Diagnosis and management of early prostate cancer. Report of a British association of urological surgeons working party.
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Biopsy↗
Biomedical subjects
D Kirk
Publications and source records attributed to D Kirk.
Sequences flanking the centromere of human chromosome 10 are a complex patchwork of arm-specific sequences, stable duplications and unstable sequences with homologies to telomeric and other centromeric locations.
Little is known about sequence organization close to human centromeres, despite empirical and theoretical data which suggest that it may be unusual. Here we present maps which physically define large sequence duplications flanking the centromeric satellites of human chromosome 10, together with a fluorescence in situ hybridization (FISH) analysis of pericentromeric sequence stability. Our results indicate that the duplications on each chromosome arm are organized into two blocks of approximately 250 and 150 kb separated by approximately 300 kb of non-duplicated DNA. The larger proximal blocks, containing ZNF11A, ZNF33A and ZNF37A (10p11) and ZNF11B, ZNF33B and ZNF37B (10q11), are inverted. However, the smaller distal blocks, containing D10S141A (10p11) and D10S141B (10q11), are not. A primate FISH analysis indicates that these loci were duplicated before the divergence of orang-utans from other Great Apes, that a cytogenetically cryptic pericentric inversion may have been involved in the formation of the flanking duplications and that they have undergone further rearrangement in other primate species. More surprising is the fact that sequences across the entire pericentromeric region appear to have undergone unprecedented levels of duplication, transposition, inversion and either deletion or sequence divergence in all primate species analysed. Extrapolating our data to the whole genome suggests that a minimum of 50 Mb of DNA in centromere-proximal regions is subject to an elevated level of mechanistically diverse sequence rearrangements compared with the bulk of genomic DNA.
Animals↗
Re: Immediate versus deferred treatment for advanced prostate cancer: initial results of the medical research council trial.
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Clinical Trials as Topic↗
Enhanced expression of the mesenchymal marker, vimentin, in hyperplastic versus normal human prostatic epithelium.
A total of 20 benign prostatic hyperplasia (BPH) tissue samples from 13 patients were evaluated for the coexpression of cytokeratins and vimentin intermediate filaments in the glandular epithelium. Vimentin expression was significantly increased (p < 0.001) in BPH epithelium compared to adjacent "normal" epithelium. The data imply that epithelial/mesenchymal (E/M) transformations may play a role in the pathogenesis of BPH.
Aged↗
Prostate cancer in the elderly.
The incidence of prostate cancer is age related and increased longevity increases the number of elderly men with the disease. Management of prostate cancer in the elderly requires a different approach. Screening and aggressive case finding to seek out early confined disease are contraindicated in those with a life expectation below 10 years. Early confined disease in the elderly is usually managed expectantly. Hormone treatment is more appropriate for locally advanced disease, and is a valuable non-surgical treatment for bladder outflow obstruction due to prostate cancer. A significant proportion of elderly men with prostate cancer still die from other diseases. Hormone refractory disease in the elderly should be managed by palliation of symptoms rather than toxic second-line therapies. The aim always is diagnosis where appropriate, treatment which will be of benefit, and quality rather than length of life.
Adult↗
GLP-2 augments the adaptive response to massive intestinal resection in rat.
To determine whether treatment with a potent protease-resistant analog of human glucagon-like peptide 2 (GLP-2) might augment the adaptive response to massive intestinal resection, rats were divided into resected, which had 75% of the midjejunoileum removed, sham-resected, and nonsurgical groups. Within each group, animals were assigned to 21 days of treatment with the drug (0.1 micrograms/g of the GLP-2 analog in phosphate-buffered saline) or vehicle alone subcutaneously twice daily. Food intake; weight gain; jejunal and ileal diameters, total and mucosal wet weights per centimeter, crypt depths, and villus heights; mucosal sucrase activity, milligrams of protein per centimeter, and micrograms of DNA per centimeter; and D-xylose absorption were measured. There was a significant increase in diameter, total and mucosal wet weights per centimeter, crypt-villus height, sucrase activity, milligrams of protein per centimeter and micrograms of DNA per centimeter in both the jejunum and ileum in response to resection and a significant additive response to the GLP-2 analog in the jejunum but not in the ileum. The ratio of milligrams of protein per centimeter to micrograms of DNA per centimeter of mucosa was not different among groups, consistent with hyperplasia. D-Xylose absorption was significantly reduced in response to resection; however, the GLP-2 analog enhanced the absorptive capacity in control animals and restored the absorptive capacity in resected animals. Thus the GLP-2 analog induces mucosal hyperplasia and enhances the rate and magnitude of the proximal intestinal adaptive response to massive resection.
