Serious Bacterial Infections Acquired During Treatment of Patients Given a Diagnosis of Chronic Lyme Disease - United States.

The term "chronic Lyme disease" is used by some health care providers as a diagnosis for various constitutional, musculoskeletal, and neuropsychiatric symptoms (1,2). Patients with a diagnosis of chronic Lyme disease have been provided a wide range of medications as treatment, including long courses of intravenous (IV) antibiotics (3,4). Studies have not shown that such treatments lead to substantial long-term improvement for patients, and they can be harmful (1,5). This report describes cases of septic shock, osteomyelitis, Clostridium difficile colitis, and paraspinal abscess resulting from treatments for chronic Lyme disease. Patients, clinicians, and public health practitioners should be aware that treatments for chronic Lyme disease can carry serious risks.

Acute flaccid paralysis with anterior myelitis - California, June 2012-June 2014.

In August 2012, the California Department of Public Health (CDPH) was contacted by a San Francisco Bay area clinician who requested poliovirus testing for an unvaccinated man aged 29 years with acute flaccid paralysis (AFP) associated with anterior myelitis (i.e., evidence of inflammation of the spinal cord involving the grey matter including anterior horn cell bodies) and no history of international travel during the month before symptom onset. Within 2 weeks, CDPH had received reports of two additional cases of AFP with anterior myelitis of unknown etiology. Testing at CDPH's Viral and Rickettsial Disease Laboratory for stool, nasopharyngeal swab, and cerebrospinal fluid (CSF) did not detect the presence of an enterovirus (EV), the genus of the family Picornaviridae that includes poliovirus. Additional laboratory testing for infectious diseases conducted at the CDPH Viral and Rickettsial Disease Laboratory did not identify a causative agent to explain the observed clinical syndrome reported among the patients. To identify other cases of AFP with anterior myelitis and elucidate possible common etiologies, CDPH posted alerts in official communications for California local health departments during December 2012, July 2013, and February 2014. Reports of cases of neurologic illness received by CDPH were investigated throughout this period, and clinicians were encouraged to submit clinical samples for testing. A total of 23 cases of AFP with anterior myelitis of unknown etiology were identified. Epidemiologic and laboratory investigation did not identify poliovirus infection as a possible cause for the observed cases. No common etiology was identified to explain the reported cases, although EV-D68 was identified in upper respiratory tract specimens of two patients. EV infection, including poliovirus infection, should be considered in the differential diagnosis in cases of AFP with anterior myelitis and testing performed per CDC guidelines.

Repeated nuclear translocations underlie photoreceptor positioning and lamination of the outer nuclear layer in the mammalian retina.

In development, almost all stratified neurons must migrate from their birthplace to the appropriate neural layer. Photoreceptors reside in the most apical layer of the retina, near their place of birth. Whether photoreceptors require migratory events for fine-positioning and/or retention within this layer is not well understood. Here, we show that photoreceptor nuclei of the developing mouse retina cyclically exhibit rapid, dynein-1-dependent translocation toward the apical surface, before moving more slowly in the basal direction, likely due to passive displacement by neighboring retinal nuclei. Attenuating dynein 1 function in rod photoreceptors results in their ectopic basal displacement into the outer plexiform layer and inner nuclear layer. Synapse formation is also compromised in these displaced cells. We propose that repeated, apically directed nuclear translocation events are necessary to ensure retention of post-mitotic photoreceptors within the emerging outer nuclear layer during retinogenesis, which is critical for correct neuronal lamination.

Transplanted Donor- or Stem Cell-Derived Cone Photoreceptors Can Both Integrate and Undergo Material Transfer in an Environment-Dependent Manner.

Human vision relies heavily upon cone photoreceptors, and their loss results in permanent visual impairment. Transplantation of healthy photoreceptors can restore visual function in models of inherited blindness, a process previously understood to arise by donor cell integration within the host retina. However, we and others recently demonstrated that donor rod photoreceptors engage in material transfer with host photoreceptors, leading to the host cells acquiring proteins otherwise expressed only by donor cells. We sought to determine whether stem cell- and donor-derived cones undergo integration and/or material transfer. We find that material transfer accounts for a significant proportion of rescued cells following cone transplantation into non-degenerative hosts. Strikingly, however, substantial numbers of cones integrated into the Nrl-/- and Prph2rd2/rd2, but not Nrl-/-;RPE65R91W/R91W, murine models of retinal degeneration. This confirms the occurrence of photoreceptor integration in certain models of retinal degeneration and demonstrates the importance of the host environment in determining transplantation outcome.

Acetaminophen, phenacetin and dipyrone do not modulate pressor responses to arachidonic Acid or to pressor agents.

