GDF11: An emerging therapeutic target for liver diseases and fibrosis.

Growth differentiation factor 11 (GDF11), also known as bone morphogenetic protein 11 (BMP11), has been identified as a key player in various biological processes, including embryonic development, aging, metabolic disorders and cancers. GDF11 has also emerged as a critical component in liver development, injury and fibrosis. However, the effects of GDF11 on liver physiology and pathology have been a subject of debate among researchers due to conflicting reported outcomes. While some studies suggest that GDF11 has anti-aging properties, others have documented its senescence-inducing effects. Similarly, while GDF11 has been implicated in exacerbating liver injury, it has also been shown to have the potential to reduce liver fibrosis. In this narrative review, we present a comprehensive report of recent evidence elucidating the diverse roles of GDF11 in liver development, hepatic injury, regeneration and associated diseases such as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis and hepatocellular carcinoma. We also explore the therapeutic potential of GDF11 in managing various liver pathologies.

Recurrent cannabis-induced catatonia: a case report and comprehensive systematic literature review.

Background: Catatonia presents itself as a complex neuropsychiatric syndrome, giving rise to various motor, speech, and behavioral challenges. It is noteworthy that approximately 10% of psychiatric hospital admissions can be attributed to this condition. It is imperative to note that cannabis-induced catatonia, while infrequent, has been linked to the use of marijuana. This connection has the potential to disrupt neurotransmitter systems, necessitating further research for a comprehensive understanding and effective treatment, particularly given the evolving trends in cannabis use. In this context, we shall delve into a unique case of recurrent cannabis-induced catatonia. Case presentation: A 23-year-old gentleman, who has previously struggled with substance use disorder, experienced the emergence of mutism, social isolation, and a fixed gaze subsequent to his use of cannabis. Remarkably, despite the absence of hallucinations, he exhibited recurrent episodes of catatonia. These episodes were effectively addressed through a combination of electroconvulsive therapy (ECT) and lorazepam administration. Notably, when the lorazepam dosage was gradually reduced to below 2 mg per day, the catatonic symptoms resurfaced; however, they promptly abated upon reinstating the medication. The diagnosis of cannabis-induced catatonia was established, and its management primarily involved a therapeutic approach encompassing ECT and lorazepam. It is pertinent to underscore that this catatonic condition can be directly linked to the individual's cannabis usage. Conclusion: The connection between cannabis and catatonia is intricate and not entirely comprehended. Although cannabis possesses therapeutic advantages, it can paradoxically trigger catatonia in certain individuals. Multiple factors, such as genetics, cannabinoids, and neurotransmitter systems, contribute to this intricacy, underscoring the necessity for additional research.

Coexistence of temporal lobe epilepsy and idiopathic generalized epilepsy.

OBJECTIVE: We investigated the frequency of coexistence of temporal lobe epilepsy (TLE) and idiopathic generalized epilepsy (IGE) in a retrospective database study. We also explored the underlying pathomechanisms of the coexistence of TLE and IGE based on the available information, using bioinformatics tools. METHODS: The first phase of the investigation was a retrospective study. All patients with an electro-clinical diagnosis of epilepsy were studied at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2023. In the second phase, we searched the following databases for genetic variations (epilepsy-associated genetic polymorphisms) that are associated with TLE or syndromes of IGE: DisGeNET, genome-wide association study (GWAS) Catalog, epilepsy genetic association database (epiGAD), and UniProt. We also did a separate literature search using PubMed. RESULTS: In total, 3760 patients with epilepsy were registered at our clinic; four patients with definitely mixed TLE and IGE were identified; 0.1% of all epilepsies. We could identify that rs1883415 of ALDH5A1, rs137852779 of EFHC1, rs211037 of GABRG2, rs1130183 of KCNJ10, and rs1045642 of ABCB1 genes are shared between TLE and syndromes of IGE. CONCLUSION: While coexistence of TLE and IGE is a rare phenomenon, this could be explained by shared genetic variations.

Bilateral Free Deep Inferior Epigastric Artery Perforator Flaps for Reconstruction following Mastectomy in Poland Syndrome Patients.

