Effects of vitamin E and selenium administration on transportation stress in pregnant dairy heifers.

We investigated the effects of road transportation and administration of the vitamin E and selenium (ESe) on circulating cortisol, haptoglobin, blood metabolites, oxidative biomarkers, white blood cell profiles, and behaviors in pregnant dairy heifers. Forty pregnant Holstein heifers were randomly assigned to one of 4 treatments: no transportation and no ESe administration, no transportation and ESe administration, transportation and no administration, and transportation and ESe administration. The ESe (70 IU/kg dry matter feed of dl-α-tocopheryl acetate and 0.3 mg/kg dry matter feed of sodium selenite) was orally delivered once a day from 7 d before transportation to 3 d after transportation. The heifers were transported in trucks designed for cattle transportation. Blood was collected 1 h before transportation, immediately after transportation (IAT), and at 6, 24, and 48 h after transportation. Behaviors were recorded using a video camera for 2 consecutive days after transportation. Transported/non-ESe-administered heifers had greater cortisol at IAT, haptoglobin at 6 and 24 h after transportation, total oxidative status at 6 h after transportation, and nonesterified fatty acid levels, white blood cell numbers, and neutrophil percentages at IAT and 6 h after transportation in the blood than nontransported heifers. Transported/non-ESe-administered heifers had lower total antioxidative status levels at 48 h after transportation and lymphocyte percentages at IAT and 6 h after transportation than nontransported heifers. Lying time was shorter in transported heifers than nontransported/non-ESe-administered heifers. Transported/ESe-administered heifers had lower cortisol, total oxidative status, nonesterified fatty acid levels at IAT, and haptoglobin concentrations at 6 and 24 h after transportation than transported/non-ESe-administered heifers. Transported/ESe-administered heifers had greater total antioxidative status levels at 48 h after transportation than transported/non-ESe-administered heifers. No ESe administration effects were observed for white blood cell number and neutrophil and lymphocyte percentages and lying time. In conclusion, road transportation caused temporary oxidative stress. Administrating ESe partially alleviated the stress, suggesting that ESe administration could be a viable strategy to reduce stress in transported pregnant heifers, providing a novel role of vitamin E and selenium for improving animal welfare.

In vitro antioxidant and cytotoxic activities of polyherbal extracts from Vetiveria zizanioides, Trichosanthes cucumerina, and Mollugo cerviana on HeLa and MCF-7 cell lines.

Various metabolites exist in the medicinal plants have lot of potential to cure various diseases and disorders. Plants such as, Vetiveria zizanioides, Trichosanthes cucumerina, and Mollugo cerviana were collected from Western Ghats, Tamilnadu, India. Phytochemicals were extracted from these plants using various organic solvents and tested against Gram-positive and Gram-negative bacteria. The phytochemicals such as, carbohydrate, alkaloids, steroids, saponins, flavonoids and tannin were detected from these medicinal plants. Among the extracts, methanol showed potent activity and this solvent was used to extract polyherbal medicinal plants. Methanol extract of V. zizanioides was found to be highly active against E. coli (27 ± 2 mm), P. mirabilis (19 ± 3 mm) and B. subtilis (18 ± 2 mm). Ethyl acetate extract showed high activity against E. coli (24 ± 2 mm), P. mirabilis (22 ± 3 mm) and B. subtilis (20 ± 1 mm). These three plants were taken at 1:1:1 ratio and extracted with methanol at 1:10 ratio and synergistic activity was tested against bacterial pathogens. Synergistic activity of polyherbal extract was analyzed. The extracted crude herbal medicine was found to be effective against Staphylococcus aureus, E. coli, Enterbacter sp., Pseudomonas aeruginosa, Bacillus subtilis and Proteus mirabilis. The zone of inhibition was 33 ± 3 mm, 17 ± 2 mm, 22 ± 2 mm, 40 ± 2 mm, 33 ± 1 mm and 38 ± 2 mm zone of inhibition against E. coli, S. aureus, P. aeruginosa, P. mirabilis, B. subtilis and Enterobacter sp. Polyherbal extract was found to be highly effective against P. mirabilis and Enterobacter sp. MIC values of polyherbal extract ranged from 29 ± 2.5 µg/ml to 34 ± 2.5 µg/ml. MIC value was found to be less against P. mirabilis and was high against S. aureus. Antioxidant property varied between 49 ± 3% and 95.3 ± 2%. At 20 µg/ml antioxidant activity was reported as 49 ± 3% and it was increased at higher concentrations of polyherbal extract. Two cell lines (HeLa and MCF cell lines) were selected to analyze cytotoxic activity of polyherbal extract. The methanol extract of polyherbal fraction showed cytotoxicity against these two cell lines. The LC50 value was 467 ± 2.9 µg/ml against HeLa cell line and >800 µg/ml against MCF-7 cell lines. The polyherbal extract showed antibacterial, antioxidant and anticancer activities.

