Metástasis Cutánea en paciente con Adenocarcinoma de Ovario / Cutaneous Metastasis in a patient with Ovarian Adenocarcinoma

RESUMEN Las metástasis cutáneas (MC) constituyen una manifestación infrecuente de neoplasias internas. Su diagnóstico requiere un alto índice de sospecha clínica, pues los hallazgos pueden ser sutiles. Estas ponen de manifiesto la presencia de un tumor maligno diseminado y pueden permitir el diagnóstico de neoplasias internas no conocidas, o indicar la diseminación o recurrencia de otras ya diagnosticadas. La MC del carcinoma de ovario suele aparecer en enfermedad avanzada e indican un mal pronóstico.Su reconocimiento temprano puede llevar a un diagnóstico preciso y rápido, con el consiguiente tratamiento oportuno, aunque en la mayoría de los casos son indicativas de un pronóstico infausto.

SUMMARY Cutaneous metastases are an infrequent manifestation of internal neoplasms. Its diagnosis requires a high index of clinical suspicion, since the findings can be subtle. These reveal the presence of a disseminated malignant tumor and can allow the diagnosis of unknown internal neoplasms, or indicate the dissemination or recurrence of others already diagnosed. MC of ovarian carcinoma usually appears in advanced disease and may indicate a poor prognosis. Early recovery can carry out an accurate and rapid diagnosis, with timely emergency treatment, although in most cases they are indicators of an unfortunate prognosis.

Feasibility of allogeneic stem-cell transplantation after azacitidine bridge in higher-risk myelodysplastic syndromes and low blast count acute myeloid leukemia: results of the BMT-AZA prospective study.

BACKGROUND: Allogeneic stem-cell transplantation (HSCT) is the only curative treatment in myelodysplastic syndromes (MDS). Azacitidine (AZA) is increasingly used prior to HSCT, however in Europe it is only approved for patients who are not eligible for HSCT. PATIENTS AND METHODS: We conducted a phase II multicenter study to prospectively evaluate the feasibility of HSCT after treatment with AZA in 70 patients with a myelodysplastic syndrome (MDS), 19 with acute myeloid leukemia (AML), and 8 with chronic myelomonocytic leukemia (CMML). After a median of four cycles (range 1-11): 24% of patients achieved complete remission, 14% partial remission, 8% hematologic improvement, 32% had stable and 22% progressive disease. Ten patients discontinued treatment before the planned four cycles, due to an adverse event in nine cases. RESULTS: A HSC donor was identified in 73 patients, and HSCT was performed in 54 patients (74% of patients with a donor). Main reasons for turning down HSCT were lack of a donor, an adverse event, or progressive disease (9, 12, and 16 patients, respectively). At a median follow-up of 20.5 months from enrolment, response to AZA was the only independent prognostic factor for survival. Compared to baseline assessment, AZA treatment did not affect patients' comorbidities at HSCT: the HCT-CI remained stable in 62% patients, and worsened or improved in 23% and 15% of patients, respectively. CONCLUSIONS: Our study shows that HSCT is feasible in the majority of patients with HR-MDS/AML/CMML-2 after AZA treatment. As matched unrelated donor was the most frequent source of donor cells, the time between diagnosis and HSCT needed for donor search could be 'bridged' using azacitidine. These data show that AZA prior to HSCT could be a better option than intensive chemotherapy in higher-risk MDS. The trial has been registered with the EudraCT number 2010-019673-1.

Decision analysis of allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome stratified according to the revised International Prognostic Scoring System.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Crucial questions in clinical decision-making include the definition of optimal timing of the procedure and the benefit of cytoreduction before transplant in high-risk patients. We carried out a decision analysis on 1728 MDS who received supportive care, transplantation or hypomethylating agents (HMAs). Risk assessment was based on the revised International Prognostic Scoring System (IPSS-R). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of different treatment policies on survival. Life expectancy increased when transplantation was delayed from the initial stages to intermediate IPSS-R risk (gain-of-life expectancy 5.3, 4.7 and 2.8 years for patients aged ⩽55, 60 and 65 years, respectively), and then decreased for higher risks. Modeling decision analysis on IPSS-R versus original IPSS changed transplantation policy in 29% of patients, resulting in a 2-year gain in life expectancy. In advanced stages, HMAs given before transplant is associated with a 2-year gain-of-life expectancy, especially in older patients. These results provide a preliminary evidence to maximize the effectiveness of allo-SCT in MDS.