Background: Poland syndrome is classically described as symbrachydactyly, with hypoplasia of the pectoralis major and other upper thoracic musculoskeletal structures. It is thought to be caused by intrauterine interruption in subclavian arterial flow and often includes breast hypoplasia. Affected vasculature can pose a challenge for reconstruction with free flaps because inflow may not be reliable in this patient population. Methods: We present the rare case of a 28-year-old woman with left-sided Poland syndrome, significant family history of breast cancer, and BRCA1+ mutation who underwent bilateral prophylactic nipple-sparing mastectomies with successful immediate bilateral deep inferior epigastric artery perforator free flap reconstruction. The surgical literature in this clinical scenario is also reviewed. Results: Preoperative computed tomography angiography of the chest successfully demonstrated the patency and quantified the caliber of the internal mammary vessels to support free flap breast reconstruction. Conclusions: Free tissue transfer is a viable option for breast reconstruction in patients with Poland syndrome undergoing mastectomy guided by preoperative computed tomography angiography to characterize the internal mammary vasculature.

Severe chronic abuse of zolpidem for over 10 years: a case report and review of similar cases.

Background: Insomnia is a major health issue, and zolpidem is an effective treatment for insomnia. However, high doses of zolpidem can cause dependence, abuse, and withdrawal symptoms, questioning its advantages. Case presentation: A 39-year-old woman who has been divorced and unemployed for 2 years was referred to an addiction treatment center with a chief complaint of "seizure-like withdrawal symptoms after consuming high doses of zolpidem (up to 6,000 mg per day) for a decade." These symptoms were in the form of body tremors, nystagmus, stress, anxiety, hot flashes, and sweaty palms. She has been undergoing detoxification by clonazepam for almost 2 months. Except for the first few days, she did not have any withdrawal symptoms, and her insomnia caused by zolpidem has improved. Conclusion: Chronic abuse of zolpidem can cause dependence, withdrawal symptoms, and abuse. High doses can lead to extreme cravings and dependence. Physicians must manage the withdrawal process.

Role of FKBP5 and its genetic mutations in stress-induced psychiatric disorders: an opportunity for drug discovery.

Stress-induced mental health disorders are affecting many people around the world. However, effective drug therapy for curing psychiatric diseases does not occur sufficiently. Many neurotransmitters, hormones, and mechanisms are essential in regulating the body's stress response. One of the most critical components of the stress response system is the hypothalamus-pituitary-adrenal (HPA) axis. The FKBP prolyl isomerase 51 (FKBP51) protein is one of the main negative regulators of the HPA axis. FKBP51 negatively regulates the cortisol effects (the end product of the HPA axis) by inhibiting the interaction between glucocorticoid receptors (GRs) and cortisol, causing reduced transcription of downstream cortisol molecules. By regulating cortisol effects, the FKBP51 protein can indirectly regulate the sensitivity of the HPA axis to stressors. Previous studies have indicated the influence of FKBP5 gene mutations and epigenetic changes in different psychiatric diseases and drug responses and recommended the FKBP51 protein as a drug target and a biomarker for psychological disorders. In this review, we attempted to discuss the effects of the FKBP5 gene, its mutations on different psychiatric diseases, and drugs affecting the FKBP5 gene.

Breast reconstruction: Review of current autologous and implant-based techniques and long-term oncologic outcome.

Implant-based reconstruction is the most common method of breast reconstruction. Autologous breast reconstruction is an indispensable option for breast reconstruction demanding keen microsurgical skills and robust anatomical understanding. The reconstructive choice is made by the patient after a discussion with the plastic surgeon covering all the available options. Advantages and disadvantages of each technique along with long-term oncologic outcome are reviewed.

A systems biology approach for discovering the cellular and molecular aspects of psychogenic non-epileptic seizure.