Adaptation, Physiological↗
Fertility levels, trends, and differentials in sub-Saharan Africa in the 1980s and 1990s.
This study presents an assessment of fertility trends in 23 countries of sub-Saharan Africa. It examines trends and differentials in proximate determinants and fertility preferences. Findings from the Demographic and Health Surveys for these countries over a period of 15 years show that desired family size has decreased significantly. Two-thirds of the countries examined show evidence of fertility decline, a particularly rapid decline in the cases of Kenya and Zimbabwe. Areas with higher education for women and lower child mortality experienced larger reductions in fertility and desired family size. Contraceptive use far exceeds other proximate determinants in explaining these changes. The striking regularity in fertility reduction across all ages indicates that contraception is practiced mostly for birth spacing and that contraceptive methods have gained wide acceptance among younger cohorts. Good prospects are seen for further intensification of fertility declines in East Africa and urban West Africa. However, low levels of education and high child mortality make rapid changes unlikely in rural West Africa.
Adolescent↗
MRC study: when to commence treatment in advanced prostate cancer.
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Journal Article↗
The economic impact on families of children's participation in junior sport.
The study investigated the socio-economic consequences for families of participation in junior sport. Two hundred and twenty families in Queensland and Victoria were surveyed from the sports of cricket, Australian football, gymnastics, hockey, netball and tennis and twenty seven of these interviewed. The study showed that parents make a substantial contribution in terms of financial support to their children's participation in junior sport. Each of the sports mode different financial demands on families depending on the yearly cycle of training and competition, distance from facilities and coaching, costs associated with coaching, equipment and uniforms, and representative level. It is concluded that family income and structure are the key factors in determining the likelihood of a child's involvement in junior sport, and that for many Australian children, financial factors may be barriers to their participation in junior sport.
Adolescent↗
Nitrogen metabolite signalling involves the C-terminus and the GATA domain of the Aspergillus transcription factor AREA and the 3' untranslated region of its mRNA.
AREA is a GATA transcription factor which mediates nitrogen metabolite repression in Aspergillus nidulans in response to intracellular glutamine levels. We have identified and localized three elements important to modulation of AREA function: a region of 13 residues within the DNA-binding GATA domain which forms a putative extended loop structure, the 12 C-terminal residues, and sequences within a 218 nucleotide region of the 3' UTR. The 12 C-terminal residues are also required for transcriptional activation at a subset of loci under areA control. Specific deletions within the 3' UTR and the C-terminus cause similar levels of derepression and the mutations are additive, implicating two principal signal transduction pathways. The contribution of the 3' UTR to AREA modulation is effected at the level of transcript stability such that the areA mRNA is at least five times more stable under nitrogen-derepressing conditions than it is under repressing growth conditions.
Amino Acid Sequence↗
Mutational analysis of the C-terminal region of AREA, the transcription factor mediating nitrogen metabolite repression in Aspergillus nidulans.
In Aspergillus nidulans the positive-acting, wide domain regulatory gene areA mediates nitrogen metabolite repression. Previous analysis demonstrated that the C-terminal 153 residues of the areA product (AREA) are inessential for at least partial expression of most genes subject to regulation by areA. Paradoxically, areAr2, a -1 frameshift replacing the wild-type 122 C-terminal residues with a mutant peptide of 117 amino acids, leads to general loss of function. To determine the basis for the areAr2 mutant phenotype, and as a means of delineating functional domains within the C-terminal region of AREA, we have selected and characterised areAr2 revertants. Deletion analysis, utilising direct gene replacement, extended this analysis. A mutant areA product truncated immediately after the last residue of the highly conserved GATA (DNA-binding) domain retains partial function. The areAr2 product retains some function with respect to the expression of uaZ (encoding urate oxidase) and the mutant allele is partially dominant with respect to nitrate reductase levels. Consistent with the areAr2 product having a debilitating biological activity, we have demonstrated that a polypeptide containing both the wild-type DNA-binding domain and the mutant C-terminus of AREA2 is able to bind DNA in vitro but no longer shows specificity for GATA sequences.
