Induction of specific brain oscillations may restore neural circuits and be used for the treatment of Alzheimer's disease.

Brain oscillations underlie the function of our brains, dictating how we both think and react to the world around us. The synchronous activity of neurons generates these rhythms, which allow different parts of the brain to communicate and orchestrate responses to internal and external stimuli. Perturbations of cognitive rhythms and the underlying oscillator neurons that synchronize different parts of the brain contribute to the pathophysiology of diseases including Alzheimer's disease, (AD), Parkinson's disease (PD), epilepsy and other diseases of rhythm that have been studied extensively by Gyorgy Buzsaki. In this review, we discuss how neurologists manipulate brain oscillations with neuromodulation to treat diseases and how this can be leveraged to improve cognition and pathology underlying AD. While multiple modalities of neuromodulation are currently clinically indicated for some disorders, nothing is yet approved for improving memory in AD. Recent investigations into novel methods of neuromodulation show potential for improving cognition in memory disorders. Here, we demonstrate that neuronal stimulation using audiovisual sensory stimulation that generated 40-HZ gamma waves reduced AD-specific pathology and improved performance in behavioural tests in mouse models of AD, making this new mode of neuromodulation a promising new avenue for developing a new therapeutic intervention for the treatment of dementia.

Clinicians' perspective on key domains in ANCA-associated vasculitis: a Delphi exercise.

OBJECTIVES: The existing set of outcomes for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) needs to incorporate views of outcome measure stakeholders to meet the current standards of outcome measurement proposed by the Outcome Measures in Rheumatology (OMERACT) initiative. This study identifies domains that clinical experts (one group of stakeholders) consider to be important to determining the impact of AAV using the International Classification of Functioning, Disability and Health (ICF), a framework that describes health along four components: body functions, body structures, activities and participation, and contextual factors. METHOD: An international group of clinicians with expertise in the clinical care of patients with vasculitis were identified through consultation with three major vasculitis societies. The relevant domains were determined using a three-round e-mail-based Delphi questionnaire. RESULTS: Eighty-two clinicians were invited to participate in this study and 41 responded. Nineteen domains were identified as important by > 80% of participants: six body functions (energy, seeing, hearing, pain, respiratory, and renal function), seven body structures (peripheral nerves, eye, ear, nose, sinuses, lungs (and airways), and kidneys), three activities and participation (carrying out daily routine, remunerative employment, and recreation and leisure), and three environmental factors (medications, support and relationships, and health services, systems, and policies). CONCLUSIONS: Clinical experts focus on the physiological effects of AAV with less importance given to the effect of AAV on patients' activities and participation in life situations and the role of contextual factors. This study represents a step towards incorporating views of a range of stakeholders into disease assessment in AAV.

Effects of iron supplementation to iron depleted and iron replete pregnant Danish women: Defining criteria for identification of women who can manage without supplements: A randomized, placebo-controlled study.

OBJECTIVE: To define criteria based on iron status parameters for the identification of healthy women who do need/do not need iron supplementation during normal pregnancy. METHODS: Randomized, double-blind, placebo-controlled study of 113 women (62 iron-, 51 placebo treated) and their newborns. Iron dose was 66 mg elemental iron as ferrous fumarate daily from 14-18 weeks gestation to delivery. Hemoglobin (Hb), serum (S)-ferritin, S-transferrin saturation percentage, and S-erythropoietin were measured during gestation, prepartum, one week and 8 weeks postpartum. The women were divided in groups according to S-ferritin levels at inclusion:<30,≥30,≥40,≥50 and≥60µg/L. Iron deficiency (ID) was defined as S-ferritin < 15µg/L; iron deficiency anemia (IDA) as S-ferritin < 15µg/L and Hb < 110 g/L. RESULTS: Placebo treated women with S-ferritin levels < 30µg/L at inclusion had a much higher incidence of ID/IDA than placebo treated women with S-ferritin levels≥30,≥40,≥50, and≥60µg/L. S-ferritin levels≥40µg/L were associated with a very low risk of ID/IDA and none of the women with levels≥50 and≥60µg/L displayed ID/IDA. CONCLUSIONS: Women having S-ferritin < 30µg/L in early pregnancy, have a high risk of ID/IDA and should be recommended ferrous iron supplements in appropriate doses. With increasing iron reserves, i.e., increasing S-ferritin, the need for iron supplements diminishes, and placebo treated women having S-ferritin ≥40µg/L seldom develop IDA. Women with S-ferritin levels≥50 and≥60µg/L or higher, have adequate iron reserves and do not need routine iron prophylaxis in pregnancy. The results support the arguments for an individual iron supplementation guided by iron status, to avoid unwanted side effects of unnecessary iron intake.

