Dehydration-responsive element-binding (DREB) transcription factors regulate diverse processes during plant development. Here, a 2-year field study was conducted to assess the potential effects of DREB-genetically modified maize (GM1) on arthropod species and ecological communities. Arthropod abundance, diversity, and community composition in GM1 and its non-transformed counterpart maize variety, Chang 7-2, were compared using whole plant inspection, pitfall trap, and suction sampler methods. Based on Shannon–Wiener diversity, Simpson’s diversity, Pielou’s indexes, number of species, and total number of individuals, GM1 had a negligible effect on arthropod abundance and diversity. Redundancy analysis indicated that the composition of arthropod community was not associated with maize type in the three investigation methods, while it exhibited significant correlation with year and sampling time in whole plant inspection and suction sample methods, and distinctly correlated with sampling time in the pitfall trap method. Nonmetric multidimensional scaling analysis of variable factors in the three investigation methods showed that sampling time, rather than maize type or year, was closely related to the composition of arthropod community in the field. Our results provide direct evidence to support that DREB-GM maize had negligible effects on arthropods in the Jilin Province under natural conditions. Furthermore, global warming has intensified the frequency of occurrence of drought, which, in recent years, has affected 2 × 10e yields .With the development of genetically modified crops, the safety of transgenic plants and their impact on biodiversity have become increasingly important for research . In ChinThe safety assessment of genetically modified maize needs to be conducted for a long-term study. Herein, we used three methods to evaluate the effects of GM1 on arthropods in 2016 and 2017 in a field study that aimed to evaluate whether genetically modified drought-resistant maize, GM1, had a significant impact on the diversity and composition of arthropods. Although many field and laboratory studies have confirmed that the effects of GM crops on arthropods were not significant , their iRhopalosiphum maidis and Monolepta hieroglyphica. Arthropods which were difficult to classify were identified to family level, such as Tenebrionidae and Formicidae. Through whole plant inspection, 2249 arthropods of 32 species and families in transgenic and 2130 of 33 species and families in non-transgenic maize (CK) were recorded over the 2-year experimental period. R. maidis and M. hieroglyphica accounted for 34.59% and 24.37%, and 33.24% and 24.98%, in transgenic and non-transgenic maize fields, respectively .In this study, arthropods that were easy to classify were identified to species level, such as ectively A. In turectively B. Finallectively C. FurtheH′), Simpson’s diversity index (D), number of species (S), Pielou’s evenness index (J), and the total number of individuals (N). Unequally spaced repeated-measures ANOVA results showed that maize type had no significant effect on H′, D, J, S, or N of arthropods, while sampling time did have a significant impact on all these parameters; however, the interactions between maize type and year, maize type and sampling time, and between maize type and year and sampling time did not influence any of them, regardless of sampling method. Furthermore, ANOVA showed that year had a significant impact on H′, D, and J, when investigated using whole plant inspection or pitfall trap, but only year influenced D and J significantly when the suction sampler method was used. The above results indicate that arthropods were affected by sampling time but not by maize type. Meanwhile, two critical arthropod groups with different feeding habits  were selected to analyze the difference of their abundance in order to verify the impact of maize types on biodiversity of critical groups, and the results show that the differences were not significant (p > 0.05). Specifically, genetically modified maize, GM1, did not influence arthropod abundance or diversity in the field  and year  were significantly correlated with the composition of the arthropod community, whereas maize type  was not correlated with it . With the whole-plant inspection method, maize type, year, and sampling time explained 36% of the total variation in the composition of the arthropod community. RDA also showed that both sampling time , whereas it was not influenced by maize type  or year   .p = 0.0020, F = 23.71, and 999 Monte Carlo permutations) and year  significantly correlated with arthropod community composition but not with maize type   .The arthropod community structures in transgenic and non-transgenic maize fields were further explored using non-metric multidimensional scaling analysis (nMDS). The distance between the two sampling points was estimated using the Bray–Curtis dissimilarity index. Differences in the composition of arthropod community among all animal samples were visualized in the nMDS plot. The samples collected in the nMDS plot were separated by sampling time but not by maize type or year , which wBiodiversity of arthropod communities is an important evaluation index for the safety of genetically modified crops. We present the analysis of the arthropod communities affected by the cultivation of the genetically modified drought-resistant maize cultivar, GM1. We provide basic safety data for the risk assessment associated to the commercialization of drought-resistant maize, GM1.Triticum aestivum L.) and genetically modified dehydration-responsive element-binding 3 (DREB3) drought-resistant soybeans have low potential weediness [Trichoderma, or Azotobacter in the rhizosphere of transgenic drought resistant soybean was not observed [Although GM crops have significantly improved crop quality and resistance, they have also sparked intense debate regarding their safety . With theediness ,27. A siobserved . In our In this study, the effects of genetically modified maize showed that sampling time and year were more related to the diversity and richness of arthropods than maize type. The results of Guo and Fan support this view ,18,40. FAnalysis of five parameters, including Shannon–Wiener, Pielou’s, Simpson’s indexes, number of species, and the total number of individuals, showed that GM1 had a negligible effect on arthropod abundance and diversity. Furthermore, RDA and nMDS of the variable factors in the three investigation methods indicated that the arthropod community composition was not associated with maize type. Moreover, the three arthropod investigation methods used in this study complemented each other to provide a more comprehensive collection of arthropods ,44,45. HThis field study evaluated the environmental safety of drought-resistant genetically modified maize, GM1, in Jilin in 2016 and 2017, when annual precipitation was normal (drought). Results revealed that the maize type had no impact on the diversity, abundance, or composition of the community of arthropods. Therefore, we concluded that planting drought-resistant genetically modified maize GM1 in Jilin Province will not adversely affect the environment.Genetically modified DREB maize (GM1) and its non-transformed counterpart (CK) were used in this study.Safety assessment trials were conducted in 2016 and 2017 at the Jilin Academy of Agricultural Sciences in Gongzhuling, Jilin Province, China .Jilin Province is a vital spring maize production region in China; however, Jilin is a rainfed agricultural area, in which various degrees of drought occur annually . In the Maize seeds were planted on 5 May in 2016 and 2017. Three replicate plots for each cultivar (GM1 and Chang 7-2 (CK)) were established in a completely randomized design ,39,40,47The Ministry of Agriculture Announcement No. 2122-10.4-2014 requires the use of whole plant inspection, pitfall trap, and suction samplers to evaluate the impact of biodiversity . The who2 around the plant. During the investigation, the number of active insects and spiders were counted.Arthropods were investigated every 7 d (depending on the weather) from day 10 after the final plant thinning to maturity. A five-spot sampling method was used to investigate the arthropods in each plot: one was located at the center of the plot, and the other four were located at the middle of the lines that connected the center of the plot and the plot corners. At each sampling spot, we randomly and gently turned over five maize plants one by one and quickly counted the visible arthropods on the plant surface and on the ground within 1 mArthropods were investigated every 10 d (depending on the weather) from day 10 after final thinning to maturity. A five-spot sampling method was used. Three pitfall traps with a spacing of 0.5 m were established at each sampling spot in every plot. For each trap, a plastic cup (15 cm in diameter × 10 cm in depth) was buried in the soil, with the upper rim of the cup level with the ground. Each cup was then placed in 5% detergent diluent (no more than 1/3 of the cup volume). Traps were exposed to the field for approximately 24 h, after which they were removed, and the trapped arthropods were collected and stored in 75% ethanol for species and number identification.2 of the plant were extracted with a suction sampler .The first investigation was conducted 15 days after final thinning of maize, and then it was repeated at the mid-whorl and late whorl stages, at the peak of the silking stage, and the late grain-filling stage. Arthropods were investigated five times in total using this method. A five-spot sampling method was used again in this case. At each sampling site, five maize plants were randomly selected, and the arthropods on the whole maize plant and on the ground within 1 mThe unknown species sampled by the above methods were collected and stored in a 5 mL plastic tube containing 75% alcohol and brought to the laboratory for identification under an insect anatomical lens .As a single method cannot comprehensively evaluate the arthropod community, it is necessary to use a combination of methods to obtain a more comprehensive understanding. Therefore, diversity indices , abundance indices, redundancy analysis (RDA), and nonmetric multidimensional scaling (nMDS) were used in this study.H′), Simpson’s diversity index (D), and Pielou’s index (J) were calculated as follows:iP is the proportion of individuals belonging to the ith taxon in a single plot.iN is the individual number in the ith taxon in one plot, and N is the total number of animals in one plot.S is the genus number of the collected arthropods in one plot.Arthropod diversity and abundance were analyzed using the Data Processing System . The Shannon–Wiener index .According to Guo’s research in 2016 ,18, thisMaize variety did not influence arthropod abundance, diversity, or community composition over 2 consecutive years of study in the field. Further, RDA indicated that maize variety did not significantly affect arthropod community composition. These results strongly suggest that the cultivation of DREB-GM maize does not affect the arthropod community. However, considering the limitations of time and area of influence inherent to this study, long-term field experimentation in a larger area is necessary to guarantee the environmental and ecological safety of genetically modified crop plants.


