Chronic iliofemoral vein obstruction - an under-recognized cause of exercise limitation.

Local symptoms of chronic venous insufficiency after deep vein thrombosis (DVT) are well described, but little is known about the effect of residual venous obstruction on exercise capacity. We tested our hypothesis that chronic residual iliofemoral vein occlusion (IFVO) after DVT may impair exercise capacity. Nine post-DVT patients with residual IFVO and effort intolerance were studied; a comparison cohort consisted of 11 healthy volunteers. Exercise tolerance was assessed by bimodality incremental symptom-limited cardiopulmonary testing, using leg and arm ergometers. In healthy subjects, leg vein obstruction was modelled by application to the thighs of cuff tourniquets inflated to 30-40 mmHg. Leg exercise tolerance as measured by oxygen uptake at peak exercise (peak ⩒'O2) was reduced in patients (median 50% predicted (range 36-83%) vs. 88% predicted (67-129%) in normal subjects, p < 0.001). Arm exercise tolerance was also reduced in patients, but less severely than in the legs - the median arm: leg ratio of peak ⩒'O2 was 0.95 (0.77-1.43) in patients vs. a normal ratio of 0.73 (0.6-1.0) in healthy subjects (p < 0.003). In healthy subjects, bilateral leg vein obstruction by tourniquets reduced peak ⩒'O2 in leg exercise to 76% predicted (range 55-108%; p < 0.001 vs. standard test). In conclusion, the comparison of arm vs. leg exercise capacity in post-DVT patients with residual IFVO and the effect of experimental venous obstruction (thigh tourniquets) in healthy subjects suggest that reduced exercise capacity in patients was at least partially caused by reduced venous return. Chronic venous obstruction should be recognized as a cause of exercise limitation.

Unexplained cough: it is time to rule out Sjogren's syndrome.

Sjogren's syndrome is associated with chronic cough, but sicca symptoms are missing from cough evaluation guidelines. We evaluated patients with unexplained cough for undiagnosed Sjogren's syndrome. Patients referred to our pulmonary clinic (Sheba Medical Center, 2009 to 2012) with unexplained cough and concomitant dry eyes were selected for evaluation. Unexplained cough was defined as chronic cough of unknown etiology despite algorithm-based evaluation and treatment. Patients were evaluated in a dedicated clinic by a pulmonologist, rheumatologist, and ophthalmologist specializing in autoimmune disease. Patients completed the Leicester Cough Questionnaire, spirometry, antibody testing for anti Ro/La, ophthalmologic examination with visual acuity, eyelid, ocular surface fluorescein staining, tear break-up time and Schirmer's test, full slit lamp, and fundus examinations. Four-year follow-up was conducted by telephone questionnaire. We identified 24 patients among which 22 (21 females) agreed for evaluation. Eight patients (36%), seven initially, and one during follow-up were diagnosed with Sjogren's syndrome (SS) (six secondary and two primary SS). At 4-year follow-up, cough tended to persist and improve in only 37% with SS. These include 2 (Scl and RA) who received rituximab and 1 (stage 1 sarcoidosis) with spontaneous improvement. In contrast, cough improved in most (64%) patients without SS; the majority (eight/nine) report intensified disease-specific treatment (five allergic and three GERD). We describe patients in whom unexplained chronic cough was associated with dry eyes. Focused workup revealed undiagnosed Sjogren's syndrome in 36%. Dry eyes, with or without SS, is under-recognized and should be added to diagnostic algorithms for unexplained cough.

Cardio-vascular reserve index (CVRI) during exercise complies with the pattern assumed by the cardiovascular reserve hypothesis.

