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Birth Control Online - Pulmonary Vascular Occlusion and Fibrosing Mediastinftis: Case Reports

Patients with fibrosing and granulomatous medi-astinitis commonly present a diagnostic challenge because of the variability of involvement of the different structures of the mediastinum. The spectrum of the disease varies from a benign condition with minor symptoms to severe pulmonary hypertension resulting in death. We have recently encountered three patients who have further broadened this spectrum. All were referred to us as potential candidates for pulmonary thromboendarterectomy with a presumptive diagnosis of pulmonary hypertension due to chronic thrombotic obstruction of major pulmonary arteries. The findings in these three patients did, in fact, remarkably mimic those in patients with chronic, large vessel thrombotic obstruction. The history and physical findings, the results of perfusion and ventilation scanning, as well as pulmonary angiographic and certain findings on right heart catheterization all paralleled those which characterize chronic, major vessel thrombotic obstruction. However, all of the findings were explained by pulmonary arterial and/or venous obstruction due to fibrosing mediastinitis. Because an attempted thromboendarterectomy in such patients would have had no positive—indeed, likely, quite adverse—effects, we feel it is important to describe this experience and to emphasize the differential diagnostic features between chronic thrombotic obstruction and this form of fibrosing mediastinitis. Case Reports Case 1 A 28-year-old white woman first noticed dyspnea on exertion in May 1982. Throughout the following months, she also noted mild intermittent cough productive of blood streaked sputum on several occasions. By May 1983, her dyspnea had progressed so that she was short of breath after one block of level walking. Her medical history was significant only for her use of birth control pills - https://mybirthcontrolonline.com/birth-control-online-pills-after-sexual-intercourse.html. She denied any symptoms of deep venous thrombosis. She was a nonsmoker. She had lived in Tennessee for 23 years prior to moving to California. In May 1983, she was evaluated at another hospital. Pulmonary ventilation and perfusion scans and right heart catheterization led to the diagnosis of probable chronic thrombotic obstruction of major pulmonary arteries. She was treated with coumadin and referred to UCSD Medical Center for possible thromboendarterectomy. Physical examination showed unlabored respiration at rest with a rate of 16. The lungs were clear. Cardiac examination showed a sustained left parasternal lift, a split S2 that widened with inspiration, and an increased Pt. There were no signs of right ventricular failure. Chest x-ray films showed cardiomegaly with a right ventricular configuration, fullness of the left hilum, right pleural thickening, and possible Kerley B lines in both lower lobes. An area of possible subcarinal calcification was seen. A perfusion scan showed near total absence of perfusion to the right lung, with only minimal perfusion to the right apex; on the left, there were several basilar subsegmental defects. Ventilation scan was normal (Fig 1). Echocardiogram revealed an enlarged right atrium and ventricle, and a normal mitral valve and left ventricle. Impedance plethysmography was normal bilaterally. At initial right heart catheterization, the pulmonary artery pressure was 87/45 (mean 60 mg Hg). The (Fick) cardiac output was 6.8 L/min. Hie pulmonary vascular resistance was elevated at 649 dynes/s/cm’. The wedge pressure was not measured for technical reasons. Pulmonary angiography showed abrupt cut-offs of the right lower and middle lobe arteries, and the right pulmonary artery was narrowed by 70 to 80 percent. On the left, there were questionable filling defects in the left lower lobe segmental vessels (Fig 2). The CT scan of the chest demonstrated a large, calcified subcarinal mass displacing the left atrium and right pulmonary artery anteriorly (Fig 3). Calcified granuloma were seen in the liver and spleen. A histoplasmin skin test was positive; PPD, negative. Results of serologic tests for histoplasmosis, blastomycosis, and coccidiodomy-cosis were negative. At repeat right heart catheterization, wedge pressures were measured in several areas: 26 mm Hg in the right lower lobe, 19 mm Hg in the right upper lobe, 26 mm Hg in the left lower lobe, and 21 mm Hg in the left upper lobe. Selective pulmonary angiography on the right showed normal vasculature distal to the previously noted “cut-offs” (Fig 4). Left heart catheterization disclosed a mean left atrial pressure of 7 mm Hg, no mitral gradient, and normal left ventricular pressures. Selective injection of pulmonary veins clearly demonstrated obstruction near the entrance to the left atrium (Fig 5). Because of severe cough, she was treated with a course of prednisone. Her cough markedly improved but the shortness of breath did not. Case 2 A 28-year-old woman was referred to UCSD Medical Center for pulmonary thromboendarterectomy. She was well until two years before when she had an episode of right pleuritic chest pain associated with shortness of breath and hemoptysis. She was treated as an outpatient with antibiotics. Three months later, she had similar symptoms and was again treated for pneumonia. After the second episode, dyspnea, a severe nonproductive cough, and wheezing persisted, despite treatment with bronchodilators. Over the subsequent two years, dyspnea on exertion slowly increased. A third episode similar to the first two resulted in admission to another hospital in April 1983. Physical examination was remarkable for a right ventricular heave without evidence of right ventricular failure. Perfusion scan showed no flow to the right lung and defects in the left upper lobe. The angiogram reportedly showed stenotic main, right upper lobe and right lower pulmonary arteries, as well as cutoffs in the left upper lobe. There was an episode of greater than 100 ml of hemoptysis after angiography. Treatment with coumadin was initiated and a Greenfield filter was placed in the inferior vena cava. In July 1983, there was another episode of severe hemoptysis that spontaneously resolved. Bronchoscopy revealed friability and increased vascularity of the mucosa of the major bronchi on the right Her other medical history was significant for a history of birth control pill use. At physical examination at UCSD, the jugular venous pressure was 8. There was a left parasternal lift. The Ps was markedly increased and split An S3, S4 and a 2/6 systolic murmur were present at the lower left sternal border. Chest x-ray film revealed a small right lung and pulmonary artery. There were increased right interstitial markings. Old films showed the right lung and pulmonary artery were normal in 1980. Right heart catheterization showed pulmonary artery pressures of 70/30 mm Hg with a mean of 45 mm Hg. The pulmonary artery wedge was 25 in LUL and LLL (cardiac output was 5.9 L/min; PVR 816 dynes s cm"). Angiography of the left lung revealed a large left PA with attenuated peripheral branches. The left upper lobe pulmonary veins appeared stenotic near their entry into the left atrium. The right PA could not be selectively catheterized, and angioscopy revealed no visible lumen (of the right PA). The CT scan of the chest showed large calcified nodes involving the subcarinal and pretracheal regions and compromising the right pulmonary artery. The histoplasmin skin test was positive. After discharge, she moved to sea level with substantial resolution of signs and symptoms of pulmonary hypertension. During this time, she was also treated with a tapering course of prednisone. Case 3 This 68-year-old woman was admitted to University Hospital on Jan 2, 1985, for evaluation for possible pulmonary thromboendarterectomy. History disclosed recurrent respiratory illness dating to her childhood. She had “always” been mildly short of breath and could not keep up with her peers by adolescence. At least one episode of “pneumonia” required two weeks of hospitalization in 1942. In 1957, she had an excisional biopsy of cervical lymph nodes. No diagnosis was made. In the mid 1960s, she was found to have a positive PPD and abnormal findings on chest x-ray film. She was treated for an unknown period for tuberculosis. In 1971, she was presented with chest pain and shortness of breath and was presumed to have a pulmonary embolus. Neither perfusion scan or angiography was done. She was anticoagulated for six months. Apparently, several ECGs were suggestive of an acute myocardial infarction. Over the next ten years, there was a slow increase in dyspnea on exertion. Recurrent episodes of cough and pleuritic chest pain continued. She also described exertional chest pain relieved by nitroglycerin and rest. Two months before admission, evaluation elsewhere led to coronary angiography, which showed triple vessel disease, and pulmonary angiography, which disclosed total obstruction of the right pulmonary artery. Chronic pulmonary thromboembolic disease was diagnosed. She denied any history of leg swelling or tenderness. She had lived in St. Louis until 1942 when she moved to San Diego. Family members were thought to have had histoplasmosis. On physical examination, she was an afebrile elderly woman coughing frequently. She was not dyspneic at rest. Chest examination revealed bilateral lower lung field crackles more prominent on the right. The jugular venous pressure was 8 to 9 cm. Cardiac examination was normal. Chest x-ray film showed biventricular cardiac enlargement, right lung volume loss, right pleural thickening, subtle bilateral Kerley B lines, and a right lower lung field infiltrate. Hie ABC showed a pH of 7.46, Pa02 of 65, and a PaC02 of 36 on room air. Impedance plethysmography was normal in both legs. Skin tests for histoplasmosis and PPD were positive. A perfusion lung scan showed no perfusion to the right lung with scattered subsegmental defects in the left lung. The ventilation scan was normal. A CT scan of the chest disclosed a large calcified subcarinal mass, right of the midline. The mass was seen to compress the right lower pulmonary vein and the right pulmonary artery. Repeat cardiac catheterization revealed RA pressure of 8 to 10, RV pressure of 70/8, and PA pressure of70/24. The mean wedge pressure was 20 in both the LUL and LLL. The P(A-a) 02 difference was 5.1 volumes percent; the 02 consumption 130 ml/min/m2. The cardiac index (Fick) was 2.6 L/min/m2. The calculated pulmonary vascular resistance was 408 dynes-s•cm. The mean left atrial pressure was 12. The LA injection showed no filling of the right pulmonary veins. As in case 1, cough was a major problem. Prednisone was instituted with substantial relief. Figure 1A (left). Perfusion scan (posterior view) shows that only the apex of the right lung is perfused. Subsegmental cuts are possibly present in the left lung. Ventilation scan (B, right) is normal. Figure 2A (left). Injection of the right PA shows a narrow right pulmonary artery with multiple “cutoffs.” (B, right) Pulmonary angiography shows a large left pulmonary artery and a question of defects in the lobar artery to the lower lobe. Figure 3. CT scan as shown is a cut just below the carina. Note the large subcarinal mass and the generous main and left pulmonary arteries. (A) Calcified subcarinal mass; (B) Ascending aorta; (C) Right mainstem bronchus; (D) Left mainstem bronchus; (£) Descending aorta; (F) Left pulmonary artery; and (C) Large main pulmonary artery. Figure 4. Selective injection of the right pulmonary artery from a more peripheral spot demonstrates that vessels are patent in areas where cutoffs had apparently been present. Figure 5. Catheterization of left atrium shows a pulmonary vein (arrow) with an abrupt “cutoff.”

