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A nuclear binding assay was developed for the purpose of having available a more predictive assay for hormone responsiveness in human cancers. The BNB assay identified specific and saturable steroid nuclear binding in human target tissues and human carcinomas. When the BNB assay was applied to a large set of breast and endometrial carcinomas, we speculate that nonfunctional receptors were detected in 20%-50% of the patients who were receptor-positive by the DCC assay. Lastly, as responsiveness to hormonal therapy in these cancer patients becomes known, the predictive value of the BNB assay can be established.

Toz-Gly-Pro-Arg-4-methylcoumaryl-7-amide is recommended for antithrombin-III (AT-III) photometry as a substrate. This substrate is cleaved by thrombin at 366 nm. AT-III photometry with this substrate is in accord with the requirements to methods used in clinical laboratory diagnosis, and the results of such measurement are in good correlation with the data of AT-III analysis with Chromozym-TH substrate. Use of photometry with methylcoumaryl substrates for measuring protease activities is more available than the traditional fluorometry.

He-Ne laser therapy included in complex of therapeutic methods for patients with unstable angina pectoris is a highly effective treatment modality; it helps essentially reduce the risk of acute myocardial infarction in these patients. Clinical efficacy of laser therapy is confirmed by its favorable action on hemostasis plasma factors, consisting in reduction of fibrinogen level, normalization of antithrombin-III (AT-III), decrease of the level of soluble fibrinomonomer complexes, this indicating a lowering of the blood coagulation potential. Absence of significant changes in plasminogen level may be an indicator of the nonenzymic route of fibrinogen system activation. Sessions of intravenous laser therapy should be administered 2-3 times a week to unstable angina pectoris patients with low AT-III levels, whereas for patients with initially high or normal AT-III levels combined laser therapy is advisable (4-5 daily invasive procedures and 6-8 skin surface ones on the Zakharyin-Head's zones). Measurements of endogenic anticoagulants is an effective means for monitoring laser therapy in this patient population.

Effect of corticosteroids (steroids) on some hemostatic parameters was serially studied in 23 children with minimal change nephrotic syndrome (MCNS). Increased platelet count, erythrocyte sedimentation rate (ESR), cholesterol, fibrinogen, fibrin(ogen) degradation products (FDP), alpha 2-macroglobulin (alpha 2M), alpha 2-antiplasmin (alpha 2AP) and protein C, and reduced antithrombin III (ATIII) and plasminogen (Plg) were noted in relapse before steroid therapy began. With institution of oral prednisolone, FDP started to fall, and platelet count, cholesterol, alpha 2M, ATIII, Plg, alpha 2AP and protein C started to increase despite unchanged nephrotic state from that before the therapy. In remission induced by prednisolone, platelet count, cholesterol, alpha 2M, ATIII, Plg, alpha 2AP and protein C were still increased, but normalized off therapy. ESR, fibrinogen, FDP, alpha 2M and protein C correlated inversely with serum albumin and directly with cholesterol and urine protein excretion. In contrast, ATIII and Plg correlated directly with serum albumin and inversely with cholesterol and urine protein excretion. A direct correlation was only noted between alpha 2AP and the dose of prednisolone. The data indicate that steroids appear to be a thrombogenic factor by accerelating thrombocytosis and hyperlipidemia, and by reducing plasma fibrinolysis in children with MCNS.

Two features of colorectal cancer have greatly aided the recent progress in understanding its genetics: firstly the majority of colorectal cancers arise from premalignant adenomatous polyps allowing the analysis of somatic genetic changes during tumorigenesis, and secondly there are several well defined inherited syndromes that predispose to colorectal cancer in an autosomal dominant manner. The familial polyposis gene has been mapped to chromosome 5q and loss of material on chromosome 5 shown in a large proportion of sporadic (non-familial) adenomas and carcinomas. Allele loss has also been found in a high proportion of colorectal cancers on chromosomes 17 and 18 and the respective genes involved identified as that coding for the oncoprotein p53 on 17p and the DCC ('deleted in colorectal carcinomas') gene on 18q. In addition activation of k-ras is found frequently in colorectal adenomas and carcinomas. The development of colorectal neoplasia is associated with the accumulation of genetic changes. Family studies of apparently sporadic colorectal cancer probands have shown an increased incidence of adenomas and carcinomas in first degree relatives. More recently pedigree studies have suggested that an inherited predisposition may be responsible for the majority of colorectal tumours.

