Chronic hyponatremia and association with osteoporosis among a large racially/ethnically diverse population.

Chronic hyponatremia may contribute to decreased bone density. We studied 341,003 men and women who underwent DXA testing and observed that individuals with chronic hyponatremia (sodium < 135 mEq/L) had an 11% greater likelihood of having osteoporosis. There was a dose-dependent effect with lower sodium and stronger association with osteoporosis. INTRODUCTION: Chronic hyponatremia has been associated with both neurologic deficits and increased risk of gait abnormalities leading to falls and resultant bone fractures. Whether chronic hyponatremia contributes to decreased bone density is uncertain. We evaluated whether chronic, mild hyponatremia based on serial sodium measurements was associated with increased risk of osteoporosis within a large, ethnically diverse population. METHODS: This is a retrospective cohort study between January 1, 1998 and December 31, 2014 within Kaiser Permanente Southern California, an integrated healthcare delivery system. Men and women were aged ≥ 55 years with ≥ 2 serum sodium measurements prior to dual-energy X-ray absorptiometry (DXA) testing. Time-weighted (TW) mean sodium values were calculated by using the proportion of time (weight) elapsed between sodium measurements and defined as < 135 mEq/L. Osteoporosis defined as any T-score value ≤ - 2.5 of lumbar spine, femoral neck, or hip. RESULTS: Among 341,003 individuals with 3,330,903 sodium measurements, 11,539 (3.4%) had chronic hyponatremia and 151,505 (44.4%) had osteoporosis. Chronic hyponatremic individuals had an osteoporosis RR (95% CI) of 1.11 (1.09, 1.13) compared to those with normonatremia. A TW mean sodium increase of 3 mEq/L was associated with a lower risk of osteoporosis [adjusted RR (95% CI) 0.95 (0.93, 0.96)]. A similar association was observed when the arithmetic mean sodium value was used for comparison. CONCLUSIONS: We observed a modest increase in risk for osteoporosis in people with chronic hyponatremia. There was also a graded association between higher TW mean sodium values and lower risk of osteoporosis. Our findings underscore the premise that chronic hyponatremia may lead to adverse physiological effects and responses which deserves better understanding.

The effects of changing vitamin D levels on anemia in chronic kidney disease patients: a retrospective cohort review.

BACKGROUND: Investigate whether changes in vitamin D levels affected erythropoiesis stimulating agent (ESA) requirements in chronic kidney disease (CKD) patients with anemia. METHODS: A retrospective cohort study of nondialysis-dependent patients with CKD of all stages. Patients were anemic and on ESA with at least 2 documented 25-hydroxylated vitamin D (D25) levels drawn 4 months apart. Patients were grouped based on the change in their D25 levels. The primary end point evaluated was absolute change in the ESA doses needed to maintain target hemoglobin levels between 11 and 12 g/dl. RESULTS: A total of 153 patients met the inclusion criteria for analysis. With the exception of the normal-to-low D25 group, patients showed a trend toward lower ESA doses with time. The low-to-normal vitamin D group showed a significant reduction in dose of 24% (1,415 units, p = 0.025). The normal-to-low group, however, showed a 22% increase in dose of 1,270 units (NS). Levels of Ca, PTH, and iron indexes were similar across all groups. CONCLUSION: Our retrospective cohort study demonstrates an ESA sparing effect in patients with vitamin D deficiency after repletion to normal levels. Conversely, there was a trend toward increased ESA requirements in patients who became vitamin D deficient from a previously normal state.

A case of pulmonary arteritis with stenosis of the main pulmonary arteries with positive myeloperoxidase-antineutrophil cytoplasmic autoantibodies.

