Endothelial ILK induces cardioprotection by preventing coronary microvascular dysfunction and endothelial-to-mesenchymal transition.

Endothelial dysfunction is an early event in coronary microvascular disease. Integrin-linked kinase (ILK) prevents endothelial nitric oxide synthase (eNOS) uncoupling and, thus, endothelial dysfunction. However, the specific role of endothelial ILK in cardiac function remains to be fully elucidated. We hypothesised that endothelial ILK plays a crucial role in maintaining coronary microvascular function and contractile performance in the heart. We generated an endothelial cell-specific ILK conditional knock-out mouse (ecILK cKO) and investigated cardiovascular function. Coronary endothelial ILK deletion significantly impaired cardiac function: ejection fraction, fractional shortening and cardiac output decreased, whilst left ventricle diastolic internal diameter decreased and E/A and E/E' ratios increased, indicating not only systolic but also diastolic dysfunction. The functional data correlated with extensive extracellular matrix remodelling and perivascular fibrosis, indicative of adverse cardiac remodelling. Mice with endothelial ILK deletion suffered early ischaemic-like events with ST elevation and transient increases in cardiac troponins, which correlated with fibrotic remodelling. In addition, ecILK cKO mice exhibited many features of coronary microvascular disease: reduced cardiac perfusion, impaired coronary flow reserve and arterial remodelling with patent epicardial coronary arteries. Moreover, endothelial ILK deletion induced a moderate increase in blood pressure, but the antihypertensive drug Losartan did not affect microvascular remodelling whilst only partially ameliorated fibrotic remodelling. The plasma miRNA profile reveals endothelial-to-mesenchymal transition (endMT) as an upregulated pathway in endothelial ILK conditional KO mice. Our results show that endothelial cells in the microvasculature in endothelial ILK conditional KO mice underwent endMT. Moreover, endothelial cells isolated from these mice and ILK-silenced human microvascular endothelial cells underwent endMT, indicating that decreased endothelial ILK contributes directly to this endothelial phenotype shift. Our results identify ILK as a crucial regulator of microvascular endothelial homeostasis. Endothelial ILK prevents microvascular dysfunction and cardiac remodelling, contributing to the maintenance of the endothelial cell phenotype.

The prognostic impact of circulating miRNAs in patients with advanced esophagogastric cancer during palliative chemotherapy.

The prognosis of patients with advanced oesophageal cancer (EC) and gastric cancer (GC) is poor. Circulating microRNAs (ci-miRNAs) may have prognostic and predictive value to improve patient selection for palliative treatment. The purpose of this study is to assess the prognostic and predictive value of specific ci-miRNAs in plasma of patients with EC and GC treated with first-line palliative gemcitabine and cisplatin. Droplet digital PCR (ddPCR) was used to quantify miR-200c-3p, miR-375, miR-21-5p, miR-148a-3p, miR-146a-5p, miR-141-3p and miR-218-5p in plasma from 68 patients. ci-miRNA expression was analyzed in relation to overall survival (OS), progression-free survival (PFS), and response to chemotherapy. ci-miRNA levels were detectable in 36 baseline (71%) samples and in 14 (47%) follow-up samples. Increased circulating miR-200c-3p in GC showed a trend (p = 0.06) towards a shorter OS. High circulating miR-375 was associated with a longer OS (p = 0.02) in patients with esophageal adenocarcinoma (EAC). No significant difference was observed in ci-miRNA expression between paired pre- and on-treatment samples. ci-miRNA expression was not associated with response to chemotherapy. ci-miRNAs can be measured in plasma samples of patients treated with first-line palliative chemotherapy using ddPCR despite prolonged storage in heparin. Elevated circulating miR-375 might be a prognostic marker for patients with EAC.

Bisphenol A induces coronary endothelial cell necroptosis by activating RIP3/CamKII dependent pathway.

