Impaired memory in Sprague-Dawley rats exposed to complex groundwater mixtures of contaminants is associated with reduced cranial blood flow and hippocampal neurotoxicity.

Exposure to industrial contaminants has been implicated in neurobehavioral toxicity in humans. To explore this potential risk, we investigated the neurotoxic effects of oral exposure to a complex groundwater mixture containing petroleum hydrocarbons, pesticides, heavy metals, and unknown parent and breakdown products using male and female Sprague Dawley rats. Rats were randomly divided into six groups and orally exposed daily via drinking water to: (i) tap water, (ii) 10 % v/v low impact groundwater, and (iii) 0.01 %, 0.1 %, 1 %, and 10 % high-impact groundwater for 60 days. Medium- and long-term memory (measured using the novel object recognition task) were impaired. However, no gross motor or coordination deficits were observed by the end of the study period (rotarod test). Doppler ultrasound of the middle cerebral and common carotid arteries was performed to examine the hemodynamic changes. The common carotid blood flow decreased in the groundwater-exposed rats compared to that in the control. However, no significant differences in cerebral blood velocity were observed between the exposed and control groups. A significant reduction in hippocampal serotonin levels was observed in groundwater-exposed rats relative to that in the control group. Collectively, these results indicate that impaired recognition memory in rats exposed to groundwater is accompanied by reduced cranial blood flow and hippocampal neurotoxicity, characterized by altered serotonergic signalling. The levels of detected contaminants known to cause neural or vascular damage were of magnitudes lower than the concentrations of contaminants found in the groundwater mixture, meaning the culprit chemical identity remains unknown. This study emphasizes the need to use whole mixture in exposures when dealing with complex contaminated sites rather than the use of individual compounds.

Linking pesticide exposure to neurodegenerative diseases: An in vitro investigation with human neuroblastoma cells.

Although many organochlorine pesticides (OCPs) have been banned or restricted because of their persistence and linkage to neurodegenerative diseases, there is evidence of continued human exposure. In contrast, registered herbicides are reported to have a moderate to low level of toxicity; however, there is little information regarding their toxicity to humans or their combined effects with OCPs. This study aimed to characterize the mechanism of toxicity of banned OCP insecticides (aldrin, dieldrin, heptachlor, and lindane) and registered herbicides (trifluralin, triallate, and clopyralid) detected at a legacy contaminated pesticide manufacturing and packing site using SH-SY5Y cells. Cell viability, LDH release, production of reactive oxygen species (ROS), and caspase 3/7 activity were evaluated following 24 h of exposure to the biocides. In addition, RNASeq was conducted at sublethal concentrations to investigate potential mechanisms involved in cellular toxicity. Our findings suggested that aldrin and heptachlor were the most toxic, while dieldrin, lindane, trifluralin, and triallate exhibited moderate toxicity, and clopyralid was not toxic to SH-SY5Y cells. While aldrin and heptachlor induced their toxicity through damage to the cell membrane, the toxicity of dieldrin was partially attributed to necrosis and apoptosis. Moreover, toxic effects of lindane, trifluralin, and triallate, at least partially, were associated with ROS generation. Gene expression profiles suggested that decreased cell viability induced by most of the tested biocides was related to inhibited cell proliferation. The dysregulation of genes encoding for proteins with anti-apoptotic properties also supported the absence of caspase activation. Identified enriched terms showed that OCP toxicity in SH-SY5Y cells was mediated through pathways associated with the pathogenesis of neurodegenerative diseases. In conclusion, this study provides a basis for elucidating the molecular mechanisms of pesticide-induced neurotoxicity. Moreover, it introduced SH-SY5Y cells as a relevant in vitro model for investigating the neurotoxicity of pesticides in humans.

Herbicides and pesticides synergistically interact at low concentrations in complex mixtures.

