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Endometriosis is the abnormal growth of endometrial tissue. The goals of the study are: (1) Is any correlation between endometriosis pain and neurotrophins in the serum, dorsal root ganglion (DRG), and peritoneal fluid (PF) in rat models of experimental endometriosis?, (2) Possible therapeutic effects of royal jelly (RJ) on pain scores, size of endometriotic lesion, and neurotrophic factors. Forty-eight Sprague Dawley female rats weighing 205.023 ± 21.54 g were maintained in a standard condition. The rats were randomly divided into one of the six groups: Control (no intervention), Sham-1 (remove of uterine horn), RJ (administration of 200 mg/kg/day RJ for 21 days), Endometriosis (induction of endometriosis), Treatment (induction of endometriosis+administration of 200 mg/kg/day RJ for 21 days), and Sham-2 (induction of endometriosis+administration of water). Formalin test performed for pain evaluation. The levels of Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), substance P, and calcitonin gene-related peptide (CGRP) were measured by enzyme-linked immunosorbent assay. The mean pain scores in all three phases of the formalin test were significantly increased by endometriosis induction (p < 0.05). The concentrations of BDNF, NGF, and CGRP in DRG of the endometriosis group were significantly higher than these factors in the Control, Sham-1, and RJ groups (p < 0.05). RJ could significantly (p < 0.001) decrease the mean lesion size and the mean pain score in the late phase (p < 0.05). The present results determine that endometriosis pain may be related to nervous system neurotrophic factors. Treatment with RJ could decrease the size of endometriosis lesions as well as pain scores. The findings may shed light on other complementary and alternative remedies for endometriosis., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Research Question: Endometriosis, an inflammatory disease, is assumed to be associated with an increased production of growth-related cytokines. Based on the emerging immunomodulatory role of vitamin D3 in different inflammatory conditions, this study aimed to examine its modulatory effect on the expression levels of the genes for platelet-derived growth factor-B (PDGFB), monocyte/macrophage-derived growth factor (MDGF, also known as PPBP) and epidermal growth factor (EGF) in peritoneal fluid mononuclear cells (PFMC) in women with and without endometriosis., Design: PFMC from 10 women with endometriosis and 10 control participants were treated with vitamin D3.The gene expression levels of PDGFB, MDGF and EGF were measured 6, 24 and 48 h following vitamin D3 administration using real-time PCR., Results: Gene expression levels of EGF and PDGFB were higher in the PFMC of women with endometriosis than the control group (P = 0.006, P < 0.001, respectively). Although MDGF expression showed an increase in the endometriosis group compared with non-endometriotic controls, no significant difference was found. Vitamin D3 significantly decreased EGF expression at 6, 24 and 48 h (P < 0.001, P < 0.001 and P = 0.007, respectively), MDGF at 24 and 48 h (P < 0.001 and P = 0.009, respectively) and PDGFB at 6 h (P = 0.047) in the endometriosis group. Vitamin D3 treatment had no significant effect on expression of the genes in the PFMC of non-endometriotic women., Conclusions: The study concluded that PDGFB and EGF gene expression increases in endometriosis, and vitamin D3 could markedly decrease this expression, suggesting its therapeutic potential in endometriosis., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Polyethylene glycol functionalization is believed to have the capacity of endowing nanomaterials with stealth characteristics, which can diminish the arrest by macrophages and adverse immunological response. However, our previous study provided evidences that polyethylene glycol-functionalized graphene oxide (GOP) stimulated a strong immunological response to macrophages despite non-internalization in vitro, raising safety concerns and potential immunostimulation use of GOP. In light of this finding, we herein systematically study the in vivo immunological response upon the exposure to GOP via intraperitoneal injection. Taking cytokines production, cell types in the peritoneal fluid, biochemical index, hematology and histopathology as in vivo indicators, we demonstrate that GOP still remains the stealth-but-activating capacity on macrophages in a time and dose-dependent manner. Specifically, the immune response can be significantly elevated after a single high-dose injection, indicating that GOP can be a new candidate adjuvant for immunotherapy. For multiple low dose injections, the immune response is gentle, temporary, and tolerable, which manifests the biocompatibility of GOP in general drug delivery. The above results can thus provide guidance for safe and rational use of GOP for various biomedical applications.

Purpose: In this exploratory study, the effect of postprocedural flushing with crystalloids after oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) on platinum concentrations in peritoneal tissue, blood, and drain fluid was studied. Interpatient variability in oxaliplatin pharmacokinetics and the relation between platinum concentration in peritoneal fluid and platinum exposure in tissue and blood was explored., Methods: Ten patients with peritoneal carcinomatosis of colorectal origin were treated with HIPEC including postprocedural flushing, followed by ten patients without flushing afterwards. Tissue, peritoneal fluid, blood, and drain fluid samples were collected for measurement of total and ultrafiltered platinum concentrations., Results: Peritoneal tissue concentration and systemic ultrafiltered platinum exposure showed large inter individual variability, ranging from 65 to 1640 µg/g dry weight and 10.5 to 28.0 µg*h/ml, respectively. No effect of flushing was found on geometric mean platinum concentration in peritoneal tissue (348 vs. 356 µg/g dry weight), blood (14.8 vs. 18.1 µg*h/ml), or drain fluid (day 1: 7.6 vs. 7.7 µg/ml; day 2: 1.7 vs. 1.9 µg/ml). The platinum concentration in peritoneal fluid at the start of HIPEC differed twofold between patients and was positively correlated with systemic exposure (p = .04) and peak plasma concentration (p = .04)., Conclusion: In this exploratory study, no effect was found for postprocedural flushing on platinum concentrations in peritoneal tissue, blood, or drain fluid. BSA-based HIPEC procedure leads to large interpatient variability in platinum exposure in all compartments. The study was registered at ClinicalTrials.gov on 7 December 2017 under registration number NCT03364907.

Species of the Vernonia genius are widely distributed across the world. In traditional communities, they are commonly used in popular medicine for the treatment of inflammatory diseases. The objective of the present study was to evaluate the anti-inflammatory activity of Vernonia polysphaera Baker hydroalcoholic extract. A λ-carrageenan-induced paw edema and peritonitis model was established in BALB/c mice. The in vitro activity of the extract was measured on LPS-stimulated RAW 264.7 cells. There was no toxic effect on mice or on the cells treated with the extract. Animals treated with V. polysphaera extract demonstrated inhibition of paw edema in comparison with the untreated animals at all the analyzed doses. In peritonitis, treatment with the extract at a dose of 500 mg/kg resulted in a lower total leukocyte count in the peritoneal fluid and blood and lower levels of IL-1β, IL-6, TNF-α and PGE-2 than the control group. Cells treated with 50 and 100 μg/mL of the extract exhibited lower levels of nitrite and pro-inflammatory cytokine production and lower COX-2, NF-κB expression. The V. polysphaera extract demonstrated an anti-inflammatory effect, interfering with cell migration, reducing pro-inflammatory cytokine levels and COX-2 expression and consequent interference with PGE-2, as well as inhibiting NF-κB transcription., Competing Interests: The authors have declared that no competing interests exist.