Stage of change and motivation to healthy diet and habitual physical activity in type 2 diabetes.

Lifestyle changes to healthy diet (HD) and habitual physical activity (HPA) are recommended in type 2 diabetes mellitus (T2DM). Yet, for most people with diabetes, it may be difficult to start changing. We investigated the stage of change toward healthier lifestyles according to Prochaska's model, and the associated psychological factors in T2DM patients, as a prerequisite to improve strategies to implement behavior changes in the population. A total of 1,353 consecutive outpatients with T2DM attending 14 tertiary centers for diabetes treatment completed the validated EMME-3 questionnaire, consisting of two parallel sets of instruments to define the stage of change for HD and HPA, respectively. Logistic regression was used to determine the factors associated with stages that may hinder behavioral changes. A stage of change favoring progress to healthier behaviors was more common in the area of HD than in HPA, with higher scores in action and maintenance. Differences were observed in relation to gender, age and duration of disease. After adjustment for confounders, resistance to change toward HD was associated with higher body mass index (BMI) (odds ratio (OR) 1.05; 95 % confidence interval (CI) 1.02-1.08). Resistance to improve HPA also increased with BMI (OR 1.06; 95 % CI 1.03-1.10) and decreased with education level (OR 0.74; 95 % CI 0.64-0.92). Changing lifestyle, particularly in the area of HPA, is not perceived as an essential part of treatment by many subjects with T2DM. This evidence must be considered when planning behavioral programs, and specific interventions are needed to promote adherence to HPA.

Urease and Helicobacter spp. antigens in pulmonary granuloma.

Pulmonary sarcoidosis, a human disease of unknown cause, has no animal model. Sarcoidosis patients have serum antibodies specific for Helicobacter pylori and its surface enzyme urease. H. pylori do not survive in the high-oxygen pulmonary atmosphere, but urease may access the lung by oesophageal reflux. A model was established in rats to study gastro-oesophageal reflux of urease into the airways. Pathology in tissues from human sarcoidosis patients was compared with that in the rat model. Changes observed in the rat model included prominent peribronchial lymphocytic infiltration, which is seen occasionally in human sarcoidosis. Granulomas, pathognomonic for human sarcoidosis, occurred occasionally in the lungs of rats given urease protein intratracheally, but were widespread when urease was coupled to microbeads and administered intravenously. Biomarkers associated with human sarcoidosis (interleukin1-ß and platelet-activating factor) were up-regulated acutely in the rat model. Further investigations with this model may provide significant insights into the origin and pathogenesis of pulmonary diseases in man and other species that carry gastric Helicobacter spp. and its associated enzyme.

Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas.

AIMS/HYPOTHESIS: Exendin-4 is a 39 amino acid agonist of the glucagon-like peptide receptor and has been approved for treatment of type 2 diabetes. Many reports describe an increased incidence of acute pancreatitis in humans treated with exendin-4 (exenatide). Previous studies have evaluated the effect of exendin-4 on beta cells and beta cell function. We evaluated the histological and biochemical effects of exendin-4 on the pancreas in rats. METHODS: We studied 20 Sprague-Dawley male rats, ten of which were treated with exendin-4 and ten of which were used as controls. The study period was 75 days. Serum and pancreatic tissue were removed for biochemical and histological study. Blood glucose, amylase, lipase, insulin and adipocytokines were compared between the two groups. RESULTS: Animals treated with exendin-4 had more pancreatic acinar inflammation, more pyknotic nuclei and weighed significantly less than control rats. They also had higher serum lipase than control animals. Exendin-4 treatment was associated with lower insulin and leptin levels as well as lower HOMA values than in the untreated control group. CONCLUSIONS/INTERPRETATION: Although the use of exendin-4 in rats is associated with decreased weight gain, lower insulin resistance and lower leptin levels than in control animals, extended use of exendin-4 in rats leads to pancreatic acinar inflammation and pyknosis. This raises important concerns about the likelihood of inducing acute pancreatitis in humans receiving incretin mimetic therapy.

