Predicting Severe Haematological Toxicity in Gastrointestinal Cancer Patients Undergoing 5-FU-Based Chemotherapy: A Bayesian Network Approach.

PURPOSE: Severe toxicity is reported in about 30% of gastrointestinal cancer patients receiving 5-Fluorouracil (5-FU)-based chemotherapy. To date, limited tools exist to identify at risk patients in this setting. The objective of this study was to address this need by designing a predictive model using a Bayesian network, a probabilistic graphical model offering robust, explainable predictions. METHODS: We utilized a dataset of 267 gastrointestinal cancer patients, conducting preprocessing, and splitting it into TRAIN and TEST sets (80%:20% ratio). The RandomForest algorithm assessed variable importance based on MeanDecreaseGini coefficient. The bnlearn R library helped design a Bayesian network model using a 10-fold cross-validation on the TRAIN set and the aic-cg method for network structure optimization. The model's performance was gauged based on accuracy, sensitivity, and specificity, using cross-validation on the TRAIN set and independent validation on the TEST set. RESULTS: The model demonstrated satisfactory performance with an average accuracy of 0.85 (±0.05) and 0.80 on TRAIN and TEST datasets, respectively. The sensitivity and specificity were 0.82 (±0.14) and 0.87 (±0.07) for the TRAIN dataset, and 0.71 and 0.83 for the TEST dataset, respectively. A user-friendly tool was developed for clinical implementation. CONCLUSIONS: Despite several limitations, our Bayesian network model demonstrated a high level of accuracy in predicting the risk of developing severe haematological toxicity in gastrointestinal cancer patients receiving 5-FU-based chemotherapy. Future research should aim at model validation in larger cohorts of patients and different clinical settings.

Polystyrene nanoplastics induce haematotoxicity with cell oxeiptosis and senescence involved in C57BL/6J mice.

Nanoplastics (NPs) has become a worrying serious environmental problem. However, the toxicological effects and mechanisms of NPs on hematopoiesis are still unknown. To this end, male C57BL/6J mice were directly exposed to the serial concentration gradient of polystyrene NPs (PSNPs, 0, 30, 60, and 120 µg d), respectively, for 42 days by intragastric administration. Results show that PSNPs were clearly visible in bone tissues, meanwhile, induced the count of major blood indicators (WBC, RBC, and LYM) decreased. H&E staining displayed that exposed to PSNPs can cause hematopoietic damage of BM and extramedullary hematopoiesis in spleen. Flow cytometry result show that the proportion of LSK represented a dose-dependent significantly decreased after PSNPs exposure. Further research found that PSNPs can cause the systemic oxidative stress occurs manifested as MDA accumulated. In addition, as the dose of PSNPs increased, the fluorescence intensity of Keap1 and p53 in femur sections gradually increased, meanwhile, the expression of cell oxeiptosis signal pathway Keap1/PGAM5/AIFM1 and the cell senescence signal pathway p53/p21 was all increased, markedly. Overall, our study demonstrated that PSNPs exposure caused oxidative stress, potentially resulting in cell oxeiptosis and senescence to develop haematotoxicity in C57BL/6J mice.

Documentation of phytochemicals, bio-toxicity and haemato-physiological responses at sub-lethal concentrations of Parthenium hysterophorus hydroethanolic extract in Cyprinus carpio: a concept of waste valorization as a phyto-ichthyotoxin.

In the present study, phytoextraction of a weed plant, Parthenium hysterophorus, was performed through aqueous, alcoholic and hydroethanolic (80%) solvents followed by phytochemical profiling and evaluation of median lethal concentration (LC50) of hydroethanolic extract in a freshwater fish, common carp (Cyprinus carpio). Haemato-physiological response was also evaluated based on LC50 (18.99 mg L-1) at two sub-lethal concentrations of extract [T1: 0.379 mg L-1 (LC50/50), T2: 0.759 mg L-1 (LC50/25) and a control: devoid of extract] at three intervals (24, 48 and 96 h). The study revealed toxic constituents in extracts and the superior extraction ability of hydroethanolic solvent which was chosen for further biological characterisation, particularly on haematotoxicity. The anti-bacterial assay revealed the inhibitory capacity of the extract, whereas the phyto-haemagglutination assay, haemagglutination limit test and haemolytic activity revealed clumping, agglutination (at 1/96th dilution) and lytic capability of extract, respectively. Later, in vivo analyses revealed a significant modulation in haemato-immunological and serum biochemical parameters upon hydroethanolic extract exposure. In conclusion, the present study emphasises locally available gajar ghas, P. hysterophorus as a non-chemical phyto-ichthyotoxin towards sustainable aquaculture.

