Noncoding RNAs implication in cardiovascular diseases in the COVID-19 era.

COronaVIrus Disease 19 (COVID-19) is caused by the infection of the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2). Although the main clinical manifestations of COVID-19 are respiratory, many patients also display acute myocardial injury and chronic damage to the cardiovascular system. Understanding both direct and indirect damage caused to the heart and the vascular system by SARS-CoV-2 infection is necessary to identify optimal clinical care strategies. The homeostasis of the cardiovascular system requires a tight regulation of the gene expression, which is controlled by multiple types of RNA molecules, including RNA encoding proteins (messenger RNAs) (mRNAs) and those lacking protein-coding potential, the noncoding-RNAs. In the last few years, dysregulation of noncoding-RNAs has emerged as a crucial component in the pathophysiology of virtually all cardiovascular diseases. Here we will discuss the potential role of noncoding RNAs in COVID-19 disease mechanisms and their possible use as biomarkers of clinical use.

Diagnostic and prognostic value of circulating microRNAs in patients with acute chest pain.

OBJECTIVES: To address the diagnostic value of circulating microRNAs (miRNAs) in patients presenting with acute chest pain. DESIGN: In a prospective, international, multicentre study, six miRNAs (miR-133a, miR-208b, miR-223, miR-320a, miR-451 and miR-499) were simultaneously measured in a blinded fashion in 1155 unselected patients presenting with acute chest pain to the emergency department. The final diagnosis was adjudicated by two independent cardiologists. The clinical follow-up period was 2 years. RESULTS: Acute myocardial infarction (AMI) was the adjudicated final diagnosis in 224 patients (19%). Levels of miR-208b, miR-499 and miR-320a were significantly higher in patients with AMI compared to those with other final diagnoses. MiR-208b provided the highest diagnostic accuracy for AMI (area under the receiver operating characteristic curve 0.76, 95% confidence interval 0.72-0.80). This diagnostic value was lower than that of the fourth-generation cardiac troponin T (cTnT; 0.84) or the high-sensitivity cTnT (hs-cTnT; 0.94; both P < 0.001 for comparison). None of the six miRNAs provided added diagnostic value when combined with cTnT or hs-cTnT (ns for the comparison of combinations vs. cTnT or hs-cTnT alone). During follow-up, 102 (9%) patients died. Levels of MiR-208b were higher in patients who died within 30 days, but the prognostic accuracy was low to moderate. None of the miRNAs predicted long-term mortality. CONCLUSION: The miRNAs investigated in this study do not seem to provide incremental diagnostic or prognostic value in patients presenting with suspected AMI.

Dissecting the transcriptome in cardiovascular disease.

The human transcriptome comprises a complex network of coding and non-coding RNAs implicated in a myriad of biological functions. Non-coding RNAs exhibit highly organized spatial and temporal expression patterns and are emerging as critical regulators of differentiation, homeostasis, and pathological states, including in the cardiovascular system. This review defines the current knowledge gaps, unmet methodological needs, and describes the challenges in dissecting and understanding the role and regulation of the non-coding transcriptome in cardiovascular disease. These challenges include poor annotation of the non-coding genome, determination of the cellular distribution of transcripts, assessment of the role of RNA processing and identification of cell-type specific changes in cardiovascular physiology and disease. We highlight similarities and differences in the hurdles associated with the analysis of the non-coding and protein-coding transcriptomes. In addition, we discuss how the lack of consensus and absence of standardized methods affect reproducibility of data. These shortcomings should be defeated in order to make significant scientific progress and foster the development of clinically applicable non-coding RNA-based therapeutic strategies to lessen the burden of cardiovascular disease.

[Pleural extramedullary hematopoiesis]. / La plèvre myéloïde.

INTRODUCTION: Agnogenic myeloid metaplasia, associated with myelofibrosis, is a myeloproliferative disorder. Extramedullary hematopoiesis in the pleura is rare and its prognosis is often severe. EXEGESIS: Herein we report a 64-year-old woman, who presented with pleural extramedullary hematopoiesis, treated by hydroxyurea-based chemotherapy with disease control. CONCLUSION: Clinical, histological, therapeutic and evolutive aspects of this uncommon entity will be reviewed.