Epidemiological studies link long term exposure to xenoestrogen Bisphenol-A to adverse cardiovascular effects. Our previous results show that BPA induces hypertension by a mechanism involving CamKII activation and increased redox stress caused by eNOS uncoupling. Recently, CamKII sustained activation has been recognized as a central mediator of programmed cell death in cardiovascular diseases, including necroptosis. However, the role of necroptosis in cardiac response to BPA had not yet been explored. Mice exposed to BPA for 16 weeks showed altered heart function, electrical conduction, and increased blood pressure. Besides, a stress test showed ST-segment depression, indicative of cardiac ischemia. The hearts exhibited cardiac hypertrophy and reduced vascularization, interstitial edema, and large hemorrhagic foci accompanied by fibrinogen deposits. BPA initiated a cardiac inflammatory response, up-regulation of M1 macrophage polarization, and increased oxidative stress, coinciding with the increased expression of CamKII and the necroptotic effector RIP3. In addition, cell death was especially evident in coronary endothelial cells within hemorrhagic areas, and Evans blue extravasation indicated a vascular leak in response to Bisphenol-A. Consistent with the in vivo findings, BPA increased the necroptosis/apoptosis ratio, the expression of RIP3, and CamKII activation in endothelial cells. Necrostatin-1, an inhibitor of necroptosis, alleviated BPA induced cardiac dysfunction and prevented the inflammatory and hemorrhagic response in mice. Mechanistically, silencing of RIP3 reversed BPA-induced necroptosis and CamKII activation in endothelial cells, while inhibition of CamKII activation by KN-93 had no effect on RIP3 expression but decreased necroptotic cell death suggesting that BPA induced necroptosis is mediated by a RIP 3/CamKII dependent pathway. Our results reveal a novel pathogenic role of BPA on the coronary circulation. BPA induces endothelial cell necroptosis, promotes the weakening of coronary vascular wall, which caused internal ventricular hemorrhages, delaying the reparative process and ultimately leading to cardiac dysfunction.

Immunostaining in whole-mount lipid-cleared peripheral nerves and dorsal root ganglia after neuropathy in mice.

Immunohistochemical characterization of primary afferent fibers (intact or after nerve damage) is traditionally performed in thin sections from dorsal root ganglia (DRGs) or in teased fibers, as light scattering in whole-mounts compromises visualization. These procedures are time-consuming, require specific equipment and advanced experimental skills. Lipid-clearing techniques are increasing in popularity, but they have never been used for the peripheral nervous system. We established a modified, inexpensive clearing method based on lipid-removal protocols to make transparent peripheral nerve tissue (inCLARITY). We compared retrograde-labeling and free-floating immunostaining with cryo-sections. Confocal microscopy on whole-mount transparent DRGs showed neurons marked with retrograde tracers applied to experimental neuromas (Retrobeads, Fluoro-ruby, Fluoro-emerald, DiI, and Fluoro-gold). After immunostaining with calcitonin gene-related peptide (peptidergic) or isolectin IB4 (non-peptidergic), nociceptors were visualized. Immunostaining in transparent whole-mount nerves allows simultaneous evaluation of the axotomized branches containing the neuroma and neighboring intact branches as they can be mounted preserving their anatomical disposition and fiber integrity. The goal of our study was to optimize CLARITY for its application in peripheral nerve tissues. The protocol is compatible with the use of retrograde tracers and improves immunostaining outcomes when compared to classical cryo-sectioning, as lack of lipids maximizes antibody penetration within the tissue.

The teratogenicity of allopurinol: A comprehensive review of animal and human studies.

Allopurinol is widely used in the management of multiple disorders including gout, kidney stones and inflammatory bowel disease. Despite of long-term experience, its safety in pregnancy has been debated due to reports on possible teratogenicity. We aimed to review the literature on the safety of allopurinol in pregnancy and offspring. In animals, allopurinol induced species-specific reproductive toxicity. In humans, a total of 53 allopurinol exposed infants were reported in the literature. Major congenital malformations were reported in two cases with a comparable pattern of multiple abnormalities. Five other infants had minor birth defects. In conclusion, the association between allopurinol and teratogenicity appears to be weak and limited to two reports with uncertain causality. However, the available data are insufficient to make a certain judgement, and as allopurinol treatment evolves, report and prospective follow-up of all exposed infants (i.e. deviant and normal cases) should be encouraged.

