Rapid emergence of daptomycin resistance in clinical isolates of Corynebacterium striatum… a cautionary tale

The objective of this study was to investigate the observation of daptomycin resistance in Corynebacterium striatum, both in vivo and in vitro. We describe a case of C. striatum bacteremia in a patient with a left ventricular assist device (LVAD); the initial isolate recovered was daptomycin susceptible with a minimum inhibitory concentration (MIC) of 0.125 μg/ml. Two months later, and after daptomycin therapy, the individual became bacteremic with an isolate of C. striatum with a daptomycin MIC of >256 μg/ml. To study the prevalence of daptomycin resistance in C. striatum, clinical isolates of C. striatum were grown in broth culture containing daptomycin to investigate the emergence of resistance to this antimicrobial. Molecular typing was used to evaluate serial isolates from the index patient and the clinical isolates of C. striatum we assayed. In vitro analysis of isolates from the index patient and 7 of 11 additional C. striatum isolates exhibited the emergence of high-level daptomycin resistance, despite initially demonstrating low MICs to this antimicrobial agent. This phenotype was persistent even after serial subculture in the absence of daptomycin. Together, these data demonstrate that caution should be taken when using daptomycin to treat high-inoculum infections and/or infections of indwelling medical devices with C. striatum. To our knowledge, this is the first report characterizing the emergence of daptomycin resistance in C. striatum.     

Autoimmunity—Basics and link with periodontal disease

Autoimmune reactions reflect an imbalance between effector and regulatory immune responses, typically develop through stages of initiation and propagation, and often show phases of resolution (indicated by clinical remissions) and exacerbations (indicated by symptomatic flares). The fundamental underlying mechanism of autoimmunity is defective elimination and/or control of self-reactive lymphocytes. Periodontal diseases are characterized by inflammatory conditions that directly affect teeth-supporting structures, which are the major cause of tooth loss. Several studies have demonstrated the involvement of autoimmune responses in periodontal disease. Evidence of involvement of immunopathology has been reported in periodontal disease. Bacteria in the dental plaque induce antibody formation. Autoreactive T-cells, natural killer cells, ANCA, heat shock proteins, autoantibodies, and genetic factors are reported to have an important role in the autoimmune component of periodontal disease. The present review describes the involvement of autoimmune responses in periodontal diseases and also the mechanisms underlying these responses.     

Lymphokines in Autoimmunity—A Critical Review

The pathogenesis of autoimmunity remains an enigma; however, growing evidence points to a possible involvement of lymphokines both in the initiation phase and especially in the effector stage of many autoimmune diseases. Although no single experimental approach can accurately mimic the highly complex interplay of genetic, hormonal, and immune factors inherent in the development of autoimmunity, several lines of evidence strongly suggest a major role for lymphokines, in particular interferons (IFN), tumor necrosis factor (TNF), and interleukins 1 and 2 (IL-1, IL-2). These include the pleiotropic biologic activities of lymphokines which often synergize and interact, and can mediate several prominent clinical and laboratory manifestations of autoimmunity. Patients undergoing therapy with IFN or IL-2 may develop varied autoimmune syndromes, often an exacerbation of previously latent autoimmunity. Likewise, the administration of IFN to experimental animals can cause or accelerate autoimmune disease and, more importantly, specific lymphokine blockade was shown to be protective. Moreover, in the animal models of autoimmunity and in many patients with autoimmune diseases, increased lymphokine levels can be demonstrated either in the circulation or locally, often correlating with disease activity. Finally, aberrant MHC class II expression on nonlymphoid cells can be identified in the target organs of most autoimmune diseases and extensive data suggest that it can present autoantigen, activate autoreactive T cells, and initiate a cascade of self-propagating autoimmunity. Thus, a local release of IFN-γ, the major inducer of MHC class II, may be pivotal to the development of organ-specific autoimmunity. The central role of cytokines in lymphocyte traffic into inflammatory sites as well as a growing understanding of lymphokine production patterns by different T cell subsets important in autoimmunity lends further support for this hypothesis, at the same time revealing that certain lymphokines may have a protective inhibitory effect on autoimmunity (e.g., IL-4, TGF-β). In conclusion, varied data strongly suggest that several lymphokines, produced mainly locally and interacting with each other, have an important role in the pathogenesis of autoimmunity. Although the initiating events and complex interactions remain largely unclear, recent advances are encouraging, and may lead to specific manipulations of lymphokines in the future treatment of autoimmune diseases.     

