Angiostatin anti-angiogenesis requires IL-12: The innate immune system as a key target

© 2009 Albini et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Assessing the effectiveness of a 3-month day-and-night home closed-loop control combined with pump suspend feature compared with sensor-augmented pump therapy in youths and adults with suboptimally controlled type 1 diabetes: a randomised parallel study protocol

$\textbf{Introduction:}$ Despite therapeutic advances, many individuals with type 1 diabetes are unable to achieve tight glycaemic target without increasing the risk of hypoglycaemia. The objective of this study is to determine the effectiveness of a 3-month day-and-night home closed-loop glucose control combined with a pump suspend feature, compared with sensor-augmented insulin pump therapy in youths and adults with suboptimally controlled type 1 diabetes. $\textbf{Methods and analysis:}$ The study adopts an open-label, multi-centre, multi-national (UK and USA), randomised, single-period, parallel design and aims for 84 randomised patients. Participants are youths (6-21 years) or adults (>21 years) with type 1 diabetes treated with insulin pump therapy and suboptimal glycaemic control (glycated haemoglobin (HbA1c) ≥7.5% (58 mmol/mol) and ≤10% (86 mmol/mol)). Following a 4-week run-in period, eligible participants will be randomised to a 3-month use of automated closed-loop insulin delivery combined with pump suspend feature or to sensor-augmented insulin pump therapy. Analyses will be conducted on an intention-to-treat basis. The primary outcome is the time spent in the target glucose range from 3.9 to 10.0 mmol/L based on continuous glucose monitoring levels during the 3-month free-living phase. Secondary outcomes include HbA1c at 3 months, mean glucose, time spent below and above target; time with glucose levels 16.7 mmol/L, glucose variability; total, basal and bolus insulin dose and change in body weight. Participants' and their families' perception in terms of lifestyle change, daily diabetes management and fear of hypoglycaemia will be evaluated. $\textbf{Ethics and dissemination:}$ Ethics/institutional review board approval has been obtained. Before screening, all participants/guardians will be provided with oral and written information about the trial. The study will be disseminated by peer-reviewed publications and conference presentations. $\textbf{Trial registration number:}$ NCT02523131; Pre-results.JDRF, National Institute for Health Research Cambridge Biomedical Research Centre, Wellcome Strategic Award (100574/Z/12/Z)

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry

OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies

HIV Integration Targeting: A Pathway Involving Transportin-3 and the Nuclear Pore Protein RanBP2

Genome-wide siRNA screens have identified host cell factors important for efficient HIV infection, among which are nuclear pore proteins such as RanBP2/Nup358 and the karyopherin Transportin-3/TNPO3. Analysis of the roles of these proteins in the HIV replication cycle suggested that correct trafficking through the pore may facilitate the subsequent integration step. Here we present data for coupling between these steps by demonstrating that depletion of Transportin-3 or RanBP2 altered the terminal step in early HIV replication, the selection of chromosomal sites for integration. We found that depletion of Transportin-3 and RanBP2 altered integration targeting for HIV. These knockdowns reduced HIV integration frequency in gene-dense regions and near gene-associated features, a pattern that differed from that reported for depletion of the HIV integrase binding cofactor Psip1/Ledgf/p75. MLV integration was not affected by the Transportin-3 knockdown. Using siRNA knockdowns and integration targeting analysis, we also implicated several additional nuclear proteins in proper target site selection. To map viral determinants of integration targeting, we analyzed a chimeric HIV derivative containing MLV gag, and found that the gag replacement phenocopied the Transportin-3 and RanBP2 knockdowns. Thus, our data support a model in which Gag-dependent engagement of the proper transport and nuclear pore machinery mediate trafficking of HIV complexes to sites of integration

An adaptable human-like gait pattern generator derived from a lower limb exoskeleton