We recently reported that renin, angiotensinogen, and angiotensin-converting enzyme were present in normal human pituitary lactotroph cells and PRL-secreting adenomas. Angiotensin-II and -III have also been shown to modulate PRL release in vitro. The present study was designed to determine whether angiotensin modulates PRL secretion in vivo. In 36 hypertensive patients with widely varying renin levels, active renin and basal PRL levels did not correlate. In 10 normal volunteers, both a sustained infusion of angiotensin-II and a graded infusion of angiotensin-III induced a 2- to 3-fold increase in aldosterone levels, but had no effect on PRL secretion. Administration of the angiotensin-converting enzyme inhibitor captopril had no effect on PRL circadian rhythm in 10 normal subjects or on PRL concentrations in 11 patients with PRL-secreting adenomas. Cross-over administration of placebo and captopril did not affect the peak PRL level measured after TRH treatment in 10 hypertensive men (placebo, 43.1 +/- 5.4; captopril, 40.0 +/- 6.2 micrograms/L; P = NS) or the rise in PRL induced by doperidone in 6 normal women (placebo, 129.5 +/- 16.2; captopril, 150.0 +/- 35.7 micrograms/L; P = NS). Further, administration of enalapril for 30 days to 6 hypertensive patients did not alter basal PRL concentrations or the peak concentrations induced by TRH. These data indicate that in humans the circulating renin-angiotensin system does not interact with diurnal PRL release or with the response to TRH or domperidone.

Diabetes mellitus is the name given to a heterogeneous group of disorders that have in common abnormal glucose tolerance. The classification given here (Table 136.1) is based on etiologic differences between these disorders rather than the formerly used phenomenologic classification. Insulin-dependent diabetes mellitus (IDDM) or type I diabetes, formerly called juvenile-onset diabetes, is characterized by absolute dependency on exogenous insulin. About 10% of all people with diabetes have this type. Non-insulin-dependent diabetes mellitus (NIDDM) or type II diabetes, formerly referred to as adult-onset, maturity-onset, is characterized by gradual onset and hyperglycemia but no tendency to ketoacidosis except under extraordinary stress. People with NIDDM may take insulin to control hyperglycemia, but it is not absolutely required. About 60 to 70% of people with NIDDM are obese, and this type is sometimes subdivided into obese and nonobese categories. Eighty-five to 90% of all people with diabetes have this type. Maturity-onset diabetes in the young (MODY) differs from NIDDM in that is has a clearly defined autosomal dominant inheritance pattern. The hyperglycemia in this type is generally quite mild. MODY is also characterized by a decreased frequency of the long-term complications of diabetes. Diabetes due to abnormalities in the amino acid sequence of insulin or abnormalities in cleavage from proinsulin causing decreased insulin action have been referred to as insulinopathies, in a manner analogous to the hemoglobinopathies. The prevalence of these abnormalities has not been established. At least three types of diabetes have been found in association with the dermatologic disorder acanthosis nigricans. These three types are associated with severe resistance to the action of insulin due to an abnormal insulin receptor (type A), antibodies to the insulin receptor (type B) or post-receptor abnormalities (type C). A number of congenital syndromes are associated with abnormal glucose tolerance, but the mechanisms responsible for the disordered carbohydrate metabolism are mostly unknown. Diabetes may be secondary, as a result of direct ablation of the beta cells in association with pancreatitis, pancreatectomy, or hemochromatosis. A separate category has been designated as gestational diabetes and refers to women whose diabetes first becomes manifest during pregnancy. Although the diabetes normally resolves upon delivery, over the following years over 50% of such women subsequently relapse into overt NIDDM. The criteria for the varying degrees of impairment in glucose tolerance are given in Table 136.2. These criteria are used for the diagnosis of diabetes mellitus but not for the type of diabetes. Three types of acute complications generally occur: severe hyperglycemia associated with a hyperosmolar, non-ketotic state; severe hperglycemia associated with ketoacidosis; and hypoglycemia. The chronic complications are generally classified into vascular and nonvascular. Macrovascular complications are caused by large vessel disease and the complications relate to the vascular system involved (e.g., cerebrovascular, coronary artery, and peripheral vascular disease). Microvascular complications are caused by small vessel disease and include retinopathy, renal glomerular disease (Kimmelstiel-Wilson disease), some of the neuropathies (mononeuropathies), and possibly cardiac and other small vessels. Non-vascular complications include cataracts and polyneuropathy, both peripheral and autonomic.