OBJECTIVES: The Cardio-vascular reserve index (CVRI) had been empirically validated in diverse morbidities as a quantitative estimate of the reserve assumed by the cardiovascular reserve hypothesis. This work evaluates whether CVRI during exercise complies with the cardiovascular reserve hypothesis. DESIGN: Retrospective study based on a database of patients who underwent cardio-pulmonary exercise testing (CPX) for diverse indications. METHODS: Patient's physiological measurements were retrieved at four predefined CPX stages (rest, anaerobic threshold, peak exercise and after 2min of recovery). CVRI was individually calculated retrospectively at each stage. RESULTS: Mean CVRI at rest was 0.81, significantly higher (p<0.001) than at all other stages. CVRI decreased with exercise, reaching an average at peak exercise of 0.35, significant lower than at other stages (p<0.001) and very similar regardless of exercise capacity (mean CVRI 0.33-0.37 in 4 groups classified by exercise capacity, p>0.05). CVRI after 2min of recovery rose considerably, most in the group with the best exercise capacity and least in those with the lowest exercise capacity. CONCLUSIONS: CVRI during exercise fits the pattern predicted by the cardiovascular reserve hypothesis. CVRI decreased with exercise reaching a minimum at peak exercise and rising with recovery. The CVRI nadir at peak exercise, similar across groups classified by exercise capacity, complies with the assumed exhaustion threshold. The clinical utility of CVRI should be further evaluated.

Exercise haemodynamics may unmask the diagnosis of diastolic dysfunction among patients with pulmonary hypertension.

AIMS: Heart failure with preserved ejection fraction can lead to pulmonary hypertension. The aim of the present study was to evaluate the role of exercise during right heart catheterization in the unmasking of diastolic dysfunction. METHODS AND RESULTS: Between 2004 and 2012, 200 symptomatic patients with exertional dyspnoea, preserved left ventricular systolic function and suspected pulmonary hypertension, underwent right heart catheterization. Included in the study were 63 patients with resting pulmonary arterial wedge pressure (PAWP) ≤15 mmHg. Patients were divided to three tertiles based on their peak exercise PAWP. Mean age was 60 ± 20 years and 29% were males. Mean pulmonary arterial pressure was 31 ± 14 mmHg at rest and 42 ± 18 mmHg upon exercise. Mean change in PAWP between rest and exercise was 0.0 ± 4.3, 4.6 ± 2.4, and 16.6 ± 7.1 mmHg in the lower, middle, and upper tertiles, respectively (P < 0.001). Higher exercise PAWP tertiles were associated with reduced pulmonary vascular resistance (8.3 ± 6.7, 2.9 ± 2.7, and 5.8 ± 4.6 Woods units, respectively; P = 0.004). A multivariate linear regression model demonstrated that each 5 kg/m(2) increase in body mass index was associated with 2.5 ± 1.0 mmHg increase in exercise PAWP (P = 0.017). A multivariate binary logistic model showed that subjects with borderline PAWP at rest (12-15 mmHg) were 4.5 times more likely to be in the upper tertile of exercise PAWP (P = 0.011). CONCLUSIONS: In symptomatic patients with pulmonary hypertension, preserved left ventricular ejection fraction and PAWP ≤15 mmHg, exercise during right heart catheterization may unmask diastolic dysfunction. This is especially true for obese patients and patients with borderline resting PAWP.

Autoimmune pulmonary alveolar proteinosis: clinical course and diagnostic criteria.

Pulmonary alveolar proteinosis (PAP) is caused by accumulation of surfactant components in the alveoli and terminal airways. All forms of PAP are caused by insufficient surfactant clearance by alveolar macrophages. Autoimmune PAP, a rare, antibody-mediated disease, that compromises 90% of cases of PAP, is causes by IgG autoantibodies that block GM-CSF effect, a crucial step for macrophage maturation. Alveolar filling may progress to respiratory insufficiency, but the course of the disease is variable. Patients usually complain of dyspnea, mainly with exertion, and cough. Chest CT shows highly suggestive ground grass opacification crossed by heavy septal lines, leading to the typical "crazy paving" appearance. Bronchoalveolar lavage reveals "milky" fluid, containing semisolid remnants of surfactant components, packed as lamellar bodies. The surfactant appears granular and pink on PAS staining, and lung architecture is preserved. These cytological and pathological characteristics are diagnostic for PAP. In addition, a high titer of IgG anti GM-CSF autoantibodies is highly sensitive and specific for the diagnosis. The trigger for antibodies formation and their role (if any) in regulation GM-CSF activity in the normal state are unknown. Based on the specificity of these characteristics we suggest a structured framework for the diagnosis of Autoimmune PAP. Lung lavage with a large volume of saline is the standard therapy, and is effective in most patients. However, immune-modulatory therapy, by either supplying exogenous GM-CSF, or by inhibiting the CD20+ antibody forming cells, with Rituximab, is also effective in many patients. The precise role of each therapy, alone or in combination, should be systematically studied.