Adenosine A1 receptor activation attenuates cardiac hypertrophy and fibrosis in response to α1 -adrenoceptor stimulation in vivo.

BACKGROUND AND PURPOSE: Adenosine has been proposed to exert anti-hypertrophic effects. However, the precise regulation and the role of the different adenosine receptor subtypes in the heart and their effects on hypertrophic signalling are largely unknown. We aimed to characterize expression and function of adenosine A1 receptors following hypertrophic stimulation in vitro and in vivo. EXPERIMENTAL APPROACH: Pro-hypertrophic stimuli and adenosine A1 receptor stimulation of neonatal rat cardiomyocytes and male C57/Bl6 mice, sc. drug administration, real-time PCR, (3) [H]-leucine-incorporation assay, immunostaining, tissue staining, Western blots, gravimetric analyses and echocardiography were applied in this study. KEY RESULTS: In neonatal rat cardiomyocyte cultures, phenylephrine, but not angiotensin II or insulin-like growth factor 1 (IGF1), up-regulated adenosine A1 receptors concentration-dependently. The hypertrophic phenotype (cardiomyocyte size, sarcomeric organization, total protein synthesis, c-fos expression) mediated by phenylephrine (10 µM), but not that by angiotensinII (1 µM) or IGF1 (20 ng·mL(-1) ), was counteracted by the selective A1 receptor agonist, N6-cyclopentyladenosine. In C57/BL6 mice, continuous N6-cyclopentyladenosine infusion (2 mg·kg(-1) ·day(-1) ; 21 days) blunted phenylephrine (120 mg·kg(-1) ·day(-1) ; 21 days) induced hypertrophy (heart weight, cardiomyocyte size and fetal genes), fibrosis, MMP 2 up-regulation and generation of oxidative stress - all hallmarks of maladaptive remodelling. Concurrently, phenylephrine administration increased expression of adenosine A1 receptors. CONCLUSIONS AND IMPLICATIONS: We have presented evidence for a negative feedback mechanism attenuating pathological myocardial hypertrophy following α1 -adrenoceptor stimulation. Our results suggest adenosine A1 receptors as potential targets for therapeutic strategies to prevent transition from compensated myocardial hypertrophy to decompensated heart failure due to chronic cardiac pressure overload.

Evidence of functional myocardial ischemia associated with myocardial dysfunction in brain-dead pigs.

BACKGROUND: Cardiac dysfunction after brain death has been documented, but its mechanisms remain unclear. Myocardial ischemia has been suggested as a possible cause. The aim of the present study was to investigate the existence of an imbalance between myocardial oxygen delivery and demand as a possible cause of myocardial dysfunction in brain-dead pigs. METHODS AND RESULTS: Interstitial myocardial lactate and adenosine concentrations were assessed with cardiac microdialysis in 2 groups of animals: brain-dead pigs (n=7) and brain-dead pigs treated with labetalol (10+/-3 mg/kg) (n=7). Heart rate (HR), left ventricular (LV) dP/dt(max), rate-pressure product (RPP), cardiac output (CO), and left anterior descending coronary artery blood flow (QLAD) were continuously monitored. Brain-dead pigs exhibited a transient significant increase in HR, LV dP/dt(max), RPP, and CO and a limited increase in QLAD. This resulted in functional myocardial ischemia attested to by the significantly increased adenosine and lactate microdialysate concentrations. In brain-dead pigs treated with labetalol, there was a moderate increase in HR, QLAD, and adenosine microdialysate concentrations; LV dP/dt(max), RPP, CO, and myocardial lactate concentrations remained stable, confirming the preservation of aerobic metabolism. CONCLUSIONS: Brain death was associated with an increase in myocardial interstitial adenosine and lactate concentrations, as well as with myocardial dysfunction; all were attenuated by labetalol, suggesting an imbalance between oxygen consumption and oxygen delivery as a possible cause of myocardial dysfunction after brain death.

Intensification of adjuvant chemotherapy: 5-year results of a randomized trial comparing conventional doxorubicin and cyclophosphamide with high-dose mitoxantrone and cyclophosphamide with filgrastim in operable breast cancer with 10 or more involved axillary nodes.

