Case Report Diagnostic Challenges of Cryptococcus neoformans in an Immunocompetent Individual Masquerading as Chronic Hydrocephalus

Cryptococcus neoformans can cause disseminated meningoencephalitis and evade immunosurveillance with expression of a major virulence factor, the polysaccharide capsule. Direct diagnostic assays often rely on the presence of the cryptococcal glucuronoxylomannan capsular antigen (CrAg) or visualization of the capsule. Strain specific phenotypic traits and environmental conditions influence differences in expression that can thereby compromise detection and timely diagnosis. Immunocompetent hosts may manifest clinical signs and symptoms indolently, often expanding the differential and delaying appropriate treatment and diagnosis. We describe a 63-year-old man who presented with a progressive four-year history of ambulatory dysfunction, headache, and communicating hydrocephalus. Serial lumbar punctures (LPs) revealed elevated protein (153-300 mg/dL), hypoglycorrhachia (19-47 mg/dL), lymphocytic pleocytosis (89-95% lymphocyte, WBC 67-303 mg/dL, and RBC 34-108 mg/dL), and normal opening pressure (13-16 cm H 2 O). Two different cerebrospinal fluid (CSF) CrAg assays were negative. A large volume CSF fungal culture grew unencapsulated C. neoformans. He was initiated on induction therapy with amphotericin B plus flucytosine and consolidation/maintenance therapy with flucytosine, but he died following discharge due to complications. Elevated levels of CSF Th1 cytokines and decreased IL6 may have affected the virulence and detection of the pathogen

RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis—Novel Targets for Therapy?

Susceptibility to ankylosing spondylitis (AS) is polygenic with more than 100 genes identified to date. These include HLA-B27 and the aminopeptidases (ERAP1, ERAP2, and LNPEPS), which are involved in antigen processing and presentation to T-cells, and several genes (IL23R, IL6R, STAT3, JAK2, IL1R1/2, IL12B, and IL7R) involved in IL23 driven pathways of inflammation. AS is also strongly associated with polymorphisms in two transcription factors, RUNX3 and T-bet (encoded by TBX21), which are important in T-cell development and function. The influence of these genes on the pathogenesis of AS and their potential for identifying drug targets is discussed here

Detection of group A Streptococcus in tonsils from pediatric patients reveals high rate of asymptomatic streptococcal carriage

<p>Abstract</p> <p>Background</p> <p>Group A <it>Streptococcus </it>(GAS) causes acute tonsillopharyngitis in children, and approximately 20% of this population are chronic carriers of GAS. Antibacterial therapy has previously been shown to be insufficient at clearing GAS carriage. Bacterial biofilms are a surface-attached bacterial community that is encased in a matrix of extracellular polymeric substances. Biofilms have been shown to provide a protective niche against the immune response and antibiotic treatments, and are often associated with recurrent or chronic bacterial infections. The objective of this study was to test the hypothesis that GAS is present within tonsil tissue at the time of tonsillectomy.</p> <p>Methods</p> <p>Blinded immunofluorescent and histological methods were employed to evaluate palatine tonsils from children undergoing routine tonsillectomy for adenotonsillar hypertrophy or recurrent GAS tonsillopharyngitis.</p> <p>Results</p> <p>Immunofluorescence analysis using anti-GAS antibody was positive in 11/30 (37%) children who had tonsillectomy for adenotonsillar hypertrophy and in 10/30 (33%) children who had tonsillectomy for recurrent GAS pharyngitis. Fluorescent microscopy with anti-GAS and anti-cytokeratin 8 & 18 antibodies revealed GAS was localized to the tonsillar reticulated crypts. Scanning electron microscopy identified 3-dimensional communities of cocci similar in size and morphology to GAS. The characteristics of these communities are similar to GAS biofilms from <it>in vivo </it>animal models.</p> <p>Conclusion</p> <p>Our study revealed the presence of GAS within the tonsillar reticulated crypts of approximately one-third of children who underwent tonsillectomy for either adenotonsillar hypertrophy or recurrent GAS tonsillopharyngitis at the Wake Forest School of Medicine.</p> <p>Trial Registration</p> <p>The tissue collected was normally discarded tissue and no patient identifiers were collected. Thus, no subjects were formally enrolled.</p