Objectives: Psychogenic non-epileptic seizure (PNES) is the most common non-epileptic disorder in patients referring to epilepsy centers. Contrary to common beliefs about the disease's harmlessness, the death rate of PNES patients is similar to drug-resistant epilepsy. Meanwhile, the molecular pathomechanism of PNES is unknown with very limited related research. Thus, the aim of this in silico study was to find different proteins and hormones associated with PNES via a systems biology approach. Methods: Different bioinformatics databases and literature review were used to find proteins associated with PNES. The protein-hormone interaction network of PNES was constructed to discover its most influential compartments. The pathways associated with PNES pathomechanism were found by enrichment analysis of the identified proteins. Besides, the relationship between PNES-related molecules and psychiatric diseases was discovered, and the brain regions that could express altered levels of blood proteins were discovered. Results: Eight genes and three hormones were found associated with PNES through the review process. Proopiomelanocortin (POMC), neuropeptide Y (NPY), cortisol, norepinephrine, and brain-derived neurotrophic factor (BDNF) were identified to have a high impact on the disease pathogenesis network. Moreover, activation of Janus kinase-signaling transducer and activator of transcription (JAK-STAT) and JAK, as well as signaling of growth hormone receptor, phosphatidylinositol 3-kinase /protein kinase B (PI3K/AKT), and neurotrophin were found associated with PNES molecular mechanism. Several psychiatric diseases such as depression, schizophrenia, and alcohol-related disorders were shown to be associated with PNES predominantly through signaling molecules. Significance: This study was the first to gather the biochemicals associated with PNES. Multiple components and pathways and several psychiatric diseases associated with PNES, and some brain regions that could be altered during PNES were suggested, which should be confirmed in further studies. Altogether, these findings could be used in future molecular research on PNES patients.

COVID-19 as a trigger of Guillain-Barré syndrome: A review of the molecular mechanism.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a pandemic with serious complications. After coronavirus disease 2019 (COVID-19), several post-acute COVID-19 syndromes (PACSs) and long-COVID sequels were reported. PACSs involve many organs, including the nervous, gustatory, and immune systems. One of the PACSs after SARS-CoV-2 infection and vaccination is Guillain-Barré syndrome (GBS). The incidence rate of GBS after SARS-CoV-2 infection or vaccination is low. However, the high prevalence of COVID-19 and severe complications of GBS, for example, autonomic dysfunction and respiratory failure, highlight the importance of post-COVID-19 GBS. It is while patients with simultaneous COVID-19 and GBS seem to have higher admission rates to the intensive care unit, and demyelination is more aggressive in post-COVID-19 GBS patients. SARS-CoV-2 can trigger GBS via several pathways like direct neurotropism and neurovirulence, microvascular dysfunction and oxidative stress, immune system disruption, molecular mimicry, and autoantibody production. Although there are few molecular studies on the molecular and cellular mechanisms of GBS occurrence after SARS-CoV-2 infection and vaccination, we aimed to discuss the possible pathomechanism of post-COVID-19 GBS by gathering the most recent molecular evidence.

FKBP5 blockade may provide a new horizon for the treatment of stress-associated disorders: An in-silico study.

OBJECTIVE: We searched for, from the FDA (Food and Drug Administration-USA)-approved drugs, inhibitors of FKBP5 with tolerable adverse effect profiles (eg, mild headache, sedation, etc.) and with the ability to cross the blood brain barrier (BBB), using bio-informatics tools (in-silico). This may pave the road for designing clinical trials of such drugs in patients with functional seizures (FS) and other stress-associated disorders. METHODS: Several databases were used to find all the approved drugs that potentially have interactions with FKBP51 protein [ie, CTD gene-chemical interaction section of FKBP51 protein of Harmonizome of Mayaanlab, DrugCenteral database, PDID (Protein Drug Interaction Database), DGIdb (the Drug Gene Interaction database)]. Other databases were also searched [eg, clinicaltrials.gov; DRUGBANK (the FASTA format of the FKBP51 protein was imported to the target sequencing section of the database to find the associated drugs), and the STITCH database (to find the related chemical interaction molecules)]. RESULTS: After a comprehensive search of the designated databases, 28 unique and approved drugs were identified. Fluticasone propionate and Mifepristone and Ponatinib, Mirtazapine, Clozapine, Enzalutamide, Sertraline, Prednisolone, Fluoxetine, Dexamethasone, Clomipramine, Duloxetine, Citalopram, Chlorpromazine, Nefazodone, and Escitalopram are inhibitors of FKBP5 and have BBB permeability. SIGNIFICANCE: While the current in-silico repurposing study could identify potential drugs (that are already approved and are widely available) for designing clinical trials in patients with stress-associated disorders (eg, FS), any future clinical trial should consider the pharmacological profile of the desired drug and also the characteristics and comorbidities of the patients in order to foster a success.

