Chronic inflammation plays a crucial role in cigarette smoke-related carcinogenesis. Accordingly, anti-inflammatory agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs), provide a rational ...strategy in cancer chemoprevention. We assayed celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, and licofelone, an inhibitor of COX-1, COX-2, and 5- lipoxygenase (5-LOX), for the ability to modulate carcinogenesis in neonatal mice exposed to mainstream cigarette smoke (MCS) for 4 months and thereafter kept in filtered air for 3.5 months. A preliminary toxicity study and a chemoprevention study involved the use of 591 Swiss H mice. Exposure to MCS caused a variety of pulmonary emphysema, alveolar and bronchial epithelial hyperplasias, proliferation of blood vessels, microadenomas, adenomas and malignant tumors, as well as kidney tubular and urinary bladder papillary epithelial hyperplasias. Celecoxib (1600 mg/kg diet) and even better licofelone (960 mg/kg diet) were able to significantly attenuate the MCS-induced alterations of inflammatory nature, including pulmonary emphysema, alveolar epithelial hyperplasias and microadenomas and urinary tract hyperplastic lesions when given to mice according to a protocol that mimics an intervention in current smokers. Moreover, celecoxib attenuated the yield of lung adenomas and both NSAIDs showed some involvement in lowering the progression to cancer in the lung. Celecoxib exhibited some protective effects even when given according to a protocol involving its administration after discontinuation of exposure to MCS. However, both agents and especially celecoxib showed some hepatotoxicity and affected survival and body weight gain of mice when administered to MCS-exposed mice in the long term.
Abstract A thrombus can develop in the left atrium during atrial fibrillation because the loss of contractile function leads to blood flow stasis. Anticoagulation therapy is indicated for prevention ...of systemic embolism, usually maintaining an international normalized ratio between 2 and 3. Rarely a massive thrombosis develops in the atrium resulting in a peduncolated ball valve thrombus or in a free-floating thrombus. These two conditions are characterized by variables in the physical findings. Such masses are hazardous and upon discovery surgical treatment, often in emergency, is mandatory. We present here the case of a patient who developed an unnoticed huge left atrial ball thrombus despite warfarin therapy after previous mitral valve surgery. < Learning objective: Risk of atrial thrombosis threatens patients suffering from atrial fibrillation. The presence of a ring and a modified valve anatomy following a surgical repair could represent an additional drive in the thrombus formation pathway. A free-floating ball thrombus in the left atrium is an unusual occurrence that may cause fatal systemic emboli or left ventricular inflow obstruction, often resulting in sudden death. In such cases, even in the absence of symptoms, prompt surgical excision is recommended.>
Persistent mixed chimerism represents a state in which recipient and donor cells stably co-exist after hematopoietic stem cell transplantation. However, since in most of the studies reported in ...literature the engraftment state was observed in the nucleated cells, in this study we determined the donor origin of the mature erythrocytes of patients with persistent mixed chimerism after transplantation for hemoglobinopathies. Results were compared with the engraftment state observed in singly picked out burst-forming unit - erythroid colonies and in the nucleated cells collected from the peripheral blood and from the bone marrow.
The donor origin of the erythrocytes was determined analyzing differences on the surface antigens of the erythrocyte suspension after incubation with anti-ABO and/or anti-C, -c, -D, -E and -e monoclonal antibodies by a flow cytometer. Analysis of short tandem repeats was used to determine the donor origin of nucleated cells and burst-forming unit - erythroid colonies singly picked out after 14 days of incubation.
The proportions of donor-derived nucleated cells in four transplanted patients affected by hemoglobinopathies were 71%, 46%, 15% and 25% at day 1364, 1385, 1314 and 932, respectively. Similar results were obtained for the erythroid precursors, analyzing the donor/recipient origin of the burst-forming unit - erythroid colonies. In contrast, on the same days of observation, the proportions of donor-derived erythrocytes in the four patients with persistent mixed chimerism were 100%, 100%, 73% and 90%. Conclusions Our results showed that most of the erythrocytes present in four long-term transplanted patients affected by hemoglobinopathies and characterized by the presence of few donor engrafted nucleated cells were of donor origin. The indication that small proportions of donor engrafted cells might be sufficient for clinical control of the disease in patients affected by hemoglobinopathies is relevant, although the biological mechanisms underlying these observations need further investigation.
