Evidence-based expert consensus on clinical management of safety of Bruton’s tyrosine kinase inhibitors(2024)

Bruton’s tyrosine kinase inhibitors(BTKis)have revolutionized the treatment of B-cell lymphomas.However,safety issues related to the use of BTKis may hinder treatment continuity and further affect clinical efficacy.A comprehensive and systematic expert consensus from a pharmacological perspective is lacking for safety issues associated with BTKi treatment.A multidisciplinary consensus working group was established,comprising 35 members from the fields of hematology,cardiovascular disease,cardio-oncology,clinical pharmacy,and evidencebased medicine.This evidence-based expert consensus was formulated using an evidence-based approach and the Delphi method.The Joanna Briggs Institute Critical Appraisal(JBI)tool and Grading of Recommendations Assessment,Development,and Evaluation(GRADE)approach were used to rate the quality of evidence and grade the strength of recommendations,respectively.This consensus provides practical recommendations for BTKis medication based on nine aspects within three domains,including the management of common adverse drug events such as bleeding,cardiovascular events,and hematological toxicity,as well as the management of drug-drug interactions and guidance for special populations.This multidisciplinary expert consensus could contribute to promoting a multi-dimensional,comprehensive and standardized management of BTKis.

Microplastic exposure disturbs sleep structure,reduces lifespan,and decreases ovary size in Drosophila melanogaster

The organ-specific toxicity resulting from microplastic(MP)exposure has been extensively explored,particularly concerning the gut,liver,testis,and lung.However,under natural conditions,these effects are not restricted to specific organs or tissues.Investigating whether MP exposure presents a systemic threat to an entire organism,impacting factors such as lifespan,sleep,and fecundity,is essential.In this study,we investigated the effects of dietary exposure to two different doses of MPs(1–5μm)using the terrestrial model organism Drosophila melanogaster.Results indicated that the particles caused gut damage and remained within the digestive system.Continuous MP exposure significantly shortened the lifespan of adult flies.Even short-term exposure disrupted sleep patterns,increasing the length of daytime sleep episodes.Additionally,one week of MP exposure reduced ovary size,with a trend towards decreased egg-laying in mated females.Although MPs did not penetrate the brain or ovaries,transcriptome analysis revealed altered gene expression in these tissues.In the ovary,Gene Ontology(GO)analysis indicated genotoxic effects impacting inflammation,circadian regulation,and metabolic processes,with significant impacts on extracellular structure-related pathways.In the brain,GO analysis identified changes in pathways associated with proteolysis and carbohydrate metabolism.Overall,this study provides compelling evidence of the systemic negative effects of MP exposure,highlighting the urgent need to address and mitigate environmental MP pollution.

Calcium Glucarate Prevents Tumor Formation in Mouse Skin

Objective Calcium Glucarate (Cag), Ca salt of D-glucaric acid is a naturally occurring non-toxic compound present in fruits, vegetables and seeds of some plants, and suppress tumor growth in different models. Due to lack of knowledge about its mode of action its uses are limited in cancer chemotherapy thus the objective of the study was to study the mechanism of action of Cag on mouse skin tumorigenesis. Methods We have estimated effect of Cag on DMBA induced mouse skin tumor development following complete carcinogenesis protocol. We measured, epidermal transglutaminase activity (TG), a marker of cell differentiation after DMBA and/or Cag treatment and [3H] thymidine incorporation into DNA as a marker for cell proliferation. Results Topical application of Cag suppressed the DMBA induced mouse skin tumor development. Topical application of Cag significantly modifies the critical events of proliferation and differentiation TG activity was found to be reduced after DMBA treatment. Reduction of the TG activ

Prognostic value of cortisol and thyroid function tests in poisoned patients admitted to toxicology ICU