Methacholine challenge testing: improved patient comfort with a 2-tiered protocol.

BACKGROUND: The methacholine challenge test (MCT) is a test of bronchial hyperreactivity used as an aid in the diagnosis of asthma. MCT results are reported as the provocation concentration at which the forced expiratory volume in 1 second (FEV1) decreases 20% (PC20). The requirement for a 20% or greater decrease in FEV1 results in precipitous decreases in FEV1 in some patients. OBJECTIVE: To improve MCT safety without compromising accuracy. METHODS: We performed a retrospective analysis of 879 consecutive MCTs (derivation cohort). A novel protocol for MCT was developed and validated in a cohort of 564 MCTs performed in a second institution. RESULTS: In comparison with a PC20 cutoff of less than 8 mg/mL, a provocation concentration at which the FEV1 decreases 10% (PC10) cutoff of 1 mg/mL or less has a sensitivity of 86%, a specificity of 98%, a positive predictive value (PPV) of 97%, and a negative predictive value (NPV) of 91%. We propose a novel 2-tiered protocol for MCT. If the PC10 is 1 mg/mL or less, bronchial hyperreactivity is present; if the PC10 is greater than 1 mg/mL, the test is continued until the provocative concentration is 8 mg/mL or a 20% decrease in FEV1 is achieved. Compared with the standard protocol, the proposed protocol has a sensitivity, specificity, PPV, NPV, and overall accuracy of 100%, 98%, 97.6%, 100%, and 99%, respectively. The modified protocol would have enabled us to avoid 26 of 42 cases (62%) in which a 40% or greater decrease in FEV1 occurred and would save 0.65 dose for every MCT performed. The 2-tiered protocol performed well in the validation cohort; sensitivity, specificity, PPV, NPV, and overall accuracy were 100%, 98%, 87%, 100%, and 98%, respectively. CONCLUSION: The proposed 2-tiered protocol is accurate, saves time, and avoids precipitous decreases in FEV1.

[Chronic thromboembolic pulmonary hypertension: can successful thrombendarterectomy normalize exercise capacity and gas exchange?].

INTRODUCTION: Chronic thromboembolic pulmonary hypertension, a rare complication of pulmonary embolism is amenable to thrombendarterectomy (TEA) and when successful, improves exercise capacity and normalizes resting pulmonary arterial pressure. GOAL: To test if exercise capacity and exercise gas exchange are also normalized after successful TEA. METHODS: Over a period of 4 years, 5 patients underwent TEA at Sheba Medical Center. All experienced marked clinical improvement; their functional capacity (NYHA class) improved by 1-3 stages and resting pulmonary blood pressure normalized. One to 3 years after surgery each underwent a 6 minute walking test and incremental exercise to measure maximal oxygen uptake. RESULTS: It was found that following TEA, the 6 minute walking distance improved by 100-215 meters and more. Maximal oxygen uptake remained below normal in 4/5 cases and ranged 42-87% of predicted values. Hemoglobin oxygen saturation that was normal after TEA at rest, fell in all with exercise to 91-96%. Exercise gas exchange remained abnormal, consistent with residual pulmonary vascuLar disease. CONCLUSIONS: Thrombendarterectomy in chronic thromboembolic pulmonary hypertension caused marked clinical improvement and normalized resting pulmonary arterial pressures. Exercise capacity also improved but peak oxygen uptake remained below normal and exercise gas exchange remained abnormal. SUMMARY: Chronic thromboembolic pulmonary hypertension can be effectively treated. However, despite remarkable improvement, residual pulmonary vascular disease persists and is not relieved following successful operation.

