Long-term outcome of patients with syncope associated with coronary artery disease and a nondiagnostic electrophysiologic evaluation

Syncope in the patient with structural heart disease and a nondiagnostic noninvasive workup is a generally accepted indication for an invasive electrophysiologic study. However, if the electrophysiologic evaluation is not highly sensitive, arrhythmic causes of syncope may not be discovered. In these patients, recurrent syncope and even sudden death may be observed at follow-up. Thus, we evaluated long-term follow-up in 68 consecutive patients who presented with syncope, coronary artery disease, and who had a negative invasive electrophysiologic evaluation. At a mean follow-up of 30 +/- 18 months (range 1 to 65), there have been 2 sudden deaths and 1 episode each of ventricular fibrillation and ventricular tachycardia in patients treated with an implantable cardioverter-defibrillator. All 4 arrhythmias occurred in patients with left ventricular fractions < or = 25%. Seventeen patients had recurrent presyncope or syncope. Bradycardia causing syncope was found in 8 of these patients. A bundle branch block at the initial evaluation predicted for the occurrence of bradycardia at follow-up. We conclude that in patients with coronary artery disease and syncope, noninducibility at electrophysiologic study predicts a lower risk of sudden death and ventricular arrhythmias. However, in patients with a reduced ejection fraction, the risk of sudden death and ventricular arrhythmias remains up to 10%/year and these patients may warrant treatment with implantable cardioverter-defibrillators. Recurrent syncope is common, and frequently a bradyarrhythmia is found to be the cause. Treatment of selected patients (especially those with bundle branch blocks) with permanent pacemakers may be justified.     

Tissue-engineered cartilage with inducible and tunable immunomodulatory properties

The pathogenesis of osteoarthritis is mediated in part by inflammatory cytokines including interleukin-1 (IL-1), which promote degradation of articular cartilage and prevent human mesenchymal stem cell (MSC) chondrogenesis. In this study, we combined gene therapy and functional tissue engineering to develop engineered cartilage with immunomodulatory properties that allow chondrogenesis in the presence of pathologic levels of IL-1 by inducing overexpression of IL-1 receptor antagonist (IL-1Ra) in MSCs via scaffold-mediated lentiviral gene delivery. A doxycycline-inducible vector was used to transduce MSCs in monolayer or within 3D woven PCL scaffolds to enable tunable IL-1Ra production. In the presence of IL-1, IL-1Ra-expressing engineered cartilage produced cartilage-specific extracellular matrix, while resisting IL-1-induced upregulation of matrix metalloproteinases and maintaining mechanical properties similar to native articular cartilage. The ability of functional engineered cartilage to deliver tunable anti-inflammatory cytokines to the joint may enhance the long-term success of therapies for cartilage injuries or osteoarthritis.     

Depletion of CD8+ T cells suppresses the development of experimental autoimmune myasthenia gravis in Lewis rats

To understand the role of CD8⁺ T cells in experimental autoimmune myasthenia gravis (EAMG), CD8⁺ T cells were depleted by injecting a monoclonal anti-rat CD8 antibody (OX8) into Lewis rats immunized with Torpedo acetylcholine receptor (AChR) in complete Freund's adjuvant (CFA). CD8-depleted EAMG rats showed strikingly less muscle weakness and lower anti-AChR IgG antibody levels compared to Hy2-15-injected control EAMG rats. Moreover, the numbers of AChR-specific IgG antibody-secreting cells, AChR-reactive interferony-γ-secreting T helper type 1-like cells and lymphocyte proliferation to AChR were lower in the CD8-depleted group than in control EAMG rats. These differences were significant among mononuclear cells from inguinal and popliteal lymph nodes, mesenteric lymph nodes and spleen, but not from thymus when examined 3, 5 and 7 weeks post-immunization. We suggest that CD8⁺ T cells are involved in the induction and persistance of EAMG by directly or indirectly affecting AChR-reactive T cells and anti-AChR IgG antibody-secreting cells.     

A New Cell Enzyme-Linked Immunosorbent Assay Demonstrates Gamma Interferon Suppression by Beta Interferon in Multiple Sclerosis

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system of unknown etiology. Immune mechanisms involving the proinflammatory cytokine gamma interferon (IFN-γ) are believed to play an important role in the pathogenesis of MS. IFN-β-1b has been introduced as a treatment for MS and was found to reduce the number and severity of clinical exacerbations. To examine the influence of IFN-β-1b on myelin basic protein (MBP)-specific and phytohemagglutinin-induced IFN-γ production, we developed a cell-released capturing enzyme-linked immunosorbent assay (CRC-ELISA), which rapidly measures spontaneous and antigen- or mitogen-induced cellular IFN-γ production. CRC-ELISA documented a significant MBP-specific T-cell response in the blood of untreated MS patients, as assessed by IFN-γ production. This response was suppressed in MS patients treated with IFN-β-1b. The present work confirms in vivo the in vitro suppressive effects of IFN-β-1b on IFN-γ production in MS. Moreover, it provides a powerful new technique for detection of cytokines.     

Increased levels of interferon-gamma (IFN-gamma), IL-4 and transforming growth factor-beta (TGF-beta) mRNA expressing blood mononuclear cells in human HIV infection.

Evidence has been presented for the involvement of IFN-gamma, IL-4 and TGF-beta in AIDS. Measured plasma levels may, however, poorly reflect in vivo production, since cytokines act auto- and paracrinally and have very short half life in plasma. In situ hybridization with complementary DNA oligonucleotide probes was used to enumerate blood mononuclear cells expressing cytokine messenger RNA (mRNA). HIV-infected patients had elevated blood levels of cells expressing each of the cytokines, with predominance for cells expressing TGF-beta mRNA. All AIDS patients included had elevated numbers of IL-4 mRNA-expressing cells, and levels of cells expressing this cytokine correlated inversely with counts of CD4+ cells in blood, reflecting the involvement of Th2-like cells in later stages of HIV infection. The described approach should be useful in further studies of cytokines in HIV infection and other diseases.     