Iron supplementation in pregnant Danish women revisited: Effects on prepartum and postpartum iron deficiency, anemia, serum erythropoietin; including iron status, erythropoietin and anthropometrics in newborns. A randomized, placebo-controlled study.

OBJECTIVE: To assess effects of iron supplementation, 66 mg elemental iron daily as ferrous fumarate, on iron status markers during normal pregnancies. METHODS: Randomized, double-blind, placebo-controlled study of 119 women (62 iron-, 57 placebo -treated) and their newborns. Hemoglobin (Hb), serum (S)-ferritin, S-transferrin saturation percentage (TSAT) and S-erythropoietin (S-EPO) were measured at 14-18, 24-27 weeks of gestation, prepartum, 1 and 8 weeks postpartum. RESULT: From 24-27 weeks gestation to 8 weeks postpartum, the iron group had higher Hb, S-ferritin and TSAT than the placebo group; prepartum, 11% had iron deficiency (ID) and 0% iron deficiency anemia (IDA) in the iron group, vs 60% and 18% in the placebo group; 8 weeks postpartum 1.6% in the iron group had ID and 1.6% IDA vs 14% and 7% in the placebo group. S-EPO levels in the iron group were lower than in the placebo group (p < 0.001). Mothers prepartum S-EPO values were correlated to newborns cord S-EPO values (p < 0.001). Newborns to iron treated mothers had higher cord S-ferritin levels than those to placebo treated mothers (p = 0.02). Newborn girls had higher cord S-ferritin levels than boys (p < 0.01). There was no impact of iron supplementation on the length of gestation, placental weight, or newborns birth weight. Birth weight was correlated only with mothers' body weight, length of gestation and placental weight. CONCLUSION: Iron supplementation had a "positive" impact on iron status and Hb both during pregnancy and postpartum, with a low frequency of ID/IDA and also a "positive" influence on newborns iron status.

A novel mutation in the NOD2 gene associated with Blau syndrome: a Norwegian family with four affected members.

BACKGROUND: Blau syndrome is a chronic granulomatous disease with an autosomal dominant trait characterized by the triad granulomatous dermatitis, arthritis, and uveitis. It is caused by mutations in the NOD2 gene, also termed the CARD15 gene. OBJECTIVE: To report a novel mutation in the NOD2 gene associated with Blau syndrome. METHODS AND RESULTS: The proband was a 68-year-old ethnic Norwegian male who had uveitis and arthritis since 10 years of age followed by lifelong recurrent arthritis and chronic eye involvement. Genetic analysis showed a heterozygous c.1814 C>A, T605N mutation in NOD2 that has not previously been described. All of his three children had Blau syndrome and had inherited the NOD2 mutation. The proband's first son had exanthema, arthritis, and uveitis from 10 years of age and later presented with granulomatous lymphadenopathy, granulomatous parotitis, and granulomatous intestinal inflammation. The proband's daughter had arthritis, uveitis, and exanthema from 3 years of age. The proband's second son had uveitis, exanthema, and arthritis from 1.5 years of age. None of the cases had any involvement of the heart or lungs. CONCLUSION: We report a novel Blau syndrome-associated mutation with an autosomal dominant heritage. Most likely the mutation has arisen de novo in the proband. Genetic counselling and antenatal diagnostics should be available to the involved families.

Heredity in sarcoidosis: a registry-based twin study.

