Differences in Disease Severity but Similar Telomere Lengths in Genetic Subgroups of Patients with Telomerase and Shelterin Mutations

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Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks?

In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice

The Dawn of Open Access to Phylogenetic Data

The scientific enterprise depends critically on the preservation of and open access to published data. This basic tenet applies acutely to phylogenies (estimates of evolutionary relationships among species). Increasingly, phylogenies are estimated from increasingly large, genome-scale datasets using increasingly complex statistical methods that require increasing levels of expertise and computational investment. Moreover, the resulting phylogenetic data provide an explicit historical perspective that critically informs research in a vast and growing number of scientific disciplines. One such use is the study of changes in rates of lineage diversification (speciation - extinction) through time. As part of a meta-analysis in this area, we sought to collect phylogenetic data (comprising nucleotide sequence alignment and tree files) from 217 studies published in 46 journals over a 13-year period. We document our attempts to procure those data (from online archives and by direct request to corresponding authors), and report results of analyses (using Bayesian logistic regression) to assess the impact of various factors on the success of our efforts. Overall, complete phylogenetic data for ~60% of these studies are effectively lost to science. Our study indicates that phylogenetic data are more likely to be deposited in online archives and/or shared upon request when: (1) the publishing journal has a strong data-sharing policy; (2) the publishing journal has a higher impact factor, and; (3) the data are requested from faculty rather than students. Although the situation appears dire, our analyses suggest that it is far from hopeless: recent initiatives by the scientific community -- including policy changes by journals and funding agencies -- are improving the state of affairs

Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus

BACKGROUND: Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease. METHODS: We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium(R) HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes. RESULTS: Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of UNC13B, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy. CONCLUSION: This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy

Scaling properties of protein family phylogenies

One of the classical questions in evolutionary biology is how evolutionary processes are coupled at the gene and species level. With this motivation, we compare the topological properties (mainly the depth scaling, as a characterization of balance) of a large set of protein phylogenies with a set of species phylogenies. The comparative analysis shows that both sets of phylogenies share remarkably similar scaling behavior, suggesting the universality of branching rules and of the evolutionary processes that drive biological diversification from gene to species level. In order to explain such generality, we propose a simple model which allows us to estimate the proportion of evolvability/robustness needed to approximate the scaling behavior observed in the phylogenies, highlighting the relevance of the robustness of a biological system (species or protein) in the scaling properties of the phylogenetic trees. Thus, the rules that govern the incapability of a biological system to diversify are equally relevant both at the gene and at the species level.Comment: Replaced with final published versio

Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case Report and systematic literature review

<p>Abstract</p> <p>Background</p> <p>Dyskeratosis congenita (DC) is a progressive, multi-system, inherited disorder of telomere biology with high risks of morbidity and mortality from bone marrow failure, hematologic malignancy, solid tumors and pulmonary fibrosis. Hematopoietic stem cell transplantation (HSCT) can cure the bone marrow failure, but it does not eliminate the risks of other complications, for which life-long surveillance is required. Pulmonary fibrosis is a progressive and lethal complication of DC.</p> <p>Case presentation</p> <p>In this report, we describe a patient with DC who developed pulmonary fibrosis seven years after HSCT for severe aplastic anemia, and was successfully treated with bilateral lung transplantation. We also performed a systematic literature review to understand the burden of pulmonary disease in patients with DC who did or did not receive an HSCT. Including our patient, we identified 49 DC patients with pulmonary disease (12 after HSCT and 37 without HSCT), and 509 with no reported pulmonary complications.</p> <p>Conclusion</p> <p>Our current case and literature review indicate that pulmonary morbidity is one of the major contributors to poor quality of life and reduced long-term survival in DC. We suggest that lung transplantation be considered for patients with DC who develop pulmonary fibrosis with no concurrent evidence of multi-organ failure.</p

Body mass index, adiposity rebound and early feeding in a longitudinal cohort (Raine study)

Objective: This study examined the influence of type and duration of infant feeding on adiposity rebound and the tracking of body mass index (BMI) from birth to 14 years. Methods: A sample of 1330 individuals over eight follows-ups was drawn from the Western Australian Pregnancy Cohort (Raine) Study. Trajectories of BMI from birth to adolescence using linear mixed model (LMM) analysis investigated the influence of age breastfeeding stopped and age other milk introduced (binomial 4-month cut-point). A sub-sample of LMM predicted BMI was used to determine BMI and age at nadir for early infant feeding groups. Results: Chi square analysis between early feeding and weight status (normal weight, overweight and obese) groups found a significant difference between age breastfeeding stopped (p Conclusions: Early infant feeding was important in the timing and BMI at adiposity rebound. The relationship between infant feeding and BMI remained up to age 14 years. Although confounding factors cannot be excluded, these findings support the importance of exclusive breastfeeding for longer than four months as a protective behaviour against the development of adolescent obesity

Patients' perspectives on high-tech home care: a qualitative inquiry into the user-friendliness of four technologies

