IL-10 has a protective role in experimental autoimmune uveoretinitis

The role of IL-10 in the regulation of ocular autoimmune disease was studied in experimental autoimmune uveoretinitis (EAU) elicited in mice by immunization with the retinal antigen interphotoreceptor retinoid binding protein. IL-10-deficient mice were susceptible to EAU, indicating that pathogenesis can occur without presence of IL-10. Treatment of normal mice with IL-10 for 5 days after uveitogenic immunization ameliorated subsequent EAU scores, and down-regulated antigen-specific production of tumor necrosis factor-alpha and IFN- gamma. A concomitant treatment with IL-4 further reduced disease, and resulted in emergence of antigen-specific IL-4 and IL-10 production, as well as in enhancement of the IgG1 antibody isotype. IL-4 by itself was not protective. Only IL-10, but not IL-4, was able to inhibit the function of differentiated uveitogenic T cells in culture. Expression of mRNA for Th1 and Th2 cytokines in the eye during the course of EAU showed that while a Th1 pattern predominated early, IL-10 mRNA expression coincided with down-regulation of the Th1 response and resolution of EAU. Systemic neutralization of IL-10 during the expression phase of EAU resulted in elevated disease scores. Our results suggest that endogenous IL-10 limits expression of EAU and may play a role in the natural resolution of disease. The data further suggest that exogenous IL-10 may be useful in therapeutic control of autoimmune uveitis. While IL-10 by itself is sufficient to suppress Th1 effector development and function, a concomitant administration of IL-4 is required to shift the autoimmune response towards a non-pathogenic Th2 pathway.      

De novo 16p13.11 microdeletion identified by high-resolution array CGH in a fetus with increased nuchal translucency

Objective  We investigated the application of high-resolution microarray-based comparative genomic hybridisation (array CGH) on a fetus showing increased nuchal translucency (NT).
Design  Case study.
Setting  Tertiary referral obstetrics unit.
Sample  Pregnant woman attended the antenatal clinic.
Methods  Conventional karyotyping and genetic test was carried out for the alpha-globin gene. High-resolution array CGH using the high-density 244K Agilent microarray was performed on fetal blood sample by cordocentesis to investigate the possibility of any genomic imbalance.
Main outcome measures  Detection of chromosomal abnormality.
Results  Karyotyping analysis showed 46,XY. Molecular genetic diagnosis confirms the fetus has Hb-H constant spring disease but cannot explain the increased NT to 3.2 mm. Array CGH analysis discovered a 1.32-Mb microdeletion on chromosome 16p13.11. Deletion at 16p13.11 has been implicated to predispose to autism and/or mental retardation. Baby was delivered at 40 weeks of gestation, and follow up was carried out at 3 months of age without sign of mental retardation/developmental delay.
Conclusions  This case study demonstrated that array CGH can accurately calibrate the size and identify de novo interstitial chromosome imbalances. However, the presence of chromosome copy variants with unknown clinical significance currently limits its wider scale application in prenatal diagnosis and needs further investigations.     

Treatment related deaths during induction and in first remission in acute lymphoblastic leukaemia: MRC UKALL X

The benefits of achieving a long term event free survival of 60-70% by using increasingly intense treatment regimens must be weighed against the increased risk of treatment toxicity. From 1985 to 1990, 1612 children with childhood acute lymphoblastic leukaemia (ALL) in the UK were treated on MRC UKALL X with intensive induction therapy, central nervous system directed therapy (cranial irradiation and intrathecal methotrexate), and continuing treatment for two years. There was a randomisation to receive blocks of additional intensification treatment at five weeks, 20 weeks, not at all, or both. The five year disease free survival was 71% for children randomised to two blocks of intensification, a 14% improvement on children randomised to no intensification treatment. Treatment related mortality in this national multicentre study has been analysed for induction and first remission (including those after intensification treatment). There were 38 induction deaths, 2.3% and 53 deaths in first remission, 3.3% (including those from a second malignancy). Thirty one (84%) of the induction deaths followed an infection: bacterial in 22 and fungal in nine. Thirty seven infective remission deaths occurred: bacterial in 11, viral in 16, fungal in seven, and three caused by Pneumocystis carinii pneumonia. Ten of these deaths followed a block of intensification treatment. The majority of noninfective remission deaths followed the development of a second tumour. Risk analysis for an induction death showed girls and children with Down's syndrome to be at greater risk. For deaths in first remission analysis showed an increased risk for bone marrow transplant (BMT) patients and children with Down's syndrome. There was no effect of age and leucocyte count for either group. Most significantly when BMT patients were excluded from the analysis, intensification treatment did not increase the risk of remission death.     

Selenium status of New Zealand infants fed either a selenium supplemented or a standard formula

Objective: New Zealand soils are deficient in the essential micronutrient, selenium. New Zealand infants have low selenium levels at birth and experience a further decline if fed cows milk based formula. This study examined the selenium status of infants fed with a new commercially available selenium supplemented formula.
Methodology Forty-four newborn infants, whose mothers wished to formula feed, were randomized in an open controlled trial to be fed a commercially available selenium supplemented cows milk formula (containing 17 μg Se/L) or an unsupplemented formula (containing 4.6 μg Se/L). Cord, 1 and 3 month blood samples were obtained for selenium status (plasma and red cell selenium and glutathione peroxidase) and thyroid function.
Results Mean plasma selenium and glutathione peroxidase values were significantly higher in supplemented than unsupplemented infants at 1 month (unpaired t -tests; P <0.0001 and P = 0.001 respectively) and 3 months ( P <0.0001 and P = 0.0005). Analysis within treatment groups between time points (paired t -tests) showed that selenium supplementation prevented the fall in plasma selenium from birth to 1 month seen in unsupplemented infants and was associated with a rise in levels between 1 and 3 months ( P = 0.002).
Conclusions Supplementing cows milk formula with selenium to replicate the levels found in breast milk is nutritionally sound. Feeding from a few days of age with a formula containing 17 μg Se/L in infants with low selenium status at birth is sufficient to cause a rise to 80% of adult levels at 3 months of age.     

