies in the United States. In the general population, a woman's lifetime risk of ovarian cancer is 1.4% but this risk can increase substantially in women with a strong family history of the disease. The high mortality rate from ovarian cancer is due primarily to the difficulty in detecting the disease in early stages; the disease tends to be asymptomatic until it is well advanced. The primary care physician needs to be alert to the possibility of an ovarian malignancy in all women with an intact ovary or ovaries who present with abdominal or pelvic complaints. There are no current recommendations for routine screening for ovarian cancer in the general population. Even in high-risk women, there are currently no convincing data to support extensive screening, although a number of studies looking at this issue are under way. Despite this lack of conclusive evidence, a consensus panel on ovarian cancer convened by the NIH recently issued guidelines for screening high-risk women. They recommend annual rectovaginal pelvic examination, testing of CA 125 level, and transvaginal ultrasonography. Color flow Doppler analysis of the ovarian vessels is also being studied as a possible screening modality. BRCA1 gene testing may soon play a role in women with a strong family history of the disease. Given its high mortality rate, primary prevention strategies for ovarian cancer should be used whenever possible. Oral contraceptive use appears to reduce the risk of ovarian cancer. Prophylactic oophorectomy may be suggested for women at particularly high risk of the disease. Here, too, the primary care physician can play an important role in helping a patient understand the risks and benefits of these options.

Biomarkers, Tumor↗

PubMed1996

Gestational trophoblastic disease.

GTD occurs in fewer than 1 in 1200 pregnancies in the United States, but it is much more common in Asia and Latin America, where its incidence may be as high as 1 in 200 pregnancies. Risk factors for GTD include advanced or young maternal age, low socioeconomic status, and prior hydatidiform mole. Early diagnosis and prompt treatment are key to a favorable outcome, and thus recognition of the signs and symptoms of the disease is important for all physicians. Because these diseases have low incidences and occur after reproductive events, screening for them in the general population is not worthwhile. No chemopreventive agents have yet been studied in women at risk for GTD, but the oral contraceptive is a good candidate.

Biomarkers, Tumor↗

PubMed1995

Weak transcriptional activation is sufficient for transformation by v-Myb.

The v-myb oncogene causes monoblastic leukemia in chickens and transforms avian myelomonocytic cells in vitro, v-Myb is a short-lived nuclear protein which binds to DNA in a sequence-specific manner and can activate gene expression in transient DNA transfections. Analysis of a series of v-Myb mutants has shown that the ability to activate transcription appears to be required for leukemic transformation. We have systematically investigated transcriptional activation by v-Myb and have made several new observations: (i) v-Myb is a very weak activator when compared to GAL4; (ii) very weak transcriptional activation by v-Myb is sufficient for transformation, whereas very strong transcriptional activation by a v-Myb-VP16 fusion protein is not; and (iii) v-Myb can activate transcription by two genetically distinct mechanisms, only one of which requires the presence of Myb-binding sites.

Adenovirus E1B Proteins↗

PubMed1992

A highly conserved cysteine in the v-Myb DNA-binding domain is essential for transformation and transcriptional trans-activation.

The v-Myb protein is nuclear, binds to DNA in a sequence-specific fashion, regulates the transcription of various reporter gene and transforms myelomonocytic cells. Cysteine is one of the most conserved residues during protein evolution and has been implicated in DNA binding, protein-protein interaction and redox regulation of various proteins. Therefore, we have now individually substituted each of the seven cysteines of v-Myb with a serine. All seven mutant proteins bound to DNA when they were expressed in E. coli. However, mutant C65S neither trans-activated transcription in vivo nor transformed myeloid cells, although it was transported into the nucleus. This cysteine is conserved in the Myb-related proteins of animals, plants, yeast and the cellular slime mold Dictyostelium discoideum. The C65S mutation and a nearby codon insertion mutation also abolished trans-activation by fusion proteins containing the v-Myb DNA-binding domain and the strong constitutive activation domain of herpes simplex virus (HSV) VP16. Because this domain of VP16 appears to activate transcription whenever it is bound upstream of an appropriate promoter, these results imply that C65 may be required for high-affinity DNA binding in vivo. In support of this hypothesis, we have also shown that, in contrast to wild-type v-Myb, mutant C65S is unable to block transcription from a reporter gene in which Myb binding sites overlap the initiation site.