The genetic link between systemic autoimmune disorders and temporal lobe epilepsy: A bioinformatics study.

OBJECTIVE: We aimed to explore the underlying pathomechanisms of the comorbidity between three common systemic autoimmune disorders (SADs) [i.e., insulin-dependent diabetes mellitus (IDDM), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA)] and temporal lobe epilepsy (TLE), using bioinformatics tools. We hypothesized that there are shared genetic variations among these four conditions. METHODS: Different databases (DisGeNET, Harmonizome, and Enrichr) were searched to find TLE-associated genes with variants; their single nucleotide polymorphisms (SNPs) were gathered from the literature. We also did a separate literature search using PubMed with the following keywords for original articles: "TLE" or "Temporal lobe epilepsy" AND "genetic variation," "single nucleotide polymorphism," "SNP," or "genetic polymorphism." In the next step, the SNPs associated with TLE were searched in the LitVar database to find the shared gene variations with RA, SLE, and IDDM. RESULTS: Ninety unique SNPs were identified to be associated with TLE. LitVar search identified two SNPs that were shared between TLE and all three SADs (i.e., IDDM, SLE, and RA). The first SNP was rs16944 on the Interleukin-1ß (IL-1ß) gene. The second genetic variation was ε4 variation of apolipoprotein E (APOE) gene. SIGNIFICANCE: The shared genetic variations (i.e., rs16944 on the IL-1ß gene and ε4 variation of the APOE gene) may explain the underlying pathomechanisms of the comorbidity between three common SADs (i.e., IDDM, SLE, and RA) and TLE. Exploring such shared genetic variations may help find targeted therapies for patients with TLE, especially those with drug-resistant seizures who also have comorbid SADs.

Extracellular vesicles as a new horizon in the diagnosis and treatment of inflammatory eye diseases: A narrative review of the literature.

Extracellular vesicles include exosomes, microvesicles, and apoptotic bodies. Their cargos contain a diverse variety of lipids, proteins, and nucleic acids that are involved in both normal physiology and pathology of the ocular system. Thus, studying extracellular vesicles may lead to a more comprehensive understanding of the pathogenesis, diagnosis, and even potential treatments for various diseases. The roles of extracellular vesicles in inflammatory eye disorders have been widely investigated in recent years. The term "inflammatory eye diseases" refers to a variety of eye conditions such as inflammation-related diseases, degenerative conditions with remarkable inflammatory components, neuropathy, and tumors. This study presents an overview of extracellular vesicles' and exosomes' pathogenic, diagnostic, and therapeutic values in inflammatory eye diseases, as well as existing and potential challenges.

The role of FGF21 and its analogs on liver associated diseases.

Fibroblast growth factor 21 (FGF21), a member of fibroblast growth factor family, is a hormone-like growth factor that is synthesized mainly in the liver and adipose tissue. FGF21 regulates lipid and glucose metabolism and has substantial roles in decreasing lipogenesis and increasing hepatic insulin sensitivity which causing lipid profile improvement. FGF21 genetic variations also affect nutritional and addictive behaviors such as smoking and alcohol consumption and eating sweets. The role of FGF21 in metabolic associated diseases like diabetes mellitus had been confirmed previously. Recently, several studies have demonstrated a correlation between FGF21 and liver diseases. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent type of chronic liver disease worldwide. NAFLD has a wide range from simple steatosis to steatohepatitis with or without fibrosis and cirrhosis. Elevated serum levels of FGF21 associated with NAFLD and its pathogenesis. Alcoholic fatty liver disease (AFLD), another condition that cause liver injury, significantly increased FGF21 levels as a protective factor; FGF21 can reverse the progression of AFLD and can be a potential therapeutic agent for it. Also, NAFLD and AFLD are the most important risk factors for hepatocellular carcinoma (HCC) which is the fourth deadliest cancer in the world. Several studies showed that lack of FGF21 induced oncogenic condition and worsened HCC. In this review article, we intend to discuss different aspects of FGF21 in NAFLD, AFLD and HCC; including the role of FGF21 in pathophysiology of these conditions, the effects of FGF21 mutations, the possible use of the FGF21 as a biomarker in different stages of these diseases, as well as the usage of FGF21 and its analog molecules in the treatment of these diseases.