Hyperpolarization-activated channels shape temporal patterns of ectopic spontaneous discharge in C-nociceptors after peripheral nerve injury.

BACKGROUND: Neuropathic pain is thought to be mediated by aberrant impulses from sensitized primary afferents, and the temporal summation of the discharges might also influence nociceptive processing. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (Ih current) generate rhythmic activity in neurons within the central nervous system and contribute to nociceptors excitability in neuropathic pain. METHODS: We searched for single fibres with ectopic spontaneous discharges from an in vitro preparation in mice containing a neuroma formed in a peripheral branch of the saphenous nerve together with the undamaged branches. RESULTS: Both damaged (axotomized) and undamaged fibres (putative intact) developed ectopic spontaneous activity with different temporal spike trains: Clock-like, Irregular or Bursts. The Ih current blocker, ZD7288, significantly suppressed ectopic spontaneous discharges in nociceptive fibres (3/5 Aδ- and 24/31 C-units and 1 nonclassified) by 64%. Additionally, ZD7288 changed the spike patterns of 5/7 Clock-like and 3/4 Burst units to Irregular. Exogenous cAMP produced a significant ~65% increase in the ectopic firing in 5 Irregular fibres, which was restored by ZD7288. In six additional fibres (three Clock-like and three Irregular), exogenous cAMP had no further effect, but co-application with ZD7288 decreased their discharge by half. These units showed significant higher levels of discharges than the cAMP-sensitive ones. CONCLUSIONS: Our data suggest that HCN channels modulate ectopic spontaneous firing in C-nociceptors and shape their temporal patterns of discharge which will, ultimately, modify the nociceptive message received and processed by second-order neurons. SIGNIFICANCE: We show an involvement of HCN channels in the modulation of ectopic spontaneous discharges from C-nociceptors. This finding exposes a mechanism of nociceptive transmission enhancement and highlights the clinical relevance of peripheral HCN blockade for spontaneous pain relief during neuropathy.

Recomendaciones sobre el diagnóstico y manejo de la enfermedad pleural y pulmonar por asbesto / Recommendations for the diagnosis and management of asbestos-related pleural and pulmonary disease

Asbesto, también conocido en España como amianto, es el término utilizado para nombrar a un conjunto de silicatos minerales que suelen romperse en fibras. Su uso ha comportado la aparición de numerosas enfermedades, especialmente pleuropulmonares, todas ellas caracterizadas por su prolongada latencia. El asbesto es, además, un carcinógeno del grupo IA reconocido por la OMS desde 1987. En España está prohibido desde 2002. La publicación en 2013 de la 3.ª edición del protocolo de vigilancia sanitaria específica del amianto junto con la aparición de nuevas técnicas diagnósticas han motivado al grupo EROM de SEPAR a promover la elaboración de esta normativa que revisa aspectos clínicos, radiológicos y funcionales de las diferentes enfermedades relacionadas. También establece recomendaciones para el diagnóstico y seguimiento de los pacientes expuestos. Dichas recomendaciones han sido establecidas mediante sistema GRADE.(AU)

Asbestos is the term used for a set of mineral silicates that tend to break up into fibers. Its use has been associated with numerous diseases affecting the lung and pleura in particular, all of which are characterized by their long period of latency. Asbestos, moreover, has been recognized by the WHO as a Group IA carcinogen since 1987 and its use was banned in Spain in 2002. The publication in 2013 of the 3rd edition of the specific asbestos health monitoring protocol, together with the development of new diagnostic techniques, prompted the SEPAR EROM group to sponsor publication of guidelines, which review the clinical, radiological and functional aspects of the different asbestos-related diseases. Recommendations have also been made for the diagnosis and follow-up of exposed patients. These recommendations were drawn up in accordance with the GRADE classification system.(AU)

Spontaneous activity in C-fibres after partial damage to the saphenous nerve in mice: Effects of retigabine.