Prevalence of HCV infection in nongastric marginal zone B-cell lymphoma of MALT.

BACKGROUND: Hepatitis C virus (HCV) infection is frequently associated with B-cell non-Hodgkin's lymphomas. We investigated the prevalence of HCV infection in nongastric marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) in order to define the relationship between the viral infection and the presenting features, treatment, and outcome. METHODS: We retrospectively studied 172 patients with a histological diagnosis of marginal zone B-cell lymphoma of MALT, except for stomach, and with available HCV serology, among a series of 208 patients. RESULTS: HCV infection was documented in 60 patients (35%). Most HCV-positive patients (97%) showed a single MALT organ involvement. HCV-positive patients showed a more frequent involvement of skin (35%), salivary glands (25%), and orbit (15%). The majority of stage IV HCV-positive patients (71%) had a single MALT site with bone marrow involvement. The overall response rate was similar in HCV-positive (93%) and HCV-negative patients (87%). Overall survival (OS) and event-free survival (EFS) did not differ according to HCV infection. In multivariate analysis, advanced disease (stage III-IV) was associated with a poorer OS (P = 0.0001), irrespective of HCV serostatus. CONCLUSIONS: This study shows that nongastric marginal zone lymphomas are characterized by a high prevalence of HCV infection. Patients with involvement of a single MALT site have the highest prevalence of HCV. HCV-positive nongastric lymphomas of MALT show an indolent course similar to HCV-negative patients and seem an ideal target for exploiting the antilymphoma activity of antiviral treatments.

Bronchiolitis obliterans induced by intratracheal papaverine: a novel animal model.

Constrictive bronchiolitis obliterans (CBO), a highly fatal syndrome seen following toxicant exposure and lung transplantation, is in need of mechanistic study. This report creates an animal model of toxicant induced CBO, validates its pathology and suggests a physiologic mechanism for its origin. Papaverine, the alkaloid in Sauropus plants and responsible for human toxicant-induced CBO, was used to create the rat model. A mini-osmotic pump delivered papaverine intratracheally for up to 28 days (0.25 microL/hr, totaling 6.4 mg). Bronchoalveolar lavage (BAL) was measured. Lung tissue was evaluated for signs of CBO (H&E and Trichrome staining). Cytokines deregulated in human CBO were also measured (TGF-beta and eNOS). Peribronchial inflammation, extensive denudation and destruction of bronchial mucosa, as well as increased peribronchial collagen (all classic signs of CBO) were observed as early as 7 days in papaverine treated animals, with more extensive damage after 28 days. Significant elevations of TGF-beta and eNOS were seen in lung homogenates. Our toxicant induced model of CBO via a novel delivery method of intratracheal papaverine accurately reproduces pathology and cytokine profiles of human CBO. Papaverine has potential for producing CBO by multiple routes. This model introduces a vehicle for both understanding and development of innovative treatment for CBO.

Reduced IL-4 associated antibody responses to vaccine in early pre-diabetes.