Racial Disparity in Immediate Breast Reconstruction; a Gap That is not Closing.

Background: Immediate breast reconstruction (IBR) is offered as part of the standard-of-care to females undergoing mastectomy. Racial disparity in IBR has been previously reported with a longstanding call for its elimination, though unknown if this goal is achieved. The aim of this study was to examine the current association between race and IBR and to investigate whether racial disparity is diminishing. Methods: Data was extracted from the National Cancer Database (NCDB) from 2004 to 2016. All variables in the database were controlled so that the comparison would be made solely between Black and White females. We also analyzed the trend in racial disparity to see if there has been a change from 2004 to 2016 after several calls for healthcare equality. Results: After propensity score matching, 69,084 White females were compared to 69,084 Black females. There was a statistically significant difference between the rate of IBR and race (23,386 [33.9%] in White females vs 20,850 [30.2%] in Black females, P-value < .001). Despite a twofold increase in the rate of IBR in both White and Black females, a persistent gap of about 4% was observed over the study period, which translates to more than 2,500 Black females not receiving IBR. Conclusions: Using the NCDB database, a racial disparity was identified for IBR between White and Black females from 2004 and 2016. Unfortunately, the gap between the groups remained constant over this 13-year period.

Historique: La reconstruction mammaire immédiate (RMI) est proposée dans le cadre des soins standards aux femmes qui subissent une mastectomie. La disparité raciale a déjà été signalée à cet égard, dont l'élimination est réclamée depuis longtemps, mais on ne sait pas si cet objectif a été réalisé. La présente étude visait à examiner l'association courante entre la race et la RMI et à examiner si la disparité raciale diminuait. Méthodologie: Les chercheurs ont extrait les données de la National Cancer Database (NCDB) entre 2004 et 2016. Ils ont contrôlé toutes les variables de la base de données pour que la comparaison porte seulement sur les femmes noires et blanches. Ils ont également analysé la tendance en matière de disparité raciale pour déterminer s'il y avait eu un changement entre 2004 et 2016, après plusieurs appels à l'égalité dans les soins de santé. Résultats: Après l'appariement des coefficients de propension, les chercheurs ont comparé 69,084 femmes blanches à 69,084 femmes noires. Il y avait une différence statistiquement significative entre le taux de RMI et la race des 23,386 femmes blanches (33.9%) et des 20,850 femmes noires (30.2%), pour une valeur P < .001. Même si le taux de RMI a doublé autant chez les femmes blanches que chez les femmes noires, les chercheurs ont observé un écart persistant d'environ 4% pendant la période de l'étude, ce qui signifie que plus de 2,500 femmes noires n'ont pas reçu de RMI. Conclusions: À l'aide de la NCDB, les chercheurs ont constaté une disparité raciale en matière de RMI chez les femmes blanches et noires entre 2004 et 2016. Malheureusement, l'écart entre les deux groupes est demeuré constant au cours de cette période de 13 ans.

Identification of hub pathways and drug candidates in gastric cancer through systems biology.