Therapeutic efficacy of the root tubers of Aconitum heterophyllum and its substitute Cyperus rotundus in the amelioration of pylorus ligation induced ulcerogenic and oxidative damage in rats.

The phenomenal increase in the demand of herbal drugs, leads to over exploitation of medicinal plants which ultimately resulted in the scarcity and endangerment of many valuable plant species. On observing the difficulties in procuring genuine herbal drugs arose the concept of substitution which was documented in many classical Ayurvedic texts. The present study made a comparative evaluation of the gastroprotective potential of hydroalcoholic extracts of an original drug Aconitum heterophyllum (HAAH) and its substitute Cyperus rotundus (HACR) in the treatment of gastric ulcer under in vivo experimental conditions. The anti-ulcer property of the plant extracts was investigated against pylorus ligation induced ulcer in Wistar albino rats. The results confirmed that both A. heterophyllum and C. rotundus deliver comparable significant protection against gastric ulcer, indicated by a decrease in the free and total acidity, volume of gastric content, total proteins and increase in pH of gastric content, total carbohydrates and total carbohydrates to total proteins ratio. The observed anti-ulcer potential of both the drugs is attributed mainly to prevention of the generation of damaging free radical cascades and oxidant radical release.

Effect of traditionally used herb Pedalium murex L. and its active compound pedalitin on urease expression - For the management of kidney stone.

Pedalium murex L. is a medicinal herb that has been used for the treatment of diseases related to kidney in the traditional system of medicine. The current study aims to study the effect of ethyl acetate extract of P. murex (EAEP) and its fractionated compound pedalitin against urease production and UreC gene expression in Proteus mirabilis. The selected reference strain Proteus mirabilis (MTCC 425) and the isolates culture of Proteus mirabilis were subjected to study the antibacterial efficacy of P. murex. Expression analysis of P. mirabilis urease gene was successfully done by QPCR. The ethyl acetate extract effectively inhibit the reference Proteus mirabilis and bacterial isolates of Proteus mirabilis in the clinical samples studied. EAEP has showed more potent activity (56.7%) against urease enzyme and pedalitin also exhibited potent activity (30.1%). Using qPCR, the expression of UreC gene of P. mirabilis was controlled by EAEP and also its bioactive compound pedalitin. The present study clearly demonstrated the potency of P. murex in controlling the growth of pathogenic P. mirabilis and to control the expression of urease enzyme production as well as to restrict the urease gene expression in P. mirabilis.

Multidrug-resistant tuberculosis in South Korea: a retrospective analysis of national registry data in 2011-2015.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) poses a threat to public health as a result of high treatment costs and unsatisfactory outcomes.OBJECTIVE: To elucidate trend, demographic and clinical characteristics and treatment outcomes of patients with MDR-TB between 2011 and 2015 in South Korea.METHOD: Data of patients with MDR-TB diagnosed between 1 January 2011 and 31 December 2015 were retrieved from the nationwide Internet-based TB notification system and analysed retrospectively.RESULTS: During the study period, 5192 MDR-TB patients were notified. We identified an increasing number of MDR-TB patients among foreign populations (from 1.3% to 7.7%), decreasing resistance rates to other anti-TB drugs (e.g., resistance to pyrazinamide, from 40.9% to 28.2%), a decreasing interval from treatment initiation to negative conversion of sputum culture (from 165.7 to 103.7 days) and shortening of treatment duration (719.7 to 613.2 days). However, treatment success rates did not change, and had an average of 65.7%.CONCLUSION: Despite decreasing resistance rates to other drugs and faster treatment responses, treatment outcomes did not improve during the study period. Strict management of MDR-TB patients on treatment should be adopted to improve treatment outcomes.

