LTBI: latent tuberculosis infection or lasting immune responses to M. tuberculosis? A TBNET consensus statement.

Tuberculosis control relies on the identification and preventive treatment of individuals who are latently infected with Mycobacterium tuberculosis. However, direct identification of latent tuberculosis infection is not possible. The diagnostic tests used to identify individuals latently infected with M. tuberculosis, the in vivo tuberculin skin test and the ex vivo interferon-gamma release assays (IGRAs), are designed to identify an adaptive immune response against, but not necessarily a latent infection with, M. tuberculosis. The proportion of individuals who truly remain infected with M. tuberculosis after tuberculin skin test or IGRA conversion is unknown. It is also uncertain how long adaptive immune responses towards mycobacterial antigens persist in the absence of live mycobacteria. Clinical management and public healthcare policies for preventive chemotherapy against tuberculosis could be improved, if we were to gain a better understanding on M. tuberculosis latency and reactivation. This statement by the TBNET summarises knowledge and limitations of the currently available tests used in adults and children for the diagnosis of latent tuberculosis infection. In summary, the main issue regarding testing is to restrict it to those who are known to be at higher risk of developing tuberculosis and who are willing to accept preventive chemotherapy.

Dietary phytoestrogen intake and mammographic density -- results of a pilot study.

The influence of dietary phytoestrogens provided by Western diets on mammographic density is not well established. Soy and soy products as source of isoflavones were found to be inversely associated with high mammographic density, a marker for breast cancer risk. Another class of phytoestrogens, the lignans, which are more frequent in Western diets, are rarely investigated. Within the European Prospective Investigation into Cancer and Nutrition cohort in Heidelberg (EPIC-Heidelberg) we explored the feasibility of mammogram collection and measurement of mammographic density in order to investigate the association between dietary phytoestrogen intake and breast density patterns. Wolfe classification was used to summarize mammographic density. Dietary habits were assessed by means of a validated food frequency questionnaire. - Out of the 505 randomly selected women, 317 (63%) returned the questionnaire and 310 (61.4%) women provided informed consent to collect mammograms. Dietary intake of seven women with dense patterns (DY) was compared with 47 women without dense patterns. A high dietary intake of fibre (p-value = 0.008) and secoisolariciresinol (p-value = 0.043) is inversely associated with non-dense breast patterns. This is also observed for a high dietary intake of soy-products (p-value = 0.004) and, in tendency, genistein (p-value = 0.069). After adjustment for energy intake and age the groups of dense and non-dense mammographic patterns were different regarding the intake of carbohydrate (p = 0.032), soy-products (p = 0.020), fibre (p = 0.046), and secoisolariciresinol (p = 0.027). - Our results suggest an inverse association between dietary lignan intake and breast density, similar to the findings for isoflavones. To our knowledge this is the first report on this association, but due to the risk of chance finding, this has to be confirmed in a study with sufficient statistical power.

Serum anti-p53 antibodies in patients with lung cancer.

Antibodies against the p53 protein are produced by some cancer patients. In some tumour entities, the presence of p53 autoantibodies have been linked to poorer survival. This study was designed to assess the prevalence and prognostic implications of p53 autoantibodies in patients with lung cancer. Serum samples of 180 patients were tested for antibodies against p53 protein using an ELISA. We studied 134 patients with primary lung cancer [histology: small cell lung carcinoma (SCLC) n=35; non-small cell lung carcinoma (NSCLC) n=99]. The control group consisted of 46 patients without lung cancer. In 17/134 (12.6%) of the cancer patients, p53 autoantibodies were detected (4/35 SCLC, 13/99 NSCLC). Most of the positive results were found in advanced stages of NSCLC (stage I-IIIA: 1/34; stage IIIB/IV: 12/65). One of the 46 control patients tested positive. Statistical analysis of survival shows no correlation with p53 antibody status in SCLC, but a significant correlation with shorter survival in NSCLC (p=0.01). After correction for stage of disease this correlation remains significant (stage IIIB/IV: p=0.02). In our series, the presence of anti-p53 autoantibodies is almost exclusively linked to the presence of malignant disease. Prognosis for patients with NSCLC, but not SCLC seems to be linked to the p53 autoantibody status.

[Abscessed pneumonia caused by Pseudomonas aeruginosa as an occupational disease in a metal driller]. / Abszedierende Pneumonie durch Pseudomonas aeruginosa als Berufskrankheit bei einem Bohrwerksdreher.

