bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting signaling pathways in acute lymphoblastic leukemia: new insights
Authors: Harrison Christine J.
Published: December 2013

The genetics of acute lymphoblastic leukemia are becoming well understood and the incidence of individual chromosomal abnormalities varies considerably with age. Cytogenetics provide reliable risk stratification for treatment: high hyperdiploidy and ETV6-RUNX1 are good risk, whereas BCR-ABL1, MLL rearrangements, and hypodiploidy are poor risk. Nevertheless, some patients within the good- and intermediate-risk groups will unpredictably relapse. With advancing technologies in array-based approaches (single nucleotide polymorphism arrays) and next-generation sequencing to study the genome, increasing numbers of new genetic changes are being discovered. These include deletions of B-cell differentiation and cell cycle control genes, as well as mutations of genes in key signaling pathways. Their associations and interactions with established cytogenetic subgroups and with each other are becoming elucidated. Whether they have a link to outcome is the most important factor for refinement of risk factors in relation to clinical trials. For several newly identified abnormalities, including intrachromosomal amplification of chromosome 21 (iAMP21), that are associated with a poor prognosis with standard therapy, appropriately modified treatment has significantly improved outcome. After the successful use of tyrosine kinase inhibitors in the treatment of BCR-ABL1–positive acute lymphoblastic leukemia, patients with alternative ABL1 translocations and rearrangements involving PDGFRB may benefit from treatment with tyrosine kinase inhibitors. Other aberrations, for example, CRLF2 overexpression and JAK2 mutations, are also providing potential novel therapeutic targets with the prospect of reduced toxicity.
Phase 4 research: what happens when the rubber meets the road?
Authors: Crowther Mark
Published: December 2013

Approval of a novel drug is oftentimes seen as the end of the development pathway. However, the appearance of rare but serious side effects in patients taking approved drugs has led to increased attention to phase 4, or postmarketing, research. Traditionally, postmarketing research relied on reports from clinicians to monitor for unexpected toxicity. However, such reporting will produce a biased assessment of risk due to underreporting of toxic effects in older medications. The availability of large, representative databases and more flexible analysis tools has led to comprehensive and near “real-time” surveillance programs. These programs have been used by the US Food and Drug Administration to explore toxicities of approved medications. The need for effective tools with which to monitor clinically relevant outcome events has been further increased by the development of accelerated pathways to drug approval. In areas without effective treatments, such pathways lead to licensure without rigorous clinical efficacy data. Continued approval is frequently made contingent on the availability of postmarketing surveillance data demonstrating improvements in clinical end points and these data can also be used to monitor for unexpected toxicity.
Which TKI? An embarrassment of riches for chronic myeloid leukemia patients
Authors: Hughes Timothy , White Deborah
Published: December 2013

With the approval in many countries of nilotinib and dasatinib for frontline therapy in chronic myeloid leukemia, clinicians now have to make a difficult choice. Because none of the 3 available tyrosine kinase inhibitors (TKIs) have shown a clear survival advantage, they all represent reasonable choices. However, in individual patients, the case may be stronger for a particular TKI. In the younger patient, in whom the prospect of eventually achieving treatment-free remission is likely to be of great importance, dasatinib or nilotinib may be preferred, although their advantage over imatinib in this setting remains to be proven. In patients with a higher risk of transformation (which is currently based on prognostic scoring), the more potent TKIs may be preferred because they appear to be more effective at reducing the risk of transformation to BC. However, imatinib still represents an excellent choice for many chronic myeloid leukemia patients. All of these considerations need to be made in the context of the patient's comorbidities, which may lead to one or more TKIs being ruled out of contention. Whatever first choice of TKI is made, treatment failure or intolerance must be recognized early because a prompt switch to another TKI likely provides the best chance of achieving optimal response.
Current management of immune thrombocytopenia
Authors: Neunert Cindy E.
Published: December 2013

Immune thrombocytopenia (ITP) is an autoimmune-mediated condition that results from antibody-mediated destruction of platelets and impaired megakaryocyte platelet production. ITP patients exhibit severe thrombocytopenia and are at risk for significant hemorrhage. Few randomized trials exist to guide management of patients with ITP. Ultimately, each patient requires an individualized treatment plan that takes into consideration the platelet count, bleeding symptoms, health-related quality of life, and medication side effects. This article provides an up-to-date review of management strategies drawing on links between the expanding amounts of clinical trial data and associated biology studies to enhance understanding of the disease heterogeneity with regard to the complex pathogenesis and response to treatment.
Genomic applications in the clinic: use in treatment paradigm of acute myeloid leukemia
Authors: Schlenk Richard F. , Döhner Hartmut
Published: December 2013

In recent years, research in genomics has resulted in the rapid uncovering of the molecular pathogenesis of acute myeloid leukemia (AML). The identification of the genetic determinants of response to standard—but also to experimental—treatment is increasingly used for patient counseling, to guide clinical decision making, and for resource-efficient care provision at diagnosis, during consolidation treatment and follow-up, and after relapse. Gene mutations now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, in particular the large subset of cytogenetically normal AML. Nonetheless, there are several challenges in evaluating the prognostic value of a specific mutation in the concert of the various concurrent mutations and determining the relative prognostic value of the genetic profile during the disease course. In particular, changes in the genetic profile in relapse compared with that at diagnosis will increasingly affect the treatment strategy at relapse, but also will give us the possibility of learning which treatment strategy during frontline therapy is best to prevent them.
Multidrug-resistant bacteria: what is the threat?
Authors: Bassetti Matteo , Righi Elda
Published: December 2013