[Normal or high maximal oxygen uptake: a target in health].

To achieve the predicted maximal oxygen consumption, many organs need to increase their output in a synchronized fashion. Therefore, maximal oxygen consumption is the single most reliable parameter predicting fitness, morbidity and mortality. Peak O2 uptake can be measured from noninvasive ventilatory parameters during short, incremental, cardiopulmonary exercise test (CPET) on a cycle ergometer or on a treadmill. Commercial systems are available and all enable breath by breath measurement of ventilation, exhaled gas concentration, oxygen saturation and additional cardiorespiratory parameters. Performance of the test requires adherence to strict guidelines and experienced technicians and physicians, although their qualification has not yet been defined by the national health authorities. There are well defined indications and benefits from CPET, among them are, determination of the anaerobic threshold, defining the cause of dyspnea, the timing for heart transplantation, exercise prescription for training and rehabilitation purposes and follow-up on disease progression or response to pharmacological or other modes of therapy. Measuring maximal oxygen consumption should be encouraged in health and disease and normal maximal oxygen consumption should be defined as a health target.

[The verge and the abyss: tiotropium (Spiriva) in COPD].

Tiotropium, a Long-acting anticholinergic bronchodilator, has many beneficial effects in chronic obstructive pulmonary disease (COPD). Among them are: a bronchodilator effect which is additive to that of beta-adrenergic agonists, that persists long-term without tolerance; reduction of dyspnea; improved exercise tolerance; enhanced response to rehabilitation; improved quality of life; and reduced frequency of exacerbations and hospital admissions. Therefore, tiotropium is widely used, and has been added to the Health Basket by the Israel Ministry of Health. In March 2008, the manufacturer informed the US Food and Drug Administration (FDAI that ongoing safety monitoring had identified a possible increased risk of stroke in patients who take this medicine. In September 2008, Singh and colleagues published a meta-analysis suggesting an increased risk of cardiovascular events in COPD patients treated with tiotropium, although there was no difference in overall mortality. A month later, the UPLIFT investigators published a 4 year placebo-controlled trial of tiotropium involving 5993 patients, in which there were slightly less cardiovascular events in the treatment group, and a trend to reduced overall mortality. The authors review the benefits and safety data, and conclude that while the benefits of tiotropium in COPD are clear, the evidence of an adverse effect on cardiovascular mortality is not sufficiently convincing. Hence, the balance of evidence supports continued use of tiotropium, especially in severe COPD.

Ventilatory response to hypercapnia in C(5-8) chronic tetraplegia: the effect of posture.

OBJECTIVE: To study the effect of posture on the hypercapnic ventilatory responses (HCVR). DESIGN: Nonrandomized controlled study. SETTING: Rehabilitation hospital and a pulmonary institute. PARTICIPANTS: Patients with neurologically stable C(5-8) tetraplegia (n=12) and healthy control subjects (n=7). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Supine and seated forced vital capacity (FVC) and HCVR, and supine and erect blood pressure. RESULTS: FVC in the sitting position was reduced in patients with tetraplegia (52+/-13% predicted); supine FVC was 21% higher (P=.0005). In the sitting position, HCVR was lower in patients than in controls (0.8+/-0.4 vs 2.46+/-0.3 L/min/mmHg, P<.001). Supine HCVR was not significantly different between the groups. When HCVR was normalized to FVC, there was still a significant difference between patients and controls in the sitting position. Patients with tetraplegia were orthostatic (mean supine blood pressure 91+/-13 mmHg vs mean erect blood pressure 61+/-13 mmHg, respectively, P<.0001). The magnitude of the orthostatism correlated with that of the postural change in HCVR (r=.93, P<.0001). CONCLUSIONS: Respiratory muscle weakness may contribute to the attenuated HCVR in tetraplegia. However, the observation that supine HCVR is still low even when normalized to FVC suggests a central posture-dependent effect on the HCVR, which may be linked to the postural effect on arterial blood pressure.