Pancreatic cancer remains one of the most lethal types of cancer. Late‑stage pancreatic cancer patients usually suffer peritoneum effusion, which severely compromises quality of life. Great efforts have been made concerning the treatment of peritoneum effusion, including treatment with β‑elemene. Although peritoneal perfusion of β‑elemene attenuates the progression of malignant effusion without severe adverse effects in the clinic, the underlying molecular mechanism underlying the activity of β‑elemene against peritoneum effusion remains unclear. In the present study, a network pharmacology approach was undertaken to explore the mechanism of β‑elemene against peritoneum effusion. Particularly, the networks of β‑elemene and pancreatic cancer target genes were constructed based on the BATMAN‑TCM and DigSee databases, respectively. Thirty‑three genes, including hypoxia inducible factor 1 subunit α (HIF1A), were discovered in both networks. A potential interaction of β‑elemene with HIF1A was revealed by molecular docking simulation and co‑expression analysis of pancreatic cancer datasets from The Cancer Genome Atlas (TCGA) database. Additionally, experimental validation by MTT assay demonstrated that β‑elemene suppressed proliferation of PANC‑1 and BxPC3 cells and cells from peritoneum effusion in patients with pancreatic cancer. Furthermore, the protein expression levels of HIF1A and vascular endothelial growth factor A (VEGFA), as detected by western blotting, were reduced by β‑elemene. Overall, this study proposes a potential molecular mechanism illustrating that β‑elemene can block the HIF1A/VEGFA pathway, thereby inhibiting the generation of peritoneum effusion in pancreatic cancer based on network pharmacology analysis, and further highlights the importance of targeting the HIF1A/VEGF pathway as a therapeutic approach to treat peritoneum effusion in patients with pancreatic cancer.

Background: We evaluated whether the administration of sildenafil in children undergoing the TCPC operation shortened the interval from the operation to the removal of the pleural and peritoneal drains., Methods: We retrospectively reviewed the data of 122 patients who had undergone the TCPC operation between 2004 and 2014. Patients were divided into two groups on the basis of their treatments. Sildenafil was orally administered pre-operatively in the morning of the procedure or within 24 hours after the TCPC operation to the sildenafil group (n = 48), which was compared to a control group (n = 60). Fourteen patients were excluded from the study., Results: The primary outcome measure was the time from the operation to the removal of the drains. The study groups had similar demographics. The median [interquartile range] time for the removal of drains (sildenafil group 11 [8-19] vs control group 11 [7-16] d, P = .532) was comparable between the groups. The median [interquartile range] fluid balance on the first post-operative day was significantly higher (P = .001) in the sildenafil group compared with controls (47 [12-103] vs 7 [-6-67] mL kg -1 ). The first post-operative day fluid balance was a significant predictor for a prolonged need for drains in the multivariate analysis., Conclusions: Sildenafil administration, pre-operatively or within 24 hours after the TCPC operation, did not reduce the required time for pleural and peritoneal drains but was associated with a significantly higher positive fluid balance., (© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Ethnopharmacological Relevance: Urtica dioica L. has been used traditionally for centuries. U. dioica leaves and roots are used as a blood purifier, emmenagogue, and diuretic, as well as to treat menstrual hemorrhage, rheumatism, and eczema. The present study aimed to evaluate the activity of U. dioica L. aerial parts in endometriosis rat model., Materials and Methods: To evaluate the effects of the plant in endometriosis, n-hexane, ethyl acetate (EtOAc), and methanol (MeOH) extracts were prepared from the aerial parts of the plant and utilized in a rat surgical endometriosis model. In this model, adhesion scores of endometriotic implants and the spherical volumes of ectopic uterine tissues were evaluated. In addition to these parameters, tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6) levels of the peritoneal fluids were evaluated. Furthermore, histopathological studies were conducted on the endometriotic tissues., Results: Post-treatment implant volumes and adhesion scores were significantly reduced in the reference and the MeOH extract treated groups. Significant differences were found between the peritoneal TNF-α, VEGF, and IL-6 levels of MeOH extract treated group and those of control group. Moreover, histopathological findings supported the biological activity results. Furthermore, isolation studies were conducted on the MeOH extract, which showed prominent activity in the rat endometriosis model. Rutin (1), isoquercetin (2), the mixture of kaempferol-3-O-rutinoside (nicotiflorin) (3a) and isorhamnetin-3-O-rutinoside (narcissin) (3b) (3), the mixture of kaempferol-3-O-glucoside (astragalin) (4a) and isorhamnetin-3-O-glucoside (4b) (4) were isolated from the active fraction., Conclusions: The present study demonstrated that aerial parts of U. dioica exhibited promising activity in the endometriosis rat model due to its flavonoids., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: The antioxidant and anticancer activity of twelve 5-substituted-4-amino-1,2,4-triazole-linked hydroxamic acid derivatives were evaluated., Methods: Previously synthesized 2-((4-amino-5-substituted-4H-1,2,4-triazol-3-yl)thio)-N-hydroxyacetamide and 3-((4-amino-5-substituted-4H-1,2,4-triazol-3-yl)thio)-N-hydroxypropanamide (6a-6l) were evaluated for in vitro antioxidant and in vivo anticancer activity. MDA-MB-231, MCF-7 and HCT 116 cell lines were used to evaluate IC 50 values, in vitro. Ehrlich ascites carcinoma (EAC)-induced mice model was used to evaluate in vivo anticancer potential. Different biological markers were examined for drug-related toxicities., Key Findings: Compound 6b revealed more potent antioxidant property among all tested compounds, even than the ascorbic acid. The IC 50 values of compound 6b were found to be 5.71 ± 2.29 μg/ml (DPPH assay) and 4.12 ± 0.5 μg/ml (ABTS assay). Histopathology of liver sections of drug-treated mice was evaluated. Survival analysis showed that compound 6b could increase the life span as of the standard drug., Conclusions: After the assessment of all in vivo anticancer study related data, it was found that compound 6b possess superior anticancer potency in terms of efficacy and toxicity. From this experimental design, it could be concluded that further modification of this prototypical structure will lead to develop more potent antioxidant as well as an anticancer agent in the future., (© 2019 Royal Pharmaceutical Society.)

Cell-free and concentrated ascites reinfusion therapy (CART) is frequently used to treat refractory ascites in Japan. However, its efficacy remains unclear. This controlled cohort study verified the serum albumin elevating effect of CART by comparisons with simple paracentesis. Ascites patients receiving CART (N = 88) or paracentesis (N = 108) at our hospital were assessed for the primary outcome of change in serum albumin level within 3 days before and after treatment. A significantly larger volume of ascites was drained in the CART group. The change in serum albumin level was +0.08 ± 0.25 g/dL in the CART group and -0.10 ± 0.30 g/dL in the paracentesis group (P < 0.001). The CART - paracentesis difference was +0.26 g/dL (95%CI +0.18 to +0.33, P < 0.001) after adjusting for potential confounders by multivariate analysis. The adjusted difference increased with drainage volume. In the CART group, serum total protein, dietary intake, and urine volume were significantly increased, while hemoglobin and body weight was significantly decreased, versus paracentesis. More frequent adverse events, particularly fever, were recorded for CART, although the period until re-drainage was significantly longer. This study is the first demonstrating that CART can significantly increase serum albumin level as compared with simple paracentesis. CART represents a useful strategy to manage patients requiring ascites drainage.

Background: Diagnosing extrapulmonary tuberculosis (EPTB) is challenging and many patients are initiated on empirical anti-TB treatment without a laboratory confirmed diagnosis. Monitoring treatment response is thus important to ensure correct diagnosis and proper disease management. The definition of satisfactory response to treatment in EPTB remains unclear. The objectives of this study were to describe the clinical presentation of EPTB and the effect of treatment on clinical parameters. Further, to assess if simple clinical parameters, without laboratory data, could evaluate treatment response., Methods: Prospective cohort study of presumptive EPTB patients at Mnazi Mmoja Hospital, Zanzibar. By using a composite reference standard, patients were categorized as TB or non-TB cases. The TB patients were followed during anti-TB treatment., Results: There were 64 TB and 62 non-TB cases. The frequency of symptoms at baseline were comparable in TB and non-TB patients, with lymphadenitis and pleuritis as the most common manifestations. Among TB cases, there was a trend towards regression of lymphadenopathy after 2 months, and at treatment completion 24/28 (86%) cases showed full regression. Weight gain ≥5% was reported in 36/49 (73%) of the TB patients at 2 months and in 38/46 (83%) at treatment completion. After 2 months of treatment, a combination of clinical parameters; improvement of symptoms (50/50), ≥5% weight gain (36/49) and regression of physical signs (45/49) correlated with the treatment response., Conclusions: An algorithm including only simple clinical parameters could be used as an easy tool to assess treatment responses in low-resource settings. However, this needs to be tested on a larger sample size.

