Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis.

Histopathologic evidence of deployment-related constrictive bronchiolitis (DRCB) has been identified in soldiers deployed to Southwest Asia. While inhalational injury to the airway epithelium is suspected, relatively little is known about the pathogenesis underlying this disabling disorder. Club cells are local progenitors critical for repairing the airway epithelium after exposure to various airborne toxins, and a prior study using an inducible transgenic murine model reported that 10 days of sustained targeted club cell injury causes constrictive bronchiolitis. To further understand the mechanisms leading to small airway fibrosis, a murine model was employed to show that sustained club cell injury elicited acute weight loss, caused increased local production of proinflammatory cytokines, and promoted accumulation of numerous myeloid cell subsets in the lung. Transition to a chronic phase was characterized by up-regulated expression of oxidative stress-associated genes, increased activation of transforming growth factor-ß, accumulation of alternatively activated macrophages, and enhanced peribronchiolar collagen deposition. Comparative histopathologic analysis demonstrated that sustained club cell injury was sufficient to induce epithelial metaplasia, airway wall thickening, peribronchiolar infiltrates, and clusters of intraluminal airway macrophages that recapitulated key abnormalities observed in DRCB. Depletion of alveolar macrophages in mice decreased activation of transforming growth factor-ß and ameliorated constrictive bronchiolitis. Collectively, these findings implicate sustained club cell injury in the development of DRCB and delineate pathways that may yield biomarkers and treatment targets for this disorder.

Clinical insights and epidemiology of central nervous system infection due to Cryptococcus neoformans/gattii species complexes: A prospective study from South India.

In the last two decades, central nervous system (CNS) cryptococcosis (CNSc) has emerged as a major opportunistic infection in the immunocompromised population of India. We have analyzed the clinical features of CNSc and epidemiology of Cryptococcus neoformans and Cryptococcus gattii. A total of 160 clinical isolates of C. neoformans/gattii recovered from CNSc patients were analyzed. The origin, clinical parameters, and imaging features of the patients were recorded, and clinical parameters were analyzed based on their human immunodeficiency virus (HIV) status and infecting species, namely, C. neoformans or C. gattii. Serotypes and mating types of the isolates were determined. Molecular typing was performed by polymerase chain reaction (PCR) fingerprinting using M13 microsatellite primer (GTG)5, and multilocus sequence typing (MLST). Majority of the patients were from Bangalore Urban, Karnataka. Among 160 cases 128 (80%) were HIV seropositive, and 32 (20%) were HIV negative. Middle-aged males (36-55 years) were highly affected. There were statistically significant differences in the clinical manifestations, imaging and CSF parameters of HIV coinfected and noninfected cases, whereas limited differences were observed in these parameters in the cases infected with C. neoformans and C. gattii. We identified 80% C. neoformans VNI, 8.75% VNII and 22.5% C. gattii (VGI), 8.75% C. tetragattii (VGIV) among clinical strains. This comprehensive study will contribute toward a better prognosis of CNS cryptococcosis patients during the hospital stay, treatment strategies for HIV coinfected and noninfected cases and will provide the molecular epidemiology of these two pathogenic fungal species in south India, which was unclear in this part of the country.

Trends of CNS Cryptococcosis during Pre- and Post-HIV era: A 38 years' retrospective cohort analysis from south India.

OBJECTIVE: Central nervous system cryptococcosis (CNSc) is an AIDS defining opportunistic infection. This retrospective study aimed to analyze the changing epidemiology of CNSc cases from the period of pre- to post-emergence of HIV epidemic in south India. METHODS: Confirmed cases of CNSc from 1978 to 2015 were analyzed for demographic and clinical details with special reference to the cases diagnosed in south India during the period 1952-1977. Geographical distribution, affected age groups, clinical aspects, and comorbidities in relation to immune status were analysed RESULTS: The highest number of CNSc cases (n = 125) were recorded in 2006, with 89.6% HIV positivity. The highest HIV-positivity (93.6%) was documented in the years 2002 and 2009. CNSc cases have majorly changed after the introduction and spread of HIV in terms of predisposing factors, comorbidities, severity, affected age groups and treatment. Notably, an overall rise was observed in non-HIV associated CNSc cases from 1997 (8.1%) to 2015 (16.9%). CONCLUSION: The peak of CNSc had already reached in south India during 2005-2006. However, the number of new infections has slowly decreased in last ten years. Progressive awareness and, early diagnosis of HIV and cryptococcosis, adequate availability of HAART and potential antifungal therapy has played crucial roles in changing epidemiology of the CNSc and its associated mortality.

