Epstein-Barr virus lymphoproliferation after bone marrow transplantation

We review 15 cases of secondary B-cell lymphoproliferative disorders that occurred among 2,475 patients who received allogeneic bone marrow transplants (BMTs) at the Fred Hutchinson Cancer Research Center (Seattle) between 1969 and 1987. The histopathologic findings in 14 of the 15 patients spanned a wide spectrum of lymphoproliferative lesions. One patient had features characteristic of angioimmunoblastic lymphadenopathy. Epstein-Barr virus (EBV) genomic sequences were identified by Southern blot analysis in each of the 13 patients evaluated. Ten of the 12 lesions evaluated originated in donor cells. In two patients, who had mixed chimerism after transplantation, the lesions originated in host cells. The combined evidence from immunoglobulin light chain staining and the analysis of immunoglobulin heavy chain gene rearrangement indicated that the lesions in most patients represented polyclonal proliferations that gave rise to clonal subpopulations. The results indicate an overall actuarial incidence of 0.6% for this complication in BMT recipients. Anti-CD3 monoclonal antibody (MoAb) treatment of acute graft-v-host disease (GVHD) and T cell depletion of the donor marrow were statistically significant risk factors, and GVHD appeared to play a contributing role, particularly in the setting of human leukocyte antigen (HLA) disparity. Two patients had no identifiable risk factors. Prophylaxis or treatment with acyclovir had no detectable effect in the patients; all but two died with uncontrolled lymphoproliferation.     

Patients’ experiences of dialysis services: are national health strategy targets being met?

Background The National Health Strategy envisages a health system incorporating patient views; and providing accessible, consultant-led dialysis services with patient choice of dialysis modality, in all regions. Aims To describe patients’ experiences of renal services against National Health Strategy objectives. Methods Telephone interviews with 192 dialysis patients from three hospitals in the Eastern region. Results One-quarter of participants (16% of haemodialysis [HD] and 46% of peritoneal dialysis patients) lived outside the Eastern region, and travelled there because dialysis was not available locally. Two-thirds (65%) had a choice of dialysis modality. High satisfaction with interpersonal care was observed (83–98% satisfaction). Dissatisfaction with physical environment included parking (39–56%), waiting areas (62–69%), HD unit space (74%). Regarding support services, dietary services were satisfactory (92–95%), with lower satisfaction ratings for social and financial support services (62%). Conclusions Structural and management issues must be addressed to advance a quality agenda for renal care in Ireland.     

The Use of an Automated,Portable Glucose Control System for Overnight Glucose Control in Adolescents and Young Adults With Type 1 Diabetes

OBJECTIVE

A key milestone in progress towards providing an efficacious and safe closed-loop artificial pancreas system for outpatient use is the development of fully automated, portable devices with fault detection capabilities to ensure patient safety. The ability to remotely monitor the operation of the closed-loop system would facilitate future physician-supervised home studies.

RESEARCH DESIGN AND METHODS

This study was designed to investigate the efficacy and safety of a fully automated, portable, closed-loop system. The Medtronic Portable Glucose Control System (PGCS) consists of two subcutaneous glucose sensors, a control algorithm based on proportional-integral-derivative with insulin feedback operating from a BlackBerry Storm smartphone platform, Bluetooth radiofrequency translator, and an off-the-shelf Medtronic Paradigm Veo insulin pump. Participants with type 1 diabetes using insulin pump therapy underwent two consecutive nights of in-clinic, overnight, closed-loop control after a baseline open-loop assessment.

RESULTS

Eight participants attended for 16 overnight studies. The PGCS maintained mean overnight plasma glucose levels of 6.4 ± 1.7 mmol/L (115 ± 31 mg/dL). The proportion of time with venous plasma glucose <3.9, between 3.9 and 8 (70 and 144 mg/dL), and >8 mmol/L was 7, 78, and 15%, respectively. The proportion of time the sensor glucose values were maintained between 3.9 and 8 mmol/L was greater for closed-loop than open-loop (84.5 vs. 46.7%; P < 0.0001), and time spent <3.3 mmol/L was also reduced (0.9 vs. 3%; P < 0.0001).

