Bioscavenger is effective as a delayed therapeutic intervention following percutaneous VX poisoning in the guinea-pig.

The prolonged systemic exposure that follows skin contamination with low volatility nerve agents, such as VX, requires treatment to be given over a long time due to the relatively short half-lives of the therapeutic compounds used. Bioscavengers, such as butyrylcholinesterase (BChE), have been shown to provide effective post-exposure protection against percutaneous nerve agent when given immediately on signs of poisoning and to reduce reliance on additional treatments. In order to assess the benefits of administration of bioscavenger at later times, its effectiveness was assessed when administration was delayed for 2h after the appearance of signs of poisoning in guinea-pigs challenged with VX (4×LD50). VX-challenged animals received atropine, HI-6 and avizafone on signs of poisoning and 2h later the same combination with or without bioscavenger. Five out of 6 animals which received BChE 2h after the appearance of signs of poisoning survived to the end of the study at 48h, compared with 6 out of 6 which received BChE immediately on signs. All the animals (n=6+6) that received only MedCM, without the addition of BChE, died within 10h of poisoning. The toxicokinetics of a sub-lethal challenge of percutaneous VX were determined in untreated animals. Blood VX concentration peaked at approximately 4h after percutaneous dosing with 0.4×LD50; VX was still detectable at 36h and had declined to levels below the lower limit of quantification (10pg/mL) by 48h in 7 of 8 animals, with the remaining animal having a concentration of 12pg/mL. These studies confirm the persistent systemic exposure to nerve agent following percutaneous poisoning and demonstrate that bioscavenger can be an effective component of treatment even if its administration is delayed.

N-acetyl-L-cysteine protects against inhaled sulfur mustard poisoning in the large swine.

CONTEXT: Sulfur mustard is a blister agent that can cause death by pulmonary damage. There is currently no effective treatment. N-acetyl-L-cysteine (NAC) has mucolytic and antioxidant actions and is an important pre-cursor of cellular glutathione synthesis. These actions may have potential to reduce mustard-induced lung injury. OBJECTIVE: Evaluate the effect of nebulised NAC as a post-exposure treatment for inhaled sulfur mustard in a large animal model. MATERIALS AND METHODS: Fourteen anesthetized, surgically prepared pigs were exposed to sulfur mustard vapor (100 µg.kg⁻¹), 10 min) and monitored, spontaneously breathing, to 12 h. Control animals had no further intervention (n = 6). Animals in the treatment group were administered multiple inhaled doses of NAC (1 ml of 200 mg.ml⁻¹ Mucomyst™ at + 30 min, 2, 4, 6, 8, and 10 h post-exposure, n = 8). Cardiovascular and respiratory parameters were recorded. Arterial blood was collected for blood gas analysis while blood and bronchoalveolar lavage fluid were collected for hematology and inflammatory cell analysis. Urine was collected to detect a sulfur mustard breakdown product. Lung tissue samples were taken for histopathological and post-experimental analyses. RESULTS: Five of six sulfur mustard-exposed animals survived to 12 h. Arterial blood oxygenation (PaO2) and saturation levels were significantly decreased at 12 h. Arterial blood carbon dioxide (PaCO2) significantly increased, and arterial blood pH and bicarbonate (HCO3⁻) significantly decreased at 12 h. Shunt fraction was significantly increased at 12 h. In the NAC-treated group all animals survived to 12 h (n = 8). There was significantly improved arterial blood oxygen saturation, HCO3⁻ levels, and shunt fraction compared to those of the sulfur mustard controls. There were significantly fewer neutrophils and lower concentrations of protein in lavage compared to sulfur mustard controls. DISCUSSION: NAC's mucolytic and antioxidant properties may be responsible for the beneficial effects seen, improving clinically relevant physiological indices affected by sulfur mustard exposure. CONCLUSION: Beneficial effects of nebulized NAC were apparent following inhaled sulfur mustard exposure. Further therapeutic benefit may result from a combination therapy approach.

The use of an exclusion-based risk-assessment model for venous thrombosis improves uptake of appropriate thromboprophylaxis in hospitalized medical patients.

BACKGROUND: Venous thromboembolism is a common condition in hospitalized medical patients. Numerous studies have demonstrated that low molecular weight heparin significantly reduces this risk but, despite this, the use of thromboprophylaxis remains poor. AIM: To evaluate the use of an exclusion based risk-assessment model (RAM) for venous thrombosis in improving the uptake of appropriate thromboprophylaxis in hospitalized medical patients. DESIGN: A survey with a subsequent audit cycle of three separate audits over 36 months. METHODS: 497 hospitalized patients with acute medical conditions on general medical wards were audited at a secondary care centre in London, UK. The survey and subsequent audits were performed by reviewing the notes and medication charts of medical patients, prior to the launch of the RAM and at 12, 28 and 36 months following its introduction. RESULTS: Prior to launching the RAM, 49% of hospitalized medical patients received appropriate thromboprophylaxis. This did not change 12 months after the RAM was introduced but increased significantly to 71% following formal education of the health care professionals involved in thromboprophylaxis prescription. This improvement was maintained as demonstrated by a subsequent audit 8 months later (75.9%). CONCLUSION: The introduction of a simple exclusion-based RAM for venous thrombosis in medical patients significantly improved delivery of thromboprophylaxis. The successful uptake of the RAM appears to have been dependent on direct education of those health carers involved in its use. A similar exclusion-based model used nationally could have a significant impact on the burden of VTE currently experienced in the UK.