Metabolomic characteristics in human CD34+ hematopoietic stem/progenitor cells exposed to polystyrene nanoplastics.

Nanoplastics is a major environmental concern and may cause potential harm to organisms. Previous studies have found that exposure to nanoplastics inhibited hematopoietic function, however, the effect of polystyrene nanoplastics (PSNPs) on the human CD34+ hematopoietic stem/progenitor cells (HSPCs) and its underlying mechanism remains unknown. In this study, the toxic effects were evaluated and the metabolites changes were systematically analyzed using the metabolomics study in combination with multivariate statistical analysis in HSPCs with PSNPs treatment. The results show that PSNPs could be uptake by cells, significantly decrease cell viability and cause cell membrane damage manifested as increased LDH release in cellular supernatant. Besides, the colony formation assay shows that PSNPs exposure can inhibit the proliferation and differentiation of HSPCs. Meanwhile, we found that PSNPs disturbed the metabolic activity, including amino acids, SCFAs, organic acids, fatty acids and carbohydrates, and mainly affect citrate cycle (TCA cycle) metabolism pathway. Those findings are helpful in evaluating the toxicity mechanisms and providing guidance in the selection of potential metabolism-related biomarkers of hematopoietic damage caused by nanoplastics exposure.

Nanocurcumin preserves kidney function and haematology parameters in DMBA-induced ovarian cancer treated with cisplatin via its antioxidative and anti-inflammatory effect in rats.

CONTEXT: Cisplatin, as a first-line treatment for ovarian cancer, is associated with debilitating adverse effects, including nephrotoxic and haematotoxic effects. OBJECTIVE: This study determines whether nanocurcumin, combined with cisplatin, would give additional benefit to kidney function and haematological parameters in rats with ovarian cancer. MATERIALS AND METHODS: Twenty-five Wistar rats were divided into five untreated rats and 20-dimethylbenz(a)anthracene (DMBA)-induced ovarian cancer rats. The 20 ovarian cancer rats were divided into four treatment groups: vehicle, cisplatin, cisplatin-curcumin, and cisplatin-nanocurcumin. Cisplatin was given at the dose of 4 mg/kg BW once weekly, while curcumin or nanocurcumin was administered at 100 mg/kg BW daily for four weeks. At the end of treatment, we analysed kidney function, haematological parameters, and inflammatory and oxidative stress markers from plasma. RESULTS: Nanocurcumin alleviates the increase in kidney function markers and abnormalities in haematological indices in rats treated with cisplatin. Compared to cisplatin-treated rats, plasma urea levels decreased from 66.4 to 47.7 mg/dL, creatinine levels lowered from 0.87 to 0.82 mg/dL, and neutrophil gelatinase-associated lipocalin (NGAL) levels declined from 8.51 to 3.59 mIU/mg protein. Furthermore, the therapy increased glutathione activities (from 2.02 to 3.23 U/µL), reduced lipid peroxidation (from 0.54 to 0.45 nmol/mL), and decreased plasma TNF-α (from 270.6 to 217.8 pg/mL). CONCLUSIONS: Cisplatin with nanocurcumin in an ovarian cancer rat model may provide additional benefits as a preventive agent against renal impairment and cisplatin-induced haematological toxicity. However, further research is required to prove that using nanocurcumin for a more extended time would not affect its anticancer properties.

Clinical and Economic Impact of a Multidisciplinary Follow-Up Program in Lymphoma Patients.

