Blood flow rate and access recirculation in hemodialysis.

We studied the effect of extracorporeal blood flow rate (BFR) on access recirculation (recirc) in 19 hemodialysis patients. BUN was determined in simultaneous peripheral (P), arterial (A), and venous (V) blood obtained at BFRs of 200, 400, and 600 ml/min. Percent recirc was calculated for each BFR using the formula (P-A)/(P-V) x 100. Venous drip-chamber (VP) and pre-blood-pump (AP) pressures were measured at each BFR. Fistulograms were performed in 10 patients, and stenoses were identified in 5, all at the proximal (arterial) end of the access. Recirc increased with increasing BFR from 200 to 400 ml/min but increased little from 400 to 600 ml/min. At all BFRs recirc in the stenotic patients was higher than that of non-stenotic or unstudied patients. Urea clearance, corrected for recirc, rose with blood flow both in stenotic and non-stenotic patients. There were no differences in AP or in VP between stenotic and non-stenotic patients. At BFR greater than or equal to 400 ml/min, a recirc threshold of 15% identified stenoses with sensitivity 100% and specificity 71%. We conclude (1) recirc increases with increasing BFR but not enough to outweight the concomitant increase in urea clearance; (2) significant access stenosis and recirc may be present even with low VP; (3) recirc was associated with arterial side stenoses; (4) at BFR greater than or equal to 400 ml/min, access stenosis is associated with recirc greater than 15%.


Prolonged extracorporeal circulation for acute myocarditis.

Total circulatory support for acute reversible myocardial failure is rarely used in clinical situations outside the postoperative period following cardiac surgery. We treated an 8-year-old girl who suffered acute viral myocarditis and sustained cardiac arrest requiring cardiopulmonary bypass for resuscitation. This was accomplished with the use of the portable cardiopulmonary support system (CPS), which consists of a centrifugal pump and a membrane oxygenator. This patient was placed on CPS in Hawaii and transported after 3 days to San Diego (4200 km) for further mechanical support and possible heart transplantation. Adequate cardiac function returned and CPS was stopped after 6 days. She is alive and well, attending school two and a half years after the event. Prolonged use of CPS for acute myocardial failure outside the operating room, including long distance transportation, is effective and easily accomplished with currently and widely available equipment, and should be used in acute, reversible catastrophic heart disease.


Electromechanical artificial heart with a new gear type and angled pump chambers.

The intrathoracic anatomical situation after explantation of the natural heart defines the maximum available space for the design of the housing as well as of the inlet- and outlet connectors of a fully implantable electromechanical artificial heart. Based on computer-assisted anatomical studies, a total artificial heart housing is designed which facilitates an oblique orientation of the pumping chambers for a better fluidmechanical and anatomical arrangement of the in- and outlet connectors. The pumping chamber geometry is based on modifications of an existing cardiac assist-system. Subsequently a mechanical gear which conforms to this anatomically adapted housing is developed.


Dynamic cardiomyoplasty in a patient with end-stage cardiomyopathy.

Dynamic cardiomyoplasty is a relatively new surgical procedure by which a transformed fatigue-resistant skeletal muscle wrapped around the heart is stimulated to contract in synchrony with it, thereby augmenting the ventricular functions of a failing heart. We performed a cardiomyoplasty with latissimus dorsii (LD) in a patient who was refused the heart transplant programme because of pulmonary hypertension and psychosocial contraindications. The patient was 34 years old, functional class grade IV of the New York Heart Association (NYHA), with a three-month history, due to ischemic cardiomyopathy with multiple vessels affected, 10% ejection fraction, arteriolar pulmonary resistance of 7.5 U Wood. Cardiomyoplasty was performed after training the LD muscle for four weeks. One week later the pacemaker was programmed in a DDD mode: amplitude 3.75 V, pulse duration 0.50 ms, AV delay 175 ms. The patient reached functional class grade I-II (NYHA). Inotrope support was discontinued and great clinical improvement was noted. The ejection fraction rose from 10% to 30%. Echocardiographic left ventricular outflow tract velocity increased from 0.33 m/s to 0.60 m/s. These values were compared with radionuclide angiocardiography and echocardiography evaluations. The great clinical improvement and positive changes in left ventricular parameters suggest that cardiomyoplasty is useful in the treatment of some cases of dilated or ischemic cardiomyopathy as an alternative to heart transplantation. Long term follow-up is necessary to evaluate this procedure.


Dynamic pumping performance of the Hemopump--a small intraventricular blood pump.

We studied the pumping characteristics of the Hemopump, a commercially available miniature intraventricular blood pump for temporary support of failing hearts. The Hemopump is an axial flow pump of which the characteristics can be described by turbomachine theory. Experiments with water and a mock circulation verified that the pumping characteristics of the Hemopump in terms of both pressure head and flow as a function of rotational speed, very well can be described by a first order differential equation. The influence of blood with its non-Newtonian character is being investigated.


Changes of intraocular pressure in patients with open-angle glaucoma in relation to the passage of atmospheric fronts and environmental contamination.

Effects of atmospheric frontal passages on intraocular pressure (IOP) in patients with open-angle glaucoma are statistically investigated to show the meteorotropism of this disease. Changes in IOP caused by frontal passages are evident; the response is not identical in all the patients near the day of the passage of a warm front, while on the third day following the passage of the front a well pronounced drop in IOP occurs. Anomalous increases of IOP over several months' duration occurred in the years 1986-7. This finding is explained in relation to the hypothesis of environmental contamination in Central Europe by radioactive cesium nuclides due to the Chernobyl accident.


Effect of inspiratory resistance to prolonged exercise in a hot environment wearing protective clothing.

The effects of inspiratory resistance on prolonged work in a hot environment wearing a nuclear, bacteriological and chemical warfare (NBCW) mask and overgarment were assessed in 10 males. Subjects walked on a treadmill at 5 km/hr, 2% gradient, until their core temperature reached 39 degrees C or for a duration of 90 min. Rectal temperature, heart rate, ventilation, oxygen consumption and rate of perceived breathing were measured. There were no differences between break-point time without the canister (62.2 +/- 21 min) and with the canister (58.9 +/- 17 min). Regression analysis indicated that the mean core temperature increased by 0.02 degrees C for every minute of work performed and heart rate by 6 beats/min for every increase of 0.2 degrees C in core temperature. Reduction in heat transfer brought about by wearing the protective overgarment and mask with or without the canister will significantly increase core temperature and limit the performance of moderate work to approximately 1 h in a moderately fit individual.


Correlation analysis between some blood properties and atmospheric environmental parameters.

S.W. Tromp made investigations of a weather effect on erythrocyte sedimentation rates (ESR) of human blood by routine checks of the blood of donor groups in Leiden from 1955 to 1985. A higher ESR was found for the summer season and lower ESR for winter and low values occurred soon after a strong cooling spell. In this report, we have continued his work using data for the years 1971-1985 from Leiden (The Netherlands). An influence of the weather on ESR was also found, but this seems to be more complicated than Tromp supposed. Some new aspects are described and elaborated, e.g. ESR already increases before warming is noticed at the ground layer. This is possibly caused by changes in the upper atmosphere, a suggestion that requires further studies. For periods of low ESR, there was a greater number of occlusion fronts passing the Netherlands. The long-term fluctuations of ESR that were found were correlated with sun spot relative numbers only in a few periods. The results of our study justify further research for a variety of other locations around the world.


Influence of season and microclimate on fertility of dairy cows in a hot-arid environment.

Records were obtained over a 3 year period from six Holstein dairy farms of 300 to 500 cows each in the Phoenix, Ariz. area. Dairies were selected on the basis of similar management practices, herd size, milk production and facilities (with the exception of cooling systems). Microclimatic modifications (two dairies each) were shade only (approximately 3.7 m2/cow), evaporative-cooled shades and low-pressure water foggers under the shades. Data were categorized by season of calving (spring, Feb.-May; summer, June-Sept.; and fall, Oct.-Jan.). Traits evaluated were calving interval, days open and services/conception. Calving interval was shortest for cows calving in the spring (378 days), intermediate in fall (382 days) and longest in summer (396 days). Similar seasonal trends were observed for days open (103, 103 and 119 days, respectively) and services/conception (1.54, 1.81 and 1.93, respectively). All differences between spring and summer were significant (P less than 0.05). Calving interval and days open were less for evaporative-cooled groups (374 and 98 days, respectively), with no difference between shade only and foggers (391 and 392 days, 112 and 116 days, respectively). Services/conception were similar for all groups (1.72 to 1.79). A significant interaction between microclimate and season for services/conception could be interpreted as (i) smaller season differences for evaporative-cooled groups than for shade or foggers, or (ii) a change in the ranking of control and fogger groups during summer versus fall. Evaporative cooling was more effective than fogging for reducing the detrimental effects of seasonal high temperatures on fertility.


The influence of thermal conditions on rectal temperature, respiration rate and pulse rate of lactating Holstein-Friesian cows in the humid tropics.

The effect of minimum, maximum and mean ambient air temperatures and the temperature-humidity index (THI) of the same and the previous day on morning (a.m.) and afternoon (p.m.) rectal temperatures (RT), respiration rates (RR) and pulse rates (PR) were studied in 17 Holstein-Friesian cows over the first 125 days in the 3rd and 4th lactations. Physiological responses showed a diurnal pattern, being lower in the mornings than the afternoons: 38.6 vs 39.0 degrees C for RT, 52.2 vs 60.7 breaths/min for RR and 58.1 vs 64.1 beats/min for PR. Correlations between RT and RR (r = -0.043 to -0.046) and RT and PR (r = -0.178 to -0.261) were low (P greater than 0.05). Correlations between RR and PR (r = 0.353 to 0.365) were moderate (P less than 0.05). Weather variables, especially ambient temperature of the previous day, were more important and influenced physiological responses to a greater extent than other thermal factors the same day. Generally, physiological responses were influenced to a greater extent by ambient temperature than THI. Weather variables explained variations in RT (5.1-59.6%), in RR (13.0-17.8%) and in PR (22.1-25.4%). Relationships between weather variables the previous day and physiological responses were contradictory, with minimum and maximum values showing a negative relationship in contrast with a positive relationship for mean values.


Plasma hormonal and electrolyte alterations in cycling buffaloes (Bubalus bubalis) during hot summer months.

