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SUMMARY A number of immunomodulatory molecules are present in the placenta, including cytokines, prostaglandins, progesterone and indoleamine 2,3-dioxygenase. An undefined factor capable of down-regulating T-cell activity has recently been reported [1] as being produced by short-term cultures of placental fragments. By careful repetition of these studies we have confirmed that chorionic villi isolated from term placenta produce a low molecular weight, heat stable factor capable of inhibiting the IL-2-dependent proliferation of mouse CTLL-2 cells. This activity was not due, however, to a previously unknown immunosuppressive molecule, but rather to prostaglandin E2 (PGE2 ). Expression of cyclooxygenase (COX)-2 was detected in the syncytiotrophoblast of chorionic villi explants using immunohistochemistry. Culture of the explants in the presence of the COX-1/COX–2 inhibitors indomethacin and diclofenac, or with the COX-2-selective inhibitor DFP, blocked the production of the immunosuppressive factor. The immunosuppressive activity was restored by adding PGE2 to the supernatants obtained from diclofenac-inhibited explants. A number of different receptors are involved in mediating the biological effects of prostaglandins. By utilizing selective antagonists of individual receptors, we have established that the immunosuppressive effect of PGE2 on CTLL-2 cells is exerted via the EP4 receptor. Thus, addition of an EP4-selective antagonist, but not of EP1 or EP3 antagonists, abolished the immunosuppressive effect of PGE2 on CTLL-2 cells. This may have implications for attempts to selectively manipulate T-cell responses. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disorder that affects the upper and lower motor neurons. Several genetic risk factors have been identified in the past decade with a hexanucleotide repeat expansion in the C9orf72 gene being the most significant. However, the presence of C9orf72 repeat expansion has not been examined in the Transcaucasian region, therefore we aimed to analyse its frequency in Georgian patients with ALS., Methods: We included 64 self-reported Georgian patients with ALS from different parts of the country, fulfilling the Gold Coast criteria. To investigate the presence of an expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene, we performed Repeat-Primed PCR (RP-PCR)., Results: In total, 62 sporadic and two familial ALS cases were identified. Patients were aged 26 to 84 years with a mean age of 58.3 years at disease onset. Bulbar onset was observed in 21.88%, upper limb onset in 34.38%, and lower limb onset in 43.75% of the patients. Frontotemporal dementia (FTD) fulfilling the Strong criteria was diagnosed in seven patients (10.94%). C9orf72 repeat expansion was detected in only one case using RP-PCR; the patient had a family history of dementia., Conclusions: Our results indicate that C9orf72 hexanucleotide expansion does not belong to the major genetic risk factor of ALS in Georgian patients. Further genetic studies in a bigger study population are needed to reveal the genetic causes of ALS in the Transcaucasian population., Competing Interests: No competing interests were disclosed., (Copyright: © 2024 Kekenadze M et al.)

Selective degeneration of motoneurons is the pathological hallmark of amyotrophic lateral sclerosis (ALS). Does serotonin (5-HT) play a role in progression or development of disease is under the research. The topic of the present paper is pressing as there is no data available regarding the spread of amyotrophic lateral sclerosis. It is also noteworthy that previous studies have indicated that the pathogenesis of ALS is closely linked to 5-hydroxytryptamine (5-HT). The clinical research was conducted in Georgia. During the last five years, 60 patients from different parts of Georgia have been studied, searched, and examined by us. Including from Samegrolo, Kartli, Adjara, Abkhazia, Guria, Kakheti regions. The Georgian Neurologists Corps participated and helped us in finding patients. Brain MRI and electromyography were also performed. 60 patients with different forms of ALS participated in the study, including 34 (56.66%) men and 26 (43.33%) women. Their age ranges from 30 to 81 years. The study was conducted after obtaining the written consent of the patients, taking into account the ethical requirements for the study. We also compared the results of the serotonin level of patients with amyotrophic lateral sclerosis with a control group of 20 people (aged 18 to 50 years) who had no neurological disease in past medical history. Patients of the first group, with LMN damage, are observed with decreased amount of serotonin (61.3) %, compared to other pairs, followed by patients of the upper neuron and bulbar syndrome groups, the level of serotonin in the control group is quite high. Thus, the level of serotonin in the group of patients with bulbar events is higher than in the other groups. Low serotonin requires further investigation. According to our research, the longer the anamnesis of amyotrophic lateral sclerosis patients is, the lower the level of serotonin is observed. It should also be taken into account that a low level of serotonin may be due to the presence of depression, which requires additional research. We speculate that 5-HT could therefore be a potential therapeutic target for amyotrophic lateral sclerosis.

