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Biomedical subjects

D McCloskey

Publications and source records attributed to D McCloskey.

At least 19 recordsLinked to original sources
PubMed2000

Delayed micromolar elevation in intracellular calcium precedes induction of apoptosis in thapsigargin-treated breast cancer cells.

Thapsigargin (TG), a highly specific inhibitor of the sarcoplasmic reticulum and endoplasmic reticulum Ca2+-ATPase pump, can induce apoptosis in a variety of epithelial and lymphoid cell types. In prostate cancer cell lines, TG induces an initial 5- to 10-fold elevation of intracellular calcium ([Ca2+]i) within a few minutes of exposure. With prolonged exposure times (i.e., 12-36 h) a second elevation of [Ca2+]i to >10 microM is observed. In this study, the human breast carcinoma cell lines MCF-7 and MDA MB 468 cells were used to determine the temporal relationship between TG-induced elevation of [Ca2+]i and activation of programmed cell death. Using a microinjection method that allows for long-term analysis of [Ca2+]i changes, we found that after TG exposure, calcium measurements in these cells demonstrated an initial rise (>4-fold) in [Ca2+]i that occurred within minutes and returned to baseline within a few hours. With prolonged TG exposure, the cells underwent a second elevation (>5 microM) of [Ca2+]i occurring stochastically between 12 and 36 h after the initial exposure to TG. Both of the cell lines were growth-inhibited by 100 nM TG after only 1 h of exposure, but clonogenic ability in the MCF-7 cells was significantly reduced only after 48 h of exposure. The induction of apoptosis by TG was demonstrated by morphological changes typical for programmed cell death and DNA fragmentation (both high molecular weight and oligonucleosomal-sized fragments were detected) after 48 h of treatment. TG induction of apoptosis in these breast cancer cells occurred subsequent to the secondary rise in [Ca2+]i, which confirmed that this secondary rise in [Ca2+]i is not prostate cancer-specific. The secondary rise in [Ca2+]i to micromolar levels may directly activate the endonucleases responsible for DNA fragmentation that occurs as part of the apoptotic process. These studies indicate that TG is an active agent in vitro against breast cancer cells. Inactive prodrug analogues of TG are currently being developed that can be activated by tissue-specific proteases, and further pursuit of this strategy as a potential treatment for breast cancer is warranted.

Apoptosis↗
PubMed1998

High-resolution sonography of the abnormal cranial suture.

OBJECTIVE: The purpose of this investigation is to elucidate the sonographic features of abnormal major cranial sutures. MATERIALS AND METHODS: Eight excised synostosed suture specimens were evaluated. The high-resolution sonographic appearance was correlated with the histological section, plain radiographs, CT and MRI. Diastatic and molded sutures were also evaluated with sonography and compared with the normal cranial suture appearance. RESULTS: Synostosed sutures demonstrated one or more of the following features: (a) loss of echo-poor fibrous gap between bony plates (five sagittal and coronal synostoses); (b) irregular thickened inner sutural margin (three lambdoid synostoses); (c) loss of bevelled edge (one lambdoid synostosis); (d) asymmetric anterior fontanelle (one coronal synostosis). Cranial molding results in an overlap of echogenic bony plates. Sutural width (the distance between bony plates) is increased in cases of elevated intracranial pressure. CONCLUSION: Sonography is an inexpensive, radiation-free modality which can confirm synostosis versus molding versus an underlying intracranial lesion as a cause of plagiocephaly. The high-resolution sonographic images also provide a relatively easy means to assess sutural width and may provide information in regard to increased intracranial pressure.

Cranial Sutures↗
PubMed1997

Sclerosing cholangitis, race and sex.

BACKGROUND: Primary sclerosing cholangitis develops in 3-10% of patients with ulcerative colitis, and may be associated with an increased cancer risk. Ulcerative colitis is probably less common in people of African origin than in populations of European descent. AIMS AND METHODS: To review the records of all patients under regular follow up for ulcerative colitis at St Bartholomew's Hospital (London, UK), a tertiary referral centre, prompted by discovering a cluster of cases with common features. RESULTS AND CONCLUSIONS: Among 166 patients with ulcerative colitis under regular follow up, only four (all women) are of African or Caribbean genetic origin, and three of these have developed sclerosing cholangitis within three years of presentation with colitis, compared with four of 162 patients of European or Asian descent (odds ratio 119, 95% confidence interval 8-3837; p = 0.0002). This cluster, which is not explained by common HLA DR or DQ type, suggests that Africans and Afro-Caribbeans, especially women, may be at increased risk of sclerosing cholangitis. This may reflect genetic influences on the development of enteric and hepatobiliary inflammatory disease.

