Dose-dependent Increase In Mortality Research Articles

In-Vitro Evaluation of Cytotoxicity and Antiinflammatory Potential of Hypnea Musciform (Rhodophyta) Collected from the Coastal Area of Karachi, Pakistan

Background: The extensive littoral zones of Karachi, Pakistan, are home to a diverse marine phytoplankton population, including the underutilized Hypnea musciformis. This red algae is an unexplored potential source of bioactive compounds for pharmacological use. Objective: This study aimed to evaluate the cytotoxicity and anti-inflammatory potential of the aqueous extract of Hypnea musciformis collected from the coastal areas of Karachi. Methods: Hypnea musciformis was collected from November 2019 to February 2021, with environmental parameters such as seawater temperature, pH, and salinity recorded. The collected samples were dried, powdered, and extracted in water. The cytotoxicity was assessed using a brine shrimp lethality test across a range of concentrations (1, 10, 100, and 1000 µg/ml), determining the LC50 value. Anti-inflammatory activity was evaluated via a membrane stabilization method on human red blood cells (HRBC), comparing the effects with the standard drug Diclofenac at concentrations ranging from 100 to 200 µg/ml. Results: The brine shrimp lethality assay showed a dose-dependent increase in mortality with the highest concentration exhibiting 83% mortality, yielding an LC50 value of 550 µg/ml. The anti-inflammatory assay demonstrated that the aqueous extract of Hypnea musciformis provided a concentration-dependent protection with a maximum protection percentage of 78.64% at 200 µg/ml, while the control substance, Diclofenac, displayed higher efficacy. Conclusion: The aqueous extract of Hypnea musciformis possesses significant cytotoxic and anti-inflammatory activities, suggesting its potential as a source of natural compounds for therapeutic purposes. However, further studies are required to elucidate the mechanisms of action and to confirm the safety and effectiveness of the extract in clinical applications.

Discordant Effects of Polyamine Depletion by DENSpm and DFMO on β-cell Cytokine Stress and Diabetes Outcomes in Mice.

Type 1 diabetes (T1D) is an autoimmune disease leading to dysfunction and loss of insulin-secreting β cells. In β cells, polyamines have been implicated in causing cellular stress and dysfunction. An inhibitor of polyamine biosynthesis, difluoromethylornithine (DFMO), has been shown to delay T1D in mouse models and preserve β-cell function in humans with recent-onset T1D. Another small molecule, N1,N11-diethylnorspermine (DENSpm), both inhibits polyamine biosynthesis and accelerates polyamine metabolism and is being tested for efficacy in cancer clinical trials. In this study, we show that DENSpm depletes intracellular polyamines as effectively as DFMO in mouse β cells. RNA-sequencing analysis, however, suggests that the cellular responses to DENSpm and DFMO differ, with both showing effects on cellular proliferation but the latter showing additional effects on mRNA translation and protein-folding pathways. In the low-dose streptozotocin-induced mouse model of T1D, DENSpm, unlike DFMO, did not prevent or delay diabetes outcomes but did result in improvements in glucose tolerance and reductions in islet oxidative stress. In nonobese diabetic (NOD) mice, short-term DENSpm administration resulted in a slight reduction in insulitis and proinflammatory Th1 cells in the pancreatic lymph nodes. Longer term treatment resulted in a dose-dependent increase in mortality. Notwithstanding the efficacy of both DFMO and DENSpm in reducing potentially toxic polyamine levels in β cells, our results highlight the discordant T1D outcomes that result from differing mechanisms of polyamine depletion and, more importantly, that toxic effects of DENSpm may limit its utility in T1D treatment.

COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

Co-prescribing of opioids and benzodiazepines/Z-drugs associated with all-cause mortality-A population-based longitudinal study in primary care with weak opioids most commonly prescribed.

