Search

Interferon is an essential component in the treatment of chronic hepatitis B and C. In chronic hepatitis B, interferon alfa and lamivudine are generally accepted as the treatment of choice. In chronic hepatitis C, the combination of interferon alfa and ribavirin is the standard treatment. A new promising therapeutic option is pegylated IFN-alfa2b (Peglntron), which can be dosed once weekly and provide a better adherence to treatment, as M. P. Manns, Hanover, demonstrated in a randomised study on 1530 patients with chronic hepatitis C. [ABSTRACT FROM AUTHOR]

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The human microbiota is believed to influence health. Microbiome dysbiosis may be linked to neurological conditions like Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's disease. We report the ability of a probiotic bacterial strain in halting neurodegeneration phenotypes. We show that Lacticaseibacillus rhamnosus HA-114 is neuroprotective in C. elegans models of amyotrophic lateral sclerosis and Huntington's disease. Our results show that neuroprotection from L. rhamnosus HA-114 is unique from other L. rhamnosus strains and resides in its fatty acid content. Neuroprotection by L. rhamnosus HA-114 requires acdh-1/ACADSB, kat-1/ACAT1 and elo-6/ELOVL3/6, which are associated with fatty acid metabolism and mitochondrial β-oxidation. Our data suggest that disrupted lipid metabolism contributes to neurodegeneration and that dietary intervention with L. rhamnosus HA-114 restores lipid homeostasis and energy balance through mitochondrial β-oxidation. Our findings encourage the exploration of L. rhamnosus HA-114 derived interventions to modify the progression of neurodegenerative diseases., (© 2022. The Author(s).)

Axonal degeneration is observed in early stages of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). This degeneration generally precedes apoptosis and therefore may be a promising therapeutic target. An increasing number of genes have been identified to actively regulate axonal degeneration and regeneration; however, only a few potential therapeutic targets have been identified in the context of neurodegenerative diseases. Here we investigate DLK-1, a major axonal regeneration pathway and its contribution to axonal degeneration phenotypes in several Caenorhabditis elegans ALS models. From this pathway, we identified the poly (ADP-ribose) (PAR) polymerases (PARP) PARP-1 and PARP-2 as the most consistent modifiers of axonal degeneration in our models of ALS. Genetic and pharmacological inhibition of PARP-1 and PARP-2 reduces axonal degeneration and improves related motor phenotypes., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Mutations in the human DNA/RNA binding protein FUS are associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration, including some aggressive and juvenile onset forms. Cytoplasmic inclusions of human FUS proteins are observed in various neurodegenerative disorders, such as Huntington's disease or spinocerebellar ataxia, suggesting that FUS proteinopathy may be a key player in neurodegeneration. To better understand the pathogenic mechanisms of FUS, we created single copy transgenic Caenorhabditis elegans strains expressing full-length, untagged human FUS in the worm's GABAergic neurons. These transgenic worms expressing human mutant FUS (mFUS) display the same ALS-associated phenotypes than our previous multiple copy transgenic model, including adult-onset age-dependent loss of motility, progressive paralysis and GABAergic neurodegeneration. These phenotypes are distinct from the transgenic worms expressing human wild-type FUS (wtFUS). We introduce here our C. elegans single copy transgenic for human mutant FUS motor neuron toxicity that may be used for rapid genetic and pharmacological suppressor screening., (Copyright: © 2021 by the authors.)

DRAXIMAGE, under exclusive licence from BTG International Ltd, is developing a technetium-99m formulation of ciprofloxacin (INFECTON), as a radioimaging agent for the potential diagnosis of infection, including fever of unknown origin, osteomyelitis, wound infection, abdominal abscess, pneumonia, appendicitis and tuberculosis.

As the natural history of HIV infection has changed following the introduction of highly active antiretroviral therapy (HAART), morbidity and mortality in the afflicted patients could be significantly reduced. The decreasing risk of suffering from opportunistic infections and tumors, however, is at the cost of antiretroviral drug-related toxicities. Today, mortality by liver disease is the major cause of death in HIV-infected patients from industrial countries. In the US and Europe about 30% of HIV-positive individuals are also infected with hepatitis C virus (HCV), and approximately 50-90% of persons who acquired HIV from injecting drugs are coinfected with HCV. In these dually infected individuals the presence of each viral infection impacts the natural history of the other one, and worsening of associated liver disease and complications within this population are increasing. The management of chronic hepatitis C (cHC) in HCV-HIV coinfection has become a major challenge, since possible interactions with antiretroviral therapies, increased risk of special side effects and compromises in adherence in patients already taking several drugs have to be taken into account. On the other hand, treatment strategies to fight HCV have been essentially ameliorated during the past 2 years by using pegylated interferon-alpha2b (Peg-IFN-alpha2b) combined with ribavirin, and there is hope that the successful therapeutic outcome in HCV-monoinfected individuals may beat least partly translated into benefits for the difficult-to-treat population of HCV-HIV dually infected persons. During the 15th International AIDS Conference in July 2002 in Barcelona, a satellite symposium, as well as a session in the main program and a number of poster presentations focussed on HCV-HIV coinfection and addressed the urgent problems and therapeutic challenges in managing cHC in the situation of underlying HIV disease.

As a complex group of naturally occurring proteins and glycoproteins produced by different human cells, interferons (IFN's) have initially been detected as the first line of defense in the natural course of viral infection. Due to their antiproliferative, differentiation-inducing and immunmodulatory properties they also were considered important new drugs in the treatment of cancer. The introduction of recombinant DNA technology in the late 1970's permitted large-scale production of highly purified substrates enabling systematic clinical investigations. After several decades of interferon research there have been peaks and troughs in estimating their therapeutical value. Today the abundant data figure as parts of a giant puzzle which have to be assembled. The identified molecular structure of IFN-alpha2b may serve as a basis for future IFN drug design. The profound knowledge of the endogenous IFN system and its pathological disturbances in the natural course of chronic diseases is a 'conditio sine qua non' to explain seeming inconsistency as e.g. the 'paradox' role of IFN-alpha in HIV-infection. A better understanding of the pathophysiologic function of the acid-lability inducing antigen (ALIA) and the physiologic role of the IFN-type I induced Mx protein will be helpful on this way. IFN signal transduction via the Jak-STAT system reveals mechanisms of action within hematological disorders. In these terms, further developments in interferon therapy as well as future design of IFN substrates have to apply a strict standard. The article critically reviews to which extent actual treatment strategies as the application of IFN-inducers, consensus IFN as well as pegylated IFN's fit into therapeutic schedules which have to take into account all these novel insights.