We report the case of a 29-year-old man without immunodeficiency who acquired Pseudomonas aeruginosa pneumonia complicated by pulmonary abscess. The source of infection could be identified as aerosolized metalworking fluid at his workplace contaminated with Pseudomonas aeruginosa. A high titer of specific IgG antibodies (type-III-sensitization, Gell & Coombs) against Pseudomonas aeruginosa has been identified in the patients serum as an indicator for longstanding occupational airborne exposure to contaminated metalworking fluid. This community-acquired pneumonia has been reported to the industrial injuries insurance as an occupational disease for discussion of legal consequences and development of effective measures of prevention.

[Aneurysm of the aortic arch: presenting as mediastinal tumor]. / Aneurysma des Aortenbogens: Präsentation als Mediastinaltumor.

We report the case of a 62-year-old woman who presented with severe abdominal pain. The routine chest x-ray showed an anterior mediastinal mass measuring approximately 10 cm in diameter. CT-Scan and angiography demonstrated an aneurysm of the aortic arch compromising the left pulmonary artery and main bronchus. An additional aneurysm of the abdominal aorta and right iliac artery was seen, which apparently led to the abdominal symptoms. Coronary angiography revealed coronary artery disease. The aortic arch aneurysm was treated by interposition of a vascular graft. Aorto-coronary bypass grafts were implanted. The abdominal aneurysm was resected in a staged approach after recovery from the first operation.

DNA amplification on chromosome 3q26.1-q26.3 in squamous cell carcinoma of the lung detected by reverse chromosome painting.

Multiple genetic lesions have been reported in small cell lung carcinoma (SCLC), while considerably less information is available on squamous cell carcinoma (SCC). We used reverse chromosome painting to screen a total of nine SCCs for DNA amplifications. In three of the nine SCCs, hybridisation signals were found at chromosome region 3q26.1-q26.3, which does not contain any known oncogene. In one of the three SCCs, there were additional hybridisation signals at 1q, 5p and 6p21.1. The high frequency of a consistent amplification (3q26.1-q26.3) in SCC strongly indicates a novel gene at 3q26.1-q26.3 that is important in the pathology of SCC.

[Fatal diffuse alveolar damage after gold medication]. / Letaler diffuser Alveolarschaden nach Goldmedikation.

We report about the case of a 74-year-old woman who suffered diffuse alveolar damage and consecutive lethal pulmonary failure after gold therapy for rheumatoid arthritis. This is the fourth documented case of fatal pulmonary failure following gold therapy. The clinical findings were dominated by severe dyspnoea that warranted respirator therapy shortly after admission. Chest radiographs showed progressing confluent perihilar patchy infiltrates that suggested interstitial involvement. Steroid therapy had only a short-lasting effect on the respiratory failure, the patient died in prolonged hypoxic circulatory failure. Post-mortem examination showed the organotypical findings of diffuse alveolar damage in proliferative stage with advanced pulmonary fibrosis. With the discontinuation of gold medication and early steroid therapy, this disease which is based on immunological pathomechanisms is usually reversible. Both the knowledge of this entity and early diagnosis are essential for a promising therapeutic intervention.

[Electronic data processing-assisted text processing at the clinic and in general practice]. / EDV-gestützte Textverarbeitung in Klinik und Praxis.

Word processing is currently the most frequent application for personal computers, and a wide variety of standard software is available. The capabilities of modern word-processing software includes the convenient typing and correction of all routine correspondence, as well as the professional layout of scientific manuscripts. The decision to purchase a certain word-processing programm should be made according to local needs and prerequisities. Three to six months may be necessary to fully adapt the organization of a clinic or private practice to the new technology.

Isolation of a porcine hepatic ferritin receptor.

1. A ferritin receptor has been isolated from porcine liver and has been partially purified using affinity chromatography. 2. A binding assay has been developed which utilizes a hepatic ferritin receptor coupled to a microparticulate support which facilitates the separation of bound and free ligand. 3. An affinity constant of 2.9 x 10(9) mol-1 litre was determined for the purified hepatic ferritin receptor. 4. The molecular weight of the receptor was estimated to be approximately 53,000 by gel electrophoresis. 5. Binding of ferritin to the insolubilized receptor was unaffected by a 100-fold excess of bovine albumin, porcine and human transferrin, and human asialo-orosomucoid. 6. Binding was specific for porcine ferritin with no demonstrable binding of rat or human ferritin.

Desialylated transferrin as a serological marker of chronic excessive alcohol ingestion.

Partly desialylated transferrin was measured in the serum of subjects with chronic alcoholism, of patients with non-alcoholic-related steatohepatitis, diabetes, and other non-alcoholic liver diseases, and of healthy controls. In non-alcoholic patients and controls the maximum desialylated transferrin expressed in relation to total transferrin was 1.5%. This value was exceeded in 18 (90%) of the 20 alcoholics. By contrast, gamma-glutamyl transferase was within the reference range in 9 of the alcoholics.