Advanced approach for antifungal susceptibility and characterization of resistance properties in clinical and environmental isolates of Cryptococcus species complex.

Background: Meningitis due to Cryptococcus neoformans/gattii is a fatal infection affecting immunocompromised population worldwide. Amphotericin B (AmB), fluconazole (FLC) and 5-flucytosine are the drugs of choice to treat the infection. We studied antifungal susceptibility pattern of clinical and environmental cryptococcal species using newer approach and analyze their resistant characteristics. Methods: Eighty clinical (54 C. neoformans and 26 C. gattii) and 18 environmental (14 C. neoformans and 4 C. gattii) isolates were subjected to antifungal susceptibility testing by automated (VITEK2C) method. Minimum inhibitory concentrations (MIC) were analyzed statistically. Genomic DNA of FLC resistant isolates was extracted and amplified to detect presence of CnAFR1 gene. Results: C. neoformans showed 1.85% and 21.4% AmB resistance, and 1.85% and 28.5% FLC- resistance, whereas C. gattii showed 25% and 50% FLC-resistance among clinical and environmental isolates respectively. MIC values were significantly (p < 0.05) different for the isolates from 2 sources. CnAFR1 gene sequence analysis revealed phylogenetic relationship among the resistant isolates. Conclusions: This pioneering study provides an insight into the sensitivity patterns of clinical and environmental cryptococcal isolates from south India. The recent emergence of AmB-resistance may transpire as a challenge for the clinicians. As the clinical and environmental isolates are phylogenetically evolved from CnAFR1 gene of Filobasidiella neoformans, the resistance is most probably an inherent attribute. This study emphasizes the need for speciation and antifungal susceptibility testing of cryptococcal isolates from clinical sources to institute appropriate antifungal therapy and to reduce the mortality and morbidity.

Environmental Factors That Contribute to the Maintenance of Cryptococcus neoformans Pathogenesis.

The ability of microorganisms to colonise and display an intracellular lifestyle within a host body increases their fitness to survive and avoid extinction. This host-pathogen association drives microbial evolution, as such organisms are under selective pressure and can become more pathogenic. Some of these microorganisms can quickly spread through the environment via transmission. The non-transmittable fungal pathogens, such as Cryptococcus, probably return into the environment upon decomposition of the infected host. This review analyses whether re-entry of the pathogen into the environment causes restoration of its non-pathogenic state or whether environmental factors and parameters assist them in maintaining pathogenesis. Cryptococcus (C.) neoformans is therefore used as a model organism to evaluate the impact of environmental stress factors that aid the survival and pathogenesis of C. neoformans intracellularly and extracellularly.

Neurobrucellosis: A neglected entity? An update from tertiary care Neurocentre of South East Asia.

Neurobrucellosis is the most serious complication of brucellosis with neither a typical clinical manifestations nor a specific cerebrospinal fluid (CSF) picture and mimics other neurological disorders leading to diagnostic dilemma. The prevalence of Neurobrucellosis ranges from 1.7 to 10% of brucellosis worldwide. This present study highlights the integrated diagnostic and clinical approaches in the diagnosis of neurobrucellosis. Cases with neurological abnormalities associated with abnormal CSF findings were included in the study. Serum and CSF samples were subjected to Rose Bengal Plate Test (RBPT), standard tube agglutination test (STAT), indirect Enzyme linked immunosorbent assay (iELISA) for IgM & IgG antibodies and polymerase chain reaction (PCR) to detect BCSP31 gene. Out of 473 cases, 278 (58.8%) were positive in serum and/or CSF by any of the methods. Out of 278, Only IgM anti-brucella antibody was positive in 105 (22.19%) cases. 122 (25.79%) cases were positive by any of the diagnostic methods in serum and not in CSF whereas 51(10.78%) cases were positive in serum and CSF and these 51 cases were considered as Neurobrucellosis among patients presenting with neurological illness. Chronic meningitis was the most common form of presentation. Multimodal differential diagnostic approaches are crucial for accurate diagnosis, effective treatment and to prevent morbidity and mortality associated with neurobrucellosis.