BACKGROUND: Sarcoidosis is a multiorgan granulomatous inflammatory disease of unknown aetiology. Familial clustering of cases and ethnic variation in the epidemiology suggests a genetic influence on susceptibility to the disease. This paper reports twin concordance and heritability estimates of sarcoidosis in order to assess the overall contribution of genetic factors to the disease susceptibility. METHODS: Monozygotic and dizygotic twins enrolled in the Danish and the Finnish population-based national twin cohorts (61,662 pairs in total) were linked to diagnostic information on sarcoidosis obtained from the Danish National Patient Registry or the Social Insurance Institution, Finland registry of reimbursed medication using the 8th and 10th editions of the International Classification of Diseases. The Fisher exact test was used to compare probandwise concordance rates in different zygosity groups. Heritability was estimated based on a multifactorial threshold liability model. RESULTS: A total of 210 twin pairs with at least one proband with a diagnosis of sarcoidosis were identified. The probandwise concordance rate was higher in monozygotic than in dizygotic twins (0.148 vs 0.012). Compared with the general population there was an 80-fold increased risk of developing sarcoidosis in co-twins of affected monozygotic brothers or sisters. The increased risk in dizygotic twins was only 7-fold. Aetiological model fitting gave a heritability of sarcoidosis of 0.66 (95% CI 0.45 to 0.80). CONCLUSIONS: This study suggests that genetic factors play an important role in the susceptibility to sarcoidosis. This result should encourage the search for molecular genetic markers of susceptibility to the disease.

Childhood sarcoidosis: long-term follow-up.

The aim of the present study was to describe clinical features and long-term survival in childhood sarcoidosis. In total, 46 ethnic Caucasian Danish children (aged <16 yrs, 24 males) with sarcoidosis were identified in 1979-1994. In 33 (72%) children, diagnosis was verified by histology and, in the remaining 13, by clinical and radiological findings. In total, 37 subjects had a follow-up examination. Median (range) age at onset of disease was 14 (0.7-15.8) yrs and median (range) clinical follow-up was 15 (3-23) yrs after onset of disease. The median (range) age at clinical follow-up was 28 (17-30) yrs. At follow-up: 36 (78%) children recovered completely; 30 (65%) showed complete clinical regression at a median (range) 0.7 (0.6-5.9) yrs after onset of disease; two (4%) recovered with organ damage (unilateral loss of vision, abnormal chest radiograph); five (11%) still had chronic active disease with multiorgan involvement and impaired lung function; and three (7%) were deceased, due to central nervous system sarcoidosis and acute myeloid leukaemia probably caused by cytostatics. In Danish children, sarcoidosis had a favourable prognosis; the majority recovered <6 yrs after onset of disease. Some developed chronic active disease and impairment of pulmonary function, demanding continuous medical treatment. Prognosis was not related to the age at onset of disease. Erythema nodosum was associated with a good prognosis, and central nervous system involvement with a poor prognosis.

Cardiac sarcoidosis and heart transplantation: a report of four consecutive patients.

Heart transplantation (HTx) is a well-established treatment for severe cardiac failure. However, HTx for cardiac sarcoidosis is rare; less than 80 patients have been reported worldwide. In many patients, the diagnosis was not made prior to HTx. The aim of this study was to describe the use of HTx in the treatment of severe cardiac sarcoidosis. The series was comprised of four Caucasian patients (1 male, 3 females), aged 25-57 years. HTx were performed in the period 1990-2006. None of the patients had clinically overt extra-cardiac sarcoidosis. In one patient the diagnosis of sarcoidosis was proven prior to HTx. In three patients, all with dilated cardiomyopathy due to myocardial sarcoidosis, the final diagnosis was obtained by examination of the explanted heart. Arrythmias (supraventricular and ventricular), heart block, mitral valve insufficiency and dilated cardiomyopathy were prominent clinical features. None of the patients had recurrence of sarcoid disease in the allograft. Two patients are long-term survivors and two are deceased, one of primary graft failure, the other from Cytomegalovirus myocarditis. In conclusion, HTx is a viable treatment for cardiac sarcoidosis with end stage cardiac failure. Cardiac sarcoidosis is difficult to diagnose. Myocardial biopsy has a low diagnostic sensitivity. However, when the newest non-invasive diagnostic methods, including magnetic resonance imaging and positron emission tomography, are applied, an endomyocardial biopsy should not be mandatory to make a diagnosis of cardiac sarcoidosis.