The secretions of rat seminal vesicles from the so-called copulatory plug when getting in contact with the secretions of the coagulating gland. Depending on the sexual activity of the respective animal and the extraction conditions, the protein pattern of the seminal vesicle secretion varies to some extent. We have studied the biochemical properties of the proteins SVS I, SVS II, sulfhydryl oxidase and SVS III-VIII. The most interesting protein is SVS II which is the main substrate of coagulating gland transglutaminase and serves as the most important monomer during semen coagulation. It is highly soluble in acidic solutions. The monomeric polypeptide has a molecular mass of 49 kDa, is glycosylated with fucose, glucose, mannose and N-acetylated sugars and has a highly basic pI of 10.5. Particularly interesting are its functional and structural relationships with actin. It is the first described protein with actin modulating properties that is secreted in an androgen-dependent manner.

The influence of endocrine therapy on the proliferation of estrogen receptor (ER)-positive cells and ER-negative cells of human breast cancer (MFC-7) serially transplanted into nude mice was analyzed by tumor growth, dextran-coated charcoal (DCC) method, ER-immunocytochemical assay (ER-ICA) and ER-immunocytochemically stained 3H-thymidine autoradiography. In the tamoxifen (TAM) group and the medroxyprogesterone acetate (MPA) group, tumor growth was inhibited, but it was promoted in the 17-beta-estradiol dipropionate (E2) group. The ER level by the DCC method was significantly decreased in the TMA, the MPA and the E2 groups. The ER-ICA showed that the percentage of ER-positive cells was decreased in the TAM and the MPA group, but it was increased in E2 group. However, the ER-immunocytochemically stained 3H-thymidine autoradiography showed that not only the labelling index of ER-positive cells but also that of ER-negative cells was significantly decreased in the TAM and the MPA groups, while the labelling index was significantly increased in the E2 groups. Therefore, it was concluded that endocrine therapy affected the proliferation of both ER-positive cells and ER-negative cells of ER-positive breast cancer.

42 dogs with non-Hodgkin's lymphoma (NHL) were randomized for treatment with either PEG-L-asparaginase 10 IU/kg intramuscularly (n = 22) or L-asparaginase 400 IU/kg intraperitoneally (n = 20). Another 20 dogs were treated with either PEG-L-asparaginase 30 IU/kg (n = 10) or L-asparaginase 400 IU/kg (n = 10). Each treatment protocol consisted of two asparaginase treatments followed by a 10-week period of induction chemotherapy and then maintenance on asparaginase until progression occurred. No significant differences were found between treatments in the response rates after 2 weeks of asparaginase therapy or in the time to relapse, the time to treatment failure or the remission period. The reaction to asparaginase after the initial 2 weeks was a prognostic factor for the total duration of remission under asparaginase maintenance therapy. No side-effects were noted in the dogs treated with PEG-L-asparaginase, whereas 14 (48%) of the L-asparaginase treated dogs had side-effects related to this drug, including anaphylactic shock (9), anorexia or vomiting (4), hypersensitivity-related oedema (3), seizures (1) and acute pancreatitis (1). No abnormalities in clotting times, fibrinogen levels or antithrombin-III levels were found in any of the 62 dogs. PEG-L-asparaginase has the same anti-tumour activity as native L-asparaginase in dogs with NHL, but lacks side-effects.

