Colonic microbiota can promote rapid local improvement of murine colitis by thioguanine independently of T lymphocytes and host metabolism.

OBJECTIVE: Mercaptopurine (MP) and pro-drug azathioprine are 'first-line' oral therapies for maintaining remission in IBD. It is believed that their pharmacodynamic action is due to a slow cumulative decrease in activated lymphocytes homing to inflamed gut. We examined the role of host metabolism, lymphocytes and microbiome for the amelioration of colitis by the related thioguanine (TG). DESIGN: C57Bl/6 mice with or without specific genes altered to elucidate mechanisms responsible for TG's actions were treated daily with oral or intrarectal TG, MP or water. Disease activity was scored daily. At sacrifice, colonic histology, cytokine message, caecal luminal and mucosal microbiomes were analysed. RESULTS: Oral and intrarectal TG but not MP rapidly ameliorated spontaneous chronic colitis in Winnie mice (point mutation in Muc2 secretory mucin). TG ameliorated dextran sodium sulfate-induced chronic colitis in wild-type (WT) mice and in mice lacking T and B lymphocytes. Remarkably, colitis improved without immunosuppressive effects in the absence of host hypoxanthine (guanine) phosphoribosyltransferase (Hprt)-mediated conversion of TG to active drug, the thioguanine nucleotides (TGN). Colonic bacteria converted TG and less so MP to TGN, consistent with intestinal bacterial conversion of TG to so reduce inflammation in the mice lacking host Hprt. TG rapidly induced autophagic flux in epithelial, macrophage and WT but not Hprt-/- fibroblast cell lines and augmented epithelial intracellular bacterial killing. CONCLUSIONS: Treatment by TG is not necessarily dependent on the adaptive immune system. TG is a more efficacious treatment than MP in Winnie spontaneous colitis. Rapid local bacterial conversion of TG correlated with decreased intestinal inflammation and immune activation.

Isolated tuberculous tenosynovitis of the forearm in an immunocompetent patient.

Primary tuberculous tenosynovitis is a rare manifestation of extraspinal musculoskeletal tuberculosis. The diagnosis may be easily delayed because of its nonspecific clinical signs. We report a case of culture-proven tuberculous tenosynovitis of the extensor carpi ulnaris tendon and common extensor tendon in a 68-year-old female without concomitant pulmonary tuberculosis, nor documented immunodeficiency. The diagnosis was initially overlooked due to the lack of appropriate histological and bacteriological analyses and the lesion recurred after surgery. MR imaging represents the most accurate method in making the diagnosis, but has no diagnostic specificity in regard to tuberculosis, therefore surgical biopsy is strongly recommended. The patient had a favorable clinical response after a combination of excision and appropriate antituberculous therapy for sensitive Mycobacterium tuberculosis. We emphasize the need for an increased awareness and high index of suspicion of tuberculosis in all cases of a chronic orrecurrent abscess in the extremities, not only in patients living in endemic areas but also in those who have emigrated from regions with a high prevalence of tuberculosis.

A follow-up study of immunotherapy-treated birch-allergic patients: effect on the expression of chemokines in the nasal mucosa.

BACKGROUND: Specific immunotherapy (SIT) is the only treatment producing lasting clinical improvement in patients with allergy. We investigated the long-term effect of SIT treatment on the expression of chemokines: eotaxin, RANTES (regulated upon activation, normal T cell expressed and secreted) and thymus and activation-regulated chemokine (TARC), and their receptors CCR3 and CCR4 in biopsies of nasal mucosa from birch-allergic individuals. METHODS: Sixteen patients who completed a 3-year treatment programme 3-5 years ago, and 12 untreated, matched controls were included in the study. Patients recorded symptoms and use of rescue medication before and during the pollen season. Nasal mucosa samples obtained before and during the season were stained for eosinophil and mast cell markers and for eotaxin, RANTES, TARC, CCR3 and CCR4. RESULTS: During the pollen season, rhinoconjunctivitis symptoms increased in both SIT and control groups (P=0.001 and 0.002, respectively). However, SIT patients had 37% fewer symptoms than controls. Medication use increased in both groups (P=0.002) during the season but the SIT group used 28% less than the controls (P=0.02). The number of eosinophils in the nasal mucosa increased in the control group (P=0.01) and the difference between the groups was significant during the season (P=0.01). No seasonal increase in the numbers of mast cells was seen, but during the pollen season, more (P=0.02) AA(+) cells were found in the controls than in the SIT group. The number of eotaxin(+) and RANTES(+) cells increased in the control group (P=0.01 and 0.03, respectively) and the difference between groups during the season was significant (P=0.01 and 0.01, respectively). The TARC(+) cell numbers were lower in the SIT group during the season (P=0.003). The CCR3(+) cells increased only in the control group during the pollen season and remained unchanged in SIT patients, while CCR4(+) cell numbers increased in both the control (P=0.03) and SIT (P=0.02) groups. CONCLUSION: This study confirmed that decreased numbers of eosinophils in the nasal mucosa is a long-lasting effect of birch SIT. SIT also prevented seasonal rises in the number of cells expressing the chemokines eotaxin and RANTES.

