Subtype 1a Research Articles

Pharmacogenetic Factors Influence Escitalopram Pharmacokinetics and Adverse Events in Youth with a Family History of Bipolar Disorder: A Preliminary Study.

Introduction: Escitalopram is an effective and generally well-tolerated antidepressant, but children of parents with bipolar disorder (BD) may be at increased risk for adverse events associated with antidepressants, including increased irritability, restlessness, impulsivity, and manic symptoms. This risk may be influenced by polymorphisms in genes encoding cytochrome P450 enzymes (CYP2C19 or CYP2D6), the serotonin transporter (SLC6A4), and the serotonin receptor 2A subtype (HTR2A). We explored whether gene-drug interactions influence the emergence of adverse events in depressed and/or anxious youth with a family history of BD. Materials and Methods: Children and adolescents aged 12-17 years with a first-degree relative with bipolar I disorder were treated with escitalopram and monitored for adverse effects, underwent pharmacogenetic testing, and provided serum escitalopram levels. Emergence of adverse events was determined by study clinicians, and symptoms were tracked using the Treatment-Emergent Activation and Suicidality Assessment Profile (TEASAP) and Pediatric Adverse Events Rating Scale. Clinical Pharmacogenetics Implementation Consortium guidelines were used to determine CYP2C19 and CYP2D6 phenotypes. Results: Slower CYP2C19 metabolizers had greater dose-normalized 24-hour area under the curve (AUC0-24; p = 0.025), trough concentrations (Ctrough; p = 0.013), and elimination half-lives (t1/2; p < 0.001). CYP2D6 phenotype was not significantly associated with any pharmacokinetic parameter. Slower CYP2D6 metabolizers had increased TEASAP akathisia (p = 0.015) scores. HTR2A A/A and A/G genotypes were associated with increased TEASAP "self-injury, suicidality, and harm to others" subscale scores (p = 0.017). Escitalopram maximum concentration, AUC0-24, CYP2C19 phenotype, and SLC6A4 genotype were not associated with adverse events. Conclusions: CYP2C19 phenotype influences escitalopram pharmacokinetics whereas CYP2D6 phenotype does not. Slower CYP2D6 metabolism was associated with increased akathisia, and HTR2A A/A or A/G genotypes were associated with increased risk of self-harm or harm to others. Larger cohorts are needed to identify associations between genetic test results and antidepressant-associated adverse events. Trial Registration: ClinicalTrials.gov identifier: NCT02553161.

Epidemiology of hepatitis C infection among pregnant women and parturients in Nizhny Novgorod

Hepatitis C is an urgent global health problem. The high prevalence of infection among the population leads to the involvement of women of reproductive age in the epidemic process. In order to study the prevalence of specific markers of hepatitis C virus in pregnant women and to assess the risk of intrauterine infection of the fetus, an epidemiologic analysis was conducted using information collections of statistical and analytical materials of Rospotrebnadzor, blood serum samples of pregnant and postpartum women (n = 28394) at admission to obstetric institutions for the period 2018–2022 were examined. According to statistical reporting, the average annual prevalence of anti-HCV prevalence in pregnant women was 1.7% (95% CI: 1.5–1.9%). Women aged 40–49 years were found to be most actively involved in the epidemic process (4.3% [95% CI: 3.3–5.6%]). Among anti-HCV-positive samples, HCV RNA was detected in 47.0% (95% CI: 41.7–52.9%) of cases, the prevalence of current infection confirmed by HCV RNA detection in pregnant women was 0.9% (95% CI: 0.8–1.0%). The pattern of HCV genotypes in pregnant women was as follows: subtype 1b was detected in 34.9% (95% CI: 25.6–45.7%) of cases, subtype 3a in 42.2% (95% DI: 32.1–52.9%), minor subtype 1a was 9.6% (95% CI: 5.0–17.9%) and genotype 2 was 7.0% (95% CI: 3.4–14.9%). Samples containing two genotypes simultaneously (1a/1b, 1b/3a) were 3.6% (95% CI: 1.2–10.1%) and non-genotyped samples were 2.4% (95% CI: 0.7–4.1%). The results of the assessment of the significance of risk factors for perinatal transmission of hepatitis C virus show a high degree of influence on vertical transmission of HCV RNA in the presence of active infection in the mother (RR = 6.4; [95% CI: 0.9–44.6%]: p &lt; 0.05), no statistical significance of HCV genotypic affiliation (p &gt; 0.05) and maternal viral load level (R = 0.00009; p &gt; 0.05). The obtained data argue the necessity of screening examinations for molecular genetic markers of hepatitis C virus in women planning pregnancy in order to conduct antiviral therapy and, as a consequence, to reduce the risk of perinatal infection of children.