Malassezia spp., along with the good response to antifungal agents, indicate the role of fungi in its pathophysiology. Sertaconazole nitrate is a relatively new imidazole antifungal agent with a particular structure, consisting in a benzothiophene ring similar to the indole ring of tryptophan, and it acts mainly through the inhibition of ergosterol synthesis and the formation of pores in the fungal cell membrane. The aim of our study was to evaluate the efficiency of sertaconazole 2% cream compared with other topical treatments in patients with SD. We performed an extensive literature search by browsing the PubMed database with the keyword combination “sertaconazole AND seborrheic dermatitis AND clinical trial”, which retrieved eight controlled clinical trials evaluating the effects of sertaconazole in SD. All of the clinical trials included a standard scoring index (SI). At 28 days since the beginning of the treatment, the sertaconazole regimen was associated with a significantly higher percentage of patients with mild SI and a lower percentage of patients with moderate or severe SI (odds ratio 0.51) than the other investigated treatments—hydrocortisone, ketoconazole, clotrimazole, metronidazole, pimecrolimus, and tacrolimus (odds ratio 1.95). In conclusion, treatment with sertaconazole 2% cream may represent an efficient alternative therapy for patients with SD.Seborrheic dermatitis (SD) is a relapsing inflammatory skin disorder that affects the seborrheic areas of the body. Its etiology is not completely elucidated; however, the link between disease exacerbations and the proliferation of  Seborrheic dermatitis (SD) is a chronic, recurrent inflammatory condition that affects approximately 1–3% of individuals worldwide. Its pathogenesis involves an interplay between several factors, such as genetic predisposition, altered skin barrier, excessive secretion of sebaceous glands, skin microbiome, and immune response . A systeMalassezia spp. The genus Malassezia belongs to the phylum Basidiomycota and includes 17 species. Malassezia spp. normally colonize the skin of healthy individuals, but under appropriate conditions, the yeasts have the ability to invade the stratum corneum and can interact directly or indirectly with keratinocytes, melanocytes, and immune cells in the epidermis [Malassezia have been isolated from human skin [M. globosa and M. restricta were most commonly isolated from patients with SD [Malassezia spp. develop favorably in hair follicle and sebum-rich areas of the body [A special role in the pathogenesis of seborrheic dermatitis is attributed to pidermis . Louis-Cpidermis . Eight sman skin . M. glob with SD . Malassethe body .Malassezia spp. [Malassezia spp. are lipophilic yeasts able to secrete lipases that lead to the formation of fatty acids, such as oleic acid and arachidonic acid, and lipid peroxides that generate an inflammatory response, epidermal proliferation, and disruption of the skin barrier [Malassezia spp. promote dendritic cell maturation and stimulate Th2 cells, inducing the activation of numerous inflammatory pathways and the release of a plethora of proinflammatory cytokines. Alteration of keratins 1, 10, and 11 and ceramides, which are important epidermal structural components, was also highlighted in SD [Malassezia furfur isolated from SD lesions produced significantly more bioactive indolic substances compared with strains isolated from the healthy skin [Alterations of the skin barrier function in individuals with a genetic predisposition, along with sebum composition abnormalities, create a suitable environment for the overgrowth of zia spp. . Malasse barrier . Malasseed in SD . Data frthy skin .Malassezia does not correlate with the severity of the disease. The alteration of bacterial diversity seems to be a better predictor [Malassezia through the hydrolysis of sebum, and in this way the required nutrients for fungal growth are provided. Thus, a predominance of Acinetobacter, Staphylococcus, and Streptococcus spp. on lesional skin was observed [Cutibacterium spp. was identified, demonstrating the role of this microorganism in maintaining a balance between microbial communities [Candida and Aspergillus are also overexpressed in patients with SD [However, the level of redictor . The skiobserved . In patimunities . Recent  with SD .Malassezia yeasts in the occurrence of SD is supported by the effectiveness of antifungal treatments and by the decrease in Malassezia cell amount in patients who experience symptom relief [The role of m relief . Sertacom relief . We condhttps://pubmed.ncbi.nlm.nih.gov accessed on 23 June 2022) with a specific combination of search terms: “Sertaconazole AND seborrheic dermatitis AND clinical trial”. This search retrieved 11 results, supplemented with another two papers retrieved by searching the “Similar articles” section displayed in PubMed when accessing a search hit. From this initial group of publications, we excluded two review papers, one paper addressing the pharmacokinetics and side effects of different sertaconazole nitrate formulations, and in the eligibility assessment phase, one paper that did not report adequate quantitative data, such as the scoring index (SI) assessment of treatment effects, as recommended by Koca et al. [We performed a web-based search of the PubMed medical literature database  Version 5.4.1, The Cochrane Collaboration, 2020 . SubsequFor the eight studies finally included in the meta-analysis, listed in The dynamics of the percentages of patients included in the mild SI groups at different moments of time , illustrated in 2 value of 18.20 (p = 0.01), and the overall effect yielded a z of 4.12 (p < 0.0001). 2 value was 18.20 (p = 0.01) and the overall effect featured a z of 4.12 (p < 0.0001). Complementary, the cumulated frequency of moderate or severe SI in the sertaconazole vs. other treatments groups , and the overall effect a z of 6.30 (p < 0.00001).Seborrheic dermatitis is a chronic inflammatory disease with a pathogenesis closely related to the abnormal proliferation of fungi on the skin . Thus, aSertaconazole nitrate is a relatively new imidazole antifungal agent with a particular structure, consisting of a benzothiophene ring similar to the indole ring of tryptophan . It exhiLiebel et al. showed that sertaconazole inhibits the release of pro-inflammatory cytokines from activated lymphocytes in animal models of irritant contact dermatitis. Compared with other antifungal agents, the best anti-inflammatory effect was observed for sertaconazole. Only fluconazole and sertaconazole inhibited neurogenic inflammation, suggesting the possible role of these antifungal agents in the relief of itching . In addiElewski et al. conducted an open-label study that evaluated sertaconazole nitrate 2% cream in SD patients, and showed that it was effective with a good safety profile and improved scaling, erythema, induration, and pruritus . Our metAll studies included in the present meta-analysis evaluated the severity of the disease by the Scoring Index (SI), as recommended by Koca et al. The score is based on the evaluation of erythema, desquamation, itching, and irritation of each area, which is graded from zero to three . The sum of the scores was considered as the SD rank (classified into three ranges: mild (0–4), moderate (5–8), and severe (9–12)). At 14 days since the beginning of the treatment, no significant differences were observed between patients treated with sertaconazole and those treated with other topical treatments. At 28 days since the beginning of the treatment, the sertaconazole regimen was associated with a significantly higher percentage of patients with mild SI and a lower percentage of patients with moderate or severe SI (odds ratio 0.51) than the other investigated topical treatments (odds ratio 1.95).This research has some limitations. The number of studies analyzed was small and the studies included reduced numbers of patients. In addition, none of the studies followed up the patients for more than one month; therefore, the data on relapses are inconclusive. Medium-/long-term studies are needed to establish if the disease-free interval is greater with one drug than with another.The presented studies support the effectiveness of sertaconazole in SD therapy. Sertaconazole treatment was associated with a high level of satisfaction 28 days after the initiation of therapy. Additional studies including larger numbers of patients are needed to validate these results.


