The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry

Susceptibility to autoimmune insulin-dependent (type 1) diabetes mellitus is determined by a combination of environmental and genetic factors, which include variation in MHC genes on chromosome 6p21 (IDDM1) and the insulin gene on chromosome 11p15 (IDDM2). However, linkage to IDDM1 and IDDM2 cannot explain the clustering of type 1 diabetes in families, and a role for other genes is inferred. In the present report we describe linkage and association of type 1 diabetes to the CTLA-4 gene (cytotoxic T lymphocyte associated-4) on chromosome 2q33 (designated IDDM12). CTLA-4 is a strong candidate gene for T cell- mediated autoimmune disease because it encodes a T cell receptor that mediates T cell apoptosis and is a vital negative regulator of T cell activation. In addition, we provide supporting evidence that CTLA-4 is associated with susceptibility to Graves' disease, another organ- specific autoimmune disease.      

Effect of IgA on respiratory burst and cytokine release by human alveolar macrophages: role of ERK1/2 mitogen-activated protein kinases and NF-kappaB

Human alveolar macrophages (HAM) express FcalphaR receptors for immunoglobulin (Ig)A which could link humoral and cellular branches of lung immunity. Here, we investigate the effects of polymeric (p-IgA) and secretory (S-IgA) IgA interaction with Fc(alpha)R on lipopolysaccharide (LPS)- and phorbol myristate acetate (PMA)-activated respiratory burst and TNF-alpha release by HAM. Activation of HAM with LPS and PMA increases the respiratory burst and TNF-alpha release through activation of the extracellular signal-related protein kinases 1 and 2 (ERK1/2) pathway, because these effects are inhibited by treatment of HAM with PD98059, a selective inhibitor of mitogen-activated protein (MAP)/ERK kinases (MEK) pathway. S-IgA and p-IgA downregulate the LPS-increased respiratory burst in HAM through an inhibition of ERK1/2 activity. In contrast, p- and S-IgA induce an increase in the respiratory burst of PMA-treated HAM. This effect is associated with an upregulation by IgA of the PMA-induced phosphorylation of ERK1/2 and is also inhibited by PD98059. Moreover, p-IgA and S-IgA enhance TNF-alpha release by HAM through an alternative pathway distinct from ERK1/2. Because LPS is known to activate nuclear factor-kappaB (NF-kappaB) in HAM, we evaluate the effect of IgA on NF-kappaB. Treatment of HAM with LPS, p- and S-IgA, but not PMA, induces NF-kappaB activation through IkappaBalpha phosphorylation and subsequent proteolysis. Antioxidants, namely N-acetylcysteine (NAC) and glutathione (GSH), have no effects on IgA-mediated NF-kappaB nuclear translocation and only a minor and late effect on that of LPS, suggesting that reactive oxygen intermediates (ROI) play a minor role in HAM activation through NF-kappaB. TNF-alpha release by LPS-activated HAM is sensitive to NF-kappaB inhibition and only partly to oxidant scavenging. In contrast, TNF-alpha release by IgA-treated HAM is not dependent on oxidants and only partly dependent on NF-kappaB. Our results show a differential HAM regulation by IgA through both dependent and independent modulation of ERK pathway. In addition, IgA activates NF-kappaB and this effect was independent on oxidants. These data may help to understand the role of IgA in both lung protection and inflammation.     

Heterotopic Ossification Negatively Influences Range of Motion After Revision Total Knee Arthroplasty