Introduction: The risk of mortality associated with the co-prescribing of benzodiazepines and opioids has been explored in a number of papers mainly focusing on strong opioids. The mortality risk associated with the use of weak opioids has not been dealt with to a similar extent. Objective: To assess the mortality risk in primary care patients with consistent 3-year co-prescribing of benzodiazepine/Z-drugs (benzodiazepine receptor modulators) and mainly weak opioids (codeine, tramadol). Methods: Of 221,804 patients contacting the primary healthcare centres, 124,436 were selected for further analysis, 88,832 participants fulfilled the inclusion criteria, aged 10–69 years and were divided into four groups with neither any use of benzodiazepines/Z-drugs nor opioids as Group 1, 3 years’ use of opioids and no/minimal benzodiazepines/Z-drugs as Group 2, with benzodiazepines/Z-drugs and no/minimal opioids as Group 3, and finally both benzodiazepines/Z-drugs and opioids as Group 4. Hazard ratios were calculated with the no-drug group as a reference, using Cox proportional hazards regression model adjusted for age, sex, number of chronic conditions and cancer patients excluded (n = 87,314). Results: Hazard ratios for mortality increased both in Group 3 where it was 2.66 (95% CI 2.25–3.09) and in Group 4 where it was 5.12 (95% CI 4.25–6.17), with increased dose and higher number of chronic conditions. In Group 4 an opioid dose-dependent increase in mortality among persons using >1000 DDDs benzodiazepines/Z-drugs was observed when those on less than ≤300 DDDs of opioids with HR 4.94 (95% CI 3.54–6.88) were compared to those on >300 DDDs with HR 7.61/95% CI 6.08–9.55). This increase in mortality was not observed among patients on <1000 DDDs of benzodiazepines/Z-drugs. Conclusion: The study supports evidence suggesting that mortality increases in a dose-dependent manner in patients co-prescribed benzodiazepines/Z-drugs and weak opioids (codeine, tramadol). An association between the number of chronic conditions and a rise in mortality was found. Long-term use of these drugs should preferably be avoided. Non-pharmacological therapy should be seriously considered instead of long-term use of benzodiazepines/Z-drugs, and deprescribing implemented for chronic users of these drugs when possible.

Alkylation of Benz[a]anthracene Affects Toxicity to Early-Life Stage Zebrafish and In Vitro Aryl Hydrocarbon Receptor 2 Transactivation in a Position-Dependent Manner.

Polycyclic aromatic hydrocarbons (PAHs) are structurally diverse organic chemicals that can have adverse effects on the health of fishes through activation of aryl hydrocarbon receptor 2 (AhR2). They are ubiquitous in the environment, but alkyl PAHs are more abundant in some environmental matrices. However, relatively little is known regarding the effects of alkylation on the toxicity of PAHs to fishes in vivo and how this relates to potency for activation of AhR2 in vitro. Therefore, the objectives of the present study were to determine the toxicity of benz[a]anthracene and three alkylated homologs representing various alkylation positions to early life stages of zebrafish (Danio rerio) and to assess the potency of each for activation of the zebrafish AhR2 in a standardized in vitro AhR transactivation assay. Exposure of embryos to each of the PAHs caused a dose-dependent increase in mortality and malformations characteristic of AhR2 activation. Each alkyl homolog had in vivo toxicities and in vitro AhR2 activation potencies different from those of the parent PAH in a position-dependent manner. However, there was no statistically significant linear relationship between responses measured in these assays. The results suggest a need for further investigation into the effect of alkylation on the toxicity of PAHs to fishes and greater consideration of the contribution of alkylated homologs in ecological risk assessments. Environ Toxicol Chem 2022;41:1993-2002. © 2022 SETAC.

Morphological and Behavioral Effects in Zebrafish Embryos after Exposure to Smoke Dyes.

Solvent Violet 47 (SV47) and Disperse Blue 14 (DB14) are two anthraquinone dyes that were previously used in different formulations for the production of violet-colored smoke. Both dyes have shown potential for toxicity; however, there is no comprehensive understanding of their effects. Zebrafish embryos were exposed to SV47 or DB14 from 6 to 120 h post fertilization (hpf) to assess the dyes’ potential adverse effects on developing embryos. The potential ability of both dyes to cross the blood–brain barrier was also assessed. At concentrations between 0.55 and 5.23 mg/L, SV47 showed a dose-dependent increase in mortality, jaw malformation, axis curvature, and edemas. At concentrations between 0.15 and 7.54 mg/L, DB14 did not have this same dose-dependence but had similar morphological outcomes at the highest doses. Nevertheless, while SV47 showed significant mortality from 4.20 mg/L, there was no significant mortality on embryos exposed to DB14. Regardless, decreased locomotor movement was observed at all concentrations of DB14, suggesting an adverse neurodevelopmental effect. Overall, our results showed that at similar concentrations, SV47 and DB14 caused different types of phenotypic effects in zebrafish embryos.

