Miracle-dz/UniFAR-FTUs huggingface dataset:
Unexplained isolated hyperferritinemia without iron overload

Although hyperferritinemia may be reflective of elevated total body iron stores, there are conditions in which ferritin levels are disproportionately elevated relative to iron status. Autosomal dominant forms of hyperferritinemia due to mutations in the L−ferritin IRE or in A helix of L−ferritin gene have been described, however cases of isolated hyperferritinemia still remain unsolved. We describe 12 Italian subjects with unexplained isolated hyperferritinemia (UIH). Four probands have affected siblings, but no affected parents or offspring. Sequencing analyses did not identify casual mutations in ferritin gene or IRE regions. These patients had normal levels of intracellular ferritin protein and mRNA in peripheral blood cells excluding pathological ferritin production at transcriptional and post‐transcriptional level. In contrast with individuals with benign hyperferritinemia caused by mutations affecting the ferritin A helix, low rather than high glycosylation of serum ferritin was observed in our UIH subjects compared with controls. These findings suggest that subjects with UIH have a previously undescribed form of hyperferritinemia possibly attributable to increased cellular ferritin secretion and/or decreased serum ferritin clearance. The cause remains to be defined and we can only speculate the existence of mutations in gene/s not directly implicated in iron metabolism that could affect ferritin turnover including ferritin secretion.
Routine standardised outcome measurement to evaluate the effectiveness of occupational therapy interventions: essential or optional?

This article presents the case for why the effectiveness of occupational therapy intervention should be monitored and reviewed by the routine use of rigorous and well-standardised outcome measures. Occupational therapists must be committed to contributing to the evidence base related to the effectiveness of occupational therapy interventions and know how to select and apply valid and reliable outcome measures in day-to-day practice, service evaluation and research activities. Drivers for evidence-based outcome measurement are explored and the need for an increased utilisation of patient reported outcome measures is discussed. Some measures, many of which are available as Norwegian versions, are suggested as potential outcome measures for occupational therapy services.
Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial

Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60‐65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.
Efficacy of the oral mTORC1 inhibitor everolimus in relapsed or refractory indolent lymphoma

Relapsed indolent lymphoma often becomes refractory to standard chemoimmunotherapy and requires new therapeutic strategies. Targeting the PI3K/mTOR pathway in several types of lymphoma has shown preclinical and clinical efficacy providing the rationale to test this strategy in the treatment of relapsed/refractory indolent lymphomas. We investigated in a phase II open label clinical trial the efficacy and safety of single agent everolimus, an inhibitor of mTORC1, in patients with relapsed/refractory indolent lymphomas. Eligible patients received oral everolimus 10 mg daily on a 28 day‐cycle schedule. The primary endpoint was to evaluate the overall response rate (ORR) and safety of single‐agent everolimus in this patient population. Fifty‐five patients with indolent lymphoma were accrued. The median age was 67 years (range: 33‐85) with a median of five prior therapies (range: 1‐10). The ORR was 35% (19/55; 95% CI: 24‐48%), with complete response unconfirmed in 4% (2/55), and partial response in 31% (17/55). The ORR was 61% (14/23) in the patients with FL. The median time to response was 2.3 months (range: 1.4‐14.1), median duration of response of 11.5 months (95%‐CI: 5.7‐30.4), and a median progression‐free survival of 7.2 months (95%‐CI: 5.5‐12.5). The most common toxicity was hematologic with grades 3‐4 anemia, neutropenia, and thrombocytopenia documented in 15% (8/55), 22% (12/55), and 33% (18/55), respectively. There were no cases of febrile neutropenia, and eight patients discontinued therapy because of adverse events. Everolimus monotherapy is a valid therapeutic option in the relapsed and/or refractory indolent non‐Hodgkin lymphoma patients and is well tolerated.
Holy Water as an Intervention for HIV/AIDS in Ethiopia