Plasma levels of progesterone, prolactin, luteinizing hormone, and electrolytes were monitored by radioimmunoassay in ten cycling buffaloes maintained at Punjab Agricultural University, Ludhiana during the hot summer months of June-July. The plasma progesterone concentration ranged from 0.28 +/- 0.04 to 3.09 +/- 0.03 ng/ml at various stages of the oestrous cycle. Prolactin values ranged from 319 +/- 23 to 371 +/- 25 ng/ml and LH levels from 0.95 +/- 0.05 to 1.35 +/- 0.08 ng/ml. Concentrations differed significantly (P less than or equal to 0.05) at various stages of the cycle. Levels of electrolytes, viz. Ca++, Na+ and K+, were well within the normal range. The high levels of prolactin, progesterone and LH during the hot summer were assessed in relation to poor reproductive efficiency in buffaloes.


Interaction between heat acclimation and exogenous insulin in brown adipose tissue of rats.

Seventy-one male Wistar strain rats (7 weeks old) were kept at 5, 25, or 34 degrees C, respectively, for 2 weeks with or without insulin administration. Insulin (Novo Lente MC) was given subcutaneously in a dose of 3.62 nmol/125 microliters saline per 100 g body weight. An apparent effect of insulin treatment was noted only in heat-exposed rats, resulting in a remarkable gain in interscapular brown adipose tissue (BAT) mass of heat-acclimated, insulin-treated rats in terms of weight or weight per unit body weight. The BAT from heat-acclimated, insulin-treated rats had significantly higher levels of protein, DNA, RNA, and triglyceride than BAT from heat-acclimated, saline-treated rats. Therefore, it seems likely that the growth of BAT in heat-acclimated, insulin-treated rats was mostly due to the anabolic effects of insulin. The uncoupling protein mRNA was, however, present in BAT of heat-acclimated, insulin-treated rats at rather a depressed level, explaining a corresponding decrease in cold tolerance. On the other hand, the expression of insulin receptor mRNA was attenuated in BAT of rats from all the insulin-treated groups, possibly due to the down-regulation of insulin. Thus, there appeared to be some linkage among BAT, heat acclimation, and insulin.


Lipoprotein(a) and CA125 levels in the plasma of patients with benign and malignant ovarian disease.

Elevated plasma levels of apolipoprotein (a) have been reported earlier in cancer patients. In order to investigate the potential of apolipoprotein(a) as an ovarian tumour marker, plasma apolipoprotein(a) and CA125 levels were measured in healthy women and women with benign or malignant pelvic masses. Among women younger than 49 years, 80% of healthy controls and ovarian cancer patients had apolipoprotein(a) levels below 350 U/l. Among women aged 49 years or older, 46% of healthy controls but 73% of ovarian cancer patients and 77% of women with successfully treated ovarian cancer, had low apolipoprotein(a) levels. For both age groups, apolipoprotein(a) is not a suitable marker for ovarian cancer. No correlation was found between apolipoprotein(a), triglyceride or cholesterol in plasma. Healthy women younger than 49 years had significantly higher CA125 levels than women 49 years or older (20 +/- 14 U/ml vs. 13 +/- 12 U/ml, p less than 0.005). Levels of CA125 above 35 U/ml were found in 12% of the younger and 4% of the older healthy women, 73% of the younger and 61% of the older patients with untreated or residual tumours, and in 33% of the younger and 31% of older patients with no evidence of disease, as well as in 58% of women of both age groups with benign pelvic masses. The sensitivity and specificity of CA125 levels for the detection of cancer were 73% and 74% respectively for women younger than 49 years, and 62% and 78% respectively for women 49 years or older.


Ornithine decarboxylase assay in human colorectal mucosa. Methodologic issues of importance to quality control.

Ornithine decarboxylase may be a useful biomarker for risk of neoplasia in colorectal tissues. Investigators have reported enzyme activities varying by as much as 10- to 20-fold using variations of the usual 14CO2 release assay. We have examined the effect of different methodologic factors on calculated ornithine decarboxylase activity. Major effects on the assay result (greater than 20% change) were produced by: (1) use of Tris vs. phosphate buffer, the former yielding 1.5- to 4-fold greater activity; (2) protein content of the reaction mixture with significant error if less than 50 micrograms; (3) use of alpha-difluoro-methylornithine-inhibited blank versus buffer-only blank. Other changes in assay conditions, including addition of sucrose, detergent, protease inhibitors, specific activity of 14C-ornithine, the nature of the trapping agent used, and incorporation of a sonication step, did not have a significant effect on ODC quantification (less than or equal to 20%). Thus, seemingly minor variations in assay conditions can greatly affect the results, which may provide a partial explanation for the variability of ODC activities reported in the literature. Strict quality control measures are mandatory in the interpretation of clinical observations utilizing this marker as an endpoint.


Secretion of gelatinases and tissue inhibitors of metalloproteinases by human lung cancer cell lines and revertant cell lines: not an invariant correlation with metastasis.

Numerous studies have reported a correlation between production of 72-kDa (MMP-2) and 92-kDa (MMP-9) type-IV collagenases/gelatinases and the metastatic potential of cancer cells. An abrogating effect of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) on metastases has also been noted. In this report we have used sensitive enzyme-linked immunoassays to measure MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in eight human lung-cancer cell lines which were characterized for biological behavior in nude mice. We demonstrated that the Calu-6 and A549 cell lines with the highest metastatic, invasive and tumorigenic potential secreted the highest levels of MMP-2. MMP-9 and TIMP-1 secretions were comparatively low in all cell lines. TIMP-2 secretion, which exceeded MMP-2 secretion for all cell lines, did not correlate with metastatic potential. To further explore these correlations, the metastatic Calu-6 cell line was transfected with a K-rev-1 cDNA expression construct. The K-rev revertant cell lines demonstrated a more differentiated phenotype and were less tumorigenic, invasive and metastatic in nude mice. Nonetheless, the Calu-6 revertant cell lines secreted higher levels of MMP-2 than the parent cell line. In conclusion, invasion and metastasis by lung-cancer cells requires not only enhanced MMP production, but also other less well-understood tumorigenic characteristics. The multiplicity of factors required by cancer cells for dissemination helps to explain the minute fraction of cancer cells from a primary tumor that ever develop into a metastasis.


Immunogenic tumor variants induced by drug treatment of the L5178Y lymphoma: search for serologically defined antigens at the clonal level.

Highly immunogenic tumor variants are generated by in vitro or in vivo treatment of the murine L5178Y lymphoma line with triazene derivatives. Most of these variants express new transplantation- and antibody-defined antigens that previous studies have shown to be closely related. One such 80-kDa protein on the surface of clone-D cells was found to be related to xenotropic MuLV gp70 molecules. To investigate the possible relevance of clone-D data to general properties of immunogenic variants in this tumor model system, polyclonal syngeneic antisera raised to a panel of immunogenic clones (including clone D) of the drug-treated L5178Y lymphoma line were employed in the immunoprecipitation of cell-surface and intrinsically labeled variant cells. In all clones, 1- and 2-dimensional electrophoretic analysis of the immunoprecipitates detected an antigen of approximately 80 kDa, and 35S-labeled 80-kDa molecules could be cross-precipitated from all clones by the panel of clone-specific antisera. In addition, 45- and 30-kDa components were also found in metabolically labeled variant cells. While the surface 80-kDa component was reactive with anti-xenotropic gp70 antibodies, the 30-kDa molecule was removed by anti-gag p30 antibody in sequential immunoprecipitation experiments. These data suggest that expression of aberrant, retrovirus-related proteins is a common finding in immunogenic cells of the drug-treated L5178Y lymphoma line.


A basement-membrane permeability assay which correlates with the metastatic potential of tumour cells.

We describe an in vitro assay for measuring the ability of tumour cells to permeabilize basement membranes, using transwell chambers coated with the reconstituted basement membrane, matrigel. Unlike previous matrigel-based procedures which quantified passage of tumour cells across a matrigel barrier, the new assay measures the ability of tumour cells to degrade the basement membrane and increase the diffusion rate of fluorescent (FL) dextran through the barrier. The procedure has the major advantage that permeability can be rapidly and accurately quantified, either by fluorometry or by the use of radiolabelled dextran, thus avoiding tedious and subjective scoring methods. Optimal conditions for the assay are described. In addition, it is demonstrated that the assay can clearly discriminate between metastatic and non-metastatic tumour cell lines, metastatic tumours permeabilizing the basement membrane and non-metastatic counterparts failing to do so. A range of enzyme inhibitors suggested that the increase in basement-membrane permeability caused by the metastatic mammary adenocarcinoma 13762 MAT is probably dependent upon the synergistic action of several degradative enzymes, namely proteases, type-IV collagenase, and heparanase. Furthermore, the ability to permeabilize the basement membrane was dependent upon intact tumour cells; tumour cell extracts, lysates and supernatants were inactive.


Glucose depletion enhances the anti-tumor effect of TNF.

Treatment of human carcinoma xenotransplants in athymic mice with recombinant human tumor necrosis factor (rh TNF) causes necrosis mainly in the central parts of the tumors, while peripheral sections remain mitotically active. As tumors are known to be supplied with adequate glucose exclusively in their periphery, the influence of the lack of glucose on the cytotoxic activity of rh TNF was studied. The absence of glucose enhanced the killing of tumor cell lines by rh TNF in tissue culture. Meth-A, a cell line known to be resistant to TNF in vitro but highly sensitive to it in vivo, was readily killed in tissue-culture medium lacking glucose. All non-transformed cell lines tested were found to be resistant to rh TNF, regardless of the presence or absence of glucose. In tumor-bearing mice a reduction of the blood glucose content augmented by insulin led to increased anti-tumor efficiency of rh TNF. The enhanced anti-tumor activity was reflected both in histological sections of the tumor xenotransplants, by extensive central necroses, and by reduction of the tumor volumes.


Induction of protein kinase C down-regulation by the phorbol ester TPA in a calpain/protein kinase C complex.

Using a calpain/protein kinase C (PKC) complex, we were able to reproduce, in vitro, the induction of PKC down-regulation by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) which had been previously observed in cells. We show that TPA initiates this phenomenon by promoting a calpain-dependent conversion of PKC to the Ca2+ phospholipid-independent protein kinase M (PKM), at physiological calcium concentrations. This effect of TPA was dependent upon the presence of phosphatidylserine and was observed only when PKC was the substrate for the protease, inactivation of calpain by autolysis not being modified by the presence of TPA. Moreover, PKM generated from the calpain-PKC complex was resistant to calpain, even after addition of TPA. These results suggest that TPA induces a conformational change in PKC, increasing the affinity of the kinase for calpain and consequently permitting its proteolysis for the basal level of calcium in cells.


