Expression of Interferon Regulatory Factor 8 (IRF8) and Its Association with Infections in Dialysis Patients.

Patients on dialysis have dysfunctions of innate and adaptive immune system responses. The transcriptional factor IRF8 (interferon regulatory factor 8) is primarily expressed in plasmacytoid cells (pDCs) and myeloid dendritic cells (mDCs), playing a crucial role in the maturation of dendritic cells, monocytes, and macrophages, and contributing to protection against bacterial infections. The current study analyzed the expression patterns of IRF8 and assessed its association with the risk of infections in 79 dialysis patients compared to 44 healthy controls. Different subsets of leukocytes and the intracellular expression of IRF8 were measured using flow cytometry. Compared to the healthy controls, the dialysis patients showed significantly reduced numbers of pDCs and significantly increased numbers of natural killer cells and classical and intermediate monocytes. The dialysis patients exhibited decreased numbers of IRF8-positive dendritic cells (pDC p < 0.001, mDC1 p < 0.001, mDC2 p = 0.005) and increased numbers of IRF8-positive monocytes (p < 0.001). IRF8 expression in pDC, mDC, and classical monocytes was lower in the dialysis patients than in the controls. Dialysis patients who required hospitalization due to infections within one year of follow-up displayed significantly reduced IRF8 expression levels in pDCs compared to patients without such infections (p = 0.04). Our results suggest that reduced IRF8 expression in pDCs is a potential risk factor predisposing dialysis patients to serious infections.

Insights into Virus-Induced Immune Mediated Liver Pathology.

In the context of chronic viral infections, the hepatic microenvironment dictates the outcome of the disease by influencing propagation of virus and regulation of cytotoxic CD8+ T cell response. Nevertheless, such regulation could be beneficial as it resolves the disease or could be detrimental as it causes liver pathological consequences. Liver pathology is a hallmark of chronic viral infection in both human and murine models. Such models show viral infection of hepatocytes and subsequent direct hepatic damage. Other compelling studies showed that liver injury was a consequence of overshooting CD8+ T cells response in experimental mice, so-called immune-mediated liver pathology. This review highlights the viral-induced immune mediated aspects of liver pathology based on the lymphocytic choriomeningitis virus (LCMV) and Hepatitis virus settings.

Arenavirus Therapy in Combination with Checkpoint Blockade as an Effective Way for Better Tumour Clearance.

Viruses have been widely used to treat cancer for many years and they achieved tremendous success in clinical trials with outstanding results, which has led to the foundation of companies that develop recombinant viruses for a better tumor treatment. Even though there has been a great progress in the field of viral tumor immunotherapy, until now only one virus, the oncolytic virus talimogene laherparepvec (TVEC), a genetically modified herpes simplex virus type 1 (T-VEC), has been approved by the FDA for cancer treatment. Although oncolytic viruses showed progress in certain cancer types and patient populations but they have yet shown limited efficacy when it comes to solid tumors. Only recently it was demonstrated that the immune stimulatory aspect of oncolytic viruses can strongly contribute to their anti-tumoral activity. One specific example in this context are arenaviruses, which have been shown to be non-cytopathic in nature lead to the massive immune activation within the tumor resulting in strong anti-tumoral activity. This strong immune activation might be also linked to their noncytopathic features, as their immune stimulatory potential is not self-limiting as is the case for oncolytic viruses due to their fast eradication by anti-viral immune effects. Because of this strong immune activation, arenaviruses appear superior to oncolytic viruses when it comes to potent and long-lasting anti-tumor effects in a broad variety of tumor types. Currently one of the most promising therapeutics which has turned to be very much beneficial for the treatment of different cancer types is represented by antibodies targeting checkpoint inhibitors such as PD-1/PD-L-1. In this review, we will summarize anti-tumoral effects of arenaviruses, and will discuss their potential to be combined with checkpoint inhibitors for a more efficient tumor treatment, which further emphasizes that arenavirus therapy as a viroimmunotherapy can be an efficient tool for the better clearance of tumors.

Replication of Influenza A Virus in Secondary Lymphatic Tissue Contributes to Innate Immune Activation.