Assessing a complex mixture of pesticides at the impacted sites has been challenging for risk assessors for 50 years. The default assumption is that at low concentrations, pesticides interact additively with one another; thus, the risk posed by each component of a complex mixture could be simply added up. The EPA interaction-based hazard index (HIInteraction) modifies this assumption using a binary weight-of-evidence (BINWOE). However, data gaps often preclude HIInteraction use at most sites. This study evaluated these assumptions using the BINWOE to estimate the hazard index (HI) of select pesticide mixtures. The lack of in vivo binary interaction data led us to use a cell line, SH-SY5Y, to obtain the data necessary for the BINWOE approach. In the risk assessment, we considered the most active exposure scenario inhaling a mixture of volatile pesticides from contaminated soil and groundwater. The potential interactions between pesticides in 15 binary mixtures were investigated using the MTT assay in SH-SY5Y cells. Our findings showed that 60% of the binary mixtures elicited synergism (in at least one concentration), 27% displayed antagonism, and 13% showed additive effects in SH-SY5Y cells. Combining human safety data with in vitro interaction data indicated that adults and toddlers were at the highest risk when considering industrial and commercial land use, respectively, compared to other subpopulations. Incorporating interaction data into the risk assessment either increased the risk by up to 20% or decreased the risk by 2%, depending on the mixture. Our results demonstrate the predominant synergistic interactions, even at low concentrations, altered risk characterization at the complex operating site. Most concerning, organochlorine pesticides with the same mechanism of action did not follow dose additivity when evaluated by SH-SY5Y cell lines. Based on our observations, we caution that current HI methods based on additivity assumptions may underestimate the risk of organochlorine mixtures.

Target Organ Toxicity in Rats After Subchronic Oral Exposure to Soil Extracts Containing a Complex Mixture of Contaminants.

Complex mixtures of unknown contaminants present a challenge to identify toxicological risks without using large numbers of animals and labor-intensive screens of all organs. This study examined soil extracts from a legacy-contaminated pesticide packaging and blending site. HepG2 cytotoxicity was used as an initial screen of 18 soil samples; then, three extracts (A, B and C) from different locations at the study site were used for testing in animals. The first two extracts were identified as the most toxic in vitro, and the latter extract obtained from a location further from these two toxic sampling sites. Then, target organ toxicities were identified following biweekly oral gavage for one month of three soil extracts (0.1% in polyethylene glycol or PEG) compared to vehicle control in male Sprague-Dawley rats (n = 9-10/group). Exposure to extract A significantly increased neutrophils and lymphocytes compared to control. In contrast, all extracts increased plasma α-2 macroglobulin and caused mild-to-moderate lymphocytic proliferation within the spleen white pulp, all indicative of inflammation. Rats exposed to all soil extracts exhibited acute tubular necrosis. Cholinesterase activity was significantly reduced in plasma, but not brain, after exposure to extract A compared to control. Increased hepatic ethoxyresorufin-o-deethylase activity compared to control was observed following exposure to extracts A and B. Exposure to soil extract C in rats showed a prolonged QTc interval in electrocardiography as well as increased brain lipid peroxidation. Candidate contaminants are organochlorine, organophosphate/carbamate pesticides or metabolites. Overall, HepG2 cytotoxicity did not successfully predict the neurotoxicity and cardiotoxicity observed with extract C but was more successful with suspected hydrocarbon toxicities in extracts A and B. Caution should be taken when extrapolating the observation of no effects from in vitro cell culture to in vivo toxicity, and better cell culture lines or assays should be explored.

Health status of fathead minnow (Pimephales promelas) populations in a municipal wastewater effluent-dominated stream in the Canadian prairies, Wascana Creek, Saskatchewan.