The human papillomavirus type 16 E7 gene encodes a nuclear oncoprotein (98 amino acids [AAs] long) consisting of three regions: regions 1 (AAs 1 to 20) and 2 (AAs 21 to 40), which show high homology to the sequences of conserved domains 1 and 2, respectively, of adenovirus E1A; and region 3 (AAs 41 to 98) containing two metal-binding motifs Cys-X-X-Cys (AAs 58 and 91 to 94). We constructed AA deletion (substitution) mutants and single-AA substitution mutants of E7 placed under the control of the simian virus 40 promoter and examined their biological functions. Stable expression of E7 protein in monkey COS-1 cells required almost the entire length of E7 and was markedly lowered by the mutations in region 3. Transactivation of the adenovirus E2 promoter in monkey CV-1 cells was lowered by the mutations. It was abolished by changing Cys-24 to Gly and markedly decreased by a mutation at His-2 or at the metal-binding motifs in region 3. Focal transformation of rat 3Y1 cells by E7 was eliminated by changing His-2 to Asp or Cys-24 to Gly and was greatly impaired by changing Cys-61 or Cys-94 to Gly. The transforming function survived mutations at Leu-13 and Cys-68 and deletion of Asp-Ser-Ser (AAs 30 to 32). The data suggest that regions 1 to 3 are required for its functions and that the meta-binding motifs in region 3 are required to maintain a stable or functional structure of the E7 protein.

Vimentin expression, growth fractions (GF), and estrogen receptor (ER) levels were determined for 90 untreated primary breast carcinomas. Coexpression of keratin and vimentin was found in approximately 20% of the tumors regardless of menopausal status. Vimentin was expressed preferentially in tumor cells of high-grade ductal breast carcinomas (15 of 28 histologic grade 3 vs. 0 of 40 grades 1 and 2). Vimentin expression was found preferentially in tumors with high GF (greater than 15% Ki-67 positive by immunoperoxidase staining) and low ER levels (less than 60 fmols/mg protein by a monoclonal enzyme immunoassay). Sixty-eight percent of tumors in this group were vimentin positive and 88% of all vimentin-positive tumors fell into this category. More than 50% of the tumor cells coexpressed vimentin and keratin. Thus, vimentin expression may be helpful in identifying a substantial subset of ER-independent breast carcinomas with poor prognostic indicators.

The effect of human thrombomodulin (TM) on the inactivation of thrombin by human antithrombin III (ATIII) was evaluated in comparison with that produced from rabbits. Human TM did not accelerate the thrombin inhibition by ATIII but rabbit TM enhanced the activity of ATIII. Also inclusion of human TM at increasing concentration suppressed the thrombin inhibitory activity of ATIII. The intensity of ATIII activity in the presence of heparin (0.01U/ml) was also diminished by the human TM. However, this ATIII- heparin cofactor activity recovered with the addition of a 10-fold amount of heparin (0.1U/ml). In SDS-polyacrylamide gel electrophoresis and immunoblotting analysis, we found a complex formation of ATIII with both human and rabbit TM (and further confirmed their presence with isoelectrofocusing electrophoresis- data not shown). These results indicate that human TM is substantially different from rabbit TM. Our results suggest that human TM show the crucial role on protein C activation system via thrombin.

The effect of tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA) on enhancer dependent polyomavirus (Py) DNA replication was examined in cells expressing Py large T antigen. The results showed that TPA enhanced Py DNA replication by stimulating the activity of the A element, one of the two cores of Py enhancer. Of the three subdomains of the A element, the biding sites of PEBP1 (PEA1), a member of AP1 family, and of PEBP5 were by themselves able to activate Py DNA replication. Furthermore, each binding site of PEBP1 and PEBP5 responded to TPA to enhance Py DNA replication. The results suggest that growth promoting signals could activate DNA replication directly via enhancer binding proteins.

Remarkable advances in the understanding of specific inherited and acquired genetic events that are important in colonic carcinogenesis have occurred in the last several years. Studies of the population genetics of colon cancer have determined that the gene responsible for familial adenomatous polyposis (FAP), and Gardner's syndrome has been localized on the long arm of chromosome 5 and have more clearly defined the importance of genetic influences in 'sporadic' colon cancer. Studies of the molecular genetics of colon cancer have identified acquired alterations in oncogenes such as the K-ras gene and in putative tumor suppressor genes such as the FAP gene on chromosome 5, the p53 gene on chromosome 17, and the DCC gene on chromosome 18, which appear to mediate important steps in the adenoma-dysplasia-carcinoma sequence. Some of these research advances (FAP gene carriage) are already being used clinically to identify individuals at risk for colon cancer, and they offer great promise for the future of both prevention and therapeutic programs.