MUC13 protects colorectal cancer cells from death by activating the NF-κB pathway and is a potential therapeutic target.

MUC13 is a transmembrane mucin glycoprotein that is over produced by many cancers, although its functions are not fully understood. Nuclear factor-κB (NF-κB) is a key transcription factor promoting cancer cell survival, but therapeutically targeting this pathway has proved difficult because NF-κB has pleiotropic functions. Here, we report that MUC13 prevents colorectal cancer cell death by promoting two distinct pathways of NF-kB activation, consequently upregulating BCL-XL. MUC13 promoted tumor necrosis factor (TNF)-induced NF-κB activation by interacting with TNFR1 and the E3 ligase, cIAP1, to increase ubiquitination of RIPK1. MUC13 also promoted genotoxin-induced NF-κB activation by increasing phosphorylation of ATM and SUMOylation of NF-κB essential modulator. Moreover, elevated expression of cytoplasmic MUC13 and NF-κB correlated with colorectal cancer progression and metastases. Our demonstration that MUC13 enhances NF-κB signaling in response to both TNF and DNA-damaging agents provides a new molecular target for specific inhibition of NF-κB activation. As proof of principle, silencing MUC13 sensitized colorectal cancer cells to killing by cytotoxic drugs and inflammatory signals and abolished chemotherapy-induced enrichment of CD133+ CD44+ cancer stem cells, slowed xenograft growth in mice, and synergized with 5-fluourouracil to induce tumor regression. Therefore, these data indicate that combining chemotherapy and MUC13 antagonism could improve the treatment of metastatic cancers.

[The serology of toxoplasmosis in uveitis]. / Aspecte ale serologiei toxoplasmozei în uveite.

Determinations for decelerating the antitoxoplasma anticorps that have been effectuated for 696 uveas proved positivity at 123 aerums (17.6%). The repartition of the positive serology concerning the clinic form of the uvea has proved 48 iridocyclitis, 26 serous central corioretinals, 23 in panuveitis, 13 in posterior uveitis, 11 muscular chorioretinitis, 2 in hyalitis. Taking into consideration only the equal or less than 1:160 titrures, these have been at 7 iridocyclitis, 4 serous central chorioretinitis, 4 panuveitis, 3 posterior uveitis and 3 atrophic central chorioretinitis. It is shown that the diagnosis of ocular toxoplasma must be effectuated just corroborating the clinic data with the positive serology. The antiparasitic treatment doesn't influence upon the low titrures of serous anticorps, which generally maintain at the same value all the life.

An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity.

We recently characterized Winnie mice carrying a missense mutation in Muc2, leading to severe endoplasmic reticulum stress in intestinal goblet cells and spontaneous colitis. In this study, we characterized the immune responses due to this intestinal epithelial dysfunction. In Winnie, there was a fourfold increase in activated dendritic cells (DCs; CD11c(+) major histocompatibility complex (MHC) class II(hi)) in the colonic lamina propria accompanied by decreased colonic secretion of an inhibitor of DC activation, thymic stromal lymphopoietin (TSLP). Winnie also displayed a significant increase in mRNA expression of the mucosal T(H)17 signature genes Il17a, IL17f, Tgfb, and Ccr6, particularly in the distal colon. Winnie mesenteric lymph node leukocytes secreted multiple T(H)1, T(H)2, and T(H)17 cytokines on activation, with a large increase in interleukin-17A (IL-17A) progressively with age. A major source of mucosal IL-17A in Winnie was CD4(+) T lymphocytes. Loss of T and B lymphocytes in Rag1(-/-) × Winnie (RaW) crosses did not prevent spontaneous inflammation but did prevent progression with age in the colon but not the cecum. Adoptive transfer of naive T cells into RaW mice caused more rapid and severe colitis than in Rag1(-/-), indicating that the epithelial defect results in an intestinal microenvironment conducive to T-cell activation. Thus, the Winnie primary epithelial defect results in complex multicytokine-mediated colitis involving both innate and adaptive immune components with a prominent IL-23/T(H)17 response, similar to that of human ulcerative colitis.