Morphometric examination of native lungs in human lung allograft recipients.

The aim of the study was to estimate the degree of lung damage in patients with alpha(1)-antitrypsin (alpha1AT) deficiency, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF) at the time of lung transplantation. Using unbiased stereological methods, lung-, bronchial- and vessel-volume, capillary length, and alveolar surface area and densities were estimated in recipient lungs from 21 consecutive patients with pre-transplant diagnoses including COPD (n=7), alpha1AT deficiency (n=6) and CF (n=8). Six unused adult donor lungs served as controls. Information relating to patient demography and pre-transplant lung function was obtained by retrospective chart review. Disease groups differed significantly with respect to demographics and pre-transplant lung function. Total lung volume was similar in all groups. Bronchial volume was significantly larger in CF patients compared to the control group (p<0.0001) and to the other two diagnostic groups: alpha1AT deficiency (p=0.0001) and COPD (p<0.0001). Alveolar surface density and capillary length density were significantly lower in patients with alpha1AT deficiency and COPD compared to controls (p<0.0001, respectively) and to patients with CF (p<0.0002, respectively). There were no correlations between clinical lung function and morphometric measurements. We conclude that unbiased microscopic stereological morphometry is an evolving science with the potential to elucidate pulmonary disease pathogenesis.

Correction: Identification of Novel Pre-Erythrocytic Malaria Antigen Candidates for Combination Vaccines with Circumsporozoite Protein.

[This corrects the article DOI: 10.1371/journal.pone.0159449.].

Microalbuminuria in patients with lung cancer.

In a prospective study of 102 outpatients with histologically proven lung cancer, the prevalence and prognostic significance of microalbuminuria (urinary albumin excretion > 20 micrograms/min) were analysed. 65 consecutive outpatients with benign lung disorders served as controls. An immunoturbidimetric assay, sensitive at low concentrations, was used to quantify the albumin excretion rate in timed overnight urine samples. Patients with malignancies had a significantly higher frequency of microalbuminuria (32.4% compared with controls, 13.8%, P < 0.01) and median urinary albumin excretion rate (13.4 versus controls, 8.9 micrograms/min, P < 0.003). Urinary albumin excretion was significantly higher in lung cancer patients with TNM stage III and IV. Patients with malignancies and microalbuminuria had a significantly lower survival rate than patients with normoalbuminuria (probability of survival 1 and 3 years after diagnosis 66% and 16% versus controls, 22% and 4%, P < 0.00001). In a multivariate model, which adjusted for age, sex, performance status, histological type and TNM stage, microalbuminuria continued to be a significant predictor of survival. In conclusion, an increased prevalence of microalbuminuria has been demonstrated in patients with lung cancer. The presence of microalbuminuria was associated with advanced disease stage and poor survival.

Bone-marrow hemosiderin iron and serum iron status markers in small-cell carcinoma of the lung.

Bone marrow haemosiderin iron grade and serum (S-) iron status markers (haemoglobin (Hb), S-iron, S-transferrin, transferrin saturation, S-ferritin) were measured in 31 patients with newly discovered small cell cancer of the lung (SCCL), and compared to the values in 53 healthy control subjects. Among SCCL patients, 2 had grade 0 (absent), 5 grade (1+) (trace), 8 grade 1+ (normal), and 16 grade 2+ (increased) marrow haemosiderin iron. Median S-ferritin values in the respective groups were 38 mug/l, 243 mug/l, 384 mug/l and 433 mug/l. There was no correlation between Hb, S-iron, S-transferrin or transferrin saturation and marrow iron grade. S-ferritin displayed a correlation with marrow iron grade (r(s) = 0.40, p <0.05) but there was marked overlap between the groups. Among the controls, 5 had grade 0, 11 grade (1+), and 37 grade 1+ marrow iron. Median S-ferritin values in the respective groups were 14 mug/l, 26 mug/l and 57 mug/l. Hb, S-iron, S-transferrin, transferrin saturation and S-ferritin were all significantly correlated to marrow iron grade; S-ferritin, r(s) = 0.64, p <0.0001. In conclusion, SCCL patients have inappropriately high S-ferritin values. In SCCL, serum iron status markers, including S-ferritin, are poor indicators of marrow haemosiderin iron and thus body iron stores. Therefore, estimation of marrow haemosiderin iron or histochemical/chemical liver iron content remains the only reliable way of assessing iron stores in SCCL.

