MicroRNA Regulation of Airway Inflammation and Airway Smooth Muscle Function: Relevance to Asthma.

Genetic and environmental factors contribute to the onset and severity of asthma. Molecular pathogenesis of asthma involves changes in gene expression by a variety of inflammatory mediators acting in autocrine and paracrine fashion on effector cells of the airways. Transcriptional regulation of gene expression in resident airway cells has been studied extensively. However, protein function in a target cell can be regulated at multiple levels starting from transcription followed by post-transcription, translation, and post-translation steps. In this context, small noncoding RNAs known as microRNAs (miRNAs) have evolved as one of the key regulators of gene expression post-transcriptionally. Most importantly, miRNA expression is dynamic in nature and can be regulated by a variety of external stimuli. Altered expression of individual or a group of miRNAs is thought to contribute to human diseases. Recent studies have implicated differential expression of miRNAs in the lungs during inflammation. Most importantly, advanced biochemical and molecular tools could be used to manipulate miRNA expression thereby effecting functional changes in target cells and organ systems. This review summarizes the current understanding of miRNA in the regulation of airway function in health and disease, and highlights the potential clinical utility of mRNAs as biomarkers of airway diseases and as potential therapeutic targets.

The GPCR OGR1 (GPR68) mediates diverse signalling and contraction of airway smooth muscle in response to small reductions in extracellular pH.

BACKGROUND AND PURPOSE: Previous studies have linked a reduction in pH in airway, caused by either environmental factors, microaspiration of gastric acid or inflammation, with airway smooth muscle (ASM) contraction and increased airway resistance. Neural mechanisms have been shown to mediate airway contraction in response to reductions in airway pH to < 6.5; whether reduced extracellular pH (pHo) has direct effects on ASM is unknown. EXPERIMENTAL APPROACH: Intracellular signalling events stimulated by reduced pHo in human cultured ASM cells were examined by immunoblotting, phosphoinositide hydrolysis and calcium mobilization assays. ASM cell contractile state was examined using magnetic twisting cytometry. The expression of putative proton-sensing GPCRs in ASM was assessed by real-time PCR. The role of ovarian cancer G protein-coupled receptor 1 (OGR1 or GPR68) in acid-induced ASM signalling and contraction was assessed in cultures subjected to siRNA-mediated OGR1 knockdown. KEY RESULTS: ASM cells responded to incremental reductions in pHo (from pH 8.0 to pH 6.8) by activating multiple signalling pathways, involving p42/p44, PKB, PKA and calcium mobilization. Coincidently, ASM cells contracted in response to decreased pHo with similar 'dose'-dependence. Real-time PCR suggested OGR1 was the only proton-sensing GPCR expressed in ASM cells. Both acid-induced signalling (with the exception of PKB activation) and contraction were significantly attenuated by knockdown of OGR1. CONCLUSIONS AND IMPLICATIONS: These studies reveal OGR1 to be a physiologically relevant GPCR in ASM cells, capable of pleiotropic signalling and mediating contraction in response to small reductions in extracellular pH. Accordingly, ASM OGR1 may contribute to asthma pathology and represent a therapeutic target in obstructive lung diseases.

Enhanced photocatalytic inactivation of bacterial spores on surfaces in air.

TiO(2) photocatalysis with ultraviolet (UV-A) light has proven to be a highly effective process for complete inactivation of airborne microbes. However, the overall efficiency of the technology needs to be improved to make it more attractive as a defense against bio-terrorism. The present research investigates the enhancement in the rate of destruction of bacterial spores on metal (aluminum) and fabric (polyester) substrates with metal (silver)-doped titanium dioxide and compares it to conventional photocatalysis (TiO(2) P25/+UV-A) and UV-A photolysis. Bacillus cereus bacterial spores were used as an index to demonstrate the enhanced disinfection efficiency. The results indicate complete inactivation of B. cereus spores with the enhanced photocatalyst. The enhanced spore destruction rate may be attributed to the highly oxidizing radicals generated by the doped TiO(2).

Ultrasound biomicroscopy of sclerotomy sites after pars plana vitrectomy for diabetic vitreous hemorrhage.

OBJECTIVE: This study was aimed at assessing changes at the sclerotomy site using the ultrasound biomicroscope (UBM) in eyes that underwent primary pars plana vitrectomy for complications of proliferative diabetic retinopathy. DESIGN: Prospective, observational case series. PARTICIPANTS: Eighty-six eyes of 84 patients with vitreous hemorrhage caused by proliferative diabetic retinopathy. INTERVENTION: Three-port pars plana vitrectomy followed by UBM evaluation of all sclerotomy sites between 6 and 8 weeks after surgery. Correlation with intraoperative findings done in case of reoperations. Forty-one eyes had repeat UBM at 6 months. MAIN OUTCOME MEASURES: The changes at the sclerotomy site were classified into six groups: well healed, gape, plaque, vitreous incarceration, fibrovascular proliferation, and anterior hyaloidal fibrovascular proliferation (AHFVP). The UBM characteristics of each of the groups were defined. The findings at 6 months were compared with those at 6 to 8 weeks. RESULTS: At 6 to 8 weeks after surgery, most sclerotomies were well healed or had either moderate to high reflective plaques bridging the site. Wound gape was seen in 22.1% of active ports, 32.6% of light ports, and 25.6% of infusion ports. Vitreous incarceration was seen most often at the infusion port (18. 6% of eyes). Fibrovascular proliferation was seen in 9.3% of active ports, 12.8% of light ports, and 15.1% of infusion ports. Thirteen eyes had recurrent vitreous hemorrhage 6 to 8 weeks after surgery. Cases with rebleeding and no fibrovascular proliferation at the sclerotomy on UBM did well with outpatient fluid-air exchange (two eyes) or observation only (three eyes). Those with fibrovascular proliferation on UBM (eight eyes) required more extensive surgery. CONCLUSIONS: UBM is helpful in detecting complications at the sclerotomy sites after pars plana vitrectomy and is an invaluable tool in the assessment of the patient before reoperation.