Methanolic extract of Kigelia africana exhibits antiatherosclerotic effects in endothelial cells by downregulating RAGE and adhesion molecules.

The Kigelia plant is used in African countries for its medicinal properties. Kigelia africana is an interesting example of a medicinal plant due to its pharmacological activities, including its anti-inflammatory effect. Atherosclerosis, the primary cause of cardiovascular disease, is related to lipoprotein oxidation, inflammation and immune responses involving the vascular endothelium and immune cells. Therefore, in this study we investigated the effects of Kigelia africana (Lam.) extract, focusing particularly on antiatherosclerotic effects in endothelial cells (ECs). The methanolic extract of Kigelia africana (MKA) showed no cytotoxicity on ECs at doses of 10~200 µg/ml. MKA reduced RAGE expression on oxLDL- or TNF-α-stimulated ECs in a dose dependent manner, showing significant inhibition at a concentration of 50 µg/ml. In addition, MKA significantly inhibited the oxLDL- or TNF-αinduced expression of vascular cell adhesion molecule-1 (VCAM-1) in ECs in a dose-dependent manner but did not affect intracellular adhesion molecule-1 (ICAM-1), resulting in downregulation of the migration and adhesion of THP-1 monocytes to ECs. These results suggest that MKA could be used for the treatment of atherosclerosis without cytotoxicity.

Methanolic extract of Kigelia africana exhibits antiatherosclerotic effects in endothelial cells by downregulating RAGE and adhesion molecules

@#The Kigelia plant is used in African countries for its medicinal properties. Kigelia africana is an interesting example of a medicinal plant due to its pharmacological activities, including its anti-inflammatory effect. Atherosclerosis, the primary cause of cardiovascular disease, is related to lipoprotein oxidation, inflammation and immune responses involving the vascular endothelium and immune cells. Therefore, in this study we investigated the effects of Kigelia africana (Lam.) extract, focusing particularly on antiatherosclerotic effects in endothelial cells (ECs). The methanolic extract of Kigelia africana (MKA) showed no cytotoxicity on ECs at doses of 10~200 μg/ml. MKA reduced RAGE expression on oxLDL- or TNF-α-stimulated ECs in a dose dependent manner, showing significant inhibition at a concentration of 50 μg/ml. In addition, MKA significantly inhibited the oxLDL- or TNF-α- induced expression of vascular cell adhesion molecule-1 (VCAM-1) in ECs in a dose-dependent manner but did not affect intracellular adhesion molecule-1 (ICAM-1), resulting in downregulation of the migration and adhesion of THP-1 monocytes to ECs. These results suggest that MKA could be used for the treatment of atherosclerosis without cytotoxicity.

Deep gray matter atrophy in neuromyelitis optica spectrum disorder and multiple sclerosis.

BACKGROUND AND PURPOSE: We investigated changes in deep gray matter (DGM) volume and its relationship to cognition and clinical factors in a large cohort of patients with neuromyelitis optica spectrum disorder (NMOSD) and compared them with results from multiple sclerosis (MS). METHODS: Brain magnetic resonance imaging (3 Tesla) and clinical data from 91 patients with NMOSD, 52 patients with MS and 44 healthy controls (HCs) were prospectively evaluated. Differences in DGM volumes were compared among groups. The relationships between DGM atrophy and clinical variables were also analysed. RESULTS: Patients with NMOSD exhibited significantly reduced thalamic volumes compared with HCs (P = 0.029), although this atrophy was less severe than that seen in patients with MS (P < 0.001). DGM atrophy was restricted to the thalamus in NMOSD, but it was broadly distributed in MS. Patients with NMOSD with cognitive impairment (CI) exhibited more severe thalamic atrophy than those with cognitive preservation (P = 0.017) and HCs (P = 0.003), whereas patients with MS with CI revealed DGM atrophy across the entire structure, with the exception of the bilateral pallidum, left hippocampus and amygdala, relative to HCs. The Expanded Disability Status Scale score was correlated with thalamic atrophy in both NMOSD and MS. Patients with NMOSD with brain lesions demonstrated more severe thalamic atrophy than did those without brain lesions and HCs (P < 0.001). CONCLUSIONS: The DGM atrophy was less severe and more selectively distributed in NMOSD than in MS. Thalamic atrophy was associated with clinical disability, including CI, in both NMOSD and MS.