Their unique hydrological and climatic conditions render surface water systems in the southern Canadian Prairies at an elevated risk from exposure to contaminants released from municipal wastewater effluents (MWWEs). The aim of this study was to characterize the potential health effects and their underlying molecular mechanisms in populations of fathead minnow (Pimephales promelas; FHM) in Wascana Creek, an effluent dominated stream in Southern Saskatchewan, Canada. Studies were conducted during the spawning season in 2014 and 2015 to assess responses in terms of overall health, reproductive functions, plasma sex steroid hormone levels, and expression of selected genes along the hypothalamus-pituitary-gonadal axis. FHM downstream of the effluent fallout had lower gonadosomatic indices and significantly greater hepatosomatic indices compared to upstream populations. In both male and female FHMs, significantly greater occurrence and severity of gonadal degradation and delayed maturation were observed in downstream fish compared to upstream fish. Downstream males also displayed lower scores of secondary sexual characteristics and a decreasing trend in plasma 11-ketotestosterone levels. Interestingly, no indications of exposure to estrogenic compounds, such as occurrence of testicular oocytes were observed, which was in accordance with the lack of presence of key biomarkers of estrogenic exposure, such as induction of vitellogenin. In general, expression of the majority of transcripts measured in FHMs downstream of the effluent fallout was significantly downregulated, which supports observations of the general deterioration of the health and reproductive status of these fish. Chemical analysis indicated that 10 pharmaceuticals and personal care products (PPCPs) were present at the downstream site, some at sufficiently great concentrations that may present a risk to aquatic organisms. With continuous exposure to a diverse number of stressors including high nutrient and ammonia levels, the presence of a variety of PPCPs and other contaminants, Wascana Creek should be considered as an ecosystem at risk.

Feed preference and feeding behaviours in grower broilers fed diets containing wheat naturally contaminated with fusarium mycotoxins.

1. Two trials were conducted to determine the effect of feeding diets contaminated with fusarium mycotoxins (primarily deoxynivalenol (DON)) on broiler chicken feed preference, feeding behaviour and growth performance. 2. A total of 120 male Ross 308 chicks (4 birds/cage, 30 cages) were fed a common corn-based starter diet from 1 to 20 d of age. At 21 d, 15 cages were randomly assigned to the feed preference trial or a feeding behaviour trial. Three wheat-based experimental diets (0.14, 2.27 and 5.84 mg/kg DON) were prepared with a clean wheat and a naturally contaminated wheat. Broilers were ad libitum fed the experimental diets during 21-27 d. 3. In the preference trial, each cage's feeder was split into two equal-sized compartments so birds were provided a choice of two diets (control vs. low, control vs. high and low vs. high DON). In the feeding behaviour trial, diets were randomly assigned to 15 cages (5 cages/diet). Feeding and drinking behaviour was recorded for 1 h before and after the dark period and 1-h period at 9 h after the light was turned on (middle of day). Growth performance was assessed at 27 d. 4. In the preference trial, broilers preferred the control diet over low (93.0 vs. 66.1 g/d, P < 0.01) and high (104.4 vs. 50.4 g/d, P < 0.01) DON diets. At all three timepoints, where behaviour was recorded, birds offered the DON diets spent more time at the feeder compared to birds provided control diets (P < 0.05). Control birds had lower feed to gain ratio (1.65) than birds fed low (1.82) and high (1.94) DON diets (P < 0.01). 5. It is clear that broilers are sensitive to the presence of fusarium mycotoxins and that moderate levels of DON negatively affect feed preference and growth performance when fed during the grower period.

Melena as an unusual presentation of gastrointestinal stromal tumour, a case report.