Furosemide in the treatment of phosgene induced acute lung injury.

METHOD: Using previously validated methods, 16 anaesthetised large white pigs were exposed to phosgene (target inhaled dose 0.3 mg kg(-1)), established on mechanical ventilation and randomised to treatment with either nebulised furosemide (4 ml of 10 mg x ml(-1) solution) or saline control. Treatments were given at 1, 3, 5, 7, 9, 12, 16 and 20 hours post phosgene exposure; the animals were monitored to 24 hours following phosgene exposure. RESULTS: Furosemide treatment had no effect on survival, and had a deleterious effect on PaO2: FiO2 ratio between 19 and 24 hours. All other measures investigated were unaffected by treatment. CONCLUSION: Nebulised furosemide treatment following phosgene induced acute lung injury does not improve survival and worsens PaO2: FiO2 ratio. Nebulised furosemide should be avoided following phosgene exposure.

Dielectric properties of porcine cerebrospinal tissues at microwave frequencies: in vivo, in vitro and systematic variation with age.

The dielectric properties of pig cerebrospinal tissues were measured in vivo and in vitro, in the frequency range of 50 MHz-20 GHz. The total combined measurement uncertainty was calculated at each frequency point and is reported over representative frequency regions. Comparisons were made for each tissue between the two sets of data and with the literature of the past decade. The in vitro study was extended to include tissue from pigs weighing approximately 10, 50 and 250 kg to re-visit the question of the variation of dielectric properties with age. White matter and spinal chord showed significant variation as function of animal age, no age-related variations were recorded for grey matter.

The influence of plasma glucose upon pulsatile ocular blood flow in subjects with type II diabetes mellitus.

AIMS/HYPOTHESIS: This study investigated the influence of plasma glucose upon pulsatile ocular blood flow in subjects with Type II (non-insulin-dependent) diabetes mellitus. METHODS: A total of 19 subjects with Type II diabetes and 8 normal control subjects undertook a meal tolerance test after an overnight fast. The pulsatile ocular blood flow, using the Ocular Blood Flow Tonometer, and plasma glucose concentrations were taken at times 0 min, 90 min and 240 min. Blood pressure and glycated haemoglobin concentrations, in the subjects with diabetes, were also measured at time 0 min. Pulsatile ocular blood flow and plasma glucose were also measured at times 0 and 90 min in 5 subjects with Type II diabetes mellitus who remained fasting. RESULTS: It was found that the subjects with diabetes who undertook the meal tolerance test showed a significant increase in both plasma glucose concentrations and pulsatile ocular blood flow from time 0-90 min, followed by a decrease from 90 min to the end of the session at 240 min. (p < 0.001 in each case). Regression analysis showed a significant correlation between the change in pulsatile ocular blood flow and the change in plasma glucose concentration (r = 0.671,p = 0.001). Control subjects showed no significant change in either plasma glucose or pulsatile ocular blood flow during the meal tolerance test. Subjects with diabetes mellitus who remained fasting also showed no significant change in pulsatile ocular blood flow or plasma glucose concentrations. No correlation was found between glycated haemoglobin concentrations or blood pressure and pulsatile ocular blood flow. CONCLUSION/INTERPRETATION: Pulsatile ocular blood flow is influenced by changes in plasma glucose concentrations in Type II diabetes mellitus, indicating that uncontrolled hyperglycaemia might result in a higher pulsatile ocular blood flow than might otherwise be expected.

A 14,000-year oxygen isotope record from diatom silica in two alpine lakes on Mt. Kenya.

Oxygen isotopes are sensitive tracers of climate change in tropical regions. Abrupt shifts of up to 18 per mil in the oxygen isotope ratio of diatom silica have been found in a 14,000-year record from two alpine lakes on Mt. Kenya. Interpretation of tropical-montane isotope records is controversial, especially concerning the relative roles of precipitation and temperature. Here, we argue that Holocene variations in delta(18)O are better explained by lake moisture balance than by temperature-induced fractionation. Episodes of heavy convective precipitation dated approximately 11,100 to 8600, 6700 to 5600, 2900 to 1900, and <1300 years before the present were linked to enhanced soil erosion, neoglacial ice advances, and forest expansion on Mt. Kenya.

New Aggressive Colletotrichum gloeosporioides Strains on Stylosanthes scabra Detected by Virulence and DNA Analysis.