The replication of viruses in secondary lymphoid organs guarantees sufficient amounts of pattern-recognition receptor ligands and antigens to activate the innate and adaptive immune system. Viruses with broad cell tropism usually replicate in lymphoid organs; however, whether a virus with a narrow tropism relies on replication in the secondary lymphoid organs to activate the immune system remains not well studied. In this study, we used the artificial intravenous route of infection to determine whether Influenza A virus (IAV) replication can occur in secondary lymphatic organs (SLO) and whether such replication correlates with innate immune activation. Indeed, we found that IAV replicates in secondary lymphatic tissue. IAV replication was dependent on the expression of Sialic acid residues in antigen-presenting cells and on the expression of the interferon-inhibitor UBP43 (Usp18). The replication of IAV correlated with innate immune activation, resulting in IAV eradication. The genetic deletion of Usp18 curbed IAV replication and limited innate immune activation. In conclusion, we found that IAV replicates in SLO, a mechanism which allows innate immune activation.

Corrigendum to: Tranexamic acid use in a patient with sickle cell disease undergoing posterior scoliosis correction surgery: safely mitigating bleeding and vaso-occlusive crises.

[This corrects the article DOI: 10.1093/jscr/rjaa559.].

Tranexamic acid use in a patient with sickle cell disease undergoing posterior scoliosis correction surgery: safely mitigating bleeding and vaso-occlusive crises.

A 15-year-old female with 2-year post-menarchal adolescent idiopathic scoliosis and sickle cell disease (SCD) underwent posterior scoliosis correction surgery. SCD is associated with higher rates of surgical complications, and these patients require careful management to prevent vaso-occlusive sickle cell crises (VOSCC); scoliosis correction surgery can be associated with high morbidity and mortality, including significant blood loss. Multiple techniques were employed to successfully prevent VOSCC in this patient including a preoperative transfusion, meticulous haemostasis at osteotomy sites, not performing a costoplasty despite presence of a rib hump, maintenance of intraoperative mean arterial pressure below 70 mmHg, aggressive postoperative hydration and the use of intraoperative tranexamic acid (TXA). This is the first reported case of the use of TXA in a patient with SCD and scoliosis correction surgery. A satisfactory correction was achieved with a longer than average inpatient stay due to non-sickle cell pain and protracted wound ooze.

Arenavirus Induced CCL5 Expression Causes NK Cell-Mediated Melanoma Regression.

Immune activation within the tumor microenvironment is one promising approach to induce tumor regression. Certain viruses including oncolytic viruses such as the herpes simplex virus (HSV) and non-oncolytic viruses such as the lymphocytic choriomeningitis virus (LCMV) are potent tools to induce tumor-specific immune activation. However, not all tumor types respond to viro- and/or immunotherapy and mechanisms accounting for such differences remain to be defined. In our current investigation, we used the non-cytopathic LCMV in different human melanoma models and found that melanoma cell lines produced high levels of CCL5 in response to immunotherapy. In vivo, robust CCL5 production in LCMV infected Ma-Mel-86a tumor bearing mice led to recruitment of NK cells and fast tumor regression. Lack of NK cells or CCL5 abolished the anti-tumoral effects of immunotherapy. In conclusion, we identified CCL5 and NK cell-mediated cytotoxicity as new factors influencing melanoma regression during virotherapy.

Dead Cells Induce Innate Anergy via Mertk after Acute Viral Infection.

Infections can result in a temporarily restricted unresponsiveness of the innate immune response, thereby limiting pathogen control. Mechanisms of such unresponsiveness are well studied in lipopolysaccharide tolerance; however, whether mechanisms of tolerance limit innate immunity during virus infection remains unknown. Here, we find that infection with the highly cytopathic vesicular stomatitis virus (VSV) leads to innate anergy for several days. Innate anergy is associated with induction of apoptotic cells, which activates the Tyro3, Axl, and Mertk (TAM) receptor Mertk and induces high levels of interleukin-10 (IL-10) and transforming growth factor ß (TGF-ß). Lack of Mertk in Mertk-/- mice prevents induction of IL-10 and TGF-ß, resulting in abrogation of innate anergy. Innate anergy is associated with enhanced VSV replication and poor survival after infection. Mechanistically, Mertk signaling upregulates suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Dexamethasone treatment upregulates Mertk and enhances innate anergy in a Mertk-dependent manner. In conclusion, we identify Mertk as one major regulator of innate tolerance during infection with VSV.

