Fetal haemopoiesis marking low-grade urinary bladder cancer.

BACKGROUND: The immunohistochemical features of fetal haemoglobin cells and their distribution patterns in solid tumours, such as colorectal cancer and blastomas, suggest that fetal haemopoiesis may take place in these tumour tissues. These locally highly concentrated fetal haemoglobin (HbF) cells may promote tumour growth by providing a more efficient oxygen supply. METHODS AND RESULTS: Biomarkers of HbF were checked in transitional cell carcinoma (TCC) of the urinary bladder, assessing this as a new parameter for disease management. Fetal haemoglobin was immunohistochemically examined in tumours from 60 patients with TCC of the bladder. Fetal haemoglobin erythrocytes and erythroblasts were mainly clonally distributed in proliferating blood vessels and not mixed with normal haemoglobin erythrocytes. The proportion of such HbF blood vessels could reach more than half of the total number of vessels. There were often many HbF erythroblasts distributed in one-cell or two-cell capillaries and present as 5-15% of cells in multi-cell vessels. This suggests a local proliferation of HbF-cell progenitors. Fetal haemoglobin cells were prominently marking lower grades of tumours, as 76% (n=21) of the patients with G1pTa were HbF+, whereas only 6.7% (n=30) of the patients with G3pT1-pT2a were HbF+. CONCLUSION: Our results suggest that HbF, besides being a potential new marker for early tumour detection, might be an essential factor of early tumour development, as in fetal life. Inhibiting HbF upregulation may provide a therapeutic target for the inhibition of tumour growth.

A potential role of fetal hemoglobin in the development of multidrug resistance.

Our previous data from a human leukemic cell line made resistant to the nucleoside analog (NA) 9-ß-D-arabinofuranosylguanine (AraG) revealed a massive upregulation of fetal hemoglobin (HbF) genes and the ABCB1 gene coding for the multidrug resistance P-glycoprotein (P-gp). The expression of these genes is regulated through the same mechanisms, with activation of the p38-MAPK pathway and inhibition of methylation making transcription factors more accessible to activate these genes. We could show that AraG, as well as other NAs, and P-gp substrates could induce global DNA demethylation and induction of Hbγ and P-gp both at the mRNA and protein expression level. We speculate that the expression of HbF prior to drug exposure or in drug-resistant cell lines is a strategy of the cancer to gain more oxygen, and thereby survival benefits. We also believe that P-gp may be induced in order to excrete Hb degradation products from the cells that would otherwise be toxic. By using Hbγ siRNA and pharmacological inhibitors of HbF production we here present a possible relationship between HbF induction and multi-drug resistance in a human leukemia cell line model.

Estimation of Vmax in auxotonic systoles from the rate of relative increase of isovolumic pressure: (dP-dt)kP.

High speed oscilloscopic recordings (4000 mm/sec) of left ventricular pressure (micromanometer) and its first derivative were used to calculate contractile element velocity (Vce) during the isovolumic period of auxotonic beats in anesthetized dogs. At 0.5-2.0 msec intervals of isovolumic systole, Vce was derived as (dP/dt)/kP, where k = 24 cm(-1). Plots of Vce and P yielded inverse curves from peak Vce to aortic valve opening pressure which averaged 27 msec in controls, and 11 msec during norepinephrine administration. Extrapolated Vmax, in muscle lengths/second, averaged 3.6 (controls), 3.6 (volume load), and 6.6 (norepinephrine). In each experimental state, Vmax was also determined from force-velocity relations of isovolumic beats (abrupt aortic occlusion) analyzed at 10 msec intervals from conventional pressure recordings. Vmax by both methods correlated well (r = 0.88). While good correlations were also noted between Vmax and maximum dP/dt, (max dP/dt)/integrated isovolumic pressure, (max dP/dt)/peak isovolumic pressure, and (max dP/dt)/kP, only the last two of these successfully distinguished changes between volume load and inotropic stimulation. Thus, assuming an unchanged series elasticity, the contractile state of the auxotonic ventricle may be determined utilizing a single high-fidelity catheter system and high speed recordings of isovolumic pressure.

Tension prolongation during recovery from myocardial hypoxia.

