Somatic amplification and addiction profile as risk factors for medication overuse headache with chronic migraine.

INTRODUCTION: Overuse of analgesics can lead to medication-overuse headache (MOH) in chronic migraine (CM) patients, and is often linked to addiction. This study explores the addiction-related characteristics and somatic amplification in patients with, CM with medication overuse headache (CM+MOH), CM, and healthy controls. METHODS: 73 CM patients and 70 CM+MOH, along with 63 healthy controls, participated in the study. Assessments included a Sociodemographic Form, Migraine Disability Assessment Scale (MIDAS), Addiction Profile Index (API), Addiction Profile Index-Clinical Version (API-C), and the Somatosensory Amplification Scale (SSAS). RESULTS: Substance use characteristics, craving, motivation for use, and addiction severity scores were higher in the CM+MOH group than in both the CM and the control group. Specifically, the SSAS scores within the CM+MOH group surpassed those of both the CM and control groups. In the CM+MOH group, SSAS scores were a strong predictor of the amount of analgesic usage. Besides, craving and motivation for substance use scores significantly predicted the number of days analgesic taken per month in the CM+MOH group CONCLUSION: CM patients with MOH exhibit a pronounced association with addiction, and a heightened manifestation of somatic symptoms. Addressing addiction characteristics and psychosomatic amplification is important to ensure comprehensive management.

Effectiveness of Intermittent Theta Burst Stimulation to Enhance Upper Extremity Recovery after Stroke: A Randomized Controlled Study.

OBJECTIVE: To first investigate the effectiveness of modified Constraint-Induced Movement Therapy (mCIMT) in low-functioning patients with stroke (PwS). Second, we aimed to investigate the efficiency of intermittent theta-burst stimulation (iTBS), applied on intermittent days, in addition to the mCIMT in PwS. DESIGN: Randomized, sham-controlled, single-blinded study. SETTING: Outpatient clinic. PARTICIPANTS: Fifteen PwS (age 66.3 ± 9.2 years (mean ± SD); 53% female) who were in the first 1-12 months after the incident were included in the study. INTERVENTIONS: PwS were divided into 3 groups: 1) mCIMT alone, 2) mCIMT + sham iTBS, and 3) mCIMT + iTBS. Each group received fifteen sessions of mCIMT (1 hour/session, 3 sessions/week). iTBS was applied with 600-pulses on impaired M1 prior to mCIMT. MAIN OUTCOME MEASURES: Upper extremity (UE) impairment was assessed with the Fugl-Meyer Test (FMT-UE), while the motor function was evaluated with the Wolf-Motor Function Test (WMFT). Motor Activity Log-28 (MAL-28) was used to evaluate the amount of use (AUS) and how well (HWS) the impaired UE movements. RESULTS: With-in-group analysis revealed that all groups had statistically significant improvements based on the FMT-UE and MAL-28 (p<0.05). However, the performance time and arm strength variables of WMFT were only increased in the mCIMT + iTBS group (p<0.05). The only between-group difference was observed in the intracortical facilitation in favor of the mCIMT + iTBS group (p<0.05). The effect size of iTBS was f=0.18. CONCLUSION: Our findings suggest that mCIMT with and without the application of iTBS has increased the UE motor function in low-functioning PwS. iTBS applied on intermittent days may have additional benefits as an adjunct therapy for facilitating cortical excitability, increasing the speed and strength of the impaired UE as well as decreasing disability.

Two siblings with Fanconi anemia (FANCQ, ERCC4/XPF) presenting with tumor-mimicking lesions in the brain and acute neurological deterioration.

The complementation Q group (FANCQ) subtype of Fanconi anemia (FA) caused by the ERCC4/XPF mutation is very rare. Two siblings, aged 13 and 10 with Fanconi phenotypic features, presented with right hemiparesis and focal-onset seizures. In both cases, cranial magnetic resonance imaging (MRI) showed mass-like lesions accompanied by peripheral edema and calcification. In one case, oral steroid treatment and surgical excision were performed, while in the other case, the cranial lesion regressed just with steroid treatment and without surgery. Both siblings remained wheelchair-bound due to neurological dysfunction. One case died due to hepatocellular carcinoma. ERCC4/XPF gene mutation was detected in both siblings.

Priming constraint-induced movement therapy with intermittent theta burst stimulation to enhance upper extremity recovery in patients with stroke: protocol for a randomized controlled study.