Objectives: The UMACOACH Lymphoma is a multidisciplinary monitoring program for patients initiating a first highly haematotoxic treatment for Hodgkin or non-Hodgkin lymphoma. Patient follow-up is based on consultation with a pharmacist and planed phone calls by nurses supervised by a clinical haematologist. Our objective was to assess effectiveness and cost of the UMACOACH Lymphoma Program (ULP) and to investigate patient satisfaction and quality of life (QoL). Methods: This French monocentric case-control study included all patients enrolled in the ULP over a one-year period (cases) matched with retrospective patients receiving usual care (controls). Numbers of adverse events (AEs), re-hospitalisations, average relative dose intensity (ARDI), treatment response and survival were compared between the two groups. Among cases, patient satisfaction and QoL using the EORTC-QLQC30 questionnaire before and after treatment were evaluated. Results: Seventy-eight cases were matched to 78 controls. Twenty-six percent grade 3−4 AEs were observed in cases versus 38% in controls (p = 0.001). There were 76 and 88 re-hospitalisations in the case and control groups, respectively (p = 0.217). ARDI > 85% was observed in 92% and 82% of cases and controls, respectively (p = 0.138). No differences were observed in terms of treatment responses and survival. Estimated cost savings were of EUR 81,782 in favour of the case group. An improvement of 5.1 points was observed in the total QoL score before and after treatment in cases. Conclusions: A nurse−pharmacist−haematologist collaboration seems to be promising to reduce grade 3−4 AEs in HL and NHL patients receiving highly haematotoxic chemotherapy regimens. Cost savings from hospitalisation being avoided were also shown.

Cisplatin Versus Carboplatin and Paclitaxel in Radiochemotherapy for Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIM: The implementation of a platinum-containing regimen is recommended for definitive and adjuvant therapy of patients with locally advanced head and neck tumour. We compared the conditions for the use of cisplatin or carboplatin/paclitaxel or for changing between these two regimens on a clinic-specific basis. PATIENTS AND METHODS: We evaluated 150 patients with advanced head and neck squamous cell carcinoma who received simultaneous radiochemotherapy at our institution between 2012 and 2017. Chemotherapy with weekly doses of cisplatin (40 mg/m2, group 1) or, in cases of impaired renal and/or cardiac function, with weekly doses of carboplatin AUC2 and paclitaxel (45 mg/m2, group 2), was performed as a first-choice therapy. If toxicities occurred in group 1, treatment was switched to the carboplatin/paclitaxel regimen (group 3). Patient- and therapy-related parameters, toxicity and survival data were compared across groups. RESULTS: We examined 99, 30, and 21 patients in each group who received at least 1 course of chemotherapy. Group 3 patients switched from cisplatin to carboplatin/paclitaxel after a median of 3 courses due to nephrotoxicity (95.2%). The target of at least 5 chemotherapy courses was most frequently achieved by patients in group 1 (69.7%), followed by group 3 (61.9%) and then group 2 (40.0%). Multivariate analysis revealed that patients who switched groups were more likely to be over 60 years old (p=0.021), undergo definitive radiochemotherapy (p=0.049) and develop higher nephrotoxicity (p=0.036) than group 1 patients. Outcomes did not differ between groups. CONCLUSION: When cisplatin application is contraindicated due to renal- or cardiotoxicity, carboplatin/paclitaxel is an appropriate option.

Evi1 involved in benzene-induced haematotoxicity via modulation of PI3K/mTOR pathway and negative regulation Serpinb2.

