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Constant exposure of human gingival fibroblasts (HGFs) to oral pathogens trigger selective immune responses. Recently, the activation of immune response to cyclic dinucleotides (CDNs) via STING has come to the forefront. Reports show that other proteins outside the STING-TBK1-IRF3 axis respond to CDNs but a global view of impacted proteome in diverse cells is lacking. HGFs are constantly exposed to bacterial-derived cyclic-di-adenosine monophosphate (c-di-AMP) and cyclic-di-guanosine monophosphate (c-di-GMP). To understand the response of HGFs to bacterial-derived CDNs, we carried out a global proteomics analysis of HGFs treated with c-di-AMP or c-di-GMP. The expression levels of several proteins modulated by CDNs were examined. Interferon signaling proteins such as Ubiquitin-like protein ISG15 (ISG15), Interferon-induced GTP-binding protein Mx1 (MX1), Interferon-induced protein with tetratricopeptide repeats (IFIT) 1 (IFIT1), and (IFIT3) were significantly upregulated. Interestingly, other pathways not fully characterized to be regulated by CDNs, such as necroptosis signaling, iron homeostasis signaling, protein ubiquitination, EIF2 signaling, sumoylation and nucleotide excision repair pathways were also modulated by the bacterial-derived CDNs. This study has added to the increasing appreciation that beyond the regulation of cytokine production via STING, cyclic dinucleotides also broadly affect many critical processes in human cells. [ABSTRACT FROM AUTHOR]

A new class of alkynyl isoquinoline antibacterial compounds, synthesized via Sonogashira coupling, with strong bactericidal activity against a plethora of Gram-positive bacteria including methicillin- and vancomycin-resistant Staphylococcus aureus (S. aureus) strains is presented. HSN584 and HSN739, representative compounds in this class, reduce methicillin-resistant S. aureus (MRSA) load in macrophages, whilst vancomycin, a drug of choice for MRSA infections, was unable to clear intracellular MRSA. Additionally, both HSN584 and HSN739 exhibited a low propensity to develop resistance. We utilized comparative global proteomics and macromolecule biosynthesis assays to gain insight into the alkynyl isoquinoline mechanism of action. Our preliminary data show that HSN584 perturb S. aureus cell wall and nucleic acid biosynthesis. The alkynyl isoquinoline moiety is a new scaffold for the development of potent antibacterial agents against fatal multidrug-resistant Gram-positive bacteria. [ABSTRACT FROM AUTHOR]

Disseminated infection with Strongyloides stercoralis refers to the massive migration of infective larvae from the gastrointestinal tract to other organs that are not involved in the normal life cycle of the parasite. We describe the case of a Nigerian male with transitional cell carcinoma of the bladder in whom larvae of S. stercoralis was identified in the urine. This report involves a 60-year old male Nigerian presenting to the Urology clinic of the Jos University teaching hospital, Nigeria with disseminated S. stercoralis. The index patient presented with a 5 month history of total haematuria, urinary frequency, urgency, nocturia, straining to pass urine, feeling of incomplete voiding and terminal dribbling. He also had episodes of suprapubic pain. Physical examination revealed a cachexic patient who had mild suprapubic tenderness. Urinary examination showed numerous red blood cells and rhabditiform larvae of S. stercoralis. Abdominal ultrasound revealed a heterogeneous mass in the urinary bladder measuring 4.0 × 3.3 cm. Abdominal computed tomography also showed an irregular mass measuring 4.2 × 3.8 cm with HU of 41 projecting into the bladder from the posterior wall towards the dome. Histology of the biopsy specimen revealed transitional cell carcinoma. The patient was treated with a single dose of oral ivermectin but died 1 week later. Physicians working in areas that are endemic for S. stercoralis should consider investigating immunocompromised patients for S. stercoralis infection given the poor prognosis of disseminated infection in this group of patients. [ABSTRACT FROM AUTHOR]