Objective: The objective of this study was to analyze the expression level and clinical role of soluble AXL (sAXL) in cancers affecting the serosal surfaces, with focus on ovarian carcinoma., Methods: sAXL protein expression by ELISA was analyzed in 572 effusion supernatants, including 424 peritoneal, 147 pleural and 1 pericardial specimens., Results: sAXL was overexpressed in peritoneal effusions compared to pleural and pericardial specimens (p < 0.001). sAXL levels were additionally significantly higher in effusions from patients with ovarian carcinoma, malignant mesothelioma and breast carcinoma compared to specimens from patients with other cancers (predominantly carcinomas of lung, gastrointestinal or uterine corpus/cervix origin) or benign reactive effusions (p < 0.001). sAXL was further overexpressed in high-grade serous carcinoma (HGSC; n = 373) compared to low-grade serous carcinoma (LGSC; n = 32; p = 0.036). In HGSC, sAXL levels were significantly lower in post-chemotherapy effusions compared to primary diagnosis pre-chemotherapy specimens (p = 0.002). sAXL levels in HGSC were unrelated to chemoresponse at diagnosis, progression-free survival or overall survival. Levels were similarly unrelated to survival in LGSC and breast carcinoma., Conclusions: sAXL is widely expressed in malignant effusions, particularly in ovarian and breast carcinoma and in malignant mesothelioma. sAXL is overexpressed in HGSC compared to LGSC and its levels are lower following exposure to chemotherapy. However, sAXL levels are not informative of chemoresponse or survival., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The increase in the prevalence of antibiotic-resistant bacteria has become a major public health concern. Antimicrobial peptides (AMPs) are emerging as promising candidates addressing this issue. In this study, we designed several AMPs by increasing α-helical contents and positive charges and optimizing hydrophobicity and amphipathicity in the Sushi 1 peptide from horseshoe crabs. A neural network-based bioinformatic prediction tool was used for the first stage evaluations of peptide properties. Among the peptides designed, Sushi-replacement peptide (SRP)-2, an arginine-rich and highly α-helical peptide, showed broad-spectrum bactericidal activity against both Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus and multidrug-resistant Acinetobacter baumannii; nevertheless, it showed little hemolytic and cytotoxic activity against mammalian cells. Atomic force microscopy results indicated that SRP-2 should interact directly with cell membrane components, resulting in bacterial cell death. SRP-2 also neutralized LPS-induced macrophage activation. Moreover, in an intraperitoneal multidrug-resistant A. baumannii infection mouse model, SRP-2 successfully reduced the bacterial number in ascitic fluid and tumor necrosis factor-α production. Our study findings demonstrate that bioinformatic calculations can be powerful tools to help design potent AMPs and that arginine is superior to lysine for providing positive charges for AMPs to exhibit better bactericidal activity and selectivity against bacterial cells.

It has been previously demonstrated that 1,25(OH)2D3 prevents the progression of epithelial to mesenchymal transition (EMT). However, it remains unclear whether 1,25(OH)2D3 has a role in peritoneal EMT stimulated by high glucose (HG) peritoneal dialysis fluid (PDF). The present study was performed to investigate the role of 1,25(OH)2D3 in the progression of EMT in the peritoneal mesothelium. A total of 35 male Kunming mice were randomly assigned into seven groups. In the control group, no diasylate or saline was infused. In the saline group, the mice were intraperitoneally injected with saline every day for 4 weeks. In the vitamin D group, the mice were subjected to intraperitoneal injections of 1 or 5 µg/kg of 1,25(OH)2D3 once weekly (every Monday) for 4 weeks. The peritoneal dialysis (PD) group were intraperitoneally injected with a conventional 4.25% PDF daily for 4 weeks. The vitamin D+PD group were intraperitoneally injected with 4.25% PDF daily and co‑treated with 1 µg/kg or 5 µg/kg 1,25(OH)2D3 once weekly, for 4 weeks. The peritoneal morphology and thickness were assessed by hematoxylin and eosin and Masson's trichrome staining. The peritoneal protein level of EMT markers (α‑smooth muscle actin, fibronectin and E‑cadherin), vitamin D receptor (VDR), B cell lymphoma‑2 (Bcl‑2), Bcl‑2‑associated X protein, transforming growth factor (TGF)‑β and Smad3 were evaluated by western blot analysis or immunohistochemical staining. Furthermore, apoptosis was assessed using a Caspase‑3 activity assay. The results demonstrated that after 4 weeks of intraperitoneal injections in mice, HG‑PDF decreased the expression of VDR, promoted EMT and apoptosis, and increased the thickness of the peritoneal membrane. However, 1,25(OH)2D3 treatment attenuated HG‑induced EMT and apoptosis, and decreased peritoneal thickness, which may partially occur through inhibition of transforming growth factor TGF‑β/Smad pathways via 1,25(OH)2D3 binding to VDR. The present study demonstrated that 1,25(OH)2D3 attenuated HG‑induced EMT and apoptosis in the peritoneal mesothelium through TGF‑β/Smad pathways. 1,25(OH)2D3 treatment in conjunction with HG dialysate may provide an improved solution to the peritoneal injury in the process of PD.

Endometriosis is a chronic, painful condition with unknown etiology. A differential expression of microRNAs in the endometriotic tissues from women with endometriosis with pain compared to those without suggested a plausible role for miRNA or epigenetic mechanisms in the etiology of endometriotic pain. The peritoneal milieu is involved in maintenance of endometriotic lesion and nociception. We recently showed the mechanistic role for oxidized-lipoproteins (ox-LDLs) present in peritoneal fluid (PF) in endometriosis and pain. We explored the possibility of ox-LDLs modulating the expression of miRNAs in a manner similar to PF from women with endometriosis. Expression levels of miRNAs and their predicted nociceptive and inflammatory targets were determined in PF and ox-LDL treated human endometrial cell-lines. Samples from IRB-approved and consented patients with and without endometriosis or pain were used. These were compared to endometrial cell-lines treated with various forms of oxidized-lipoproteins. RNA (including miRNAs) were isolated from treated endometrial cells and expression levels were determined using commercial miRNome arrays. Cell lysates were used in immunoblotting for inflammatory proteins using a protein array. Twenty miRNAs including isoforms of miR-29, miR-181 and let-7 were mutually differentially expressed in cells treated with PF from endometriosis patients with pain and those treated with ox-LDL components. The ox-LDLs and endo-PF treatment also produced significant overexpression of microRNA predicted target genes nerve growth factor, interleukin-6 and prostaglandin E synthase and overexpression of their downstream protein targets Mip1α and MCP1. This study showed similarities between miRNA regulation in PF from endometriotic women and ox-LDLs present in abundance in the PF of these women. Key miRNAs responsible for targeting nociceptive and inflammatory molecules were downregulated in the presence of ox-LDLs and endo-PF, thus playing a role in the etiology of endometriotic pain. These redox-sensitive miRNAs can be of potential use as targets in the treatment of endometriosis-associated pain., (Copyright © 2017. Published by Elsevier B.V.)

Classification of body cavity effusions is an important step in the investigation and diagnosis of disease in cats. Feline inflammatory effusions are often highly proteinaceous and viscous, which can cause clumping of white cells and subsequently inaccurate nucleated cell counts (NCCs) using automated and manual methods. Microscopic assessment of cellularity can also be difficult given the variable thickness of smears and cell clumping, which skews white cell distribution. The ADVIA 120 uses 2 white cell-counting channels, the basophil/lobularity (WBC/baso) and differential/peroxidase channels, which can provide quite different results in highly viscous feline samples and often disagree with smear assessment of cellularity. We investigated the effects of pre-incubation of feline effusion samples with hyaluronidase and its effects on NCCs and cellularity assessment. NCCs were obtained by automated analysis using the ADVIA 120 and by manual counting methods. Agreement was assessed using a Bland-Altman chart. Pretreatment of samples with hyaluronidase resulted in good agreement between the ADVIA basophil channel and manual counting methods in all samples in the study. However, improvements in NCCs after hyaluronidase treatment were significantly greater in clumped samples, and cell distribution of these samples on direct smears was also improved. Therefore, when nucleated cell clumping is observed on a direct smear, pretreatment of the sample with hyaluronidase prior to analysis on an automated analyzer is advised, with the WBC/baso channel displaying the most accurate NCC.

Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of micafungin in the plasma and burn eschar of severely burned patients with those of micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 ± 0.47 versus 0.15 ± 0.06 h(-1), respectively; P < 0.05). Most patients would achieve plasma PK/pharmacodynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of ≤0.008 mg/liter and ≤0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Bleomycin (BLM) is an effective anti-carcinogen. With the main detrimental effects of inducing pulmonary fibrosis on patients, its clinical use is limited. Developing agents that enhance the efficacy and attenuate the side effects of cancer chemotherapy are critical. Andrographolide (Andro), an active diterpenoid labdane component extracted from Andrographis panicula, is generally prescribed for treatment of inflammatory associated diseases. The study showed that BLM combined with Andro was significantly more effective than BLM alone on inhibiting the tumor growth, arresting the cell cycle at G0/G1 phase, promoting the capase-3 and capase-8 activity to induce cancer cell apoptosis. The underlying mechanisms may be related to the transcriptional regulation of P53/P21/Cyclin pathways. Moreover, BLM induced pulmonary fibrosis in tumor-bearing mice, but BLM combined with Andro dramatically alleviated the lesion in pulmonary fibrosis by activating the SOD, suppressing MDA and HYP production, in the meanwhile attenuating the IL-1β, TNF- α, IL-6 and TGF-β1 level. These mechanisms were associated with its effect on inhibition of protein expression of TGF-β, α-SMA, p-Smad2/3, enhanced expression of Smad7. Thus, it demonstrated that Andro might be a potential adjuvant therapeutic agent for BLM., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: The in vitro fertilization (IVF) pregnancy rate of women with advanced stage endometriosis is nearly half that of the general population, suggesting incomplete targeting of the pathophysiology underlying endometriosis-associated infertility. Compelling evidence highlights inflammation as the etiologic link between endometriosis and infertility and a potential target for adjunctive treatment. The objective of this study was to examine the effect of dexamethasone on murine embryos exposed to human endometriotic peritoneal fluid (PF) using the established murine embryo assay model., Methods: PF was obtained from women with and without severe endometriosis. Murine embryos were harvested and randomly allocated to five groups of culture media conditions: (1) human tubal fluid (HTF), (2) HTF and 10 % PF from women without endometriosis, (3) HTF and 10 % PF from women with endometriosis (PF-E), (4) HTF with PF-E and 0.01 mcg/mL dexamethasone, and (5) HTF with PF-E and 0.1 mcg/mL dexamethasone. Embryos were cultured in standard conditions and evaluated for blastocyst development., Results: A total of 266 mouse embryos were cultured. Baseline blastulation rates were 63.6 %. The addition of peritoneal fluid from women with endometriosis decreased the blastocyst development rate to 38.9 % (P = 0.008). The addition of 0.1 mcg/mL of dexamethasone to the culture media restored the blastulation rate to near baseline levels (61.2 %; P = 0.019)., Conclusions: The results of our in vitro study demonstrate the capacity of dexamethasone to mitigate the deleterious impact of endometriotic PF on embryo development. If confirmed in vivo, dexamethasone may prove a useful adjunct for the treatment of endometriosis-associated infertility.

Ovarian hyperstimulation syndrome (OHSS) is a serious iatrogenic complication that can occur during assisted reproductive techniques. The aim of this study is to investigate the effects of the leukotriene receptor antagonist (montelukast) treatment in prevention of OHSS and compare to cabergoline treatment. Twenty-four immature female Wistar rats were assigned to four groups. Group 1 was the control group. In the remaining three groups, OHSS was induced through ovarian stimulation with gonadotropins. No treatment was given to Group 2. Group 3 was administered a low-dose 100 mg/kg cabergoline treatment and Group 4 was received 20 mg/kg montelukast. Body weight, ovarian weight, vasculary permability (VP), peritoneal fluid vascular endothelial growth factor (VEGF) values and VEGF immune-expression were compared between the groups. Both cabergoline and montelukast prevented progression of OHSS compared to the OHSS group. Body weight, ovarian weight, VP, peritoneal fluid VEGF values and VEGF expression were significantly lower in both cabergoline- and montelukast-treated rats than in those not treated OHSS group. In conclusion, montelukast is an effective option for prevention of OHSS, as well as cabergoline. Montelukast may be a new treatment option to prevent and control the OHSS.

Background: The poor prognosis of patients with drug resistant ovarian cancer and the lack of targeted therapy have raised the need for alternative treatments. Albendazole (ABZ) is an anti-parasite compound capable of impairing microtubule formation. We hypothesized that ABZ could be repurposed as a potential anti-angiogenic drug due to its potent inhibition of vascular endothelial growth factor (VEGF) in ovarian cancer with ascites. However, the poor aqueous solubility of ABZ limits its potential for cancer therapy. In this study, we have assembled ABZ with bovine serum albumin into nanoparticles with a size range of 7-10 nm (BSA-ABZ) and 200-250 nm (Nab-ABZ). We further examined the anticancer effects of ABZ carrying nanoparticles in ovarian cancer cells, in both in vitro and in vivo models., Results: Drug release studies demonstrated that about 93% of ABZ was released from BSA-ABZ 10 nm in comparison to 83% from Nab-ABZ 200 nm at pH 7.4 in 8 days. In vitro cell proliferation studies showed that the BSA-ABZ 10 nm exhibited the highest killing efficacy of ovarian cancer cells with surprisingly least toxicity to healthy ovarian epithelial cells. Confocal microscopy and fluorescence activated cell sorting analysis (FACS) revealed more efficient internalization of the BSA-ABZ 10 nm by cancer cells. For in vivo studies, we examined the tumor growth, ascites formation and the expression of VEGF and secreted protein acidic and rich in cysteine (SPARC) in tumor samples and only VEGF in plasma samples. The BSA-ABZ 10 nm reduced the tumor burden significantly (p < 0.02) at a much lower drug dose (10 μg/ml) compare to free drug. Both formulations were capable of suppressing the ascites volume significantly (p < 0.05) and reducing the number of ascites cells. The expression of VEGF and SPARC was also reduced, which indicates the underlying therapeutic mechanism of the ABZ., Conclusion: Our data suggest that the BSA-ABZ may hold promise for the treatment and control of progression of ovarian cancer with ascites. However further studies are required to examine the efficacy of both the formulations in aggressive models of recurrent ovarian cancer with respect to particle size and dosing parameters.

The early phase of the ConA-induced inflammatory ascites was studied, with special reference to histamine. Concanavalin A (ConA), a cell-surface binding lectin was injected i.p. (25 mg/kg bw) to mice. After 1 h the animals were killed, the ascitic fluid collected and measured. Other agents were injected s.c., 10 min before the ConA-challenge. Exogenous histamine markedly inhibited the ConA-induced ascites. Release of endogenous vasoactive agents from the mast cells by Compound 48/80 had a similar, but slight effect. Cromolyn, a mast cell stabilizing agent, and chloropyramine, a histamine H1 receptor antagonist was ineffective. Although histamine increases endothelial permeability, it did not enhance the formation of ascitic fluid, on the contrary, it inhibited the ConA-induced ascites, presumably due to its known hypotonic effect. It is concluded that ConA-induced ascites is not mediated by mast cell histamine.