BACKGROUND: Spontaneous pain is the most devastating positive symptom in neuropathic pain patients. Recent data show a direct relationship between spontaneous discharges in C-fibres and spontaneous pain in neuropathic patients. Unfortunately, to date there is a lack of experimental animal models for drug testing. METHODS: We recorded afferent fibres from a new experimental model in vitro. The preparation contains a neuroma formed in a peripheral branch of the saphenous nerve together with the undamaged branches, which maintain intact terminals in a skin flap. RESULTS: Fibres with stable rates of ectopic spontaneous discharges were found among axotomized (5 A- and 18 C-fibres, mean discharge 0.48 ± 0.08 Hz) and 'putative intact' fibres (12 C-fibres, mean discharge 0.28 ± 0.08 Hz). A proportion (~9%) of axotomized fibres had mechanical receptive fields in the skin far beyond the site of injury. Collision experiments demonstrated that action potentials evoked from neuroma and skin travelled by the same fibre, indicating functional cross-talk between neuromatose and putative intact fibres. Retigabine, the specific Kv7 channel opener, depressed spontaneous discharges by 70% in 15/18 units tested. In contrast, responses to mechanical stimulation of the skin were unaltered by retigabine. CONCLUSIONS: Partial damage to a peripheral nerve may increase the incidence of spontaneous activity in C-fibres. Retigabine reduced spontaneous activity but not stimulus-evoked activity, suggesting an important role for ion channels in the control of spontaneous pain and demonstrating the utility of the model for the testing of compounds in clinically relevant variables. WHAT DOES THIS STUDY ADD?: Our in vitro experimental model of peripheral neuropathy allows for pharmacological characterization of spontaneously active fibres. Using this model, we show that retigabine inhibits aberrant spontaneous discharges without altering physiological responses in primary afferents.

Effects of centrally acting analgesics on spinal segmental reflexes and wind-up.

BACKGROUND: The spinal cord is a prime site of action for analgesia. Here we characterize the effects of established analgesics on segmental spinal reflexes. The aim of the study was to look for the pattern of action or signature of analgesic effects on these reflexes. METHODS: We used a spinal cord in vitro preparation of neonate mice to record ventral root responses to dorsal root stimulation. Pregabalin, clonidine, morphine and duloxetine and an experimental sigma-1 receptor antagonist (S1RA) were applied to the preparation in a cumulative concentration protocol. Drug effects on the wind-up produced by repetitive stimulation of C-fibres and on responses to single A- and C-fibre intensity stimuli were analysed. RESULTS: All compounds produced a concentration-dependent inhibition of total spikes elicited by repetitive stimulation. Concentrations producing ∼50% reduction in this parameter were (in µM) clonidine (0.01), morphine (0.1), pregabalin (1), duloxetine (10) and S1RA (30). At these concentrations clonidine, pregabalin and S1RA had significant effects on the wind-up index and little depressant effects on responses to single stimuli. Morphine and duloxetine did not depress wind-up index and showed large effects on responses to single stimuli. None of the compounds had strong effects on the amplitude of the non-nociceptive monosynaptic reflex. CONCLUSIONS: morphine and duloxetine had general depressant effects on spinal reflexes, whereas the effects of clonidine, pregabalin and S1RA appeared to be restricted to signals originated by strong repetitive activation of C-fibres. Results are discussed in the context of reported behavioural effects of the compounds studied.

Axotomy-induced changes in activity-dependent slowing in peripheral nerve fibres: role of hyperpolarization-activated/HCN channel current.

