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.

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.

Analgesic Choice in Management of Rib Fractures: Paravertebral Block or Epidural Analgesia?

BACKGROUND: Rib fractures are commonly encountered in the setting of trauma. The aim of this study was to assess the association between the clinical outcome of rib fracture and epidural analgesia (EA) versus paravertebral block (PVB) using the National Trauma Data Bank (NTDB). METHODS: Using the 2011 and 2012 versions of the NTDB, we retrieved completed records for all patients above 18 years of age who were admitted with rib fractures. Primary outcome was in-hospital mortality. Secondary outcomes were length of stay (LOS), intensive care unit (ICU) admission, ICU LOS, mechanical ventilation, duration of mechanical ventilation, development of pneumonia, and development of any other complication. Clinical outcomes were first compared between propensity score-matched EA and PVB patients. Then, EA and PVB patients were combined into the procedure group and the outcomes were compared with propensity score-matched patients that received neither intervention (no-procedure group). RESULTS: A total of 194,766 patients were included in the study with 1073 patients having EA, 1110 patients having PVB, and 192,583 patients having neither procedure. After propensity score matching, comparison of primary and secondary outcomes between EA and PVB patients showed no difference. Comparison of propensity score-matched procedure and no-procedure patients showed prolonged LOS and more frequent ICU admissions in patients receiving a procedure (both P < .0001), yet having no procedure was associated with a significantly increased odds of mortality (odds ratio: 2.25; 95% confidence interval, 1.14-3.84; P = .002). CONCLUSIONS: Using the NTDB, EA and PVB were not found to be significantly different in management of rib fractures. There was an association between use of a block and improved outcome, but this could be explained by selection of healthier patients to receive a block. Prospective study of this association is recommended.

Utility of Prophylactic Antibiotics in Nonoperative Facial Fractures.

Facial fractures are commonly managed nonoperatively. Patients with facial fractures involving sinus cavities commonly receive 7 to 10 days of prophylactic antibiotics, yet no literature exists to support or refute this practice. The aim of this study was to compare the administration and duration of antibiotic prophylaxis on the incidence of soft tissue infection in nonoperative facial fractures. A total number of 289 patients who were admitted to our level I trauma center with nonoperative facial fractures from the beginning of 2012 to the end of 2014 were studied. Patients were categorized into 3 groups: no antibiotic prophylaxis, short-term antibiotic prophylaxis (1-5 days), and long-term antibiotic prophylaxis (>5 days). The primary outcome was the incidence of facial soft tissue infection and Clostridium difficile colitis. Fifty patients received no antibiotic prophylaxis. Sixty-three patients completed a short course of antibiotic prophylaxis and 176 patients received long-term antibiotics. Ampicillin/sulbactam, amoxicillin/clavulanic acid, or a combination of both were used in 216 patients. Twenty-three patients received clindamycin due to penicillin allergy. Short and long courses of antibiotic prophylaxis were administered more commonly in patients with concomitant maxillary and orbital fractures (P <0.0001). No mortality was found in any group. Soft tissue infection was not identified in any patient. C. difficile colitis was identified in 1 patient who had received a long course of antibiotic prophylaxis (P = 0.7246). There was no difference in the outcome of patients receiving short-term, long-term, and no antibiotic prophylaxis. Prospective randomized studies are needed to provide further clinical recommendations.

Murine membranous nephropathy: immunization with α3(IV) collagen fragment induces subepithelial immune complexes and FcγR-independent nephrotic syndrome.

Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults and a significant cause of end-stage renal disease, yet current therapies are nonspecific, toxic, and often ineffective. The development of novel targeted therapies requires a detailed understanding of the pathogenic mechanisms, but progress is hampered by the lack of a robust mouse model of disease. We report that DBA/1 mice as well as congenic FcγRIII(-/-) and FcRγ(-/-) mice immunized with a fragment of α3(IV) collagen developed massive albuminuria and nephrotic syndrome, because of subepithelial deposits of mouse IgG and C3 with corresponding basement membrane reaction and podocyte foot process effacement. The clinical presentation and histopathologic findings were characteristic of MN. Although immunized mice produced genuine anti-α3NC1 autoantibodies that bound to kidney and lung basement membranes, neither crescentic glomerulonephritis nor alveolitis ensued, likely because of the predominance of mouse IgG1 over IgG2a and IgG2b autoantibodies. The ablation of activating IgG Fc receptors did not ameliorate injury, implicating subepithelial deposition of immune complexes and consequent complement activation as a major effector pathway. We have thus established an active model of murine MN. This model, leveraged by the availability of genetically engineered mice and mouse-specific reagents, will be instrumental in studying the pathogenesis of MN and evaluating the efficacy of novel experimental therapies.

Making the "inoperable" tumors "operable": Harvey Cushing's contributions to the surgery of posterior fossa tumors.

Harvey Cushing played a pivotal role in establishing neurosurgery as a distinct surgical discipline. One of his most important contributions was defining the surgical removal of posterior fossa tumors. Compulsive preoperative evaluation followed by meticulous surgical technique as well as incorporation of maneuvers such as ventricular puncture and electrocautery further advanced resection of tumors in this region. Herein, the authors review Cushing's contributions to posterior fossa surgery.

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.

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.

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.

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.

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.

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.

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.

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.

Diagnostic values of GHSR DNA methylation pattern in breast cancer.

DNA methylation patterns have been recognised as cancer-specific markers with high potential for clinical applications. We aimed at identifying methylation variations that differentiate between breast cancers and other breast tissue entities to establish a signature for diagnosis. Candidate genomic loci were analysed in 117 fresh-frozen breast specimens, which included cancer, benign and normal breast tissues from patients as well as material from healthy individuals. A cancer-specific DNA methylation signature was identified by microarray analysis in a test set of samples (n = 52, p < 2.1 × 10(-4)) and its performance was assessed through bisulphite pyrosequencing in an independent validation set (n = 65, p < 1.9 × 10(-7)). The signature is associated with SFRP2 and GHSR genes, and exhibited significant hypermethylation in cancers. Normal-appearing breast tissues from cancer patients were also methylated at these loci but to a markedly lower extent. This occurrence of methylated DNA in normal breast tissue of cancer patients is indicative of an epigenetic field defect. Concerning diagnosis, receiver operating characteristic curves and the corresponding area under the curve (AUC) analysis demonstrated a very high sensitivity and specificity of 89.3 and 100 %, respectively, for the GHSR methylation pattern (AUC >0.99). To date, this represents the DNA methylation marker of the highest sensitivity and specificity for breast cancer diagnosis. Functionally, ectopic expression of GHSR in a cell line model reduced breast cancer cell invasion without affecting cell viability upon stimulation of cells with ghrelin. Our data suggest a link between epigenetic down-regulation of GHSR and breast cancer cell invasion.