BACKGROUND: Prognostic value of cortisol and thyroid function tests(TFTs) has previously been evaluated in medical ICUs. We aimed to evaluate prognostic efficacy of cortisol and TFTs in critically ill poisoned patients admitted to toxicology intensive care unit(ICU).METHODS: In a prospective study of consecutively enrolled subjects admitted to the toxicology ICU, lab analyses included TFTs(total T3 and T4 as well as TSH) and cortisol levels drawn between 8 am–10 am during period of the first 24 hours post-ingestion/exposure. Simplified Acute Physiology Score Ⅱ(SAPS Ⅱ) and Acute Physiology and Chronic Health Evaluation Ⅱ(APACHE Ⅱ) were recorded. All scores were compared to detect the best prognostic factor. Type of poisoning was also included.RESULTS: In 200 patients evaluated, 129 were male and mean age was 31 years. In general, SAPS Ⅱ, T4, and cortisol could prognosticate death. After regression analysis, only cortisol had such efficacy(P=0.04; OR=1.06; 95%CI=1.05–1.08; cut-off=42 μg/d L; sensitivity=70%; specificity=82%). Between aluminium phosphide(ALP)-and non ALP-poisoned patients, level of consciousness, mean arterial pressure, and cortisol level could prognosticate death in ALP poisoning(all Ps<0.001 in both uni and multivariate analyses). Median(interquartile range; IQR) GCS was 7(6, 10) and 15(8, 15) in non-ALP and ALP-poisoned patients(P<0.003). SAPS Ⅱ and APACHE Ⅱ could not prognosticate death at all.CONCLUSION: Cortisol best prognosticated outcomes for subjects admitted to the toxicology ICU. Its level is higher in ALP-poisoned patients probably due to the higher stress while they remain conscious till the final stages of toxicity and are aware of deterioration of their clinical condition or may be due to their significantly lower blood pressures.

Celecoxib enhances the detoxification of diethylnitrosamine in rat liver cancer

AIM： To study the effect of celecoxib （CXB） on diethylnitrosamine activation through the regulation of cytochrome P450 in a hepatocarcinogenesis model.METHODS： Six-week-old male Sprague-Dawley rats were randomly divided into five groups, a non-treated group （NT）, a diethylnitrosamine-treated group （DEN）, a DEN＋CXB-treated group （DEN＋CXB）,and CXB 8 d-treated and CXB 32 d-treated groups. The effects of celecoxib on the enzymatic activities of CYP1A1, 2A, 2B1/2, and 2E1 were assessed in hepatic microsomes 24 h after DEN administration.Changes in CYPIA1 and CYP2B1/2 protein expression were also evaluated. The rate of DEN metabolism was measured by the production of the deethylation metabolite acetaldehyde, and the denitrosation metabolite nitrite.RESULTS： DEN＋CXB administration produced a significant increase in the enzymatic activities ofCYP2B1/2 and 1A1, whereas it did not change the activities of CYP2A and 2E1, compared to that of the DEN group. CXB treatment for eight days did not produce a significant effect on enzymatic activity when compared to the NT group; however, when it was administered for prolonged times （CXB 32 d group）,the enzymatic activities were increased in a similar pattern to those in the DEN＋CXB group. The observed increase in the enzymatic activities in the DEN＋CXB group was accompanied by an increase in the CYP2B1/2 protein levels; no changes were observed in the levels of CYPIA1. In vitro, CXB increased the denitrosation of DEN, a pathway of metabolic detoxification. The addition of SKF-525A, a preferential inhibitor of CYP2B, abrogated the denitrosation of DEN.CONCLUSION： These results suggest that the mechanism of action of CXB involves enhancement of the detoxification of DEN by an increasing denitrosation via CYP2B1/2.