The families of eight unrelated patients were studied with regard to a hereditary deficiency in antithrombin III (ATIII), protein C, or protein S. These deficiencies were recognized in the course of investigations for deep-vein thrombosis (DVT) in the eight patients. A group of 31 individuals (patients and family members), mostly less than 40-year-old was explored. Two cases of AT III deficiency were discovered, as well as 21 of protein C deficiency, and seven of protein S. Ten of the 30 have had recurrent venous thrombosis at the time of bedrest, trauma, surgery, pregnancy, postpartum or during oral contraceptive treatment. Spontaneous DVT occurred in three cases. Seventeen patients had remained asymptomatic till then. Such patients need antithrombotic treatment during surgery or pregnancy. Prophylactic treatment with enoxaparin in one patient (deficiency in protein C) during her second pregnancy is discussed. It seems that low molecular weight heparin may be a safe alternative to unfractionated heparin. Oral anticoagulants are efficient in preventing reoccurring venous thromboembolism in patients with AT III deficiency. The questions of whether oral anticoagulants should be continued in the long-term in patients with protein C or protein S deficiency who have had a DVT, and whether asymptomatic deficient patients should be given any antithrombotic treatment outside circumstances likely to induce a DVT, remain as yet unanswered.

Struvite urolithiasis forms as a consequence of a urinary tract infection by urease-producing species of bacteria such as Proteus mirabilis. Ammonia, produced by the enzymatic hydrolysis of urea, elevates urine pH causing a supersaturation and precipitation of Mg++ as struvite (NH4MgPO4). Calcium often precipitates as well, forming the mineral carbonate-apatite (Ca10(PO4)6CO3). We have developed a procedure based on direct observation by light microscopy whereby struvite crystal growth can be quickly monitored in response to chemical changes in urine. As struvite crystals assume a characteristic shape or crystal habit based on their growth rate, the effect of urine chemistry and the action of various crystallization or urease inhibitors on struvite formation can be quickly shown. In addition preliminary effects of alkaline pH, or the presence of toxic compounds on bacteria can also be shown through their loss of motility.

In a pilot study, estrogen receptors (ER) were assayed on 42 surgically removed breast tumors by the following 3 methods: biochemical assay with dextran coated charcoal (DCC), Abbott immunoenzymatic (ER-EIA) and immunocytochemical (ER-ICA) technics. DCC and ER-EIA were performed on biopsy specimens while ER-ICA was run on cytocentrifugated cells obtained by fine needle aspiration (FNA). ER contents were expressed according to an index taking into account the proportion of colored neoplastic cells and the intensity of staining. Statistical correlation coefficient (Spearman and Kendall) concordance, sensitivity and specificity between the results were calculated (ER - ICA/ER - EIA: P less than 0.001, r = 0.38, concordance = 83%, sensitivity = 86%, specificity = 77%; ER - ICA/DCC: P less than 0.05, r = 0.22, concordance = 77%, sensitivity = 85%, specificity = 63%; ER - EIA/DCC: P less than 0.001, (r = 0.60). As previously reported, both immunoassays showed good agreement. The weaker but nevertheless significant correlation found with reference DCC may be due to the heterogeneity of tumoral ER content. This hypothesis is supported by the variability of ER - ICA assays on multiple FNA performed in 16 cases from our series. Use of multidirectional FNA slightly improved the results. Nevertheless, ER - ICA appear to be a good semi-quantitative method and might be helpful in the follow-up of metastasis treated with anti-estrogen, especially in small lesions not assayable by DCC.

Yersinia enterocolitica septicemia is described in a patient with transfusional iron overload and a myelodysplastic syndrome. The organism was biotype 1 serotype 0:5,27 and carried a virulence-encoding plasmid. It was calcium-dependent, autoagglutinating and virulent to orally challenged mice, but not resistant to the bacteriocidal activity of serum. The patient had depressed neutrophil chemotaxis and bactericidal activity. In this case, both host and microbial factors were present to select out this particular bacteremic disease. Patients with iron overload states should be recognized as compromised hosts and potentially susceptible to spontaneous sepsis due to Y enterocolitica.