Benzene is a widely used chemical and an environmental pollutant. Exposure to benzene can cause blood diseases, but the mechanisms underlying benzene haematotoxicity have not been fully clarified. Ecotropic virus integration site-1 (Evi1), a transcription factor, plays important roles in normal haematopoiesis and haematological diseases. In this study, we investigated the role and mechanism of Evi1 in benzene-induced haematotoxicity. We found that benzene exposure significantly increased Evi1 level in white blood cells (WBCs) in occupational benzene workers as well as mouse bone marrow cells. Further in vitro results demonstrated that compared with control cells exposed to same 1,4-benzoquinone (1,4-BQ, an important active metabolite of benzene) concentration, Evi1 downregulation significantly reduced cell proliferation, and disrupted cell viability, apoptosis, erythroid and megakaryotic cell differentiation and cell cycle. Additionally, down-regulation of Evi1 suppressed phosphoinositide 3-kinase (PI3K)/mTOR signalling pathway and elevated its target gene Serpinb2 following 1,4-BQ exposure. Moreover, the PI3K activator could partially relieve the inhibitory effect of down-regulation of Evi1 on cell proliferation and increase cell arrest in in G2/M phase. What's more, downregulation of Serpinb2 could partially alleviate proliferation inhibition and reverse cell cycle changes in G0/G1 phase and S phase induced by Evi1 inhibition. In conclusion, our data revealed that Evi1 downregulation aggravated the inhibition of cell proliferation and arrested cells in the G0/G1 phase when exposed to 1,4-BQ, potentially by inactivating the PI3K/mTOR pathway and upregulating downstream target gene Serpinb2. Our study provides novel insights on mechanism by which Evi1 participates in benzene-induced haematotoxicity.

A review emphasizing on utility of heptad repeat sequence as a tool to design pharmacologically safe peptide-based antibiotics.

Extensive usage of antibiotics has created an unprecedented scenario of the rapid emergence of many drug-resistant bacteria, which has become an alarming public health concern around the globe. Search for better alternatives that are as efficacious as antibiotics led to the discovery of antimicrobial peptides (AMPs). These small cationic amphiphilic peptides have emerged as a promising option as antimicrobial agents, owing to their multifaceted implications against varied pathogens. Recent years have witnessed tremendous growth in research on AMPs resulting in them being tested in clinical trials of which six got approved for topical application. The relatively less successful outcome has been attributed to the poor cell selectivity shown by most of the naturally occurring AMPs. This drawback needs to be circumvented by identifying strategies to design safe and effective peptides. In the present review, we have emphasized the importance of heptad repeat sequence (leucine and/or phenylalanine zipper motif) as a tool that has shown great promise in remodeling the toxic AMPs to safe antimicrobial agents.

The study of clinical profile and outcome of patients with snakebite in a rural community.

CONTEXT: Snakebite remains an underrated cause of accidental death in modern India, primarily in rural India, where people fail to reach out to modern medicine and fall victim to the handful of quacks using traditional healing methods. If promptly diagnosed and treated based on various clinical determinants like mode of presentation, time of medical intervention, recognition of the species, and analysis of a series of reliably identified bites, the treatment outcome would be more promising. We aimed to study snakebite patients' clinical profile and treatment outcome in a rural tertiary care setup. MATERIALS AND METHOD: This is a retrospective study in which the data evaluated from an epidemiological viewpoint; gender and age of the snake bite victim, time when bitten, interval between the bite and medical consultation, pattern of toxicity, and response to anti-snake venom (ASV). RESULTS: Of a total of 200 patients bitten by a snake, 121 were males, with 77% adults. In nearly all cases, the type of snake was unknown; however, most of the bites were poisonous, showing one or the other type of toxicity. One hundred seventy-one patients survived the snake bite, and 29 succumbed. When Logistic regression was done with Death/discharge as the dependent variable and "Time to bite and reaching hospital, Age, Sex, number of ASV given, Ventilation needed or not, pack cell volume (PCV) numbers, Fresh Frozen Plasma (FFP) numbers, Dialysis and presence or absence of toxicity" as the independent variables, the model developed did not account for any respectable amount of variation in the outcome. The only variable found to be predicting the outcome significantly was FFP. CONCLUSION: It is often difficult to identify the type of snake, and thus polyvalent antisnake venom remains the only available treatment resource. Readily available treatment resources, timely intervention, appropriate referral, and close ICU will alleviate mortality.

Hematological immune related adverse events after treatment with immune checkpoint inhibitors.

INTRODUCTION: With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes. PATIENTS AND METHODS: Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres. RESULTS: In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1-128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis). CONCLUSION: Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection.

LncRNA-OBFC2A targeted to Smad3 regulated Cyclin D1 influences cell cycle arrest induced by 1,4-benzoquinone.

