Inhibitory rTMS of secondary somatosensory cortex reduces intensity but not pleasantness of gentle touch.

Research suggests that the discriminative and affective aspects of touch are processed differently in the brain. Primary somatosensory cortex is strongly implicated in touch discrimination, whereas insular and prefronal regions have been associated with pleasantness aspects of touch. However, the role of secondary somatosensory cortex (S2) is less clear. In the current study we used inhibitory repetitive transcranial magnetic stimulation (rTMS) to temporarily deactivate S2 and probe its role in touch perception. Nineteen healthy adults received two sessions of 1-Hz rTMS on separate days, one targeting right S2 and the other targeting the vertex (control). Before and after rTMS, subjects rated the intensity and pleasantness of slow and fast gentle brushing of the hand and performed a 2-point tactile discrimination task, followed by fMRI during additional brushing. rTMS to S2 (but not vertex) decreased intensity ratings of fast brushing, without altering touch pleasantness or spatial discrimination. MRI showed a reduced response to brushing in S2 (but not in S1 or insula) after S2 rTMS. Together, our results show that reducing touch-evoked activity in S2 decreases perceived touch intensity, suggesting a causal role of S2 in touch intensity perception.

Association between the Mediterranean-style Dietary Pattern Score and Physical Performance: Results from TRELONG Study.

OBJECTIVE: To determine the association between Mediterranean-Style Dietary Pattern Score and physical performance. DESIGN: Data analysis of a longitudinal study of a representative, age stratified, population sample. SETTING: The TREVISO LONGEVA (TRELONG) Study, in Treviso, Italy. PARTICIPANTS: In 2010, 123 men and 181 women, age 77 years and over (mean age 86.3 ± 6.8 years). MEASUREMENTS: Performing a logistic regression in a multivariate analysis, hand grip strength and Short Physical Performance Battery (SPPB) were tested in relation to Mediterranean-Style Dietary Pattern Score (MSDPS). RESULTS: The hand grip mean value was 10.9 kg (± 9.5) and the SPPB score was 6.3 (± 3.8). The MSDPS mean value in this study sample was 38.1/100 (± 8.1). A significant association (p=0.036) between a high adherence to the Mediterranean diet (fourth quartile) and higher performance lower limbs (SPPB>7) was found. No correlation was reported for the hand grip strength. CONCLUSION: We found an association statistically significant between a high adherence to the Mediterranean diet and higher physical performance.

Hypersensitivity Pneumonitis: A Comprehensive Review.

Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a complex pulmonary syndrome mediated by the immune system and caused by inhalation of a wide variety of antigens to which the individual has been previously sensitized. The pathobiology of the disease is not fully understood, but in addition to the triggers that initiate the disease, host/genetic factors are likely to be important, as only a minority of exposed individuals develop HP. Due to the lack of a diagnostic gold standard, the diagnosis of HP is not straightforward and relies on the integration of a number of factors, including history of exposure, precipitating antibodies to the offending antigen, clinical features, bronchoalveolar lavage, and radiological and pathologic features. However, in the appropriate setting, a high index of suspicion is critically important and may obviate the need for more invasive tests. Clinical presentation and natural history vary widely. Acute forms generally resolve without sequelae, while chronic forms, which are caused by persistent low-grade exposures, are associated with poor prognosis. Corticosteroids may be useful in acute episodes for symptomatic relief or in chronic and progressive disease, but their long-term efficacy has never been validated in prospective clinical trials. Ideally, patients with HP should be referred to centers with expertise, as the overlap with other forms of interstitial lung disease may be substantial. Making the correct diagnosis has critical therapeutic and prognostic implications.

Idiopathic pulmonary fibrosis: Recent advances on pharmacological therapy.