AIMS/HYPOTHESIS: The aim of this study was to determine whether beta-cell autoimmunity is associated with immune response bias to exogenous antigens. METHODS: IgG subclass responses against tetanus toxoid and rubella were measured after vaccination in children with (n=36) and without (n=73) islet autoantibodies participating in the BABYDIAB prospective study of offspring of parents with Type I (insulin-dependent) diabetes mellitus. All children had been vaccinated against tetanus toxoid antigen before 6 months of age and at 18 months of age, and against live attenuated rubella virus at 18 months of age and again before 5 years of age. Tetanus toxoid specific IgG subclasses and cytokine responses were compared in a second cohort of subjects. RESULTS: Responses to tetanus toxoid in islet-autoantibody-negative children were characterized by early IgG1 antibodies at 9 months of age followed by the appearance of IgG4 and lesser IgG2 antibodies at 2 years of age. Children who had developed islet autoimmunity before one year of age (n=15) did not have the shift to IgG4 and IgG2 anti-TT after booster vaccination (p<0.01), and had undetectable or IgG1 restricted responses. This defect was independent of HLA class II genotype, was restricted to children who had islet autoimmunity before 1 year of age, and was most evident in children who already had multiple islet autoantibodies by 9 months of age. IgG4 and IgG2 anti-TT correlated with IL-4 (p<0.005), but not IFNgamma responses. Antibody responses to the IFNgamma-inducing rubella vaccination were strongly IgG1 dominated and no differences were observed between islet autoantibody positive and negative children. CONCLUSIONS/INTERPRETATION: These data are consistent with a reduced capacity to make IL-4 promoted antibody responses to exogenous antigen in early pre-diabetes.

Prevention of radiation-induced nephropathy and fibrosis in a model of bone marrow transplant by an angiotensin II receptor blocker.

Nephropathy, interstitial pneumopathy, and renal and lung fibrosis are major complications of bone marrow transplantation (BMT). This study evaluated the antifibrotic property of an angiotensin II (A2) type-1 receptor blocker (L-159,809) and compared it with those of Captopril and Enalapril, two angiotensin-converting enzyme (ACE) inhibitors, in a rat model of BMT. Male WAG/Rij/MCW rats received a preparative regimen of 60 mg/kg body wt of cytoxan (i.p., Days 9 and 8) and 18.5 Gy of total body irradiation (TBI) in six twice daily fractions (Days 2, 1, and 0) followed immediately (Day 0) by BMT. Modifiers were given in drinking water from Day 10 until autopsy, 8 weeks after BMT. Rats treated with TBI plus cytoxan alone developed severe nephropathy. Trichrome staining showed marked collagen deposition in glomeruli, renal interstitium, and renal arteries and arterioles (especially in their adventitia). Collagen deposition and renal damage were markedly reduced by the three modifiers. Of the three, L-158,809-treated rats had slightly thinner vessels and slightly less collagen than nonirradiated normal controls. The study shows the effectiveness of these drugs in the protection of the renal parenchyma from the development of radiation-induced fibrosis. It also indicates a role for angiotensin II in the modulation of collagen synthesis.

Mucormycosis in hematologic malignancies: an emerging fungal infection.

BACKGROUND AND OBJECTIVES: In recent years pulmonary mucormycosis has been reported in patients with leukemia and lymphoma and bone marrow transplant recipients. It carries an extremely poor prognosis. We report our experience of clinical findings, diagnostic procedures, treatment and outcome of mucormycosis diagnosed in neutropenic patients affected by hematologic neoplasms admitted to our Department. DESIGN AND METHODS: From November 1987 to July 1999 we observed 13 cases of Mucor. Their median age was 61 years (range 20-75), and they were predominantly in the aplastic post-chemotherapy period (12/13), affected by acute myeloid leukemia (11 cases ) or non-Hodgkin's lymphoma (2 cases). Six patients (all with leukemia) were receiving inductionEth consolidation therapy, 7 had progressive hematologic disease. At the onset of infection all patients were neutropenic (N < 0.5x10(9)/L). No patients had diabetes mellitus. Two patients had been receiving steroid therapy for 5 and 7 days. RESULTS: The lung was involved in all cases (13/13); disseminated disease was present in 8/13 patients. All cultures (blood, sputum, nasal swabs and bronchoalveolar lavage) were negative. In 3 patients a histologic diagnosis was made in vivo: in 1 patient by percutaneous pulmonary biopsy, in 1 patient by pulmonary lobectomy, and in the last patient by percutaneous pulmonary biopsy confirmed by excision of a cerebellar abscess. In the remaining 10 cases diagnosis was made post-mortem. Five patients were not treated, 2 because of poor clinical condition and 3 because fungal infection was not suspected. Amphotericin B (1 mg/kg/day) was given empirically to 6 patients and 2 responded to treatment. The remaining 2 patients with neurologic symptoms at the onset of infection were treated with liposomal amphotericin, Ambisome, one with 3 and one with 5 mg/kg/day; of these two patients the first died in 4 days; the second, with both pulmonary and cerebellar localizations, was treated successfully with 5 mg/kg/day for 4 weeks and then with 3 mg/kg/day, and excision of a brain abscess at neutrophil recovery (total dose of Ambisome: 12,000 mg). The 3 surviving leukemic patients were able to complete subsequent consolidation therapy using amphotericin B or liposomal amphotericin as secondary prophylaxis during aplasia. INTERPRETATION AND CONCLUSIONS: In neutropenic hematologic patients Mucor is rarely suspected. In our patients infection was often characterized by disseminated disease and a rapidly fatal course; only early aggressive amphotericin B (or Ambisome) treatment together with neutrophil recovery appeared to improve the outcome. Diagnosis is very important for programming antifungal therapy and secondary prophylaxis with amphotericin B, because Mucor is usually resistant to itraconazole.