Insulin-like growth factor II in two human colon-carcinoma cell lines: gene structure and expression, and protein secretion.

Abnormal expression and structural modification of the IGF-II gene in correlation with high IGF-II production have recently been described in human colorectal tumors in comparison with normal adjacent tissues. Here, we have studied IGF-II in 2 human colon-carcinoma cell lines, HT29 and COLO 320DM. RFLP analyses revealed no apparent alteration at the IGF-II locus in these 2 cell lines. HT29 cells weakly expressed IGF-II mRNA in comparison with the high over-expression previously observed in some colorectal tumors, and only the 4.8-kb mRNA species was present. In addition, the serum-free medium conditioned by HT29 cells contained high IGF-II levels (approx. 900 ng/10(8) cells), as measured in a specific IGF-II radioimmunoassay (RIA). After chromatography on Bio-Gel P-60, we observed that 64% of the total IGF-II secreted by HT29 cells were present as a high-molecular-weight form of about 17 kDa. In contrast, no detectable expression of the IGF-II gene was observed in COLO 320DM cells, and low IGF-II levels were secreted by these cells in the serum-free medium, with only 9% total IGF-II represented by the large species.


Production of stable phenotypes from 9L rat brain tumor multicellular spheroids treated with 1,3-bis(2-chloroethyl)-1-nitrosourea.

During chemotherapy and regrowth of brain tumors, tumor-cell heterogeneity, and possibly tumor progression, may change as a result of both the selective forces and mutagenic effects of treatment. We have isolated and characterized drug-response variants of multicellular rat 9L brain-tumor spheroids exposed to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Ten colonies were isolated from spheroids disaggregated immediately after treatment, and 10 colonies were isolated from treated spheroids disaggregated after 1 week in suspension culture. The sensitivity to BCNU was determined by assays of sister chromatid exchange and colony-forming efficiency in monolayer cultures of each subline after a 1-hr exposure to graded doses of BCNU. Three classes of response were found: BCNU sensitivity increased, decreased, or was comparable to that of uncloned, parent 9L cells. Resistant phenotypes were predominant (8/10) in sublines from spheroids disaggregated immediately after treatment, whereas hypersensitive phenotypes (4/8) were isolated only from spheroids disaggregated after 1 week of regrowth. Since subpopulations isolated immediately after treatment do not have the same biological characteristics as those isolated after a period of regrowth, these data suggest that tumor-cell heterogeneity may be generated by distinct processes at various times during therapy. The predominance of hypersensitive sublines obtained by the regrowth protocol may have resulted from the recovery of cells that would have died if isolated but were instead able to repair the drug-induced damage when left in contact with neighboring, possibly resistant cells. Two resistant and two hypersensitive sublines were studied further.


Influence of the estrous cycle at gamma-ray exposure on radiation-induced mammary tumorigenesis in virgin rats.

Wistar rats received whole body irradiation with 260 cGy gamma-rays at 10 a.m. of individual phases of their estrous cycle and then had diethylstilbestrol pellets implanted for 1 year. When the radiation was given during di-estrus II, the highest incidence (73.3%) of mammary tumorigenesis was observed, and mean latency until the first tumor appearance was 8.5 +/- 0.7 months. Also, rats irradiated on estrus had significantly lower incidence (35.3%) of mammary tumors than those irradiated on pro-estrus and di-estrus II, but there was no significant difference in latency period. Iball's indices of total mammary tumors, fibroadenoma plus adenocarcinoma, were 14.3 +/- 0.9, 28.8 +/- 2.1, 23.3 +/- 0.8 and 12.2 +/- 0.2 in rats irradiated during di-estrus I, di-estrus II, pro-estrus and estrus respectively. The percentage of adenocarcinomas was comparatively uniform (25.0 to 34.8%) throughout the various phases of the estrous cycles. Also, Iball's indices calculated from adenocarcinoma indicated no significant differences between all groups. From our results, the highest incidence of mammary tumors arose in rats after irradiation at di-estrus II with minimum level of prolactin in serum. We discuss different mechanisms of radiation-induced and chemical-carcinogen-induced tumorigenesis of mammary glands.


Enhanced epidermal growth factor receptor synthesis in human squamous carcinoma cells exposed to low levels of oxygen.

Exposure of human A431 squamous carcinoma cells to levels of hypoxia found in some solid tumors causes 2-fold increases in epidermal growth-factor receptor (EGF-R) mRNA levels and rate of receptor protein synthesis compared with aerobic cells. Similar results are shown for receptor message from other squamous carcinoma cells, human keratinocytes, and human W138 fibroblasts. Less basal tyrosine phosphorylation of the receptor occurs in hypoxic compared with aerobic A431 cells. Scatchard analysis also shows that reoxygenated A431 cells display enhanced surface expression of the EGF-R compared with aerobic control cells. Possible mechanisms and implications for tumor therapy are discussed.


Distribution and photosensitizing efficiency of porphyrins induced by application of exogenous 5-aminolevulinic acid in mice bearing mammary carcinoma.

By means of a chemical extraction procedure and confocal laser scanning microscopy, we investigated the kinetic patterns of uptake and biolocalization of 5-aminolevulinic acid (ALA)-induced porphyrins in s.c. transplanted tumors, adjacent normal skin and muscle, and liver of mice bearing mammary carcinoma, after i.p. injection of 250 mg/kg ALA or topical application of ALA (20% in an oil-in-water emulsion). Furthermore, we evaluated the tumor responses after either i.p. injection or topical application of 5-ALA followed by laser irradiation (632 nm, 150 mW/cm2, 25 min) by measuring the treated tumor regression/regrowth time and by light and electron microscopy. Strong fluorescence of ALA-induced porphyrins was detected in the tumor, skin and liver tissues, while little fluorescence was seen in the adjacent muscle tissue. Moreover, the highest amounts of ALA-induced porphyrins in the tumor and skin tissues were found 1 hr after i.p. injection, whereas the amounts of the porphyrins in both tissues increased with increasing time after topical application of ALA. The fluorescence of the porphyrins was localized in several components of the skin tissue (epidermis, hair follicles and their associated sebaceous glands). Furthermore, the fluorescence was diffusely distributed in the s.c. transplanted tumor tissue. Little could be observed under a confocal laser scan microscope (CLSM) in the muscle tissue. The uptake and biolocalization data correlate well with the results of PCT efficiency of the same tumor model with ALA-induced porphyrins. Light and electron microscopy showed that the mitochondria of the tumor cells and of the endothelial cells and the basal lamina of vascular walls beneath the endothelium in the tumor tissue were initially extensively destroyed after PCT with ALA-induced porphyrins. Thereafter, diffuse degeneration followed by local and/or diffuse severe necrosis of the tumor cells was found. This may be due mainly to the initial damage to mitochondria in the cancerous and endothelial cells and also to the destruction of the vascular wall in the tumor tissue.


Bile acids, non-phorbol-ester-type tumor promoters, stimulate the phosphorylation of protein kinase C substrates in human platelets and colon cell line HT29.

Protein kinase C (PKC) is the target for a number of tumor promoters. The mechanism underlying the promoting effects of bile acids in colorectal cancer is not understood. We report that sodium deoxycholate (DOC) triggered activation of PKC in physiological conditions. The biphasic effects of DOC upon PKC activation were Ca(2+)-stimulated and did not require phosphatidylserine (PtdSer) as phospholipid co-factor. The optimal rate of activation was obtained at 0.4 mM DOC and reached approximately half the maximal rate of activation obtained in the presence of PtdSer. Similarly to PtdSer, DOC supported diacylglycerol- as well as phorbol-ester-mediated PKC activation. The reciprocal effects of PtdSer and DOC upon PKC in either 0.5 mM CaCl2 or 0.5 mM EGTA suggest that DOC interacts with the phospholipid-binding domain to elicit PKC activation. DOC-supported enzyme activation exhibited substrate specificity different from that of PtdSer-supported enzyme activation. All tested primary and secondary bile acids activated PKC to various extents, with DOC being the most potent. We suggest that amphipathic bile acids acting in a PtdSer-like manner provide the hydrophobic environment required for PKC activation. Treatment of 32P-labeled platelets and colonic cells HT29 Cl.19A with DOC enhanced the phosphorylation of endogenous substrates for PKC. Colonic cells responsive at 50 microM DOC, appeared to be 10-fold more sensitive than platelets. We suggest that direct or indirect activation of PKC by bile acids may account for the promoting effects of these non-phorbol-ester-type tumor promoters.


Spontaneously transformed rat-liver epithelial-cell line producing autocrine and paracrine growth factors.

A spontaneously transformed rat-liver epithelial-cell line that could proliferative in unsupplemented, serum-free medium and be passaged with trypsinization has been established. At the time of writing, the line has undergone more than 100 passages in serum-free culture. This cell line produced an autocrine growth-stimulatory factor (AGSF) and a paracrine growth-stimulatory factor (PGSF). AGSF had a remarkable growth-stimulatory effect on transformed rat-liver epithelial-cells, but had no such effect on non-transformed rat-liver epithelial-cells that could not proliferate in serum-free medium. AGSF did not show a growth-inhibitory or stimulatory effect on normal rat kidney (NRK) cells in monolayer culture, and did not induce anchorage-independent growth in soft-agar culture even with epidermal growth factor (EGF) or transforming growth factor (TGF)-beta. AGSF was protease-sensitive, but heat- and acid-stable. The molecular weight was about 700 Dalton (Da) on size-exclusion chromatography. PGSF showed a growth-stimulatory effect on NRK cells and induced anchorage-independent growth in soft-agar culture without EGF or TGF-beta. On the other hand, PGSF slightly inhibited the growth of the spontaneously transformed rat-liver epithelial cells. PGSF was heat-, protease- and acid-sensitive. The molecular weight was 30 kDa on size-exclusion chromatography.


Specific growth stimulation in the absence of specific cellular adhesion in lung colonization by retinoic-acid-treated F9 teratocarcinoma cells.