Alpha-7 Nicotinic Receptor Agonist Protects Mice Against Pulmonary Emphysema Induced by Elastase.

Pulmonary emphysema is a primary component of chronic obstructive pulmonary disease (COPD), a life-threatening disorder characterized by lung inflammation and restricted airflow, primarily resulting from the destruction of small airways and alveolar walls. Cumulative evidence suggests that nicotinic receptors, especially the α7 subtype (α7nAChR), is required for anti-inflammatory cholinergic responses. We postulated that the stimulation of α7nAChR could offer therapeutic benefits in the context of pulmonary emphysema. To investigate this, we assessed the potential protective effects of PNU-282987, a selective α7nAChR agonist, using an experimental emphysema model. Male mice (C57BL/6) were submitted to a nasal instillation of porcine pancreatic elastase (PPE) (50µl, 0.667IU) to induce emphysema. Treatment with PNU-282987 (2.0mg/kg, ip) was performed pre and post-emphysema induction by measuring anti-inflammatory effects (inflammatory cells, cytokines) as well as anti-remodeling and anti-oxidant effects. Elastase-induced emphysema led to an increase in the number of α7nAChR-positive cells in the lungs. Notably, both groups treated with PNU-282987 (prior to and following emphysema induction) exhibited a significant decrease in the number of α7nAChR-positive cells. Furthermore, both groups treated with PNU-282987 demonstrated decreased levels of macrophages, IL-6, IL-1β, collagen, and elastic fiber deposition. Additionally, both groups exhibited reduced STAT3 phosphorylation and lower levels of SOCS3. Of particular note, in the post-treated group, PNU-282987 successfully attenuated alveolar enlargement, decreased IL-17 and TNF-α levels, and reduced the recruitment of polymorphonuclear cells to the lung parenchyma. Significantly, it is worth noting that MLA, an antagonist of α7nAChR, counteracted the protective effects of PNU-282987 in relation to certain crucial inflammatory parameters. In summary, these findings unequivocally demonstrate the protective abilities of α7nAChR against elastase-induced emphysema, strongly supporting α7nAChR as a pivotal therapeutic target for ameliorating pulmonary emphysema.

The role of recombination variability to the formation of the population the HIV‐1 population circulating in the Primorsky Krai, Russia

Aim. To research the molecular epidemiological features of the territorial spread of HIV infection and the influence of recombination variability on the formation of the HIV‐1 population in the Primorsky Krai, Russia. Materials and Methods. A comprehensive analysis of the molecular genetic characteristics of HIV‐1 and clinical‐epidemiological data of 127 HIV‐infected residents of Primorsky Krai was performed. The nucleotide sequences of the pol gene region encoding protease, reverse transcriptase and integrase of HIV‐1 were obtained by the sequencing of amplified fragments of the virus. Genotyping, phylogenetic, and mutational analyses were performed using specialised software resources. Results. In the samples studied of HIV‐1 isolated in the Primorsky Krai, the dominance of HIV‐1 subtype A6 was detected as 40.9 %. The prevalence of subtype B viruses is high compared to other Russian regions – 29.9 %. The HIV‐1 subtype C was found in 6.3 % of the samples studied; circulating recombinant forms CRF63_02A6 – 6.3 %, CRF02_AG – 0.8 %. Unique viruses resulting from the recombination of HIV subtypes A6 and B, A6 and C, C and B were found in 15.7 % of cases (URF_A6C, URF_CB, URF_BA6). Of the 18 HIV‐1 URFs described, 14 were variants of URF_A6C (11 %). Analysis of the near full‐length genome (NFLG) of URF_A6C made it possible to find and describe a new HIV genovariant spreading in Primorye ‐ CRF157_A6C. Conclusion. The analysis of HIV‐1 circulating in the Primorsky Krai confirmed that a specific molecular epidemic situation is developing in the region, which is characterized by active transmission of viruses not only of subtype A6, but also of subtypes B and C, which is not observed in other regions of Russia. For the first time in the Far East, a high frequency of HIV‐1 new unique recombinant forms occurrence has been described, some variants of which are beginning to spread among residents of the Primorsky Krai. An increase in the genetic heterogeneity of the viral population due to recombination variability of HIV is a negative prognostic factor for the territorial epidemic progress of HIV infection in the Far East.

UHPLC-MS/MS combined with microdialysis for simultaneous determination of nicotine and neurotransmitter metabolites in the rat hippocampal brain region: application to pharmacokinetic and pharmacodynamic study.