The aim of our study was to evaluate the effectiveness of resveratrol in experimentally induced endometrial implants in rats through inhibiting angiogenesis and inflammation. Endometrial implants were surgically induced in 24 female Wistar-Albino rats in the first surgery. After confirmation of endometriotic foci in the second surgery, the rats were divided into resveratrol (seven rats), leuprolide acetate (eight rats), and control (seven rats) groups and medicated for 21 d. In the third surgery, the measurements of mean areas and histopathological analysis of endometriotic lesions, VEGF, and MCP-1 measurements in blood and peritoneal fluid samples, and immunohistochemical staining were evaluated. After treatment, significant reductions in mean areas of implants (p < 0.01) and decreased mean histopathological scores of the implants (p < 0.05), mean VEGF-staining scores of endometriotic implants (p = 0.01), and peritoneal fluid levels of VEGF and MCP-1 (p < 0.01, for VEGF and p < 0.01, for MCP-1) were found in the resveratrol and leuprolide acetate groups. Serum VEGF (p = 0.05) and MCP-1 (p = 0.01) levels after treatment were also significantly lower in the resveratrol and leuprolide acetate groups. Resveratrol appears to be a potential novel therapeutic agent in the treatment of endometriosis through inhibiting angiogenesis and inflammation. Further studies are needed to determine the optimum effective dose in humans and to evaluate other effects on reproductive physiology.

Background and Aim: NK cells are one of the major immune cells in endometriosis pathogenesis. While previous clinical studies have shown that helixor A to be an effective treatment for endometriosis, little is known about its mechanism of action, or its relationship with immune cells. The aim of this study is to investigate the effects of helixor A on Natural killer cell (NK cell) cytotoxicity in endometriosis, Materials and Methods: We performed an experimental study. Samples of peritoneal fluid were obtained from January 2011 to December 2011 from 50 women with endometriosis and 50 women with other benign ovarian cysts (control). Peritoneal fluid of normal control group and endometriosis group was collected during laparoscopy. Baseline cytotoxicity levels of NK cells were measured with the peritoneal fluid of control group and endometriosis group. Next, cytotoxicity of NK cells was evaluated before and after treatment with helixor A. NK-cell activity was determined based upon the expression of CD107a, as an activation marker., Results: NK cells cytotoxicity was 79.38±2.13% in control cells, 75.55±2.89% in the control peritoneal fluid, 69.59±4.96% in endometriosis stage I/II endometriosis, and 63.88±5.75% in stage III/IV endometriosis. A significant difference in cytotoxicity was observed between the control cells and stage III/IV endometriosis, consistent with a significant decrease in the cytotoxicity of NK cells in advanced stages of endometriosis; these levels increased significantly after treatment with helixor A; 78.30% vs. 86.40% (p=0.003) in stage I/II endometriosis, and 73.67% vs. 84.54% (p=0.024) in stage III/IV. The percentage of cells expressing CD107a was increased significantly in each group after helixor A treatment; 0.59% vs. 1.10% (p=0.002) in stage I/II endometriosis, and 0.79% vs. 1.40% (p=0.014) in stage III/IV., Conclusions: Helixor A directly influenced NK-cell cytotoxicity through direct induction of CD107a expression. Our results open new role of helixor A as an imune modulation therapy, or in combination with hormonal agents, for the treatment of endometriosis.

Purpose: High-dose methotrexate (HD-MTX) has been used to treat children with central nervous system tumors. Accumulation of MTX within pleural, peritoneal, or cardiac effusions has led to delayed excretion and increased risk of systemic toxicity. This retrospective study analyzed the association of intracranial post-resection fluid collections with MTX plasma disposition in infants and young children with brain tumors., Methods: Brain MRI findings were analyzed for postoperative intracranial fluid collections in 75 pediatric patients treated with HD-MTX and for whom serial MTX plasma concentrations (MTX) were collected. Delayed plasma excretion was defined as (MTX) ≥1 μM at 42 hours (h). Leucovorin was administered at 42 h and then every 6 h until (MTX) <0.1 μM. Population and individual MTX pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling., Results: Fifty-eight patients had intracranial fluid collections present. Population average (inter-individual variation) MTX clearance was 96.0 ml/min/m² (41.1 CV %) and increased with age. Of the patients with intracranial fluid collections, 24 had delayed excretion; only 2 of the 17 without fluid collections (P < 0.04) had delayed excretion. Eleven patients had grade 3 or 4 toxicities attributed to HD-MTX. No significant difference was observed in intracranial fluid collection, total leucovorin dosing, or hydration fluids between those with and without toxicity., Conclusions: Although an intracranial fluid collection is associated with delayed MTX excretion, HD-MTX can be safely administered with monitoring of infants and young children with intracranial fluid collections. Infants younger than 1 year may need additional monitoring to avoid toxicity.

Objective: To determine the effects of captopril on experimentally induced endometriosis in a rat model., Study Design: Twenty-four adult, mature female Wistar-Albino rats in which endometriotic implants were induced by transplanting autologous uterine tissue to ectopic sites on the peritoneum. After the endometriotic implants were formed surgically, the 24 rats were randomly divided into three groups. Group 1 (captopril group, eight rats) were given 50 mg kg(-1)d(-1) of oral captopril for 21 d. Group 2 (leuprolide acetate group, eight rats) were given a single 1 mg kg(-1) subcutaneous injection of leuprolide acetate. Group 3 (control) were given no medication and served as controls (eight rats). The surface area of the endometriotic implants and the score of histologic analysis. Also, VEGF and MCP-1 levels in peritoneal fluids and bloods were analyzed., Results: At the beginning of the medical treatment, the mean surface areas of the endometriotic implants were comparable in all three groups. At the end of the treatment the mean implant surface area in the captopril group and leuprolide acetate group was less than that in the control group. Mean histopathological examination score for the implants post treatment was lower in the captopril and leuprolide acetate groups. Peritoneal fluids VEGF level in the captopril and leuprolide acetate groups was lower than that in the control group. The post-treatment MCP-1 level was also lower in the captopril and leuprolide acetate groups than in the control group. The serum VEGF and MCP-1 levels post treatment were significantly lower in the captopril and leuprolide acetate groups than in the control group., Conclusion: Administration of captopril reduced the size and progression of endometriotic lesions in a rat model., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Results of treatment of 229 patients, suffering an acute necrotic pancreatitis, complicated by peripancreatic infiltrate, were analyzed. To all the patients antibiotic prophylaxis and antibiotic therapy were conducted. In 63 (27.5%) patients the methods of extracorporal hemocorrection were applied, and in 108 (47.1%)--the "four--catheters" rule (catheter for epidural anesthesia, installment of the feeding intestinal probe further than the Treitz ligament level, the central vein catheterization, the programmed laparocentesis). In 31 (13.5%) patients there were determined the activity of mononuclear phagocytes and production of ROS (the oxygen active forms) by them in peripheral blood with objective for the purulent-septic complications prognostication. In 14 (6.1%) patients purulent--septic complications have occurred, postoperative lethality was 21.4%, general lethality--3.4%.