The mechanical behavior of isolated cat, rat, and dog ventricular muscle was examined during hypoxia and after reoxygenation. During hypoxia, an early abbreviation of tension duration was followed by a decline in the rate of tension development. After reoxygenation, a marked, early prolongation of tension development and relaxation time was invariably observed with little, if any, increase in peak tension. As recovery progressed, the duration of contraction gradually shortened as tension returned to control levels. This phenomenon was also observed in the intact dog heart after release of a coronary artery ligature. Isometric tension gauges sewn to ischemic portions of the left ventricle demonstrated that after reinstitution of coronary flow, segment tension duration "outlasts" the duration of left ventricular pressure development and is associated with ventricular irritability. Epicardial electrograms showed shortening of the QT interval within the ischemic segment with prolongation of the QT interval after release of the coronary ligature. Prolongation of tension development during recovery from hypoxia was not observed in experiments with rat skeletal muscle. These observations identify localized mechanical abnormalities during recovery from myocardial ischemia which may be important in the syndrome of acute coronary heart disease.

Development of fetal haemoglobin-blood cells (F cells) within colorectal tumour tissues.

AIM: To evaluate the sources of fetal haemoglobin (HbF) as an indicator in cancer. An immunohistochemical study was carried out on some of the most common kinds of cancer. All of these cancers had serologically high levels of HbF as evaluated previously. METHODS: Immunoaffinity-purified anti-HbF was immunohistochemically used to study F cell distribution in the following cancers: colorectal adenocarcinoma, urinary bladder transitional cell carcinoma, brain tumours, lung carcinoma, breast adenocarcinoma, leukaemia, Burkitt's lymphoma and endometrial carcinoma. RESULTS: In colorectal adenocarcinoma, HbF-containing red blood cells (FRBC) were present within thin-walled vessels or were disposed in dense clusters within the tumour. Some of these cells were nucleated or binucleated HbF-erythroblasts or HbF-normoblasts (FNBS). In two cases, high levels of mitoses within HbF-erythroblasts were observed. In half of the cases with transitional cell carcinoma of the urinary bladder, regional intratumoral blood vessels were found to contain 5-50% FRBC. In the other tumours examined, F cells were not observed. FRBCs, however, were occasionally observed in the regional lymph nodes of some of these cancers. CONCLUSIONS: The evaluation of HbF as a potential plasma marker is suggested by the high concentration of FRBCs in colorectal tumours. The apparent development of FRBCs in colorectal tumour tissues is an interesting observation, as these cells were previously thought to develop in medullary or lymphoid tissues. It is thus suggested that the colonic microenvironment may stimulate extramedullary fetal-type haematopoiesis.

Effect of managed care on cardiovascular specialists: involvement, attitudes and practice adaptations.

OBJECTIVES: This study was undertaken to determine the extent to which cardiovascular specialists are involved with and affected by managed care and to ascertain their attitudes toward it. This survey also served as the follow-up to an initial study on the subject performed by the American College of Cardiology in 1993. BACKGROUND: The initial 1993 study was performed to address the lack of any comprehensive examination of the impact of managed care on cardiovascular specialists. In 1995, to reexplore this question and follow up the 1993 findings, the College conducted a survey of its membership in the following areas: 1) physician relationship with managed care plans; 2) number of managed care contracts; 3) breakdown of revenue by payment source; 4) changes in practice in response to managed care; and 5) physician attitudes toward managed care. To the extent feasible, the 1995 questionnaire paralleled the 1993 instrument to facilitate comparisons. METHODS: A questionnaire was mailed to 5,147 practicing College members in the United States, who were categorized by specialty as pediatric cardiologists, adult cardiologists or cardiovascular surgeons. Mailings were sent to 1) all pediatric cardiologists and cardiovascular surgeons; 2) randomly selected adult cardiologists practicing in 10 states with high managed care penetration; and 3) randomly selected adult cardiologists in the nine U.S. census areas who were not practicing in the 10 states with high managed care penetration. RESULTS: Usable surveys were returned by 1,236 respondents, for an overall response rate of 24%. Involvement with at least one type of managed care organization was reported by 89% of respondents, up from 76% in 1993. Although managed care relationships had increased across physician age, region, practice and specialty, respondents indicated that, on average, well below 50% of their practice revenues stem from managed care contracts. To adapt to the managed care environment, strategic practice changes, such as joining a cardiovascular network, implementing continuous quality improvement systems and adopting clinical pathways, were being instituted by most respondent practices of nine or more physicians. Smaller groups were less active. Most respondents involved with managed care disliked its effects, particularly in clinical matters. Their attitudes toward the assumption of risk, managed fee-for-service arrangements and a private versus single-payer system show that there is no uniformity of opinion regarding the best means to contain costs and promote efficiency. CONCLUSIONS: Managed care has become an established part of cardiovascular specialist practice in the United States. Although this trend is viewed with some disfavor, most respondents are making practice changes to adapt to this new environment.

Blood cells with fetal haemoglobin (F-cells) detected by immunohistochemistry as indicators of solid tumours.