In most studies concerning organ-specific metastasis, different or selected lines are compared with one another. Here we report results with the same cell line (the F9 murine teratocarcinoma) which can be directed towards liver or lung, depending on whether or not it is treated with retinoic acid and cyclic AMP. Thus, organ-specific colonization by tail-vein-injected murine F9 teratocarcinoma cells shows a particular pattern: unselected, undifferentiated F9 cells preferentially colonize the liver of the syngeneic animal. The lungs, the first capillary bed encountered by cells thus injected, are only very rarely colonized. By contrast, the lungs become the main target organ of F9 cells induced to differentiate by treatment with retinoic acid and cyclic AMP. We have recently shown that liver colonization by undifferentiated F9 cells correlated with the adhesiveness of the cells (higher to fibronectin and liver-derived extracellular matrix than to laminin and lung-derived extracellular matrix) as well as with their growth response to organ-derived extracts (no response with lung extracts and good response with liver extracts). The data reported below indicate that induction of differentiation causes at most a decreased adhesiveness of F9 cells to all the substrata tested (laminin, fibronectin, type-IV collagen, organ-derived extracellular matrix), suggesting that the shift in organ colonization observed with differentiated F9 cells is not due to an enhancement of the specific adhesion to the lung matrix. On the other hand, differentiated cells, but not undifferentiated ones, were able to respond to growth stimulation mediated by lung-derived extracts, thereby implying a relevant role for organ-specific growth stimulation in lung colonization by differentiated F9 cells.


Activation of c-fos and c-fes in metastatic lympho-macrophage hybrids.

The expression of proto-oncogenes involved in myelomonocytic differentiation was studied in 3 metastatic murine lympho-macrophage hybrids (ESb, EbF1, EbF2-C4) which display several antigenic and functional macrophage properties. Constitutive expressions of fos and fesmRNA, which were not detectable in the weakly metastatic parent lymphoma (Eb), was shown in all the proliferating hybrid lines. By contrast, c-myc and c-myc expressions were shared by the tumor parent and the hybrids. The c-fos transcripts observed in the hybrids were atypical in size, 2.3 kb, but standard 2.2-kb transcripts could be detected in serum-induced cells, even in the non-expressing Eb lymphoma. The kinetics of the induced fos mRNA was found to conform to the features reported in the literature for a large variety of cells. No structural alteration of the c-fos gene was detected by Southern analysis. PCR amplification of the 2.3- and 2.2-kb fos mRNA showed that they are identical in size in both the coding and the 3' untranscribed region. A longer poly A tail is thought to account for the additional 100 bp in the 2.3-kb fos mRNA, as both the 2.3- and 2.2-kb transcripts attain the same size following de-adenylation.


TGF-alpha production correlates with tumorigenicity in clones of the SW613-S human colon carcinoma cell line.

The c-myc gene is amplified and the c-Ki-ras gene is mutated in the SW613-S human colon carcinoma cell line. Two cell types with different levels of c-myc amplification are present in the SW613-S cell population and representative cell clones can be isolated. The clones with a high level of amplification and expression of the c-myc gene are tumorigenic in nude mice whereas those with a low level are not. The tumorigenic clones secrete transforming growth factor alpha (TGF-alpha) in the culture medium whereas the non-tumorigenic clones do not produce any detectable amount. Accordingly the level of TGF-alpha mRNA is higher and the transcription rate of the gene is increased in the tumorigenic clones. The acquisition of the tumorigenic phenotype by cells of non-tumorigenic clones, following introduction of c-myc gene copies by transfection, is accompanied by an increase in the steady-state level of TGF-alpha mRNA. These findings suggest a role for an elevated level of TGF-alpha production in the tumorigenic phenotype of SW613-S cells. The possibility that this role is indirect is discussed.


Experimental photodynamic therapy with a copper metal vapor laser in colorectal cancer.

In an attempt to define the best conditions for an adjunctive treatment of residual colonic microtumors by photodynamic therapy (PDT), an experimental model has been defined. S.c. HT29 colonic-cancer-cell tumors grown in nude mice were used and, 48 hr after i.p. administration of 30 mg/kg Photofrin (PH), laser illumination was performed with 75 or 150 Joules/cm2. The efficiencies of 2 lasers, the classically used rhodamine laser (RL) and a copper metal vapor laser (CMVL), were compared. The effects of PDT were assessed by histological and immunocytochemical (detection of a digestive enzyme, dipeptidyl-peptidase IV, as a marker of cell viability) follow-up and by the growth curve of the tumors after illumination. We conclude that, although the depth of necrosis resulting from PDT was nearly 3 mm at 75 J/cm2 and nearly 4-5 mm at 150 J/cm2 with both lasers, complete necrosis was obtained only with the CMVL at 150 J/cm2 (in 50% of the tumors). Under the other conditions, a layer of unaffected cells persisted at the pole opposite to laser illumination, resulting in growth curves lower than but parallel to those of the controls. Analysis of drug concentrations in the tumors and various organs, 48 hr after injection, i.e., at the time of laser illumination, revealed the presence of 21 micrograms/g dry weight PH in the tumors. The tumor vs. host-organ ratios were equal to or higher than 1 for the small bowel, colon, stomach, lung, skin and muscle. In contrast, the ratios were below 1 for the spleen, pancreas, kidney and liver.


Human melanoma cell-derived factor(s) stimulate fibroblast glycosaminoglycan synthesis.

Conditioned media from cultures of human metastatic Hs294T melanoma cells contain a factor/factors that promote(s) fibroblast-mediated contraction of collagen lattices, and stimulate(s) fibroblast glycosaminoglycan (GAG) synthesis. Complete medium from melanoma cell cultures stimulated fibroblast hyaluronate synthesis 9.3-fold, and sulphated GAG synthesis 2.6-fold, as measured by 3H-glucosamine incorporation. 35SO4 incorporation into sulphated GAGS was essentially unaltered, the net result being a decrease in the degree of sulphation. Fibroblasts synthesized hyaluronate with an increased molecular weight when grown in the presence of the melanoma-cell culture medium, while the molecular weights of heparan and chondroitin sulphates remained essentially unaltered. Our results indicate that the tumour-cell-derived factor(s) stimulate(s) changes in fibroblast glycosaminoglycan synthesis, and that these changes may facilitate tumour cell invasion in vivo.


Insulin resistance and breast-cancer risk.

Life-style has a major influence on the incidence of breast cancer. To evaluate the effects of life-style related metabolic-endocrine factors on breast cancer risk we conducted a case-control study comparing 223 women aged 38 to 75 years presenting with operable (stage I or II) breast cancer and 441 women of the same age having no breast cancer, who participated in a population-based breast cancer screening program. Women reporting diabetes mellitus were excluded. Sera from 110 women of the same age group presenting with early stage melanoma, lymphoma or cervical cancer were used as a second 'other-cancer control group'. Serum levels of C-peptide were significantly higher in early breast cancer cases compared to controls. The same was found for the ratios C-peptide to glucose or C-peptide to fructosamine, indicating insulin resistance. Sex hormone binding globulin was inversely, triglycerides and available estradiol were positively related to C-peptide. Serum C-peptide levels were related to body mass index (BMI), and to waist/hip ratio (WHR), in particular in controls. However, the relative increase of C-peptide, C-peptide to glucose or C-peptide to fructosamine in cases was independent of BMI or WHR. The log relative risk was linearly related to the log C-peptide levels. Relative risk according to quintiles, and adjusted for age, family history, BMI and WHR, for women at the 80% level was 2.9 as compared with those at the 20% level for C-peptide. Elevated C-peptide or C-peptide to fructosamine values were not observed in the sera from women belonging to the 'other-cancer control group'. This study suggests that hyperinsulinemia with insulin resistance is a significant risk factor for breast cancer independent of general adiposity or body fat distribution.


HLA-B5-restricted auto-tumor-specific cytotoxic T cells generated in mixed lymphocyte-tumor-cell culture.

T-cell-enriched lymphocyte populations derived from the malignant exudate of a patient with ovarian carcinoma were exposed to autologous tumor cells in the mixed lymphocyte-tumor-cell culture (MLTC) and propagated for 42 days. Proliferation of lymphocytes depended on exposures to autologous tumor cells and on the presence of IL-2. After 7 days, the MLTC-lymphocytes lysed K562 and the autologous tumor cells. The latter effect was not inhibited by monoclonal antibodies (MAbs) reactive with MHC class-I antigens or with CD3. After 7 restimulations, the culture was enriched in CD8+ cells (92%) and showed selective lytic activity against the autologous tumor. This function was inhibited by the alpha-class I or alpha-CD3 MAbs, and also by antibodies reactive with the HLA B locus or B5 allele products. The antibodies reactive with HLA A molecules had no such effect. It seems therefore that the function of the CTLs was restricted by HLA B5. Analysis of the TCR beta genes indicated clonal T-cell expansion in this culture. This MLTC was 1 of 21 initiated with 11 blood- and 10 tumor-derived lymphocyte (TIL) populations prepared from the malignant effusions of ovarian carcinoma patients. None of these ex-vivo lymphocytes lysed autologous tumor cells. In 17 MLTCs the lymphocytes did not proliferate, and in 3 cultures the proliferation was maintained only for 2-3 weeks. In 3 of 4 cultures auto-tumor cytotoxicity was induced.


Characterization of a lung-cancer-associated auto-antigen.

An antigen, protein X (Px), was purified from immune complexes isolated from malignant pleural effusions from patients with adenocarcinoma of the lung by EDTA treatment, PEG 8000 precipitation, protein A affinity chromatography, and Sephadex G-200 separation in the presence of 3 M NaCl. The purified antigen had a M(r) 17,000 by SDS-PAGE, and consisted of isoelectric species of pI 6.3 and 6.6. Purified Px recombined with Ig isolated from pleural fluids from patients with lung adenocarcinoma, but not with Ig from patients with breast carcinoma. Using an autologous human and heterologous chicken antibody, Px was found, by immunohistology, in the cytoplasm of some of the well-differentiated lung adenocarcinoma cells, but was not seen in normal lung or a variety of other malignant tissues. A liquid-phase competitive-inhibition RIA was developed. Over 30 ng/ml of Px were found in 9 of 15 pleural fluids from patients with lung carcinoma, none of 20 from patients with breast, ovary, stomach or colon cancer, and in 3 of 15 patients with unknown primary tumor. Our data suggest that Px may be a lung-cancer-associated autoantigen which can elicit a host humoral response in vivo.


Carcinogenic effect of tobacco smoking and alcohol drinking on anatomic sites of the oral cavity and oropharynx.

A series of 359 male patients with 424 cancer lesions of the oral cavity and oropharynx identified at a US Department of Veterans Affairs Medical Center were divided according to site of origin of the lesion and compared with 2,280 controls from the same hospital with respect to exposure to tobacco smoking and alcohol drinking. Sites of origin were: floor of the mouth (153), oral tongue (50), anterior tonsillar pillar (49), soft palate (44), lingual aspect of retromolar trigone (11), alveolar ridge (5), buccal mucosa (4), and hard palate (2). Forty-one patients had cancers in multiple sites. Tobacco smoking was more strongly associated with soft-palate lesions than with lesions in more anterior sites. Patients with cancer of floor of the mouth and oral tongue had higher odds ratios for alcohol drinking than subjects with cancers of other sites. This study supports the hypothesis of the carcinogenic effect of tobacco smoke and alcoholic beverages on the oral mucosa through direct contact.