Nicotine crosses the blood-brain barrier and interacts with nicotinic acetylcholine receptors, initiating a cascade of neurotransmitter effects with potential therapeutic implications for neurodegenerative conditions such as Alzheimer's and Parkinson's disease. The hippocampus, pivotal for cognitive processes, plays a crucial role in nicotine-mediated cognitive enhancement due to its abundant expression of nicotinic acetylcholine receptors, particularly the α7 subtype, which is heavily implicated in hippocampus-related behavioral functions and dysfunctions. However, the intricate process of nicotine metabolism within the hippocampus remains poorly understood, impeding our comprehension of how nicotine and its metabolites modulate neurotransmitter dynamics. To address this gap, we have developed and validated a novel methodology combining microdialysis with UHPLC-MS/MS, enabling simultaneous detection of 12 neurotransmitters, nicotine, and its seven metabolites within the rat hippocampus. The linearity range of the targeted compounds is satisfactory (R2 > 0.9970), with intra-day and inter-day precision not exceeding 12.7%, and accuracy ranging from -12.4% to 13.7%. Our findings reveal differential pharmacokinetics of nicotine and its metabolites in the α7KO group compared to the control group, characterized by heightened nicotine absorption and slower elimination and distribution in the former. Notably, the pharmacokinetic parameters of cotinine exhibit similarity across both groups. Studies investigating the impact of nicotine on monoamine neurotransmitters have elucidated its capacity to augment the release of dopamine, serotonin, norepinephrine, glutamate, and acetylcholine in the rat hippocampus. This integrated approach facilitates a comprehensive analysis of neurotransmitter alterations within the hippocampal region following nicotine administration, thereby providing robust technical support and scientific rationale for understanding the neurochemical effects of nicotine and its metabolites. Further exploration into the pharmacokinetics and pharmacodynamics of nicotine holds promise for uncovering novel therapeutic avenues in the management of neurodegenerative diseases such as Alzheimer's.

The molecular epidemiology of hepatitis E virus genotype 3 in Canada.

Autochthonous hepatitis E virus (HEV) infection is increasingly reported in industrialized countries and is mostly associated with zoonotic HEV genotype 3 (HEV-3). In this study, we examined the molecular epidemiology of 63 human clinical HEV-3 isolates in Canada between 2014 and 2022. Fifty-five samples were IgM positive, 45 samples were IgG positive and 44 were IgM and IgG positive. The majority of the isolates belong to the subtypes 3a, 3b, and 3j, with high sequence homology to Canadian swine and pork isolates. There were a few isolates that clustered with subtypes 3c, 3e, 3f, 3h, and 3g, and an isolate from chronic infection with a rabbit strain (3ra). Previous studies have demonstrated that the isolates from pork products and swine from Canada belong to subtypes 3a and 3b, therefore, domestic swine HEV is likely responsible for the majority of clinical HEV cases in Canada and further support the hypothesis that swine serve as the main reservoirs for HEV-3 infections. Understanding the associated risk of zoonotic HEV infection requires the establishment of sustainable surveillance strategies at the interface between humans, animals, and the environment within a One-Health framework.

Genotype Variation of HIV/HCV Co-infections in Karachi, Pakistan

Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) are among major health issues that affect a large section of the world's population. While HCV affects around 170 million people worldwide, HIV affects 3% of the global population, with 10 million HCV cases documented in Pakistan alone. Co-infection with HIV and HCV results in a variety of genotypic patterns, with significant global heterogeneity in the incidence of spontaneous resolution of hepatitis C and the distribution of HCV genotypes among co-infected individuals. Co-infection is usually transmitted by sexual contact, contaminated blood supplies, and mother-to-child transmission, with high-risk populations like intravenous drug users (IDUs), and men who have sex with men (MSM) having increased vulnerability. This study, conducted in Karachi, Pakistan, aimed to explore the predominant genotypes and viral load of HIV and HCV. The genetic features of the HIV Gag and HCV NS5b genes were examined using genotyping techniques and phylogenetic methodology. The study revealed that out of the 150 individuals examined, 70 were diagnosed with HIV alone, 55 with HCV only, and 25 had both HIV and HCV infections concurrently. Furthermore, genetic analysis demonstrated that HIV-1 subtype A1 was the predominant genotype, with subtype C closely following. In the case of HCV, genotype 3a was the most prevalent in both mono- and co-infected individuals. Notably, individuals with dual infections exhibited limited genotypic variability for each virus. In the case of HIV co-infection, there was an elevation in viral load, while HCV demonstrated lower viremia relative to mono-infection. In conclusion, the study revealed the predominance of HIV-1 subtype A1 and HCV genotype 3a, as well as an elevated level of HIV and a lowered level of HCV in co-infection.