Estrogen and progesterone receptors in gynecomastia.

The etiology of gynecomastia is unknown. There seems to be no increased incidence of malignancies in patients with idiopathic gynecomastia; however, patients with Klinefelter syndrome exhibit an increased incidence of malignancy. The authors reviewed the results of 34 patients with gynecomastia diagnosed in adolescence who, following initial evaluation, had a mastectomy. The estrogen and progesterone receptors were analyzed in these patients. Three of the patients were diagnosed with Klinefelter syndrome. These three patients exhibited elevated amounts of estrogen and progesterone receptors. None of the patients who were not diagnosed with this syndrome demonstrated significant elevation of their estrogen or progesterone receptors. The presence of elevated estrogen and progesterone receptors in patients with Klinefelter syndrome provides a potential mechanism by which these patients may develop breast neoplasms. The absence of elevated estrogen and progesterone receptors in patients with idiopathic gynecomastia may serve to clarify why these patients' disease rarely degenerates into malignancy.

Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker.

PURPOSE: This report summarizes our experiences on the protective effect of angiotensin-converting enzyme (ACE) inhibitors, especially captopril and an angiotensin II type 1 receptor blocker on radiation-induced pulmonary injury. METHOD: In the first series of experiments, adult male Sprague Dawley rats were given a single dose of either 20 or 30 Gy of gamma rays to a 35 cm2 right hemithorax port, whilst shielding the left, contralateral, lung. Perfusion scans and autopsies were performed at intervals up to 12 months post-radiation. Three different ACE inhibitors, penicillamine and pentoxifylline were given as radiation protectors and their activity compared. A model of irradiation for total bone marrow transplant (BMT) was used for the second group of experiments. Male WAC/Rij/MCW rats received total-body irradiation and a regimen of cyclophosphamide (CTX) in preparation for bone marrow transplant. The modifiers were two ACE inhibitors, captopril and enalapril, and L-158,809, an angiotensin II (A II) type 1 receptor blocker. All drugs were administered in the rats' drinking water and all were well-tolerated. RESULTS: In the irradiated rats, pulmonary damage progressed from the presence of blebs and detachment from basement membranes of endothelial cells a few days after injury, to severe arteritis and interstitial collagen deposition at 3 months, and then on to severe pneumonitis and extensive pulmonary fibrosis at 6 months. Marked increase of hydroxyproline was also found in the lungs at 6 months. These morphological changes were associated with significant decrease of ACE and plasminogen activator activity (PLA) and a marked increase of prostaglandins (PG12) and thromboxane (Txa2), substances considered as indicators of endothelial pulmonary damage. ACE inhibitors captopril, CL 24817, enalapril and CGS 13945 prevented the markers of endothelial dysfunction. Captopril and CL 24817, which contain a sulphydryl (-SH) radical in their moiety and the AII type 1 receptor blocker, L-158,809, were the most efficient in protecting the lung parenchyma from the inflammatory response and subsequent fibrosis. Penicillamine, an SH-containing compound with weak ACE inhibitory activity was also a strong antifibrotic agent but showed only modest anti-inflammatory properties. Additionally, in the irradiated rats, captopril also reduced the incidence of squamous cell skin carcinomas and subcutaneous sarcomas consequent to the highest doses of radiation. CONCLUSION: ACE inhibitors and one AII type 1 receptor blocker were effective in protecting lungs from radiation-induced pneumonitis and the development of lung fibrosis in two models of rat radiation injury. In the first series of experiments (unilateral irradiation), those ACE inhibitors containing a sulphydryl radical were more effective than those without it. This observation led to the question of whether this protective effect is related to inhibition of AII synthesis or rather to some of the collateral pharmacologic properties of these drugs, such as anti-oxidation or protease inhibition. The AII receptor blocker, however, was shown to be equally effective, if not better, in its antifibrotic capacity than any ACE inhibitor with or without an SH radical, reaffirming the role of AII in modulation of collagen synthesis.