Schizophrenia is the subject of many studies. There have been reports of taste disturbances in mental disorders. We found a possible relationship between deficit symptoms of schizophrenia and the dysgeusia of monosodium glutamate (MSG). Dysgeusia is a disorder that distorts the sense of taste. People describe all foods as tasting sweet, sour, bitter, or metallic. We aimed to verify whether the level of MSG taste perception may be related to the severity of deficit symptoms. MSG detection threshold was assessed via sublingual administration of three fluid samples containing MSG or water. The MSG samples had different concentrations in each sample. The task was to indicate which of the samples contained MSG, determine the intensity of the taste, and assess the taste as pleasant, unpleasant, or neutral. The study group included 200 patients diagnosed with paranoid schizophrenia according to ICD-10. We found a significant negative correlation between mean intensity of taste and the number of deficit symptoms. The symptoms of taste disturbances reported by the patient should be monitored by clinicians and differentiated between the actual deficits in the field of taste perception and the taste hallucinations as a symptom of psychosis. It is important to continue research in this area. Schizophrenia is a chronic mental illness with periods of exacerbation and remission. As shown in the studies from the last half-century, it occurs globally with a similar frequency . Using pThe disease manifests itself via in the presence of positive symptoms, for example, delusions and hallucinations, which result in incorrect interpretation of reality, negative symptoms, for example apathy, disturbance, or lack of social functioning, impaired motivation, and reduction in spontaneous speech. There may be cognitive impairment, for example, difficulty concentrating or problems with working memory, ,5,6,7. GMale patients also exhibit greater manifestation of negative symptoms, not only concerning affective bluntness, apathy, impaired activity, or social isolation , but alsCurrently, second-generation antipsychotics (SGA) are recommended for the treatment of schizophrenia ,20, and Patients with schizophrenia frequently report numerous comorbid conditions. These include mental disorders such as depressive disorders, generalized anxiety disorder, panic disorder, or obsessive-compulsive disorder, but also somatic diseases, including cardiovascular and obstetric complications in women, hyperlipidemia, diabetes, sexual dysfunction, or osteoporosis. The presence of comorbidities may complicate the course of schizophrenia, while also affecting administered pharmacotherapy, resulting in side effects or various adverse interactions . AdverseThere is a growing body of evidence that schizophrenia is a heterogenous diagnostic construct in terms of clinical manifestation and outcomes. Studies investigating this heterogeneity have demonstrated the existence of the deficit subtype of schizophrenia characterized by occurrence of primary and persistent negative symptoms. Given its genetic underpinnings, it is considered to be one of the endophenotypes of schizophrenia . The preOn the other hand, postmortem studies have demonstrated an increased density of interstitial white matter cells in their temporal and frontal cortex as compared to healthy subjects ,32. In tIn a study using the neurovisceral integration model of fear (NVI-f), patients with more severe negative symptoms had greater difficulty in the fear conditioning in the interpersonal condition. It is believed that the fear conditioning process involves the hippocampus, amygdala, and medial prefrontal cortex, and damage to these areas of the brain may be associated with persistent negative symptoms (after the first episode of psychosis), due to reduced volume of the right hippocampus, the left amygdala, and white and gray matter in the frontal cortex. Thus, these structural abnormalities are believed to be related to the failure of fear conditioning in people with schizophrenia .It is also known that the anterior cingulate cortex (ACC) is an area in the brain that regulates cognitive control. It has been found to be involved in conflict monitoring, error monitoring, attention control, and detection ,38,39,40As suggested by other reports, the ACC is an important node of the salience network (SN), responsible for identification of stimuli from the environment, as well as default-mode networks and control cognitive processes in the central executive control system ,47,48. BRecent reports also emphasize the potential role of mitochondrial dysfunction in a number of neurodegenerative and mental diseases such as Parkinson’s diseases, Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis or Friedreich’s ataxia , or psycOf note, neurodegenerative diseases (NDDs), including schizophrenia, are characterized by impairments in social interaction and cognitive function. These alterations in social functioning and cognitive performance are attributable to altered activity within subcortical and cortical brain structures , which sResearchers highlight the role of γ-aminobutyric acid (GABA), glutamate, and dopamine, implicated both in the pathogenesis of schizophrenia and the olfactory processes ,76. In tWhile there is evidence of smell perception deficits in patients with schizophrenia, there is a paucity of studies on dysgeusia in those with its deficit form. In his work, Faurion (1991) proposed that the receptors involved in monosodium glutamate (MSG) taste detection in the mouth may be identical to the glutamatergic receptors in the brain, which may be related to the taste sensation of MSG . The tasn = 102 and n = 98, respectively). The inclusion criteria were age 18–60 years, and clinical diagnosis of paranoid schizophrenia according to the International Statistical Classification of Diseases and Related Health Problems (ICD-10) criteria for at least 18 months. Each patient was examined by licensed psychiatrists during hospitalization in the Department of Psychiatry of Pomeranian Medical. Diagnosis included interview, clinical observation, PANSS score, and analyses of past medical documentation.The sample included 200 unrelated women and men of Polish origin diagnosed with paranoid schizophrenia , dementia or significant organic brain damage, epilepsy, addiction to alcohol or other psychoactive substances, poor general health . The adopted criteria were to enable the most precise selection of patients with paranoid schizophrenia, whose diagnosis was made following a detailed psychiatric examination, based on the ICD-10 criteria .The patient was to refrain from smoking, consuming food, and fluids for at least one hour prior to the taste assessment. The MSG detection threshold was assessed via sublingual administration of three fluid samples , containing MSG (one sample) or water (two samples). The MSG samples had different concentrations in each triplet. Prior to the assessment and after each triplet, the patient was to rinse their mouth with water (Aqua pro injection). Assessment results were marked on a separate answer sheet. The task was to: (i) indicate which one of the three samples contained MSG—the patient’s response was recorded by the doctor on the answer sheet; (ii) determine the intensity of the taste on a scale from 0 to 100 points measured in mm (1 mm = 1 point)—the patient made an assessment on their own in the presence of the doctor; and iii) assess the taste as pleasant, unpleasant, or neutral. Pleasant tastes were to be marked on a scale from 0 to 50 points (mm), unpleasant tastes on a scale from 0 to minus 50 points, while the neutral ones were to be marked with 0—the patient made an assessment on their own in the presence of the doctor. In the experiment, we used seven triplets. In triplet 1, the first sample contained MSG at a concentration of 0.001%, while the remaining two contained water. In triplet 2, the first two samples contained water, while the third one contained MSG at a concentration of 0.003%. Triplet 3 contained water in the first and third sample, and MSG at a concentration 0.01% in the second sample. Triplet 4 contained water in the first and third sample, and MSG at a concentration of 0.03% in the second sample. Triplet 5 contained water in the first two samples, while the third sample contained 0.1% MSG. Triplet 6 contained 0.3% MSG in the first sample, while the remaining two samples contained water. In the last triplet, there was water in the first and third sample, while the second sample contained MSG at a concentration of 1%. As shown, each subsequent triplet (1–7) contained increasing concentrations of MSG.MSG concentrations and locations in each triplet are presented in The diagnosis of paranoid schizophrenia was made after a detailed psychiatric examination, based on the ICD-10 criteria . The defSymptomatic severity was assessed with the use of the Positive and Negative Syndrome Scale (PANSS) ,92. ThisAll participants received pharmacological treatment in accordance with the current standards of care in schizophrenia ,20,93. Ap < 0.05. Data analysis was carried out using the Statistical Package for Social Sciences, version 20 .Descriptive statistics were presented as mean and standard deviation or the number of cases and percentage. Correlations between taste identification parameters  and psychopathological symptoms  were tested using Spearman rank correlation coefficients. In case of significant bivariate correlations, linear regression analysis was performed to control for the effects of age, sex, body mass index (BMI), cigarette smoking status, and chlorpromazine equivalent dosage. The level of significance was set at A standardized research tool (PANSS) was used to assess the course of the disease. The deficit type was distinguished using the SDS. Sociodemographic and clinical data  were collected with the use of self-designed questionnaires.n = 102 and n = 98, respectively). The study sample included 98 females (48%) and 102 males (52%), whose mean age was 39.9 years. 36 persons (18%) had higher education, 94 (47%) secondary education, 44 (22%) vocational education, and the remaining 26 (13%) elementary education. Mean BMI was 27.6. The place of residence of 185 participants was the city, while the remaining 15 resided in the country. 