Distribution pattern, molecular transmission networks, and phylodynamic of hepatitis C virus in China.

In China, few molecular epidemiological data on hepatitis C virus (HCV) are available and all previous studies were limited by small sample sizes or specific population characteristics. Here, we report characterization of the epidemic history and transmission dynamics of HCV strains in China. We included HCV sequences of individuals belonging to three HCV surveillance programs: 1) patients diagnosed with HIV infection at the Beijing HIV laboratory network, most of whom were people who inject drugs and former paid blood donors, 2) men who have sex with men, and 3) the general population. We also used publicly available HCV sequences sampled in China in our study. In total, we obtained 1,603 Ns5b and 865 C/E2 sequences from 1,811 individuals. The most common HCV strains were subtypes 1b (29.1%), 3b (25.5%) and 3a (15.1%). In transmission network analysis, factors independently associated with clustering included the region (OR: 0.37, 95% CI: 0.19-0.71), infection subtype (OR: 0.23, 95% CI: 0.1-0.52), and sampling period (OR: 0.43, 95% CI: 0.27-0.68). The history of the major HCV subtypes was complex, which coincided with some important sociomedical events in China. Of note, five of eight HCV subtype (1a, 1b, 2a, 3a, and 3b), which constituted 81.8% HCV strains genotyped in our study, showed a tendency towards decline in the effective population size during the past decade until present, which is a good omen for the goal of eliminating HCV by 2030 in China.

Comprehensive Genetic Characterization of Four Novel HIV-1 Circulating Recombinant Forms (CRF129_56G, CRF130_A1B, CRF131_A1B, and CRF138_cpx): Insights from Molecular Epidemiology in Cyprus.

Molecular investigations of the HIV-1 pol region (2253-5250 in the HXB2 genome) were conducted on sequences obtained from 331 individuals infected with HIV-1 in Cyprus between 2017 and 2021. This study unveiled four distinct HIV-1 putative transmission clusters, encompassing 19 previously unidentified HIV-1 recombinants. These recombinants, each comprising eight, three, four, and four sequences, respectively, did not align with previously established Circulating Recombinant Forms (CRFs). To characterize these novel HIV-1 recombinants, near-full-length genome sequences were successfully obtained for 16 of the 19 recombinants (790-8795 in the HXB2 genome) using an in-house-developed RT-PCR assay. Phylogenetic analyses, employing MEGAX and Cluster-Picker, along with confirmatory neighbor-joining tree analyses of subregions, were conducted to identify distinct clusters and determine subtypes. The uniqueness of the HIV-1 recombinants was evident in their exclusive clustering within generated maximum likelihood trees. Recombination analyses highlighted the distinct chimeric nature of these recombinants, with consistent mosaic patterns observed across all sequences within each of the four putative transmission clusters. Conclusive genetic characterization identified four novel HIV-1 CRFs: CRF129_56G, CRF130_A1B, CRF131_A1B, and CRF138_cpx. CRF129_56G exhibited two recombination breakpoints and three fragments of subtypes CRF56_cpx and G. Both CRF130_A1B and CRF131_A1B featured seven recombination breakpoints and eight fragments of subtypes A1 and B. CRF138_cpx displayed five recombination breakpoints and six fragments of subtypes CRF22_01A1 and F2, along with an unclassified fragment. Additional BLAST analyses identified a Unique Recombinant Form (URF) of CRF138_cpx with three additional recombination sites, involving subtype F2, a fragment of unknown subtype origin, and CRF138_cpx. Post-identification, all putative transmission clusters remained active, with CRF130_A1B, CRF131_A1B, and CRF138_cpx clusters exhibiting further growth. Furthermore, international connections were identified through BLAST analyses, linking one sequence from the USA to the CRF130_A1B strain, and three sequences from Belgium and Cameroon to the CRF138_cpx strain. This study contributes valuable insights into the dynamic landscape of HIV-1 diversity and transmission patterns, emphasizing the need for ongoing molecular surveillance and global collaboration in tracking emerging viral variants.

Interplay between HIV and Human Pegivirus (HPgV) Load in Co-Infected Patients: Insights from Prevalence and Genotype Analysis.