Expression of the matrix Gla protein in urogenital malignancies.

Matrix Gla protein (MGP), is a vitamin-K-dependent protein which is synthesized in a variety of tissues such as lung, heart, kidney, cartilage and bone. The function of MGP in these tissues is unclear. We have previously reported elevated MGP mRNA levels in a breast-cancer cell line, 600PEI, as compared to normal breast epithelium. Here we describe high MGP expression in primary renal-cell carcinomas, prostate carcinomas and testicular germ-cell tumors, as determined by Northern analysis. MGP was over-expressed in 21 out of 28 patients with renal-cell carcinoma, and in 16 out of 29 patients with testicular germ-cell tumors, as compared to matched normal tissues. For the renal-cell carcinomas, a statistically significant inverse correlation was observed between the level of MGP expression and tumor size, lymph-node metastasis and tumor grade. MGP was also highly expressed in 13 primary prostatic carcinomas as compared to prostate cell lines derived from metastatic tumors, and to lymph-node metastasis. Our findings indicate that the loss of MGP expression may be associated wih tumor progression and metastasis.


International variations in the incidence of neuroblastoma.

The International Agency for Research on Cancer has coordinated a worldwide study of childhood cancer incidence, with data from over 50 countries. We present here the results for neuroblastoma. In predominantly white Caucasian populations the age-standardized rate was 7-12 per million, and 6-10% of all childhood cancers were neuroblastomas. Rates were highest in the first year of life (25-50 per million, 30% of total neuroblastoma incidence), and decreased with age to 15-20 per million (50% of the total) at age 1-4, 2-4 per million (15%) at 5-9 and 1-1.5 per million (5%) at 10-14. In the United States, black children had an incidence of 8.5 per million compared with 11.5 among Whites; Blacks tended to be older than Whites at diagnosis. The highest rate in Africa was in Bulawayo, Zimbabwe (8.0 per million) and the lowest in West Nile, Uganda, with no cases registered. Incidence in Israel was similar to that in many white populations, with Jews having a particularly high rate. In other parts of West Asia neuroblastoma had a low relative frequency, suggesting that incidence is low. Rates were also low throughout much of southern and eastern Asia, including India and China. Incidence in Japan was somewhat higher, though less than in Western countries, with the deficit most pronounced in the first year of life; these data relate to the period before mass screening of infants for neuroblastoma in the regions concerned. Incidence was generally higher in regions and among ethnic groups enjoying a higher standard of living, though previous studies within single countries had suggested that neuroblastoma is more common among less affluent groups. Blacks in Africa and the United States may have a weaker genetic predisposition to neuroblastoma, but some of the deficit in many developing countries is likely to be due to under-diagnosis.


PCR assay for chromosome 1p deletion in small neuroblastoma samples.

Deletion of the short arm of chromosome 1 is among the most recurrent cytogenetic alterations found in neuroblastoma and has been associated with short survival. However, this prognostic information, which relies on time-consuming techniques, is not yet routinely exploited. In order to set up a reliable and simple routine test to determine 1p deletion in neuroblastoma, we have used the polymerase chain reaction to genotype neuroblastoma DNA at 2 loci containing a variable number of tandem repeats and located on the distal part of the short arm of chromosome 1. Agarose gel electrophoresis and ethidium bromide staining of the amplification products enable a simple determination of constitutional and tumor genotypes at these loci to be made. A total of 37 samples from 29 patients were studied with this technique. Loss of heterozygosity (LOH) could be identified in 8 cases. In each case the results obtained were in agreement with those achieved by the Southern procedure. This technique will be of particular interest in the pretherapeutic analysis of 1p deletions in small tumor samples obtained by fine-needle aspirates of the primary tumor. It should also enable retrospective studies from paraffin-embedded tumor fragments to be made and provide information for the analysis of tumor heterogeneity in neuroblastoma and in other tumors with 1p deletions.


Descriptive epidemiology and survival analysis of nasopharyngeal carcinoma in the United States.

Population-based incidence data on nasopharyngeal carcinomas (NPC) from the Surveillance, Epidemiology and End Results program in the United States were examined for the years 1973-1986. The 1,645 cases showed incidence rates varying according to ethnic origin, with chinese having the highest, followed by Filipinos, Blacks and Whites. In females the incidence was about half of that seen in males, in each of these groups. There was no evidence of changes in incidence rates during the study period. An analysis of survival with NPC was undertaken using hazard function regression models to allow for control of multiple variables. Survival was found to be independently influenced by age and stage at diagnosis, histologic type, grade and sex. Significant ethnic differences in survival remained after adjustment for these factors, with Chinese surviving longest followed by Filipinos, Whites and Blacks. These difference in survival remained after control for the variation in population-wide mortality rates associated with age, ethnicity, sex and calendar year. We present evidence that survival has improved for this disease over time.


A population-based case-control study of cancers of the nasal cavity and paranasal sinuses in Shanghai.

A population-based case-control study of cancer of the nasal cavity and sinuses, involving interviews of 60 incident cases and 414 controls, was conducted in Shanghai. Cigarette smoking was associated with a mild elevation in risk of squamous-cell carcinoma but not cancers of other cell types. Occupational exposures to wood and silica dusts and to petroleum products, and the use of wood and straw as cooking fuel, were linked to moderate increases in risk, while 4-fold or greater increases were associated with a history of chronic nasal diseases, including those occurring 10 or more years prior to cancer diagnosis. Dietary analyses revealed a significant protective effect of consumption of allium vegetables, oranges and tangerines, with a 50% reduced risk of nasal cancer among individuals in the highest intake group of these foods. Consumption of salt-preserved vegetables, meat and fish was associated with a significantly increased risk of nasal cancer in a dose-response fashion, with a 5-fold excess observed for the heaviest intake of these salted foods. These findings suggest that dietary factors may contribute to the development of nasal cancer.


Risk factors for renal-cell cancer in Shanghai, China.

A population-based case-control study of 154 histologically verified renal-cell cancer patients and 157 controls was performed in Shanghai, China, an area with low rates for this tumor. Elevated risks were observed for cigarette smoking (odds ratio (OR) = 2.3; 95% confidence interval (CI): 1.1 to 4.9), and for increasing categories of body weight and meat consumption, while reduced risks were seen for increasing categories of fruit and vegetable intake. An increased risk was also observed for regular use of phenacetin-containing analgesics (OR = 2.3; 95% CI:0.7 to 7.0). These findings are consistent with earlier studies in Western countries, and indicate that many of the same etiologic factors for renal-cell cancer operate in low- and high-risk societies.


Effect of smoking on folate levels in buccal mucosal cells.

The objective of the study was to document the existence of localized deficiency of folate in a tissue exposed to cigarette smoke, by analysis of oral and circulatory levels of this vitamin in smokers and non-smokers. Buccal mucosal cells and blood samples were collected from 25 smokers and 34 non-smokers. The Health Habits and History Questionnaire was completed by each subject. A 96-well plate L. casei assay, along with preincubation with a folate-free chick pancreas pteroyl-gamma-glutamyl hydrolase, was used to quantitate total buccal mucosal cell folates. The reproducibility (CV 5 to 7%) and recovery (95 to 106%) of the folate assay were satisfactory. Smokers had significantly lower buccal mucosal cell folate levels than did non-smokers. The mean plasma folate level of smokers although within normal limits, was also significantly lower than that of non-smokers. There were no significant differences in mean dietary folate intake or in alcohol consumption between the 2 groups. The strength of the positive association between smoking and plasma and buccal mucosal cell folate deficiency (by any definition) was moderate to strong and statistically significant. Our results indicate that cigarette smoking may result in a localized folate deficiency in buccal mucosal cells, independent of the plasma folate levels.


Frequent loss of heterozygosity on chromosomes Xp and 13q in human ovarian cancer.

Loss of heterozygosity (LOH) was examined at 27 loci on chromosomes 3p, 6q, 11p, 13q, 17 and X in 42 human ovarian tumors. LOH was detected in 12 of 26 (46%) and 5 of 12 (42%) informative cases at 2 chromosome 13q loci, D13S32 and D13S34 respectively. On chromosome Xp, tumor-specific allele loss was observed in 9 out of 15 informative cases (60%) at the ornithine transcarbamylase (OTC) gene locus. Examination of 12 additional Xp and 13q loci has mapped the common deletion regions to Xp21.1-->p11.4 and 13q33-->q34. The observation of significant LOH on Xp represents a strong indication of genetic changes in the X chromosome in a human malignancy. The allele losses on 13q which have been reported for other cancers suggest that chromosome 13, in addition to the retinoblastoma gene, may contain other growth-regulating gene(s) important in the development of several tumor types, including ovarian malignancies.


Immunohistochemical determination of androgen receptors in relation to oestrogen and progesterone receptors in female breast cancer.

The expression of oestrogen (ER), progesterone (PR) and androgen (AR) receptors in female breast cancer was investigated by immunohistochemistry on snap-frozen tissue specimens of a series of 100 breast cancers. For detection of the AR we used a recently developed mouse monoclonal antibody specific for the N-terminal domain of the human AR. Expression of AR was compared with that of ER and PR as well as with tumour grade and age. Of the breast cancers investigated, 76% were AR-positive. This high percentage corresponds well with previous data on AR expression in breast cancer determined with ligand-binding assays. In 53% of the tumours AR, ER and PR were present, while 9% of the tumours were positive for AR and negative for ER and PR. In 13% of the tumours no ER, PR or AR expression was seen; these were all grade-III tumours. A positive correlation was found between age and ER expression, but no correlation was seen between age and PR or AR. Future studies should establish the prognostic value of the combination ER, PR and AR determinations on female breast cancer with regard to biological behaviour and response rate to hormonal therapy.


The gene encoding for MC56 determinant (drug-sensitivity marker) is located on the short arm of human chromosome 11.