Adolescent↗
PubMed1997

Sonography of normal cranial sutures.

OBJECTIVE: The purpose of this study was to describe the normal sonographic appearance and measurement of normal major cranial sutures in neonates and infants. SUBJECTS AND METHODS: High-resolution sonograms of sagittal, coronal, and lambdoid sutures were obtained for two autopsy specimens and correlated with histologic sections obtained at identical locations. Also, 50 neonates and infants (0-5 months old [corrected age]) who had normally shaped craniums underwent sonography of the brain that produced normal findings. These neonates and infants also underwent sutural sonograms. The width and thickness of each of the major cranial sutures (sagittal, coronal, and lambdoid) were measured, with mean values established. Measurements were analyzed with paired t tests for interobserver variability. Linear regression was used for correlation of measurements with age. RESULTS: With a scan plane perpendicular to the suture line, sonograms revealed sutures as hypoechoic gaps between two hyperechoic bony plates. On sonograms, sagittal sutures had an end-to-end appearance instead of the beveled junction seen throughout most of the coronal and lambdoid sutures. In the 50 patients, sonograms revealed the mean width to be 0.89 +/- 0.35 mm (mean +/- SD) for coronal sutures. 0.93 +/- 0.28 mm for sagittal sutures, and 0.96 +/- 0.39 mm for lambdoid sutures. On sonograms, mean thickness was 1.97 +/- 0.54 mm for coronal sutures, 1.88 +/- 0.56 mm for sagittal sutures, and 2.49 +/- 0.86 mm for lambdoid sutures. We found no interobserver variability (p < or = .05). With linear regression analysis, we found no correlation between suture width or thickness and patient age (r = .01). CONCLUSION: In our study, high-resolution sonography proved to be a reliable and inexpensive technique capable of defining cranial sutures. Preliminary normative data obtained for cranial suture width and thickness showed no correlation with age in our population group. The normative data obtained will allow recognition of abnormal sutures, particularly synostotic or diastatic sutures.

Cranial Sutures↗
PubMed1996

Evaluation of the flow cytometric crossmatch. Preliminary results of a multicenter study.

The flow cytometric crossmatch is a technique that is increasingly being used by clinical transplant laboratories. In this multicenter study by the British Society for Histocompatibility and Immunogenetics Flow Cytometry Group, a series of crossmatches were carried out to determine whether different centers obtained same results when performing the same crossmatch. There was greater than 80% agreement among participating laboratories on the results of 35/54 tests. There was no clear agreement in the remaining 20 cases. Quantitative analysis, estimating the number of cell-bound fluorescein molecules, demonstrated that differences in the criteria used by each center to define a positive crossmatch were responsible for some discordant results. When applied, definition of positivity based on the molecules of fluorescein increased concordance from 57.5% to 81.4%.l. These results suggest that a criterion for the interpretation of results based on quantitative analysis of bound antibody may be more reliable than methods in current routine use.

Flow Cytometry↗
PubMed1994

Recurrent erythema multiforme: tissue typing in a large series of patients.

Previous reports have shown an increased frequency of certain HLA antigens in association with erythema multiforme, including HLA-B15(B62), HLA-B35, HLA-A33, HLA-DR53 and, more recently, HLA-DQB1*0301. A strong association with HLA-DQ3 has been documented in patients with recurrent erythema multiforme. We have performed HLA typing in 39 patients with recurrent erythema multiforme, of whom 33 were associated with herpes simplex virus infection. The results were compared with 309 controls. In the recurrent erythema multiforme patients there was a statistically significant increase in HLA-B62 and HLA-B35. An increase in HLA-DR53 was also found, although this did not reach statistical significance. There was no increase in HLA-A33. The presence of HLA-DQ3 in the study population approached that in the controls. Finally, the study population demonstrated a trend towards a reduction in the HLA antigens A1, B8 and DR3. The study confirms the previously reported associations with HLA-B62 (B15), HLA-B35 and HLA-DR53. We have been unable to confirm an association of HLA-A33 or HLA-DQ3 with erythema multiforme. The HLA antigens A1, B8, and DR3 are associated with autoimmune disease, reflecting an increased host response to tissue self antigens. Their absence in patients with recurrent erythema multiforme (REM) may be an indicator of a poor host response to an antigen, which in the case of REM is the herpes simplex virus.

