Histological evolution of pleuroparenchymal fibroelastosis.

AIMS: To investigate the histological evolution in the development of pleuroparenchymal fibroelastosis (PPFE). METHODS AND RESULTS: We examined four patients who had undergone surgical lung biopsy twice, or who had undergone surgical lung biopsy and had been autopsied, and in whom the histological diagnosis of the first biopsy was not PPFE, but the diagnosis of the second biopsy or of the autopsy was PPFE. The histological patterns of the first biopsy were cellular and fibrotic interstitial pneumonia, cellular interstitial pneumonia (CIP) with organizing pneumonia, CIP with granulomas and acute lung injury in cases 1, 2, 3, and 4, respectively. Septal elastosis was already present in the non-specific interstitial pneumonia-like histology of case 1, but a few additional years were necessary to reach consolidated subpleural fibroelastosis. In case 3, subpleural fibroelastosis was already present in the first biopsy, but only to a small extent. Twelve years later, it was replaced by a long band of fibroelastosis. The septal inflammation and fibrosis and airspace organization observed in the first biopsies were replaced by less cellular subpleural fibroelastosis within 3-12 years. CONCLUSIONS: Interstitial inflammation or acute lung injury may be an initial step in the development of PPFE.

[Bone and Nutrition. Nutritional management of osteoporosis].

Calcium intake was negatively associated with bone resorption marker such as DPD, NTX, and P1NP in Japanese postmenopausal osteoporotic patients. Not only to suppress bone resorption but also to keep higher hip bone mineral density were observed in the patients with higher intake of calcium than 800mg/day and higher vitamin D condition (more than 50nmol/L of serum 25 (OH) D). Higher calcium intake than 800mg/day from dairy and Tofu products, higher intake of vitamin D than 10µg/day from fish, and higher intake of vitamin K from vegetables should be recommended in Japanese postmenopausal osteoporotic patients. We should also pay attention to their losing weight and excess intake of these nutrients from supplements.

Elevation of serum C-reactive protein predicts failure of the initial antimicrobial treatment for febrile neutropenia with lung cancer.

Febrile neutropenia frequently develops after chemotherapy, and the prompt administration of antimicrobial agents is required for treatment. In the present study, we searched for predictive factors for the failure of the initial antimicrobial agents used for febrile neutropenia (FN) in patients with lung cancer. Sixty FN patients treated in our ward from June 2005 to May 2011 were retrospectively analyzed. The definition of FN and the response to antimicrobial agents were determined by the Japanese guidelines. We divided the FN patients into two groups by their response to the initial antimicrobial agents. Next, the characteristics of the two groups were compared. The Multinational Association of Supportive Care in Cancer (MASCC) score did not differ between the two groups. The non-responder group demonstrated significant elevation of serum C-reactive protein (CRP) level. A multivariate analysis demonstrated that a CRP level higher than 10 mg/dl is an independent risk factor for the failure of initial antimicrobial agents for FN with lung cancer (OR 11.0, 95 % CI 1.635-74.5). When the CRP score was added to the MASCC score, the scoring system could more precisely predict the failure of initial antimicrobial agents in patients with lung cancer who developed febrile neutropenia.

Vitamin D insufficiency defined by serum 25-hydroxyvitamin D and parathyroid hormone before and after oral vitamin D3 load in Japanese subjects.

Vitamin D insufficiency is a risk for both skeletal and nonskeletal health. However, some ambiguity remains about threshold serum 25(OH)D for vitamin D insufficiency. To determine the threshold serum 25(OH)D to maintain normal calcium availability without elevation in serum parathyroid hormone (PTH) among Japanese subjects with various calcium intakes, we conducted a multicenter prospective open-labeled study. We recruited 107 ambulatory subjects without disorders affecting vitamin D metabolism to whom oral vitamin D3 800 IU/day for 4 weeks or 1,200 IU/day for 8 weeks was given. Serum 25(OH)D, PTH, calcium, phosphate, and magnesium were measured before and after vitamin D3 supplementation. Calcium intake was assessed by questionnaires. When all the data were combined, serum 25(OH)D was negatively correlated with PTH. The cubic spline curve between serum 25(OH)D and PTH indicated PTH reached its plateau between 35 and 40 pg/ml at 25(OH)D between 25 and 30 ng/ml. Vitamin D3 supplementation increased serum 25(OH)D and decreased PTH. Change in PTH correlated positively with baseline serum 25(OH)D. From the regression analyses, baseline serum 25(OH)D above 28 ng/ml corresponded to the threshold level without reduction in PTH after vitamin D3 supplementation. In multivariate regression analyses, age but not calcium intake was a significant determinant of PTH. We concluded that a serum 25(OH)D level of 28 ng/ml was identified as a threshold for vitamin D insufficiency necessary to stabilize PTH to optimal levels.