A panel of mouse x human B- and T-cell hybrids was analyzed for the expression of MC56 determinant which marks the drug-sensitive state of CEM cells. Karyotypic and phenotypic analyses of the tested clones showed that the expression of MC56 determinant correlated to the presence of human chromosome 11 and segregated concordantly to the epitopes recognized by monoclonal antibodies in the CD44 cluster. By using a particular class of interspecific rodent x human-cell hybrids in which the human genome counterpart is represented in the different clones only by human chromosome 11 or its fragments, we showed that the gene encoding for MC56 determinant is located on the region p13-pter of the short arm of chromosome 11. Therefore, the hypothesized homology between the drug-sensitivity marker MC56 and the CD44 determinant is supported also by gene mapping studies.


Characterization of a mouse-human chimeric antibody to a cancer-associated antigen.

In an attempt to obtain a therapeutic antibody, the murine monoclonal antibody (MAb) MBrI (IgM,k), directed against human carcinomas, was converted in a mouse/human chimeric MAb of gamma I isotype. The chimeric MAb, gamma I CHI-MBrI, retains the ability to specifically bind tumor cells and tissues with no modification in its binding to the normal material tested. gamma I CHI-MBrI recognizes mucins and high-molecular-weight glycoproteins carrying the antigenic determinant and stains a neutral glycolipid extracted from MCF-7 cells. The chimeric and the murine MBrI efficiently cross-inhibit each other on the reference cell line MCF-7 and the calculated affinity constants amount to 3.8 x 10(7) and 1.7 x 10(8) M-1, respectively. The human constant region allows gamma I CHI-MBrI to bind with the FcR on the human monocytic cell line U937 and to efficiently mediate antibody-dependent cellular cytotoxicity in the presence of human lymphocytes activated by IL2. In addition, gamma I CHI-MBrI, like the murine MBrI, mediates complement-dependent tumor-cell lysis. Thus, by modelling a molecule with reduced size and increased functional characteristics, we have obtained a reagent which is more suitable for in vivo therapeutic approaches.


The lipoxygenase metabolite 12(S)-HETE promotes alpha IIb beta 3 integrin-mediated tumor-cell spreading on fibronectin.

Tumor-cell interaction with the vessel wall during metastasis involves adhesion, induction of endothelial-cell retraction and spreading on the exposed sub-endothelial matrix. The signals for initiation of tumor-cell spreading and the receptors involved are unknown. A protocol was developed to distinguish between initial tumor-cell (B16 amelanotic melanoma; B16a) adhesion to and spreading on fibronectin. The time for maximum spreading was 50 min. Treatment with a lipoxygenase metabolite of arachidonic acid [12(S)-HETE] resulted in maximum spreading in 15 min (max. effect approx. 0.1 microM). Other lipoxygenase metabolites were ineffective. 12(S)-HETE treatment induced a rearrangement of F-actin, vinculin, vimentin intermediate filaments and integrin alpha IIb beta 3, but not integrin alpha 5 beta 1. Antibodies to alpha IIb beta 3 but not alpha 5 beta 1 blocked the 12(S)-HETE effect on B16a spreading. B16a-cell attachment to fibronectin resulted in increased metabolism of arachidonic acid to 12(S)-HETE, which was inhibited by lipoxygenase but not by cyclo-oxygenase inhibitors. Accordingly, lipoxygenase inhibitors but not cyclo-oxygenase inhibitors blocked spontaneous B16a-cell spreading. The protein-kinase-C inhibitors calphostin C, H7 and staurosporine also inhibited spreading, while the protein-kinase-A inhibitor H8 was ineffective. These data suggest that B16a-cell spreading on fibronectin is initiated by a lipoxygenase metabolite [12(S)-HETE] of arachidonic acid and is mediated by protein kinase C.


Involvement of histo-blood-group antigens in the susceptibility of colon carcinoma cells to natural killer-mediated cytotoxicity.

The susceptibility to natural-killer-cell lysis and expression of histo-blood-group antigens of 2 clones from a rat colon adenocarcinoma, of variants derived from them and of 17 human colon carcinoma cell lines were assessed in an attempt to determine if the major glycosidic tissue antigens of epithelial cells could influence the NK susceptibility of tumor target cells of epithelial origin. The rat REGb clone, which is relatively NK-sensitive, expressed higher levels of precursor structures T and Tn and lower levels of H antigenic determinants than the PROb clone, which displays higher resistance to NK-cell lysis. Cell variants were obtained from these 2 clones; it appeared that whether the cell variants were selected on the basis of expression of a blood-group antigenic determinant or on the basis of altered susceptibility to NK-cell lysis, there was a link between increased resistance and higher expression of cell-surface A and H histo-blood-group antigens, or conversely, between increased sensitivity and higher expression of precursor structures. Similar conclusions were obtained upon study of the human cell lines, since a significant correlation was found between the level of expression of T or Tn antigens and sensitivity to NK-cell lysis. A significant relationship was found between the expression of Lewis antigens and increased resistance to NK-cell-mediated cytotoxicity.


Cytotoxicity of a transferrin-adriamycin conjugate to anthracycline-resistant cells.

Conjugates of adriamycin coupled to transferrin by glutaraldehyde are cytotoxic to human promyelocytic (HL-60) and erythroleukemic (K562) cells. Growth inhibition of adriamycin-sensitive cells, as evaluated by thymidine incorporation and the MTT-assay, was higher for conjugates than for free adriamycin. The cytotoxicity toward adriamycin-resistant K562 and HL-60 cells was 3-fold and more than 10-fold higher, respectively, for the transferrin-adriamycin conjugate than for the free drug. The effect of the conjugate was dependent on its adriamycin content, i.e., on its conjugation number.


Immunotoxins directed against the high-molecular-weight melanoma-associated antigen. Identification of potent antibody-toxin combinations.

To study factors influencing the cytotoxicity of immunotoxins (ITs), we compared the in vitro cytotoxicity of conjugates in which the plant toxin abrin and the bacterial toxin Pseudomonas exotoxin A (PE) were coupled by 2 different procedures to 2 MAbs, 9.2.27 and NR-ML-05, which bind to different epitopes on the melanoma-associated antigen p250. The individual target cell lines differed widely in sensitivity to the different ITs, as assessed by measurement of protein synthesis inhibition. The action of the ITs was highly specific, as the toxicity of abrin and PE conjugates was respectively 20-540 and 2,200-550,000 times higher in antigen-positive cell lines (FEMX, SESX, OHS) than in the antigen-negative line KPDX. The PE conjugates prepared with the 2 different MAbs differed in potency by factors of 16-126 in the target-cell lines, but were consistently more toxic than the abrin ITs. The results demonstrate that the cytotoxicity of ITs varies with the nature of both of its moieties and that optimal results require that toxins and MAbs be matched. Moreover, the 2 coupling procedures affected differentially the binding and potency of some ITs. Each of the 2 toxins was conjugated to a sheep anti-mouse antibody (SAM) and the toxicity of these 2 conjugates was tested in an indirect approach using 9.2.27 and NR-ML-05 as primary MAbs. The results showed that the indirect procedure would have correctly predicted the most potent antibody-toxin pair, indicating that the approach may be valid for selecting suitable combinations of MAbs and toxins for use as direct ITs.


Cystatin C and cathepsin B in human colon carcinoma: expression by cell lines and matrix degradation.

Expression of the cysteine proteinase cathepsin B and its physiological inhibitor cystatin C was analyzed in vitro in 1 human fibrosarcoma and 4 human colon carcinoma cell lines. Cystatin C antigen as well as cathepsin B activity were detected in the conditioned media of the 5 cell lines. The corresponding cell extracts expressed high levels of cathepsin B activity, whereas only trace amounts of cystatin C antigen could be found. Northern-blot analysis revealed the presence in the 5 cell lines of a 0.8-kb cystatin C mRNA transcript and 2 cathepsin B transcripts of 2.3 and 4.3 kb. Pepsin treatment of tumor-cell-released cathepsin B induced an average 7.3-fold increase in activity, indicating that the enzyme was mainly present as a latent form in conditioned medium. The pepsin-activated cathepsin B from one colon carcinoma cell line was further characterized using the cysteine proteinase inhibitors E-64, recombinant cystatin C, a cystatin-C-derived peptidyl inhibitor (Z-LVG-CHN2), and cathepsin-B-specific diazomethyl ketone inhibitors (Z-FT(OBzl)-CHN2, Z-FS(OBzl)-CHN2). This activity was totally neutralized by recombinant cystatin C, suggesting a potential for interaction between released extracellular cathepsin B and cystatin C. In vitro assays of degradation of extracellular matrix showed that cysteine proteinase inhibitors could decrease matrix degradation induced by pepsin-activated conditioned media. With colon cells, this inhibition was not observed, indicating a requirement for an extracellular activation of latent cathepsin B. Our data provide evidence that cystatin C and latent cathepsin B are both released extracellularly by colon carcinoma cells in vitro. They suggest that cystatin C and cathepsin B interactions may participate, in an as yet unelucidated way, in the modulation of the invasive phenotype of human colonic tumors.


Genes involved in tumor invasion and metastasis are differentially modulated by estradiol and progestin in human breast-cancer cells.

Invasion of basement membranes by cancer cells is a critical step in metastasis, which requires the coordinated expression of specific genes such as laminin receptors and metalloproteinases. Estradiol and progesterone modulate the clinical progression of steroid-sensitive breast cancers; however, little is known about the molecular regulation of the invasive phenotype by these hormones. We therefore examined the effects of 10 nM estradiol and/or 10 nM progestin R5020 on the expression of 2 non-integrin laminin binding proteins, the 67-kDa laminin receptor (67LR) and HLBP31 as well as the 72-kDa type-IV collagenase (MMP-2) and its inhibitor, TIMP-2, in steroid-receptor-positive (T47D and MCF-7) and -negative (MDA-MB 231) human breast-cancer cells. The relative steady-state level of 67LR mRNA was increased 2- to 3-fold by estradiol in both MCF-7 (p < 0.001) and T47D (p < 0.001) cells, also by R5020, alone or in combination with estradiol, in T47D cells (p < 0.001) and to a much less extent in MCF-7 cells. HLBP31 mRNA and protein levels were increased 2- to 3-fold (p < 0.001) by R5020 alone or in combination with estradiol, but not by estradiol alone. None of the steroid treatments affected the expression or activity of MMP-2. Interestingly, however, TIMP-2 mRNA levels and protein expression in MCF-7 and T47D cells were 50% down-regulated (p < 0.001) by treatment with R5020 or R5020 plus estradiol, but not by treatment with estradiol alone. None of these genes were modulated in steroid-independent MDA-MB231 cells. The data suggest that estradiol and progesterone might act as coordinators regulating specific genes in the steroid-sensitive breast-cancer cell, leading to the acquisition of the metastatic phenotype.