A growing number of people living with HIV/AIDS in Ethiopia today are relocating to holy water sites, in search of spiritual care. This article documents the experiences of 17 people living with HIV/AIDS, based on their in-depth interviews by the author. The use of holy water is considered by them to be an alternative and complementary treatment for HIV/AIDS. In addition, there are some other spiritual practices that can be considered spiritual treatment. The issue of using antiretroviral treatment together with holy water treatment remains controversial among the research participants. The article shows areas of intervention for social workers regarding the people living with HIV/AIDS who are heading to holy water sites for relief.
A multicenter prospective study on efficacy and safety of imatinib generics: A report from Polish Adult Leukemia Group imatinib generics registry

The efficacy and safety of imatinib generics were not studied and reported on larger cohort of patients yet. We report on efficacy and safety of imatinib generics in 726 chronic myeloid leukemia patients in chronic phase who completed one-year observation, prospectively assessed within Polish Adult Leukemia Group imatinib generics registry. In 99 previously untreated patients the rate of early molecular response achieved at 3 months and major molecular response achieved at 12 months was 65.7% and 53.4% respectively. Complete cytogenetic response at 6 months was achieved in 55.4% of patients. In 627 patients switched from branded to generic imatinib the molecular response was sustained in 64.8%, worsened in 15% and improved in 19% of them. Complete cytogenetic response, major molecular response and MR4,5 were lost in 0.3%, 1.3% and 10.3%, respectively. Hematologic toxicity (grade 3 or 4) and non-hematologic toxicity (any grade) occurred in 3% and 40% of 99 previously untreated patients and in 0.2% and 14.4% of "switched" patients, respectively. In one-year observation the efficacy and safety of tested imatinib generics are not inferior to branded imatinib. No increased switching rate from first to second generation tyrosine kinase inhibitors was noticed This article is protected by copyright. All rights reserved.
Functional Identification of Two Nonredundant Arabidopsis α(1,2)Fucosyltransferases Specific to Arabinogalactan Proteins*

Virtually nothing is known about the mechanisms and enzymes responsible for the glycosylation of arabinogalactan proteins (AGPs). The glycosyltransferase 37 family contains plant-specific enzymes, which suggests involvement in plant-specific organs such as the cell wall. Our working hypothesis is that AtFUT4 and AtFUT6 genes encode α(1,2)fucosyltransferases (FUTs) for AGPs. Multiple lines of evidence support this hypothesis. First, overexpression of the two genes in tobacco BY2 cells, known to contain nonfucosylated AGPs, resulted in a staining of transgenic cells with eel lectin, which specifically binds to terminal α-linked fucose. Second, monosaccharide analysis by high pH anion exchange chromatography and electrospray ionization mass spectrometry indicated the presence of fucose in AGPs from transgenic cell lines but not in AGPs from wild type cells. Third, detergent extracts from microsomal membranes prepared from transgenic lines were able to fucosylate, in vitro, purified AGPs from BY2 wild type cells. Susceptibility of [14C]fucosylated AGPs to α(1,2)fucosidase, and not to α(1,3/4)fucosidase, indicated that an α(1,2) linkage is formed. Furthermore, dearabinosylated AGPs were not substrate acceptors for these enzymes, indicating that arabinosyl residues represent the fucosylation sites on these molecules. Testing of several polysaccharides, oligosaccharides, and glycoproteins as potential substrate acceptors in the fucosyl transfer reactions indicated that the two enzymes are specific for AGPs but are not functionally redundant because they differentially fucosylate certain AGPs. AtFUT4 and AtFUT6 are the first enzymes to be characterized for AGP glycosylation and further our understanding of cell wall biosynthesis.
Mutations of the integrin αIIb/β3 intracytoplasmic salt bridge cause macrothrombocytopenia and enlarged platelet α‐granules

Rare gain‐of‐function mutations within the ITGA2B or ITGB3 genes have been recognized to cause macrothrombocytopenia (MTP). Here we report three new families with autosomal dominant (AD) MTP, two harboring the same mutation of ITGA2B, αIIbR995W, and a third family with an ITGB3 mutation, β3D723H. In silico analysis shows how the two mutated amino acids directly modify the salt bridge linking the intra‐cytoplasmic part of αIIb to β3 of the integrin αIIbβ3. For all affected patients, the bleeding syndrome and MTP was mild to moderate. Platelet aggregation tended to be reduced but not absent. Electron microscopy associated with a morphometric analysis revealed large round platelets; a feature being the presence of abnormal large α‐granules with some giant forms showing signs of fusion. Analysis of the maturation and development of megakaryocytes reveal no defect in their early maturation but abnormal proplatelet formation was observed with increased size of the tips. Interestingly, this study revealed that in addition to the classical phenotype of patients with αIIbβ3 intracytoplasmic mutations there is an abnormal maturation of α‐granules. It is now necessary to determine if this feature is a characteristic of all mutations disturbing the αIIb R995/β3 D723 salt bridge.
Phosphorylation of Tau at Thr212, Thr231, and Ser262 Combined Causes Neurodegeneration*