Despite big advances in antimicrobial therapies and infection strategies, the emergence of antibiotic resistance represents an emergency situation, especially in immunocompromised hosts. Specifically, infections due to multidrug resistant, gram-negative pathogens are responsible for high mortality rates and may leave few effective antimicrobial options. Furthermore, although new compounds are available for severe methicillin-resistant staphylococcal infections, there is a paucity of novel classes of antimicrobials to target resistant gram-negatives. A careful assessment of the clinical conditions and underlying comorbidities, along with knowledge about the previous history of colonization or infections due to multidrug-resistant bacteria, represent key points in approaching the hematological patient with signs of infection. A de-escalation therapy with initial use of wide-spectrum antimicrobials followed by a reassessment after 72 hours of treatment may represent a good option in severe infections if a resistant pathogen is suspected. Prompt empiric or targeted therapy using combination regimens (ie, antipseudomonal beta-lactam plus an aminoglycoside or a quinolone) with the addition of colistin, along with increased dosage and therapeutic drug monitoring, represent options for these life-threatening infections. Continuous epidemiological surveillance of local bacteremias is necessary, along with stringent enforcement of antibiotic stewardship programs in cancer patients.
Targeting the epigenome and other new strategies in diffuse large B-cell lymphoma: beyond R-CHOP
Authors: Cerchietti Leandro , Leonard John P.
Published: December 2013

Diffuse large B-cell lymphoma, the most common lymphoma subtype, is curable in the majority of patients. However, one of the greatest unmet needs in lymphoma treatment remains novel approaches to prevent relapsed or refractory disease. Genomic profiling has provided important prognostic information that is being used in the development of novel therapeutic strategies currently in clinical trials. It is clear, however, that epigenetic alterations provide an additional series of targets that can be pharmacologically modified and offer great potential to improving patient outcomes. Greater understanding of this area is providing important new insights that are now being explored in the clinical setting. Demethylating agents and drugs that disrupt histone modifiers are in early clinical trials with promising results, and other approaches targeting epigenetic pathways are in active preclinical and early clinical development.
Does hematopoietic stem cell transplantation benefit infants with acute leukemia?
Authors: Sison Edward Allan R. , Brown Patrick
Published: December 2013

A 6-month-old girl was diagnosed with acute lymphoblastic leukemia (ALL). She has completed induction therapy and is currently in first complete remission (CR1). You are asked by your resident if hematopoietic stem cell transplantation (HSCT) would benefit infants with acute leukemia.
Hemochromatosis: the new blood donor
Authors: Leitman Susan F.
Published: December 2013

Hereditary hemochromatosis (HH) due to homozygosity for the C282Y mutation in the HFE gene is a common inherited iron overload disorder in whites of northern European descent. Hepcidin deficiency, the hallmark of the disorder, leads to dysregulated intestinal iron absorption and progressive iron deposition in the liver, heart, skin, endocrine glands, and joints. Survival is normal if organ damage is prevented by early institution of phlebotomy therapy. HH arthropathy is the symptom most affecting quality of life and can be debilitating. Genotype screening in large population studies has shown that the clinical penetrance of C282Y homozygosity is highly variable and can be very low, with up to 50% of women and 20% of men showing a silent phenotype. Targeted population screening for the HFE C282Y mutation is not recommended at present, but might be reconsidered as a cost-effective approach to management if counseling and care were better organized and standardized. Referral of patients to the blood center for phlebotomy therapy and use of HH donor blood for transfusion standardizes treatment, minimizes treatment costs, and may benefit society as a whole. Physician practices should be amended such that HH subjects are more frequently referred to the blood center for therapy.
Junctional adhesion molecule-A suppresses platelet integrin αIIbβ3 signaling by recruiting Csk to the integrin-c–Src complex
Authors: Naik Meghna U. , Caplan Jeffrey L. , Naik Ulhas P.
Published: December 2013