AIMS: Fetal hemoglobin (HbF) is an established serological indicator of cancer. However, its distribution in tumour tissues is rarely investigated. Therefore, HbF was studied immunohistologically in different cancers characterised by high blood HbF concentrations. METHODS: Anti-HbF was immunoaffinity purified and used to study HbF immunohistochemically in the following cancers: germ cell tumour (GCT), trophoblastic disease (TD), lymphoma, myelodysplastic syndrome (MDS), multiple myeloma (MM), and ovarian adenocarcinoma (OA). RESULTS: In GCT a distinction was made between tumours substantially without HbF positive red blood cells (F-RBC) and those with F-RBC. Those without F-RBC were non-metastatic mature teratomas and dermoid cysts. Those containing F-RBC were mainly embryonal carcinomas and metastatic teratomas. HbF positive myeloid cells (F-MLC), HbF positive normoblasts (F-NBS), and F-RBC were common in the bone marrow and in the lymphoid tissues of lymphoma, MDS, and MM. In TD, normal and nucleated F-RBC were seen in the trophoblastic villi in one case with incomplete molar pregnancy (ICM) but not in other cases of ICM and complete molar pregnancy. However, F-RBC and F-MLC were seen in the decidua of both types of TD. Generally, F-cells were observed either within blood vessels or concentrated in certain areas of the neoplastic tissue. CONCLUSIONS: HbF was evaluated as an inducible marker within different tumour tissue blood cells. The dual distribution of these cells-circulating in the blood or concentrated in areas of the neoplastic tissues-might reflect the two independent serological indicators of HbF: one in whole blood and the other in plasma of patients with cancer.

Improved haemagglutination reagent for detecting antibodies to insulin in diabetic and non-diabetic young and old patients.

A stable reagent of insulin-coated erythrocytes was developed for easy measurement of antibodies to insulin. For this measurement, the principle of graded haemagglutination (GH) was successfully applied. All of 100 healthy, young- to middle-aged controls, had no detectable antibodies. The incidence of antibodies was not higher in diabetic patients injected with highly purified porcine insulin, than in those not injected. A high incidence of antibodies to insulin was found among chronic elderly patients, amounting to 41% of the symptomatically non-diabetic and 77% of the diabetic.

Mood and the use of scripts: does a happy mood really lead to mindlessness?

The authors tested whether happy moods increase, and sad moods decrease, reliance on general knowledge structures. Participants in happy, neutral, or sad moods listened to a "going-out-for-dinner" story. Happy participants made more intrusion errors in recognition than did sad participants, with neutral mood participants falling in between (Experiments 1 and 2). Happy participants outperformed sad ones when they performed a secondary task while listening to the story (Experiment 2), but only when the amount of script-inconsistent information was small (Experiment 3). This pattern of findings indicates higher reliance on general knowledge structures under happy rather than sad moods. It is incompatible with the assumption that happy moods decrease either cognitive capacity or processing motivation in general, which would predict impaired secondary-task performance.

[A thermostable toxin-producing E. coli and infantile diarrhea].

An E. coli strain producing only a thermostable toxin (ST) and belonging to serogroup 0153 (ETEC 0153; ST) was isolated from the stools of 9 infants with diarrhea, 4 of them premature, during the last half of August, 1988. All the 4 prematures passed frequent fluid stools. In 5 of the 9 infants, other pathogens were found in addition to the ETEC strain, including rotavirus, Plesiomonas and Shigella sonnei. Until recently, ETEC strains like that described were considered rare all over the world. During the past 2 years ETEC strains belonging to that serogroup and toxin type were reported as a major cause for infantile diarrhea in Spain in 5 outbreaks. Infantile diarrhea caused by an ETEC strain in Israel is reported here for the first time.

[Multiresistant Escherichia coli from elderly patients].

We examined all ceftriaxone-resistant Escherichia coli isolates obtained from clinical samples during 16 months (1 Dec. '97-31 Mar. '99). A total of 97 resistant isolates from 36 patients were obtained, mostly from urine specimens. Of these patients, 35/36 were over 75 years old, most lived in nursing homes, were dependent on nursing in their daily lives, and were incontinent and/or had indwelling catheters. All 97 isolates had similar susceptibility profiles: resistant to ciprofloxacin, gentamicin, ampicillin, amoxycillin/clavulanate, tricarcillin/clavulanate, aztreonam, and cefuroxime; decreased susceptibility to ceftazidime and cefepime; and susceptible to imipenem and meropenem. Double-disc tests indicated that all strains produced extended spectrum beta-lactamase(s). All the isolates belonged to 1 of 3 E. coli serotypes: 79 were 0153:H31, 13 were 0142:H10, and 5 were 0102:H6.