Background: We investigated predictors of in-hospital mortality and length of hospital stay among adults with community-acquired pneumonia (CAP) in Nigeria in order to provide recommendations to improve CAP outcomes in developing countries. Methods: This was a multi-centre case control study of patients ≥18 years who were admitted with CAP between 2008 and 2012. Case notes of 100 consecutive patients who died (cases) and random sample of 300 patients discharged (controls) were selected. Results: Mean ages were 55.4±19.6 (cases) and 49.3±19.2 (controls). Independent predictors of mortality were CURB-65 score ≥3: adjusted odds ratio (aOR) 24.3, late presentation: aOR 8.6, co-morbidity: aOR 3.9, delayed first dose antibiotics (>4 hours): aOR 3.5, need for supplemental oxygen: aOR 4.9, multilobar pneumonia: aOR 4.0, non-pneumococcal aetiology: aOR 6.5, anaemia: aOR 3.8 and hyperglycemia: aOR 8.6. CURB-65 ≥3 predicted mortality with a high specificity (96.1%) but low sensitivity (75%); positive predictive value of 88.2% and negative predictive value of 90.8%. Care in hospital A and B: aOR 3.3 and 2.2 respectively, male gender aOR 2.1, co-morbidity aOR 3.0, anaemia aOR 2.1 and elevated serum creatinine aOR 6.3 independently predicted length of hospital stay >10 days among survivors. Conclusions: Several modifiable patient-related and process-of-care factors predicted in-hospital mortality, and length of hospital stay among survivors. Our findings should be used to improve CAP outcomes in developing countries. [ABSTRACT FROM AUTHOR]

Background: A clear knowledge of the pathogens responsible for community-acquired pneumonia (CAP) in a given region and their antibiotic sensitivity patterns is necessary for optimal treatment. We determined the common bacterial pathogens causing CAP in Nigeria and further reviewed their antibiotic senstivity patterns with a view to providing recommendations to improve antibiotic management of CAP. Methods: Case notes of all adult patients who were 18 years or more admitted to four major tertiary hospitals in South East Nigeria with a diagnosis of CAP between 2008 and 2012 were retrospectively studied. To be eligible, patients were required to have sputum culture and sensitivity results available. Socio-demographic, clinical, pre-admission and in-hospital treatment data were also obtained. Results: Of 400 patients with a radiologically confirmed diagnosis of CAP, 232 fulfilled the study criteria; 122 (52.6%) were women and the mean age was 50.6 ± 18.8 years. Aetiological agents were identified from sputum in 189 (81.5%) patients. Streptococcus pneumoniae ( n = 90, 47.6%) was the most frequent isolate followed by Klebsiella pneumoniae ( n = 62, 32.8%), Staphylococcus aureus ( n = 24, 12.7%) and Streptococcus pyogenes ( n = 13, 6.9%). The pathogens were most sensitive to levofloxacin (77%), ceftazidime (75.5%) and ofloxacin (55.8%). The susceptibility of the isolates to antibiotics most frequently presecribed for empirical therapy was low (co-amoxiclav, 47.6%; ciprofloxacin, 45.9% and ceftriaxone, 47.6%) and this was associated with higher mortality and/or longer duration of hospital stay in survivors. Conclusion: Strep. pneumoniae and K. pneumoniae were the most common causes of CAP. The pathogens were most sensitive to levofloxacin and ceftazidime. We suggest that these antibiotics should increasingly be considered as superior options for empirical treatment of CAP in Nigeria. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VRE) have been deemed as serious threats by the CDC. Many chronic MRSA and VRE infections are due to biofilm formation. Biofilm are considered to be between 10–10,000 times more resistant to antibiotics, and therefore new chemical entities that inhibit and/or eradicate biofilm formation are needed. Teichoic acids, such as lipoteichoic acids (LTAs) and wall teichoic acids (WTAs), play pivotal roles in Gram-positive bacteria's ability to grow, replicate, and form biofilms, making the inhibition of these teichoic acids a promising approach to fight infections by biofilm forming bacteria. Here, we describe the potent biofilm inhibition activity against MRSA and VRE biofilms by two LTA biosynthesis inhibitors HSGN-94 and HSGN-189 with MBICs as low as 0.0625 µg/mL against MRSA biofilms and 0.5 µg/mL against VRE biofilms. Additionally, both HSGN-94 and HSGN-189 were shown to potently synergize with the WTA inhibitor Tunicamycin in inhibiting MRSA and VRE biofilm formation. [ABSTRACT FROM AUTHOR]

Ectonucleotide pyrophosphatase/phosphodiesterase I (ENPP1) was identified several decades ago as a type II transmembrane glycoprotein with nucleotide pyrophosphatase and phosphodiesterase enzymatic activities, critical for purinergic signaling. Recently, ENPP1 has emerged as a critical phosphodiesterase that degrades the stimulator of interferon genes (STING) ligand, cyclic GMP–AMP (cGAMP). cGAMP or analogs thereof have emerged as potent immunostimulatory agents, which have potential applications in immunotherapy. This emerging role of ENPP1 has placed this "old" enzyme at the frontier of immunotherapy. This review highlights the roles played by ENPP1, the mechanism of cGAMP hydrolysis by ENPP1, and small molecule inhibitors of ENPP1 with potential applications in diverse disease states, including cancer. [ABSTRACT FROM AUTHOR]