Abdominal pain related to adulterated opium:An emerging issue in drug addicts

Lead may contaminate opium,heroin and illicit opiates and is particularly observed in Iran.Lead,a natural heavy metal is able to interfere with several organ functions after ingestion or inhalation.Lead poisoning manifestations are non-specific and thus lead poisoning remains difficult to diagnose.Among the manifestations,abdominal pain is almost the most frequent symptom causing patients to seek medical care.In patients with a history of opium addiction presenting with moderate-to-severe abdominal pain,lack of diagnosis of lead toxicity may thus result in time-consuming and unnecessary medical work-ups that can end up in invasive surgery.This paper aims to briefly review abdominal pain as an emergency issue and the leading symptom of lead poisoning that brings most of the patients to healthcare facilities.All published adult cases and case series of opium addicts admitted with abdominal pain due to leadadulterated opium consumption have been reviewed.A trend of increasing numbers of lead poisoning cases has recently emerged among opium addicts in Iran.Due to the non-specific manifestations and hazardous effects,psychiatrists and emergency physicians should consider lead poisoning in patients with a past or present history of opium addiction referred for acute abdominal pain,particularly in case of colicky abdominal pain.

Effect of sample treatment on determination of arsenic （Ⅲ） and arsenic （Ⅴ） in aqueous and tissue samples by hydride generation atomic absorption spectrometry

The purpose of this procedure was to optimize and improve a method that used for the determination of arsenic （Ⅲ） and arsenic （Ⅴ） in biological and environmental samples. The method is based on hydride generation and atomic absorption spectrometry. For both As （Ⅲ） and As （Ⅴ） the parameters such as NaBH4, HCI concentration, and pH were optimized. Absorption signal of As （Ⅴ） was approximately 17% of As （Ⅲ） signal. Therefore, for estimation of As （Ⅲ） and As （Ⅴ） concentrations in various samples the difference between the absorbance obtained for arsenic, without and with previous treatment of samples with potassium iodide （KI）, can be applied. The calibration graphs were linear （r〉0.99）, and the detection limits of the method based on three times the standard deviation of the blank were 0.14 and 0.64 μL^-1 for As （Ⅲ） and As （Ⅴ）, respectively. The relative standard deviation （R.S.D.） of measurements was less than 10%. As a means of checking performance method, water samples were spiked with known concentrations of both As （Ⅲ） and As （Ⅴ）, and recovery above 94% was obtained. The proposed method was applied successfully to determine inorganic As （Ⅲ） and As （Ⅴ） in various environmental and total As in biological samples.

Severity of the metabolic syndrome as a predictor of prediabetes and type 2 diabetes in first degree relatives of type 2 diabetic patients:A 15-year prospective cohort study

BACKGROUND Type 2 diabetes mellitus(T2DM)has high morbidity and mortality worldwide,therefore there is of paramount importance to identify the risk factors in the populations at risk early in the course of illness.A strong correlation between severity of metabolic syndrome(MetS)and HbA1c,fasting insulin and insulin resistance has been reported.Accordingly,the MetS severity score(or MestS Zscore)can potentially be used to predict the risk of T2DM progression over time.AIM To evaluate the association the of MestS Z-score in first degree relatives(FDRs)of T2DM with the risk of prediabetes and type 2 diabetes in future.METHODS A prospective open cohort study was conducted between 2003-2018.At baseline,the sample comprised of 1766 FDRs of patients with T2DM who had a normal glucose tolerance test.Relative risk(RR)and 95%confidence interval were calculated based on logistic regression.The receiver-operator characteristic analysis and area under the curve based on MetS Z-score were used to evaluate the risk of prediabetes and diabetes among the FDR population.RESULTS Baseline MetS Z-scores were associated with the its latest values(P<0.0001).Compared with individuals who were T2DM free at the end of follow up,those who developed T2DM had higher MetS Z-score at baseline(P<0.001).In multivariable logistic regression analyses for every unit elevation in MetS Z-score at the baseline,the RR for developing future T2DM and prediabetes was(RR=1.94,RR=3.84),(RR=1.5,RR=2.17)in total population and female group,respectively(P<0.05).The associations remained significant after adjusting the potential confounding variables.A cut off value of 0.97 and 0.94 was defined in the receiver-operator characteristic curve based on the MetS Z-score for differentiating female patients with diabetes and prediabetes from the normal population,respectively.CONCLUSION The MetS Z-score was associated with an increased risk of future T2DM.Appropriate interventions at earlier stages for preventing and attenuating MetS effects may be considered as an effective strategy for FDR as at-risk population.