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Birth Control Online about Pulmonary Vascular Occlusion and Fibrosing Mediastinftis

These three patients presented with many of the historic, physical, and laboratory features we have found to be associated with chronic thrombotic obstruction of major pulmonary arteries. However, as documented, each proved to have pulmonary arterial and venous obstruction due to fibrosing mediastinitis. Like patients with chronic thromboembolic obstruction, they had a history of progressive dyspnea on exertion of obscure origin. As in many patients with thromboembolic obstruction, a clear cut history of venous thromboembolism was lacking. However, hemoptysis, pleuritic chest pain, and dyspnea suggested that possibility, and all three had been treated for embolism. Physical findings of pulmonary hypertension were present in two patients. None had evidence of lower extremity venous thrombosis; but many patients with proven thrombotic obstruction lack such findings. Laboratory findings were also, in the main, remarkably similar to those in chronic thrombotic obstruction. Electrocardiographic findings were not distinctive, nor were the results of pulmonary spirometric or rest and exercise studies. The first differential clue was provided by the chest roentgenogram. All three patients demonstrated Kerley B lines, a finding present (and less marked) in only two of our more than 30 patients with chronic thrombotic obstruction. Clearly, the presence of Kerley B lines should raise suspicion about the diagnosis of chronic thromboembolic pulmonary hypertension. Noteworthy, however, is the fact that subcarinal calcification was seen on the standard roentgenogram in only one patient; and, even in that instance, was “suggestive” (even in retrospect). Very deceptive, in this context, were the perfusion scan results. All disclosed large perfusion defects which, on ventilation scan, were normally ventilated. Such large “mismatched” defects are not seen in primary pulmonary hypertension, but are characteristic in thromboembolic hypertension. However, in these patients with fibrosing mediastinitis, they proved to be due to regional decrements in pulmonary arterial flow secondary either to fibrotic obstruction of the pulmonary arteries or of major pulmonary veins. That this was the case was documented by angiographic studies. However, even pulmonary angiograms may mimic thrombotic obstruction. An occluded pulmonary artery may represent thrombus or periarterial fibrosis, as demonstrated in case 3. Furthermore, apparent thromboembolic “cutoffs” in these patients can result from regional pulmonary venous pressure differences, as in case 1. Right heart catheterization should have been the definitive procedure documenting, at the least, that the pulmonary arterial hypertension was due to some “downstream” process that had elevated pulmonary venous pressure. However, in patients with large right atria and ventricles and pulmonary hypertension, technical difficulties are often encountered in obtaining satisfactory pulmonary “wedge pressures,” and that was the case in these patients. Two had been catheterized previously without “wedge” pressures obtained. Indeed, when this differential is entertained, not only is a “wedge” pressure essential, but such pressures should be obtained in several regions. Pulmonary venous obstruction is not uniform, resulting in variable degrees of pulmonary venous hypertension in regions drained by different pulmonary veins. Once the presence of pulmonary venous hypertension is established, the differential must include all the known causes, including fibrosing mediastinitis. Thus, left heart catheterization and angiographic studies of the type described here are indicated. The mediastinal CAT scan provided the most striking evidence of the structural problem in each patient. Large calcific masses were readily identified, even though routine roentgenography did not disclose them. It is also worth noting that none of these patients had lived in an area endemic for histoplasmosis for some years. Yet all had lived in such areas during childhood and all had positive skin reactions to histoplasmin antigen (though serologic tests were negative). Thus, the clues suggesting the diagnosis of pulmonary arterial and/or venous obstruction due to fibrosing mediastinitis—rather than chronic thromboembolism—were present in each patient. Yet, those of us involved were impressed with how easily one might have bypassed the clues, made the diagnosis of chronic thrombotic obstruction, and proceeded to attempt thromboendarterectomy. Fibrosing mediastinitis is a rather uncommon condition, a factor which further obscures ready diagnosis. The fibrotic process is thought to be a sequel of active granulomatous diseases, especially histoplasmosis. Immunogenic material is thought to leak from caseous nodes and cause an intense fibrotic reaction. Alternatively, an abnormal host response, in this case elaborating large amounts of collagen, has been suggested to be the problem. If organisms are seen, they are likely to be suggestive of Histoplasma capsulatum. However, in lesions with thick capsules, organisms rarely grow from the lesions. The disease has the capacity to affect almost all mediastinal structures. The common symptoms and signs include superior vena cava (SVC) syndrome, cough, hemoptysis, dyspnea, wheezing, and dysphagia." Among the most common complications is involvement of the tracheobronchial tree. Collagenous tissue actually invades bronchial walls and may grow into the airway lumen causing obstruction. It is this process which often is responsible for recurrent hemoptysis, cough, and dyspnea. Care needs to be taken at bronchoscopy as endobronchial tissue is friable and tends to bleed. There is at least one reported death from massive hemoptysis induced at bronchoscopy. Most authors note, however, that mortality and morbidity are most likely in patients with pulmonary artery or vein involvement. Pulmonary hypertension previously has been reported from obstruction of arteries, veins, or both.*'* Pulmonary venous obstruction occurred in three of 64 patients with fibrosing mediastinitis in the series of Schowengerdt et al, zero of seven in the series of Prager et al, two of 31 of Dines et al, and six of 38 of Goodwin et al. Two more recent cases have been reported, who presented with dyspnea and hemoptysis. There are a few cases in the literature in which this disease closely mimicked mitral stenosis. Left atrial myxoma has also been considered in the differential diagnosis. Whether any effective medical therapy exists for fibrosing mediastinitis and mediastinal granuloma is not clear. Because of the small number of cases, no controlled trials are available. Amphotericin B has not proven to be effective. This is not surprising given that fibrosing mediastinitis does not seem to be associated with active infection. Steroids have been advocated, but there is little evidence demonstrating efficacy. Davis and Andrus treated two of their patients for a three month course and neither showed improvement. Hicks treated his patient for hemoptysis with only ten mg QOD of prednisone, with rapid resolution of symptoms; however, the patient had a surgical procedure at the same time making the possible benefit of steroids impossible to evaluate. Surgical resection of advanced cases such as ours is said to be technically very difficult. However, there have been reports of some success when surgery is employed to control severe hemoptysis. Dye et al and Hicks separately reported patients with severe hemoptysis and dyspnea who underwent right middle and lower lobe resection with improvement of dyspnea and resolution of hemoptysis. Perhaps these good outcomes were made possible by the feet that both patients had focal pulmonary venous obstruction. Most other reported patients in whom surgery was attempted proved unresectable. Our three patients have been treated with corticosteroids with some improvement. Itoo had marked improvement of cough. The other had relief of dyspnea, but her steroid treatment coincided with moving from an altitude of 5,000 feet to sea level. Anticoagulant therapy was discontinued in those patients in whom it had been initiated. The substantial incidence of hemoptysis from bronchial mucosa or venous obstruction would appear to place those patients at particular risk of anticoagulant-induced pulmonary hemorrhage.

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Birth Control Online: Peripheral Airways Obstruction in Idiopathic Pulmonary Artery Hypertension

The patients had most of the features of the entity called idiopathic or primary pulmonary artery hypertension and fulfilled the accepted criteria for the diagnosis. Accordingly, in three patients, the lung biopsy or the necropsy specimens showed the arterial histopathologic spectrum described for IPAH. It has been previously stated that pulmonary mechanical function is close to normal in IPAH patients. However, using lung function tests that detect peripheral airways disease, this concept can no longer be supported. Our patients were nonsmokers, and no other cause of airway disease was identified. Therefore, the abnormalities seen were most likely related to IPAH. Normal forced exhaled flow rates may be preserved in the presence of significant peripheral airways obstruction. If tests to detect such peripheral airways abnormalities had not been performed, only three of our patients would have shown an increased airways resistance as measured by the observed MMEF and Raw values (cases 4,5, and 10). Also, such abnormalities could only explain the abnormal increase in RV documented in three of the seven patients.When MMEF values are adjusted for air density at high altitude, two additional patients showed an abnormality (case 1 and 6) that could explain the increase in RV. A measurement of FEF 75-85 percent lower than 75 percent of the predicted value is capable of identifying subjects with small airways disease. In the present study, this index was abnormal in eight patients, three of whom had a normal MMEF with an increased RV (case 1,3, and 6). With the indices derived from the flow-volume curves with air, it could only be possible to detect abnormalities in exhaled flow rates in four patients in whom the MMEF and FEF 75-85 percent were abnormal. Be protected from severe and unwanted ramifications with Birth Control Online - https://mybirthcontrolonline.com/birth-control-online-with-oral-contraceptives.html. The habitat of the studied population was 2,240 m and the predicted normal values used to detect airways obstruction were taken from sea level studies and also from the FEVj/FVC, MMEF, and FEF 75-85 percent reported at a higher altitude of 3,100 m. The latter data were considered because, although flow limitation may not be apparent in airways in which flow is turbulent, the diminished air density at a higher altitude could underestimate an abnormal resistance to air flow. Using flow-volume curves with He-Oj, an increased resistance to air flow in the peripheral airways was found in eight of the cases studied. On the other hand, the closing volume and the closing capacity were also abnormal in eight cases. As far as we know, there is no evidence that values obtained from the flow-volume curves with He-02 or from indices derived from the single breath nitrogen curves might be different at our altitude relative to those obtained at sea level. Flow rates may be reduced solely by loss of elasticity, and the airways themselves may appear structurally normal. None of the IPAH patients studied showed a loss of elasticity. In fact, in four, the elastic recoil was increased. The abnormal figures recorded for the MMEF curves, for the FEF 75-85 percent, for the Vmax 50 percent VC and Vmax 25 percent VC (with air), for the CV/VC, for the closing capacity in the absence of loss of elastic recoil, and in the presence of close to normal Raw measurements, represent abnormalities that reflect peripheral airways obstruction in the IPAH patients. An increase in flow at 50 percent of VC when breathing He-02 was observed in eight of the patients. This is independent of lung elastic recoil, and thus, may be more specific for detecting abnormality in peripheral airways. These findings in IPAH patients support the idea that the caliber of the small airways is reduced. This feature could explain the increase in RV observed in this entity. Our findings are also supported by the pathologic observations in the three cases studied that showed small airways disease. The observed changes in lung compliance and elastic recoil in IPAH cannot be attributed to a reduction in the number of air spaces (ie, pulmonary fibrosis). It is, however, possible that such changes might be the result of the pathologic changes present in the pulmonary vasculature. As has been proposed previously by our group, and by other investigators, it could be the result of perivascular and vascular thickening which may render the air-vessel space less distensible. Clearly, the real explanation for the observed changes in lung compliance and elastic recoil remain speculative. It has been observed that arterial oxygen saturation decreases with progression of the disease and that hypoxemia and/or widened P(A-a)Oa is caused mainly by V/0 inequality and low mixed venous oxygen content without evidence of a diffusion impairment. In some cases, it is also due to an intracardiac shunt secondary to a patent foramen ovale.The development of hypoxemia and the increased ratio of dead space to TV observed in some of our patients in the absence of evidence suggesting alveolar destruction, also suggest abnormalities of ventilation distribution. Also Vd/Vt changes could result from the vascular abnormality causing a decrease in perfusion with secondary increase in airways resistance to flow in nonperfused areas. The anatomic lesions of IPAH primarily cause a restriction of the pulmonary vascular bed that results in maldistribution of the pulmonary blood flow. On the other hand, as a result of abnormalities in the peripheral airways with secondary maldistribution of alveolar ventilation, a ventilation-blood flow imbalance ensues. The knowledge of the peripheral airways obstruction that occurs in IPAH patients could help to better understand the impairment in gas exchange when present in this entity. The results from this study indicate that in IPAH, besides the pulmonary microcirculation, the peripheral airways are affected. In considering the relation of vascular and airway disease, we cannot, however, distinguish between cause/effect or independent processes.

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Results of Peripheral Airways Obstruction in Idiopathic Pulmonary Artery Hypertension

Pulmonary function data for the IPAH patients are shown in Table 1. The TLC was normal in all patients, and VC was decreased in cases 4 and 5. The RV, measured as thoracic gas volume, was outside the limits of normality in seven out of the ten patients. The FEV,/FVC ratio was normal in all patients, the MMEF was decreased in three patients, and the FEF 75-85 percent was abnormal in eight out of the ten patients. When air flow was adjusted for decreased air density at 3,100 m (Mexico City altitude is 2,240 m), the mean average values of the observed MMEF and FEF 75-85 percent for altitude became statistically different when compared to the values calculated according to the regression equations for sea level. The MMEF for sea level is 84±22 percent predicted; MMEF for an altitude of 3,100 m 67 ±18 percent predicted (p<0.001); FEF, 75-85 percent for sea level = 70 ±28 percent predicted; for high altitude, 46 ±14 percent predicted (p<0.01).

Using the regression equation for MMEF at an altitude of 3,100 m, six out of eight patients showed a decreased MMEF. Cases 2 and 7 that showed normal FEF 75-85 percent values, according to the regression equation for high altitude became abnormal. The Raw was found abnormal in two patients (cases 4 and 5). The V,,** 50 percent and V,^ 25 percent was abnormal in four out of the ten patients. Using all these indices (the MMEF, the FEF 75-85 percent, Raw, 50 percent VC, and the V^ 25 percent VC), bronchial obstruction was found in nine out of the ten patients. When air flow was adjusted for the air density at high altitude, bronchial obstruction was present in all cases (case 7 showed a MMEF of 70 percent predicted and a FEF 75-85 percent = 73 percent predicted). The Cst was decreased in four patients (cases 1,3,5, and 7), and the elastic recoil pressure at 90 percent of TLC was abnormal in seven patients.

The values for helium-air flow ratios derived from the MEFV curves at 50 percent VC and 25 percent VC, the closing volume, the closing capacity, the slope of phase 3 and the behavior of the Cdyn are shown in Table 2; the helium-air flow ratios at 50 percent VC and 25 percent VC were abnormal in eight out of ten patients.