Diaphragmatic paralysis: a clinical imitator of cardiorespiratory diseases.

Diaphragmatic paralysis has a predictable effect on lung function. However, the symptoms depend on the preexisting heart-lung diseases and may mimic various cardiorespiratory processes. We describe the presentation in six patients. In a fit man, unilateral diaphragmatic paralysis caused dyspnea only at strenuous exercise. In a patient with emphysema it caused dyspnea mainly when carrying light weights. In another patient with emphysema it caused life-threatening hypoxemia simulating parenchymal lung disease. A patient with mild chronic obstructive lung disease and nocturnal wheezing following the onset of ULDP was believed for 15 years to have asthma. A patient with bilateral diaphragmatic weakness had severe choking sensation only in the supine position, simulating upper airway obstruction or heart failure. Afemale patient suffered nocturnal sweating due to ULDP. The clinical manifestations of diaphragmatic paralysis vary and can mimic a wide range of cardiorespiratory diseases.

Exercise training in advanced heart failure patients: discordance between improved exercise tolerance and unchanged NT-proBNP levels.

BACKGROUND: Exercise training can improve aerobic capacity and symptoms in congestive heart failure (CHF) patients. AIMS: To test the feasibility of exercise training in advanced CHF patients, and examine the potential benefit from peripheral vascular and muscular conditioning as well as improved central hemodynamic and neurohumoral status. METHODS AND RESULTS: Thirty NYHA functional class III, CHF patients (mean age 61+/-13 yr, ejection fraction 27+/-4%, VO2max 11.3+/-3.9 ml/kg/min) were enrolled. Exercise capacity, cardiovascular parameters and serum levels of brain natriuretic peptide (NT-proBNP) were determined at baseline and after 18 weeks of moderate intensity exercise training. Twenty eight (93%) patients, who completed the exercise program, experienced marked improvements in the 6 min walk (+39%) and exercise duration on the modified Bruce protocol (+66%). Smaller improvements were recorded in the cardiac index (a 15% increase), in the maximal oxygen consumption (a 13% increase in VO2max), in the left ventricular ejection fraction (an 11% increase) and in the systemic vascular resistance and pulmonary artery pressure (an 11% decrease). NT-proBNP levels were not significantly affected. They correlated with exercise capacity and VO2max on baseline measurement, but these correlations were not found after training. CONCLUSION: Rehabilitation is feasible, even in advanced CHF, and leads to markedly improved exercise performance, but does not affect the level of the principal neurohumoral marker of prognosis - NT-proBNP. Resting cardiovascular performance and maximal oxygen consumption improve less than functional capacity, suggesting that an important benefit is derived from muscle conditioning and improved peripheral vascular response to exercise.

Breath sound distribution images of patients with pneumonia and pleural effusion.

OBJECTIVE: To determine whether breath sound distribution maps can differentiate between patients with pneumonia or pleural effusion versus healthy controls. METHODS: We recorded breath sounds from 20 patients conventionally diagnosed as having pleural effusion, 20 patients conventionally diagnosed as having pneumonia, and 60 healthy controls, of whom 20 served as a learning sample. All subjects were examined with a computer-based multi-sensor breath sound mapping device that records, analyzes, and displays a dynamic map of breath sound distribution. The physicians who interpreted the breath sound images were first trained in identifying common characteristics of the images from the learning sample of normals. Then the images from the 40 patients and the 40 controls were interpreted as either normal or abnormal. RESULTS: In the normal images, the left and right lung images developed synchronously and had similar size, shape, and intensity. The sensitivity and specificity of blinded differentiation between normal and abnormal images when the physician interpreter did not know the patient's workup were 82.5% and 80%, respectively. The sensitivity and specificity of blinded detection of normal and abnormal images when the interpreter did know the patient' workup were 90% and 88%, respectively. CONCLUSIONS: Computerized dynamic imaging of breath sounds is a sensitive and specific tool for distinguishing pneumonia or pleural effusion from normal lungs. The role of computerized breath sound analysis for diagnosis and monitoring of lung diseases needs further evaluation.