A 53-year-old woman was referred to our hospital with the main symptoms of productive cough, fever and exertional dyspnoea. Chest X-ray revealed enlargement of the left hilar shadow and cavitary infiltration in the right upper lobe. 99mTechnetium-macroaggregated albumin (99mTc-MAA) perfusion scintigram showed complete hypoperfusion through the entire right lung. A pulmonary angiogram revealed stenotic lesions in the right and left main pulmonary arteries. Right cardiac catheterization showed an elevated right ventricular systolic pressure. There was no evidence of systemic arterial lesions nor vasculitis. The patient was positive for myeloperoxidase (MPO)-antineutrophil cytoplasmic autoantibodies (ANCA) (168 EU). The Mycobacterium avium complex sputum culture was positive. The pulmonary stenotic lesions were surgically resected. The resected pulmonary arterial lesions were pathologically diagnosed as non-specific vasculitis. The cavitary lesion disappeared 6 months after the surgery. Two years after the surgery, although the MPO-ANCA level had decreased to 12 EU, stenosis of the pulmonary arteries reappeared. It is suggested that the patient became positive for MPO-ANCA in association with the Mycobacterium avium complex infection, and that the presence of MPO-ANCA may not be related to the development of pulmonary stenosis of the main pulmonary arteries.

[Pulmonary thromboembolism accompanied by abnormal plasminogen].

A 38-year-old man was admitted to our hospital because of sudden chest pain and bloody sputum. Lung perfusion scintigraphy disclosed segmental defects in both lungs. An enhanced thin-section computed tomographic scan of the chest showed a low-density area in the right main pulmonary artery. These findings yielded a diagnosis of pulmonary thromboembolism. Serum plasminogen activity was low, not only in the patient but in his elder brother and daughter. Gene analysis revealed a point mutation at exon 15 of the plasminogen gene, suggesting abnormal plasminogen. Abnormal plasminogen is more prevalent in Japan than in the USA or Europe, and is usually asymptomatic. Thromboembolism in patients with abnormal plasminogen is very rare. Further studies are needed to elucidate the relationship between plasminogen abnormalities and pulmonary thromboembolism.

[Total collapse of the right lung in a patient with allergic bronchopulmonary aspergillosis].

A 29-year-old man was admitted to the hospital because of a high fever and dyspnea. He had a history of bronchial asthma and had had a bullectomy of the right lung at 15 years of age. He had visited a family physician because of fever and non productive coughing. Medications had no effect on his symptoms, and dyspnea developed. A chest X-ray film showed total collapse of the right lung, and he was referred to our hospital. Laboratory data showed eosinophilia and a high titer of IgE. Total obstruction of the right main stem bronchus by mucous plug was found during fiberoptic bronchoscopy. Aspergillus was detected by pathological examination of bronchial lavage fluid. Tests for aspergillus-specific IgE and IgG antibody were positive, as was immediate skin reactivity to Aspergillus. Allergic bronchopulmonary aspergillosis (ABPA) was diagnosed. Infusion and inhalation of a corticosteroid and fluconazole were effective; the symptoms resolved and X-ray findings improved. While migratory infiltration, proximal bronchiectasis and segmental or subsegmental atelectasis caused by a mucous plug are common X-ray findings in allergic bronchopulmonary aspergillosis, total collapse is rare.

Inhaled corticosteroid reduced lamina reticularis of the basement membrane by modulation of insulin-like growth factor (IGF)-I expression in bronchial asthma.

BACKGROUND: Pathological studies of bronchial biopsy specimens have confirmed the apparent thickening of lamina reticularis of the epithelial basement membrane. Corticosteroids have proven to be most effective in modifying airway inflammation. However, there is not much data on the effects of corticosteroid-treatment on the basement membrane. OBJECTIVE: To investigate the effects of inhaled beclomethasone dipropionate (BDP) on the thickness of basement membrane and cellular infiltration into the bronchial mucosa, and the expression of growth factors in patients with asthma. METHODS: We studied bronchial biopsies from 24 asthmatic patients before and after treatment with inhaled BDP, 400 microg twice a day or placebo, for 6 months in a double-blind manner. Each subject recorded daily asthma symptoms and peak expiratory flow (PEF). Lung function and bronchial responsiveness to methacholine were measured before and after treatment. The thickness of the basement membrane was determined by electron microscopy. Inflammatory cells and the expression of growth factors were examined by immunohistochemistry in endobronchial biopsy specimens. RESULTS: After 6 months of treatment, we observed a significant improvement of asthma symptoms (P<0.01), PEF (P<0.01), diurnal variation of PEF (P<0.05), and airway responsiveness (P< 0.05) in the BDP group compared with the placebo group. This was accompanied by a significant decrease in the thickness of the lamina reticularis (P < 0.001), and in the number of activated eosinophils (P<0.01), T-lymphocytes (P<0.01), and fibroblasts (P < 0.05) in BDP-treated patients. There was also a reduction in the expression of insulin-like growth factor (IGF)-I (P < 0.01). Significant correlation was found between the IGF-I expression and collagen thickening (rs = 0.34, P<0.01), and the number of fibroblasts (rs = 0.45, P < 0.01). CONCLUSION: These results suggest that corticosteroid treatment in asthma can reduce the lamina reticular thickness by modulation of IGF-I expression with consequent inhibition of the airway infiltration by inflammatory cells, and therefore may help to prevent remodelling of the airways.