The ultrastructural morphology of localized skin calcifications without associated diseases and with normal serum calcium and phosphate ion values is still unknown. In a case of superficial dystrophic calcinosis cutis (DCC), the role of collagen, elastin and ground substance in the process of calcification and the organization of the apatite crystals could be studied by light and electron microscopy despite technical difficulties in sectioning the hard tissue. Ultrastructural investigation revealed the nucleation of calcification being related to collagen and elastic fibers. No intracellular calcification was found. A flower-like arrangement of pleomorphic crystals was found around single collagen fibrils resembling the calcification of collagen seen in bone tissue. The elastic fibers showed a different pattern of calcification compared with other diseases (e.g. pseudoxanthoma elasticum) with known calcification of the elastic fibers. The process of mineralization was initially linked to the microfibrils of the elastic fiber.

One hundred and fourty-eight insulin-dependent diabetic patients were available for this study; 56 males and 92 females. For the investigation of coagulation activation we determined activated partial thromboplastin time, thrombin time, and fibrinogen besides fibrin monomers and thrombin-antithrombin III complexes (TAT-III). We assessed large percentages of increased fibrinogen levels but non-significant increases of the mean values in comparison with the reference group. The values for thrombin time were significantly prolonged, although relatively small percentages were exceeding the reference range. For the activated partial thromboplastin time, the values exceeded the upper reference limit, and the mean values were significantly higher than those of the reference group. Also for the fibrin monomers we obtained often enhanced values, and moreover, the values were significantly higher as compared with the reference subjects. The amount of TAT-III concentrations above the reference range was much smaller than for the fibrin monomers and the TAT-III levels were not significantly enhanced. The results presented here are indicative of coagulation activation in diabetics, as indicated by the fibrin monomers and more or less by the TAT-III levels. Moreover, there could be demonstrated a positive correlation between fibrin monomer levels and HbA1 concentrations.

Allelic deletions involving chromosome 18q occur in more than 70 percent of colorectal cancers. Such deletions are thought to signal the existence of a tumor suppressor gene in the affected region, but until now a candidate suppressor gene on this chromosomal arm had not been identified. A contiguous stretch of DNA comprising 370 kilobase pairs (kb) has now been cloned from a region of chromosome 18q suspected to reside near this gene. Potential exons in the 370-kb region were defined by human-rodent sequence identities, and the expression of potential exons was assessed by an "exon-connection" strategy based on the polymerase chain reaction. Expressed exons were used as probes for cDNA screening to obtain clones that encoded a portion of a gene termed DCC; this cDNA was encoded by at least eight exons within the 370-kb genomic region. The predicted amino acid sequence of the cDNA specified a protein with sequence similarity to neural cell adhesion molecules and other related cell surface glycoproteins. While the DCC gene was expressed in most normal tissues, including colonic mucosa, its expression was greatly reduced or absent in most colorectal carcinomas tested. Somatic mutations within the DCC gene observed in colorectal cancers included a homozygous deletion of the 5' end of the gene, a point mutation within one of the introns, and ten examples of DNA insertions within a 0.17-kb fragment immediately downstream of one of the exons. The DCC gene may play a role in the pathogenesis of human colorectal neoplasia, perhaps through alteration of the normal cell-cell interactions controlling growth.

In some ovarian tumors, such as endometrioid adenocarcinoma, dysfunctional uterine bleeding occurs, and the endocrinological aspects were studied in the following way: 1) In 3 patients with epithelial ovarian tumor and postmenopausal uterine bleeding, preoperative plasma estradiol (E2) and progesterone (P) concentrations were significantly high, but dropped to normal following complete resections of the ovarian tumor. Plasma E2, P and testosterone concentrations in ovarian veins were 3 to 7 times as great as in peripheral veins. 2) Tissues obtained from 25 ovarian tumors were immunohistochemically examined by the PAP method. In 9 cases of endometrioid adenocarcinoma, positive stainings for both E2 and P were demonstrated in cancer cells from 3 patients (33%) and in connective tissues from 7 patients (78%), respectively. In contrast, 16 tumors of other histological types gave only one positive staining for E2 on cancer cells and connective tissues. As for P, in 3 patients there was a positive stain on cancer cells and in 2 patients on connective tissues. 3) Five out of 8 patients with immunohistochemically positive staining for E2 on connective tissues in ovarian tumors demonstrated dysfunctional uterine bleeding. 4) Cytosolic estrogen receptor (ER) and progesterone receptor (PR) in ovarian tumors obtained from 26 patients were measured by the DCC method. All of three patients with endometrioid adenocarcinoma had both ER and PR. The former were 19-202 fmol/mg, and the latter 535-1,000 fmol/mg, which were significantly higher levels and positive rates than those from other patients.(ABSTRACT TRUNCATED AT 250 WORDS)

