Secretion of Tumour Necrosis Factor α and Lymphotoxin α in Relation to Polymorphisms in the TNF Genes and HLA-DR Alleles. Relevance for Inflammatory Bowel Disease

The genes for tumour necrosis factor alpha (TNFα) and lymphotoxin alpha (LTα; TNFβ) are tandemly arranged in the central region of the MHC. They may, therefore, be of importance for the aetiology of MHC-associated diseases. The authors have prospectively studied the secretion of TNFα and LTα in relation to polymorphisms at positions -308 and -238 in the TNFα gene (TNFA), and two polymorphisms in the first intron of the LTα gene (LTA), as well as HLA-DR in 30 patients with chronic inflammatory bowel diseases (IBD) and 12 healthy controls. In the Dutch population, the alleles of these four polymorphisms are present in only five combinations, called TNF-haplotypes: TNF-C, -E, -H, -I, and -P. Significant associations between TNF haplotypes and TNFα and LTα secretion were found when PBMC were cultured with T-cell activators, irrespective of disease. Mean TNFα secretion of individuals carrying the HLA-DR3 associated TNF-E haplotype was significantly higher, as compared to individuals without this haplotype (26 441 pg/ml versus 19 629 pg/ml; P = 0.014). Individuals carrying the TNF-C haplotype produced the lowest amount of TNFα (17 408 pg/ml; P = 0.022). The TNF-C and TNF-E haplotypes differ only at position -308 in the promoter of TNFA. Individuals carrying the HLA-DR1 associated TNF-I haplotype produced significantly less LTα when compared to those who lack this haplotype (1979 pg/ml versus 3462 pg/ml; P = 0.006). As the TNF-I haplotype is also associated with low TNFα secretion, this haplotype thus defines a ‘low secretor phenotype’. In conclusion, this is the first study to show associations between TNF haplotypes and TNFα and LTα secretion when T-cell stimulators are used. These findings will contribute to define disease heterogeneity in IBD and may be of relevance for understanding the pathogenesis of autoimmune diseases.     

Capsaicin-sensitive extrinsic afferents are involved in acid-induced activation of distinct myenteric neurons in the rat stomach

Challenge of the rat gastric mucosa with 0.5 mol L(-1) HCl activates nitrergic neurons in the myenteric plexus as visualized by c-Fos immunohistochemistry. In the present study, we characterized the activated neurons more extensively by their chemical coding and investigated whether a neural pathway that involves capsaicin-sensitive extrinsic afferents and/or cholinergic neurons transmitting via nicotinic receptors contributes to the activation of myenteric neurons. In multiple labelling experiments, c-Fos was examined for co-localization with nitric oxide synthase (NOS), vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), enkephalin (ENK), gastrin-releasing peptide (GRP), substance P (SP), calbindin D-28k (CALB) and neurofilament 145 (NF 145). All c-Fos-positive neurons were immunoreactive for NOS, VIP, NPY and NF 145, but not for SP, ENK, GRP and CALB. Nerve fibres co-expressing NOS, VIP and NPY were predominantly found in the external muscle layer and in the muscularis mucosae but rarely in the mucosa. Pre-treatment with capsaicin or hexamethonium or a combination of both pre-treatments reduced HCl-induced c-Fos expression by 54, 66 and 63%, respectively. Acid challenge of the stomach, therefore, leads to activation of presumably inhibitory motor neurons responsible for muscle relaxation. Activation of these neurons is partly mediated by capsaicin-sensitive afferents and involves ganglionic transmission via nicotinic receptors.     

Effect of nasal anaesthesia on lacrimal function after nasal allergen challenge

Ocular symptoms in allergic rhinoconjunctivitis arise partly from direct contact of the allergen with the conjunctiva and presumably partly from a naso-lacrimal reflex. The aim was to study the importance of this reflex in allergic rhinitis after topical anaesthesia of the nose. Ten patients with allergic rhinoconjunctivitis lo birch pollen were challenged with increasing intranasal doses of allergen until allergic symptoms occurred. The same dose of allergen was used in two other provocations, when the nasal cavity was anaesthetized with topical lidocaine in a double-blind rundomized cross-over manner. The effect on the eyes was evaluated by Shirmer's test, a routine method for measuring tear production. Lidocaine per se and/or allergen challenge had no significant effect on tear production. The naso-lacrimal reflex was not involved in the eye symptoms, in allergic conjunctivitis.     

Richter's syndrome with different immunoglobulin light chains and different heavy chain gene rearrangements

In a patient with Richter's syndrome, the chronic lymphocytic leukemia (CLL) expressed lambda, mu, and delta immunoglobulin (lg) chains and the non-Hodgkin lymphoma (NHL) kappa, mu, and delta lg chains. The difference in lg light chain expression suggests that the CLL and NHL are independent malignancies, or that the oncogenic event occurred in a B cell differentiation stage after the heavy chain gene rearrangements but before the selection of the light chain. Analysis of DNA by Southern blotting revealed that the lg heavy chain genes of the two malignancies were rearranged in a different way. We therefore conclude that in this patient the NHL cannot be regarded as a progression of the CLL but should most likely be considered as an independent B cell malignancy, which arose in a susceptible host.     

Two cases of long lasting bacteremia due to Mycobacterium avium complex despite new macrolides-containing regimens in patients with acquired immunodeficiency syndrome

The prognosis of Mycobacterium avium complex (MAC) infection has been improved by new macrolides-containing regimens and the use of highly active antiretroviral therapy (HAART) in the treatment of acquired immunodeficiency syndrome (AIDS). We report on two AIDS cases with long lasting bacteremia due to MAC under this regimen. Both patients experienced problems due to side effects from the anti-MAC regimen and from an immune-reconstitution syndrome related to HAART. MAC infection persisted despite treatment, however, no anti-MAC drug-resistant isolates emerged throughout the clinical course in either case. These cases demonstrate that therapy for disseminated MAC infection is sometimes difficult even with HAART and macrolides-containing regimens.     

A case of thoracolithiasis diagnosed thoracoscopically

INTRODUCTIONThoracolithiasis is quite rare with only 18 cases reported in the literature.PRESENTATION OF CASEThe 65-year-old female was referred to us for the abnormality on the chest X-ray. The serial computed tomographic (CT) scans showed a mobile calcified nodule of about 10 mm in diameter. Exploratory thoracoscopy was performed. A 15 mm pearl-like pleural stone was removed with uneventful postoperative course.DISCUSSIONThoracolithiasis is very rare, and its etiology as well as its epidemiology still remains to be unclear. Preoperative diagnosis is always difficult. However, specific radiological findings could let us recognize the probability of that lesion and avoid unnecessary major operation.CONCLUSIONThoracolithiasis should never be overlooked as a differential diagnosis in a pulmonary calcified nodule.