Amino Acid Sequence↗

PubMed1988

A comparison of enprostil and ranitidine in treatment of duodenal ulcer.

Enprostil is a new synthetic prostaglandin E2 with antisecretory and mucosal-protective effects. We compared it with ranitidine in the healing of duodenal ulcer and also examined the subsequent relapse rate. Three hundred thirteen patients were recruited in 15 centers in Europe, of whom 158 were treated with enprostil (E) 35 micrograms twice daily and 155 with ranitidine (R) 150 mg twice daily for up to 6 weeks, using a double-blind method. Patients in both groups were of comparable demography. Healing was significantly quicker with ranitidine. Of patients randomized to treatment, healing (intention-to-treat analysis) at 4 weeks was E 47% and R 69%, and at 6 weeks it was E 66% and R 88%. In patients who met all protocol criteria and completed treatment, healing at 4 weeks was E 58% and R 80%, and at 6 weeks it was E 81% and R 92%. Early relief of pain, both during the day and at night, was significantly quicker with ranitidine. Nausea, diarrhea, vomiting, and abdominal pain occurred more often with enprostil. There were no clinically important abnormalities in hematology or biochemistry. Relapse rates were similar. In conclusion, enprostil is not as effective as ranitidine in healing duodenal ulcers.

Adolescent↗

PubMed1985

Plasma membrane orientation of simian virus 40 T antigen in three transformed cell lines mapped with monoclonal antibodies.

Simian virus 40 large T antigen transforms cells from several species. Recent studies show that it is present on the cell surface. As in other tumor virus systems, this may be important for transformation. We have used a radioimmunoassay to map antigenic determinants on living and formaldehyde-fixed transformed cells with six different monoclonal antibodies to T antigen. Nonrelevant monoclonal antibodies of the same subclasses served as controls. With the transformed mouse line SVT2, antibody PAb 101, which reacts with the C-terminal region of T antigen, and PAb 1700, which is directed against an internal region of T, reacted with both formaldehyde-fixed and living cells. Antibodies PAb 402 (C terminus) and 419 (N terminus) reacted only with living cells, their determinants being destroyed upon formaldehyde fixation. Antibodies PAb 405 (C terminus) and 100 (internal) fail to react on either fixed or living cells. Similar results were obtained on the simian virus 40-transformed human line SV80 and the fixed hamster line CHLwt23, although all antibodies failed to react with living CHLwt23 cells. The data suggest that T antigen is inserted into the plasma membrane of transformed cells in a specific, nonrandom manner, with the C and N termini exposed on the cell surface and the midportion either buried in the lipid bilayer, hidden by the tertiary structure of T antigen, or masked by a post-translational modification such as fatty acid acylation.

Animals↗

PubMed1985

Simian virus 40 large T antigen oligomers: analysis of electrophoresis in the absence of detergent.

Large T antigen of simian virus 40 is found as monomeric and oligomeric species in transformed cells. These can be demonstrated in cell extracts by velocity centrifugation in sucrose gradients. We analyzed them further in a transformed human line cell (SV80) and a transformed mouse line cell (SVT2). Individual fractions from sucrose gradients were subjected to polyacrylamide gel electrophoresis in the absence of detergent. T-antigen species were then detected by protein blotting and antibody overlay with polyclonal anti-D2 T antibody or monoclonal Pab419, Pab101, or Pb1700 antibody. The rapidly sedimenting species (14S and larger) of large T antigen from both cell lines reproducibly showed two major bands with estimated molecular weights of 670,000 and 850,000. A third band of 1,200,000 was more prominent in SVT2 cells than in SV80 cells. In SV80 cells the slowly sedimenting species of large T antigen (5S to 11S) contained two reproducible bands. A band with a molecular weight of 95,000 was the predominant one in all fractions between 5S and 11S. A relatively minor band with a molecular weight of 230,000 was found in fractions between 9S and 11S. The low-molecular-weight forms were seen in SVT2 cells only when a prominent peak at 5S to 7S was present, that is, when extracts were stored before analysis. In fresh extracts, the low-molecular-weight bands and slowly sedimenting forms were absent.

Animals↗