Abnormal hyperphosphorylation of the microtubule-associated protein Tau is a hallmark of Alzheimer disease and related diseases called tauopathies. As yet, the exact mechanism by which this pathology causes neurodegeneration is not understood. The present study provides direct evidence that Tau abnormal hyperphosphorylation causes its aggregation, breakdown of the microtubule network, and cell death and identifies phosphorylation sites involved in neurotoxicity. We generated pseudophosphorylated Tau proteins by mutating Ser/Thr to Glu and, as controls, to Ala. These mutations involved one, two, or three pathological phosphorylation sites by site-directed mutagenesis using as backbones the wild type or FTDP-17 mutant R406W Tau. Pseudophosphorylated and corresponding control Tau proteins were expressed transiently in PC12 and CHO cells. We found that a single phosphorylation site alone had little influence on the biological activity of Tau, except Thr212, which, upon mutation to Glu in the R406W background, induced Tau aggregation in cells, suggesting phosphorylation at this site along with a modification on the C-terminal of the protein facilitates self-assembly of Tau. The expression of R406W Tau pseudophosphorylated at Thr212, Thr231, and Ser262 triggered caspase-3 activation in as much as 85% of the transfected cells, whereas the corresponding value for wild type pseudophosphorylated Tau was 30%. Cells transfected with pseudophosphorylated Tau became TUNEL-positive.
Structural Basis of Dimerization-dependent Ubiquitination by the SCFFbx4 Ubiquitin Ligase♦

The F-box proteins are the substrate recognition subunits of the SCF (Skp1-Cul1-Rbx1-F- box protein) ubiquitin ligase complexes that control the stability of numerous regulators in eukaryotic cells. Here we show that dimerization of the F-box protein Fbx4 is essential for SCFFbx4 (the superscript denotes the F-box protein) ubiquitination activity toward the telomere regulator Pin2 (also known as TRF1). The crystal structure of Fbx4 in complex with an adaptor protein Skp1 reveals an antiparallel dimer configuration in which the linker domain of Fbx4 interacts with the C-terminal substrate-binding domain of the other protomer, whereas the C-terminal domain of the protein adopts a compact α/β fold distinct from those of known F-box proteins. Biochemical studies indicate that both the N-terminal domain and a loop connecting the linker and C-terminal domain of Fbx4 are critical for the dimerization and activation of the protein. Our findings provide a framework for understanding the role of F-box dimerization in the SCF-mediated ubiquitination reaction.
CARACTERIZAÇÃO DO MODELO INFLAMATÓRIO DE CISTITE INDUZIDA POR CICLOFOSFAMIDA EM CAMUNDONGOS SWISS