Widespread use of Stylosanthes scabra cv. Seca to improve native pastures in northern Australia makes it necessary to monitor changes in the anthracnose pathogen, Colletotrichum gloeosporioides, because new damaging races have arisen to devastate many agronomically promising cultivars in the past. A total of 103 isolates collected during the past 20 years were analyzed by using virulence and molecular markers to determine whether aggressive strains have evolved in the field. Data on severity for eight host differentials were obtained from a greenhouse assay and analyzed by linear discriminant functions developed from existing data on 182 isolates of known races. A molecular analysis of a subset of 21 isolates by random amplified polymorphic DNA (RAPD) and electrophoretic karyotyping gave comparable results for both markers, although electrophoretic karyotyping detected a higher level of polymorphism. The majority of the 103 isolates were placed into three groups on the basis of RAPD analysis. Virulence analysis detected isolates that were highly aggressive toward Seca. During the past 20 years, the frequency of aggressive isolates has increased. Many of the aggressive isolates were collected during the 1990s, and one had a distinct RAPD genotype. The lack of a strong association between RAPD genotypes and pathogen races suggests that races have arisen independently within each genetic group. This work highlights the need for regular monitoring of the pathogen population.

Effective treatment of B16 melanoma by direct delivery of bleomycin using electrochemotherapy.

Electrochemotherapy (ECT), chemotherapy administered in combination with electric fields, has the potential to be an effective localized treatment for cutaneous malignancies. Bleomycin's cytotoxicity was enhanced by exposing tumour cells to electrical fields following intravenous injection of the chemotherapeutic agent. Two issues associated with this procedure are the existence of a narrow but optimal time-window for effective treatment and the fact that a systemic drug dose is administered for a localized therapy. In order to address these issues, a study was initiated to examine the effectiveness of administering bleomycin by intratumoural injection. A dose-response relationship for intratumoural injection was determined. In addition, the minimal effective field strength necessary for ECT was established. Results of this study indicated drastic reductions in tumour volume for ECT-treated groups. In addition, ECT-treated groups showed increased survival over control groups. The minimum effective dose for the ECT intratumour bleomycin group was 0.025 units. The minimum effective field strength was found to be 1250 V/cm. The results demonstrate that intratumoural injection of bleomycin in combination with electric pulses is effective, and this information will be used to initiate clinical trials.

Enhanced effects of multiple treatment electrochemotherapy.

Electrochemotherapy has been demonstrated to be an effective treatment for cutaneous cancers. The treatment includes administering a chemotherapeutic agent followed by electric pulses which are applied directly to the tumour. The pulses facilitate delivery of drug through the plasma membrane. Enhanced delivery is restricted to the area that has been electrically treated. Currently, electrochemotherapy is administered as a single treatment. Complete response rates are high; however, partial responses are obtained in a fraction of the treated tumours. An issue associated with this is whether or not multiple treatments would result in an improved therapy for these partially responding tumours. A multiple treatment electrochemotherapy study was implemented in order to address this issue. The study utilized subcutaneously induced murine B16 melanoma tumours in C57B1/6 mice. Results showed large tumour volume reductions in multiple treatment groups. In addition, a twofold increase in tumour doubling time and greater percentages of complete responses were found as a result of multiple treatment. These results will be utilized to augment existing clinical trials with respect to retreating tumours that have partially responded to a single electrochemotherapy treatment.

Bleomycin-mediated electrochemotherapy of basal cell carcinoma.

BACKGROUND: A new technique, electroporation, enhances the antitumor effects of a variety of chemotherapeutic agents. When used in combination with conventional chemotherapy, the procedure is termed electrochemotherapy. Exposure of cancerous tissues to pulses of electricity during electrochemotherapy appears to increase cell membrane permeability and thus intracellular access to cytotoxic drugs. Electrochemotherapy has been shown to have potent antitumor activity in a variety of in vitro studies, animal tumor models, as well as in clinical trials with squamous cell carcinomas of the head and neck. OBJECTIVE: The purpose of the study was to determine the effects of bleomycin-mediated electrochemotherapy on several basal cell carcinomas (BCCs) in two patients with nevoid BCC syndrome. METHODS: Electrical pulses were delivered to tumor nodules by means of caliper electrodes after systemic doses of bleomycin were administered. Vital signs were closely monitored during application of the electrical pulses. RESULTS: Partial responses were observed in tumors from both of the patients treated with electrochemotherapy; three partial responses were observed in one patient, and one partial response was observed in the other patient. Complete responses were seen in two lesions. Only minimal local or systemic side effects were noted in response to the therapy. CONCLUSION: To our knowledge, this is the first study that documents the effects of bleomycin-mediated electrochemotherapy on BCC. Studies are ongoing with intralesional bleomycin during electrochemotherapy to see whether additional antitumour effects can be produced in patients with BCC by this route of administration.