BackgroundThe incidence of heterotopic ossification (HO) after total knee arthroplasty (TKA) varies and is of unclear clinical significance. This study aimed to identify the incidence of HO in patients undergoing revision TKA for either stiffness or aseptic loosening/instability and determine if the presence of HO is associated with inferior absolute range of motion (ROM) and ROM gains.MethodsEighty-seven patients were prospectively enrolled and separated into 2 cohorts to evaluate ROM after revision TKA (2017-2019). Group 1 (N = 40) patients were revised for stiffness, while group 2 (N = 47) patients were revised for either aseptic loosening or instability. Goniometer-measured ROM values were obtained preoperatively and at 6 weeks, 6 months, and 1 year postoperatively. Statistical analysis included a Fisher’s exact test to assess for an association between preoperative HO and final ROM at 1 year after revision TKA.ResultsHO was identified on preoperative radiographs in 17 patients (20%). There was a significantly higher rate of preoperative HO in patients revised for stiffness compared to patients revised for instability or loosening (30% vs 11%; P = .03). Five cases of HO qualitatively identified as most clinically severe were associated with lower ROM at each time point compared to the remainder of HO cases in this study cohort (P < .02).ConclusionThe presence of HO is greater in patients undergoing revision TKA for stiffness. Additionally, HO severity appears to have a major effect on preoperative and postoperative ROM trajectory. This information should help guide patient expectations and highlight the need for a comprehensive, standardized classification system for HO.     

Selective transperineal prostate biopsy for fluoroquinolone-resistance patients reduces sepsis and cost

Background:Urosepsis is a recognized complication of transrectal ultrasound-guided prostate biopsy (TRUS-Bx). Pre-biopsy rectal swabs have been used to identify patients with microorganisms in the rectal flora resistant to the conventionally used empirical prophylaxis. The transperineal route of biopsy (TP-Bx) has a lower complication risk but comes at an increased cost.Materials and methods:Retrospective cohort study including patients undergoing prostate biopsies between October/2015 and April/2018. The intervention cohort, a rectal swab was performed, the result of which dictated the biopsy route; TRUS-Bx against TP-Bx. TP-Bx for patients with fluoroquinolone resistance or extended-spectrum β-lactamase. The control cohort underwent TRUS without a rectal swab receiving empirical antibiotics—oral ciprofloxacin and intravenous gentamicin.Results:Total 1000 patients were included in which 500 underwent a swab, 14 (2.8%) developed post-TRUS biopsy infective complications with 3 having positive bacteremia (0.6%); 500 had no swab, 47 (9.4%) developed post-TRUS biopsy infective complications with 22 (4.4%, p < 0.05) having positive bacteremia. Three patients (0.6%) of patients who underwent swab developed urinary tract infection symptoms whilst 12 (2.4%) had urinary tract infection in the control group. In those patients that underwent a swab, 14 required hospitalization with mean length of stay of 2.5 days versus 43 patients of the control with 3.6 days. Cost analysis concluded savings of this strategy was £18,711.Conclusions:We have demonstrated a protocol that reserves template biopsies for higher risk patients and can significantly reduce sepsis and other infectious complication rates whilst also proving to be a cost-efficient strategy. We recommend that units not utilizing rectal swabs to uncover the fluoroquinolone resistance rate by introducing them. We advocate units that already utilize rectal swabs, to introduce transperineal biopsy for their higher risk patients.     

Comparative translocation of enteropathogenic Campylobacter spp. and Escherichia coli from the intestinal tract of gnotobiotic mice.

In C3H gnotobiotic mice, no significant difference was observed between the translocation of nine clinical isolates of enteropathogenic Campylobacter spp. and that of seven nonisogeneic Escherichia coli strains with or without various determinants of pathogenicity. In addition, there was no correlation found between the intensity of translocation of Campylobacter strains and the signs of invasiveness in the patients from whom the strains had been isolated.     

Malignant thymoma in children: a 20-year review

Malignant thymomas are extremely rare in children, with only 27 cases reported thus far in the pediatric surgical literature. We report four additional cases diagnosed at this institution over the past 20 years (ages 3 to 14 years). Clinical presentations included superior vena cava syndrome, cough, dyspnea, cyanosis, enlarging mediastinal mass, spontaneous pneumothorax, and pleuropericardial effusion. Three patients underwent incomplete resection of the mass or biopsy because of "unresectability" and were treated with radiotherapy and adjunctive chemotherapy. One patient underwent near complete macroscopic resection as well as radiotherapy and chemotherapy. All patients died at intervals ranging from 6 months to 2 1/2 years after diagnosis. Three patients were found to have metastatic disease prior to death or at autopsy. In one case, the initial pathological diagnosis was lymphocytic thymoma. After ultrastructural studies were performed, the diagnosis was changed to thymic T-cell lymphoma. This patient subsequently developed acute lymphoblastic leukemia 3 months after surgical resection followed by radiotherapy. Malignant thymomas are highly aggressive tumors in children. A radical surgical approach with complete excision of the tumor and contiguous structures in continuity, with adjunctive radiotherapy and chemotherapy remains the only hope for survival in children with these rare lesions.     