Liver-specific drug delivery platforms: Applications for the treatment of alcohol-associated liver disease

Alcohol-associated liver disease(ALD)is a common chronic liver disease and major contributor to liver disease-related deaths worldwide.Despite its prevalence,there are few effective pharmacological options for the severe stages of this disease.While much pre-clinical research attention is paid to drug development in ALD,many of these experimental therapeutics have limitations such as poor pharmacokinetics,poor efficacy,or off-target side effects due to systemic administration.One means of addressing these limitations is through liver-targeted drug delivery,which can be accomplished with different platforms including liposomes,polymeric nanoparticles,exosomes,bacteria,and adenoassociated viruses,among others.These platforms allow drugs to target the liver passively or actively,thereby reducing systemic circulation and increasing the‘effective dose’in the liver.While many studies,some clinical,have applied targeted delivery systems to other liver diseases such as viral hepatitis or hepatocellular carcinoma,only few have investigated their efficacy in ALD.This review provides basic information on these liver-targeting drug delivery platforms,including their benefits and limitations,and summarizes the current research efforts to apply them to the treatment of ALD in rodent models.We also discuss gaps in knowledge in the field,which when addressed,may help to increase the efficacy of novel therapies and better translate them to humans.

Trend of blood lactate level in acute aluminum phosphide poisoning

BACKGROUND: Aluminum phosphide(Al P) poisoning is common in the developing countries. There is no specifi c antidote for the treatment of acute Al P poisoning. Early diagnosis of poisoning and outcome predictors may facilitate treatment decisions. The objective of this study was to determine the trend of blood lactate level in acute Al P poisoning to evaluate its role as a prognostic factor.METHODS: This was a prospective study on acute Al P intoxicated patients during one year. Demographic data, clinical and laboratory data on admission, and outcome were recorded in a selfmade questionnaire. Blood lactate levels were analyzed every two hours for 24 hours.RESULTS: Thirty-nine(27 male, 12 female) patients were included in the study. The mortality rate was 38.5%. The mean blood pressure, pulse rate, blood p H and serum bicarbonate level were significantly different between the survivors and non-survivors groups. Blood lactate level was signifi cantly higher in the non-survivors group during 8 to 16 hours post ingestion.CONCLUSION: Blood lactate level could be used as an index of severity of acute Al P poisoning.

Ameliorating Effect and Potential Mechanism of Camellia Oil on Constipated Mice

Constipation is a global epidemic. To evaluate the ameliorating effect of camellia oil on constipation,two slowtransit costive mice models were established by water deprivation or sucralfate gavage. Administration of camellia oil（ 4. 0 and 8. 0 mL/kg/day） significantly shortened the defecation time,increased defecation mass and fecal water content,with efficacies comparable to that of hemp seed oil. Intestinal propulsion test showed that camellia oil significantly enhanced the propelling rates of the charcoal powder in the intestine. Meanwhile,camellia oil also significantly decreased the serum levels of nitric oxide（ NO）,nitric oxide synthase（ NOS） and vasoactive intestinal peptide（ VIP） and increased serum substance P in costive animals. These results suggested that camellia oil can largely relieve slowtransit constipation and enhance the gastrointestinal motility through modulation of serum gastrointestinal motility key factors such as NO,NOS and VIP and substance P.