BACKGROUND: Slowing refers to the gradual decrease in conduction velocity evoked by repetitive electrical stimuli. The underlying mechanisms are still poorly understood, and its physiological/pathological relevance scarcely discussed; however, changes in axonal conduction properties might unmask abnormal nociceptor function and alter the encoding time window at the spinal cord. METHODS: Here, we characterized and compared the slowing in isolated units recorded from intact and axotomized saphenous nerves from mice, in vitro. We evaluated the role of hyperpolarization-activated/HCN channel current, Ih , in the generation of slowing, by examining the effect of the specific Ih blocker ZD7288. RESULTS: Based on their degree of slowing, intact C-fibres were classified as presumed nociceptors or non-nociceptors (>13% or <7% latency increase, respectively). Upon ZD7288 treatment, slowing was significantly augmented in 19/25 of the presumed C-nociceptors. In nerve-end neuromas, axotomized C-fibres could not be classified by their degree of slowing, which, in addition, was unrelated to the presence of ectopic mechanosensitivity. Axotomized fibres showed a ∼2.5-fold reduction in their slowing as compared with intact units and the effects of ZD7288 were more prominent, both in magnitude and percentage of sensitive fibres. Interestingly, in control conditions, all fibres sensitive to ZD7288 were more resistant to slowing. CONCLUSIONS: Under our experimental conditions, slowing seems largely dependent on functional Ih . The marked decrease in slowing after axotomy in C-fibres fits with the increased expression of functional hyperpolarization-activated/HCN channel current and may underlie the analgesic effects of the specific Ih blocker ZD7288 previously described in neuropathic pain models.

Previous outpatient antibiotic use in patients admitted to hospital for COPD exacerbations: room for improvement.

PURPOSE: Several studies have analyzed factors associated to hospitalization in chronic obstructive pulmonary disease (COPD) patients. However, data are lacking on the quality of treatment received by patients prior to hospital admission. The present study analyzed how often patients requiring hospitalization for a COPD exacerbation had received previous treatment for the exacerbation, particularly antibiotics. METHODS: This was a multicenter, cross-sectional, observational study conducted in 30 Spanish hospitals among COPD patients aged >40 years who were hospitalized for an acute exacerbation. Patients were grouped according to whether or not they had received treatment prior to admission and, subsequently, according to whether or not they had received antibiotics. Patient eligibility for antibiotic therapy was assessed using both national and European guidelines. RESULTS: The study population consisted of 298 patients, of which 277 (93 %) were men, with a mean [standard deviation (SD)] age of 69.1 (9.5) years. One hundred and thirty-three patients (45 %) had received treatment prior to admission; among these, 76/133 (57 %) had received antibiotic therapy. However, 81-91 % of these patients fulfilled criteria for this therapy. Antibiotic use was significantly associated with yellow or green-yellow sputum prior to the exacerbation, a higher number of exacerbations in the previous year, more visits to emergency departments, and bronchiectasis. On the other hand, 10-20 % of patients who did receive antibiotics were not eligible for this therapy according to guidelines. CONCLUSIONS: This study demonstrates a low rate of previous outpatient treatment and antibiotic use among patients with a COPD exacerbation requiring hospital admission.

Niveles séricos de mesotelina. Valor pronóstico en mesotelioma pleural maligno / Serum levels of mesothelin. Prognosis value in malignant pleural mesothelioma

El mesotelioma pleural maligno (MPM) es un tumor agresivo que surge del epitelio pleural. Se han detectado concentraciones aumentadas de proteínas solubles relacionadas con la mesotelina (SMRP) en suero de pacientes con MPM (..) (AU)

Malignant pleural mesothelioma (MPM) is an aggressive tumour that arises from pleural epithelium. Increased concentrations of soluble mesothelin related proteins (SMRP)

Ultrastructural characterization of relationship between serotonergic and GABAergic structures in the ventral part of the oral pontine reticular nucleus.