Map3k14 as a Regulator of Innate and Adaptive Immune Response during Acute Viral Infection.

The replication of virus in secondary lymphoid organs is crucial for the activation of antigen-presenting cells. Balanced viral replication ensures the sufficient availability of antigens and production of cytokines, and both of which are needed for virus-specific immune activation and viral elimination. Host factors that regulate coordinated viral replication are not fully understood. In the study reported here, we identified Map3k14 as an important regulator of enforced viral replication in the spleen while performing genome-wide association studies of various inbred mouse lines in a model of lymphocytic choriomeningitis virus (LCMV) infection. When alymphoplasia mice (aly/aly, Map3k14aly/aly, or Nikaly/aly), which carry a mutation in Map3k14, were infected with LCMV or vesicular stomatitis virus (VSV), they display early reductions in early viral replication in the spleen, reduced innate and adaptive immune activation, and lack of viral control. Histologically, scant B cells and the lack of CD169+ macrophages correlated with reduced immune activation in Map3k14aly/aly mice. The transfer of wildtype B cells into Map3k14aly/aly mice repopulated CD169+ macrophages, restored enforced viral replication, and resulted in enhanced immune activation and faster viral control.

The Diverse Functions of the Ubiquitous Fcγ Receptors and Their Unique Constituent, FcRγ Subunit.

Fc gamma receptors (FcγRs) are widely expressed on a variety of immune cells and play a myriad of regulatory roles in the immune system because of their structural diversity. Apart from their indispensable role in specific binding to the Fc portion of antibody subsets, FcγRs manifest diverse biological functions upon binding to their putative ligands. Examples of such manifestation include phagocytosis, presentation of antigens, mediation of antibody-dependent cellular cytotoxicity, anaphylactic reactions, and the promotion of apoptosis of T cells and natural killer cells. Functionally, the equilibrium between activating and inhibiting FcγR maintains the balance between afferent and efferent immunity. The γ subunit of the immunoglobulin Fc receptor (FcRγ) is a key component of discrete immune receptors and Fc receptors including the FcγR family. Furthermore, FcγRs exert a key role in terms of crosslinking the innate and adaptive workhorses of immunity. Ablation of one of these receptors might positively or negatively influence the immune response. Very recently, we discovered that FcRγ derived from natural cytotoxicity triggering receptor 1 (NCR1) curtails CD8+ T cell expansion and thereby turns an acute viral infection into a chronic one. Such a finding opens a new avenue for targeting the FcγRs as one of the therapeutic regimens to boost the immune response. This review highlights the structural heterogeneity and functional diversity of the ubiquitous FcγRs along with their featured subunit, FcRγ.

Integrin Alpha E (CD103) Limits Virus-Induced IFN-I Production in Conventional Dendritic Cells.

Early and strong production of IFN-I by dendritic cells is important to control vesicular stomatitis virus (VSV), however mechanisms which explain this cell-type specific innate immune activation remain to be defined. Here, using a genome wide association study (GWAS), we identified Integrin alpha-E (Itgae, CD103) as a new regulator of antiviral IFN-I production in a mouse model of vesicular stomatitis virus (VSV) infection. CD103 was specifically expressed by splenic conventional dendritic cells (cDCs) and limited IFN-I production in these cells during VSV infection. Mechanistically, CD103 suppressed AKT phosphorylation and mTOR activation in DCs. Deficiency in CD103 accelerated early IFN-I in cDCs and prevented death in VSV infected animals. In conclusion, CD103 participates in regulation of cDC specific IFN-I induction and thereby influences immune activation after VSV infection.

NK cell-intrinsic FcεRIγ limits CD8+ T-cell expansion and thereby turns an acute into a chronic viral infection.