Objective - to identify risk factors in patients diagnosed with Amyotrophic Lateral Sclerosis in Georgia directed to The First University Clinic of TSMU and P. Sarajishvili Institute of Neurology. Totally 53 patients, aged 24 to 82 years, were investigated with Amyotrophic Lateral Sclerosis (ALS), defined by "Gold Coast " criteria. We have used the Questionnaire for Environmental Exposures, Toxins, and Neurological diseases developed by Dartmouth-Hitchcock Medical center to identify risk factors, and categorized patients according to the place of settlement and environmental hazards. The control consisted of age and sex matched 50 healthy individuals. The brain was visualized by MRI (1.5T), and Electromyography (EMG) was performed on all patients. ALS risk was higher among those ever holding a job in mechanics, painting, or construction (p<0.05), head trauma or concussion that caused a "blackout" or loss of consciousness was associated with a higher risk of ALS (p<0.01). Demographically more ALS cases were found in Tbilisi and Imereti, compared to other regions (p<0.05). According to our research on Georgian ALS cases, several occupational jobs, Head trauma is associated with developing ALS in Georgia, Research is needed to identify environmental risk factors attributing to higher rates of ALS in Tbilisi and Imereti.

Amyotrophic Lateral sclerosis (ALS ) is a fatal progressive neurodegenerative disease that affects the upper and lower motoneurons. .The disease is characterized by a plethora of neurological symptoms. There is a lot of information in the medical literature about ALS phenotypes, but the clinical diversity of ALS has not been studied in the Caucasus region and a unified clinical picture has not been conclusively established. In this regard, it is very important to study the symptoms among patients with ALS in Georgia. From 2018 to 2021, we examined 47 patients with ALS living in Georgia from different parts of the country, 23 - female, 24 - male, diagnosed based on clinical picture, electromyographic studies (AWAJI) and who met the EL ESCORIAL -Revised criteria. Also clinical symptom studies were conducted using the Mayo Clinic Laboratory Neurological Questionnaire. Cognitive changes were assessed using Addenbrooke's Cognitive Examination scale (ACE III) and the Frontal Behavioral Questionnaire, the patient's quality of life was assessed by ALSFRS-R. Patients were 26 to 84 years old, the age of onset of the disease was 58-60 years in men, 55-57 years in women. The bulbar type was observed in 21.3%, the upper limb type in 38.3% and the lower limb type in 40.4%. Frontotemporal dementia (FTD), diagnosed in 6 patients (12.7%). No reliable correlation was found between the forms of ALS and FTD. The results of the study showed that ALS is a multisystem disease and is not limited to damage to motoneurons. It is safe to say that ALS has characteristics of polysystemic degeneration, with the predominance of motorneuron damage. Therefore, we consider it advisable to screen all patients with ALS for additional symptoms with a focus on the examination of cognitive function, which ensures the proper management of the disease in the future.

In mice, the initial stage of nephrotoxic serum-induced nephritis (NTN) mimics antibody-mediated human glomerulonephritis. Local immune deposits generate tumor necrosis factor (TNF), which activates pro-inflammatory pathways in glomerular endothelial cells (GECs) and podocytes. Because TNF receptors mediate antibacterial defense, existing anti-TNF therapies can promote infection; however, we have previously demonstrated that different functional domains of TNF may have opposing effects. The TIP peptide mimics the lectin-like domain of TNF, and has been shown to blunt inflammation in acute lung injury without impairing TNF receptor-mediated antibacterial activity. We evaluated the impact of TIP peptide in NTN. Intraperitoneal administration of TIP peptide reduced inflammation, proteinuria, and blood urea nitrogen. The protective effect was blocked by the cyclooxygenase inhibitor indomethacin, indicating involvement of prostaglandins. Targeted glomerular delivery of TIP peptide improved pathology in moderate NTN and reduced mortality in severe NTN, indicating a local protective effect. We show that TIP peptide activates the epithelial sodium channel(ENaC), which is expressed by GEC, upon binding to the channel's α subunit. In vitro, TNF treatment of GEC activated pro-inflammatory pathways and decreased the generation of prostaglandin E2 and nitric oxide, which promote recovery from NTN. TIP peptide counteracted these effects. Despite the capacity of TIP peptide to activate ENaC, it did not increase mean arterial blood pressure in mice. In the later autologous phase of NTN, TIP peptide blunted the infiltration of Th17 cells. By countering the deleterious effects of TNF through direct actions in GEC, TIP peptide could provide a novel strategy to treat glomerular inflammation., (Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