Abnormal values for closing capacity were found in eight of the ten patients (Fig 2). The alveolar plateau was abnormal in two patients (cases 3 and 5). Frequency dependence of compliance was demonstrated in nine of the ten patients.

Figure 3 shows the static pressure-volume curves obtained during expiration and separated in age groups. The shaded area is the range of normal values given by Turner and co-workers. In six patients, it was found shifted downwards and to the right (cases 1,2,4,5,7, and 8). In two patients (cases 9 and 10), there was a shift upwards and to the left at low lung volume.

The maximum voluntary ventilation was abnormal (<80 percent predicted) in four patients, and the mean average value for the whole group was 79 ± 18 percent predicted.

Table 3 shows the physiologic dead space, the pulmonary gas exchange, and the anatomic veno-arterial shunt results for the IPAH patients studied. The physiologic dead space-tidal volume ratio (Vd/Vt) was abnormal in eight patients, and the VD was abnormal in five. The P(A-a)02 was increased (>15 mm Hg) in six patients and a decreased Pa02(<65 mm Hg) was found in four patients in whom PaC02 was in the range of normality for our altitude (30 to 35 mm Hg). ThePaC02 was below 30 mm Hg in four patients, two of whom showed an abnormal P(A-a)02 (case 4 and 9). The 0s/0t was greater than 5 percent in seven patients. No significant correlation was found between the pulmonary function parameters and the level of the mean pulmonary artery pressure. Necropsy and lung biopsy specimens (cases 2,4 and 7) showed narrowing of small airways with thickened walls, infiltrated by a great number of lymphocytes, some plasma cells, and a few polymorphonuclear leukocytes (Fig 4). Some airways contained mucus plugs. There were no features suggesting emphysema.

Figure 2. Closing volume (CV/VC%) and closing capacity (CC/ TLC%) results for the idiopathic pulmonary artery hypertension patients. The CV/VC% were abnormal in two cases and CCATLC% values were abnormal in eight patients. Normal values are from Buist and co-workers.

Figure 3. Static deflation pressure-volume curves for the IPAH patients, divided into different age group. In six patients (cases 1,2,4,5,7, and 8), it was found downwards and to the right, and in two (cases 9 and 10), the pressure-volume curve was shifted upwards and to the left at low lung volume. The shaded area is the range of normal values given by Turner and co-workers.

Figure 4. Small airways infiltrated by a great number of lymphocytes, some plasma cells, and a few polymorphonuclear leukocytes (hematoxylin-eosin, original magnification x 256).

Table 1—Pulmonary Function Test in the IPAH Patients

CaseNo. Age,yr PAP, mm Hg TLCt vet RVt FEV./FVC MMEF FEF75-85% Raw u n/I at50% VC V^ at 25% VC Pst (1) cm* Cst H20 at L/cm H20 90% TLC Valuet Valuet Valuet Valuet Valuet Valuet Chi rijx-J/l-is/FRC 1 20 134 91 81 133 86 88 87 75 63 54 1.03 89 106 0.050 49.3 2 21 38 110 95 196 93 89 103 80 133 71 1.1 57 £7 0.143 27.6 3 28 53 102 92 142 86 88 100 82 70 45 2.0 103 84 0.061 29.4 4 17 106 87 71 141 80 63 69 M 67 57 0.071 35.8 5 36 81 87 60 172 81 88 46 31 30 21 xo 51 48 0.027 44.8 6 42 51 102 82 167 83 86 85 75 50 49 0.78 70 70 0.143 12.9 7 30 46 88 80 120 97 88 80 70 103 73 1.4 112 140 0.061 20.0 8 16 62 98 107 60 80 120 11 2.6 113 129 0.101 25.0 9 21 61 112 119 94 81 93 93 73 60 40 2.25 109 118 0.110 14.1 10 28 35 96 81 146 81 88 62 42 60 40 1.25 102 112 0.089 17.0 Mean±SD 25±8 65 ±30 97 ±9 87 ±17 137 ±39 84±5§ 88±2 84 ±22)| 67 ± 18 70 ± 2811 46 ±14 1.09 ±0.9 87.8 ±27 92±34 0.085± 0.03 27.5±12 No. patients outside 10 0 2 7 0 0 3 6/8 8 8/8 2 4 4 4 7 limits of normality Normal values 24,36 16,17 16,17 16,17 20 21 20 21 34 21 16 18,19 18,19 16 29 from references

Table 2—Helium/Air Flow Ratios, Closing Volume, Closing Capacity, Slope of Phase 3 and Dynamic Compliance in IPAH Patients

Case Helium/Air Flow Ratio at 50% VC 25% VC Closing Volume (% VC) Closing Capacity (%TLC) % N*/L Slope Phase 3 Frequency Dependence of Compliance 1 100 105 12.5 38 1.0 D 2 139 144 13.7 43 0.97 D 3 118 100 17 40 L6 D 4 100 109 9.3 38 1 D 5 100 108 23.4 60 3,3 D 6 100 100 19 51 0.57 D 7 132 130 12.8 38 1.17 ND 8 110 109 14 25 0.8 D 9 118 100 25 37 0.82 D 10 106 113 13.2 44.8 1.73 D Mean± SD 87 ±27 110±16 16 ±5 41.4±9 1.3±0.8 No. patients outside limits 8 8 2 8 2 9 of normality

Table 3—Physiologic Dead Space, Pulmonary Gas Exchange, and Anatomical Shunt in IPAH Patients

Case Vd/Vt ratio Vd, ml P (A-а) 02, mm Hg PaOz, mm Hg PaC02, mm Hg Qs/Qt% 1 0.48 289 24.3 55 30 18 2 0.36 179 13.4 64 31 8 3 0.58 243 22.4 65 30 6 4 0.27 98 19.5 68 24 5 5 0.51 187 19.3 64 30 6 6 0.42 166 15.0 67 26 7 7 0.50 207 18.8 59 32 10 8 0.40 143 4.9 78 31 4 9 0.30 166 16.4 72 26 6 10 0.44 100 6.2 82 27 4 Mean ± SD 0.42 ±0.10 177 ±59 16±6 67 ±8 29 ±2 7±4 No. patients outside of 8 5 6 4 4 7 limits of normality Normal values from 16 26 24,25 24,25 24,25 27 references

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Approach to Peripheral Airways Obstruction Offered by Birth Control Online

Primary or idiopathic pulmonary artery hypertension (IPAH) is a rare entity. A number of theories have been advocated to explain its origin in the absence of concurrent cardiopulmonary disease. Recently, a better understanding of the hemodynamics of this entity and the benefit seen in some patients under vasodilator therapy has helped to explain its phys-iopathology. Little is known about pulmonary function tests in IPAH, particularly those concerning lung mechanics. Some have referred to pulmonary function tests as being normal or close to normal. Others have suggested an abnormal diffusing capacity, increased residual volume, and reduced maximum voluntary ventilation. A severe restrictive ventilatory defect in a patient with IPAH that worsened during his clinical course has also been reported. Our study describes the mechanical properties of the lung in ten patients with IPAH, and shows, in most of them, evidence of peripheral airways obstruction and abnormal lung compliance. Methods The diagnosis of IPAH was made after the exclusion of other known diseases capable of producing pulmonary artery hypertension (PAH), following accepted criteria. There were five male and five female subjects, ranging from 16 to 42 years of age (mean 25 years). At the time of the studies, they had been symptomatic for an average of eight years (range two to 12 years). All patients presented with a history of dyspnea on exertion. Five patients gave an additional history of syncope. Chest pain on exertion was present in three patients. None had cough or sputum production. All patients had clinical signs of PAH, ECG evidence of right ventricular enlargement, as well as suggestive roentgenographic signs of PAH. Their mean pulmonary artery pressure was 65.7 ±30 mm Hg, (normal: ^16 mm Hg); the pulmonary arteriolar resistance was 1165 ± 240 dynes/sec/cm~) (normal: ^100 dynes/sec/cm ~); and the pulmonary wedge pressure was normal (6.2±3 mm Hg). The mean cardiac index was 3.0±1.1 L.min/m2. There were no smokers or obese patients in the group, and none of the women had taken oral contraceptive medication suggested by Birth control Online here - https://mybirthcontrolonline.com/i-have-one-drug-to-another-birth-control.html. None of the patients had taken appetite depressant drugs. No patient was included in the study if known to have signs or symptoms of right heart failure, respiratory infection, or history of pulmonary embolism. However, three patients had experienced right cardiac failure and recovered between eight and ten months before the study. None had clinical evidence of air space or restrictive lung disease, and the lung parenchyma was normal roentgenographically in all cases. All patients were permanent residents of Mexico City (altitude 2,240 m). In all cases, the following laboratory examination results were normal or negative: antinuclear antibodies, lupus erythematosus cells, latex fixation, rheumatoid factor, protein electrophoresis, cryoglobulins, Schirmer test, Ab for Sjogren, pigeons and PPD. A lung biopsy specimen was obtained in one patient (case 7) and necropsy specimens in two (cases 2 and 4). Paraffin sections were done and stained by the hematoxylin-eosin, Massons trichrome, Ziehl-Nielsen, PAS, and Van Giesons techniques. All cases examined under the light microscope showed the vascular histopathologic spectrum described in IPAH (Fig 1). All sections were evaluated according to the Heath and Edwards classification of pulmonary hypertensive arterial disease. Two subjects (2 and 7) corresponded to grade 3 (medial hypertrophy, intimal fibrosis and early generalized vascular dilatation, and one (4) to grade 4 (progressive generalized vascular dilatation and occlusion by intimal fibrosis and fibroelastosis, plexiform lesions). Small airways abnormalities were evaluated according to previously reported histologic changes found in patients with these disorders. No cardiac defects in subjects 2 and 4 were demonstrated. Two of the patients were on long-term sublingual isoproterenol therapy which was suspended on the ward 24 hours before the study. None of the remaining cases was receiving bronchodilator or vasodilator therapy at the time of the study. After the lung function results, cases 4, 5, and 10 were given bronchodilator therapy. The research protocol was approved by the Institutes Ethics Committee for Clinical Investigation. Lung volume measurements were made with the patients seated in a volume displacement plethysmograph. Total lung capacity (TLC) was measured with the method of Du Bois and co-workers. Recordings were made on an oscillographic photographic recorder. Lung static compliance (Cst) and airway resistance (Raw) measurements were made with the esophageal balloon technique. Static pulmonary compliance was obtained from the slope of the pressure-volume curve from functional residual capacity (FRC) to 1 L above. Pulmonary function results were compared to the normal values reported by Comroe and colleagues and Baldwin and associates and are expressed as a percentage of the predicted normal value. Dynamic compliance (Cdyn) was measured at 20, 30, 60, and 90 breaths per minute with the patient seated. Tidal volume was measured in the plethysmograph. Esophageal pressure was used as an index of pleural pressure and was measured by an esophageal balloon (length 10 cm, perimeter 3.5 cm) containing 0.6 ml of air and positioned in the midesophagus. Balloon volume was such that it was relatively independent of balloon pressure, and esophageal pressure was checked for artifacts according to the method of Milic-Emili and co-workers. Pressure was also measured at the mouth and trans-pulmonary pressure was derived as the difference between mouth and esophageal pressures. The flow measurements were made with a Hans-Rudolph heated pneumotachygraph and an Statham transducer. All signals were recorded. A marker in front of the patient helped the subject to keep his end-expiratory volume at FRC and his tidal volume (TV) near that of resting TV at various respiratory frequencies. A constant volume history of inflation to TLC preceded the measurement of Cdyn at each frequency. Maximum expiratory flow volume (MEFV) curves were obtained by plotting flow against volume on the oscillographic photographic recorder. Flow rates from the pneumotachygraph were calibrated for air and helium to correct for gases with different viscosity. Several MEFV curves were obtained on air from the seated subject. The patient then inhaled the helium-oxygen mixture (He20 percent-0280 percent) to vital capacity (VC) and then repeated the MEFV maneuvers. The best air and helium MEFV curves were selected. From the air MEFV curve, flow rates were calculated at 50 percent of the VC (V^ 50 percent VC) and 25 percent of the VC (Уma 25 percent VC). Flow rates were calculated in liters per second. Results were compared to the normal values of Chemiack and coworkers, Zapletal and associates, Morris and colleagues, and for an altitude of 3,100 m from Kryger and co-workers. Due to age limitations, the data reported for high altitude could only be applied to eight of the ten patients (case 4 was 17 years and case 8, 16 years old). Flow rates at 50 percent and 25 percent of VC were also determined on the helium MEFV curves. The flow ratios between the helium and air curves (helium V^/air Vm„) at 50 percent and 25 percent of VC were calculated. Closing capacities were measured by the residual gas (NJ technique. Three reproducible curves were obtained in each subject and mean values taken. Each curve was analyzed in terms of the slopes of phase 3, phase 4, and the junction of phase 3 and phase 4. Closing volume was identified as the onset of phase 4 and closing capacity defined as the volume of phase 4 plus RV. Results were compared to the normal values of Buist and colleagues. With the patient seated, expired air was collected for three minutes in a Tissot spirometer. Midway through the collection of expired air, blood samples were obtained from the radial artery over a one-minute period (normal values for Mexico City, arterial Po2 67.5 ± 2.5 mm Hg and arterial Pco2 32.5 ±2.5 mm Hg) and immediately analyzed using a gas analyzer (127 bath, 213 electrometer). From these data, the physiologic dead space (using Bohr’s equation) and the alveolar-arterial Po2 difference (P[A-a] ОД using the alveolar air equation, were calculated. Normal values for the physiologic dead space are from Harris and co-workers. The methodology for determining the pulmonary shunt calculation (Qs/Qt) has been reported elsewhere and the data presented were obtained during a previous catheterization. Diffusing capacity for CO was not performed as part of the protocol. We tried to correlate our lung function findings with the level of the mean pulmonary artery pressure. Statistical analysis was performed using standard analysis for linear regression and the t-test for independent variables. All results are expressed as mean ± SD. Figure

1. There is a marked intimal thickening and proliferation of the elastic fibers. Tbese changes can be attributed to pulmonary artery hypertension (elastic Van Gieson, original magnification X256).