In contrast to nonsteroidal anti-inflammatory drugs (NSAIDs), the nonopioid analgesics phenacetin, acetaminophen and dipyrone exhibit weak anti-inflammatory properties. An explanation for this difference in pharmacologic activity was provided by the recent discovery of a new cyclooxygenase isoform, cyclooxygenase (COX)-3, that is reported to be inhibited by phenacetin, acetaminophen and dipyrone. However, COX-3 was found to be a spliced variant of COX-1 and renamed COX-1b. Although recent studies provide evidence for the existence of this new COX isoform, it is uncertain whether this COX-3 (COX-1b) isoform, or putative acetaminophen-sensitive pathway, plays a role in the generation of vasoactive prostaglandins. NSAIDs increase systemic blood pressure by inhibiting the formation of vasodilator prostanoids. Angiotensin II, norepinephrine and other vasoconstrictor agents have been reported to release prostaglandins. It is possible that this acetaminophen-sensitive pathway also modulates pressor responses to these vasoconstrictor agents. Therefore, the purpose of the present study was to determine whether this acetaminophen-sensitive pathway plays a role in the generation of vasoactive products of arachidonic acid or in the modulation of vasoconstrictor responses in the pulmonary and systemic vascular bed of the intact-chest rat. In the present study, the nonopioid analgesics did not attenuate changes in pulmonary or systemic arterial pressure in response to injections of the prostanoid precursor, arachidonic acid, to the thromboxane A(2) mimic, U46619, or to angiotensin II or norepinephrine. The results of the present study do not provide evidence in support of a role of a functional COX-3 (COX-1b) isoform, or an acetaminophen-sensitive pathway, in the generation of vasoactive prostanoids or in the modulation of responses to vasoconstrictor hormones in the intact-chest rat.

Expression of Aspergillus niger CAZymes is determined by compositional changes in wheat straw generated by hydrothermal or ionic liquid pretreatments.

BACKGROUND: The capacity of fungi, such as Aspergillus niger, to degrade lignocellulose is harnessed in biotechnology to generate biofuels and high-value compounds from renewable feedstocks. Most feedstocks are currently pretreated to increase enzymatic digestibility: improving our understanding of the transcriptomic responses of fungi to pretreated lignocellulosic substrates could help to improve the mix of activities and reduce the production costs of commercial lignocellulose saccharifying cocktails. RESULTS: We investigated the responses of A. niger to untreated, ionic liquid and hydrothermally pretreated wheat straw over a 5-day time course using RNA-seq and targeted proteomics. The ionic liquid pretreatment altered the cellulose crystallinity while retaining more of the hemicellulosic sugars than the hydrothermal pretreatment. Ionic liquid pretreatment of straw led to a dynamic induction and repression of genes, which was correlated with the higher levels of pentose sugars saccharified from the ionic liquid-pretreated straw. Hydrothermal pretreatment of straw led to reduced levels of transcripts of genes encoding carbohydrate-active enzymes as well as the derived proteins and enzyme activities. Both pretreatments abolished the expression of a large set of genes encoding pectinolytic enzymes. These reduced levels could be explained by the removal of parts of the lignocellulose by the hydrothermal pretreatment. The time course also facilitated identification of temporally limited gene induction patterns. CONCLUSIONS: The presented transcriptomic and biochemical datasets demonstrate that pretreatments caused modifications of the lignocellulose, to both specific structural features as well as the organisation of the overall lignocellulosic structure, that determined A. niger transcript levels. The experimental setup allowed reliable detection of substrate-specific gene expression patterns as well as hitherto non-expressed genes. Our data suggest beneficial effects of using untreated and IL-pretreated straw, but not HT-pretreated straw, as feedstock for CAZyme production.

Genetic Variation in the IL-6 and HLA-DQB1 Genes Is Associated with Spontaneous Clearance of Hepatitis C Virus Infection.

Background. Millions of people are infected with hepatitis C virus (HCV) worldwide and 30% spontaneously clear the infection. Reasons for HCV clearance without antiviral treatment are not well understood. Methods. Blood was collected for DNA analysis from patients with chronic HCV infection or evidence of spontaneous clearance. To overcome anticipated limitations of small sample size, primary analyses consisted of a candidate gene analysis of 12 preselected genes based on known association with host immunologic response to HCV infection. To further reduce the impact of multiple testing on power, a single likelihood ratio test was conducted for each gene using all associated SNPs assayed on the Illumina Quad 610/660W chip. Step-down permutation methods were used to adjust for multiple testing in all analyses. Results. Ninety-five and 62 patients with HCV chronic infection or spontaneous clearance, respectively, were included for analysis. HLA-DQB1 (p = 1.76⁎10(-5)) and IL-6 (p = 0.0007) genes were significantly associated with spontaneous HCV clearance. IL-28B was not significantly associated with spontaneous clearance (p = 0.17). Conclusion. Our whole-gene analytic strategy identified a previously unreported association of IL-6 with spontaneous clearance of HCV infection. We also confirmed the finding that HLA-DQB1 is associated with spontaneous resolution of HCV infection.