Protective Effect of Eupatilin Pretreatment Against Hepatic Ischemia-Reperfusion Injury in Mice.

BACKGROUND: Eupatilin, a pharmacologically active flavone derived from Artemisia species, is known to have antioxidant and antiinflammatory activities. Ischemia-reperfusion injury (IRI) is a major critical event that commonly occurs after liver transplantation and resection. Furthermore, inflammatory responses to IRI exacerbate the resultant hepatic injury. In this study, we investigated whether eupatilin protects against IR-induced acute liver injury in mice. MATERIALS AND METHODS: Partial (70%) hepatic IRI was induced in male C57BL/6 mice by portal triad pedicle occlusion for 90 minutes followed by reperfusion for 6 hours. Eupatilin (10 mg/kg body weight, oral) was administered 4 days before the IRI. RESULTS: Treatment with eupatilin significantly decreased serum alanine aminotransferase and serum aspartate aminotransferase as well as liver histologic changes. Eupatilin also prevented hepatic glutathione depletion and increased malondialdehyde levels induced by IRI. Western blotting indicated that eupatilin significantly increased the levels of heat shock protein and B-cell lymphoma 2 protein, attenuated inducible nitric oxide synthase, and cleaved caspase-3 levels 6 hours after IRI. The expression of the Toll-like receptor 2/4, and phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor was significantly decreased in the eupatilin pretreatment group. CONCLUSIONS: Eupatilin improved the acute hepatic IRI by reducing inflammation and apoptosis. These findings suggest that eupatilin is a promising therapeutic agent against acute IR-induced hepatic damage.

Red Ginseng Administration Before Islet Isolation Attenuates Apoptosis and Improves Islet Function and Transplant Outcome in a Syngeneic Mouse Marginal Islet Mass Model.

BACKGROUND: Transplantation of isolated islets is a promising treatment for diabetes. Red ginseng (RG) is steamed ginseng and has been reported to enhance insulin secretion-stimulating and anti-apoptotic activities in pancreatic ß-cells. In this study, we examined the hypothesis that pre-operative RG treatment enhances islet cell function and anti-apoptosis and investigated whether RG improves islet engraftment by transplant of a marginal mass of syngeneic islets pretreated with RG in diabetic mice. METHODS: Balb/c mice were randomly divided into 2 groups, and 1 group was administered RG (400 mg/kg/day orally) for 7 days before islet isolation. In vitro islet viability and function were assessed. After cytokine treatment, cell viability, function, and apoptosis of islet cells were analyzed. Furthermore, we studied the effects of RG in a syngeneic islet graft model. A marginal mass of syngeneic mouse islets was transplanted into diabetic hosts. RESULTS: Islet pretreatment with RG showed 1.4-fold higher glucose-induced insulin secretion than did control islets. RG pretreatment upregulated B-cell lymphoma 2 (Bcl-2) expression and downregulated Bcl-associated X protein (BAX), caspase-3, and inducible nitric oxide synthase (iNOS) expression. Glucose-induced insulin release, NO, and apoptosis were significantly improved in RG-pretreated islets compared with cytokine-treated islets. RG-pretreated mice exhibited improved marginal mass islet graft survival compared with controls. CONCLUSIONS: These results suggest that pre-operative RG administration enhanced islet function before transplantation and attenuated cytokine-induced damage associated with apoptosis. These studies indicate that inhibition of apoptosis by RG significantly improved islet cell and graft function after isolation and transplantation, respectively.