Idiopathic pulmonary fibrosis (IPF) is the most common and lethal of the idiopathic interstitial pneumonias with an estimated 5-year survival of approximately 20%. In the last two decades our understanding of disease pathogenesis has substantially evolved and novel compounds have been developed consequent to the increasing knowledge of the mechanisms underlying disease pathobiology. The disease appears to be driven - following chronic injury - by abnormal/dysfunctional alveolar epithelial cells that promote fibroblast recruitment and proliferation, resulting in scarring of the lung and irreversible loss of function. With very few exceptions, clinical trials evaluating novel potential therapies have provided disappointing results. More recently, pirfenidone and nintedanib, two compounds with pleiotropic mechanisms of action, have proven effective in slowing functional decline and disease progression in IPF patients with mild to moderate functional impairment, highlighting the importance of timely diagnosis and administration of treatment in early stages of disease. However, due to the complexity and uncertainties intrinsic to IPF, it is essential that each therapeutic strategy be tailored to the individual patient, after evaluation of potential benefits and risks. This article provides an overview of the most recent clinical trials in IPF and discusses how their results are going to change the clinical and clinical research landscape in IPF. A number of agents with high potential are currently being tested and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing patients with IPF.

Hypersensitivity pneumonitis: a comprehensive review

Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a complex pulmonary syndrome mediated by the immune system and caused by inhalation of a wide variety of antigens to which the individual has been previously sensitized. The pathobiology of the disease is not fully understood, but in addition to the triggers that initiate the disease, host/genetic factors are likely to be important, as only a minority of exposed individuals develop HP. Due to the lack of a diagnostic gold standard, the diagnosis of HP is not straightforward and relies on the integration of a number of factors, including history of exposure, precipitating antibodies to the offending antigen, clinical features, bronchoalveolar lavage, and radiological and pathologic features. However, in the appropriate setting, a high index of suspicion is critically important and may obviate the need for more invasive tests. Clinical presentation and natural history vary widely. Acute forms generally resolve without sequelae, while chronic forms, which are caused by persistent low-grade exposures, are associated with poor prognosis. Corticosteroids may be useful in acute episodes for symptomatic relief or in chronic and progressive disease, but their long-term efficacy has never been validated in prospective clinical trials. Ideally, patients with HP should be referred to centers with expertise, as the overlap with other forms of interstitial lung disease may be substantial. Making the correct diagnosis has critical therapeutic and prognostic implications (AU)

La neumonitis por hipersensibilidad (NH), también conocida como alveolitis alérgica extrínseca, es un síndrome pulmonar complejo mediado por el sistema inmune y provocado por la inhalación de una amplia variedad de alérgenos frente a los cuales el paciente está previamente sensibilizado. La patogénesis de la enfermedad se conoce parcialmente; sin embargo, además de los activadores iniciales que dan lugar al desarrollo de la enfermedad hay factores genéticos que tienen importancia también, de tal forma que solo una minoría de los individuos expuestos desarrollan la enfermedad. Debido a la falta de un 'gold estándar' para el diagnóstico de NH, se hace necesaria la integración de un número de factores, entre los que se encuentran la historia de exposición al alérgeno, la presencia de anticuerpos precipitantes frente al Ag ofensor, datos clínicos y datos patológicos en el lavado broncoalveolar, y radiológicos. En cualquier caso un alto índice de sospecha clínica es crítica y puede obviar la necesidad de otros test más invasivos. La presentación clínica y la historia natural de la enfermedad puede variar ampliamente desde las formas agudas que generalmente se resuelven sin secuelas a las formas crónicas fibróticas que son provocadas por la exposición de grado bajo mantenida y que se asocian con un peor pronóstico. Los corticosteroides pueden ser útiles en el tratamiento sintomático de los episodios agudos o en la enfermedad crónica progresiva, pero su eficacia a largo plazo nunca ha sido validada en ensayos clínicos diseñados para ese fin. La dinámica adecuada debe dirigir a los pacientes con MH a centros especializados expertos, dado que puede haber otras formas solapadas de enfermedad pulmonar y el diagnóstico correcto es crítico para la aplicación de un correcto tratamiento y un mejor pronóstico (AU)

Doppler echocardiographic evidence of pulmonary hypertension in dogs: a retrospective clinical investigation.

