Activation of the contact system at the surface of Fusobacterium necrophorum represents a possible virulence mechanism in Lemièrre's syndrome

Fusobacterium necrophorum causes Lemièrre's syndrome, a serious disease with septic thrombophlebitis of the internal jugular vein, pulmonary involvement, and systemic inflammation. The contact system is a link between inflammation and coagulation, and contact activation by the bacteria could therefore contribute to the abnormal coagulation and inflammation seen in patients with Lemièrre's syndrome. In this study, F. necrophorum was found to bind radiolabeled high-molecular-weight kininogen (HK), a central component of the contact system. Binding was inhibited by the addition of unlabeled HK and domain D5 of HK but not other components of the contact system, indicating a specific interaction mediated through the D5 region. Binding of HK was significantly reduced after pretreatment of the bacteria with trypsin, suggesting that surface proteins are involved in HK binding. Incubation of the bacteria with human plasma resulted in an HK breakdown pattern suggestive of bradykinin release, and bradykinin was also detected in the supernatant. In addition, we show that factor XI (FXI), another component of the contact system, binds to F. necrophorum and that the bound FXI reconstitutes the activated partial thromboplastin time of FXI-deficient plasma. Thrombin activity was detected at the surface of the bacteria following incubation with plasma, indicating that the intrinsic pathway of coagulation is activated at the surface. This activity was completely blocked by inhibitors of the contact system. The combined results show that the contact system is activated at the surface of F. necrophorum, suggesting a pathogenic role for this system in Lemièrre's syndrome.     

Molecular diagnosis of Fusobacterium necrophorum infection (Lemierre’s syndrome)

Presented here is the case of a 27-year-old male with atypical features of Lemierres syndrome in which a definitive diagnosis was achieved using molecular methods. While routine investigations, including bacterial cultures, were unhelpful, two real-time PCR assays demonstrated Fusobacterium necrophorum-specific DNA in aspirates from brain and renal abscesses. This is the first report demonstrating that a laboratory diagnosis can be made using molecular methods in suspected cases of Lemierres syndrome. Use of these methods can thus resolve diagnostic confusion, prevent unnecessary investigation, and direct specific antimicrobial treatment.     

A cost-effectiveness analysis of identifying Fusobacterium necrophorum in throat swabs followed by antibiotic treatment to reduce the incidence of Lemierre’s syndrome and peritonsillar abscesses

The main purpose of this paper was to estimate the cost per quality-adjusted life year (QALY) saved by identifying Fusobacterium necrophorum in throat swabs followed by proper antibiotic treatment, to reduce the incidence of Lemierre’s syndrome and peritonsillar abscesses (PTA) originating from a pharyngitis. The second purpose was to estimate the population size required to indicate that antibiotic treatment has an effect. Data from publications and our laboratory were collected. Monte Carlo simulation and one-way sensitivity analysis were used to analyse cost-effectiveness. The cost-effectiveness analysis shows that examining throat swabs from 15- to 24-year-olds for F. necrophorum followed by antibiotic treatment will probably be less costly than most other life-saving medical interventions, with a median cost of US$8,795 per QALY saved. To indicate a reduced incidence of Lemierre’s syndrome and PTA in Denmark, the intervention probably has to be followed for up to 5 years. Identifying F. necrophorum in throat swabs from 15- to 24-year-olds followed by proper antibiotic treatment only requires a reduction of 20–25 % in the incidence of Lemierre’s syndrome and PTA to be cost-effective. This study warrants further examination of the effect of antibiotic treatment on the outcome of F. necrophorum acute and recurrent pharyngitis, as well as the effect on Lemierre’s syndrome and PTA.     

The potential role for infections in the pathogenesis of autoimmune Addison’s disease

Autoimmune Addison’s disease (AAD), or primary adrenocortical insufficiency, is a classical organ-specific autoimmune disease with 160 years of history. AAD is remarkably homogeneous with one major dominant self-antigen, the cytochrome P450 21-hydroxylase enzyme, which is targeted by both autoantibodies and autoreactive T cells. Like most autoimmune diseases, AAD is thought to be caused by an unfortunate combination of genetic and environmental factors. While the number of genetic associations with AAD is increasing, almost nothing is known about environmental factors. A major environmental factor commonly proposed for autoimmune diseases, based partly on experimental and clinical data and partly on shared pathways between anti-viral immunity and autoimmunity, is viral infections. However, there are few reports associating viral infections to AAD, and it has proved difficult to establish which immunological processes that could link any viral infection with the initiation or progression of AAD. In this review, we will summarize the current knowledge on the underlying mechanisms of AAD and take a closer look on the potential involvement of viruses.     

Maternal depressive symptoms and children’s cognitive school readiness: the role of gene-environment interplay

Archives of Women's Mental Health - Maternal depressive symptoms are a robust risk factor for poor cognitive outcomes in children, yet the role of gene-environment interplay in this association...     