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More Teen Girls Are Using Long-Term Birth Control

More U.S. teens are using long-term forms of birth control that they don’t have to remember every day, but these methods are still relatively uncommon, according to a new report from the Centers for Disease Control and Prevention.

In 2013, among teens seeking birth control, 7.1 percent used intrauterine devices (IUDs) or birth control implants , whereas just 0.4 percent of these teens used one of these methods in 2005, the study found. Use of these methods varied widely by state: In 2013, nearly 26 percent of teens seeking birth control in Colorado used IUDs or implants, compared to just 0.7 percent in Mississippi.

Because these methods, known as long-acting reversible contraception (LARC), are the most effective types of birth control for teens, more efforts are needed to increase access to them, the CDC says.

Learn more on http://www.huffingtonpost.com/2015/04/08/teens-using-long-term-birth-control_n_7024440.html.

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What are oral contraceptives?

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Discussion of Bilateral Chemosis and Conjunctival Venous Engorgement in Cardiopulmonary Failure

The conjunctival venous system empties into the cavenous sinus at the posterior aspect of the orbit. The cavenous sinus, through its connection with the sagittal sinus, drains into the internal jugular vein. This latter system eventually connects to the superior vena cava via the common jugular. In addition to the above, a rich lymphatic network also helps drain the conjunctiva. These channels eventually empty into the venous system after passing through the parotid and submaxillary lymphatic chain. The conjunctival vasculature is thus potentially exposed to pressure changes that may be generated in the right side of the heart. That biventricular and/or right ventricular failure is not often associated with conjunctival (chemosis, venular engorgement) or retinal (papilledema, engorged veins) vascular abnormalities is attested to not only by clinical experience, but by the dearth of reports in the literature. The nine patients reported herein did manifest severe right-sided failure (left ventricular failure was also apparent in seven) with associated marked jugular venous distention and peripheral edema. The incidence of left ventricular failure (78 percent) in this group of patients is much higher than usually reported in patients with lung disease. The reason for this phenomenon is not readily apparent but may be attributable to the following: 1) severe hypoxemia and hypercapnia, 2) undetected coronary artery disease, 3) a bias in selecting the patients, or 4) some combination of the above. Nonetheless, the left-sided failure with attendant elevated left ventricular pressures would tend to further worsen the pulmonary artery pressures, thus increasing the load on the right heart. Also transudation of fluid into alveoli and intraalveolar septi would occur. In addition the decreased cardiac output associated with left ventricular dysfunction would lead to further intra- and extravascular fluid accumulation. The final result of these events would be both a further rise in systemic venous pressure and worsening of the hypoxemia. Severe hypoxemia and moderate hypercapnia was also present in all but one patient (no. 3). Five of the nine patients also had hematocrits greater than 55 percent. The conjunctival chemosis and venous engorgement slowly disappeared as the patient’s clinical condition, blood gases, and edema improved (Fig 3). It would appear, since jugular venous distention per se is not the sole cause of the conjunctival vasculature alterations, that some other factor or factors must be involved to explain this phenomenon. The best candidates would seem to be the associated hypoxemia and/or hypercapnia. The role of hypoxemia in retinal vascular reactivity (which may not be directly applicable to conjunctival vessels) has been explored by Sieker and Hickam. When these investigators exposed normal subjects acutely to 10 percent oxygen, their retinal veins and arteries dilated. The reverse effect was obtained by having the subjects breathe 99.6 percent oxygen. These results agreed with earlier reports. These investigators also had their subjects inhale 5 percent CO2, 21 percent O2 + 74 percent N2 without any apparent changes in retinal vasculature diameter. These latter results are in disagreement with the later studies of Spalter et alls who increased the РаСОг of anesthetized dogs while keeping CSF pressure normal and recorded marked dilatation of retinal vessels. They concluded that ocular vessels can dilate directly when exposed to elevated РаСОг levels without a concomitant elevation of CSF pressure. Simpson also felt that the papilledema associated with emphysema could best be explained by the direct effects of РаСОг, since CSF pressure was normal in his patients. Spalter and Bruce, in a clinical study on the ocular changes in cystic fibrotic children, reported a spectrum of retinal changes including venous engorgement, macular edema, retinal hemorrhages and papilledema. They noted that many of the children with the highest jugular venous pressures secondary to heart failure had no retinal vascular changes and that in some of these children, as the heart failure improved with treatment and the venous pressures decreased, the retinal changes could actually progress. None of their subjects had elevated CSF pressures. They felt the primary cause for the retinal vasculature alterations could be explained on the basis of hypercapnia with possibly some contribution from increased blood volumes and viscosity. The only study of which I am aware concerning the conjunctival vasculature in association with respiratory failure is that of Pontoni and Del Guer-cio. Conjunctival microdrculatory studies revealed that patients with decompensated respiratory failure (in contrast to those with mild or compensated respiratory failure) manifested abnormally enlarged venules and arterioles. The authors’ criteria for respiratory failure and the patients’ clinical status and blood gases are not reported. It would seem both from our data and from those reviewed above, either hypoxemia and/or hypercapnia is needed to cause ocular vasculature changes in most cases of right ventricular failure. Whether both elevated РаСОг with lowered РаОг are simultaneously necessary cannot be stated categorically. It would appear that hypercapnia is not absolutely essential as at no time did patient No. 3 manifest an elevated РаСОг (Fig 3) but still experienced severe chemosis and conjunctival venular engorgement (Fig 1). Even when the severe hypoxemia noted in this patient (and the others) was reversed by the administration of supplemental oxygen, the conjunctival changes did not reverse until the jugular venous pressure was decreased by the use of diuretics. The mechanically ventilated patients are interesting in that, to maintain reasonable blood gases, they all required relatively high inspiratory pressures (30 to 40 cm H2O) probably due to their underlying lung disease. It is possible that these pressures further increased jugular venous distentions and although their original hypoxemia (but not their hy-percapnea) was corrected this was not sufficient to reverse the conjunctival changes in the face of further elevation of venous pressures. As a final note, several other patients with an essentially normal cardiorespiratory system have been encountered who also manifested conjunctival chemosis and venular engorgement. These patients all had the following in common: barbiturate overdosage; a variable period of being comatose; mechanical ventilatory support. Whether in these cases, a period of profound hypoxemia and hypercapnia prior to intubation and supportive ventilation caused their conjunctival changes or, whether a direct effect of barbiturates can be implicated, is unclear at this time.

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Birth Control Online: Examples of Bilateral Chemosis and Conjunctival Venous Engorgement in Cardiopulmonary Failure

Case Reports (see Table 1 for details of patients) Case 1 A 57-year-old man with a ten-year history of bronchitis was admitted to the hospital in 1965 with respiratory failure; capillary blood gas analysis (obtained from the reddened ear lobe) on that admission revealed а Рсог of 89 mm Hg, and a pH of 7.24. Following discharge, his Pcx>2 was stabilized at 55 mm Hg. The patient was again readmitted in 1970 with respiratory failure; capillary Pco2 was 97 mm Hg and pH 7.25. On discharge, his Pcc>2 was 76 mm Hg and his P02 was 56 mm Hg capillary blood. Following that discharge, the patient had noted progressive weight gain, increasing shortness of breath, lethargy, poor coordination, and decreased appetite without increasing sputum production. For the several weeks prior to admission he was treated with digoxin, diuretics, cortisone, and an occasional phlebotomy. Due to progressive deterioration, he was readmitted to the hospital. Blood pressure was 130/80, pulse rate 120/min and regular, temperature 37* C, and respiration 32/min and regular. There was neck vein distention to the angle of the jaw at 90*, bilateral conjunctival venous engorgement and chemosis, asterixis, moist rales in both lower lung fields to the angle of the scapulae, and a right ventricular heave; P2 was greater than A2; Ae liver edge was down one finger below the right costal margin and there was a trace of pretibial edema. РаОг was 40 mm Hg, РаСОг was 71 mm Hg and pH 7.32. Chest x-ray film revealed cardiomegaly with an increase in cardiothoracic ratio to 55 percent and filling in of the retrosternal airspace, pulmonary congestion and Ae elevated right diaphragm. Sputum smear, culture and sensitivity were negative. Treatment consisted of bed rest, continuation of digoxin, low salt diet and 2)4 liters of oxygen by nasal cannula. On the first hospital day, 80 mg IV furosemide was administered and this was continued over the ensuing three to four days. The patient had a prompt and rapid diuresis. On discharge, his blood gases had improved, (РаСОг 40 mm Hg, РаОг 65 mm Hg, pH 7.39) he had lost 10 kg (Fig 3, Table 2) and his conjunctival chemosis and venous engorgement had disappeared. Home medications were digoxin, furosemide and KC1. Discharge diagnosis was: 1) bronchitis, 2) emphysema, 3) post resection for bronchiectasis, 4) biventricular failure. It is interesting to know how birth control pills are connected with weight gain or loss. Find the answer on Birth Control Online - https://mybirthcontrolonline.com/birth-control-online-pills-and-diet.html.

Case 2

A 66-year-old man was first found to have chronic obstructive pulmonary disease in 1965. His symptoms consisted of shortness of breath and sputum production. Since this diagnosis he has stopped smoking, but had not seen a physician. One month prior to his hospital admission a flu-like illness developed with cough, fever, chills, increasing shortness of breath, ankle edema, fatigue, and malaise. On admission, his blood pressure was 120/80, pulse regular at 118 per minute and respirations were 36 per minute. There was jugular venous distention to the angle of the jaw at 60*, marked bilateral chemosis and conjunctival venous engorgement, asterixis, crepitant dry rales in the left anterior chest, right ventricular heave, right sided protodiastolic gallop, and a trace of ankle edema. Arterial blood gas analysis revealed P02 35 mm Hg, Рсог 66 mm Hg and pH of 7.33. Chest x-ray film demonstrated cardiomegaly and pulmonary edema. Treatment consisted of digitalization, cortisone, 2)4 liters of oxygen nasally, and a low sodium diet. Eighty mg of furosemide was administered and prompt diuresis ensued. By the 5th hospital stay, he had а РаОг 50 mm Hg, РаСОг 60 mm Hg, pH 7.44 (room air) and his asterixis and conjunctival chemosis and venous engorgement had disappeared. Neck veins were 1 cm above the clavicle at 60*. By discharge (9th hospital day) blood gases on room air were: РаОг-бО mm Hg, РаСОг-55 mm Hg, pH-7.42 (Fig 3, Table 2). His post hospital treatment includes digoxin, furosemide, SSKI and oral KC1. Discharge diagnosis was: 1) bronchitis, 2) emphysema, 3) biventricular failure.