Pulmonary hypertension (PH) decreases resistance to fatigue and life expectancy. The aim of this study was to correlate some indirect Doppler indices of PH with tricuspid and pulmonary regurgitation criteria and to relate PH on different indices with the severity of clinical signs. Furthermore the pathogenetic mechanisms associated to PH development were discussed. Dogs with Doppler echocardiographic evidence of PH diagnosed by assessment of pulmonary and tricuspid regurgitant jet velocity were selected, their clinical records were reviewed and a clinical score was computed. Seventeen cases of PH were identified. The degree of PH was assessed based on systolic or diastolic pulmonary pressure and the indirect Doppler indices (AT/ET and Tei Index) were calculated; data were statistically evaluated. Indirect Doppler indices were calculated also in a control group of seven healthy dogs. The most common clinical signs were coughing, dyspnea and syncope; the most common condition associated to PH development was the left-sided valvular heart disease. A significant positive correlation was found between Tei Index and both the systolic pressure and the severity of PH while no correlations were found between PH on different indices and clinical score and/or severity of clinical signs. Results of this study suggest that Tei-index could be an useful support not only to reveal PH but also to give information on the severity of PH. The clinical picture in dogs with PH is apparently unpredictable and not strictly correlated with the severity of PH.

Rationale, design and methods of CTCA-PRORECAD (Computed Tomography Coronary Angiography Prognostic Registry for Coronary Artery Disease): a multicentre and multivendor registry.

PURPOSE: This study was done to assess the prognostic value of computed tomography coronary angiography (CTCA) in a large multicentre population of patients with suspected coronary artery disease (CAD) and, in particular, its incremental value compared with traditional methods for risk stratification. MATERIALS AND METHODS: This is a retrospective observational study that began in January 2003 conducted on patients with suspected CAD assessed with CTCA on the basis of symptoms (chest pain, dyspnoea) and/or abnormal or equivocal stress test and/or a high cardiovascular risk profile. The participating centres will provide data obtained with CTCA performed with 16-slice or higher equipment. Exclusion criteria are renal insufficiency, allergy to iodinated contrast material, pregnancy and previous myocardial infarction or revascularisation (percutaneous coronary intervention and/or coronary artery bypass graft). All patients are stratified by means of clinical assessment and/or data retrieved from a clinical database. Risk factors considered are hypertension, dyslipidaemia, diabetes mellitus, smoking, family history and obesity. Symptoms are classified as absent, typical chest pain, atypical chest pain and dyspnoea. Primary endpoints are death, major adverse cardiovascular events (cardiac death, unstable angina requiring hospitalisation, acute myocardial infarction) and shifting of cardiovascular risk category on the basis of coronary plaque burden. The secondary endpoint is coronary revascularisation. Telephone interviews and/or clinical databases are used for the follow-up. The study will be conducted on a population >1,000 patients. CONCLUSIONS: The information collected from the Prognostic Registry for Coronary Artery Disease (PRORECAD) will provide insight into the prognostic value of CTCA in addition to demographic and clinical features. The results will allow for better use and interpretation of CTCA for prognostic purposes.

Diagnostic accuracy of 64-slice computed tomography coronary angiography in a large population of patients without revascularisation: registry data on the comparison between male and female population.

PURPOSE: This study was undertaken to evaluate the diagnostic accuracy of computed tomography coronary angiography (CTCA) for detecting significant coronary artery stenosis (≥50% lumen reduction) compared with conventional coronary angiography (CAG) in a male and female population. MATERIAL AND METHODS: A total of 1,372 patients (882 men, 490 women; mean age 59.3 ± 11.9 years) in sinus rhythm imaged with CTCA (64-slice technology) and CAG were enrolled. Diagnostic accuracy and likelihood ratios (LR+ and LR-) of CTCA were assessed against CAG for the male and female populations. RESULTS: The prevalence of obstructive disease was 53% (men 58%; women 43%). CAG demonstrated the absence of significant coronary artery disease (CAD) in 47% (men 42%; women 56%), single-vessel disease in 25% (men 36%; women 22%) and multivessel disease in 29% (men 32%; women 23%) of patients. In the per-patient analysis, sensitivity, specificity and positive (PPV) and negative (NPV) predictive values of CTCA were 99% (men 98%; women 100%), 92% (men 92%; women 92%), 94% (men 95%; women 90%) and 99% (men 98%; women 100%), respectively. The per-patient likelihood ratios (LR) in the total population (LR+=12.4 and LR-=0.011), the male (LR+=12.9 and LR-=0.016) and female (LR =11.9 and LR-=0) populations were very good. We observed no significant differences in diagnostic accuracy between male and female populations. CONCLUSIONS: CTCA is a reliable diagnostic modality with high sensitivity and NPV in the female population.