INTRODUCTION: Gastrointestinal Stromal Tumors (GISTs) are a rare slow growing malignancy, accounting for less than 1% of all gastrointestinal (GI) tract tumors. These tumors are usually discovered incidentally by endoscopy, surgery or radiology. However on occasions they may present with significant symptoms including GI blood loss. This case report discusses an atypical presentation of a GIST in a 57-year-old female. CASE PRESENTATION: A 57-year-old woman presented to the emergency department following one episode of melena. This occurred on a background of two previous presentations with melena over a 10-year period. She had a preceding surgery for a Meckel's Diverticulum. She was admitted for monitoring and investigation. An emergency upper endoscopy showed no upper gastrointestinal pathology to account for the bleeding. Her condition deteriorated with development of hypovolemic shock, requiring blood transfusion. An urgent CT angiogram identified a large mass in the distal ileum. The patient underwent an emergency laparotomy, where a 9.1 cm tumor located on the distal one-third of the ileum was resected. Histopathology confirmed the mass was a GIST. The patient had a successful post-operative period and subsequent treatment with Imatinib. DISCUSSION: The majority of GISTs are found incidentally. This case report describes an unusual presentation of a GIST in which the tumor bled into the intestinal lumen causing significant melena and life threatening hemorrhage. CONCLUSION: We conclude that GIST should be considered as a possible differential in rare cases of GI bleeding where more common causes have been ruled out.

Needle-free small-volume liquid injection system powered by a rotary actuator.

Controllable jet injection could provide a fast, repeatable method for delivery of small volume, high viscosity drugs to the dermis. We have developed a compact, lightweight jet injector that uses a small commercial rotary motor and differential screw to create a jet of fluid with sufficient force to deliver drug into tissue. Clear tissue analogue and ex vivo tissue were used to demonstrate repeatable delivery of <;10 µL of fluid using the device. The fluid when forced through a narrow orifice (108 µm) reaches a velocity of >250 m/s with an injection time of <;3 ms.

High-speed X-ray analysis of liquid delivery during jet injection.

The effect of varying velocity during jet injection on the dispersion of fluid into tissue is investigated using a custom-built X-ray imaging system. Injections are performed into ex-vivo porcine abdominal tissue using a voice coil actuated injection device. Single velocity and two-phase velocity injections reveal the complex nature of the dispersion of the fluid jet in layered tissue and highlight the effects of changing the jet velocity following the initial penetration of the liquid into the tissue.

Ampoule and nozzle development for needle-free injections.

A rigid, compact, multi-piece ampoule has been designed and fabricated as a platform to conveniently house different nozzle inserts one at a time to offer increased jet consistency and functional flexibility. Three different nozzle geometries that respectively produce a single axial jet, radial jets, and intersecting jets are designed and fabricated. Through high-speed imaging and injection into tissue analog and ex vivo porcine tissue, these nozzles are demonstrated to have potential for a range of injection applications including intradermal, intratympanic, and traditional uses. The presented ampoule is more successful than a commercial jet injection ampoule in adhering to desired position and velocity trajectories and the energy efficiencies of jet ejections are compared.

Delivery of immunoreactive antigen using a controllable needle-free jet injector.

Intradermal immunization of mice against hepatitis B surface antigen (HBsAg) using a novel real-time controlled jet injector was assessed by comparison with intradermal and subcutaneous injection of antigen using a 27G needle and syringe. Three doses of aluminium-absorbed HBsAg were delivered at 0, 14, and 28days. Antibodies to HBsAg were detected only in mice injected with antigen with antibody levels increasing with secondary injections. Mice vaccinated by intradermal injection using the jet injector or subcutaneous needle injection exhibited comparable immune responses at day 47. Differences in titer observed between intradermal jet injected and needle injected animals reflect differences in the volume of antigen delivered. With the exception of minor bleeding at the injection site in a few animals injected either by jet injection or needle, no adverse events were observed in any of the mice used in the study.

Total hip arthroplasty in patients with haemophilia - What are the risks of bleeding in the immediate peri-operative period?