Cytokine genetic profile in Whipple’s disease

Whipple’s disease (WD) is a very rare chronic systemic condition characterised by a Th2/T regulatory (Treg) dysregulated immune response versus Tropheryma whipplei, a bacterium widely diffuse in the environment. To investigate whether this Th2/Treg polarised response has a genetic background, we investigated the Th1, Th2, Th17 and Treg cytokine genetic profile of 133 patients with WD. Thanks to the European Consortium on WD (QLG1-CT-2002-01049), the polymorphism of 13 cytokine genes was analysed in 111 German and 22 Italian patients using the polymerase chain reaction with sequence-specific primers (PCR-SSP) technique. The frequencies of the genotypes, haplotypes and functional phenotypes were compared with those obtained in 201 German and 140 Italian controls. Clinical heterogeneity was also considered. Functionally, WD patients may be considered as low producers of TGF-β1, having an increased frequency of the genotype TGF-β1+869C/C,+915C/C [12.3?% vs. 3.81?%, odds ratio (OR)?=?4.131, p?=?0.0002] and high secretors of IL-4, carrying the genotype IL-4-590T/T (5.34?% vs. 1.17?%, OR?=?5.09, p?=?0.0096). No significant association was found between cytokine polymorphism and clinical variability. Analogously to the recent cellular findings of a Th2/Treg polarised response, we showed that the cytokine genetic profile of WD patients is skewed toward a Th2 and Treg response. This was similar in both German and Italian populations. However, the significant deviations versus the controls are poorer than that expected on the basis of these recent cellular findings.     

Should we be more cre-tical? A cautionary tale of recombination

The cre-loxP system has been revolutionary in the field of immunology. The technology enables genetic deletion in mice with unprecedented precision. It is therefore now widely used to investigate gene functions in animal models of disease, and in fundamental studies of the immune response. This widespread adoption of cre-loxP technology has allowed a thorough investigation of its strengths and weaknesses. Here we highlight an important paper which not only describes potential problems with the commonly-used screening procedures used when identifying offspring of the correct genotype, but also describes how this screening can be improved to ensure that the right animals are produced.     

A cautionary tale: Is this APOB whole-gene duplication actually pathogenic?

A 22-year-old woman presented with elevated low-density lipoprotein (LDL) cholesterol and clinically suspected familial hypercholesterolemia. Initial genetic analysis by Sanger sequencing found no causal variants in LDLR or other familial hypercholesterolemia genes. More than a decade later, her 9-year-old daughter was also found to have elevated LDL cholesterol. Re-analysis using current genetic methodology detected a novel whole-gene duplication of APOB in both individuals, which was tentatively assumed to explain their elevated LDL cholesterol based mainly on biological plausibility. However, on further assessment with cascade screening and cosegregation analysis involving multiple family members, the APOB duplication was eventually discounted as being causative. This case illustrates the risk of assuming pathogenicity of a novel genetic variant without undertaking corroborative diagnostic measures. It further highlights the time and skill required for accurate variant analysis and emphasizes the challenges faced by clinicians who are increasingly expected to rapidly interpret such results without sufficient time or resources to pursue supportive or corroborating evidence.     

Autoimmunity in dry eye disease – An updated review of evidence on effector and memory Th17 cells in disease pathogenicity

The classic Th1/Th2 dogma has been significantly reshaped since the subsequent introduction of several new T helper cell subsets, among which the most intensively investigated during the last decade is the Th17 lineage that demonstrates critical pathogenic roles in autoimmunity and chronic inflammation – including the highly prevalent dry eye disease. In this review, we summarize current concepts of Th17-mediated disruption of ocular surface immune homeostasis that leads to autoimmune inflammatory dry eye disease, by discussing the induction, activation, differentiation, migration, and function of effector Th17 cells in disease development, highlighting the phenotypic and functional plasticity of Th17 lineage throughout the disease initiation, perpetuation and sustention. Furthermore, we emphasize the most recent advance in Th17 memory formation and function in the chronic course of dry eye disease, a major area to be better understood for facilitating the development of effective treatments in a broader field of autoimmune diseases that usually present a chronic course with recurrent episodes of flare in the target tissues or organs.     

