Toxoplasma gondii is an obligate intracellular parasite which is known to infect one-third of the total world population chronically though it is asymptomatic in immunocompetent patients. However, in ...an immunocompromised patient or an infected fetus, it may cause devastating effects. The parasite may cross the placenta of an infected pregnant woman and probably infect the fetus congenitally. The severity of the infection depends on the gestational age at which the infection has occurred i.e., if it has occurred in the early phase, the rate of transmission is low but the severity is high if the fetus is infected and if it has occurred in the later phase then transmission rate is higher while the severity would be low. Congenital toxoplasmosis may result in non-specific consequences like abortion, intra-uterine growth restriction, jaundice, hepatosplenomegaly or even intra-uterine death. It may also result in neurological or ocular manifestations like intracranial calcifications, hydrocephalus or retinochoroiditis. The diagnosis may be done by serological screening of anti-Toxoplasma antibodies (IgM and IgG) while PCR of the amniotic fluid or the placenta is the confirmatory test. Acute or chronic infections may be differentiated by IgG avidity tests. The treatment regimens include spiramycin to prevent congenital transmission from an infected mother, pyrimethamine, sulfadoxine and folinic acid to treat the infected fetus, CSF shunting for the treatment of hydrocephalus and a combination of pyrimethamine, azithromycin, and corticosteroids for treating ocular toxoplasmosis.
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•T. gondii is an intracellular parasite which can infect all warm blooded animals.•It can cause congenital toxoplasmosis by penetrating a developing fetus.•Congenital toxoplasmosis causes neurological and/or ocular symptoms in the fetus/infant.•Presumptive diagnosis is difficult as the pregnant mother may be asymptomatic.•Treatment regimen has evolved with time but still more research needs to be done.
This article attempts to provide an insight into the experiences of drug addicts at a rehabilitation center, run by the provincial Social Welfare Department in Lahore, Pakistan, through a qualitative ...approach. The menace of drugs is increasing worldwide, including Pakistan. Effective treatment and rehabilitative services can lower the prevalence rate of drug addiction. The aim of this research was to understand/explore the experiences of research participants about the phenomenon of drug addiction and rehabilitation services provided in the field of social welfare. This research extends the current knowledge of individuals’ drug addiction by revealing the complexities and intricacies of this behavior.
The coronavirus disease 2019 (COVID-19) that is wreaking havoc on worldwide public health and economies has heightened awareness about the lack of effective antiviral treatments for human ...coronaviruses (CoVs). Many current antivirals, notably nucleoside analogs (NAs), exert their effect by incorporation into viral genomes and subsequent disruption of viral replication and fidelity. The development of anti-CoV drugs has long been hindered by the capacity of CoVs to proofread and remove mismatched nucleotides during genome replication and transcription. Here, we review the molecular basis of the CoV proofreading complex and evaluate its potential as a drug target. We also consider existing nucleoside analogs and novel genomic techniques as potential anti-CoV therapeutics that could be used individually or in combination to target the proofreading mechanism.
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Robson et al. examine the molecular basis of the coronavirus proofreading mechanism and how this contributes to the resistance of this family of viruses to nucleoside analog (NA) antiviral drugs. They discuss antisense oligonucleotide (ASO) therapy in combination with NAs to potentially improve the potency and delivery of antiviral drugs.
Histone deacetylases (HDACs) are epigenetic regulators and additionally control the activity of non-histone substrates. We recently demonstrated that inhibition of HDAC8 overexpressed in various of ...cancers reduces hepatocellular carcinoma tumorigenicity in a T cell-dependent manner. Here, we present alkylated hydrazide-based class I HDAC inhibitors in which the n-hexyl side chain attached to the hydrazide moiety shows HDAC8 selectivity in vitro. Analysis of the mode of inhibition of the most promising compound 7d against HDAC8 revealed a substrate-competitive binding mode. 7d marked induced acetylation of the HDAC8 substrates H3K27 and SMC3 but not tubulin in CD4+ T lymphocytes, and significantly upregulated gene expressions for memory and effector functions. Furthermore, intraperitoneal injection of 7d (10 mg/kg) in C57BL/6 mice increased interleukin-2 expression in CD4+ T cells and CD8+ T cell proportion with no apparent toxicity. This study expands a novel chemotype of HDAC8 inhibitors with T cell modulatory properties for future therapeutic applications.