Amino Acid Sequence↗
Human endometrial matrix metalloproteinase-2, a putative menstrual proteinase. Hormonal regulation in cultured stromal cells and messenger RNA expression during the menstrual cycle.
Proteinases are likely effectors of endometrial menstrual breakdown. We have investigated proteinase production by human endometrial stromal cells subjected in vitro to progesterone (P) withdrawal, the physiologic stimulus for menstruation. Culture media of cells exposed to estradiol, P, or estradiol plus P had low levels of proteolytic activity similar to cultures maintained in the absence of steroids. P withdrawal, or addition of RU486 to P-treated cultures, stimulated proteinase secretion. The stromal cell proteinase was characterized by gelatin zymography, inhibitor profile, and organomercurial activation, as a metalloproteinase present mostly as a 66-kD proenzyme with lower levels of a 62-kD active form. The P withdrawal-induced metalloproteinase was identified as matrix metalloproteinase-2 (MMP-2) by Western blotting. The increase of MMP-2 induced by P withdrawal was associated with the metalloproteinase-dependent breakdown of stromal cultures, involving dissolution of extracellular matrix and dissociation of stromal cells. Northern analysis showed the differential expression of MMP-2 mRNA in late secretory phase endometrium. These findings are consistent with the involvement of stromal cell-derived MMP-2 in the proteolysis of extracellular matrix promoting cyclic endometrial breakdown and the onset of menstrual bleeding.
Blotting, Western↗
Detection and distribution of heat shock proteins 27 and 90 in human benign and malignant prostatic tissue.
OBJECTIVE: To determine whether it is possible to predict the behaviour of prostate tumours by identifying cellular characteristics, specifically specific heat shock proteins (HSPs). MATERIALS AND METHODS: An immunohistochemical study staining for HSP 27 and 90 was undertaken on 15 benign and 13 malignant samples of freshly frozen prostatic tissue obtained from patients with a similar age range in each group (benign, mean age 71.6 years, range 61-86; malignant, mean age 72.7 years, range 58-87). Gleason scores for the tumours ranged from 2 to 8. RESULTS: Consistent patterns of cytoplasmic staining were seen in all sections of tissue from benign prostatic hyperplasia (BPH). The stroma stained strongly positive for HSP 27, but negatively for HSP 90 and glandular epithelium showed positive apical staining for both HSPs. Stromal patterns in prostatic carcinoma tissue were similar to that of BPH tissue for both HSP 27 and 90. Areas of prostatic intra-epithelial neoplasia stained as strongly as did adjacent areas of BPH. For HSP 27, there was varied staining of individual epithelial cells, suggesting cellular heterogeneity, with an apparent reduction in staining with increasing Gleason score and invasiveness. For HSP 90, this pattern was less marked, with a predominance for positive staining throughout all grades of carcinoma. CONCLUSIONS: The distribution of HSPs, primarily HSP 27, may aid in identifying different cell populations within prostatic carcinomas and thus help forecast biological behaviour.
Aged↗
Retroperitoneal surgery: its wider role in the management of malignant teratoma.
OBJECTIVE: To review the results of the use of laparotomy to excise retroperitoneal metastases in patients with malignant teratoma of the testis. PATIENTS AND METHODS: The results of surgery for retroperitoneal teratoma metastases in 37 patients during the 5-year period from 1988 to 1993 were reviewed. Information on sexual dysfunction was obtained using a postal questionnaire. RESULTS: Patients were divided into three groups: the first comprised 28 patients who underwent elective surgery (excision of residual disease) after platinum and bleomycin-based chemotherapy. The second group comprised four patients who underwent interventional surgery to excise disease not responding to treatment, after which they completed chemotherapy. The third group comprised five patients who underwent surgery for relapsed disease; two had suffered an early and three a late relapse. Overall, 34 patients are alive, four are considered to have residual disease and two have recently undergone re-operation. CONCLUSIONS: In addition to removing residual disease after primary chemotherapy, surgery has a wider role in the management of metastatic teratoma. Carefully timed interventional surgery for disease not responding to chemotherapy can be lifesaving. Surgery for early relapse should be preceded by chemotherapy but surgery alone is appropriate where relapse occurs several years after primary treatment, although raised levels of tumour markers or extensive recurrence might be an indication for preliminary chemotherapy.