BACKGROUND: The treatments based on motor control and motor learning principles have gained popularity in the last 20 years, as well as non-invasive brain stimulations that enhance neuroplastic changes after stroke. However, the effect of intermittent theta burst stimulation (iTBS) in addition to evidence-based, intensive neurorehabilitation approaches such as modified constraint-induced movement therapy (mCIMT) is yet to be investigated. AIM: We aim to establish a protocol for a randomized controlled study investigating the efficiency of mCIMT primed with iTBS after stroke. METHODS: In this randomized controlled, single-blind study, patients with stroke (N = 17) will be divided into 3 groups: (a) mCIMT + real iTBS, (b) mCIMT + sham iTBS, and (c) mCIMT alone. 600-pulse iTBS will be delivered to the primary motor cortex on the ipsilesional hemisphere, and then, patients will receive mCIMT for 1 h/session, 3 sessions/week for 5 weeks. Upper extremity recovery will be assessed with Fugl-Meyer Test-Upper Extremity and Wolf Motor Function Test. Electrophysiological assessments, such as Motor-Evoked Potentials, Resting Motor Threshold, Short-Intracortical Inhibition, and Intracortical Facilitation, will also be included. CONCLUSIONS: In this study, a protocol of an ongoing intervention study investigating the effectiveness of iTBS on ipsilesional M1 prior to the mCIMT in patients with stroke is proposed. This will be the first study to research priming mCIMT with iTBS and it may have the potential to reveal the true effect of the iTBS when it is added to the high-quality neurorehabilitation approaches. TRIAL REGISTRATION: Trial registration number: NCT05308667.

Cerebrotendinous Xanthomatosis patients with late diagnosed in single orthopedic clinic: two novel variants in the CYP27A1 gene.

BACKGROUND: Cerebrotendinous Xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder caused by loss of function variants in the CYP27A1 gene which encodes sterol 27-hydroxylase, on chromosome 2q35. Although the symptoms begin commonly in infancy, CTX diagnosis is often delayed. The aim of this study is to review the orthopedic findings of the disease by providing an overview of the clinical features of the disease. It is to raise awareness of this condition for which early diagnosis and treatment are important. METHODS: We retrospectively evaluated the clinical, laboratory, radiological, and genetic findings of eight patients from four families who were admitted to our Orthopedics and Traumatology Department between 2017 and 2022 due to bilateral Achilles tendon xanthomas, were found to have high cholestanol and CYP27A1 gene mutations. RESULTS: The mean age of patients was 37, and five of them were male. The mean age at the onset of symptoms was 9.25 years. The mean age of initial diagnosis was 33.75 years. Between symptom onset and clinical diagnosis, an average delay of 24.5 years was observed. All patients had bilateral Achilles tendon xanthoma. Notably, a novel variant (c.670_671delAA) in CYP27A1 gene was identified in three patients who also presented with peripheral neuropathy and bilateral pes cavus. One patient had osteoporosis and four patients had osteopenia. Five patients had a history of bilateral cataracts. Furthermore, three of the patients had early-onset chronic diarrhea and three of the patients had ataxia. Two of the patients had epilepsy and seven of the patients had behavior-personality disorder. All patients had low intelligence, but none of them had cardiac disease. CONCLUSION: We present the diagnostic process and clinical features which the largest CTX case series ever reported from single orthopedic clinic. We suggest that patients with normal cholesterol levels presenting with xanthoma being genetically analyzed by testing at their serum cholestanol level, and that all siblings of patients diagnosed with CTX be examined.

Brain metastases with unusual MRI features in an infant with relapsed clear cell sarcoma of the kidney: A case report.

Clear cell sarcoma of the kidney (CCSK) is a rare primary renal tumor in children. It is known for its propensity to metastasize to bones and lungs at initial diagnosis. Distant metastatic relapses occur in about 15-16% of the patients, with the brain being the most frequent site of relapse. Imaging features of brain metastases from CCSK have only been reported in a few cases and most reports lack a detailed description of the imaging findings. We present brain magnetic resonance imaging (MRI) findings in an infant with relapsed CCSK who developed multiple parenchymal metastases with concentric signal alterations and no tumor-associated edema.

Thrombin generation assay in platelet-poor plasma in children with iron deficiency anemia.