Human pegivirus (HPgV) is transmitted through sexual or parenteral exposure and is common among patients receiving blood products. HPgV is associated with lower levels of human immunodeficiency virus (HIV) RNA and better survival among HIV-infected patients. This study aimed to investigate the prevalence of HPgV and determine its subtypes in HIV-infected individuals living in Istanbul, which has the highest rate of HIV infection in Türkiye. Total RNA extraction from plasma, cDNA synthesis, and nested PCR were performed for HPgV on plasma samples taken from 351 HIV-1-infected patients. The HPgV viral load was quantified on HPgV-positive samples. HPgV genotyping was performed by sequencing the corresponding amplicons. In the present study, the overall prevalence of HPgV RNA in HIV-infected patients was 27.3%. HPgV subtypes 1, 2a, and 2b were found, with subtype 2a being the most frequent (91.6%). Statistical analysis of HIV-1 viral load on HPgV viral load showed an opposing correlation between HIV-1 and HPgV loads. In conclusion, these data show that HPgV infection is common among HIV-positive individuals in Istanbul, Türkiye. Further comprehensive studies are needed to clarify both the cellular and molecular pathways of these two infections and to provide more information on the effect of HPgV on the course of the disease in HIV-infected individuals.

A COMPREHENSIVE REVIEW ON PHARMACOLOGICAL POTENTIALS OF CAFFEINE

Caffeine is a naturally occurring methylxanthine compound found in various plants, such as coffee beans, tea leaves, and cocoa beans. It is widely consumed worldwide in the form of beverages, dietary supplements, and medications. Caffeine exerts its pharmacological effects primarily through its interaction with adenosine receptors, resulting in widespread physiological and neurological changes. In the field of medicinal chemistry, caffeine has been extensively studied due to its diverse pharmacological actions and potential therapeutic applications. This abstract highlights the key pharmacological actions of caffeine and its relevance in medicinal chemistry research. Caffeine acts as a non-selective antagonist of adenosine receptors, particularly the A1 and A2A subtypes. By inhibiting adenosine binding, caffeine prevents the activation of these receptors, leading to increased neural activity and the release of neurotransmitters such as dopamine and glutamate. This mechanism of action underlies caffeine’s stimulant effects, including increased alertness, reduced fatigue, and improved cognitive function. Caffeine exhibits broncho dilatory effects by acting as a phosphodiesterase inhibitor, primarily targeting phosphodiesterase type 4 (PDE4). Inhibition of PDE4 prevents the breakdown of cyclic adenosine monophosphate (cAMP), leading to smooth muscle relaxation and bronchodilation. This property of caffeine has been utilized in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Furthermore, caffeine possesses diuretic properties by inhibiting the reabsorption of sodium in the renal tubules. This leads to increased water excretion and urine production. The diuretic effects of caffeine have found applications in the management of fluid overload conditions, such as edema and heart failure. Additionally, caffeine has been investigated for its potential anticancer properties. Several studies have shown that caffeine can enhance the cytotoxic effects of certain chemotherapeutic agents, inhibit DNA repair mechanisms, and induce apoptosis in cancer cells. These findings have sparked interest in caffeine as an adjuvant therapy for cancer treatment, although further research is needed to establish its clinical efficacy and safety. In conclusion, caffeine exhibits a wide range of pharmacological actions, making it a versatile compound in medicinal chemistry research. Its interactions with adenosine receptors, phosphodiesterase, and renal tubules contribute to its stimulant, broncho dilatory, diuretic, and potentially anticancer effects. The understanding of caffeine’s pharmacological actions provides valuable insights for the development of novel drugs and therapeutic approaches in various fields of medicine.

First Molecular Characterization of Small Ruminant Lentiviruses Detected in Romania

Small ruminant lentiviruses (SRLVs) are a group of retroviruses that cause multisystem chronic diseases in goats and sheep and lead to production losses in these animals, negatively affecting animal health and welfare. Although molecular characterization of SRLV field isolates has been performed in many countries, there is currently no information on SRLV genotypes circulating in sheep and goats in Romania. Therefore, the main objective of this study was to conduct a molecular and phylogenetic analysis of SRLVs from Romania and determine the degree of genetic relatedness of the obtained sequences to other known SRLV reference strains. A total of 81 sheep lung tissue samples and 41 sheep lung lymph node samples were tested using nested real-time PCR, and samples positive for real-time PCR were used to amplify an 800 bp gag-pol fragment and an overlapping 625 bp fragment of the gag gene. Pairwise DNA distance and phylogenetic analysis showed that the Romanian SRLV strains were closely related to the A2 and A3 strains based on gag-pol sequences and to the A3 and A17 subtypes based on gag sequences. No recombination events were found. Our results revealed that the Romanian sequences have similar epitope patterns to other existing subtypes, although E/K and R/K mutations in epitope 3 were found only in the Romanian sequences, which may have potential value in serological diagnosis. This study is the first report on the genetic characterization of SRLV strains circulating in Romania and provides new information on SRLV heterogeneity. Further detailed studies should be conducted to better understand the divergence of SRLV Romanian strains.