Retroviruses in autoimmune liver disease: genetic or environmental agents?

Retroviruses have been implicated in the pathogenesis of several human autoimmune conditions including Sj?gren's syndrome, primary biliary cirrhosis, immune mediated diabetes, and multiple sclerosis. The human intracisternal A type particle derived from Sj?gren's syndrome patients' salivary glands was the first retrovirus to be isolated from a human autoimmune disorder but the agent has yet to be cloned. In primary biliary cirrhosis patients, virus like particles have been observed by electron microscopy in biliary epithelium, endogenous retroviral sequences have been cloned from liver samples, and antibody reactivity to the human intracisternal A type particle has been observed in the majority of patients tested. However, there is no evidence to link the endogenous retroviral sequences in primary biliary cirrhosis patients to the retroviral antibody reactivity or virus like particles. In other patients with liver disease, reactivity to the human intracisternal A type particle was observed in a small but significant proportion of patients with hepatitis C virus infection. If the intracisternal A type particle is an endogenous retrovirus, it is interesting to speculate that hepatitis C virus infection may modulate the endogenous retroviral expression, as chronic hepatitis C has been linked with the development of Sj?gren's syndrome. Furthermore, many patients with chronic hepatitis C virus infection have reactivity to an autoantigen of unknown significance known as GOR that has protein sequence homology with both hepatitis C virus nucleocapsid protein as well as HTLV-1 gag. This may be an another example of an endogenous retroviral protein acting as an autoantigen in liver disease patients. At this time, there is little evidence to suggest that endogenous retroviruses are infectious agents that cause autoimmune disease but they may be implicated as either genetic elements or antigens. Further studies will be required to characterize the role that both exogenous and endogenous retroviruses play in the pathogenesis of autoimmune liver diseases.     

Advances in avian immunology—prospects for disease control: a review

In order to develop novel solutions to avian disease problems, including novel vaccines and/or vaccine adjuvants, and the identification of disease resistance genes which can feed into conventional breeding programmes, it is necessary to gain a more thorough understanding of the avian immune response and how pathogens can subvert that response. Birds occupy the same habitats as mammals, have similar ranges of longevity and body mass, and face similar pathogen challenges, yet birds have a different repertoire of organs, cells, molecules and genes of the immune system compared to mammals. This review summarises the current state of knowledge of the chicken's immune response, highlighting differences in the bird compared to mammals, and discusses how the availability of the chicken genome sequence and the associated postgenomics technologies are contributing to theses studies and also to the development of novel intervention strategies againts avian and zoonotic disease.     

Mitochondrial DNA polymorphisms and haplogroups in Parkinson’s disease and control individuals with a similar genetic background

Mitochondrial complex I deficiency has been implicated in the pathogenesis of Parkinson’s disease (PD), but as yet no mitochondrial DNA (mtDNA) variations have been identified that could account for the impaired complex I activity. On the other hand, it has been suggested that mtDNA polymorphisms (mtSNPs) or haplogroups may modify the risk of developing PD. Here, we determined the distributions of ten mtSNPs that define the nine major European haplogroups among 224 PD patients and 383 controls from Crete, an island of 0.6 million inhabitants who share a similar genetic background and a common environment. The recruitment of patients and controls was restricted to individuals of Cretan origin for at least three generations from both parental sides in order to avoid population admixture and subsequent genetic heterogeneity. We found no mtSNP or mtDNA haplogroup that predisposes to PD, although there was a trend for haplogroups J, T, U and I and the supercluster of haplogroups UKJT to be slightly underrepresented in our PD patients as compared to controls. While a combination of common mtSNPs (present in ≥5% of the general population) may decrease the chance of developing PD, this effect was minor in the Cretan population.     