Long-term exposure to benzene is associated with adverse health effects such as leukemia. Abnormal cell cycle progression has been reported participating in tumorigenesis. Our previous study found that lncRNA-OBFC2A was involved in benzene toxicity through regulating cell proliferation. However, the function of lncRNA-OBFC2A in the regulation of cell cycle remains obscure and the precise mechanisms need to be explored. In vitro study, results showed that benzene metabolic, 1,4-Benzoquinone (1,4-BQ), induced cell cycle arrest at the G1 phase accompanied with decreased expression of Cyclin D1 in a dose-dependently manner. Interestingly, lncRNA-OBFC2A overexpression was found in AHH-1 cells treated with 1,4-BQ and while interference with lncRNA-OBFC2A, the expression of Cyclin D1 were reversed. Further, we found that lncRNA-OBFC2A can interact with Smad3 to control cell cycle via modulating Cyclin D1 expression. In benzene exposed workers, the expression of lncRNA-OBFC2A and Smad3 increased while cyclin D1 decreased which was consistent with the in vitro experiment, meanwhile, the significant associations among them were also found. Thus, these findings indicate that lncRNA-OBFC2A targeted to Smad3 regulated cyclin D1 influences cell cycle arrest induced by 1,4-BQ. LncRNA-OBFC2A, Smad3 and Cyclin D1 as a set of biomarkers play important roles in benzene haematotoxicity.

Risk factor analysis for linezolid-associated thrombocytopenia in critically ill patients.

Linezolid is an antibiotic used against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Its primary adverse effect is haematotoxicity. The objective of this study was to analyse the risk factors for onset of thrombocytopenia in critically ill patients treated with linezolid. This was a retrospective, single-centre study of 72 patients. Platelets were measured from D0 to D20 after the start of treatment. The risk factors for thrombocytopenia were identified using a multivariate logistic regression analysis following a Monte Carlo simulation. Following ROC curve analysis, a baseline platelet count lower than 108 × 109/L and a Cmin higher than 4 mg/L, with respective odds ratios of 117 (95% CI [97-206]) and 3 (95% CI [1.5-6.2]) in the simulated population, were identified as risk factors. Among the source population patients combining these 2 factors, a significantly higher number developed thrombocytopenia (66.7% vs. 33.3%, p = 0.0042). A baseline platelet count lower than 108 × 109/L and a Cmin higher than 4 mg/L are risk factors for the onset of thrombocytopenia in critically ill patients treated with linezolid.

Effects of proton pump inhibitors on severe haematotoxicity induced after first course of pemetrexed/carboplatin combination chemotherapy.

WHAT IS KNOWN AND OBJECTIVE: Pemetrexed/carboplatin combination chemotherapy has shown efficacy as a first-line treatment for advanced non-small-cell lung cancer. However, severe haematotoxicity is often observed during this combination chemotherapy. Some studies have suggested that concomitant drugs may be the risk factors for severe adverse events. However, those studies identified the predictive risk factors without paying attention to the relative dose intensities (RDIs) of the anticancer drugs. The objective of this study was to clarify the effects of concomitant drugs on the severe haematotoxicity induced by pemetrexed/carboplatin combination chemotherapy using multiple logistic regression analysis incorporating RDIs of the anticancer drugs. METHODS: We retrospectively reviewed the records of 61 patients who had received first-line treatment with this combination chemotherapy at Yamato Municipal Hospital between April 2011 and May 2017. Severe haematotoxicity was defined as grade 3 or 4 according to the Common Terminology Criteria for Adverse Events, version 4.0. To clarify the influence of concomitant drugs on haematotoxicity, we performed multiple logistic regression analysis. RESULTS: Among the 61 patients, 18 (29.5%) developed grade 3 or 4 haematotoxicity. Multiple logistic regression analysis showed that body weight <54.5 kg [odds ratio: 5.21, 95% confidence interval (CI): 1.17-23.08, P = 0.030], haemoglobin <12.0 g/dL [odds ratio: 7.13, 95% CI: 1.54-33.11, P = 0.012], and coadministration of proton pump inhibitors (PPIs) [odds ratio: 5.34, 95% CI: 1.06-26.94, P = 0.042] were significantly associated with severe haematotoxicity in patients receiving pemetrexed/carboplatin combination chemotherapy after adjustment using non-steroidal anti-inflammatory drugs and RDIs of the anticancer drugs. WHAT IS NEW AND CONCLUSION: Multiple logistic regression analysis incorporating RDIs of the anticancer drugs revealed that low baseline body weight, low baseline haemoglobin level, and coadministration of PPIs were the independent risk factors for predicting severe haematotoxicity induced by pemetrexed/carboplatin combination chemotherapy.

