Lemierre Syndrome with Extensive Thrombosis: A Unique Case Report and Literature Review.

Background: Lemierre syndrome (LS) is a rare complication of upper aerodigestive tract infections characterized by proximal and distal septic emboli, commonly including internal jugular vein (IJV) thrombosis. Diagnosis can be challenging, and treatment delays can result in increased patient morbidity and mortality. We present a rare case of LS with extensive thrombosis and multiple sites of distal infection and a narrative review of the literature. Case Presentation. A 52-year-old Caucasian male was transferred to the emergency department (ED) with an altered level of consciousness and clinical findings of acute bacterial pharyngotonsillitis. Medical history included cervical spine disorder and traumatic brain injury in the past, as well as the recent use of pain relievers due to acute cervical pain. Imaging studies revealed left IJV thrombosis that extended into multiple venous cerebral sinuses and infiltrates of the right lung. LS was considered the most likely diagnosis. The patient was intubated and transferred to the intensive care unit (ICU). Treatment included intravenous broad-spectrum antibiotics and anticoagulation therapy. Response to treatment was satisfactory. After extubation, he was transferred to a ward and discharged with resolution of clinical and imaging findings. Conclusion: LS is a rare disease and may have an insidious course. Timely diagnosis and appropriate treatment strategies, mainly broad-spectrum antibiotics, offer favorable outcomes in otherwise healthy individuals. The indications for anticoagulation therapy still remain controversial. Anticoagulants are usually administered to patients with extensive thrombosis. Surgical treatment includes abscess drainage, while IJV ligation and excision are reserved for nonresponders to medical treatment.

The negative costimulatory molecule PD-1 modulates the balance between immunity and tolerance via miR-21.

Disruption of the programmed death-1 (PD-1) pathway leads to breakdown of peripheral tolerance and initiation of autoimmunity. The molecular pathways that mediate this effect remain largely unknown. We report here that PD-1 knockout (PD-1(-/-) ) mice develop more severe and sustained Ag-induced arthritis (AIA) than WT animals, which is associated with increased T-cell proliferation and elevated levels of IFN-γ and IL-17 secretion. MicroRNA analysis of Ag-specific CD4(+) T cells revealed a significant upregulation of microRNA 21 (miR-21) in PD-1(-/-) T cells compared with WT controls. In addition, PD-1 inhibition, via siRNA, upregulated miR-21 expression and enhanced STAT5 binding in the miR-21 promoter area. Computational analysis confirmed that miR-21 targets directly the expression of programmed cell death 4 (PDCD4) and overexpression of miR-21 in cells harboring the 3'UTR of PDCD4 resulted in reduced transcription and PDCD4 protein expression. Importantly, in vitro delivery of antisense-miR-21 suppressed the Ag-specific proliferation and cytokine secretion by PD-1(-/-) T cells, whereas adoptive transfer of Ag-specific T cells, overexpressing miR-21, induced severe AIA. Collectively, our data demonstrate that breakdown of tolerance in PD-1(-/-) mice activates a signaling cascade mediated by STAT5, miR-21, and PDCD4 and establish their role in maintaining the balance between immune activation and tolerance.

Correlation of blood pressure, obesity, and adherence to the Mediterranean diet with indices of arterial stiffness in children.

UNLABELLED: The aim of the study was to assess the hypothesis that obesity, blood pressure (BP), and dietary habits (adherence to the Mediterranean diet) are related to indices of arterial stiffness (AS) in childhood. Two hundred and seventy-seven children aged 12 years were measured with the R6.5 Pulsecor® monitor, which performs measurements using an upper arm BP cuff held at above systolic pressure for a short time. The augmentation index (AI) in the brachial artery, the peripheral pulse pressure to central pulse pressure (PPP/CPP) ratio, and the reflected wave transit time to height ratio were used as indices of AS. The degree of adherence to the Mediterranean diet was assessed by the KIDMED index which includes 16 questions on specific dietary habits. Forty-three percent of the children were overweight and obese. Overweight and obese children had significantly lower PPP/CPP and KIDMED score in comparison to children with normal body mass index (BMI). In multivariate regression models, indices of AS were related to mean peripheral BP, heart rate, and height, while BMI had an independent correlation to PPP/CPP. The KIDMED index also had a negative correlation with AI independently of obesity. CONCLUSION: Obesity and adherence to the Mediterranean diet patterns are factors related independently to indices of AS even in 12-year-old children.