PURPOSE: To determine whether intensifying the dose of adjuvant chemotherapy improves the outcome of women with primary breast cancer and 10 or more involved axillary nodes. PATIENTS AND METHODS: Patients (n = 150) were randomized to receive either four cycles of standard doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks (arm A) or four courses of intensified mitoxantrone 23 mg/m(2) plus cyclophosphamide 600 mg/m(2), with filgrastim 5 g/kg/d from days 2 to 15, every 3 weeks (arm B). Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were determined using life-table estimates. RESULTS: There were no significant differences in DFS (P =.44), DDFS (P =.67), or OS (P =.99) between the two groups at 5 years; DDFS was 45% (arm A) versus 50% (arm B), and DFS was 41% versus 49%, respectively. Five-year survival was similar in both arms (61% v 60%, respectively). Failure to note an intergroup difference in outcome was unrelated to relative dose-intensity. Analysis of patients with 15 or more positive nodes revealed a significant difference in 5-year DDFS (19% v 49% in arm B; P =.01). Toxicity was generally mild in both groups, with no toxic death. The incidence of febrile neutropenia was low (0.3% v 3%). Alopecia was less frequent in arm B (P <.001). CONCLUSION: This randomized trial confirms the feasibility of administering mitoxantrone 23 mg/m(2) with cyclophosphamide and filgrastim. Although there was no significant difference between conventional and intensified arms at 5 years, according to subgroup analysis, intensified treatment may decrease the risk of relapse in patients with 15 or more positive nodes compared with doxorubicin an cyclophosphamide.

Bone marrow transplantation prolongs survival after relapse in aggressive-lymphoma patients treated with the LNH-84 regimen.

PURPOSE: Of the 737 patients with aggressive lymphoma who were treated with the LNH-84 regimen, 244 with progressive disease after complete remission or partial response were analyzed retrospectively to determine the influence of intensive chemotherapy with bone marrow transplantation (BMT) on survival. PATIENTS AND METHODS: Forty-four patients were treated with salvage chemotherapy, followed by autologous bone marrow transplantation (ABMT) in 40 and allogeneic BMT in four. The other 200 patients were treated with chemotherapy only. RESULTS: Salvage treatment produced an objective response in 57% of the patients; 23% achieved a second complete remission. Median overall survival was longer for patients who were treated with ABMT than for those who were treated with chemotherapy only (12.4 v 6.7 months), as was median freedom from progression (FFP) survival (7.7 v 4 months). In multiparametric analysis, ABMT and normal initial lactic dehydrogenase (LDH) level were the primary parameters associated with longer survival. This is also true when (1) only patients younger than 60 years of age, (2) only patients who responded to salvage regimen, or (3) only patients with both conditions were included in the analysis. Patients who were not transplanted had a 1.69 to 2.26 relative risk of dying from their disease compared with those who were treated with intensive chemotherapy plus ABMT. CONCLUSION: This study produced more evidence of the favorable impact of intensive chemotherapy with bone marrow rescue on survival in lymphoma patients who had relapsed.

Continuous-infusion daunorubicin and carboplatin for high-risk acute myeloid leukemia in the elderly.

Since continuous infusion of daunorubicin and of carboplatin have shown efficacy and reduced toxicity in early phase studies in acute myeloid leukemia (AML), 34 elderly patients with high-risk AML were treated with continuous infusion daunorubicin, 30 mg/m2 per day, from day 1 to day 4, and carboplatin, 200 mg/m2 per day from day 3 to day 7. Seven patients had therapy-related AML and/or AML following a myelodysplastic syndrome at diagnosis, 15 were in first and two in second relapse, and 10 were resistant to previous anthracycline and cytarabine therapy. Nine patients or 26%, with a 95% confidence interval (CI) ranging from 18-67%, achieved complete remission, including one patient at diagnosis (14%, CI: 0-58%), seven with relapsed AML (41%, CI: 18-67%), and one with resistant AML (10%, CI: 0-45%). Median durations of neutropenia below 0.5 x 10(9)/l and of thrombocytopenia below 20 x 10(9)/l were 24 and 20 days respectively. Severe toxicity included infections in 20 patients (59%), bleeding in two (6%), cardiac anomalies in two (6%), and vomiting in one (3%). Overall four patients (12%) died from chemotherapy related toxicity and 21 (62%) had resistant disease. Median overall survival was 4 months and median disease-free survival 8 months. We conclude that this regimen had efficacy with reduced toxicity in relapsed patients. Higher dosages for the same drugs could be tolerated by better risk patients for precise evaluation of cross reactivity with cytarabine-based regimens.

