Transcription factors STAT-4, STAT-6 and CREB regulate Th1/Th2 response in leprosy patients: effect of M. leprae antigens.

BACKGROUND: Leprosy is an ideal human disease to study T cell regulation as patients show correlation between cytokine skewed Th1-Th2 responses and clinical forms of the disease. The Role of transcription factors on the modulation of Th1 and Th2 responses by M. leprae antigens has not been adequately studied. In the present study, we studied the effect of M. leprae antigens on transcription factors STAT-4, STAT-6 and CREB and their correlation with Th1/Th2 cell mediated immune responses in leprosy. METHODS: Leprosy patients of both categories of tuberculoid leprosy (BT/TT) and lepromatous leprosy (BL/LL) were selected from the OPD of NJ1L & OMD, (ICMR), Agra and healthy individuals (H) were chosen from the staff and students working in the institute. Peripheral blood mononuclear cells (PBMCs) of the study subjects were stimulated with M. leprae antigens (WCL, MLSA, and PGL-1). Sandwich ELISA was done in the culture supernatants of healthy and leprosy patients to detect IL-4, IL-10 and IFN-γ. Further, expression of IFN-γ and IL-4 and activation of STAT4, STAT6 and CREB transcription factors in CD4+ T cell with or without stimulation of M. leprae antigens was investigated by flow cytometry. RESULTS: Lepromatous leprosy patients showed significantly lower IFN-γ and higher IL-4 levels in culture supernatant and significantly low expression of IFN-γ and higher expression of IL-4 by CD4+ T cells than healthy individuals with or without antigenic stimulation. Antigenic stimulation significantly increased IL-10 in BL/LL patients but not in BT/TT patients or healthy individuals. PGL-1 stimulation led to significantly higher activation of STAT-6 in BT/TT and BL/LL patients in comparison to healthy individuals. All the three antigens led to activation of CREB in healthy and BT/TT patients but not in BL/LL patients. CONCLUSION: Our findings show that M. leprae antigens differentially modulate activation of T cell transcription factors STAT-4/STAT-6 and CREB. These transcription factors are well known to regulate Th1 and Th2 mediated immune response which in turn could play vital role in the clinical manifestations of leprosy. These observations may help to determine how these T cell transcription factors affect the development of immune dysfunction and whether these new pathways have a role in immunomodulation in intracellular diseases like leprosy and TB.

Cost analysis of three techniques of administering sevoflurane.

Background. This study aimed to evaluate and compare total cost of sevoflurane and propofol for 1.0 MAC-hour of anaesthesia, employing three anaesthetic techniques. Methods. Adult patients scheduled for surgical procedures under general anaesthesia anticipated to last approximately an hour were randomized into three groups (n = 15 each), to receive anaesthesia using one of the following techniques: low flow technique involving induction with propofol, followed by sevoflurane delivered using initial fresh gas flows of 6 L/min till MAC reached 1.0 and then reduced to 0.5 L/min; alternate method of low flow entailing only a difference in fresh gas flow rates being maintained at 1 L/min throughout; the third technique involving use of sevoflurane for both induction and maintenance of anaesthesia. Results. Cost of sevoflurane to maintain 1 MAC-hour of anaesthesia was clinically least with low flow anaesthesia, though statistically similar amongst the three techniques. Once the cost of propofol used for induction in two of the three groups was added to that of sevoflurane, cost incurred was least with the technique using sevoflurane both for induction and maintenance of anaesthesia, as compared to low flow and alternative low flow techniques, a 26% and 32% cost saving, respectively (P < 0.05).

Synthesis and biological evaluation of some novel 1-substituted fentanyl analogs in Swiss albino mice.

Fentanyl [N-(1-phenethyl-4-piperidinyl)propionanilide] is a potent opioid analgesic agent, but a has narrow therapeutic index. We reported earlier on the synthesis and bioefficacy of fentanyl and its 1-substituted analogs (1-4) in mice. Here we report the synthesis and biological evaluation of four additional analogs, viz. N-isopropyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (5), N-t-butyl-3-(4-(N-phenylpropionamido)piperidin-1-yl)propanamide (6), isopropyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (7) and t-butyl 2-[4-(N-phenylpropionamido)piperidin-1-yl]propionate (8). The median lethal dose (LD50) determined by intravenous, intraperitoneal and oral routes suggests these analogs to be comparatively less toxic than fentanyl. On the basis of observational assessment on spontaneous activities of the central, peripheral, and autonomic nervous systems, all the analogs were found to be similar to fentanyl. Naloxone hydrochloride abolished the neurotoxic effects of these analogs, thereby ascertaining their opioid receptor-mediated effects. All the analogs displayed significant analgesic effects, measured by formalin-induced hind paw licking and tail immersion tests at their respective median effective dose (ED50). They also exhibited 8-12 fold increase in therapeutic index over fentanyl. However, 5 and 6 alone produced lower ED50 (20.5 and 21.0 µg/kg, respectively) and higher potency ratio (1.37 and 1.33, respectively) compared to fentanyl. They could thus be considered for further studies on pain management.

Practice trends in use of morphine for control of intraoperative pain: An audit.

BACKGROUND: When using morphine as the sole analgesic during conduct of anesthesia, the fear of its adverse postoperative effects primarily sedation and respiratory depression may impede adequate dosing and analgesia. AIM AND OBJECTIVES: This audit aims to explore the dosing schedules of morphine used during general anesthesia in our institution and to analyze whether the fear of major side effects leads to suboptimal dosing of morphine with inadequate pain relief. MATERIALS AND METHODS: All subjects scheduled for surgery under general anesthesia wherein morphine was used exclusively for intraoperative analgesia were included in the audit. The audit proforma was completed by the attending anesthesiologist wherein the study period extended from beginning of anesthesia to immediate postoperative period. RESULT: The study population comprised of 158 patients having mean age 33 ± 14 years and mean weight 52 ± 14 kg. The dose of morphine administered at induction varied widely from 0.05 to 0.3 mg/kg i.v. The VAS (Visual Analogue Scale) score in immediate postoperative period varied from 0 to 10 (mean 1.7 ± 2.0) and sedation score from 1 to 5 (mean 3.94 ± 1.05). Inadequate analgesia with a VAS score ≥4 was seen in 15% patients. Morphine dosage of >0.1 mg/kg was associated with highly significant increase in quality of postoperative analgesia with VAS score <4, and an increase in sedation with sedation score ≤3 (P value < 0.01). However, none of the patients required active intervention for cardiorespiratory support. CONCLUSION: The practice of dosing morphine in our institution is highly variable with doses ranging from 0.05 to 0.3 mg/kg. This results in inadequate analgesia in 15% patients in postoperative period. Titrating the dose of morphine to expected pain levels inflicted upon by surgical procedures may result in better pain control and less sedated patients postoperatively.