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It has been known for over 70 years that adrenal catecholamine secretion can be modulated or elicited by noncholinergic neurotransmitters and hormones. However, our understanding of the cellular mechanisms by which these agents produce their effects and the physiological conditions under which they act are not well characterised. Here we briefly review the mechanisms by which one such agent (the neuropeptide substance P) modulates the cholinergic secretory response of adrenal chromaffin cells, and another agent (angiotensin II) elicits catecholamine secretion independently of the cholinergic innervation.

A study was made of the incidence of p53 mutations in Japanese males with prostate cancer or benign prostatic hyperplasia. Polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) was used as a primary screening technique with gene sequencing being carried out in positive cases. Two out of 21 prostate cancers (9.5%) were found to have p53 mutations. These were stage B2 and D2 prostate cancers. No abnormalities were found in the remaining cases or benign prostatic hyperplasia. Mutations of the p53 gene would thus appear infrequent in the tumourigenesis of primary prostate cancer.

Methods and results from the quality assurance program of the Atherosclerosis Risk in Communities (ARIC) Study regarding hemostasis variables are presented, following up previous reports in this journal on standardized procedures for blood collection and processing (7) and an organized plan for the performance of those procedures (8). Efforts were made to control for and assess all sources of variability, from venipuncture to laboratory analysis, including also local field center processing and sample shipping. The quality control program included (a) a standardized protocol for blood collection and processing; (b) training, certification, and annual recertification of field center personnel for blood collection and processing; (c) monitoring of fasting times, phlebotomy times, processing times, and shipping problems; (d) hemostatic laboratory internal quality control; (e) a replicate blood sample program; (f) an intraindividual variability study; and (g) continual monitoring of quality control and study participants' data. This paper focused on items (c), (d), and (e). Measures of variation, generally standard deviations and coefficients of variation, are estimated for replicate blood sampling and internal quality control data, for activated partial thromboplastin time, fibrinogen, factor VII and VIII activity, von Willebrand factor, antithrombin-III, and protein C. The results demonstrate that it is possible to reliably measure these hemostatic variables in a large multicenter study.

The pentasaccharide (PS) comprising the minimal heparin structure capable of binding with antithrombin III (ATIII) and exhibiting anti-factor Xa (anti-fXa) activity in plasma without producing detectable antithrombin activity, has been evaluated for its relative antithrombotic and antihemostatic effects in a baboon model combining both platelet-rich and fibrin-rich thrombosis. Thrombosis was produced in a two-component thrombogenic device incorporated into an exteriorized femoral arteriovenous (AV) shunt in baboons; the proximal component constituted a segment of collagen-coated tubing and induced platelet-rich arterial-type thrombus, while the distal component consisted of an expanded chamber producing static and disturbed flow and initiated fibrin-rich venous-type thrombosis. Thrombus formation was measured as the deposition of 111In-platelets and the accumulation of 125I-fibrin. PS was administered intravenously to maintain plasma anti-fXa activity at three different levels: a) low dose (LD) 0.3 +/- 0.1 U/ml; b) intermediate dose (ID) 0.6 +/- 0.1 U/ml; and c) high dose (HD) 5.6 +/- 0.4 U/ml. In untreated controls, thrombus formed rapidly, reaching a plateau by 40 min of 2.3 +/- 0.2 x 10(9) platelets and 0.62 +/- 0.04 mg fibrin deposited on the collagen segments, and 1.9 +/- 0.4 x 10(9) platelets and 3.3 +/- 0.4 mg fibrin accumulated in the chambers.(ABSTRACT TRUNCATED AT 250 WORDS)

Heparin effectively prevents the complications of unstable angina but disease reactivation has been documented following its discontinuation. To investigate whether this could be related to antithrombin-III depletion, 50 patients with unstable angina had serial determinations of activated partial thromboplastin time and of the plasma levels of heparin, antithrombin-III activity and of the thrombin-antithrombin-III complex before, during and, in a subgroup of 8 patients, 4 hours after heparin discontinuation. Heparin was administered intravenously at therapeutic doses for a mean of 7.6 +/- 4.1 days. Plasma antithrombin-III activity decreased rapidly from 1.05 +/- 0.03 to 1.0 +/- 0.03 U/ml (p < 0.03) following heparin initiation with no further significant subsequent decrease. Antithrombin-III activity returned to the control values 4 hours after the discontinuation of heparin. Thus, heparin treatment is associated with small, non-cumulative and rapidly reversible decrease in antithrombin-III activity. Reactivation of unstable angina after discontinuation of heparin must be explained by a mechanism other than antithrombin-III deficiency.