Honeybee colonies compensate for pesticide-induced effects on royal jelly composition and brood survival with increased brood production

Sublethal doses of pesticides affect individual honeybees, but colony-level effects are less well understood and it is unclear how the two levels integrate. We studied the effect of the neonicotinoid pesticide clothianidin at field realistic concentrations on small colonies. We found that exposure to clothianidin affected worker jelly production of individual workers and created a strong dose-dependent increase in mortality of individual larvae, but strikingly the population size of capped brood remained stable. Thus, hives exhibited short-term resilience. Using a demographic matrix model, we found that the basis of resilience in dosed colonies was a substantive increase in brood initiation rate to compensate for increased brood mortality. However, computer simulation of full size colonies revealed that the increase in brood initiation led to severe reductions in colony reproduction (swarming) and long-term survival. This experiment reveals social regulatory mechanisms on colony-level that enable honeybees to partly compensate for effects on individual level.

The Association Between Secondhand Smoke Exposure and Survival for Patients With Heart Failure

The effect of secondhand tobacco smoke (SHS) exposure on patients with heart failure (HF) is uncertain. We investigated the association of mortality with SHS exposure for patients with HF. Nonsmokers with clinical HF were enrolled from 2003 to 2008 in a single-center longitudinal cohort study. The effect of SHS exposure determined by high-sensitivity urinary cotinine on mortality was estimated by multivariable proportional hazards modeling. Mortality was assessed after median 4.3 years. Of 202 patients, enrollment urinary cotinine levels were below the limit of detection for 106 (52%) considered unexposed to SHS. The median detectable cotinine was 0.47 ng/mL (interquartile range: [0.28, 1.28]). Participants were 41% female, 65 ± 17 years old, and 57% white race. Elevated cotinine was associated with increased mortality after multivariate adjustment: hazard ratio (HR) per 1 ng/mL increase in urinary cotinine: 1.15, 95% confidence interval (CI): 1.08-1.23, P < .001. Higher age (HR per 5-year increase: 1.32, 95% CI: 1.22-1.43, P < .001), male sex (HR vs female: 1.52, 95% CI: 1.02-2.28, P = .040), and New York Heart Association class (HR for class III vs I: 2.91, 95% CI: 1.71-4.99, P < .001) were also associated with mortality. SHS exposure is associated with a dose-dependent increase in mortality for patients with HF.

Developmental neurotoxicity of maneb: Notochord defects, mitochondrial dysfunction and hypoactivity in zebrafish (Danio rerio) embryos and larvae