Allelic replacement of the streptococcal cysteine protease SpeB in a Δsrv mutant background restores biofilm formation

<p>Abstract</p> <p>Background</p> <p>Group A <it>Streptococcus </it>(GAS) is a Gram-positive human pathogen that is capable of causing a wide spectrum of human disease. Thus, the organism has evolved to colonize a number of physiologically distinct host sites. One such mechanism to aid colonization is the formation of a biofilm. We have recently shown that inactivation of the streptococcal regulator of virulence (Srv), results in a mutant strain exhibiting a significant reduction in biofilm formation. Unlike the parental strain (MGAS5005), the streptococcal cysteine protease (SpeB) is constitutively produced by the <it>srv </it>mutant (MGAS5005Δ<it>srv</it>) suggesting Srv contributes to the control of SpeB production. Given that SpeB is a potent protease, we hypothesized that the biofilm deficient phenotype of the <it>srv </it>mutant was due to the constitutive production of SpeB. In support of this hypothesis, we have previously demonstrated that treating cultures with E64, a commercially available chemical inhibitor of cysteine proteases, restored the ability of MGAS5005Δ<it>srv </it>to form biofilms. Still, it was unclear if the loss of biofilm formation by MGAS5005Δ<it>srv </it>was due only to the constitutive production of SpeB or to other changes inherent in the <it>srv </it>mutant strain. To address this question, we constructed a Δ<it>srv</it>Δ<it>speB </it>double mutant through allelic replacement (MGAS5005Δ<it>srv</it>Δ<it>speB</it>) and tested its ability to form biofilms <it>in vitro</it>.</p> <p>Findings</p> <p>Allelic replacement of <it>speB </it>in the <it>srv </it>mutant background restored the ability of this strain to form biofilms under static and continuous flow conditions. Furthermore, addition of purified SpeB to actively growing wild-type cultures significantly inhibited biofilm formation.</p> <p>Conclusions</p> <p>The constitutive production of SpeB by the <it>srv </it>mutant strain is responsible for the significant reduction of biofilm formation previously observed. The double mutant supports a model by which Srv contributes to biofilm formation and/or dispersal through regulation of <it>speB</it>/SpeB.</p

Dispersal of Group A Streptococcal Biofilms by the Cysteine Protease SpeB Leads to Increased Disease Severity in a Murine Model

Group A Streptococcus (GAS) is a Gram-positive human pathogen best known for causing pharyngeal and mild skin infections. However, in the 1980's there was an increase in severe GAS infections including cellulitis and deeper tissue infections like necrotizing fasciitis. Particularly striking about this elevation in the incidence of severe disease was that those most often affected were previously healthy individuals. Several groups have shown that changes in gene content or regulation, as with proteases, may contribute to severe disease; yet strains harboring these proteases continue to cause mild disease as well. We and others have shown that group A streptococci (MGAS5005) reside within biofilms both in vitro and in vivo. That is to say that the organism colonizes a host surface and forms a 3-dimensional community encased in a protective matrix of extracellular protein, DNA and polysaccharide(s). However, the mechanism of assembly or dispersal of these structures is unclear, as is the relationship of these structures to disease outcome. Recently we reported that allelic replacement of the streptococcal regulator srv resulted in constitutive production of the streptococcal cysteine protease SpeB. We further showed that the constitutive production of SpeB significantly decreased MGAS5005Δsrv biofilm formation in vitro. Here we show that mice infected with MGAS5005Δsrv had significantly larger lesion development than wild-type infected animals. Histopathology, Gram-staining and immunofluorescence link the increased lesion development with lack of disease containment, lack of biofilm formation, and readily detectable levels of SpeB in the tissue. Treatment of MGAS5005Δsrv infected lesions with a chemical inhibitor of SpeB significantly reduced lesion formation and disease spread to wild-type levels. Furthermore, inactivation of speB in the MGAS5005Δsrv background reduced lesion formation to wild-type levels. Taken together, these data suggest a mechanism by which GAS disease may transition from mild to severe through the Srv mediated dispersal of GAS biofilms

Rationale, design and methods for a randomised and controlled trial of the impact of virtual reality games on motor competence, physical activity, and mental health in children with developmental coordination disorder.