Key Points

Phosphorylated JAM-A associates with resting integrin αIIbβ3. JAM-A suppresses outside-in signaling by recruiting Csk to the integrin-c–Src complex.
Telomere length in circulating leukocytes is associated with lung function and disease
Authors: Albrecht Eva , Sillanpää Elina , Karrasch Stefan , Alves Alexessander Couto , Codd Veryan , Hovatta Iiris , Buxton Jessica L. , Nelson Christopher P. , Broer Linda , Hägg Sara , Mangino Massimo , Willemsen Gonneke , Surakka Ida , Ferreira Manuel A.R. , Amin Najaf , Oostra Ben A. , Bäckmand Heli M. , Peltonen Markku , Sarna Seppo , Rantanen Taina , Sipilä Sarianna , Korhonen Tellervo , Madden Pamela A.F. , Gieger Christian , Jörres Rudolf A. , Heinrich Joachim , Behr Jürgen , Huber Rudolf M. , Peters Annette , Strauch Konstantin , Wichmann H. Erich , Waldenberger Melanie , Blakemore Alexandra I.F. , de Geus Eco J.C. , Nyholt Dale R. , Henders Anjali K. , Piirilä Päivi L. , Rissanen Aila , Magnusson Patrik K.E. , Viñuela Ana , Pietiläinen Kirsi H. , Martin Nicholas G. , Pedersen Nancy L. , Boomsma Dorret I. , Spector Tim D. , van Duijn Cornelia M. , Kaprio Jaakko , Samani Nilesh J. , Jarvelin Marjo-Riitta , Schulz Holger
Published: December 2013

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function.

Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status.

We observed negative associations between telomere length and asthma (β= −0.0452, p=0.024) as well as COPD (β= −0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1(p=1.07×10−7), FVC (p=2.07×10−5), and FEV1/FVC (p=5.27×10−3). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients.

Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.
Pulmonary matrix metalloproteinase-9 activity in mechanically ventilated children with respiratory syncytial virus
Authors: Kong Michele Y.F. , Clancy John P. , Peng Ning , Li Yao , Szul Tomasz J. , Xu Xin , Oster Robert , Sullender Wayne , Ambalavanan Namasivayam , Blalock J. Edwin , Gaggar Amit
Published: December 2013

Respiratory syncytial virus (RSV) infection is a potent stimulus for airway epithelial expression of matrix metalloproteinase (MMP)-9. MMP-9 activityin vivois a predictor of disease severity in children with RSV-induced respiratory failure.

Human airway epithelial cells were infected with RSV A2 strain and analysed for MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 (a natural inhibitor of MMP-9) release. In addition, endotracheal samples from children with RSV-RF and controls (non-RSV pneumonia and nonlung disease controls) were analysed for MMP-9, TIMP-1, human neutrophil elastase and myeloperoxidase activity.

RSV infection of airway epithelia was sufficient to rapidly induce MMP-9 transcription and protein release. Pulmonary MMP-9 activity peaked at 48 h in infants with RSV-induced respiratory failure. In the RSV group, MMP-9 activity and MMP-9/TIMP-1 ratio imbalance predicted higher oxygen requirement and worse paediatric risk of mortality scores. The highest levels of human neutrophil elastase and myeloperoxidase activity were measured in the RSV cohort; however, unlike MMP-9, these neutrophil markers failed to predict disease severity.

These results support the hypothesis that RSV is a potent stimulus for MMP-9 expression and release from human airway epithelium, and that MMP-9 is an important biomarker of disease severity in mechanically ventilated children with RSV lung infection.
Treatment options in severe fungal asthma and allergic bronchopulmonary aspergillosis
Authors: Moss Richard B.
Published: December 2013

Severe asthma with fungal sensitisation and allergic bronchopulmonary aspergillosis encompass two closely related subgroups of patients with severe allergic asthma. Pulmonary disease is due to pronounced host inflammatory responses to noninvasive subclinical endobronchial infection with filamentous fungi, usuallyAspergillus fumigatus. These patients usually do not achieve satisfactory disease control with conventional treatment of severe asthma,i.e.high-dose inhaled corticosteroids and long-acting bronchodilators. Although prolonged systemic corticosteroids are effective, they carry a substantial toxicity profile. Supplementary or alternative therapies have primarily focused on use of antifungal agents including oral triazoles and inhaled amphotericin B. Immunomodulation with omalizumab, a humanised anti-IgE monoclonal antibody, or "pulse" monthly high-dose intravenous corticosteroid, has also been employed. This article considers the experience with these approaches, with emphasis on recent clinical trials.
Does exercise test modality influence dyspnoea perception in obese patients with COPD?
Authors: Ciavaglia Casey E. , Guenette Jordan A. , Ora Josuel , Webb Katherine A. , Neder J. Alberto , O’Donnell Denis E.
Published: December 2013

The purpose of this study was to investigate whether differences in physiological responses to weight-bearing (walking) and weight-supported (cycle) exercise influence dyspnoea perception in obese chronic obstructive pulmonary disease (COPD) patients, where such discrepancies are probably exaggerated.

We compared metabolic, ventilatory and perceptual responses during incremental treadmill and cycle exercise using a matched linearised rise in work rate in 18 (10 males and eight females) obese (mean±sdbody mass index 36.4±5.0 kg·m−2) patients with COPD (forced expiratory volume in 1 s 60±11% predicted).

Compared with cycle testing, treadmill testing was associated with a significantly higher oxygen uptake, lower ventilatory equivalent for oxygen and greater oxyhaemoglobin desaturation at a given work rate (p<0.01). Cycle testing was associated with a higher respiratory exchange ratio (p<0.01), earlier ventilatory threshold (p<0.01) and greater peak leg discomfort ratings (p=0.01). Ventilation, breathing pattern and operating lung volumes were similar between tests, as were dyspnoea/work rate and dyspnoea/ventilation relationships.