Broad applications and exposure to the fungicide maneb can lead to toxicity in non-target organisms. Maneb is also associated with neurogenerative diseases such as Parkinson's disease (PD). The objectives of this study were to determine the acute toxicity of maneb to zebrafish by measuring mitochondrial bioenergetics, locomotor activity, and the expression of genes related to the oxidative damage response, as well as those related to dopamine signaling due to its association with PD. Zebrafish embryos at 6 h post-fertilization (hpf) were exposed to either solvent control (0.1% DMSO, v/v), or one dose of 0.1, 0.5, 1.0 and 10.0 µM maneb for 96 h. Maneb was moderately toxic to zebrafish embryos, and had a 96-h LC50 value of 4.29 μM (~ 1.14 mg/L). Maneb induced a dose-dependent increase in mortality, decreased hatching rate, and increased notochord deformity rate at both 1.0 and 10.0 µM after 72 and 96 h. Total body length was also significantly reduced with 1.0 µM maneb. A 50–60% decrease in mean basal oxygen consumption rate was also observed in embryos following a 24 hpf exposure to 10.0 µM maneb but oligomycin-induced ATP production and FCCP-induced maximum respiration remained unaffected. No change was detected in the expression levels of genes associated with oxidative stress (sod1 and sod2), nor those related to dopamine synthesis (th1), dopamine transporter (dat), dopamine receptors (drd1, drd2a, drd3, and drd4b). Thus, modifying the expression of these transcripts may not be a mechanism for maneb-induced developmental toxicity in zebrafish. To assess the potential for neurotoxicity, a dark photokinesis assay was conducted in larvae following 7 d exposure to 0.1, 0.5 and 1.0 μM maneb. Larvae exposed to 0.5 and 1.0 μM maneb showed signs related to hypoactivity, and this reduced activity is hypothesized to be associated with notochord defects as this deformity was prevalent at higher concentrations of maneb. Overall, these data demonstrate that maneb negatively affects embryonic development (i.e. notochord development), affects basal oxygen consumption rates of embryos, and induces hypoactivity in larval fish. This study improves understanding regarding the developmental neurotoxicity of the fungicide maneb to zebrafish.

Evaluation of Noxious Consequence of Bark Extract of Onosma echioides Linn Root: Hematology, Biochemistry, and Histopathological Findings

Onosma echioides is a perennial herb widely used for the treatment of various ailments such as sciatica, gout, and rheumatism. This study focused on toxicological assessment of bark extract of O. echioides root. In subacute toxicity study, 20 Sprague Dawley rats (140 ± 10 g body weight) were randomly grouped into two groups of 10 rats each (5 male and 5 female). Effect of the n-hexane extract of O. echioides (100 mg/kg body weight/day) was studied for a period of 28 days using control and treated groups. Effects of the extract on body weight, food consumption, water intake, serum glucose, and hematology, biochemistry, and histopathology were evaluated. The histopathology was carried out to evaluate the degenerative changes in liver, heart, and kidney. Result of acute toxicity study showed dose-dependent increase in mortality. LD50 was found to be 1,000 mg/kg body weight. The subacute toxicity data showed that the treated group did not show any change in behavior and urinalysis whereas an increase in body weight was observed in the male treated group. A significant but nontoxic effect was observed on food and water consumption. Significant increases in RBC (female treated group; **p < .01), neutrophil (both male and female treated group; **p < .01), MCV (female treated group, **p < .01), MCH (both male and female treated groups; **p < .01), and MCHC (both male and female treated groups; *p < .05) levels were observed; a significant changes were observed in total bilirubin (*p < .05), BUN (**p < .01), potassium (*p < .05), and ALT (**p < .01) levels. The relative organ weights of vital organs at this dose did not show any significant change. In conclusion, the toxicity data showed that the bark extract of O. echioides root does not possess any adverse effect at a fixed dose, which provides a support for its further safety study and biocompatibility application.

Neonatal and Maternal Temperature Regulation During and After Delivery.

An important goal of obstetric anesthesia is to provide for the safety and comfort of the mother as well as to optimize physiologic outcomes for the neonate. Markers of neonatal physiologic outcome include cord umbilical artery pH and Apgar scores. Neonatal temperature has often been overlooked by anesthesiologists as an important physiologic outcome measure, but it may be significantly affected by operating room conditions and obstetric anesthesia technique at cesarean delivery. There is a dose-dependent increase in mortality with decreasing body temperature as well as an increased likelihood for more severe early respiratory distress. Multiple neonate-focused strategies have been shown to decrease the incidence of neonatal hypothermia. Because fetal temperature is affected by maternal temperature, strategies to mitigate maternal hypothermia at the time of delivery may also be important in preventing neonatal hypothermia. This focused review will examine the importance of neonatal temperature and discuss its relationship to maternal temperature as well as strategies for maintaining neonatal normothermia after delivery.

Biocontrol of the oriental armyworm, Mythimna separata, by the tachinid fly Exorista civilis is synergized by Cry1Ab protoxin.