This is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: A healthy start to life requires adequate motor development and physical activity participation. Currently 5-15% of children have impaired motor development without any obvious disorder. These children are at greater risk of obesity, musculoskeletal disorders, low social confidence and poor mental health. Traditional electronic game use may impact on motor development and physical activity creating a vicious cycle. However new virtual reality (VR) game interfaces may provide motor experiences that enhance motor development and lead to an increase in motor coordination and better physical activity and mental health outcomes. VR games are beginning to be used for rehabilitation, however there is no reported trial of the impact of these games on motor coordination in children with developmental coordination disorder. METHODS: This cross-over randomised and controlled trial will examine whether motor coordination is enhanced by access to active electronic games and whether daily activity, attitudes to physical activity and mental health are also enhanced. Thirty children aged 10-12 years with poor motor coordination (≤ 15th percentile) will be recruited and randomised to a balanced ordering of 'no active electronic games' and 'active electronic games'. Each child will participate in both conditions for 16 weeks, and be assessed prior to participation and at the end of each condition. The primary outcome is motor coordination, assessed by kinematic and kinetic motion analysis laboratory measures. Physical activity and sedentary behaviour will be assessed by accelerometry, coordination in daily life by parent report questionnaire and attitudes to physical activity, self-confidence, anxiety and depressed mood will be assessed by self report questionnaire. A sample of 30 will provide a power of > 0.9 for detecting a 5 point difference in motor coordination on the MABC-2 TIS scale (mean 17, sd = 5). DISCUSSION: This is the first trial to examine the impact of new virtual reality games on motor coordination in children with developmental coordination disorder. The findings will provide critical information to understand whether these electronic games can be used to have a positive impact on the physical and mental health of these children. Given the importance of adequate motor coordination, physical activity and mental health in childhood, this project can inform interventions which could have a profound impact on the long term health of this group of children. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12611000400965.This randomised and controlled trial is funded by the National Health and Medical Research Council (NHMRC) of Australia through project grant #533526. Professor Leon Straker and Doctor Anne Smith are supported by fellowships awarded from the NHMRC. No funding or other input to the study has been received from any electronic game design, manufacture or supply company

Disseminated tuberculosis with prostatic abscesses in an immunocompromised patient—A case report and review of literature

We describe a case of disseminated Mycobacterium tuberculosis (mTB) with prostatic abscess in a newly diagnosed HIV patient in the United States. The patient is a 34 year-old male who presented with respiratory symptoms and was diagnosed with HIV/AIDS complicated by disseminated mTB infection of the lungs, liver, and prostate. His prostate showed abscess formation on imaging that required drainage however he did not present with any genitourinary complaints. Our literature review revealed that prostatic involvement in mTB in the form of granulomatous prostatitis is uncommon; however, abscess formation is extremely rare and only few such cases have been published. Nearly 50% of the patients with prostatic abscess formation present without symptoms and therefore a high level of suspicion should be maintained; imaging should be performed early and prophylactic antibiotics for non-specific urinary symptoms should be avoided as this may lead to drug resistance of mTB to flouroquinolones

Bordetella petrii recovered from chronic pansinusitis in an adult with cystic fibrosis

AbstractTo date Bordetella petrii has infrequently been identified within the clinical setting likely due to the asaccharolytic nature of this organism. We present a case of B. petrii recovered on two separate events in a patient with adult cystic fibrosis experiencing chronic pansinusitis

Reduced dosage of the modifiers of epigenetic reprogramming Dnmt1, Dnmt3L, SmcHD1 and Foxo3a has no detectable effect on mouse telomere length in vivo

Studies carried out in cultured cells have implicated modifiers of epigenetic reprogramming in the regulation of telomere length, reporting elongation in cells that were null for DNA methyltransferase DNA methyltransferase 1 (Dnmt1), both de novo DNA methyltransferases, Dnmt3a and Dnmt3b or various histone methyltransferases. To investigate this further, we assayed telomere length in whole embryos or adult tissue from mice carrying mutations in four different modifiers of epigenetic reprogramming: Dnmt1, DNA methyltransferase 3-like, structural maintenance of chromosomes hinge domain containing 1, and forkhead box O3a. Terminal restriction fragment analysis was used to compare telomere length in homozygous mutants, heterozygous mutants and wild-type littermates. Contrary to expectation, we did not detect overall lengthening in the mutants, raising questions about the role of epigenetic processes in telomere length in vivo