To investigate the role of protein kinase C-α (PKC-α) in glomerulonephritis, the capacity of PKC-α inhibition to reverse the course of established nephrotoxic nephritis (NTN) was evaluated. Nephritis was induced by a single injection of nephrotoxic serum and after its onset, a PKC-α inhibitor was administered either systemically or by targeted glomerular delivery. By day seven, all mice with NTN had severe nephritis, whereas mice that received PKC-α inhibitors in either form had minimal evidence of disease. To further understand the underlying mechanism, label-free shotgun proteomic analysis of the kidney cortexes were performed, using quantitative mass spectrometry. Ingenuity pathway analysis revealed 157 differentially expressed proteins and mitochondrial dysfunction as the most modulated pathway. Functional protein groups most affected by NTN were mitochondrial proteins associated with respiratory processes. These proteins were down-regulated in the mice with NTN, while their expression was restored with PKC-α inhibition. This suggests a role for proteins that regulate oxidative phosphorylation in recovery. In cultured glomerular endothelial cells, nephrotoxic serum caused a decrease in mitochondrial respiration and membrane potential, mitochondrial morphologic changes and an increase in glycolytic lactic acid production; all normalized by PKC-α inhibition. Thus, PKC-α has a critical role in NTN progression, and the results implicate mitochondrial processes through restoring oxidative phosphorylation, as an essential mechanism underlying recovery. Importantly, our study provides additional support for targeted therapy to glomeruli to reverse the course of progressive disease., (Copyright © 2018 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

The authors present a case of 75-year-old male patient with typical clinical and electroneuromyographic signs of Amyotrophic Lateral Sclerosis (ALS), manifested in 4 years after a diagnosis of generalized Myasthenia Gravis (MG) had been made. The aim of the article is to assess the possibility of pathogenetic integrated comorbidity of MG and ALS, which may have resulted from a common aberrant immune process and to emphasize the importance of detailed clinical analysis and adequate diagnostic methods essential for correct diagnosis and treatment. Only several cases of coexistence of MG and ALS have been described in medical literature. Exploring the pathogenetic association between MG and ALS may lead to dysregulation of thea immune system. Deficiency of T-regulatory cells, increased activity of atrophy-related atrogenes, anomalies of neuronal nitric oxide synthase can be found in both diseases. Immunoglobulin isolated from ALS patients can affect neuromuscular junction and activate AChRs, which plays an important role in the innervation and re-innervation of muscle fibers. Immunoglobulin also changes the function of Ca2+ channels. Blood level of circulatory Heat Shock Protein 70 (HSP70) antibodies in MG patients is elevated. HSP70 maintains normal conformation of cell proteins. Conversely, HSP70 antibodies cause HSP70's dysfunction and therefore, abnormal protein synthesis, which can be the main reason of neurodegenerative diseases, such as ALS. Experimental evidence indicates, that muscle and neuromuscular junctions may be initial targets of ALS. According to the "dying-back" hypothesis, neuromuscular junction damage and failure in MG patients may precede lower and upper motor neuron loss, and thus increase risk of developing ALS. Pathogenetic mechanisms of MG and ALS are the subjects of further studies. Refining the etiology of these two diseases will answer the question whether it is a transformation or a coexistence of MG and ALS in our case. The presented case demonstrates, that in spite of meeting all diagnostic criteria it is, sometimes, impossible to make the correct diagnosis. Only a detailed clinical analysis and adequate diagnostic methods contribute to correct diagnosis and adequate therapy.

Current therapies to limit kidney disease progression lack specificity and often have systemic toxicity. To approach this problem, we postulated that a human monoclonal antibody (F1.1), directed against the noncollagenous-1 domain (NC1) of α3(IV) collagen that localizes in glomeruli, could serve as a vehicle for targeted drug delivery. Given enhanced exposure of the NC1 domain of α3(IV) during glomerular diseases, with limited epitope expression in other organs, α3(IV)NC1 provides an ideal target for delivery of disease-modifying agents. As a potential disease-modifying agent, we initially took advantage of recent observations that PGE2 promoted recovery after established injury during the course of nephrotoxic nephritis. To address the general applicability of the approach, the efficacy of glomerular delivery of dexamethasone was also examined. To achieve glomerular targeted therapy, PGE2 and dexamethasone were coupled to F1.1. After confirmation of the composition and activity of the conjugates, both glomerular localization and the capacity of the conjugates to modify disease were evaluated. After injection into mice with established nephritis, resolution of disease was enhanced with both agents, with normalization of histology and improved blood urea nitrogen levels in conjugate-treated mice compared with untreated mice. The results provide a novel means of targeting glomeruli during nephritis, irrespective of cause, by providing efficient drug delivery, with the potential of limiting systemic effects., (Copyright © 2015 the American Physiological Society.)