Case 3 (Fig 1)

A 56-year-old woman’s history dated back 1.5 years when she was admitted to another hospital for dyspnea on exertion (DOE), marked edema, and cyanosis. Work-up including closed lung biopsy, revealed marked interstitial fibrosis. She was discharged with the diagnosis of severe, far advanced idiopathic interstitial fibrosis with maiked hypoxemia and cor pulmonale. Six months later she was admitted to Orange County Medical Center with a several week history of lethargy, marked weight gain, ankle and leg swelling and severe dyspnea. On admission, the blood pressure was 122/80, pulse 111 per minute and regular and respiratory rate 42 per minute. Physical examination revealed marked central cyanosis, jugular venous distention to the angle of the jaw at 90', severe bilateral chemosis and conjunctival venous engorgement, bilateral dry fine rales in the posterior lung fields, right ventricular heave and gallop, hepatomegaly and 4+ pitting edema to the knees. Blood gases on admission revealed РаОг 32 mm Hg, РаСОг 36 mm Hg and pH 7.43. Treatment consisted of low flow nasal oxygen, IV furosemide, low sodium diet, bed rest and digitalis. On discharge nine days later, she had lost 16 kg, her blood gases revealed а РаОг 54 mm Hg, РаСОг 38 mm Hg, pH 7.45. Chemosis and conjunctival venous engorgement had disappeared. Home medications included continuous low flow O2, furosemide, low sodium diet and digitalis. Discharge diagnosis was: 1) pulmonary fibrosis, etiology undetermined, 2) cor pulmonale.

Case 4

A 53-year-old man was first admitted to the hospital in 1971 with progressive shortness of breath. The patient had a seven to eight year history of dyspnea on exertion and a past history of smoking one to two packages of cigarettes per day, (total of 68 pack years). As early as 1968, he was noted to be a carbon dioxide retainer with a re-breathing Рсог as high as 77 mm Hg. Treatment over the ensuing years had included digoxin, diuretics, low salt diet, cortisone, IPPB and intermittent nasal oxygen at home. Nonetheless, he had experienced increasing weight gain and lethargy, incoordination, decreased appetite and marked shortness of breath. On admission, his blood pressure was 140/90, pulse 100/min and regular, and respiratory rate 30/min and regular. There was jugular venous distention to the angle of the jaw at 90*, bilateral conjunctival chemosis and venous engorgement, asterixis, decreased breath sounds at both bases, right ventricular gallop, P2 greater than A2, and 2+ ankle edema. Chest x-ray examination showed cardiomegaly with a cardio-thoracic ratio of 50 percent and pulmonary congestion. In the hospital, digoxin, 3 liters nasal oxygen flow, low salt diet and bed rest were continued. Forty to 80 milligrams of IV furosemide were administered daily over four days with prompt diuresis. On discharge the patient had lost 10 kg, his blood gases had improved (Fig 3, Table 2) and his conjunctival chemosis and venous engorgement had disappeared. The patient is symptomatically better on low flow oxygen at home 12 to 16 hours per day, digoxin, furosemide, and a low sodium diet. Discharge diagnosis was: 1) bronchitis, 2) emphysema, 3) biventricular failure.

Case 5

A 71-year-old man was first admitted to the hospital in 1971 with respiratory failure, secondary to chronic obstructive pulmonary disease. On that admission, the patient’s original blood gas values showed Рсог 65 mm Hg, P02 43 mm Hg, and pH 7.38. He was treated with a low salt diet recommended by Birth Control Online, bed rest, diuretics and digoxin with a diuresis of 7.5 kg. On discharge, his arterial Pcog was 50 mm Hg, P02 57 mm Hg and pH 7.39 (room air). Over the ensuing months, the patient took his medications very laxly. He began smoking again and noticed increasing weight gain and shortness of breath. On re-admission to the hospital his weight was noted to be 91 kg, blood pressure 150/100, pulse rate 80/min and regular and respiratory rate 32/min. There was jugular venous distention to the angle of the jaw at 90“, marked bilateral conjunctival chemosis and venous engorgement, asterixis, decreased breath sounds at the right lower posterior base, and 4-j- pretibial edema. Arterial blood gas analysis showed P02 32 mm Hg, Pcx>2 66 mm Hg and pH 7.30. Chest x-ray film demonstrated marked cardiomegaly with a pleural effusion occupying one-half the right hemithorax. Treatment in the hospital consisted of digoxin, low sodium diet, oral KC1 and 40 to 80 mg furosemide IV every 8 to 12 hours over the first several days. By the third hospital day, the patient had lost 8 kg. Over the ensiling hospital stay, the patient's weight further declined and by discharge, his blood gases were much improved (Fig 3, Table 2). There was no residual of the conjunctival chemosis and venous engorgement. The patient is symptomatically better and is taking digoxin, and oral KC1. Discharge diagnosis was: 1) bronchitis, 2) emphysema, 3) biventricular failure.

Case 6

A 59-year-old woman had been admitted to the hospital in 1971 with evidence of both respiratory and cardiac failure. She had a history of pulmonary tuberculosis and heavy smoking. During that hospitalization, tracheostomy was performed and she was placed on a ventilator. One week later she had been weaned and right heart catheterization revealed elevation of pulmonary wedge pressures to 15 mm Hg and pulmonary artery pressures to 35 mm Hg. She was discharged on digitalis and furosemide. The patient was seen every six months in the out-patient department. In 1973 she was noted to have gained 10 kg since discharge. Her blood pressure was 146/96, pulse rate 108/min and respiratory rate 32/min. Physical examination revealed jugular venous distention to the angle of the jaw at 45°, bilateral chemosis and conjunctival venous engorgement, bilateral basilar pulmonary rales, left ventricular heave and gallop and 1-2+ pretibial edema. Blood gases were РаОг 55 mm Hg, РаСОг 49 mm Hg, pH 7.42. Discharge diagnosis: 1) bronchitis, 2) emphysema, 3) biventricular failure.

Case 7 (Fig 2)

A 48-year-old man with long history of intrinsic asthma, bronchitis and left ventricular failure entered the hospital in 1973. He had been discharged one month previously with the above diagnosis and was maintained at home on cortisone, digitalis and furosemide. During the interval between hospitalizations he gained 12 kg, experienced orthopnea and paroxysmal nocturnal dyspnea and noted increased wheezing. On admission his blood pressure was 160/105, pulse rate 130 per minute and regular and respiration rate 46 per minute. Physical examination revealed marked jugular venous distention to the angle of the jaw at 60*, bilateral chemosis and conjunctival venous distention, audible wheezing, left ventricular gallop and 2-3-)- pretibial edema. Chest x-ray examination was compatible with left ventricular failure and biventricular enlargement. Due to his distress and abnormal blood gases, he had an endotracheal tube passed and was placed on a volume ventilator. After treatment with IV furosemide, he lost 5 kg and was able to be weaned easily from die respirator. The remainder of his hospital stay was uneventful and he was discharged with improved blood gases (РаОг 50 mm Hg; РаСОг 50 mm Hg; pH 7.38), (Fig 3, Table 2) and no chemosis or conjunctival venous engorgement. Discharge diagnosis: 1) asthma, 2) bronchitis, 3) biventricular failure.

Case 8

74-year-old woman was found semi-comatose at home and was brought to the hospital. She had a history of severe emphysema. On admission her blood pressure was 90/60, pulse rate 122/min and irregular, and respiratory rate 32/min. Physical examination revealed a semicomatose woman with jugular venous distention to the angle of the jaw at 45*, bilateral pulmonary rales, left ventricular gallop and 2-f presacral edema. Due to severe respiratory acidosis, (Fig 3, Table 2) the patient was placed on a volume ventilator. The following day she was noted to have bilateral conjunctival venous engorgement and chemosis. Over the ensuing two weeks she was able to be weaned, her weight decreased by 9 kg, her blood gases improved with а РаОг 64 mm Hg, РаСОг 69 mm Hg, pH 7.36 and her eye signs slowly disappeared. Discharge diagnosis was: 1) bronchitis, 2) emphysema, 3) biventricular failure.

Case 9

A 70-year-old white man was found comatose in his hotel room. On admission, he had a severe, unexplained lactic acidosis (serum lactate—45 mg percent) which cleared slowly over three days. Several days later he awoke but no further history was available. Workup revealed COPD and carcinoma of the lung. He was discharged only to return three weeks later complaining of shortness of breath and ankle swelling. On admission, blood pressure was 100/60, pulse rate 116 per minute and regular, and respiratory rate 26 per minute. Physical examination revealed jugular venous distention to the angle of the jaw at 30", bilateral chemosis and conjunctival venous engorgement, right ventricular heave, hepatomegaly and 3+ pretibial pitting edema. Treatment consisted of low flow oxygen at 2 L/min, furosemide, low salt diet and IPPB. The patient was progressing nicely with weight loss and an increasing РаОг (Fig 3, Table 2) when he was found dead in bed.

Figure 1. Patient 3: РаОг 32 mm Hg, РаСОг 36 mm Hg.

Figure 2. Patient 7: РаОг 35 mm Hg, РаСОг 84 mm Hg.

Figure: 3. Admission and discharge blood gases and weights in all nine patients.

Table 1—Clinical and Laboratory Data of Patients

Patient No Sex Age : Diagnosis Lung Rales Heart Rate Jugular Venous Distention Peripheral Edema Chest X-ray * Vital FEV, Capacity (%pred) (% pred) Symbols for Fig 3 Group 1- —Patients Not on Respirator 1 M 57 COPDt RLL re-section-bronchi-ectasis-LV failureft + 120 + + 3+ 65 30 0 2 M 66 COPD-LV failure + 118 + + 3+ 71 26 • 3 F 56 Idiopathic pulmonary fibrosis-corpulmonale 0 110 + + 1 + 94 72 О 4 M 53 COPD-LV failure + 100 + + 3+ 72 31 □ 5 M 71 COPD-LV failure + 80 + + 3+ 80 21 ■ 6 F 59 Bronchitis-old TBC-LV failure Wheezes 108 + + 3 + 72 23 □ Group 2- —Patients on Respirator 7 M 48 Asthma-LV failure + 130 + + 3+ 90 52 A 8 F 74 COPD-LV failure + 122 + + 3 + — — ▲ 9 M 70 COPD-Ca. of lung-cor pulmonale 0 116 + + 1+ — — Д

Table 2—Blood Gat Data on 8 Hospitalised Patients

PaO,** mm Hg РаСОг mm Hg Hospital Day Patient No 1 3 5 7 • 9 1 3 5 7 9 1. 40 — 47 56* 65 71 — 65 60 50 2. 35 41 50* — 60 66 61 60 — 55 3. 32 — 50 — 54* 36 — 36 — 38 4. 32 — 58* 67 — 78 — 60 46 — 5. 32 36 53 65* — 66 63 56 50 — 6. 31 34 — 50* — 78 71 — 50 — 7.t 35 34 — — 60* 84 80 — — 71 s.tt 33 — 42 — 55* 60 — 56 — 52

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Bilateral Chemosis and Conjunctival Venous Engorgement in Cardiopulmonary Failure: Clinical Observations

Despiratory failure, through its effect on arterial blood gases and cardiac output, may саше physiologic dysfunction of remote organ systems. Well reported are the following: somnolence, confusion, irritability, (CNS); asterixis (neuromuscular); arrhythmias (cardiac); sodium and water retention, edema (renal);2 papilledema, retinopathy (ocular). Reported herein are nine cases of acute superimposed on chronic respiratory failure in which all patients presented with chemosis and conjunctival venous engorgement with associated jugular venous distention, peripheral edema, hypoxemia and hypercapnia. The ocular manifestations disappeared as the underlying respiratory and cardiac embarrassment was corrected. Patients were classified as being in chronic stable respiratory failure by the following: РаОг in the range of 50-55 mm Hg and a PaCOa in the range of 45-55 mm Hg associated with an essentially normal pH of 7.35-7.38 or greater when the patient’s clinical condition was stable. Acute respiratory failure was defined as a further decrease in РаОг below 50 mm Hg and/or a rise in РаСОг above 55 mm Hg with a pH less than 7.35 associated with an elevated serum bicarbonate greater than 30 mEq/L. Left ventricular failure was diagnosed if three or more of the following signs and symptoms were present: paroxysmal nocturnal dyspnea; orthopnea; pulmonary rales; left ventricular gallop; chest x-ray film fulfilling McHugh et al’s criteria for pulmonary edema; elevated PWP>12 mm Hg. Cor pulmonale was defined as present if three or more of Ae following signs were present wiA or wiAout evidence of left ventricular failure: right ventricular enlargement by physical examination and/or radiograms (decrease in size of retrosternal airspace: elevation of cardiac apex in association wiA cardiomegaly) and/or ECG (RAD: R equal or greater Aan S in Vi wiA T wave in opposite direction to R; intrinsicoid deflection in Vi greater Aan 0.045 sec); right ventricular gallop; loud P2 and/or widely split P2 and/or inspiratory widening of P2; marked jugular venous distention; hepatomegaly; and peripheral edema. Blood gas analyses were done eiAer on an IL 113 or Radiometer PM 71 blood gas apparatus.

