RESUMEN
BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy. PATIENTS AND METHODS: Patients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes. RESULTS: Of 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the 'CIS' versus 'no-CIS' groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63-1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01-1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23-2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34-0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82-1.35; p = 0.70). CONCLUSION: In this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.
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Antineoplásicos/uso terapéutico , Carcinoma in Situ/terapia , Cistectomía , Quimioterapia de Inducción , Terapia Neoadyuvante , Neoplasias de la Vejiga Urinaria/terapia , Anciano , Carcinoma in Situ/mortalidad , Carcinoma in Situ/patología , Cisplatino/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
There is considerable evidence that matrix metalloproteinases (MMPs) are up- and/or downregulated in chronic obstructive pulmonary disease (COPD), particularly in emphysema, in which they probably participate in proteolytic attack on the alveolar wall matrix. Recent data suggest that MMPs also have major roles in driving inflammation or shutting it down, as well as modifying the release of fibrogenic growth factors, processes that are important in the genesis of the various lesions of COPD. In cigarette smoke-induced animal models of emphysema, MMP-12 appears to play a consistent and important role, whereas the data for other MMPs are difficult to interpret. In human lungs, evidence for a role for MMPs is more tenuous and there are numerous contradictions in the literature. Little is known about the effects of MMPs in small airway remodelling, smoke-induced pulmonary hypertension and chronic bronchitis, but MMP-12 participates in experimental small airway modelling. To date, the accumulated data suggest that selective inhibition of MMP-12 might be a viable therapy for emphysema and small airway remodelling, but subtle differences in the functions of MMP-12 in animals and humans mandate caution with this approach. Whether inhibition of other MMPs might be useful is unclear.
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Metaloproteinasas de la Matriz/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/enzimología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Animales , Bronquitis/enzimología , Colágeno/metabolismo , Enfisema/metabolismo , Humanos , Hipertensión Pulmonar/enzimología , Inflamación , Ratones , Ratones Endogámicos C57BL , Modelos Biológicos , Fumar , Resultado del TratamientoRESUMEN
CONTEXT: Cigarette smoke is known to be associated with pulmonary hypertension in humans and in animal models. Although the etiology of pulmonary hypertension in smokers is not understood, recent work has suggested a role for inducible nitric oxide synthase (iNOS) in inducing oxidative stress. OBJECTIVE AND METHODS: To further evaluate this question, we assessed eNOS-/- mice exposed to air or cigarette smoke for the presence of pulmonary hypertension and examined vascular remodeling and expression of nitrotyrosine, a marker of reactive nitrogen species-induced oxidative damage, using immunohistochemistry. To ascertain whether oxidants may play a role in humans, we also examined lung tissue from nonsmokers, and patients with chronic obstructive pulmonary disease (COPD) with and without pulmonary hypertension. RESULTS: We found that eNOS(-/-) mice developed increased pulmonary arterial pressure after six months cigarette smoke exposure, and this was associated with vascular remodeling and increased vascular nitrotyrosine staining. iNOS gene expression was decreased in the pulmonary arteries of the smoke exposed animals, and no protein was detectable by immunohistochemistry. In humans, vascular nitrotyrosine staining intensity was increased in smokers with COPD compared to nonsmokers, and further increased in smokers with combined COPD and pulmonary hypertension. CONCLUSIONS: We conclude that cigarette smoke-induced pulmonary hypertension is associated with evidence of oxidative vascular damage by reactive nitrogen species, but that iNOS does not appear to be the major contributor to such damage. Most likely the source of reactive nitrogen species is the cigarette smoke itself.
