Effect of cladribine treatment on ß-2 microglobulin and soluble intercellular adhesion molecule 1 (ICAM-1) in patients with multiple sclerosis

β-2 Microglobulin ( β2M) is a low molecular weight protein located extracellularly and associated with class 1 antigens of the major histocompatibility complex and is considered a marker for disease activity in immune disorders. Cladribine (2-chloro-2-deoxyadenosine, 2-CDA) is a potent lymphocytotoxic agent under investigation in the treatment in MS patients. As β2M levels may indicate inflammatory events in CNS we determined CSF- β2M and serum β2M levels in patients with relapsing-remitting MS before and after cladribine treatment as well as in a control group. There was a significant β2M decrease in sera but not in CSF in MS patients after the cladribine treatment, associated with a slight but significant clinical improvement measured by Kurtzke's Expanded Disability Status Scale. We also found a significant decrease in sICAM-1 level in CSF but not in sera in MS patients. The data support a role of cladribine in MS therapy and deliver new information on cladribine immunological effects in MS patients

Information processing and signal integration in bacterial quorum sensing

Bacteria communicate using secreted chemical signaling molecules called autoinducers in a process known as quorum sensing. The quorum-sensing network of the marine bacterium {\it Vibrio harveyi} employs three autoinducers, each known to encode distinct ecological information. Yet how cells integrate and interpret the information contained within the three autoinducer signals remains a mystery. Here, we develop a new framework for analyzing signal integration based on Information Theory and use it to analyze quorum sensing in {\it V. harveyi}. We quantify how much the cells can learn about individual autoinducers and explain the experimentally observed input-output relation of the {\it V. harveyi} quorum-sensing circuit. Our results suggest that the need to limit interference between input signals places strong constraints on the architecture of bacterial signal-integration networks, and that bacteria likely have evolved active strategies for minimizing this interference. Here we analyze two such strategies: manipulation of autoinducer production and feedback on receptor number ratios.Comment: Supporting information is in appendi

Ketamine but not glycine potentiates antidepressant like action of citalopram in mice exposed to chronic mild stress

Background: The present study was designed to investigate the effect of citalopram, ketamine, glycine and their combinations on animal models of depression. Methods: Swiss Albino male mice were subjected to chronic mild stress for 6 weeks for inducing depression, and randomly divided into different groups: citalopram (5 and 10 mg/kg), ketamine (17.5 and 35 mg/kg), glycine (50 and 100 mg/kg), ketamine (17.5 mg/kg) + citalopram (5 mg/kg) and ketamine (17.5 mg/kg) + glycine (50 mg/kg). Two behavioural tests were utilized for the assessment of depression, namely tail suspension test (TST) and forced swim test (FST). Immobility time was recorded for 6 min, before and after administration of drug. Results: Citalopram (10 mg/kg) administration caused significant decrease in the immobility time in TST model only but not in FST. Citalopram (5 mg/kg) and ketamine (17.5 mg/kg) caused insignificant decrease in immobility time in both the models. Moreover, ketamine in combination with Citalopram significantly reduced the immobility time in both the models. Glycine at a dose of 100 mg/kg (but not 50 mg/kg) significantly increased the immobility time in both the models as compared to control group. Further, ketamine when administered with glycine caused increase in the immobility time on both the paradigms, though insignificant. Conclusions: Ketamine demonstrated antidepressant like action in both TST and FST models. Moreover, it potentiated the antidepressant effect of citalopram that might be due to the role of NMDA receptors

Plasma Aβ40 and Aβ42 and Alzheimer's Disease: Relation to Age, Mortality, and Risk

BACKGROUND: Plasma amyloid [beta]-peptide (A[beta]) 40 and A[beta]42 levels are increased in persons with mutations causing early-onset familial Alzheimer's disease (AD). Plasma A[beta]42 levels were also used to link microsatellite genetic markers to a putative AD genetic locus on chromosome 10 and were observed in patients with incipient sporadic AD. METHODS: The authors measured plasma A[beta]40 and A[beta]42 levels using a sandwich ELISA after the initial examination of 530 individuals participating in an epidemiologic study of aging and dementia. Participants were examined at 18-month intervals, and plasma A[beta]40 and A[beta]42 levels were repeated in 307 subjects 3 years after baseline. RESULTS: Compared with individuals who never developed AD, patients with AD at baseline and those who developed AD during the follow-up had significantly higher A[beta]42, but not A[beta]40, plasma levels. The risk of AD in the highest quartile of plasma A[beta]42 was increased by more than twofold over that in the lowest quartile. The highest plasma A[beta]42 levels were observed in patients with AD who died during the follow-up. Plasma A[beta]42, but not A[beta]40, levels decreased over time in patients with newly acquired AD. CONCLUSIONS: Plasma A[beta]40 and A[beta]42 increase with age and are strongly correlated with each other. Plasma A[beta]40 and A[beta]42 levels are elevated in some patients before and during the early stages of AD but decline thereafter. High plasma A[beta]42 levels may also be associated with mortality in patients with AD

Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an alzheimer's disease model mouse

<p>Abstract</p> <p>Background</p> <p>Alzheimer's Disease (AD) is the most common of the conformational neurodegenerative disorders characterized by the conversion of a normal biological protein into a β-sheet-rich pathological isoform. In AD the normal soluble Aβ (sAβ) forms oligomers and fibrils which assemble into neuritic plaques. The most toxic form of Aβ is thought to be oligomeric. A recent study reveals the cellular prion protein, PrP^C, to be a receptor for Aβ oligomers. Aβ oligomers suppress LTP signal in murine hippocampal slices but activity remains when pretreated with the PrP monoclonal anti-PrP antibody, 6D11. We hypothesized that targeting of PrP^Cto prevent Aβ oligomer-related cognitive deficits is a potentially novel therapeutic approach. APP/PS1 transgenic mice aged 8 months were intraperitoneally (i.p.) injected with 1 mg 6D11 for 5 days/week for 2 weeks. Two wild-type control groups were given either the same 6D11 injections or vehicle solution. Additional groups of APP/PS1 transgenic mice were given either i.p. injections of vehicle solution or the same dose of mouse IgG over the same period. The mice were then subjected to cognitive behavioral testing using a radial arm maze, over a period of 10 days. At the conclusion of behavioral testing, animals were sacrificed and brain tissue was analyzed biochemically or immunohistochemically for the levels of amyloid plaques, PrP^C, synaptophysin, Aβ40/42 and Aβ oligomers.</p> <p>Results</p> <p>Behavioral testing showed a marked decrease in errors in 6D11 treated APP/PS1 Tg mice compared with the non-6D11 treated Tg groups (p < 0.0001). 6D11 treated APP/PS1 Tg mice behaved the same as wild-type controls indicating a recovery in cognitive learning, even after this short term 6D11 treatment. Brain tissue analysis from both treated and vehicle treated APP/PS1 groups indicate no significant differences in amyloid plaque burden, Aβ40/42, PrP^Cor Aβ oligomer levels. 6D11 treated APP/PS1 Tg mice had significantly greater synaptophysin immunoreactivity in the dentate gyrus molecular layer of the hippocampus compared to vehicle treated APP/PS1 Tg mice (p < 0.05).</p> <p>Conclusions</p> <p>Even short term treatment with monoclonal antibodies such as 6D11 or other compounds which block the binding of Aβ oligomers to PrP^Ccan be used to treat cognitive deficits in aged AD transgenic mice.</p

Targeting eosinophils in respiratory diseases: Biological axis, emerging therapeutics and treatment modalities

Eosinophils are bi-lobed, multi-functional innate immune cells with diverse cell surface receptors that regulate local immune and inflammatory responses. Several inflammatory and infectious diseases are triggered with their build up in the blood and tissues. The mobilization of eosinophils into the lungs is regulated by a cascade of processes guided by Th2 cytokine generating T-cells. Recruitment of eosinophils essentially leads to a characteristic immune response followed by airway hyperresponsiveness and remodeling, which are hallmarks of chronic respiratory diseases. By analysing the dynamic interactions of eosinophils with their extracellular environment, which also involve signaling molecules and tissues, various therapies have been invented and developed to target respiratory diseases. Having entered clinical testing, several eosinophil targeting therapeutic agents have shown much promise and have further bridged the gap between theory and practice. Moreover, researchers now have a clearer understanding of the roles and mechanisms of eosinophils. These factors have successfully assisted molecular biologists to block specific pathways in the growth, migration and activation of eosinophils. The primary purpose of this review is to provide an overview of the eosinophil biology with a special emphasis on potential pharmacotherapeutic targets. The review also summarizes promising eosinophil-targeting agents, along with their mechanisms and rationale for use, including those in developmental pipeline, in clinical trials, or approved for other respiratory disorders