Endothelium-independent vasorelaxant effect of a Berberis orthobotrys root extract via inhibition of phosphodiesterases in the porcine coronary artery.

BACKGROUND: Berberis orthobotrys Bien ex Aitch. (Berberidaceae) is a plant indigenous of Pakistan that is locally used for the treatment of hypertension. HYPOTHESIS: This study evaluated the vasoactive properties of a Berberis orthobotrys root extract and its fractions, and investigated the role of the endothelium and the underlying mechanism. STUDY DESIGN: An aqueous methanolic extract of Berberis orthobotrys roots was prepared and submitted to a multi-step liquid-liquid fractionation with solvents of increasing polarity. Vascular reactivity of the different fractions was assessed using porcine coronary artery rings either with or without endothelium, and in the presence or absence of specific pharmacological tools. The ability of Berberis orthobotrys extracts to affect phosphodiesterase (PDE) activity was evaluated using a radioenzymatic method and purified phosphodiesterases. RESULTS: The aqueous methanol extract induced similar relaxations in coronary artery rings with and without endothelium, and, amongst the three derived preparations, the butanol fraction (BFBO) was slightly but significantly more effective than the ethyl acetate fraction and the aqueous residue in rings without endothelium. Analysis of the butanol fraction (BFBO) by LC-ELSD-MS indicated the presence of four major isoquinoline alkaloids including berberine. BFBO significantly potentiated the relaxations induced by cyclic GMP- and cyclic AMP-dependent relaxing agonists, and inhibited contractions to KCl, CaCl2, and U46619 in endothelium denuded rings. In contrast, BFBO did not affect relaxations to endothelium-dependent vasodilators. BFBO concentration-dependently inhibited the cyclic GMP-hydrolyzing activity of basal PDE1, calmodulin-activated PDE1 and PDE5, and of cyclic AMP-hydrolyzing activity of PDE3 and PDE4 with IC50 values ranging from 40 to 130µg/ml. CONCLUSION: The butanol fraction of the aqueous methanol extract of Berberis orthobotrys roots induced pronounced endothelium-independent relaxations and inhibited contractile responses by acting directly at the vascular smooth muscle in the coronary artery. Moreover, BFBO potentiated relaxations induced by both cyclic GMP- and cyclic AMP-dependent vasodilators most likely due to its ability to inhibit several vascular PDEs, and in particular PDE4 and PDE5.

Effect of preoperative autologous blood donation on patients undergoing bimaxillary orthognathic surgery: a retrospective analysis.

The efficacy of preoperative autologous blood donation (PABD) was evaluated according to preoperative haemoglobin (Hb) values. The records of 295 patients who underwent bimaxillary orthognathic surgery between July 2007 and August 2008 were reviewed. The records for autologous blood donation, intraoperative transfusion, and related laboratory studies were also evaluated. The transfusion trigger used during this period was Hb < 10 g/dl. A total of 189 patients (64.1%) made a PABD and 106 patients (35.9%) did not. The incidence of allogeneic blood transfusion was significantly lower in the PABD group than in the no PABD group (15.9% vs. 29.2%, P = 0.007). This difference was greater in patients with a preoperative Hb < 14 g/dl (20.3% vs. 62.5%, P < 0.0001), and no difference was found in patients with Hb ≥ 14 g/dl (13.3% vs. 14.9%, P = 0.83). PABD reduced the incidence of allogeneic blood transfusion in patients undergoing bimaxillary orthognathic surgery, particularly in patients with a preoperative Hb < 14 g/dl. PABD could be used to reduce the frequency of intraoperative allogeneic blood transfusion in these patients.

Phylogenetic group distributions, virulence factors and antimicrobial resistance properties of uropathogenic Escherichia coli strains isolated from patients with urinary tract infections in South Korea.