Adult↗
PubMed1990

Heterogeneity of HLA-DR4 in Greeks including a unique DR4-DQw2 association.

It has been shown that Greek RA patients do not show an increased frequency of HLA-DR4 compared with Greek controls. As only the Dw4 and Dw14 subtypes of DR4 are implicated in RA, we have characterised DR4-positive Greek RA patients and controls using serology, MLC typing and RFLP analysis to see whether the distribution of DR4 subtypes or other HLA antigens associated with DR4 could account for these findings. In the 10 patients and 12 controls studied, Dw10 was common, being present in almost half the controls. Dw4 was not detected in the controls, but was present in three of the RA patients, indicating that there may be some relationship between Dw4 and RA in this population; Dw13 and Dw14 were also found, Dw15 was not detected. Eight of the subjects did not type as any of the HLA-D antigens mentioned. Three controls had unusual DR4-DQ associations, two having DR4-DQw2 and one possessing DR4-DQw4. Analysis of the TaqI DRB RFLP of the subjects showed that one control did not have the 6.1 kb band characteristic of DR4s. All these results indicate that DR4 is a heterogeneous antigen in this population and that several as yet undescribed variants of DR4 may be present.

Arthritis, Rheumatoid↗
PubMed1988

A comparative serological and molecular study of linear IgA disease and dermatitis herpetiformis.

The class I and class II HLA serologically defined antigens and DQ alpha and DX alpha restriction fragment length polymorphism (RFLP) in 23 patients with linear IgA disease (LAD) were determined and their frequencies compared with those in a group of patients with dermatitis herpetiformis (DH) and healthy controls. In LAD there was a significant increase in HLA-B8 and DR3 and a larger increase in the DQw1-DR2/DRw6 related DQ alpha 6.2 kb and 6.8 kb RFLP. In DH there was a significantly increased frequency of HLA-A1, B8, DR3, and DQw2 with a concomitant increase in the DR3-DQw2 related DQ alpha 4.6 kb RFLP. The difference in DR3 frequencies and the increased frequency of DQw1 rather than DQw2 in LAD indicates that different susceptibility genes operate in the two diseases.

Dermatitis Herpetiformis↗
PubMed1986

Different HLA associated gene combinations contribute to susceptibility for coeliac disease and dermatitis herpetiformis.

Forty two white patients of British or Irish descent with coeliac disease and 28 with dermatitis herpetiformis were typed for class I HLA-A, B, and C, and class II DR and DQ antigens. In coeliac disease there was a significant increase in the frequencies of A1, B8, DR3, DR7, and DQw2 compared with controls but no increase of DR2. In dermatitis herpetiformis there were similarly increased frequencies of A1, B8, DR3, and DQw2. In contrast with coeliac disease, however, the frequency of DR7 (18%) was no different from the control group but there was an increased frequency of DR2.

Adolescent↗
PubMed1986

HLA and rheumatoid arthritis: an analysis of multicase families.

In a study of multicase RA families, significantly raised frequencies of the HLA antigens DR4, DR1, Bw62, Cw3, A2, A31 and significantly lower frequencies of DR2, DR3, and B8 were found in probands compared to normal controls. When haplotype frequencies were compared between probands and controls, two haplotypes A2-B44-DR4 and A2-Bw62-DR4 were at higher frequency in probands. These differences no longer reached significance when only DR4-containing haplotypes were compared between probands and controls. A significantly lower haplotype frequency of A1-B8-DR3 was observed in probands compared to controls. This difference did not remain significant when only non-DR4 haplotypes were compared. Using an affected sibling pair ratio method, significant linkage between HLA and RA was found (P less than 0.01). Significant linkage was also observed between HLA and seropositivity. Analysis of Hardy-Weinberg equilibrium for the DR locus did not support the suggestion that DR4-associated RA susceptibility was inherited as a dominant trait. In addition it did not support the notion of an additive effect of DR4 and DR1 in RA susceptibility as these antigens were not found together more frequently than predicted by their individual gene frequencies.

Arthritis, Rheumatoid↗