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Hipertensión Pulmonar/inducido químicamente , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fumar/efectos adversos , Animales , Biomarcadores , Humanos , Pulmón/irrigación sanguínea , Ratones , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
We assessed differences in locoregional outcome based on receptor status combinations in a cohort of stage II-III breast cancer patients treated with modern trimodality therapy. Medical records of 582 consecutively treated patients receiving post-mastectomy radiation (PMRT) between 1/1999 and 12/2009 were reviewed. Rate of local regional recurrence (LRR) was estimated by the method of cumulative incidence allowing for competing risks. The effect of prognostic factors was examined by Gray's test and by Fine and Gray's modeling approach. Median follow-up was 44.7 months. Five-year progression-free survival (PFS) was 73.9% and overall survival (OS) was 84%. The cumulative 5-year incidence of LRR as first site of failure was 6.2% (95% CI 4.2-8.7). Five-year cumulative incidence of LRR was 8.6 versus 4.4% for estrogen receptor (ER) negative versus ER positive (P = 0.017), 8.5 versus 3.4% for progesterone receptor (PR) negative versus PR positive (P = 0.011), and 1.7 versus 7.5% for HER2 positive (86% received trastuzamab) versus HER2 negative (P = 0.032). Five-year cumulative incidence of LRR was 11.8% for the triple negative subtype and 3.9% for other receptor combinations (P < 0.001). Among patients whose disease is ER positive, 5-year LRR rate was 7.8 versus 3.4% for PR negative versus PR positive (P = 0.130). The prognostic value of the triple negative and HER2 negative subtypes was maintained on multivariate analysis. In the era of HER-2 targeted therapy, tumors that are HER-2 over expressing and are treated with trastuzumab have a very low rate of LRR. ER negative, PR negative, and triple negative status are associated with increased risk of LRR.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Mastectomía , Recurrencia Local de Neoplasia , Radioterapia , Riesgo , Adulto , Anciano , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Terapia Combinada , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Resultado del TratamientoRESUMEN
N-{[5-(methanesulfonyl)pyridin-2-yl]methyl}-6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (AZD9668) is a novel, oral inhibitor of neutrophil elastase (NE), an enzyme implicated in the signs, symptoms, and disease progression in NE-driven respiratory diseases such as bronchiectasis and chronic obstructive pulmonary disease via its role in the inflammatory process, mucus overproduction, and lung tissue damage. In vitro and in vivo experiments were done to evaluate the binding kinetics, potency, and selectivity of AZD9668, its effects in whole-blood and cell-based assays, and its efficacy in models of lung inflammation and damage. In contrast to earlier NE inhibitors, the interaction between AZD9668 and NE was rapidly reversible. AZD9668 was also highly selective for NE over other neutrophil-derived serine proteases. In cell-based assays, AZD9668 inhibited plasma NE activity in zymosan-stimulated whole blood. In isolated human polymorphonuclear cells, AZD9668 inhibited NE activity on the surface of stimulated cells and in the supernatant of primed, stimulated cells. AZD9668 showed good crossover potency to NE from other species. Oral administration of AZD9668 to mice or rats prevented human NE-induced lung injury, measured by lung hemorrhage, and an increase in matrix protein degradation products in bronchoalveolar lavage (BAL) fluid. In an acute smoke model, AZD9668 reduced the inflammatory response to cigarette smoke as indicated by a reduction in BAL neutrophils and interleukin-1ß. Finally, AZD9668 prevented airspace enlargement and small airway wall remodeling in guinea pigs in response to chronic tobacco smoke exposure whether dosed therapeutically or prophylactically. In summary, AZD9668 has the potential to reduce lung inflammation and the associated structural and functional changes in human diseases.
