Investigating Extended Linker Analogues of Risperidone for Treatment of Multiple Sclerosis

<p>Risperidone is a second-generation antipsychotic used to treat psychiatric disorders such as schizophrenia, bipolar disorder and autism. It targets dopamine D2 and serotonin 5-HT2A receptors and has immunomodulatory properties. Multiple sclerosis is a chronic inflammatory disease that affects over 2 million people worldwide and currently has no cure. Recent research at Victoria University of Wellington has shown that risperidone is able to reduce disease severity in mouse models of multiple sclerosis. Further research has demonstrated that truncated and unsaturated analogues of risperidone have varying immunomodulatory effects in immune cells. The current research describes the synthesis and preliminary in vitro testing of four extended-linker analogues of risperidone. Structure-activity relationship studies with neurotropic drugs have shown that altering the length of the alkyl chain found in many of these compounds can have significant effects on receptor binding profiles. Synthesis and cytokine production assays of these analogues begin to provide further insight into how risperidone exerts its immunomodulatory effects and may contribute to the development of new treatments for multiple sclerosis.</p>

Investigating Extended Linker Analogues of Risperidone for Treatment of Multiple Sclerosis

<p>Risperidone is a second-generation antipsychotic used to treat psychiatric disorders such as schizophrenia, bipolar disorder and autism. It targets dopamine D2 and serotonin 5-HT2A receptors and has immunomodulatory properties. Multiple sclerosis is a chronic inflammatory disease that affects over 2 million people worldwide and currently has no cure. Recent research at Victoria University of Wellington has shown that risperidone is able to reduce disease severity in mouse models of multiple sclerosis. Further research has demonstrated that truncated and unsaturated analogues of risperidone have varying immunomodulatory effects in immune cells. The current research describes the synthesis and preliminary in vitro testing of four extended-linker analogues of risperidone. Structure-activity relationship studies with neurotropic drugs have shown that altering the length of the alkyl chain found in many of these compounds can have significant effects on receptor binding profiles. Synthesis and cytokine production assays of these analogues begin to provide further insight into how risperidone exerts its immunomodulatory effects and may contribute to the development of new treatments for multiple sclerosis.</p>

Mesenchymal stromal cell apoptosis is required for their therapeutic function

Multipotent mesenchymal stromal cells (MSCs) ameliorate a wide range of diseases in preclinical models, but the lack of clarity around their mechanisms of action has impeded their clinical utility. The therapeutic effects of MSCs are often attributed to bioactive molecules secreted by viable MSCs. However, we found that MSCs underwent apoptosis in the lung after intravenous administration, even in the absence of host cytotoxic or alloreactive cells. Deletion of the apoptotic effectors BAK and BAX prevented MSC death and attenuated their immunosuppressive effects in disease models used to define MSC potency. Mechanistically, apoptosis of MSCs and their efferocytosis induced changes in metabolic and inflammatory pathways in alveolar macrophages to effect immunosuppression and reduce disease severity. Our data reveal a mode of action whereby the host response to dying MSCs is key to their therapeutic effects; findings that have broad implications for the effective translation of cell-based therapies.

A semisynthetic glycoconjugate provides expanded cross-serotype protection against Streptococcus pneumoniae

Streptococcus pneumoniae infections are the leading cause of child mortality globally. Current vaccines fail to induce a protective immune response towards a conserved part of the pathogen, resulting in new serotypes causing disease. Therefore, new vaccine strategies are urgently needed. Described is a two-pronged approach combining S.pneumoniae proteins, pneumolysin and PspA, with a precisely defined synthetic oligosaccharide, whereby the carrier protein acts as a serotype-independent antigen to provide additional protection. Proof of concept in mice and swine models revealed that the conjugates inhibit colonization of the nasopharynx, decrease the bacterial load and reduce disease severity in the bacteria challenged model. Immunization of piglets provided the first evidence for the immunogenicity and protective potential of synthetic glycoconjugate vaccine in a large animal model. A combination of synthetic oligosaccharides with proteins from the target pathogen opens the path to create broadly cross-protective ("universal") pneumococcal vaccines.

Sero-monitoring of health care workers reveals complex relationships between common coronavirus antibodies and SARS-CoV-2 severity

Recent common coronavirus (CCV) infections are associated with reduced COVID-19 severity upon SARS-CoV-2 infection, however the immunological mechanisms involved are unknown. We completed serological assays using samples collected from health care workers to identify antibody types associated with SARS-CoV-2 protection and COVID-19 severity. Rare SARS-CoV-2 cross-reactive antibodies elicited by past CCV infections were not associated with protection; however, the duration of symptoms following SARS-CoV-2 infections was significantly reduced in individuals with higher common betacoronavirus (betaCoV) antibody titers. Since antibody titers decline over time after CCV infections, individuals in our cohort with higher betaCoV antibody titers were more likely recently infected with common betaCoVs compared to individuals with lower antibody titers. Therefore, our data suggest that recent betaCoV infections potentially limit the severity of SARS-CoV-2 infections through mechanisms that do not involve cross-reactive antibodies. Our data are consistent with the emerging hypothesis that cellular immune responses elicited by recent common betaCoV infections transiently reduce disease severity following SARS-CoV-2 infections.