Effects of exercise training on quadriceps muscle gene expression in chronic obstructive pulmonary disease.

Exercise capacity and training response are limited in chronic obstructive pulmonary disease (COPD), but the extent to which this is related to altered skeletal muscle function is not fully understood. To test the hypothesis that muscle gene expression is altered in COPD, we performed needle biopsies from the vastus lateralis of six COPD patients and five sedentary age-matched healthy men, before and after 3 mo of exercise training. RNA was hybridized to Affymetrix U133A Genechip arrays. In addition, peak O(2) uptake and other functional parameters (e.g., 6-min walk) were measured before and after training. The 6-min walk test increased significantly following training in both groups (53.6 +/- 18.6 m in controls, P = 0.045; 37.1 +/- 6.7 m in COPD, P = 0.002), but peak O(2) uptake increased only in controls (19.4 +/- 4.5%, P = 0.011). Training significantly altered muscle gene expression in both groups, but the number of affected genes was lower in the COPD patients (231) compared with controls (573). Genes related to energy pathways had higher expression in trained controls. In contrast, oxidative stress, ubiquitin proteasome, and COX gene pathways had higher expression in trained COPD patients, and some genes (e.g., COX11, COX15, and MAPK-9) were upregulated by training only in COPD patients. We conclude that both COPD and control subjects demonstrated functional responses to training but with somewhat different patterns in muscle gene expression. The pathways that are uniquely induced by exercise in COPD (e.g., ubiquitin proteasome and COX) might indicate a greater degree of tissue stress (perhaps by altered O(2) and CO(2) dynamics) than in controls.

Detection of non-diploid cells in premalignant and malignant oral lesions using combined morphological and FISH analysis - a new method for early detection of suspicious oral lesions.

Alteration in DNA content is an early event in oral carcinogenesis. We have examined oral brush samples to detect non-diploid cells (NDC) using simultaneous morphological and cytogenetic analysis. The study included 8 oral squamous cell carcinomas (OSCC), 22 premalignant lesions (OPLs), and 25 control individuals. Slides stained with Giemsa followed by FISH using chromosome 2 centromeric DNA probe, were scanned and fluorescent signals were simultaneously analyzed in parallel with the morphology. The proportion of NDC increased with the severity of the diagnosis. In two control subjects, 1-1.5% of the examined cells were NDC. Over 2% NDC were present in all OSCC cases and in 11 of the OPLs, of which, in 8 the histologic diagnosis was either epithelial hyperplasia or mild dysplasia. A significant number of NDC had normal morphology when cytomorphology and FISH were compared. Two patients with OPLs developed OSCC these patients had a significant proportion of NDC. We suggest that the combined morphological and cytogenetic analysis of cells collected by a non-invasive brush sampling can enhance early detection of potentially malignant cells.

Do angiotensin-converting enzyme (ACE) inhibitors enhance the effect of exercise rehabilitation in patients with hypertension and ACE DD and DI genotypes?

OBJECTIVE: To test whether pharmacologic angiotensin-converting enzyme (ACE) inhibition in carriers of the ACE DD or DI (D, deletion; I, insertion of 287 base pairs) genotypes can simulate the genetic advantage of the II genotype and thereby enhance the conditioning effects of aerobic exercise. DESIGN: Nonrandomized controlled trial. SETTING: Pulmonary institute. PARTICIPANTS: Twelve sedentary men with controlled hypertension (5 with DD genotype, 7 with DI genotype; age, 53+/-7y) treated by ACE inhibitors (study group) and 10 patients (8 men, 2 women; 2 with DD genotype, 8 with DI genotype; age, 54+/-10y) who were treated by other antihypertensive drugs (controls). INTERVENTION: Exercise training. MAIN OUTCOME MEASURES: Training effect was measured by maximal oxygen uptake (Vo(2)max) anaerobic threshold (Vo(2AT)), and the corresponding work rates (WR) (in watts)-WRmax and WR(AT)-before and after 10 weeks of training. RESULTS: Vo(2)max increased by a mean of 10% (200mL/min) and WRmax by 14% (25W) in each group (P<.001). Vo(2AT) and WR(AT) tended to increase more in the study group (Vo(2AT): 10% [186+/-35mL/min] vs 5% [100+/-1mL/min]; P<.006; WR(AT): 19% [19+/-2W] vs 12% [11+/-3W]; P<.03; respectively). CONCLUSIONS: This study did not show an enhancement of exercise-related conditioning by pharmacologic ACE inhibition among hypertensive patients with ACE DD and DI genotypes, comparable to the advantage conferred by the II genotype.