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Consideration of a-Antitrypsin Deficiency in 26-Year-Old Subjects

This study was initiated in the 1970s to determine the natural histories of liver and lung disease in AAT deficiency and the possible effects of exogenous and endogenous factors. Other important aims were to prevent smoking and to study possible compensatory changes in the protease/protease inhibitor balance. The 26-year-old individuals with AAT deficiency have normal lung function, as defined by a normal FEV-/FEV ratio and no difference from an age-matched control group. Seven percent of those answering the questionnaire were current smokers, compared with 17% of men and 20% of women aged 25 to 44 years in the Swedish population. We found a decreased mean FEV1/FEV ratio in 26-year-old subjects with AAT deficiency who had reported recurrent wheezing at 2 years of age. No difference was found now for individuals wheezing at the age of 4 years. However, transient wheezing in infants is usually not associated with a family history of asthma. The primary risk factor for this phenotype appears to be reduced lung function even in children with normal AAT. Day-care attendance in early childhood is another potential risk factor for transient wheezing and reduced lung function. Day care in this study had no significant effect on lung function in early adulthood. Exposure to environmental tobacco smoke, both prenatal and postnatal, is linked to decreased lung growth and respiratory problems. The risk seems to be greatest for exposure during the intrauterine period and the first years of life. A negative effect of such exposure on lung function seen at 18 years was not evident 8 years later. In the present study, 29 of the AAT-deficient individuals (24%) reported occupational exposure to airway irritants, another potential risk factor for lung disease.- Their lung function did not differ significantly from nonexposed AAT-deficient individuals. The exposure duration is still however quite short. Recurrent wheezing was common among both the PiSZ and PiZ 26-year-olds (31% vs 22%, respectively). A diagnosis of asthma was reported by the physician in 14% and 16% of the PiSZ and PiZ subjects, respectively. The prevalence of asthma is 5 to 12% in the Swedish adult population. An association between asthma and the PiZ phenotype has been suggested previously. PiZ individuals with clinical and laboratory signs of liver disease in infancy have a significantly lower FEV1/FVC ratio. Similar findings have been reported previously. Covariance analysis indicated that the difference was independent of birth weight. Thus, optimal nutrition during the months of cholestasis may be important to best attain normal lung growth. The risk of severe liver disease is substantial during infancy and again after 50 to 60 years of age.’ None of the AAT-deficient young adults had any clinical symptoms of liver disease, and few (< 10%) had but marginally elevated liver test results. Within the normal range, a difference was found of the S-ALAT and S-GT levels between individuals having a genotype with two alleles, one allele, and no Z allele. This finding supports the accumulation theory of liver injury in AAT deficien-cy. Plasma proteins, which may be affected by liver disease, were also analyzed. A significantly lower (7%) concentration of albumin was found in AAT-deficient individuals. The difference, however, is marginal. The ceruloplasmin difference is probably due to the fact that more women in the control group used estrogen-containing oral contraceptives than PiZ women (PiZ, n = 2; PiSZ, n = 2; compared to seven PiM control women). Since subjects were 8 years of age, A2M has been followed in AAT-deficient and control children.' Both A2M and AAT form complexes with elastase and collagenase in a molar combining ratio of 1:1. The molar concentration of AAT in blood of normal adults exceeds that of A2M by approximately 12 times. In the PiZ-deficiency state, the capacity of AAT to bind elastase is severely reduced by 80 to 90%. The concentration of A2M is considerably increased in childhood and adolescence and was even higher in AAT-deficient children. The level of A2M has dropped from 310 at 8 years to 215 at 18 years and now approximately 100% at 26 years of age. During childhood, the high level of A2M has theoretically protected the PiZ individuals from severe consequences of septic chock, pancreatitis, and peritonitis. In animal experiments, animals die when the capacity of A2M to bind elastase is deplet-ed. The practical implication of this knowledge is that AAT-substitution therapy may be indicated in AAT-deficient adult subjects during severe infections with Gram-negative bacteria in particular. It is not yet known whether increases in plasma A2M seen during childhood are due to upregulation of A2M biosynthesis in monocytes and macrophages. A high secretion of A2M by alveolar macrophages may be of utmost importance in the AAT-deficiency state. Inflammatory cytokines are also modulated by A2M. We also found that neutrophil lipocalin, analyzed as a marker of leukocyte activity, was reduced in AAT-deficient 18-year-old and 26-year-old subjects to approximately 70% of the normal concentration. The very low concentrations of HEAT in the AAT-deficiency state indicated that elastase is complexed with A2M to a great extent. A2M may act as a sensor for situations requiring coordinated cellular response. Complexed A2M may downregulate neutrophil proteases, partially compensating for the AAT deficiency, as indicated by the NGAL and HEAT test results. Neutrophil lipocalin, NGAL, binds tightly to ferric siderophores and is proposed as participating in the antibacterial iron depletion strategy of the innate immune system. When subjects were 26 years old, but not 18 years old, SLPI was significantly higher in individuals with AAT deficiency than in control subjects. SLPI is responsible for approximately 90% of the elastase inhibitory capacity of bronchial secretions against elastase and is also thought to efficiently inhibit neutrophil elastase released into the interstitium. There is a correlation between serum concentration and inflammation in the respiratory tract. The level of CRP, however, was identical in AAT-defi-cient and control subjects. Thus, an increased SLPI secretion may serve as a protection for the respiratory tract and lung tissue. In conclusion, 26-year-old individuals with AAT deficiency have essentially normal lung function, and only 7% of the 134 answering the questionnaire smoke. None have clinical symptoms of liver disease, and < 10% have marginally abnormal liver test results. Low levels of NGAL in AAT-deficient subjects indicate reduced leukocyte activity, ie, compensatory mechanisms. However, the NGAL level was considerably higher at age 26 years than at 18 years. The A2M concentration has been reduced from approximately 300% in childhood to the normal 100% adult level. The increased SLPI concentration at age 26 years indicates compensatory mechanisms. The roles of the protease inhibitors as not only inhibitors of leukocyte proteinases but also as regulators of leukocyte function, tissue repair, matrix production, and host defense against infection, normally and in the AAT-deficiency state, require further study.

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Birth Control Online in Explanation of a-Antitrypsin Deficiency in 26-Year-Old Subjects

Clinical Examination and Lung Function

Of the 178 AAT-deficient individuals, 119 subjects (67%) underwent clinical examination at age 26 years. The patient questionnaire was answered by 134 individuals (81%). The control group of healthy volunteers included 44 PiMM individuals (21 men) with a normal AAT concentration.

Lung function test results are shown in Table 1. No significant differences in lung function were found between the Pi subgroups. A reversibility test was performed in 71 AAT-deficient and 40 PiMM individuals. An increase of FEV1 > 12% after inhaled (32-agonist was found in 4 of 51 PiZ subjects (8%), in 2 of 20 PiSZ subjects (10%), and in none of the control subjects.

Eighteen of the PiZ subjects (22%) and 11 of the PiSZ subjects (31%) reported recurrent wheezing. Three of the PiZ subjects (4%) and one of the PiSZ subjects (3%) reported chronic phlegm. The prevalence of respiratory symptoms did not differ between the PiZ and SZ groups. The physicians reported a diagnosis of asthma in 13 PiZ subjects (16%) and 5 PiSZ subjects (14%). Other diagnoses were rheumatoid arthritis (PiSZ, n = 2), hepatitis C (PiSZ, n = 1), ulcerative colitis (PiZ, n = 1), and depression/psychological problems (PiZ, n = 2; PiSZ, n = 1).

The two PiZ— women had never smoked and had no respiratory problems. Their FEV1 percentage of predicted values were 92% and 112%, and their FEV1/FVC ratios were 79% and 78%, respectively.

Six AAT-deficient individuals participating in spirometry (5%) were current smokers, and 14 subjects (12%) were ex-smokers. Lung function did not differ significantly between the smoking subgroups and AAT-deficient nonsmokers. Four of the 6 current smokers (67%) and 25 of 118 ex-smokers/never-smok-ers (22%) reported recurrent wheezing (p = 0.03).

Lung function test results were compared between PiZ individuals with neonatal cholestasis and PiZ subjects with a normal neonatal period. No differences in FEV1 or FVC percentage were found, The mean FEV1 /FVC ratio was 77% (95% confidence interval [CI], 74 to 80%) in the neonatal cholestasis subgroup and 83% (95% CI, 81 to 85%) in the remainder of the PiZ subjects (p = 0.02). With birth weight as a covariable, the difference was still significant (p = 0.007). Birth Control Online - https://mybirthcontrolonline.com/how-effective-are-the-birth-control-options-available.html describes what birth control pills are more suitable.

Eleven individuals (PiZ, n = 9; PiSZ, n = 2) had recurrent wheezing at 2 years of age. No significant differences were found in FEV1 or FVC among these individuals and the remaining cohort. The mean FEV1 /FVC ratio was 78% (95% CI, 74 to 81%) in the 2-year-old wheezers and 83% (95% CI, 81 to 85%) in the remainder of the AAT-deficient individuals (p = 0.025). No differences in lung function were found between AAT-deficient individuals with mothers smoking at age 4 years (n = 39), both parents smoking (n = 21), or day-care attendance in early childhood (n = 24) and the remainder of the AAT-deficient subjects.

Thirty-four subjects (PiZ, n = 22; PiSZ, n = 12) subjects did not attend the follow-up or answer a postal survey. According to the National Bureau of Population Statistics, all of them are alive.

Liver Tests

No subjects had clinical symptoms of liver disease. Abnormal liver test results were defined as S-ALAT > 0.75 microkatals (^kat) per liter and 1.10 ^kat/L. and S-GT > 0.75 ^kat/L and > 1.30 ^kat/L for women and men respectively. The numbers with abnormal liver test results are given in Table 2.

Three individuals had abnormal S-ALAT levels both at 26 years and 22 years of age (PiZ male, 1.58 ^kat/L and 2.37 ^kat/L; PiSZ male, 1.20 ^kat/L and 1.90 ^kat/L; and PiSZ male, 3.60 ^kat/L and 2.49 ^kat/L, respectively). Two subjects had abnormal S-GT levels at 26 years and 22 years of age (PiZ female, 0.86 ^kat/L and 0.89^kat/L; PiSZ male, 2.10 ^kat/L and 1.20 ^kat/L, respectively).

Results of liver tests and plasma protein analyses for the subgroup of PiZ, PiSZ, and control subjects are given in Table 3. Significant differences between the AAT-deficiency and control groups were observed for S-ALAT, S-GT, plasma albumin, and ceruloplasmin. None had a definite electrophoretic liver pattern. No difference was observed in the concentrations of IgG, IgA, and IgM between the PiMM and AAT-deficiency groups.

Markers of Protease/Protease Inhibitor Balance.

Significant differences in the concentrations of SLPI, NGAL, and HEAT were evident among PiZ, SZ, and MM individuals (Table 4). The A2M concentration had decreased to the normal adult level, and no difference of C-reactive protein (CRP) was observed in AAT-deficient compared to control individuals.