Prompted by the excitement from the description of single layer graphene, increased attention for potential applications in the biomedical field has been recently placed on graphene oxide (GO). Determination of the opportunities and limitations that GO offers in biomedicine are particularly prone to inaccuracies due to wide variability in the preparation methodologies of GO material in different laboratories, that results in significant variation in the purity of the material and the yield of the oxidation reactions, primarily the Hummers method used. Herein, the fabrication of highly pure, colloidally stable, and evenly dispersed GO in physiologically-relevant aqueous buffers in comparison to conventional GO is investigated. The purified GO material is thoroughly characterized by a battery of techniques, and is shown to consist of single layer GO sheets of lateral dimensions below 500 nm. The cytotoxic impact of the GO in vitro and its inflammation profile in vivo is investigated. The purified GO prepared and characterized here does not induce significant cytotoxic responses in vitro, or inflammation and granuloma formation in vivo following intraperitoneal injection. This is one of the initial steps towards determination of the safety risks associated with GO material that may be interacting with living tissue., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objectives: To enhance the effectiveness of peritoneal dialysis (PD), new biocompatible PD solutions may be needed. The present study was designed to test the efficacy and biocompatibility of hyperbranched polyglycerol (HPG)-a nontoxic, nonimmunogenic water-soluble polyether polymer-in PD., Methods: Adult Sprague-Dawley rats were instilled with 30 mL HPG solution (molecular weight 3 kDa; 2.5% - 15%) or control glucose PD solution (2.5% Dianeal: Baxter Healthcare Corporation, Deerfield, IL, USA), and intraperitoneal fluid was recovered after 4 hours. Peritoneal injury and cellular infiltration were determined by histologic and flow cytometric analysis. Human peritoneal mesothelial cells were assessed for viability in vitro after 3 hours of PD fluid exposure., Results: The 15% HPG solution achieved a 4-hour dose-related ultrafiltration up to 43.33 ± 5.24 mL and a dose-related urea clearance up to 39.17 ± 5.21 mL, results that were superior to those with control PD solution (p < 0.05). The dialysate-to-plasma (D/P) ratios of urea with 7.5% and 15% HPG solution were not statistically different from those with control PD solution. Compared with fluid recovered from the control group, fluid recovered from the HPG group contained proportionally fewer neutrophils (3.63% ± 0.87% vs 9.31% ± 2.89%, p < 0.0001). Detachment of mesothelial cells positive for human bone marrow endothelial protein 1 did not increase in the HPG group compared with the stain control (p = 0.1832), but it was elevated in the control PD solution group (1.62% ± 0.68% vs 0.41% ± 0.31%, p = 0.0031). Peritoneal biopsies from animals in the HPG PD group, compared with those from control PD animals, demonstrated less neutrophilic infiltration and reduced thickness. Human peritoneal mesothelial cell survival after HPG exposure was superior in vitro (p < 0.0001, 7.5% HPG vs control; p < 0.01, 15% HPG vs control). Exposure to glucose PD solution induced cytoplasmic vacuolation and caspase 3-independent necrotic cell death that was not seen with HPG solution., Conclusions: Our novel HPG PD solution demonstrated effective ultrafiltration and waste removal with reduced peritoneal injury in a rodent model of PD.

It is important to understand the mechanisms that regulate macrophage activation to establish novel therapies for inflammatory diseases, such as sepsis; a systemic inflammatory response syndrome generally caused by bacterial lipopolysaccharide (LPS). In this study, we investigated the involvement of extracellular ATP-mediated autocrine signaling in LPS-induced macrophage activation. We show here that ATP release via exocytosis, followed by activation of P2Y11 receptor, is a major pathway of the macrophage activation, leading to release of cytokines. Treatment of human monocyte THP-1 cells with LPS induced rapid ATP release from cells, and this release was blocked by knockdown of SLC17A9 (vesicular nucleotide transporter, VNUT), which is responsible for exocytosis of ATP. ATP-enriched vesicles were found in cytosol of THP-1 cells. These data suggest the involvement of vesicular exocytosis in the release of ATP. Knockdown of SLC17A9, the P2Y11 antagonist NF157 or knockdown of P2Y11 receptor significantly suppressed both M1-type polarization and IL-6 production in THP-1 cells, indicating an important role of activation of P2Y11 receptor by released ATP in macrophage activation. Next, the effect of NF157 on LPS-induced immune activation was examined in vivo. Administration of LPS to mice caused increase of serum IL-1ß, IL-6, IL-12 and TNF-alpha levels at 3-24 h after the administration. Pre-treatment of LPS-treated mice with NF157 suppressed both elevation of proinflammatory cytokines in serum and M1 polarization of peritoneal/spleen macrophages. Moreover, post-treatment with NF157 at 30 min after administration of LPS also suppressed the elevation of serum cytokines levels. We conclude that vesicular exocytosis of ATP and autocrine, positive feedback through P2Y11 receptors is required for the effective activation of macrophages. Consequently, P2Y11 receptor antagonists may be drug candidates for treatment of inflammatory diseases such as sepsis.

Ovarian cancers are heterogeneous and contain stemlike cells that are able to self-renew and are responsible for sustained tumor growth. Metastasis in the peritoneal cavity occurs more frequently in ovarian cancer than in other malignancies, but the underlying mechanism remains largely unknown. We have identified that ovarian cancer stemlike cells (CSCs), which were defined as side population (SP) cells, were present in patients' ascitic fluid and mesenchymally transformed cell lines, ES-2 and HO-8910PM. SP cells, which were sorted from both cell lines and implanted into immunocompromised mice, were localized to the xenografted tumor boundary. In addition, SP cells exhibited an epithelial phenotype and showed a distinct gene expression profile with reduced expression of cell adhesion molecules (CAMs), indicating that SP cells exert an important role in ovarian cancer progression on the basis of their delicate interaction with the surrounding microenvironment and anatomical localization in tumors. In contrast, non-SP cells exhibited a more mesenchymal phenotype and showed more increased invasive potential than SP cells. This heterogeneity was observed as an endogenous transformation via the epithelial-mesenchymal transition (EMT) process. Inhibition of the EMT process by Snail1 silencing reduced the SP cell frequency, and affected their invasive capacity and engraftment. These findings illustrate the interplay between epithelial ovarian CSCs and the EMT, and exert a link to explain tumor heterogeneity and its necessity for ovarian cancer maintenance, metastasis and progression.

The present study investigated the effects of a new bradykinin B(1) receptor antagonist, R-954, on the development of Ehrlich ascitic tumor (EAT) induced by the intraperitoneal inoculation of EAT cells in mice and the formation of a solid tumor by the subcutaneous injection of the cells in rat paw. The development of the tumor was associated with an increase in mouse total cell counts in bone marrow (10.8-fold), ascitic fluid (14.6-fold), and blood (12.6-fold). R-954 (2mg/kg, s.c.) significantly reduced the ascitic fluid volume (63.7%) and the mouse weight gain (30.5%) after 10 consecutive days of treatment. The B(1) antagonist as well as the anti-neoplasic drug vincristine also significantly inhibited the increase in total cell count in bone marrow, ascitic fluid, and blood. R-954 reduced significantly the total protein extravasation (57.3%), the production of nitric oxide (56%), PGE(2) production (82%), and TNFα release (85.7%) in mice peritoneal cavity whereas vincristine reduced the release of these inflammatory mediators by 84-94%. The increase in paw edema after intraplantar injection of EAT cells was reduced by approximately 52% by either R-954 or vincristine treatment. In conclusion, this study presents for the first time the antitumoral activity of a new bradykinin B(1) receptor antagonist on ascitic and solid tumors induced by Ehrlich cell inoculation in mice and rats., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Postpartum uterine scar dehiscence is a rare but potentially lethal complication of cesarean deliveries., Case: Concurrent abdominal and uterine dehiscences after cesarean delivery for arrest of descent with chorioamnionitis occurred in a 16-year-old patient after her first delivery. The uterine and fascia incisions were reclosed during exploratory laparotomy. Streptococcus anginosus was isolated from the peritoneal fluid. The patient remained afebrile and was discharged 6 days after relaparotomy and took levofloxacin and metronidazole orally for 5 more days., Conclusion: Uterine scar separation needs to be considered in patients with a fascial dehiscence after cesarean delivery for arrest of labor. Selected cases can be managed conservatively (uterine reclosure), but patients should be counseled about the possible need for hysterectomy at the time of relaparotomy.