Walking rehabilitation processes include many repetitions of the same physical movements in order to replicate, as close as possible, the normal gait trajectories, and kinematics of all leg joints. In these conventional therapies, the therapist's ability to discover patient's limitations-and gradually reduce them-is key to the success of the therapy. Lower-limb robotic exoskeletons have strong deficiencies in this respect as compared to an experienced therapist. Most of the currently available robotic solutions are not able to properly adapt their trajectories to the biomechanical limitations of the patient. With this in mind, much research and development is still required in order to improve artificial human-like walking patterns sufficiently for valuable clinical use. The work herein reported develops and presents a method to acquire and saliently analyze subject-specific gait data while the subject dons a passive lower-limb exoskeleton. Furthermore, the method can generate adjustable, yet subject-specific, kinematic gait trajectories useful in programming controllers for future robotic rehabilitation protocols. A human-user study with ten healthy subjects provides the experimental setup to validate the proposed method. The experimental protocol consists in capturing kinematic data while subjects walk, with the donned H2 lower-limb exoskeleton, across three experimental conditions: walking with three different pre-determined step lengths marked on a lane. The captured ankle trajectories in the sagittal plane were found by normalizing all trials of each test from one heel strike to the next heel strike independent of the specific gait features of each individual. Prior literature suggests analyzing gait in phases. A preliminary data analysis, however, suggests that there exist six key events of the gait cycle, events that can adequately characterize gait for the purposes required of robotic rehabilitation including gait analysis and reference trajectory generation. Defining the ankle as an end effector and the hip as the origin of the coordinate frame and basing the linear regression calculations only on the six key events, i.e., Heel Strike, Toe Off, Pre-Swing, Initial Swing, Mid-Swing, and Terminal Swing, it is possible to generate a new calculated ankle trajectory with an arbitrary step length. The Leave-One-Out Cross Validation algorithm was used to estimate the fitting error of the calculated trajectory vs. the characteristic captured trajectory per subject, showing a fidelity average value of 95.2, 96.1, and 97.2%, respectively, for each step-length trial including all subjects. This research presents method to capture ankle trajectories from subjects and generate human-like ankle trajectories that could be scaled and computed on-line, could be adjusted to different gait scenarios, and could be used not only to generate reference trajectories for gait controllers, but also as an accurate and salient benchmark to test the human likeness of gait trajectories employed by existing robotic exoskeletal devices.The research was partially funded by CONACyT Doctoral program, Tecnolgico de Monterrey/Robotics Lab and research chair program for distinguished professors in Biomechatronics

APOBEC3 Proteins Expressed in Mammary Epithelial Cells Are Packaged into Retroviruses and Can Restrict Transmission of Milk-Borne Virions

SummaryViruses, including retroviruses like human immunodeficiency virus (HIV) and mouse mammary tumor virus (MMTV), are transmitted from mother to infants through milk. Lymphoid cells and antibodies are thought to provide mammary gland and milk-borne immunity. In contrast, little is known about the role of mammary epithelial cells (MECs). The APOBEC3 family of retroviral restriction factors is highly expressed in macrophages and lymphoid and dendritic cells. We now show that APOBEC3 proteins are also expressed in mouse and human MECs. Lymphoid cell-expressed APOBEC3 restricts in vivo spread of MMTV to lymphoid and mammary tissue. In contrast, mammary gland-expressed APOBEC3 is packaged into MMTV virions and decreases the infectivity of milk-borne viruses. Moreover, APOBEC3G and other APOBEC3 genes are expressed in human mammary cells and have the potential to restrict viruses produced in this cell type. These data point to a role for APOBEC3 proteins in limiting infectivity of milk-transmitted viruses

Use and helpfulness of self-administered stress management therapy in patients undergoing cancer chemotherapy in community clinical settings

The purpose of this multicenter longitudinal randomized controlled trial was to examine the efficacy of self-administered stress management training (SSMT) in improving quality of life and reducing psychological distress among patients receiving cancer chemotherapy. Participants were randomized to SSMT (n = 111) or usual psychosocial care only (n = 109). Mixed linear modeling demonstrated no significant improvements in primary outcome measures; however, participants assigned to SSMT reported using significantly more relaxation techniques (p \u3c 0.0001), showed improvements on emotional adjustment scores, and demonstrated a stabilizing effect on the functional adjustment scores. Findings highlight the usefulness of SSMT in community clinical settings. © 2012 Copyright Taylor and Francis Group, LLC

Use and helpfulness of self-administered stress management therapy in patients undergoing cancer chemotherapy in community clinical settings

The purpose of this multicenter longitudinal randomized controlled trial was to examine the efficacy of self-administered stress management training (SSMT) in improving quality of life and reducing psychological distress among patients receiving cancer chemotherapy. Participants were randomized to SSMT (n = 111) or usual psychosocial care only (n = 109). Mixed linear modeling demonstrated no significant improvements in primary outcome measures; however, participants assigned to SSMT reported using significantly more relaxation techniques (p < 0.0001), showed improvements on emotional adjustment scores, and demonstrated a stabilizing effect on the functional adjustment scores. Findings highlight the usefulness of SSMT in community clinical settings