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Elastasa de Leucocito/antagonistas & inhibidores , Piridonas/farmacología , Inhibidores de Serina Proteinasa , Sulfonas/farmacología , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/tratamiento farmacológico , Animales , Líquido del Lavado Bronquioalveolar/citología , Perros , Relación Dosis-Respuesta a Droga , Enfisema/inducido químicamente , Enfisema/patología , Femenino , Glicina/análogos & derivados , Glicina/farmacología , Cobayas , Humanos , Cinética , Ratones , Ratones Endogámicos BALB C , Oxadiazoles/farmacología , Neumonía/tratamiento farmacológico , Unión Proteica , Pirimidinonas/farmacología , Ratas , Especificidad de la Especie , Especificidad por Sustrato , Sulfonamidas/farmacología , Porcinos , Contaminación por Humo de Tabaco/efectos adversosRESUMEN
BACKGROUND: Cisplatin-based neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) is associated with improved overall and cancer-specific survival. The post-NAC pathological stage has previously been reported to be a major determinant of outcome. OBJECTIVE: To develop a postoperative nomogram for survival based on pathological and clinical parameters from an international consortium. DESIGN, SETTING, AND PARTICIPANTS: Between 2000 and 2015, 1866 patients with MIBC were treated at 19 institutions in the USA, Canada, and Europe. Analysis was limited to 640 patients with adequate follow-up who had received three or more cycles of NAC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A nomogram for bladder cancer-specific mortality (BCSM) was developed by multivariable Cox regression analysis. Decision curve analysis was used to assess the model's clinical utility. RESULTS AND LIMITATIONS: A total of 640 patients were identified. Downstaging to non-MIBC (ypT1, ypTa, and ypTis) occurred in 271 patients (42 %), and 113 (17 %) achieved a complete response (ypT0N0). The 5-yr BCSM was 47.2 % (95 % confidence interval [CI]: 41.2-52.6 %). On multivariable analysis, covariates with a statistically significant association with BCSM were lymph node metastasis (hazard ratio [HR] 1.90 [95% CI: 1.4-2.6]; p < 0.001), positive surgical margins (HR 2.01 [95 % CI: 1.3-2.9]; p < 0.001), and pathological stage (with ypT0/Tis/Ta/T1 as reference: ypT2 [HR 2.77 {95 % CI: 1.7-4.6}; p < 0.001] and ypT3-4 [HR 5.9 {95 % CI: 3.8-9.3}; p < 0.001]). The area under the curve of the model predicting 5-yr BCSM after cross validation with 300 bootstraps was 75.4 % (95 % CI: 68.1-82.6 %). Decision curve analyses showed a modest net benefit for the use of the BCSM nomogram in the current cohort compared with the use of American Joint Committee on Cancer staging alone. Limitations include the retrospective study design and the lack of central pathology. CONCLUSIONS: We have developed and internally validated a nomogram predicting BCSM after NAC and radical cystectomy for MIBC. The nomogram will be useful for patient counseling and in the identification of patients at high risk for BCSM suitable for enrollment in clinical trials of adjuvant therapy. PATIENT SUMMARY: In this report, we looked at the outcomes of patients with muscle-invasive bladder cancer in a large multi-institutional population. We found that we can accurately predict death after radical surgical treatment in patients treated with chemotherapy before surgery. We conclude that the pathological report provides key factors for determining survival probability.
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Cistectomía , Neoplasias de la Vejiga Urinaria , Cistectomía/métodos , Humanos , Músculos/patología , Terapia Neoadyuvante/métodos , Nomogramas , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
BACKGROUND: Internationally, foot trimming is used by most farmers, and parenteral antibacterials by some, to treat sheep with footrot. Nonsteroidal anti-inflammatory drugs (NSAID) are sometimes used. No clinical trials have compared these treatments. OBJECTIVES: To investigate the above treatments on time to recovery from lameness and foot lesions in sheep with footrot. ANIMALS: Fifty-three sheep with footrot on a commercial farm in England. METHODS: In a randomized factorial design, the sheep were allocated to 6 treatment groups. The treatments were oxytetracycline spray to all sheep (positive control) and one or more of parenteral administration of long-acting oxytetracycline, flunixine meglumine, and foot trimming on day 1 or 6 of diagnosis. Follow-up was for 15 days. Time to recovery from lameness and lesions was investigated with discrete-time survival models. RESULTS: There was significant association (P < .05) between recovery from lameness and lesions. Sheep receiving antibacterials parenterally recovered faster from lameness (odds ratio [OR]: 4.92 [1.20-20.10]) and lesions (OR: 5.11 [1.16-22.4]) than positive controls, whereas sheep foot trimmed on day 1 (lameness-OR: 0.05 [0.005-0.51]; lesions-OR: 0.06 [0.008-0.45]) or day 6 of diagnosis (lameness OR: 0.07 [0.01-0.72]; lesions OR: 0.07 [0.01-04).56]) recovered more slowly than positive controls. NSAID had no significant effect on recovery. CONCLUSIONS AND CLINICAL IMPORTANCE: If foot trimming on day 1 or 6 of diagnosis was stopped and parenteral antibacterials were used, then over 1 million sheep/annum lame with footrot in the United Kingdom would recover more rapidly with benefits to productivity. Globally, this figure would be much higher.