Co-trimoxazole effect on human alveolar macrophages of AIDS patients.

Compelling evidence suggests that co-trimoxazole prophylaxis reduces mortality in HIV-infected patients, although it is unclear whether these effects are directly related to antimicrobial activities. We evaluated in vitro phagocytosis and killing of Staphylococcus aureus in alveolar macrophages (AM) obtained from AIDS patients who smoke, treated (n=19) or not treated (n=13) with co-trimoxazole, as compared to non-HIV-infected healthy smokers (n=15). Phagocytosis and killing of Staphylococcus aureus by AM obtained from non-co-trimoxazole treated AIDS patients were significantly lower compared to non-HIV-infected healthy smokers. In contrast, AIDS patients treated with co-trimoxazole prophylaxis showed phagocytosis and killing levels similar to those of healthy controls. These results might help to clarify the observed positive effect of co-trimoxazole on survival in HIV-infected patients.

Defining the clinical outcome status (COS) in sarcoidosis: results of WASOG Task Force.

The clinical outcome of sarcoidosis is quite variable. Several scoring systems have been used to assess the level of disease and clinical outcome. The definition of clinical phenotypes has become an important goal as genetic studies have identified distinct genotypes associated with different clinical phenotypes. In addition, treatment strategies have been developed for patients with resolving versus non resolving disease. A task force was established by the World Association of Sarcoidosis and Other Granulomatous diseases (WASOG) to define clinical phenotypes of the disease based on the clinical outcome status (COS). The committee chose to examine patients five years after diagnosis to determine the COS. Several features of the disease were incorporated into the final nine categories of the disease. These included the current or past need for systemic therapy, the resolution of the disease, and current status of the condition. Sarcoidosis patients who were African American or older were likely to have a higher COS, indicating more chronic disease. The COS may be useful in future studies of sarcoidosis.

Diagnostic accuracy of 64-slice computed tomography coronary angiography in a large population of patients without revascularisation: registry data in NSTEMI acute coronary syndrome and influence of gender and risk factors.

PURPOSE: This study sought to evaluate the diagnostic accuracy of computed tomography coronary angiography (CTCA) for detecting significant coronary artery stenosis (≥50% lumen reduction) compared with conventional coronary angiography (CAG) in non-ST-elevation myocardial infarction-acute coronary syndrome (NSTEMI-ACS) and in subgroups selected by gender and number of risk factors (RF). MATERIALS AND METHODS: We selected from a population of 1,500 patients in a multicentre registry with NSTEMI-ACS who had undergone CTCA and CAG, (n=237; 187 men, mean age 63±10 years). Diagnostic accuracy and likelihood ratios (LR) of CTCA were assessed against CAG in the total population and subgroups (men, women: 0 RF = absence of RF, 1-2 RF = presence of one or two RF, >2 RF = presence of more than two RF). RESULTS: The prevalence of obstructive disease was 53%. In the per-patient analysis, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CTCA were 100% (men 100%; women 100%; 0 RF 100%; 1-2 RF 100%; >2 RF 100%), 95% (men 98%; women 50%; 0 RF NA% (NA, not assessable); 1-2 RF 96%; >2 RF 96%), 95% (men 98%; women 91%; 0 RF 91%; 1-2 RF 96%; >2 RF 96%), 100% (men 100%; women 100%; 0 RF NV%; 1-2 RF 100%; >2 RF 100%), respectively. The per-segment analysis showed a reduction in PPV (ranging between 56% and 67%). The per-patient LR+ ranged between 18 and 27, whereas LR-were always 0. We observed no significant differences in diagnostic accuracy between subgroups. CONCLUSIONS: CTCA is a reliable diagnostic modality with high sensitivity and NPV in NSTEMI-ACS patients who are not candidates for early revascularisation, regardless of gender and number of risk factors.

Diagnostic accuracy of 64-slice computed tomography coronary angiography in a large population of patients without revascularisation: registry data on the impact of calcium score.