95 participants (47.5%) reported cigarette smoking. Mean disease duration was 13.6 years. As the participants received varied pharmacological treatment, all administered antipsychotic medications were converted into chlorpromazine equivalence (CPZE) with mean dosage of 820.5 mg/day. Symptom severity was assessed with the use of the PANSS, with mean positive symptom severity of 7.7, mean negative symptom severity of 12.6, and mean depressive symptom severity of 4.3. Mean SDS score was 4.7 points.The characteristics of the study sample are presented in the table below . The samDescriptive statistics of the sample and bivariate correlations between taste identification tests and psychopathological manifestation are shown in -p = 0.517 (Number of correctly recognized samples); r = −0.215, p = 0.002 (Mean intensity of taste); r = 0.004, p = 0.958 (Mean pleasure of taste)SDS scale—number of deficit symptoms: r = −0.046, -p = 0.491 (Number of correctly recognized samples); r = −0.022, p = 0.760 (Mean intensity of taste); r = −0.036, p = 0.616 (Mean pleasure of taste)PANSS scale—positive symptoms: r = −0.049, -p = 0.134 (Number of correctly recognized samples); r = −0.071, p = 0.322 (Mean intensity of taste); r = −0.020, p = 0.784 (Mean pleasure of taste)PANSS scale—negative symptoms: r = −0.106, -p = 0.896 (Number of correctly recognized samples); r = −0.029, p = 0.683 (Mean in-tensity of taste); r = −0.112, p = 0.114 (Mean pleasure of taste)PANSS scale—depressive symptoms: r = −0.009, In the conducted study, the following results were obtained:p = 0.005) after adjustment for age , sex , BMI , cigarette smoking status , and CPZE .There was a significant negative correlation between mean intensity of taste and the number of deficit symptoms . Other mCorrelations between taste perception and the number of deficit symptoms are presented graphically in Taste disturbances that may occur in people with schizophrenia are usually overlooked in everyday clinical practice. The senses, including the sense of taste, affect perception of the surrounding world, and their disturbances in schizophrenia manifest themselves in the form of auditory, olfactory, or gustatory hallucinations. A disturbed taste recognition or assessment of its intensity does not necessarily have to be related to a mental illness and constitute a psychopathological symptom. It may be a symptom of, e.g., damage of the brain structures responsible for its perception, the taste pathways, or damage of the taste buds themselves .In 1991, Faurion proposed that the receptors associated with MSG taste detection in the oral cavity may be identical to the glutamatergic receptors in the brain . TherefoThere is a relative scarcity of data on MSG taste detection. What is more, available evidence applies to healthy populations. In a study conducted on a healthy Romanian population, Iordachescu et al.  found thAs for clinical samples, literature data describe the perception of MSG taste in individuals with alcohol use disorders and patients with bulimia nervosa. In a study on patients with bulimia nervosa (BN), observed differences in neuronal activation of the brain after MSG administration were linked to a subjectively lower assessment of its solution in terms of both pleasure and liking of MSG compared to the control group. Functional magnetic resonance imaging (fMRI) showed greater activation of the right insula in the BN group versus the controls. Hence, BN patients exhibited not only an altered taste perception , but also an altered brain activity , thus explaining the disturbed eating behavior .n = 35) and compared against a control group (n = 25), demonstrating no significant differences [Another study considered responses to MSG in people with alcohol use disorders. The intensity and pleasure of MSG were assessed in a sample of chronic male alcoholics  would have to be taken into account, potentially affecting test results.In our study, we found a significant negative correlation between mean taste intensity and the number of deficit symptoms . Other mA significant negative correlation between mean intensity of taste and the number of deficit symptoms were present in this study. Other measures of taste identification  were not associated with the levels of psychopathological symptoms.Findings from the present study imply that deficit symptoms of schizophrenia might be associated with lower intensity of taste identification. Future studies need to further explore this observation taking into account limitations of the present study, which are described below. Longitudinal studies exploring a number of potential confounding factors and neural substrates are needed to provide additional insights into the association between altered taste identification and the deficit subtype of schizophrenia. There is no doubt that our results warrant further investigation, with an extended MSG concentration range, or on a test group with a parallel healthy control group. Extending the study sample could impact the overall results, including the number of correctly recognized samples and hedonic appraisal of the MSG taste.A research direction to consider would also be its replication in patients suffering from other schizophrenia dimensions. Performing the same protocol in a non-paranoid subtype of schizophrenia could lead to substantially different results.Additionally, what cannot be ignored is that the current study was cross-sectional and its results were not compared against a control group. Therefore, adding a control group could perhaps have a significant effect on the conclusions presented in this paper.The present study is characterized by certain limitations. First, we did not include healthy controls, and thus it is not possible to claim as to whether individuals with schizophrenia show deficits of taste identification. Second, there might be several latent confounding factors due to the fact that we did not record a number of potentially important clinical characteristics. These include duration and lifetime exposure to antipsychotics and other medications, as well as comorbid physical health impairments. Third, our sample may not be representative due to the fact that we did not record the initial number of patients approached for participation, as well as reasons of non-participation. Fourthly, patients recruited to the study received first and second generation antypsychotics (FGA and SGA) treatment, frequently at the same time. They were not divided into separate groups based on primary or add-on treatment . On the other hand, the assessment itself was performed at symptom remission, stable mental state, and the intake of target doses of drugs. Notwithstanding, taking medications from different groups could have had an effect on the outcomes, so we considered it amongst the limitations of this study. Fifthly, another limitation of the study was the smoking status of the participants. In order for this aspect to have as little impact on the outcomes as possible, each patient was to refrain from smoking (or consuming food or liquids) for at least one hour prior to taste assessment. Perhaps in the future, a group of non-smoking patients should be created. Sixthly, the study did not take into account whether the participants were in psychotherapy during the study. Considering this aspect, we cannot rule out that it could have an impact on the obtained results. It therefore seems that this should be considered as a limitation of our study and should be taken into account when designing similar studies in the future. Finally, a cross-sectional design does not allow for conclusions regarding causal associations.


NLR was significantly higher in postmenopausal women with osteoporosis . Our findings suggest the associations of NLR and PLR with osteoporosis. NLR and PLR constitute potential targets in osteoporosis screening.Osteoporosis is characterized by low bone mass and increased bone fragility. Numerous studies have suggested that inflammation contributes to its pathogenesis. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are simple, noninvasive biomarkers that can reflect the inflammation status on human body. However, evidence on their associations with osteoporosis remains scant. The PubMed, Embase, and Cochrane Library databases were searched for relevant studies from their inception to April 2022. Observational studies providing complete NLR or PLR data in both the osteoporosis and normal bone mineral density (BMD) groups were included. Studies involving individuals at risk of secondary osteoporosis or restricted to a certain disease population were excluded. The main outcome was the associations of NLR and PLR with osteoporosis. Between-group differences were measured using mean differences (MDs) and 95% confidence intervals (CIs). In our analysis, both NLR and PLR were significantly higher in the osteoporosis group (MD = 0.494, 95% CI: 0.339–0.649,  Osteoporosis is a metabolic skeletal disease characterized by reduced bone mass, increased bone fragility, and the microarchitectural deterioration of bone tissue, which result in susceptibility to fracture . OsteopoOsteoporosis is a multifactorial disease, which may be attributed to endocrine, metabolic, and mechanical factors. Risk factors for osteoporosis include older age, being female, estrogen deficiency, and long-term use of medications such as glucocorticoids . EmerginThe neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), the ratio of absolute neutrophil and platelet count to absolute lymphocyte count, are simple, cost-effective, and noninvasive biomarkers that can reflect the inflammation status on human body . SeveralConsidering the limited and inconclusive state of the literature, we performed a meta-analysis probing the differences in NLR and PLR between individuals with and without osteoporosis. We hypothesized that both NLR and PLR were higher in individuals with osteoporosis.This study was performed in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement (PRISMA) . The twoThe inclusion criteria were as follows: (1) published observational studies with full texts, (2) studies measuring BMD with validated methods such as dual energy X-ray absorptiometry and providing clear definition of osteoporosis (such as a T score of ≤−2.5 standard deviations), and (3) studies providing complete data on NLR or PLR in both the osteoporosis and normal BMD groups.The exclusion criteria were as follows: (1) studies including patients at risk of secondary osteoporosis (such as those with parathyroid diseases), (2) studies including patients with certain clinical conditions which may interfere with NLR or PLR values , (3) studies including patients restricted to a certain disease population, or (4) studies in which NLR or PLR data corresponding to the osteoporosis and normal BMD group were unavailable or incomplete.The two reviewers (Y.-C.L. and T.