Investigation of lectin complement proteins in urinary schistosomiasis and visceral leishmaniasis

Complement lectins are pathogen recognition receptors (PRRs) that bind to pathogen associated molecular patterns (PAMPs) of various microbes. The circulating serum levels and functional genetic variants of four such innate immune recognition elements, namely the human mannose-binding lectin (MBL), ficolin-2 (FCN2), collectin 11 (CL-K1), mannose-binding associated serine protease-2 (MASP2) were studied in intracellular (visceral leishmaniasis) and extracellular (urinary schistosomiasis) parasitic diseases. In extracellular Schistosoma haematobium infection, MBL, MASP2, and collectin-11 (CL- K1) and their functional variants were associated with relative protection. In intra-cellular Leishmania donovani infection, MBL, ficolin-2 and their functional variants were observed to be a susceptible host factor. IL-6 was observed to regulate the lectin expression during distinct parasitic infections. In conclusion, this dissertation provides probable evidence on the differential role of lectins in intra and extracellular infections.Komplement-Lektine sind sogenannte “pathogen recognition receptors” (PRRs), welche Pathogen-assoziierte molekulare Muster (“pathogen associated molecular patterns”, PAMPs) diverser Krankheitserreger erkennen. Ich untersuchte zirkulierenden Serumlevel und funktionelle genetische Varianten von vier solcher PRRs in einer intrazellulären (viszerale Leishmaniose) und einer extrazellulären (urogenitale Schistosomiase) Krankheit: Mannose-bindendes Lektin (MBL), Ficolin 2 (FCN2), Collektin 11 (CL-K1), und MBL assoziierte Serinprotease 2 (MASP2). In der extrazellulären Schistosoma haematobium Infektion waren MBL, MASP2, und Collektin 11, sowie deren funktionelle Varianten mit einem relativen Schutz gegen die Krankheit assoziiert. In der intrazellulären Leishmania donovani Infektion waren MBL, Ficolin 2, und deren funktionelle Varianten Suszeptibilitätsfaktoren. Während distinkter parasitischer Infektionen regulierte IL-6 die Lektinexpression. Zusammenfassend erbringt diese Dissertation diverse Beweise für die differentielle Rolle von Lektinen in intra- und extrazellulären parasitischen Infektionen

TrkA Signalling and Parkinson’s Dementia

Cognitive impairment and dementia are the most frequently occurring nonmotor symptoms in Parkinson’s disease (PD), yet these symptoms are mostly overlooked and are not diagnosed and treated exceptionally like the cardinal motor symptoms in clinical practice. It is only in the late twentieth century that dementia has been recognized as a major clinical manifestation in PD. The possible mechanisms that cause dementia are complex with different patterns of cognitive behavior that disrupt the patient’s quality of life. It is preeminently considered that the cholinergic denervation in the basal forebrain region mediates dementia in PD. So far, dopamine-based therapy is the key objective in the treatment of PD and the nonmotor symptoms are mostly neglected. Interestingly, the loss of Tyrosine kinase receptor-A (TrkA) signaling in basal forebrain results in neuronal atrophy, which precedes cholinergic denervation and cognitive impairment. Nerve Growth Factor (NGF) binds to TrkA receptors, inducing a cascade of events like PI-3Kinase/Akt and MAPK signaling pathways that render cholinergic degeneration and upregulate the choline acetyltransferase activity and neuronal differentiation. Hence, TrkA receptor activation by small molecules might attenuate the dementia symptoms associated with PD, and may be targeted as a novel treatment strategy along with regular clinical agents

Natural Products Altering GABAergic Transmission

Gamma-amino butyric acid (GABA) is a major inhibitory neurotransmitter found in several regions of the brain and known to have various significant physiological roles as a potent bioactive compound. Malfunction of GABAergic neuronal signaling prompts to cause severe psychiatric symptoms in numerous mental disorders. Several drugs are available in clinical practice for neuropsychiatric disorders targeting through GABAergic pathway, with notable adverse effects. Interestingly, in recent years, researchers are focusing on natural compounds altering GABAergic neurotransmission for various psychiatric disorders due to its wide range of therapeutic efficacy and safety. The enormous variety of natural compounds, namely alkaloids, flavonoids, terpenoids, polyacetylenic alcohols, alkanes and fatty acids were reported to alter the GABAergic transmission through its receptors and or by influencing the transmission, synthesis and metabolism of GABA. Natural compounds are able to cross the blood brain barrier and influence the GABA functions in order to treat anxiety, mania, schizophrenia and cognitive disorders. Therefore, this current chapter describes on natural products which have the potential to alter the GABAergic neurotransmission and its therapeutical benefits in treating several neuropsychiatry disorders using various pharmacological methods

Association of Ficolin-2 serum levels and FCN2 genetic variants with Indian Visceral Leishmaniasis