Treatment of threshold retinopathy of prematurity.

This report deals with our experience in the management of threshold retinopathy of prematurity (ROP). A total of 45 eyes of 23 infants were subjected to treatment of threshold ROP. 26.1% of these infants had a birth weight of > 1,500 gm. The preferred modality of treatment was laser indirect photocoagulation, which was facilitated by scleral depression. Cryopexy was done in cases with nondilating pupils or medial haze and was always under general anaesthesia. Retreatment with either modality was needed in 42.2% eyes; in this the skip areas were covered. Total regression of diseases was achieved in 91.1% eyes with no sequelae. All the 4 eyes that progressed to stage 5 despite treatment had zone 1 disease. Major treatment-induced complications did not occur in this series. This study underscores the importance of routine screening of infants upto 2,000 gm birth weight for ROP and the excellent response that is achieved with laser photocoagulation in inducing regression of threshold ROP. Laser is the preferred method of treatment in view of the absence of treatment-related morbidity to the premature infants.

Surgical management of retinal detachments related to coloboma of the choroid.

OBJECTIVE: This study aimed to develop a rationale for the management of retinal detachments related to choroidal coloboma and to study the outcome of their management. DESIGN: The study design was a retrospective study. PARTICIPANTS: A total of 85 eyes of 81 patients with retinal detachments related to coloboma of the choroid participated. INTERVENTION: All eyes underwent pars plana vitrectomy with internal tamponade using silicone oil (80 eyes) or perfluropropane gas (5 eyes). Behavior of the retina on fluid-air exchange was used to guide the further steps of surgery. Endolaser was performed along the coloboma border. Silicone oil was removed in 80% of eyes. The main outcome measures were retinal reattachment and visual recovery. RESULTS: Recurrent retinal detachment occurred in 16.3% of silicone oil-filled eyes and 60% of gas-filled eyes. After silicone oil removal, 15.6% of eyes had recurrent retinal detachment. After a mean follow-up of 13.4 months, 81.2% of eyes had attached retina and 69.4% recovered equal to or better than 10/200 visual acuity. CONCLUSION: Retinal detachment secondary to coloboma of choroid is treated best by pars plana vitrectomy along with silicone oil tamponade. Gas tamponade has limited indications. Clinical evaluation of the extent of retinal detachment within the colobomatous area and the behavior of the retina on fluid-air exchange help the authors understand the pathogenesis of the retinal detachment and plan a rational therapy.

Subretinal fibrosis and nonrhegmatogenous retinal detachment associated with multifocal central serous chorioretinopathy.

PURPOSE: To report the rare occurrence of subretinal fibrosis in patients with multifocal central serous chorioretinopathy and evaluate the role of systemic corticosteroids and the effects of laser photocoagulation on multifocal leaks. METHODS: A total of 29 patients (mean age, 37.7 years; 89.7% male) treated for subretinal fibrosis and multifocal central serous chorioretinopathy from 1983-1995 were reviewed retrospectively. Mean follow up was 26 months (range, 6.8-81 months). RESULTS: Retinal detachment involved the macula in 72.4% cases. Fluorescein angiography showed a mean of 6.7 (range, 2-22) central serous chorioretinopathy leaks and a mean of 1.8 (range, 1-5) retinal pigment epithelial detachments. The fundus pictures of 23 patients who were taking systemic corticosteroids showed no improvement. Following laser treatment, however, retinal reattachment was obtained in all eyes, and improvement in visual acuity of > 2 Snellen lines was noted in 68.9% of patients. CONCLUSIONS: The presence of subretinal fibrosis with secondary retinal detachment in otherwise healthy young patients, particularly in men, should alert the physician to look for multifocal central serous retinopathy leaks. Systemic corticosteroids did not prove effective in treating these patients, although laser treatment is recommended for each leak identified on an angiogram.

Early detection of cervical cancer by visual inspection: a population-based study in rural India.

A total of 3784 women aged 35 and above living in 26 villages in rural Maharashtra state, India, were invited to undergo a pelvic examination, to evaluate the performance of unaided visual inspection by trained paramedical workers in detecting cervical cancer. Of this number, 2135 (56.4%) women complied with the invitation. Paramedical workers scored 1120 (57.3%) and 118 (6%) women as having abnormal cervices using the low- and high-threshold criteria respectively. There was good agreement between the visual findings of the paramedical workers and those of a gynaecologist. All subjects had a cervical smear. A total of 10 cervical cancers were detected by cytology/histology. The sensitivity of visual inspection by paramedical workers to detect cervical cancer was 90.0% using the low threshold and 60.0% with the high threshold to define a positive test. The values for specificity were 42.8% and 94.5% respectively. The results obtained by the gynaecologist were very similar. Cost savings implied by limiting cytology/other investigations to approximately half of the population pre-selected on the basis of visual inspection are likely to be offset by the necessity to repeat the test at frequent intervals, repeated follow-up visits and other investigations.