Despite significant between-test differences in physiological responses, ventilation, operating lung volumes and dyspnoea intensity were similar at any given external power output during incremental walking and cycling exercise in obese COPD patients. These data provide evidence that either exercise modality can be selected for reliable evaluation of exertional dyspnoea in this population in research and clinical settings.
The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis
Authors: Fu Zeze , Deng Biyong , Liao Yuxin , Shan Liancheng , Yin Fei , Wang Zhuoying , Zeng Hui , Zuo Dongqing , Hua Yingqi , Cai Zhengdong
Published: December 2013

Background

Osteosarcoma is the most frequent primary malignant bone tumor, notorious for its lung metastasis. Shikonin, an effective constituent extracted from Chinese medicinal herb, was demonstrated to induce necroptosis in some cancers.

Methods

MTT assay was performed to detect cell survival rate in vitro. Flow cytometry was used to analyze cell cycle and cell death. Western blot was performed to determine the expression levels of RIP1, RIP3, caspase-3, caspase-6 and PARP. The tibial primary and lung metastatic osteosarcoma models were used to evaluate the anti-tumor effect of shikonin in vivo.

Results

The cell survival rate was decreased in a dose and time dependent manner when treated with shikonin. No major change in cell cycle was observed after shikonin treatment. The cell death induced by shikonin could be mostly rescued by specific necroptosis inhibitor necrostatin-1, but not by general caspase inhibitor Z-VAD-FMK. The number of necrotic cells caused by shikonin was decreased after being pretreated with Nec-1 detected by flow cytometry in K7 cells. After 8-hour treatment of shikonin, the expression levels of RIP1 and RIP3 were increased while caspase-3, caspase-6 and PARP were not activated in K7 and U2OS cells determined by Western blot. Size of primary tumor and lung metastasis in shikonin treated group were significantly reduced. The protein levels of RIP1 and RIP3 in primary tumor tissues were increased by shikonin. The overall survival of lung metastatic models was longer compared with control group (p < 0.001).

Conclusions

Shikonin had prompt but profound anti-tumor effect on both primary and metastatic osteosarcoma, probably by inducing RIP1 and RIP3 dependent necroptosis. Shikonin would be a potential anti-tumor agent on the treatment of primary and metastatic osteosarcoma.
Reformulating partially hydrogenated vegetable oils to maximise health gains in India: is it feasible and will it meet consumer demand?
Authors: Downs Shauna M , Gupta Vidhu , Ghosh-Jerath Suparna , Lock Karen , Thow Anne Marie , Singh Archna
Published: December 2013

Background

The consumption of partially hydrogenated vegetable oils (PHVOs) high in trans fat is associated with an increased risk of cardiovascular disease and other non-communicable diseases. In response to high intakes of PHVOs, the Indian government has proposed regulation to set limits on the amount of trans fat permissible in PHVOs. Global recommendations are to replace PHVOs with polyunsaturated fatty acids (PUFAs) in order to optimise health benefits; however, little is known about the practicalities of implementation in low-income settings. The aim of this study was to examine the technical and economic feasibility of reducing trans fat in PHVOs and reformulating it using healthier fats.

Methods

Thirteen semi-structured interviews were conducted with manufacturers and technical experts of PHVOs in India. Data were open-coded and organised according to key themes.

Results

Interviewees indicated that reformulating PHVOs was both economically and technically feasible provided that trans fat regulation takes account of the food technology challenges associated with product reformulation. However, there will be challenges in maintaining the physical properties that consumers prefer while reducing the trans fat in PHVOs. The availability of input oils was not seen to be a problem because of the low cost and high availability of imported palm oil, which was the input oil of choice for industry. Most interviewees were not concerned about the potential increase in saturated fat associated with increased use of palm oil and were not planning to use PUFAs in product reformulation. Interviewees indicated that many smaller manufacturers would not have sufficient capacity to reformulate products to reduce trans fat.

Conclusions

Reformulating PHVOs to reduce trans fat in India is feasible; however, a collision course exists where the public health goal to replace PHVOs with PUFA are opposed to the goals of industry to produce a cheap alternative product that meets consumer preferences. Ensuring that product reformulation is done in a way that maximises health benefits will require shifts in knowledge and subsequent demand of products, decreased reliance on palm oil, investment in research and development and increased capacity for smaller manufacturers.
The retinoic acid receptor-α modulators ATRA and Ro415253 reciprocally regulate human IL-5+ Th2 cell proliferation and cytokine expression
Authors: Wansley Daniel L , Yin Yuzhi , Prussin Calman
Published: December 2013

Background

Th2 cytokine responses are enhanced by all trans retinoic acid (ATRA), the bioavailable form of vitamin A. Retinoic acid receptor alpha (RARα) is the high affinity receptor for ATRA that mediates these pro-Th2 effects. We have previously characterized two major human Th2 subpopulations: IL-5- Th2 (IL-5-, IL-4+, IL-13+) and IL-5+ Th2 cells (IL-5+, IL-4+, IL-13+), which represent less and more highly differentiated Th2 cells, respectively. We hypothesized that the pro-Th2 effects of ATRA may differentially affect these Th2 subpopulations.