The ventral part of the oral pontine reticular nucleus (vRPO) is involved in the generation and maintenance of rapid eye movement (REM) sleep. Both GABAergic and serotonergic neurotransmission have been implicated in the control of the sleep-wakefulness cycle. Nevertheless, the synaptic organization of serotonergic terminals in the vRPO has not yet been characterized. We performed an electron microscope study of serotonin-immunoreactive (5-HT-IR) terminals using immunoperoxidase or immunogold-silver methods. In a second set of experiments, combining GABA immunoperoxidase and 5-HT immunogold-silver techniques, we examined inputs from GABA-immunoreactive (GABA-IR) terminals to serotonergic neurons. 5-HT-IR terminals were located primarily on dendrites and occasionally on somata of unlabeled and 5-HT-IR neurons. The majority of the synapses formed by 5-HT-IR terminals were of the symmetrical type, making contacts primarily with unlabeled dendritic profiles. Moreover, 5-HT-IR terminals contacted unlabeled axon terminals that formed asymmetric synapses on dendrites. Double immunolabeling experiments showed 5-HT-IR and GABA-IR afferents, in apposition to each other, making synapses with the same dendrites. Finally, GABA-IR terminals innervated 5-HT-IR and GABA-IR dendrites. Our findings indicate that serotonin would modulate the neuronal activity through inhibitory or excitatory influences, although the action of serotonin on the vRPO would predominantly be inhibitory. Moreover, the present results suggest that the serotonin modulation of vRPO neurons might involve indirect connections. In addition, GABA might contribute to the induction and maintenance of REM sleep by inhibiting serotonergic and GABAergic neurons in the vRPO.

Efficacy of moxifloxacin in the treatment of bronchial colonisation in COPD.

This study was designed to investigate the efficacy of moxifloxacin for the eradication of bacterial colonisation of the airways in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Out of 119 stable patients with COPD screened, 40 (mean age 69 yrs, mean forced expiratory volume in 1 s 50% predicted) were colonised with potentially pathogenic microorganisms (PPMs) and were included in a randomised, double-blind, placebo-controlled trial with moxifloxacin 400 mg daily for 5 days. Eradication rates were 75% with moxifloxacin and 30% with placebo at 2 weeks (p = 0.01). Bacterial persistence at 8 weeks was still higher (not significantly) in the placebo arm (five (25%) out of 20 versus one (5%) out of 20; p = 0.18). The frequencies of acquisition of a new PPM were high and similar in both treatment groups; consequently, the prevalence of colonisation at 8 weeks was also similar between treatment arms. No difference was found in the number of patients with exacerbations during the 5-month follow-up. Only the acquisition of a new PPM during follow-up showed a statistically significant relationship with occurrence of an exacerbation. Moxifloxacin was effective in eradicating PPMs in patients with positive sputum cultures. However, most patients were recolonised after 8 weeks of follow-up. Acquisition of a new strain of bacteria was associated with an increased risk of developing an exacerbation.

GABAergic structures in the ventral part of the oral pontine reticular nucleus: An ultrastructural immunogold analysis.

GABA mediates inhibitory effects in neurons of the ventral part of the oral pontine reticular nucleus (vRPO). Evidence increasingly suggests that GABA plays an important role in the modulation of rapid eye movement (REM) sleep generation in the cat vRPO. Here, we investigate the anatomical substrate of this modulation using GABA immunocytochemistry. Immunoperoxidase labeling revealed a few small GABA-immunoreactive cell bodies scattered throughout the vRPO. The numerical densities of all vRPO synapses and the GABA-immunoreactive synapses were estimated, at the electron microscopical level, by using a combination of the physical disector and the post-embedding immunogold techniques. We estimated that 30% of all vRPO synaptic terminals were immunoreactive to GABA. Our findings support the hypothesis that vRPO neuron activity is significantly controlled by inhibitory GABAergic terminals that directly target somata and the different parts of the dendritic tree, including distal regions. GABAergic input could inhibit vRPO REM sleep-inducing neurons during other states of the sleep-wakefulness cycle such as wakefulness or non-REM sleep.