-I.Y.) independently identified potentially relevant studies, reviewed the full texts of the articles, and extracted baseline and outcome information from either the datasets or figures and tables. Extracted information included the author, country, published year, study design, sample size, sex distribution, mean age, methodology for the measurement of bone mineral density, prediction model for osteoporosis (NLR or PLR), and complete NLR or PLR data. For studies reporting NLR and PLR data as median with full range, a conversion into mean with standard deviation was conducted following a validated statistical method .The methodological quality of the included studies was assessed using a modified version of the Newcastle–Ottawa scale (NOS) , adaptedThe main outcome of interest was the associations of NLR and PLR with osteoporosis, evaluated by differences in NLR and PLR values between the osteoporosis and normal BMD groups. We performed subgroup analysis to furtherly determine the association of NLR with osteoporosis in postmenopausal population. Considering that age and diabetes mellitus (DM) are confounders of NLR value ,16, whicp value of < 0.05 indicated significance. The random-effect model was selected for analysis. Heterogeneity among the included studies was examined using the standard chi-square test and I2 test; significance was set at p < 0.05 for standard chi-square test. Publication bias was evaluated using a funnel plot and through Egger’s test.For meta-analysis, the data were analyzed using Comprehensive Meta-Analysis Software . Differences in NLR and PLR between the osteoporosis and normal BMD groups were estimated using mean differences (MDs) and 95% confidence intervals (CIs); a The methodological quality of the included studies was assessed using the modified NOS, with results shown in p  <  0.0001; I2: 46%, p = 0.055; As mentioned, all included studies provided data on NLR in both the osteoporosis and normal BMD groups. Our analysis showed that NLR was significantly higher in the osteoporosis group than in the normal BMD group (MD = 0.494, 95% CI: 0.339–0.649, p <  0.0001; I2: 0%, p = 0.497; In subgroup analysis, we furtherly analyzed the difference in NLR between the osteoporosis and normal BMD groups in postmenopausal women. Six of the included studies provided NLR data in both groups and involved postmenopausal women only ,21,25,26p = 0.478; regression coefficient = −0.1417, p = 0.444, respectively; We performed meta regression to evaluate the potential confounding effects of age and the inclusion of DM patients on the between-group differences in NLR. The mean age of the enrolled individuals in the included studies ranged from 54.2 to 74.9 years. Four of the studies excluded individuals with DM ,22,24,25p = 0.014; I2: 79%, p =  0.001; Five of the included studies provided PLR data in both the osteoporosis and normal BMD groups ,19,21,22We evaluated publication bias in analyses involving five or more studies. Funnel plots of all the examined analyses were shown in In the present study, our analysis showed that both NLR and PLR were higher in individuals with osteoporosis compared to those with normal BMD. In the subgroup analysis of postmenopausal population, NLR was significantly higher in postmenopausal women with osteoporosis. Through meta regression, we found that the differences in NLR between the osteoporosis and normal BMD groups would not be affected by age and the inclusion of patients with DM. To the best of our knowledge, this is currently the first and the most extensive study investigating the associations of NLR and PLR with osteoporosis. Our findings support our hypothesis, demonstrating the link between these two inflammatory biomarkers and osteoporosis.The concept that inflammation may contribute to the pathogenesis of osteoporosis has been proposed in recent years ,27. The Another possible interpretation can be given for the higher NLR and PLR of individuals with osteoporosis; that is, osteoporosis may result in higher NLR and PLR values because of its association with impaired hematopoiesis and an unbalanced decline in myeloid and lymphoid cells ,34. Two In our study, we investigated the difference in NLR between individuals with and without osteoporosis in postmenopausal population; NLR was significantly higher in postmenopausal women with osteoporosis. In addition, we conducted meta regression to examine whether age and the inclusion of patients with DM would affect the differences in NLR between the osteoporosis and normal BMD groups. Both age and DM have been reported to be confounding factors of NLR value ,16; oldeIn our analyses of NLR, heterogeneity among the analyzed studies was generally nonsignificant, suggesting the strong association between NLR and osteoporosis. However, significant heterogeneity was detected in our analysis of PLR. Due to the small number of analyzed studies, we failed to find possible explanations for the high heterogeneity through subgroup analysis or other approaches. In our opinion, the heterogeneity may be attributed to the between-study variations, such as inclusion/ exclusion criteria and enrolled patients’ baseline characteristics or comorbidities. Furthermore, we performed mathematical conversion to obtain adequate PLR data for outcome pooling for some studies, which may also affect the results, and thereby the heterogeneity.Some limitations of our study need to be addressed. Firstly, as mentioned, the number of the included studies investigating the association of PLR with osteoporosis is small, which makes our findings regarding PLR less conclusive and comprehensive. Secondly, although we have provided possible explanations for the increase of NLR and PLR in patients with osteoporosis, no causal relationships between them can be established because of the cross-sectional design of all included studies. Thirdly, due to insufficient data, we could not identify cutoff values of NLR and PLR with acceptable sensitivity and specificity for predicting osteoporosis; considering the easy accessibility of these two biomarkers, this may be a future research direction since clinicians may start early interventions, such as lifestyle modifications, for those at higher risk of osteoporosis, based on their NLR or PLR values.Both NLR and PLR are higher in individuals with osteoporosis in comparison to those with normal BMD, which suggests the associations of these two inflammatory biomarkers with osteoporosis. Further research is warranted to elucidate the roles of NLR and PLR as predictors of osteoporosis, as well as to identify their applicability to osteoporosis screening in clinical practice.


Background: Cyclophosphamide (CP) (Cytoxan or Endoxan) is an efficient anti-tumor agent, widely used for the treatment of various neoplastic diseases. The study aimed to investigate the protective role of vitamin E (vit E) in improving cardiotoxicity in rats induced by CP. Materials and methods: Forty male Wistar rats were divided randomly into four experimental groups (each consisting of ten rats); the control group was treated with saline. The other three groups were treated with vit E, CP, and the combination of vit E and CP. Serum lipid profiles, enzyme cardiac biomarkers, and cardiac tissue antioxidants were evaluated, as well as histological and ultrastructure investigations. Results: CP-treated rats showed a significant increase in serum levels of cardiac markers , lipid profiles, a reduction in the antioxidant enzyme activities , and an elevation in the level of lipid peroxidation (LPO). The increase in the levels of troponin, LDH, AST, ALP, and triglycerides is a predominant indicator of cardiac damage due to the toxic effect of CP. The biochemical changes parallel cardiac injuries such as myocardial infarction, myocarditis, and heart failure. Vitamin E played a pivotal role, as it attenuated most of these changes because of its ability to scavenge free radicals and reduce LPO. In addition, vit E was found to improve the histopathological alterations caused by CP where no evidence of damage was observed in the cardiac architecture, and the cardiac fibers had regained their normal structure with minimal hemorrhage. Conclusions: As a result of its antioxidant activity and its stabilizing impact on the cardiomyocyte membranes, vit E is recommended as a potential candidate in decreasing the damaging effects of CP. Chemotherapy is one of the most successful ways to treat cancer, but most people who take it experience varying degrees of its side effects, which include the possibility of DNA damage and inflammation in healthy cells ,2. DespiCP was found to cause acute cardiac damage, including necrosis, hemorrhage, and fibrosis, as well as severe inflammation . Additio2O2), and molecular oxygen, which is then removed by GPx and CAT and it converts lipid hydroperoxides to non-toxic alcohols. CAT catalyzes the breakdown of toxic H2O2 into water and oxygen [Free radical scavenging enzymes are the first line of cellular defense against the toxic effects of ROS then, the nonenzymatic , such asd oxygen , while tNatural antioxidant products have gained attention for their protective effects against drug-induced toxicities, especially whenever free radical generation is involved . In compVitamin E (α-tocopherol) is a naturally occurring, potent lipid soluble, chain-breaking antioxidant that acts as a free radical scavenger and protects against oxidative damage . Due to According to our knowledge, there is not enough effort in research conducted on the effectiveness of vitamin E as an intervention program (protective/remodeling) and its efficacy on cardiotoxicity. Therefore, the objective of this study was to investigate the curative role of vitamin E against CP-induced cardiotoxicity in rats.Endoxan CP (anhydrous cyclophosphamide) ampoules (1000 mg) were obtained from the local pharmacy and manufactured in Spain for Baxter Oncology, Germany. The drug was prepared by ITS dissolved in saline. Commercial vitamin E (α-tocopherol) was obtained from Al-Kahira Pharma and Chem. Ind. Co.,  in the form of soft gelatinous capsules.Sexually mature Wistar male rats (Weighing 225.3 ± 25 g) were obtained from the animal’s house of the Faculty of Medicine, Alexandria University, Alexandria, Egypt. Rats were kept on a basal diet and tap water ad libitum. They were acclimated under controlled environmental conditions at room temperature (25 ± 2 °C) with humidity (50 ± 10%) and a 12 h light/dark cycle. The experiments and the protocol were carried out according to the guidelines of the Zoology Department, Faculty of Science, Alexandria University. All experimental procedures were approved and performed in compliance with the guidelines of the Research Ethical Committee of the Zoology Department, Faculty of Science, Alexandria University, Alexandria, Egypt .The forty male Wistar rats were divided randomly into four groups (each consisting of ten rats) and treated for three months (three times/a week) as follows. G I control rats took daily 0.5 mL saline solution; G II (CP-treated rats) rats orally received CP at a dose of 1.5 mg/kg of BW, and CP alleviated the histological signs of inflammation and changed superoxide dismutase activity ; G III  level was carried out according to the method of Allain et al. . The triHeart tissues from each experimental group were quickly removed, washed with saline and cut into pieces, homogenized with 9 volumes of phosphate buffer , and centrifuged at 3000 rpm for 15 min. The supernatant was saved for the determination of oxidative stress markers and antioxidant enzyme activities.Lipid peroxidation (LPO) end product (MDA) was determined according to the method of Ohkawa et al. . The actSmall pieces of heart tissue of all experimental groups and the control were excised out carefully, fixed in 10% formalin solution, dehydrated using ascending graded series of ethanol, and cleared with xylem. The specimen was then embedded in paraffin wax according to the routine processing protocol . Serial Very small pieces of heart tissue of all experimental groups and the control were immediately fixed in 4% formalin and 1% glutaraldehyde (4FIG fixative mixture), and rinsed in a 0.1 M phosphate buffer (pH = 7.4) at 