Peritoneal macrophages from mice immunized with the delipidified cell component (DCC) of Mycobacterium leprae showed changes in various parameters such as increased protein synthesis, levels of hydrolytic enzyme and augmented phagocytic ability indicating activation of the cells. Furthermore, the surface structure of the cells were quite different from that of the macrophages of normal mice. These observations indicate that the peritoneal macrophages have been activated to phagocytose and kill M. leprae better in the immunized mice. The ability to kill the pathogen by these cells was reported by us earlier.

The following developments have considerably influenced the pathological management of breast materials: The wide use of aspiration cytology, increase of specimens from small non palpable lesions detected by mammography, an increase of cases difficult to diagnose histologically, increase in the number of conservative surgery cases which require examination of semi-serial sections, and the development of immunohistochemical procedures using breast cancer tissues. Under these changing circumstances in the department of pathology, we report our current practices and some of the results; About 75% of breast cancer cases initially treated in our hospital were diagnosed by aspiration cytology only. A retrospective, simulation study on quadrantectomy of breast cancers for selected T1N0N1a examined by semi-serial sections in non-conservative mastectomy cases revealed residual carcinoma foci located in a region outside the primary quadrant in about 25% cases. GCDFP-15 (Gross cystic disease fluid protein-15) is a fairly specific marker for breast cancer. Good correlation was obtained using estrogen and progesterone receptors routinely measured by ICA (Immunocytochemical assay), instead of the biochemical method using DCC (Dextran-coated charcoal). c-erbB-2 and p53 which were positive in 45.8%, and 28.6%, respectively, in our breast cancer cases, seemed to be good markers of biological malignancy in the breast cancer.

This is a four-year prospective study on patients admitted or referred with thromboembolic disease to Jordan University Hospital or to the Thrombosis/Haemostasis Laboratory at the University of Jordan. The aim of the study was to find the relative prevalence of hereditary thrombophilia. For the purpose of this work, hereditary thrombophilia was diagnosed in the absence of an acquired cause of thrombophilia in addition to two of the following: 1) positive family history of thrombophilia, 2) confirmed same deficiency in a closely related family member, 3) the deficient protein is constantly below 2 SD of the normal mean on repeated testing. All ages were admitted to the study. Acquired systemic factors or local factors known to cause thrombosis or affect the levels of proteins opposing thrombosis were excluded. There were a total of 217 patients (102 males and 115 females) with confirmed thromboembolic disease. Their mean age was 34 years. A total of 49 patients (26 males and 23 females) fulfilled the criteria of hereditary thrombophilia. There were 17 cases of protein C deficiency (PC), 15 protein S deficiency (PS), 10 antithrombin III deficiency (ATIII), 3 dyfibrinogenemia, 2 heparin cofactor II deficiency, and 2 plasminogen defects. In this group most of the thrombosis was venous. A positive family history was obtained in 65.3% of patients with hereditary thrombophilia. Twenty-seven additional relatives with deficiency were identified upon family studies. The calculated prevalence of hereditary thrombophilia in Jordan is put at 1/25,000. Screening for PC, PS, and ATIII is advocated in young patients who have thromboembolic disease, especially when there is a positive family history of thrombosis.

It is now apparent that multiple genetic alterations, including oncogene activation and tumor suppressor gene inactivation, are necessary steps in carcinogenesis. We have studied this concept in renal cancers by looking at specific tumor suppressor genes implicated in several allelotyping studies. Primary, predominantly low stage renal tumors of varying grades and histologic subtypes were investigated for allelic loss of 3p, 17p and the p53 gene, the DCC gene and the Rb gene and its product. 3p loss occurred in 47% of tumors studied and was much more common in clear cell cancers (85%). 17p and p53 gene loss were relatively uncommon events with only 6 of 42 tumors demonstrating loss. None of the tumors with typical histologies had allelic loss of the DCC gene, though loss did occur in leiomyosarcoma and a collecting duct tumor. Allelic loss of the Rb gene occurred in one clear cell tumor, the leiomyosarcoma, and, interestingly, in both collecting duct tumors in this series. Allelic loss of the Rb gene was correlated with little or no RB protein expression as judged by immunohistochemistry. At all loci studied, allelic loss did not appear to correlate with tumor grade or stage. These results suggest that inactivation of the p53, Rb, and DCC genes by allelic loss are uncommon events in the early stages of renal carcinogenesis.