Benzene induces haematotoxicity by promoting deacetylation and autophagy.

Chronic exposure to benzene is known to be associated with haematotoxicity and the development of aplastic anaemia and leukaemia. However, the mechanism underlying benzene-induced haematotoxicity, especially at low concentrations of chronic benzene exposure has not been well-elucidated. Here, we found that increased autophagy and decreased acetylation occurred in bone marrow mononuclear cells (BMMNCs) isolated from patients with chronic benzene exposure. We further showed in vitro that benzene metabolite, hydroquinone (HQ) could directly induce autophagy without apoptosis in BMMNCs and CD34+ cells. This was mediated by reduction in acetylation of autophagy components through inhibiting the activity of acetyltransferase, p300. Furthermore, elevation of p300 expression by Momordica Antiviral Protein 30 Kd (MAP30) or chloroquine reduced HQ-induced autophagy. We further demonstrated that in vivo, MAP30 and chloroquine reversed benzene-induced autophagy and haematotoxicity in a mouse model. Taken together, these findings highlight increased autophagy as a novel mechanism for benzene-induced haematotoxicity and provide potential strategies to reverse this process for therapeutic benefits.

Protective Effects of Acridocarpus smeathmannii (DC.) Guill. & Perr. Root Extract against Phenylhydrazine-Induced Haematotoxicity, Biochemical Changes, and Oxidative Stress in Rats.

Several strategies for discovering drugs from unexplored natural products continue to strengthen research and development with current commercial evidence supporting their applications. We assessed the effects of the hydroethanolic extract of Acridocarpus smeathmannii root (HEASR) against phenylhydrazine (PHZ)-induced haematotoxicity, biochemical changes, and oxidative stress in male Wistar rats. Groups 1 and 2 controls received normal saline (10 mL/kg/day) and PHZ (60 mg/kg, day 4 and 5), respectively, via oral gavage. Groups 3, 4, and 5 were administered dexamethasone (DXM, 0.014 mg/kg/day, p.o.), HEASR1 (50 mg/kg/day, p.o.) and HEASR2 (200 mg/kg/day, p.o.), respectively. Groups 6, 7, and 8 received HEASR2 (200 mg/kg/day), DXM (0.014 mg/kg/day), or their combination, respectively, and further received PHZ (60 mg/kg/day) intervention on day 4 and 5 only. Treatments lasted for 7 days. Phenylhydrazine toxicity manifested as lowered haemoglobin, white blood cells, lymphocytes, red blood cells, and platelet levels by 45.86%, 53.47%, 75.69%, 46.89%, and 30.29%, respectively, in rats. This was accompanied by an increase in serum alanine (ALT; 108.25%) and aspartate (AST; 78.79%) aminotransferases, urea (84.36%), total cholesterol (81.55%), and triglycerides (123.42%) levels. Similarly, malondialdehyde levels and serum cyclooxygenase-2 activity were elevated (P < 0.05) in the rats liver and spleen, respectively. Just HEASR alone, or in combination with DXM, preserved haematological and biochemical parameters, cyclooxygenase-2 activity, and corticosterone levels during PHZ intoxication and restored renal histopathological alterations in rats. The HEASR was found to contain high flavonoid and phenolic phytochemicals and demonstrated better in vitro antioxidants inhibitory action.

Acute coumaphos organophosphate exposure in the domestic dogs: Its implication on haematology and liver functions.

