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.     

Magnitude of serum and intestinal antibody responses induced by sequential replicating and nonreplicating rotavirus vaccines in gnotobiotic pigs and correlation with protection

A sequential mucosal prime-boost vaccine regimen of oral attenuated (Att) human rotavirus (HRV) priming followed by intranasal (i.n.) boosting with rotavirus protein VP2 and VP6 rotavirus-like particles (2/6-VLPs) has previously been shown to be effective for induction of intestinal antibody-secreting cell (ASC) responses and protection in gnotobiotic pigs. Because serum or fecal antibody titers, but not intestinal ASC responses, can be used as potential markers of protective immunity in clinical vaccine trials, we determined the serum and intestinal antibody responses to this prime-boost rotavirus vaccine regimen and the correlations with protection. Gnotobiotic pigs were vaccinated with one of the two sequential vaccines: AttHRV orally preceding 2/6-VLP (VLP2x) vaccination (AttHRV/VLP2x) or following VLP2x vaccination (VLP2x/AttHRV) given i.n. with a mutant Escherichia coli heat-labile toxin (mLT) as adjuvant. These vaccines were also compared with three i.n. doses of VLP+mLT (VLP3x) and one and three oral doses of AttHRV (AttHRV1x and AttHRV3x, respectively). Before challenge all pigs in the AttHRV/VLP2x group seroconverted to positivity for serum immunoglobulin A (IgA) antibodies. The pigs in this group also had significantly higher (P < 0.05) intestinal IgA antibody titers pre- and postchallenge and IgG antibody titers postchallenge compared to those in the other groups. Statistical analyses of the correlations between serum IgM, IgA, IgG, and virus-neutralizing antibody titers and protection demonstrated that each of these was an indicator of protective immunity induced by the AttHRV3x and the AttHRV/VLP2x regimens. However, only IgA and not IgM or IgG antibody titers in serum were highly correlated (R2 = 0.89; P < 0.001) with the corresponding isotype antibody (IgA) titers in the intestines among all the vaccinated groups, indicating that the IgA antibody titer is probably the most reliable indicator of protection.     

Different pattern of pleiotrophin and midkine expression in neuropathic pain: Correlation between changes in pleiotrophin gene expression and rat strain differences in neuropathic pain

Pleiotrophin (PTN) and midkine (MK) are two growth factors highly redundant in function that exhibit neurotrophic actions and are upregulated at sites of nerve injury, both properties being compatible with a potential involvement in the pathophysiological events that follow nerve damage (i.e. neuropathic pain). We have tested this hypothesis by comparatively studying PTN and MK gene expression in the spinal cord and dorsal root ganglia (DRG) of three rat strains known to differ in their behavioural responses to chronic constriction injury (CCI) of the sciatic nerve: Lewis, Fischer 344 (F344) and Sprague–Dawley (SD). Real time RT-PCR revealed minimal changes in PTN/MK gene expression in the spinal cord after CCI despite the strain considered, but marked changes were detected in DRG. A significant upregulation of PTN gene expression occurred in injured DRG of the F344 strain, the only strain that recovers from CCI-induced mechanical allodynia 28 days after surgery. In contrast, PTN was found to be downregulated in injured DRG of SD rats, the most sensitive strain in behavioural studies. These changes in PTN were not paralleled by concomitant modifications of MK gene expression. The results demonstrate previously unidentified differences between PTN and MK patterns of expression. Furthermore, the data suggest that upregulation of PTN, but not MK, could play an important role in the recovery from CCI.     

Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse)

Congenital central hypoventilation syndrome (CCHS, Ondine's curse) is a rare disorder of the chemical control of breathing. It is frequently associated with a broad spectrum of dysautonomic symptoms, suggesting the involvement of genes widely expressed in the autonomic nervous system. In particular, the HASH-1-PHOX2A-PHOX2B developmental cascade was proposed as a candidate pathway because it controls the development of neurons with a definitive or transient noradrenergic phenotype, upstream from the RET receptor tyrosine kinase and tyrosine hydroxylase. We recently showed that PHOX2B is the major CCHS locus, whose mutation accounts for 60% of cases. We also studied the proneural HASH-1 gene and identified a heterozygous nucleotide substitution in three CCHS patients. To analyze the functional consequences of HASH-1 mutations, we developed an in vitro model of noradrenergic differentiation in neuronal progenitors derived from the mouse vagal neural crest, reproducing in vitro the HASH-PHOX-RET pathway. All HASH-1 mutant alleles impaired noradrenergic neuronal development, when overexpressed from adenoviral constructs. Thus, HASH-1 mutations may contribute to the CCHS phenotype in rare cases, consistent with the view that the abnormal chemical control of breathing observed in CCHS patients is due to the impairment of noradrenergic neurons during early steps of brainstem development.     

Effect of the Penultimate Unit on the C?ON Bond Homolysis in SG1‐Based Alkoxyamines

The effect of the penultimate unit on the C? ON bond homolysis rate constant k_d was studied for model alkoxyamines. It was shown that the k_d for fragments containing penultimate and antepenultimate units were nicely predicted by the tri‐parametric relationship developed in Macromolecules 2005 , 38, 2638 and Eur. J. Org. Chem. 2006 , 7, 1755 (log k_d = ?14.33 + 15.06 × σ_RS + 20.00 × σ_I + 6.96 × υ). A striking effect was observed only for a tert‐butyl‐like group as the penultimate unit.

     

Systemic and intestinal antibody secreting cell responses and protection in gnotobiotic pigs immunized orally with attenuated Wa human rotavirus and Wa 2/6-rotavirus-like-particles associated with immunostimulating complexes

The undesirable side effects and variable efficacy of some oral live rotavirus vaccines in infants have necessitated alternative vaccine approaches. We evaluated a recombinant RFVP2/WaVP6 rotavirus-like-particle (2/6VLP) oral vaccine, using an immunostimulating complex (ISCOM) matrix as adjuvant, in a gnotobiotic (Gn) pig model of human rotavirus (HRV) disease. The 2/6VLPs adhered to the ISCOM-matrix (2/6VLP-ISCOM ) and were antigenic, but they failed to induce protection. However, when combined with attenuated (Att) HRV for oral priming, the 2/6VLP-ISCOM vaccine was effective as a booster and induced partial protection against virulent Wa HRV. The 250 microg 2/6VLP dose was more effective than 100 microg. The highest mean numbers of IgA antibody secreting cells evaluated by ELISPOT in intestinal lymphoid tissues were in pigs receiving AttHRV+2/6VLP-ISCOM or three doses of AttHRV and were associated with the highest protection rates.     

A meta-analysis of effectiveness of influenza vaccine in persons aged 65 years and over living in the community

AIM: To estimate the effectiveness of inactivated influenza vaccine in persons aged 65 years and over living in the community. SCOPE: A meta-analysis of studies selected using predetermined criteria without language restriction. CONCLUSION: Influenza vaccine was effective in reducing influenza-like illness by 35% (95% confidence interval (CI) 19-47%), hospitalization for pneumonia and influenza by 33% (CI 27-38%), mortality following hospitalization for pneumonia and influenza by 47% (CI 25-62%); and mortality from all causes by 50% (CI 45-56%).