Spontaneous bacterial peritonitis: a prospective Greek multicenter study of its epidemiology, microbiology, and outcomes.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is an ominous complication of decompensated cirrhosis. This study aimed to assess several epidemiological, clinical, microbiological and outcome characteristics in Greek patients with SBP, as no solid representative nationwide data of this type was available. METHODS: During a 3-year period, 77 consecutive patients with SBP (61 male; median age: 67 years; model for end-stage liver disease [MELD] score: 20), diagnosed and followed in 5 tertiary liver units, were prospectively recruited and studied. Various prognostic factors for disease outcome were studied. RESULTS: Thirty-eight patients had alcohol-related cirrhosis, 17 viral hepatitis, 6 non-alcoholic steatohepatitis, 6 autoimmune liver diseases, and 10 cryptogenic cirrhosis. Hepatocellular carcinoma (HCC) was present in 23 (29.9%), whereas 10 (13%) had portal vein thrombosis. The first SBP episode at baseline was community-acquired in 53 (68.8%), while in 24 (31.1%) was hospital-acquired, with predominant symptoms abdominal pain and encephalopathy. A positive ascitic culture was documented in 36% of patients in the initial episode, with almost equal gram (+) and gram (-) pathogens, including 3 multidrug-resistant pathogens. Significant factors for 6-month survival were: higher MELD score, previous b-blocker use, lower serum albumin, higher lactate on admission and need for vasopressors, while factors for 12-month survival were MELD score and lactate. For overall survival, higher MELD score and lactate along with HCC presence were negative predictive factors. CONCLUSIONS: MELD score, lactate, albumin, HCC and treatment with vasopressors were predictive of survival in SBP patients. In hospital-acquired SBP the prevalence of difficult-to-treat pathogens was higher.

Anti-tumor necrosis factor therapy improves insulin resistance, beta cell function and insulin signaling in active rheumatoid arthritis patients with high insulin resistance.

INTRODUCTION: Prevalence of insulin resistance and the metabolic syndrome has been reported to be high in rheumatoid arthritis (RA) patients. Tumor necrosis factor (TNF), a pro-inflammatory cytokine with a major pathogenetic role in RA, may promote insulin resistance by inducing Ser312 phosphorylation (p-Ser312) of insulin receptor substrate (IRS)-1 and downregulating phosphorylated (p-)AKT. We examined whether anti-TNF therapy improves insulin resistance in RA patients and assessed changes in the insulin signaling cascade. METHODS: Prospective study of RA patients receiving anti-TNF agents (infliximab, n = 49, adalimumab, n = 11, or etanercept, n = 1) due to high disease activity score in 28 joints (DAS28 > 5.1). A complete biochemical profile was obtained at weeks 0 and 12 of treatment. Insulin resistance, insulin sensitivity and pancreatic beta cell function were measured by the Homeostasis Model Assessment (HOMA-IR), the Quantitative Insulin Sensitivity Check Index (QUICKI) and the HOMA-B respectively. Protein extracts from peripheral blood mononuclear cells were assayed by western blot for p-Ser312 IRS-1 and p-AKT. RA patients treated with abatacept (CTLA4.Ig) were used as a control group for insulin signaling studies. RESULTS: At study entry, RA patients with high insulin resistance (HOMA-IR above median) had significantly higher mean DAS28 (P = 0.011), serum triglycerides (P = 0.015), and systolic blood pressure levels (P = 0.024) than patients with low insulin resistance. After 12 weeks of anti-TNF therapy, patients with high insulin resistance demonstrated significant reduction in HOMA-IR (P < 0.001), HOMA-B (P = 0.001), serum triglycerides (P = 0.039), and increase in QUICKI (P < 0.001) and serum HDL-C (P = 0.022). Western blot analysis in seven active RA patients with high insulin resistance showed reduction in p-Ser312 IRS-1 (P = 0.043) and increase in p-AKT (P = 0.001) over the study period. In contrast, the effect of CTLA4.Ig on p-Ser312 IRS-1 and p-AKT levels was variable. CONCLUSIONS: Anti-TNF therapy improved insulin sensitivity and reversed defects in the insulin signaling cascade in RA patients with active disease and high insulin resistance. The impact of these biochemical changes in modifying cardiovascular disease burden in active RA patients remains to be seen.