Endoscopic ultrasonography and real-time guided fine-needle aspiration biopsy of solid lesions of the mediastinum suspected of malignancy.

STUDY OBJECTIVE: The study details our preliminary experience with endoscopic ultrasonography (EUS) guided fine-needle aspiration biopsy (FNAB) of mediastinal masses suspected of malignancy. DESIGN: Prospective uncontrolled study. PATIENTS: Nine patients had lesions suspected of malignancy ranging from 1 to 9 cm in diameter in various locations of the mediastinum. INTERVENTIONS: The EUS examination was performed with a gastroscope (Hitachi/Pentax FG-32 UA) equipped with an adjustable 5- or 7.5-MHz curved array ultrasonic transducer. The scanning plane is in the long axis of the endoscope allowing endosonographically guided biopsy to be performed. A 21-gauge (0.8 mm), full-length steel needle housed in a biopsy handle (type: Hancke/Vilmann; GIP-Medizin Technik; Grassau, Germany) was used for the biopsies. RESULTS: Nine patients had biopsy specimens taken from 13 lesions. The total number of needle passes was 18 (range, 1 to 3; median, 1.4). The cytologic diagnosis was conclusive for cancer in ten lesions and consistent with a benign lesion in three lesions. All ten malignant diagnoses and two benign diagnoses were confirmed either by operation or follow-up. In the last patient with lung cancer, a final diagnosis of the EUS-guided biopsy of an enlarged lymph node could not be obtained. No false-positive or negative biopsy diagnoses were recorded. The biopsy procedure was well tolerated by all patients, and there were no complications. CONCLUSIONS: EUS-guided aspiration biopsy is a significant advance in the differentiation between malignant and benign lesions of the mediastinum carrying a high diagnostic potential.

Hyaluronan and procollagen type III aminoterminal peptide in serum and bronchoalveolar lavage fluid from patients with pulmonary fibrosis.

Previous studies of the collagen synthesis markers hyaluronan (hyaluronic acid) (HA) and procollagen type III aminoterminal peptide (PIIINP) in pulmonary fibrosis have reported elevated levels in bronchoalveolar lavage fluid (BALF) and suggested an association with disease activity. The objective of the present study was to evaluate whether HA and PIIINP in BALF and serum (S) correlated with paraclinical markers of disease activity (chest X-ray profusion score, pulmonary function tests (FEV1, FVC, TLC, DLCO)) in patients with pulmonary fibrosis. The material comprised 27 patients with biopsy-proven pulmonary fibrosis (12 cryptogenic and 15 due to connective tissue diseases) and 24 control subjects with normal lung function. BAL was performed in the right middle lobe with 250 ml saline. HA and PIIINP were measured in the cell-free BALF supernatant and in serum. Patients had higher BALF-HA (mean 86 +/- 17 (SEM) micrograms/l) than controls (39 +/- 2 micrograms/l (p < 0.01)), higher BALF-albumin (124 +/- 24 mg/l) than controls (58 +/- 4 mg/l (p < 0.01)) and higher BALF/S-HA ratio (2.4 +/- 0.6) than controls (1.2 +/- 0.6 (p < 0.05)). There were no significant differences respecting BALF-PIIINP, S-HA, or S-PIIINP. Patients (n = 14) with progressive disease had higher BALF-HA, higher BALF-albumin, higher S-PIIINP, and higher S-immunoglobulins than those with stable disease, but the differences did not reach statistical significance. Smokers (n = 18) had lower BALF-HA, lower S-HA, lower S-PIIINP, lower S-immunoglobulins, and higher lung function tests than non-smokers, but the differences did not reach statistical significance. In patients, significantly positive correlations were found between BALF-HA and BALF-albumin, between BALF-PIIINP and BALF-albumin, and a significantly negative correlation between S-PIIINP and TLC. None of the BALF or serum markers correlated with chest X-ray profusion score or any of the other lung function measurements. It is concluded that disease activity may be associated with elevated HA and PIIINP levels. Smoking may influence the immunological processes in pulmonary fibrosis and may be a confounder in studies of these patients.