4 °C for 24 hr. This was followed by post-fixation using 1% Buffered Osmium tetroxide (OsO4) at 4 °C for 2 hr. Then, the samples were washed several times with a phosphate buffer for 30 min and dehydrated through ascending grades of ethanol concentrations at 4 °C. Then, the specimen was treated with propylene oxide and embedded in a 1:1 mixture of E.pon-Araldite resin mixture . Ultrathp-value ≤ 0.05 (n = 10 for each group). One-way analysis of variance (ANOVA) was used for normally distributed quantitative variables and the post hoc test (Tukey) was for pairwise comparison.Data were fed to the computer and analyzed using IBM SPSS software package version 20.0. . The Shapiro–Wilk test was used to verify the normality of distribution. Quantitative data were described using mean ± S.D. Significance consideration at The results revealed significant decreases in the body weights after treatment with CP as compared to the control rats; however, vit E-treated rats did not show any significant variation in body weight throughout the experiment. The combination of vit E with CP showed a partial increase in body weight as compared to CP-treated animals .It was noticed that both AST and ALT activities were increased significantly in the CP-treated rats compared to the control rats. However, the levels were decreased significantly in vit E-treated rats, as well as in vit E + CP-treated rats . The actThe data represented in A significant increase in CK activity in CP-treated rats was noticed as compared to the control animals. In vit E-treated rats, the results showed an insignificant decrease in CK concerning the control rats. However, in rats treated with CP + vit E, the results exhibited a significant decrease in CK, compared to CP-treated animals .The data presented in The malondialdehyde (MDA) levels, as an indicator of LPO, showed a significant increase in the serum of rats treated with CP as compared to the control. However, the levels in the serum of vit E-treated rats were less than the control. In CP + vit E-treated rats, serum samples revealed a marked depletion in MDA levels compared to CP-treated rats . The levSections obtained from the hearts of the control rats showed the normal histological pattern of cardiac muscle fibers, and the myocardial cells exhibited regular transverse striations. Alternating dark and light bands, as well as delicate connective tissues (endomysium), were observed in between and surrounding the bundles of the cardiomyocytes a. In addHistological examination of the heart sections of CP-treated rats revealed degenerative changes in the cardiac muscle fibers which were separated from each other with the increase in the interfiber spaces and appearance of interstitial edema b. In addSections of the heart in vitamin E-treated rats displayed the normal pattern of myocytes together with clear transverse sarcoplasmic striations. Myofibrils were uniformly arranged, and nuclei are in a typical shape with noticeable nucleoli c. IntactThe heart sections of CP-treated rats in combination with vit E showed that most of the cardiac muscle fibers attained their ordinary shape and arrangement compared to CP-treated rats. The myocytes were cylindrical, branched, and striated d. The nuUltrathin heart sections from control rats showed regular banding and normal striation pattern of the myofibrils. Also, the other treated groups are presented in The electron micrograph of cardiac sections of rats treated with 1.5 mg/kg of CP revealed that the myofibrils were irregular, loose, and discontinuous in many areas, resulting in a widening between myofibril and a disruption of the regular striated appearance, in addition to the severe irregularities of the perinuclear cisternae c–e. HencOn the other hand, in rats administrated with 100 mg/kg of vit E, the electron micrographs revealed a normal appearance of heart muscles. The cardiac cells possessed an oval nucleus with normal morphology and the mitochondria have a normal pattern of cristae f,g. The Examination of electron micrographs of treated rats with 1.5 mg/kg of CP in combination with 100 mg/kg of vit E confirmed that most cardiac fibers regained their normal structure with minimal alterations h,i. UltrAlkylating antineoplastic agent cyclophosphamide is one of the most effective medications with a broad range of therapeutic efficacy. It has been used as an immunosuppressive medication for the treatment of autoimmune and immune-mediated disorders, as well as for a variety of cancer treatments. Due to multiple toxicities, its clinical application is now restricted, partly due to oxidative stress induction in various tissues . Vit E iIn the present investigation, serum cardiotoxicity indices, such as troponin, LDH, AST, ALP, and CK, have occurred as predominant indicators of myocardial necrosis. The observed increase in sensitive biomarker enzymes (LDH and CK) activities in CP-treated rats was described before by Alhumaidha et al. . The eleOur results are consistent with the data presented by Gunes et al. , who demAs the thick and thin filaments slide past each other, the cell becomes shorter and fatter in a mechanism, which is known as cross-bridge cycling. Myosin, in the thick filament, can then bind to actin, pulling the thick filaments along the thin filaments. When the concentration of calcium within the cell falls, troponin and tropomyosin once again cover the binding sites on actin, causing the cell to relax . MusculaIn the current study, the troponin level did not change after CP administration because its determination detects the presence of cardiotoxicity very early, significantly before impairment of cardiac function can be revealed by any other diagnostic technique. Immediately after the last chemotherapy administration, troponin determination allows for the discrimination of patients at high risk for cardiotoxicity; CP treatment  for three days resulted in a significant high cardiac troponin I in male rats .The existing study has demonstrated hypercholesterolemia and hypertriglyceridemia caused by CP, which are well-known risk factors for cardiovascular diseases. These changes could be that CP can change the cholesterol profile by different mechanisms involving oxidation, glycation, homocysteinylation, or enzymatic degradation .Free radical scavenging enzymes, such as SOD, CAT, GPx, and GST, are the first line of cellular defense against the toxic effects of ROS  and theyIn the ongoing investigation, rats treated with CP had significantly reduced SOD, CAT, and GPx activities, decreased GSH levels, and elevated MDA levels, which is a result of the overproduction of ROS-induced cardiotoxicity . AdditioCP is metabolized into active metabolites, phosphoramide mustard, and acrolein by the liver microsomal enzyme . These mThe toxicity of CP was reported to be mediated by the deleterious effects of oxidative stress on the mitochondria . The mitIt has been reported that free radicals generated during treatment with CP cause membrane injury, which resulted in the loss of function and integrity of the myocardial membrane due to a decrease in cardiac antioxidants and GSH , as showIn the present results, the observed photomicrographs of the cardiac muscles of rats treated with 0.05 mg/Kg of CP showed disruption of myocyte structure, including cytoplasmic vacuolization, loss of myofibrils, and marked congestion. Inconsistent with the results of Nishikawa et al. , who fouIn addition to the importance of the mitochondria in energy metabolism in heart tissue, they are involved in calcium homeostasis, production of ROS, have an interface with other cellular organelles, such as sarcoplasmic reticulum calcium stores and myofibrillary complexes to coordinate contractile activity, act as central regulators of cell death, and apoptosis . The stuMitochondrial affection might be responsible for other degenerative changes in cardiac muscle because the heart is particularly susceptible to metabolic perturbations, as it does not store energy as efficiently as other tissues and it must produce high-energy phosphates continually, as needed .CP had a detrimental effect on the ultrastructural myocardial changes and mitochondrial matrix. Furthermore, one of the characteristic features of cardiac injury in this study was the mitochondrial degenerative change. Some mitochondria showed partial or complete loss of cristae and vacuolation. Guo et al.  reported+-K+ pump mechanism. Impairment is most likely due to the drop in ATP level that alters the sarcolemma homeostatic capacity, resulting in an influx of H2O and Na with the expansion of the cell and vacuolation of the sarcoplasm, as mentioned by Haouem and Hani [Regarding the nuclear changes, it was observed in this study that it may be due to DNA damage caused by oxidative stress and this nuclear affection can lead to cellular dysfunction and death, as the cardiomyocytes nuclei of this group showed too many irregularities, especially in their nuclear envelope, and the chromatin is highly condensed, in addition to the vacuolization that appeared around the nucleus. The vacuolated spaces around the nucleus and scattered in the sarcoplasm that was observed in the current results of CP-treated mice may signify degenerating focal zones of the sarcoplasm leaving empty spaces. These degenerative changes may be induced by increased LPO, as explained by Olayinka et al. , in Adriand Hani  in cadmiVit E has been reported to interrupt the radical chain reaction and protects against oxidative damage . The curThe role of vitamin E as an antioxidant in cardiovascular diseases in human beings is controversial. LPO is a significant establishment and progression of atherosclerosis, which is crucial in the development of cardiac vascular diseases (CVDs) . Vit E fMoreover, the most active form of vitamin E, tocopherol, is membrane-bound in animals and is thought to play a dual role in stabilizing the membrane and acting as an antioxidant on the membrane’s surface. Lateral methyl groups in the side chain are thought to fill in gaps left by cis double bonds in the fatty acids .The results revealed that the treated rats with 100 mg/Kg of vit E showed histological patterns of myocytes. Howard et al.  declaredIn conclusion, the treated rat’s damage resulted from administration with CP at a dose of 1.5 mg/kg. Vit E at a dose of 100 mg/kg showed a marked protective effect in most of the tissue; this includes the regular organization of the myofibrils. Ordinary organization sarcomere appeared between the Z-lines with dark and light bands, normal chromatin distribution in the nuclei, fewer glycogen particles and lipid droplets, and a normal appearance of a convoluted intercalated disc. Additionally, all the cardiac biomarkers were improved. According to our knowledge, there is not enough effort in research conducted on the effectiveness of vit E as an intervention protective and its efficacy on cardiotoxicity. Overall, vitamin E application with CP over time could alleviate the toxic potential of CP. Therefore, we consider vit E as a sole candidate in CP remediation efforts, and its impact on medical conditions should always be properly considered.