Diagnosis Performance of Different MR Imaging Signs of Cirrhosis: the Caudate to Right Lobe Ratio, the Posterior Right Hepatic Notch, and the Expanded Gallbladder Fossa.

Background & Aims The purpose of the study is to evaluate the accuracy of the C/RL, RPN, and EGF in diagnosing cirrhosis. Methods The study population included 95 cirrhotic patients in the cirrhosis group (56 men, 39 women, age range 14-76;mean age 52.3) and 57 subjects in the control group (26 men, 31 women, age range 18-83;mean age 51). All MR examinations were performed by using the same protocol. Two radiologists independently assessed data sets in two different reading sessions. The sensitivity, specificity, and accuracy and the relative risk of the signs in diagnosing cirrhosis were calculated. The diagnosis accuracy of the C/RL sign was calculated using the ROC curve. The statistical significance of any difference of each sign between different classes of cirrhosis was also calculated. Results The interobserver agreement between the readers was excellent (κ≥ 0.81;95% CI:0.92, 1.0). There was a significant statistical difference of the diagnostic value of C/RL, RPN, and EGF between cirrhotic patients and control group (p<0.001). The sensitivity, specificity, and accuracy of C/RL were 72%, 87%, and 78%; 67%, 87%, and 75% for RPN; and 49%, 91%, and 65% for EGF. C/RL (OR=18.95) and RPN (OR=14.74) showed a higher risk for cirrhosis compared to EGF (OR=14.74). There was a statistical significance difference between C/RL and EGF (p=0.002) and between RPN and EGF for Child A class of cirrhosis (p-0.037). Conclusion The C/RL and RPN have similar performance regarding the diagnosis of cirrhosis having a higher diagnostic performance compared to EGF in cirrhosis.

Increased expression of lipoxygenase enzymes during pollen season in nasal biopsies of pollen-allergic patients.

BACKGROUND: Exposure of patients sensitized to pollen triggers development of seasonal allergic rhinitis symptoms (SAR). Eicosanoids are a group of arachidonic acid metabolites contributing to the symptoms of SAR. The aim of this study was to investigate seasonal changes in the expression of enzymes of the eicosanoid pathway in the nasal mucosa of patients with SAR. METHODS: Twenty SAR patients allergic to birch or grass and eight healthy subjects were included in the study. Patients registered rhinoconjunctivitis symptoms and use of rescue medication before and during the pollen season. Nasal biopsies were obtained before and around the peak of the season, sectioned and stained using markers for eosinophils, mast cells, T cells and neutrophils. Antibodies against the following enzymes were also used: cyclo-oxygenase (COX-1, COX-2), 5-lipoxygenase (5-LO), 5-lipoxygenase-activating factor (FLAP), LTA4 hydrolase (LTA4h) and LTC4 synthase (LTC4s). RESULTS: During the pollen season symptoms of rhinoconjunctivitis and medication score increased significantly (P=0.001; P=0.001 respectively). During the pollen season numbers of eosinophils (P=0.02) and cell positive 5-LO (P=0.02), LTC4s (P=0.04) and LTA4h (P=0.02) increased significantly. During season number of mast cells and cells expressing 5-LO and LTA4h were higher in SAR than in healthy controls group (P=0.02; P=0.01; P=0.03 respectively). CONCLUSION: In sensitized patients exposure to pollen allergen results in increased expression of enzymes of the eicosanoid pathway.

[The immediate effect of beta-isoket on the internal ocular pressure in patients with chronic simple glaucoma (author's transl)]. / Wirkung von Oxycardin im Akutversuch auf den Augeninnendruck von Patienten mit chronischem Glaucoma simplex

In 27 patients with non-compensated or medically compensated chronic simple glaucoma, the I.O.P. was measured after the administration of two tablets of beta-isoket (which contain 5 mg isosorbiddinitrate and 40 mg bupranolol). In none of the 54 eyes was the I.O.P. higher after administration of the drug. On the contrary, the I.O.P. was siginificantly or highly significantly reduced for more than 2 hours, probably because of the beta-receptor-blocking component of the preparation.

[Lowering of intraocular pressure by aqueous solution of bupranolol in chronic uncomplicated glaucoma simplex (author's transl)]. / Uber die Drucksenkung mit Bupranolol in wässriger Lösung beim chronischen Glaucoma simplex.