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Clonixina/análogos & derivados , Enfermedades del Pie/terapia , Oxitetraciclina/uso terapéutico , Enfermedades de las Ovejas/terapia , Crianza de Animales Domésticos , Animales , Antibacterianos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Clonixina/uso terapéutico , Cojera Animal/terapia , OvinosRESUMEN
Claw lesion treatment records were recorded by farmers on 27 dairy farms (3,074 cows, 36,432 records) in England and Wales between February 2003 and February 2004. These were combined with farm environment and management data collected using a combination of direct observations, interviews with farmers, and milk recording data. Multilevel models were constructed for the 3 most frequently reported lesions related to lameness, namely, sole ulcers, white line disease, and digital dermatitis. Risks associated with an increased incidence of sole ulcers were parity 4 or greater, the use of roads or concrete cow tracks between the parlor and grazing, the use of lime on free stalls, and housing in free stalls with sparse bedding for 4 mo or more. The risks for white line disease were increasing parity and increasing herd size, cows at pasture by day and housed at night, and solid grooved concrete floors in yards or alleys. Solid grooved flooring was also associated with an increased risk of digital dermatitis, and cows 6 or more months after calving had a decreased risk of a first case of digital dermatitis. These results improve our understanding of the specific risks for 3 important lesions associated with bovine lameness and could be used as interventions in future clinical studies targeted at the reduction of specific lesions.
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Enfermedades de los Bovinos/epidemiología , Enfermedades del Pie/veterinaria , Animales , Bovinos , Industria Lechera , Inglaterra/epidemiología , Femenino , Enfermedades del Pie/epidemiología , Pezuñas y Garras/patología , Embarazo , Factores de Riesgo , Gales/epidemiologíaRESUMEN
The pathogenesis of cigarette smoke-induced pulmonary hypertension is not understood. We have previously shown that smoke rapidly and persistently, but discoordinately, upregulates gene expression of mediators that control vasoconstriction, vasoproliferation, and vasorelaxation in small intrapulmonary arteries. To investigate the possibility that smoke also induces endothelial dysfunction, a finding common to other forms of pulmonary hypertension, we exposed guinea pigs to smoke or air (control) daily for 2 wk and then prepared precision-cut lung slices. After exposure to endothelin-1, a vasoconstrictor, intra-acinar arteries in lung slices derived from smoke-exposed animals constricted more rapidly (greater constriction at a given concentration of endothelin) than did vessels from air-exposed animals. To examine relaxation responses, arteries were constricted with the vasoconstrictor U-46619 and then relaxed with progressively increasing doses of acetylcholine. Vessels from smokers had a delayed response to acetylcholine compared with vessels from controls. The NO synthase inhibitor N(G)-nitro-L-arginine methyl ester reduced relaxation in both control and smoke-exposed arteries, whereas the NO donor sodium nitroprusside increased relaxation of the smoke-exposed arteries, confirming that endothelial dysfunction with decreased effective NO production is present. These findings show that precision cut lung slices can be used to examine the physiological effects of cigarette smoke on intra-acinar pulmonary arteries and indicate that even relatively short-term exposure to smoke produces endothelial dysfunction with a resulting tendency to earlier constriction and later relaxation in cigarette smokers. These changes may be important in the development of pulmonary hypertension.