Methods

Specific cytokine producing Th2 subpopulations were identified using intracellular cytokine staining. Proliferation was measured using the Cell Trace Violet proliferation tracking dye. Apoptotic cells were identified using either annexin-V or active caspase 3 staining. Th2 gene expression was measured using quantitative polymerase chain reaction.

Results

ATRA increased the output of Th2 cells from house dust mite allergen (HDM) specific short-term cell lines, and this enhancement was limited to the IL-5+ Th2 subpopulation. Conversely, the RARα antagonist Ro415253 decreased Th2 cell output from these cultures, and this effect was again limited to the IL-5+ Th2 subpopulation. ATRA and Ro415253 respectively augmented and inhibited Th2 cell proliferation, and this affect was more pronounced for the IL-5+ vs. IL-5- Th2 subpopulation. ATRA and Ro415253 respectively augmented and inhibited the expression of IL5 in a significant manner, which was not found for IL4 or IL13.

Conclusions

We report that the reciprocal regulation of Th2 cytokine expression and proliferation by RARα modulators are largely limited to modulation of IL-5 gene expression and to proliferation of the highly differentiated IL-5+ Th2 subpopulation. These results suggest that RARα antagonism is a potential means to therapeutically target allergic inflammation.

Trial registration

Clinicaltrials.gov identifier:NCT01212016
RETRACTED ARTICLE: Mir-655 up-regulation suppresses cell invasion by targeting pituitary tumor-transforming gene-1 in esophageal squamous cell carcinoma
Authors: Wang Yuanyuan , Zang Wenqiao , Du Yuwen , Ma Yunyun , Li Min , Li Ping , Chen Xudong , Wang Tao , Dong Ziming , Zhao Guoqiang
Published: December 2013

Background

MicroRNAs (miRNAs) can act as either oncogenes or tumor suppressor genes under different conditions and thus can play a significant role in cancer development. We investigated miR-655 expression in a cohort of esophageal squamous cell carcinoma (ESCC) to assess the impact of this miRNA on ESCC cell invasion and metastasis.

Methods

A qRT-PCR assay was used to quantify miR-655 expression levels in 34 paired ESCC samples and adjacent non-tumor tissues. Wound healing and transwell assays were used to evaluate the effects of miR-655 expression on the invasiveness of ESCC cells. Luciferase reporter and western blot assays were used to determine whether the mRNA encoding pituitary tumor-transforming gene-1 (PTTG1) is a major target of miR-655.

Results

The expression level of miR-655 in ESCC tissues was found to be lower than in adjacent non-tumor tissues (P < 0.05). This relatively low expression level was significantly associated with the occurrence of lymph node metastases (P < 0.05). Migration rates were significantly lower for two ESCC-derived cell lines (EC9706 and KYSE150) transfected with miR-429 mimics (P < 0.05). Subsequent western blot and luciferase reporter assays demonstrated that miR-655 could bind to putative binding sites within the PTTG1 mRNA 3’-untranslated region (3’-UTR) and thus reduce the expression.

Conclusions

miR-655 is expressed at low levels in primary ESCC tissues, and up-regulation of miR-655 inhibits ESCC cell invasiveness by targeting PTTG1. Our findings suggest that PTTG1 may act as a major target of miR-655. This study improves our understanding of the mechanisms underlying ESCC pathogenesis and may promote the development of novel targeted therapies.
HIBCH mutations can cause Leigh-like disease with combined deficiency of multiple mitochondrial respiratory chain enzymes and pyruvate dehydrogenase
Authors: Ferdinandusse Sacha , Waterham Hans R , Heales Simon JR , Brown Garry K , Hargreaves Iain P , Taanman Jan-Willem , Gunny Roxana , Abulhoul Lara , Wanders Ronald JA , Clayton Peter T , Leonard James V , Rahman Shamima
Published: December 2013

Background

Deficiency of 3-hydroxy-isobutyryl-CoA hydrolase (HIBCH) caused byHIBCHmutations is a rare cerebral organic aciduria caused by disturbance of valine catabolism. Multiple mitochondrial respiratory chain (RC) enzyme deficiencies can arise from a number of mechanisms, including defective maintenance or expression of mitochondrial DNA. Impaired biosynthesis of iron-sulphur clusters and lipoic acid can lead to pyruvate dehydrogenase complex (PDHc) deficiency in addition to multiple RC deficiencies, known as the multiple mitochondrial dysfunctions syndrome.

Methods

Two brothers born to distantly related Pakistani parents presenting in early infancy with a progressive neurodegenerative disorder, associated with basal ganglia changes on brain magnetic resonance imaging, were investigated for suspected Leigh-like mitochondrial disease. The index case had deficiencies of multiple RC enzymes and PDHc in skeletal muscle and fibroblasts respectively, but these were normal in his younger brother. The observation of persistently elevated hydroxy-C4-carnitine levels in the younger brother led to suspicion of HIBCH deficiency, which was investigated by biochemical assay in cultured skin fibroblasts and molecular genetic analysis.