Abstract. Purpose Our study aimed to estimate the effects of a supervised, intensive, home-based-pulmonary-rehabilitation (HBPR) program for mild and moderate chronic-obstructive-pulmonary-disease ...(COPD) patients. Participants and Methods A retrospective, case-control study. Forty-three (N=43) patients were observed, divided into Treatment-Group (TG) and Control-Group (CG). The TG (N=23) underwent a 4-week training program, consisting of endurance and strength training sessions, performed 4-times per week. In addition, inspiration muscle training was performed, with a threshold device. The primary outcome was dyspnea improvements, measured by the modified-Borg-scale (mBS), and the secondary outcome was the determination of diaphragm excursion and function, using ultrasound (US) assessment to measure clinical parameters. Results The results suggested significantly improved mBS scores, measured for the ΔT0-T1 and ΔT0-T2 time points ; improved diaphragm-excursion (Dia-Ex) at ΔT0-T1 and ΔT0-T2 ; and improved maximum Dia-Ex at ΔT0-T1 and ΔT1-T2 in the TG compared with the CG. Moreover, the results showed improvements over time for all parameters in the TG versus CG, suggesting a constant improvement in respiratory pathology. Conclusion A supervised HBPR plan was effective in reducing dyspnea by the mBS, and improving diaphragmatic function, as determined by US evaluation, and lastly improving quality of life in patients with mild-to-moderate COPD.
A review of almost 2000 studies showed that the large majority of 39 putative cancer chemopreventive agents induced "spontaneous" apoptosis. Inhibition of the programmed cell death triggered by a ...variety of stimuli was consistently reported only with ascorbic acid, alpha-tocopherol, and N-acetylcysteine (NAC). We performed experimental studies in rodents exposed to cigarette smoke, either mainstream (MCS) or environmental (ECS), and UV-A/B-containing light. The nonsteroidal anti-inflammatory drug sulindac did not affect the apoptotic process in the skin of light-exposed mice and in the lungs of ECS-exposed mice. Likewise, 5,6-benzoflavone, indole-3-carbinol, 1,2-dithiole-3-thione and oltipraz failed to modulate apoptosis in the respiratory tract of ECS-exposed rats. Phenethyl isothiocyanate further enhanced the frequency of apoptosis in pulmonary alveolar macrophages and bronchial epithelial cells, and upregulated several genes in the lung of ECS-exposed rats. Both individually and in combination with oltipraz, NAC inhibited apoptosis in the respiratory tract of rats exposed either to MCS or ECS. Moreover, NAC attenuated the ECS-related overexpression of proapoptotic genes and normalized the levels of proapoptotic proteins in rat lung. The transplacental administration of NAC to mice considerably attenuated gene overexpression in the liver of fetuses exposed to ECS throughout pregnancy. Inhibition of apoptosis by chemopreventive agents reflects their ability to counteract certain upstream signals, such as genotoxic damage, redox imbalances, and other forms of cellular stress that trigger apoptosis. On the other hand, enhancement of apoptosis is a double-edged sword, since it represents a protective mechanism in carcinogenesis but may contribute to the pathogenesis of other degenerative diseases. We suggest that stimulation of apoptosis by so many chemopreventive agents, as reported in the literature, may often reflect the occurrence of toxic effects at high doses.
In spite of the major role played by smoking tobacco in the epidemiology of chronic degenerative diseases, it is difficult to mimic the genotoxic and carcinogenic effects of this complex mixture in ...animal models. We undertook an experimental study evaluating the time-course induction, persistence and modulation of cytogenetic alterations induced in BDF1 mice exposed whole-body to mainstream cigarette smoke. The animals were divided into five groups, including: (i) 72 sham-exposed mice; (ii) 72 mice exposed to smoke for up to 3 weeks; (iii) 72 mice treated daily with the thiol N-acetylcysteine (NAC, 0.5 g/kg body weight) with drinking water; (iv) 72 mice exposed to smoke and treated daily with NAC, starting 5 days before exposure to smoke; and (v) 48 mice exposed to smoke and treated daily with NAC, starting 1 day after discontinuation of exposure to smoke. After 1, 2, 3, 4, 5, 6, 7, 10 and 14 weeks since the start of exposure to cigarette smoke, eight mice per group were killed, and cytogenetic parameters were evaluated. Exposure to smoke induced a high frequency of micronucleated and binucleated (BN) pulmonary alveolar macrophages, which persisted for at least 14 weeks. The frequency of micronuclei increased early in bone marrow polychromatic erythrocytes, but declined to background levels upon discontinuation of exposure to smoke. By comparison, their induction in circulating normochromatic erythrocytes (NCE) was slightly delayed, less intense but still significant, and persisting for an additional 3 weeks. Administration of NAC, throughout duration of the experiment, strongly inhibited the smoke-induced formation of micronuclei in alveolar macrophages and had some transiently significant effect on the induction of BN macrophages. NAC did not significantly decrease the smoke-induced formation of micronuclei in bone marrow cells, whereas it attenuated the formation of micronuclei in peripheral blood NCE. When given after discontinuation of exposure to cigarette smoke, NAC did not affect the cytogenetic alterations but normalized the altered bronchoalveolar lavage cellularity. The present data provide a detailed analysis of time-related cytogenetic alterations in smoke-exposed mice, both in the respiratory tract and at a systemic level, and show the effects of NAC on these parameters and on the pulmonary inflammatory response.
