The role of PKA and PKCε pathways in prostaglandin E2-mediated hypernociception

Background and purpose:

Protein kinase (PK) A and the ε isoform of PKC (PKCε) are involved in the development of hypernociception (increased sensitivity to noxious or innocuous stimuli) in several animal models of acute and persistent inflammatory pain. The present study evaluated the contribution of PKA and PKCε to the development of prostaglandin E₂ (PGE₂)-induced mechanical hypernociception.

Experimental approach:

Prostaglandin E₂-induced mechanical hypernociception was assessed by constant pressure rat paw test. The activation of PKA or PKCε was evaluated by radioactive enzymic assay in the dorsal root ganglia (DRG) of sensory neurons from the hind paws.

Key results:

Hypernociception induced by PGE₂ (100 ng) by intraplantar (i.pl.) injection, was reduced by i.pl. treatment with inhibitors of PKA [A-kinase-anchoring protein St-Ht31 inhibitor peptide (AKAPI)], PKCε (PKCεI) or adenylyl cyclase. PKA activity was essential in the early phase of the induction of hypernociception, whereas PKC activity was involved in the maintenance of the later phase of hypernociception. In the DRG (L4-L5), activity of PKA increased at 30 min after injection of PGE₂ but PKC activity increased only after 180 min. Moreover, i.pl. injection of the catalytic subunit of PKA induced hypernociception which was markedly reduced by pretreatment with an inhibitor of PKCε, while the hypernociception induced by paw injection of PKCε agonist was not affected by an inhibitor of PKA (AKAPI).

Conclusions and implications:

Taken together, these findings are consistent with the suggestion that PKA activates PKCε, which is a novel mechanism of interaction between these kinases during the development of PGE₂-induced mechanical hypernociception.     

Molecular mechanisms of traumatic brain injury: the missing link in management

Background

Cholecystectomy has been the treatment of choice for symptomatic gallstones, but remains the greatest source of post-operative biliary injuries. Laparoscopic approach has been recently preferred because of short hospitalisation and low morbidity but has an higher incidence of biliary leakages and bile duct injuries than open one due to a technical error or misinterpretation of the anatomy. Even open cholecystectomy presents a small number of complications especially if it was performed in urgency. Hemobilia is one of the most common cause of upper gastrointestinal bleeding from the biliary ducts into the gastrointestinal tract due to trauma, advent of invasive procedures such as percutaneous liver biopsy, transhepatic cholangiography, and biliary drainage.

Methods

We report here a case of massive hemobilia in a 60-year-old man who underwent an urgent open cholecystectomy and a subsequent placement of a transhepatic biliary drainage.

Conclusion

The management of these complications enclose endoscopic, percutaneous and surgical therapies. After a diagnosis of biliary fistula, it's most important to assess the adequacy of bile drainage to determine a controlled fistula and to avoid bile collection and peritonitis. Transarterial embolization is the first line of intervention to stop hemobilia while surgical intervention should be considered if embolization fails or is contraindicated.     

Preoperatively determinable factors predictive of diabetes mellitus remission following Roux-en-Y gastric bypass: a review of the literature

It is well established that weight loss in general and bariatric surgery in particular can improve glycaemic control in diabetics. Current NICE guidelines recommend that those patients with type 2 diabetes mellitus and a BMI of 35 kg/m² or more should be considered for bariatric surgery in order to optimise their glycaemic control and minimise their risk of long-term complications. The commonest bariatric procedure in the UK is the Roux-en-Y gastric bypass that has been shown to result in long-standing type 2 diabetes resolution in 83 % of patients. Since such surgery carries a small but significant risk of mortality, as well as posing considerable lifestyle implications for the patient, numerous studies have been performed with a view to identifying which patients and which procedures are most likely to result in these desired benefits. This paper summarises the existing literature on this topic.     