CONCLUSIONS

These results suggest that the PGCS, an automated closed-loop device, is safe and effective in achieving overnight glucose control in patients with type 1 diabetes.Intensive management of type 1 diabetes is necessary to achieve near-normal glucose levels to obtain A1C values associated with a reduced risk of microvascular and macrovascular complications. Large-scale studies have revealed that in some patients, such efforts are associated with an increased risk of severe hypoglycemia (1). The effects of intensive management on the incidence of severe hypoglycemia may be even greater in children and adolescents (2), particularly in the setting of diminished counterregulatory hormone responses (3,4). Despite the development of insulin analogs and increasing use of insulin pump therapy, approximation of physiologic insulin delivery has not been achievable by most. Presently, children with an A1C <7% spend approximately one-quarter of each 24-h period with glucose levels >11.1 mmol/L (200 mg/dL) (3). Even with use of sensor-augmented pump therapy, the epitome of technology currently available to patients, one-third or less patients achieve an A1C target <7% (5,6), and the incidence of severe hypoglycemia is not reduced.Currently, there are two principal approaches to β-cell replacement therapy. Islet-cell transplantation has demonstrated promising results in recovery of hypoglycemia awareness and reduction in episodes of hypoglycemia (7). Unfortunately, there are risks associated with immunosuppressive therapy (8), and currently, <75% of patients are insulin-independent 4 years after transplant (7). The second and, arguably, more promising therapeutic approach to β-cell replacement is a closed-loop artificial pancreas incorporating a continuous glucose sensor, insulin pump, and control algorithm.Commercially available insulin pumps and glucose sensors are considered sufficiently accurate for use in a closed-loop system (9,10). Despite the delays inherent in absorption and action of insulin delivered subcutaneously, previous studies have demonstrated superiority of such systems over standard pump therapy (11–18). Automation of insulin delivery is not a novel concept (11,12); however, the closed-loop system in many reports was not fully automated. In some studies, sensor glucose was entered manually every 5 to 15 min (15–17) or changes to the pump delivery rate were made manually by a physician or research nurse (13–17). Furthermore, insulin delivery in studies published to date was based on a control algorithm contained in a desktop or laptop computer (11–18), implying that the system was not readily portable or practical in an ambulatory setting. A key milestone in progress toward making a closed-loop artificial pancreas system available for outpatient use is the development of fully automated, portable devices with fault detection capabilities to ensure safety. An additional desirable feature of these devices is the ability to remotely monitor the operation of the closed-loop system via data transmitted over a wireless network, facilitating future physician-supervised home studies.The Medtronic Portable Glucose Control System (PGCS) is a portable, automated, closed-loop device consisting of a BlackBerry Storm smartphone (Research in Motion, Waterloo, ON, Canada), an unmodified Medtronic Paradigm Veo insulin pump, two MiniLink REAL-Time Transmitters (Medtronic Minimed, Northridge, CA) modified to transmit at 1-min rather than 5-min intervals, two Enlite glucose sensors (Medtronic Minimed), and a Medtronic custom-built radiofrequency translator, as illustrated in Fig. 1.Open in a separate windowFigure 1The components of the Medtronic PGCS.In this study, we describe the safety and efficacy of the PGCS, an automated closed-loop device, focusing on overnight glucose control in adolescents and young adults with type 1 diabetes.     

In vivo tracking in cardiac stem cell-based therapy

Cell-based therapy has been heralded as a promising, novel therapeutic strategy for cardiovascular diseases. Despite a rapid transition from animal studies to clinical trials, there remain numerous unresolved, and at times, controversial issues with respect to underlying molecular mechanisms. In parallel, recent advances in the field of molecular imaging has provided a means to bridge the gap in knowledge through in vivo stem cells tracking. Herein, we review current in vivo imaging techniques and future directions for tracking the effects of cell-based therapy.     

Genome comparison of virulent and avirulent strains of the Pichinde arenavirus

A virulent (P18) strain of the Pichinde arenavirus produces a disease in guinea pigs that somewhat mimics human Lassa fever, whereas an avirulent (P2) strain of this virus is attenuated in infected animals. It has been speculated that the composition of viral genomes may confer the degree of virulence in an infected host; the complete sequence of the viral genomes, however, is not known. Here, we provide for the first time genomic sequences of the S and L segments for both the P2 and P18 strains. Sequence comparisons identify three mutations in the GP1 subunit of the viral glycoprotein, one in the nucleoprotein NP, and five in the viral RNA polymerase L protein. These mutations, alone or in combination, may contribute to the acquired virulence of Pichinde virus infection in animals. The three amino acid changes in the variable region of the GP1 glycoprotein subunit may affect viral entry by altering its receptor-binding activity. While NP has previously been shown to modulate host immune responses to viral infection, we found that the R374 K change in this protein does not affect the NP function of suppressing interferon-beta expression. Four out of the five amino acid changes in the L protein occur in a small region of the protein that may contribute to viral virulence by enhancing its function in viral genomic RNA synthesis.     

Role of regulatory invariant CD1d-restricted natural killer T-cells in protection against type 1 diabetes

Invariant CD1d-restricted natural killer T (iNKT) cells function during innate and adaptive immune responses. A functional and numerical deficiency of iNKT cells is well documented in both nonobese diabetic (NOD) mice and humans with autoimmune type 1 diabetes (T1D). Restoring the numerical and/or functional deficiency of iNKT cells in NOD mice by either treatment with α-galactosylceramide, transgenic induction of V α14-Jα18 expression, or transgenic expression of CD1d in NOD islets under the control of the human insulin promoter confers protection from T1D in these mice. Recently, considerable progress has been made in understanding the developmental and functional activities of iNKT cells. In this review, we discuss the role of iNKT cell deficiency and defective development in the onset of T1D in NOD mice and the different protective mechanisms known to restore these defects.     

Origin and primary dispersal of the Mycobacterium tuberculosis Beijing genotype: clues from human phylogeography

We suggest that the evolution of the population structure of microbial pathogens is influenced by that of modern humans. Consequently, the timing of hallmark changes in bacterial genomes within the last 100,000 yr may be attempted by comparison with relevant human migrations. Here, we used a lineage within Mycobacterium tuberculosis, a Beijing genotype, as a model and compared its phylogeography with human demography and Y chromosome-based phylogeography. We hypothesize that two key events shaped the early history of the Beijing genotype: (1) its Upper Palaeolithic origin in the Homo sapiens sapiens K-M9 cluster in Central Asia, and (2) primary Neolithic dispersal of the secondary Beijing NTF::IS6110 lineage by Proto-Sino-Tibetan farmers within east Asia (human O-M214/M122 haplogroup). The independent introductions of the Beijing strains from east Asia to northern Eurasia and South Africa were likely historically recent, whereas their differential dissemination within these areas has been influenced by demographic and climatic factors.