Central versus peripheral cardiovascular limitation to exercise: the role of two-modality testing.

BACKGROUND: Uncertainty arises when physiological findings indicate a cardiovascular limitation but the limiting constituents within the cardiovascular system cannot be identified. OBJECTIVES: It was the aim of this study to investigate the value of two-modality exercise testing to assess effort intolerance when the cause remains obscure despite standard exercise testing. METHODS: A second modality maximal exercise test to fatigue, using either upper extremity or supine exercise, was performed following a nonconclusive standard sitting ergometry. Six patients (4 males) with a mean age of 56 +/- 22 years with severe exercise intolerance were enrolled in the study. RESULTS: In 4 of the patients, arm exercise capacity exceeded leg capacity, indicating peripheral limitation. In 1 of these patients, hemoglobin saturation decreased markedly only during sitting exercise while it remained normal during arm exercise, indicating a unique, iatrogenic abnormality. In another patient, supine leg exercise capacity exceeded sitting capacity, indicating peripheral venous limitation, and in an additional patient, leg capacity exceeded arm capacity pointing towards a central abnormality. In all 6 patients, the second modality test highlighted the correct diagnosis. CONCLUSIONS: Arm exercise that is added to a standard leg exercise may distinguish between central circulatory and peripheral vascular lower extremity limitation. Supine posture augments venous return to the heart and is useful when preload may be limiting. These modes of exercise may be added to a standard sitting or upright test in order to differentiate between central cardiovascular versus peripheral vascular (arterial or venous) causes of exercise limitation.

Necrotizing granulomata in the lung preceding colonic involvement in 2 patients with Crohn's disease.

Extraintestinal involvement, including the chest, is common in the late course of Crohn's disease. We describe 2 female patients in whom the course of the disease was unique in two aspects: (1) each had a pulmonary mass with granulomatous inflammation and necrosis, and (2) these findings had preceded the colonic involvement by 5 years. This sequence supports some of the theories on the pathogenesis of Crohn's disease and on its possible relation with sarcoidosis, another idiopathic granulomatous disease.

Familial Mediterranean fever gene and protection against asthma.

BACKGROUND: Asthma is an inflammatory airway disease caused by interaction between susceptibility genes and diverse environmental factors. In Israel, asthma seems to be familial and more severe in patients of Iraqi Jewish descent. On the other hand, asthma is less frequent in individuals with familial Mediterranean fever, an autoinflammatory disease prevalent in the Iraqi Jewish community and linked to mutations in the familial Mediterranean fever gene, designated MEFV. OBJECTIVES: To explore a possible role for mutated MEFV in the reduced susceptibility to asthma and to determine its expression in Israeli subjects of Iraqi origins. METHODS: Using a case-control approach, we studied the presence of the 3 most common MEFV mutations (M694V, V726A, and E148Q) in DNA samples from 75 patients with asthma and 45 asymptomatic first-degree relatives, all of Iraqi Jewish origin. The severity of asthma was evaluated using a published severity score. RESULTS: Eleven patients with asthma and 14 of their relatives carried 1 or 2 mutations in the MEFV gene, a carrier rate significantly lower in patients with asthma than in their first-degree relatives and in ethnically matched healthy individuals (P < .03 and P < .003, respectively). Carriers of MEFV mutations had less severe disease, compared with noncarriers (P < .002). CONCLUSION: These findings suggest that MEFV mutations may have a protective effect in the pathogenesis of asthma.