Case report with review describes X-linked muscular dystrophy with contractures in 28 years old man and his cousin. The disease revealed itself in an early stage (age 5-10), the process was progressing with apparent tendons retraction and contraction, limited movement in the areas of the neck and back of spine, atrophy of shoulder and pelvic yard and back muscles. Intellect was intact. Cardyomyopathy was exhibited. CK was normal. EMG showed classic myopathic features. Muscle biopsy showed different caliber groups of muscle fibers, growth of endo-perimesial connective tissue. Clinical manifestations together with electrophysiological and histological data suggest consistency with Rotthauwe-Mortier-Bayer X-linked muscular dystrophy.

Inflammatory kidney disease is a major clinical problem that can result in end-stage renal failure. In this article, we show that Ab-mediated inflammatory kidney injury and renal disease in a mouse nephrotoxic serum nephritis model was inhibited by amino acid metabolism and a protective autophagic response. The metabolic signal was driven by IFN-γ-mediated induction of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme activity with subsequent activation of a stress response dependent on the eIF2α kinase general control nonderepressible 2 (GCN2). Activation of GCN2 suppressed proinflammatory cytokine production in glomeruli and reduced macrophage recruitment to the kidney during the incipient stage of Ab-induced glomerular inflammation. Further, inhibition of autophagy or genetic ablation of Ido1 or Gcn2 converted Ab-induced, self-limiting nephritis to fatal end-stage renal disease. Conversely, increasing kidney IDO1 activity or treating mice with a GCN2 agonist induced autophagy and protected mice from nephritic kidney damage. Finally, kidney tissue from patients with Ab-driven nephropathy showed increased IDO1 abundance and stress gene expression. Thus, these findings support the hypothesis that the IDO-GCN2 pathway in glomerular stromal cells is a critical negative feedback mechanism that limits inflammatory renal pathologic changes by inducing autophagy., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Objectives: There is a large spectrum of viral, bacterial, fungal, and prion pathogens that cause central nervous system (CNS) infections. As such, identification of the etiological agent requires multiple laboratory tests and accurate diagnosis requires clinical and epidemiological information. This hospital-based study aimed to determine the main causes of acute meningitis and encephalitis and enhance laboratory capacity for CNS infection diagnosis., Methods: Children and adults patients clinically diagnosed with meningitis or encephalitis were enrolled at four reference health centers. Cerebrospinal fluid (CSF) was collected for bacterial culture, and in-house and multiplex RT-PCR testing was conducted for herpes simplex virus (HSV) types 1 and 2, mumps virus, enterovirus, varicella zoster virus (VZV), Streptococcus pneumoniae, HiB and Neisseria meningitidis., Results: Out of 140 enrolled patients, the mean age was 23.9 years, and 58% were children. Bacterial or viral etiologies were determined in 51% of patients. Five Streptococcus pneumoniae cultures were isolated from CSF. Based on in-house PCR analysis, 25 patients were positive for S. pneumoniae, 6 for N. meningitidis, and 1 for H. influenzae. Viral multiplex PCR identified infections with enterovirus (n = 26), VZV (n = 4), and HSV-1 (n = 2). No patient was positive for mumps or HSV-2., Conclusions: Study findings indicate that S. pneumoniae and enteroviruses are the main etiologies in this patient cohort. The utility of molecular diagnostics for pathogen identification combined with the knowledge provided by the investigation may improve health outcomes of CNS infection cases in Georgia.

We postulated that prostaglandin E2 (PGE2), which exhibits regulatory functions to control immune-mediated inflammation, fibrosis, oxidative stress, and tissue/cellular regeneration, has the potential to improve the course of nephritis. Therefore, the therapeutic potential of prostanoid on established nephritis in mice was evaluated focusing on its role on renal cellular recovery, with emphasis on its cytoprotecting and growth-promoting effects. Acute nephritis was induced in mice by single injection of nephrotoxic serum (NTS), followed by PGE2 administration with severity of nephritis evaluated over time. Mice injected with PGE2 recovered promptly with normalization of blood urea nitrogen and urine protein levels and histology. Recovery was observed with dosing of prostanoid at day 1, as well as day 4. With the use of selective EP1-4 receptor agonists, EP3 receptor has been identified as important in mediating beneficial effects of PGE2 in our system. PGE2 normalized glomerular cell losses during nephrotoxic serum-induced nephritis, restored synaptopodin distribution and F-actin filaments arrangement in glomeruli. In cell culture, PGE2 reduced nephrotoxim serum (NTS)-induced apoptosis of glomerular cells and promoted cell reproliferation after NTS-mediated injury. In conclusion, PGE2 treatment promotes resolution of glomerular inflammation. Consistent with this observation, the regenerative and cytoprotective effects of prostanoid on glomerular cells in culture were observed, suggesting that PGE2 may be beneficial in the treatment of glomerulonephritis.