Simple radioimmunoassay for transferrin using insolubilized antitransferrin antibodies: its application to cultured cells.

A radioimmunoassay (RIA) for transferrin is described. The assay uses antitransferrin antibodies covalently coupled to the particulate support Matrex Pel 102, and is simple, sensitive, reproducible, and rapid. Transferrin measurement with this assay is independent of the degree of iron saturation of the protein. The RIA was applied to the measurement of transferrin concentrations in a variety of cultured human cells. Each of 11 cell lines studied contained endogenous transferrin, but the greatest concentration was found in Chang liver cells. Red blood cells were used as a negative control.

Characterization of the binding of ferritin to the rat liver ferritin receptor.

The binding characteristics and specificity of the rat hepatic ferritin receptor were investigated using ferritins prepared from rat liver, heart, spleen, kidney and serum, human liver and serum, guinea pig liver and horse spleen as well as ferritins enriched with respect to either H- or L-type subunit composition, prepared by chromatofocusing of rat liver ferritin on Mono-P or by reverse-phase chromatography of ferritin subunits on ProRPC 5/10. No significant difference was apparent in the binding of any of the tissue ferritins, or of ferritins of predominantly acidic or basic subunit composition. However, serum ferritin bound with a lower affinity. The effect of carbohydrate on the ferritin-receptor binding was examined by glycosidase treatment of tissue and serum ferritins. Tissue ferritin binding was unaffected, while serum ferritin binding affinity was increased to that of the tissue ferritins. Inhibition of ferritin binding by lactoferrin was not due to common carbohydrate moieties as previously suggested but was due to direct binding of lactoferrin to ferritin. Therefore, carbohydrate residues do not appear to facilitate receptor-ferritin binding, and sialic acid residues present on serum ferritin may in fact interfere with binding. The results indicate that the hepatic ferritin receptor acts preferentially to remove tissue ferritins from the circulation. The lower binding affinity of serum ferritin for the ferritin receptor explains its slower in vivo clearance relative to tissue ferritins.

Use of chromatofocusing to detect a transferrin variant in serum of alcoholic subjects.

We describe a technique for detecting an abnormal (pl 5.7) transferrin component in serum, which appears after prolonged heavy consumption of alcohol. Serum transferrin was purified by chromatography on DEAE-Affi-Gel Blue and analyzed by chromatofocusing on an ion-exchange column (Mono P). The abnormal transferrin component was detected in 17 of 20 patients (85%) with a history or prolonged consumption of alcohol (100 g per day), and in control subjects who ingested up to 80 g of alcohol per day for seven days, but not in 14 normal control subjects or 14 patients with liver disease unrelated to alcohol. The variant consistently disappeared from the serum within three weeks of cessation of alcohol consumption. It is apparently produced by desialylation of ordinary human transferrin. We find that chromatofocusing on an ion-exchange column is a sensitive and reliable technique for its identification and conclude that detection of this desialylated transferrin indicates recent prolonged alcohol ingestion.

The effect of acute liver damage on circulating ferritin levels in vivo and in the isolated perfused rat liver.

The effects of minimal acute liver injury on circulating ferritin levels have been examined in the rat both in vivo and in the isolated perfused liver. Liver damage produced by 6 mmol/kg of D-galactosamine (GalN) in vivo resulted in a marked rise in plasma ferritin levels 4 h after administration, 2 h before any significant increase in plasma aspartate transaminase. In the isolated perfused liver, damage produced by 5mM GalN introduced into the perfusate also produced an early increase in circulating ferritin before any evidence of release of intracellular enzymes, or alteration in liver histology as assessed by light microscopy was apparent. It is concluded that minimal acute liver damage results in a pronounced increase in circulating ferritin levels before other evidence of liver dysfunction. This is unlikely to be due solely to increased release from damaged cells but may rather result from an alteration in the mechanism responsible for ferritin homeostasis.

Detection and isolation of a hepatic membrane receptor for ferritin.

A ferritin receptor has been detected on isolated rat hepatocytes and has been partially purified from rat liver using affinity chromatography. Isolated hepatocytes exhibit approximately 30,000 ferritin binding sites/cell with a binding association constant (Ka) of 1 x 10(8) mol-1 liter. A binding assay has been developed which utilizes a hepatic ferritin receptor coupled to a microparticulate support to facilitate separation of bound and free ligand. This method yielded a Ka of 3 x 10(8) mol-1 liter for the purified hepatic ferritin receptor. Binding of ferritin to the insolubilized receptor was partially inhibited by human lactoferrin but unaffected by 200-fold molar excess of bovine albumin, rat transferrin, or human asialoorosomucoid.