PURPOSE: This study evaluated the diagnostic accuracy of computed tomography coronary angiography (CTCA) for detecting significant coronary artery stenosis (≥50% lumen reduction) at different coronary calcium score (CACS) values with conventional coronary angiography (CAG) as the reference standard. MATERIAL AND METHODS: A total of 1,500 patients (928 men, mean age 58.2±12.5 years) in sinus rhythm who underwent CTCA (64-slice technology) and CAG were enrolled. Diagnostic accuracy and likelihood ratios (LR) of CTCA were evaluated against CAG for the total population and in different CACS classes (0; 1-10; 11-100; 101-400; 401-1,000; >1,000). RESULTS: The prevalence of obstructive disease was 51% (23.5% single vessel; 27.5% multivessel; progressive increase from 17.9% to 94% through the CACS classes). In the per-patient analysis, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CTCA were 99%, 92%, 94% and 99%, respectively. Per-patient analysis showed a worse PPV of CTCA (76-77%) in classes with low CACS (1-10/11-100). Per-patient LR were higher in classes with extreme CACS values (0 = LR+ 18.3 and LR- = 0.0; c1,000 = LR+ 17.0 and LR- = 0.0) with values always >7 for LR+ and <0.033 for LR- for all CACS classes. CONCLUSIONS: CTCA is a reliable diagnostic modality, with high sensitivity and NPV regardless of CACS.

The complex interrelationships between chronic lung and liver disease: a review.

Lung complications may occur as a result of hepatic disease from any cause and represent a highly heterogeneous group of conditions. Early recognition of such complications may be challenging but is crucial both in forming a meaningful differential diagnosis and in avoiding severe sequelae and irreversible damage. Although a number of different pathogenetic mechanisms are likely to be involved, chronic liver dysfunction may cause pulmonary manifestations because of alterations in the production or clearance of circulating cytokines and other mediators. This is likely to be the case in hepatopulmonary syndrome, portopulmonary hypertension and primary biliary cirrhosis, although their pathogenesis remains largely speculative. Moreover, the severity of lung manifestations may or may not correspond to that of liver impairment, making disease outcome often unpredictable. Congenital and inflammatory disorders, however, may primarily affect both the liver and lung. Apart from specific diseases, a number of medications can also result in pulmonary and hepatic toxic effects. This is particularly important with cytokine therapy - used to treat viral hepatitis, among other diseases - because treatment consists of drug discontinuation, which, in turn, may cause reactivation or progression of the underlying disease that the drug was used for. This review summarizes salient diagnostic and therapeutic aspects of these often misdiagnosed conditions and highlights, based on the most recent literature, the need for early referral of such patients to centres with specific expertise in the field. In fact, a multidisciplinary approach involving pulmonologists, hepatologists and, in particularly severe cases, transplant surgeons has been already proven successful.

CC chemokine receptor 5 gene polymorphisms in beryllium disease.

CC chemokine receptor 5 (CCR5) is expressed on type-1 T-helper cells, which are involved in the pathogenesis of the granulomatous lung disease chronic beryllium disease (CBD). CCR5 gene (CCR5) polymorphisms are associated with sarcoidosis severity. The present study explores associations between CCR5 polymorphisms and CBD and its disease progression. Eight CCR5 polymorphisms were genotyped in CBD (n = 88), beryllium sensitisation (BeS; n = 86) and beryllium-exposed nondiseased controls (n = 173) using PCR with sequence-specific primers. Pulmonary function and bronchoalveolar lavage data were examined for associations with genotypes. There were no significant differences in genotype and allele frequency between CBD, BeS individuals and controls. In CBD, associations were found with decline in forced expiratory volume in 1 s and forced vital capacity and the CCR5 -3458 thymidine (T)T genotype (p<0.0001), and an increase in alveolar-arterial oxygen tension difference at rest (p = 0.003) and at maximum exercise (p = 0.01) and the -5663 adenine allele. Increased bronchoalveolar lavage lymphocyte numbers were associated with CCR5 -2459 guanine/-2135T (p = 0.01) only in the combined CBD and BeS group. This is the first study showing that CCR5 polymorphisms are associated with worsening pulmonary function over time in CBD, suggesting that CCR5 is important in the progression of pulmonary function in CBD. Further studies would be useful to clarify the mechanism whereby CCR5 polymorphisms affect progression of CBD.