The p53 gene is contained within 16-20 kb of cellular DNA located on the short arm of human chromosome 17 at position 17p13.1. This gene encodes a 393-amino-acid nuclear phosphoprotein involved in the regulation of cell proliferation. Current evidence suggests that loss of normal p53 function is associated with cell transformation in vitro and development of neoplasms in vivo. More than 50% of human malignancies of epithelial, mesenchymal, haematopoietic, lymphoid, and central nervous system origin analysed thus far, were shown to contain an altered p53 gene. The oncoproteins derived from several tumour viruses, including the SV40 large T antigen, the adenovirus E1B protein and papillomavirus E6 protein, as well as specific cellular gene products, e.g. murine double minute-2 (MDM2), were found to bind to the wild-type p53 protein and presumably lead to inactivation of this gene product. Therefore, the inactivation of p53 tumour suppressor gene is currently regarded as an almost universal step in the development of human cancers. The current data on p53-associated tumourigenesis are briefly discussed in this minireview.

No abstract available.

We previously immortalized human oral keratinocytes by transfection with recombinant human papillomavirus type 16 (HPV-16) DNA and established two cell lines. These transfected cells were morphologically different from the normal counterpart, contained intact HPV-16 DNA in an integrated form, and expressed numerous viral genes. These cells contained lower levels of wild-type p53 protein and higher levels of c-myc mRNAs compared to normal cells. However, they proliferated only in keratinocyte growth medium containing a low level of calcium and were not tumorigenic in nude mice. A HPV-16-immortalized cell line was exposed to either 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone or N-methyl-N'-nitro-N-nitrosoguanidine. Four chemically transformed cell colonies were isolated. These cells proliferated well in Dulbecco's minimum essential medium containing a physiological level of calcium. They contained, similar to the immortalized counterpart, integrated HPV-16 sequences and lower levels of both wild-type p53 protein and DCC messages compared to normal cells. Among the chemically transformed cells, two colonies obtained from 4-(methyl-nitrosamino)-1-(3-pyridyl)-1-butanone exposure demonstrated an enhanced proliferation capacity in nude mice and transcribed a substantially higher amount of HPV-16 E6/E7, epidermal growth factor receptors, and c-myc genes compared with the immortalized counterpart. These experiments indicate that malignant transformation of oral keratinocytes can be caused by a sequential combined effect of "high risk" HPV and tobacco-related carcinogens.

Two monoclonal antibodies (MAbs), IC5 and ID5, were produced using spleen cells from BALB/c mice immunized with recombinant estrogen-receptor protein (RER). On immunoblotting, both MAbs reacted with the 67-kDa polypeptide chain obtained by transformation of E. coli and transfection of COS cells with plasmid vectors expressing ER. The epitopes of both MAbs were in the N-terminal domain (A/B region) of the receptor. In normal human tissues, IC5 and ID5 reacted with cells known to contain large amount of ER, such as cells of the mammary gland and the uterus. Staining was localized predominantly in nuclei with little or no cytoplasmic reactivity. IC5 and ID5 were unreactive with tissues usually considered to be negative for ER. The reactions of these 2 MAbs were further tested on different tumor types, using immunohistochemical (IHC) method on frozen sections. In breast cancer, a good correlation was found between the results obtained on frozen sections and those using the conventional radioligand dextran-coated charcoal (DCC) assay. Immunostaining with IC5 and ID5 MAbs was also assessed on routinely processed paraffin sections using the antigen-retrieval method. Staining was comparable to that obtained on frozen sections in virtually all the breast carcinomas. Negative reactions were consistently obtained with both antibodies on human neoplasms derived from other non-estrogen-dependent organs. IC5 and ID5 MAbs may thus be of value in routine diagnostic histopathology for assessment of the estrogen-receptor content in human carcinomas.