Alpha-1-antitrypsin deficiency: optimal therapeutic regimen based on population pharmacokinetics.

BACKGROUND: Exogenous doses of 60 mg/kg alpha(1)-antitrypsin (AAT) every 7 days are recommended in patients with severe AAT deficiency. However, long term administration of weekly doses is not well accepted by patients. Using pharmacokinetic simulations, we evaluated whether steady state minimum concentrations of total AAT can be maintained above the threshold of 0.5 g/l with longer intervals between doses. METHODS: Several sets of exogenous AAT versus time simulations were studied using a non-linear mixed effect approach with dosage regimens every 7, 14, 21, and 28 days. For each regimen the mean exogenous AAT trough concentrations and 5/95th percentiles were determined. The results obtained were applied to estimate the individual optimal dose at 7, 14, and 21 days in six patients using Bayesian analysis. RESULTS: The simulations showed that a dose of 50 mg/kg AAT every 7 days was sufficient to obtain nadir concentrations. Doses of 120 and 100 mg/kg every 14 days were also adequate, but 180 mg/kg given every 21 days required total AAT monitoring to avoid underdosage. Longer intervals were inappropriate. Dosage individualisation confirmed that AAT infusions given every 14 days maintained the nadir level of 0.5 g/l without a significant dose increase compared with current practice. When the time span between doses was fixed at 21 days, a mean relative AAT dose enhancement of 91% and 13%, respectively, was required to achieve sustained total AAT concentrations above the target level for 100% and 85% of the interval between doses. CONCLUSIONS: It is feasible to extend the interval between doses of AAT to 14 or 21 days to achieve adequate trough total AAT concentrations. This study might be used as a starting point for clinical evaluation of the regimens described.

[Attitudes toward the diagnosis of chronic obstructive pulmonary disease in primary care]. / Problemas con el diagnóstico de la EPOC en atención primaria.

OBJECTIVE: Although the prevalence of chronic obstructive pulmonary disease (COPD) has increased among women, it is still considered a disease that mainly affects men. This study aimed to identify the diagnostic attitudes of primary care physicians toward patients with COPD according to gender and spirometric results. METHODS: A representative sample of 839 primary care physicians participated in the study. Each physician dealt with 1 of 8 hypothetical cases based on a patient diagnosed with COPD. In half the cases, the physician was told the patient was a man. The other half of the physicians were told the same patient was a woman. After presentation of the medical history and results of physical examination, the physicians were asked to state a probable diagnosis and indicate the diagnostic tests that were necessary. They were then told the results of spirometry, which indicated obstruction ranging from moderate to severe. Negative results of bronchodilator tests and oral corticosteroid tests were then communicated. RESULTS: COPD was more likely to be the preliminary diagnosis for male patients than for females (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.15-2.1). This gender bias disappeared once the physicians were shown the abnormal results of spirometry. Patients with severe obstruction were more likely to be diagnosed with COPD than those with moderate obstruction (OR, 1.5; 95% CI, 1.08-2.09). CONCLUSIONS: There is gender bias in the diagnosis of COPD. Patients with moderate obstruction are often believed not to have COPD. These biases may compromise the early diagnosis of the disease in a group of patients with ever increasing risk.

Problemas con el diagnóstico de la EPOC en atención primaria / Attitudes toward the diagnosis of Chronic Obstructive Pulmonary Disease in primary care