[Nutrition in bone growth and development].

The greatest increase in bone density was observed around ages 10-14 years in girls and thereafter peak bone mass was attained. Maximizing peak bone mass during adolescence is one of the most important strategies to decrease osteoporotic fractures later in life. Initial bone mass adjusted by height and weight in 10-year-old girl was associated positively with intakes of dairy products and small fish. Annual increase in bone mass from age 10 years to 11 years was associated positively with increased intake of fish, fruit, vegetables, and soybeans. Thus, not only calcium but also adequate dietary patterns such as increased intake of fish, fruit, vegetables, and soy products lead to higher peak bone mass in adolescent and will decrease the risk of bone fracture in postmenopausal age.

[Diet for lifestyle-related diseases to maintain bone health].

Dieting methods for preventing age-related diseases such as cardiovascular disease, hypertension and diabetes, as well as osteoporosis are proposed here. Losing weight to prevent and ameliorate metabolic syndrome can lead to loss of bone and muscle mass. However, when subjects had milk before dinner while dieting, their fat mass was efficiently decreased and their muscle mass increased without any change of bone mass. Increased intake of vitamin D enhanced these effects. Therefore we suggest that people with high risk of metabolic disorders should take more low fat dairy products and fish, together with fruits, vegetables, and soy in order to increase their intake of calcium, vitamin D, n-3 polyunsaturated fatty acids, protein, antioxidants, various vitamins and minerals, and fiber to protect them from the deterioration of arteries and bones.

[Present knowledge in nutritional aspects of fracture].

Bone fractures are affected by bone mineral density, bone turnover, and risk of falls. Nutritional status could influence all these factors. The preventive effect of higher intake of calcium (1200 - 1500 mg/day) and vitamin D (10 - 20 microg/day) on osteoporotic fractures is well established and these are strongly recommended for the prevention of fractures in European and North American countries. Comparing to Western people, Japanese calcium intake (529+/-285 mg/day, n = 8,964) is much lower. We discuss recent data of other nutrients and factors which may be associated with fractures risk, such as vitamin K, C, B(12), potassium, magnesium, soy isoflavon, and homocysteine, and suggest several recipes and proper food intake to decrease fracture risk in Japanese elderly people as follows. Japanese elderly is recommended to add milk to traditional dish such as Miso soup for enhancement of calcium intake. They should take fish at least every other day to take more vitamin D and protein. Also, reinforcements of soy, fruit, and vegetable intake to increase vitamin K, vitamin C, potassium, magnesium, soy isoflavon and to decrease in homocysteine formation are recommended.

[Nutrition-related bone disease].

Bone disorders clearly related to nutrition are osteomalacia and osteoporosis. Osteomalacia is caused by a deficiency of vitamin D or a disturbance of its metabolism. Dietary deficiency of phosphate or excess of aluminum or cadmium will also cause osteomalacia. Osteoporosis is associated with low intake of calcium and other nutrients. Dietary copper deficiency might stimulate bone metabolism and increase in hip fractures. Excess vitamin A intake was also associated with lower bone mineral density and higher risk of hip fractures. Excess vitamin D sometimes causes mental simplicity, congenital heart disease and calcification of soft tissue. Therefore not only diet but also drugs and supplements of nutrients should be carefully observed in older women.

Heterogeneous clinical features in patients with pulmonary fibrosis showing histology of pleuroparenchymal fibroelastosis.

BACKGROUND: The histological pattern of pleuroparenchymal fibroelastosis (PPFE) is well defined, but its clinical features remain unclear. METHODS: We retrospectively examined the predominantly involved lung-fields (based on abnormal opacities on computed tomography [CT] images), and the initial value and annual decline of respiratory function in patients with pulmonary fibrosis presenting with histologically confirmed PPFE. RESULTS: Thirteen female and nine male subjects were included. Eleven interpreters independently analyzed 231 CT image series. One-third of the CT series (78/231) was interpreted as demonstrating equal involvement of the upper and lower lung fields, i.e., six out of 21 patients had equal involvement of the upper and lower lung fields, based on a majority decision of the interpreters. The residual volume/total lung capacity (RV/TLC) was increased and correlated inversely with forced vital capacity (FVC) at the initial measurement. FVC followed two patterns of decline over time: a gradual decline over a follow-up period of more than 6 years (-55mL/year, R(2)=0.799), and a relatively rapid decline over a shorter period (-364mL/year, R(2)=0.855) as determined by mixed-effect linear regression. CONCLUSIONS: The predominantly involved sites seen on CT images of PPFE were not limited to the upper lobes. In some cases, upper lung fields were predominantly involved, but in other cases, both upper and lower lung fields were equally involved. Two patterns of FVC decline exists: a rapid decline over a short period and a slow decline over a longer period, suggesting that the disease follows a heterogeneous clinical course.