Results

Specific spectrophotometric enzyme assay revealed HIBCH activity to be below detectable limits in cultured skin fibroblasts from both brothers. Direct Sanger sequence analysis demonstrated a novel homozygous pathogenic missense mutation c.950G <A; p.Gly317Glu in theHIBCHgene, which segregated with infantile-onset neurodegeneration within the family.

Conclusions

HIBCH deficiency, a disorder of valine catabolism, is a novel cause of the multiple mitochondrial dysfunctions syndrome, and should be considered in the differential diagnosis of patients presenting with multiple RC deficiencies and/or pyruvate dehydrogenase deficiency.
Efficient transmission of Cassava brown streak disease viral pathogens by chip bud grafting
Authors: Wagaba Henry , Beyene Getu , Trembley Cynthia , Alicai Titus , Fauquet Claude M , Taylor Nigel J
Published: December 2013

Background

Techniques to study plant viral diseases under controlled growth conditions are required to fully understand their biology and investigate host resistance. Cassava brown streak disease (CBSD) presents a major threat to cassava production in East Africa. No infectious clones of the causal viruses, Cassava brown streak virus (CBSV) or Ugandan cassava brown streak virus (UCBSV) are available, and mechanical transmission to cassava is not effective. An improved method for transmission of the viruses, both singly and as co-infections has been developed using bud grafts.

Findings

Axillary buds from CBSD symptomatic plants infected with virulent isolates of CBSV and UCBSV were excised and grafted onto 6–8 week old greenhouse-grown, disease-free cassava plants of cultivars Ebwanateraka, TME204 and 60444. Plants were assessed visually for development of CBSD symptoms and by RT-PCR for presence of the viruses in leaf and storage root tissues. Across replicated experiments, 70-100% of plants inoculated with CBSV developed CBSD leaf and stem symptoms 2–6 weeks after bud grafting. Infected plants showed typical, severe necrotic lesions in storage roots at harvest 12–14 weeks after graft inoculation. Sequential grafting of buds from plants infected with UCBSV followed 10–14 days later by buds carrying CBSV, onto the same test plant, resulted in 100% of the rootstocks becoming co-infected with both pathogens. This dual transmission rate was greater than that achieved by simultaneous grafting with UCBSV and CBSV (67%), or when grafting first with CBSV followed by UCBSV (17%).

Conclusions

The bud grafting method described presents an improved tool for screening cassava germplasm for resistance to CBSD causal viruses, and for studying pathogenicity of this important disease. Bud grafting provides new opportunities compared to previously reported top and side grafting systems. Test plants can be inoculated as young, uniform plants of a size easily handled in a small greenhouse or large growth chamber and can be inoculated in a controlled manner with CBSV and UCBSV, either singly or together. Disease symptoms develop rapidly, allowing better studies of interactions between these viral pathogens, their movement within shoot and root systems, and how they induce their destructive disease symptoms.
Blunt abdominal trauma to a pregnant woman resulting in a child with hemiplegic spastic cerebral palsy and permanent eye damage
Authors: Taha Elmuntasir , Nasralla Khalid , Khalid AbdulRahman , Ali AbdelAziem A
Published: December 2013

Background

In today's life trauma is a common and important complication of pregnancy and remains one of the major contributors to maternal and fetal morbidity and mortality.

Case presentation

The authors reported a case of 4 years old child with hemiplegic spastic cerebral palsy and permanent left eye damage due to antenatal trauma. He was an off spring to a 33 years old woman gravida 6 para 5 from western Sudan, who sustained a domestic blunt abdominal trauma during her routine daily activities. The abdominal trauma occurred during the third trimester at 36th week gestation of the pregnancy when the mother hit herself by the woody part of an axe non intentionally.

Conclusions

The findings from this case conclude that relatively minor trauma can have significant adverse effects on the fetus and can be devastating.
Coconut shells as filling material for anaerobic filters
Authors: Cruz Luana Mattos de Oliveira , Stefanutti Ronaldo , Coraucci Filho Bruno , Tonetti Adriano Luiz
Published: December 2013

In rural areas of developing countries, there is a lack of sanitation services and the installation of such infrastructure is hampered by the high investment costs for initial implementation and by the limited availability of qualified personnel. An alternative to traditional sanitation services include an anaerobic filter, but the high cost of appropriate filling material can be an obstacle to its wide-spread implementation. To decrease this construction cost, the objective of this work was to study the use of coconut shells as filling material for anaerobic filters. Anaerobic filters were built and filled with the studied material and operated with up flow and hydraulic retention time of 9 hours. The reactors provided a removal of 79 ± 16% in BOD terms, indicating that the coconut shell filling had efficiency consistent with the literature data. In addition, the husks were found to retain their tensile strength following use in the reactors. Coconut husks have more empty bed volume than other low cost materials, such as crushed stone, nearing properties of traditional materials. The results of this study indicate that coconut husks may prove to be a low cost alternative to traditional fillers for anaerobic treatment in rural communities.
On elongations of QTAG-modules
Authors: Mehdi Alveera , Sikander Fahad , R K Naji Sabah A
Published: December 2013