OBJECTIVES: Iron deficiency anemia (IDA) is the most common type of anemia in childhood and it leads to a hypercoagulable state. We investigated endogenous thrombin production in platelet-poor plasma before and after oral iron replacement in children with IDA using the thrombin generation assay (TGA). METHODS: A total of 72 children diagnosed with IDA (IDA group) and 60 healthy children (control group) were included in the study. Blood samples were collected from the patients before and 1 month after oral iron replacement. TGA parameters [lag time, time to peak, peak height, endogenous thrombin potential (ETP)] were studied. RESULTS: In the IDA group, the lag time and time to peak decreased by 8.3% and 10.6%, respectively, and the endogenous thrombin potential (ETP) and peak height both increased by 30% compared to those of the control group. Compared to the values before iron replacement, 1 month after iron replacement, the lag time and time to peak increased by 8.7% and 5%, respectively, and the ETP and peak height decreased by 31% and 31.3%, respectively, and became similar to those of the control group. CONCLUSION: Children with IDA have increased endogenous thrombin production in platelet-poor plasma and a tendency for hypercoagulability. These changes are reversible, and the ETP values become similar to those of healthy children 1 month after iron replacement.

Higher TP53 somatic mutation prevalence from liquid biopsy analysis in ever smoker non-small-cell lung cancer patients.

OBJECTIVE: Cigarette smoking is a primary risk factor, linked to 80% of LC deaths. TP53, a key gene, is implicated in various cancers, with TP53 alterations in 36.7% of cancers. This research aims to investigate TP53 mutations detected in NSCLC patients by liquid biopsy and explore the relationship between these mutations and smoking history. MATERIAL AND METHOD: The study enrolled a total of 340 patients diagnosed with non-small cell lung cancer (NSCLC). For sequencing, the Illumina NextSeq 500 system was utilized. The oncogenicity of the variants was assessed according to the ClinGen/CGC/VICC SOP and the variants were categorized into four tiers according to AMP/ASCO/CAP. RESULTS: The most common mutations were in TP53 (48.7%), followed by EGFR, PIK3CA, and PTEN. Missense mutations were frequent, with TP53 and EGFR having higher rates in ever-smokers. No indels or complex mutations were found in ever-smokers. Patient age ranged from 20 to 86 years. Tier I-II variants were more common in ever-smokers, while Tier III variants were prevalent in never-smokers. TP53 mutations were more frequent in ever-smokers, showing a strong association with smoking. Domain distribution showed differences in PIK3CA. Transversion/transition ratios varied by gene and smoking status. DISCUSSION: The presence of TP53 mutations is strongly associated with both cigarette smoking and elevated Tv/Ti ratios. The tier status of TP53, EGFR, and PTEN variants does not show a specific domain distribution, but interesting associations are observed between the tier status and domain distribution in PIK3CA variants. Therefore, further comprehensive investigations are needed to explore this entity, as well as the underlying factors contributing to the increased Tv/Ti rates in the TP53 gene. Such research will provide deeper insights into the genetic alterations associated with smoking and tumor heterogeneity, ultimately aiding in the development of targeted therapies.

Upper limb dysfunction in people with early-stage Multiple Sclerosis: Perceived performance can be misleading.

BACKGROUND: Although the necessity of upper limb (UL) (dys)function assessment in people with Multiple Sclerosis (pwMS) has been demonstrated in recent years, this is still neglected at an early-stage. OBJECTIVE: The aim of our study was to comprehensively examine bilateral UL in early-stage pwMS who are thought to have no or minimal involvement in activities of daily living for the UL. METHODS: UL muscle strength, sensation and dexterity of 44 pwMS (EDSS score<4, disease duration<5 years, who did not report problems in daily living activities specifically for the UL) were evaluated bilaterally and compared with 44 healthy controls (HC). The relationship between UL function and muscle strength, sensation, cognitive function, fatigue, mood status, participation, EDSS, and disease duration were examined. The results of the outcome measures evaluating the UL function objectively and subjectively were analyzed. RESULTS: Muscle strength, sensation and dexterity were similar in the dominant and nondominant extremities of pwMS and were affected compared to HC. A fair relationship was found between UL function and proximal muscle strength, fatigue, cognitive function, home participation and EDSS. According to the cut-off value (18 s) of Nine Hole Peg Test, only 9.09% of pwMS was unaffected, but 79.54% of affected pwMS had a full ABILHAND score. CONCLUSION: Early-stage pwMS are unaware of the dysfunction since their UL involvement does not affect their daily living activities yet. Patient-reported outcome measures such as ABILHAND can be misleading and have a ceiling effect in the early-stage of the disease. Objective functional evaluations reveal that UL capacity is affected from the early period. Even if pwMS do not report UL involvement, clinicians and researchers should evaluate UL function and include it in the treatment program from an early-stage to prevent further disease burden.