Regulation of plasma ferritin by the isolated perfused rat liver.

The isolated perfused rat liver has been used to investigate the regulation of plasma ferritin in normal, iron-deficient and iron-overloaded states. Both 125I-labelled and non-labelled rat liver ferritins were rapidly cleared from the perfusion circuit with a half-life of approximately 30 min. Perfusion of livers from normal, iron-loaded or iron-deficient rats with blood obtained from normal, iron-loaded or iron-deficient rats showed that the liver takes up plasma ferritin, and releases ferritin into the perfusate to achieve a perfusate ferritin level appropriate to the iron stores of the animal from which the liver was taken. It is concluded that the liver is capable of both uptake and release of ferritin and that within the liver there resides a mechanism which maintains circulating ferritin concentrations at a level appropriate to body iron stores.

The kinetics of serum and tissue ferritins: relation to carbohydrate content.

Significant differences were observed in the rate of disappearance from plasma of ferritins purified from rat serum and from different organs. Ferritin from all sources including purified serum ferritin was rapidly removed from plasma by the liver. No difference in biological half-life was observed between apoferritin prepared by ultracentrifugation of liver ferritin and whole liver ferritin and iron-loaded animals cleared injected serum ferritin from plasma at a comparable rate to normal rats. When amounts of 100 microgram of ferritin were injected into rats the half-life was significantly lengthened. The study confirmed the fact that ferritin iron and ferritin protein were removed from plasma at the same rate. No consistent effect of acidic or more basic isoferritin composition on biological half-life was apparent. After chromatography on concanavalin A-Sepharose 6B those ferritins which were predominantly bound to Con A-Sepharose had a half-life which was approximately twice that of ferritins which did not bind. It is concluded that the variation in plasma disappearance of ferritins of different tissue origin was explainable on the basis of carbohydrate content of the molecule.

Duodenal ferritin content and structure: relationship with body iron stores in man.

The relationship between serum ferritin and duodenal ferritin was examined in normal subjects and in patients with iron deficiency, secondary iron overload, or idiopathic hemochromatosis (IHC). A positive correlation between serum ferritin and duodenal ferritin concentrations was found in all groups. In the iron-overload conditions, duodenal ferritin concentration was lower at all levels of serum ferritin in comparison with normal and iron-deficient subjects. Patients with secondary iron overload did not differ from those with IHC, which indicates that any decrease in duodenal ferritin concentration was secondary to the excess body iron stores. Purified duodenal ferritin from normal subjects and patients with iron-overload conditions showed the same two distinct isoferritins by isoelectric focusing. After the oral administration of iron, two additional isoferritins were detected. These resembled the major isoferritins of liver.

Iron absorption in the rat: the search for possible intestinal mucosal carriers.

The biological relevance of four iron-containing fractions previously detected in rat intestinal mucosal cells has been studied. The distribution of iron in these fractions obtained by chromatography on Sepharose 6B has been examined after in vivo and in vitro incubation of mucosal cells with 59Ce. In addition, the effects of phenobarbitone, cycloheximide, iron-deficiency and iron-loading on the uptake and distrubution of iron within the four mucosal cell fractions was studied. The iron in fraction I was mostly bound to intracellular membrane particles. Fraction II was shown to be ferritin. Fraction III contained some transferrin and also a protein of molecular weight similar to transferrin but which was not precipitable by antitransferrin antiserum. Quantited with the results of 'chaser' experiments suggested that, in addition to ferritin, at least two of the fractions (I and III) were involved in the process of iron absorption by the mucosal cell.

Immunological detection of isoferritins in normal human serum and tissue.

A method is described which permits the detection of isoferritins in normal human serum and tissues. The technique makes use of 125I-labelled monospecific anti-human-liver-ferritin antibody to demonstrate the isoferritins after isoelectric focussing of the purified ferritin in polyacrylamide gels. The organ-specific variation in tissue isoferritin profile previously reported in normal subjects has been confirmed by this technique using only 50 ng of each ferritin sample. Serum ferritin from normal healthy subjects was also shown to exhibit a microheterogeneity on isoelectric focussing; six clearly defined isoferritin peaks were detected in the pH range of 5.04 to 5.62. This isoferritin profile of normal serum contained isoferritins over the whole range of the various tissue isoferritins suggesting that a number of organs may contribute to the normal serum ferritin pool.