Biology of senescent liver peroxisomes: role in hepatocellular aging and disease.

Despite rising interest in the health problems of the elderly, information on senescence-related alterations in essential metabolic pathways and their responses to various chemicals is scarce. Although peroxisomal pathways are involved in a multitude of cellular functions, little attention has been given to the potential relationship between senescence of these organelles and the process of aging and disease. Although the prevailing experimental evidence points to a decline in liver peroxisomal enzyme activities and a muted response to peroxisome-proliferating chemicals in aged animals, it is also evident that aged animals are more susceptible, in comparison to their young counterparts, to the hepatocarcinogenic effects of these chemicals. Furthermore, little is known about extraperoxisomal effects of peroxisome proliferators in aged animals. This review evaluates published studies on the impact of aging on basal hepatic peroxisomal metabolism, response to peroxisome proliferators, and changes in signal transduction pathways involved in these processes, with the aim of stimulating research efforts in this important area. The potential intricate relationship among senescent peroxisomes, aged hepatocytes, and health are also discussed.     

Evaluation of crude and purified Toxocara canis antigens in serodiagnosis of human toxocariasis

Three serological tests: Immunodiffusion (ID), Counterimmunoelectrophoresis (CIEP) and Enzyme-linked immunosorbent assay (ELISA) were used to study the role of crude adult worm antigen (CAWA) of Toxocara canis and each of its purified fractions in the serodiagnosis of human toxocariasis. Sensitivities of the three tests were lower in the ocular than in the visceral group, using different antigens. Purified fraction 1 showed more sensitive and specific reactions in the three tests, compared to CAWA or purified fraction 2 (P-F2) antigen. The other purified fractions (P-F3, P-F4 and P-F5) gave no positive reactions in any of the three tests. Using P-F1 antigen, ELISA was the most sensitive technique for diagnosis of both visceral and ocular toxocariasis followed by CIEP and then ID and the difference was statistically significant. However, CIEP was the most specific test followed by ELISA and lastly ID test. The ELISA test using Excretory-Secretory (E-S) larval antigen of Toxocara canis was less sensitive than the ELISA test using P-F1, although it was 100% specific. Thus, ELISA test using P-F1 is the test of choice for diagnosis of human toxocariasis, but when the specificity of a reaction is in doubt, CIEP test using the same antigen can be of value.     

The vasa vasorum and angioplasty

Interruption of flow in the vasa vasorum may lead to medial necrosis and aneurysm formation. The purpose of this study was to determine whether angioplasty produces significant alterations in the morphology or blood flow of the vasa vasorum of the dilated artery. The morphology of the canine vasa vasorum was studied before and after angioplasty; in a separate experiment vessel wall blood flow (VWBF) in canine carotid arteries was measured after angioplasty to determine whether physiologic regulation of the blood flow was disrupted by arterial dilation. No morphologic changes could be demonstrated in the vasa vasorum of the dilated artery; however, VWBF was increased by 1194 +/- 215% (mean +/- standard error, p less than 0.01) between 90 and 120 minutes after angioplasty. VWBF in the adjacent nondilated arterial segment was also increased (720 +/- 177% between 10-30 minutes, p less than 0.01) but returned toward normal after 60 minutes. Adenosine caused a "paradoxical" decrease in VWBF (p less than 0.05) of the dilated arterial segment while causing increased VWBF (p less than 0.05) in the thoracic aorta. Angioplasty appears to produce persistent hyperemia in the dilated arterial wall. A paradoxical response to adenosine suggests that vasa vasorum in the dilated arterial segment are maximally vasodilated. This may be due to mechanical disruption of vasomotor tone or to release of vasoactive substances.