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Arterias/patología , Endotelio Vascular/efectos de los fármacos , Pulmón/patología , Nicotiana , Humo/efectos adversos , Enfermedades Vasculares/inducido químicamente , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Acetilcolina/farmacología , Animales , Relación Dosis-Respuesta a Droga , Endotelina-1/farmacología , Inhibidores Enzimáticos/farmacología , Femenino , Cobayas , Contracción Muscular/efectos de los fármacos , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Nitroprusiato/farmacología , Técnicas de Cultivo de Órganos , Circulación Pulmonar/efectos de los fármacos , Circulación Pulmonar/fisiología , Enfermedades Vasculares/patología , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiología , Vasodilatadores/farmacologíaRESUMEN
The milk yields of 1824 cows were used to investigate the effect of lesion-specific causes of lameness, based on farmer treatment and diagnosis of lame cows, on milk yield. A three-level hierarchical model of repeated test day yields within cows within herds was used to investigate the impact of lesion-specific causes of lameness (sole ulcer, white line disease, digital dermatitis and other causes) on milk yield before and after treatment compared with unaffected cows. Cattle which developed sole ulcer (SU) and white line disease (WLD) were higher yielding cattle before they were diagnosed. Their milk production fell to below that of the mean of unaffected cows before diagnosis and remained low after diagnosis. In cattle which developed digital dermatitis (DD) there was no significant difference in milk yield before treatment and a slightly raised milk yield immediately after treatment. The estimated milk loss attributable to SU and WLD was approximately 570 and 370 kg, respectively. These results highlight that specific types of lameness vary by herds and within herds they are associated with higher yielding cattle. Consequently lesion-specific lameness reduction programmes targeting the cow and farm specific causes of lameness might be more effective than generic recommendations. They also highlight the importance of milk loss when estimating the economic impact of SU and WLD on the farms profitability.
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Enfermedades de los Bovinos/fisiopatología , Enfermedades del Pie/veterinaria , Pezuñas y Garras/patología , Cojera Animal/fisiopatología , Leche/metabolismo , Bienestar del Animal , Animales , Bovinos , Dermatitis/fisiopatología , Dermatitis/veterinaria , Inglaterra/epidemiología , Femenino , Enfermedades del Pie/fisiopatología , Úlcera del Pie/fisiopatología , Úlcera del Pie/veterinaria , Lactancia , Gales/epidemiologíaRESUMEN
BACKGROUND: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. METHODS: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. RESULTS: Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 × 10-2) and IL4 (rs2070874; HR 1.22; p-value = 1.1 × 10-3) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 × 10-2). CONCLUSIONS: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.
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Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Mutación de Línea Germinal , Interleucina-4/genética , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/mortalidad , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Ensayos Clínicos como Asunto , Estudios de Cohortes , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias de la Próstata/patología , Tasa de SupervivenciaRESUMEN
The effect of pulmonary blood flow on the exchange between the circulating was marginating pool of polymorphonuclear leukocytes (PMN) was examined in three sets of experiments. In the first we used the double indicator dilution technique with labeled PMN and erythrocytes (RBC) to calculate the percent extraction and percent recovery of PMN at different levels of cardiac output (CO). In the second group of experiments we took advantage of the wide range of blood flow in the lung to determine the effect of regional blood flow on regional PMN retention, and in the third set we measured total leukocyte (WBC) and PMN counts in simultaneous samples from the pulmonary artery and aorta over a wide range of cardiac output. The studies showed that 80-90% of the labeled PMN were removed in a single pass through the lung and that regional retention of labeled PMN and A-V differences for unlabeled PMN increased with decreasing blood flow. The data for regional retention of labeled PMN and the A-V differences observed for unlabeled cells both fit the equation Y = A + Be-cx (where A + B = 100), which showed that PMN accumulate in the lung as blood flow is reduced. We conclude that a dynamic equilibrium exists between the circulating and marginating pools of leukocytes in the lung and that blood flow primarily effects the reentry of cells into the circulating pool so that the marginating pool of PMN within the lung accumulates cells when blood flow is reduced below 7 ml/min per g.