A 6-month-old infant developed a left ventricular thrombus in association with low antithrombin-III activity following the repair of a truncus arteriosus. Conservative management was associated with spontaneous resolution of the clot. The significance of this association is discussed.

The proliferative activity of 163 primary breast cancers was assessed by immunocytochemistry with the mouse monoclonal antibody Ki-67, which recognizes a nuclear antigen expressed in all phases of the cell cycle except for Go. The overall frequency distribution of Ki-67 staining was of exponential type, with percentage of positive staining cells ranging from 0.3 to 88.3%, with a median value of 10.1%. No relationship was observed between Ki-67 values and menopausal status of patients. A significant positive correlation was found between Ki-67 values and tumor grade, especially mitotic grade. Estrogen Receptors (ER) were assayed by immunocytochemistry with ER-ICA method and by dextran-coated charcoal method (DCC) in 129 and 141 tumors, respectively. A negative correlation was found between the ER content by both methods and Ki-67 score. Eighty-nine percent of cases with Ki-67 value less than 10.1% contained more than 10% ER-ICA-positive cells. Progesterone receptors (PgR) were assayed by immunocytochemistry with PgR-ICA method and by DCC in 62 and 141 tumors, respectively. A negative correlation was observed between the PgR content by both methods and Ki-67 score. No correlation was found between Ki-67 score and lymph node involvement by tumor. These findings suggests that Ki-67 score could be used as an independent prognostic marker, useful to distinguish different risk for recurrence within the two clinically heterogeneous groups of N- and N+ patients.

Kinetic analyses were made of the thrombin/antithrombin III (ATIII) reaction in the presence of catalytic amounts of three kinds of mammalian HA-heparin (bovine, pig and whale), which have the same affinities for ATIII. In the absence of NaCl, the first-order rate constant was higher with whale HA-heparin than with the other two HA-heparins. However, the strength of the interactions of thrombin with the HA-heparins was in the order, bovine greater than pig greater than whale. Thus, the slow reactions in the case of bovine and pig HA-heparins were probably due to preferential binding of the two HA-heparins to thrombin rather than to ATIII, thus causing the HA-heparins to be inhibitory for the reaction by reducing the turnover rates of the polysaccharides as catalysts. In the presence of 0.15M NaCl, the first-order rate constants were slightly higher in the case of pig HA-heparin than of the other two HA-heparins. Since the strength of the interactions of these HA-heparins with thrombin was in the order, pig greater than or equal to bovine greater than whale, the faster reactions were probably due to higher associations of the enzyme with the essential HA-heparin-ATIII complex.

"Receptogram Analysis" has been developed as a pattern-oriented approach for predicting endocrine response in breast cancer based upon quantification of the estrogen receptor immunocytochemical assay (ERICA), using a Quantimet Imaging System. Response prediction was evaluated in 58 stage III and IV patients receiving endocrine therapy (primarily Tamoxifen). The Receptogram is a composite of the univariate distributions of nuclear receptor content, IOD(S), and concentration (MOD), and their bivariate contour plot; where (S) is the calculated nuclear radius in section. MOD distributions were classified into four types based upon peak modality and kurtosis (I-IV), and contour plots were classified into four subtypes (A-D) based upon contour slope. Patients failing therapy were ERICA--or their receptogram revealed co-existent ER+ and ER- tumor cells (type II), highly skewed MOD distributions lacking defined peaks (type IV), or contours with nearly horizontal slope (type C). Response was realized in 9/16 type I patients, with a single positive MOD peak, and in 9/15 type III patients, with discrete, multimodal MOD peaks. In contrast, 0/8 type II, 0/12 type IV, and 0/10 type C patients were responders. Receptogram analysis was superior to cytosol assay (DCC) as a response discriminant: positive predictive value, 53% vs. 33%; negative predictive value, 100% vs. 75%; sensitivity, 100% vs. 83%; specificity, 68% vs. 23%; and accuracy, 78% vs. 41%, respectively. Alternately, patients were assigned to potentially responsive or non-responsive groups based upon thresholded mean receptor parameters: field MOD, mean nuclear MOD (NMOD), and mean NMOD(PF) where PF is the ER+ nuclear fraction. While these parameters correlated with DCC (r = .72, 0.69, and 0.69), they were only marginally better in predictive value.