Tritrophic interactions between Mythimna separata, its tachinid parasite Exorista civilis and the Cry1Ab were examined. Although 6th instar M. separata mortality increased with increasing Cry1Ab concentration, some tolerance was evident. Likewise, parasitization by E. civilis resulted in only 18% host mortality. However, combination of Cry1Ab and E. civilis parasitization resulted in a significant Cry1Ab dose-dependent increase in mortality over that of either alone, including a 50–56% synergistic increase in efficacy at the two concentrations tested. Pupal weight, adult emergence and lifetime fecundity of M. separata derived from larvae surviving both agents were negatively affected. The ability of E. civilis to parasitize and subsequently develop on the host was not adversely influenced by Cry1Ab. Instead, pupation rate increased significantly among host larvae fed 3.125 μg/g Cry1Ab diet. Overall, our results demonstrate that use of Cry1Ab to control M. separata not only is compatible with the use of the tachinid parasitoid, but that the two methods can act synergistically to manage this destructive pest, provide support for the safety of transgenic Cry1Ab Bt plants in China. This example of two independent pest management strategies acting synergistically against a difficult pest offers a new perspective of broad significance in striving for agricultural sustainability.

Lagos lagoon sediment organic extracts and polycyclic aromatic hydrocarbons induce embryotoxic, teratogenic and genotoxic effects in Danio rerio (zebrafish) embryos.

An expansion of anthropogenic activity around Lagos lagoon, Nigeria, has raised concerns over increasing contaminants entering the lagoon’s ecosystem. The embryotoxicity, teratogenicity and genotoxicity of sediment organic extracts from four sampling zones around Lagos lagoon, Ilaje, Iddo, Atlas Cove and Apapa, as well as the dominant polycyclic aromatic hydrocarbons (PAHs) identified in water measured during the wet season (naphthalene, phenanthrene, pyrene, benzo[a]pyrene and a mixture of these), were assessed with Danio rerio embryos. Embryos were exposed to varying concentrations of toxicants from 0–72 h post-fertilization (hpf). Embryotoxicity at 72 hpf showed a dose-dependent increase in mortality upon exposure to extracts from all zones, except Atlas Cove. Similarly, higher levels of teratogenic effects, such as increased oedema, and haemorrhage and developmental abnormalities resulted from exposure to extracts from Ilaje, Iddo and Apapa zones. Treatment with single PAHs revealed that significant levels of detrimental effects were obtained only for phenanthrene. The modified comet assay revealed that the oxidative damage to DNA was generally low (<12 %) overall for all sediment extracts, but was significantly elevated with Ilaje and Iddo sediment extracts when compared with solvent controls. Oxidative damage was observed with the single PAHs, phenanthrene and benzo[a]pyrene, as well as with the PAH mixture. This study highlights that Lagos lagoon sediment extracts have teratogenic, embryotoxic and genotoxic properties, which are likely due to the high molecular weight PAHs present in the extracts, some of which are known or are suspected human carcinogens.

A model of acute kidney injury in mice with cirrhosis and infection.

Infectious acute kidney injury (AKI) is a life threatening complication of cirrhosis with limited therapeutic options. The aim of this study was to develop a model of infectious AKI in cirrhotic mice. Cirrhosis was established by intragastric administration of carbon tetrachloride (CCl4 ). Systemic haemodynamics was assessed invasively while cardiac function was assessed by echocardiography. AKI was induced using varying doses of lipopolysaccharide (LPS) titrated to produce 50% lethality. Renal function was assessed from serum creatinine and urine output (UOP). Renal injury was evaluated by urinalysis (proteinuria and casts) and renal histology. These mice were compared to: (i) normal mice, (ii) normal mice + LPS, and (iii) mice treated with CCl4 alone. Cirrhosis with increased cardiac output, decreased systemic vascular resistance, activation of renin-angiotensin-aldosterone axis developed after 12 weeks of CCl4 administration. LPS injection produced a dose-dependent increase in mortality (33% at 2 mg/kg vs. 80% at 6 mg/kg) without urine (casts or proteinuria) or histological evidence of tubular injury. 2 mg/kg LPS injection produced a rise in creatinine (0.79 ± 0.27 mg/dl in CCl4 +LPS compared to 0.45 ± 0.14 in CCl4 alone, P < 0.05) and a decrease in UOP (0.86 ± 0.4 ml/16 h in CCl4 + LPS compared to 1.70 ± 0.7 ml/16 h in CCl4 mice, P < 0.05). UOP remained low in mice that died while it recovered over 48-72 h in those that recovered. Control mice treated with 2 mg/kg LPS did not experience AKI. Cirrhotic CCl4 treated mice develop functional AKI and mimic most of the features of infectious AKI following LPS injection.