Vitamin A deficiency injures lung and liver parenchyma and impairs function of rat type II pneumocytes.

The purpose of this research was to determine the effects of vitamin A deficiency on liver and lung morphology and type II pneumocyte function. Weanling rats were fed a retinol-adequate (control) or -deficient diet for 6 wk. Average food intakes and body weights were not different between the vitamin A-deficient and -adequate rats. Histologic examination revealed that the lungs of vitamin A-deficient rats had less collagen in the adventitia of small caliber arteries and arterioles and in the alveolar septa, which appeared thinner than that of controls. Many areas of the lungs of the same rats were also emphysematous (increased size of air spaces distal to the terminal bronchiole, with thinning and partial or total destruction of septal wall). Content of elastin also was lower in the lung parenchyma, as well as in the small arteries and arterioles, but not in the larger ones. Peribronchial collagen was not affected by the deficient diet. Scattered inflammation was observed in most of the vitamin A-deficient rats; a mild inflammatory reaction also was seen in one of the controls. Vitamin A-deficient rats also exhibited hepatocyte vacuolization and mild inflammation in the liver, specifically in the periportal tracts. Surfactant synthesis and ornithine decarboxylase activity were significantly lower in type II pneumocytes isolated from vitamin A-deficient rats. In conclusion, our data provide evidence that vitamin A deficiency produces profound morphologic alterations in liver and lung parenchyma and impairs pneumocyte function.

Dietary beta-carotene protects lung and liver parenchyma of rats treated with monocrotaline.

Some studies have indicated that the injury induced by the hepato- and pneumotoxin monocrotaline (MCT) is in part mediated by oxidation. Because beta-carotene is a potent antioxidant, we hypothesized that it would protect the lung and liver parenchyma against MCT-induced injury. Twenty rats were assigned randomly to four groups. All rats were fed a standard AIN93G diet with or without beta-carotene. After 1 week on the purified diets, half of the rats fed the control (standard) diet and half of the rats fed the beta-carotene-supplemented diet were injected subcutaneously with 60 mg MCT/kg body weight or its vehicle (water). All rats were sacrificed at 4 weeks. Histological examination showed that beta-carotene alone did not affect lung or liver structure. On the other hand, lungs of MCT-treated rats had severe focal pneumonia, extensive deposition of collagen in the septa, marked inflammation of the small arteries and arterioles, and arterialization of the small venules. Livers of MCT-treated rats showed some fatty infiltration and diffuse hemorrhages, more prominent sometimes in the centrilobular area and sometimes in the periportal region. Concomitant treatment with beta-carotene protected the lung parenchyma from the inflammatory reaction and the septal fibrosis, but did not prevent cardiac right ventricular hypertrophy and only slightly reduced the thickening of the wall of small arteries and arterioles. Incidence of steatosis and hemorrhages was decreased in the liver. These results indicate that MCT-induced pulmonary vascular remodeling occurs in the absence of inflammatory cell infiltration. Furthermore, beta-carotene prevented inflammation and protected the lung and liver parenchyma of MCT-treated rats.