Peripheral Blood Mononuclear Cell Gene Expression Remains Broadly Altered Years after Successful Interferon-Based Hepatitis C Virus Treatment.

BACKGROUND: Inflammatory gene expression in peripheral blood mononuclear cells (PBMCs) is altered in chronic Hepatitis C Virus (HCV) infection. Duration of changes after pegylated interferon- (peg-IFN-) based HCV treatment is unclear. METHODS: PBMC mRNA expression of 184 inflammatory response genes was analyzed (nCounter GX Human Inflammation Kit, Nanostring) from peg-IFN treatment nonresponders (NR, n = 18), sustained virologic responders (SVR, n = 22), and spontaneous clearers (SC, n = 15). Logistic regression was used for comparison. RESULTS: Median time from last treatment was 2 and 2.7 years in SVR and NR, respectively (p = NS). Mean mRNA counts were significantly different for 42 and 29 genes comparing SVR to SC patients and NR to SC, respectively, and no genes comparing SVR to NR. Differential expression of 24 genes was significantly different in both SVR and NR groups compared to SC. Among these 24 acute and chronic inflammatory cascade genes, significant upregulation was noted for proinflammatory transcription regulators Fos, CEBPB, and MyD88 in SVR and NR compared to SC. HDAC4 was significantly downregulated in SVR and NR compared to the SC group. CONCLUSIONS: PBMC inflammatory gene expression patterns in SVR resemble NR more than SC patients. A generalized inflammatory response persists in PBMCs long after successful peg-IFN treatment for HCV infection.

Expression of Mitochondrial Cytochrome C Oxidase Chaperone Gene (COX20) Improves Tolerance to Weak Acid and Oxidative Stress during Yeast Fermentation.

INTRODUCTION: Saccharomyces cerevisiae is the micro-organism of choice for the conversion of fermentable sugars released by the pre-treatment of lignocellulosic material into bioethanol. Pre-treatment of lignocellulosic material releases acetic acid and previous work identified a cytochrome oxidase chaperone gene (COX20) which was significantly up-regulated in yeast cells in the presence of acetic acid. RESULTS: A Δcox20 strain was sensitive to the presence of acetic acid compared with the background strain. Overexpressing COX20 using a tetracycline-regulatable expression vector system in a Δcox20 strain, resulted in tolerance to the presence of acetic acid and tolerance could be ablated with addition of tetracycline. Assays also revealed that overexpression improved tolerance to the presence of hydrogen peroxide-induced oxidative stress. CONCLUSION: This is a study which has utilised tetracycline-regulated protein expression in a fermentation system, which was characterised by improved (or enhanced) tolerance to acetic acid and oxidative stress.

MicroRNA and hepatitis C virus--challenges in investigation and translation: a review of the literature.

Investigations into the role of microRNA (miRNA) in hepatitis C virus (HCV) infection, disease pathogenesis and host immune and treatment response have potential to produce innovations in diagnosis, prognosis and therapy. However, investigational challenges remain in generating clinically useful and reproducible results. We review the literature with a primary emphasis on methods and technologies used to construct our current understanding of miRNA and HCV disease. A second emphasis is to understand potential clinical research applications and provide clarification of previous study results. Many miRNA have key roles in viral and immunopathogenesis of HCV infection across multiple tissue compartments. Controversy exists among published studies regarding relative measurements, temporal changes and biological significance of specific miRNA and HCV infection. To reconcile diverging data, additional research into optimal sample processing, in vitro models, techniques for microarray differential expression of miRNAs, practices for sample result normalization, and effect of HCV genotype variation on expression are all necessary. Microarray and miRNA isolation techniques should be selected based on ability to generate reproducible results in the sample type of interest. More direct comparisons of efficacy and reliability of various multiplex microarrays and an improved consensus around miRNA normalization and quantitation are necessary so that data can be compared across studies.

Potential application for mesenchymal stem cells in the treatment of cardiovascular diseases.

Stem cells isolated from various sources have been shown to vary in their differentiation capacity or pluripotentiality. Two groups of stem cells, embryonic and adult stem cells, may be capable of differentiating into any desired tissue or cell type, which offers hope for the development of therapeutic applications for a large number of disorders. However, major limitations with the use of embryonic stem cells for human disease have led researchers to focus on adult stem cells as therapeutic agents. Investigators have begun to examine postnatal sources of pluripotent stem cells, such as bone marrow stroma or adipose tissue, as sources of mesenchymal stem cells. The following review focuses on recent research on the use of stem cells for the treatment of cardiovascular and pulmonary diseases and the future application of mesenchymal stem cells for the treatment of a variety of cardiovascular disorders.