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Pulmón/fisiología , Neutrófilos/fisiología , Circulación Pulmonar , Animales , Aorta Torácica/fisiología , Velocidad del Flujo Sanguíneo , Gasto Cardíaco , Movimiento Celular , Perros , Ápice del Flujo Espiratorio , Vena Cava Inferior/fisiologíaRESUMEN
Although small airway remodeling (SAR) leading to airflow obstruction is a common consequence of human cigarette smoking, the airways have been largely ignored in animal models of chronic obstructive pulmonary disease (COPD). We examined lung structure in a guinea pig model of chronic cigarette smoke exposure to ascertain whether smoke induced SAR, and to evaluate how these anatomic lesions correlate with physiologic changes. We used tissue from guinea pigs exposed to cigarette smoke or air for 6 mo. Pulmonary function tests were performed, and histologic sections were prepared. Airspace size (Lm) and changes in the structure of the small airways were evaluated by morphometric analysis. Chronic smoke exposure was associated with increased airway wall thickness and increased amounts of thick collagen fibers in the walls of the small airways, as well as with increased Lm. The increase in thick collagen fibers related negatively to peak expiratory volume (PEF) and the ratio of forced expiratory volume in 1 s to forced ventilatory capacity (FEV(0.1)/FVC), and positively to airway resistance. Physiologic lung volumes were predicted by airspace size, but residual volume (RV) and total lung capacity (TLC) also were related to airway wall thickness. Amounts of smooth muscle were not changed and did not predict any physiologic abnormalities. We conclude that cigarette smoke exposure results in SAR in the guinea pig, alterations that are reflected in increased airways resistance with diminished airflow and air trapping, mimicking human disease. This model should prove useful in further investigations into the mechanisms of airway remodeling.
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Modelos Animales de Enfermedad , Enfermedad Pulmonar Obstructiva Crónica/patología , Mucosa Respiratoria/patología , Fumar/patología , Animales , Femenino , Cobayas , Enfermedad Pulmonar Obstructiva Crónica/etiología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Pruebas de Función Respiratoria/métodos , Mucosa Respiratoria/fisiopatología , Fumar/efectos adversos , Fumar/fisiopatologíaRESUMEN
Forty-nine farms in England and Wales were visited on 4 occasions between February 2003 and March 2004. A total of 21,693 scores of locomotion were assigned to 7,722 cattle. Locomotion was assessed on a 3-point scale by observing the posture of a cow's back while standing and walking (1 = sound, 2 = not sound, 3 = lame). Data on measurable factors potentially associated with locomotion were collected from all farms using direct observations of the farm environment and a comprehensive farmer interview. The mean herd locomotion score was 1.77 +/- 0.02. There was no significant difference in mean herd locomotion scores between 5 herds housed in straw yards (1.72 +/- 0.02) and 44 herds housed in free stalls (1.78 +/- 0.02), possibly because of lack of power. A GLM was produced using data from the 44 herds housed in free stalls, with the mean farm locomotion score of all cows examined on all 4 visits as the outcome variable. Factors associated with an elevated locomotion score were dry cows kept in straw yards compared with free stalls (increase in locomotion score = 0.06 +/- 0.03), pregnant heifers kept with milking cows in winter compared with being kept with dry cows (increase in locomotion score = 0.09 +/- 0.03), aisle widths of < 3 m compared with widths of > or = 3 m (increase in locomotion score = 0.06 +/- 0.02), a curb height of < or = 15 cm compared with a height of > 15 cm (increase in locomotion score = 0.07 +/- 0.03), routine trimming of hooves of all cows by a hoof trimmer or by the farmer compared with no routine hoof trimming (increase in locomotion score = 0.18 +/- 0.04 and 0.13 +/- 0.03 respectively), feeding corn silage to milking cows compared with feeding other forage types (increase in locomotion score = 0.10 +/- 0.03), and the use of automatic scrapers in the free-stall barn compared with tractor scrapers (increase in locomotion score = 0.10 +/- 0.03). These variables were correlated with many other management variables. The use of automatic scrapers was correlated with the use of sawdust on rubber mats in free stalls. Curb height was negatively correlated with increasing distance of the neck rail from the front (head end) of the free stall. These putative risk factors support the hypothesis that locomotion score is linked to management factors; in particular, the combination of sawdust on rubber mats with automatic scrapers was associated with elevated locomotion scores.