UNLABELLED: Urinary tract infections (UTIs) are one of the most common diseases by which humans seek medical help and are caused mainly by uropathogenic Escherichia coli (UPEC). Studying the virulence and antibiotic resistance of UPEC with respect to various phylogenetic groups is of utmost importance in developing new therapeutic agents. Thus, in this study, we analysed the virulence factors, antibiotic resistance and phylogenetic groups among various UPEC isolates from children with UTIs. The phylogenetic analysis revealed that majority of the strains responsible for UTIs belonged to the phylogenetic groups B2 and D. Of the 58 E. coli isolates, 79·31% belonged to group B2, 15·51% to group D, 3·44% to group A and 1·72% to B1. Simultaneously, the number of virulence factors and antibiotic resistance exhibited were also significantly high in groups B2 and D compared to other groups. Among the isolates, 44·8% were multidrug resistant and of that 73% belonged to the phylogenetic group B2, indicating the compatibility of antibiotic resistance and certain strains carrying virulence factor genes. The antibiotic resistance profiling of UPEC strains elucidates that the antimicrobial agents such as chloramphenicol, cefoxitin, cefepime, ceftazidime might still be used in the therapy for treating UTIs. SIGNIFICANCE AND IMPACT OF THE STUDY: As the antibiotic resistance pattern of uropathogenic Escherichia coli varies depending on different geographical regions, the antibiotic resistance pattern from this study will help the physicians to effectively administer antibiotic therapy for urinary tract infections. In addition, the frequency of virulence factors and antibiotic resistance genes among various phylogenic groups could be effectively used to draw new targets for uropathogenic Escherichia coli antibiotic-independent therapies. The study emphasizes need of public awareness on multidrug resistance and for more prudent use of antimicrobials.

Laughter and Stress Relief in Cancer Patients: A Pilot Study.

The purpose of this study was to examine the effect of a therapeutic laughter program and the number of program sessions on anxiety, depression, and stress in breast cancer patients. A randomized controlled trial was conducted involving 31 patients who received four sessions of therapeutic laughter program comprised and 29 who were assigned to the no-program control group. Scores for anxiety, depression, and stress were measured using an 11-point numerical rating scale. While no change was detected in the control group, the program group reported reductions of 1.94, 1.84, and 2.06 points for anxiety, depression, and stress, respectively (p < 0.01, p < 0.01, and p < 0.01). Scores decreased significantly after the first therapeutic laughter session (p < 0.05, p < 0.01, and p < 0.01). As the therapeutic laughter program was effective after only a single session in reducing anxiety, depression, and stress in breast cancer patients, it could be recommended as a first-line complementary/alternative therapy.

Lactoferrin causes IgA and IgG2b isotype switching through betaglycan binding and activation of canonical TGF-ß signaling.

Lactoferrin (LF), a pleiotropic iron-binding glycoprotein, is known to modulate the humoral immune response. However, its exact role in Ig synthesis has yet to be elucidated. In this study, we investigated the effect of LF on Ig production by mouse B cells and its underlying mechanisms. LF, like transforming growth factor (TGF)-ß1, stimulated B cells to produce IgA and IgG2b, while downregulating other isotypes. Using limiting dilution analysis, LF was shown to increase the frequency of IgA-secreting B-cell clones. This was paralleled by an increase in Ig germ-line α (GLα) transcripts, indicating that LF plays a role as an IgA switch factor. Interestingly, LF directly interacted with betaglycan (TGF-ß receptor III, TßRIII) and in turn induced phosphorylation of TßRI and Smad3 through formation of the TßRIII/TßRII/TßRI complex, leading to IgA isotype switching. Peroral administration of LF increased intestinal/serum IgA production as well as number of IgA plasma cells in lamina propria. Finally, we found that LF has an adjuvant activity when nontoxigenic Salmonella typhimurium was inoculated perorally, conferring protection against intragastrical infection of toxigenic S. typhimurium. These results suggest that LF has an important effect on the mucosal/systemic IgA response and can contribute to protection against intestinal pathogens.

NOD2 Mediates Odontoblast Differentiation and RANKL Expression.