Langerhans' cell histiocytosis with thyroid involvement masquerading as thyroid carcinoma

A 28-year-old woman was admitted to our Hospital with a chief complaint of progressive gingival swelling and loosening of teeth over about a year. According to past history, she had received total thyroidectomy 2 years previously due to thyromegaly. The thyroidectomy specimen was at first interpreted as 'poorly differentiated carcinoma of the thyroid'. One year ago, she began to be aware of gingival swelling and loosening of teeth. A gum biopsy was taken and the pathologic features were similar to her 'thyroid carcinoma'. Subsequent investigations, including immunohistochemical stain, showed the gum was heavily infiltrated with histiocyte-like Langerhans' cells which were positive for S-100 protein. Ultrastructural examination of the cells under electron microscope revealed many typical intra-cytoplasmic Birbeck granules. Langerhans' cell histiocytosis was diagnosed. Langerhans' cell histiocytosis with thyroid involvement is extremely rare and may run a relatively indolent course. Even on a retrospective examination, it may easily be confused with poorly differentiated carcinoma of the thyroid. We suspect that this error may have been made on other occasions and that the occurrence of this condition may be underreported.      

Analyses of mutation and loss of heterozygosity of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human gastric cancer

Mutations in the transforming growth factor beta type II receptor (TGFbetaRII) gene have been detected in several human cancer types exhibiting microsatellite instability. Using intron primers previously reported for examination of the entire coding region of the TGFbetaRII gene, 29 sporadic gastric cancers were screened with non-radioactive single strand conformation polymorphism and subsequent DNA sequencing analysis. Mutations of the TGFbetaRII gene were detected in three out of 29 tumors (10%). Two cases showed deletions in a polyadenine tract in both alleles and was positively associated with replication error. One case had an insertion of GA dinucleotide sequence in one allele. Mutations of the TGFbetaRII gene were restricted to exon 3 and other coding regions were not affected. Loss of heterozygosity was detected by analyzing a polymorphic site in intron 2. Three out of nine (33%) informative cases, which were all of intestinal type and advanced cases, showed loss of heterozygosity but neither TGFbetaRII mutation nor replication error was found in these cases. Immunoreactivity of TGFbetaRII in tumor tissues was reduced to a different extent in the gastric cancer with genetically abnormal transforming growth factor. Although the numbers studied are small, homozygous (A)10 deletion or loss of heterozygosity of TGFbetaRII is involved in tumorigenesis and progression of at least some part of sporadic gastric cancer.      

Possible relationship between degenerative cardiac valvular pathology and lyme disease

We report an unusual clinical presentation of Lyme carditis in a previously healthy 20-year-old black woman without any epidemiologic history of Lyme disease, fulminant in nature, involving a heart valve necessitating emergent mitral valve replacement, and requiring further surgical intervention because of the development of pericardial effusion and tamponade. A dilated right ventricle with normal contractility and severe tricuspid regurgitation with increase in the right atrial size diagnosed later remains under close surveillance.     

Neurogenic vasoreactivity of human internal thoracic artery is unaffected by endothelial cell integrity

BACKGROUND: The role of internal thoracic artery (ITA) nervous supply has not been previously considered as a potential factor influencing excellent long-term patency of an ITA graft. To define the interaction between the primary afferent neurons and endothelial cells of ITA, we investigated the effects of acute capsaicin administration in vitro on the isometric tension of human ITAs. METHODS: Vessels were obtained from patients undergoing coronary bypass or from multi-organ transplant donors. Thirty-three ITA segments (5 mm wide) were suspended as rings between two stainless-steel stir-ups in water-jacketed (37 degrees C) tissue baths. The tissue baths contained 10 ml physiological salt solution (PSS) of the following composition (mM/L): NaCl 119, KCl 4.7, NaH2PO4 1.0, MgCl2 0.5, CaCl2 2.5, NaHCO3 25, and glucose 11, aerated continuously with 95% O2 and 5% CO2. Peptidase inhibitors, phosphoramidon (1 microM) and captopril (1 microM), were added to PSS to decrease peptide degradation. Mechanical responses were measured isometrically and recorded on a polygraph via isometric force transducers. Vessels were preconstricted with submaximal concentrations of norepinephrine. After the tension had stabilized, capsaicin was added cumulatively to the tissue bath. The viability of ITA was verified by its responses to endothelial-dependent (acetylcholine, 1 microM) (n=20) and endothelial-independent (sodium nitroprusside, 10 microM) (n=13) vasodilators. RESULTS: The exposure of capsaicin (3 microM) to human ITA produced varied effects on ITA irrespective of its endothelium. Capsaicin induced contraction of the ITA smooth muscle in 13 endothelium-intact ITA segments while it produced vasoconstriction in 9 endothelium-denuded ITAs (p=0.6437). In response to capsaicin, relaxation of ITA smooth muscle was observed in 7 ITA rings with endothelium, while vasodilation was present in 4 ITA segments without endothelium (p=0.4099). CONCLUSIONS: Capsaicin-sensitive neurons encircling human ITA produce a neurogenic vasoreactive response independent of ITA endothelial cell integrity.