The effect of silver nanoparticles on zebrafish embryonic development and toxicology

The unique physical and chemical characteristics of nanomaterials, such as the effects of their small size, surface effects, very high rates of reaction, and quantum tunnel effect, have aroused great interest among scholars. However, improper usage has led to an increasing number of nanomaterials entering the environment through various channels, greatly threatening the security of the ecological environment and human health. The urgent need for a scientific assessment of their biosafety can enable nanomaterials to truly benefit humanity. However, the current research in this field is extremely limited with regard to safety standards and waste disposal. In this study, we used silver nanoparticles (nano-Ag) and zebrafish embryos as experimental subjects, and we have reported the deleterious effect on zebrafish embryos treated with different concentrations of nano-Ag, with respect to morphological features (mortality, deformity rate, and heartbeat) and the analysis of expression of relevant genes (sox17, gsc, ntl, otx2); we found a dose-dependent increase in mortality and hatching delay. The results of in situ hybridization indicated that nano-Ag causes a dose-dependent toxicity in embryonic development, and would affect their development and lead to deformity, delayed development, and even death. The safety limit for the concentration of nano-Ag was found to be less than 5 mg/L.

Spirulina platensis Lacks Antitumor Effect against Solid Ehrlich Carcinoma in Female Mice.

Spirulina is a blue-green alga used as a dietary supplement. It has been shown to possess anti-inflammatory, antioxidant, and hepatoprotective properties. This study was designed to evaluate the antitumor effect of spirulina (200 and 800 mg/kg) against a murine model of solid Ehrlich carcinoma compared to a standard chemotherapeutic drug, 5-fluorouracil (20 mg/kg). Untreated mice developed a palpable solid tumor after 13 days. Unlike fluorouracil, spirulina at the investigated two dose levels failed to exert any protective effect. In addition, spirulina did not potentiate the antitumor effect of fluorouracil when they were administered concurrently. Interestingly, their combined administration resulted in a dose-dependent increase in mortality. The present study demonstrates that spirulina lacks antitumor effect against this model of solid Ehrlich carcinoma and increased mortality when combined with fluorouracil. However, the implicated mechanism is still elusive.

Update on the Comparative Safety of Colloids

To provide an updated systematic review on the comparative safety of colloids based on recent clinical studies. Recent investigations, including large-scale randomized trials and meta-analyses, have sought to determine the effects of colloids on mortality and morbidity. Hypothesized differences in safety profile between hydroxyethyl starch (HES) solutions have also been evaluated in randomized trials. Clinical studies reported since 2002 with safety data for acutely ill patients receiving HES, gelatin, dextran, or albumin were sought by computer searches and other methods. Safety endpoints included mortality, morbidity, bleeding and impaired coagulation, and acute kidney injury (AKI). Data extracted from the included study reports were qualitatively summarized. Sixty-nine clinical studies were included. Of those, 42 were randomized controlled trials (RCTs) with 10,382 total patients. New safety data, since 2002, predominantly concerned albumin or HES. A large RCT of intensive care unit patients showed that albumin does not adversely affect survival. Acute kidney injury and a dose-dependent increase in mortality were observed in a large RCT of patients with severe sepsis or septic shock receiving HES. Impaired coagulation and clinical bleeding were frequently reported after HES infusion, especially in cardiac surgery. In head-to-head randomized comparisons of different HES solutions, observed effects on coagulation and renal function were similar. Gelatin showed less impairment of coagulation than HES. Very few safety data related to dextran were identified. Albumin displayed a more favorable safety profile than HES. Available evidence does not support the existence of consistent safety differences between HES solutions.