Bronchoalveolar lavage in radiologically detected diffuse lung disease. Diagnostic value of total and differential cell count in a series of 130 patients.

During a 7-year period bronchoalveolar lavage (BAL) was performed as a routine diagnostic procedure at fiberoptic bronchoscopy in 172 consecutive patients with diffuse pulmonary lesions. In 42 patients, BAL was technically insufficient or data were incomplete. These patients were excluded. The remaining 130 patients consisted of 78 men and 52 women with a median age of 43 years (range 19-79); 59 were smokers. They were divided into 6 groups: I. sarcoidosis (n = 77); II. cryptogenic fibrosing alveolitis (n = 16); III. secondary fibrosing alveolitis (n = 7); IV. malignancy (n = 7); V. allergic alveolitis (n = 6); VI. miscellaneous (n = 17). Group VI was not included in the statistical evaluation, which involved only the 113 patients in groups I-V. BAL was performed in a segment of the right middle lobe with 150-200 ml isotonic saline. The return fluid (BALF) was filtered through two layers of cotton gauze, and total and differential cell counts were assessed. Median BALF return volume was 67% (range 35-90). Eighty percent of the procedures were performed by the same operator. Total cell count displayed no significant difference amongst the five diagnostic groups (p = 0.06). Differential cell count displayed differences amongst the groups respecting macrophages (p = 0.002), lymphocytes (p = 0.0004), neutrophils (p = 0.0001) and eosinophils (p = 0.04). Patients with sarcoidosis had a higher percentage of lymphocytes, patients with secondary fibrosis a higher percentage of neutrophils, and patients with cryptogenic fibrosis a higher percentage of eosinophils than the other groups. Malignant cells were observed in BALF in 14.3% of patients with malignant lesions. Among the patients with sarcoidosis, 75% had a lymphocyte-dominated BALF (> 10%) compared with 31% of the patients with cryptogenic fibrosis, 14% of the patients with secondary fibrosis, and 43% of the patients with malignancy. Dominance of neutrophils (> 10%) and/or eosinophils (> 5%) in BALF was observed in cryptogenic and secondary fibrosis. In most patients, BAL cannot provide a definite diagnosis, but may support the clinical suspicion of a specific diagnosis. In clinical practice, BAL seems to be of limited value in the diagnostic evaluation of radiologically detected diffuse, non-infectious pulmonary lesions.

Search for Mycobacterium paratuberculosis DNA in tissue from patients with sarcoidosis by enzymatic gene amplification.

The etiology of sarcoidosis has not yet been established, but several mycobacterial species have been implicated in the pathogenesis of this disease. We have used a nested primer polymerase chain reaction (PCR) specific for the IS900 Mycobacterium paratuberculosis insertion element to analyse paraffin-embedded mediastinal lymphoid tissue from 18 patients with pulmonary sarcoidosis verified by mediastinoscopy. Only the positive control contained M. paratuberculosis-specific DNA. The present study does not support a role for M. paratuberculosis in the pathogenesis of sarcoidosis. However, further studies are needed in order to clarify the possible role of other mycobacteria in this disease.

Comparison of alveolar macrophage and blood monocyte oxidative burst response in pulmonary sarcoidosis.