Immunomodulation Targeting Abnormal Protein Conformation Reduces Pathology in a Mouse Model of Alzheimer's Disease

Many neurodegenerative diseases are characterized by the conformational change of normal self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high β-sheet content and resistance to degradation. The most common is Alzheimer's disease (AD) where the normal soluble amyloid β (sAβ) peptide is converted into highly toxic oligomeric Aβ and fibrillar Aβ that deposits as neuritic plaques and congophilic angiopathy. Currently, there is no highly effective treatment for AD, but immunotherapy is emerging as a potential disease modifying intervention. A major problem with most active and passive immunization approaches for AD is that both the normal sAβ and pathogenic forms are equally targeted with the potential of autoimmune inflammation. In order to avoid this pitfall, we have developed a novel immunomodulatory method that specifically targets the pathological conformations, by immunizing with polymerized British amyloidosis (pABri) related peptide which has no sequence homology to Aβ or other human proteins. We show that the pABri peptide through conformational mimicry induces a humoral immune response not only to the toxic Aβ in APP/PS1 AD transgenic mice but also to paired helical filaments as shown on AD human tissue samples. Treated APP/PS1 mice had a cognitive benefit compared to controls (p<0.0001), associated with a reduction in the amyloid burden (p = 0.0001) and Aβ40/42 levels, as well as reduced Aβ oligomer levels. This type of immunomodulation has the potential to be a universal β-sheet disrupter, which could be useful for the prevention or treatment of a wide range of neurodegenerative diseases

Plasma BDNF Levels Vary in Relation to Body Weight in Females

Brain derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of depression as well as neuropsychiatric and neurodegenerative disorders. Recent studies show a role of BDNF in energy metabolism and body weight regulation. We examined BDNF levels in plasma and cerebrospinal fluid (CSF) samples from age matched elderly depressed and control subjects. Also, the association of BDNF levels with age, gender, body weight, body mass index (BMI), and cognitive performance was evaluated. We did not find any significant differences in plasma and CSF BDNF levels between depressed and control subjects. Plasma BDNF levels were negatively correlated with age (but not with BMI and body weight), when analyses were performed including both depressed and control subjects. A significant reduction in plasma BDNF levels was observed in females as compared to male subjects, and the change in BDNF levels were significantly and positively related to body weight in females. Furthermore, significant increases in Total Recall and Delayed Recall values were found in females as compared to males. In conclusion, the lower BDNF levels observed in females suggest that changes in peripheral BDNF levels are likely secondary to an altered energy balance. However, further studies using larger sample size are warranted

Intraneuronal Aβ immunoreactivity is not a predictor of brain amyloidosis-β or neurofibrillary degeneration

Amyloid β (Aβ) immunoreactivity in neurons was examined in brains of 32 control subjects, 31 people with Down syndrome, and 36 patients with sporadic Alzheimer’s disease to determine if intraneuronal Aβ immunoreactivity is an early manifestation of Alzheimer-type pathology leading to fibrillar plaque formation and/or neurofibrillary degeneration. The appearance of Aβ immunoreactivity in neurons in infants and stable neuron-type specific Aβ immunoreactivity in a majority of brain structures during late childhood, adulthood, and normal aging does not support this hypothesis. The absence or detection of only traces of reaction with antibodies against 4–13 aa and 8–17 aa of Aβ in neurons indicated that intraneuronal Aβ was mainly a product of α- and γ-secretases (Aβ(17–40/42)). The presence of N-terminally truncated Aβ(17–40) and Aβ(17–42) in the control brains was confirmed by Western blotting and the identity of Aβ(17–40) was confirmed by mass spectrometry. The prevalence of products of α- and γ -secretases in neurons and β- and γ-secretases in plaques argues against major contribution of Aβ-immunopositive material detected in neuronal soma to amyloid deposit in plaques. The strongest intraneuronal Aβ(17–42) immunoreactivity was observed in structures with low susceptibility to fibrillar Aβ deposition, neurofibrillary degeneration, and neuronal loss compared to areas more vulnerable to Alzheimer-type pathology. These observations indicate that the intraneuronal Aβ immunoreactivity detected in this study is not a predictor of brain amyloidosis or neurofibrillary degeneration. The constant level of Aβ immunoreactivity in structures free from neuronal pathology during essentially the entire life span suggests that intraneuronal amino-terminally truncated Aβ represents a product of normal neuronal metabolism