Many SARS-CoV-2 variants have mutations at key sites targeted by antibodies. However, it is unknown if antibodies elicited by infection with these variants target the same or different regions of the ...viral spike as antibodies elicited by earlier viral isolates. Here we compare the specificities of polyclonal antibodies produced by humans infected with early 2020 isolates versus the B.1.351 variant of concern (also known as Beta or 20H/501Y.V2), which contains mutations in multiple key spike epitopes. The serum neutralizing activity of antibodies elicited by infection with both early 2020 viruses and B.1.351 is heavily focused on the spike receptor-binding domain (RBD). However, within the RBD, B.1.351-elicited antibodies are more focused on the "class 3" epitope spanning sites 443 to 452, and neutralization by these antibodies is notably less affected by mutations at residue 484. Our results show that SARS-CoV-2 variants can elicit polyclonal antibodies with different immunodominance hierarchies.
HIV cerebrospinal fluid (CSF) escape, where HIV is suppressed in blood but detectable in CSF, occurs when HIV persists in the CNS despite antiretroviral therapy (ART). To determine the virus ...producing cell type and whether lowered CSF ART levels are responsible for CSF escape, we collected blood and CSF from 156 neurosymptomatic participants from Durban, South Africa. We observed that 28% of participants with an undetectable HIV blood viral load showed CSF escape. We detected host cell surface markers on the HIV envelope to determine the cellular source of HIV in participants on the first line regimen of efavirenz, emtricitabine, and tenofovir. We confirmed CD26 as a marker which could differentiate between T cells and macrophages and microglia, and quantified CD26 levels on the virion surface, comparing the result to virus from in vitro infected T cells or macrophages. The measured CD26 level was consistent with the presence of T cell produced virus. We found no significant differences in ART concentrations between CSF escape and fully suppressed individuals in CSF or blood, and did not observe a clear association with drug resistance mutations in CSF virus which would allow HIV to replicate. Hence, CSF HIV in the face of ART may at least partly originate in CD4+ T cell populations.
Exposure histories to SARS-CoV-2 variants and vaccinations will shape the specificity of antibody responses. To understand the specificity of Delta-elicited antibody immunity, we characterize the ...polyclonal antibody response elicited by primary or mRNA vaccine-breakthrough Delta infections. Both types of infection elicit a neutralizing antibody response focused heavily on the receptor-binding domain (RBD). We use deep mutational scanning to show that mutations to the RBD's class 1 and class 2 epitopes, including sites 417, 478, and 484-486 often reduce binding of these Delta-elicited antibodies. The anti-Delta antibody response is more similar to that elicited by early 2020 viruses than the Beta variant, with mutations to the class 1 and 2, but not class 3 epitopes, having the largest effects on polyclonal antibody binding. In addition, mutations to the class 1 epitope (e.g., K417N) tend to have larger effects on antibody binding and neutralization in the Delta spike than in the D614G spike, both for vaccine- and Delta-infection-elicited antibodies. These results help elucidate how the antigenic impacts of SARS-CoV-2 mutations depend on exposure history.
Abstract
Periodontal diseases are prevalent and have significant implications for oral health and overall well‐being. Current diagnostic methods have limitations in accuracy and standardization. The ...recent Food and Drug Administration approval of Videa Perio Assist (VPA), an AI model for diagnosing periodontal diseases, presents a breakthrough in dental diagnostics. VPA is a cloud‐based, AI‐powered software that automatically measures and visualizes bone levels associated with each tooth from radiographic images. Clinical testing has demonstrated VPA's efficacy in accurately diagnosing periodontal diseases with high sensitivity and specificity. The integration of AI in dentistry has the potential to revolutionize periodontal disease diagnosis, improve patient care, and enhance decision‐making. However, further research, education, cost‐effectiveness, and collaboration are essential for maximizing the benefits of AI in dental settings. The approval and implementation of VPA mark a significant advancement in dental diagnostics, paving the way for more effective solutions and a healthier global population.
Implantation of biomaterials and devices into soft tissues leads to the development of the foreign body response (FBR), which can interfere with implant function and eventually lead to failure. The ...FBR consists of overlapping acute and persistent inflammatory phases coupled with collagenous encapsulation and currently there are no therapeutic options. Initiation of the FBR involves macrophage activation, proceeding to giant cell formation, fibroblast activation, and collagen matrix deposition. Despite the recognition of this sequence of events, the molecular pathways required for the FBR have not been elucidated. We have identified that the acute inflammatory response to biomaterials requires nucleotide-binding domain and leucine-rich repeat-containing 3 (Nlrp3), apoptosis-associated speck-like protein containing CARD (Asc), and caspase-1, as well as plasma membrane cholesterol, and Syk signaling. Full development of the FBR is dependent on Asc and caspase-1, but not Nlrp3. The common antiinflammatory drug aspirin can reduce inflammasome activation and significantly reduce the FBR. Taken together, these findings expand the role of the inflammasome from one of sensing damage associated molecular patterns (DAMPs) to sensing all particulate matter irrespective of size. In addition, implication of the inflammasome in biomaterial recognition identifies key pathways, which can be targeted to limit the FBR.
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