Bronchoalveolar lavage and response to cyclophosphamide in scleroderma alveolitis.

OBJECTIVES: Systemic sclerosis (SSc) is characterized by abnormal fibrosis of the skin and internal organs, particularly the lungs. Recent reports have revealed a lack of correlation between bronchoalveolar lavage (BAL) variations and response to cyclophosphamide (CYC) in patients with scleroderma-related alveolitis. Our study aimed to evaluate whether the normalization of BAL cellularity correlates with long-term response to CYC. METHODS: We retrospectively studied 26 consecutive SSc patients with alveolitis diagnosed by BAL and treated with CYC therapy (cumulative dosage 26.5 +/- 11.7 g; 21.1 +/- 8.9 months of treatment). We evaluated high-resolution computed tomography (HRCT), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) variations before and after CYC. Radiological and functional parameters were re-evaluated in 23 patients after 1-year follow-up. RESULTS: BAL cellularity normalized after CYC therapy in 12/26 (46.2%) patients (group 1), while it remained abnormal in 14/26 (53.8%) (group 2). FVC and DLCO of group 1 slightly increased after CYC (p = 0.014 and p = 0.07, respectively) and remained stable at follow-up, whereas in group 2 they did not change after CYC and at follow-up (p = not significant). Moreover, at the end of CYC, FVC and/or DLCO showed a clinical improvement/stabilization in all patients of group 1 versus 8/14 of group 2, while at the re-evaluation 1 year after completing CYC, 2/11 patients of group 1 worsened versus 5/12 of group 2. HRCT progression was observed in 1/11 of group 1 and 8/12 of group 2 (p = 0.009). CONCLUSIONS: BAL fluid normalization after CYC therapy correlated with long-term response to treatment, contrary to what is observed in individuals with persistent alveolitis.

Diagnostic accuracy of 64-slice computed tomography coronary angiography in a large population of patients without revascularisation: registry data and review of multicentre trials.

PURPOSE: This study was undertaken to evaluate the diagnostic accuracy of computed tomography coronary angiography (CT-CA) for the detection of significant coronary artery stenosis (> or =50% lumen reduction) compared with conventional coronary angiography (CCA) in a registry and to review major multicentre trials. MATERIALS AND METHODS: A total of 1,372 patients (882 men, 490 women; mean age 59.3+/-11.9 years) in sinus rhythm were studied with CT-CA (64-slice technology) and CCA. The diagnostic accuracy of CT-CA was evaluated against quantitative CCA as a reference standard for coronary artery stenosis. Positive and negative likelihood ratios and inter- and intraobserver agreement were calculated. RESULTS: The prevalence of disease was 53%. CCA demonstrated the absence of significant coronary artery disease in 46.6% (639/1372), single-vessel disease in 24.7% (337/1372) and multivessel disease in 28.9% (396/1372) of patients. In per-patient analysis sensitivity, specificity and positive and negative predictive value of CT-CA were 99% [confidence interval (CI) 97-99], 92% (CI 89-94), 94% (CI 91-95) and 99% (CI 97-99), respectively. Per-patient and per-segment likelihood ratios (LR+=12.4 and LR-=0.011; LR+=18.3 and LR-=0.064, respectively), were good. Inter- and intraobserver variability was 0.78 and 0.85, respectively. CONCLUSIONS: CT-CA is a reliable diagnostic modality both in terms of sensitivity and negative predictive value. Differences in trial results are also due to the different parameters used for patient inclusion.

CARD15/NOD2 polymorphisms are associated with severe pulmonary sarcoidosis.