A Cistite Hemorragica e um problema de saude importante no mundo causado pelo uso da oxazoforinas. Apesar dos tratamentos disponiveis, ha uma incidencia de 2 ate 40% em pacientes tratados com Ciclofosfamida (CYP). O objetivo deste trabalho foi caracterizar um modelo experimental de cistite induzida por CYP em camundongos Swiss. Para isto, camundongos femeas foram distribuidos em 5 grupos com 7 animais, onde 4 grupos sofreram eutanasia apos 0,5, 6, 12 e 24h da aplicacao de 150mg/kg de CYP via intraperitoneal. O grupo controle recebeu salina tamponada pela mesma via. Foram avaliados o peso da bexiga e seu aspecto histopatologico, o hemograma, e a contagem celular de medula ossea e linfonodo iliaco. Os resultados demonstraram que houve aumento signiﬁcativo do peso da bexiga nos tempos de 6 e 12h. Houve aumento na infamacao aguda nestes dois tempos. Apos 24 horas houve diminuicao da resposta inﬂamatoria aguda e inicio da ﬁbrose. O numero de leucocitos foi menor em todos os tempos em relacao ao controle. Da mesma forma, o numero de celulas da medula ossea foi menor nos tempos de 6, 12 e 24h. Por outro lado, o numero de celulas do linfonodo aumentou apos 12 horas. Concluimos que houve aumento progressivo da inﬂamacao ate as 12h e que apos 24h ja ha um processo de resolucao do quadro inﬂamatorio. Sendo assim, sugerimos a utilizacao do tempo de 12h como padrao experimental por ser o de maior disponibilidade de parâmetros elevados para avaliacao da inﬂamacao. Descritores: Cistite. Ciclofosfamida. Camundongo. Modelo experimental. Abstract Characterization of cyclophosphamide-induced cystitis inﬂammatory model in Swiss mice. The Hemorragic Cystitis (HC) is an important health problem over the world caused by oxazoforines. Despite the available treatments, still have an incidence of 2 to 40% of HC in patients following treatment with Cyclophosphamide (CYP). The aim of this work was characterize a model of CYP-induced cystitis in Swiss mice. Female mice were divided in 5 groups with 7 animals each, 4 groups were killed 0.5, 6, 12 and 24h after an injection of CYP (150mg/kg). The control group received phosphate buffered saline at the same way. In each time the bladders were collected, weighted and prepared to histopathology analyses. The complete blood count was evaluated. The cell number from lymph nodes and bone marrow was quantiﬁed. The results showed that bladder weight was increased at 6thand 12th hour pos cystitis induction. There was acute inﬂammation increased after 6 and 12h. After 24h there was an initial ﬁbrosis. The leucocytes count was decreased in all times. The cells number was decreased at 6th, 12th, and 24th hours in bone marrow and it was increased at 12th in lymph nodes. We concluded that there is an increase in inﬂammatory parameters until the 12th hour pos CYP injection which are decreased at 24th hour. We suggest using the time of 12h as the standard experimental time because of the biggest availability parameters for evaluating. Descriptors: Cyclophosphamide. Cystitis. Mice. Experimental model.
Domain Cross-talk during Effector Binding to the Multidrug Binding TTGR Regulator*

A major mechanism of antibiotic resistance in bacteria is the active extrusion of toxic compounds through membrane-bound efflux pumps. The TtgR protein represses transcription of ttgABC, a key efflux pump in Pseudomonas putida DOT-T1E capable of extruding antibiotics, solvents, and flavonoids. TtgR contains two distinct and overlapping ligand binding sites, one is broad and contains mainly hydrophobic residues, whereas the second is deep and contains polar residues. Mutants in the ligand binding pockets were generated and characterized using electrophoretic mobility shift assays, isothermal titration calorimetry, and promoter expression. Several mutants were affected in their response to effectors in vitro: mutants H70A, H72A, and R75A did not dissociate from promoter DNA in the presence of chloramphenicol. Other mutants exhibited altered binding to the operator: L66A and L66AV96A mutants bound 3- and 15-fold better than the native protein, whereas the H67A mutant bound with 3-fold lower affinity. In vivo expression assays using a fusion of the promoter of ttgA to lacZ and antibiotic tolerance correlated with the in vitro observations, namely that mutant H67A leads to increased basal expression levels and enhances antibiotic tolerance, whereas mutants L66A and L66AV96A exhibit lower basal expression levels and decreased resistance to antibiotics. The crystal structure of TtgR H67A was resolved. The data provide evidence for the inter-domain communication that is predicted to be required for the transmission of the effector binding signal to the DNA binding domain and provide important information to understand TtgR/DNA/effector interactions.
systematic review of the effectiveness and roles of advanced actice nursing in older people n