Background: Visceral leishmaniasis (VL), one of the neglected tropical diseases, is endemic in the Indian subcontinent. Ficolins are circulating serum proteins of the lectin complement system and involved in innate immunity. Methods: We have estimated ficolin-2 serum levels and analyzed the functional variants of the encoding gene FCN2 in 218 cases of VL and in 225 controls from an endemic region of India. Results: Elevated levels of serum ficolin-2 were observed in VL cases compared to the controls (adjusted P<0.0001). The genetic analysis revealed that the FCN2 structural variant +6359 C>T (p.T236M) was associated with VL (OR=2.2, 95% CI = 1.23-7.25, P = 0.008) and with high ficolin-2 serum levels. We also found that the FCN2*AAAC haplotype occurred more frequently among healthy controls when compared to cases (OR = 0.59, 95% CI = 0.37-0.94, P = 0.023). Conclusions: Our findings indicate that the FCN2 variant +6359C>T is associated with the occurrence of VL and that ficolin-2 serum levels are elevated in Leishmania infections

Identifying behaviour change techniques in 287 randomized controlled trials of audit and feedback interventions targeting practice change among healthcare professionals

Background: Audit and feedback (A&F) is among the most widely used implementation strategies, providing healthcare professionals with summaries of their practice performance to prompt behaviour change and optimize care. Wide variability in effectiveness of A&F has spurred efforts to explore why some A&F interventions are more effective than others. Unpacking the variability of the content of A&F interventions in terms of their component behaviours change techniques (BCTs) may help advance our understanding of how A&F works best. This study aimed to systematically specify BCTs in A&F interventions targeting healthcare professional practice change. / Methods: We conducted a directed content analysis of intervention descriptions in 287 randomized trials included in an ongoing Cochrane systematic review update of A&F interventions (searched up to June 2020). Three trained researchers identified and categorized BCTs in all trial arms (treatment & control/comparator) using the 93-item BCT Taxonomy version 1. The original BCT definitions and examples in the taxonomy were adapted to include A&F-specific decision rules and examples. Two additional BCTs (‘Education (unspecified)’ and ‘Feedback (unspecified)’) were added, such that 95 BCTs were considered for coding. / Results: In total, 47/95 BCTs (49%) were identified across 360 treatment arms at least once (median = 5.0, IQR = 2.3, range = 129 per arm). The most common BCTs were ‘Feedback on behaviour’ (present 89% of the time; e.g. feedback on drug prescribing), ‘Instruction on how to perform the behaviour’ (71%; e.g. issuing a clinical guideline), ‘Social comparison’ (52%; e.g. feedback on performance of peers), ‘Credible source’ (41%; e.g. endorsements from respected professional body), and ‘Education (unspecified)’ (31%; e.g. giving a lecture to staff). A total of 130/287 (45%) control/comparator arms contained at least one BCT (median = 2.0, IQR = 3.0, range = 0–15 per arm), of which the most common were identical to those identified in treatment arms. / Conclusions: A&F interventions to improve healthcare professional practice include a moderate range of BCTs, focusing predominantly on providing behavioural feedback, sharing guidelines, peer comparison data, education, and leveraging credible sources. We encourage the use of our A&F-specific list of BCTs to improve knowledge of what is being delivered in A&F interventions. Our study provides a basis for exploring which BCTs are associated with intervention effectiveness. / Trial registrations: N/A

Characterisation and hydrometallurgical processing of nickel from tropical agromined bio-ore

Hyperaccumulator plants ("metal crops") can be used for selective extraction of Ni from low-grade resources, thereby producing a high-grade "bio-ore". This so-called agromining (or phytomining) technology involves farming select metal crops on ultramafic soils, mineral wastes, or overburden that are sub-economic Ni resources for conventional extractive technology. Key to profiting from agromining is the efficient recovery of Ni and by-products from the bio-ore, either directly from freshly harvested biomass or from the ash after incineration. Bio-ore of wild grown specimens of the Ni hyperaccumulator plants Rinorea bengalensis and Phyllanthus securinegoides were collected in Malaysia. After incineration, the ash composites contained 5.5.and 12.7 wt% Ni for Rinorea and Phyllanthus respectively, along with substantial amounts of Ca, K, C, Mg, P, Na, S and Cl. Other minor impurities included Si, Fe, Al, Mn and Zn. The solids were characterised in detail by SEM-EDS, XRD and XANES. The effect of solution chemistry on the leaching behaviour of the bio-ore (dried biomass and ash) was also assessed. A hydrometallurgical process for recovering Ni from the bio-ore was then demonstrated. The processes involves the bio-ore (ash) being water-washed, yielding >90% recovery of K to solution. After water washing, >95% Ni recovery was achieved by H2SO4 leaching at 60 degrees C, although long residence times and high acid concentrations were required. Ni(OH)(2) was then precipitated from solution using the K2CO3 rich wash-water. The bio-ore generated precipitant was compared with NaOH and MgO used industrially. (C) 2017 Elsevier B.V. All rights reserved