Two novel SNPs in the promoter region of PKR gene in hepatitis C patients and their impact on disease outcome and response to treatment

Background and study aims

The double-stranded RNA dependent protein kinase (PKR) plays a vital role in the immune system. During HCV infection, PKR has antiviral effect by inhibition of protein synthesis of the HCV. The functional single nucleotide polymorphisms (SNPs) in PKR promoter region might have a relation to HCV disease outcome and response to treatment. The objective of the present work was threefold. First, it proposed an optimized protocol for PCR amplification of PKR promoter. Second, it screened the promoter region of PKR gene in HCV Egyptian patients to detect the possible SNPs’ function. Third, to study the association between the detected SNPs and the response to treatment.

HCV Infection in Egyptian Patients with Acute Hepatitis

The diagnostics of community-acquired acute HCVhepatitis in an endemic area was studied in 110 Egyptianpatients with acute jaundice. In the first week of thejaundiced period 30 of 110 patients (27.3%) had anti-HCVantibodies. The majority already showed high levels ofanti-HCV IgG (25/30), associated with anti-HCV IgM innine of them. Five patients showed only an HCV IgMreactivity. Seven had also anti-HEV and/or anti-HBV: their jaundice couldthen be related to an acute infection caused by thoseviruses. All patients were infected with genotype 4a, inthree associated with the 3a. During the follow-up five patients seroconverted for IgG, whiletheir anti-HCV IgM did not show a uniform pattern ofreactivity. Patients with positive serology suspected ofan acute HCV infection were older than the patients with other acute hepatitis and showed a lowerpeak of ALT level. Seroconversion during acute hepatitisstrongly indicated HCV as the etiologic agent. However,the detection of anti-HCV IgG antibodies in the jaundiced period showed that the majorityof patients had already seroconverted to anti-HCVantibodies; in most of them it is possible tohypothesize a reactivation of a chronic HCVinfection.     

Residents from non‐English‐speaking countries of birth in Australian aged care facilities

Objective

To describe the activity of daily living and behavioural and complex care needs of residents born in non‐English‐speaking countries in Australian aged care facilities.

Methods

De‐identified cross‐sectional data were provided by the Australian Institute of Health and Welfare for all residents in government‐funded facilities on 30 June 2015. Analyses included t‐tests, chi‐squared tests and logistic regressions.

Results

A total of 33 168 (19%) residents were born in one of 188 non‐English‐speaking countries. Compared to residents born in English‐speaking countries, they were significantly younger, lived in larger facilities, were more likely to be male and live in an urban area. Their care requirements were greater for activities of daily living and behavioural and complex care. Residents from non‐English‐speaking countries living in ethno‐specific facilities had higher levels of these needs.

Conclusion

The needs of residents born in non‐English‐speaking countries should be considered when planning aged care services.

     

Help seeking in older Asian people with dementia in Melbourne: Using the Cultural Exchange Model to explore barriers and enablers

The prevalence of dementia is increasing in Australia. Limited research is available on access to Cognitive Dementia and Memory Services (CDAMS) for people with dementia from Culturally and Linguistically Diverse (CALD) communities. This study aimed to determine the barriers and enablers to accessing CDAMS for people with dementia and their families of Chinese and Vietnamese backgrounds. Consultations with community members, community workers and health professionals were conducted using the “Cultural Exchange Model” framework. For carers, barriers to accessing services included the complexity of the health system, lack of time, travel required to get to services, language barriers, interpreters and lack of knowledge of services. Similarly, community workers and health professionals identified language, interpreters, and community perceptions as key barriers to service access. Strategies to increase knowledge included providing information via radio, printed material and education in community group settings. The “Cultural Exchange Model” enabled engagement with and modification of the approaches to meet the needs of the targeted CALD communities.     

Structural plasticity of 4-α-helical bundles exemplified by the puzzle-like molecular assembly of the Rop protein