Uncommon variants detected via hereditary cancer panel and suggestions for genetic counseling.

OBJECTIVE: Hereditary cancer syndromes constitute 5-10% of all cancers. The development of next-generation sequencing technologies has made it possible to examine many hereditary cancer syndrome-causing genes in a single panel. This study's goal was to describe the prevalence and the variant spectrum using NGS in individuals who were thought to have a hereditary predisposition for cancer. MATERIAL AND METHOD: Analysis was performed for 1254 who were thought to have a familial predisposition for cancer. We excluded 46 patients who were carrying BRCA1/2 variants in this study, for focusing on the rare gene mutations. Sequencing was performed using the Sophia Hereditary Cancer Solution v1.1 Panel and the Qiagen Large Hereditary Cancer Panel. The Illumina MiSeq system was used for the sequencing procedure. The software used for the data analyses was Sophia DDM and QIAGEN Clinical Insight (QCITM) Analyze. The resulting genomic changes were classified according to the current guidelines of ACMG/AMP. RESULTS: Pathogenic/likely pathogenic variants were detected in 172 (13.7%) of 1254 patients. After excluding the 46 BRCA1/2-positive patients, among the remaining 126 patients; there were 60 (4.8%) breast cancer, 33 (2.6%) colorectal cancer, 9 (0.7%) ovarian cancer, 5 (0.4%) endometrium cancer, 5 (0.4%) stomach cancer, 3 (0.2%) prostate cancer patients. The most altered genes were MUTYH in 27 (2.1%) patients, MMR genes (MLH1, MSH6, MSH, MSH2, PMS2 and EPCAM) in 26 (2%) patients, and ATM in 25 (2%) patients. We also examined the genotype-phenotype correlation in rare variants. Additionally, we identified 11 novel variations. CONCLUSION: This study provided significant information regarding rare variants observed in the Turkish population because it was carried out with a large patient group. Personalized treatment options and genetic counseling for the patients are therefore made facilitated.

Use of dual energy CT urography in evaluation of urinary stone and complex cyst.

BACKGROUND: Dual-energy computed tomography scans can provide significant benefits to the urinary system. The aim of this study is to determine the limitations and benefits of using dual energy CT urography in patients with urinary system stones and cysts. METHODS: In the analysis of the images, the virtual noncontrasted images obtained from the combined nephrogenicexcretory phase and the true noncontrasted images were evaluated. The true noncontrast images were accepted as the gold standard for stone detection. RESULTS: Eighty-three different stones were detected in 26 of the 115 patients included in the study. Sensibilities of virtual noncontrast images in detecting urinary system stones were 66.7% and 65.4% according to the first and second radiologists, respectively. In this study, 32 hyperdense cysts were detected. According to iodine map images, there was no enhancement in 26 of 32 cysts; only 5 cysts showed minimal contrast enhancement. One patient could not decide on contrast enhancement. DISCUSSION: As a result, if CT urography is performed with dual energy, it can provide additional information in patients with urinary system disorder.

Evaluation of abdominal computed tomography findings in patients with COVID-19: a multicenter study

PURPOSE: To evaluate the frequency of abdominal computed tomography (CT) findings in patients with coronavirus disease-2019 (COVID-19) and interrogate the relationship between abdominal CT findings and patient demographic features, clinical findings, and laboratory test results as well as the CT atherosclerosis score in the abdominal aorta. METHODS: This study was designed as a multicenter retrospective study. The abdominal CT findings of 1.181 patients with positive abdominal symptoms from 26 tertiary medical centers with a positive polymerase chain-reaction test for severe acute respiratory syndrome coronavirus 2 were reviewed. The frequency of ischemic and non-ischemic CT findings as well as the association between CT findings, clinical features, and abdominal aortic calcific atherosclerosis score (AA-CAS) were recorded. RESULTS: Ischemic and non-ischemic abdominal CT findings were detected in 240 (20.3%) and 328 (27.7%) patients, respectively. In 147 patients (12.4%), intra-abdominal malignancy was present. The most frequent ischemic abdominal CT findings were bowel wall thickening (n = 120; 10.2%) and perivascular infiltration (n = 40; 3.4%). As for non-ischemic findings, colitis (n = 91; 7.7%) and small bowel inflammation (n = 73; 6.2%) constituted the most frequent disease processes. The duration of hospital stay was found to be higher in patients with abdominal CT findings than in patients without any positive findings (13.8 ± 13 vs. 10.4 ± 12.8 days, P < 0.001). The frequency of abdominal CT findings was significantly higher in patients who did not survive the infection than in patients who were discharged after recovery (41.7% vs. 27.4%, P < 0.001). Increased AA-CAS was found to be associated with a higher risk of ischemic conditions in abdominal CT examinations. CONCLUSION: Abdominal symptoms in patients with COVID-19 are usually associated with positive CT findings. The presence of ischemic findings on CT correlates with poor COVID-19 outcomes. A high AA-CAS is associated with abdominal ischemic findings in patients with COVID-19.