During viral infection, tight regulation of CD8+ T-cell functions determines the outcome of the disease. Recently, others and we determined that the natural killer (NK) cells kill hyperproliferative CD8+ T cells in the context of viral infection, but molecules that are involved in shaping the regulatory capability of NK cells remain virtually unknown. Here we used mice lacking the Fc-receptor common gamma chain (FcRγ, FcεRIγ, Fcer1g-/- mice) to determine the role of Fc-receptor and NK-receptor signaling in the process of CD8+ T-cell regulation. We found that the lack of FcRγ on NK cells limits their ability to restrain virus-specific CD8+ T cells and that the lack of FcRγ in Fcer1g-/- mice leads to enhanced CD8+ T-cell responses and rapid control of the chronic docile strain of the lymphocytic choriomeningitis virus (LCMV). Mechanistically, FcRγ stabilized the expression of NKp46 but not that of other killer cell-activating receptors on NK cells. Although FcRγ did not influence the development or activation of NK cell during LCMV infection, it specifically limited their ability to modulate CD8+ T-cell functions. In conclusion, we determined that FcRγ plays an important role in regulating CD8+ T-cell functions during chronic LCMV infection.

Antibiograms, toxin profiling and molecular typing of Staphylococcus aureus isolates from two tertiary hospitals in Jordan.

INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of hospital-associated infections. This study was undertaken to investigate toxin profiles as well as antibiotic resistance patterns of S. aureus isolates form two tertiary hospitals in Jordan. METHODOLOGY: A total of 250 S. aureus isolates from clinical samples of two tertiary hospitals were analyzed for the presence of the mecA, vanA, vanB, and 16 Staphylococcus toxin encoding genes using PCR. The isolates were further tested for antimicrobial sensitivities using the disc diffusion method. DNA from all the isolates were fingerprinted by coa gene Restriction Fragment Length Polymorphism (RFLP) to study relationships between isolates from the two hospitals. RESULTS: 73.2% of the isolates contained the mecA gene and thus were designated MRSA. All MRSA isolates showed high levels of resistance to many of the antibiotics compared to those of MSSA. All MRSA isolates were susceptible to vancomycin and teicoplanin while all MSSA isolates were susceptible to nitrofurantoin, teicoplanin, vancomycin, cefoxitin, clindamycin, erythromycin and gentamycin. The isolates exhibited high prevalence of the toxin genes and none of the isolates contained less than 4 genes with one isolate contained 14 genes with no apparent differences in gene profiles among MRSA and MSSA. About 60% of the isolates contained 12 to 13 toxin genes and were isolated either from pus or blood. CONCLUSION: Antibiograms of the MRSA isolates were significantly different from MSSA antibiograms while there were no apparent differences in the toxin genes profiles. Further, coagulase gene RFLP of the isolates showed that the isolates are very heterogenic.

A feasibility study of mobile phone text messaging to support education and management of type 2 diabetes in Iraq.

BACKGROUND: We undertook a feasibility study to evaluate feasibility and utility of short message services (SMSs) to support Iraqi adults with newly diagnosed type 2 diabetes. SUBJECTS AND METHODS: Fifty patients from a teaching hospital clinic in Basrah in the first year after diagnosis were recruited to receive weekly SMSs relating to diabetes self-management over 29 weeks. Numbers of messages received, acceptability, cost, effect on glycated hemoglobin (HbA1c), and diabetes knowledge were documented. RESULTS: Forty-two patients completed the study, receiving an average 22 of 28 messages. Mean knowledge score rose from 8.6 (SD 1.5) at baseline to 9.9 (SD 1.4) 6 months after receipt of SMSs (P=0.002). Baseline and 6-month knowledge scores correlated (r=0.297, P=0.049). Mean baseline HbA1c was 79 mmol/mol (SD 14 mmol/mol) (9.3% [SD 1.3%]) and decreased to 70 mmol/mol (SD 13 mmol/mol) (8.6% [SD 1.2%]) (P=0.001) 6 months after the SMS intervention. Baseline and 6-month values were correlated (r=0.898, P=0.001). Age, gender, and educational level showed no association with changes in HbA1c or knowledge score. Changes in knowledge score were correlated with postintervention HbA1c (r=-0.341, P=0.027). All patients were satisfied with text messages and wished the service to be continued after the study. The cost of SMSs was €0.065 per message. CONCLUSIONS: This study demonstrates SMSs are acceptable, cost-effective, and feasible in supporting diabetes care in the challenging, resource-poor environment of modern-day Iraq. This study is the first in Iraq to demonstrate similar benefits of this technology on diabetes education and management to those seen from its use in better-resourced parts of the world. A randomized controlled trial is needed to assess precise benefits on self-care and knowledge.