The dimeric Repressor of Primer (Rop) protein, a widely used model system for the study of coiled-coil 4-α-helical bundles, is characterized by a remarkable structural plasticity. Loop region mutations lead to a wide range of topologies, folding states, and altered physicochemical properties. A protein-folding study of Rop and several loop variants has identified specific residues and sequences that are linked to the observed structural plasticity. Apart from the native state, native-like and molten-globule states have been identified; these states are sensitive to reducing agents due to the formation of nonnative disulfide bridges. Pro residues in the loop are critical for the establishment of new topologies and molten globule states; their effects, however, can be in part compensated by Gly residues. The extreme plasticity in the assembly of 4-α-helical bundles reflects the capacity of the Rop sequence to combine a specific set of hydrophobic residues into strikingly different hydrophobic cores. These cores include highly hydrated ones that are consistent with the formation of interchain, nonnative disulfide bridges and the establishment of molten globules. Potential applications of this structural plasticity are among others in the engineering of bio-inspired materials.Recurrent motifs of tertiary structure are convenient model systems for studying protein folding and potentially also for the design of bio-inspired materials. For protein design purposes, structural plasticity is an important, although poorly understood, parameter to be considered, as it is among the main reasons that the re-engineering of proteins toward novel materials is not yet satisfactorily manageable (1, 2).The present study focuses on the structural plasticity associated with the 4-α-helical bundle (4HB) motif. 4HBs consist of four amphipathic α-helices packed in a parallel or antiparallel fashion (3, 4). Their folding is largely determined by a repeating pattern of hydrophobic and hydrophilic residues, organized on the basis of seven-residue repeats (heptads) (5). Being the simplest tertiary motif, 4HBs have been subject to numerous protein-folding studies; attempts have been made to exploit them as building blocks for bio-inspired materials (6).A paradigm of a highly regular 4HB is the RNA-binding ColE1 Repressor of Primer (Rop) protein (7–9), also referred to as RNA-one-modulator (ROM). Each monomer is an α-helical hairpin consisting of two antiparallel α-helices connected by a short loop. The sequence of Rop displays a heptad repeats pattern that is interrupted only in the loop region.Structural simplicity makes Rop an attractive model system for the study of the folding of 4HBs. The loop region and the hydrophobic core have thereby attracted particular attention, as these regions are linked with the remarkable ability of Rop mutants to adopt altered topologies and properties (10–15). Striking examples of loop variants include mutant Loopless Rop (LLR), in which an uninterrupted pattern of heptad repeats is established through a five-residue deletion in the loop. In this “loopless” mutant, the α-helical hairpin of the monomer is converted into a single helix (15, 16). The complete LLR molecule is a tetramer that is completely reorganized relative to the dimeric wild-type (WT) Rop, thereby becoming a hyper-thermostable protein (16). On the other hand, establishment of an uninterrupted heptad periodicity through a two-residue insertion in the loop produces minimal changes relative to WT in terms of structure and properties (12). Thus, these two mutants with uninterrupted patterns of heptads reveal that there is a considerable structural plasticity inherent to the Rop sequence, but the relationship between heptad periodicity and the structural/physicochemical properties is complex.Extreme structural plasticity producing completely altered 4HB topologies is also associated with point mutations in the loop region. Replacement of loop residue Ala31 by Pro (17) results in a complete reorganization of the entire protein, which is converted from the canonical left-handed, all-antiparallel form into a right-handed mixed-parallel and antiparallel 4-α-helical bundle, displaying a “bisecting U” topology that is to a large extent determined by the local conformation at residue 31 (18). Mutant A31P displays two variations of the bisecting U topology; these differ in the relative juxtaposition of the α-helices (19). These conformations crystallize in different space groups (orthorhombic and monoclinic); both space groups have been occasionally observed in the same crystallization drop, indicating the coexistence of the two forms in solution. Molecular dynamics simulations for A31P have demonstrated a potential for the interconversion between the two conformations (14).Hydrophobic core mutants occasionally also display structural plasticity producing a new (“syn”) topology (20) that results from the “anti”-topology of WT through a 180° flip of one monomer around the dyad axis normal to the long axis of WT. The competition between the anti and syn topologies and the mixture of the two structures have been studied in detail for some Rop mutants (21, 22).Apart from structural plasticity, a closely related issue associated with the folding of Rop is the role of Cys residues (Cys-38 and Cys-52). Both residues are buried in the hydrophobic core and are not involved in the formation of disulfide bridges in any of the known structures of WT and its mutants. Surprisingly, however, a Cys-free variant (CYSfree) that conserves the structure, stability, and in vivo activity of WT exhibits dramatically faster unfolding kinetics (23).The present study focuses on the role of the loop region and Cys residues in the structural plasticity of Rop. To explore the conversion of the WT anti-topology into the bisecting U topology of A31P, the three double mutants D30P/A31G (PG), D30G/A31P (GP), and D30P/A31P (PP) have been constructed for loop positions 30 and 31. These mutations combine the effects of the most constrained amino acid (Pro) and of the least constrained one (Gly). In addition, the potential role of Cys residues in Rop folding is explored by following the effects of reducing agents.     

Epidemiology,clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.     

Neuroprotective effect of Crocus sativus against cerebral ischemia in rats

Metabolic Brain Disease - The present study aimed to investigate the role of vascular endothelial growth factor (VEGF) in the neuroprotective effect of Crocus sativus (saffron) against cerebral...     

Childhood Verbal Abuse: A Risk Factor for Depression in Pre-Bariatric Surgery Psychological Evaluations

The present study evaluated the importance of multimodal assessment of childhood verbal abuse (CVA) in pre-bariatric surgery psychological evaluations, and the role of CVA as a predictor of depression. Data from the psychological evaluations of 184 pre-bariatric surgery patients were retrospectively examined. Using two self-report measures and an interview-based screen, 52.2 % of participants reported experiencing some form of CVA; conversely, assessments of CVA based on only one measure yielded significantly lower prevalence rates. Endorsement of CVA on multiple measures was associated with more severe depressive symptomatology and greater likelihood of mood disorder diagnosis. Based on these data, a self-report measure and interview-based screen for CVA should be included in pre-bariatric psychological evaluations; either of these assessments may be conducted via a single-item screen. Lastly, patients who endorse CVA on multiple measures should be monitored closely for symptoms of depression post-surgery.