Posture shifting after spinal cord injury using functional neuromuscular stimulation--a computer simulation study

The ability for individuals with spinal cord injury (SCI) to affect changes in standing posture with functional neuromuscular stimulation (FNS) was explored using an anatomically inspired musculoskeletal model of the trunk, pelvis and lower extremities (LE). The model tracked trajectories for anteriorly and laterally shifting movements away from erect stance. Forces were applied to both shoulders to represent upper extremity (UE) interaction with an assistive device (e.g., a walker). The muscle excitations required to execute shifting maneuvers with UE forces <10% body-weight (BW) were determined via dynamic optimization. Nine muscle sets were examined to maximize control of shifting posture. Inclusion of the Psoas and External Obliques bilaterally resulted in the least relative UE effort (0.119, mean UE effort = 45.3N ≡ 5.4% BW) for anterior shifting. For lateral shifting, the set including the Psoas and Latissimus Dorsi bilaterally yielded the best performance (0.025, mean UE effort = 27.8 N ≡ 3.3% BW). However, adding the Psoas alone bilaterally competed favorably in overall best performance across both maneuvers. This study suggests suitable activation to specific muscles of the trunk and LE can enable individuals with SCI to alter their standing postures with minimal upper-body effort and subsequently increase reach and standing work volume.     

Evaluation of the Clinical and Cost Effectiveness of Intermediate Care Clinics for Diabetes (ICCD): A Multicentre Cluster Randomised Controlled Trial

Background

Configuring high quality care for the rapidly increasing number of people with type 2 diabetes (T2D) is a major challenge worldwide for both providers and commissioners. In the UK, about two thirds of people with T2D are managed entirely in primary care, with wide variation in management strategies and achievement of targets. Pay for performance, introduced in 2004, initially resulted in improvements but disparities exist in ethnic minorities and the improvements are levelling off. Community based, intermediate care clinics for diabetes (ICCDs) were considered one solution and are functioning across the UK. However, there is no randomised trial evidence for the effectiveness of such clinics.

Trial Design, Methods and Findings

This is a cluster-randomised trial, involving 3 primary care trusts, with 49 general practices randomised to usual care (n = 25) or intervention (ICCDs; n = 24). All eligible adult patients with T2D were invited; 1997 were recruited and 1280 followed-up after 18-months intervention. Primary outcome: achievement of all three of the NICE targets [(HbA1c≤7.0%/53 mmol/mol; Blood Pressure <140/80 mmHg; cholesterol <154 mg/dl (4 mmol/l)]. Primary outcome was achieved in 14.3% in the intervention arm vs. 9.3% in the control arm (p = 0.059 after adjustment for covariates). The odds ratio (95% CI) for achieving primary outcome in the intervention group was 1.56 (0.98, 2.49). Primary care and community clinic costs were significantly higher in the intervention group, but there were no significant differences in hospital costs or overall healthcare costs. An incremental cost-effectiveness ratio (ICER) of +£7,778 per QALY gained, indicated ICCD was marginally more expensive at producing health gain.

Conclusions

Intermediate care clinics can contribute to improving target achievement in patients with diabetes. Further work is needed to investigate the optimal scale and organisational structure of ICCD services and whether, over time, their role may change as skill levels in primary care increase.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00945204","term_id":"NCT00945204"}}NCT00945204; National Research Register (NRR) M0014178167.     

A locus conferring tolerance to Theileria infection in African cattle

East Coast fever, a tick-borne cattle disease caused by the Theileria parva parasite, is among the biggest natural killers of cattle in East Africa, leading to over 1 million deaths annually. Here we report on the genetic analysis of a cohort of Bos indicus (Boran) cattle demonstrating heritable tolerance to infection with T. parva (h² = 0.65, s.e. 0.57). Through a linkage analysis we identify a 6 Mb genomic region on bovine chromosome 15 that is significantly associated with survival outcome following T. parva exposure. Testing this locus in an independent cohort of animals replicates this association with survival following T. parva infection. A stop gained variant in a paralogue of the FAF1 gene in this region was found to be highly associated with survival across both related and unrelated animals, with only one of the 20 homozygote carriers (T/T) of this change succumbing to the disease in contrast to 44 out of 97 animals homozygote for the reference allele (C/C). Consequently, we present a genetic locus linked to tolerance of one of Africa’s most important cattle diseases, raising the promise of marker-assisted selection for cattle that are less susceptible to infection by T. parva.     

Characterization of oxidative stress in blood from diabetic vs. hypercholesterolaemic patients,using a novel synthesized marker