Mechanism of captopril toxicity to a human mammary ductal carcinoma cell line in the presence of copper.

Captopril (D-3-mercapto-2-methylpropanoyl-L-proline) is an angiotensin converting enzyme (ACE) inhibitor, used widely in the treatment of hypertension and congestive heart failure. Captopril also inhibits proliferation of a variety of cell types, including several lacking ACE and renin acitvity. We have previously demonstrated that human mammary ductal carcinoma cells are among the cell types whose mitotic activity is inhibited by captopril. In those cells, captopril also reduces estrogen receptor (ER) and increases progesterone receptor (PR) concentrations. The present study evaluated the mechanism of captopril's antiproliferative action in an ER/PR-negative human mammary ductal carcinoma cell line, Hs578T. Cells grown in a 10% serum medium showed negligible changes in the presence of captopril alone. However, in the presence of subphysiologic concentrations of copper salts or copper-loaded ceruloplasmin, captopril caused a dose-dependent reduction in cell number, thymidine incorporation and mitochondrial dehydrogenase activity. In contrast, iron salts and iron-saturated transferrin had no effect on captopril activity. Catalase and horseradish peroxidase nullified the cytotoxic effects of captopril/Cu++, whereas H2O2 mimicked those effects. These data are consistent with the notion of a copper-catalyzed oxidation of captopril, leading to the generation of H2O2 as the cytotoxin to this clinically important cell type.

Pleurodesis by autologous blood, doxycycline, and talc in a rabbit model.

BACKGROUND: Management of recurrent spontaneous pneumothorax or symptomatic pleural effusion often uses thoracoscopic pleurodesis, about which many questions remain. Both effectiveness and toxicity of agents currently used for pleurodesis were evaluated in a rabbit model. METHODS: Agents administered were autologous blood 1 mL/kg, talc slurry (70 mg x mL(-1) x kg(-1)), and doxycycline 10 mg/mL, given through a chest tube to 30 rabbits. Controls had only chest tubes inserted. At 30 days surfaces were graded by gross observation and histologic examination. Blood and lung tissue from all animals were analyzed for enzymes and blood chemistries. RESULTS: Gross observations showed mediastinal thickening and adhesions with doxycycline, and threadlike adhesions with talc. Autologous blood was only slightly more effective than a chest tube alone. Talc significantly increased angiotensin converting enzyme activity in serum, whereas doxycycline changed liver function enzymes and produced tissue toxicity. CONCLUSIONS: Doxycycline produced effective pleurodesis but yielded remarkably severe local effects. The distant sequelae of talc and doxycycline pleurodesis-histologic changes in the contralateral lung and serum enzyme elevations-suggests undesirable systemic effects for the commonly used agents, and autologous blood exhibited no significant pleurodesis, short-term. The search for the ideal agent for chemical pleurodesis continues.

Ex vivo manipulation of hematopoietic stem cells for transplantation: the potential role of amifostine.

High-dose chemotherapy with autologous stem cell transplantation is an increasingly used procedure in oncohematologic diseases and represents a promising strategy in selected patients with solid tumors. In autologous stem cell transplantation, the risk of reinfusion of clonogenic tumor cells is a remarkable biologic obstacle that can be at least partly overcome by ex vivo graft purging to reduce residual tumor. Mafosfamide and 4-hydroxyperoxycyclophosphamide, active metabolites of cyclophosphamide, are the most widely used pharmacologic agents for ex vivo bone marrow purging. However, in addition to killing tumor cells, they are toxic to normal bone marrow as measured by reduced colony-forming unit granulocyte-macrophage (CFU-GM). Thus, the therapeutic index of these alkylating agents is narrow, and parameters for dose selection must include toxicity to normal bone marrow progenitor cells that can delay bone marrow engraftment and increase risk of infections, bleeding complications, hospitalization, and the need for a costly transplantation procedure. Amifostine (WR-2771, Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) selectively protects human CFU-GM progenitor cells from the cytotoxicities of active metabolites of cyclophosphamide without altering its cytotoxic effect on malignant cells. This has been demonstrated both in preclinical and clinical studies in patients with breast cancer, malignant lymphomas, and acute leukemia. Amifostine use during the ex vivo procedure significantly shortened the time to bone marrow engraftment with decreased incidence of infections and need for red blood cell transfusions.