Objetivo: La prevalencia de la enfermedad pulmonar obstructiva crónica (EPOC) ha aumentado en el sexo femenino, pero aún se considera una enfermedad que afecta sobre todo a los varones. Este estudio pretendió identificar las actitudes diagnósticas de los médicos de atención primaria frente a pacientes con EPOC según su sexo y los resultados de la espirometría. Método: Participó en el estudio una muestra representativa de 839 médicos de atención primaria. Cada uno de ellos resolvió uno entre 8 casos posibles de pacientes con EPOC. La mitad de éstos correspondía a un paciente varón y la otra mitad a una mujer con historia clínica y exploración física idénticas. Tras la historia y la exploración física se solicitó a los participantes un diagnóstico provisional, así como las pruebas diagnósticas necesarias. Se facilitaron después los resultados de la espirometría que mostraban una obstrucción de carácter moderado o grave. Los resultados negativos de una prueba broncodilatadora y de una prueba con corticoides orales se dieron a continuación. Resultados: La EPOC fue un diagnóstico provisional más probable para los pacientes varones que para las mujeres (odds ratio [OR]: 1,55; intervalo de confianza [IC] del 95%, 1,15-2,1). Este sesgo desaparecía después de mostrar los resultados anormales de la espirometría. Los pacientes con una obstrucción de carácter grave eran diagnosticados con mayor probabilidad de EPOC que aquellos con una obstrucción moderada OR: 1,5; IC del 95%, 1,08-2,09). Conclusiones: Existe un sesgo diagnóstico en función del sexo del paciente. En muchas ocasiones no se diagnostica a los pacientes con EPOC que presentan una obstrucción moderada. Estos sesgos podrían comprometer el diagnóstico precoz de la EPOC en un grupo cada vez más frecuente de individuos en riesgo

Objective: Although the prevalence of chronic obstructive pulmonary disease (COPD) has increased among women, it is still considered a disease that mainly affects men. This study aimed to identify the diagnostic attitudes of primary care physicians toward patients with COPD according to gender and spirometric results. Methods: A representative sample of 839 primary care physicians participated in the study. Each physician dealt with 1 of 8 hypothetical cases based on a patient diagnosed with COPD. In half the cases, the physician was told the patient was a man. The other half of the physicians were told the same patient was a woman. After presentation of the medical history and results of physical examination, the physicians were asked to state a probable diagnosis and indicate the diagnostic tests that were necessary. They were then told the results of spirometry, which indicated obstruction ranging from moderate to severe. Negative results of bronchodilator tests and oral corticosteroid tests were then communicated. Results: COPD was more likely to be the preliminary diagnosis for male patients than for females (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.15-2.1). This gender bias disappeared once the physicians were shown the abnormal results of spirometry. Patients with severe obstruction were more likely to be diagnosed with COPD than those with moderate obstruction (OR, 1.5; 95% CI, 1.08-2.09). Conclusions: There is gender bias in the diagnosis of COPD. Patients with moderate obstruction are often believed not to have COPD. These biases may compromise the early diagnosis of the disease in a group of patients with ever increasing risk

Results of a case-detection programme for alpha1-antitrypsin deficiency in COPD patients.

Alpha1-antitrypsin (alpha1-AT) deficiency is an underdiagnosed condition in patients with chronic obstructive pulmonary disease (COPD). The present authors have conducted a nationwide case detection programme of alpha1-AT deficiency in unselected patients with COPD using dried blood spots. The first phase analysed samples from 971 patients by determining alpha1-AT concentrations and identifying the deficient Z allele by genotyping using rapid real-time PCR. The second phase analysed 1,166 samples with alpha1-AT concentrations and identified both the S and the Z allele, but only in samples with low alpha1-AT concentrations. A total of eight (0.37%) individuals with the severe deficiency PiZZ were detected. In addition, three patients were identified with the PiSZ genotype in the second phase (0.3%). The global cost of the programme was 41,512, which represents 19.42 per sample and 5,189 per PiZZ detected. A sensitivity analysis demonstrated that performing Z genotype to all samples would have resulted in increased costs of 28 per sample and 7,479.5 per PiZZ case identified. In conclusion, a case detection programme of alpha1-antitrypsin deficiency in patients with chronic obstructive pulmonary disease using dried blood spots is feasible and at a reasonable cost per case detected. Diagnostic yield and costs depend largely on inclusion criteria and the protocol for processing of samples.