Sex and sport: chlamydia screening in rural sporting clubs

Background  

Chlamydia trachomatis is the most common notifiable disease in Australia, mainly affecting those aged 15 to 29 years. Testing rates are low in Australia and considerably lower in rural areas, with access and confidentiality of sexual health services being problematic in rural and regional areas. This study aimed to determine the feasibility of establishing a pilot chlamydia testing outreach program among 16–25 year old males and females in rural Victoria (Australia) undertaken at local sporting clubs and to determine the prevalence of chlamydia and acceptability of the program in this population.     

Unresolved questions regarding human hereditary deafness

Human hearing loss is a common neurosensory disorder about which many basic research and clinically relevant questions are unresolved. This review on hereditary deafness focuses on three examples considered at first glance to be uncomplicated, however, upon inspection, are enigmatic and ripe for future research efforts. The three examples of clinical and genetic complexities are drawn from studies of (i) Pendred syndrome/DFNB4 (PDS, OMIM 274600), (ii) Perrault syndrome (deafness and infertility) due to mutations of CLPP (PRTLS3, OMIM 614129), and (iii) the unexplained extensive clinical variability associated with TBC1D24 mutations. At present, it is unknown how different mutations of TBC1D24 cause non‐syndromic deafness (DFNB86, OMIM 614617), epilepsy (OMIM 605021), epilepsy with deafness, or DOORS syndrome (OMIM 220500) that is characterized by d eafness, o nychodystrophy (alteration of toenail or fingernail morphology), o steodystrophy (defective development of bone), mental r etardation, and s eizures. A comprehensive understanding of the multifaceted roles of each gene associated with human deafness is expected to provide future opportunities for restoration as well as preservation of normal hearing.     

Elevated monoclonal and polyclonal serum immunoglobulin free light chain as prognostic factors in B‐ and T‐cell non‐Hodgkin lymphoma

The serum immunoglobulin free light chain (FLC) assay quantitates free kappa (κ) and lambda (λ) light chains. FLC elevations in patients with diffuse large B‐cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL) are associated with an inferior survival. These increases in FLC can be monoclonal (as in myeloma) or polyclonal. The goal was to estimate the frequency of these elevations within distinct types of B‐cell and T‐cell non‐Hodgkin lymphoma (NHL) and whether the FLC measurements are associated with event‐free survival (EFS). We studied serum for FLC abnormalities using normal laboratory reference ranges to define an elevated κ or λ FLC. Elevations were further classified as polyclonal or monoclonal. Four hundred ninety‐two patients were studied: 453 B‐cell and 34 T‐cell NHL patients. Twenty‐nine % (142/453) of patients had an elevated FLC of which 10% were monoclonal elevations. Within B‐cell NHL, FLC abnormalities were most common in lymphoplasmacytic (79%), mantle cell (68%), and lymphomas of mucosa associated lymphoid tissue (31%); they were least common in follicular (15%). The hazard ratio (HR) for EFS in all patients was 1.41 (95% CI; 1.11–1.81); in all B‐cell NHL the HR was 1.44 (95% CI 1.11–1.96); in all T‐cell NHL the HR was 1.17 (95% CI 0.55–2.49). FLC abnormalities predicted an inferior OS (HR = 2.75, 95% CI: 1.93–3.90, P < 0.0001). The serum FLC assay is useful for prognosis in both B‐cell and T‐cell types of NHL. In B‐cell NHL further discrimination between a monoclonal and polyclonal elevation may be helpful and should be analyzed in prospective clinical trials. Am. J. Hematol. 89:1116–1120, 2014. © 2014 Wiley Periodicals, Inc.     

Expression of interleukin-4 and interleukin-13 and their receptors in colorectal cancer

Purpose

Interleukin-4 (IL-4) and interleukin-13 (IL-13) are anti-inflammatory and immunomodulatory cytokines which can influence cancer-directed immunosurveillance. Nothing is presently known about expression of these cytokines and their receptors (IL-4R and IL-13R) in colorectal cancer. The aim of this study was to characterize their expression in primary colorectal cancer specimens and to evaluate possible functions for this disease.

Methods

Expression of IL-4, IL-13, IL-4R, and IL-13R protein was characterized by immunohistochemistry in 359 patients with Union for International Cancer Control stage I–III colorectal cancer and evaluated by uni- and multivariate analysis for their prognostic relevance.

Results

All four proteins were expressed in colorectal cancer specimens. In the cancer cells, high IL-4, IL-13, IL-4R, and IL-13R immunoreactivity were present in 33 % (118/359), 50 % (181/359), 36 % (129/359), and 42 % (152/359), respectively. Patients with high expression of IL-4, IL-4R, and IL-13R had a lower frequency of lymph node metastases. Expression of IL-13 did not influence the frequency of lymph node metastases. However, high IL-13-immunoreactivity was associated with a better overall survival (p?=?0.041). Expression of IL-4, IL-4R, or IL-13R did not influence survival. Multivariate analysis revealed that besides pT classification and tumor recurrence, IL-13 expression was an independent prognostic factor for overall survival.

Conclusions

Expression of IL-4, IL-4R, and IL-13R are involved in the process of local metastases in colorectal cancer, while IL-13 expression has an impact on survival. These interleukins and their receptors may become attractive targets for the treatment of colorectal cancer.