One-third of all extraintestinal manifestations are mucocutaneous findings in patients with Crohn’s disease and there is a relationship between some risk factors. Our aim is to evaluate factors associated with mucocutaneous manifestations in our cohort of patients with Crohn’s disease with a follow-up duration of up to 25 years.. The demographic characteristics, Crohn’s disease-related data, and accompanying mucocutaneous manifestations were recorded. The cumulative probability of mucocutaneous extraintestinal manifestations and possible risk factors were analyzed.In the study, 336 patients with Crohn’s disease who were followed up between March 1986 and October 2011 were includedP = .003) and corticosteroid use  are independently associated with the development of skin manifestations, while family history  and inflammatory-type disease  were independently associated with the development of oral ulcers.Oral and skin involvement were detected in 109 (32%) and 31 (9.2%) patients, respectively. The cumulative probability of developing oral and skin manifestations were 43.2% and 20.3%, respectively. Cox regression analysis showed that female gender (odds ratio: 3.28, 95% CI: 1.51-7.14, Mucocutaneous extraintestinal manifestations are associated with female gender, corticosteroid use, family history, and disease type in a large cohort of patients with Crohn’s disease. Defining the specific relationships of immune-mediated diseases will help to better understand the pathogenesis of Crohn’s disease and associated mucocutaneous manifestations and to use more effective treatments. The cumulative probability of developing skin and oral involvement in their 25-year follow-up was 20.3% and 43.2%, respectively. Compared to the other population, skin involvement was similar, but oral involvement was more common in the Turkish population.P = .003) and corticosteroid use  are independently associated with the development of skin manifestations, family history  and inflammatory-type disease  were independently associated with the development of oral ulcers.Cox regression analysis showed that female gender  is a group of diseases consisting of Crohn’s disease (CD) and ulcerative colitis, with chronic inflammation in the gastrointestinal tract. In genetically sensitive individuals, IBD is thought to develop secondary to inappropriate and persistent inflammatory responses following the complex interaction of genetic, environmental, and immunoregulatory factors with the gut microbiota and antigens. Chronic inflammation in the intestines causes edema, ulceration, bleeding, diarrhea, and fluid–electrolyte loss.4 As a result of extraintestinal manifestations (EIMs) involving the musculoskeletal system, skin, eyes, hepatobiliary system, kidneys, lungs, cardiovascular, hematological, and immunological systems, it negatively affects the quality of life by impaired functional status.6 Extraintestinal manifestations are sometimes mild and transient, sometimes progressing very severely, and maybe more prominent than intestinal symptoms.7 Joint and mucocutaneous involvements are frequently seen in CD.6 It is reported that EIMs occur approximately in one-third of CD patients and one-third of these EIMs are mucocutaneous manifestations, including but not limited to erythema nodosum (EN), pyoderma gangrenosum (PG), and aphthous ulcers.11Although CD is primarily defined as chronic inflammation of the intestines, it has been observed that it is not limited to the gastrointestinal tract but affects many organ systems.11 In studies examining the various risk factors associated with the development of mucocutaneous findings, the results appear to be contradictory, as patient populations and study designs are different. However, factors such as disease activity, gender, location, type of disease, family history, drugs used, and perianal disease are reported to be very important in skin and oral involvement.14 We aimed to investigate mucocutaneous involvement only in patients with CD, since skin involvement in ulcerative colitis patients is better known and oral involvement differs from other populations in our country. So in our study, we aimed to determine the frequency of oral aphthous stomatitis and skin involvement and the cumulative probability of the development of mucocutaneous manifestations at 25-year follow-up. In addition, we also aimed to identify independent risk factors that influence the development of oral aphthous stomatitis and skin involvement.It is known that some genetic and environmental factors play a role in the development of mucocutaneous manifestations in patients with CD. It was also reported that 1 EIM may trigger the development of another EIM and the probability of developing multiple EIMs ranged from 4% to 25%. This is thought to be due to the common underlying pathological pathways and genetic features.In the study, 336 patients who were followed up between March 1986 and October 2011 with the diagnosis of CD in the gastroenterology outpatient clinic of our hospital were included. Our study was designed as a single-center retrospective cohort study. The diagnosis of CD was made using radiological, endoscopic, histopathological, and clinical examinations. There is no single gold standard for the diagnosis of CD and diagnosis is made by clinical evaluation including a detailed history, physical examination, and combination of endoscopic findings, histology, radiologic findings, and laboratory investigations. The typical symptoms of CD are abdominal pain, diarrhea, and weight loss. Initial laboratory investigations include CBC, C-reactive protein, and serum chemistry. Ileocolonoscopy and biopsies are recommended as the first-line procedures to establish the diagnosis. Typical endoscopic findings of CD are a non-continuous distribution of longitudinal ulcers, cobblestone mucosal appearance, and aphthous ulcerations arranged in a longitudinal fashion. Focal and patchy chronic inflammation, focal crypt irregularity, and non-caseating granulomas are usual microscopic features of CD. Patients with CD who were followed up for at least 6 months were included in the study. Patients with ulcerative colitis, indeterminate colitis or unclassified IBD, and other inflammatory diseases of the bowel were not included in the study. The patients who were included in the study were confirmed after the systematic physical examination by a gastroenterologist and then evaluated by a dermatologist for the diagnosis of mucocutaneous lesions. Before starting the study, a power analysis was performed to determine the number of patients to be included in the study and the follow-up period.Patients with existing oral and skin symptoms were consulted with the dermatology department. The findings were accepted as an EIM of CD after exclusion of other primary or secondary etiologies that would lead to similar findings. Drug-related, malnutrition, and malabsorption-related pathologies were not accepted as EIM. The studies were analyzed, and the presence of psoriasis was sometimes evaluated as an accompanying autoimmune disease and sometimes as an EIM. We evaluated psoriasis as EIM. The time of development of oral and skin findings was recorded either it is before the diagnosis of CD or during the follow-up. The cumulative probability for the development of mucocutaneous findings was calculated.Erythema nodosum: Erythema nodosum was defined as a rapid onset, bilateral, multiple, symmetrical and painful red nodule(s). It was observed that the lesions healed in approximately 3-5 weeks without leaving ulcers and scars. In biopsies taken by the dermatologist, immune complex deposition was observed in the subcutaneous adipose tissue.Pyoderma gangrenosum: Pyoderma gangrenosum was defined as an inflammatory papule or pustule that can progress to a painful ulcer. Pyoderma gangrenosum often develops in the lower extremities, starts as an erythematous area, but later turns into a painful ulcer with sterile necrotic areas. Since the current findings may occur in syphilis, bacterial, fungal and mycobacterial infections, exposure to iodide and bromide, and spider bites, biopsy, and culture were taken from all patients, and the presence of other etiologies was excluded.Oral involvement: Oral involvement was defined as aphthous ulcers or pain in the mouth and gums. Oral symptoms and findings were accepted as CD-linked EIMs after eliminating inflammatory or rheumatological diseases including infections, Reiter’s syndrome, and Behçet’s disease, which may cause similar clinical findings.15 Type of disease was classified into 3 different categories including inflammatory, structuring, and penetrating-type considering the presence or development of intestinal complications such as abscess, fistula, and stricture.16 Patients with perianal fissure, abscess, and perianal fistula were determined as isolated perianal diseases based on the Montreal classification.15 Patients’ smoking status was questioned and all smokers were referred to the smoking cessation clinics. Surgery due to intestinal complications and/or perianal disease was recorded as a history of surgical operation. The relationship between the development of mucocutaneous findings and age of disease onset, location, type and duration of disease, gender, family history, perianal disease, surgery, and smoking were analyzed.Demographic data of patients, age of onset, disease duration, positive family history of IBD, location and type of disease, and presence of perianal disease were documented. Age of onset, location and type of disease, and presence of perianal disease were determined according to the Montreal classification.Medications including aminosalicylates, antibiotics, budesonide or systemic corticosteroids, immunosuppressive drugs , and biologics  were administered according to individualized treatment needs and indications. Treatment failures, perianal disease, and uncontrolled extraintestinal manifestations were treated by using biologic agents after January 2003. We used aminosalicylates in patients with mild forms of the disease. Systemic corticosteroids and budesonide were used as the main treatment for remission induction and flare-up episodes. Immunosuppressive drugs  were administered for the maintenance of the remission, and intramuscular methotrexate (25 mg/week) was used as an alternative immunosuppressive in patients with intolerance to thiopurine therapy. Anti-TNF treatment was applied in patients whose disease activity continued despite standard immunosuppressive therapy. The relationship between the development of mucocutaneous manifestations and treatment was analyzed.All participants provided their written consent for participation in the study. Approval for conducting this study was obtained from the Local Ethical Committee (2011/831-577) at our hospital. All procedures were in accordance with the ethical standards of the committee on human experimentation of our institution and with the Declaration of Helsinki.P < .05 value was considered statistically significant.The results of our study were analyzed with the Statistical Package for Social Sciences 