Ex vivo amplification of human hematopoietic stem cells (HSC) without loss of their self-renewing potential represents an important target for transplantation, gene and cellular therapies. Valproic ...acid is a safe and widely used neurologic agent that acts as a potent inhibitor of histone deacetylase activities. Here, we show that valproic acid addition to liquid cultures of human CD34+ cells isolated from cord blood, mobilized peripheral blood, and bone marrow strongly enhances the ex vivo expansion potential of different cytokine cocktails as shown by morphologic, cytochemical, immunophenotypical, clonogenic, and gene expression analyses. Notably, valproic acid highly preserves the CD34 positivity after 1 week (range, 40-89%) or 3 weeks (range, 21-52%) amplification cultures with two (Flt3L + thrombopoietin) or four cytokines (Flt3L + thrombopoietin + stem cell factor + interleukin 3). Moreover, valproic acid treatment increases histone H4 acetylation levels at specific regulatory sites on HOXB4, a transcription factor gene with a key role in the regulation of HSC self-renewal and AC133, a recognized marker gene for stem cell populations. Overall, our results relate the changes induced by valproic acid on chromatin accessibility with the enhancement of the cytokine effect on the maintenance and expansion of a primitive hematopoietic stem cell population. These findings underscore the potentiality of novel epigenetic approaches to modify HSC fate in vitro.
Summary Background We previously demonstrated that high doses of environmental cigarette smoke (ECS) induce alopecia in mice. This effect was prevented by the oral administration of N -acetylcysteine ...(NAC), an analogue and precursor of l -cysteine and reduced glutathione. Objectives The present study aimed at assessing whether l -cystine, the oxidized form of l -cysteine, which is a key hair component, may behave like NAC in inhibiting ECS-induced alopecia and modulating the mechanisms responsible for this condition. Methods C57BL/6 mice were exposed whole-body to ECS in a smoking machine. Groups of mice received in the diet, at three dose levels, a mixture of l -cystine with vitamin B6, which plays a role in l -cystine incorporation in hair cells. Occurrence of alopecia areas and apoptosis of hair bulb cells were evaluated for up to 6 months of exposure, and the time course induction of micronucleated erythrocytes in peripheral blood was investigated. Results The frequency of micronucleated erythrocytes was increased by ECS, irrespective of treatment with l -cystine/vitamin B6. ECS-induced alopecia and apoptosis of hair bulb cells in all exposed mice. l -Cystine/vitamin B6 inhibited alopecia in a dose-dependent fashion. Conclusions High-dose ECS induces apoptosis-related alopecia in mice, and oral administration of l -cystine/vitamin B6 is an effective preventive treatment.
Chemoprevention by dietary and pharmacological means provides a strategy for attenuating the health risks resulting from cigarette smoking and in particular from passive exposure to environmental ...cigarette smoke (ECS). We evaluated the ability of the glucocorticoid budesonide and of the natural agent phenethyl isothiocyanate (PEITC) to affect DNA damage in bronchoalveolar lavage (BAL) cells of CD-1 mice exposed to ECS, starting within 12 h after birth and continuing until the end of the experiment. After weanling, based on a preliminary subchronic toxicity study, groups of mice received daily either budesonide (24 mg/kg diet) or PEITC (1,000 mg/kg diet). After 2 weeks of treatment, all mice were sacrificed and subjected to BAL, mainly recovering pulmonary alveolar macrophages. Evaluation of single-cell DNA strand breaks was made by using the alkaline-halo test, a modification of the comet assay. The analysis of 481 BAL cells yielded the following results (expressed as nuclear spread factor): (a) Sham-exposed mice: mean 0.84 (lower-upper 95% confidence intervals 0.74-0.94); (b) ECS-exposed mice: 2.77 (2.46-3.09); (c) ECS-exposed mice treated with PEITC: 1.15 (1.05-1.26); (d) ECS-exposed mice treated with budesonide: 1.37 (1.25-1.49). Thus, exposure to ECS resulted in a significant increase of DNA damage as compared with sham, and both PEITC and budesonide significantly attenuated this damage. In conclusion, the analysis of sentinel cells collected by BAL, a semi-invasive technique that is commonly used in humans for diagnostic purposes, showed that the investigated chemopreventive agents are able to revert the DNA damage produced by passive exposure to cigarette smoke.
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