Imipramine blocks acute silicosis in a mouse model.

BACKGROUND: Inhalation of crystalline silica is associated with pulmonary inflammation and silicosis. Although silicosis remains a prevalent health problem throughout the world, effective treatment choices are limited. Imipramine (IMP) is a FDA approved tricyclic antidepressant drug with lysosomotropic characteristics. The aim of this study was to evaluate the potential for IMP to reduce silicosis and block phagolysosome membrane permeabilization. METHODS: C57BL/6 alveolar macrophages (AM) exposed to crystalline silica ± IMP in vitro were assessed for IL-1ß release, cytotoxicity, particle uptake, lysosomal stability, and acid sphingomyelinase activity. Short term (24 h) in vivo studies in mice instilled with silica (± IMP) evaluated inflammation and cytokine release, in addition to cytokine release from ex vivo cultured AM. Long term (six to ten weeks) in vivo studies in mice instilled with silica (± IMP) evaluated histopathology, lung damage, and hydroxyproline content as an indicator of collagen accumulation. RESULTS: IMP significantly attenuated silica-induced cytotoxicity and release of mature IL-1ß from AM in vitro. IMP treatment in vivo reduced silica-induced inflammation in a short-term model. Furthermore, IMP was effective in blocking silica-induced lung damage and collagen deposition in a long-term model. The mechanism by which IMP reduces inflammation was explored by assessing cellular processes such as particle uptake and acid sphingomyelinase activity. CONCLUSIONS: Taken together, IMP was anti-inflammatory against silica exposure in vitro and in vivo. The results were consistent with IMP blocking silica-induced phagolysosomal lysis, thereby preventing cell death and IL-1ß release. Thus, IMP could be therapeutic for silica-induced inflammation and subsequent disease progression as well as other diseases involving phagolysosomal lysis.

Clitoral Length and Anogenital Ratio in Indian Newborn Girls.

OBJECTIVE: To generate normative data on clitoris length, anogenital distance and anogenital ratio in Indian newborns. DESIGN: Cross-sectional study. SETTING: Neonatal unit of a tertiary care teaching hospital in Kolkata. PARTICIPANTS: 378 female neonates, who were hemo-dynamically stable without critical illness or chromosomal anomaly, and without any vulval hematoma or genital abnormalities. INTERVENTIONS: Measurements were recorded using a digital vernier caliper between 24-72 hours. Infant was held in position by an assistant, while the investigator measured clitoral length by gently retracting the labia majora. Anogenital distance (centre of the anus to posterior convergence of the fourchette) and anogenital ratio (anogenital distance divided by the distance from centre of the anus to base of the clitoris) was also measured. MAIN OUTCOME MEASURES: Gestational age- and birthweight-wise normative values of clitoral length, anogenital distance and anogenital ratios. RESULTS: Mean clitoral length was 3.1 (1.54) mm for the whole cohort while anogenital distance and anogenital ratio were 10.2 (2.78) mm and 0.34 (0.07) mm, respectively. The gestation age-wise percentile charts of clitoral length, anogenital distance and anogenital ratio have been generated. There was no correlation between clitoral length and gestational age, body length, head circumference and birth weight. Correlations were also weak for anogenital distance. CONCLUSION: The normative values generated can serve as reference standard in the assessment of clitoromegaly, ambiguous genitalia, virilizing effects and suspected in utero androgen exposure.

Animal Bites and Rabies Prophylaxis in Rural Children: Indian Perspective.

A prospective observational study was conducted in a tertiary care hospital to study clinicoepidemiological profile of potentially rabid animal bite cases from rural India. Total of 308 children (median age 6 years) admitted to hospital, were recruited over 1 year and followed up till completion of antirabies vaccine course. Dog was the commonest (77.27%) offending animal. Of the exposures, 66.88% were scratches, 88.96% were unprovoked and 27.27% were categorized as Class III. The median times to wound toileting and reporting to health facility were 1 and 6 h, respectively. Majority received prompt PEP in hospital, and RIG was administered in 34.55% of Class II and 90.48% of Class III exposures. Compared with their older counterparts, children aged <5 years suffered more bites on face and trunk and more Class III exposures. The rabies prophylaxis scenario is encouraging, when compared with earlier studies, but there are gaps to be addressed.

Role of lysosomes in silica-induced inflammasome activation and inflammation in absence of MARCO.

MARCO is the predominant scavenger receptor for recognition and binding of silica particles by alveolar macrophages (AM). Previously, it was shown that mice null for MARCO have a greater inflammatory response to silica, but the mechanism was not described. The aim of this study was to determine the relationship between MARCO and NLRP3 inflammasome activity. Silica increased NLRP3 inflammasome activation and release of the proinflammatory cytokine, IL-1ß, to a greater extent in MARCO(-/-) AM compared to wild type (WT) AM. Furthermore, in MARCO(-/-) AM there was greater cathepsin B release from phagolysosomes, Caspase-1 activation, and acid sphingomyelinase activity compared to WT AM, supporting the critical role played by lysosomal membrane permeabilization (LMP) in triggering silica-induced inflammation. The difference in sensitivity to LMP appears to be in cholesterol recycling since increasing cholesterol in AM by treatment with U18666A decreased silica-induced NLRP3 inflammasome activation, and cells lacking MARCO were less able to sequester cholesterol following silica treatment. Taken together, these results demonstrate that MARCO contributes to normal cholesterol uptake in macrophages; therefore, in the absence of MARCO, macrophages are more susceptible to a greater inflammatory response by particulates known to cause NLRP3 inflammasome activation and the effect is due to increased LMP.

Potential role of the inflammasome-derived inflammatory cytokines in pulmonary fibrosis.

Pulmonary fibrosis is a progressive, disabling disease with mortality rates that appear to be increasing in the western population, including the USA. There are over 140 known causes of pulmonary fibrosis as well as many unknown causes. Treatment options for this disease are limited due to poor understanding of the molecular mechanisms of the disease progression. However, recent progress in inflammasome research has greatly contributed to our understanding of its role in inflammation and fibrosis development. The inflammasome is a multiprotein complex that is an important component of both the innate and adaptive immune systems. Activation of proinflammatory cytokines following inflammasome assembly, such as IL-1ß and IL-18, has been associated with development of PF. In addition, components of the inflammasome complex itself, such as the adaptor protein ASC have been associated with PF development. Recent evidence suggesting that the fibrotic process can be reversed via blockade of pathways associated with inflammasome activity may provide hope for future drug strategies. In this paper we will give an introduction to pulmonary fibrosis and its known causes. In addition, we will discuss the importance of the inflammasome in the development of pulmonary fibrosis as well as discuss potential future treatment options.

Giant condyloma acuminata in pediatric HIV.

We report a 2 year 6 months old girl suffering from HIV infection and presenting with two giant condyloma acuminata of perianal and perivulvar region along with oral candidiasis.