Mehdi studied (ω+k)-projective QTAG-modules with the help of their submodules contained in H

k
(M) (the submodule generated by the elements of exponents at most k). These modules contain nice submodules N contained in H

k
(M) such that M/N is a direct sum of uniserial modules. Here, we investigate the class

"Equation missing" of QTAG-modules, containing nice submodules N⊆H

k
(M) such that M/N is totally projective. We also study strong ω-elongation of totally projective QTAG-modules by (ω+k)-projective QTAG-modules.
FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis in rheumatoid arthritis
Authors: Ramos Maria I , Perez Samuel Garcia , Aarrass Saida , Helder Boy , Broekstra Pleun , Gerlag Daan M , Reedquist Kris A , Tak Paul Peter , Lebre Maria C
Published: December 2013

Introduction

The FMS-related tyrosine kinase 3 ligand (Flt3L)/CD135 axis plays a fundamental role in proliferation and differentiation of dendritic cells (DCs). As DCs play an important role in rheumatoid arthritis (RA) immunopathology we studied in detail the Flt3L/CD135 axis in RA patients.

Methods

The levels of Flt3L in (paired) serum and synovial fluid (SF) were quantified by enzyme-link immunosorbent assay (ELISA). Expression of Flt3L and CD135 in paired peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) was quantified by fluorescence-activated cell sorting (FACS). The expression of Flt3L, CD135 and TNF-Converting Enzyme (TACE) in synovial tissues (STs) and in vitro polarized macrophages and monocyte-derived DCs (Mo-DCs) was assessed by quantitative PCR (qPCR). CD135 ST expression was evaluated by immunohistochemistry and TACE ST expression was assessed by immunofluorescence. Flt3L serum levels were assessed in RA patients treated with oral prednisolone or adalimumab.

Results

Flt3L levels in RA serum, SF and ST were significantly elevated compared to gout patients and healthy individuals (HI). RA SF monocytes, natural killer cells and DCs expressed high levels of Flt3L and CD135 compared to HI. RA ST CD68+ and CD163+ macrophages, CD55+ fibroblast-like synoviocytes (FLS), CD31+ endothelial cells or infiltrating monocytes and CD19+ B cells co-expressed TACE. IFN-γ-differentiated macrophages expressed higher levels of Flt3L compared to other polarized macrophages. Importantly, Flt3L serum levels were reduced by effective therapy.

Conclusions

The Flt3L/CD135 axis is active in RA patients and is responsive to both prednisolone and adalimumab treatment. Conceivably, this ligand receptor pair represents a novel therapeutic target.
Laboratory study of spectral induced polarization responses of magnetite — Fe2+ redox reactions in porous media
Authors: Hubbard Christopher G. , West L. Jared , Rodriguez-Blanco Juan Diego , Shaw Samuel
Published: December 2013

Spectral induced polarization (SIP) phase anomalies in field surveys at contaminated sites have previously been shown to correlate with the occurrence of chemically reducing conditions and/or semiconductive minerals, but the reasons for this are not fully understood. We report a systematic laboratory investigation of the role of the semiconductive mineral magnetite and its interaction with redox-active versus redox-inactive ions in producing such phase anomalies. The SIP responses of quartz sand with 5% magnetite in solutions containing redox-inactive [Formula: see text] and [Formula: see text] versus redox-active [Formula: see text] were measured across the pH ranges corresponding to adsorption of these metals to magnetite. With redox inactive ions [Formula: see text] and [Formula: see text], SIP phase response showed no changes across the pH range 4–10, corresponding to their adsorption, showing [Formula: see text] anomalies peaking at [Formula: see text]–74 Hz. These large phase anomalies are probably caused by polarization of the magnetite-solution interfaces. With the redox-active ion [Formula: see text], frequency of peak phase response decreased progressively from [Formula: see text] to [Formula: see text] as effluent pH increased from four to seven, corresponding to progressive adsorption of [Formula: see text] to the magnetite surface. The latter frequency (3 Hz) corresponds approximately with those of phase anomalies detected in field surveys reported elsewhere. We conclude that pH sensitivity arises from redox reactions between [Formula: see text] and magnetite surfaces, with transfer of electrical charge through the bulk mineral, as reported in other laboratory investigations. Our results confirm that SIP measurements are sensitive to redox reactions involving charge transfers between adsorbed ions and semiconductive minerals. Phase anomalies seen in field surveys of groundwater contamination and biostimulation may therefore be indicative of iron-reducing conditions, when semiconductive iron minerals such as magnetite are present.
Evaluating the feasibility of complex interventions in mental
health services: standardised measure and reporting
guidelines
Authors: Bird Victoria J. , Boutillier Clair Le , Leamy Mary , Williams Julie , Bradstreet Simon , Slade Mike
Published: December 2013

Background

The feasibility of implementation is insufficiently considered in
clinical guideline development, leading to human and financial resource
wastage.

Aims

To develop (a) an empirically based standardised measure of the
feasibility of complex interventions for use within mental health
services and (b) reporting guidelines to facilitate feasibility
assessment.

Method

A focused narrative review of studies assessing implementation blocks and
enablers was conducted with thematic analysis and vote counting used to
determine candidate items for the measure. Twenty purposively sampled
studies (15 trial reports, 5 protocols) were included in the psychometric
evaluation, spanning different interventions types. Cohen's kappa (κ) was
calculated for interrater reliability and test–retest reliability.