Indiscriminate use of organophosphate acaricides especially among livestock and dog owners in the control of ticks and other ectoparasites has taken a worrisome dimension. In the present study, we investigated, the effects of acute dermal exposure in the form of acaricides baths of coumaphos at different concentrations on the haematology, blood pressure and liver functions in local mongrel dogs. Twenty-four, male mongrel dogs of about 8 months of age with an average weight of 9.88 ±â€¯0.4 kg were used for the study. The dogs were divided into four groups consisting of six dogs per group. Group A (control) was bathed with ordinary water, while group B was bathed with the recommended concentration of 0.016% (160 ppm) Coumaphos in water. Groups C and D were bathed with 10 and 20 times the recommended dose (1600 ppm and 3200 ppm), respectively. Significant leucopenia, increased plasma urea and decreased low density lipoprotein (LDL) values were observed at 8 h post exposure, which worsened with time. At 24 and 36 hrs post exposure, normochromic normocytic anaemia, pan leucopenia, bloody diarrhoea, retching, vomiting and paddling were observed in affected animals. Post mortem examination revealed severe lungs, liver and stomach congestion. Multifocal areas of necrosis in the liver and kidney, serosal and mucosal haemorrhages and haemorrhagic meningitis were also observed. The use of excessively high concentration of organophosphate as acaricides bath is associated with severe anticholinesterase poisoning, which may result in death of affected animals.

Assessment of interactions of efavirenz solid drug nanoparticles with human immunological and haematological systems.

BACKGROUND: Recent work has developed solid drug nanoparticles (SDNs) of efavirenz that have been demonstrated, preclinically, improved oral bioavailability and the potential to enable up to a 50% dose reduction, and is currently being studied in a healthy volunteer clinical trial. Other SDN formulations are being studied for parenteral administration, either as intramuscular long-acting formulations, or for direct administration intravenously. The interaction of nanoparticles with the immunological and haematological systems can be a major barrier to successful translation but has been understudied for SDN formulations. Here we have conducted a preclinical evaluation of efavirenz SDN to assess their potential interaction with these systems. Platelet aggregation and activation, plasma coagulation, haemolysis, complement activation, T cell functionality and phenotype, monocyte derived macrophage functionality, and NK cell function were assessed in primary healthy volunteer samples treated with either aqueous efavirenz or efavirenz SDN. RESULTS: Efavirenz SDNs were shown not to interfere with any of the systems studied in terms of immunostimulation nor immunosuppression. Although efavirenz aqueous solution was shown to cause significant haemolysis ex vivo, efavirenz SDNs did not. No other interaction with haematological systems was observed. Efavirenz SDNs have been demonstrated to be immunologically and haematologically inert in the utilised assays. CONCLUSIONS: Taken collectively, along with the recent observation that lopinavir SDN formulations did not impact immunological responses, these data indicate that this type of nanoformulation does not elicit immunological consequences seen with other types of nanomaterial. The methodologies presented here provide a framework for pre-emptive preclinical characterisation of nanoparticle safety.

Clinical presentation and management of an Aruban rattlesnake bite in the Netherlands.

Bites by Aruban Rattlesnake (Crotalus durissus unicolor) are rare and not known to induce severe envenomations. Here, we present a case of a 57 year-old man bitten by his pet Aruban Rattlesnake (Crotalus durissus unicolor). He was admitted to hospital within 15 min. Three and a half hours later his fibrinogen concentration decreased to 0.6 g/L (normal: 2.0-4.0). Nine hours post-bite, he was treated with polyvalent snake antivenom covering Crotalus durissus. Three hours later his fibrinogen became undetectable while at that time clotting times were prolonged (PT 38.7 s (normal: 12.5-14.5) and aPTT 40 s (normal: 25-35)). His platelet count remained within normal limits. Creatine kinase (CK) concentrations reached a maximum of 1868 U/L (normal: <200) 16 h post-bite. After a second antivenom dose, 10.5 h after the first antivenom administration, clotting times returned to normal. Fibrinogen was restored to normal within three days. He was discharged from hospital on day five. In conclusion, administration of polyvalent snake antivenom covering Crotalus durissus snakebites shows cross-neutralization and is effective in the treatment of patients bitten by Crotalus durissus unicolor.