Table 1—Lung Function in 83 PiZ, 36 PiSZ, and 44 PiMM Individuals

Variables PiZt PiSZj PiM Age, yr 26.2 (0.9) 26.3 (0.5) 26.4 (1.2) FEVb % predicted 97(4) 98 (14) 100 (11) FVC, % predicted 97(13) 98 (13) 97 (11) FEVj/FVC ratio, % 82 (8) 82 (7) 84 (6)

Table 2—Abnormal Liver Test Results

Variables PiZ PiSZ S-ALAT (PiZ, n = 70; PiSZ, n = 32) 4 3 S-GT (PiZ, n = 55; PiSZ, n = 24) 4 1

Table 3—Liver Test Results and Plasma Protein Concentrations in a Subsample of PiZ, PiSZ, and PiMM Individuals

Variables PiZ (n = 32) PiSZ (n = 18) PiM (n = 37) p Valuef PiMM-Z MM-SZ Z-SZ S-ALAT, |xkat/L 0.54 (0.23) 0.42 (0.23) 0.39(0.18) 0.006 NS 0.06 S-GT, |xkat/L 0.48 (0.25) 0.39 (0.20) 0.33(0.16) 0.004 NS NS Plasma albumin, g/L 44.9 (3.1) 44.8 (2.9) 48.1 (3.0) 0.0001 0.0002 NS Plasma orosomucoid, g/L 0.70 (0.14) 0.72 (0.17) 0.67 (0.20) NS NS NS Plasma haptoglobin, g/L 0.97 (0.41) 0.94 (0.54) 0.92 (0.47) NS NS NS Plasma ceruloplasmin, g/L 0.28 (0.09) 0.30(0.11) 0.34(0.15) 0.03 NS NS

Table 4—Protease, Protease Inhibitor, and Complex Concentrations, With Neutrophil Lipocalin (NGAL) Analyzed as an Indicator of Leukocyte Activity

Variables PiZ (n = 37) PiSZ (n = 18) PiMM (n = 40) p Valuef PiMM-Z MM-SZ Z-SZ AAT, g/L 0.21 (0.05) 0.61 (0.11) 1.52 (0.34) 0.0001 0.0001 0.0001 A2M, g/L 1.9 (0.6) 1.8 (0.4) 2.0 (0.6) NS NS NS SLPI, ^g/L 32 (5) 31 (5) 24 (3) 0.0001 0.0001 NS NGAL, ^g/L 108 (28) 106 (41) 141 (36) 0.0004 0.002 NS HEAT, ^g/L 21 (8) 40 (31) 77 (41) 0.0001 0.0001 0.02 CRP, mg/L 1.5 (1.8) 0.9 (0.8) 1.5 (2.6) NS NS NS

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a-Antitrypsin Deficiency in 26-Year-Old Subjects

The development of clinical symptoms of liver and lung disease in individuals with severe a1-anti-trypsin (AAT) deficiency is highly variable. Gene/environmental interactions, environmental influences, and modifier genes may be of importance from fetal life onwards. During 1972 to 1974, 200,000 Swedish newborns were screened for AAT deficiency. Important aims of the research project were to study the epidemiology, natural history, and pathophysiology of AAT deficiency in childhood and adolescence and to protect adolescents from smoke and environmental air pollution. Serial reports from the prospective follow-up of these PiZ and SZ individuals have been published up to age 22 years. With subjects at 26 years of age, we have focused on clinical health, lung and liver function tests, and plasma markers of the protease/protease inhibitor balance. In addition, the potential effect of environmental factors during early childhood on lung function was investigated. Study Population AH surviving 178 AAT-deficient subjects (PiZ, n = 122; PiZ—, n = 2; and PiSZ,/PiS —, n = 53) identified by the 1972-to-1974 screening were invited to participate. Clinical examination, spirometry, and routine blood tests were performed by a chest physician at the local hospital. An age-matched control group was recruited from the University Hospital in Malmo. Questionnaire The physician answered a questionnaire concerning diagnosis, spirometry, and liver function tests. The patient completed a modified version of the adult respiratory disease questionnaire used in epidemiologic research. Lung Function Tests Standard spirometric tests were performed at the respective department of respiratory medicine. FEV1 and FVC were expressed as a percentage of predicted values.8 The FEV1/FVC ratio was expressed as a percentage. Reversibility tests were ordered but not consistently performed. Serum Protein Profile and Liver Tests Serum albumin, AAT, orosomucoid, haptoglobin, ceruloplas-min, IgG, IgA, and IgM were quantified by immune nephelom-etry with Image Instrument (Beckman-Coulter; Fullerton, CA) calibrated with a CRM 470 calibrator (Beckman-Coulter;). The method has a lower reporting level of 0.10 g/L. The serum samples were also subjected to capillary electrophoresis, the patterns being interpreted by J. C.9 The serum alanine aminotransferase (S-ALAT) and 7-glutamyl transferase (S-GT) tests were analyzed at the routine clinical chemistry laboratories of the respective hospitals with standard methods. Protease Inhibitors and Protease/Protease Inhibitor Complex Determinations Serum was drawn from a subgroup of the AAT-deficient subjects and the age-matched control group. All of them were clinically healthy. The samples were centrifuged within 30 min, and the samples were stored at - 20° until analyzed. a2-macro-globulin (A2M), secretory leukocyte protease inhibitor (SLPI), human elastase/a1-antitrypsin complex (HEAT), and neutrophil gelatinase-associated lipocalin (NGAL) were analyzed with methods described previously. Statistical Analysis The Fisher Exact Text and the x2 test were used to compare categorical variables. The Sstudent’s t test and analysis of variance (ANOVA) were used for group comparisons of continuous variables. Covariance analysis was used in the comparison of lung function between the subgroup of PiZ individuals with history of liver disease in early childhood and the remainder of PiZ individuals, with birth weight as the covariate. A p value < 0.05 was considered significant.

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Study cites new link between artery plaque and birth control pills

The article does a competent job of conveying findings about a potential link between some birth control pills and arterial plaques in a small population study. The article includes necessary information about the preliminary nature of the findings and the shortcomings of the research methodology. The crucial question about this article is whether it should have been done at all. It also raises fundamental questions about journalists’ roles as gatekeepers of medical study information. The findings are riddled with caveats that raise serious questions about their value. To cite a few of the most important: - The study was done on a homogenous population of women living in one small town in Belgium. - The study linked a firm clinical endpoint (ultrasound data on arterial plaques) to drug exposure that was not controlled and about which critical data–including which drug was taken, at what dose and at what age–is missing. - The article does not report on whether the data was controlled for other potential confounders, including smoking, diet and underlying risk of heart disease. - The study has not been submitted to the rigorous peer review required before publication in a major journal. While the article notes these caveats at least briefly, and in some cases thorougly, it does so in the context of a story that implictly raises fear about a widely used drug. For instance, the article states: The theory needs much more rigorous testing than this single small study, but is important because of the sheer number of women now taking the pill — 100 million worldwide. It could be argued that this same reason–the fact that so many women take or have taken this drug–could disqualify this study from news coverage at this point. Is it in the public interest to report at length about such preliminary, uncertain findings about a drug that is so widely used? Start reading right now on http://www.healthnewsreview.org/review/1089/.

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Birth Control Online about Sarcoidosis: Lung Function Testing

The Test That Could Not Rise to Its Potential The diagnostic test that occupies an exalted place in the annals of differential diagnoses of sarcoidosis is the Kveim-Siltzbach skin test, first described by Williams and Nickerson. The antigen was prepared by suspending skin tissue in saline solution, sterilized, and then injected into four patients with sarcoidosis. Within 24 h appeared a firm nodule that was still present after a week. Dr. Kveim, an Oslo dermatologist, added that the papule consisted of granulomatous reaction and asserted that the test was useful to differentiate sarcoidosis from tubercu-losis. Louis Siltzbach popularized the test and carried extensive clinical studies. Kveim test antigen is thought to contain antigen/ antigens that induce an immune-mediated granulomatous reaction. To date, no causative antigen has been identified in the Kveim suspension. A pro-teomic approach to identify unique proteins in sarcoidosis tissue might be helpful. The 1960s and 1970s were the “golden years” for lung function investigation related to sarcoidosis. Nils Svanborg systematically studied cardiopulmonary functions and published the monograph that has been surpassed in merit and pragmatic and academic value. The workers at Albert Einstein Medical College Hospital demonstrated that even in stage I disease, airway resistance and diffusing capacity may be severely impaired and cause symptoms, particularly the dry, persistent cough. BAL and Pathogenesis of Sarcoidosis Immunologic alterations have long been described in sarcoidosis. Hypergammaglobulinemia and the presence of cutaneous anergy were recognized early in the history of the disease. However, the widespread use of bronchoscopy and bronchoalveolar fluid studies that began in the mid 1970s led to recognition of increased lymphocytes in BAL and the concept of “active alveolitis.” Ronald Crystal et al popularized bronchoscopy during the 1980s. In early sarcoidosis, a large number of CD4 cells appear at the site of inflammation. The cytokine profile is T-helper type 1. The activated cells express increased interleukin (IL)-2 receptors and the spontaneous release of IL-2 by these cells. There is associated macrophage activation, and IL-18 and interferon-7 production. Know more about birth control pills on Birth Control Online - https://mybirthcontrolonline.com/tips-about-birth-control-pills-and-acne.html. Soon after, monoclonal antibody evaluation of lymphocytes quickly established the typical patterns of sarcoid lung involvement. The events that lead to spontaneous resolution of the granuloma formation include an influx of CD8+ cells. IL-10 helps resolution, as it suppresses the inflammatory response. However, the cytokines associated with chronic disease are IL-8, IL-12, and tumor necrosis factor (TNF). Patients with chronic disease have raised IL-8 levels. An increase in IL-8 is associated with an increase of transforming growth factor, a cytokine that promotes fibrosis. The role of BAL in diagnosing sarcoidosis remains unsettled. Louis Siltzbach and Burrell M. Crohn: Sarcoidosis and Crohn Disease Louis E. Siltzbach worked at the Mount Sinai Hospital, NY, and so did Burrell M. Crohn. Dr. Siltzbach spent all his life studying sarcoidosis in its infinite details. Dr. Crohn did the same for the disease that bears his name. For years, we have compared and contrasted sarcoidosis with Crohn disease because of the histologic similarity. No causal connection has ever been established between the two disorders, and no one knows the cause. Both granulomatous disorders can cause hypercalcemia. At Los Angeles County, University of Southern California Medical Center, John Adams and col-leagues demonstrated that activated alveolar macrophages and granulomas produced 1-25-dihydroxy-vitamin D that caused hypercalcemia by increasing calcium absorption by the gut. Thus, granulomas of sarcoidosis and Crohn disease not only look similar, they have also have similar biochemical properties. About 20 years ago, the first report of isolation of Mycobacterium avium subspecies paratuberculosis (MAP) from patients with Crohn disease appeared. Recently, Saleh Naser reported the detection of MAP DNA in circulation of patients with inflammatory bowel disease, and viable MAP organisms were cultured in the patients with Crohn disease. There is strong evidence that Crohn disease is a complex genetic disease with an environmental factor. Genome-wide scans have found many chromosomal region links with Crohn disease, including the human leukocyte antigen (HLA) region of chromosome 6, cytokine gene clusters on chromosome 5, and the region for CARD 15/NOD2 gene on chromosome 16. The gene product of CARD 15 appears to be an intramolecular pattern-recognition molecule for bacterial peptidoglycans. The CARD 15 mutations in Crohn disease are loss-of-function mutations. Homozygous loss-of-function mutations are associated with high relative risk of Crohn disease in humans and in cattle with Johnne disease. Genetic susceptibility to sarcoidosis involves several genes; as yet no single gene responsible for the disease has been found. The major histocompatibility complex (MHC) region on chromosome 6 continues to be an area of interest. The genes that encode the HLA portion of the MHC gene play an important role in determining the risk and clinical course of sarcoidosis; HLA DQB*0602 is transmitted more often than expected to affected offspring and appears to associated with progression of the disease, whereas HLA DQB*1201 is found half as often as expected. HLA DR-11, -12, -14, -15, and -17 seem to confer susceptibility to the disease, and HLA DR-1, DR-4, and HLA DQ*0202 seem to be protective. The TNF complex located near the MHC class II loci on the chromosome 6 appears to play an important part in determining severity of disease together with MHC class I alleles. The — 308 promotor polymorphism of TNF-a is associated with Lofgren syndrome, a form of sarcoidosis with good prognosis. Concept of Acute and Chronic Sarcoidosis In 1960, James, in the Second International Congress on Sarcoidosis, introduced the concept of acute and chronic sarcoidosis. Acute disease is characterized by hilar adenopathy and erythema nodosum. The combination reflects good genes and occurs frequently in white patients. Erythema nodosum is not seen in Japanese patients. Lupus pernio, however, represents the chronic, progressive disease with fibrosis and bone lesions. The diagnosis of sarcoidosis is best made when the clinical or radiologic picture is enhanced by the demonstration of noncaseating granulomas and exclusion of tuberculosis and other infections. Biopsy is almost always needed to exclude other causes of granulomatous diseases. The Present In sarcoidosis, clinical presentation, organ involvement, course, and response to treatment vary with the genetic makeup of the host. There are many drugs used for controlling sarcoidosis, but none cure the disease. In selected cases, organ transplantation (lungs, heart, and liver) is successful. The disease, however, returns and attacks the newly transplanted organ. Sarcoidosis keeps its distance. It stubbornly refuses to reveal its identity. We persevere and keep in mind what another Bostonian had so perceptively observed: We dance around in a ring and suppose, but the secret sits in the middle and knows.