Results

In total, 95 influences on implementation were identified from 299
references. The final measure – Structured Assessment of FEasibility
(SAFE) – comprises 16 items rated on a Likert scale. There was excellent
interrater (κ = 0.84, 95% CI 0.79–0.89) and test–retest reliability (κ =
0.89, 95% CI 0.85–0.93). Cost information and training time were the two
influences least likely to be reported in intervention papers. The SAFE
reporting guidelines include 16 items organised into three categories
(intervention, resource consequences, evaluation).

Conclusions

A novel approach to evaluating interventions, SAFE, supplements efficacy
and health economic evidence. The SAFE reporting guidelines will allow
feasibility of an intervention to be systematically assessed.
Friedrich List and the Economic Fate of Tropical Countries
Authors: Boianovsky Mauro
Published: December 2013

The goal of this article is twofold. It examines how Friedrich List’s interpretation of the economic dynamics of “tropical” countries (countries located in tropical climates) as nonindustrial exporters of primary commodities fits in his analytical framework and accords with his emphasis on the explanatory value of environmental factors and on the role of colonialism in the development of “temperate” countries (countries located in temperate climates). This is followed by a selective investigation of the reception of List’s ideas in some Latin American countries (particularly Brazil) between the late nineteenth and mid-twentieth centuries, as an attempt to establish whether List’s readers in those countries took any notice of his point that the infant-industry argument did not apply to tropical areas and that such economies should not embark on an industrialization process.
Martin Luther, Martin Guerre, and Ways of Knowing
Authors: Davis Natalie Zemon
Published: December 2013

Responding to a quip by a fellow historian, who feared that Martin Guerre might become better known than Martin Luther, this guest column, by the author of The Return of Martin Guerre, affirms that they are part of the same universe of historical inquiry. Knowing about Martin Guerre brings understanding of the peasant world, which is also important for the trajectory of Luther's Reformation. Knowing about Martin Luther brings knowledge of major religious change, essential to understanding Martin Guerre's village world and what happened in it. Themes of “imposture” and “dissimulation” and the fashioning of identity are central to social conflicts and social and personal aspiration across the spectrum in the sixteenth century: they are found in the actual lives of both men and in Martin Luther's sermons, as well as in the Martin Guerre trial.
Modes of Syncretism
Authors: Law John , Afdal Geir , Asdal Kristin , Lin Wen-yuan , Moser Ingunn , Singleton Vicky
Published: December 2013

In this contribution to the Common Knowledge symposium “Fuzzy Studies,” the authors, all of whom work in the field of science, technology, and society, begin from the assumption that, as Bruno Latour has put it, “we have never been modern.” They accept the STS thesis that, while modern practices purport to be entirely rational and coherent, on closer inspection they turn out to be as much noncoherent as coherent. This article poses the question of what forms “noncoherences” take and how they are managed. The basic argument is that there is a range of styles of noncoherence or “modes of syncretism.” In small case studies, the authors identify six such modes or styles, which they term denial, domestication, separation, care, conflict, and collapse. Given that consistency and coherence seem less important now than they were once taken to be — and given that the conditions of possibility for purity are, in any case, in decline — this list and its supporting case studies, while not meant to be definitive, are offered as a way of understanding how practices that do not cohere may still function and fit together admirably.
Testing the constant-volume hypothesis by magnetic resonance imaging of the mussel heart in theMytilus galloprovincialis
Authors: Seo Eriko , Ohishi Kazue , Maruyama Tadashi , Imaizumi-Ohashi Yoshie , Murakami Masataka , Seo Yoshiteru
Published: December 2013

The constant-volume (CV) hypothesis was tested using the Mytilus galloprovincialis heart under two conditions. The volume of the ventricle, auricles and pericardium, and the flow in the heart and adjacent vessels were measured by magnetic resonance imaging. In synthetic sea water at 23°C (immersed condition), the end-diastolic (EDV), end-systolic (ESV) and stroke (SV) volumes were 50%, 21% and 29% of the heart volume, respectively, and the auricle volume (VA) was maximized at the end-systole. Assuming a constant volume in the heart, venous return to the auricles (IV) was constant, and out-flow from the pericardium to the kidney (IPK) was 2/3 of SV. During aerial exposure (emersed condition), EDV, ESV and SV decreased to 33%, 22% and 11%, respectively. The VA was maximized at the end-diastole and associated with the decrease of the systolic IV to 1/2 of the diastolic IV, while the IPK remained at 80% of the immersed condition. Based on these results, in addition to two postulates of the CV hypothesis: 1) the total volume of the heart is always the same, and 2) ventricle contraction causes a decrease in the pressure in the pericardium, we modified two postulate: 3) the low pericardial pressure maintains venous return from the anterior oblique vein to the auricle, and 4) the pressure difference between the auricle and the pericardium drives haemolymph filtration through the auricle walls. We also added a new postulate: 5) dilatation of the ventricle is associated with the haemolymph output to the kidney via the renopericardial canals.