Pefloxacin and vancomycin vs. gentamicin, colistin sulphate and vancomycin for prevention of infections in granulocytopenic patients: a randomised double-blind study.

To test the value of pefloxacin for the prevention of infections in patients with chemotherapy-induced neutropenia, oral pefloxacin plus vancomycin (PV) (n = 76) or gentamicin, colistin sulphate and vancomycin (GCV) (n = 74) were administered in a randomised double-blind study. Infections were significantly less severe in the PV than in the GCV group. Patients receiving PV had significantly fewer episodes of bacteraemia and central venous line infections than patients treated with GCV. Gram-positive and gram-negative infections were significantly less frequent in patients receiving PV, because of fewer infections with Staphylococcus species and enterobacteriaceae. Stool culture detected significantly more gram-positive organisms in the PV group and more gram-negative organisms in the GCV group. Thus, PV was more efficacious than GCV for the prevention of gram-positive and gram-negative infections in the neutropenic patients, despite lower efficacy in eradicating gram-positive organisms from the lower intestinal tract.

Increase in myocardial interstitial adenosine and net lactate production in brain-dead pigs: an in vivo microdialysis study.

BACKGROUND: Brain death-related cardiovascular dysfunction has been documented; however, its mechanisms remain poorly understood. We investigated changes in myocardial function and metabolism in brain-dead and control pigs. METHODS: Heart rate, systolic (SAP) and mean (MAP) arterial pressure, left ventricular (LV) dP/dtmax, rate-pressure product, cardiac output (CO), left anterior descending coronary artery blood flow, lactate metabolism, and interstitial myocardial purine metabolite concentrations, monitored by cardiac microdialysis, were studied. A volume expansion protocol was performed at the end of the study. RESULTS: After brain death, a transient increase in heart rate (from 90 [67-120] to 158 [120-200] beats/min) (median, with range in brackets), MAP (82 [74-103] to 117 [85-142] mmHg), LV dP/dtmax (1750 [1100-2100] to 5150 [4000-62,000] mmHg x sec(-1), rate-pressure product (9100 [7700-9700] beats mmHg/min to 22,750 [20,000-26,000] beats mmHg/min), CO (2.2 [2.0-4.0] to 3.3 [3.0-6.0] L/min), and a limited increase in left anterior descending coronary artery blood flow (40 [30-60] to 72 [50-85] ml/min) were observed. Net myocardial lactate production occurred (27 [4-40] to -22 [-28, -11] mg/L, P<0.05) and persisted for 2 hr. A 6-7-fold increase in adenosine dialysate concentration was observed after brain death induction (2.9 [1.0-5.8] to 15.8 [7.0-50.7] micromol/L), followed by a slow decline. Volume expansion significantly increased MAP, CO, and LV dP/dtmax in control animals, but decreased LV dP/dtmax and slightly increased CO in brain-dead animals. A significant increase in adenosine concentration was observed in both groups, with higher levels (P<0.05) in brain-dead animals. CONCLUSIONS: Brain death increased oxygen demand in the presence of a limited increase in coronary blood flow, resulting in net myocardial lactate production and increased interstitial adenosine concentration consistent with an imbalance between myocardial oxygen demand and supply. This may have contributed to the early impairment of cardiac function in brain-dead animals revealed by rapid volume infusion.

Premenopausal patients with node-positive resectable breast cancer. Preliminary results of a randomised trial comparing 3 adjuvant regimens: FEC 50 x 6 cycles vs FEC 50 x 3 cycles vs FEC 75 x 3 cycles. The French Adjuvant Study Group.