Phosphoprotein B23 translocation and modulation of actinomycin D and doxorubicin cytotoxicity by dipyridamole in HeLa cells.

During continuous exposure, cells were more responsive to doxorubicin (DOX) in the presence of dipyridamole (DPM). Translocation of nucleolar phosphoprotein B23 and inhibition of cell growth occurred with a lower dose of DOX and in a shorter incubation time in the presence of DPM. DPM did not change translocation induced by actinomycin D (Act-D). Short exposure of HeLa cells to Act-D induced "reversible" translocation of protein B23 as well as "reversible" inhibition of cell growth. DPM included in the cell culture after removal of Act-D inhibited the recovery of cell growth as well as the corresponding relocalization of protein B23 from the nucleoplasm to nucleoli. DPM administered in the fresh medium after 30 min exposure to DOX had little effect on the potentiation of the induced translocation of protein B23 and inhibition of cell growth. Our results indicated that "B23 translocation" is closely associated with states of cell growth. The potentiation of the inhibition of cell growth by DPM is associated with the extent of enhanced protein B23 translocation. "B23 translocation" may therefore be a simple and rapid method for assessing the inhibition of cell growth and for determining the efficacy of combination cancer chemotherapy.


The presence of concanavalin-A(Con-A)-like molecules on natural-killer (NK)-sensitive target cells: their possible role in swainsonine-augmented human NK cytotoxicity.

In the present study we examined the expression of concanavalin-A(Con-A)-like molecules on natural-killer (NK)-sensitive target cells and investigated their possible role in the human NK-cell phenomenon. The incubation of either peripheral-blood lymphocytes (PBL) or large granular lymphocytes (LGL) with swainsonine (SW), an inhibitor of mannosidase II, resulted in the augmentation of cytotoxicity against K562 leukemia cells. The enhanced cytotoxicity was associated with increased binding of fluorescein isothiocyanate-conjugated Con-A to SW-treated effector cells, and immunofluorescence staining of the target K562 cells using goat anti-Con-A antibody (Ab) showed a significant positive shift in the flow cytometric pattern. Electrophoretic separation and immunoblotting analysis revealed that 4 components with a molecular weight of approximately 95, 80, 60 and 50 kDa were recognized by anti-Con-A Ab from the detergent-extract of K562 cells. The addition of Con-A during the antibody incubation step of the Western blotting abolished their expression, thus excluding non-specific binding of the antibody. The addition of Con-A also strongly inhibited the cytotoxicity of SW-treated effector cells (PBL or LGL) against K562 cells, and this inhibition was abolished by 40 mM alpha-methyl-mannopyranoside (alpha-MM), which binds to Con-A. Furthermore, Con-A increased the binding frequency of SW-treated LGL to K562, in spite of the inhibited cytotoxicity, and this effect could be neutralized by the further addition of alpha-MM. Our results suggest that Con A-like molecules might play an important role in cell-cell interactions between SW-treated effector cells and NK target cells.


Inadvertent hypnosis during interrogation: false confession due to dissociative state; mis-identified multiple personality and the Satanic cult hypothesis.

Induction of a dissociative state followed by suggestion during interrogation caused a suspect to develop pseudo-memories of raping his daughters and of participation in a baby-murdering Satanic cult. The pseudo-memories coupled with influence from authority figures convinced him of his guilt for 6 months. During this time, the suspect, the witnesses, and all the evidence in the case were studied. No evidence supported an inference of guilt and substantial evidence supported the conclusion that no crime had been committed. An experiment demonstrated the suspect's extreme suggestibility. The conclusion reached was that the cult did not exist and the suspect's confessions were coerced-internalized false confessions. During the investigation, 2 psychologists diagnosed the suspect as suffering from a dissociative disorder similar to multiple personality. Both psychologists were predisposed to find Satanic cult activity. Each concluded that the disorder was due to "programming" by the non-existent Satanic cult.


Effects of "deepening" techniques on hypnotic depth and responding.

The present study attempted to assess the effectiveness of commonly used deepening techniques and of surreptitiously provided stimulation on hypnotizability scores, in-hypnosis depth reports, retrospective realness ratings, and the Field Inventory of Hypnotic Depth (Field, 1965). High, medium, and low hypnotizables were assigned in equal numbers to 1 of 3 groups, each containing 54 Ss. Controls were compared to Ss receiving 2 deepening techniques or 2 suggestions for positive and negative hallucinations that were surreptitiously enhanced. Of the 4 dependent measures employed, the only significant difference between groups related to a change in depth reports for the manipulation items themselves, leading to the conclusion that the effect of the techniques was at best minimal and transient. Some methodological and conceptual issues are also discussed.


Prospective time estimation and hypnotizability in a simulator design.

The present study of prospective time estimation examined the effects of hypnosis on short time intervals using a real-simulator design. The major hypothesis predicted a 2-way interaction between group (high hypnotizable, low hypnotizable, and simulator) and condition (waking and hypnotic) across all 4 time intervals (30, 60, 120, and 240 seconds). It was further hypothesized that on a "suggested" task (a measure of hypnotic depth), high hypnotizable Ss and simulators would not differ from each other but would differ from low hypnotizable Ss. 42 undergraduates were screened on both the Creative Imagination Scale (Wilson & Barber, 1977) and the Stanford Hypnotic Clinical Scale for Adults (Morgan & J. R. Hilgard, 1975, 1979) and assigned to 1 of 3 groups (high hypnotizable, low hypnotizable, simulator) based on combined hypnotizability scores. Ss verbally estimated time intervals of 30, 60, 120, and 240 seconds, 3 times each, both while in a waking and a hypnotic condition. Hypnotic depth was assessed once following each time interval. Partial support was found for the first hypothesis where, for both the 60- and 120-second intervals, high hypnotizable Ss increased their overestimation in the hypnotic condition. Low hypnotizable and simulator Ss showed no such increase. The second hypothesis, that high hypnotizable and simulator Ss would differ from low hypnotizables on the "suggested" task, was confirmed. The partial replication of previous research was examined in the context of choice of hypnotizability measure and reliability of time estimation.


Experience of peripheral temperature change during hypnotic analgesia.

Many Ss who experience hypnotic analgesia in a portion of their body often report that it is accompanied by sensations of coldness in the affected area. Experiments were conducted to determine if such reports are the result of a physical change in peripheral temperature or are due to psychological factors. When analgesia was induced in a limb or in the back of the neck, a concomitant physical change in temperature was not observed. Ss did report experiencing coldness, however, in the affected body part. Such experiences were attributed to associations that Ss developed between numbness or analgesia and a drop in peripheral temperature. As a result, coldness as an associate of hypnotic analgesia is suggested as a manipulation check for the presence of such sensation reduction.


Smokeless tobacco consumption in Grant County, New Mexico.

A telephone survey was conducted in order to assess the prevalence of smokeless tobacco consumption in Grant County, New Mexico. Systematic random sampling was used, and 1 out of 25 phone numbers were selected from the county telephone directory. One hundred seventy-eight respondents were surveyed. Thirty-three percent of 96 males and 7% of 82 females identified themselves as smokeless tobacco users.


Perceptions of drinking problems among undergraduate students in the United States and Scotland.

This study compares the perceptions of problem drinking and preferred explanations for problem drinking held by 440 undergraduate students in the United States and 185 in Scotland. Respondents' drinking habits influenced perceptions of drinking problems in both nations. The Scottish sample, with drinking habits statistically controlled, was less likely to perceive drinking problems than the United States sample and was less likely to endorse a physiological explanation for drinking problems. The importance of different perceptions in influencing decisions to seek help is discussed.


Conscious and unconscious perceptions of self in children of alcoholics.

The conscious and unconscious self-concept was examined in three groups of children: 23 children of alcoholics (COA), 19 children from nonalcoholic but dysfunctional families, and 23 children from normal families without alcoholism or family dysfunction. Self-concept was assessed both objectively, using the Piers-Harris Children's Self Concept Scale, and subjectively, using the Draw-A-Person Test and the Thematic Apperception Test from rating systems designed to tap unconscious dimensions of self. The COAs and normal controls were also compared for behavioral problems with the Achenbach Child Behavior Checklist. We found that COAs made more positive self-statements on objective measures of self-concept than children from families without alcoholism, whether or not the families were dysfunctional. Subjective analyses of projective test responses revealed unconscious differences in self-concept among the COAs, though this was not corroborated with objective scores, probably due to the crudeness of the rating instrument in failing to tap these dimensions. Also COAs had significantly more behavior problems, based on parental reports, which contrasts with their objective reports of self. Implications of these findings were discussed.


Family structure and adolescent risk-taking behavior: a comparison of Mexican, Cuban, and Puerto Rican Americans.

We use the Hispanic HANES to examine whether family structure is related to alcohol and drug use among Mexican, Puerto Rican, and Cuban American adolescents. Mexicans adolescents living in female headed households have higher rates of drinking, drug use, and overall risk-taking behaviors than those living with both parents. Puerto Ricans adolescents living in female-headed households have higher rates of overall risk-taking behaviors than those living with both parents. Family structure is unrelated to Cuban adolescent risk-taking behavior. There is no evidence that gender modifies the effect of family structure for adolescent risk-taking behaviors.


Young heavy drinkers and their drinking experiences: predictors of later alcohol use.

This study illustrated the impact of late adolescent and young adult alcohol experiences on current level of alcohol use. Additional factors investigated include reported age of problem onset, initial age of alcohol use, marital status, and life-span risk-taking behavior. A stepwise discriminant analysis was used to determine the importance of various subtypes of drinking experiences and combinations of these subtypes. Correct classification of current light and heavy alcohol drinkers by use of these experiences was 83.7% for late adolescent experiences and 77.5% for young adulthood experiences. The results suggest that early drinking experiences are useful predictors of future drinking patterns.


Recommendations for improving drug treatment.

Recognizing that drug use is both chronic and relapsing once an individual is addicted, and that treatment is effective in reducing drug use/misuse, improving drug misuse treatment is examined and research as well as practice recommendations are presented. Drug misuse treatment is now recognized in the United States to meet the expanding drug use problem and for reducing the spread of HIV. With that background, the current status of drug misuse treatment is reviewed, clinical issues are emphasized, and policy issues are noted. Recommendations include the need for uniform funding, linkage with community agencies, technology transfer, training, and expanding research and evaluation efforts.


The role of significant life events in discriminating help-seeking among illicit drug users.