Novel role of plasmacytoid dendritic cells in humans: induction of interleukin-10-producing Treg cells by plasmacytoid dendritic cells in patients with rheumatoid arthritis responding to therapy.

OBJECTIVE: Reestablishing immune tolerance and long-term suppression of disease represent major therapeutic goals in rheumatoid arthritis (RA). Dendritic cells (DCs) likely play a central role in such regulation via the expansion and/or induction of Treg cells. The present study was undertaken to explore the contribution of DCs to the development of Treg cells in a human autoimmune disease setting. METHODS: DC subsets were characterized by flow cytometry in the peripheral blood and synovial fluid of patients with RA. Proliferation of and cytokine release by naive CD4+CD25- T cells were measured in cocultures of these cells with DCs from patients with RA and healthy controls. The suppressive capacity of DC-polarized T cells was explored in vitro by a standard suppression assay. RESULTS: Only very low numbers of both plasmacytoid DCs (CD303+) and myeloid DCs (CD1c+) were present in the peripheral blood of patients with active RA. In contrast, patients with therapy-induced remission of RA exhibited higher numbers of circulating plasmacytoid DCs. Mature plasmacytoid DCs from RA patients with low disease activity, but not those from healthy controls, expressed high levels of indoleamine 2,3-dioxygenase and promoted the differentiation of allogeneic naive CD4+CD25- T cells into interleukin-10-secreting Treg cells, or Tr1 cells, that showed poor proliferation in vitro. Importantly, these plasmacytoid DC-primed Treg cells potently suppressed the proliferation of autologous naive CD4+ T cells, in a dose-dependent manner. CONCLUSION: These results demonstrate, for the first time, that human plasmacytoid DCs may be educated within the rheumatoid microenvironment to acquire a tolerogenic phenotype. Modulation of the immune response by plasmacytoid DCs might provide novel immune-based therapies in autoimmunity and transplantation.

STAT4 is not associated with type 2 diabetes in the genetically homogeneous population of Crete.

Current classifications of diabetes distinguish between type 1 diabetes (T1D) and type 2 diabetes (T2D). However, recent evidence highlights overlap between T1D and T2D. In a recent study, we have suggested for the first time that STAT4 gene polymorphism is associated with increased risk for the development of T1D in the island of Crete, a well-defined area with genetically homogeneous population. The objective of this study was to investigate the putative association of STAT4 polymorphism with T2D. STAT4 encodes a transcription factor that transmits signals induced by several key cytokines, including interleukin-12 (IL-12) and interferon-gamma, a key indicator of T-cell differentiation into type 1 helper T (Th1) cells. Mutated allele T was more common in controls than in individuals with T2D (odds ratio [OR] = 1.59, 95% confidence interval [CI] = 1.022-2.470, p = 0.039). Mutated genotype G/T was more common in nondiabetic individuals than in T2D patients (OR = 1.735, 95% CI = 1.077-2.793, p = 0.024). Our results indicate that whilst allele T of the STAT4 rs7574865 gene polymorphism is associated with susceptibility to T1D, it is not associated with increased risk for and T2D, and thus does not represent a common genetic factor for diabetes.