Basics on the use of acid-sensing ion channels' inhibitors as therapeutics

Since the discovery of acid-sensing ion channels in 1997, their importance in the health of neurons and other non-neuronal cells has gained significant importance. Acid-sensing ion channels play important roles in mediating pain sensation during diseases such as stroke, inflammation, arthritis, cancer, and recently migraine. More interestingly, acid-sensing ion channels may explain the sex differences in pain between males and females. Also, the ability of acid-sensing ion channel blockers to exert neuroprotective effects in a number of neurodegenerative diseases has added a new dimension to their therapeutic value. The current failure rate of ～45% of new drugs(due to toxicity issues) and saving of up to 7 years in the life span of drug approval makes drug repurposing a high priority. If acid-sensing ion channels' blockers undergo what is known as "drug repurposing", there is a great potential to bring them as medications with known safety profiles to new patient populations. However, the route of administration remains a big challenge due to their poor penetration of the blood brain and retinal barriers. In this review, the promise of using acid-sensing ion channel blockers as neuroprotective drugs is discussed.     

Comparing the results of Pap smear and Direct Visual Inspection (DVI) with 5% acetic acid in cervical cancer screening

Background:

Cervical cancer is the most second common cancer among Iranian women. This study was carried out to compare the results of Pap smear method and Direct Visual Inspection (DVI) with 5% acetic acid in cervical cancer screening in Tabriz, Iran.

Material and Methods:

This cross-sectional study was carried out in Alzahra Therapeutic-Educational Centre, Tabriz, Iran in 2013 on 1000 women. First, Pap smear was done for all women, and then the cervix exposed with 5% acetic acid by cotton swab for 30 seconds and observed under adequate light. At the end, women with abnormal results in Pap smear or DVI method were referred to colposcopy and biopsy. Test''s sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), LR+, LR- and confidence interval (CI) were determined (P < 0.05).

Results:

Nine-hundred and seventy-four (94.7%) cases were normal and had no abnormal findings and 26 (2.6%) participants had positive results in Pap smear or DVI test. Twelve women had abnormal Pap smear (nine women with atypical squamous cells of undetermined significance, ASCUS, three women with dysplasia, atypical endocervical, and low-grade squamous intraepithelial lesion, LSIL results) and 14 women had positive DVI (four women with human papillomavirus, HPV or koilocyte,) and one women with abnormality in both method had carcinoma in biopsy that referred to oncologist. In this study the sensitivity, specificity, PPV and NPV for DVI were 71.4%, 50%, 35.7%, and 81.8% respectively in comparison with 14.3%, 50%, 10%, and 60% for Pap smear.

Conclusion:

As the DVI method has higher sensitivity and positive predictive value than Pap smear, it could be used as a useful method beside the Pap smear.     

Soluble HLA class I molecules in malignant pleural and peritoneal effusions and its possible role on NK and LAK cytotoxicity

PURPOSE: To examine the amount of sHLA-I in malignant pleural and peritoneal effusions and its possible role in natural immune defense. METHODS: Three groups of patients (75 patients with malignancy, 21 with infection, and 27 with other diseases) were studied for sHLA-I value using an ELISA method. Cytolytic activity of freshly isolated pleural and peritoneal effusion-associated lymphoid (EAL) cells from 14 of cases with malignancy were examined and compared to that of ten non-cancerous patients. EAL cells were co-cultured with the autologous cell-free effusions immediately after collection and 3 days after incubation with IL-2. RESULTS: The mean value of sHLA-I in effusions was 1.01+/-1.36 micro g/ml, 0.97+/-1.20 micro g/ml, and 0.49+/-0.45 micro g/ml, respectively. Despite higher mean sHLA-I levels in malignant and infected patients, no significant difference between these groups was observed ( P >0.05). Generally, the amount of sHLA-I in peritoneal effusions was higher than that for pleural effusions, but the difference was not significant. There were also no statistical differences in the sHLA-I levels between sub-groups of patients with malignancy. EAL cells' killing activity in malignant and infected effusions was 68.15+/-11.73 and 78.28+/-14.41, respectively ( P=0.08). No correlation between sHLA-I level and NK activity of EAL cells from the patients was found. Almost all malignant cases after exposure to cell-free effusions displayed an increase in NK activity (from 68.66+/-11.13 to 74.2+/-12.39, P=0.042) and a decrease in LAK activity (74.5+/-18.30 vs 67.72+/-16.46, P=0.040). Whereas, the same experiment performed for non-malignant effusions showed a decrease in both NK activity and LAK activity. Changes in NK and LAK activity were not correlated with the amount of sHLA-I in the effusions. CONCLUSION: The presence of sHLA-I, particularly in malignant effusions, suggests a role for these molecules in tumor immunity in the peritoneal or plural environment; however, at least with these group of patients, sHLA-I appears not to be a unique determining factor on EAL cells' killing activity.