The precise regulation of odontoblast differentiation and osteoclastogenic cytokine expression in human dental pulp cells (HDPCs) is crucial for the pathology of bacteria-related pulpitis. Although the up-regulation of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) has been reported in inflamed human dental pulps, the role of NOD2 in the differentiation of HDPCs remains unclear. Here, we show the involvement of NOD2 in odontoblast differentiation together with osteoclastogenic cytokine expression in HDPCs. Treatment with muramyl dipeptide (MDP), a known NOD2-agonist, significantly inhibited odontoblast differentiation of HDPCs, as revealed by reduced ALP activity, osteoblast/odontoblast marker expression, and mineralized nodule formation. Importantly, the forced down-regulation of NOD2 by small interfering RNA (siRNA) recovered MDP-down-regulated odontoblast differentiation. MDP-elicited suppression of odontoblast differentiation resulted from the increased expression of MKP-1 protein and the subsequent decline of MAPKs phosphorylation, which is a prerequisite for odontoblast differentiation. Furthermore, we found that MDP treatment elevated the expression of osteoclastogenic cytokines in HDPCs, which was also reversed by NOD2 silencing. Analysis of these data, taken together, suggests that the regulation of NOD2 expression upon MDP challenge might serve as an intrinsic mechanism that underlies the hindered dentin formation and accelerated dentin resorption in bacterial infection-mediated pulpitis.

Distinctive role of 6-month teriparatide treatment on intractable bisphosphonate-related osteonecrosis of the jaw.

UNLABELLED: The administration of teriparatide (TPTD) in conjunction with periodontal care could provide faster and more favorable clinical outcomes in previously refractory bisphosphonate-related osteonecrosis of the jaws (BRONJ) cases compared to conventional dental care, combination of surgery and antimicrobial treatment. We also found that underlying vitamin D levels might influence the response to TPTD treatment. INTRODUCTION: Treatment of BRONJ is quite challenging and there are no standard treatment modalities. In this retrospective, longitudinal study, we examined whether additional TPTD administration could be beneficial for the resolution of BRONJ lesions compared to conservative management, such as antimicrobial treatment with or without surgery, and also studied the factors influencing the response to TPTD. METHODS: Twenty-four cases of intractable BRONJ were included: 15 subjects were assigned to the TPTD group and the other 9 subjects, who refused TPTD administration, were assigned to the non-TPTD group. All subjects in both groups continued calcium and vitamin D supplementation and the TPTD group additionally received a daily subcutaneous injection of 20 µg TPTD for 6 months. RESULTS: While 60.0% of the non-TPTD group showed one stage of improvement in BRONJ, 40.0% of the group did not show any improvement in disease status. In the TPTD group, 62.5% of the treated subjects showed one stage of improvement and the other 37.5% demonstrated a marked improvement, including two stages of improvement or complete healing, and there was not a single case that did not improve. The clinical improvement of BRONJ was statistically better in the TPTD group after the 6-month treatment (p < 0.05). Moreover, patients with higher baseline serum 25(OH)D levels showed better clinical therapeutic outcomes with TPTD. CONCLUSIONS: We observed the beneficial effects of TPTD on BRONJ, and subjects with optimal serum vitamin D concentrations seemed to reap the maximum therapeutic effects of TPTD. A prospective, randomized, controlled trial should be needed to further evaluate the therapeutic efficacy of TPTD in the resolution of BRONJ.

Antinociceptive curcuminoid, KMS4034, effects on inflammatory and neuropathic pain likely via modulating TRPV1 in mice.