The Distribution and Accretion of Some Heavy Metals in Makkah Wells

The aim of this study is to determine the types of heavy metals frequently present in Makkah wells and the possible environmental causes of their distribution and accumulation. Makkah lies in a mountain range dominated by different types of rocks from the Precambrian and Lower Paleozoic eras, as well as subordinate sedimentary rocks and basaltic lava flow from the Tertiary and Quaternary periods. Natural contaminants in Makkah wells water can be attributed to the unique location. Many epidemiological studies have identified associations between the ingestion of wells water contaminated with heavy metals and increased risk of some illnesses. This study presents exclusive information on the levels and distribution of 9 heavy metals—arsenic, barium, cadmium, chromium, cobalt, copper, lead, mercury, and selenium—in the wells water in various rural and urban areas of Makkah city. These naturally occurring elements are considered significant markers of water purity. More than 160 wells were involved in this three-year investigation. Water samples were collected during different seasons in order to assess any changes in the distribution and concentration of these heavy metals throughout the year. The collected water samples were filtered and digested before analysis using inductively coupled plasma mass spectrometry (ICP/MS). We found the following sequence of concentrations of heavy metals in the studied wells: Ba > Se >Cr > As > Co > Cu> Hg > Pb > Cd. Arsenic, barium, chromium, and selenium were the most abundant contaminants in the wells studied. The concentrations of the other heavy metals ranged from non-detectable to 3 μg/L. Although low, these values are also reported in comparisons with the local and international strict values and standards which govern the maximum contaminant levels permitted for long-term daily consumption.

Modeling Distribution of Selective Ions in Urban and Rural Areas Using Geographical Information System

The main objective of this study is to evaluate the distributions of selective ions in Makkah wells using GIS. The present study focuses on the presence and accumulation of several ions in the ground water of Makkah City. This study exhibits selected measurements of the levels and distribution of 4 ions (nitrate, nitrite, chloride and sulphate) in wells water using the Geographical Information System (GIS). The study covered 27 areas of Makkah City and its environs. Two layers were made using the Arc-Map program: the first layer was called internal wells (Central Makkah, urban) and the second layer was called external wells (rural). The total number of wells covered by this study was 145, and the samples were collected in different seasons. The samples were analyzed following standard procedures and compared with local and international standards. The results showed that the relative abundance of the major ions in the ground water was SO4 > Cl-1 > NO3 > NO2, with the presence of SO4 being dominant.

Chelation in Metal Intoxication XLVI:Synthesis of Someα-Mercapto-β-Substituted Aryl Acrylic Acids and TheirIn vitro Cadmium Chelating Ability

Objective To synthesize some new a-mercapto-β-substituted aryl acrylic acids, characterize them and investigate their in vitro cadmium chelating ability. Methods Six α-mercapto-β-substituted aryl acrylic acids were prepared by the alkaline hydrolysis of 5- (aryl methylene) rhodanines, obtained from the condensation of substituted aldehydes and rhodanine following the reported procedure. The new compounds were characterized by elemental analysis, infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy. The liver and kidney from cadmium chloride pre-administered rats were homogenized and their nuclear mitochondrial fraction (NMF) and supernatant cytosol fraction (SCF) were separated. A measured volume of each fraction was dialyzed separately using 'dialysis sack' against buffered-KCl medium containing a compound in the final concentration of 1×10-3 mol/L for 3 h at 37℃. The whole content of 'sack' was subjected to cadmium estimation following digestion with cone. Nitric acid was detected using flame atomic absorption spectrometer. Results The in vitro screening showed that α-mercapto-β-(p-methoxyphenyl) acrylic acid (compound 2) andα-mercapto-β-(m-methoxy, p-hydroxyphenyl) acrylic acid (compound 4) were more effective than α-mercapto-β-thienyl acrylic acid (compound 1) and a-mercapto-β-(p-dimethylaminophenyl) acrylic acid (compound 3) in mobilizing cadmium as their dialyzable chelates. The presence of a methoxy group on the phenyl moiety (compounds 2 and 4) increases the metal chelating ability of mercapto acrylic acids. Conclusions Compounds 2 and 4 seem to have accessibility to the cellular system and capability of chelating-out the intracellularly bound cadmium.