In two previous studies the effects of topically applied 1% and 0.2% solutions of bupranolol on intraocular pressure were investigated in 21 and respectively 20 eyes with chronic uncomplicated open-angle glaucoma.--As early as 30 minutes after both solutions a very significant pressure drop, without concomittant pupillary reaction, was recorded. The 1% bupranolol solution was less well tolerated and caused some ocular irritation. The present study was therefore initiated in order to find out whether a 0.2% solution of bupranolol would yield significantly different results in comparison with the former.--Statistical evaluation, based on variance analysis linked with multiple t-tests, showed a barely significant difference between the pressure-lowering effects of the 1% and 0.2% solutions after one hour, whereas after 2 hours the difference became clearly significant in favour of the 0.2% solution. Furthermore, the 0.2% solution clearly showed a tendency to prolonged duration of effect, beyond the two-hour observation time. It therefore seems justified to supplement the present findings by long-term studies aimed at assessing optimal concentrations of the drug on the one hand, and its long-acting properties on the other. In this way, bupranolol is likely to gain recognition as an antiglaucomatous agent.

[The use of piroxicam in the treatment of inflammatory diseases of the eyeball]. / Asocierea piroxicamului la tratamentul afectiunilor inflamatorii ale globului ocular.

The action of phyroxicam was studied in the treatment of inflammatory affections of the eye globe. Pyroxicam proved to be an efficient nonsteroid anti-inflammatory drug in the treatment of iridocyclitis, keratoiridocyclitis, uveitis etc.

[Effectiveness of transcutaneous levator resection in congenital ptosis of the upper lid]. / Die Wirksamkeit der transkutanen Levatorresektion bei der kongenitalen Ptosis des Oberlides.

Thirteen patients (15 eyes) were treated for simple congenital blepharoptosis by means of transcutaneous levator resection. The patients' ages ranged from 6 to 23 years, the postoperative follow-up period from 29 to 63 months. In 2 cases the operation was performed because of residual ptosis following transconjunctival levator resection. In 11 eyes the results were very good, with postoperative ptosis of between 0 and +/- 0.5 mm and complete lid closure. In 3 eyes the results were good, with ptosis between greater than + 0.5 mm and + 1.5 mm and complete lid closure; and there was one failure, with postsurgical ptosis of greater than + 1.5 mm. The major cosmetic defect in all cases was lid lag on extreme downward gaze. In view of these good results and the multiple advantages of the anterior transcutaneous levator resection procedure as compared to the posterior (conjunctival) approach, the authors feel able to claim that transcutaneous levator resection is the method of choice for most types of simple ptosis. The operation is extremely laborious but fully justified by the good results.

[The possibilities for early diagnosis in primary open-angle glaucoma]. / Posibilitati de diagnostic precoce in glaucomul primar cu unghi deschis.

The study was carried out on a group of 127 patients, admitted into the Cluj-Napoca Clinic of Ophthalmology, suspected of primary glaucoma with open angle. The complex antiglaucomatous investigation confirmed the diagnosis in 57 cases.

The effect of specific immunotherapy on the expression of costimulatory molecules in late phase reaction of the skin in allergic patients.

BACKGROUND: Specific immunotherapy (SIT) modulates immune responses to allergens resulting in improvement of allergic symptoms. However, the mechanisms behind the clinical changes are not clear. Participation of costimulatory molecules on antigen-presenting cells and T cells in the process of antigen recognition is suggested to be of essential importance. The SIT effect on expression of costimulatory molecules has not been earlier examined. METHODS: Forty-one birch-allergic patients were treated with SIT or placebo. After 1 year of treatment skin biopsies were obtained 24 h following allergen challenge. Sections were stained with antibodies against: EG2 (eosinophils), CD4 (T cells), CD68 (macrophages), CD1a (Langerhans cells), CD28 (on T cells) and costimulatory molecules (CD80, CD86). RESULTS: Following allergen challenge number of the CD4(+) and CD68(+) cells increased significantly (P=0.002, 0.0001, respectively) in the placebo, but not in the SIT-treated patients. The difference between groups was significant (P=0.003, 0.01, respectively). The numbers of EG2(+) cells increased significantly in both groups. CD80(+) cell numbers increased in the placebo (P=0.01) but not in the SIT group. The number of CD86(+) cells increased in both groups (placebo, P=0.001; SIT, P=0.01) but significantly less in the SIT group (P=0.05). The numbers of CD28(+) cells increased in the placebo (P=0.001) but remained unchanged in the SIT group. The difference between the groups was significant (P=0.05). CONCLUSION: There were lower numbers of cells expressing costimulatory molecules in SIT-treated than in placebo-treated patients. Decreased costimulation may lead to diminished immune response following allergen exposure. This could be an important factor contributing to the clinical improvement after SIT.