Adenoid Cystic Carcinoma of the Lung with an EGFR Mutation.

An 80-year-old woman was referred to our hospital due to the presence of a mass that was identified on a chest X-ray. A further investigation demonstrated advanced adenoid cystic carcinoma of the lungs. Anti-cancer chemotherapy with docetaxel was carried out and the lesion remained as stable disease. Subsequently, pleural effusion was detected, and an investigation of the pleural effusion revealed the existence of malignant cells with an epidermal growth factor (EGFR) mutation. Gefitinib was administered and the pleural effusion resolved. This is the first case of a positive EGFR mutation of adenoid cystic carcinoma of the lung with a favorable response to an EGFR-tyrosine kinase inhibitor.

A new active vitamin D, ED-71, increases bone mass in osteoporotic patients under vitamin D supplementation: a randomized, double-blind, placebo-controlled clinical trial.

CONTEXT: ED-71 has been shown to increase lumbar bone mineral density (BMD) in osteoporotic subjects. However, vitamin D insufficiency might have influenced the effect of ED-71 on BMD. OBJECTIVE: Our objective was to examine whether ED-71 can increase BMD in osteoporotic patients under vitamin D supplementation. DESIGN, SETTING, AND PATIENTS: We conducted a randomized, double-blind, placebo-controlled clinical trial of 219 osteoporotic patients (49-87 yr of age). INTERVENTIONS: Subjects were randomly assigned to receive placebo or 0.5, 0.75, or 1.0 microg/d ED-71 for 12 months. All the subjects received 200 or 400 IU/d vitamin D(3). MAIN OUTCOME MEASURES: We assessed changes in lumbar and hip BMD and bone turnover markers from baseline. RESULTS: Lumbar BMD increased with ED-71 treatment for 12 months (2.2, 2.6, and 3.1% from baseline and 2.9, 3.4, and 3.8% vs. placebo group in subjects receiving 0.5, 0.75, and 1.0 microg ED-71, respectively). Total hip BMD also increased with 0.75 and 1.0 microg ED-71 (-0.8, 0.6, and 0.9% from baseline and 0.1, 1.5, and 1.8% vs. placebo group in the 0.5, 0.75, and 1.0 microg ED-71 groups, respectively). Bone formation and resorption markers were suppressed by approximately 20% after 12 months of 0.75 and 1.0 microg ED-71 treatment. Transient hypercalcemia over 2.6 mmol/liter occurred in 7, 5, and 23% of subjects in the 0.5, 0.75, and 1.0 microg ED-71 groups, respectively, but none of them developed sustained hypercalcemia. CONCLUSIONS: These results demonstrate that ED-71 treatment at around 0.75 microg/d can effectively and safely increase lumbar and hip BMD in osteoporotic patients with vitamin D supplementation.

[Osteoporosis and intake of vitamins].

Subclinical vitamins deficiency is common in the elderly, especially in osteoporotic patients. However, most physicians in this area are just focused on drugs for the treatment of osteoporosis. It is already established that several vitamins influence bone turnover, bone mineral density, or even the risk of hip fractures. Improving these vitamins status may help to treat and prevent osteoporosis in elderly people. Recently higher vitamin D intake is recognized to be needed to keep not only bone health but also muscle strength. More sun exposure might be needed for improved bone health in the elderly. Deficiency of Vitamin K, C, or B(12) may be also important modifiable risk factors for osteoporosis and bone fracture. Excessive retinal supplementation may become associated with higher bone loss. Thus such diet rich in fruit and vegetables together with fish and meat could fulfill a balance among these vitamins and should be recommended for prevention or treatment of osteoporosis.

[Dietary guidelines for osteoporosis-comparison among different countries].

Physician's guidelines for osteoporosis based on evidence from randomized, controlled clinical trials were available in many countries. Most of these guidelines include not only pharmacological therapies but also non-pharmacological treatments. Non-pharmacological treatments include nutrition as high intake of calcium and vitamin D. The calcium intakes are 1,200-1,500 mg/day in WHO, North America, and Europe, while that in Japan is as low as 800 mg/day. The vitamin D intakes are 10-20 microg/day in all other countries except Japan, in which the intake is about 5 microg/day. Other dietary guidelines in most of the countries including having optimal body weight, maintaining adequate protein intake, balanced diet, and avoiding excess sodium and caffeine are similar to Japanese guidelines. However, enough intakes of vitamin K and other vitamins and minerals are not included in these guidelines except Japan because of weak evidences so far.