The alveolitis of sarcoidosis is dominated by lymphocytes and mononuclear phagocytes and chronic macrophage activation may play a role in the pulmonary interstitial fibrosis of sarcoidosis. We measured superoxide anion release of alveolar macrophages from sarcoidosis patients after in vitro stimulation, as toxic oxygen radicals have been proposed as mediators of chronic tissue damage. In untreated patients alveolar macrophage activity was normal, but significantly lower than in blood monocytes. However, a negative correlation between lymphocytosis in bronchoalveolar lavage fluid and macrophage oxidative metabolism was observed, showing that only patients with high intensity alveolitis have a decreased oxidative burst response after in vitro stimulation. This may reflect in vivo activation of the cells with subsequent reduced ability to respond after additional stimulation in vitro. Patients with radiological stage I had lower alveolar macrophage response than patients in stage II or III. There was no correlation with SACE levels, lung function tests or smoking habits. Nine patients were reinvestigated after treatment with prednisolone. Although the lymphocytosis of lavage fluid was only insignificantly changed, all but one patient showed improved macrophage release of superoxide anion. Blood monocyte oxidative burst response was normal in all patients before and after treatment. In conclusion, only mononuclear phagocytes of the target organ (lung) showed an altered function and the most pronounced decrease was observed in sarcoid patients with active alveolitis. Chronic low grade toxic oxygen radical release of alveolar macrophages may be involved in the pathology of pulmonary sarcoidosis.

Distribution of liver haemosiderin iron in 187 patients with various types of hepatic diseases.

The purpose of this study was to evaluate the distribution of haemosiderin iron in various regions of the liver (central, intermediary and peripheral hepatocytes, Kupffer cells, portal macrophages and bile duct epithelial cells) in 174 patients with different hepatic diseases (alcoholic cirrhosis (n = 49), alcoholic steatosis (n = 60), non-alcoholic cirrhosis (n = 16), acute hepatitis (n = 20), clinically overt untreated hereditary haemochromatosis (n = 3), miscellaneous disorders (n = 26)), and in 13 subjects with a normal liver biopsy. Furthermore, the relationship between liver haemosiderin iron, biochemical iron status markers and biochemical liver tests was investigated. In haemochromatosis iron was consistently present in all examined regions of the liver, and in 43% of patients with alcoholic liver disease haemosiderin was present in at least one region of the liver lobule. In 65% of patients with acute hepatitis, haemosiderin was present in macrophages and Kupffer cells. In other hepatic diseases and in normal livers, haemosiderin was rarely seen. Regression analyses showed a correlation between iron status markers in most patients, except in those with high serum aspartate aminotransferase levels. In conclusion, haemosiderin iron is distributed in a typical pattern in haemochromatosis, alcoholic liver disease and acute hepatitis. Both histochemical liver iron and serum ferritin are of value as indirect markers of liver iron stores in patients with moderate hepatocellular damage.

Superoxide anion release from blood monocytes and alveolar macrophages in patients with diffuse lung fibrosis.

Superoxide anion release (O2-) after stimulation with phorbol myristate acetate was measured in alveolar macrophages (AM) obtained by bronchoalveolar lavage and in blood monocytes from 47 patients with diffuse interstitial lung disease: idiopathic pulmonary fibrosis (N = 15), hypersensitivity pneumonitis (N = 7), pneumoconiosis (N = 6) and sarcoidosis (N = 19). Differential cell counts demonstrated a lymphocyte predominance in patients with hypersensitivity pneumonitis (HP) and sarcoidosis while the other groups had neutrophil predominance. No correlation between O2- activity in alveolar macrophages (AM) or blood monocytes (BM) compared to lung function (VC and diffusing capacity) could be demonstrated. Smoking pneumoconiotics had significantly decreased BM O2- release (1.25 +/- 0.25 (SEM) nmol/min/10(6) cells) and significantly increased AM/BM O2- ratios (2.04 +/- 0.26) compared to smokers with idiopathic pulmonary fibrosis (IPF) who had the following mean values: BM O2- release = 2.58 +/- 0.25 and AM/BM O2- ratio = 0.86 +/- 0.23. When matched for sex and smoking, a significantly increased AM/BM O2- ratio was seen among patients with HP (2.19 +/- 0.98) in comparison with patients who had sarcoidosis (0.40 +/- 0.18). Patients with either HP or pneumoconiosis had generally elevated AM O2- release and reduced BM O2- release. These results suggest that environmentally related interstitial lung disorders (HP and pneumoconiosis) may be associated with elevated AM O2- release relative to BM O2- release in comparison to non-environmentally related disorders (IPF or sarcoidosis).