19.0  program. The data that had continuous values were given as (mean ± standard deviation), and the categorical data were given as frequency and percentage . The cumulative probabilities of developing extraintestinal manifestations during the follow-up were calculated using Kaplan–Meier method and log-rank test. The chi-square test was employed to test the categorical data. Logistic regression analysis was used to determine the risk factors affecting the development of mucocutaneous findings in Crohn’s patients and Cox regression analysis was used to determine the independent risk factors. The results are reported as hazard ratios (HR) with 95% CIs. In these analyzes, Three hundred thirty-six patients with CD were included in the study (2535 patient-years follow-up with an average of 7.54 years [range: 0.5-25.4 years]); 55.4% (n = 186) of the patients were male. While the number of patients with a disease duration <10 years was 238 (70.8%), 98 (29.2%) patients had a disease duration ≥10 years. The mean age at the time of diagnosis was 30.6 (range: 10.3-68.2) years.Oral aphthous ulcer(s) and skin involvement were detected in 109 (32%) and 31 (9.2%) patients, respectively. The distribution of skin manifestations were as follows: EN in 12 (3.6%) patients, PG in 12 (3.6%), psoriasis in 2 (0.6%), dermatitis in 2 (0.6%), erythema multiforme in 1 (0.3%), and erythema bullosa in 1 (0.3%) patient(s). While 14 (45.1%) of those with skin involvement did present before the diagnosis of CD, 17 (54.9) presented after the diagnosis of CD. Forty-six (42.2%) patients with oral involvement had associated symptoms before the diagnosis of CD, and 63 (57.8%) patients were diagnosed during the course of CD.The cumulative probability of development of mucocutaneous involvement during the follow-up was calculated. The cumulative probability of developing skin involvement was 4.2% of patients when diagnosed CD, 6.7% of patients in the first year of the disease, 8.3% of the 5th year of the disease, 13.6% of the 10th year of the disease, 20.3% of the 15th year of the disease, 20.3% of the 20th year of the disease, 20.3% of the 25th year of the disease . The cumP < .005). The disease duration, age of onset, disease type, smoking status, family history of IBD, and need for surgical operation were not found to be associated with the development of skin findings (P < .001). When multivariate logistic regression analysis is performed to determine independent risk factors, female gender , presence of perianal disease , corticosteroid use , antibiotic use , and anti-TNF use  were found to be independent risk factors for the development of skin findings.Female gender, colon involvement, and perianal disease were significantly associated with the development of skin findings in the univariate analyses (findings . There wfindings . It was P < .05). Disease duration, age of onset, smoking status, and perianal disease were not found to be associated with the development of oral ulcers (P < .001). When multivariate logistic regression analysis is performed to determine independent risk factors; female gender , positive family history , inflammatory-type CD  and absence of a surgical operation history  were found to be independent risk factors for the development of oral ulcers.Development of oral findings was found to be significantly higher in patients with female gender, colon involvement, positive family history, inflammatory-type CD, and those without a history of intestinal surgery (l ulcers . We did l ulcers . Skin inP = .003) and corticosteroid use  were found to be independent risk factors for the development of skin findings. Family history  and presence of inflammatory disease  were found to be independent risk factors for the development of oral ulcers  patients had skin involvement consisting of EN, pyoderma gangrenosum and psoriasis, and oral aphthous ulcers developed in 39 (33%) patients.12 In a study from Portugal, 44.4% of the patients had skin involvement among 342 patients with IBD, but this rate was 14.9% when nutritional deficiency and drug-related manifestations were excluded.23 Similarly, in a study from Greece including 1001 CD patients, 169 patients (16.9%) had mucocutaneous involvement of whom 69 (6.9%) had oral aphthous ulcers.8 In our study, skin involvement was observed in 9.2% of patients and oral aphthous ulcers developed in 32%. In addition, after up to 25 years of follow-up, the cumulative probability of skin involvement and oral aphthae development was 20.3% and 43.2%, respectively. Mucocutaneous involvement had developed in approximately 40% of patients before the diagnosis of CD and there was a significant correlation between the development of skin and oral manifestations.Crohn’s disease is known to be associated with extraintestinal findings. In studies with a large patient population, the rate of EIMs was reported to be over 40%.22 showed that mucocutaneous involvement was significantly higher in women, in those with a positive family history, in early disease onset and perianal abscess. In addition, it was shown that corticosteroid, immunomodulator, antibiotics, and anti-TNF drug usage were higher in those with mucocutaneous involvement.22 Vide et al.23 reported that mucocutaneous involvement was significantly higher in patients with an early-onset disease and in women. Many studies have reported that EN and PG development is higher in women and patients with colon involvement.25 Similarly, oral ulcer development is more common in patients with positive family history and colon involvement, but its relationship with gender is not clear. In some studies, it was more common in men, while in others it was reported to be significantly higher in the female gender.26 Colitis-related extraintestinal manifestations were more frequent in the colonic location of CD. This phenomenon probably has its explanation in the loss of the function of the intestine as a barrier, which occurs in inflammatory intestinal conditions and, in consequence, allows the flow of certain substances into systemic circulation mainly bacterial and food components at, predominantly, the colonic level, which would manage to reach the systemic circulation and activate the immune system, thus unleashing extraintestinal manifestations. Predominance in women, as seen in many other autoimmune conditions, may only be in relation to certain hormonal influences in the immune system. Triggers of the autoimmune responses in certain organs seem to be influenced by genetic factors. Concordance in EIM was present in 70% of parent–child pairs and 84% in sibling pairs. Associations of EIM in IBD with major histocompatibility complex loci have been demonstrated.22 In our study, we showed that skin findings were higher in patients with colon involvement and in female patients. In addition, it was shown that oral aphthae developed more frequently in patients with positive family history and in women. In addition, while there are parallels between some EIM findings and disease activity in studies, some are still unclear. While skin findings such as pyoderma gangrenosum have not been clarified in general, it has been reported that there is a relationship between other skin findings and oral stomatitis and disease activation.20 In our study, we showed that stomatitis and skin findings were higher in patients using corticosteroids, antibiotics, and anti-TNF drugs. In this context, closer follow-up of patients with mucocutaneous findings in terms of Crohn’s disease activation will contribute to the initiation of optimum treatment in a timely manner.In the published studies, the frequency of mucocutaneous findings in CD patients varies as well as the factors affecting EIM development. Roth et al.27 However, it has been shown that there are many common pathways such as intestinal pathology secondary to granulomatosis inflammation and neutrophil-related autoimmune inflammation as a result of the abnormal neutrophil function.28 In this context, Roth et al.22 reported a significant relationship between perianal abscess and the development of mucocutaneous findings. Similarly, in our study, there was a significant relationship between perianal disease and the development of skin findings.Perianal lesions such as erythema, ulcer, fissure, fistula, and abscess are common skin findings in CD patients but are not considered as an EIM.29 Mucosal T cells are thought to abnormally migrate from the intestines to the mucocutaneous space and cause damage as a result of exposure to antigens.30 In addition to many pathological pathways that play a role in skin involvement, the Th17 pathway and IL-17 expression have an important role, along with Th1 and Th2 lymphocytes. Th17 has been shown to play an important role in many inflammatory and autoimmune diseases, especially atopic dermatitis, psoriasis, Behçet’s disease, and systemic lupus erythematosus.31 In recent studies, IL-17 and IL-23 produced by Th17 are shown to contribute to the pathogenesis of IBD. It is thought that excessive IL-23 synthesis plays a role in the development of treatment-resistant skin findings.32 In addition, as the duration of the disease increases, it can be said that the development of other EIMs increases as a result of the increase in the exposure of neutrophil and lymphocyte-related autoimmune inflammation.Mucosal T cells play an important role in the continuation of intestinal homeostasis by providing a balance between mucosal epithelium and intestinal bacteria and host immune response. EIMs are known to occur due to lymphocyte-mediated destructive processes as a result of immune dysregulation.Although our study is important in terms of determining risk factors associated with the development of mucocutaneous findings in CD patients, there are some limitations. It may not reflect the whole Turkish population, since data is received only from a single tertiary center where complicated cases may cause a referral bias. Secondly, it should be noted that some findings may be overlooked due to the retrospective setting of the study. Our analyses for the relationship between the development of mucocutaneous findings and duration of disease, large sample size, long-term follow-up, and the evaluation of independent predictive risk factors affecting the development of mucocutaneous findings in CD patients are the strengths of our study.In conclusion, the cumulative probability of skin involvement and oral aphthous ulcer development was found to be substantial in our study. We also showed that female gender, family history, colon involvement, and perianal disease play an important role in the development of mucocutaneous findings. It is suspected that there are common pathological pathways due to the existence of mucocutaneous findings before and after the diagnosis of CD. The immunological and clinical connections between these diseases and CD have not been fully elucidated. However, identifying specific relationships of immune-mediated diseases will help better understand the pathogenesis of CD and associated mucocutaneous findings to facilitate better treatment strategies.