Hydatid disease of the spine: a report on nine patients.

PURPOSE: The author presents this prospective study of nine cases of pathologically confirmed spinal hydatid disease. METHOD: Hydatid disease is a difficult diagnosis in non endemic areas but it should be considered in the differential diagnosis of spinal pathology in endemic areas. Spinal involvement is very unusual. There is nothing typical of spinal involvement. Nine patients presented with hydatid disease of the spine between September 2001 and October 2010. The patients were clinically evaluated as well as by the latest imaging modalities, haematological and serological tests. All had decompressive surgery with or without fixation and the diagnosis was confirmed by histopathological examination. All received albendazole and praziquantel for ten months. RESULTS: MRI was the best diagnostic test, CAT scan was also useful, eosinophilia was a constant finding, and ESR was above normal in five patients. All had decompression laminectomy and clearance; in addition, transpedicular fixation was done to three patients. After surgery one patient had complete recovery with no recurrence, seven patients showed recurrence over time and residual disease was observed, and one patient died within 24 hours of surgery. CONCLUSION: Diagnosis was easy from the start, but eradication was difficult, and recurrence rate was very high despite the use of chemotherapy.

Postoperative disc space infection after discectomy: a report on thirty-five patients.

PURPOSE: The focus of this study was to analyse the patient with disc space infection and the need for re-exploration. METHOD: Thirty-five patients were analysed within the period from April 1992 and May 2011. The diagnosis was confirmed by the cardinal clinical features, raised erythrocyte sedimentation rate [ESR], raised C-reactive protein and MRI findings. All received 500-mg intravenous amikacin and one gram ceftriaxone at the time of anaesthetic induction and six hours after surgery. RESULTS: Age range was between 25-62 years. The appearance of symptoms was between four days and three weeks. Nine patients had silent chronic urinary tract infection. Twenty-nine patients had re-exploration while the others did well on conservative treatment. Neurological deficit was not recorded. All recovered well within six to nine months. CONCLUSION: Re-exploration is recommended if no response is achieved after four day's conservative treatment for or if the patient's condition is critical.

Health effects associated with geographical area of residence during the 1991 Gulf War: a comparative health study of Iraqi soldiers and civilians.

CONTEXT: Although Iraqis sustained the gravest exposure conditions during the 1991 Gulf War (GW), little is known about the possible relationship between environmental exposures during the GW and long-term health in Iraqis. OBJECTIVE: To study the relationship between distance from Kuwait during the GW and somatic health among Iraqi Soldiers vs civilians. METHODS: A survey questionnaire was distributed to a sample of 742 GW veterans and 413 civilians in Iraq. The odds ratios were calculated for somatic disorders as a function of distance from Kuwait during the GW, as well as a self-reported environmental exposure index. RESULTS: Soldiers reported a significantly higher prevalence of somatic disorders as compared to civilians. Soldiers closest to Kuwait reported significantly more somatic disorders as compared to Soldiers deployed further away from Kuwait. CONCLUSION: Iraqi GW veterans are at an increased risk of numerous somatic disorders. Soldiers are at an increased risk compared to civilians, suggesting that war-associated exposures are of etiologic relevance.

Psychiatric aspects of orthopaedics.

Although psychiatric problems are seen less frequently than previously, the orthopaedic surgeon must remain aware of their possible effect. A high index of suspicion for the presence of psychiatric disorders is important in treating the orthopaedic patient with multiple trauma, chronic disease, factitious disorder, or suspected malingering or who fails to improve with recognized treatment. Recognition of a psychiatric problem should be part of preoperative planning in orthopaedic practice, and a formal psychiatric referral for diagnosis and treatment should be made for the patient with significant psychiatric involvement. When associated psychiatric disease is diagnosed and controlled before orthopaedic treatment commences, the patient is more likely to comply with the treatment regimen, which may lead to better results.