Tandem high-dose chemotherapy followed by autologous stem cell transplantation: An infant with trilateral retinoblastoma.

BACKGROUND: Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Advanced RB, associated with exceedingly poor prognosis, requires more intensive multiagent chemotherapy than conventional regimens. Rescue of the bone marrow after intensive chemotherapy is achieved with stem cell transplantation. The sequential courses (tandem transplantation) of high-dose chemotherapy followed by autologous stem cell transplantation allow for even greater dose intensity in consolidation with the potential to use different active chemotherapeutics at each transplant and have proven feasible and successful in treating children with recurrent/refractory solid tumors. CASE DESCRIPTION: We report an infant with trilateral high-risk RB who received tandem high-dose chemotherapy (HDC) followed by autologous stem cell transplantation after the conventional chemotherapy. A 5-month-old female patient presented with strabismus, and the ophthalmoscopic examination showed intraocular tumoral lesions in both eyes. Magnetic resonance imaging (MRI) concluded the trilateral retinoblastoma diagnosis due to a tumoral mass in the optic chiasm. The follow-up ophthalmologic examinations and the MRI detected stable disease after six cycles of multiagent chemotherapy. CONCLUSIONS: Rescue with autologous stem cell transplantation after HDC allows for an increase in chemotherapy intensity. Tandem transplantation provides the chance to perform different chemotherapeutics at each transplant and enables an increase in the chemotherapy intensity, thus providing a positive effect on disease-free survival.

Protoporphyrin IX (PpIX) Fluorescence during Meningioma Surgery: Correlations with Histological Findings and Expression of Heme Pathway Molecules.

Background: The usefulness of 5-ALA-mediated fluorescence-guided resection (FGR) in meningiomas is controversial, and information on the molecular background of fluorescence is sparse. Methods: Specimens obtained during 44 FGRs of intracranial meningiomas were analyzed for the presence of tumor tissue and fluorescence. Protein/mRNA expression of key transmembrane transporters/enzymes involved in PpIX metabolism (ABCB6, ABCG2, FECH, CPOX) were investigated using immunohistochemistry/qPCR. Results: Intraoperative fluorescence was observed in 70 of 111 specimens (63%). No correlation was found between fluorescence and the WHO grade (p = 0.403). FGR enabled the identification of neoplastic tissue (sensitivity 84%, specificity 67%, positive and negative predictive value of 86% and 63%, respectively, AUC: 0.75, p < 0.001), and was improved in subgroup analyses excluding dura specimens (86%, 88%, 96%, 63% and 0.87, respectively; p < 0.001). No correlation was found between cortical fluorescence and tumor invasion (p = 0.351). Protein expression of ABCB6, ABCG2, FECH and CPOX was found in meningioma tissue and was correlated with fluorescence (p < 0.05, each), whereas this was not confirmed for mRNA expression. Aberrant expression was observed in the CNS. Conclusion: FGR enables the intraoperative identification of meningioma tissue with limitations concerning dura invasion and due to ectopic expression in the CNS. ABCB6, ABCG2, FECH and CPOX are expressed in meningioma tissue and are related to fluorescence.