BACKGROUND: The delivery of technology-enhanced home care is growing in most industrialized countries. The objective of our study was to document, from the patient's perspective, how the level of user-friendliness of medical technology influences its integration into the private and social lives of patients. Understanding what makes a technology user-friendly should help improve the design of home care services. METHODS: Four home care interventions that are frequently used and vary in their technical and clinical features were selected: Antibiotic intravenous therapy, parenteral nutrition, peritoneal dialysis and oxygen therapy. Our qualitative study relied on the triangulation of three sources of data: 1) interviews with patients (n = 16); 2) interviews with carers (n = 6); and 3) direct observation of nursing visits of a different set of patients (n = 16). Participants of varying socioeconomic status were recruited through primary care organizations and hospitals that deliver home care within 100 km of Montreal, the largest urban area in the province of Quebec, Canada. RESULTS: The four interventions have both a negative and positive effect on patients' lives. These technologies were rarely perceived as user-friendly, and user-acceptance was closely linked to user-competence. Compared with acute I.V. patients, who tended to be passive, chronic patients seemed keener to master technical aspects. While some of the technical and human barriers were managed well in the home setting, engaging in the social world was more problematic. Most patients found it difficult to maintain a regular job because of the high frequency of treatment, while some carers found their autonomy and social lives restricted. Patients also tended to withdraw from social activities because of social stigmatization and technical barriers. CONCLUSIONS: While technology contributes to improving the patients' health, it also imposes significant constraints on their lives. Policies aimed at developing home care must clearly integrate principles and resources supporting the appropriate use of technology. Close monitoring of patients should be part of all technology-enhanced home care programs

A rare case of concomitant huge exophytic gastrointestinal stromal tumor of the stomach and Kasabach-Merritt phenomenon

<p>Abstract</p> <p>Background</p> <p>We report an extremely rare case of concomitant huge exophytic GIST of the stomach and Kasabach-Merritt phenomenon (KMP).</p> <p>Case presentation</p> <p>The patient was a 67-year-old man experiencing abdominal distension since September 2006. A physical examination revealed a 25 × 30 cm hard mass that was palpable in the middle and lower left abdomen minimal intrinsic mobility and massive ascites. Since the admitted patient was diagnosed with DIC, surgery could not be performed. The patient received a platelet transfusion and the DIC was treated. Due to this treatment, the platelet count recovered to 7.0 × 10⁴; tumor resection was performed at 16 days after admission. Laparotomy revealed a huge extraluminal tumor arising from the greater curvature of the stomach that measured 25 × 30 cm and had not ruptured into the peritoneal cavity or infiltrated other organs. Partial gastric resection was performed. The resected mass measured 25 × 25 × 20 cm. In cross section, the tumor appeared hard and homogenous with a small polycystic area. Histopathology of the resected specimen showed large spindle cell GIST with >5/50 HPF (high-power field) mitotic activity. The postoperative course was uneventful, and the coagulopathy improved rapidly.</p> <p>Conclusion</p> <p>Since the characteristic of tumor in this case was hypervascularity with bleeding and necrotic lesions, coagulopathy was thought to be caused by the trapping of platelets within a large vasculized tumor mass.</p

The socio-technical organisation of community pharmacies as a factor in the Electronic Prescription Service Release Two implementation: a qualitative study

Background The introduction of a new method of transmitting prescriptions from general practices to community pharmacies in England (Electronic Prescription Service Release 2 (EPS2)) has generated debate on how it will change work practice. As EPS2 will be a key technical element in dispensing, we reviewed the literature to find that there were no studies on how social and technical elements come together to form work practice in community pharmacies. This means the debate has little point of reference. Our aim therefore was to study the ways social and technical elements of a community pharmacy are used to achieve dispensing through the development of a conceptual model on pharmacy work practice, and to consider how a core technical element such the EPS2 could change work practice. Method We used ethnographic methods inclusive of case-study observations and interviews to collect qualitative data from 15 community pharmacies that were in the process of adopting or were soon to adopt EPS2. We analysed the case studies thematically and used rigorous multi-dimensional and multi-disciplinary interpretive validation techniques to cross analyse findings. Results In practice, dispensing procedures were not designed to take into account variations in human and technical integration, and assumed that repetitive and collective use of socio-technical elements were at a constant. Variables such as availability of social and technical resources, and technical know-how of staff were not taken into account in formalised procedures. Yet community pharmacies were found to adapt their dispensing in relation to the balance of social and technical elements available, and how much of the social and technical elements they were willing to integrate into dispensing. While some integrated as few technical elements as possible, some depended entirely on technical artefacts. This pattern also applied to the social elements of dispensing. Through the conceptual model development process, we identified three approaches community pharmacies used to appropriate procedures in practice. These were ‘technically oriented’, ‘improvising’ or ‘socially oriented’. Conclusion We offer a model of different work approaches community pharmacies use to dispense, which suggests that when adopting a core technical element such as the EPS2 system of dispensing there could be variations in its successful adoption. Technically oriented pharmacies might find it easiest to integrate a similar artefact into work practice although needs EPS2 to synchronise effectively with existing technologies. Pharmacies adopting an improvising-approach have the potential to improve how they organise dispensing through EPS2 although they will need to improve how they apply their operating procedures. Socially oriented pharmacies will need to dramatically adapt their approach to dispensing since they usually rely on few technical tools