In the present study, we extend our novel concept of designing and using exogenous markers for the characterization of oxidative stress (OS) and OS-associated diseases. The aim was to use such a synthetic compound as a tool for studying OS in blood from diabetic and hypercholesterolaemic (Hc) patients. The marker used N-linoleoyl tyrosine (LT) was constructed from tyrosine and linoleic acid (LA); both components are known to be easily oxidized upon exposure to different types of reactive oxygen/nitrogen species (ROS/RNS), and to generate specific oxidized products, depending on the type of oxidants present in vivo. Using the LT probe, we showed that the ratios of oxidized LT to total LT (Ox-LT/LT) is significantly higher in blood samples obtained from diabetic patients, than in Hc patients or healthy control subjects. LC/MS analysis revealed that blood from diabetic patients oxidizes the marker with predominant formation of Ox-LT hydroperoxide (LT-OOH) and epoxide (epoxy-LT), where the LA moiety is oxidized to hydroperoxide and to epoxide, respectively. Analysis of oxysterol levels in these samples (GC/MS) revealed that the blood of both diabetic and Hc patients contained significantly more oxysterols than blood of control subjects. Consumption of pomegranate juice by diabetic patients for 3 months suppressed their blood capacity to oxidize the LT and similarly also reduced their blood oxysterol/total cholesterol ratio by 93%. The use of an exogenous marker to characterize OS in blood samples yields important information on the extent of OS, and can provide a fingerprint for the early identification of different pathological conditions associated with OS.     

Determination of plasma microRNA for early detection of gastric cancer

Gastric cancer is the fourth most prevalent malignancy worldwide and remains the second most common cause of cancer-related death globally. Understanding the molecular structure of gastric carcinogenesis might identify new diagnostic and therapeutic strategies for this disease. Thus, early detection of gastric cancer is a key measure to reduce the mortality and improve the prognosis of gastric cancer. There have recently been several reports that microRNAs (miRNAs) circulate in highly stable, cell-free forms in blood. Because serum and plasma miRNAs are relatively easy to access, circulating miRNAs also have great potential to serve as non-invasive biomarkers. Although a number of miRNAs associated with gastric cancer have been identified, the underlying mechanism of these miRNAs in tumorigenesis and tumor progression remains to be investigated. The purpose of this study is to identify the potential of serum miRNAs as biomarkers for early detection of gastric cancer patients. RNA was isolated using the High Pure miRNA Isolation Kit (Roche) following the manufacturer’s protocol. cDNA and preamplification protocols were obtained from the isolated plasma miRNAs. The BioMark? 96.96 Dynamic Array (Fluidigm Corporation) for real-time qPCR was used to simultaneously quantite the expression of 740 miRNAs. All statistical analyses were performed using the Biogazelle’s qbase PLUS 2.0 software. In this study, among 740 miRNAs that we analyzed only miR-195-5p was significantly (p < 0.05, fold changes = 13, 3) down-regulated in gastric cancer patients compared with control. We demonstrated that miR-195-5p is a novel tumor suppressor miRNA and may contribute to gastric carcinogenesis. The miRNA expression profile described in this study should contribute to future studies on the role of miRNAs in gastric cancer.     

Climate‐induced warming imposes a threat to north European spring ecosystems

Interest in climate change effects on groundwater has increased dramatically during the last decade. The mechanisms of climate‐related groundwater depletion have been thoroughly reviewed, but the influence of global warming on groundwater‐dependent ecosystems (GDEs) remains poorly known. Here we report long‐term water temperature trends in 66 northern European cold‐water springs. A vast majority of the springs (82%) exhibited a significant increase in water temperature during 1968–2012. Mean spring water temperatures were closely related to regional air temperature and global radiative forcing of the corresponding year. Based on three alternative climate scenarios representing low (RCP2.6), intermediate (RCP6) and high‐emission scenarios (RCP8.5), we estimate that increase in mean spring water temperature in the region is likely to range from 0.67 °C (RCP2.6) to 5.94 °C (RCP8.5) by 2086. According to the worst‐case scenario, water temperature of these originally cold‐water ecosystems (regional mean in the late 1970s: 4.7 °C) may exceed 12 °C by the end of this century. We used bryophyte and macroinvertebrate species data from Finnish springs and spring‐fed streams to assess ecological impacts of the predicted warming. An increase in spring water temperature by several degrees will likely have substantial biodiversity impacts, causing regional extinction of native, cold‐stenothermal spring specialists, whereas species diversity of headwater generalists is likely to increase. Even a slight (by 1 °C) increase in water temperature may eliminate endemic spring species, thus altering bryophyte and macroinvertebrate assemblages of spring‐fed streams. Climate change‐induced warming of northern regions may thus alter species composition of the spring biota and cause regional homogenization of biodiversity in headwater ecosystems.     

Cloning, expression, and purification of recombinant protein from a single synthetic multivalent construct of Mycobacterium tuberculosis

Tuberculosis remains a major infectious disease with over 8 million new cases and 2 million deaths annually. Therefore, a vaccine more potent than BCG is desperately needed. In this regard, an approximately 800 bp DNA encoding a mycobacterial synthetic gene designated as VacIII (containing ubiquitin gene UbGR and four immunogenic mycobacterial epitopes or genes of ESAT-6, Phos1, Hsp 16.3, and Mtb8.4) was sub-cloned into a bacterial expression vector of pRSET-B resulting in a 6 x His-VacIII fusion gene construction. This recombinant clone was over expressed in Escherichia coli BL-21 (DE-3). The expressed fusion protein was found almost entirely in the insoluble form (inclusion bodies) in cell lysate. The inclusion bodies were solubilized with 8M urea and the recombinant protein was purified by Ni-NTA column and dialyzed by urea gradient dialysis. This method produced a relatively high yield of recombinant VacIII protein and the cloned VacIII gene offers the potential development of other vaccine formats such as DNA vaccine and recombinant vaccine.