叶酸受体介导的靶向纳米给药系统研究进展

叶酸受体在许多恶性肿瘤细胞表面过度表达,而在正常细胞中则几乎不表达或只有少量表达。利用叶酸受体表达的特性,通过将叶酸修饰于药物载体表面,可使药物靶向输送至叶酸受体过度表达的肿瘤细胞中,从而避免对正常细胞产生毒性,提高药物疗效;而纳米给药系统因粒径较小等原因可使药物在肿瘤部位浓集。本文对近年来叶酸受体介导的靶向纳米给药系统进行了综述。     

Cytotoxicity evaluation and hepatoprotective potential of bioassay guided fractions from Feronia limmonia Linn leaf

Objective

To evaluate the cytotoxicity and hepatoprotective potentials of extracts, fractions or isolated compound from the leaves of Feronia limonia (F. limonia).

Methods

Qualitative phytochemical analysis of extracts, fractions or compound was performed by means of thin layer chromatography and spectroscopic assays. The % purity of compound was measured by analytical HPLC. Extracts, fractions or compound have been individually evaluated for their cytotoxicity effects (10, 20, 100, 250, 500, 750 and 1 000 µg/mL). Based on the inhibitory concentration (IC₅₀) obtained from the cell viability assay, graded concentrations of extracts, fractions or isolated compound were assessed (10, 20, 50, 100, 200 µg/mL) for its hepatoprotective potential against CCl₄-induced hepatotoxicity by monitoring activity levels of serum glutamatic pyruvatic transaminase (SGPT) and serum glutamic oxaloacetic transaminase (SGOT).

Results

Results indicated that the methanol extract of F. limonia was non-toxic and hepatoprotective in nature as compared with the petroleum ether extract. The acetone fraction of methanolic extract also showed similar properties but the subsequent two fractions were cytotoxic. However, the pure compound isolated from the penultimate fraction of methanolic extract was non-toxic and hepatoprotective in nature. Biochemical investigations (SGOT, SGPT) further corroborated these cytological observations.

Conclusions

It can be concluded from this study that F. limonia methanol extract, some fractions and pure isolated compound herein exhibit hepatoprotective activity. However, cytotoxicity recorded in the penultimate fraction and investigation of structural details of pure compound warrants further study.     

Therapeutic drug monitoring of lopinavir/ritonavir in pregnancy

Objectives

The aim of the study was to determine total and unbound lopinavir (LPV) plasma concentrations in HIV‐infected pregnant women receiving lopinavir/ritonavir (LPV/r tablet) undergoing therapeutic drug monitoring (TDM) during pregnancy and postpartum.

Methods

Women were enrolled in the study who were receiving the LPV/r tablet as part of their routine prenatal care. Demographic and clinical data were collected and LPV plasma (total) and ultrafiltrate (unbound) concentrations were determined in the first, second and third trimesters using high‐performance liquid chromatography–tandem mass spectrometry (HPLC‐MS/MS). Postpartum sampling was performed where applicable. Antepartum and postpartum trough concentrations (C_trough) were compared independently [using analysis of variance (anova )] and on a longitudinal basis (using a paired t‐test).

Results

Forty‐six women were enrolled in the study (38 Black African). Forty women initiated LPV/r treatment in pregnancy. Median (range) gestation at initiation was 25 (15–36) weeks and median (range) baseline CD4 count and viral load were 346 (14–836) cells/μL and 8724 (<50–267408) HIV‐1 RNA copies/mL, respectively. Forty women (87%) had LPV concentrations above the accepted minimum effective concentration for wild‐type virus (MEC; 1000 ng/mL). Geometric mean (95% confidence interval [CI]) total LPV concentrations in the first/second [3525 (2823–4227) ng/mL; n=16] and third [3346 (2813–3880) ng/mL; n=43] trimesters were significantly lower relative to postpartum [5136 (3693–6579) ng/mL; n=12] (P=0.006). In a paired analysis (n=12), LPV concentrations were reduced in the third trimester [3657 (2851–4463) ng/mL] vs. postpartum (P=0.021). No significant differences were observed in the LPV fraction unbound (fu%). Conclusions The above target concentrations achieved in the majority of women and similarities in the fu% suggest standard dosing of the LPV/r tablet is appropriate during pregnancy. However, reduced LPV concentrations in the second/third trimesters and potentially compromised adherence highlight the need for TDM‐guided dose adjustment in certain cases.