Asunto(s)
Enfermedades de los Bovinos/prevención & control , Industria Lechera/métodos , Cojera Animal/prevención & control , Locomoción/fisiología , Animales , Bovinos , Enfermedades de los Bovinos/epidemiología , Inglaterra/epidemiología , Femenino , Pisos y Cubiertas de Piso , Vivienda para Animales , Cojera Animal/epidemiología , Modelos Lineales , Embarazo , Factores de Riesgo , Estaciones del Año , Índice de Severidad de la Enfermedad , Estadística como Asunto , Gales/epidemiologíaRESUMEN
A 3-point locomotion scoring system was used that incorporated the position of the back of cows while standing and when walking to investigate risk factors for elevated locomotion scores of 1,450 dairy cows on 19 farms in The Netherlands. Each of the farms was visited twice in an 18-mo period from February 2003 to July 2004. At each visit, all milking and dry cows were scored for locomotion by a single observer. Two multivariable regression models were constructed to identify factors associated with elevated mean locomotion score (increased abnormality) and the percentage of cows with the highest score (score 3). Risk factors for increased locomotion score were having a hoof-trimming stall with foot-lifting apparatus compared with not having such apparatus (increase in locomotion score = 0.15), presence of a footbath at the parlor exit or other site compared with not having a footbath on the farm (increase in locomotion score = 0.17 and 0.19, respectively), not providing supplemental vitamins and minerals to lactating cows compared with supplementing animals (increase in locomotion score = 0.17) and feeding corn silage to heifers compared with not doing so (increase in locomotion score = 0.10). The results provide a framework for hypotheses for future investigations of risk factors for high locomotion scores.
Asunto(s)
Bovinos/fisiología , Locomoción/fisiología , Análisis de Varianza , Animales , Enfermedades de los Bovinos/diagnóstico , Enfermedades de los Bovinos/fisiopatología , Industria Lechera/instrumentación , Industria Lechera/métodos , Dieta , Femenino , Pezuñas y Garras/fisiología , Lactancia , Cojera Animal/diagnóstico , Cojera Animal/fisiopatología , Minerales/administración & dosificación , Países Bajos , Análisis de Regresión , Factores de Riesgo , Ensilaje , Encuestas y Cuestionarios , Vitaminas/administración & dosificación , Zea maysRESUMEN
BACKGROUND: The TMPRSS2:ERG (T2E) gene fusion is the most common rearrangement in prostate cancer (PCa). It is unknown if these molecular subtypes have a different etiology. We evaluated aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) in association with T2E fusion status. METHODS: Subjects were from a population-based case-control study of PCa. T2E fusion status for prostatectomy cases (n=346) was determined by fluorescence in situ hybridization. Medication use was determined from questionnaires. Logistic regression, controlling for age, race, PCa family history and PSA screening, was used to evaluate the association of T2E fusion status according to medication use. RESULTS: T2E fusion was present in 171 (49%) cases, with younger cases more likely to be fusion positive (P<0.01). Current aspirin use was associated with a 37% risk reduction of T2E-positive tumors (adjusted odds ratio (OR) 0.63, 95% confidence interval 0.43-0.93). Aspirin use was not associated with T2E negative PCa (adjusted OR 0.99, 0.69-1.42). There were no associations between PCa fusion status and use of nonaspirin NSAIDs or acetaminophen. CONCLUSIONS: Aspirin was associated with a significant reduction in the relative risk of T2E fusion positive, but not T2E negative, PCa. As inflammation and androgen pathways are implicated in prostate carcinogenesis, additional studies of anti-inflammatory medications in relation to these PCa subtypes are warranted.
