Cirrhosis-induced defects in innate pulmonary defenses against Streptococcus pneumoniae

<p>Abstract</p> <p>Background</p> <p>The risk of mortality from pneumonia caused by <it>Streptococcus pneumoniae </it>is increased in patients with cirrhosis. However, the specific pneumococcal virulence factors and host immune defects responsible for this finding have not been clearly established. This study used a cirrhotic rat model of pneumococcal pneumonia to identify defect(s) in innate pulmonary defenses in the cirrhotic host and to determine the impact of the pneumococcal toxin pneumolysin on these defenses in the setting of severe cirrhosis.</p> <p>Results</p> <p>No cirrhosis-associated defects in mucociliary clearance of pneumococci were found in these studies, but early intrapulmonary killing of the organisms before the arrival of neutrophils was significantly impaired. This defect was exacerbated by pneumolysin production in cirrhotic but not in control rats. Neutrophil-mediated killing of a particularly virulent type 3 pneumococcal strain also was significantly diminished within the lungs of cirrhotic rats with ascites. Levels of lysozyme and complement component C3 were both significantly reduced in bronchoalveolar lavage fluid from cirrhotic rats. Finally, complement deposition was reduced on the surface of pneumococci recovered from the lungs of cirrhotic rats in comparison to organisms recovered from the lungs of control animals.</p> <p>Conclusion</p> <p>Increased mortality from pneumococcal pneumonia in this cirrhotic host is related to defects in both early pre-neutrophil- and later neutrophil-mediated pulmonary killing of the organisms. The fact that pneumolysin production impaired pre-neutrophil-mediated pneumococcal killing in cirrhotic but not control rats suggests that pneumolysin may be particularly detrimental to this defense mechanism in the severely cirrhotic host. The decrease in neutrophil-mediated killing of pneumococci within the lungs of the cirrhotic host is related to insufficient deposition of host proteins such as complement C3 on their surfaces. Pneumolysin likely plays a role in complement consumption within the lungs. Our studies, however, were unable to determine whether pneumolysin more negatively impacted this defense mechanism in cirrhotic than in control rats. These findings contribute to our understanding of the defects in innate pulmonary defenses that lead to increased mortality from pneumococcal pneumonia in the severely cirrhotic host. They also suggest that pneumolysin may be a particularly potent pneumococcal virulence factor in the setting of cirrhosis.</p

Ocular Point-of-Care Ultrasonography to Diagnose Posterior Chamber Abnormalities: A Systematic Review and Meta-analysis

Importance: Diagnosing posterior chamber ocular abnormalities typically requires specialist assessment. Point-of-care ultrasonography (POCUS) performed by nonspecialists, if accurate, could negate the need for urgent ophthalmologist evaluation. Objective: This meta-analysis sought to define the diagnostic test characteristics of emergency practitioner-performed ocular POCUS to diagnose multiple posterior chamber abnormalities in adults. Data sources: PubMed (OVID), MEDLINE, EMBASE, Cochrane, CINAHL, and SCOPUS were searched from inception through June 2019 without restrictions. Conference abstracts and trial registries were also searched. Bibliographies of included studies and relevant reviews were manually searched, and experts in the field were queried. Study selection: Included studies compared ocular POCUS performed by emergency practitioners with a reference standard of ophthalmologist evaluation. Pediatric studies were excluded. All 116 studies identified during abstract screening as potentially relevant underwent full-text review by multiple authors, and 9 studies were included. Data extraction and synthesis: In accordance with PRISMA guidelines, multiple authors extracted data from included studies. Results were meta-analyzed for each diagnosis using a bivariate random-effects model. Data analysis was performed in July 2019. Main outcomes and measures: The outcomes of interest were diagnostic test characteristics of ocular POCUS for the following diagnoses: retinal detachment, vitreous hemorrhage, vitreous detachment, intraocular foreign body, globe rupture, and lens dislocation. Results: Nine studies (1189 eyes) were included. All studies evaluated retinal detachment, but up to 5 studies assessed each of the other diagnoses of interest. For retinal detachment, sensitivity was 0.94 (95% CI, 0.88-0.97) and specificity was 0.94 (95% CI, 0.85-0.98). Sensitivity and specificity were 0.90 (95% CI, 0.65-0.98) and 0.92 (95% CI, 0.75-0.98), respectively, for vitreous hemorrhage and were 0.67 (95% CI, 0.51-0.81) and 0.89 (95% CI, 0.53-0.98), respectively, for vitreous detachment. Sensitivity and specificity were high for lens dislocation (0.97 [95% CI, 0.83-0.99] and 0.99 [95% CI, 0.97-1.00]), intraocular foreign body (1.00 [95% CI, 0.81-1.00] and 0.99 [95% CI, 0.99-1.00]), and globe rupture (1.00 [95% CI, 0.63-1.00] and 0.99 [95% CI, 0.99-1.00]). Results were generally unchanged in sensitivity analyses of studies with low risk of bias. Conclusions and relevance: This study suggests that emergency practitioner-performed ocular POCUS is an accurate test to assess for retinal detachment in adults. Its utility in diagnosing other posterior chamber abnormalities is promising but needs further study

Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect

Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1-EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects.CRANIRAREUniversite Paris Descartes-Sorbonne Paris Cite Pole de Recherche et d'Enseignement SuperieurAgence Nationale de la Recherche (project EvoDevoMut)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)National Health and Medical Research Council of AustraliaUniv São Paulo, Inst Biociencias, Dept Genet & Biol Evolut, Ctr Pesquisas Genoma Humano & Celulas Tronco, BR-05508090 São Paulo, BrazilUniv Paris 05, Sorbonne Paris Cite, INSERM, U1163, Paris, FranceUniv São Paulo, HRCA, Dept Clin Genet, Bauru, BrazilUniv Melbourne, Royal Childrens Hosp, Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Melbourne, Vic, AustraliaUniv Melbourne, Dept Paediat, Melbourne, Vic, AustraliaRoyal Childrens Hosp, Dept Plast & Maxillofacial Surg, Melbourne, Vic, AustraliaHosp Sick Children, Dept Otolaryngol Head & Neck Surg, Toronto, ON M5G 1X8, CanadaUniv São Paulo, Inst Biosci, BR-05508090 São Paulo, BrazilLeiden Univ, Med Ctr, Leiden Genome Technol Ctr, Leiden, NetherlandsUniversidade Federal de São Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos, BrazilHop Necker Enfants Malad, AP HP, Dept Genet, Paris, FranceUniversidade Federal de São Paulo, Inst Ciencia & Tecnol, Sao Jose Dos Campos, BrazilUniversite Paris Descartes-Sorbonne Paris Cite Pole de Recherche et d'Enseignement Superieur: SPC/JFG/2013-031National Health and Medical Research Council of Australia: 607431Web of Scienc

Effects of Thioglycolic Acid on Parthenogenetic Activation of Xenopus Oocytes

BACKGROUND: Existing in Permanent-wave solutions (PWS), thioglycolic acid (TGA) is widely used in hairdressing industry for its contribution to hair styling. However, the toxicity of TGA, especially its reproductive toxicity, gradually calls the attention of more and more researchers. METHOD: In this work, xenopus oocytes were pretreated with different concentration of TGA, and then activated by calcium ionophore A23187. During culture, the oocytes activation rates were taken note at different time after adding calcium ionophore A23187. At the end of the culture period, the nuclear status was detected under confocal microscope. In addition, some other samples were collected for Western-Blotting analysis. RESULT: TGA significantly inhibited the oocytes activation rate and pronuclear formation. It may be resulted from the inhibition of the degradation of p-ERK1, Mos and CyclinB2. CONCLUSION: TGA inhibits in vitro parthenogenetic activation of xenopus oocytes with inhibited the degradation of proteins involved in mitogenic-activated protein kinase (MAPK) and maturation-promoting factor (MPF) pathways

Alpha-1-Antitrypsin in Pathogenesis of Hepatocellular Carcinoma

Context: Alpha-1-antitrypsin (A1AT) is the most abundant liver-derived, highly polymorphic, glycoprotein in plasma. Hereditary deficiency of alpha-1-antitrypsin in plasma (A1ATD) is a consequence of accumulation of polymers of A1AT mutants in endoplasmic reticulum of hepatocytes and other A1AT-producing cells. One of the clinical manifestations of A1ATD is liver disease in childhood and cirrhosis and/or hepatocellular carcinoma (HCC) in adulthood. Epidemiology and pathophysiology of liver failure in early childhood caused by A1ATD are well known, but the association with hepatocellular carcinoma is not clarified. The aim of this article is to review different aspects of association between A1AT variants and hepatocellular carcinoma, with emphasis on the epidemiology and molecular pathogenesis. The significance of A1AT as a biomarker in the diagnosis of HCC is also discussed. Evidence Acquisitions: Search for relevant articles were performed through Pub Med, HighWire, and Science Direct using the keywords "alpha-1-antitrypsin", "liver diseases", "hepatocellular carcinoma", "SERPINA1". Articles published until 2011 were reviewed. Results: Epidemiology studies revealed that severe A1ATD is a significant risk factor for cirrhosis and HCC unrelated to the presence of HBV or HCV infections. However, predisposition to HCC in moderate A1ATD is rare, and probably happens in combination with HBV and/or HCV infections or other unknown risk factors. It is assumed that accumulation of polymers of A1ATD variants in endoplasmic reticulum of hepatocytes leads to damage of hepatocytes by gain-of-function mechanism. Also, increased level of A1AT was recognized as diagnostic and prognostic marker of HCC. Conclusions: Clarification of a carcinogenic role for A1ATD and identification of pro-inflammatory or some still unknown factors that lead to increased susceptibility to HCC associated with A1ATD may contribute to a better understanding of hepatic carcinogenesis and to the development of new drugs