BACKGROUND: Undergoing a major surgical intervention such as total hip arthroplasty (THA) with an underlying clotting disorder like haemophilia poses its own unique challenges. Despite the advances in factor replacement and medical management, the potential for excessive and uncontrolled haemorrhage still exists. The aim of this study was to quantify blood loss, peri-operative transfusion requirements and risk of haematoma formation in a cohort of patients with haemophilia undergoing THA. METHODS: All patients with haemophilia types A or B who had undergone THA in the previous 10 years were identified from the Hospital In-Patient Enquiry system and theatre logs. A comprehensive review of operative records, laboratory parameters and peri-operative haematological management was conducted. RESULTS: Eleven male patients (12 THA) were identified. The mean age was 56 years (range 28-76). The mean intra-operative blood loss was 502 ml (100-1250 ml) compared to an established normal blood loss of 400 ml. The mean drop in haemoglobin was 3.25 g/dl in 48 h. Only one patient required a post-operative transfusion of two units of red cell concentrate. There were no complications of haematoma formation. CONCLUSION: The results in our institution compare favourably with the established blood loss reported in the literature and by assessment with International Guidelines. Average blood loss in patients with haemophilia was higher than the established normal, but there was no increased transfusion requirement.

Iatrogenic common bile duct injuries: Increasing complexity in the laparoscopic era: A prospective cohort study.

PURPOSE: Iatrogenic bile duct injury (BDI) is the most significant associated complication to laparoscopic cholecystectomy (LC). Little is known about the evolution of the pattern of BDI in the era of laparoscopy. The aim of the study is to assess the pattern of post-LC BDIs managed in a tertiary referral centre. METHODS: Post-LC BDI referred over two decades were studied. Demographic data, type of BDI (classified using the Strasberg System), clinical symptoms, diagnostic investigations, timing of referral, post-referral management and morbidity were analysed. The pattern of injury, associated vascular injuries rate and their management were compared over two time periods (1992-2004,2005-2014). RESULTS: 78 BDIs were referred. During the second time period Strasberg A injuries decreased from 14% to 0 and Strasberg E1increased from 4% to 23%, the rate of associated vascular injury was six time higher (3.6% versus 22.7%), more patients had an attempted repair at the index hospital (16% versus 35%) sand fewer patients could be managed without surgical intervention at the referral hospital (28% versus 4%). CONCLUSION: Complexity of referred BDIs and rate of associated vascular injuries have increased over time. These findings led to more patients managed requiring surgical intervention at the referral hospital.

Analysis of Moving-Coil Actuator Jet Injectors for Viscous Fluids.

OBJECTIVE: A jet injector is a device that can be used to deliver liquid drugs through the skin using a fluid jet, without the use of a needle. Most jet injectors are designed and used for the delivery of inviscid liquids, and are not optimized for the delivery of viscous drug compounds. To better understand the requirements for delivering viscous drugs, we have developed a mathematical model of the electromechanics of a moving-coil actuated jet injector as it delivers viscous fluids. METHODS: The model builds upon previous work by incorporating the nonlinear electrical properties of the motor, compliant elements of the mechanical piston and ampoule system, and the effect of viscosity on injector characteristics. The model has been validated by monitoring the movement of the piston tip and measurements of the jet force. RESULTS: The results of the model indicate that the jet speed is diminished with increasing fluid viscosity, but overshoot and ringing in the jet speed is unaffected. However, a stiffer ampoule and piston will allow for a better control of the jet speed profile during an injection, and reduce ringing. CONCLUSION: We identified that the piston friction coefficient, the compliance of the injector components, and the viscous properties of the fluid are important determinants of performance when jet-injecting viscous fluids. SIGNIFICANCE: By expanding upon previous jet injector models, this study has provided informative simulations of jet injector characteristics and performance. The model can be used to guide the design of future jet injectors for viscous fluids.

A needle-free technique for interstitial fluid sample acquisition using a lorentz-force actuated jet injector.