Sarcoidosis and Crohn's disease are heterogeneous systemic diseases characterised by granulomatous inflammation. Caspase recruitment domain (CARD)15 is a major susceptibility gene for Crohn's disease, and specifically for ileal and fibrostenotic subtypes. The C-C chemokine receptor (CCR)5 gene has been associated with both parenchymal pulmonary sarcoidosis and perianal Crohn's disease. This study explored associations between CARD15 polymorphisms, CCR5 haplotype and distinct pulmonary sarcoidosis subtypes. 185 Caucasian sarcoidosis patients were genotyped for CARD15 and CCR5 polymorphisms. The genetic data were compared with 347 healthy controls and were examined for associations with serial pulmonary function tests and chest radiographs. CARD15 genotypes did not differ between the unselected sarcoidosis cohort and controls. However, patients carrying the functional 2104T (702W) polymorphism were more likely to have radiographic stage IV disease at 4-yr follow-up. All patients possessing both CARD15 2104T and CCR5 HHC haplotype had stage IV disease at presentation. Carriage of 2104T was associated with worse forced expiratory volume in 1 s, whereas carriage of the CARD15 1761G (587R) polymorphism was associated with better lung function. For the first time, an association between two CARD15 polymorphisms and specific sarcoidosis phenotypes has been demonstrated, as well as an additive effect of possessing CARD15 2104T and CCR5 HHC haplotype.

Sex differences in emphysema phenotype in smokers without airflow obstruction.

Data on sex differences in emphysema are limited to chronic obstructive pulmonary disease. We aimed to verify whether such differences also exist in smokers without airflow obstruction, weighting their influence on the relationship between emphysema and clinical features. We evaluated both clinical and multidetector computed tomography (MDCT) data of 1,011 heavy smokers recruited by a lung cancer screening project. MDCT scans were analysed with software allowing lobar quantification of emphysema features. For these measures, multiple regression models were applied to assess the effect of patients sex, after allowance for age, body mass index (BMI), smoking history, forced expiratory volume in 1 s (FEV(1)) and forced vital capacity. The final study cohort consisted of 957 smokers without airflow obstruction. Compared with males, females exhibited an emphysema phenotype less extensive in each pulmonary lobe, characterised by smaller emphysematous areas and less concentrated in the core of the lung. However, in females, the increase of emphysema with age was more pronounced and displayed a more significant relationship with FEV(1)% decline; conversely, in males there was a stronger association with the decrease in BMI. Males and females respond differently to the type and location of lung damage due to tobacco exposure. In smokers, sex influences the relationship between emphysema and clinical features.

A common haplotype of the C-C chemokine receptor 2 gene and HLA-DRB1*0301 are independent genetic risk factors for Löfgren's syndrome.

AIM: Sarcoidosis is a heterogeneous disorder with a strong genetic influence. Genetic factors are also thought to influence disease severity and outcome. We sought to determine whether polymorphisms within CCR2 gene predispose to Löfgren's syndrome--a clinically and genetically distinct sarcoidosis phenotype--and, importantly, whether this association is independent of the known association with the HLA-DRB1*0301 allele. METHODS: We investigated 5 CCR2 variants and HLA-DRB1*0301 by sequence-specific primer (SSP) polymerase chain reaction (PCR) in 176 Spanish (76 Löfgren's syndrome, 100 controls) and 387 Swedish subjects (126 Löfgren's syndrome, 77 non-Löfgren sarcoidosis, 184 controls). RESULTS: One of the deduced haplotypes (CCR2 haplotype 2) was associated with Löfgren's syndrome in both Spanish (OR: 2.03, uncorrected P = 0.02; permuted P = 0.041 vs. controls) and Swedish patients (OR: 3.02, uncorrected P = 0.0007; permuted P = 0.0027 vs. non-Löfgren sarcoidosis; OR: 2.46, uncorrected P = 0.0005; permuted P = 0.0031 vs. controls). HLA-DRB1*0301 allele frequency was also increased in Spanish (OR: 3.52, P = 0.0004 vs. controls) and Swedish patients with Löfgren's syndrome (OR: 10.98, P < 0.0001 vs. non-Löfgren sarcoidosis, OR: 7.71, P < 0.0001 vs. controls). Finally, multivariate analysis revealed that the CCR2 association was independent of HLA-DRB1*0301 in both Spanish (P = 0.02 vs. controls) and Swedish cohorts (P = 0.002 vs. non-Löfgren sarcoidosis, P = 0.001 vs. controls). CONCLUSIONS: This study confirms that CCR2 haplotype 2 and HLA-DRB1*0301 are independent genetic risk factors for Löfgren's syndrome.