EBV and other viruses as triggers of tertiary lymphoid structures in primary Sjögren’s syndrome

Sjögren's syndrome (SS) is an autoimmune disease that targets salivary (SG) and lachrymal glands, leading to exocrine dysfunction. Several viruses have been associated with SS, although the role of persistent viral infections in triggering and/or perpetuating the disease is still a matter of controversy. Together with exocrine dysfunction, SS is characterised by the production of autoantibodies and the presence of lymphomonocytic periductal aggregates in the SG, which in 30/40% of the patients display features of tertiary lymphoid structures (TLS) supporting an ectopic germinal centre response. Here we first review i) the relevance of TLS in SS and ii) the evidence in support of a role for viruses in SS insurgence and/or persistence; next, iii) we review recent data which links viral infection with TLS formation in the SG and suggests that viral-host interactions within TLS favour breach of tolerance and development of autoimmunity in SS.     

Absence of haemosporidian parasite infections in the long-lived Cory’s shearwater: evidence from molecular analyses and review of the literature

Parasitology Research - The apparent scarcity or absence of blood parasites in some avian groups, such as seabirds, has been related to intrinsic and extrinsic factors including host immunological...     

Bioenergetics and biomechanics of cycling: the role of ‘internal work’

The ‘dissection’ of energy expenditure of cycling into the metabolic equivalent of the different forms of mechanical work done, inaugurated 30 years ago by di Prampero and collaborators, has been much debated in the last few decades. The mechanical internal work, particularly, which is currently associated to the movement of the lower limbs, has been approached, estimated and discussed in several different ways and there is no agreed consensus on its role in cycling. This paper, through re-processing previously published data of oxygen consumption during pedalling at different frequency, external load and limb mass, proposes a model equation and a multiple non-linear regression as the method to assess the internal work of cycling. With that tool a very consistent metabolic equivalent of the internal work is obtained. However, a software simulation of pedalling limbs showed, as suggested in the literature, that the link with the chain ring allows the system to passively revolve forever, after an initial push. This result challenges the very existence of the ‘kinematic internal work’ of cycling. We conclude and suggest that the ‘viscous internal work’, an often neglected and almost unmeasurable portion of the internal work that could be proportional to the ‘kinematic’ form, is responsible for the extra metabolic expenditure as measured when the pedalling frequency of cycling increases.     

Chemotherapy in alveolar echinococcosis of multi-organs: what’s the role?

The aim of this study was to investigate the clinical efficiency of chemotherapy for the treatment of human alveolar echinococcosis (AE). Twenty-four patients who suffered from late-stage AE were enrolled in this study. The classification of the disease stages was performed according to the PNM (parasite lesion, neighboring organ invasion, metastases) classification system established by the World Health Organization Informal Working Group on Echinococcosis and classification standards. Radical surgery (n?=?3), palliative surgery plus chemotherapy (n?=?11), and sole chemotherapy (n?=?10) were given, respectively. For those with AE metastasis with spleen and kidney, radical surgery was effective for the treatment. However, the treatment efficiency for those with AE metastasis to bone tissues was unfavorable. Significant improvement was noted in those with cerebral lesions after chemotherapy. Stable health conditions were observed in those with pulmonary lesions after chemotherapy. For those with liver lesion, long stable health conditions were noted after chemotherapy. However, surgical interventions were needed as the occurrence of bile duct complications. With regards to the other lesions, radical surgeries were recommended. Satisfactory treatment outcomes were obtained in those with AE after chemotherapy.     

Muscle abnormalities of the chest in Poland’s syndrome: variations and proposal for a classification

Purposes  

Poland’s syndrome (PS) is a rare congenital malformation, which combines anomalies of the chest and the homolateral upper limb. The purposes of the paper are to study the chest musculoskeletal malformations of the syndrome and propose a classification for the thoracic anomalies through our experience and taking into account the literature.     

Human herpesvirus 8: Biology and role in the pathogenesis of Kaposi’s sarcoma and other aids-related malignancies

Human herpesvirus type 8, or Kaposi’s sarcoma-associated herpesvirus (KSHV), is the only known human γ ₂ herpesvirus (rhadinovirus) and the most recently discovered tumor virus. KSHV is associated with Kaposi’s sarcoma and two other lymphoproliferative disorders in the AIDS setting: primary effusion lymphoma and the plasma cell variant of multicentric Castleman’s disease. This review offers an update on the epidemiology and the role of KSHV genes in the development of disease.     