Exploring Psilocybe spp. mycelium and fruiting body chemistry for potential therapeutic compounds

Psilocybe mushrooms, otherwise known as “magic” mushrooms, owe their psychedelic effect to psilocin, a serotonin subtype 2A (5-HT2A) receptor agonist and metabolite of psilocybin, the primary indole alkaloid found in Psilocybe species. Metabolomics is an advanced fingerprinting tool that can be utilized to identify the differences among fungal life stages that may otherwise be unaccounted for. In this study, by using targeted and untargeted (metabolomic) multivariate analysis, we demonstrate that the chemical composition of Psilocybe differs among mycelia, grain mycelia, and fruiting bodies. The preferential accumulation of psilocybin, baeocystin, tryptophan, ergothioneine, and phenylethylamine in fruiting bodies differentiated them from mycelia; however, the levels of alpha-glycerylphosphorylcholine (α-GPC), N-acetylglucosamine, and trimethylglycine were found to be proportionally higher in mycelia than in fruiting bodies based on Pareto-scaled data. Considering the wealth of compounds with therapeutic potential that have been isolated from various fungal genera, it would be pertinent to study the compounds found in Psilocybe mycelia as potential naturally derived therapeutic targets.

ApoE Mimic Peptide COG1410 Reduces Aβ Deposition and Improves Cognitive Function by Inducing the Transformation of A1/A2 Reactive Astrocytes and Increasing the BDNF Concentration in Brain of APP/PS1 Double Transgenic Mice

The main clinical manifestation of Alzheimer's disease is progressive cognitive decline, and its pathological features are β-amyloid (Aβ) deposition, neurofibrillary tangles, synaptic dysfunction and neuron death. Neuroinflammation is an important reason for the occurrence and development of AD, which is mainly manifested by the accumulation of activated microglia and reactive astrocytes. Apolipoprotein E (ApoE) is one of the most important apolipoprotein in the brain, which is related to metabolism, aggregation and toxicity of Aβ. However, the underlying mechanism needs to be further explored. In this study, we studied the effect of ApoE mimetic peptide COG1410 on spatial learning and memory functions, deposition of Aβ in the dentate gyrus (DG) of APP/PS1 transgenic mice, and the different effects of A1 and A2 subtypes of reactive astrocytes. Administration of COG1410 effectively improved performance in spatial learning and memory of APP/PS1 mice, reduced Aβ deposition and significantly reverted the ratio of A1/A2 reactive astrocytes, which could be associated with BDNF/TrkB signaling pathway. On the whole, the present findings suggest new possibility of using apolipoprotein E mimetic peptide to treat AD with potential effectiveness.

HTLV-1-associated myelopathy in Spain

BackgroundHTLV-1 infection is a neglected disease. Over 10 million people are infected worldwide, with hot spots of high endemicity across all continents. Roughly 5% of HTLV-1 carriers develop HTLV-1-associated myelopathy (HAM), a progressive subacute neurological disabling disease. MethodsWe report the main features of patients diagnosed with HAM up to date in Spain, a non-endemic country with a relatively high migrant flow from Latin America and Equatorial Africa, where HTLV-1 is endemic. ResultsA total of 451 cases of HTLV-1 had been recorded in Spain until the end of year 2022. HAM had been diagnosed in 58 (12.9%). The current incidence is of 2-3 new cases per year. Women represent 76%. Mean age at diagnosis is 49 years-old. Nearly 60% are Latin Americans. Although sexual transmission is the most likely route of HTLV-1 acquisition, up to 6 individuals had been infected following solid organ transplantation. Rapid onset myelopathy developed in all but one of these transplant recipients from three HTLV-1-positive donors. HTLV-1 subtype 1a transcontinental was the only variant recognized in HAM patients. HTLV-1 proviral load was significantly greater in HAM patients than in asymptomatic HTLV-1 carriers (677 vs 104 HTLV-1 DNA copies/104 PBMC; p=0.012). Symptom relief medications and physiotherapy have been the only treatment providing some benefit to HAM patients. Neither significant clinical nor virological efficacy was noticed using antiretrovirals in at least 9 HAM patients. Two thirds of HAM patients ended up in a wheelchair and with urinary/fecal sphincter incontinence. ConclusionHAM is the most frequent clinical manifestation of HTLV-1 infection in Spain, a non-endemic country. Middle aged women migrants from Latin America are the most frequently affected. Two thirds end up in a wheelchair despite using antiretroviral therapy.