Adolescent↗
Demographic transition theory.
Demography is a science short on theory, rich in quantification. Nevertheless, demography has produced one of the best documented generalizations in the social sciences: the demographic transition. What is the demographic transition? Stripped to its essentials it is the theory that societies progress from a pre-modern regime of high fertility and high mortality to a post-modern regime of low fertility and low mortality. The cause of the transition has been sought in the reduction of the death rate by controlling epidemic and contagious diseases. Then, with modernization, children become more costly. Cultural changes weaken the importance of children. The increasing empowerment of women to make their own reproductive decisions leads to smaller families. Thus there is a change in values, emphasizing the quality of children rather than their quantity. In short, the fertility transition is becoming universal phenomenon, in which every country may be placed on a continuum of progress in the transition.
Demography↗
The international terazosin trial: a multicentre study of the long-term efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia. The ITT Group.
OBJECTIVE: To evaluate the long-term efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia (BPH). METHODS: Thirty-three sites in 13 countries enrolled men with BPH who had an International Prostate Symptom Score (IPSS) > or = 12 [corrected]. After a 2-week, no-treatment lead-in period and a 26-week, single-blind treatment period, patients responding to terazosin were randomly assigned to receive either terazosin or placebo for a 24-week, double-blind withdrawal period. RESULTS: Of the initial 427 patients enrolled, 378 were evaluable, 273 of whom completed the single-blind period, of which 186 patients were randomized. During the single-blind treatment period, IPSS, quality-of-life score (QOL), peak flow rate (PFR), and nocturia score (NOC) improved significantly (p < or = 0.05). During the double-blind withdrawal period, IPSS, QOL, PFR, and NOC deteriorated significantly in the placebo group compared with the terazosin group. The most common adverse event resulting in premature termination from the study was dizziness. There were no clinically important mean reductions in diastolic blood pressure (DBP) for patients normotensive at baseline. Terazosin significantly reduced mean DBP in hypertensive patients during the single-blind period and maintained the reduction during the double-blind period. CONCLUSION: Treatment with terazosin has a beneficial effect on BPH, continuing for at least 12 months, and can be safely considered for medium- to long-term use in those who benefit.
Adrenergic alpha-Antagonists↗
Prostate disease: management options for the primary healthcare team. Report of a working party of the British Prostate Group.
The prostate gland has attracted a remarkable increase in interest in the past few years. The two most common diseases of this gland, benign prostatic hyperplasia and carcinoma of the prostate, have been brought into greater prominence by new diagnostic methods, public interest, and a wider choice of surgical and non-surgical treatments. Uncertainty about the significance of these changes has occurred because of the rapidity of change, the profusion of statements, opinions and promotions, and the relatively little guidance available from the profession. Ten urologists and two general practitioners have reviewed the relevant evidence about these two prostate diseases and the newer diagnostic methods; their conclusions are summarised here. Management options and guidance on clinical practice are also discussed. Because of a number of unresolved diagnostic and management issues, detailed requirements for practice guidelines have not been specified.
Adult↗
Immediate versus deferred treatment for advanced disease.
The timing of hormonal treatment has been controversial for the last 50 years. The VACURG studies suggested that deferring treatment in symptom free patients might not compromise survival. Recent studies of maximal androgen blockade have revived an old observation that disease presenting earlier may be more hormone sensitive. The arguments in favour of immediate versus deferred treatment depend on the balance of advantages against side effects and costs, but a clear advantage in terms of survival from immediate treatment has yet to be demonstrated. An MRC study of this issue has recruited 1938 patients and should make it first report in 1996. Meanwhile, in many men, deferred treatment remains a valid management option, provided it is used with caution and careful follow-up.
Androgen Antagonists↗