This paper examines the role of significant life events in distinguishing two samples of illicit drug users: 120 help-seekers (the "agency group") and 120 not seeking help (the "non-agency group"). We examined 10 life areas clustered around the general categories of "substance use," "social functioning," and "emotional and interpersonal functioning." A range of objective and self-reported information was collected regarding each life area covering the 12 months prior to interview. Analysis revealed that the agency group experienced a greater number of negatively perceived drug-related life events than the non-agency group. These life events were also more likely to have occurred in recent months, prompting reported "concern" and "need for help" among the agency group. Additionally, length of use of current primary drug was seen to be a contributory variable in distinguishing between the groups.


Acculturation, alcohol consumption, and casualties among United States Hispanics in the emergency room.

The association of alcohol consumption and casualties was analyzed among Hispanic emergency room patients to determine whether level of acculturation and accompanying changes in drinking patterns influence risk of alcohol-related injuries. A sample of patients admitted to a county hospital emergency room during a 1-year period was breathalyzed and interviewed (N = 1,102). Of these, 112 identified themselves as Hispanic. Hispanic males were more likely than non-Hispanics to have positive breathalyzer readings, to report drinking prior to the event, and to attribute a causal association of drinking with the event. These findings were most pronounced among those in the moderate and high acculturation groups.


Relationships between mood around slip-up and recovery of abstinence in smoking cessation attempts.

Data are presented from 201 slip-up episodes in attempts at smoking cessation. Analysis as a function of whether the person recovered and resumed abstinence broadly confirmed previous findings. Emotions immediately before and after the slip-up episode were assessed, as were feelings about having slipped-up. Feeling bad prior to the slip-up cigarette was associated with reduced recovery. By contrast, reporting that the slip-up cigarette made the person feel worse was associated with increased recovery. Feeling bad about slipping-up was not associated with relapse, contrary to predictions from Marlatt and Gordon's theorizing about the Abstinence Violation Effect.


The prediction of long-term outcome of male alcoholics after inpatient treatment: the case of a clinical population in German-speaking Switzerland.

373 out of 497 patients treated between 1975 and 1984 in a Swiss clinic for male alcoholics could be traced for a follow-up study in 1988. Of these, 24% died between the time of leaving the clinic and the time of the interview. Among the survivors, almost 50% reported abstinence for at least the last 12 months. However, 132 (26%) of the former patients could not be traced. In many studies the majority of those lost cases are supposed to have died or to be unremitted, thus the effective results of the follow-up study are supposed to be less favorable had those cases been traced. In order to clarify this hypothesis, a discriminant analysis was performed to designate the actual life status/drinking status of those unknown cases using sociodemographic and drinking-style data of the statistical records of the clinic as independent (predictor) variables. The results show that the number of survivors among the untraced cases is estimated to be equal to those traced. However, the number of problem drinkers among the survivors is estimated to be higher amid the untraced than among those interviewed in the follow-up.


A case-control study of risk factors of alcohol misuse in Czech women: are there four types of female alcoholism?

Three samples of Prague women aged 20-49 were interviewed with regard to hypothetical risk factors of alcoholism: 139 inpatients diagnosed as alcohol dependent, 39 inebriated females admitted for 1-day detoxification, and 718 randomly selected women (the controls). Irrespective of case definition, father's alcoholism, incomplete family of origin, conduct disorders in childhood and adolescence, and social surroundings marked by heavy drinking were supported as risk factors of alcoholism. A factor analysis of alcohol-related problems led to two dimensions (dependence, disruptiveness) and consequently to four types of female alcoholism with different patterns of risk factors.


Young people, alcohol, and driving in two Australian states.

Road traffic accidents are the single largest cause of death in Australia among people aged 15-24. The proposition that a broadly based deterrence measure, such as random breath testing (RBT), would be sufficient to change the behavior of young drivers was tested in a comparison of young drivers in New South Wales (NSW), which has had RBT for 6 years, with young drivers in Western Australia (WA), where there was no RBT. The results demonstrated that NSW young drivers were less likely to drink and drive and more likely to believe their peers would disapprove of drink-driving than were their counterparts in WA. It was concluded that RBT had altered the drink-driving behavior and possibly the beliefs about drink-driving of young people in NSW.


Has socialism failed? An analysis of health indicators under socialism.

This article analyzes the widely held assumption in academia and the mainstream press that capitalism has proven superior to socialism in responding to human needs. The author surveys the health conditions of the world's populations, continent by continent, and shows that, contrary to dominant ideology, socialism and socialist forces have been, for the most part, better able to improve health conditions than have capitalism and capitalist forces. In the underdeveloped world, socialist forces and regimes have, more frequently than not, improved health and social indicators better than capitalist forces and regimes, and in the developed world, countries with strong socialist forces have been better able to improve health conditions than those countries lacking or with weak socialist forces. The socialist experience has, of course, also included negative developments that have negated important components of the socialist project. Still, the evidence presented in this article shows that the historical experience of socialism has not been one of failure. To the contrary: it has been, for the most part, more successful than capitalism in improving the health conditions of the world's populations.


Why the United States does not have a national health program: the medical-industry complex and its PAC contributions to congressional candidates, January 1, 1981, through June 30, 1991. Common Cause.

The Common Cause study presents data on medical-industry PAC contributions to Members of Congress during the period January 1, 1981, through June 30, 1991. Included are listings of the top 25 congressional recipients, the top 25 Senate recipients, and the top 50 House recipients of contributions from medical-industry PACs; medical-industry PAC contributions to members of the four key congressional committees and to the congressional leadership; top congressional recipients of contributions from medical professionals' PACs, including the American Medical Association, from health insurance PACs from pharmaceutical PACs, and from hospitals and care-provider PACs; and the top medical-industry PACs. State-by-state lists of medical-industry PAC contributions to Senators and to Representatives, including breakdowns of insurance, AMA, and pharmaceutical contributions, are given in the appendixes.


From equal access to health care to equitable access to health: a review of Canadian provincial health commissions and reports.

Having achieved equality of access to health care, Canadian policymakers are setting new policy goals, within resource constraints, primarily to achieve equity of access to health. Across the country, provincial royal commissions have explored a number of policy options to achieve this goal. These options are reviewed and critically analyzed within the context of such challenges in health policy as insufficient access to high-technology care and the limits of medical care, and such external challenges as economic and demographic trends, federal-provincial disputes, and ideological beliefs. Particular attention is given to the implications of a broader definition of health and the concept of regional health authorities. Based on the provincial reviews, the authors conclude that Canada wants to achieve equitable access to health. With the shift of health policy away from the formerly protected arena of medical care, achieving equitable access to health will require both an alteration of priorities and values and considerable political will. Canada will be forced to meet these new challenges to maintain current achievements and to make its system even more successful.


Employer control and the work environment: a study of the Swedish Public Dental Service.

The Public Dental Service in Sweden has a system of surveillance and supervision based on time studies, piecework wages for dentists, and detailed time reporting. This control system and its development are described in this article. The focus is on the effects of the system on the staff. A representative group of Swedish dentists (n = 896) and dental nurses (n = 600) was asked to participate in a questionnaire study exploring the work environment in the Public Dental Service. The response rate was 87 percent. The dentists reported that they felt constantly supervised and evaluated. Their work tempo was related to surveillance, competition, and demands of the employer. There was no correlation between work tempo and piecework results. A high percentage of the staff mentioned weaknesses in the charging and piecework system that they thought could result in an undesirable influence on dentists' work. A majority would have preferred fixed salaries. The results are discussed in terms of gender, motivation, proletarianization, and management style.


Leaving it up to the workers: sociological perspective on the management of health and safety in small workplaces.

Small workplaces present particular challenges for the promotion of occupational health and safety. However, little is known about the social organization of work in such settings and how it relates to matters of health and safety. The research on which this article is based relates patterns of occupational health behavior to the nature of social relationships within the workplace. From a qualitative analysis of interviews with 53 small business owners, the author describes the most common approach to managing workplace health and safety: leaving it up to the workers. This posture is explained in terms of the owners' perception of risk, particularly their understanding of workplace hazards, and their assessment of the social costs of ignoring or addressing such issues. Owners tended to discount or normalize health hazards, and to believe that management intervention in employee health behavior was paternalistic and inconsistent with prevailing patterns of labor relations and norms respecting individual autonomy. Many owners understood health and safety not as a bureaucratic function of management but as a personal moral enterprise in which they did not have legitimate authority. The conceptualization of the owners' responses in terms of "social rationality" has implications for addressing problems of health and safety in small workplaces.


The industrial safety professionals: a comparative analysis from World War I until the 1980s.

The birth of industrial society produced demand for the services of professionals specialized in matters related to industrial safety. Three professions--safety engineering, industrial medicine, and ergonomics--are examined. These professions are observed to either submit to single sets of demands, to integrate contradictory demands, or to experience scission. Until the late 1960s their growth appears to have been relatively peaceful and uncontroversial. From this period onward, controversy breaks out over questions related to industrial safety, and professions and government administrations grow. Increasingly, the traditional approach of safety professionals is called into question, and they adopt new orientations. These changes are mapped through the examination of data drawn principally from the United States, France, Great Britain, and to a lesser extent Brazil. The traditional standards approach competes with cost-benefit analysis and with systemic safety for influence; in addition, an emergent approach that analyzes accident causes in terms of social relations of work is detected. From Bhopal to Chernobyl, new technologies subject civilian populations to risks of catastrophic accidents, and the action of safety professionals comes under the spotlight. The analysis constructed permits new understandings of the past and the future of these professions.


Environmental justice, regulation, and the local community.

This article examines the sociological significance of the concept of "environmental justice" for grassroots groups responding to toxic contamination in their local communities. Taking into account nationwide mobilization patterns in such communities, the author documents a precedent-setting episode in the city of Jacksonville, Arkansas, where citizen protests and support from national environmental groups led the Environmental Protection Agency to withdraw three Technical Assistance Grants inappropriately awarded to a group with links to a polluting industry, and subsequently to rewrite the rules for participation in such grants. As the first such challenge nationally, the Jacksonville scenario is an important "test case" and permits a theoretical and practical evaluation of the relationship between social groups, technology, and the governmental regulatory process. More particularly, it gives insight into the Technical Assistance Grants program, which was set up to enable citizens living close to contaminated sites to interpret and evaluate technical information relating to such sites, but which has been undercut by a weak EPA and cooptation efforts by industries. The article concludes with an exploration of the concept of community in relation to the new construction of environmental justice engaged in by grassroots groups fighting contamination locally and nationally.