Subcategorization of suspicious non-mass-like enhancement lesions(BI-RADS-MRI Category4)

BackgroundThis study aims to providing a reliable method that has good compliance and is easy to master to improve the accuracy of NMLE diagnosis.MethodsThis study retrospectively analyzed 122 cases of breast non-mass-like enhancement (NMLE) lesions confirmed by postoperative histology. MRI features and clinical features of benign and malignant non-mass enhancement breast lesions were compared by using independent sample t test, χ2test and Fisher exact test. P < 0.05 was considered statistically significant. Statistically significant parameters were then included in logistic regression analysis to build a multiparameter differential diagnosis modelto subdivide the BI-RADS Category 4.ResultsThe distribution (odds ratio (OR) = 8.70), internal enhancement pattern (OR = 6.29), ADC value (OR = 5.56), and vascular sign (OR = 2.84) of the lesions were closely related to the benignity and malignancy of the lesions. These signs were used to build the MRI multiparameter model for differentiating benign and malignant non-mass enhancement breast lesions. ROC analysis revealed that its optimal diagnostic cut-off value was 5. The diagnostic specificity and sensitivity were 87.01% and 82.22%, respectively. Lesions with 1–6 points were considered BI-RADS category 4 lesions, and the positive predictive values of subtypes 4a, 4b, and 4c lesions were15.79%, 31.25%, and 77.78%, respectively.ConclusionsComprehensively analyzing the features of MRI of non-mass enhancement breast lesions and building the multiparameter differential diagnosis model could improve the differential diagnostic performance of benign and malignant lesions.

Pyrazolo-triazolo-pyrimidine Scaffold as a Molecular Passepartout for the Pan-Recognition of Human Adenosine Receptors.

Adenosine receptors are largely distributed in our organism and are promising therapeutic targets for the treatment of many pathologies. In this perspective, investigating the structural features of the ligands leading to affinity and/or selectivity is of great interest. In this work, we have focused on a small series of pyrazolo-triazolo-pyrimidine antagonists substituted in positions 2, 5, and N8, where bulky acyl moieties at the N5 position and small alkyl groups at the N8 position are associated with affinity and selectivity at the A3 adenosine receptor even if a good affinity toward the A2B adenosine receptor has also been observed. Conversely, a free amino function at the 5 position induces high affinity at the A2A and A1 receptors with selectivity vs. the A3 subtype. A molecular modeling study suggests that differences in affinity toward A1, A2A, and A3 receptors could be ascribed to two residues: one in the EL2, E168 in human A2A/E172 in human A1, that is occupied by the hydrophobic residue V169 in the human A3 receptor; and the other in TM6, occupied by H250/H251 in human A2A and A1 receptors and by a less bulky S247 in the A3 receptor. In the end, these findings could help to design new subtype-selective adenosine receptor ligands.

The relevance of using methods of molecular epidemiology of HIV to characterize territorial epidemics: Sakhalin region, Russia

Aim. To investigate the molecular-epidemiological characteristics of the territorial distribution of HIV infection in the Sakhalin region.Materials and Methods. A comprehensive analysis of molecular-genetic characteristics of HIV-1 and clinical-epidemiological data of 64 HIV-infected residents of the Sakhalin region was conducted. Nucleotide sequences of the pol gene region encoding protease, reverse transcriptase, and integrase of HIV-1 were obtained by sequencing amplified virus fragments. Genotyping, phylogenetic and mutational analyses were performed using specialized software resources.Results. Among the HIV-1 cases studied, the HIV-1 subtype A6 was detected in 81.3 % of cases, with 58.4 % of them reliably clustering into closely related HIV groups, indicating the development of internal epidemic networks of infection transmission. Additionally, HIV-1 CRF63_02A6 and 06_cpx were detected in 4.7 % of cases each, subtype B and B/G in 3.1 %, subtypes C and A1 in 1.6 %. HIV-1 A6, B/G variants, and subtype A1 similar to Mediterranean HIV were detected in the MSM group. In 10.8 % of cases, treatment-naive patients had HIV-1 with the K103N mutation, and in one case, multiple drug resistance was identified.Conclusion. The contemporary territorial epidemic of HIV infection in the Sakhalin region is characterised by the presence of internal epidemic networks and the registration and spread of imported HIV. Key population groups with HIV infection require special attention due to the documented transmission of ART-resistant viruses. Studying the peculiarities of HIV infection spread in individual regions of Russia is important for the development of effective measures aimed at ending HIV transmission in the country.