VACCINATION WITH MMR MAY REDUCE DISEASE SEVERITY IN COVID-19 PATIENTS

We hypothesise that MMR vaccination is possibly a safe, cheap, effective and readily available method to reduce the severity of COVID-19 disease course in health care workers, elderly patients and other people at risk. The evidence is based on relevant literature. Suggestions for further studies are given.

Antioxidant Carbon Nanoparticles Inhibit Fibroblast-Like Synoviocyte Invasiveness and Reduce Disease Severity in a Rat Model of Rheumatoid Arthritis

Reactive oxygen species have been involved in the pathogenesis of rheumatoid arthritis (RA). Our goal was to determine the effects of selectively scavenging superoxide (O2•−) and hydroxyl radicals with antioxidant nanoparticles, called poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs), on the pathogenic functions of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and on the progression of an animal model of RA. We used human FLS from patients with RA to determine PEG-HCC internalization and effects on FLS cytotoxicity, invasiveness, proliferation, and production of proteases. We used the pristane-induced arthritis (PIA) rat model of RA to assess the benefits of PEG-HCCs on reducing disease severity. PEG-HCCs were internalized by RA-FLS, reduced their intracellular O2•−, and reduced multiple measures of their pathogenicity in vitro, including proliferation and invasion. In PIA, PEG-HCCs caused a 65% reduction in disease severity, as measured by a standardized scoring system of paw inflammation and caused a significant reduction in bone and tissue damage, and circulating rheumatoid factor. PEG-HCCs did not induce lymphopenia during PIA. Our study demonstrated a role for O2•− and hydroxyl radicals in the pathogenesis of a rat model of RA and showed efficacy of PEG-HCCs in treating a rat model of RA.

Sensitivity of Zasmidium citri-griseum to Fenbuconazole and Control of Citrus Greasy Spot in Panama

Citrus greasy spot, caused by Zasmidium citri-griseum ( = Mycosphaerella citri) is the most prevalent fungal disease of citrus in Panama, causing premature defoliation and yield reduction. Fungicide applications are generally needed for the control of greasy spot. In this study, the sensitivity to fenbuconazole of 34 isolates of Z. citri-griseum from Panama was determined by calculating the effective concentration needed to reduce mycelial growth by 50% (EC50). Two field trials were conducted from 2011 to 2013, to evaluate the efficacy of fenbuconazole to reduce disease severity and yield loss. The EC50 values for fenbuconazole ranged from 0.09 to 7.62 μg mL−1, with a mean EC50 value of 2.66 ± 0.36 SE μg mL−1 for mycelial growth. These data can be used for monitoring sensitivity shifts in Z. citri-griseum to fenbuconazole and reduce risk of fungicide resistance in Panama. In the field trials, sprays with fenbuconazole significantly reduced (p < 0.0001) the severity of greasy spot on leaves compared with the non-treated control. Greater disease control was obtained when three sprays of fenbuconazole were applied instead of one. Nevertheless, no significant differences (p > 0.05) were detected in yield.

Yoga may prevent cytokine storm in COVID-19

: The pandemic outbreak of coronavirus disease (COVID-19) has emerged as the most threatening public health challenge. The clinical presentation range from asymptomatic and mild clinical symptoms to acute respiratory-distress syndrome (ARDS) and death. Apart from the respiratory system, other organ systems like cardiovascular, renal, and gastrointestinal systems are also involved. Cytokine storm is a condition of systemic inflammatory cytokine rampage through the bloodstream leading to life-threatening complications. There is an urgent need for prevention of infection and effective management. Yoga is a profound science with both immunity-boosting and immune-modulating capacity. We propose that yoga-based intervention may aid in improving health with its immunity-boosting potential and preventing the exuberant inflammatory cytokine storm, thus reducing the severity of the disease. It can also reduce stress, anxiety, and co-morbid depression by promoting neuroplasticity and prevents persistent activation of hypothalamus pituitary adrenal axis and thus may reduce disease severity. It may also enhance the immunity of caretakers and make them more emotionally resilient. Thus yoga can be useful for enhancing immunity, stress reduction and may prevent the exaggerated immune response the cytokine storm.

Malaria and HIV Infection among Febrile Patients in a Large Area of Southwestern Nigeria

Background: Malaria and HIV/AIDS are two major diseases that represent serious public health threats in Nigeria. They have been ascribed diseases of poverty, and therefore their distribution is expected to be overlapping.Aim: The aim of this study was to determine the prevalence of malaria parasites and HIV among febrile patients in the Ikeja area of Lagos State, Nigeria.Materials and Methods: The study was conducted on 300 patients attending medical consultation and referred to blood screening for malaria parasites at Reddington Hospital, Lagos State. Malaria parasites were identified microscopically, and HIV screening was carried out using rapid diagnostic tests (RDT).Results: The prevalence of malaria and HIV was 98.7% and 3.7%, respectively. All HIV-positive individuals were also infected by malaria parasites. Mean parasitemia was significantly higher in HIV-positive individuals (16,507.9 ± 2,280.7 P/μL) than in HIV-negative subjects (3,252.505 ± 236.3 P/μL) (p <0.05).Conclusions: Our results suggest that HIV-infected individuals are more susceptible to infection with malaria parasites. Prompt HIV management is necessary in malaria-endemic areas to reduce disease severity in case of coinfection with HIV.