Olprinone is a specific phosphodiesterase (PDE)-III inhibitor, which has been found to have anti-inflammatory effects in addition to its main inotropic and peripheral vasodilatory effects. In the present study we investigated the effects of olprinone (0.2mg/kg, i.p.) on the development of zymosan-induced multiple organ failure in mice. Treatment with olprinone attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. Olprinone also attenuated the lung, liver and pancreatic injury, renal dysfunction as well as the increased lung and intestine myeloperoxidase (MPO) activity caused by zymosan. Immunohistochemical analysis for inducible nitric oxide synthase (iNOS), nitrotyrosine, poly(ADP-ribose) (PAR), tumor necrosis factor-α (TNF-α) and interleuchin-1β (IL-1β) revealed positive staining in pancreatic and intestinal tissue obtained from zymosan-injected mice. The degree of staining for nitrotyrosine, iNOS, PAR, TNF-α and IL-1β was markedly reduced in tissue sections obtained from zymosan-injected mice, which had received olprinone. In addition, administration of zymosan caused a severe illness in the mice characterized by significant loss of body weight and a 60% of mortality at the end of observation period (7 days). Treatment with olprinone significantly reduced the development of systemic toxicity, loss in body weight and mortality, caused by zymosan. This study provides evidence that olprinone attenuates the degree of zymosan-induced shock in mice., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background/aims: Optimal delivery of intraperitoneal (i.p.) chemotherapy is dependent on adequate drug distribution. An accurate understanding of the limitations of i.p. distribution is critical if we are to improve cytotoxic delivery through this route., Methods: Using repeated scintigraphic peritoneography we investigated peritoneal fluid distribution in patients receiving i.p. therapy. Both early (1-6 h) and late (24-48 h) images were performed. The peritoneal cavity was divided into six regions; pouch of Douglas, left and right paracolic gutters, left and right subphrenic spaces and the right subhepatic space. The distribution in each region was classified as absent (0), faint (1) or intense (2). A total distribution score was calculated from the summation of distribution values for each of the six regions. Distribution was then graded according to the total distribution score as follows: Grade 0 = 0-3; Grade 1 = 4-6; Grade 2 = 7-9; and Grade 3 = 10-12., Results: Twenty-six participants were included in the study: all 26 patients had early imaging performed and 21 of these also had late imaging. Thirteen (50%) and 15 (71%) patients had grade 1 or 2 i.p. distribution on early and late imaging respectively. The most common abdominal regions to show maldistribution were the subphrenic spaces., Conclusions: This study highlights the deficiencies of distribution following i.p. drug delivery, with the majority of patients demonstrating multiple regions of faint or absent uptake on scintigraphic peritoneography imaging. Future large clinical studies investigating i.p. chemotherapy should include analyses of i.p. distribution to improve our understanding of optimal drug delivery through this route., (© 2011 The Authors. Internal Medicine Journal © 2011 Royal Australasian College of Physicians.)

Malignant peritoneal effusions often arise in patients with ovarian carcinoma. They are a hazardous complication of cancer. Systematic intraperitoneal chemotherapy is not necessarily followed by long-term remission and may even induce untoward side effects. Intraperitoneal interleukin-2 (IL-2) and IL-2/lymphokine-activated killers (LAK) biotherapy showed high efficacy in treatment of ovarian carcinoma patients suffering from peritoneal effusions. The objective effect was 80.1% and 82.6%, respectively. Our results suggest that intraperitoneal biotherapy may be extended to dealing with malignant peritoneal effusions in ovarian carcinoma.

Proton pump inhibitors (PPI) are being considered for antineoplastic therapeutic regimens due to their ability to reverse H(+) homeostasis in tumor microenvironment and induce tumor cell death. In order to explore additional mechanism(s) underlying antitumor action of PPI, the present investigation was undertaken to investigate the effect of a PPI pantoprazole (PPZ) on the activation of tumor-associated macrophages (TAM) to tumoricidal state in a murine model of a transplantable T cell lymphoma of spontaneous origin growing in ascitic form. In vivo administration of PPZ to tumor-bearing mice resulted in an enhanced TAM recruitment in tumor microenvironment with M1 macrophage phenotype and augmented activation of TAM to tumoricidal state along with expression of tumor cytotoxic molecules. The study also demonstrates that TAM activating action of PPZ is of indirect nature mediated via its antitumor activity, reversal of tumor-induced immunosuppression and a consequent shift of cytokine balance in the tumor microenvironment favoring polarization of macrophages to M1 type. The study further shows that adoptive transfer of TAM harvested from PPZ-administered tumor-bearing hosts causes an efficient retardation of tumor growth. Possible mechanisms and significance of these observations with respect to the designing of antitumor therapy using PPI are discussed., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Excessive complement-activated product complement 5a (C5a) has been implicated in the pathogenesis of sepsis development. Herein, we employed in vitro and in vivo models of sepsis to investigate the functional relationship between overtly produced C5a and IL-8. Our data revealed that C5a could strongly amplify IL-8 expression from human whole blood cells induced by LPS and other types of TLR agonists. ERK1/2 and p38, but not JNK, were mainly participated in signaling pathways for IL-8 production. In the whole blood stimulated by Escherichiacoli, C5a levels were quickly elevated and blockage of C5a significantly decreased E. coli-elicited IL-8 production. In the mouse model of sepsis induced by cecal ligation and puncture (CLP), the markedly increased keratinocyte-derived cytokine (KC) could be strongly suppressed by blockage of C5a. These data suggest that excessive C5a functions as a critical inflammatory mediator to enhance IL-8 production mainly through MAPK signaling pathways., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective and Design: In the present experiment, we aimed to determine the feasibility and curative effects of emodin combined with danshensu on experimental severe acute pancreatitis (SAP) and the mutual benefit of this synergistic strategy by a prospective animal study., Material: Eighty Wistar rats were randomly divided into four groups (n = 20)., Treatment: SAP was elicited by a retrograde infusion of 5.0% sodium taurocholate into the pancreatic main duct. SAP rats in each group received no further intervention, emodin alone, danshensu (DSS) alone, and emodin combined with DSS (EDSS), respectively., Methods: 48 h after SAP induction, all surviving animals were sacrificed to collect blood and tissue samples for the following measurements: serum levels of amylase, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), endotoxin and D-lactate. Pancreatic levels of TNF-alpha, IL-1beta, maleic dialdehyde (MDA), myeloperoxidase (MPO) activity, nuclear factor-kappaappaB (NF-kappaB) activation as well as wet-dry weight ratio were also evaluated. Ascitic fluid was quantified and the severity of pancreatic damage was analyzed by pathological grading and scoring., Results: Compared with the SAP group, the emodin, DSS and EDSS groups had significant differences in every index. Furthermore, EDSS obviously improved all the parameters mentioned above so as to counteract inflammatory response and oxidative stress, as well as most effectively abating pancreatic and intestinal barrier injury., Conclusions: EDSS exerted protective effects on SAP rats and remarkably alleviated the severity of experimental SAP. Mechanisms that might account for the beneficial effects include protecting the intestinal barrier, inhibiting over-inflammatory reaction and abating oxidative stress. The combined strategy proved to be more effective than either emodin or DSS alone and may cause synergistic effects in combination in the early stage of SAP. Broad potential for future clinical practice is foreseeable.

Background and Objectives: A microdialysis study of meropenem distribution in the peritoneal fluid of patients with peritonitis has suggested that there is significant peripheral drug degradation. The aims of the present study were to investigate the plasma and peritoneal fluid pharmacokinetics of imipenem, a relatively unstable antibacterial, in patients with severe peritonitis, and to relate measured unbound concentrations to the minimum inhibitory concentrations required for susceptible and intermediately susceptible bacteria., Methods: Microdialysis catheters were placed into the peritoneal cavity through peritoneal drains in nine critically patients. Imipenem concentrations in plasma and in peritoneal fluid were analysed using compartmental modelling., Results: A model that considered elimination from a peripheral compartment described the data and was used to simulate steady-state concentration profiles in plasma and peritoneal fluid during various dosing regimens. Using recommended dosing regimens (500 mg every 6 hours, 1000 mg every 8 hours and 1000 mg every 6 hours), simulated unbound peritoneal fluid concentrations of imipenem in patients with severe peritonitis reached values sufficient for antibacterial effects against susceptible bacteria. However, the adequacy of regimens in patients with severe peritonitis whose infections involve intermediately susceptible bacteria is questionable., Conclusion: The results of this study are consistent with those previously observed with meropenem and confirm the usefulness of microdialysis for assessment of peritoneal fluid distribution of antibacterials.