Differential expression of fibroblast growth factor receptor-1, -2, and -3 and syndecan-1, -2, and -4 in neonatal rat mandibular condyle and calvaria during osteogenic differentiation in vitro.

Fibroblast growth factors (FGFs) play important roles in the control of skeletal cell growth and differentiation. To identify the mechanisms of regulation of FGF actions during chondrogenesis and osteogenesis, we investigated, by immunohistochemistry, the spatiotemporal expression of the high-affinity FGF receptors (FGFR-1, -2, and -3) and coreceptors (syndecans-1, -2, and -4) in newborn rat condyle and calvaria during chondrogenesis and osteogenesis in vitro. During chondrogenesis at 4 days of culture, condyle chondrocytes showed weak FGFR-1, FGFR-2, and syndecan-1 immunoreactivity; stronger syndecan-2 expression; and marked FGFR-3 and syndecan-4 immunolabeling. At a later stage (i.e., 9 days of culture), FGFR-1, -2, and -3 were coexpressed with syndecan-4 in chondrocytes. Condyle progenitor cells located in the condyle perichondrium initially expressed strong syndecan-2 and -4 and weak syndecan-1 labeling, whereas no FGFR was detectable. When these cells differentiated into osteoblasts, they expressed syndecan-2 and -4 coincidently with FGFR-1, -2, and -3 at 9 days of culture. In newborn rat calvaria, syndecan-1, -2, and -4 were coexpressed mainly with FGFR-1 and -2 in osteoblasts. In the two models, treatment with FGF-2 (100 ng/mL) at 4-9 days of culture increased cell growth and decreased glycosaminoglycan or collagen synthesis, respectively, suggesting interactions of FGF-2 with distinct FGFRs and syndecans during chondrogenesis and osteogenesis. The coincident or distinct spatiotemporal expression pattern of FGFRs and syndecans in chondrocytes, progenitor cells, and osteoblasts represents a dynamic mechanism by which FGF effects on skeletal cells may be controlled in a coordinate manner during cartilage and bone formation in vitro.

A subdepressor low dose of ramipril lowers urinary protein excretion without increasing plasma potassium.

Angiotensin-converting enzyme (ACE) inhibitors are increasingly administered to patients with chronic renal disease. One issue of concern with the use of ACE inhibitors in patients with impaired renal function is the possible development of hyperkalemia. We reasoned that the impact of ACE inhibitors on plasma potassium could be minimized by administering these agents at very low doses. To examine this issue, we investigated the effect of a low dose of ramipril (1.25 mg orally once daily) and an eight-fold higher dose (10 mg orally once daily) on plasma potassium in 13 patients with proteinuria and mild chronic renal insufficiency. The study was divided into four phases: placebo (4 weeks), low-dose ramipril (8 weeks), high-dose ramipril (8 weeks), and washout phase (4 weeks). With the low dose of ramipril, urinary protein excretion decreased significantly as early as after 1 week of administration (from 4.4 +/- 0.5 to 3.7 +/- 0.4 g/24 h; P < 0.025) and did not decrease any further thereafter even when the dose was increased eight-fold. Mean arterial blood pressure and plasma potassium did not change significantly with the low dose of ramipril, whereas with the higher dose, mean arterial blood pressure decreased significantly (from 107 +/- 2.0 to 100 +/- 2.0 mm Hg, P < 0.005), and plasma potassium increased significantly (from 4.53 to 4.78 mEq/L, P < 0.05). We conclude that a low dose of ramipril can reduce proteinuria to the same extent as an eight-fold higher dose without significantly lowering blood pressure or increasing plasma potassium. This latter feature may be advantageous for the treatment of patients at risk for hyperkalemia who require ACE inhibitors.