Incompetence of Neutrophils to Invasive Group A streptococcus Is Attributed to Induction of Plural Virulence Factors by Dysfunction of a Regulator

Group A streptococcus (GAS) causes variety of diseases ranging from common pharyngitis to life-threatening severe invasive diseases, including necrotizing fasciitis and streptococcal toxic shock-like syndrome. The characteristic of invasive GAS infections has been thought to attribute to genetic changes in bacteria, however, no clear evidence has shown due to lack of an intriguingly study using serotype-matched isolates from clinical severe invasive GAS infections. In addition, rare outbreaks of invasive infections and their distinctive pathology in which infectious foci without neutrophil infiltration hypothesized us invasive GAS could evade host defense, especially neutrophil functions. Herein we report that a panel of serotype-matched GAS, which were clinically isolated from severe invasive but not from non-invaive infections, could abrogate functions of human polymorphnuclear neutrophils (PMN) in at least two independent ways; due to inducing necrosis to PMN by enhanced production of a pore-forming toxin streptolysin O (SLO) and due to impairment of PMN migration via digesting interleukin-8, a PMN attracting chemokine, by increased production of a serine protease ScpC. Expression of genes was upregulated by a loss of repressive function with the mutation of csrS gene in the all emm49 severe invasive GAS isolates. The csrS mutants from clinical severe invasive GAS isolates exhibited high mortality and disseminated infection with paucity of neutrophils, a characteristic pathology seen in human invasive GAS infection, in a mouse model. However, GAS which lack either SLO or ScpC exhibit much less mortality than the csrS-mutated parent invasive GAS isolate to the infected mice. These results suggest that the abilities of GAS to abrogate PMN functions can determine the onset and severity of invasive GAS infection

A systematic review of the diagnostic accuracy of physical examination for the detection of cirrhosis

BACKGROUND: We conducted a review of the diagnostic accuracy of clinical examination for the diagnosis of cirrhosis. The objectives were: to identify studies assessing the accuracy of clinical examination in the detection of cirrhosis; to summarize the diagnostic accuracy of reported physical examination findings; and to define the effects of study characteristics on estimates of diagnostic accuracy. METHODS: Studies were identified through electronic literature search of MEDLINE (1966 to 2000), search of bibliographic references, and contact with authors. Studies that evaluated indicants from physical examination of patients with known or suspected liver disease undergoing liver biopsy were included. Qualitative data on study characteristics were extracted. Two-by-two tables of presence or absence of physical findings for patients with and without cirrhosis were created from study data. Data for physical findings reported in each study were combined using Summary Receiver Operating Characteristic (SROC) curves or random effects modeling, as appropriate. RESULTS: Twelve studies met inclusion criteria, including a total of 1895 patients, ranging in age from 3 to 90 years. Most studies were conducted in referral populations with elevated aminotransferase levels. Ten physical signs were reported in three or more studies and ten signs in only a single study. Signs for which there was more study data were associated with high specificity (range 75–98%), but low sensitivity (range 15–68%) for histologically-proven cirrhosis. CONCLUSIONS: Physical findings are generally of low sensitivity for the diagnosis of cirrhosis, and signs with higher specificity represent decompensated disease. Most studies have been undertaken in highly selected populations

The Influence of Dormitory Architecture On Resident Behavior

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66943/2/10.1177_001391657300500402.pd

Evolution of Burkholderia pseudomallei in Recurrent Melioidosis

Burkholderia pseudomallei, the etiologic agent of human melioidosis, is capable of causing severe acute infection with overwhelming septicemia leading to death. A high rate of recurrent disease occurs in adult patients, most often due to recrudescence of the initial infecting strain. Pathogen persistence and evolution during such relapsing infections are not well understood. Bacterial cells present in the primary inoculum and in late infections may differ greatly, as has been observed in chronic disease, or they may be genetically similar. To test these alternative models, we conducted whole-genome comparisons of clonal primary and relapse B. pseudomallei isolates recovered six months to six years apart from four adult Thai patients. We found differences within each of the four pairs, and some, including a 330 Kb deletion, affected substantial portions of the genome. Many of the changes were associated with increased antibiotic resistance. We also found evidence of positive selection for deleterious mutations in a TetR family transcriptional regulator from a set of 107 additional B. pseudomallei strains. As part of the study, we sequenced to base-pair accuracy the genome of B. pseudomallei strain 1026b, the model used for genetic studies of B. pseudomallei pathogenesis and antibiotic resistance. Our findings provide new insights into pathogen evolution during long-term infections and have important implications for the development of intervention strategies to combat recurrent melioidosis