Development of a Combined Radiation and Burn Injury Model

Combined radiation and burn injuries are likely to occur after nuclear events, such as a meltdown accident at a nuclear energy plant or a nuclear attack. Little is known about the mechanisms by which combined injuries result in higher mortality than by either insult alone, and few animal models exist for combined radiation and burn injury. Herein, the authors developed a murine model of radiation and scald burn injury. Mice were given a single dose of 0, 2, 4, 5, 6, or 9 Gray (Gy) alone, followed by a 15% TBSA scald burn. All mice receiving ≤4 Gy of radiation with burn survived combined injury. Higher doses of radiation (5, 6, and 9 Gy) followed by scald injury had a dose-dependent increase in mortality (34, 67, and 100%, respectively). Five Gy was determined to be the ideal dose to use in conjunction with burn injury for this model. There was a decrease in circulating white blood cells in burn, irradiated, and combined injury (5 Gy and burn) mice by 48 hours postinjury compared with sham (49.7, 11.6, and 57.3%, respectively). Circulating interleukin-6 and tumor necrosis factor-α were increased in combined injury at 48 hours postinjury compared with all other treatment groups. Prolonged overproduction of proinflammatory cytokines could contribute to subsequent organ damage. Decreased leukocytes might exacerbate immune impairment and susceptibility to infections. Future studies will determine whether there are long lasting consequences of this early proinflammatory response and extended decrease in leukocytes.

Developmental Neurotoxicity of Pyrethroid Insecticides in Zebrafish Embryos

Pyrethroid insecticides are one of the most commonly used residential and agricultural insecticides. Based on the increased use of pyrethroids and recent studies showing that pregnant women and children are exposed to pyrethroids, there are concerns over the potential for developmental neurotoxicity. However, there have been relatively few studies on the developmental neurotoxicity of pyrethroids. In this study, we sought to investigate the developmental toxicity of six common pyrethroids, three type I compounds (permethrin, resmethrin, and bifenthrin) and three type II compounds (deltamethrin, cypermethrin, and lambda-cyhalothrin), and to determine whether zebrafish embryos may be an appropriate model for studying the developmental neurotoxicity of pyrethroids. Exposure of zebrafish embryos to pyrethroids caused a dose-dependent increase in mortality and pericardial edema, with type II compounds being the most potent. At doses approaching the LC(50), permethrin and deltamethrin caused craniofacial abnormalities. These findings are consistent with mammalian studies demonstrating that pyrethroids are mildly teratogenic at very high doses. However, at lower doses, body axis curvature and spasms were observed, which were reminiscent of the classic syndromes observed with pyrethroid toxicity. Treatment with diazepam ameliorated the spasms, while treatment with the sodium channel antagonist MS-222 ameliorated both spasms and body curvature, suggesting that pyrethroid-induced neurotoxicity is similar in zebrafish and mammals. Taken in concert, these data suggest that zebrafish may be an appropriate alternative model to study the mechanism(s) responsible for the developmental neurotoxicity of pyrethroid insecticides and aid in identification of compounds that should be further tested in mammalian systems.

Toxicity of dietary avidin and streptavidin to the cowpea bruchid, Callosobruchus maculatus (F.)

Avidin, a large protein from egg whites, powerfully binds biotin, a vitamin for many insects. When avidin was incorporated into the diets of larval Callosobruchus maculatus (F.), the cowpea bruchid, at relatively low levels (10–30 ppm), there was a marked dose-dependent increase in mortality, as well as a small increase in the developmental time of survivors. Avidin toxicity was prevented when biotin was added to the diet together with avidin. Sub-lethal doses of avidin caused reductions in fecundity. Avidin had no effect on the larval feeding rates during the first three instars, even when the larvae were consuming amounts of the protein that would later cause death. In the fourth instar there was a dose-dependent reduction in the rates of feeding as the avidin level in the food increased. Death of the C. maculatus larvae usually occurred at the pupal/adult stage still within the host seed. Streptavidin, a biotin-binding protein from a bacterial source, had effects similar to chicken egg avidin.