Expression of growth factors and remodelling of the airway wall in bronchial asthma.

BACKGROUND: Bronchial asthma is characterised by airway structural changes, including mucosal inflammatory infiltration and subepithelial collagen deposition, that may represent the morphological basis for the chronicity of the disease. The relationship between airway wall thickness and growth factors in asthma has not been elucidated. METHODS: Bronchial biopsy specimens were obtained from 21 asthmatic patients and eight healthy subjects and the basement membrane thickness was measured by light microscopy and electron microscopy. At the same time the numbers of eosinophils and fibroblasts were assessed and the expression of transforming growth factor beta 1 (TGF-beta 1), platelet derived growth factor (PDGF), and insulin like growth factor (IGF) I in the bronchial mucosa was examined by immunostaining. The relationship between the degree of thickening of the subepithelial layer and both the clinical data and pulmonary function were also investigated. RESULTS: The basement membrane of the asthmatic patients was thicker than that of the healthy controls (median 8.09 versus 4.02 microns). Electron microscopic examination of the basement membrane revealed thickening of the subepithelial lamina reticularis; this thickening significantly correlated with the number of fibroblasts in the submucosa in the asthmatic subjects (rs = 0.88) but not in the controls (rs = 0.70). There was a significantly higher number of eosinophils in the airways of the asthmatic subjects than in the healthy subjects (EG1 + cells: 52.0 versus 2.0/mm2, EG2 + cells: 56.0 versus 1.5/mm2). The expression of each growth factor in the bronchial mucosa was similar in asthmatic and healthy subjects (TGF-beta 1: 18.0% versus 16.0%, PDGF: 37.0% versus 32.5%, IGF-I: 15.0% versus 8.0%). A weak but statistically significant correlation was found between the number of fibroblasts and the expression of TGF-beta 1 in asthmatic subjects (rs = 0.50). There was a significant correlation between the thickness of the subepithelial layer in asthmatic subjects and the attack score (rs = 0.58) and a significant inverse correlation between the subepithelial collagen thickness in asthmatic subjects and airway hypersensitivity (rs = -0.65). CONCLUSIONS: These findings indicate that the thickening of the subepithelial layer in bronchial asthma is due to an increase in fibroblasts, and that the thickness of the subepithelial collagen appears to be linked to an increase in bronchial responsiveness and exacerbation of clinical manifestations.

A comparative study of the effects of ketotifen, disodium cromoglycate, and beclomethasone dipropionate on bronchial mucosa and asthma symptoms in patients with atopic asthma.