Asunto(s)
Antiinflamatorios no Esteroideos/administración & dosificación , Aspirina/administración & dosificación , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Próstata/tratamiento farmacológico , Adulto , Anciano , Andrógenos/genética , Andrógenos/metabolismo , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Próstata/efectos de los fármacos , Próstata/patología , Prostatectomía , Neoplasias de la Próstata/clasificación , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patologíaRESUMEN
BACKGROUND: Obesity is a risk factor for incident prostate cancer (PC) as well as risk of disease progression and mortality. We hypothesized that men diagnosed with lower-risk PC and who elected active surveillance (AS) for their cancer management would likely initiate lifestyle changes that lead to weight loss. METHODS: Patients were enrolled in the Prostate Active Surveillance Study (PASS), a multicenter prospective biomarker discovery and validation study of men who have chosen AS for their PC. Data from 442 men diagnosed with PC within 1 year of study entry who completed a standard of care 12-month follow-up visit were analyzed. We examined the change in weight and body mass index (BMI) over the first year of study participation. RESULTS: After 1 year on AS, 7.5% (33/442) of patients had lost 5% or more of their on-study weight. The proportion of men who lost 5% or more weight was similar across categories of baseline BMI: normal/underweight (8%), overweight (6%) and obese (10%, χ2 test P=0.44). The results were similar for patients enrolled in the study 1 year or 6 months after diagnosis. By contrast, after 1 year, 7.7% (34/442) of patients had gained >5% of their weight. CONCLUSIONS: Only 7.5% of men with low-risk PC enrolled in AS lost a modest (⩾5%) amount of weight after diagnosis. Given that obesity is related to PC progression and mortality, targeted lifestyle interventions may be effective at this 'teachable moment', as men begin AS for low-risk PC.
Asunto(s)
Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Pérdida de Peso/fisiología , Anciano , Índice de Masa Corporal , Peso Corporal/fisiología , Progresión de la Enfermedad , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Obesidad/patología , Estudios Prospectivos , Factores de RiesgoRESUMEN
Alpha1-antitrypsin (alpha1AT) therapy is used as a treatment for alpha1AT deficiency. It has also been proposed as a therapy for cigarette smoke-induced emphysema, although the efficacy of such therapy is as yet unproven. Moreover, the optimal route of delivery of alpha1AT to the lung interstitium, the crucial locus of action, is unknown. We created transgenic mice with expression of the human alpha1AT gene directed by a human surfactant protein C (SpC) promoter fragment or a rat Clara cell 10-kDa protein (CC10) promoter fragment in order to examine the ability of pulmonary epithelial cell expression of alpha1AT to deliver protein to the interstitium, and to produce a model that would allow studies on the efficacy of alpha1AT in preventing lung damage after cigarette smoke exposure. Four transgenic lines were studied. In situ hybridization and light microscopic immunohistochemistry showed that two CC10 driven lines expressed human alpha1AT in type 11 alveolar cells and airway epithelial cells; alpha1AT expression was seen in the alveolar parenchyma in two SpC driven lines, and in small airway epithelium in one of the SpC lines. Electron microscopic immunochemistry showed the presence of the human alpha1AT protein in the interstitium in all lines. Mean levels of human protein varied from 0.37 to 2.9 microg/g lung protein and serum levels from 0.72 to 1.3 microg/ml, compared to normal human serum alpha1AT levels of 2-5 mg/ml. We conclude that transgene-mediated expression of alpha1AT in pulmonary epithelial cells results in diffuse expression of the transgene in the alveolar parenchyma and reproducibly leads to transfer of protein to the interstitium. The present model is, however, limited by low levels of protein production; limited protein production may be a problem in other forms of gene therapy in which relatively large amounts of extracellular protein are needed in the lung for a therapeutic effect.