Maltoma of the thyroid and Sjögren’s syndrome in a woman with Hashimoto’s thyroiditis

We report the case of a 70-yr-old woman with maltoma of the thyroid, Sjögren’s syndrome, and a history of Hashimoto’s thyroiditis. The patient underwent a total thyroidectomy for a recently growing mass of the thyroid, while being treated with l-thyroxine for Hashimoto’s thyroiditis. Postoperatively, routine histologic examination was consistent with the diagnosis of chronic lymphocytic thyroiditis of autoimmune etiology. Three years later, the patient presented with high temperature, anorexia, and coughing. This time, a microscopic examination of deeper thyroid tissue sections and an immunohistochemical study revealed a low-grade, non-Hodgkin lymphoma, MALT type. Simultaneously, the diagnosis of Sjögren’s syndrome was established and the patient is currently under investigation for generalized lymphoma. This case clearly demonstrates the difficulty in differentially diagnosing Hashimoto’s thyroiditis from low-grade MALT lymphoma by the use of routine histologic examination.     

The role of the immune system in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common neurodegenerative disorder where the accumulation of amyloid plaques and the formation of tau tangles are the prominent pathological hallmarks. Increasing preclinical and clinical studies have revealed that different components of the immune system may act as important contributors to AD etiology and pathogenesis. The recognition of misfolded Aβ and tau by immune cells can trigger a series of complex immune responses in AD, and then lead to neuroinflammation and neurodegeneration. In parallel, genome-wide association studies have also identified several immune related loci associated with increased - risk of AD by interfering with the function of immune cells. Other immune related factors, such as impaired immunometabolism, defective meningeal lymphatic vessels and autoimmunity might also be involved in the pathogenesis of AD.Here, we review the data showing the alterations of immune cells in the AD trajectory and seek to demonstrate the crosstalk between the immune cell dysfunction and AD pathology. We then discuss the most relevant research findings in regards to the influences of gene susceptibility of immune cells for AD. We also consider impaired meningeal lymphatics, immunometabolism and autoimmune mechanisms in AD. In addition, immune related biomarkers and immunotherapies for AD are also mentioned in order to offer novel insights for future research.     

Effect of liposomall-Dopa on the Parkinson’s syndrome in mice

The effects of freel-Dopa andl-Dopa enclosed in small monolamellar liposomes consisting of egg phosphatidylcholine and cholesterol (molar ratio 7:3) on the severity of Parkinson’s syndrome are studied. The syndrome is modeled in C57B1/6 mice by repeated injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A single injection of liposomes withl-Dopa on day 7 after the start of MPTP administration has no effect on this syndrome. Repeated injections (for 14 days) ofl-Dopa solution (50 mg/kg) into MPTP-treated mice with oligokinesia and muscle rigidity increase their locomotor activity and the number of upright postures 7-fold and decrease muscle rigidity for 1 h after the last injection. The inhibitory effect of a 10-fold lower dose of liposomes withl-Dopa on oligokinesia and muscle rigidity is 2- to 3-fold stronger and 5207 h longer compared with that of freel-Dopa. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 123, No. 1, pp. 29–33, January, 1997     

Dysfunctional mitochondria as critical players in the inflammation of autoimmune diseases: Potential role in Sjögren’s syndrome

Relevant reviews highlight the association between dysfunctional mitochondria and inflammation, but few studies address the contribution of mitochondria and mitochondria-endoplasmic reticulum (ER) contact sites (MERCs) to cellular homeostasis and inflammatory signaling. The present review outlines the important role of mitochondria in cellular homeostasis and how dysfunctional mitochondrion can release and misplace mitochondrial components (cardiolipin, mitochondrial DNA (mtDNA), and mitochondrial formylated peptides) through multiple mechanisms. These components can act as damage-associated molecular patterns (DAMPs) and induce an inflammatory response via pattern recognition receptors (PRRs). Accumulation of damaged ROS-generating mitochondria, accompanied by the release of mitochondrial DAMPs, can activate PRRs such as the NLRP3 inflammasome, TLR9, cGAS/STING, and ZBP1. This process would explain the chronic inflammation that is observed in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type I diabetes (T1D), and Sjögren’s syndrome.This review also provides a comprehensive overview of the importance of MERCs to mitochondrial function and morphology, cellular homeostasis, and the inflammatory response. MERCs play an important role in calcium homeostasis by mediating the transfer of calcium from the ER to the mitochondria and thereby facilitating the production of ATP. They also contribute to the synthesis and transfer of phospholipids, protein folding in the ER, mitochondrial fission, mitochondrial fusion, initiation of autophagosome formation, regulation of cell death/survival signaling, and regulation of immune responses. Therefore, alterations within MERCs could increase inflammatory signaling, modulate ER stress responses, cell homeostasis, and ultimately, the cell fate.This study shows severe ultrastructural alterations of mitochondria in salivary gland cells from Sjögren’s syndrome patients for the first time, which could trigger alterations in cellular bioenergetics. This finding could explain symptoms such as fatigue and malfunction of the salivary glands in Sjögren’s syndrome patients, which would contribute to the chronic inflammatory pathology of the disease. However, this is only a first step in solving this complex puzzle, and several other important factors such as changes in mitochondrial morphology, functionality, and their important contacts with other organelles require further in-depth study. Future work should focus on detecting the key milestones that are related to inflammation in patients with autoimmune diseases, such as Sjögren´s syndrome.