Asthma is a chronic inflammatory disorder of the airways that is characterized by infiltration of many inflammatory cells into the bronchial mucosa. We compared the effects of ketotifen, disodium cromoglycate (DSCG), and beclomethasone dipropionate (BDP) on inflammatory cells in the bronchial mucosa and on the asthma symptoms of patients with atopic asthma. In this 12-week parallel study, 32 patients were randomly allocated to either the ketotifen group (2 mg day-1, n = 13), DSCG group (8 mg day-1, n = 9) or BDP (400 micrograms day-1, n = 10). Each subject recorded daily asthma symptoms and peak expiratory flow (PEF). Before and after treatment, pulmonary function and bronchial responsiveness to methacholine were evaluated, and fibreoptic bronchoscopy and biopsy were performed before and after treatment. Biopsy specimens were obtained by bronchoscopy. We performed immunohistochemistry using specific monoclonal antibodies for activated eosinophils (EG2), mast cells (AA1), and T cells (CD3, CD4, and CD8). Our clinical findings showed significant improvement in symptom score and bronchial responsiveness (P < 0.01) each) in all groups. Both the DSCG and the BDP groups had significantly better symptom scores than the ketotifen group (P < 0.05, both groups). PEF significantly increased in the DSCG group in comparison to the ketotifen (P < 0.01) and BDP (P < 0.05) groups, FEV1% increased significantly in the DSCG (P < 0.01) and BDP (P < 0.05) groups in comparison to the ketotifen group. Compared with their baseline values, treatment significantly decreased EG2+ activated eosinophils, and CD3+ and CD4+ T cells, in each group (P < 0.01). Both the DSCG (P < 0.05) and the BDP groups (P < 0.01) exhibited significant decreases in AA1+ mast cell count, but this was not observed in the ketotifen group. Comparing before- and after-treatment values, only the DSCG group exhibited a significant decrease in the number of CD8+ T cells (P < 0.01). Ketotifen, DSCG, and BDP all showed anti-inflammatory activity as determined by examination of the bronchial mucosa of asthmatic patients; and both the DSCG and BDP groups had better clinical responses than the ketotifen group.

Effect of the leukotriene receptor antagonist pranlukast on cellular infiltration in the bronchial mucosa of patients with asthma.

BACKGROUND: It has been reported that pranlukast reduces the antigen induced immediate and late phase asthmatic responses, airway hyperreactivity to acetylcholine, and pulmonary eosinophil accumulation in guinea pigs. A study was undertaken to test the hypothesis that pranlukast may reduce the number of inflammatory cells in the bronchial mucosa of patients with asthma. METHODS: A double blind, placebo controlled study was performed in 17 mild to moderate asthmatic subjects to examine changes in inflammatory cell infiltration in response to pranlukast (225 mg orally twice per day for four weeks). Comparisons of the mean daily beta 2 agonist use, symptom score, FEV1 percentage predicted, and airway methacholine responsiveness were made before and after treatment. Using fibreoptic bronchoscopy, bronchial biopsy specimens were obtained before and after treatment with either pranlukast (n = 10) or placebo (n = 7). Immunohistology was performed using monoclonal antibodies for CD3, CD4, CD8, CD68, NP57, AA1, EG1, EG2, gamma GTP and CD19. RESULTS: When the pranlukast and placebo treated groups were compared there were decreases in beta 2 agonist use, symptom score, and airway methacholine responsiveness after pranlukast but no increase in FEV1 was seen. The clinical response in patients treated with pranlukast was accompanied by a reduction in CD3 (median difference -37, 95% confidence interval (CI) -69 to -1; p < 0.05), CD4 (median difference -28, 95% CI -49 to -8; p < 0.01), AA1 (median difference -15, 95% CI -26 to 0; p < 0.05) and EG2 positive cells (95% CI -35 to 0; p < 0.05), but not in EG1 positive eosinophils, gamma GTP positive cells, and CD19 positive plasma cells. CONCLUSIONS: These results support the view that pranlukast may act by inhibition of bronchial inflammation in patients with asthma.

[An application of semiquantitative analysis of pulmonary scintigram to pulmonary tuberculosis sequelae].

We performed ventilation-perfusion scintigraphy in 13 patients with pulmonary tuberculosis sequelae and 21 with chronic obstructive pulmonary disease. We used 99mTc-MAA for perfusion scintigram and 133Xe gas for ventilation scintigram. We added the radioactivities during the rebreathing phase of the ventilation scintigram to make a computerized image of the lung volume. Regions of interest (ROIs) were derived from radioactivities on each image. ROIs included each whole lung on lung volume (L) image and areas where radioactivity was greater than 70% of the highest radioactivity on perfusion (P70) image. We counted the area of ROIs on L and P70, and used the ratio of perfusion to lung volume (P70/L) as a parameter of pulmonary perfusion. P70/L in patients with pulmonary tuberculosis sequelae was significantly higher than that in those with COPD. This suggested that the area of high pulmonary perfusion is larger in the patients with pulmonary tuberculosis sequelae as compared with those with COPD.