Gastric cancer is the fourth cause of cancer death globally, and gastric adenocarcinoma is its most common type. Efforts for the treatment of gastric cancer have increased its median survival rate by only seven months. Due to the relatively low response of gastric cancer to surgery and adjuvant therapy, as well as the complex role of risk factors in its incidences, such as protein-pomp inhibitors (PPIs) and viral and bacterial infections, we aimed to study the pathological pathways involved in gastric cancer development and investigate possible medications by systems biology and bioinformatics tools. In this study, the protein-protein interaction network was analyzed based on microarray data, and possible effective compounds were discovered. Non-coding RNA versus coding RNA interaction network and gene-disease network were also reconstructed to better understand the underlying mechanisms. It was found that compounds such as amiloride, imatinib, omeprazole, troglitazone, pantoprazole, and fostamatinib might be effective in gastric cancer treatment. In a gene-disease network, it was indicated that diseases such as liver carcinoma, breast carcinoma, liver fibrosis, prostate cancer, ovarian carcinoma, and lung cancer were correlated with gastric adenocarcinoma through specific genes, including hgf, mt2a, mmp2, fbn1, col1a1, and col1a2. It was shown that signaling pathways such as cell cycle, cell division, and extracellular matrix organization were overexpressed, while digestion and ion transport pathways were underexpressed. Based on a multilevel systems biology analysis, hub genes in gastric adenocarcinoma showed participation in the pathways such as focal adhesion, platelet activation, gastric acid secretion, HPV infection, and cell cycle. PPIs are hypothesized to have a therapeutic effect on patients with gastric cancer. Fostamatinib seems a potential therapeutic drug in gastric cancer due to its inhibitory effect on two survival genes. However, these findings should be confirmed through experimental investigations.

Machine learning applications to differentiate comorbid functional seizures and epilepsy from pure functional seizures.

PURPOSE: We have utilized different methods in machine learning (ML) to develop the best algorithm to differentiate comorbid functional seizures (FS) and epilepsy from those who have pure FS. METHODS: This was a retrospective study of an electronic database of patients with seizures. All patients with a diagnosis of FS (with or without comorbid epilepsy) were studied at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2021. We arbitrarily selected 14 features that are important in making the diagnosis of patients with seizures and also are easily obtainable during history taking. Pytorch and Scikit-learn packages were used to construct various models including random forest classifier, decision tree classifier, support vector classifier, k-nearest neighbor, and TabNet classifier. RESULTS: Three hundred and two patients had FS (82.5%), while 64 patients had FS and comorbid epilepsy (17.5%). The "TabNet classifier" could provide the best sensitivity (90%) and specificity (74%) measures (accuracy of 76%) to help differentiate patients with FS from those with FS and comorbid epilepsy. CONCLUSION: These satisfactory differentiating measures suggest that the current algorithm could be used in clinical practice to help with the difficult task of distinguishing patients with FS from those with FS and comorbid epilepsy. Based on the results of the current study, we have developed an Application (SeiDx). This App is freely accessible at the following address: https://drive.google.com/file/d/1rAgBXKNPW9bmUCDioaGHHzLBQgzZ-HZ2/view. This App should be validated in a prospective assessment.

Genetic basis of Guillain-Barre syndrome.

Guillain-Barré syndrome (GBS) is an autoimmune disease in which the peripheral nerves are affected. GBS has different subtypes, such as acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Infections, e.g. Campylobacter jejuni, influenza, etc., can lead to GBS. Both environmental and genetic factors play a major role in the occurrence of GBS. Several studies have investigated the genetic basis of GBS. Human leukocyte antigens (HLA) genes, Cluster of Differentiation (CD) 1A, FAS, Fc gamma receptors (FcGR), Intercellular adhesion molecule-1 (ICAM1), different interleukins, Nucleotide oligomerization domain (NOD), Toll-like receptor 4 (TLR4), Tumor necrosis factor-α (TNF-α) are among the genes reported to be involved in susceptibility to the disease. Dysregulation and dysfunction of the mentioned gene products, even though their role in the pathogenesis of GBS is controversial, play a role in inflammatory pathways, regulation of immune cells and system, antigen presentation, axonal degeneration, apoptosis, and cross-reaction. This review aims to summarize associated genes with GBS to contribute to better understanding of GBS pathogenesis and discover the gene pathways that play role in GBS occurrence.