Anthracyclines are among the most active drugs for the treatment of advanced breast cancer. Epirubicin has been found to be as effective as doxorubicin at equimolar doses but significantly better tolerated, especially in terms of alopecia, leucopenia, and cardiac toxicity. The role of anthracycline-containing regimens in adjuvant treatment of breast cancer has been studied by only a few clinical trial teams. In 1986, the French Adjuvant Study Group (FASG) began a randomised trial aimed to investigate the concept of dose intensity as well as the optimal duration of treatment in patients with early breast cancer. Between 1986 and 1990, 621 patients were included in the trial, of whom 595 were evaluable. Patients were randomised to 1 of 3 treatment groups: Group A (n = 207) received FEC 50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2 plus cyclophosphamide 500 mg/m2) every 21 days for 6 cycles; Group B (n = 193) received FEC 50 every 21 days for 3 cycles; Group C (n = 195) received FEC 75 (fluorouracil 500 mg/m2, epirubicin 75 mg/m2 plus cyclophosphamide 500 mg/m2) every 21 days for 3 cycles. Locoregional radiotherapy was administered after the third cycle of chemotherapy in all treatment arms. Clinical prognostic factors were similar between treatment groups. Approximately 62% of all patients had 1 to 3 positive lymph nodes; 50% of patients were hormone receptor positive and 73% were Scarff-Bloom Richardson (SBR) grade 2 to 3. Toxicity was evaluated in 595 patients (207, 193 and 195 patients in Groups A, B and C, respectively), who received a total of 2301 chemotherapy cycles.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclophosphamide/mitoxantrone/melphalan (CMA) regimen prior to autologous bone marrow transplantation (ABMT) in metastatic breast cancer.

Dose-intensive treatment followed by ABMT is currently used in different approaches to treat breast cancer patients. An active non cross-resistant regimen combining cyclophosphamide (C), mitoxantrone (M) and melphalan (A) (CMA), was developed as the conditioning regimen before ABMT. The purpose of this phase II study was to evaluate this protocol and the duration of its effect in metastatic patients, who responded to chemotherapy. Criteria for inclusion included histologically documented breast cancer, age < 55 years and the first detection of measurable metastatic lesions. Following first-line chemotherapy in responding patients, histologically negative bone marrow was collected and cryopreserved. Then, intensification with cyclophosphamide (120 mg/kg), mitoxantrone (60 mg/m2), and melphalan (140 mg/m2) was followed by ABMT. Sixty-one metastatic breast cancer patients with a mean age of 40 years were included. Sites of measurable metastases included: liver 24, lung 14, central nervous system four, pleura three, skin six, and chest wall six, nodes eight and bone marrow one. Nineteen patients had lesions in two or more sites, and 22 had bone involvement. The response of 60 patients could be evaluated: before ABMT 31 were in clinical complete response (CR), 22 in partial response > 50% (PR), and seven had new progression. After ABMT, 36 patients were in CR, 16 in PR, one progressed and one was stable. Seven (11.5%) toxic deaths occurred. Mean time for hematological recovery was 32.5 days, without hematopoietic growth factors. Median survival was 33 +/- 9.4 months from the start of therapy, and 25.7 +/- 4.6 months from the date of ABMT. Median event-free survival was 20 months from the start of therapy, and 13 +/- 2 months from ABMT. With a median follow-up of 51 months, probability of actuarial survival, measured from the beginning of initial chemotherapy, was 36%, and event-free survival was 18%. In metastatic breast cancer responding to chemotherapy, high-dose consolidation with CMA and ABMT resulted in a median survival of 33 months. These results lay the ground work for evaluation in a randomized trial in metastatic breast cancer.

Heterogeneity of neoplastic and reactive cell proliferation in non-Hodgkin's lymphomas linked to patient survival.