БОТУЛОТОКСИН. МЕХАНИЗМ ТОКСИЧЕСКОГО ВОЗДЕЙСТВИЯ. ПРИНЦИП ДЕЙСТВИЯ ЛЕКАРСТВЕННЫХ ПРЕПАРАТОВ НА ОСНОВЕ РАЗНЫХ СЕРОТИПОВ БОТУЛОТОКСИНА. ПРИМЕНЕНИЕ В МЕДИЦИНЕ

The paper discusses the most recent understanding of the mechanisms of action of naturally occurring botulinum toxins in the context of chemical analysis, the types of botulism, the conditions of their origin, causes of development, as well as the methods of prevention of the toxic process, according to the type of lesion. The structural and pathogenic mechanisms of these toxins (A, B, C, D, E, F, G) are very similar (due to the property of inhibiting the exocytosis of neurotransmitter and causing muscle paralysis). However, because each type of toxin has a unique receptor, they have different affinities for the three transporter proteins found in SNAR (VAMP, SNAP, and syntaxin). If in the process of pathogenesis BTA (botulotoxin A) cleaves the protein in the synaptose, BTB cleaves synaptobrevin, while the intracellular target of BTC (which is still in the research stage) are two proteins of the transporter complex (synaptotagmin and syntaxin) at the same time, which has a positive effect on some pharmacological features. The existence of the A1 and A2 subtypes of BTA is discussed, and a chemical justification is provided for why even a minor alteration in the amino acid sequence results in a difference in the biological and immunological characteristics of these subtypes. Furthermore, evidence supports the idea that reducing the amount of complexing proteins is a strategy to lessen toxicity, reduce immune-resistance, assure a long-lasting myorelaxant impact, and thereby increase the potential of botulinum toxin therapy. And this can be achieved by reducing the inactive toxins in the mixture, the ways of which are presented. Meanwhile, on the basis of that same mechanism, one of the unique manifestations of A and B botulinum toxins acting as active drugs, the phenomenon of botulinum toxin therapy, is explained, if of course they are completely free of toxic substances and act in minimal amounts. In the meantime, the phenomena of botulinum toxin therapy, one of the distinctive manifestations of A and B botulinum toxins operating as active medications, is explained on the basis of that same mechanism, assuming, of course, that they are completely free of toxic components and act in minimal levels. This is when they are converted from poison to medicine as “wonderful forces of nature that are meant to help people with diseases that were previously thought to be incurable”. The uniqueness of their mechanism of action, the availability of the drug in any zone of injection, the long duration of the pharmacological effect and, most importantly, the absence of systematic and side effects already justify the demand for drugs, based on botulinum toxins, in neurology, surgery, traumatology, nephrology, dentistry, ophthalmology, aesthetic medicine and later also prospective possibilities of their application in other clinical fields.

Characterization of HIV-1 CRF02_AG/A3/G unique recombinant forms identified among children in Larkana, Pakistan.

Co-circulation of different human immunodeficiency virus type 1 HIV-1 subtypes among infected populations can lead to the generation of new recombinants. In Pakistan, subtype A1 and CRF02_AG are the dominant strains circulating among key populations. The high prevalence of new HIV infections among the key populations highlights the possibility of recombination between the dominant strains, which can lead to the generation of new recombinants. Here, we identified a recombinant cluster composed of CRF02_AG, sub-subtype A3, and subtype G among HIV-infected children in Larkana. For the study, 10 retrospectively collected samples, with recombination signals in the pol gene, were used to perform a near full-length genome NFLG sequencing. Of the 10 samples, NFLG was successfully sequenced from seven samples. Phylogenetic analysis of the seven NFLGs showed that all recombinants formed a distinct monophyletic cluster and were distinct from known HIV-1 circulating recombinant forms CRFs. Recombination analyses showed that all seven NFLGs shared a similar recombinant structure consisting of CRF02_AG, sub-subtype A3, and subtype G, with a sub-subtype A3 fragment inserted into pol and vif regions spanning from (HXB2: 4218-5518), and a subtype G fragment inserted into vpu, rev, tat and env regions spanning from (HXB2: 5957-8250) of the CRF02_AG backbone. The identification of unique recombinant forms may indicate the presence and transmission of several co-circulating lineages in Larkana, giving rise to newer CRFs. This study also highlights the importance of continuous molecular surveillance to fully understand HIV-1 genetic diversity in Pakistan, particularly in Larkana, which is the epicenter of HIV outbreaks.