Proteomics analysis on hypolipidemic mechanisms of total phenylpropanoid glycosides from Ligustrum robustum(Roxb.) Blume in hamsters fed a high fat diet

OBJECTIVE To explore the hypolipidemic mechanisms of the total phenylpropanoid glycosides fromLigustrum robustum(Roxb.) Blume(LRTPG) in hamsters using proteomics technique.METHODS The hamsters were fed with a high fat diet to induce hyperlipidemia.Then LRTPG of high(1.2 g·kg^(-1)),medium(0.6 g·kg^(-1)) and low(0.3 g·kg^(-1)) doses were administrated daily for 4 weeks.Then the concentrations of plasma and hepatic lipids were determined using enzymic methods.The total protein was extracted from livers of the model group and the group treated with the high dose of LRTPG for label-free quantitative proteomics.RESULTS LRTPG significantly reduced the concentrations of plasma and hepatic lipids in hamsters fed a high fat diet.The proteomics data showed that a total of 2231 proteins were identified,and 549 proteins were found to be differentially expressed between the model group and the group treated with LRTPG.Among the 549 proteins,93 proteins were up-regulated and 59 proteins were down-regulated,and 397 proteins were absent or not.And some of these proteins were much related to the lipid metabolism.Further,gene ontology(GO) analysis indicated metabolic process,transport,oxidation-reduction process,phosphorylation,signal transduction,lipid metabolic process were the main biological processes that those differentially expressed proteins participated.KEGG pathway analysis showed that those proteins were involved in several metabolic pathways including oxidative phosphorylation,non-alcoholic fatty liver disease(NAFLD),PI3K-Akt signaling pathway,cAMP signaling pathway,cGMP-PKG signaling pathway.CONCLUSION The proteomics study could provide valuable clues to help us to understand the hypolipidemic mechanisms of LRTPG much better.

Aptamer-Based Extraction of Ergot Alkaloids from Ergot Contaminated Rye Feed

Ergot alkaloids are mycotoxins which can be found in food based on cereal-crops, due to a contamination of plants by fungi of the genus Claviceps. The ingestion of ergot contaminated cereal crops can lead to a severe poisoning known as ergotism. For food and feed safety purposes, the extraction of ergot alkaloids from ergot contaminated flour was investigated. For the specific recognition of ergot alkaloids, DNA aptamer ligands specially selected for ergot alkaloids were grafted onto silica gel in order to construct a specific solid phase extraction system. The aptamer-functionalized silica gels were used to extract ergot alkaloids from a contaminated rye feed sample. The presence of ergot alkaloids eluted from the aptamer-functionalized silica gels was analyzed using LC-QTOF-MS. By using this simple system, it was possible to specifically extract ergosine, ergokryptine and ergocornine from an ergot contaminated rye feed sample. This aptamer-based extraction tool shows the applicability of aptamers for the specific extraction of toxins or natural compounds from turbid matrices in a one-step procedure.

Inhibition of Hepatitis C Virus Genotype 1a Non-Structural Proteins by Small Interference RNA in Human Hepatoma Cell Lines

Hepatitis C virus (HCV) infection and associated liver diseases are still challenging and represent a significant health care burden around the world. Although, the treatment strategies have been improved by the development of novel direct-acting antivirals, but such therapeutic options are still expensive and beyond the financial range of the most infected individuals in developing or even in resource replete countries. It demands an urgent need to search novel and improved alternate treatment strategies to treat the infection. The present study was aimed to develop an in vitro stable cell culture system, persistently expressing HCV genotype 1a non-structural genes and to characterize the inhibitory effects of synthetic siRNAs (short interference RNA) directed against the most conserved regions of nonstructural genes in an in vitro cell culture model. The continuous expression of nonstructural genes for more than 30 days post transfection was detected by reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis in stable human hepatoma cell line (Huh-7). The gene expression studies revealed significantly reduced gene expression of HCV nonstructural genes (i.e., NS2, NS4A and NS5A) both at mRNA and protein levels when treated against genome specific synthetic siRNAs in stable cell lines (51%, 47% and 54% respectively, p < 0.05). Similarly, a vivid decrease in HCV viral titer was exhibited by synthetic siRNAs in an in vitro viral replicate cell culture model (58%, 48% and 50%, respectively, p < 0.05) determined by quantitative Real-Time PCR (qPCR). Our data indicate that siRNA mediated gene silencing may be considered a promising alternate treatment strategy against HCV in combination with other effective therapeutic regimens in future.