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Murray Kornfeld, American College of Chest Physician, and Sarcoidosis: a Historical Footnote

Emerson wrote, “A great institution is the lengthened shadow of one man. If this is so, the American College of Chest Physicians is the lengthened shadow of Murray Kornfeld. Son of a successful New York businessman, Murray was born in 1893 in the city’s East Side. Tuberculosis afflicted him in his adolescent years, but the disease went into natural remission. Soon after, he joined the South American division of an exporting firm. At the age of 30, tuberculosis came back and Murray was admitted to America’s “magic mountain,” the sanatorium at Saranac Lake founded by another tuberculosis patient, Edward Livingston Trudeau. In 1876, Dr. Edward Livingston Trudeau (18481915), ailing from consumption, came to Saranac Lake for the hospitable climate that was conducive to healing. His health improved, and in 1884 he started Adirondack Cottage Sanatorium that became the Trudeau Sanatorium after his death. The hospital attracted patients with tuberculosis and other types of chest diseases, including bronchiectasis, chronic bronchitis, lung abscess, and lung fibrosis. Dr. Trudeau employed the open-air treatment of the disease and organized the first laboratory for the study of tuberculosis. In that era, it was not uncommon for sarcoidosis patients to be admitted to tuberculosis sanatoriums because of the clinical similarities between the two diseases. Many years before Murray’s admission to the sanatorium, Robert Louis Stevenson stayed at the Saranac Lake Hospital (1887-1889). He had shortness of breath and cough but no weight loss, fever, or other systemic symptoms. Repeated sputum examinations by Dr. Trudeau failed to reveal any tubercle bacilli. It is probable that Stevenson had sarcoidosis, In 1894, at the young age of 44 years, while in Samoa, a slow heart rate developed and he died suddenly. Did the creator of Dr. Jekyll and Mr. Hyde die of myocardial sarcoidosis?1 There were, during Murray Kornfeld’s long stay at the sanatorium, patients with sarcoidosis masquerading as tuberculosis, These patients, however, remained undetected for sarcoidosis was not yet discovered in America. Murray Kornfeld was curious and energetic, The medical and social aspects of tuberculosis fascinated him. He was keen on developing new approaches to teach tuberculosis to medical practitioners and the general public. In 1924, he started a monthly journal called Woodland Whispers. He was able to persuade the townspeople and local merchants to underwrite its costs. Later, he invited Dr. Charles Hendricks, a chest physician with an interest in writing, to edit a journal on chest diseases. In early 1935, the first issue of Diseases of the Chest, the predecessor of present CHEST, appeared. In the later part of that year, in Albuquerque, NM, the Federation of American Sanatoria was created, which was renamed the American College of Chest Physicians in June 1937. The Beginning In the earlier decades of the 20th century, sarcoidosis was not a significant illness; its existence was shrouded in the veil of tuberculosis. The disease was not in any of the editions of William Osler’s Textbook of Medicine or in the medical tomes by Drs. Austin Flint and George Pepper. Nevertheless, I believe that the case of Hannah W., a 14-year-old African-American girl admitted to the Johns Hopkins Medical Center, published in the American Journal of Medical Sciences, reported by Osler, had sarcoidosis. The patient had bilateral parotid and lacrimal enlargement, lung disease, and pleural involvement. At autopsy, no evidence of tuberculosis was found.2 In 1937, the first significant publication of the disease that hitherto had not gained much attention in America appeared; it was a 75-page review from Johns Hopkins Hospital by Longcope,3 which introduced sarcoidosis to the American medical audience. This event took place almost 6 decades after the first recorded and illustrated case of sarcoidosis by Jonathan Hutchinson, a London dermatologist, who published the case of John W, in Illustrations of Clinical Surgery in 1877, just a year after Dr. Trudeau opened the doors of his institution, under the title of “Case of livid papillary psoriasis.“4 In 1895, Dr. Hutchinson presented a 64-year-old woman to the Dermatological Society of London5: I have to describe a form of skin disease which has, I believe, escaped especial recognition. It may not improbably be a tuberculous affection and one of the lupus families, but if so it differs widely from all other forms of lupus, both in features and its course. The multiplicity of the patches; their occurrence in groups; their bilateral symmetry; and the absence of all tendencies to ulcerate or form crusts are the features that separate the malady from lupus vulgaris... I prefer to recognize it by the name of one of its subjects, as Mortimer’s malady. When Dr. Hutchinson suggested skin biopsy for histologic proof, Mrs. Mortimer promptly disappeared. In 1897, Caesar Boeck presented to the Medical Society of Christiania a 34-year-old police constable with “multiple benign sarkoid of the skin” and drew attention to its similarity to the Mortimer malady. Unlike Mrs. Mortimer, Dr. Hutchinson’s patient, Dr. Boeck’s patient agreed to undergo a skin biopsy. The histologic picture showed sharp, well-defined foci of epithelioid cells with some giant cells permeating the corium. Caesar Boeck became the first physician to describe histology of sarcoid granulo-ma.6 With the advent of chest radiography in 1915, two Swedish physicians, Jorgen Schaumann, a dermatologist, and Sven Lofgren, a general practitioner, defined the typical features of hilar and mediastinal node enlargement and linked them with noncaseat-ing granulomas. Although Dr. Hutchinson’s teachings of sarcoidosis had not reached America, he remained the most sought-after teacher and physician in Britain and parts of Europe. Dr. Hutchinson’s contemporary, Dr. Arthur Conan Doyle, creator of the fictional character Sherlock Holmes, made a skin disease— most likely cutaneous sarcoidosis—the basic ingredient of the plot of the Adventures of the Blanched Soldier.8 Whether or not Dr. Doyle ever discussed patients with Dr. Hutchinson remains unclear, but one can safely surmise that the two most likely had met and exchanged ideas during the London Medical Society Meetings, where Dr. Hutchinson was a member and regular presenter and discussant. Dr. Doyle practiced at 2 Devonshire Street, just a few steps away from 10 Chandos Street, home of the Medical Society of London. In a letter to The Lancet, Dr. Doyle described a family in which three members had systemic illness resembling sarcoidosis. This most likely was the first allusion to familial sarcoidosis. The familial occurrence of sarcoidosis is now established. Recent studies from the United Kingdom and the United States and A Case Control Etiologic Study of Sarcoidosis show that the relative risk of sarcoidosis developing ranges from 36 to 73 if a first-degree or a second-degree family member has sarcoidosis. The Granuloma In 1954, in India, during my first year of pathology class, I was told that the sarcoidosis granuloma first described by Dr. Boeck was an example of perimeter defense mounted by the immune system against invading antigens or organisms. Tuberculosis then, as now, a widespread cause of granulomatous inflammation, was an excellent example of the phenomenon. However, granulomas were also seen in fungal disorders, tropical parasites (schistosomiasis and leishmaniasis), syphilis, brucellosis, and foreign body reactions. Sarcoid granuloma, we were told, was different: it was noncaseating and in it no organisms were to be seen, no matter how hard we tried in our laboratory. Because of clinical and radiologic similarities, however, sarcoidosis was then considered “atypical” tuberculosis. Sarcoidosis, particularly in India and in Africa, is also confused with leprosy; in tuberculoid leprosy, the granuloma is noncaseating and indistinguishable from a sarcoid granuloma. During the middle of the last century, most of the poor countries had no economic resources to sustain radiograph departments and functional biochemical and pathology laboratories. The differentiation between sarcoidosis and leprosy rested mainly on clinical examination. If a patient with noncaseating granulomas in a skin biopsy had anesthetic skin patches on the body, it was leprosy; if not, it was sarcoidosis. We used to carry a hatpin in our coat lapel to examine for the sensory loss! If the patient had palpable supraclavicular nerves or thickened ulnar nerve, the diagnosis of leprosy was clinched. Elusive Etiology Mankiewicz and Van Wallbeck proposed that sarcoidosis resulted from tissue invasion by phage-infected mycobacteria in individuals who lacked the capacity to form phage-neutralizing antibodies, Kozmin-Sokolow and Kostina, however, found my-cobacteriophage in only 2 of 40 samples from 22 patients with sarcoidosis and in 1 of 26 samples from 9 patients with tuberculosis. Chapman and Speight showed that 90% of their patients with sarcoidosis had significant titers of antibodies to atypical mycobacteria. Reid and Wolinski found no evidence of precipitating antibodies to atypical mycobacteria in their 29 sarcoidosis patients. In an exhaustive study, Bowman and associates were unable to find any acid-fast bacteria, fungi, or Mycoplasma from sarcoid granulomas. Milman and associates subjected lymph node biopsy specimens from 15 patients with sarcoidosis to prolonged culture (12 months) looking for mycobacteria. No evidence of Mycobacterium tuberculosis and paratuberculosis was found. Many investigators have used polymerase chain reaction (PCR) technology to detect mycobacterial DNA in clinical specimens from patients with sarcoidosis; only half of the studies showed mycobacterial DNA. Vokurka and colleagues, using highly sensitive PCR technology, which it can detect as few as one copy of the genome, were unable to identify any mycobacterial DNA in patients with sarcoidosis. Brown and associates, however, recovered cell wall-deficient mycobacteria with equal frequency from sarcoidosis patients as well as control subjects. Hosoda and colleagues analyzed a series of health surveillance data in a Japanese work population of 460,000 employees. The work population underwent radiography and tuberculin testing annually. Hilar adenopathy was observed as a common marker of the two diseases. Primary tuberculosis showed unilateral hilar adenopathy, whereas sarcoidosis displayed bilateral hilar adenopathy. The incidence of tuberculosis and sarcoidosis showed a reversed relationship; in a community, the disappearance of unilateral hilar adenopathy caused by tuberculosis was followed by appearance of bilateral hilar adenopathy due to sarcoidosis. In both diseases, hilar adenopathy subsided within a few years; however, resolution of sarcoid hilar adenopathy was delayed if accompanied by extrapulmonary lesions. Age distribution of sarcoidosis incidence showed a bimodal curve but that of tuberculosis had mono-modal curve increasing with advanced age. Sarcoidosis had a higher standardized prevalence ratio in northern Japan, while tuberculosis is higher in southern Japan. The authors found no epidemiologic evidence of any causal relationship between tuberculosis and sarcoidosis. Propionibacterium acnes has been reported extensively. Abe and colleagues found that lymph nodes from 31 of 40 sarcoidosis patients (77%) and 38 samples of nonsarcoidosis tissue (21.1%) also revealed P acnes in culture. The difference was significant (p < 0.001). Ishige et al used PCR analysis and observed that 15 of 15 sarcoidosis tissue samples were positive for propionibacterial (P acnes or Propionibacterium granulosum) RNA; only 3 were positive for mycobacterial DNA. However, 2 of 15 tissue samples from patients with tuberculosis were positive for propionibacteria and 15 of 15 samples were positive for mycobacteria. In an international study, propionibacterial DNA was detected in all but 2 of 108 sarcoidosis lymph node samples compared with M tuberculosis DNA, which was found in 0 to 9% of the samples. Propionibacterial DNA was also found in 0 to 60% of M tuberculosis and control samples.