Objectives: To identify, assess and summarize available scientific evidence about the effect of interventions deployed by advanced practice nurses when providing care to older people in different care settings, and to describe the roles and components of the interventions developed by these professionals. Background: In older people, evidence of advanced practice roles remains dispersed along different contexts, approaches and settings; there is little synthesis of evidence, and it is not easy to visualize the different practice models, their components, and their impact. Design: Systematic review. Data sources: Sixteen electronic databases were consulted (1990–2014). The research also included screening of original studies in reviews and reports from Centers of Health Services Research and Health Technology Agencies. Review methods: Studies were assessed by two reviewers with the Cochrane risk of bias tool. They were classified depending on the type of follow-up (long and short-term care) and the scope of the service (advanced practice nurses interventions focused on multimorbid patients, or focused on a specific disease). Results: Fifteen studies were included. In long-term settings, integrative, multi-component and continuous advanced practice nursing care, reduced readmissions, and increased patients’ and caregivers’ satisfaction. Advanced practice nurses were integrated within multidisciplinary teams and the main interventions deployed were patient education, multidimensional assessments and coordination of multiple providers. Conclusion: Positive results have been found in older people in long-term care settings, although it is difficult to discern the specific effect attributable to them because they are inserted in multidisciplinary teams. Further investigations are needed to evaluate the cost-effectiveness of the two modalities detected and to compare internationally the interventions developed by advanced practice nurses. 2015 Elsevier Ltd. All rights reserved. Corresponding author at: Department of Nursing, Faculty of Health nces, University of Málaga, C/ Arquitecto Francisco Peñalosa, 3 pus de Teatinos), 29071 Malaga, Spain. +34 951952833; fax: +34 951952835. E-mail address: jmmasen@uma.es (J.M. Morales-Asencio).
Oleate Inhibits Steryl Ester Synthesis and Causes Liposensitivity in Yeast*

In the yeast Saccharomyces cerevisiae, neutral lipids can be synthesized by four acyltransferases, namely Dga1p and Lro1p producing triacylglycerols (TAG) and Are1p and Are2p forming steryl esters (SE). TAG and SE are stored in an organelle called lipid particles/droplet. Growth of yeast cells on oleate-supplemented media strongly induced proliferation of lipid particles and specifically the synthesis of TAG, which serve as the major pool for the excess of fatty acids. Surprisingly, SE synthesis was strongly inhibited under these conditions. Here, we show that this effect was not due to decreased expression of ARE2 encoding the major yeast SE synthase at the transcriptional level but to competitive enzymatic inhibition of Are2p by free oleate. Consequently, a triple mutant dga1Δlro1Δare1ΔARE2+ grown on oleate did not form substantial amounts of SE and exhibited a growth phenotype similar to the dga1Δlro1Δare1Δare2Δ quadruple mutant, including lack of lipid particles. Growth of these mutants on oleate was strongly delayed, and cell viability was decreased but rescued by adaptation. In these strains, oleate stress caused morphological changes of intracellular membranes, altered phospholipid composition and formation of an additional lipid class, ethyl esters of fatty acids. In summary, our data showed that exposure to oleate led to disturbed lipid and membrane homeostasis along with liposensitivity of the yeast.
Genomic and immunophenotypical differences between hepatocellular carcinoma with and without cirrhosis

Tretiakova M S, Shabani‐Rad M T, Guggisberg K, Hart J, Anders R A & Gao Z‐h (2010) Histopathology 56, 683–693 Genomic and immunophenotypical differences between hepatocellular carcinoma with and without cirrhosis
Development of antiinflammatory therapy for Alzheimer's disease

Inflammatory mechanisms are active in the Alzheimer's disease (AD) brain. Studies that range from epidemiological surveys to therapeutic trials in transgenic mice provide growing support for the theory that antiinflammatory drugs may be useful in the prevention and/or treatment of the disease. Randomized controlled trials in humans have not yet confirmed this theory. However, prevention and treatment trials continue to test specific antiinflammatory strategies for AD. Drug Dev. Res. 56:421–427, 2002. © 2002 Wiley‐Liss, Inc.
Differential gene expression in classic giant cell tumours of bone: Tenascin C as biological risk factor for local relapses and metastases

Pazzaglia L, Conti A, Chiechi A, Novello C, Magagnoli G, Astolfi A, Pession A, Krenacs T, Alberghini M, Picci P & Benassi M S (2010) Histopathology 57, 59–72 Differential gene expression in classic giant cell tumours of bone: Tenascin C as biological risk factor for local relapses and metastases