This study was undertaken to determine the characteristics of the proliferation of malignant and reactive cells in non-Hodgkin's lymphoma (NHL). Cell kinetics were studied in 76 previously untreated cases of NHL by flow cytometry after a double labeling of membrane antigen and DNA. Results were analyzed according to clinical and biologic characteristics of the patients. In B-cell NHL, percentages of B and T cells in S-phase were strongly linked (r = .82). The level of proliferation of malignant B cells and reactive T cells was significantly higher in aggressive lymphomas, compared with low grade, diffuse small cleaved cell NHL or reactive lymph nodes (P < .001). The percentages of malignant B cells in S-phase were lower when reactive T cells were more numerous (n = 59, r = -.264, P < .05), particularly in high-grade NHL (n = 16, r = -.78, P < .001). In the whole population of patients, survival was longer when the percentage of cells in S-phase (n1 = 38, n2 = 33) or S+G2 + mitosis (M) (n1 = 36, n2 = 35) was less than 3.2% and 7.25%, respectively (P < .005). When considering only B-cell NHL, survival was longer when the percentage of B cells in S-phase was less than 4.5% (n1 = 31, n2 = 28, P < .04). Among the slowly proliferative groups of lymphomas, this prognostic value was retained when S-phase value was less than 1% (n1 = 16, n2 = 13, P < .002). Furthermore, prognosis was better when the percentage of T cells in S-phase was less than 2.75% (n1 = 30, n2 = 29, P < .01) or when reactive CD4-positive T cells were more than 14.5% (n1 = 24, n2 = 24, P < .04). This result remained true in the group of highly proliferative lymphomas. These results illustrate the complexity of the interactions between malignant and reactive cells in NHL, with possible opposite effects on tumor cell growth.

Association of t(15;17) and t(8;21) in the initial phase of an acute promyelocytic leukemia.

Two clones were observed at the initial phase of an acute myelogenous leukemia (AML): 46,XX,t(15;17) and 46,XX,t(8;21),t(15;17). Clinical, immunologic, and morphologic findings were in favor of expression of both chromosomal anomalies. Relapse occurred after 12 months of complete remission with typical acute promyelocytic leukemia (APL) syndrome when t(15;17) alone was then most predominant.

Phase II trial of plicamycin and hydroxyurea in acute myelogenous leukemia.

A total of 23 patients with high-risk acute myelogenous leukemia (AML) at diagnosis (2 patients), relapsing AML (14) or resistant AML (6) were treated with 25 micrograms/kg i.v. plicamycin every other day for 3 weeks and 500-4,000 mg hydroxyurea per day p. o. according to the WBC count. Aplasia was observed in only two patients. Severe extrahematologic toxicity included sepsis (four cases), vomiting (four patients), toxic hepatitis (three cases), and fibrinopenia (one patient). No partial or complete responses were observed. The 95% confidence interval limit of the overall response rate (CR + PR) was 0-14%.

Biological response of human aortic endothelial cells exposed to acellular hemoglobin solutions developed as potential blood substitutes.

The cardiovascular effects of hemoglobin-based oxygen carriers (HBOCs) are mainly related to their nitric oxide (NO) scavenging properties but other effects such as the impact of these hemoglobins on the endothelial cell (EC) biology are not well understood. We hypothesized that HBOCs could modify EC functions by altering gene expression, in particular the endothelial NO synthase (NOS3) and/or by activating EC. Cultured human aortic endothelial cells (HAEC) were incubated for 3 hours with purified cell-free Hb, Dex-BTC-Hb or alpha alpha-Hb (16 g/L). Expression of NOS3 mRNA and protein were assessed by semi-quantitative RT-PCR and Western blot respectively immediately after and 24 hours after incubation. The expression and localization of the adhesion molecule ICAM-1 were detected by fluorescence microscopy. None of the solutions tested modified NOS3 mRNA and protein expression despite adequate controls that up- or down-regulate NOS3 expression. The expression and the localization of ICAM-1 on the cell membrane were modified after 3 hours of incubation with all the hemoglobin solutions tested in a manner similar to tumor necrosis factor-alpha. In conclusion, HAEC incubation with clinically relevant concentrations of HBOCs induced changes in the pattern of ICAM-1 expression consistent with cell activation/cell signaling mechanisms. However, HBOCs did not alter NOS3 gene expression.

[Prognostic factors of survival in infiltrating urothelial bladder carcinoma. A retrospective study of 158 patients treated by radical cystectomy]. / Facteurs pronostiques de survie dans les carcinomes urothéliaux infiltrants de vessie. Etude rétrospective de 158 cas traités par cystectomie radicale.