The potential for immunohistochemical detection of progesterone receptors (PRs) in routinely formalin-fixed and paraffin-embedded cancer tissues by use of the monoclonal antibody Mi 60-10 (mPR1, Dianova GmbH, Hamburg) was evaluated. The PR content of breast cancer tissue was investigated in 170 cases. A positive reaction to Mi 60-10 was found exclusively in the nuclei of benign or malignant epithelial cells. The distribution of PRs was heterogeneous. Immunohistochemical reaction was scored by multiplying the percentage of positive tumour cells by their prevalent degree of staining (Immunoreactive Score or IRS). The IRS values of formalin-fixed tissues (n = 170) were compared with those in snap frozen tissues (n = 82), with the PR content assayed by a DCC (dextran-coated charcoal) method (n = 170), with histopathological grading according to Bloom and Richardson and with the menopausal status of the patient. There was an acceptable ranked correlation (r = 0.74) between IRS in formalin-fixed and paraffin-embedded parts and snap frozen parts of the same carcinoma. A good correlation (r = 0.72) was also found, when the semiquantitative results of immunohistochemical PR detection in formalin-fixed and paraffin-embedded tissues were compared to PR concentrations measured by a DCC method in tumor cytosols. There was an 80% concordance between the two methods for qualitative discrimination of PR-negative and PR-positive carcinomas. IRS correlated significantly with the degree of histological differentiation of the tumors (P less than 0.001) but not with the menopausal status of the women (P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

We have performed a retrospective review of the incidence and etiologies of acute renal failure (ARF) in 105 adult patients receiving liver transplants. The prevalence of chronic renal failure was also determined. ARF occurred in 94.2% of these patients. Acute tubular necrosis was the leading cause of ARF and was associated with the highest mortality. Factors associated with increased mortality included: (1) peak serum creatinine greater than 3 mg/dl, (2) multiple liver transplants and (3) the need for dialysis. Pretransplant renal failure did not increase mortality. Chronic renal failure developed in 83% of patients at latest follow-up (mean: 30.5 +/- 7.9 months).

Sixteen rabbits were fed a 1% cholesterol diet with an intraperitoneal injection of saline (n = 8) (cholesterol-diet group), or 50 mg glycosaminoglycans-polysulfate (GAG-PS) (n = 8) (GAG-PS group). After 10 weeks all rabbits were sacrificed and studied. Eight rabbits on a standard diet with an intraperitoneal injection of saline (n = 8) (standard-diet group) were processed in the same manner. After 10-weeks of feeding, the plasma total cholesterol of the GAG-PS group was significantly lower than that of lower than that of the control group (P less than 0.02). The VLDL cholesterol of the GAG-PS group was also significantly lower than that of the cholesterol-diet group. There were no differences in LDL-cholesterol, HDL-cholesterol or plasma triglycerides between the groups. Total lipoprotein lipase activity (T-LPL) (LPL + HTGL) of the GAG-PS group at 10 weeks was higher than that of the cholesterol-diet group. These elevated T-LPL levels were mainly due to an increase in the LPL from peripheral tissues. ADP-induced platelet aggregability of the GAG-PS group significantly decreased at 10 weeks when compared to the cholesterol-diet group, and antithrombin-III activity of the GAG-PS group was inversely increased when compared to the cholesterol-diet group. Although there were no differences in aortic levels of total cholesterol and uronic acid between the GAG-PS group and the cholesterol-diet group, the surface involvement of the aorta in the GAG-PS group was significantly lower than that in the cholesterol-diet group. The aortic levels of free cholesterol, hydroxyproline and calcium of the GAG-PS group were significantly decreased when compared to the cholesterol-diet group. These findings suggest that GAG-PS has antiatherosclerotic effects.