We present a novel method of quickly acquiring dermal interstitial fluid (ISF) samples using a Lorentz-force actuated needle-free jet injector. The feasibility of the method is first demonstrated on post-mortem porcine tissue. The jet injector is used to first inject a small volume of physiological saline to breach the skin, and the back-drivability of the actuator is utilized to create negative pressure in the ampoule and collect ISF. The effect of the injection and extraction parameters on sample dilution and extracted volumes is investigated. A simple finite element model is developed to demonstrate why this acquisition method results in faster extractions than conventional sampling methods. Using this method, we are able to collect a sample that contains up to 3.5% ISF in 3.1s from post-mortem skin. The trends revealed from experimentation on post-mortem skin are then used to identify the parameters for a live animal study. The feasibility of the acquisition process is successfully demonstrated using live rats; the process is revealed to extract samples that have been diluted by a factor of 111-125.

Jet injection of a monoclonal antibody: A preliminary study.

Monoclonal antibodies (mAbs) represent a major group of biotherapeutics. The high concentration and volume of drug administered together with a shift to administration via the subcutaneous route have generated interest in alternative delivery technologies. The feasibility of using a novel, highly controllable jet injection technology to deliver a mAb is presented. The effect of delivery parameters on protein structure were evaluated and compared with delivery using a conventional needle and syringe. Injection of mAb into a rat model showed that jet injection using the device resulted in more rapid absorption and longer duration of exposure.

Adaptive controller for a needle free jet-injector system.

A nonlinear, sliding mode adaptive controller was created for a needle-free jet injection system. The controller was based on a simplified lumped-sum parameter model of the jet-injection mechanics. The adaptive control scheme was compared to a currently-used Feed-forward+PID controller in both ejection of water into air, and injection of dye into ex-vivo porcine tissue. The adaptive controller was more successful in trajectory tracking and was more robust to the biological variations caused by a tissue load.

The effect of jet shape on jet injection.

The effects of the dispersion pattern of a needle-free jet injector are explored. The shape of the jets were compared using a high-speed video camera and jet injections of collimated and dispersed fluid jets with a Lorentz-force actuated jet injector were made into acrylamide gel and post-mortem porcine tissue. A custom-built high-speed X-ray imaging system was used in order to observe the dynamics of the dispersion mechanism for each injection in real time. We show that a collimated jet stream results in greater tissue penetration than a dispersed jet stream.

Unscheduled undergraduate teaching in surgery: a multi-institutional analysis.

A significant amount of valuable undergraduate medical teaching may be informal, unscheduled and delivered by non-consultant hospital doctors (NCHDs). 800 Questionnaires were distributed to consultants, NCHDs and medical students in Irish teaching hospitals. The aim was to quantify the level of unscheduled teaching carried out in these hospitals and the manner in which it was performed. The response rate was 46% (364/800). 71% of doctors who replied are independently teaching undergraduate medical students (77/109), including 71% of interns and senior house officers (48/68). Students tend to prefer small group teaching. Fifty-six percent of students suggest they would benefit from more surgical teaching time (144/255). No interns surveyed were scheduled to teach as part of a formal curriculum. A significant amount of unscheduled teaching by interns and senior house officers takes place in Irish hospitals. It may prove beneficial to incorporate interns into scheduled surgical teaching curricula.

Retroileal colorectal anastomosis: an old technique, still relevant.

Retroileal colorectal anastomosis is an infrequently used technique providing tension-free anastomosis after extended left-sided colonic resection, which was first described by Turnbull in 1972. The authors describe the use of a retroileal colorectal anastomosis in a patient with chronic Candida albicans and Enterococcal retroperitoneal abscess. The patient's condition was most likely secondary to an anastomotic leak and colonic fistula post en bloc resection for recurrence of a left renal cell carcinoma. After failure of antimicrobial therapy and percutaneous drainage, surgical intervention was required. This involved resection of the existing colocolonic anastomosis and drainage of the retroperitoneal abscess. A retroileal colorectal anastomosis was then necessary to ensure a tension-free anastomosis. To the best of our knowledge, this is the first reported case of retroileal anastomosis used for this purpose. It highlights the importance of this technique in the surgeon's armamentarium.