BACKGROUND: Curcumin, the active ingredient of turmeric (Curcuma longa), has a wide range of beneficial effects including anti-inflammation and analgesia. However, poor bioavailability of curcumin hinders its clinical application. To overcome this limitation, we modified the structure of curcumin and synthesized new derivatives with favourable pharmacokinetic profiles. Recently, curcumin has been shown to have an antagonizing effect on transient receptor potential vanilloid type 1 (TRPV1) ion channels. We investigated the antinociceptive activity of KMS4034 which had the most favourable pharmacokinetics among the tested curcumin derivatives. METHODS: To evaluate the mechanism of the antinociceptive effects of KMS4034, capsaicin (I(CAP))- and heat (I(heat))-induced currents in TRPV1 expressing HEK293 cells were observed after the application of KMS4034. Nociceptive behavioural measurement using the hot-plate test, formalin test, and chronic constriction injury (CCI) model were evaluated in mice. Also, calcitonin gene-related peptide (CGRP) was stained immunohistochemically in the L4/5 dorsal horns in mice with neuropathic pain. RESULTS: I(CAP) (P<0.01) and I(heat) (P<0.05) of TRPV1 were significantly blocked by 10 µM KMS4034. Behaviourally, noticeable antinociceptive effects after 10 mg kg(-1) of KMS4034 treatment were observed in the first (P<0.05) and second phases (P<0.05) of the formalin and hot-plate tests. The mechanical threshold of CCI mice treated with 10 mg kg(-1) KMS4034 was significantly increased compared with control. Immunohistochemical CGRP expression was decreased in the lamina I-II of the lumbar dorsal horns in KMS4034-treated CCI mice compared with the control (P<0.05). CONCLUSIONS: KMS4034 may be an effective analgesic for various pain conditions.

Molecular mechanisms of large-conductance ca (2+) -activated potassium channel activation by ginseng gintonin.

Gintonin is a unique lysophosphatidic acid (LPA) receptor ligand found in Panax ginseng. Gintonin induces transient [Ca(2+)]i through G protein-coupled LPA receptors. Large-conductance Ca(2+)-activated K(+) (BKCa) channels are expressed in blood vessels and neurons and play important roles in blood vessel relaxation and attenuation of neuronal excitability. BKCa channels are activated by transient [Ca(2+)]i and are regulated by various Ca(2+)-dependent kinases. We investigated the molecular mechanisms of BKCa channel activation by gintonin. BKCa channels are heterologously expressed in Xenopus oocytes. Gintonin treatment induced BKCa channel activation in oocytes expressing the BKCa channel α subunit in a concentration-dependent manner (EC50 = 0.71 ± 0.08 µg/mL). Gintonin-mediated BKCa channel activation was blocked by a PKC inhibitor, calphostin, and by the calmodulin inhibitor, calmidazolium. Site-directed mutations in BKCa channels targeting CaM kinase II or PKC phosphorylation sites but not PKA phosphorylation sites attenuated gintonin action. Mutations in the Ca(2+) bowl and the regulator of K(+) conductance (RCK) site also blocked gintonin action. These results indicate that gintonin-mediated BKCa channel activations are achieved through LPA1 receptor-phospholipase C-IP3-Ca(2+)-PKC-calmodulin-CaM kinase II pathways and calcium binding to the Ca(2+) bowl and RCK domain. Gintonin could be a novel contributor against blood vessel constriction and over-excitation of neurons.

Vein involvement during pancreaticoduodenectomy: is there a need for redefinition of "borderline resectable disease"?

INTRODUCTION: Current National Comprehensive Cancer Network guidelines recommend neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma to increase the likelihood of achieving R0 resection. A consensus has not been reached on the degree of venous involvement that constitutes borderline resectability. This study compares the outcome of patients who underwent pancreaticoduodenectomy with or without vein resection without neoadjuvant therapy. METHODS: A multi-institutional database of patients who underwent pancreaticoduodenectomy was reviewed. Patients who required vein resection due to gross vein involvement by tumor were compared to those without evidence of vein involvement. RESULTS: Of 492 patients undergoing pancreaticoduodenectomy, 70 (14 %) had vein resection and 422 (86 %) did not. There was no difference in R0 resection (66 vs. 75 %, p = NS). On multivariate analysis, vein involvement was not predictive of disease-free or overall survival. CONCLUSION: This is the largest modern series examining patients with or without isolated vein involvement by pancreas cancer, none of whom received neoadjuvant therapy. Oncological outcome was not different between the two groups. These data suggest that up-front surgical resection is an appropriate option and call into question the inclusion of isolated vein involvement in the definition of "borderline resectable disease."