Retrieval and Amplification of DNA from Unstained Histopathological Sections

Testing of compounds for carcinogenic potential in vivo involves various experimental designs. A few of these techniques are directed to demonstrate the genotoxicity and mutagenicity of the compound by histopathology. These changes shown by histochemical means include monoclonal antibody directed cellular markers. Development of the polymerase chain reaction technique (PCR) for amplification of DNA has facilitated the investigation of molecular events related to the formation of malignant neoplasms. We describe here a method for screening tissues for mutations of the H-ras gene using monoclonal antibodies directed toward normal and mutant p21 proteins. Formalin-fixed, paraffin-embedded tissue sections are used to subsequently confirm the gene mutation by PCR amplification of the H-ras gene. The results indicated a successful application of this technique to demonstrate the presence of p21 oncoprotein in the tissues tested.

Association between Aspergillus flavus Colonization and Aflatoxins Production in Immature Grains of Maize Genotypes

Aspergillus flavus maize colonization leads to crop contamination by toxic secondary metabolites and carcinogens called aflatoxins （AF）; it has negative effects in public health and has caused economic losses in agricultural activities. Eleven genotypes of immature maize grain frequently used in Mexico were inoculated in vitro with two indigenous toxigenic strains ofA. flavus. The size of inoculum, temperature, humidity and presence of other phytopathogens were assessed. Genotypes Popcorn, C-526, Garst 8366, As910 and 30G40 showed resistance to rating of fungal colonization （FC） and AF accumulation, while 3002W, 30R39, Creole, C-922, HV313 and P3028W genotypes were less resistant. AFB~ had the highest concentrations （26.1 mg/kg ± 14.7 mg/kg）, while AFB2, AFG1 and AFG2 showed only residual concentrations 1.6, 2.0 and 4.0 ~tg/kg, respectively. Concerning FC and AF, there were significant differences （P 〈 0.01） between strains and genotype. Both strains showed significant association （P 〈 0.01） between FC and the concentrations of AFB1 and AFB2 （R2： 99.5% and 93.2%; 87.2% and 73.2%, respectively）. Results suggest that the level of resistance to fungus infection and AF accumulation is related to maize genotype. It emphasizes the relevance of developing A. flavus resistant maize genotypes as an alternative to control contamination in foodstuff intended for human and animal consumption.

16～20年前暴露于硫芥子气的伊朗退伍军人发生延迟性皮肤和免疫系统并发症

Background: Extensive cutaneous burns caused by alkylating chemical warfare agent sulfur mustard (SM) have been associated with the severe suppression of the immune system in humans. We aimed to study the association between late cutaneous and immunological complications of SM poisoning. Methods: Skin examination was performed on all SM-poisoned Iranian veterans in the province of Khorasan, Iran, who had significant clinical complications, and their SM intoxication was confirmed by toxicological analysis. Light microscopy was performed on eight skin biopsies. Blood cell counts, serum immunoglobulin and complement factor, as well as flow cytometric, analyses were performed on all the patients. The severity of cutaneous complications were classified into four grades and compared with hematological and immunological parameters, using Spearman’s rank correlation test. Results: Forty male subjects, confirmed with SM poisoning 16-20.years earlier, were studied. The main objective findings were hyperpigmentation (55%), dry skin (40%), multiple cherry angiomas (37.5%), atrophy (27.5%), and hypopigmentation (25%). Histopathologic findings were nonspecific and compatible with hyperpigmented old atrophic scars. Except for the hematocrit and C4 levels, hematological and immunological parameters revealed no significant correlation with the severity grades of cutaneous complications. Conclusion: Sulfur mustard is an alkylating agent with prolonged adverse effects on both the skin and the immune system. Allthough skin is a major transporting system for SM’s systemic absorption, there is probably no correlation between the severity of late cutaneous and immunological complications of SM poisoning.