Influence of genetic and cardiometabolic risk factors in Alzheimer’s disease

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder. Cardiometabolic and genetic risk factors play an important role in the trajectory of AD. Cardiometabolic risk factors including diabetes, mid-life obesity, mid-life hypertension and elevated cholesterol have been linked with cognitive decline in AD subjects. These potential risk factors associated with cerebral metabolic changes which fuel AD pathogenesis have been suggested to be the reason for the disappointing clinical trial results. In appreciation of the risks involved, using search engines such as PubMed, Scopus, MEDLINE and Google Scholar, a relevant literature search on cardiometabolic and genetic risk factors in AD was conducted. We discuss the role of genetic as well as established cardiovascular risk factors in the neuropathology of AD. Moreover, we show new evidence of genetic interaction between several genes potentially involved in different pathways related to both neurodegenerative process and cardiovascular damage.     

Abnormalities in the handling of intracellular bacteria in Crohn’s disease: a link between infectious etiology and host genetic susceptibility

The etiology of Crohn's disease (CD) is still poorly understood, but recent advances have highlighted the importance of the innate immune system and the critical relationship between the gut flora and the intestinal mucosa. Several combinations of genetic factors predisposing to CD have been described, with the most significant replicable associations including genes for intracellular receptors of bacterial cell walls (NOD2/CARD15) and for bacterial clearance and antigen processing via autophagy (ATG16L1 and IRGM). One theoretical link between susceptibility genes NOD2/CARD15, ATG16L1, and IRGM is that CD is primarily induced by the presence of a dysfunctional immunological response to persistent infection by intracellular bacterial pathogens such as Mycobacterium avium subspecies paratuberculosis or adherent-invasive Escherichia coli, both first-rank candidates on the basis of host genetic susceptibility, which concerns impaired functions in the defense against intracellular bacteria.     

Hypoxia-induced genetic instability—a calculated mechanism underlying tumor progression

The cause of human cancers is imputed to the genetic alterations at nucleotide and chromosomal levels of ill-fated cells. It has long been recognized that genetic instability-the hallmark of human cancers-is responsible for the cellular changes that confer progressive transformation on cancerous cells. How cancer cells acquire genetic instability, however, is unclear. We propose that tumor development is a result of expansion and progression-two complementary aspects that collaborate with the tumor microenvironment-hypoxia in particular, on genetic alterations through the induction of genetic instability. In this article, we review the recent literature regarding how hypoxia functionally impairs various DNA repair pathways resulting in genetic instability and discuss the biomedical implications in cancer biology and treatment.     

How many cases of disease in a pedigree imply familial disease?

The ability to perform whole‐exome and, increasingly, whole‐genome sequencing on large numbers of individuals has led to increased efforts to identify rare genetic variants that affect the risk of both common and rare diseases. In such applications, it is important to identify families that are segregating the rare variants of interest. For rare diseases or rare familial forms of common diseases, pedigrees with multiple affected members are clearly harbouring risk variants. For more common diseases, however, it may be unclear whether a family with a few affected members is segregating a familial disease, is the result of multiple sporadic cases, or is a mixture of familial cases and phenocopies. We provide calculations for the probability that a family is harbouring familial disease, presented in general terms that admit working guidelines for selecting families for current sequencing studies. Using examples motivated by our own studies of thyroid cancer and published studies of colorectal cancer, we show that for common diseases, families with exactly two affected first‐degree relatives have only a moderate probability of segregating familial disease, but this probability is higher for families with three or more affected relatives, and those families should therefore be prioritised in sequencing studies.     

Is the ornithine transcarbamylase gene a genetic determinant of Alzheimer’s disease?

Expression of ornithine transcarbamylase (OTC) is strongly induced in the brain of individuals suffering from Alzheimer's Disease (AD). Association studies in a population from northern France have revealed that two SNPs -389 G/A (rs5963409) and -241 A/G (rs5963411) located in the promoter of the OTC gene are associated with the risk of developing AD. In the present work, these association studies were extended to a population of 2113 AD cases and 1580 controls from northern France, western France, the United Kingdom and Italy. The rs5963409 minor allele was weakly but significantly associated with an increased risk of developing AD (OR=1.19, p=0.004). This association was independent of age and ApoE status. Our results support that the OTC gene may be a minor genetic determinant of AD.     

Interleukin-23 receptor genetic polymorphisms and Crohn’s disease susceptibility: a meta-analysis

Objective  

This study was designed to evaluate whether interleukin-23 receptor (IL-23R) polymorphisms were associated with Crohn’s disease (CD) susceptibility.