The mast cell-mediated allergic reactions are involved in many allergic diseases, such as asthma, allergic rhinitis and sinusitis. Stimulation of mast cells initiates the process of degranulation, resulting in the release of mediators such as histamine and an array of inflammatory cytokines. In this report, we investigated the effect of gossypin (a biflavonoid) and suramin (a synthetic polysulphonated naphtylurea) on the mast cell-mediated allergy model, and studied the possible mechanism of their action. Both gossypin and suramin inhibited (P<0.001) compound 48/80-induced systemic anaphylaxis reactions, antiprurities (P<0.001) and reduced the histamine release in rats. Further, both showed significant (P<0.001) protection against rat peritoneal mast cells activated by compound 48/80. Thus, our findings provide evidence that gossypin and suramin inhibit mast cell-derived allergic reactions.

Ehrlich ascites carcinoma is a spontaneous murine mammary adenocarcinoma adapted to ascites form and carried in outbred mice by serial intraperitoneal (i/p) passages. The previous work from our laboratory showed that honey having higher phenolic content was potent in inhibiting colon cancer cell proliferation. In this work, we extended our research to screen the antitumor activity of two selected honey samples and eugenol (one of the phenolic constituents of honey) against murine Ehrlich ascites and solid carcinoma models. Honey containing higher phenolic content was found to significantly inhibit the growth of Ehrlich ascites carcinoma as compared to other samples. When honey containing higher phenolic content was given at 25% (volume/volume) intraperitoneally (i/p), the maximum tumor growth inhibition was found to be 39.98%. However, honey was found to be less potent in inhibiting the growth of Ehrlich solid carcinoma. On the other hand, eugenol at a dose of 100 mg/kg i/p was able to inhibit the growth of Ehrlich ascites by 28.88%. In case of solid carcinoma, eugenol (100 mg/kg; i/p) showed 24.35% tumor growth inhibition. This work will promote the development of honey and eugenol as promising candidates in cancer chemoprevention.

A novel ruthenium(II)-complex containing 4-carboxy N-ethylbenzamide (Ru(II)-CNEB) was found to interact with and inhibit M4-lactate dehydrogenase (M4-LDH), a tumor growth supportive enzyme, at the tissue level. The present article describes modulation of M4-LDH by this compound in a T-cell lymphoma (Dalton's Lymphoma: DL) vis a vis regression of the tumor in vivo. The compound showed a dose dependent cytotoxicity to DL cells in vitro. When a non toxic dose (10 mg/kg bw i.p.) of Ru(II)-CNEB was administered to DL bearing mice, it also produced a significant decline in DL cell viability in vivo. The DL cells from Ru(II)-CNEB treated DL mice showed a significant decline in the level of M4-LDH with a concomitant release of this protein in the cell free ascitic fluid. A significant increase of nuclear DNA fragmentation in DL cells from Ru(II)-CNEB treated DL mice also coincided with the release of mitochondrial cytochrome c in those DL cells. Importantly, neither blood based biochemical markers of liver damage nor the normal patterns of LDH isozymes in other tissues were affected due to the treatment of DL mice with the compound. These results were also comparable with the effects of cisplatin (an anticancer drug) observed simultaneously on DL mice. The findings suggest that Ru(II)-CNEB is able to regress Dalton's lymphoma in vivo via declining M4-LDH and inducing mitochondrial dysfunction-apoptosis pathway without producing any toxicity to the normal tissues.

Tissue and blood eosinophilia can be associated with a variety of infectious, allergic, and systemic diseases. Eosinophilia can range from mild and clinically inconsequential levels to high-grade eosinophilia with severe and potentially fatal consequences. Because of its ability to degranulate and produce cytotoxic mediators such as major basic protein and eosinophil peroxidase the eosinophil has the potential to cause considerable tissue damage, including potentially fatal conditions such as endomyocardial fibrosis. The most common infectious cause of eosinophilia worldwide is the parasitic helminth; fungal infection as a cause of eosinophilia is rarer, but must also be considered in the differential diagnosis. In this article we describe a unique case of reactive eosinophilia.

Purpose: 1,3,4-Oxadiazoles are an important class of heterocyclic compounds, which play a pivotal role in various pharmaceutical applications. Here, we investigated the antiangiogenic and antiproliferative effects of the derivatives and explored its mechanism of action on EAT cells., Methods: The cytotoxic effect of the derivatives on EAT and HEK293 cells was assessed by MTT assay. Effect of the derivatives on ALP activity and proliferation was measured. Swiss albino mice transplanted with EAT cells were used as a model system to study the effect of the derivatives in vivo. Inhibition of angiogenesis in mice peritoneum, CAM and Cornea of the rat were studied. Finally, the effects on VEGF gene expression, HIF-1alpha translocation and cell cycle arrest were determined., Results: The IC50 range for growth inhibition of EAT cells was found to be 140-175 microM. In contrast normal HEK293 cells were resistant to the derivatives at this range. Treatment with derivatives in vivo was demonstrated by the down regulation of VEGF in EAT cells and inhibition of blood vessels formation in mice peritoneum, CAM and cornea of rat, indicating the potent angioinhibitory effect of the derivatives. VEGF promoter-luciferase reporter gene expression analysis showed suppression of VEGF gene expression in vitro. The derivatives proved to be potent antiproliferative agents as shown by FACS analysis and decreased ALP activity. Furthermore, expression of HIF-1alpha was also down regulated by derivatives by repressing its nuclear translocation., Conclusions: Oxadiazole derivatives are strong bioactive compounds with antiangiogenic and antiproliferative potential both in vitro and in vivo. We postulate that diminished HIF-1alpha nuclear presence in oxadiazole treated EAT cells could be responsible for decreased VEGF expression and antiangiogenic effects.

The aim of this study was to evaluate the efficacy of recombinant adenovirus p53 agent (rAd-p53) injection combined with cisplatin (CDDP) for the treatment of malignant pleural or peritoneal effusion. After puncture drainage, patients in the treatment group (n = 27) received intracavitary administration of rAd-p53 (2 x 10(12) virus particles) once a week for 4 weeks. At 48 h after each rAd-p53 injection, patients were given intracavitary administration of cisplatin 60 mg/m(2). This administration procedure continued once a week for 4 weeks. The control group (n = 21) received the same intracavitary therapy as the treatment group but without rAd-p53 therapy. Efficacy was evaluated by clinical observations, computed tomography, tumour markers, Karnofsky score and short-term follow-up. The total effective rates for the treatment group (63.0%) were significantly higher than for the control group (42.9%), suggesting that the treatment group benefited over the control group. In conclusion, rAd-p53 therapy is a safe and effective treatment for advanced malignant pleural or peritoneal effusion.

Objective: The present study was designed to examine the effect of tetrandrine on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers., Methods: Primary cancer cells were isolated from the pleural fluids (n=13) or ascites (n=21) of patients. Compared with culture cell lines, the response of these cancer cells to tetrandrine and chemotherapeutic agents commonly used in clinical practice were determined by WST-8 assay. Tetrandrine-induced apoptosis in primary cancer cells was determined by Annexin V-FITC assay. Quantitative RT-PCR was used to examine the role of apoptotic associated genes in the anticancer effect of tetrandrine., Results: The primary cancer cells isolated from effusions showed sensitivity to tetrandrine with IC50 values of 38.23+/-25.77microM, similar to the IC50 in established cell lines. Patients with gastric cancers were more sensitive to tetrandrine than patients with lung cancers (P=0.04). Four cancer cells isolated from effusions were resistant to tetrandrine, which also had increased tolerance to docetaxel, cisplatin and 5-fluorouracil. We also observed a weak but significant correlation between sensitivity to tetrandrine and cellular expression of bcl-2 (P=0.035, r=-0.364)., Conclusions: Using cancer cells isolated from the ascites or pleural fluids, this study shows the potential anticancer effect of tetrandrine against primary cancer cells.