[Nutritional condition affect the potency of pharmacological therapy].

Recent development of pharmacological treatments with proven efficacy will increase demand for the more effective management of patients with osteoporosis. Osteoporosis is a chronic disease concerned many risk factors such as diet and nutrition, and pharmacological efficacy could much depend on such nutritional conditions in patients as calcium, vitamin D, and protein, etc. Especially Japanese elderly usually took extremely low calcium and protein intake as well as low vitamin D, however, physicians usually give just pharmacological prescription. Therefore firstly we had better assess the nutritional conditions in each patient by body weight, serum albumin, and dietary questionnaires and give them selected pharmacological prescription together with dietary and nutritional guidance for their effective treatment of drugs. Thus we can manage each patient with not only pharmacological but also nutritional treatments that will be effective in cost-performance and good compliance for chronic disease as osteoporosis. Moreover combined nutritional treatments could work more effective in the patients of osteoporosis with inflammatory disease and high nutritional metabolic rate.

[A case of Osler-Weber-Rendu syndrome: therapeutic embolization of the pulmonary artery and bronchial artery].

We encountered a case in which the symptoms of hypoxia and hemoptysis improved after performing repeated pulmonary artery embolizations and bronchial artery embolization. A 22-year-old man was hospitalized in our institution with high fever, headache and unconsciousness in May of 2001. Subendocranial abscess was diagnosed, so we performed antibiotic therapy and drainage, but at that time he showed symptoms of hypoxia. We diagnosed Osler-Weber-Rendu syndrome because of multiple small nodular shadows in his chest CT, multiple arteriovenous fistulae in both lungs on pulmonary arteriography, and telangiectasis. We performed pulmonary artery embolization 6 times, and his hypoxia and right to left shunts improved. In the course of our therapy, hemoptysis appeared and dilatation of vessels was detected in the left bronchial arteriography, so we performed embolization of the left bronchial artery and the symptom improved. We concluded that we should take care to detect not only pulmonary arterial lesions but also bronchial arterial leisions in the diagnosis and therapy of respiratory symptoms of Osler-Weber-Rendu syndrome.

[Different way of thinking in an adequate vitamin D intake for bone health between Japan and the West].

Japanese recommended dietary allowance of vitamin D is quite low and about half to one third of the West, however, 1alpha-OH-D as a drug is popular usage for osteoporosis patients in Japan. The different way of thinking of vitamin D may come from quite low calcium intake in Japanese and more biosynthesized vitamin D owing to a location lower in latitude of Japan. Still, recommended dietary allowance of vitamin D in the West will be raised much higher level in near future owing to many evidences demonstrating the shortages of vitamin D for optimal bone health in Western elderly. More researches will be needed to decide adequate intake of vitamin D for Japanese.

[Nutrients and osteoporosis in children and adolescents].

It is widely accepted that development of a higher peak bone mass during adolescent years protects against postmenopausal osteoporosis. It is wise to instill in children good eating habits before adolescence. However, low intake of calcium, frequent intake of fast food, convenience food and oily snack as well as cyclical dieting often observed in recent Japanese children. Educating children about osteoporosis at school could accelerate higher bone mass accumulation by improvement of their diet and other lifestyle factors. Significantly higher bone accruals was observed in Japanese children who had increased intake of vegetable, fruit, fish and small fish along with consciousness of bone measurement.

[Exercise and other lifestyle factors for prevention of osteoporosis during growth and young adulthood].

Increased mechanical loading of the skeleton results in bone gain, whereas unloading the skeleton leads to bone loss. Regular exercise, especially resistance and high-impact activities, contributes to development of high peak bone mass and the greatest effects on bone mass appear to occur in early adolescence. Therefore, it seems reasonable to turn our attention to intervening in the younger population to establish lifelong exercise habit that maximize peak bone mass. Adequate calcium intake together with exercise is crucial to develop optimal peak bone mass and to preserve bone mass throughout life. This lifelong exercise may prevent osteoporosis and reduce fracture risk by attenuating age-related bone loss and lowering the incidence of falls. Moreover such lifestyle as sitting on Tatami mat could also stimulate bone accumulation in early adolescent girls. Sports participation may offset the negative effect of smoking on bone mass.

[Strategies for the prevention of osteoporosis in young and middle aged adults].

Strategies for the prevention of osteoporosis in young and middle aged adults include: a balanced diet which provides a calcium intake of at least 800 mg/day; encouragement of a physically active lifestyle; avoidance of smoking and of high alcohol and caffeine intakes; minimization of glucocorticoid use; promotion of intake of vitamin D, protein, vitamin K, vitamin C and potassium.