Effect of Different Surface Treatments on Retention of Cement-Retained, Implant-Supported Crowns

PURPOSE: To evaluate the effect of different treatments applied to titanium implant abutment surfaces on the retention of implant-supported cement-retained crowns using resin cement. MATERIALS AND METHODS: A total of 72 titanium implant abutments were divided into six groups (n = 12 each) based on the selected surface treatments: (1) untreated; (2) airborne particle abrasion; (3) hydrogen peroxide etching; (4) atmospheric plasma; (5) chemical mechanical polishing; and (6) titanium dioxide (TiO2) nano coating. After the surface treatments, scanning electron microscopy analyses and surface roughness measurements of the abutment surfaces were performed. Seventy-two metal copings were fabricated and cemented on the abutments with dual-curing resin cement. After a thermal cycling process, crown retention was measured using a universal testing machine. The experimental results were statistically evaluated with one-way analysis of variance, Tukey honest significant difference, and Tamhane's T2 tests. RESULTS: The highest surface roughness values were obtained with the airborne-particle abrasion group (1.44 µm), which also resulted in the highest retention values (828.5 N), followed by the hydrogen peroxide-etching group (490.7 N), the atmospheric plasma group (466.5 N), the chemical mechanical polishing group (410.8 N), and the control group (382.6 N). CONCLUSION: It was determined that airborne particle abrasion, hydrogen peroxide etching, and atmospheric plasma treatments significantly increased the crown retention and that all alternative treatments, except for TiO2 nano coating, worked better than the untreated control.

Enhancement of motor skill acquisition by intermittent theta burst stimulation: a pilot study.

OBJECTIVE: This study aims to analyze the effects of intermittent theta burst stimulation (iTBS) on motor skill acquisition of healthy subjects when applied on alternate days to ensure high adherence to treatment. MATERIALS AND METHODS: Ten healthy participants (40-54 years) were included in the study. The control group (CG) (60% female) only received motor training (i.e., finger tapping task-FTTa), whereas the experimental group (EG) (100% female) received iTBS in addition to the motor training (every other day for 5 sessions). Cortical excitability measurements were taken with TMS. The correct sequences of the finger tapping test (FTTe) were recorded for behavioral analysis. RESULTS: While SICI was increased by 0.03 in EG, ICF was increased by 0.18 between pre-and post-treatment. On the other hand, CG had a lower ICF difference (MD: 0.05) and a higher SICI difference (MD: 0.21). There was no difference between EG and CG in FTTe at the end of the intervention (p > 0.05 for all variables), except for the increased number of correct sequences within the EG (p = 0.018). There was a significant difference in FTTa between EG and CG, in favor of EG (p = 0.042). The effect size was 0.62. CONCLUSION: Although no difference was found in terms of cortical excitability and FTTe between the EG and CG at the end of the alternate-day treatment, it seemed like iTBS increased cortical facilitation further than CG. Furthermore, the number of correct sequences in FTTe and FTTa was significantly increased in EG, showing that intermittent iTBS might improve motor learning and performance.

Predictive Analysis of Errors During Robot-Mediated Gamified Training.

This paper presents our approach to predicting future error-related events in a robot-mediated gamified physical training activity for stroke patients. The ability to predict future error under such conditions suggests the existence of distinguishable features and separated class characteristics between the casual gameplay state and error prune state in the data. Identifying such features provides valuable insight to creating individually tailored, adaptive games as well as possible ways to increase rehabilitation success by patients. Considering the time-series nature of sensory data created by motor actions of patients we employed a predictive analysis strategy on carefully engineered features of sequenced data. We split the data into fixed time windows and explored logistic regression models, decision trees, and recurrent neural networks to predict the likelihood of a patient making an error based on the features from the time window before the error. We achieved an 84.4% F1-score with a 0.76 ROC value in our best model for predicting motion accuracy related errors. Moreover, we computed the permutation importance of the features to explain which ones are more indicative of future errors.

Antifungal Azole Derivatives Featuring Naphthalene Prove Potent and Competitive Cholinesterase Inhibitors with Potential CNS Penetration According to the in Vitro and in Silico Studies.

Cholinesterase inhibition is of great importance in the fight against neurodegenerative disorders such as Alzheimer's disease. Azole antifungals have come under the spotlight with recent discoveries that underline the efficacy and potential of miconazole and its derivatives against cholinesterase enzymes. In this study, we evaluated a library of azoles against acetylcholinesterase and butyrylcholinesterase using in vitro and in silico methods to identify potent inhibitors. Low micromolar IC50 values were obtained for imidazole derivatives, which were further tested and found potent competitive cholinesterase inhibitors via enzyme kinetics study. The active derivatives showed negligible toxicity in in vitro cytotoxicity tests. Molecular modeling studies predicted that these derivatives were druglike, could penetrate blood-brain barrier, and tightly bind to cholinesterase active site making key interactions via the imidazole moiety at protonated state. Thus, current study identifies potent and competitive cholinesterase inhibitor azoles with minor toxicity and potential to pass into the central nervous system.