The clinical files of 158 patients who were treated by radical cystectomy for infiltrating bladder carcinoma were retrospectively reviewed to define prognostic factors. PATIENTS AND METHODS.--All patients had a radical cystectomy with bilateral pelvic lymph node dissection for an infiltrating operable bladder urothelial tumor. Each tumor was classified according the pTNM staging system and were analysed for the presence of vascular invasion, carcinoma in situ and tumor grade. Twenty-three patients (14.5%) had an irradiation. Sixty-seven patients (42%) received chemotherapy (neoadjuvant in 31, adjuvant in 30, both in 6). RESULTS.--The median overall survival of the whole group was 19 months. The 5 years disease free survival (DFS) and overall survival (OS) were 44% and 31%, respectively. In the univariate analysis, the factors with significant prognostic value were: pT stage and the tumor size for OS, age and lymph node involvement for DFS, presence of carcinoma in situ (CIS) and tumor size for local recurrence free survival (LRFS) and sex and lymph node involvement for metastatic free survival (MFS). The following variables attained significant prognostic value in the multivariate analysis: pT stage and an interaction between lymph node involvement and vascular invasion for OS, pT stage and presence of CIS for LRFS, pT stage for MFS. CONCLUSION.--The pT stage, lymph node involvement and vascular invasion are the most important prognostic factors of survival in infiltrating bladder cancer.

Consequences of labetalol administration on myocardial beta adrenergic receptors in the brain dead pig.

OBJECTIVES: Cardiac dysfunction following brain death is associated with highly increased myocardial norepinephrine, lactate and adenosine concentrations. Administration of labetalol, a mixed alpha-, beta-adrenergic receptor antagonist, attenuates metabolic disturbances and improves myocardial function. The purpose of this study was to investigate beta-adrenergic receptor (beta AR) density and affinity in the presence or absence of labetalol administration, as a possible mechanism of the protective effects of this drug. METHODS: Experimental animals were divided into three groups: sham-operated, brain-dead pigs, and brain-dead pigs treated with labetalol (10 +/- 3 mg/kg). The maximum number of binding sites (Bmax) and the dissociation constant (Kd) of beta AR were determined with (-)-[125I]cyanopindolol on myocardial samples harvested 3 hours after brain death. RESULTS: Left ventricular beta AR density and affinity were identical in brain-dead and sham-operated animals. Labetalol-treated pigs exhibited a significant decrease of Bmax and an increase of Kd as compared with brain-dead pigs. Bmax decrease was due to the persistence of labetalol in the membrane preparations. Increased Kd was too low to be biologically significant. Therefore, beta AR number and affinity can be considered as unchanged after adrenergic blockade with labetalol. CONCLUSIONS: The protective mechanism of labetalol on brain death-induced myocardial dysfunction cannot be explained by changes in beta AR density and affinity but is probably related to a preservation of the oxygen consumption/oxygen delivery balance during the autonomic storm.

[Cerebral aspergillosis in immunocompromised patients]. / Aspergillose cérébrale chez l'immunodéprimé.

Three cases of central nervous system (CNS) aspergillosis in immunocompromised patients are reported. All three had neurological symptoms with normal cerebrospinal fluid (CSF). The CT scan showed poorly defined low density lesions which were not enhanced by contrast medium. They also had pulmonary signs and fever despite antibiotic treatment. Aspergillus fumigatus was isolated from bronchoalveolar lavage fluid. Antifungal therapy was started promptly, associating amphotericin B, itraconazole and flucytosine. Unfortunately, they died within 2 days to 2 weeks after admission in the intensive care unit. Postmortem examinations revealed disseminated aspergillosis with colonization of brain, lung, heart and kidney. The CT scan signs were quite different from those seen with the more usual bacterial ring lesions. In immunocompromised patients, the agents responsible for producing these findings are Aspergillus, Nocardia, Cryptococcus, Toxoplasma and Mycobacterium tuberculosis. Signs involving organs other than the CNS, and an examination of the CSF, should provide elements for establishing a differential diagnosis. Early antifungal treatment is the only chance of survival. Recrudescent fever and pulmonary signs occurring in neutropenic patients after antibacterial antibiotic treatment has been started are sufficient criteria for empirically starting amphotericin B administration unless clinical judgement dictates otherwise.